SECTION 24 Neurological disorders Section editor C 24.10 Specific conditions affecting the central ne 24.10 Specific conditions affecting the central nervous system 6010 24.10.1 Stroke: Cerebrovascular disease 6010 J. van Gijn (revised by Peter M. Rothwell) 24.10 Specific conditions affecting the central nervous system CONTENTS 24.10.1 Stroke: Cerebrovascular disease  6010 J. van Gijn (revised by Peter M. Rothwell) 24.10.2 Demyelinating disorders of the central nervous system  6026 Alasdair Coles and Siddharthan Chandran 24.10.3 Traumatic brain injury  6042 Tim Lawrence and Laurence Watkins 24.10.4 Intracranial tumours  6048 Jeremy Rees 24.10.5 Idiopathic intracranial hypertension  6054 Alexandra Sinclair 24.10.1  Stroke: Cerebrovascular disease J. van Gijn (revised by Peter M. Rothwell) ESSENTIALS Cerebrovascular diseases include many pathological conditions but the principal categories are (1)  infarction—​through occlusion of major arteries, small arteries or venous sinuses; and (2) haemor- rhage—​most often through rupture of small arteries, arterial aneur- ysms, or capillaries. Epidemiology Strokes are common, with annual incidence rates for subjects aged over 55 ranging from 420 to over 1000 per 100 000. They are the most important case of disability in developed Western nations and the second most frequent cause of death after coronary heart dis- ease. About 80% of strokes are caused by cerebral infarcts, with the remainder due to haemorrhage, with 20% of these attributable to a bleeding cerebral aneurysm. The annual incidence of transient is- chaemic attacks is about 50–​100 per 100 000. General considerations Strokes typically present with a sudden onset of focal neurological deficit. Urgent imaging with CT or MRI allows rapid differentiation between haemorrhagic and ischaemic causes—​with critical benefit for the introduction of appropriate treatment—​and serial imaging may reveal the development of important complications such as rebleeding, ischaemia, or hydrocephalus that mandate specific interventions. The consequences of stroke are often devastating: sudden loss of a large amount of brain tissue affects much more than specific, local- ized functions such as movement, sensation, vision, and language. Mood, initiative, sense of humour, and speed of thought are among the essential aspects of mental life that can be severely affected. Management of patients with stroke requires their complex needs to be comprehensively addressed. The introduction of specialized clinical units for the multidisciplinary care of patients with stroke has been shown to improve clinical diagnosis and recovery, reducing the risk of death or institutionalized care by 14%. The introduction of urgent stroke prevention services for transient ischaemic attacks and minor stroke has reduced the risk of early recurrent stroke by about 80%. Pathophysiology of arterial occlusive disease Atherothrombosis is the main cause of occlusion of major arteries in the brain, typically by embolism from a source in the carotid artery, aorta, or heart. Whether occlusion of an artery supplying brain tissue actually leads to ischaemia depends on collateral pathways, which may be by (1) the circle of Willis, (2) connections between extracra- nial and intracranial vessels, (3) leptomeningeal anastomoses. Arterial occlusive disease—​transient ischaemic attacks These, by definition, are due to ischaemia of a part of the brain, pro- ducing symptoms/​signs that last for less than 24 h (usually for min- utes). The main presentations are with transient (1)  hemiparesis, (2) dysphasia, (3) monocular visual loss, or (4) hemianopia. Without treatment (see ‘Secondary prevention’), the risk of stroke after a transient ischaemic attack is up to 20% in the first year and 7% in subsequent years. 24.10.1  Stroke: Cerebrovascular disease 6011 Arterial occlusive disease—​cerebral infarction Classification—​this has been attempted on the basis of time course (‘progressive’, ‘completed’), anatomy (which artery?), cause (e.g. large artery atherosclerosis, cardioembolism), or functional deficit (e.g. modified Rankin scale). The Oxfordshire Community Stroke Project system provides a useful and widely accepted compromise, defining four types of cerebral infarction: (1) total anterior circulation infarcts—​with both cortical and subcortical involvement; (2) partial anterior circulation infarcts—​more restricted and predominantly cor- tical infarcts; (3) posterior circulation infarcts—​clearly associated with the vertebrobasilar arterial territory; (4) lacunar infarcts, confined to the territory of the deep perforating arteries. Specific treatments—​several medical interventions aim at dissolving (thrombolysis and antithrombotics) or extracting (thrombectomy) the occluding clot, or at least preventing it from growing. Those of widest application are:  (1) Thrombolysis—​treatment of highly selected patients within 4.5 h of the stroke event (and the sooner the better) with intravenous recombinant tissue plasminogen ac- tivator (r-​tPA) will avoid death or dependence in 55 patients per 1000 treated. (2) Thrombectomy is more effective than thrombolysis alone in selected patients with documented large artery occlusion. (3)  Antiplatelet agents—​treatment with aspirin, started within 48 h of onset, will avoid death or dependence in 13 patients per 1000 treated. Other interventions that are occasionally required include hemicraniectomy, which is effective in reducing mortality in patients with malignant hemispheric infarction and posterior decompression in patients with large cerebellar infarcts or haematoma. Secondary prevention—​aside from control of lifestyle factors (ces- sation of smoking, reducing overweight, daily exercise), specific measures to reduce the risk of threatened stroke include (1) Carotid endarterectomy—​substantially decreases the risk of stroke in pa- tients with severe, symptomatic carotid stenosis. (2)  Antiplatelet drugs—​aspirin produces relative risk reduction of 13% in long-​term risk of stroke, with addition of dipyridamole providing some further benefit, but the benefits of antiplatelet treatment in the acute phase are much greater; clopidogrel should be added to aspirin in the acute phase and may be continued as alternative long-​term monotherapy. (3) Anticoagulants—​with embolic sources in the heart, mostly from atrial fibrillation, coumadin anticoagulants (INR 2.5–​4) remain a choice in the absence of contraindications, although new oral anti- coagulants appear to be at least as effective and safer. (4) Statins—​re- duce the risk of stroke by about 20% per mmol/​litre reduction in low-​density lipoprotein cholesterol. (5) Antihypertensive drugs—​the level of blood pressure is by far the most powerful risk factor for stroke; in individuals with a history of stroke or transient ischaemic attack, a blood-​pressure-​lowering regimen reduces the risk of stroke by 25 to 50% depending on the degree of blood pressure lowering, regardless of whether or not the blood pressure at baseline was con- sidered too high. Venous occlusive disease Aetiology—​cerebral venous thrombosis often occurs in the context of a combination of predisposing factors (e.g. the oral contraceptive pill, pregnancy, or post-​partum), in combination with some inherited disorder of coagulation such as the factor V Leiden mutation. Clinical features, investigation, and treatment—​manifestations include headache, focal deficits, seizures, and impairment of consciousness. Imaging with CT/​MRI reveals ‘venous’ infarcts that do not correspond to a known arterial territory and evidence of the underlying sinus thrombosis. Most physicians treat with anticoagu- lants, but evidence for their efficacy is not strong. Mortality is 5–​30%. Primary intracerebral haemorrhage Aetiology—​primary intracerebral haemorrhage usually occurs in the context of a combination of (1) anatomical factors—​cerebral vas- cular lesions or malformations (e.g. arteriovenous or cavernous malformations, ruptured perforating arteries, amyloid angiopathy); (2) haemodynamic factors—​most notably blood pressure, which is the most important treatable risk factor; and (3) haemostatic fac- tors—​relating to platelet function or the coagulation system (e.g. oral anticoagulants). Clinical features, investigation, and treatment—​in most cases history and examination provide few clues to the cause of an intracerebral haemorrhage, other than hypertension, but specific enquiry should always be made about use of oral anticoagulants and the pos- sibility of malignant disease (with bleeding into a metastasis), and evidence of a generalized haemostatic disorder should be sought. Brain imaging (CT or MRI) is the most important single investigation in patients with suspected intracerebral bleeding. There is no specific treatment for most patients, but therapeutic anticoagulation should be reversed, and surgical evacuation of large cerebellar haematomas should be considered. Subarachnoid haemorrhage Aetiology—​ruptured aneurysms cause 85% of non​traumatic sub- arachnoid haemorrhages. Clinical features and investigation—​presentation is with sudden, severe, and unaccustomed headache, with loss of consciousness at onset in 50%. Imaging with CT is the most important investiga- tion: scanning within three days reveals extravasation of blood in the basal cisterns in 95% of cases. Lumbar puncture is indicated if the history is convincing, but the CT scan is negative: xanthochromia of the supernatant after centrifugation of the cerebrospinal fluid sample is the most reliable diagnostic finding. CT and MR angiography are the methods of choice for demonstrating or excluding an aneurysm as the source of haemorrhage. Treatment—​aside from general nursing and supportive measures, key issues are (1) prevention of rebleeding—​without intervention, the risk of this is 30% in the month after presentation, with immediate mortality of 50%. Endovascular treatment (‘coiling’) is the preferred method to occlude the aneurysm and prevent rebleeding, but not all aneurysms can be treated in this way and operative clipping is still necessary for these patients. (2) Delayed cerebral ischaemia—​occurs in up to 25% of patients with a ruptured aneurysm, most commonly 5–​14 days after the initial bleed. Nimodipine reduces the frequency of cerebral ischaemia and poor outcome by about one-​third. Introduction History Intracerebral haemorrhage was first recorded by the Swiss phys- ician Wepfer (1620–​95) and in more detail by Morgagni (1682–​ 1771) in Padua. Non​haemorrhagic stroke, ‘serous apoplexy’, section 24  Neurological disorders 6012 greatly puzzled the medical community until cerebral softening (‘ramollissement’) was recognized as a pathological entity in 1820 by Rostan (1790–​1866), in Paris. Initially it was regarded as an inflammatory condition. The relationship of brain softening with arterial occlusion and atherosclerosis gradually dawned on the pathologists; it was firmly established by Rokitansky (1804–​ 78) in Vienna and Virchow (1821–​1902) in Berlin. The term ‘in- farction’ was coined by Cohnheim, one of Virchow’s disciples. Subarachnoid haemorrhages and their usual source, intracranial aneurysms, were first recognized at the start of the 19th century; the diagnosis could (sometimes) be made during life from the start of the 20th century. In 1931 the Edinburgh neurosurgeon Norman Dott (1897–​1973) carried out the first intracranial operation for a ruptured aneurysm, by wrapping it in muscle. Understanding cerebrovascular disease received great impetus with the advent of CT in the 1970s. Before that time, observations de- pended on post-​mortem studies and on indirect neuroradiological studies such as angiography and pneumoencephalography. CT al- lowed rapid and reliable distinction between haemorrhagic and ischaemic stroke during life. Subsequently, CT and the newer tech- nique of MRI identified several subtypes of stroke, each requiring specific therapeutic measures. The rapid increase in diagnostic ac- curacy coincided with the emergence of the randomized clinical trial, which added considerably to pathophysiological reasoning as a basis for many medical interventions. Epidemiology of stroke Worldwide, stroke is the second most common cause of death after coronary heart disease, although it is the most important single cause of adult disability in the Western world. Stroke incidence is not technically difficult to measure but requires a great deal of time and resources. The few reliable studies, mostly from industrial coun- tries, show that age-​ and sex-​standardized annual incidence rates for individuals aged 55 or more are between 420 and over 1000 per 100 000, depending on geographical region. More than half of strokes occur in people aged over 75 years. In Western Europe the overall age-​adjusted incidence rates are falling, but the absolute number of strokes occurring remains approximately the same be- cause of the ageing population. The pathological type varies, even between studies with a high rate of CT, but a general estimate is that out of every five strokes four are infarcts and one a haemorrhage, and that one out the five haemorrhages is from a ruptured aneurysm (subarachnoid haemorrhage). The incidence of transient ischaemic attacks (TIAs) is about 50–​100 per 100 000, but many more patients with a possible TIA are seen in clinical practice. In terms of an average general practice of 2400 people in Western Europe (1000 aged >55 years), four patients will have a stroke per annum, versus one having a TIA. Intracerebral haemorrhage will occur about twice every 3 years, and subarachnoid haemorrhage once every 8 years. Arterial occlusive disease The cerebral circulation and its disorders Brain tissue is critically dependent on a constant supply of oxygen and glucose. The cerebral blood flow (c.800 ml/​min) accounts for 15–​20% of the entire cardiac output, whereas the brain (c.1350 g) accounts for only 2% of the normal adult body weight. Neurons in the brain require a constant supply of adeno- sine triphosphate to maintain concentration gradients of ions across their membranes, necessary for the generation of action potentials. The resting brain consumes energy at the same rate as a 20-​W light bulb. Whether occlusion of an artery in the brain or in the neck actually leads to ischaemia depends on collateral pathways. If an end-​artery is occluded and there is no collateral circulation at all, ischaemic symptoms will occur within seconds. Neurons will start dying within minutes and within hours the entire supply area of the artery will be irreversibly damaged. In contrast, permanent occlusion of a major artery (e.g. the internal carotid artery) may be asymptomatic in the presence of adequate collateral circulation. Broadly speaking, three levels of collateral circulation can be distinguished (Fig. 24.10.1.1; these can be thought of as three lines of defence): 1 The circle of Willis (Fig. 24.10.1.2)—​even if no blood at all is flowing to the brain from one or even both internal carotid ar- teries, collateral flow from the other internal carotid artery or the basilar artery, via an intact circle of Willis, may ensure an ad- equate blood supply in the territory of the occluded artery. 2 Connections between extracranial and intracranial vessels—​ if the internal carotid artery is occluded at its origin, collateral channels may develop via the external carotid artery. Branches supplying the outer orbit may connect with branches to the retina, resulting in a reversed flow in the ophthalmic artery. From there, blood reaches the distal part of the internal carotid artery. Similarly, branches of the occipital arteries (normally supplying the neck muscles) may fill the basilar artery if this is occluded at its origin. 3 Leptomeningeal anastomoses—​if, for example, the main stem of the middle cerebral artery is occluded, its terminal branches at the surface of the brain may anastomose with similar branches of Posterior cerebral artery Vertebral artery Ophthalmic artery Basilar artery Junction of vertebral arteries Common carotid Internal carotid External carotid Posterior communicating artery Fig. 24.10.1.1  Arterial supply of the brain. The drawing shows, on the right side, the internal carotid artery, external carotid artery, and vertebral artery. If a main artery is occluded, then collateral flow may occur via the circle of Willis (see also Fig. 24.10.1.2). 24.10.1  Stroke: Cerebrovascular disease 6013 the anterior and posterior cerebral arteries; in this way the cere- bral cortex in the territory of the occluded artery is spared, partly or wholly, although the deep territory will still be ischaemic. Atherothrombosis is the major cause of occlusion of major arteries in the brain or the neck. Two important qualifications should be made. First, atherosclerosis of intracranial arteries is relatively un- common, at least in white people at younger ages (vs. black or East Asian people). This means that, in the Western world, brain infarc- tion is usually caused by embolism, in which thrombus has been dislodged from an upstream lesion. The source can be the carotid ar- tery, aorta, or heart. Second, atherosclerosis is not a sufficient cause in itself: not every person with severe atherosclerotic disease has an ischaemic stroke. Other relevant factors are collateral circulation, ir- regularity of the plaque, blood turbulence, platelet aggregation, and the balance of clotting factors. Diagnosis of transient ischaemic attacks (TIAs) TIAs are important to diagnose because they are potential harbin- gers of stroke. They precede cerebral infarction probably in about 25% of cases. The term ‘transient ischaemic attack’ is rather imprecise, because it tacitly implies three restrictions. To begin with, it refers only to the brain and not to angina pectoris or intermittent claudication. Also excluded is transient ischaemia of the entire brain, such as occurs in syncope or ventricular fibrillation. In medical usage, only ischaemia of a part of the brain corresponds with the term TIA. Finally, how transient is transient? Traditionally the limit for the duration of symptoms has been set at 24 h. Obviously, this threshold has more to do with astronomy than with biology or disease. In fact, most TIAs last minutes, not hours. The longer an attack lasts, the greater the chance that CT or MRI afterwards will show a relevant ischaemic lesion. In terms of patient management, the essential question is not whether the attack has lasted 3 minutes, 3 days, or 3 weeks, but what its cause is and how recurrences can be prevented. Moreover, in recent years, diffusion-​weighted MRI scanning has shown that about 30% of patients with TIA have small high-​signal lesions on brain imaging that usually correspond clinically with the symptoms of the event and appear to represent areas of acute cerebral infarc- tion. Acute diffusion-​weighted imaging (DWI) changes increase in frequency as the duration of symptoms increases and are associated with a higher early risk of major stroke. What actually happens in the brain during a given period of is- chaemia can often only be guessed at. The usual assumption is that an embolus, most often consisting of platelets or loosely organized thrombus, temporarily blocks an intracerebral vessel and then dis- solves into smaller fragments. There is scant evidence for this phe- nomenon, apart from chance observations during fundoscopy, angiography, or surgery. Other explanations, applicable only to a minority, include marginal flow, secondary to severe narrowing or occlusion of arteries. The role of hypertension is also uncertain, but many patients with TIA have high blood pressure in the acute phase, which might be important in influencing susceptibility to cerebral ischaemia in the presence of embolization. The diagnosis of a TIA is problematic. That one has to rely on the history alone is a first difficulty (it requires time, skill, and patience). A greater source of error is that the term TIA is an interpretation ra- ther than a description. Main varieties of transient ischaemic attacks There are four kinds of symptoms that can safely be regarded as TIAs, given that the onset is sudden (within seconds), all symptoms appear at the same time, without ‘march’, and there is no better explanation. Transient weakness of one-​half of the body Apart from weakness, there may also have been numbness. Isolated numbness or pins and needles on one side of the body are a less common manifestation of transient cerebral ischaemia; other causes such as overbreathing or focal seizures should also be considered. Weakness and numbness are closely related perceptions, and one should not take these or other expressions (‘an arm gone dead’) for granted. It is important to make sure that the problem had to do with moving the limbs or the face on one side (facial weakness on one side often manifests itself through slurred speech or drooling), and not with what it felt like when those body parts were touched or with spontaneous sensations. It is also important to verify whether the problem was in two of three body areas, and that it was not just a leg or arm gone to sleep after a nap in older people. Transient loss of the ability to find words or to understand them The medical term for this type of TIA is dysphasia or aphasia; in this case patients and relatives may not recognize the episode as representing a problem of language but will often describe the at- tack as ‘confusion’. It is helpful to ask specific questions about the ability to put thoughts into words (motor dysphasia), and about having been able to understand what was said (sensory dysphasia). If a patient can write sentences but cannot speak, the cause is almost certainly psychological. A frequent problem is the distinction be- tween dysphasia (disorder of language) and dysarthria (disorder of Anterior communicating artery Basilar artery Posterior communicating artery Internal carotid artery Middle cerebral artery Anterior cerebral artery Posterior cerebral artery Posterior inferior cerebrellar artery Vertebral artery Fig. 24.10.1.2  The arterial circle of Willis, at the base of the brain. section 24  Neurological disorders 6014 articulation). To ask whether pronunciation was difficult may not be very helpful. After all, in both cases the patient’s thoughts are clear and the distinction between the right words and the right sounds is rather academic. A more useful question is whether the words made sense and whether they were in the right order. Dysphasia implies a lesion of the left hemisphere in right-​handed people, and in 30% of strong left-​handers. Transient loss of vision in one eye The difficulty in this case is to distinguish transient monocular blindness from loss of vision on one side in both eyes (hemianopia). Either type of attack can be interpreted by the patient as a problem in one eye. The distinction has practical implications, as monocular attacks of blindness should lead to investigation of the ipsilateral internal carotid artery in the neck with a view to angiography and surgery, whereas isolated hemianopia mostly (in 80%) reflects a dis- order in the vertebrobasilar circulation, in which case treatment will often be medical. The key question to ask is whether patients have alternately covered each eye during the attack. A surprisingly large proportion of patients have done so, but they will not always offer this information without prompting. On having covered the ‘good eye’ in case of hemianopia, the patient should still have been able to see with the ‘bad eye’, although only the nasal half of the visual field. With a monocular disorder the blindness should have been com- plete after covering the unaffected eye. In practice, however, the dis- tinction between hemianopia and monocular visual loss can still be difficult, particularly if the hemianopia was macular-​sparing, such that central vision (i.e. faces or written text) was preserved. Transient loss of vision in one hemifield Hemianopia reflects dysfunction of the occipital lobe. It is also a common aura in migraine attacks; these auras may occur without ensuing headache, especially in older people. It is, therefore, im- portant for the physician to enquire about the mode of onset: flashing lights, bright colours, zigzag lines, and a gradually expanding deficit all argue in favour of a migrainous attack, rather than ischaemia in its restricted sense of a stroke warning. Differential diagnosis of TIAs Box 24.10.1.1 lists types of attacks that should in general not be regarded as TIAs, either because of positive phenomena, such as rhythmic jerking, that are rarely due to focal ischaemia, or because other causes are much more likely. In particular, the tendency to label any episode of ‘dizziness’ in older people as ‘vertebrobasilar ischaemia’ or, even worse, ‘vertebrobasilar insufficiency’ should be resisted unless there is compelling evidence of severe disease of the vertebral or basilar arteries. The other isolated neurological symp- toms listed in the box can sometimes be due to TIAs, but there is less diagnostic certainty and these events are sometimes referred to as transient neurological attacks (TNAs). Recent research shows that the risk of major stroke after a TNA is relatively low, but that they are associated with a relatively high long-​term risk of vascular events. In addition, some specific disorders other than atherosclerosis may cause attacks that are more or less indistinguishable from true TIAs as just defined. They are listed in Box 24.10.1.2. These rare but im- portant causes are reason enough to order a CT or MRI scan of the brain in patients with cerebral TIAs (not necessarily in those with transient monocular blindness). A  chronic subdural haematoma should always be suspected in older people, especially if they are on anticoagulants. Hypoglycaemia should come to mind in patients with diabetes. Focal weakness may follow an epileptic seizure (Todd’s paralysis) and may be misdiagnosed as a TIA if the initial jerking is missed or misinterpreted. Tumours may also cause temporary deficits without focal epilepsy. Transient global amnesia is a disorder of memory possibly caused by migrainous vasospasm or venous con- gestion; although technically ischaemic in nature, it is not associated with an increased risk of stroke or other vascular disease. Prognostic implications of TIAs Without treatment, the risk of stroke after a TIA can be estimated at up to 20% in the first year and 7% in subsequent years, and the average risk of death, stroke, or myocardial infarction in the first five years at 10% per annum. Heart disease and stroke each account for about one-​third of all deaths. It is important to recognize that the risk of stroke is highest soon after the first episode if patients are not treated urgently: 8% in the first week, 12% at 1 month, and 17% at 3 months. Patients at particularly high risk can be identified by means of the ABCD2 score (see ‘Further reading’): A for age (>60 years), B for blood pressure (>140/​90 mm Hg), C for clinical features (2 points for unilateral weakness, 1 point for speech disturbance without weak- ness), and D for duration (2 points for >60 min, 1 point for >10 min) and for diabetes (1 point). The risk of stroke within 2 days is approxi- mately 8% in patients with a score of 6 or 7, 4% in those with a score of 4 or 5, and much less in the others. These risks are reduced by urgent medical treatment, particularly by antiplatelet treatment. Investigations in patients with cerebral ischaemia There is no great difference between searching for the cause of a TIA and searching for the cause of an ischaemic stroke. Very early Box 24.10.1.1  Attacks that should generally not be regarded as definite TIAs • Any attack with loss of consciousness • Any attack with involuntary jerking (with the rare exception of limb shaking TIA due to low blood flow distal to a carotid occlusion) • Any attack with positive visual phenomena (bright lights, and so on), particularly if the symptoms progressed over minutes • Any attack with only one of the following: • numbness • dizziness (with or without spinning sensations) • double vision • slurred speech • unsteady walking Box 24.10.1.2  Disorders that may mimic genuine TIAs • Chronic subdural haematoma • Intracranial tumour (glioma, metastasis, meningioma) • Hypoglycaemia • Focal deficits following a partial epileptic seizure • Transient global amnesia • Myasthenia gravis 24.10.1  Stroke: Cerebrovascular disease 6015 CT or MRI is mandatory, mainly to exclude intracerebral haemor- rhage and the occasional structural lesion mimicking stroke and to demonstrate infarcts. Box 24.10.1.3 lists the major and con- tributory causes of TIA and ischaemic stroke, with corresponding investigations. In general, first-​line investigations are full blood count, erythrocyte sedimentation rate (ESR), plasma glucose, creatinine and electrolytes, plasma lipids, ECG, duplex ultrasound scanning of the arteries in the neck, and unenhanced CT or MRI of the brain. Ideally, CT or MR angiography of the intracranial arteries and the posterior circulation should also be performed, both in major stroke (to help determine the need for thrombolysis or thrombectomy) and in TIA and minor stroke (to understand aetiology and optimize secondary prevention). Prolonged ambu- latory cardiac rhythm monitoring (e.g. 7-​day R-​test) is indicated to identify patients with paroxysmal atrial fibrillation if no other clear cause of the TIA or stroke is found. Evidence on the usefulness of routine echocardiography is limited and conflicting. Diagnosis of cerebral infarction Distinction from other types of stroke From a practical point of view, the first step is to distinguish is- chaemic stroke from intracerebral haemorrhage. In the past, when a certain distinction could be made only at operation or postmortem examination, a decreased level of consciousness and headache were considered typical of intracerebral haemorrhage. After CT became available in the 1970s, it soon became clear that smaller haemorrhages are not associated with headache and drow- siness. Given that 4 out of 20 strokes are haemorrhagic, and on the assumption that half of all haemorrhages lack distinctive clin- ical features, a diagnosis of cerebral infarction based on clinical features alone will be wrong in approximately every tenth case. Even complex clinical scoring methods hardly improve on this error rate. On CT, acute parenchymal haemorrhage is of higher density than normal brain tissue (see Fig. 24.10.1.6). The hyperdensity occurs immediately—​it is caused by the iron molecules in haemo- globin. In small haemorrhages, the hyperdensity can be lost within two to three days, such that the CT appearances are then easily confused with cerebral infarction. It is important therefore that brain imaging is performed quickly even in minor strokes. With the advent of very iron-​sensitive MR imaging techniques, such as gradient-​echo imaging, signs of previous haemorrhages are much easier to spot. These techniques often also identify multiple small areas of iron-​deposition, which are thought to be ‘microbleeds’. These lesions are associated with hypertension and with cerebral amyloid angiopathy. Signs of infarction are more difficult to detect at an early stage. In the first decade of CT this was not possible until after three days, when frank tissue necrosis caused a hypodense lesion on the scan. With improved CT technology, subtle early signs of cerebral in- farction have been recognized, at least when the area of infarction is large. These features include loss of normal differentiation be- tween grey and white matter (such as the normal outline of the insular ribbon and the lentiform nucleus) (Fig. 24.10.1.3) and ef- facement of cortical sulci. With the advent of diffusion-​weighted MR imaging, which is very sensitive to early changes in cerebral infarction, it is much easier to identify acute ischaemia, but not all acute stroke patients will tolerate an MRI scan and MRI is contra- indicated in about 10% of older patients due to metallic implants of various kinds. Within the first few days, CT will show that the area of infarc- tion changes into a slightly hypodense, ill-​defined, and somewhat swollen lesion; towards the end of the first week it becomes more Box 24.10.1.3  Major and contributory ‘causes’ of transient ischaemic attack (TIA) or ischaemic stroke, with corresponding investigations Investigations marked with an asterisk () have proven implications for management. Arterial atheroma • Internal carotid artery in the neck—​duplex ultrasound study • Intracranial arteries—​angiogram (with MR, CT, or catheter) Small vessel disease • Aorta—​transoesophageal echocardiography • MRI brain imaging to identify asymptomatic lacunes and microbleeds Other arterial disease • Congenital arterial anomalies—​angiogram (with MR, CT, or catheter) • Moya-​moya syndrome—​angiogram (with MR, CT, or catheter) • Arterial dissection—​MRI; angiogram (with MR, CT, or catheter) • Giant cell arteritisa—​ESR*, temporal artery biopsy* • Systemic vasculitis—​antinuclear antibodies*, tissue biopsy* • Embolization from arterial aneurysms—​MRI; angiogram (with MR, CT, or catheter) • Cholesterol embolization syndrome—​biopsy of skin, muscle, or kidney • Meningitis, encephalitis—​cerebrospinal fluid*, brain biopsy* • Drugs of abuse—​toxicological screening of urine • Genetic conditions (mitochondrial encephalomyopathy, lactic acid- osis, and stroke-​like episodes (MELAS), analysis of mitochondrial or nuclear DNA, cerebral autosomal dominant arteriopathy with sub- cortical infarcts and leukoencephalopathy (CADASIL), Fabry’s disease), α-​galactosidase A* • Irradiation • Migraine Embolism from the heart • Atrial fibrillation—​ECG*; long-​term monitoring of heart rhythm* • Recent myocardial infarction—​ECG* • Rheumatic valvular disease—​echocardiogram* • Infective endocarditis—​echocardiogram*, blood cultures* • Open foramen ovale—​venography*, echocardiogram, bubble TCD • Atrial myxoma—​echocardiogram* Haemostatic factors • Polycythaemia or iron deficiency anaemia —​haematocrit* • Sickle cell disease—​peripheral blood smear, sickling test • Thrombocytosis—​platelet count* • Leukaemia—​white cell count*, morphological analysis* • Disseminated intravascular coagulation—​platelet count, prothrombin, and activated partial thromboplastin times, fibrinogen, fibrinogen degradation products, D-​dimers Contributing risk factors • Hypertension—​serial measurement of blood pressure* • Diabetes—​fasting glucose*, HbA1c? • Hypercholesterolaemia—​plasma cholesterol* • Hyperhomocysteinaemia—​plasma homocysteine level ESR, erythrocyte sedimentation rate. a Only with involvement of optic nerve or occipital lobe. section 24  Neurological disorders 6016 clearly demarcated and hypodense (Fig. 24.10.1.3). Occasionally there may be massive swelling with the potential for brain hernia- tion or haemorrhagic transformation. During the second week the infarct may again gradually increase in density, because the degrad- ation products of necrotic brain tissue more readily absorb X-​rays; in the third and fourth weeks the infarcted area may even become isodense, being temporarily almost indistinguishable from normal brain, the so-​called ‘fogging effect’. Eventually a sharply demarcated, atrophic, hypodense (similar to cerebrospinal fluid) defect remains. It is not always possible to determine how old an infarct is, or to dis- tinguish it from the scar of a haemorrhage that occurred weeks or years before. Intravenous injection of X-​ray contrast may in the first weeks cause some enhancement of adjacent brain tissue. The proportion of patients in whom CT shows an appropriate in- farct depends not only on the time of scanning and the generation of the scanner, but also on the size of the infarct and its location; even- tually more than 90% of infarcts will show up. MRI is especially useful for demonstrating small infarcts and lesions in the posterior fossa; diffusion-​weighted imaging is also much more sensitive than CT in the early phases of brain is- chaemia. Signal changes on T2-​weighted images occur after 6 to 8 h. Infarcts of any size are visible within minutes on diffusion-​weighted imaging. The distinction from intracerebral haemorrhage is less ob- vious than on CT, but after a few hours the paramagnetic effects of deoxyhaemoglobin can be identified. Classification of cerebral infarction Time course has often been the guiding principle in the classification of stroke in the era before brain imaging. From the point of view of management and prognosis, however, the distinction between ‘pro- gressive stroke’ and ‘completed stroke’ is hardly useful, let alone that between ‘permanent stroke’ and ‘reversible ischaemic neurological deficit’ (a kind of ‘extended TIA’ with complete recovery within 3 or 6 weeks, depending on local convention). What counts is the even- tual severity of the functional deficit and, conversely, the remaining functions that are at risk. The anatomical classification distinguishes infarcts according to the territory of major cerebral arteries: in the cerebral hemi- spheres infarcts can be located in the supply areas of anterior cere- bral artery, middle cerebral artery, or posterior cerebral artery, or in the border zones between these three main branches; the cere- bellum and brainstem are supplied by branches of the vertebral arteries and the basilar artery. The problems are that there is little if any relationship with handicap, mostly no distinction is made between partial and complete infarcts in a given territory, and the boundaries between different territories vary substantially be- tween individuals. Classification according to the cause of ischaemic stroke is of interest for studies aiming to describe or influence the pathophysio- logical background of strokes. The so-​called TOAST classification, for example, distinguishes five subtypes of ischaemic stroke:  (1) large artery atherosclerosis, (2) cardioembolism, (3) small vessel oc- clusion, (4) stroke with other specific cause, and (5) stroke with un- determined cause. At present about 40% of patients would currently end up in the category ‘undetermined’, even in specialized stroke services. Also, the classification may change according to the extent of ancillary investigations. Finally, and most important, the system is not suited for assessing the severity of stroke. Rehabilitation specialists are more interested in the functional abilities of patients than in the niceties of neurological nosology. They mostly grade patients’ disability on a scale for activities of daily life (such as the Barthel scale, which ranks 10 in-​house activ- ities in hierarchical order, from bowel continence to taking a bath), or on a scale that includes some elements of social role fulfilment (‘handicap’), such as the Rankin scale (Table 24.10.1.1). A system that strikes a useful compromise between the restric- tions of lifestyle and the anatomical point of view is the classification of the Oxfordshire Community Stroke Project. Four categories are distinguished: (a) (b) Fig. 24.10.1.3  Acute cerebral infarction in a 78-​year-​old man. (a) CT scan about 6 h after symptom onset. In the left brain hemisphere (on the reader’s right) there are subtle changes in the region of the basal ganglia: other than on the normal side, it is difficult to distinguish the different brain nuclei and their separation by white matter. (b) CT scan 4 days after symptom onset shows marked hypodensity in the entire territory of the left middle cerebral artery. 24.10.1  Stroke: Cerebrovascular disease 6017 1 Total anterior circulation infarcts (TACIs), with both cortical and subcortical involvement, representing about one-​sixth of all ischaemic strokes in the community 2 Partial anterior circulation infarcts (PACIs), with more restricted and predominantly cortical infarcts (one-​third of all infarcts) 3 Posterior circulation infarcts (POCIs), clearly associated with the vertebrobasilar arterial territory (one-​quarter) 4 Lacunar circulation infarcts (LACIs), confined to the territory of the deep perforating arteries (one-​quarter) Although the classes are anatomically defined, they contain im- portant prognostic information: case fatality is highest by far in the TACI group and lowest by far in the LACI group. Syndromes of cerebral infarction Occlusion of the internal carotid artery may cause no symptoms at all or infarction, at its worst in the entire territory of the ipsi- lateral anterior and middle cerebral artery (and sometimes of the posterior cerebral artery or contralateral anterior cerebral artery as well), depending on the presence of a complete circle of Willis and other collaterals. If arterial dissection is the cause of carotid occlusion, subadventitial bulging of the artery may cause Horner’s syndrome and lower cranial nerve palsies, with or without infarc- tion. Occlusion of the anterior, middle, and posterior cerebral ar- teries may lead to complete or partial infarction in their respective territories, depending on collaterals at the surface of the brain. Obviously, branch occlusions cause smaller infarcts. What follows is a description of syndromes associated with complete infarction in the average territory of the main cerebral arteries, although there is much individual variation in practice. Middle cerebral artery infarcts, if complete, typically present with contralateral hemiplegia (most marked in the arm), sensory deficit, hemianopia, and cognitive defects such as aphasia (dominant hemisphere) or contralateral neglect (non​dominant hemisphere). Massive infarction of the entire territory of the middle cerebral ar- tery may lead to massive brain swelling followed by herniation, es- pecially in young patients without cerebral atrophy. Occlusion of a vertebral artery involving the origin of the posteroinferior cerebellar artery causes Wallenberg’s syndrome, with ipsilateral cerebellar ataxia through infarction of the inferior part of the cerebellum, and a—​for students, slightly bewildering—​ combination of deficits from infarction of the dorsolateral me- dulla: decreased skin sensation in the ipsilateral half of the face and the contralateral half of the body; ipsilateral Horner’s syndrome; ipsilateral weakness of the soft palate, larynx, and pharynx; and ro- tatory vertigo. The full basilar artery syndrome, with infarction of most of the pons and midbrain, consists of coma, tetraparesis including facial movements, and loss of all eye movements and of pupillary and cor- neal reflexes. There are two characteristic partial syndromes of the basilar artery. One is the locked-​in syndrome (infarction of the base of the pons), with tetraparesis, including facial movements and loss of horizontal eye movements. Consciousness is preserved through sparing of the reticular formation, but patients can communicate only through vertical eye movements; these may not always be cor- rectly interpreted or even noticed. The other is the top-​of-​the-​basilar syndrome, with variable combinations of hemianopia or complete cortical blindness (occipital lobes), amnesia (inferior temporal lobes) and vertical gaze palsies, pupillary disturbances, and hallu- cinations (perforating branches to the midbrain). The posterior cerebral artery syndrome may include hemianopia (occipital lobe), amnesia (lower temporal lobe), and oculomotor disorders or disturbances of language or visuospatial function, by involvement of perforating branches to the thalamus. Occlusion of a single perforating artery, one of the many that originate at right angles from a large parent artery to supply a small area in the deep regions of the brain or brainstem (Fig. 24.10.1.4), may be clinically silent, or cause a so-​called ‘lacunar syndrome’. A necessary condition for the clinical diagnosis of a lacunar syn- drome is the absence of ‘cortical’ deficits such as aphasia, neglect, Table 24.10.1.1  Modified Rankin scale (or Oxford Handicap Scale) for measuring outcome after stroke (but suitable for other purposes as well) Grade Description 0 No symptoms 1 Minor symptoms that do not interfere with lifestyle 2 Symptoms that lead to some restriction of lifestyle but do not interfere with the patient’s capacity to look after himself 3 Symptoms that restrict lifestyle and prevent a completely independent existence 4 Symptoms that clearly prevent independent existence though no constant attention is required (patients are usually wheelchair-​bound) 5 Totally dependent patient requiring constant attention, night and day (patients are often bed-​bound) Infarcts in the area of the anterior cerebral artery cause contralateral hemiparesis, more marked in the leg than in the arm, with no or only mild sensory deficit. Other frontal lobe features include mutism, incontinence, and apathy or, conversely, disinhibition. Fig. 24.10.1.4  Small, deep infarct (‘lacune’) in a 63-​year-​old woman. CT scanning shows a small area of hypodensity (distinct from sulci) in the left brain hemisphere (on the reader’s right), just lateral to the internal capsule. section 24  Neurological disorders 6018 hemianopia, or conjugate deviation of the eyes. The most common and archetypal form is pure motor stroke. In those cases, the small deep infarct strategically involves corticospinal fibres (pyramidal tract) to the motor neurons of the limbs, anywhere in its course. Analogous fibres to the facial nucleus in the pons may be affected as well. The infarct can be located in the corona radiata, adjoining the wall of the body of the lateral ventricle, or slightly more caud- ally, in the posterior limb of the internal capsule, or, less com- monly, in the pons or the medulla. Other ‘lacunar syndromes’ are sensorimotor stroke (corona radiata or internal capsule), pure sensory stroke (thalamus), and ataxic hemiparesis (usually the base of the pons). Lacunar infarcts in the brainstem may lead to an almost infinite range of syndromes, often with the name of a French 19th-​century neurologist attached to it. Often such syn- dromes consist of an ipsilateral cranial nerve deficit and a contra- lateral hemiparesis. Treatment of acute cerebral infarction Several interventions aim at removing (thrombectomy) or dissolving (thrombolysis) the occluding clot, or at least preventing it from growing (antiplatelet agents and anticoagulants). A different strategy, not yet proven in clinical trials, is to protect ischaemic brain tissue (neuroprotection by drugs or manipulation of physiological param- eters such as fever or hyperglycaemia). In addition, some underlying causes of stroke need urgent treatment, such as endocarditis. Before considering these specific measures, it is appropriate to consider the appropriate hospital setting in which stroke patients should be cared for. Stroke units compared with treatment on general hospital wards A specially organized stroke unit can be a ward or team that exclu- sively manages stroke patients (a dedicated stroke unit) or a ward or team that provides a generic disability service (a mixed assess- ment or rehabilitation unit). According to a meta-​analysis of 23 randomized trials, stroke unit care reduces the risk of death or in- stitutionalized care by 14%. The observed benefits are independent of patient age, sex, or stroke severity, and appeared to be better in stroke units based in a separate ward. No single element responsible for the benefits of organized stroke care has so far been identified, and probably there is none. The strength of stroke units lies in good clinical leadership and in the integration of multidisciplinary ef- forts: stroke physician, nursing staff, physiotherapists, occupational therapists, speech and language therapists, rehabilitation phys- icians, and social workers. With the evidence that thrombolysis and thrombectomy improve stroke outcome in a significant pro- portion of patients, there has been a move to develop hyperacute stroke units. Thrombolysis Restoration of blood flow, to reperfuse the ischaemic brain as soon as possible after the cerebral artery has been occluded, irrespective of its cause, should theoretically lead to reduction in the volume of brain damaged by ischaemia and to improvement in clinical out- come, analogous to myocardial infarction. The main agents tested so far in stroke are intravenous recom- binant tissue plasminogen activator (rt-​PA) and intravenous streptokinase. Almost all patients in the trials were treated within 6 h of stroke onset. The evidence for efficacy is statistically signifi- cant for rt-​PA, if administered within 4.5 h and after exclusion of intracerebral haemorrhage by CT. Even within this period, the adage is ‘the sooner, the better’. For patients treated within 90 min, the point estimates for survival with at most moderate disability im- proved from 54% in the placebo groups to 63% for patients in the rt-​PA groups (absolute gain 9%), whereas for patients treated be- tween 91 and 180 min after stroke onset the gain was 7% (from 57% to 64%). Taken together, a benefit of 8% means that some 12 patients must be treated to save a single patient from death or the nursing home. These calculations have already taken into account the fact that there is a risk of secondary haemorrhage after treatment with rt-​PA. More convenient single injection thrombolysis drugs, such as tenectoplase, are currently in large-​scale clinical trials. There are, however, many contraindications to thrombolysis in view of the risk of cerebral haemorrhage, and only a minority of patients admitted with cerebral infarction can be treated with thrombolysis. Thrombectomy Thrombectomy is the retrieval of clot from an occluded artery by one of several intra-​arterial devices. In 2015, several randomized trials reported highly consistent results showing that thrombectomy resulted in better outcomes than control in patients who had acute stroke and an appropriate arterial occlusion on vascular imaging. Thrombectomy was beneficial as a primary treatment and also in patients who had a persisting vessel occlusion after thrombolysis. However, the logistics of providing a 24/​7 thrombectomy service are substantial and may be beyond the reach of many healthcare systems. Antiplatelet agents More than 99% of the evidence from randomized trials in treat- ment of acute stroke relates to aspirin. The pooled results of two very large trials with aspirin (160–​300 mg), started within 48 h of onset, concluded that 13 fewer patients are dead or dependent for every 1000 patients treated. In some 800 patients who had been ­inadvertently randomized after a haemorrhagic stroke there was no evidence of net hazard. Much of the benefit of aspirin is in preven- tion of early recurrent stroke rather than in reducing the severity of the existing stroke. Anticoagulants Anticoagulants tested in clinical trials are standard unfractionated heparin, low-​molecular-​weight heparins, heparinoids, oral anti- coagulants, and thrombin inhibitors. There is no evidence that anti- coagulant therapy reduces the odds of being dead or dependent at the end of follow-​up. Neuroprotective agents There are many steps in the destructive cascade between vessel occlusion and irreversible cell death where pharmacological intervention might be beneficial, at least theoretically. The pharma- ceutical industry has developed several compounds for clinical 24.10.1  Stroke: Cerebrovascular disease 6019 development and testing. There is no doubt that in animal models many neuroprotective agents, given either before or after the onset of ischaemia, reduce the area of cerebral infarction. So far, none of these agents has been proven to reduce disability in patients, despite dozens of clinical trials. Surgical decompression of space-​occupying infarcts To prevent brain herniation and death from supratentorial infarction, a large part of the skull vault can be removed by hemicraniectomy. A pooled analysis (three trials) of 93 patients randomized within 48 h of stroke onset showed not only that the case fatality rate was much lower in operated patients (22%) than in patients who were treated conservatively (71%), but also that operated patients sur- vived significantly more often (43%) with mild or moderate dis- ability (modified Rankin grade 3 or less, see Table 24.10.1.1), against 21% in the conservative group. This has to be weighed against an increased proportion of survivors with severe disability (modified Rankin grade 4 or 5): 35% against 7%. With operations for space-​ occupying infarcts of the cerebellum there is no controlled evidence, but less uncertainty. Without surgery swelling of a cerebellar infarct can be fatal, whereas the deficits after surgical evacuation are sur- prisingly mild. In some patients it is sufficient to relieve obstructive hydrocephalus by external ventricular drainage. Secondary prevention of ischaemic stroke In the long-​term management of patients with TIAs or moderately disabling ischaemic strokes, control of lifestyle factors is a primary concern: cessation of smoking, reducing weight if overweight, and daily exercise. Specific measures to reduce the risk of threatened stroke are mostly pharmacological. Carotid endarterectomy or stenting is the only local treatment that is of proven value. Carotid endarterectomy and stenting This operation was increasingly performed from the 1960s onwards, but not until the 1980s were two randomized trials performed, one in Europe, and one in North America. In patients with severe, symp- tomatic carotid stenosis (70–​99% lumen diameter reduction) the risk of disabling or fatal stroke substantially decreases after end- arterectomy. On average, about six patients need to undergo sur- gery to prevent one ipsilateral ischaemic stroke within 5 years. This basic risk difference varies with age and sex, and it levels off after 3 or more years from randomization (i.e. 3.5 years after the qualifying event). It should be kept in mind that carotid endarterectomy is in- dicated in only a minority (<10%) of patients with TIAs or moder- ately disabling ischaemic strokes: the attacks have to be in the carotid territory, the patients should be fit and willing to undergo the oper- ation, and the angiogram should show an accessible stenosis of over 70% at the carotid bifurcation. A possible alternative for endarterectomy is carotid stenting, with or without devices to prevent emboli being carried downstream during the procedure. Despite the less invasive nature of this pro- cedure, the perioperative risk of stroke is higher than or endarterec- tomy, although stenting appears to be as durable as endarterectomy in reducing the subsequent long-​term risk of stroke. For the demonstration of severe carotid stenosis, it is no longer necessary to perform catheter angiography, at least if the results of duplex ultrasound agree with those of CT angiography or MR angiography. Antiplatelet drugs The preventive effect of aspirin, in different doses, has been studied in placebo-​controlled randomized trials in over 8000 patients after a TIA or moderately disabling stroke. There is virtually no differ- ence between the risk reduction for daily doses between 30 mg and 1300 mg. The overall relative reduction in long-​term risk of stroke is about 13% (95% confidence interval 6–​19%), but most of that benefit accrues in the first 12 weeks and the risks and benefits of longer-​term treatment versus gradual withdrawal ae uncertain. Side effects of aspirin, mainly indigestion, nausea, heartburn, and gastrointestinal bleeding, are more common as the dose is higher. Addition of dipyridamole 200 mg twice daily to aspirin provides a further risk reduction of approximately 18%, compared with aspirin alone. Headache is a common side effect of dipyridamole; it can be avoided by starting with smaller doses. Clopidogrel, a thienopyridine derivative, is marginally more ef- fective than aspirin, with a relative risk reduction of 8.7% (95% con- fidence interval 0.3–​16.5), whereas the combination of clopidogrel and aspirin has no advantage over aspirin alone; clopidogrel should be prescribed only in patients who are intolerant to aspirin. A large trial comparing clopidogrel with aspirin plus dipyridamole in long-​term secondary prevention of stroke showed no difference in effectiveness. Anticoagulants With sources in the heart, mostly from atrial fibrillation, coumadin anticoagulants (INR 2.5–​4) are the first choice in the absence of contraindications; no evidence exists for a fixed age limit. In pa- tients with a presumed arterial cause of cerebral ischaemia, anti- coagulants may prevent some ischaemic events, but this benefit is offset or even outweighed by the risk of haemorrhages, especially in the brain, depending on the intensity of anticoagulation. In recent years, several new oral anticoagulants have been developed and have been shown to be at least as effective as coumadin anticoagulants in preventing ischaemic stroke and systemic embolism and to have a lower risk of intracranial bleeding. Statins The protective effect on major cardiovascular events of statins, or, with the full name of 3-​hydroxy-​3-​methylglutaryl coenzyme A  (HMG-​CoA) reductase inhibitors, has been proved in clin- ical trials involving more than 100, 000 patients with cardio- vascular disease or risk factors, including cerebral ischaemia. The reduction in the 5-​year incidence of major coronary events, coronary revascularization, and stroke is about 20% per mmol/​ litre reduction in low-​density lipoprotein (LDL)-​cholesterol, largely irrespective of the initial lipid profile or other presenting characteristics. Antihypertensive drugs Observational studies provide overwhelming evidence that the level of blood pressure is by far the most powerful risk factor for section 24  Neurological disorders 6020 stroke. That lowering the blood pressure prevents stroke has also been confirmed by several controlled clinical trials in primary pre- vention as well as in patients with previous TIA or stroke. In indi- viduals with a history of stroke or TIA, a blood pressure-​lowering regimen reduces the risk of stroke, regardless of whether or not the blood pressure at baseline was considered too high. The reduction of the stroke risk ranges from one-​quarter to one-​half, depending on the degree of blood pressure lowering. In terms of the choice of antihypertensive drug-​class, there is some evidence that calcium channel blockers and diuretics are most effective in prevention of stroke, with ACE-​inhibitors being less effective and β-​blockers least effective. In conclusion, the optimal strategy for secondary prevention of stroke depends on the probable source of embolism. In patients with atrial fibrillation oral anticoagulants are the preferred treat- ment. Patients in sinus rhythm should be treated with a trio of drugs: an antiplatelet agent, a statin, and sufficient antihypertensive treatment to control any hypertension. In most cases, baseline values for cholesterol or blood pressure should not influence the decision to administer statins and antihypertensive drugs, only the choice of the dose and subsequent increases in intensity of treat- ment. In addition, patients with ischaemic events in the carotid territory should be investigated non​invasively for the presence of severe stenosis in the ipsilateral internal carotid artery, with a view to carotid endarterectomy, or stenting if there are reasons to avoid endarterectomy. Venous occlusive disease The advent of non​invasive brain imaging methods in the last few decades has resulted in increased recognition of cerebral venous thrombosis. Before that time, physicians only rarely considered the diagnosis in patients with otherwise unexplained headache, focal deficits, seizures, impaired consciousness, or combinations of these features. Causal factors Unlike arterial occlusion, cerebral venous thrombosis is only rarely (in c.10%) associated with damage to the vessel wall—​by infection, tumour growth, or trauma. Much more frequent causes are inherited disorders of coagulation. The most common form is factor V Leiden mutation, found in some 20% of patients without other causes. In 20% of patients no causal factors can be identified. Often there is not a single cause but a combination of contrib- uting factors (e.g. the post-​partum period and protein S deficiency; pregnancy and Behçet’s disease; or oral contraceptive drugs and the factor V Leiden mutation). The risk of cerebral venous thrombosis in the post-​partum period increases with maternal age and with the performance of caesarean section. In neonates, cerebral venous thrombosis is usually associated with acute systemic illness, such as shock or dehydration; in older chil- dren the most frequent underlying conditions are local infection (the leading cause before the antibiotic era), coagulopathy, and in Mediterranean countries Behçet’s disease. Diagnosis of cerebral venous thrombosis The clinical features of cerebral venous thrombosis consist essen- tially of headache, focal deficits, seizures, and impairment of con- sciousness, in various combinations and degrees of severity. The symptoms and signs depend on which sinus is affected, and for a large part on whether the thrombotic process is limited to the dural sinus or extends to the cortical veins. In the case of the superior sagittal sinus, which is affected in 70 to 80% of all cases, cerebral venous thrombosis alone will lead to the syndrome of intracranial hypertension (i.e. headache and papilloedema). Up to 30% of patients with so-​called ‘ideopathic intracranial hypertension’ may in fact have sinus thrombosis—​most commonly men and non​obese women. Papilloedema can cause transient visual obscurations and sometimes irreversible constric- tion of visual fields, beginning in the inferonasal quadrants. The increased pressure of the cerebrospinal fluid may also give rise to cranial nerve VI palsies, and sometimes to other cranial nerve deficits. The onset of the headache is usually gradual, but in up to 15% of patients it is sudden and may initially suggest the diagnosis of a ruptured aneurysm. Involvement of cortical veins causes one or more areas of venous infarction, with or without haemorrhagic transformation. If the affected veins drain into the superior sagittal sinus the venous in- farcts are typically located near the midline in the rolandic and parieto-​occipital regions, often on both sides. In the case of the lateral sinus the venous infarct is usually located in the posterior temporal area. Clinically the infarcts manifest themselves through epileptic seiz- ures or focal deficits such as hemiparesis or dysphasia. If unilateral weakness develops (with thrombosis originating in the superior sa- gittal sinus), it tends to predominate in the leg, in keeping with the parasagittal location of most venous infarcts. Obstruction of cortical veins draining into the posterior part of the superior sagittal sinus or into the lateral sinus will commonly lead to hemianopia, dysphasia, or a confusional state. Impairment of consciousness may result from multiple lesions in the cerebral hemispheres, or from transtentorial herniation and compression of the brainstem. Either epilepsy or a focal deficit is a presenting feature in 10–​15% of patients; in the course of the illness seizures occur in 10–​60% of reported series, and focal deficits in 30–​80%. Involvement of the cortical veins alone, without sinus thrombosis and its associated signs of increased cerebrospinal fluid pressure, is an extremely rare occurrence. Thrombosis of the deep venous system, including the great vein of Galen (great cerebral vein), may lead to bilateral haemorrhagic infarction of the corpus striatum, thalamus, hypothalamus, ventral corpus callosum, medial occipital lobe, and upper part of the cerebellum. In those cases, the clinical picture is often dominated by deep coma and disturbance of eye movements and pupillary reflexes. Investigations CT will readily show ‘venous’ infarcts. These do not correspond to a known arterial territory, and often show haemorrhagic trans- formation (Fig. 24.10.1.5); they are sometimes bilateral, in the parasagittal area, supra-​ as well as infratentorial, or in the deep 24.10.1  Stroke: Cerebrovascular disease 6021 regions of the brain. In addition, CT will often provide evidence of the underlying sinus thrombosis: the hyperdense sinus sign or, less reliable, the so-​called empty δ-sign after injection of intravenous contrast material. MRI has made catheter angiography redundant in the diagnosis of cerebral venous thrombosis. It is not sufficient to rely on non-​ visualization of a cerebral sinus on MR venography, because this may represent hypoplasia. Demonstration of the thrombus itself is essential, but this depends very much on the interval from disease onset. Three stages can be distinguished. In the acute stage (days 1–​5) the thrombus appears strongly hypointense in T2-​weighted im- ages and isointense in T1-​weighted images. In the subacute stage (up to day 15) the thrombus signal is strongly hyperintense, initially on T1-​weighted images and subsequently also on T2-​weighted images (Fig. 24.10.1.5). The third stage begins 3 or 4 weeks after symptom onset: the thrombus signal becomes isointense on T1-​weighted im- ages but on T2-​weighted images it remains hyperintense, although often inhomogeneous. Recanalization may occur over months in up to one-​third of patients, but persistent abnormalities are common and do not signify recurrent thrombosis. Treatment and prognosis Anticoagulant treatment is plausible, but the evidence from con- trolled clinical trials is sparse. In the acute phase heparin (either by intravenous route or, subcutaneously, as low-​molecular-​weight hep- arin) seems preferable to oral anticoagulants, because its intensity can be closely monitored. The evidence for heparin treatment rests on no more than 80 randomized patients; there is a non​significant trend towards better outcome in treated patients. At least heparin treatment seems safe, even in patients with haemorrhagic infarcts. Local thrombolysis via endovascular catheters has been performed only in uncontrolled studies. Death rates in different series range between 5% and 30%, and probably depend more on case mix than on treatment. Residual deficits consist mostly of hemispherical deficits or visual impair- ment from optic atrophy. The risk of recurrence has seldom been systematically addressed; it is probably of the order of 10%. It seems wise to advise other means of contraception than the combined oral contraceptive pill (see Chapter 9.9). In women with a peripartum episode of cerebral venous thrombosis, the available evidence does not warrant the advice to avoid a further pregnancy, although in patients with the factor V Leiden mutation the risk of a recurrent episode is probably higher than average. Long-​term anticoagulation is usually recom- mended in patients with a definite thrombophilia or in those with previous venous thrombosis in other territories. Primary intracerebral haemorrhage Causes of primary intracerebral haemorrhage In most cases there is no single cause for primary intracerebral haemorrhage. Even in the classic example of a so-​called hypertensive haemorrhage in the region of the basal ganglia, the question remains about which anatomical or other factors distinguished this patient from others, with similar degrees and duration of hypertension but without brain haemorrhage. Even a combination of recognized ‘causes’, such as that of hypertension and anticoagulants, does not invariably lead to intracerebral haemorrhage. In general, therefore, it is likely that several causal factors combine. These can be broadly distinguished into three categories (Box 24.10.1.4): anatomical fac- tors (lesions or malformations of brain vasculature), haemodynamic factors (blood pressure), and haemostatic factors (to do with platelet function or the coagulation system). Abnormalities of the vascular (b) (a) Fig. 24.10.1.5  Cerebral venous thrombosis in a 27-​year-​old woman. (a) This CT scan shows a small infarct with haemorrhagic transformation in the right brain hemisphere, adjacent to the top of the lateral ventricle. (b) Magnetic resonance imaging, focused on venous structures, shows non​filling of the frontal part (on the reader’s left) of the superior sagittal sinus. section 24  Neurological disorders 6022 system account for most haemorrhages. The type of underlying ab- normality varies with age: below the age of 40 arteriovenous or cav- ernous malformations are the most common single causes, whereas between 40 and 70 the most frequent sources are ruptured perfor- ating arteries (deep haemorrhages); in older people one also finds haemorrhages in the white matter (‘lobar’ haemorrhages), com- monly attributed to amyloid angiopathy. ‘Hypertensive’ intracerebral haemorrhage ‘Hypertensive’ intracerebral haemorrhage results from degenerative changes in small perforating vessels, in the deep regions of the brain (basal ganglia and thalamus—​Fig. 24.10.1.6), or in the cerebellum or brainstem. Risk factors other than hypertension are age, male sex, and high alcohol intake. Microaneurysms occur on these vessels but are not necessarily the only site of rupture. There is a high risk of early, rapid expansion of intracerebral haematomas, sometimes seen during a single scanning procedure or on serial scanning. A stable phase is usually reached in a matter of hours. Deep brain haemorrhages are not always a one-​off event. The recur- rence rate in the first year is 7%, against 2% per year over the subse- quent 6 years, but is reduced by intensive control of any hypertension. Amyloid angiopathy This condition accounts overtly for about 10% of intracerebral haem- orrhages, but its significance has probably been underestimated in the pre-​MRI era. Its frequency rises with age, but so does that of ‘hypertensive’ haemorrhage. The underlying abnormality consists of patchy deposits of amyloid in the muscle layer of small and medium-​ sized cortical arteries of the occipital, parietal, and frontal lobes. Amyloid can also be found in asymptomatic individuals, the propor- tion increasing with age. It is not found outside the brain and does not represent generalized amyloidosis. Haemorrhages associated with amyloid angiopathy typically occur at the border of the grey and white matter of the cerebral hemispheres. Recurrent haemorrhage associated with amyloid angiopathy is much more common than with ‘hypertensive’ small vessel disease. Hereditary forms of amyloid angiopathy account for only a small minority of all cases. Possible manifestations of amyloid angiopathy other than haem- orrhage are transient episodes of focal neurological deficits (amyloid spells), and also intellectual deterioration, associated with diffuse demyelination of the subcortical white matter (leucoaraiosis). Cerebral arteriovenous malformations Arteriovenous malformations (AVMs) are tangles of dilated ar- teries and veins, without a capillary network between them. On angiography, they are recognizable by large feeding arteries and rapid shunting of blood to enlarged and tortuous veins, via a cen- tral nidus of dilated vessels. Haemorrhage is the initial clinical manifestation in 50–​60% of symptomatic AVMs. Other clinical features include epileptic seizures, headaches, and progressive neurological deficits. Demonstrable AVMs are the most common single cause of intracerebral haemorrhage in patients under 45 years (c. 30%). In 10–​20% AVMs are associated with thin-​walled saccular an- eurysms. These occur on peripheral feeding arteries, not at the classic sites at the circle of Willis, and are likely sources of bleeding. In AVMs in which one or more aneurysms have formed, the an- nual risk of rebleeding is as high as 7%, against 2–​3% per annum for other AVMs. If there is no associated aneurysm, the site of rupture is mostly on the venous side of the malformation. Box 24.10.1.4  Causes of primary intracerebral haemorrhage Anatomical factors • Lipohyalinosis (complex small vessel disease) and microaneurysms • Cerebral amyloid angiopathy • Saccular aneurysms • Cerebral arteriovenous malformations • Cavernous angiomas • Venous angiomas • Telangiectasias • Dural arteriovenous fistulae • Haemorrhagic transformation of an arterial infarct • Intracranial venous thrombosis • Septic arteritis and mycotic aneurysms • Moya-​moya syndrome • Arterial dissection • Caroticocavernous fistula Other factors • Arterial hypertension • Migraine • Haemostatic factors • Anticoagulants • Antiplatelet drugs • Thrombolytic treatment (for non​neurological indications) • Clotting factor deficiency • Leukaemia and thrombocytopenia • Intracerebral tumours • Alcohol • Amphetamines • Cocaine and other drugs • Vasculitis • Trauma (‘Spät-​Apoplexie’) Fig. 24.10.1.6  Primary intracerebral haemorrhage in a 52-​year-​old man. This CT scan shows a hyperdense lesion in the right thalamus; the haemorrhage has ruptured into the ventricular system. 24.10.1  Stroke: Cerebrovascular disease 6023 Cavernous malformations Cavernous malformations consist of sharply demarcated areas with widely dilated and thin-​walled vascular channels, without intervening brain tissue. They are often asymptomatic and are en- countered in 0.5% of routine post-​mortem examinations, in the white matter or cortex of a cerebral hemisphere in about one-​half of all cases, in the posterior fossa in one-​third, and in the basal ganglia or thalamus in one-​sixth. If a cavernous malformation is at all symp- tomatic, seizures are at least as common a manifestation as haem- orrhage. The annual risk of haemorrhage in patients in whom the lesion presents with seizures or focal deficits is rather low, between 0.25% and 0.6%. After a first rupture, rebleeding is more frequent, around 4.5% per annum. Haemorrhages from a cavernous malfor- mation are rarely fatal. Familial forms of the disorder occur in several countries around the world, and should be suspected if multiple lesions are found. Several specific genetic defects have now been identified and should be tested for in patients with a strong family history or multiple malformations. Diagnosis of primary intracerebral haemorrhage The history sometimes suggests the cause of the haemorrhage. Previous seizures should raise suspicions about the presence of an AVM, cavernous malformation, or tumour. Amyloid angiopathy should come to mind in patients over 65 years of age with a history of TIAs, intellectual deterioration, or both. A record of long-​standing hypertension indicates small vessel diseases as the most probable underlying condition in a patient with a haematoma in the basal ganglia or in the posterior fossa; on the other hand, hypertension is so common that it may coexist with other conditions. If the pa- tient is known to have had cancer, haemorrhage into a brain me- tastasis is a possibility. The use of oral anticoagulants is a vital piece of information in patients with intracerebral haemorrhage, because their action should be neutralized as soon as possible. It is equally important to know about the use of recreational drugs, particularly cocaine and amphetamines. Finally, the circumstances preceding intracerebral haemorrhage may help to identify its cause, such as puerperium (intracranial venous thrombosis, choriocarcinoma) or neck trauma (dissection of the vertebral or carotid artery). The physical examination will provide rather few clues to the cause of an intracerebral haemorrhage, except petechiae or bruising, which indicate a generalized haemostatic disorder, signs of malig- nant disease such as cutaneous melanoma, a collapsed lung or en- largement of the liver or spleen, or telangiectasias in the skin and mucous membranes. Finding a high blood pressure on admission is the rule, but only in about 50% is there evidence of long-​standing hypertension. Retinal haemorrhages indicate intracranial bleeding in general, most often subarachnoid haemorrhage. Heart mur- murs may be coincidental but should at least raise the possibility of infective endocarditis, as should the finding of needle marks in possible drug addicts. The neurological examination will show focal deficits corresponding to the site of the lesion, with or without a de- creased level of consciousness. Investigations should start with the usual tests of blood and serum. These will sometimes uncover a cause of intracerebral haem- orrhage, such as a low platelet count or massive liver damage. Brain imaging (CT or MRI) is the single most important investigation in patients with suspected intracerebral haematomas. The location of the haematoma may to some extent indicate the underlying cause. Intraventricular extension of the haemorrhage occurs relatively often with deep, ‘hypertensive’ haemorrhages. A grossly irregular margin of a lobar haematoma in older patients suggests amyloid angiopathy, as do multiple or recurrent haemorrhages in the white matter. Intracranial venous thrombosis should be suspected with irregularly shaped haemorrhages in the parasagittal region. Repeat brain CT after injection of contrast may pick up underlying lesions. Sometimes these can be identified only weeks later, when the lesion is no longer obscured by mass effects. Treatment of primary intracerebral haemorrhage Factors predicting the chances of survival of patients with primary intracerebral haemorrhage are:  level of consciousness (Glasgow Coma Scale); age; volume of haematoma (poor prognosis if supratentorial haematoma more than 50 ml), subsequent expansion of the haematoma, and intraventricular extension of haemorrhage (poor prognosis if volume >20 ml). The possible interventions out- lined next, of course, apply only to patients who have a chance of survival. In patients on oral coumadin anticoagulants the first step is intra- venous injection of 10–​20 mg of vitamin K, at not more than 5 mg/​ min, followed by infusion of a concentrate of the coagulation factors II, VII, IX, and X, or of fresh frozen plasma. Specific agents for re- versal of the newer oral anticoagulants are also in development. Intracranial pressure is often raised. Factors other than the local effects of the haematoma may contribute, such as fever, hypoxia, hypertension, seizures, and elevations of intrathoracic pressure. An unsolved question is the use, in comatose patients, of monitoring and, if judged appropriate, lowering intracranial pressure. There are many believers in this area but few controlled studies. Insertion of a ventricular catheter may be a definitive measure in patients with cerebellar haemorrhage and no signs of direct compression of the brainstem. For surgical treatment of supratentorial haematoma, randomized trials have failed to show benefit, including those employing endo- scopic evacuation. In patients with cerebellar haematomas there is no doubt that surgical evacuation can be life-​saving, often with sur- prisingly few neurological sequelae. Sound indications for evacu- ation of a cerebellar haematoma are the combination of a depressed level of consciousness with signs of progressive brainstem compres- sion (unless all brainstem reflexes have been lost for more than a few hours, in which case a fatal outcome is unavoidable), or haematoma greater than 3–​4 cm. If the patient has a depressed level of conscious- ness and hydrocephalus, without signs of brainstem compression and with a haematoma less than 3 cm, ventriculostomy can be car- ried out as an initial (and sometimes only) procedure. Subarachnoid haemorrhage Causes of subarachnoid haemorrhage Ruptured aneurysms are by far the most common source of non​traumatic subarachnoid haemorrhage, in about 85%. Around section 24  Neurological disorders 6024 10% are non​aneurysmal peri-​mesencephalic haemorrhages, the re- maining 5% is made up by rarities (Box 24.10.1.5). Cerebral aneurysms are not congenital; they develop during the course of life. Therefore, aneurysmal haemorrhage in a child is extremely rare. The aneurysms are saccular in shape and mostly arise at sites of arterial branching at the base of the brain, at or near the circle of Willis (Fig. 24.10.1.7). It is largely unknown why some adults develop aneurysms. There are families with two or more affected first-​degree relatives, but these account for less than 5% of all subarachnoid haemorrhages. Many classic risk factors for stroke in general also apply to subarachnoid haemor- rhage: smoking, hypertension, heavy drinking, and oral contra- ceptives. Not all aneurysms rupture. Their prevalence can be estimated, from angiographic studies (for other purposes) and post-​mortem studies at approximately 2–​3% in middle age, up to 5% at the end of life. On the assumption that this proportion is 1% for a standardized population across all age groups, and given that the incidence of subarachnoid haemorrhage is approximately 6 per 100 000 (of the entire population), the annual risk of rupture of an aneurysm is about 0.6%. Non​aneurysmal perimesencephalic haemorrhage is a distinct and benign variety of subarachnoid haemorrhage, in which the distribution of extravasated blood on the brain CT scan is different from that with aneurysms, in the cisterns around the midbrain or ventral to the pons. The angiogram is completely normal, and the long-​term outcome is invariably excellent. This subtype con- stitutes 10% of all subarachnoid haemorrhages and two-​thirds of subarachnoid haemorrhages with a normal angiogram. Diagnosis of subarachnoid haemorrhage The key feature in the history is that of a sudden, severe, and un- usual headache. In 50% there is loss of consciousness at onset; the headache may emerge only later in these patients. The diagnosis is most difficult in patients with headache as the only feature. In general practice, sudden-​onset forms of common headaches (‘thunder-​clap’ headache) outnumber ruptured aneurysms. The incidence of aneurysmal haemorrhage being about 6 per 100 000 population per year, the average general practitioner will, on average, see one such patient every 8 years. There are no single or combined features of the headache that distinguish reliably and at an early stage between subarachnoid haemorrhage and innocuous types of sudden headache. The physical examination is unhelpful in patients with headache alone, without loss of consciousness or focal deficits. Neck stiffness takes about 6 h to develop, so its absence soon after the onset does not exclude the diagnosis of subarachnoid haemorrhage at all. CT brain imaging is the most important investigation in sus- pected subarachnoid haemorrhage. This will show extravasation of blood in the basal cisterns of the brain in at least 95% of patients with a ruptured aneurysm, if the scan is performed within 3 days (see Fig. 24.10.1.7). After that interval the sensitivity of CT quickly decreases. In patients with a negative CT scan but a convincing history, lumbar puncture is indicated. If the cerebrospinal fluid is blood stained, it is essential to distinguish subarachnoid haemor- rhage reliably from a traumatic tap. For that purpose, at least 6 and preferably 12 h should have elapsed from symptom onset. In case of subarachnoid haemorrhage sufficient lysis of red cells will have oc- curred in the meantime for bilirubin and oxyhaemoglobin to have formed. These pigments give the cerebrospinal fluid a yellow tinge after centrifugation (xanthochromia); they are invariably detect- able until at least 2 weeks later. The ‘three tube test’ (a decrease in red cells in consecutive tubes in the case of a traumatic puncture) can be helpful, but is unreliable. If the supernatant seems crystal (a) (b) Fig. 24.10.1.7  Aneurysmal subarachnoid haemorrhage in a 31-​year-​ old woman. (a) CT scanning shows evidence of extravasated blood throughout the basal cisterns. (b) CT angiogram, with intravenous contrast, shows an aneurysm at the anterior communicating artery. Box 24.10.1.5  Causes of subarachnoid haemorrhage • Ruptured aneurysm (85%) • Non​aneurysmal perimesencephalic haemorrhage (of venous origin?) (10%) • Rarities (5%) — Arterial dissection (transmural) — Cerebral arteriovenous malformation — Dural arteriovenous fistula — Pituitary apoplexy — Mycotic aneurysm — Cardiac myxoma — Sickle cell disease — Tumours — Spinal arteriovenous malformation or aneurysm — Trauma (without contusion) — Cocaine abuse 24.10.1  Stroke: Cerebrovascular disease 6025 clear, the specimen should be stored in darkness until the absence of blood pigments is confirmed by spectrophotometry. Bilirubin can be formed only in vivo; its demonstration by spectrophotom- etry therefore proves that red blood cells cannot have been intro- duced during the lumbar puncture, whereas oxyhaemoglobin can be formed if a cerebrospinal fluid specimen with red blood cells is left standing before the sample is spun down. Catheter angiog- raphy is rapidly being replaced by CT and MR angiography as a method for demonstrating or excluding an aneurysm as the source of haemorrhage. Treatment of aneurysmal subarachnoid haemorrhage Several complications may occur after a first episode of aneur- ysmal subarachnoid haemorrhage, of which rebleeding and cere- bral ischaemia are the most dreaded. Despite advances in surgical and medical management, the population-​based case fatality rate is still around 50%, with half of survivors remaining more or less disabled. As general nursing measures, continuous observation and an intravenous access are essential. A bladder catheter is necessary for monitoring fluid balance. Headache should be relieved in a stepwise approach, with paracetamol and codeine as first steps. Distressing anxiety can be alleviated with short-​acting benzodiazepines. Stools should be kept soft with oral laxatives and also by an adequate intake of fluids. Prevention of rebleeding is challenging, if only because any effective measure tends to be offset by an increased risk of is- chaemia. Moreover, at least 10% of all patients with subarach- noid haemorrhage suffer a further bleed within hours of the initial haemorrhage. Over the next 4 weeks the rate of rebleeding without intervention is at least 30%. The immediate case fa- tality of rebleeding is 50%. Endovascular treatment (‘coiling’) is the preferred method to occlude the aneurysm and prevent rebleeding, but not all aneurysms can be treated in this way and surgical treatment by clipping is still necessary for these patients. Antifibrinolytic drugs decrease the rate of rebleeding but do not improve overall outcome. Delayed cerebral ischaemia occurs in up to 25% of patients with a ruptured aneurysm, mainly between day 5 and day 14 after the initial bleed. Understanding of its pathogenesis has been im- peded by simplistic notions about ‘vasospasm’ or ‘clots around vessels’. Narrowing of the arteries at the base of the brain is a factor but not a sufficient one. The total amount of subarachnoid blood is a potent risk factor, but only after rupture of an artery, and the distribution of blood in the subarachnoid space does not predict the site of ischaemia. The calcium antagonist nimodipine, in a dose of 60 mg every 4 h by mouth or nasogastric tube, re- duces the frequency of cerebral ischaemia and poor outcome by about a third; its mode of action is incompletely understood. Hypertension should as a rule be left untreated; it is a compensa- tory reaction to maintain cerebral perfusion. The plasma volume should not be allowed to fall; hyponatraemia is caused by renal sodium depletion and not, as still often believed, by dilution as a result of inappropriate secretion of antidiuretic hormone. Fluids should therefore be replaced and not restricted. The basic intake should be at least 3 litres/​day, with intravenous fluids supple- menting oral intake; compensation should be made for fever or a negative fluid balance. FURTHER READING Antithrombotic Trialists’ (ATT) Collaboration (2009). Aspirin in the primary and secondary prevention of vascular disease: collabora- tive meta-​analysis of individual participant data from randomised trials. Lancet, 373, 1849–​60. Ariesen MJ, et al. (2003). Risk factors for intracerebral hemorrhage in the general population: a systematic review. Stroke, 34, 2060–​5. Cholesterol Treatment Trialists’ (CTT) Collaboration (2015). Efficacy and safety of LDL-​lowering therapy among men and women: meta-​ analysis of individual data from 174,000 participants in 27 random- ised trials. Lancet, 385, 1397–​405. de Schryver EL, et al. (2007). Dipyridamole for preventing stroke and other vascular events in patients with vascular disease. Cochrane Database Syst Rev, 3, CD001820. Diener HC, et  al. (2004). Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient is- chaemic attack in high-​risk patients (MATCH):  randomised, double-​blind, placebo-​controlled trial. Lancet, 364, 331–​7. EAFT (European Atrial Fibrillation Trial) Study Group (1993). Secondary prevention in non-​rheumatic atrial fibrillation after tran- sient ischaemic attack or minor stroke. Lancet, 342, 1255–​62. Emberson J, et al. (2014). Effect of treatment delay, age, and stroke se- verity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-​analysis of individual patient data from randomised trials. Lancet, 384, 1929–​35. European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee (2008). Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis, 25, 457–​507. Feigin VL, et al. (2014). Global and regional burden of stroke during 1990–​2010: findings from the Global Burden of Disease Study 2010. Lancet, 383, 245–​54. Giles MF, et al. (2007). Risk of stroke early after transient ischaemic attack:  a systematic review and meta-​analysis. Lancet Neurol, 6, 1063–​72. Johnston SC, et al. (2007). Validation and refinement of scores to pre- dict very early stroke risk after transient ischaemic attack. Lancet, 369, 283–​92. Kernan WN, et al. (2014). Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/​ American Stroke Association. Stroke, 45, 2160–​236. MacMahon S, et al. (2001). Randomised trial of a perindopril-​based blood-​pressure-​lowering regimen among 6105 individuals with pre- vious stroke or transient ischaemic attack. Lancet, 358, 1033–​41. Madden KP, et al. (1995). Accuracy of initial stroke subtype diagnosis in the TOAST study. Neurology, 45, 1975–​9. Mendelow AD, et  al. (2005). Early surgery versus initial conser- vative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet, 365, 387–​97. Molyneux AJ, et al. (2005). International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet, 366, 809–​17. Rodrigues FB, et al. (2016). Endovascular treatment versus medical care alone for ischaemic stroke: systematic review and meta-​ana- lysis. BMJ, 353, i1754. 24.10.2 Demyelinating disorders of the central ner 24.10.2 Demyelinating disorders of the central nervous system 6026 Alasdair Coles and Siddharthan Chandran section 24  Neurological disorders 6026 Rothwell PM, et al., on behalf of the Early use of Existing Preventive Strategies for Stroke (EXPRESS) Study (2007). Major reduction in risk of early recurrent stroke by urgent treatment of TIA and minor stroke: EXPRESS Study. Lancet, 370, 1432–​42. Rothwell PM, et al. (2003). Analysis of pooled data from the random- ised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet, 361, 107–​16. Rothwell PM, et al. (2004). Change in stroke incidence, mortality, case-​ fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study). Lancet, 363, 1925–​33. Rothwell PM, et al. (2011). Medical treatment in acute and long-​term secondary prevention after transient ischaemic attack and ischaemic stroke. Lancet, 377, 1681–​92. Sacco RL, et al. (2008). Aspirin and extended-​release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med, 359, 1238–​51. Sandercock PA, et al. (2014). Oral antiplatelet therapy for acute is- chaemic stroke. Cochrane Database Syst Rev, 3, CD000029. Stam J (2005). Thrombosis of the cerebral veins and sinuses. N Engl J Med, 352, 1791–​8. Stroke Unit Trialists’ Collaboration (2002). Organised inpatient (stroke unit) care for stroke. Cochrane Database Sys Rev, 4, CD000197. Vahedi K, et al. (2007). Early decompressive surgery in malignant in- farction of the middle cerebral artery: a pooled analysis of three ran- domised controlled trials. Lancet Neurol, 6, 215–​22. van der Zwan A, et al. (1992). Variability of the territories of the major cerebral arteries. J Neurosurg, 77, 927–​40. van Gijn J, et  al. (2007). Subarachnoid haemorrhage. Lancet, 369, 306–​18. Wang Y, et al. (2013). CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med, 369, 11–​19. Warlow CP, et al. (2007). Stroke—​practical management, 3rd edition. Blackwells, Oxford. 24.10.2  Demyelinating disorders of the central nervous system Alasdair Coles and Siddharthan Chandran ESSENTIALS The common feature of all of the demyelinating diseases is that, ini- tially at least, the oligodendrocyte-​myelin unit is the primary target, with the axon comparatively spared. There are a range of causes, both acquired and inherited. Multiple sclerosis is the commonest and protoypic condition. Pathophysiology—​demyelination is followed by predictable elec- trophysiological consequences including impaired conduction and over time progressive neuronal injury with variable re-​myelination. Multiple sclerosis Epidemiology—​a disease of northern Europeans, occurring less fre- quently in other racial groups. The leading causing of acquired adult neurological disability in many industrialized nations. Pathology—​characterized histologically by breakdown of the blood–​brain barrier and multifocal inflammatory-​mediated de- myelination leading to ‘plaques’ throughout the central nervous system. Neurodegeneration is prominent in the later stages of disease. Aetiology—​unknown, but involves interplay between genes (fa- milial recurrence rate 15%, modest increase in risk from many genes) and the environment (possible effects from vitamin D status, smoking, and viral infection in childhood or adolescence). Clinical features—​fatigue is common. Acute demyelinating optic neuritis is a first manifestation in up to 20% of patients. Impaired mo- bility affects most patients, usually as a result of spinal cord disease. Altered sensation is almost universal, autonomic symptoms occur in most, and cerebellar involvement is common. Abnormalities of eye movement are frequent, including ‘internuclear ophthalmoplegia’, a sign that is nearly always due to multiple sclerosis. Cognitive impair- ment occurs in up to 65% of patients. Clinical course—​variable and unpredictable. Most patients ex- perience a relapsing and remitting course, characterized over time by three phases—​relapse with full recovery, relapse with persistent deficits, and secondary progression. Diagnosis—​multiple sclerosis can reliably be diagnosed using clinical criteria and without laboratory support. There is no single diagnostic laboratory investigation, but the most useful investiga- tions are (1) MRI demonstrating lesions disseminated in time and/​ or space; (2) cerebrospinal fluid analysis revealing oligoclonal im- munoglobulin bands; (3) electrophysiology showing demyelination in central pathways. Management—​the complex and progressive nature of disability requires a multidisciplinary approach. Symptomatic manage- ment may be required, for example, for bladder symptoms, con- stipation, or spasticity. Corticosteroids are effective in reducing the duration of acute demyelinating episodes but have no impact on the eventual degree of recovery or the subsequent disease course. Disease-​modifying treatments are effective only in the inflamma- tory relapse-​remitting phase of disease and include β-​interferons, glatiramer acetate, fingolimod, and the humanized monoclonal antibodies natalizumab and alemtuzumab. There is not yet a con- sensus on how early and how aggressively multiple sclerosis should be treated. Introduction: demyelinating disorders as potentially treatable conditions A distinguishing feature of vertebrate development is the forma- tion of compact myelin around axons, produced by oligodendro- cytes in the central nervous system and Schwann cells in the peripheral nervous system. This insulating material reduces the escape of current across the axon and allows for passive propa- gation of the action potential down myelinated segments of the nerve until it arrives at a break in the myelin, at a node of Ranvier, where a new action potential is actively triggered. The advantage of this ‘saltatory’ conduction is speed, and greater efficiency of energy and space. Myelinated nerves conduct the action potential more rapidly than in unmyelinated fibres. In demyelinating disorders of 24.10.2  Demyelinating disorders of the central nervous system 6027 the central nervous system, the oligodendrocyte-​myelin unit is the primary target of pathology and conduction of the nerve impulse first slows and then fails. Multiple sclerosis, the prototypic demyelinating disorder of the central nervous system, is the leading causing of neurological dis- ability among young adults in many industrialized nations. In the last two decades therapies have been licensed with increasing cap- acity to suppress the inflammation which underlies the condition, leading to durable benefits to patients. The next most prevalent demyelinating disease is neuromyelitis optica. Originally thought to be a variant of multiple sclerosis, it is now recognized to be a distinct disease whose treatment is radically different from mul- tiple sclerosis. The common feature of all of the demyelinating diseases (listed in Table 24.10.2.1) is that, initially at least, the axon is compara- tively spared with the dominant pathology being inflammatory-​ mediated damage to the oligodendrocyte-​myelin unit. This means that anatomical connections are not disrupted, which makes the task of functional repair considerably easier than in disorders which destroy neuronal pathways. Treatments to promote remyelination are currently under investigation in multiple sclerosis and the leukodystrophies. In some demyelinating disorders, most notably multiple scler- osis, there is a later phase of progressive disability which is due to neuronal loss. These observations raise questions about the de- pendence of neuronal integrity on myelin and glial support. The predominant strategies to prevent the neurodegeneration of mul- tiple sclerosis are early treatment to prevent demyelination along with, conceivably in the future, combinatorial neuroprotective treatments such as remyelination therapy to restore the glial-​axon relationships. Neurobiology of demyelination and remyelination Origin of oligodendrocytes Oligodendrocytes synthesize and maintain the compact myelin that ensheathes axons. Oligodendrocytes, in contrast to neurons, are pre- dominantly specified postnatally and continue to divide and migrate as oligodendrocyte precursor cells (OPCs). Identification of the Olig genes has significantly advanced understanding of the molecular regu- lation of developmental and adult oligodendrogenesis. In addition to its established role in specifying neurons and OPCs in the developing CNS, emerging evidence implicates Olig in self-​renewal of neural stem cells and adult oligodendrogenesis in the normal and injured brain. These findings—​together with accumulated insights into the prolif- erative, migratory, and survival requirements of OPCs—​have resulted in the oligodendrocyte lineage being the best characterized of all cells of the central nervous system. The application of that knowledge may in time lead to the development of potential neuroprotective thera- peutic targets in the context of demyelinating disease. Myelination Myelination occurs when the membranous processes of mature oligodendrocytes contact and wrap serially around axons. The result is compaction of myelin sheaths at two points of apposition, apparent on ultrastructural analysis as major and minor dense lines. Myelin is predominantly composed of lipids (70–​80% dry weight; cholesterol, phospholipid, and galactolipids) and protein (20–​30% dry weight). The major myelin-​specific lipid galactocerebroside can be used to identify myelinating glia. The major proteins are proteolipid protein, myelin basic protein, and the myelin-​specific enzyme 2’,3’-​Cyclic-​ nucleotide 3’-​phosphodiesterase. Table 24.10.2.1  Classification of demyelinating disorders of the central nervous system Disease Features Acquired Inflammatory Multiple sclerosis Very common: starts with relapsing-​remitting episodes of e.g. optic nerve, spinal cord, and brainstem demyelination; later secondary progressive disease Neuromyelitis optica spectrum disorder Common: combinations of longitudinally extensive myelopathy, area postrema, and optic nerve lesions; due to anti-​aquaporin 4 antibodies Acute disseminated encephalomyelitis Common: postinfectious, extensive cortical and brainstem demyelination Longitudinally extensive myelitis Common: postinfectious, or as part of NMO spectrum disorder Relapsing optic neuritis Rare: some associated with anti-​MOG antibodies and others dependent on corticosteroids Balo’s concentric sclerosis Rare: rings of demyelination and unaffected tissue causing lobar syndromes Harding’s disease Rare MS-​like disease in people with Leber’s mitochondrial mutations Non​inflammatory Central pontine myelinolysis Common: occurs with rapid correction of hyponatraemia Toxic disseminated encephalomyelitis Rare: due to inhaled vapour of opiates and cocaine Inherited Adrenoleukodystrophy Rare: in adults causes myelopathy, neuropathy, and adrenal failure Metachromatic leukodystrophy Rare: causes progressive epilepsy, neuropathy, and cognitive impairment Pelizaeus–​Merzbacher disease Very rare: eye movement disorders, cognitive impairment, and neuropathy; due to proteolipid protein gene mutations Krabbe’s disease Very rare: epilepsy, cognitive impairment, and neuropathy; due to deficiency of α-​galactocerebrosidase Autosomal-​dominant adult leukodystrophies Very rare as adult section 24  Neurological disorders 6028 Each high resistance myelin segment is separated by the unmyelin­ ated high conductance node of Ranvier. This specialized struc- ture, characterized by clusters of voltage-​gated sodium channels, is the site of active generation of the action potential. Myelinated internodal segments contain dispersed sodium channels at a much lower density insufficient to support conduction. Pathophysiology of demyelination Demyelination is followed by predictable electrophysiological con- sequences including impaired saltatory conduction, decreased con- duction velocity, and variable degrees of conduction block. The extent to which these changes cause symptoms is less predictable and depends upon the redundancy within the pathway affected and the capacity of the nervous system to circumvent the lost func- tion. There are several mechanisms of symptom recovery early in the course of multiple sclerosis. Plastic functional reorganization of the nervous system may circumvent the disrupted pathway. An adaptation of the axon to demyelination is that sodium channels are expressed in demyelinated patches of axon membrane. This can re- store active conduction. But it may also be maladaptive; the ensuing increase in intracellular sodium concentration requires greater ac- tivity of the sodium-​potassium exchanger. Especially when nerve firing is rapid, the metabolic strain of extruding sodium may cause axonal degeneration. As with many disorders of the nervous system, the clinical symp- toms and signs may be negative (loss of function), or positive (spon- taneous, involuntary, and paroxysmal). Either category can prove equally disabling. But there are features specific to demyelination, not seen in axonal loss. For instance, electrophysiological tests of optic tract function (‘visual evoked potentials’) will often show slowing of conduction following inflammatory demyelination in the optic nerve. Similar slowing may also be seen in brainstem and somatosensory evoked potentials after demyelination of the relevant pathways. In partially demyelinated axons, the action potential may propa- gate normally but can break down more easily to external chal- lenges. The best example is the ‘Uhthoff phenomenon’: symptoms occur on exercise or heating (e.g. in a hot bath) and disappear on cooling. As myelin is heated, so its insulating capacity reduces; cur- rent escapes from the axon, fails to trigger a new action potential at the node of Ranvier and so conduction fails. Also, the partially demyelinated nerve may discharge with mechanical stretching. Typical movement-​induced symptoms including flashes of light on eye movement, and the electric sensation that spreads down the spine, limbs, or anterior chest wall after neck flexion—​Lhermitte’s symptom and sign. Ephaptic transmission occurs between neigh- bouring and partially demyelinated axons giving rise to paroxysmal symptoms of demyelination usually manifesting as trigeminal neur- algia, ataxia, and dysarthria, or tonic brainstem seizures. These are often triggered by touch or movement. Remyelination Endogenous remyelination may restore function in demyelinating disease. In multiple sclerosis, it has long been known that acute lesions frequently show an increase in the number of oligo- dendrocyte precursors and may undergo remyelination, evident as shadow plaques. Remyelination, found at all stages of disease, is histologically identified by inappropriately thin myelin lamellae, with a short internode, and widened nodes of Ranvier. The finding that remyelination is associated with less axonal injury compared with inactive demyelinated plaques, suggests that remyelination is neuroprotective. The source of remyelinating cells is presumed to be the oligodendrocyte progenitor, which is found in the lesions of multiple sclerosis, although recent evidence also suggests a role for adult subventricular zone derived stem cells. It is clear that remyelination is not sufficient to prevent disability in most cases of multiple sclerosis. This may be because the waves of inflammation overwhelm endogenous capacity for repair, or that there is a pri- mary failure of remyelination, perhaps increasing with age. Multiple scler osis Pathology The most common demyelinating disorder is multiple sclerosis, characterized histologically by breakdown of the blood–​brain bar- rier and the development of multifocal foci of inflammation in the brain and cord, called ‘plaques’. In all but the most severe forms, perivascular inflammation evolves through stages of acute axonal injury, demyelination, oligodendrocyte depletion, remyelination, astrocytosis and chronic neurodegeneration (Fig. 24.10.2.1). The order and relationship of these separate components is still de- bated, but the consensus based on a wealth of evidence is that mul- tiple sclerosis is primarily an inflammatory disease with secondary neurodegeneration. Plaques are widely distributed, but concen- trated around venous networks, the ventricles, and in the corpus callosum, optic nerves, brainstem, and cervical cord. A simplified scheme is that multiple sclerosis starts with inappro- priate activation of a peripheral T cell directed against a myelin antigen. This T cell then proliferates, crosses the intact blood-​brain-​ barrier, and enters the central nervous system. There it encounters its antigen and sets up an acute inflammation with release of cyto- kines and chemokines, which attract and activate microglia, and produce immunoglobulins that together culminate in damage to the myelin-​oligodendrocyte unit. These inflammatory processes lead to disruption of the myelin membrane with increased spacing, ves- icular disruption, splitting, vacuolation, and fragmentation of the lamellae. Multiple sclerosis plaques can be classified into ‘acute’ or ‘chronic’, depending on the presence or absence of acute inflammatory cells. There are also different patterns of pathology. One scheme describes T cell infiltrates and macrophage associated tissue injury (pattern 1); antibody and complement-​mediated immune reactions against cells of the oligodendrocyte lineage and myelin (pattern 2); hypoxia-​ like injury, resulting either from inflammation-​induced vascular damage or macrophage toxins that impair mitochondrial function (pattern 3); and a genetic defect resulting in primary susceptibility of the oligodendrocytes to immune injury (pattern 4). The evidence for pathological heterogeneity, as opposed to complexity in which additional effector molecules are recruited to the evolving lesions following initial T cell infiltration of the CNS, has recently been challenged. Rather, the various pathological features are now seen as stages in the development of a ubiquitous pathological end-​game, in which apparent heterogeneity may disappear over time as different pathways converge on one general mechanism of demyelination—​ the presence of complement, antibody and Fc γ-receptor on 24.10.2  Demyelinating disorders of the central nervous system 6029 phagocytic macrophages, indicating that antibody dependent cell-​ mediated cytotoxicity is primarily responsible for demyelination in established multiple sclerosis. The focus on inflammation and demyelination had until recently obscured the extent and significance of neuronal and axonal injury. Axonal injury is present at all stages of multiple sclerosis. Recent recognition of the fundamental role oligodendrocytes play in pro- viding metabolic support to axons through glial glycolysis products adds to the multiple mechanisms by which disruption and loss of the oligodendrocyte-​myelin unit can lead to axonal injury and ul- timately neuronal loss. Key modes of injury that are now implicated, include glial-​mediated production of reactive oxygen/​nitric oxide species, mitochondrial injury, intra-​axonal cation excess, altered astroglial environment, and cellular excitotoxicity. Early axonal in- jury evident by axonal transection and accumulation of amyloid precursor protein tends to occur when inflammatory demyelination is prominent. Whether the immune process directly targets axons or merely involves these structures as part of non​specific collateral damage is unclear. Similarly, it is uncertain whether axonal loss in normal appearing white matter merely reflects axon dropout due to time-​delayed Wallerian degeneration. Later, chronic axonal loss is associated with microglial activation throughout the brain paren- chyma and away from the postinflammatory chronic demyelinated lesions. In addition, several lines of evidence also implicate loss of oligodendrocyte-​myelin-​derived metabolic and trophic support as contributory to the mechanism of progressive neurodegeneration. The recognition that neurodegeneration is the dominant patho- logical substrate of progressive disability brings into focus the importance of understanding the relationship between focal lymphocytic inflammation—​clinically manifest as relapses—​and the neurodegeneration that drives the progressive phase of the dis- ease. A widely-​held position is that inflammation drives the cascade of events leading to neurodegeneration, or conditions a genetic pre- disposition to axon degeneration that would not be exposed without the inflammatory trigger. Aetiology The aetiology of multiple sclerosis involves interplay between genes and the environment. It is a disease of northern Europeans and oc- curs less frequently in other racial groups. There is a female pre- dominance that may be increasing. The familial recurrence rate is approximately 15%. Meta-​analysis among relatives of probands from three population-​based series shows that the age-​adjusted risk is highest for siblings (3%), then parents and children (2%), with lower rates in second-​ and third-​degree relatives. Recurrence in monozygotic twins is around 35%. Conversely, the frequency of multiple sclerosis in adoptees is similar to the population risk for Europeans. The age-​adjusted risk for half-​siblings is intermediate between ‘social’ and biological relatives. Recurrence is higher in the children of conjugal pairs with multiple sclerosis (age-​adjusted 20%) than the offspring of single affecteds (2%) (Fig. 24.10.2.2). Population studies carried out in the 1970s, demonstrated an as- sociation between the linked class II MHC alleles (DR15 and DQ6) and their corresponding genotypes. Extensive searches, using as- sociation and linkage studies over many years, until recently, had yielded very few additional candidates for susceptibility. However, Clinical neurological dysfunction Axonalloss Progressive stage Relapsing-remitting stage Relapsing with persistent deficits (a) Disease progression and axonal loss in multiple sclerosis Axonal loss Inflammation & demyelination Loss of oligodendrocyte /myelin signals (b) Contribution of demyelination to axonal loss Fig. 24.10.2.1  Inflammation, demyelination, axonal loss, and disease progression in multiple sclerosis. (a) The early stage of relapsing-​remitting multiple sclerosis is characterized by transient neurological deficits that return to normal and pathology dominated by focal inflammation and demyelination. However, as the disease progresses neurological dysfunction becomes fixed and accumulates. The pathological correlate of the progressive phase of the disease is axonal loss. (b) The early events of demyelination and inflammation are believed to contribute to axonal loss by numerous mechanisms including loss of oligodendrocyte/​myelin-​ derived trophic and structural support. The schematic diagram shows a single oligodendrocyte (black and white) myelinating three axons (axon purple, myelin blue). Early in the course of multiple sclerosis, the oligodendrocyte is damaged through inflammatory driven mechanisms resulting in demyelination of the axon. The loss of oligodendrocyte contributes and culminates in axonal loss as found in progressive multiple sclerosis. section 24  Neurological disorders 6030 recent large-​scale genome-​wide association studies involving tens of thousands of cases and controls have identified well over 100 loci that, individually, confer a modest increase in risk. Collectively these studies underline a central role for the immune system in the devel- opment of MS beyond the longstanding HLA association, as well as revealing that multiple sclerosis clusters with other autoimmune conditions. Functional studies of these genes are broadly lacking but it is of considerable interest that most of these genes are non​coding and frequently mapping to regulatory regions on immune cell types. This evidence from genetic analysis is one of the most compelling reasons for concluding that multiple sclerosis is primarily an im- munological disorder. Apart from informing ideas on the pathogen- esis of multiple sclerosis, within this list of over 100 susceptibility genes are several that inform current therapeutic strategies or sug- gest new approaches to treatment. For example, the variant respon- sible for the association between multiple sclerosis and TNFRSF1A confers functional properties on immune cells that increase their production of soluble TNFα, reproducing the pattern previously shown to increase disease activity after administration of anti-​TNFα therapeutic antibody of TNFα-​receptor blockade, illustrating the potential for pharmacogenomics to inform future treatment selec- tion and stratification. Ongoing genetic studies are aimed at dis- covery of further heritability genes with estimates of 30–​50% still unaccounted, along with functional studies of known genes and fi- nally the role of genetics in determining disease course. Studies of concordance in multiplex families show that genetic factors influence the risk of progression but, as yet, no responsible loci are identified. Genetic analysis may also contribute to the de- bate on whether multiple sclerosis is one disease. Mutations of mito- chondrial DNA are responsible for a multiple sclerosis-​like illness characterized by disproportionate involvement of the anterior visual pathway, although mitochondrial genes do not contribute generally to susceptibility in multiple sclerosis. A major part of future studies in the genetics of multiple sclerosis will be to resolve the question of disease heterogeneity. The distribution of multiple sclerosis cannot be explained only on the basis of population genetics. In white South African people and in Australia, prevalence rates are half those documented for many parts of northern Europe. There is a gradient in frequency, both in Australia and in New Zealand, which does not follow genetic clines. The risk is higher for English-​speaking white people migrating into South Africa as adults than in childhood. Multiple sclerosis oc- curs at a low frequency in the Caribbean population, but the risk increases substantially in their first-​generation descendants raised in the United Kingdom. Over and above the effect of racial predis- position, migration influences distribution of the disease. Surveys of multiple sclerosis have prompted speculation on the occurrence of post-​Second World War epidemics in Iceland, the Orkney and Shetland Islands, and the Faroes, but others prefer the interpretation that these merely reflect improved case recognition. Noting the association with latitude, and other apparent epi- demiological features such as seasonality for month of birth in people who later develop multiple sclerosis, it has been suggested that the environmental effect is conferred by variable light exposure and vitamin D status. Without much in the way of mechanistic in- terpretation or compelling evidence, this has led to widespread self-​prescribing of vitamin D among affected individuals, often con- doned by physicians. Probably harmless in small doses, it will never- theless take time to establish whether the hypothesis for a role of vitamin D, ubiquitously deficient in the normal population at risk of multiple sclerosis, is substantiated. A second risk factor that has some support from epidemiological and genetic studies is smoking. Here, the analogy with rheumatoid arthritis in which proteins are shown to be abnormally citrullated following passage through the lungs of smokers has some mechanistic logic. The widely accepted formulation that multiple sclerosis is the outcome of unknown envir- onmental factors, conditioned by age at exposure, acting on a genet- ically vulnerable population has led to a largely unrewarding search for such environmental agents. However, the risk of developing multiple sclerosis is increased for individuals exposed to measles, mumps, rubella and (especially) Epstein–​Barr virus infection rela- tively late in childhood or adolescence. These studies suggest that an age-​linked period of susceptibility to viral exposure exists in those who are constitutionally at risk of developing the disease. Relationship Genetic sharing 100% 50% 25% 12.5% 0% MZ twin Sibling, 2 affected parents Sibling,1 affected parent DZ twin Sibling Parent Child Half sibling Aunt/uncle Nephew/niece Cousin Adoptee General population 0 5 10 15 20 25 30 35 Age-adjusted lifetime risk Fig. 24.10.2.2  Lifetime risk for multiple sclerosis among European people and in biological and social relatives of affected individuals. The increased risk with relatedness implicates genetic factors, whereas the incomplete concordance in identical twins reflects the contribution made by environmental conditions. 24.10.2  Demyelinating disorders of the central nervous system 6031 Symptoms and signs of multiple sclerosis Fatigue Difficult to define and capture for analysis, nonetheless fatigue is one of the most characteristic symptoms of multiple sclerosis. Patients report overwhelming lassitude after undertaking a physical or cog- nitive task, forcing them to stop and rest. However, they do not feel the need to sleep. Fatigue may occur acutely, in the context of a re- lapse, or be a persistent symptom. It may be disabling, particularly in individuals attempting to maintain demanding occupations or hobbies. Optic neuritis and visual symptoms Acute demyelinating optic neuritis is a first manifestation of mul- tiple sclerosis in up to 20% of patients. This presents with pain on eye movement, followed by subacute visual loss, which evolves over hours or days, sometimes to complete blindness; patients may be aware of selective loss of colour vision and flashes of light (phosphenes) on eye movement. Other signs of optic neuropathy at presentation include unilateral afferent pupillary defect and visual field loss. The pain disappears within a few days; vision begins to im- prove within 4 weeks and improves in 90% of patients over months, but defects of colour perception frequently persist. The lesion responsible for optic neuritis can be imaged in vivo; inflammation within the intracanalicular portion of the nerve and long lesions are associated with delayed or incomplete recovery of vision. Correlations between imaging, symptoms and neuro- physiological changes indicate that the visual deficits in optic neuritis arise at the time of altered blood–​brain barrier perme- ability. They are associated with conduction block and precede demyelination or axonal degeneration. Optical coherence tom- ography provides a non​invasive quantitative measure of retinal nerve fibre loss after optic neuritis, and is increasingly being used as a surrogate outcome measure in treatment trials. Optic neur- itis may be clinically silent and revealed by delayed conduction of visual evoked potentials; this can be useful in the diagnosis of multiple sclerosis. Optic neuritis can be a feature of other conditions and clinicians should be aware of the red flags of: positive family history, bilateral onset, failure to improve or dependence on steroids (see next). It can be mimicked by acute glaucoma, infection (especially viral), ischaemic optic neuropathy, sarcoidosis, systemic lupus erythematosus, and vasculitis. Visual failure in Leber’s hereditary optic neuropathy can mimic bilateral sequential optic neuritis in men, so a family history of mitochondrial inheritance should be sought. The postchiasmal visual pathway is occasionally involved in mul- tiple sclerosis resulting in hemianopic field defects. Motor symptoms and signs Impaired mobility affects most patients with multiple sclerosis, usu- ally as a result of spinal cord disease. Movements are slow, weakness differentially affecting extensors in the arms and flexors in the legs, and there are the expected signs of upper motor neurone lesions. Spasticity may be more problematic than weakness and all aspects of immobility are frequently complicated by fatigue. Cerebellar in- volvement causes incoordination of speech, bulbar control, eye movements, the individual limbs, or balance, usually in combin- ation with corticospinal damage. Damage to the superior cerebellar peduncle or red nucleus produces a disabling proximal wild flinging tremor. Parkinsonism does not occur in multiple sclerosis. Lower motor neurone signs occur when there is extensive demyelination adjacent to the dorsal root entry zone. Sensory symptoms and signs Altered sensation occurs at some stage in nearly every patient with multiple sclerosis, usually due to partial disruption of the spinal cord sensory pathways. Often they are described in complex and graphic terms: ‘as though water is dripping down my face’, ‘it feels as though something is twisting a towel repeatedly around my legs’. Damage to the posterior columns in the cervical cord produces tight, burning, twisting, tearing, or pulling sensations, which are usually unpleasant. Associated loss of proprioception severely com- promises function. Spinothalamic tract involvement leads to loss of thermal and pain sensation. The commonest physical sign found in multiple sclerosis, in the absence of symptoms, is impaired vibra- tion sense in the legs. Autonomic involvement Autonomic symptoms occur in most patients with multiple scler- osis. Bladder symptoms are common and can be due to impaired bladder emptying (leading to urinary retention) or filling (leading to urgency and hesitancy). Often these coexist. Impaired control of the rectal sphincter is much less common. Erectile impotence oc- curs frequently in males and is usually a manifestation of spinal cord disease. Mechanical difficulties, spasticity, altered sensation, skin ex- coriation, and indwelling catheters all may affect sexual fulfilment, in both genders. Other autonomic features in multiple sclerosis occur rarely, but include loss of thermoregulation leading to in- appropriate sweating, fever, and hypothermia; Horner’s syndrome; abnormalities of cardiac rhythm and vascular responses with acute pulmonary oedema; weight loss; and inappropriate secretion of vasopressin. Eye movements Abnormalities of eye movement are frequent in multiple sclerosis. A sign that is nearly always due to multiple sclerosis, and is usually asymptomatic, is the ‘internuclear ophthalmoplegia’: slowness of the adducting eye and nystagmus in the abducting eye on horizontal gaze, due to a lesion of the medial longitudinal fasciculus. It is often bilateral and may coexist with gaze paresis to produce the ‘one and one-​half’ syndrome. They commonest sign is first-​degree symmetrical horizontal jerking nystagmus. Weakness of the lateral rectus is more common than isolated third and fourth nerve palsy. Vertical up-​beating nystagmus can occur and is often associated with bilateral inter- nuclear ophthalmoplegia. Down-​beating nystagmus may occur, but is a red flag for alternative, structural causes. Ocular flutter (hori- zontal saccadic oscillations without an intersaccadic interval) and opsoclonus, in which the saccadic movements occur in all direc- tions, tend to occur late in multiple sclerosis and can be visually disabling. Other brainstem manifestations Feelings of unsteadiness are common. Acute brainstem demyelin- ation causes severe positional vertigo, vomiting, ataxia, and head- ache. Taste may be subjectively abnormal but ageusia is rarely section 24  Neurological disorders 6032 described. Deafness may occur in multiple sclerosis, but is a red flag for other conditions (Susac’s and Cogan’s syndromes). Facial weakness, indistinguishable from Bell’s palsy, occurs in patients with multiple sclerosis, alone or in association with other signs of brainstem disease, including hemifacial spasm and diffuse rippling of muscle fibres (myokymia). Exceptionally, there may be unilateral involvement of the hypoglossal and recurrent laryngeal nerves. Extensive brainstem demyelination may produce disturb- ances of consciousness and respiratory failure. Occasional mani- festations include the locked-​in state, persistent hiccup, and lateral medullary syndrome. Paroxysmal symptoms are invariably brief, but repetitive and usu- ally occur in bouts lasting a few weeks or months before remitting. Symptomatic trigeminal neuralgia may begin in the first division or bilaterally, at a younger age than the idiopathic condition, and with associated signs of trigeminal involvement including motor weakness and sensory loss. It is usually associated with demyelinating lesions of the dorsal root entry zone, but may coexist with compression of the fifth cranial nerve by ectatic vessels. Other than trigeminal neuralgia, isolated involvement of the fifth nerve is rare. Paroxysmal dysarthria and ataxia with a clumsy arm, complex disturbances of sensation, and painful tetanic posturing of the limbs lasting 1 or 2 min are often triggered by movement and preceded by positive sensory symptoms on the side opposite to the muscular spasm. These are easily recog- nized and treated. Bursts of pain and paraesthesias, sensory distor- tion, itching, cough, and hiccup, painful extensor spasm, akinesia, kinesogenic choreoathetosis, and complex gaze palsies—​any of which may respond to anticonvulsants, especially carbamazepine—​ also appear to be paroxysmal manifestations of multiple sclerosis. Cognitive and affective symptoms Cognitive impairment occurs in up to 65% of patients with mul- tiple sclerosis. It may occur at all stages of the disease, and be compounded by cognitive fatigue and depression. Reductions in attention, information processing speed, working memory, and ex- ecutive functions are typical and likely reflect both a white matter disconnection syndrome, as well as increasingly recognized cortical structural abnormalities. Specific cognitive deficits due to hypothalamic involvement, including the Korsakoff state and the syndrome of bulimia, lack of social restraint, apathy, and mutism are sometimes seen. Discrete cortical syndromes, such as aphasia, are rare and should prompt in- vestigation for other causes. Depression occurs more frequently in multiple sclerosis than in patients with comparable neurological disability; hypomania is occasionally seen, but should not be confused with pathological laughter and crying, arising from loss of central inhibition of facial and bulbar reflexes in association with extensive brainstem disease. Psychosis is rarely a feature of multiple sclerosis. Rare manifestations of multiple sclerosis The list of rare clinical manifestations (some already described) includes massive cerebral lesions, aphasia, headache, fever, move- ment disorders, epilepsy, hypothalamic and pituitary symptoms, re- spiratory failure, and peripheral neuropathy. Narcolepsy, Sjögren’s syndrome, ankylosing spondylitis, type I  neurofibromatosis, and autoimmune thyroid disease have periodically been associated with multiple sclerosis. Childhood multiple sclerosis 2% of patients with multiple sclerosis present before the age of 10, and up to 10% before 16 years. Fever and meningism, impaired con- scious level due to cerebral oedema with swollen optic discs, and seizures are regular features and the distinction from acute dis- seminated encephalomyelitis can often only be made by the later occurrence of relapse and remission. A recent European study of the natural history of childhood onset disease confirms a higher fe- male to male ratio (3:1), disease course that is invariably relapsing-​ remitting and a delayed time by 10 years to secondary progression compared with adult-​onset disease. Current international guide- lines recommend disease-​modifying treatment for childhood ac- tive relapsing-​remitting multiple sclerosis on lines similar to adult patients. Clinical course and prognosis Most patients present as a young adult. In many, a history of symp- toms attributable to demyelination may be elicited from years earlier. But where this is not the case, patients are said to have a ‘clin- ically isolated syndrome’ (Fig. 24.10.2.3) and magnetic resonance imaging discriminates disease that is ‘active’, indicating a high prob- ability of further clinical attacks, or ‘inactive’. The latest diagnostic criteria (Table 24.10.2.2) would classify someone in the active group as having ‘multiple sclerosis’ already. The subsequent illness passes through the three phases of relapse with full recovery, relapse with persistent deficits, and secondary progression (Fig. 24.10.2.1). There is considerable variation in how rapidly people progress through these phases, but typically sec- ondary progression starts around the age of 40 years. In the minority 20%, a ‘primary progressive’ syndrome starts also around the age of 40, but without preceding relapses. Few (perhaps 5%) escape dis- ability and are classified as having ‘benign multiple sclerosis’. It is very rare to die directly from demyelination of the nervous system (although possible with, for instance, a large brainstem plaque), but the secondary effects of disability associated with the disease reduce life expectancy by around 10 years. Relapses build up over days or a few weeks and then plateau before recovery, partial or complete, occurs over weeks or months. They are most frequent (less than once a year) at the outset of the disease and Clinically isolated syndrome Relapsing-remitting multiple sclerosis active inactive active inactive Fig. 24.10.2.3  Early multiple sclerosis may be classified on the basis: (i) of the number of attacks, for exmple, clinically isolated syndrome where there has been only one clinical attack and relapsing-​remitting multiple sclerosis for two or more episodes; and (ii) of activity, defined by one or more relapses, or one or more new MRI lesions, over a 12-​month period. Under the McDonald criteria, the ‘active’ form of clinically isolated syndrome may be re-​classified as multiple sclerosis. 24.10.2  Demyelinating disorders of the central nervous system 6033 decrease steadily thereafter. Some 25% of relapses are triggered by an infection, especially upper respiratory and gastrointestinal; but careful studies have shown that vaccinations do not induce attacks. Major life events, such as bereavement, increase the risk of a re- lapse. The timing of relapses, but not the overall relapse rate, is al- tered by pregnancy. There is a reduction in the prepregnancy relapse rate for each trimester, balanced by a threefold higher risk in the puerperium. The clinical course is uninfluenced by breast feeding or anaesthesia. There is no evidence that trauma influences multiple sclerosis. Counterintuitively, there is only a weak relationship between re- lapse rate and a patient’s long-​term prognosis. The strongest prog- nostic factor is a short interval between the initial episode and first relapse. Classical rules are that the prognosis is relatively good when sensory or visual symptoms dominate the illness and there is com- plete recovery from individual episodes; conversely, motor involve- ment, especially when co-​ordination and balance are disturbed, has a less good prognosis. Once progressive multiple sclerosis has started, either primary or secondary, it proceeds relentlessly. Its onset is largely age-​related, at the age of 40 years, and its rate is similar between individuals and unrelated to previous disease history or relapse rate. These obser- vations raise unresolved questions around the relationship between inflammation, manifesting as relapse, and neurodegeneration, the primary substrate of progression. The nature of the disability that progresses in ‘secondary progres- sion’ reflects areas of previous damage in relapses. Usually it is the spinal cord that bears the brunt of progressive multiple sclerosis, but optic nerve, cerebral, and brainstem disease may also advance slowly. Primary progressive spinal disease is the usual mode of pres- entation when multiple sclerosis develops beyond the fifth decade. It is characterized by an absence of acute attacks with gradual de- cline from onset and, although cerebrospinal fluid analysis is similar to relapsing-​remitting disease, there are comparatively more spinal and fewer brain abnormalities on MRI. Current disease-​modifying agents have no demonstrable effect on primary progressive disease. Investigations Multiple sclerosis can reliably be diagnosed using clinical criteria and without laboratory support. There is no single diagnostic laboratory investigation, but they can be used to demonstrate the anatomical dissemination of lesions; to provide evidence for intra- thecal inflammation; to demonstrate that conduction is altered in a form consistent with demyelination; and to exclude conditions that mimic demyelinating disease. Magnetic resonance imaging Variations in the imaging protocols are beginning to distinguish separate components of the underlying pathological process. Imaging can highlight inflammation (gadolinium–​DTPA enhance- ment of T1-​weighted lesions, indicating that the lesion is of recent origin), demyelination and remyelination (magnetization transfer ratio), astrocytosis (T1-​weighted lesions, the signal arising from increased water content), and axonal damage (reduction in dif- fusion tensor imaging anisotropy and N-​acetyl-​aspartate spectra with chemical shift imaging, or the presence of focal atrophy and T1-​weighted black holes; see Fig. 24.10.2.4). The evolving lesion starts with increased blood–​brain barrier permeability, which lasts for up to four weeks, and is revealed by demonstration of enhance- ment after intravenous gadolinium. These lesions may disappear Table 24.10.2.2  Diagnosis of multiple sclerosis (McDonald 2011 criteria) History Examination Dissemination in space demonstrated by: Dissemination in time demonstrated by: Relapsing-​remitting multiple sclerosis Two clinical episodes compatible with demyelination Signs of two or more anatomical sites affected Examination History Two clinical episodes compatible with demyelination Signs of only one anatomical site affected MRI. More than one lesion in at least two of 4 typical sites for multiple sclerosis plaques History One clinical episode compatible with demyelination Signs of only one anatomical site affected MRI. More than one lesion in at least two of 4 typical sites for multiple sclerosis plaques MRI. Either simultaneous presence of lesions of different age at presentation, or new lesions on a second MRI scan at any time after the first Primary progressive multiple sclerosis One year of progression of a typical syndrome (spinal, cerebellar) 2/​3 of: MRI lesions in at least two of 4 typical sites for multiple sclerosis plaques More than one spinal cord lesion on MRI Ccerebrospinal fluid oligoclonal bands Fig. 24.10.2.4  Typical plaques of multiple sclerosis in a MRI brain and cord. Note the periventricular, callosal and juxtacortical lesions in the brain and that the spinal cord lesions are no greater than one vertebral segment in length. section 24  Neurological disorders 6034 but reactivation is sometimes seen, the cycles lasting about 8 weeks. Fluid attenuated inversion recovery (FLAIR), proton-​density, and T2 sequences best demonstrate demyelination. The periventricular lesions, which characterize multiple sclerosis, correlate with areas of persistent demyelination and astrocytosis. A  mixture of new, evolving, and recovering lesions may be seen in an individual pa- tient at any one time. Magnetic resonance lesions occur about 10 times more frequently than new clinical events. Eventually, there is a reduction in the frequency of new lesions as patients move from the relapsing to progressive phases of the disease and evidence for at- rophy is then more apparent. The number or volume of lesions cor- relates poorly—​if at all—​with disease severity or course, but there is less cerebral involvement in patients who present with primary pro- gressive disease compared with those with similar disability from secondary progression. Progressive loss of brain volume—​occurs at a rate of 0.5–​1.0% p.a. in patients with multiple sclerosis, com- pared to a rate of 0.1% p.a. in age-​matched controls—​is also quan- tifiable using T1-​weighted MR brain-​imaging and is increasingly utilized as an outcome measure in trials of putative neuroprotective agents. Brain atrophy is significantly correlated with disability and cognitive impairment in multiple sclerosis. However, the imaging abnormalities of multiple sclerosis are not specific and similar changes occur with other inflammatory or vascular lesions and with advancing age. MRI scans are used in the diagnosis, prognosis, and treatment of multiple sclerosis. In diagnosis, they are first used to determine the pathology of the lesion causing current symptoms, whether structural or not. For instance, it is mandatory to scan the spinal cord of someone presenting with a myelopathy. Secondly, scans are used to identify ‘dissemination of lesions in space’, that is to show the presence of other (asymptomatic) lesions in the brain or spinal cord. Thirdly, MRI scans can also be used to demonstrate ‘dissemination of lesions in time’. If a patient has had several dis- crete clinical episodes of demyelination over time, this is not ne- cessary. But, for those patients with a clinically isolated syndrome, new lesions that appear on interval scans mean that ‘multiple sclerosis’ can be diagnosed (Table 24.10.2.2). This process can be further contracted; a MRI brain with lesions of different ages (for instance, some with and some without gadolinium enhancement) is sufficient to establish ‘dissemination in time’ and diagnose mul- tiple sclerosis at the time of a clinically isolated syndrome. MRI scans are useful in guiding prognosis in the clinically iso- lated syndrome. If there are no brain lesions at presentation, the chance of having a second demyelinating clinical episode over 20 years is only 20%. However, this rises to 80% if the initial brain MRI shows three or more plaques. There is a consensus, perhaps more than justified by the evidence, that rapid accumulation of MRI lesion load is a poor prognostic sign in multiple sclerosis. It is intuitive that the early appearance of brain atrophy is also a poor sign, although this has not yet become a routine clinical MRI measure. In determining the response to treatment it is established that new MRI lesion formation during the first year of first-​line disease-​ modifying treatments, is a biomarker for a poor disability outcome. It is logical to consider augmenting treatment as a result, but while this can be effective in substantially reducing or even eliminating further radiological ‘events’, the long-​term effect on disability re- mains uncertain. Cerebrospinal fluid With the increasing availability and sophistication of magnetic res- onance imaging, confidence in making the diagnosis of multiple sclerosis with supportive imaging alone has risen and fewer lumbar punctures are performed. There are two situations where they are commonly done: in patients over the age of 50 years (where non-​ specific lesions obscure the ability of MRI scans to discriminate de- myelination) and to diagnose primary progressive multiple sclerosis. The cerebrospinal fluid cell count rarely exceeds 50 lymphocytes/​ ml, even during periods of clinical activity, and is normal in more than 50% of patients. There is a rise in total protein (usually <1 g/​l), with a specific increase in the immunoglobulin concentration. The most characteristic abnormality is the presence of oligoclonal im- munoglobulin bands on protein electrophoresis in the cerebrospinal fluid and not in the serum. This pattern is seen in more than 90% of patients and its absence is a ‘red flag’ for an alternative diagnosis. Despite their ubiquity, the relationship of this intrathecal synthesis of immunoglobulins to disease pathogenesis is mysterious. Electrophysiology Demyelination in pathways can be detected using visual, auditory, somatosensory, central motor, and event-​related potentials; charac- teristically their latencies are delayed but amplitudes are unaffected. Their main use is to detect involvement of clinically unaffected path- ways and so show ‘dissemination of space’. Optical coherence tomography Optical coherence tomography (OCT) is a non​invasive imaging technique that uses back-​scattered infrared light to detect the ret- inal layers. Thinning of the retinal nerve fibre layer is seen in mul- tiple sclerosis and the degree of thinning, reflecting axonal loss, is associated with quantitative measures of visual impairment. More recently introduced high resolution spectral-​domain OCT can also measure the retinal nerve ganglion cell and inner plexiform layer, and thinning, reflecting ganglion cell loss, is significantly correlated with measures of visual dysfunction. OCT is a rapid, non​invasive, and increasingly used measure to provide quantitative and longitu- dinal measures of retinal neuronal status that potentially also serves as a surrogate for wider CNS neuronal health. Differential diagnosis The commonest error in clinical practice is to make the diagnosis of multiple sclerosis in patients with progressive spinal disease in whom a structural lesion has not been adequately excluded. Rarely, a spinal tumour presents with intermittent symptoms creating dif- ficulties for the unwary; it is not safe to assume the diagnosis of multiple sclerosis in patients with symptoms and signs restricted to a single site, whatever the clinical course, without appropriate in- vestigation. Lesions at the foramen magnum are particularly well placed to cause confusion through appearing to produce evidence for independent spinal and brainstem lesions. Errors also arise with progressive and relapsing manifestations of brainstem or spinal ar- teriovenous malformations. Care must be taken in the diagnosis of multiple sclerosis when several members are affected within one family. Hereditary spastic paraplegia mimics familial multiple sclerosis and this should also be considered in isolated cases of progressive spastic para- plegia, when pyramidal manifestations occur in isolation and 24.10.2  Demyelinating disorders of the central nervous system 6035 with disproportionate spasticity. Other familial disorders con- fused with multiple sclerosis, include the hereditary ataxias, adult-​ onset leukodystrophies (see next) and vasculopathies (CADASIL). Pedigrees with affected males and maternal inheritance may be ex- amples of X-​linked adrenoleucodystrophy, and the phenotype of multiple sclerosis occurs in families with the clinical and genetic features of Leber’s hereditary optic atrophy. Clinical, immunological, and imaging abnormalities indistin- guishable from multiple sclerosis occur with granulomatous and vasculitic diseases of the brain, especially the cerebral variant of systemic lupus erythematosus, which often occurs in the absence of systemic manifestations, although headache and prominent cogni- tive impairment are clues to a vasculitic aetiology. Sarcoidosis may present with clinical involvement of the central nervous system, typ- ical magnetic resonance and cerebrospinal fluid abnormalities, and without pulmonary or cutaneous manifestations; uveitis also occurs in multiple sclerosis and so is not necessarily a useful discriminator. Orogenital ulceration in a patient with the clinical manifestations of multiple sclerosis suggests the diagnosis of Behçet’s disease. Alternative diagnoses need to be considered when multiple scler- osis is diagnosed in African or Asian people in whom progres- sive spinal disease, sometimes with visual involvement, is more probably due to HTLV1-​associated tropical spastic paraplegia or neuromyelitis optica. Infections of the nervous system can mimic the isolated demyelinating syndromes and multiple sclerosis. These include tuberculous and other chronic meningitides, and the neuro- logical manifestations of acquired immunodeficiency syndrome and Lyme disease, which can also cause a chronic or relapsing disorder of the central nervous system, but which is usually preceded by a characteristic painful polyradiculitis and facial palsy. Similarities be- tween multiple sclerosis and neurosyphilis should not be forgotten in the context of opportunistic infection complicating HIV infec- tion. The age distribution and clinical manifestations usually make it easy to distinguish subacute combined degeneration of the spinal cord from multiple sclerosis, but focal spinal lesions, accompanied by Lhermitte’s sign, occur in vitamin B12 deficiency. Treatment of demyelinating disease Therapies in multiple sclerosis are aimed at managing individual symptoms, resolving acute attacks, preventing new relapses, limiting disability, and (for the future) preventing progression and repairing the damage. Symptomatic management The complex and progressive nature of disability requires a multi- disciplinary approach to patients with multiple sclerosis. Several manifestations of the disease can be treated successfully. The first step in managing bladder symptoms is a postmicturition bladder volume assessment: if less than 100 ml, urgency and frequency of micturition can be treated with anticholinergic drugs (oxybutinin or terodoline), whereas a volume greater than 100 ml requires clean self-​intermittent catheterization, which is easily adopted by motiv- ated patients retaining adequate visual and arm function. It ensures complete bladder emptying, often with unimagined advantages to social activities and sleep. Other options include intravesical botox injections to reduce reflex bladder contractions or a suprapubic catheter with closure of the lower urinary tract, which is preferable to an indwelling urethral catheter or, worse still, constant dribbling incontinence, which usually leads to skin excoriation. These man- oeuvres have largely replaced urinary diversion through an ileal conduit, insertion of an artificial mechanical sphincter, or electrical stimulation of the spinal nerve roots in an attempt to synchronize sphincter contraction and relaxation. Constipation in multiple sclerosis is managed by dietary alteration and the use of bulk laxatives. Loperamide may be useful where the predominant complaint is rectal urge incontinence. Psychological factors contribute to impotence in males with multiple sclerosis, but in most cases the complaint is a direct consequence of spinal demyelination, and usually well treated with sildenafil—​a phospho- diesterase inhibitor which acts by increasing local production of ni- tric oxide in response to sexual stimulation. Spasticity causes pain and, in more disabled patients, can inter- fere with personal care. Baclofen, a GABA agonist acting on spinal cord reflexes, is still the most widely used effective antispastic agent. The principal adverse effect, like most conventional antispasticity agents, is sedation and increased weakness. Gabapentin introduced as an anticonvulsant, but now more frequently used to relieve neuro- pathic pain, is also effective. Benzodiazepines reduce spasticity by increasing presynaptic spinal inhibition. Dantrolene sodium acts by uncoupling excitation–​contraction mechanisms in individual muscle fibres. Tizanidine, an α-2 agonist that modulates activity of excitatory presynaptic interneurones, may reduce spasticity without increasing weakness. Intrathecal baclofen can be more effective than systemic administration, delivering a greater concentration of drug to the target cord reflexes, but carries the disadvantage of an implanted device, prone to failure and infection. It is mainly ap- propriate for patients with advanced disease. Targeted reduction in focal spasticity is achievable with local injection of botulinum toxin. There may be a role for surgical interruption of the reflex pathways or tenotomy and peripheral nerve block with phenol or alcohol. Tremor is very difficult to treat, although some improvement may be seen with β-​blockers; alternatives include anticonvulsants, isoniazid, ondansetron, and hyoscine. Physical restraint is rarely successful. Stereotactic procedures involving stimulation of the ventrolateral nucleus produce results comparable to destructive pro- cedures, but the dividend is small. Unsteadiness arising from altered vestibular input may improve with the use of a vestibular sedative. Fatigue as a dominant symptom in multiple sclerosis is common and frequently disabling, although its pathophysiological basis is poorly understood. It may well be multifactorial and compounded by depression. Some evidence suggests improvement with amantadine or modafanil. The paroxysmal manifestations of multiple sclerosis usually stop abruptly with the use of carbamazepine or gabapentin; this and other anticonvulsants, especially gabapentin, may also relieve tri- geminal neuralgia or the more refractory forms of pain arising from spinal demyelination. Nerve block and chemical or surgical destruc- tion of nerve fibres are sometimes an acceptable method for redu- cing pain in multiple sclerosis. All these sensations are coped with less well in the context of impaired mood and can respond usefully to antidepressants. For those who develop significant disabilities and impairments, comprehensive care includes access to physical and occupational therapists, social workers, and other health-​care staff with expertise in the management of chronic neurological illness. Complications are best prevented by awareness and anticipation since they usually section 24  Neurological disorders 6036 develop quickly yet take months to resolve. Minimizing handicap by attention to social, vocational, marital, sexual, and psychological aspects of the illness is more important for many patients than drug treatment. In situations where the natural history has already led to loss of mobility, the early use of mechanical aids and home adapta- tions should be encouraged despite the associated stigma. Management of the acute episode Corticosteroids are effective in reducing the duration of acute demyelinating episodes in multiple sclerosis and related disorders, but have no impact on the eventual degree of recovery or the subse- quent disease course. So their use is restricted to relapses which are painful or disabling. There is no evidence that intravenous steroids offer any advantage over oral, so the common prescription is oral methylprednisolone 500–​1000 mg, daily for 3–​5 days. Among patients with steroid-​resistant relapses, 50% will improve with plasma exchange. These responders have been shown at biopsy to have lesions characterized histologically by immunoglobulin de- position and complement activation, but these patients cannot be identified prospectively. There is no evidence for reduction in re- lapse frequency or long-​term disability using either corticosteroids or plasma exchange. Disease-​modifying treatment in multiple sclerosis Multiple sclerosis has two distinct clinical phases, each re- flecting a dominant role for interrelated pathological processes. Inflammation drives activity during the relapsing-​remitting stage and neurodegeneration represents the principal substrate of pro- gressive disability. Current disease-​modifying agents target the in- flammatory component and are effective at reducing relapse rate and the accumulation of disability over the medium term (3–​5 years); evidence beyond that is less robust. In contrast, there are no proven therapies for progressive disease independent of relapses. The first drugs to be licensed for multiple sclerosis, in the 1990s, were the injectable treatments, the β-​interferons and glatiramer acetate. These are still used, because of their excellent safety record. But the newer therapies are either more efficacious or more con- venient (for instance oral treatments). Roughly speaking (see Fig. 24.10.2.5), the more efficacious drugs are also associated with more safety concerns. A simple classification scheme, from the Association of British Neurologists, is of two classes of drug: those of ‘moderate efficacy’ (β-​interferons glatiramer acetate, teriflunomide, dimethyl fu- marate, and fingolimod) and drugs of ‘high efficacy’ (alemtuzumab, natalizumab, and ocrelizumab). β-​interferons (Rebif®, Avonex®, and Betaseron®) and glatiramer acetate (Copaxone®) are administered subcutaneously or intramus- cularly, are generally well tolerated and reduce relapse frequency by around 30%. They somewhat reduce the accumulation of dis- ability for people with relapsing-​remitting multiple sclerosis, but—​ perhaps surprisingly—​do not have a long-​term effect on disability when given earlier in the course of the disease, at the stage of the clinically isolated syndrome. Their mechanism of action is poorly understood. The interferons were first used because of their antiviral action, but their reduction of lymphocyte migration, Th17 expres- sion, and microglial class II expression is more likely. It is claimed that glatiramer, a random mixture of amino acids, acts by specific- ally suppressing antimyelinn lymphocytes. Teriflunomide is a pyr- imidine synthesis inhibitor that exerts selective antiproliferative effects on activated lymphocytes; it is as effective as the interferons and its main advantage is that it is taken orally. Fingolimod was the first oral drug approved for multiple scler- osis. It is a fungal derivative that upon phosphorylation acts as a sphingosine receptor agonist and non​specifically limits lymphocyte egress from lymphoid organs. Dimethyl fumarate has two likely modes of action; anti-​inflammatory through its suppression of nu- clear factor-​κβ and antioxidative due to activation of the nuclear factor like 2 transcriptional pathway. Fingolimod and dimethyl fu- marate are preferable to the interferons because they are available as tablets and are more effective at reducing relapse frequency, per- haps by up to 50%. But this increased efficacy comes with higher risk:  of gastrointestinal symptoms with dimethyl fumarate, and Alemtuzumab Natalizumab for JC neg patients Natalizumab for JC+ positive patients Fingolimod Dimethyl fumarate Increasing efficacy Glatiramer Teriflunomide Interferon-β Increasing burden of treatment (worse safety, more difficult administration) Fig. 24.10.2.5  A simplified scheme of the risk-​benefit analysis of current licensed disease-​modifying therapy. Note that the risk of progressive multifocal leucoencephalopathy with natalizumab treatment rises from 1:10 000, if the patient is John Cunningham (JC) virus serology negative, to as high as 1:100 if positive and on prolonged treatment. 24.10.2  Demyelinating disorders of the central nervous system 6037 first-​dose bradycardia, macular oedema, opportunistic viral infec- tions, and increased skin malignancy risk with fingolimod. Both are also associated with a very low risk of progressive multifocal leukoencephalopathy (see next). The advent of humanized monoclonal antibodies allows se- lective treatments targeting discrete stages in the immune-​ pathogenesis of multiple sclerosis. Two are currently licensed (natalizumab and alemtuzumab). Natalizumab is a recombinant antibody, delivered by monthly infusion, that prevents activated T cells entering the brain by binding to leucocyte α4 integrin. It is highly effective, reducing relapse frequency by 80%, and nor- mally very well tolerated. However, its use is associated with pro- gressive multifocal leucoencephalopathy, an opportunistic CNS infection due to John Cunningham (JC) virus, which is often fatal. The overall risk of progressive multifocal leucoencephalopathy with natalizumab use is 0.1%, but this risk can be personalized; it is highest, up to 2%, in those with a high concentration of anti-​ JC virus antibodies, who have received immunosuppressants prior to natalizumab, and who have been exposed to the drug for more than two years. Alemtuzumab works differently: it targets and de- pletes lymphocytes. It is given by intravenous infusion daily for five days, then a second cycle of three days is given at month 12, and then re-​treatments are given only with evidence of break through disease. The aim is to reconstitute an immune repertoire that is no longer autoreactive for myelin. Alemtuzumab reduces the relapse rate by 80–​90% and is the first drug to show consistent superiority against an active comparator (interferon-β-1a) across clinical and MRI measures. It is not associated with progressive multifocal leukoencephalopathy, but does cause a range of autoimmune dis- eases (thyroid in 30%, immune thrombocytopenia in 2% and renal disease in 0.1%). Several monoclonal antibodies are close to licensing. Daclizumab, targeting the CD25 antigen, reduces the activity of T lymphocytes and increases CD56 regulatory NK cells, and is proven more effica- cious than β-​interferon. B-​cell depletion with rituximab or its fully humanized equivalent, ocrelizumab, have shown highly significant reductions in clinical and radiological activity. Ocrelizumab has the distinction of being the only drug to have reduced the accumula- tion of disability in progressive multiple sclerosis, in a phase 3 trial. However, the trial population was not typical for progressive disease, in being enriched for patients with a high inflammatory load. The most radical, and efficacious, treatment for multiple sclerosis is autologous haematopoietic stem cell transplantation. However, it also has the most significant toxicity, with mortality of 2% in most large series and significant morbidity around the time of the trans- plant. Thus, it is not considered appropriate as a routine treatment of multiple sclerosis. Timing and sequencing of immunotherapy in multiple sclerosis Stepping back from individual drug analyses, it is clear that a growing range of immunological therapies is becoming available, with varying efficacy and toxicity. All are agreed that early treatment will lead to optimum outcomes, and that immunotherapies are inef- fective in the progressive phase. However, there is not yet a consensus on how early and how ag- gressively multiple sclerosis should be treated. In the United States and most European countries, it is routine to start β-​interferons or glatiramer acetate in all cases of clinically isolated syndrome; but long-​term follow-​up of trials of this approach does not demonstrate an effect on the accumulation of disability over placebo. In the more conservative United Kingdom, such treatments are only given with ‘active CIS’ (Fig. 24.10.2.3). Although permitted by current EU li- censing, alemtuzumab is rarely used in this situation. Not all patients with relapsing-​remitting multiple sclerosis have sufficiently active disease to justify the risks and inconvenience of treatment. A  consensus view is that people with fewer than two relapses in the preceding two years may reasonably remain off treatment. There is also debate about how to sequence disease-​modifying treatment. Those proposing an ‘escalation’ approach start with safer drugs, and only introduce more effective treatments if there is break- through disease activity. Alternatively, the ‘induction’ approach uses the most efficacious drugs first line; this gives greatest dividends in terms of preventing disability worsening, but raises the dilemma of exposing individuals who may never develop disability to the unpredictable hazards of prolonged immunosuppression. A  key determinant in these negotiations is the patient’s attitude to the un- certainty of their prognosis and the risks of therapy. Therapies may be switched because of adverse effects or lack of efficacy. Neutralizing antibodies occur against the β-​interferons (5–​ 40% depending on the formulation), and rarely against natalizumab and alemtuzumab. The increasing risk of progressive multifocal leucoencephalopathy with prolonged exposure to natalizumab often leads to switching (to fingolimod or alemtuzumab) despite main- tained efficacy. Once patients have entered the secondary progressive phase or become wheelchair bound, immunotherapies have no useful effect, although stopping therapy needs to be broached compassionately. Neuroprotection and repair strategies A body of evidence supports the hypothesis that chronically de- myelinated axons, devoid of myelin-​derived support, are vulner- able to degeneration. Spontaneously remyelinated plaques show no significant axonal injury compared with inactive demyelin- ated lesions. Together with the recognition that spontaneous remyelination contributes to restoration of structure and function and that neurodegeneration underlies progressive disability, this supports the idea that myelin repair will prove neuroprotective. Two approaches are under consideration. In the first, oligodendrocyte precursors or neural stem cells are injected into the brain or cere- brospinal fluid. In the second, small molecules are used to promote endogenous remyelination by oligodendrocyte precursors already present in the brain. A parallel strategy is to interfere with the mechanisms underlying the neurodegeneration which follows demyelination noting that there is a consensus that ‘maladaptive ionic’ response to demye- lination sets in train a negative cycle of energy failure and linked processes, including reactive oxygen species production by glia, mitochondrial inhibition and likely convergence around a common process of intra-​axonal cation excess that initiates secondary cal- cium mediated injury and ultimately death cascades, including excitotoxicity. For instance, sodium channel blockade may reduce the sodium influx that follows sodium channel redistribution. Perhaps this explains how phenytoin can slightly reduce the nerve cell damage following optic neuritis. Other agents that are believed section 24  Neurological disorders 6038 to be beneficial through pleiotropic mechanisms, including statins are also under clinical trial in the progressive phase of disease. Other inflammatory demyelinating disorders Neuromyelitis optica spectrum disorder Neuromyelitis optica (NMO), originally known as Devic’s disease, was considered a variant of multiple sclerosis until its very different pathogenesis and prognosis was recognized in the early 2000s. The prototypical form is the simultaneous appearance of severe bilat- eral optic nerve and spinal cord inflammation. But the discovery of a biomarker (‘anti-​aquaporin 4 antibodies’) has led to expansion of the phenotype. The unifying term ‘NMO spectrum disorder’ (Table 24.10.2.3) is now used for a condition which can include demyelination of the optic nerve, spinal cord, area postrema, and other brainstem, diencephalic, or cerebral sites. The target of the common pathogenic antibodies in neuromyelitis optica are the water channels, aquaporin-​4, which are particularly present in the foot processes of astrocytes. Complement-​mediated death of the astrocytes leads to secondary loss of oligodendro- cytes and neuronal injury. A minority of cases of neuromyelitis optica have circulating antibodies to myelin-​oligodendrocyte glycoprotein (MOG). Compared to multiple sclerosis, episodes of neuromyelitis optica are more severe and lead to greater residual disability but, for reasons which are unclear, do not lead to secondary progressive disability. Optic neuritis and myelitis may occur simultaneously or sequentially, which would be unusual in multiple sclerosis. Hiccups, persistent vomiting, and painful sensory symptoms are also seen more frequently in neuromyelitis optica. The cerebro- spinal fluid lacks oligoclonal bands. On MRI, the spinal lesion is ‘longitudinally extensive myelitis’, extending over three or more vertebral segments and involving the whole cross-​section of the cord, in contrast to multiple sclerosis plaques, which occupy one to two vertebral segments in length and only part of the cross-​ sectional area. The MRI brain may be normal, show symmetrical bilateral diencephalic lesions or large cortical lesions. Although disability may be significant, from incomplete recovery from re- lapses, secondary progressive disability worsening is not seen in neuromyelitis optica. Cases of neuromyelitis optica associated with anti-​MOG antibodies have more frequent episodes of optic neuritis, and fewer of myelitis, with a better prognosis than anti-​ aquaporin 4 disease. Distinguishing neuromyelitis optica from multiple sclerosis is important because several drugs that are effective in the latter ei- ther exacerbate (interferon-β and natalizumab) or are ineffective (alemtuzumab) in neuromyelitis optica. Instead, acute treatment of neuromyelitis optica episodes involves corticosteroids and often plasma exchange, and maintenance therapy is with cortico- steroids and azathioprine or mycophenolate, with breakthrough disease leading to escalation to B-​cell depletion (rituximab or ocrelizumab). Acute disseminated encephalomyelitis Typically, acute disseminated encephalomyelitis is a monophasic illness that develops within days or a few weeks after an infection or, more rarely, following vaccination. Formerly, it affected 1 in 1000 children with exanthematous illnesses, particularly measles and rubella, but these childhood illnesses, and hence their com- plications, are now less prevalent. A greater variety of causative organisms has been implicated in adult-​onset acute disseminated encephalomyelitis, but in both groups a presumptive diagnosis often must be made in the absence of an identifiable preceding infection. Headache, drowsiness, meningeal irritation, signs of systemic infection, focal or generalized fits, and combinations of lesions indicating damage to the cerebrum, optic nerves, brainstem, or spinal cord evolve over the course of a few days. About 50% of cases occurring after Varicella infection present with a pure cere- bellar syndrome. The cerebrospinal fluid contains a mixture of polymorphonuclear cells and lymphocytes with raised protein and a slight reduction in glucose; oligoclonal bands are usually not pre- sent. The key features of magnetic resonance imaging are that the lesions are all the same age (e.g. all enhancing at the same time) and no new lesions develop beyond the first four weeks of the illness. The individual lesions are usually more extensive and frequently involve the thalamic and basal ganglia grey matter, compared to multiple sclerosis. While there is an appreciable mortality, most patients sur- vive, sometimes with persistent neurological deficits. Table 24.10.2.3  Classification of neuromyelitis optica (NMO) spectrum disorder Classification Aquaporin 4 antibody result Number of required core clinical characteristics Positive At least one Negative At least two, of which one must be optic neuritis, myelitis, or area postrema syndrome Additional MRI requirements Core clinical characteristics Additional MRI requirements if AQP4 negative Optic neuritis Brain normal, involvement of > ½ optic nerve length Acute myelitis MRI lesion extending over 3 or more vertebral segments Area postrema syndrome (hiccups, vomiting) Dorsal medullary MRI lesion Acute brainstem syndrome Typical brainstem MRI lesion Symptomatic narcolepsy or diencephalic syndrome Symptomatic cerebral syndrome with typical NMOSD brain lesions 24.10.2  Demyelinating disorders of the central nervous system 6039 The hyperacute form of acute disseminated encephalomyelitis (Hurst’s disease) starts with headache and progresses over hours to disorientation, confusion, drowsiness, and coma. Events move quickly and the illness often proves fatal even before the diagnosis has been established. The combination of pyrexia and a marked cerebrospinal fluid pleocytosis with a predominantly neutro- phil response mimics pyogenic infection of the central nervous system, but the course is not influenced by antimicrobial treatment. Occasionally, the clinical and pathological features of acute haemor- rhagic leucoencephalitis are focal and suggest a rapidly expanding tumour or herpes simplex encephalitis. There is poor quality evidence to guide treatment of acute dis- seminated encephalomyelitis. Most important is appropriate supportive care, which often involves intensive care treatment. Monitoring of intracranial pressure can be helpful in severe cases, and decompressive hemispherectomy has been life-​saving in a few individuals. For immunotherapy, early use of high-​dose intravenous steroids is advised and, among those who do not respond to steroids, improvement is seen in 50% cases with plasmapheresis. There is little role for intravenous immunoglobulin. Acute disseminated encephalomyelitis does not recur. The entity of ‘multiphasic disseminated encephalomyelitis’ has not gained general acceptance. However, multiple sclerosis can rarely present with a similar picture, following which more typical epi- sodes of demyelination occur. Clues to this ‘encephalopathic presentation’ of multiple sclerosis are the presence, of cerebro- spinal fluid oligoclonal bands and MRI lesions of varying age, or new MRI lesions forming five or more weeks after the initial symptoms. Longitudinally extensive transverse myelitis Longitudinally extensive transverse myelitis is a feature of neuromyelitis optica, as described earlier. But it may also occur in isolation, often but not always with an antecedent infection, similar to acute disseminated encephalomyelitis in adults. Presentation is with pain at the site of the lesion, followed by weakness in the legs, sensory symptoms, and sphincter involvement. The weakness in- creases, and the clinical picture is that of spinal shock—​features that are rarely seen in acute cord lesions due to multiple sclerosis. On imaging, the cord lesion usually extends over three vertebral segments. The spinal fluid shows an increased mononuclear cell count, numerically intermediate between the marked pleocy- tosis of acute necrotizing myelitis and the marginal abnormalities seen in multiple sclerosis; total protein is raised and oligoclonal bands may be present on electrophoresis, but the glucose is usu- ally normal. Transverse myelitis is more common in adults than children; there is a high frequency of persistent disability, but a much lower conversion to multiple sclerosis than following optic neuritis. Acute necrotizing myelitis causes rapidly progressive flaccid areflexic paraplegia with anaesthesia and loss of sphincter con- trol. The intensity of inflammation may result in severe pain with meningism, pyrexia, and systemic symptoms. The condition can mimic cord compression; and the cerebrospinal fluid changes often resemble pyogenic or tuberculous infection of the central nervous system. For these reasons, treatment with high-​dose intravenous steroids, which may usefully influence mortality and limit long-​term disability, is often withheld. Acute necrotizing myelitis has been described in association with herpes virus in- fection, and as a complication of acute lymphocytic leukaemia, lymphoma, carcinoma, and acquired immune deficiency syndrome. Relapsing optic neuritis Outside of multiple sclerosis, recurrent demyelinating inflamma- tory optic neuropathies occur with neuromyelitis optica, particu- larly those associated with anti-​MOG antibodies. Chronic relapsing idiopathic neuropathy is a distinct entity with important treatment implications. People with this condi- tion typically have severe optic neuritis with considerable pain, which responds well to corticosteroids but recurs on steroid with- drawal. MRI brain and cord scans (other than the optic nerves themselves) and cerebrospinal fluid are normal. This steroid-​ dependence marks it out from regular optic neuritis. Maintenance therapy with steroids and immunotherapy, such as mycophenolate or azathioprine, should be considered to prevent what is other- wise a poor visual outcome. Balo’s concentric sclerosis The literature on this rare phenomenon is confusing. The pathognomic feature of Balo’s lesions, seen pathologically and radiologically, are con- centric rings of demyelination separated by unaffected tissue. Such lesions may be seen alongside typical plaques in cases of multiple scler- osis, in which case it is best to think of them as one of the heterogenous pathological forms of multiple sclerosis lesion. However, some patients only present with Balo’s lesions, which may be extensive and cause progressive lobar syndromes. The prog- nosis of these cases is very variable, from progressive deterioration causing a neurological death to spontaneous recovery. It is not even clear that this is a primary inflammatory disorder; some argue that the rings are a response to hypoxic injury with unaffected tissue pro- tected by ‘hypoxic preconditioning’. Unsurprisingly, there is no clear treatment guidance. Harding’s disease Patients with Leber’s mitochondrial mutations may present with a syndrome that is identical to multiple sclerosis except that visual failure is more prominent. Curiously, this is more common in women, despite the fact that Leber’s hereditary optic neuropathy is more common in men. Leber’s mitochondrial mutations are not seen more commonly in cohorts of regular multiple sclerosis. There is no evidence to guide practice, but we recommend using standard disease-​modifying therapies for multiple sclerosis. Non​inflammatory demyelinating diseases Central pontine myelinolysis Central pontine myelinolysis seems to result from overzealous correction of a low (and occasionally also high) serum sodium. Demyelination correlates both with the degree of hyponatraemia and rate at which this is corrected; starting levels of less than 110 mmol/​litre or rates of correction of more than 2 mmol/​litre/​h substantially increase the risk of central pontine myelinolysis. Rapid changes in sodium are better tolerated in acute than chronic section 24  Neurological disorders 6040 hyponatraemia. The clinical context is usually hospital treatment of hyponatraemia, which may be due to liver disease, as a compli- cation of uraemia and haemodialysis, after prolonged vomiting or excess diuretic therapy. The illness affects central pontine pathways and spreads centri- fugally. The fully evolved clinical picture is of flaccid paralysis with facial and bulbar weakness, disordered eye movements, loss of balance, and altered consciousness. Extrapontine manifestations, including movement disorders and other features of extrapyramidal disease, may be seen. The clinical features are distinctive and present no diagnostic difficulties unless the reduction in serum sodium has been overlooked. Patients on intensive care may present with cen- tral pontine myelinolysis as a failure to wean from ventilation. The characteristic radiological changes may not appear for a few days after the clinical syndrome and often persist after clinical recovery. Prognosis depends on the underlying metabolic disorder. With sta- bilization of the serum sodium and management of bulbar failure, neurological recovery is usually complete, and the condition does not recur spontaneously. Toxic disseminated encephalomyelitis Rarely, a picture very similar to inflammatory disseminated enceph- alomyelitis can be induced by inhalation of cocaine or heroin vapour (from ‘chasing the dragon’). Prognosis is variable. Inherited leucodystrophies The leucodystrophies are characterized by non​inflammatory demye- lination. They include a heterogeneous group of conditions, often due to mutations affecting genes that determine the synthesis, main- tenance, and structure of myelin. Although rare even in paediatric practice, these need to be considered in young adults with atypical syndromes combining physical and intellectual deficits, sometimes with peripheral nerve involvement, in whom imaging shows con- fluent lesions confined to white matter. The term diffuse cerebral sclerosis (Schilder’s disease) was originally used to identify a mixed group of diseases affecting cerebral white matter and the term is now redundant. Adrenoleucodystrophy This important group of disorders is characterized by deposition of saturated fatty acids in the brain and other lipid-​containing tissues as a result of defective very long chain fatty acyl-​CoA synthetase activity in peroxisomes. Mutations are present in the ABC trans- porter gene. The molecular defect may result from failure of the adrenoleucodystrophy gene product to anchor very long chain fatty acids into the peroxisomal membrane or translocate these into per- oxisomes. Diagnosis can be made by serum analysis of very long chain fatty acids. Evidence of adrenal insufficiency is a valuable dis- criminator from multiple sclerosis. Pathological findings vary but may include inflammation; although considered reactive by most commentators, immunosuppression has been used in these condi- tions, to no useful effect. Four related syndromes share this biochemical abnormality: child- hood adrenoleucodystrophy and adult-​onset adrenomyeloneuropathy are X-​linked; neonatal adrenoleucodystrophy and Zellweger’s syn- drome are autosomal recessive disorders. X-​linked childhood adrenoleucodystrophy presents with behav- ioural disturbance, dementia, and epilepsy, followed by involvement of special senses and motor systems. Although a significant propor- tion of children later develop adrenal insufficiency, Addison’s dis- ease may precede the neurological manifestations by several years. Treatment has been proposed with a dietary supplement containing a 4:1 mixture of glyceryl trioleate and trieructate, popularly known as Lorenzo’s oil. This lowers the plasma levels of very long chain fatty acids, but does not appear to influence the phenotype in individ- uals with established neurological disease, although there may be a prophylactic role. Bone marrow transplantation may be successful in early symptomatic cases. Adrenomyeloneuropathy presents in young adult men with spastic paraparesis and sensory loss in the legs. Clues to the cor- rect diagnosis are an associated peripheral neuropathy or adrenal insufficiency. It may be associated with dementia later in the dis- ease course. Identification of the peroxisomal defect in easily sam- pled body tissues has led to the description of cases with obscure clinical manifestations; these include focal cerebral lesions, Kluver–​ Bucy syndrome, dementia, and spinocerebellar degeneration. Mild spastic paraparesis with sphincter involvement and peripheral neur- opathy may occur in obligate heterozygote female carriers with ele- vated very long chain fatty acids. Carriers tend not to have adrenal insufficiency, although abnormal brain MRI and delayed evoked po- tentials may be present. Autosomal recessive adrenoleucodystrophy and Zellweger’s syn- drome present in infancy with seizures, hypotonia, retardation, ret- inal degeneration, and hepatic involvement. Metachromatic leucodystrophy Metachromatic leucodystrophy is an autosomal recessive lyso- somal storage disorder due to arylsulphatase A deficiency, leading to increased urinary sulphatide excretion with a deficiency of arylsulphatase A  in urine, peripheral blood leucocytes and skin fibroblasts, or showing metachromatic material in peripheral nerve biopsies having segmental demyelination and remyelination. There is diffuse white matter involvement due to non​inflammatory de- myelination with loss of oligodendrocytes, axon preservation, and reactive astrocytes which, together with macrophages, con- tain the metachromatic material, especially in the most extensively demyelinated areas. The clinical phenotype varies with the amount of surviving arylsulphatase A  depending on heterozygosity of the mutant al- lele; pseudodeficiency refers to those individuals with low levels of arylsulphatase A that are sufficiently high not to display a clinical phenotype. Some affected individuals have a genetic defect of the arylsulphatase A activator and this is associated with a more com- plex pattern of sphingomyelin storage, biochemically and in terms of the tissue distribution. The most common form of metachromatic leucodystrophy de- velops in late infancy with delayed walking due to the neuropathy, which may be painful. There are also features of brainstem involve- ment and the emergence of diffuse upper motor neurone signs with reduced intellectual development, optic atrophy, and death within 24.10.2  Demyelinating disorders of the central nervous system 6041 about five years from presentation. In later-​onset childhood cases, after several years of normal development, there are behavioural changes with poor school performance, anticipating cerebellar and upper motor neurone disability, which then follows much the same course as in younger patients, although with less evidence for neur- opathy. The early adult form of metachromatic leucodystrophy is rare, or perhaps seldom diagnosed, and tends to present with in- tellectual or emotional abnormalities. Onset with dementia and behavioural disorders is usual with ataxia, paralysis, and optic at- rophy only developing at late stages; the presentation is occasion- ally with paraparesis or cerebellar ataxia and the condition can then more easily be mistaken for multiple sclerosis. Clinical evidence for peripheral neuropathy may be revealed by slowed nerve conduc- tion. Treatments have included dietary manipulation with reduced vitamin A and sulphur-​containing substances, and bone marrow transplantation, but the successes are limited. Multiple sulphatase deficiency combines the features of meta- chromatic leucodystrophy with mucopolysaccharidosis. It also has neonatal, early childhood, and juvenile forms. The pattern of combined motor and mental regression or lack of development re- flecting widespread dysmyelination with peripheral neuropathy is associated with dysmorphic features and organomegaly. The more severe phenotype also reflects extensive neuronal loss due to the combination of stored sulphatide, sulphated steroids, and muco- polysaccharides. The enzyme defects are complex involving many sulphatases, including arylsulphatase A. Pelizaeus–​Merzbacher disease The three phenotypes of X-​linked Pelizaeus–​Merzbacher disease usually present in childhood. The clinical features which may distin- guish the otherwise ubiquitous motor and developmental delay with epilepsy are abnormal eye movements, dystonia and choreoathetosis, and laryngeal paralysis. Affected individuals often stabilize with severe disabilities and live into early adult life. Some cases do not manifest until early adult life. MRI either fails to show myelin or de- picts myelin that is immature and with an atrophic brain. The molecular defect is most frequently due to duplication of a variable length of genome containing the proteolipid protein gene. Recent evidence implicates defects in the replication mechanism that leads to the complex rearrangements seen in Pelizaeus–​Merzbacher disease. Proteolipid protein is normally involved in stabilizing the lamellar structure of central myelin. Gene dosage abnormalities re- sult in oligodendrocyte loss and failure of myelination. Krabbe’s disease Globoid cell leucodystrophy, an autosomal recessive condi- tion, usually presents as an early infantile disorder. The very rare late-​onset form may be mistaken initially for multiple sclerosis. However, the disease usually progresses to include:  progressive intellectual and motor deterioration, epilepsy, visual failure, and peripheral neuropathy leading to severe disabilities; pyrexia and other autonomic features usher in the onset of a vegetative state. Visual evoked potentials are delayed, and the spinal fluid has a raised protein level, but does not contain oligoclonal bands. MRI shows periventricular lesions subsequently extending into exten- sive white matter changes. The deficiency of α-​galactocerebrosidase, best demonstrated in peripheral blood leucocytes or skin fibro- blasts, leads to the accumulation of galactocerebroside in oligo- dendrocytes and Schwann cells and characteristic myelin-​laden macrophages or globoid cells. Adult-​onset dominant leucodystrophies Forms of dominantly inherited leucodystrophy also occur ­exclusively in adults and may closely resemble chronic progres- sive multiple sclerosis. MRI shows diffuse, non​discrete, white matter disease, and there are no oligoclonal bands in the spinal fluid. It remains uncertain whether all the adult-​onset dominant leucodystrophies are one and the same disorder, and many are dif- ficult to distinguish from the heterogeneous group of hereditary spastic paraplegias. FURTHER READING Barnes D, et  al. (1997). 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Polman CH, et  al. (2006). A randomised, placebo-​controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med, 354, 899–​910. Polman CH, et al. (2011). Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 69, 292–​302. Renoux R, et  al. (2007). Natural history of multiple sclerosis with childhood onset. N Engl J Med, 356, 2603–​13. Scolding N, et al. (2015). Association of British Neurologists: revised (2015) guidelines for prescribing disease-​modifying treatments in multiple sclerosis. Pract Neurol, 15, 273–​9. Sibley WA, Bamford CR, Clark K (1985). Clinical viral infections and multiple sclerosis. Lancet, i, 1313–​15. Srivastava R, et al. (2012). Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med, 367, 115–​23. Waxman SG (2006). Axonal conduction and injury in multiple scler- osis: the role of sodium channels. Nat Rev Neurosci, 7, 932–​41. Wingerchuk DM, et al. (2007). The spectrum of neuromyelitis optica. Lancet Neurol, 6, 805–​15. Wingerchuk DM, et al. (2015). International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology, 85, 177–​89. Youl BD, et al. (1991). The pathophysiology of acute optic neuritis: an association of gadolinium leakage with clinical and electrophysio- logical deficits. Brain, 114, 2437–​50. 24.10.3  Traumatic brain injury Tim Lawrence and Laurence Watkins ESSENTIALS Traumatic brain injury is one of the leading causes of death and dis- ability worldwide. It is an extremely heterogenous condition with respect to mech- anism, pathophysiology, injury pattern, and investigation findings, with highly variable outcomes, posing a significant challenge to clin- icians treating it. Essential to the management of traumatic brain injury is an inte- grated, multidisciplinary approach from rapid resuscitation and early intervention through to rehabilitation. The pathophysiology can be divided into primary and secondary injury, where primary represents the injury at the point of trauma and secondary the progression of injury due to a cascade of downstream events occurring as a consequence of the primary injury and subse- quent physiological insults. Treatment Adequate resuscitation in the first few minutes is vital to prevent progression of injury. Life-​threatening extracranial injuries that compromise the airway, breathing, and circulation take priority. Attention to these also facilitates neuroprotection. All patients with head injuries should be assumed to have injury to the cervical spine until this can be excluded. 24.10.3  Traumatic brain injury 6043 Following resuscitation identification and treatment of life-​ threatening expanding intracranial lesions becomes paramount. Deterioration in conscious level, routinely assessed by serial re- cording of the Glasgow Coma Score (GCS), requires immediate ac- tion, with initial management depending on the severity of head injury. (1) Severe (GCS 3–​8/​15)—​immediate referral to a neurosur- gical unit is required; elective intubation and ventilation may be required prior to transfer; ventilation should maintain Pco2 4.0 to 4.5 kPa, and mean arterial pressure should be kept above 90 mm Hg; a CT scan will be required. (2) Moderate (GCS 9–12/15)—​an urgent CT scan followed by urgent neurosurgical referral and management as for severe head injury if this reveals an intracranial abnormality. (3) Mild (GCS 13–15)—​patients with GCS 15, no history of loss of consciousness, and none of a defined list of criteria for investiga- tion, may be considered for discharge according to local head injury protocols. The availability of CT scanning at all times in centres re- ceiving patients with acute head injury, together with neurological and neurointensive care facilities, is critical for the best outcomes. Complications, prognosis, and prevention (1) Acute subdural and extradural haemaotomas—​rapid detection and surgical drainage is of proven value. (2) Infection—​most neuro- surgeons recommend early use of prophylactic antibiotics in pene- trating injuries. (3) Cognitive symptoms—​85% of adults with severe head injuries remain disabled at one year; long-​term care requires multidisciplinary support in focused programmes of rehabilitation. Even ‘mild’ injuries can lead to significant ‘postconcussional symp- toms’ including headache, dizziness, poor concentration, memory impairment, and personality change. Prevention—​this is a major concern for health and safety legisla- tion, town planning and traffic laws (e.g. compulsory wearing of seat belts and crash helmets). Epidemiology Traumatic brain injury is the leading cause of death and disability in high income countries in people between the ages of 5 and 45. Epidemiological data regarding traumatic brain injury from the United States suggests that 1.7 million people seek medical help fol- lowing a head injury every year. It is estimated that there are 88/​ 100 000 population hospital admissions with 5.2 million living with disability following a traumatic brain injury and 52 000 deaths per year with a total cost to society of $77 billion. In Europe there are thought to be 2.5 million traumatic brain injury sufferers per year leading to 262/​100 000 population hospital admissions and approxi- mately 75 000 deaths. It is estimated that each year in the United Kingdom approxi- mately 1 million people attend hospital. Almost one-​half of these are children under 16 years of age. Head injuries cause 9 deaths per 100 000 population per year in the United Kingdom. This rep- resents 1% of all deaths, but 15–​20% of deaths for those aged be- tween 5 and 35 years. As mainly young people are affected, the prevalence of disability caused is very significant, with an esti- mated 135 000 people in the United Kingdom dependent on care after brain trauma. While the high mortality associated with traumatic brain injury is striking, there is increasing concern regarding long-​term disability fol- lowing all severities of head injury, many of which have previously been considered mild or moderate by conventional classification systems. Traumatic brain injury severity can be classified using the Glasgow Coma Scale, a system for assessing levels of consciousness based on clinical signs such as eye opening, verbal response, and limb movement. Approximately 80–​90% of all traumatic brain in- jury patients are classified as mild injury, the remainder classified as moderate or severe. The death rate for patients admitted to hospital with a moderate brain injury (GCS <13) may be as high as 30%. For those presenting with a GCS less than 8 after resuscitation the death rate may be as high as 50%. The long-​term outcome of survivors of severe traumatic brain injury is poor. Only around 20% will make a good recovery when assessed using the Glasgow Outcome Score (extended) (GOSe). Basic concepts Primary and secondary injury Primary injury is the damage caused to the brain at the moment of impact. It encompasses diffuse axonal injury and focal contusions. Medicine has little to offer for primary injury; prevention, however, is a major concern for health and safety legislation, town planning, and traffic laws (such as the compulsory wearing of seat belts and crash helmets). The focus of medical intervention is the prevention of secondary damage. The pathophysiological processes involved develop over hours to days and include disturbed ionic homeostasis, excitotoxicity, cell wall and mitochondrial disruption, inflamma- tion, and derangements in oxidative metabolism. The causes of secondary brain damage can be divided into extra- cranial (e.g. hypoxia and hypotension) and intracranial (e.g. haema- toma, brain swelling, and infection). Grading the severity of injury Only 20% of patients are admitted to hospital and most of these are discharged in less than 48 h. About 1 in 500 of the patients attending hospital will develop intracranial haemorrhage. The doctor’s task is to manage patients in such a way that those with preventable causes of secondary injury are identified and treated effectively. The British Society of Rehabilitation Medicine defines three broad groups depending on their Glasgow Coma Scale (GCS) score after initial resuscitation: • Mild—​GCS 13 to 15 • Moderate—​GCS 9 to 12 • Severe—​GCS 3 to 8 This is a useful categorization for decision-​making in head injury management. However, a review by the American National Institute for Neurological Disorder and Stroke suggested that ‘the use of the Glasgow Coma Scale failed to reflect the heterogeneity of traumatic brain injury and consequently limited the findings of trials that used it as a classifier for patient inclusion’. It should not be confused with other schemes, which are generally retrospective and used for epi- demiological and statistical purposes. section 24  Neurological disorders 6044 The golden hour Taking into account the practicalities of computed tomography (CT), interhospital transfer, and preparation for theatre, the time available for initial assessment, resuscitation and treatment of other injuries in the hospital emergency department is less than 1 h. This is sometimes referred to as the ‘golden hour’ in which rapid action is critical to the patient’s outcome. In a typical series of patients who had surgery for acute subdural haematoma, over 70% had a functional recovery (good recovery or moderate disability) if the delay from injury to operation was less than 2 h. If the delay was between 2 and 4 h, just over 60% made a functional recovery. In contrast, for those whose operation was more than 4 h after the injury, less than 10% made a functional recovery (Fig. 24.10.3.1). Such observations led to the Royal College of Surgeons’ guide- line stating that evacuation of haematoma, when required, should be done within 4 h. The National Institute for Health and Care Excellence (NICE) guidelines specified that CT should be per- formed and assessed within 1 h of the initial request, when indicated. Despite this consensus for rapid assessment and intervention, the realities of resources and interhospital transfer still make this diffi- cult to achieve. Patients who ‘talk and die’—​the importance of deteriorating conscious level A classic paper, by Jennett and his team, coined the phrase ‘talk and die’ to describe patients whose primary injury was mild, but who succumbed to secondary injury—​usually an intracranial haema- toma. Deterioration in conscious level is an urgent clinical sign that requires immediate action. The GCS (Table 24.10.3.1) is now widely used in the United Kingdom and elsewhere, giving objective recording of conscious level, with a high correlation between different observers. Any de- terioration is thus more likely to be noticed. When communicating about a patient with head injury, it is good practice to specify ob- servations of each parameter, rather than to use the corresponding numerical scores, which are open to misinterpretation, for ex- ample, a patient scoring 12 based on scores of 4 on eye opening, 3 on verbal response, and 5 on motor response should be communi- cated as E4, V3, M5. The overall sum should be given and should specify the denominator, to avoid confusion (e.g. 12/​15). The most significant parameter in most cases is the motor score. Changes in motor score of even 1 point can reliably indicate that the patient has deteriorated. Change in consciousness level is the most useful clinical sign in head injury assessment. Generally, a patient with primary brain injury shows a gradually improving conscious level. A pa- tient whose conscious level deteriorates is very likely to have a secondary brain injury and, therefore, requires further in- vestigation and treatment. Conscious level must, therefore, be assessed at the earliest opportunity, and then reassessed at fre- quent intervals. Early management of the patient with a head injury Extracranial injuries Life-​threatening extracranial injuries always take priority over the head injury. However severe the head trauma, the patient needs to be stabilized for safe transfer. In addition, hypotension and hypoxia are important causes of secondary brain injury. Time-​consuming de- finitive surgery such as the internal fixation of limb fractures should, however, be postponed if possible. Airway, breathing, and circulation are the first priorities. Management should follow the general recommendations taught in the Advanced Trauma Life Support (ATLS) courses. In particular, assessment should include consideration of respiratory problems, shock, and possible internal injuries. All patients with head injury should also be assumed to have a cervical spine injury until proven otherwise. Cervical immobiliza- tion should be established, unless the patient is fully conscious, co- operative, and able to convince the examining doctor that he or she has no neck pain or tenderness, a full range of cervical movement, and no neurological deficit. There are rare exceptions to this guide- line, for example, a patient with a fixed flexion deformity due to an- kylosing spondylitis might present with a cervical fracture; in that circumstance placing the neck in a ‘neutral’ position, in a cervical collar, might actually produce neurological injury. Fig. 24.10.3.1  Typical CT appearances of acute subdural haematoma. Fresh haemorrhage appears hyperdense (white). A subdural haemorrhage conforms to the surface of the brain, typically in a thin crescent. There is effacement of the lateral ventricle on the side of haematoma and midline shift away from it. An extradural haematoma, in contrast, usually appears biconvex, with well-​defined edges because it is confined between the bone and dura. 24.10.3  Traumatic brain injury 6045 Initial management of head injuries After initial assessment, resuscitation, and stabilization of extracra- nial injuries, the patient is graded for the severity of the head injury. These categories then give a useful broad guide to management. Severe All patients with severe traumatic brain injury (GCS 3–​8) should be discussed with the neurosurgical unit and managed in the neuro- science centre. Intubation and ventilation is necessary to maintain oxygen saturations greater than 95%, Pco2 in the range 4.0 to 4.5 kPa, and the Po2 at more than 12 kPa. At this stage, the intracranial pres- sure is unknown, but should be assumed to be high; therefore, a mean arterial pressure of at least 90 mm Hg should be maintained. One episode of hypotension (systolic <90 mm Hg), in severe trau- matic brain injury, can lead to a 50% increase in mortality. Hypoxia can also have a profound detrimental impact, although not as sig- nificant as hypotension. The main purpose of a CT scan in trauma is to identify a lesion that requires urgent neurosurgical evacuation. Indications for scan are clearly outlined in the NICE guidelines. If the guidelines are followed it should be expected that a relatively high proportion of patients attending the hospital emergency department with a head injury will require a CT scan. In most of those cases the scan will need to be done within 1 h. Mannitol and hypertonic saline can be used to treat intracranial hypertension if there is clinical evidence of life-​threatening raised intracranial pressure. However, this is not a definitive treatment and should be used while the patient is rapidly prepared for transfer to the neurosurgical unit. Moderate If the head injury was moderate (GCS 9–12), an urgent CT scan would be advisable. If the CT scan detects an intracranial ab- normality, urgent neurosurgical referral is appropriate and the immediate management is similar to that for severe head injuries given here earlier. If no abnormalities are detected on a CT, care should be taken to exclude metabolic and other causes of reduced conscious level (such as hypoglycaemia or drug overdose). If it ap- pears that diffuse brain injury is the only cause of depressed con- scious level, the care of the patient is discussed with the neurosurgical unit. Moderate traumatic brain injury patients may also need to be managed in a neuroscience unit as they are at risk of secondary brain injury and may require specialist neuroscience care. Mild Most head injuries are mild (GCS 13–15). After initial assessment, the next decision is whether further investigation is required. Patients who have a GCS of 15, no history of loss of conscious- ness, and none of the criteria for investigation may be considered for discharge according to the local head injury protocol. They must be under the supervision of a responsible adult and written informa- tion must be provided concerning symptoms and signs that would warrant seeking further urgent medical advice. In this context, the criteria for CT scan include: • GCS less than 13 at any point since the injury • GCS less than 15 at 2 h after the injury • Suspected open or depressed skull fracture • Any sign of skull base fracture (‘panda eye’ periorbital bruising, cerebrospinal fluid flowing from nose or ear, Battle’s sign, haemotympanum, subconjunctival haemorrhage with no pos- terior limit) • Post-​traumatic seizure • Focal neurological deficit • More than one episode of vomiting • Amnesia for more than 30 min of events before the impact If there has been any loss of consciousness or amnesia, a CT scan should also be immediately requested in patients with any of the fol- lowing risk factors: • Age 65 or older • High-​energy mechanism of injury, such as a pedestrian hit by a vehicle, an occupant ejected from a vehicle, or a fall from a height greater than 1 m (about five stairs) • Anticoagulation or known coagulopathy • Significant maxillofacial injuries • Difficulty in assessment, whether due to extremes of age (very young or very old) or intoxication The validated adult rules on imaging of the head may also be safely used in children and infants, but additional criteria include: • Fall from a height greater than the height of the child • Tense fontanelle • Any suspicion of non​accidental injury. If non​accidental injury is suspected in a child then a skull radiograph (as part of a skeletal survey) is also useful, together with other examination such as ophthalmology for retinal haemorrhage If the CT scan shows no abnormality, the patient should be ad- mitted for observation until the consciousness level has returned to normal. Even in those patients with a GCS of 15, they should Table 24.10.3.1  The Glasgow Coma Scale Motor function Obeying commands 6 Localizing 5 Flexion 4 Abnormal flexion 3 Extension 2 None 1 Verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible 2 None 1 Eye opening Spontaneous 4 To speech 3 To pain 2 None 1 section 24  Neurological disorders 6046 be admitted if there are other sources of concern to the clinician such as persistent vomiting, severe headache, drug or alcohol in- toxication, other injuries, shock, suspected non​accidental injury, meningism, or leak of cerebrospinal fluid. If the CT scan does show an intracranial abnormality, the care of the patient should be dis- cussed with the neurosurgical unit. In most cases, transfer to the neurosurgical unit is advised. Management of intracranial complications Intracranial haematoma In almost all cases of intracranial haematoma, urgent evacuation is indicated, bearing in mind that, the longer the delay, the greater the risk of death or disability. The aforementioned guidelines for CT scan/​transfer to neurosurgical unit are all aimed at the earliest diagnosis of the minority of patients with an intracranial haematoma. The risk of a traumatic intracranial haematoma depends on consciousness level and whether a skull fracture is present (Table 24.10.3.2), although the decision to proceed with CT is no longer based on initial skull radiograph, but instead on the clinical features as specified in the NICE guidelines. Even in patients with diffuse brain swelling, rather than an intra- cranial haematoma, neurosurgical intervention may be indicated. Intracranial pressure (ICP) monitoring can be useful in guiding therapy, such as judicious use of inotropes to maintain the cere- bral perfusion pressure. In patients who have persistently raised ICP despite optimization of medical management, a decompressive craniectomy can be considered. This intervention has been the subject of multicentre randomized trials. Infection Meningitis and brain abscess can develop after any head injury in which a communication has been made between the environment and the intracranial contents. The most obvious example is a com- pound depressed fracture, where comminuted bone fragments have been forced inwards, breaching the dura. With some penetrating in- juries (such as a fall on to a sharp object or assault with a pointed weapon) the visible wound may be small and appear insignificant. As the injury may have been low velocity, the patient may have a de- ceptively normal consciousness level. Such patients should always be referred for neurosurgical assessment. CSF rhinorrhoea or otorrhoea indicates that a skull base fracture has breached the dura. This places the patient at risk of meningitis while the cerebrospinal fluid leak continues. Ninety per cent of such cases close spontaneously within 2 weeks, and usually neurosurgical intervention is not considered until this time has elapsed. An excep- tion is a fracture of the posterior wall of the frontal sinus, visualized on a CT scan. Such cases should be discussed with the neurosurgeon or the craniofacial team (if one exists locally) with a view to possible early anterior fossa repair. The use of antibiotics in cerebrospinal fluid leaks is controversial, but a working party reviewing the literature concluded that the avail- able evidence does not support the use of prophylactic antibiotics in patients with cerebrospinal fluid fistulas. Most neurosurgeons do, however, recommend early use of prophylactic antibiotics in penetrating injuries, and there is some evidence for their use in that context. Follow-​up and late complications of head injury Cognitive symptoms After head injury there is a variable period before memory function returns and ongoing memories again begin to be stored. This period is referred to as post-​traumatic amnesia and is a useful measure of the severity of brain damage, for example, when questioned after re- covery, a patient may not remember the accident but clearly recall being placed on a stretcher and taken into the ambulance: this would suggest a relatively short post-​traumatic amnesia of a few minutes. The post-​traumatic amnesia is fixed for a given injury and memories of this period do not later ‘recover’. It is also common for a patient to lose memory of events immedi- ately before the injury. This is known as retrograde amnesia. Unlike post-​traumatic amnesia, the period of retrograde amnesia often pro- gressively reduces as the patient recovers. Incomplete recovery after a head injury has behavioural, cogni- tive, emotional, social, and economic effects. For adults with severe head injuries, 85% remained disabled at 1 year following the acci- dent. In the intermediate group, 63% remained disabled at 1 year. Even those with so-​called ‘minor’ injuries can face considerable problems: at 3-​month follow-​up 79% still have headaches, 59% have symptomatic memory impairment, and 34% have not returned to work. In view of this ongoing impairment, patients who have been admitted for more than 48 h following a head injury should be re- ferred for neuroscience involvement in their follow-​up. The most widely used measure of outcome after head injury is the Glasgow Outcome Scale (Table 24.10.3.3). These are broad Table 24.10.3.2  The risk of intracranial haematoma Risk factor Risk of haematoma No skull fracture Oriented 1:5983 Not oriented 1:121 Skull fracture Oriented 1:32 Not oriented 1:4 A closed depressed fracture does not require surgery except for cosmetic reasons if it is on a visible part of the skull. Table 24.10.3.3  The Glasgow Outcome Scale Good recovery Able to resume preinjury lifestyle Moderate disability Independent, but unable to resume full preinjury activities Severe disability Dependent on the care of others for the activities of daily living Vegetative No sign of psychologically mediated responses Dead 24.10.3  Traumatic brain injury 6047 categories, which miss the subtleties of impairment in many who have had mild injuries. The Extended GOS (GOSE) provides more detailed categorization into eight categories by subdividing the categories of severe disability, moderate disability, and good re- covery into a lower and upper category. Its wide adoption and recognition make the Glasgow Outcome Scale invaluable for statistical comparisons. Even ‘mild’ injuries, with early brief loss of consciousness and an initial GCS of 14 to 15, can lead to significant symp- toms that can interfere with return to previous activities. These ‘postconcussional symptoms’ include headache, dizziness, poor concentration, memory impairment, and personality change. The patient’s relatives often report personality changes, such as ‘bad temper’ and lack of motivation. Such symptoms usually improve over six months, especially if the patient and family are warned to expect such problems and reassured that they are eventually likely to resolve. Rehabilitation after severe head injury requires multidiscip- linary input from rehabilitation neurology, physiotherapy, occupa- tional therapy, speech and language therapy, and neuropsychology. Other specialists and therapy services are accessed as appropriate for each individual patient. At least as far as the Glasgow Outcome Scale is concerned, 60% of patients reach their final outcome category by 3 months after the injury. Ninety per cent (90%) reach their final score by the end of 6 months. Seizures The probability of seizures within 5 years of a traumatic brain in- jury, according to the severity, is 0.7% in patients suffering a mild injury, 1.2% in those with moderate injuries, and 10.0% in the severe group. The probability increases over 30 years to 2.1% for those with mild injuries, 4.2% for moderate and 16.7% for severe injury. Seizures are more common if there has been an intracranial haematoma, a depressed skull fracture, or post-​traumatic amnesia of more than 24 h. A single seizure, within 1 week of the injury, is of less significance than repeated seizures or those occurring after the first week. Any patient who has had a seizure, craniotomy, or depressed skull fracture should be advised not to drive or operate dangerous machinery. They should also contact the Driver and Vehicle Licensing Authority (DVLA). Chronic subdural haematoma Chronic subdural haematoma is a very different condition to acute subdural haematoma in terms of pathophysiology, treatment, and patient demographics. The initial injury may have seemed very minor and may have occurred many weeks previously. The most common symptom is headache, progressively worsening and even- tually accompanied by vomiting. There may also be a focal deficit, which can vary in severity. Increasing intracranial pressure may lead to cognitive impairment and eventually a depressed level of consciousness. In contrast to traumatic brain injury described so far, chronic subdural haematomas tend to occur in an older people with a degree of cerebral atrophy, and are often associated with anticoagulant use. Whatever the pathophysiology, the treatment of choice is evacuation of the subdural collection, usually via burr holes, and irrigation of the subdural space with isotonic saline at body tem- perature. This is a relatively small operation, which can, if neces- sary, be performed under local anaesthetic, so even advanced age and general frailty do not contraindicate its use. Hydrocephalus Hydrocephalus occasionally occurs after head injury, particu- larly if there has been traumatic subarachnoid or intraventricular haemorrhage. It can be distinguished from post-​traumatic cerebral atrophy by the appearances on the CT scan: in hydro- cephalus, the sulci will be small or effaced relative to the large ventricles and there may be periventricular lucency due to inter- stitial oedema. FURTHER READING American College of Surgeons Committee on Trauma (1997). Advanced trauma life-​support for doctors. Student course manual, 6th edition. American College of Surgeons, Chicago, IL. Annegers JF, et al. (1998). A population based study of seizures after traumatic brain injuries. N Engl J Med, 338, 20–​24. British Society of Rehabilitation Medicine (1998). Rehabilitation after traumatic brain injury. British Society of Rehabilitation Medicine, London. Commission on the Provision of Surgical Services (1986). Report of the working party on head injuries. Royal College of Surgeons, London. Infection in Neurosurgery Working Party of the British Society for Antimicrobial Chemotherapy (1994). Antimicrobial prophylaxis in neurosurgery and after head injury. Lancet, 344, 1547–​51. Maas A, et al. (2008). Moderate and severe traumatic brain injury in adults. Lancet Neurology, 7, 728–​41. McMillan T, Greenwood R (1991). Rehabilitation programmes for the brain injured adult: current practice and future options in the UK. A discussion paper for the Department of Health. Department of Health, London. Mendelow AD, Teasdale GM, Jennett B (1983). Risks of intracranial haematoma in head injured adults. BMJ, 287, 1173–​6. National Institute for Health and Care Excellence (NICE) (2003). Head injury: triage, assessment, investigation and early management of head injury in infants, children and adults. https://​www.nice.org. uk/​guidance/​cg56 Peeters W, et al. (2015). Epidemiology of traumatic brain injury in Europe. Acta Neurochir, 157, 1683–​96. Reilly PL, et al. (1975). Patients with head injury who talk and die. Lancet, ii, 375–​7. Rimel RW, et al. (1981). Disability caused by minor injury. Neurosurgery, 9, 221–​8. Saatman KE, et al. (2008). Classification of traumatic brain injury for targeted therapies. J Neurotrauma, 25, 719–​38. Seelig JM, et al. (1981). Traumatic acute subdural haematoma. Major mortality reduction in comatose patients treated within 4 h. N Engl J Med, 304, 1511–​18. Teasdale GM (1995). Head injury. J Neurol Neurosurg Psychiatry, 58, 526–​39. Working Party on the Management of Patients with Head Injuries (1999). Report of the working party on the management of patients with head injuries. Royal College of Surgeons, London. 24.10.4 Intracranial tumours 6048 Jeremy Rees 24.10.4 Intracranial tumours 6048 Jeremy Rees section 24  Neurological disorders 6048 24.10.4  Intracranial tumours Jeremy Rees ESSENTIALS Intracranial tumours represent about 2% of all cancers. There are no known risk factors apart from prior irradiation to the skull and brain and a few rare neurogenetic syndromes (e.g. neurofibroma- tosis, von Hippel–​Lindau syndrome, Li–​Fraumeni syndrome). They may be intrinsic or extrinsic, which determines potential resectability. Neuroepithelial tumours (predominantly gliomas) account for 50–​60% of all primary tumours. Molecular analysis has now been added to the histological grade and subtype to provide an integrated diagnosis which provides more accurate information for treatment and prognosis. As systemic anti-cancer treatments evolve and pro- duce long-term control of visceral and bone disease, brain metas- tases are becoming increasingly common and are best treated with either stereotactic radiosurgery or neurosurgery to avoid the cogni- tive decline associated with whole brain radiotherapy. Clinical features Early neurological symptoms of intracranial tumours are non​specific. Typical manifestations include (1)  progressive focal neurological deficit—​typically subacute; present in over 50% of patients at time of diagnosis; (2) seizures—​may be focal or secondarily generalized; the presenting symptom in 25–​30% of patients and particularly frequent in patients with low-grade gliomas; (3) raised intracranial pressure—​ the classic picture of headache, vomiting, visual obscurations, and papilloedema is easily recognized, but most patients present before this develops; and (4) altered mental state—​cognitive and personality changes. More incidental tumours are now being discovered as a re- sult of the increased availability of cranial imaging. Diagnosis, treatment, and prognosis Diagnosis—​this is made by a combination of CT/​MRI scanning and pathological examination of either a biopsy or resection specimen. Genetic information relating to 1p19q, IDH, and MGMT methylation status is becoming increasingly important for guiding treatment and prognosis. Treatment—​the conventional methods are (1)  surgery—​may be curative for extrinsic tumours, but rarely so for intrinsic tumours; (2)  radiotherapy—​as primary or adjuvant treatment; (3)  chemo- therapy—​concomitant treatment with temozolomide and radical radiotherapy followed by adjuvant temozolomide has improved survival in glioblastoma; certain tumours may respond particularly well to the combination of radiotherapy and chemotherapy, for ex- ample, oligodendrogliomas with chromosome 1p/​19q deletion. (4) biological agents—​antiangiogenic agents are being used in re- lapsed malignant glioma but they do not improve overall survival. There is increasing interest in immunotherapy either as a tumour vaccine or as immune checkpoint inhibitors but, to date, the evi- dence for a clear survival benefit is not available. Prognosis—​this is determined by age at presentation (young > old), performance status (high > low), histological grade (low > high), and genetic mutations (1p19q, IDH mutation). As a general rule, survival with glioblastoma is 1–​2 years, anaplastic astrocytomas 2–​5 years, anaplastic oligodendrogliomas and low-​grade gliomas 5–​15 years. Benign tumours, such as meningiomas and pituitary adenomas, have over 90% 10-​year survival if diagnosed before irreversible neuro- logical damage has occurred. Introduction Intracranial tumours comprise primary tumours that originate from the brain, cranial nerves, pituitary gland, or meninges, and secondary tumours (metastases) that arise from organs outside the nervous system. These tumours present to many different specialists and their management is difficult because of their anatomical loca- tion, variable clinical manifestations, and innate resistance to con- ventional cytotoxic treatments. Aetiology There are no known risk factors apart from prior irradiation to the skull and brain and a few rare neurogenetic syndromes, such as neurofibromatosis (optic nerve glioma, meningioma, vestibular schwannoma) (Fig. 24.10.4.1), von Hippel–​Lindau syndrome (haemangioblastoma), and Li–​Fraumeni syndrome (glioma). The role of mobile (cellular) phones has not been proven. Epidemiology Intracranial tumours represent the eighth most common neoplasm in adults (c.2% of all cancers) and the second most common neoplasm in children. After stroke, intracranial tumours are the leading cause of death from neurological disease in the United Kingdom and are responsible for 7% of years of life lost from cancer before the age of 70. The crude annual incidence for primary intracranial tumours is 7.4 per 100 000 (males 9.1/​100 000, females 6.1/​100 000) and for secondary tumours 14.3 per 100 000 population. Just under 10 000 new cases of brain cancer present every year in the United Kingdom. The incidence has increased by approximately 25% over the last 40 years, particularly in older patients. Different tumour types present at different ages. Supratentorial gliomas, the most frequent primary brain tumour, are rare under the age of 30 years, but become increasingly prevalent thereafter. The most frequent tu- mours of middle life (third and fourth decades) are astrocytomas, meningiomas, pituitary adenomas, and vestibular schwannomas, whereas glioblastoma and metastases are more frequent in the fifth and six decades of life. In contrast, children tend to have infratentorial tumours: 70% of childhood primary intracranial tu- mours originate in the posterior fossa, whereas in adults the figure is only 25%. There is a strong female preponderance of meningiomas and schwannomas, whereas gliomas are more common in men. Pathogenesis Gliomas are thought to arise from neoplastic transformation of glial cells. Recently, there has been increasing incidence in the role of stem cells in the origins of brain tumours—​stem cells are defined as having the ability to renew themselves in perpetuity and to differentiate into 24.10.4  Intracranial tumours 6049 mature cells. The existence of a cancer stem cell has now been proven for glioblastoma and medulloblastoma, and may explain why these tumours recur after treatment. Certain genetic lesions are associated with brain tumours. Chromosomal deletions—​particularly chromo- some 10, which contains multiple tumour-​suppressor genes—​are found in astrocytic tumours, occurring in up to 70% of glioblast- omas. Mutations of a tumour-​suppressor gene, TP53, located on chromosome 17p, have also been reported in approximately 40% of astrocytic tumours. A novel mutation of isocitrate dehydrogenase-​ 1 (IDH1) has been found in a large percentage of gliomas of many different grades and histologies. This is a favourable prognostic marker in low-​grade and high-​grade gliomas and is being used to help with diagnosis of various histologically ambiguous tumours. As a metabolic enzyme in the Krebs cycle, it presents a unique in- sight into the understanding of gliomas and raises the potential for new mechanisms of treatment. In general, the accumulation of pre- dictable genetic alterations is associated with increasing malignant progression. Primary glioblastomas arise in older patients and are associated with wild-​type IDH, amplification and overexpression of the epidermal growth factor receptor (EGFR) gene, whereas sec- ondary glioblastomas occur in younger people and are associated with IDH mutations and early loss of TP53. Recent data have shown that IDH wild-​type astrocytomas (irrespective of grade) are molecu- larly similar to glioblastoma, with implications for management. Clinical features With increasing sophistication of neuroimaging, tumours are being detected at an earlier stage than before. Patients typically present with one or more of four clinical syndromes: • progressive neurological deficit • seizures (e) (b) (a) (c) (d) Fig. 24.10.4.1  Contrast-​enhanced CT and MR scans of a patient with neurofibromatosis type 2 and multiple intracranial tumours. (a) CT of the brain with contrast enhancement showing a large right parietal convexity meningioma surrounded by vasogenic oedema exerting considerable mass effect. There is also a smaller falx meningioma in the right occipital region. (b) Coronal T1-​weighted MRI of the brain with gadolinium enhancement showing multiple meningiomas in the right temporoparietal region, right parafalcine region, and both cavernous sinuses. (c) Contrast-​enhanced CT scan of the orbits showing bilateral optic nerve sheath meningiomas with intracranial extension into the right cavernous sinus, causing partial right nerve III and nerve VI palsies. (d) Axial T1-​weighted MRI of the brain with gadolinium enhancement, showing bilateral vestibular nerve schwannomas and a large cisterna magna tumour. (e) Sagittal T1-​weighted MRI of the spinal cord with gadolinium enhancement showing three discrete meningiomas encroaching on the spinal column at midcervical, midthoracic, and upper lumbar levels. section 24  Neurological disorders 6050 • raised intracranial pressure • altered mental states The particular combination of clinical features varies depending on the location, histology, and rate of growth of the tumour, for example, patients with low-​grade gliomas present typically with a seizure disorder that may remain static for many years, whereas pa- tients with malignant gliomas typically develop a rapidly progressive neurological deficit and raised intracranial pressure. More patients are being diagnosed with incidental tumours as a result of the in- creased availability of CT and MRI scans. Progressive neurological deficit Focal neurological symptoms due to brain tumour are typically sub- acute and progressive, with over 50% of patients having focal signs by the time of diagnosis. However, they may also present as a ‘stroke’ mimic and even as a transient ischaemic attack. Cortical tumours produce contralateral weakness, sensory loss, dysphasia, dyspraxia, and visual field loss depending on their location. Bilateral tumours (e.g. butterfly gliomas), may present with confusion, unsteadiness, and urinary incontinence. Posterior fossa tumours cause ataxia and cranial nerve palsies. Vestibular schwannomas cause progressive unilateral deafness fol- lowed by ipsilateral facial sensory loss and ataxia due to brainstem compression. Pituitary tumours may cause a bitemporal hemianopia if there is chiasmal compression or endocrine disturbances due to ei- ther hypopituitarism or hypersecretion of specific hormones. Seizure disorder Brain tumours account for about 5% of epilepsy cases although they are overrepresented in cases of intractable epilepsy. Seizures are the presenting symptom in 25–​30% of patients with brain tu- mours and are present at some stage of the illness in 40–​60% overall. Approximately one-​half of the patients have focal seizures (usually frontal or temporal lobe) and the other half have secondarily gen- eralized seizures. Low-​grade gliomas are associated with seizures in over 90% of cases and these frequently remain the only complaint for many years. About 50% of low-​grade glioma patients have intract- able seizures. Conversely, patients with malignant gliomas have a lower frequency of seizures, presumably because of their more rapid growth and destructive characteristics. In these patients, seizures are associated with a better prognosis. Seizures are also common initial manifestations of meningiomas (40–​60%) and metastases (15–​20%). Supratentorial tumours and those located in the cortex are particu- larly likely to cause seizures, particularly in the frontal and temporal lobes. Todd’s paresis, which may persist, is an uncommon but charac- teristic feature of tumour-​associated epilepsy. About 10% of patients presenting anew in status epilepticus have an underlying tumour. Raised intracranial pressure Intracranial tumours increase intracranial pressure by a direct mass effect, provoking cerebral oedema, or producing obstructive hydro- cephalus. The most common symptom of raised intracranial pressure is headache, which is the initial presenting symptom in 25% of pa- tients and in 50% of patients at hospital presentation; papilloedema is found in up to 50% of patients with headache due to tumours. The classic picture of headache, vomiting, and visual obscurations (tran- sient fogging of vision usually on rapid changes in posture) due to raised intracranial pressure is well known and easily recognized, but most patients present before this develops. Less than 0.1% of patients presenting with isolated headache have a brain tumour. Most brain tumour headaches are intermittent and non​specific and may be indistinguishable from tension headaches. Supratentorial tumours typically produce frontal headaches, whereas posterior fossa tumours usually result in occipital headache or neck pain. Certain features of a headache are suggestive but not pathogno- monic of raised intracranial pressure. These include headaches that wake the patient at night or are worse on waking and improve over the course of the day. Patients with rapidly expanding tumours or who have cystic com- ponents or intratumoral haemorrhage may present with increasing drowsiness, vomiting, pupillary dilatation, and visual loss due to downward uncal and transtentorial herniation. Mental state changes These are an uncommon presentation of brain tumours, usually found in slow growing orbitofrontal tumours (e.g. meningiomas). Personality changes may initially be quite subtle and may show themselves as an inability to cope at work, apathy, and loss of social inhibition. In these cases, it is essential to obtain a collateral history from relatives or colleagues at work. Later, as the tumours progress, personality change is quite common and may lead to breakdown of family relationships. Pathology Neuroepithelial tumours (predominantly gliomas) account for approximately 50 to 60% of all primary brain tumours. The other common types are meningiomas (20%), pituitary adenomas (15%), vestibular schwannomas (5%), and primary central nervous system (CNS) lymphomas (5%) (Fig. 24.10.4.2). Brain metastases are much Fig. 24.10.4.2  Axial T1-​weighted MRI with gadolinium enhancement showing a homogeneously enhancing left anterior temporal lesion which was biopsied and shown to be a primary CNS lymphoma. 24.10.4  Intracranial tumours 6051 more common than primary brain tumours and are increasing in frequency due to improvements in systemic anti-cancer treat- ments. The most common sites of origin of brain and meningeal metastases are lung (50%), breast (15%), melanoma (10%), and unknown (15%). The classification systems that have been traditionally used to describe degrees of anaplastic change are the basis of histo- logical diagnosis and grading correlate with prognosis. The most widely accepted classifications of gliomas is the World Health Organization (WHO) system (Table 24.10.4.1). These systems have been retrospectively applied to large series of patients and have been shown to provide reproducible and prognostically useful information. They have recently been updated to include some new diagnostic entities. The gliomas are a family of neoplasms that are thought to arise from astrocytes, oligodendrocytes, and ependymal cells. Astrocytomas are the most common type of glioma and are infiltrating neoplasms composed of fibrillary astrocytes. WHO grade II gliomas have the propensity to undergo anaplastic change to a more malignant le- sion. Thus, a fibrillary astrocytoma (Fig. 24.10.4.3) progresses to an anaplastic astrocytoma (Fig. 24.10.4.4) and then to the most malig- nant form, glioblastoma (Fig. 24.10.4.5). The oligodendroglioma is WHO grades of select CNS tumours Diffuse astrocytic and oligodendroglial tumours Diffuse astrocytoma, IDH-​mutant Anaplastic astrocytoma, IDH-​mutant Glioblastoma, IDH-​wildtype Glioblastoma, IDH-​mutant Diffuse midline glioma, H3K27M-​mutant Oligodendroglioma, IDH-​mutant and 1p/​19q-codeleted Anaplastic oligodendroglioma, IDH-​mutant and   1p/​19q-​codeleted II III IV IV IV II III Other astrocytic tumours Pilocytic astrocytoma Subependymal giant cell astrocytoma Pleomorphic xanthoastrocytoma Anaplastic pleomorphic xanthoastrocytoma I I II III Ependymal tumours Subependymoma Myxopapillary ependymoma Ependymoma Ependymoma, RELA fusion–​positive Anaplastic ependymoma I I II II or III III Other gliomas Angiocentric glioma Chordoid glioma of third ventricle I II Choroid plexus tumours Choroid plexus papilloma Atypical choroid plexus papilloma Choroid plexus carcinoma I II III Neuronal and mixed neuronal-​glial tumours Dysembryoplastic neuroepithelial tumour Gangliocytoma Ganglioglioma Anaplastic ganglioglioma Dysplastic gangliocytoma of cerebellum (Lhermitte-​Duclos) I I I III I Desmoplastic infantile astrocytoma and ganglioglioma Papillary glioneuronal tumour Rosette-​forming glioneuronal tumour Central neurocytoma Extraventricular neurocytoma Cerebellar liponeurocytoma I I I II II II Tumours of the pineal region Pineocytoma Pineal parenchymal tumour of intermediate differentiation Pineoblastoma Papillary tumour of the pineal region I II or III IV II or III Embryonal tumours Medulloblastoma (all subtypes) Embryonal tumour with multilayered rosettes, C19MC-​altered Medulloepithelioma CNS embryonal tumour, NOS Atypical teratoid/​rhabdoid tumour CNS embryonal tumour with rhabdoid features IV IV IV IV IV IV Tumours of the cranial and paraspinal nerves Schwannoma Neurofibroma Perineurioma Malignant peripheral nerve sheath tumour (MPNST) I I I II, III or IV Meningiomas Meningioma Atypical meningioma Anaplastic (malignant) meningioma I II III Mesenchymal, non​meningothelial tumours Solitary fibrous tumour /​ haemangiopericytoma Haemangioblastoma I, II or III I Tumours of the sellar region Craniopharyngioma Granular cell tumour Pituicytoma Spindle cell oncocytoma I I I I Fig. 24.10.4.3  Low-​grade glioma. Coronal and axial T2-​weighted MRI of the brain showing a diffuse lesion in the right frontal lobe, which returns high signal. It is seen extending from the cortex into the deep white matter and infiltrating across the corpus callosum. There is mass effect causing compression of the frontal horn of the lateral ventricle. The tumour does not enhance with gadolinium. This patient presented with generalized seizures and has remained well after 8 years of follow-​up. Biopsy revealed a fibrillary astrocytoma (WHO grade II). Table 24.10.4.1  Pathological classification of astrocytomas section 24  Neurological disorders 6052 characterized by the presence of uniform round nuclei with small nu- cleoli. This also has the propensity to undergo anaplastic change but, unlike anaplastic astrocytomas, oligodendrogliomas are frequently chemosensitive (see next) and patients may live for many years. Diagnosis The diagnosis of a brain tumour is made by a combination of CT/​MR scanning and pathological examination of either a biopsy or a resection specimen. Advanced MRI techniques include MR spectroscopy, perfusion and permeability sequences, and meta- bolic imaging (positron emission tomography (PET)). These may permit a non​invasive method of differentiating between low-​grade and high-​grade gliomas and between tumour recurrence and ra- diation necrosis. However, histology is still the gold standard, now complemented with molecular information, for example, IDH mu- tation, chromosomal deletions of 1p19q (found in oligodendroglial tumours and associated with a better prognosis), and methyl guanyl methyl transferase (MGMT) promoter methylation (which predicts response to temozolomide chemotherapy in glioblastoma). Treatment The three conventional methods of treatment for brain tumours are surgery, radiotherapy, and chemotherapy. Targeted biological agents, gene therapy and immunotherapy have still not been widely taken up because of the lack of proven benefit over and above standard therapies. In line with other areas of oncology, there is increasing use of combination therapies, particularly concomitant chemoradiation to improve survival. Surgery Advances in tumour neurosurgery include the use of computerized frameless neuronavigation techniques, intraoperative imaging with ultrasound and MRI and intraoperative cortical mapping during awake craniotomy. Preoperatively, important anatomicofunc­ tional information can be derived from functional MRI (fMRI) which allows localization of eloquent motor, speech, and memory cortex as well as diffusion tractography, which can delineate the anatomical relationship between tumour and important white matter tracts. Fluorescence guided resection using the porphyrin 5-​aminolaevulinic acid (5-​ALA) has been shown to increase com- plete resection of glioblastoma, resulting in a prolonged period free of progression (but not overall survival) and delayed neurological deterioration. Fig. 24.10.4.5  Glioblastoma. Axial T2-​weighted (a) and coronal T1-​weighted with gadolinium enhancement (b) MRI showing large vascular (dark serpiginous structures) and heterogeneous intrinsic architecture with extensive peritumoral vasogenic oedema (shown as white matter ‘fingers’ on (a)) and the irregular rim enhancement and central necrosis (on b). Fig. 24.10.4.4  Anaplastic astrocytoma. Coronal T1-​weighted MRI of the brain with gadolinium enhancement showing a large heterogeneous enhancing tumour arising from the right frontal lobe exerting considerable mass effect in a patient presenting with a 2-​month history of complex partial seizures, headaches, and papilloedema. 24.10.4  Intracranial tumours 6053 Surgery is indicated as a first-​line treatment for gliomas, meningiomas, and non​secreting pituitary adenomas. As a gen- eral rule, extra-​axial tumours (e.g. meningiomas), may be cured by surgery alone as well as a small proportion of low-​grade gliomas (e.g. pilocytic astrocytomas). For most types of glioma, however, surgical removal is not curative. Although surgery is of undoubted benefit in relieving the symptoms and signs of raised intracranial pressure or an evolving focal deficit, there are no prospective randomized data to support its use for prognostic purposes alone, particularly in pa- tients with malignant gliomas. However, the conventional surgical wisdom is that maximal safe resection (cytoreduction) improves pro- gression-​free survival in patients with high-​grade gliomas and that complete macroscopic or subtotal resections (leaving a residual tu- mour volume of <10 ml) improves overall survival in patients with low-​grade gliomas when compared with tumours that are biopsied and treated with radiotherapy alone. Overall, about 50% of patients with medically refractory seizures derive considerable seizure reduc- tion from surgery. Complete resection of solitary or oligo (2–​3) brain metastases is becoming increasing accepted as the gold standard of treatment for patients with good performance status and controlled systemic dis- ease. In contrast, the only role of surgery in primary CNS lymphoma (PCNSL) is for tissue diagnosis—​therefore, any patient with a sus- pected PCNSL (on radiological grounds) should have a biopsy only, ideally without previous treatment with corticosteroids. Radiotherapy Radiotherapy is the only treatment that has been proved to extend survival in patients with primary malignant brain tumours and may be given with radical or palliative intent. Patients with malignant gliomas are treated with radical radiotherapy to a dose of 60Gy in 30 fractions over 6 weeks. Temozolomide, an oral alkylating agent, has been shown to improve survival in patients with newly diag- nosed glioblastoma when given together with radiotherapy (con- comitantly) and then for six monthly cycles after chemoradiation (adjuvantly). This is known as the Stupp protocol and was the first significant advance in the treatment of glioblastoma for over 30 years. Although the improvement in median survival compared with radiotherapy alone is modest (12.1 vs. 14.6 months), the pro- portion of patients alive at 2 years increased from 10% to 26%, and at 5 years from 2% to 10%. These data were published in 2005 and rekindled enthusiasm for chemotherapy trials in tumours previ- ously regarded as chemoresistant. Whether this treatment can im- prove the survival of patients with anaplastic astrocytomas is being tested in clinical trials. The elderly patient with glioblastoma poses particular challenges, as they have poorer cerebral reserve, less tol- erance of brain radiotherapy and more comorbidities—​as a result, they are usually excluded from clinical trials and so the best treat- ment has not been determined. Early radiotherapy for adult low-​grade gliomas prolongs progression-​free survival by about 2 years but has no effect on overall survival, compared with radiotherapy given at the time of tumour pro- gression. Radiotherapy is effective in controlling seizures in patients with refractory brain tumour-​associated epilepsy. Meningiomas are also partially radioresponsive and should be treated with radio- therapy where there is atypical or malignant histology or where there is recurrent tumour that is not surgically accessible. Long-​term (>10 years) control rates for meningiomas are around 90%. Advances in technology have allowed greater accuracy of radio- therapy delivery and, in particular, the use of stereotactic frames that permit the focusing of radiation to a small tumour with minimal dosage to the surrounding normal tissue. This can be done either in a single high dose (stereotactic radiosurgery or γ knife) or in smaller fractions (stereotactic radiotherapy) and is predominantly indicated for lesions less than 3 cm in diameter which are well circumscribed, extra-​axial, and more than 5 mm away from organs at risk e.g. optic chiasm, or for brain metastases. Intensity-​modulated radiotherapy (IMRT) allows more precise ‘dose painting’ whereby different re- gions of the tumour are treated with varying doses of radiotherapy, and minimises the amount of normal brain tissue that is irradiated. ‘Cyberknife’ radiotherapy has incorporated a robotic mounting device with real-​time image guidance to improve accuracy of de- livery and to ‘target’ the tumour during normal respiration. None of these advanced techniques have been compared against each other, and nor have they have been shown to be superior to stereotactic fractionated radiotherapy. Recently, two large randomized studies have shown similar survival benefits and functional independence between patients with 1 to 3 brain metastases treated with stereo- tactic radiosurgery (SRS) versus SRS plus whole-​brain radiotherapy (WBRT). As a result, WBRT is no longer used routinely in patients with solitary or oligometastases with good performance status. Chemotherapy There has been increased awareness of the chemosensitivity of certain tumours, particularly anaplastic oligodendrogliomas and primary CNS lymphomas in adults, and diencephalic gliomas in children. Approximately two-​thirds of anaplastic oligodendrogliomas re- spond dramatically to a combination of treatment with procarbazine, lomustine, and vincristine; updated (12-​year follow-​up) data from a phase III trial have demonstrated a clear survival benefit for adjuvant vincristine over and above radiotherapy in patients with anaplastic oligodendrogliomas, but only those with the presence of combined deletions of chromosomes 1p and 19q. Similarly, a recently pub- lished phase III randomized trial has demonstrated a 5.5-​year im- provement in survival with the addition of procarbazine, lomustine, and vincristine chemotherapy in patients with ‘high-​risk’ low-​grade glioma over radiotherapy alone. However, the trial was completed over 10 years ago and, in that time novel molecular markers (see next) and newer drugs (e.g. temozolomide) have been developed, so it is difficult to know how to best incorporate these results into clinical practice. Adjuvant nitrosurea chemotherapy is used in patients with malig- nant gliomas although it offers only a marginal survival advantage. Carmustine wafers allow local delivery of carmustine (a nitrosourea) into the resection cavity of a malignant glioma, hence avoiding the systemic toxicity of these compounds, but are associated with in- creased risk of infection, oedema and wound breakdown so are used in highly selected cases only. The role of temozolomide chemo- therapy in patients with low-​grade gliomas over radiotherapy alone is currently being evaluated in a clinical trial and interim data do not suggest any survival advantage. There is no chemotherapy that is effective for the treatment of meningiomas. 24.10.5 Idiopathic intracranial hypertension 6054 24.10.5 Idiopathic intracranial hypertension 6054 Alexandra Sinclair section 24  Neurological disorders 6054 Chemotherapy of recurrent malignant glioma is associated with poor response rates, so new agents are constantly being in- vestigated, including dendritic cell vaccines, immune checkpoint inhibitors, and antiangiogenesis agents. To date, no new treat- ment has been shown to be more effective than nitrosurea-​based chemotherapy. Prognosis Overall survival from brain tumours has increased over the last 40 years but is still poor, around 40% at 1 year and 18% at 5 years. The four most important favourable prognostic factors for patients with gliomas are young age (less than 40 years), good perform- ance status, low-​grade oligodendroglial histology and molecular subtype (IDH1 mutation and, 1p/​19q codeletion). The survival advantage for different treatments is modest in comparison. Any trial claiming a significant survival advantage for a new treatment therefore needs to show that this effect is independent of other prognostic factors. The median survival for patients with malignant gliomas varies from 6 months to 5 years, dependent on the afore- mentioned conditions. Generally, patients with glioblastoma sur- vive for 1–​2 years, whereas patients with anaplastic gliomas survive for 2 to 5 years, the exception being anaplastic oligodendrogliomas where survival can extend up to 10-20 years. The outlook for patients with low-​grade gliomas is considerably better, with a median survival of 5–​15 years depending on age, pre- operative performance status, histology, and tumour growth rate. Oligodendrogliomas have a more indolent course and are more chemosensitive than astrocytomas, so their prognosis is corres- pondingly better, with patients surviving 15–​20 years after diag- nosis, even with anaplastic histology. A recent genome wide analysis of almost 300 adult lower-​grade gliomas correlating molecular data with clinical outcomes has shown that these tumours can be cat- egorized into three molecular classes—​those with IDH mutations and either 1p19q codeletions (most favourable outcome) or TP53 mutations and those with IDH wild-​type tumours, which behaved clinically more like glioblastoma. At least 40% of primary intracranial tumours are extra-​axial (not arising from within the brain substance itself) and are thus readily treatable, if not curable. Some tumours, such as meningiomas and pituitary adenomas, are associated with 10-​year survival rate of over 90% if diagnosed before irreversible neurological damage has occurred. FURTHER READING Counsell CE, Collie DA, Grant R (1996). Incidence of intracranial tumours in the Lothian region of Scotland, 1989–​90. J Neurol Neurosurg Psychiatry, 61, 143–​50. Cancer Genome Atlas Research Network, Brat DJ, et  al. (2015). Comprehensive, integrative genomic analysis of diffuse lower-​grade gliomas. N Engl J Med, 372, 2481–​98. Hollon T, et al. (2015). Advances in the surgical management of low-​ grade glioma. Seminars in Radiation Oncology, 25, 181–​8. Kocher M, et al. (2011). Adjuvant whole-​brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-​26001 study. J Clin Oncol, 29, 134–​41. Leroy HA, et  al. (2015). Fluorescence guided resection and glio- blastoma in 2015: a review. Lasers Surg Med, 47, 441–​51. Louis DN, et al. (2007). The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol, 114, 97–​109. Rachett B, et al. (2008). Survival from brain tumours in England and Wales up to 2001. Br J Cancer, 99, S98–​101. Schomas DA, et al. (2009). Intracranial low-​grade gliomas in adults: 30 years’ experience with long-​term follow-​up at Mayo Clinic. Neuro-​Oncology, 11, 437–​45. Stupp R, et al. (2005). Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med, 352, 987–​99. Stupp R, et al. (2009). Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-​year analysis of the EORTC-​NCIC trial. Lancet Oncol, 10, 459–​66. Taphoorn MJB, Klein M (2004). Cognitive deficits in adult patients with brain tumours. Lancet, 3, 159–​68. Van den Bent MJ, et al. (2005). Long-​term efficacy of early versus delayed radiotherapy for low-​grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet, 366, 985–​90. van den Bent MJ (2014). Practice changing mature results of RTOG study 9802:  another positive PCV trial makes adjuvant chemo- therapy part of standard of care in low-​grade glioma. Neuro-​ oncology, 16, 1570–​4. 24.10.5  Idiopathic intracranial hypertension Alexandra Sinclair ESSENTIALS Idiopathic intracranial hypertension is a condition of raised intra- cranial pressure of unknown cause predominantly affecting obese women of childbearing age. Impaired absorption or increased pro- duction of cerebrospinal fluid, or raised venous pressure, may be contributory. Secondary causes include cerebral venous thrombosis, anaemia, endocrinopathies, and drugs (particularly tetracycline and vitamin A derivatives or supplements). Clinical features Characteristic presentation is with headache, which may be typ- ical of raised intracranial pressure but is frequently non​specific. Papilloedema is present, visual field defects are common, and (rarely) there may be sixth nerve palsy. Diagnosis, treatment, and prognosis Brain imaging, including venography, should exclude other causes of raised intracranial pressure. Lumbar puncture reveals pressure greater than 250 mm  cerebrospinal fluid with normal constitu- ents. Treatments aim to prevent permanent visual loss and manage 24.10.5  Idiopathic intracranial hypertension 6055 headaches. Therapy includes weight loss and acetazolamide, and other diuretics are sometimes used (without evidence of efficacy). For those with rapid visual decline, urgent surgical intervention (ventriculoperitoneal/​lumboperitoneal shunt with a valve or optic nerve decompression) is essential. A  temporizing lumbar drain should be considered if surgery is delayed. For most patients this is a chronic condition characterized by significantly disabling headaches and relapses, typically precipitated by weight gain. Introduction Idiopathic intracranial hypertension (IIH) (also called pseudotumour cerebri and, previously, benign intracranial hypertension) is a syn- drome of raised intracranial pressure in the absence of an intracranial mass lesion, enlargement of the cerebral ventricles, or venous sinus thrombosis. IIH affects predominantly obese women of childbearing age (>90%). The condition has considerable morbidity from per- manent visual loss (up to 25% of cases) and chronic disabling head- aches, which result in poor quality of life. Patients presenting acutely with papilloedema must be evaluated urgently for secondary causes of raised intracranial pressure (e.g. space occupying lesion and venous thrombosis). After this, the priority is to assess accurately the threat to vision. In most patients, the condition becomes chronic and the disease burden is mostly from chronic headaches, which need ac- tive management, alongside visual monitoring. This chapter does not cover paediatric IIH. The IIH management guidelines reflect the con- sensus from the Association of British Neurologists, The Royal Collage of Opthalmologists, The Society for British Neurological Surgeons, key international opinion leaders and patients group (open access ref- erence below) and are a key pragmatic resource for this condition. Aetiology Elevated intracranial pressure (ICP) is caused by alterations in the volume of either cerebral blood, cerebrospinal fluid (CSF), or brain tissue. CSF volume is tightly regulated and is dependent upon the balance between CSF secretion and drainage. The mechanisms in- volved in regulation of CSF dynamics are poorly understood. Epidemiology Idiopathic intracranial hypertension is comparatively rare in the general population, with an annual incidence of approximately 1 in 100 000, but this figure rises to 19 in 100 000 in obese women of child- bearing age. Although more than 90% of patients are obese women, IIH can also occur in childhood and is rarely observed in men. Pathogenesis The underlying pathogenesis is not fully understood, but is driven by disordered CSF dynamics. This may be through either exces- sive CSF production at the choroid plexus, reduced CSF drainage (predominantly by the arachnoid granulations) or elevated venous sinus pressure, or a combination of more than one of these factors. The mechanisms underlying the elevated intracranial pressure are not fully understood. As typical patients are obese and female, a patho- genic role for sex hormones and adipokines has been speculated. Clinical features Characteristic presentation is with headache (94%) and papilloedema (although rarely patients can be diagnosed with IIH without papilloedema (IIHWOP)). Other symptoms include transient visual obscurations, pulsatile tinnitus, visual disturbance, double vision and, in some, non​specific back pain, neck pain, and dizziness. Headache This is the most common symptom and is present to some degree in almost every case. In those with significantly raised intracranial pres- sure (typically at presentation) the headache phenotype typically re- flects that of raised intracranial pressure (worse in the mornings, on lying down, on bending down, and with Valsalva manoeuvres). The International Headache Society criteria for the diagnosis of headache associated with IIH (criteria 7.1.1) lists a headache with daily occur- rence, which is diffuse and or constant (typically non-​pulsating) and aggravated by coughing and bending. These features are not exclusive to IIH (exacerbation of headache with coughing occurs in 70% of IIH patients and 35% of migraineurs while bending exacerbates 50% of IIH headaches and 44% of migraineurs). IIH headaches can resemble migraine and additionally may coexist with migraine. IIH headaches improve after lumbar puncture and CSF drainage in 72% (but im- provement is also documented in 25% of migraineurs). Papilloedema This is a virtually universal finding, but IIH without papilledema (IIHWOP) is sometimes observed. Papilloedema results from swelling of the intraocular (prelaminar) portion of the optic nerve head. Severity of papilloedema can be classified using Frisen Grading (Fig. 24.10.5.1). Choriodal-​retinal folds may be noted in IIH. Although typically identification of papilloedema is not chal- lenging (particularly when there is moderate to severe swelling), distinguishing between mild papilloedema and pseudopapilloedema (e.g. due to anomalous discs or optic nerve head drusen) can be a challenge. There is a risk that once a patient is labelled with papilloedema the diagnosis is then not questioned, which can lead to inappropriate investigations and treatment. An accurate assessment of the optic disc is, therefore, essential and if there is any doubt as to whether there is true papilloedema of the optic disc, an opinion by a senior ophthalmologist or neuro-​ophthalmologist should be sought. Investigations that might be helpful include optical coher- ence tomography to quantify elevation of the retinal nerve fibre and identify drusen; orbital ultrasound B-​scan can identify drusen and measure fluid in the optic nerve sheath and fluorescein angiography to look for early leakage from the blood vessels in papilloedema. Papilloedema and drusen may coexist in a minority of patients. Loss of spontaneous venous pulsations, particularly in a patient where they were previously noted, is an indicator of raised ICP. However, spontaneous venous pulsations cannot be identified in a large portion section 24  Neurological disorders 6056 of normal individuals, making absence of this sign an unreliable in- dicator of elevated intracranial pressure. Significant compression of the optic nerve can result in permanent loss of retinal nerve fibres leading to optic atrophy. An atrophic optic nerve head cannot subse- quently swell if there is disease recurrence. Papilloedema is typically bilateral but can be more severe in one eye or very rarely unilateral (unilateral papilloedema requires a more extensive imaging to ex- clude a lesion compressing the optic nerve). Visual symptoms In patients with papilloedema, transient visual obscurations (black- ening or greying out of the vision, usually in both eyes for a few seconds, particularly on Valsalva or bending) likely result from intermittent ischaemia of the optic nerve. These episodes do not correlate with visual loss. Diplopia is most frequently horizontal due to a sixth cranial nerve palsy (false localizing sign resulting from elevated ICP). Monocular diplopia is extremely rare and can occur due to macula oedema (early) or epiretinal membrane (late) in the setting of significant papilloedema. Symptoms of visual loss are common and variable (e.g. dark area (scotoma), tunnel visual from peripheral constriction). Pulsatile tinnitus Occurring in 60% of patients with active disease, this is usually bilateral but can be unilateral. It may be described as whooshing or akin to a heartbeat. Jugular venous compression can temporarily eliminate the sound. Diagnosis Terminology The term pseudotumour cerebri denotes elevated intracranial pressure in the absence of space occupying lesion, which may be due to several causes. If no underlying cause is identified, then the term IIH is appropriate. If an underlying cause is identified, the term secondary pseudotumour cerebri may be used with a descrip- tion of the underlying cause (e.g. pseudotumour cerebri secondary to anaemia). The term fulminant IIH is used to describe patients with rapidly deteriorating vision of less than four weeks’ duration. The term benign intracranial hypertension is no longer used. Diagnostic criteria See Table 24.10.5.1. Differential diagnosis IIH is a diagnosis of exclusion. Once papilloedema has been confirmed and space occupying lesion, hydrocephalus, and venous thrombosis excluded on imaging, a full history, drug history, and system enquiry are vital to elicit any treatable or underlying causes (Table 24.10.5.2). Investigations Once papilloedema has been confirmed, urgent imaging must be conducted to exclude hydrocephalus, space occupying lesions, and venous sinus thrombosis. MRI or CT with MR venography or CT venography is recommended. Imaging features which can be asso- ciated with IIH include: small ventricles, empty pituitary sella, optic nerve sheath fluid, and tortuosity and flattening of the posterior aspect of the optic globe. Cerebral venous sinus narrowing is often VFI: 98% MD: 1.98 DB P<10% PSD: 1.84 DB P<10% (g) (e) VFI: 100% MD: +0.09 DB PSD: 1.54 DB (h) (f) VFI: 96% MD: -3.75 DB P<1% PSD: 2.72 DB P<2% 30 30 30 30 (c) (a) (d) VFI: 85% MD: -3.51 DB P<2% PSD: 2.95 DB P<2% (b) LEFT RIGHT BASELINE 12MONTHS Fig. 24.10.5.1  A 32-​year-​old lady presented to her local optician with a three-​month history of headaches. She was diagnosed with papilloedema and sent to the local casualty department. On further questioning she admitted to pulsatile tinnitus and occasional bilateral blacking-​out of her vision for a few seconds, particularly on bending down. Secondary causes of raised intracranial pressure were excluded (including normal MRI and MR venography). Examination revealed bilateral papilloedema (a, b), visual acuity was maintained at 6/​4 bilaterally, Humphrey visual fields showed an enlarged blind spot particularly on the right (c, d), lumbar puncture pressure 41 cmCSF, and BMI 41. She was treated with a weight loss programme and at 12 months her BMI was 34, lumbar puncture pressure 28 cmCSF, and the papilloedema and perimetry had significantly improved (e, f, g, h). 24.10.5  Idiopathic intracranial hypertension 6057 noted, typically in the transverse sinus; these usually reverse with CSF drainage after lumbar puncture or shunting. Blood pressure measurement to exclude malignant hypertension and blood tests (blood count, ESR, CRP, and renal function) are recommended. Cerebrospinal fluid pressure Lumbar puncture (LP) should be performed in the lateral de- cubitus position. More than one monometer may be needed to ac- curately measure the pressure if it is above 40 cmCSF. Once the LP needle is in position, the legs should be straightened slightly to prevent the legs applying pressure to the abdomen which can falsely elevate pressure. Sufficient time must be allowed to let the pressure settle before a reading is taken (the pressure should fluc- tuate with respiration and can sometimes take a few minutes to settle). Draining the CSF to a reading of 17 cmCSF is undertaken in some centres but is not evidence based, nor is the importance of recording a closing pressure. Certainly, in those with significantly elevated pressure, draining CSF may have a temporary therapeutic effect. In some patients, LP is challenging, and image guidance may be needed. CSF should be analysed for microscopy, protein, and glucose (with paired serum glucose) to facilitate identification of secondary causes. A definitive cut-​off for elevated LP pressure is debated. Those with pressure greater than 25 cmCSF should be evaluated for IIH. Only a weak, non​significant relationship exists between LP pressure and obesity. In normal individuals, pressures up to 28 cmCSF have been recorded. It should be remembered that LP pressure is a snap shot recording. LP pressure varies over 24 hours and the LP technique can impact on the reading; multiple LP attempts which puncture the dura may falsely lower the pressure while abdominal compression from the legs or Valsalva (breath-​ holding or crying) can falsely elevate the pressure. If the LP reading is out of keeping with the clinical picture it should be questioned and, in some cases, repeated. Atypical patients In patients with an atypical phenotype (men, children, and non-​obese women) more extensive investigations are recommended to look for a secondary cause. MRI imaging with intravenous contrast (to ex- clude meningeal infiltration) and potentially MRI imaging of the proximal jugular veins (to identify proximal stenosis) may be indi- cated. A more extensive blood workup (vitamin A, endocrine testing) and sleep apnoea monitoring may identify alternative pathologies. Management Patients given a diagnosis of idiopathic intracranial hypertension are usually bewildered and frightened. It is important to provide a simple explanation of the nature of the condition and the rationale for treatment. Most patients are obese and weight loss is disease modifying; however, discussions regarding the importance of weight loss need to be sensitively managed. Table 24.10.5.1  Diagnostic criteria for idiopathic intracranial hypertension (IIH) Diagnostic criteria for adult IIH Diagnostic criteria for adult IIH without papilloedema (IIHWOP) A. Papilloedema • B–​E satisfied with additional sixth nerve palsy B. Normal neurological examination except for cranial nerve abnormalities C. Neuroimaging: normal brain parenchyma without evidence of hydrocephalus, mass, or structural lesion and no abnormal meningeal enhancement or venous sinus thrombosis on MRI and magnetic resonance venography; if MRI is unavailable or contraindicated, contrast-​enhanced CT may be used • In the absence of sixth nerve palsy, IIHWOP can be suggested if B–​E are satisfied and at least 3 of: • Empty sella • Flattening of the posterior aspect of the optic globe • Optic nerve sheath distention +/​-​tortuous optic nerve • Transverse sinus stenosis D. Normal cerebrospinal fluid (CSF) composition E. Elevated lumbar puncture opening pressure (≥25 cmCSF) in a properly performed lumbar puncture A diagnosis of IIH is definite if A–​E are fulfilled. The diagnosis is probable if A–​D are met, but the CSF pressure is lower than specified. Table 24.10.5.2  Causes of raised intracranial pressure Secondary causes of raised intracranial pressure Drug-​related causes of raised intracranial pressure a Venous sinus thrombosis (rarely internal jugular vein thrombosis) Fluoroquinolones and Tetracycline class antibiotics (this will save room over listing them) Anaemia Sulphonamides (e.g. trimethoprim/​nitrofurantoin) Obstructive sleep apnoea Lithium CSF Hyperproteinaemia/​Hypercellularity (e.g. spinal cord tumour/​meningitis/​Guillain Barré syndrome /​subarachnoid haemorrhage) Depo provera and combined oral contraceptive pill Renal failure Vitamin A excess and retinoids Endocrine diseases (e.g. Addison’s/​Cushing’s /​hypothyroidism) Corticosteroids (and withdrawal)/​Beclomethasome Ciclosporin a The most common drug-​related causes are listed but others have been documented in case reports. section 24  Neurological disorders 6058 Monitoring Visual monitoring is essential in active disease (Table 24.10.5.3). Imaging the fundus (e.g. colour fundus photography) is useful for longitudinal assessment. Optical coherence tomography (OCT) is increasingly being utilized to objectively monitor changes in the ret- inal nerve fibre layer. OCT must be interpreted cautiously as a reduc- tion in elevation of the retinal nerve fibre layer may indicate resolving papilloedema and/​or loss of retinal nerve fibres leading to optic atrophy. Treatment Weight loss Weight loss is the only current disease modifying therapy for IIH; however, the amount of weight loss needed is not fully elucidated. In the prospective study by Sinclair et al., weight loss (15% body weight) significantly reduced intracranial pressure and induced disease remission. Even modest weight loss of 5–​10% can improve disease. Weight loss strategies are, however, notoriously difficult to achieve and maintain, and options for long-​term weight manage- ment in IIH (such as bariatric surgery) need further evaluation. Drug treatments Pharmacological strategies aim to reduce CSF secretion and con- sequently ICP. The most frequently used is acetazolamide, a car- bonic anhydrase inhibitor. There is class 1 evidence of efficacy to use acetazolamide in the subgroup of IIH patient with mild visual loss (the dose of acetazolamide used was higher than what is used in most centres; 40% were on doses of 4 g). In these patients, a small improvement in the visual fields was noted, although there was no improvement in visual acuity or headache disability. Studies have also demonstrated that up to 48% of patients may discontinue acetazolamide due to side effects (paraesthesia, altered taste, and nausea), despite moderate doses (1.5 g daily). The 2015 Cochrane re- view concluded that there was insufficient evidence to recommend or reject the efficacy of acetazolamide for treating IIH. In reality, prescribing practices vary and many patients are managed without acetazolamide. Modified release preparations may reduce patient-​ reported side effects and doses of 1 g daily are often adequate. If acetazolamide is not tolerated, other diuretics may be pre- scribed although there is no evidence of their efficacy. Topiramate is being increasingly prescribed as it is a useful migraine prophylactic agent, but also has weak carbonic anhydrase inhibitor activity and is an appetite suppressant in about 10% of patients. However, caution is needed as there are no randomized controlled trials supporting topiramate therapy in IIH and, additionally, the side effects of cogni- tive impairment and depression limit its use. Venous stenoses Venous sinus stenoses (narrowing), predominantly in the transverse sinuses, are noted in IIH and are thought to arise as a consequence of the raised ICP. CSF drainage (through LP) with reduction in ICP has been shown to eliminate the stenoses. Consequently, the stenoses are not thought to represent an underlying cause of IIH but may ex- acerbate the condition by further impeding CSF drainage. Some spe- cialist centres documented improvement in case series of IIH patients using stenting; however, recurrent stenoses adjacent to the stent and serious complications have been highlighted (venous sinus perfor- ation, stent migration, in-​stent thrombosis, subdural haemorrhage). Further evaluation in large clinical trials is required to evaluate short-​ and long-​term efficacy before this treatment can be used routinely. Surgery Surgical options are typically reserved for patients with rapidly declining visual function (fulminant IIH). Surgical options in- clude shunting procedures (most commonly lumboperitoneal or ventriculoperitoneal shunts) or optic nerve sheath fenestration. These approaches can rapidly reduce intracranial pressure to help preserve vision acutely. However, in the longer-​term shunt dysfunc- tion is common and more than 50% of shunts need replacing; mostly in the first year after insertion (30% of patients will require multiple revisions). Low-​pressure headaches after shunt insertion are also common (28%). Patients with ventriculoperitoneal shunts, particu- larly those with adjustable valves, which enable the degree of CSF drainage to be titrated, may have a better outcome but trial evidence is lacking in this area. CSF shunting in those with raised ICP but with unaffected visual function is not recommended. Shunting, as a treatment for headache, is rare due to documented shunt complica- tions and development of secondary headaches post shunt. This may be an option for some patients in the setting of a specialist headache service. Shunting should be considered a temporary measure to save vision, but while the shunt is functioning the underlying disease still needs to be addressed, usually through weight loss. Table 24.10.5.3  Visual monitoring Visual acuity Should not be used in isolation as it is not sensitive to the type of visual loss seen in IIH. Rapidly declining acuity occurs late in the fulminant disease course with severe optic nerve ischaemia and should be urgently evaluated. Colour vision Typically evaluated with Ishihara plates and indicates optic nerve dysfunction. Pupil examination A relative afferent pupillary defect may be seen if there is asymmetrical optic nerve dysfunction. Extraocular muscles A unilateral or bilateral sixth nerve palsy maybe noted. Visual field assessment Formal automated visual field test must be performed (e.g. Humphrey or Goldmann visual field). Typical defects include enlarged blind spot, inferior nasal loss, and generalized constriction. An unreliable field may reflect poor patient technique and may improve with familiarization or changing to an alternate test such as Goldmann. If the perimetry is not in keeping with the rest of the visual assessment it should be interpreted cautiously as medically unexplained visual loss can occur. Confrontational visual fields are not sensitive and only pick up gross defects. Dilated fundus examination To document optic nerve head and macula findings, and to exclude ocular causes of disc swelling. Ideally assessed using a slit lamp (stereoscopic view). Contrast sensitivity is also a useful marker of optic nerve function. Visual evoked potentials are not useful and loss only occurs very late as optic atrophy develops. 24.10.5  Idiopathic intracranial hypertension 6059 For patients with fulminant IIH, urgent shunting is sight saving. If there is any delay to surgery, admission for a lumbar drain to lower ICP can help to preserve vision until a definitive shunting procedure is performed. Headache management For many patients, headache is the most disabling aspect of the disease and may continue for many years. The headache phenotype is often highly variable and multiple headache types can coexist (migraine, ten- sion type, and medication overuse). Patients with cerebrospinal fluid shunts may have low-​pressure headaches (due to shunt overdrainage) and cough headaches can occur (due to cerebellar tonsillar descent post lumboperitoneal shunting). There is a lack of evidence to guide treat- ment of this aspect of the condition. Identifying and treating the prin- cipal headache types is suggested. Medication overuse is common and needs to be considered and managed. Migraine prophylactic agents may benefit those with predominant migraine phenotype headache (but the drug side effects such as weight gain (pizotifen, β-​blockers, tricyclic antidepressants), depression (β-​blockers, topiramate, flunarazine), and cognitive slowing (topiramate) can be counterpro- ductive). ICP monitoring can be diagnostically helpful. Special circumstances Pregnancy IIH may develop de novo in the setting of a pregnancy. More often a patient with existing IIH becomes pregnant. Acetazolamide has terato- genic effects in animal studies; effects in patients are not extensively studied but no adverse events were noted in a case series of 50 women using acetazolamide in the first trimester. A discussion of the potential risks and benefits of acetazolamide is thus essential prior to concep- tion. In those with stable disease, omitting acetazolamide, particularly during the first trimester is a reasonable approach. Dietetic advice on the amount of weight gain to target during pregnancy is very helpful, as rapid excessive weight gain may precipitate a flare up of the IIH (5–​9 kg weight gain during the pregnancy is suggested for those with a body mass index (BMI) ≥30 kg/​m2). Normal vaginal delivery is suitable in the majority unless there is rapidly declining vision, in which case a caesarean section may be considered to avoid a prolonged second stage of labour. There is no contraindication to spinal or epidural anaesthesia in IIH. For those with rapidly declining visual function during the first trimester, serial LPs may help control the ICP and allow CSF shunting surgery to be delayed until the second trimester. Contraception IIH has been documented secondary to contraceptive use, particu- larly combined oral preparations. For most patients with established stable disease, starting contraceptives does not affect disease course. IIH without papilloedema (IIHWOP) IIH has been documented in the absence of papilloedema but is rare. In the absence of papilloedema other features suggestive of raised ICP should be sought (symptoms and imaging features). The diagnostic criteria are shown in Table 24.10.5.1. In those with borderline raised pressure, particularly in the absence of other features of raised ICP, the diagnosis of IIHWOP is much less likely. As these patients do not have and do not develop papilloedema, visual monitoring is not needed. Prognosis The course of disease in IIH is variable. In a minority, ICP will settle following a single diagnostic LP. Incipient visual loss needs to be ag- gressively managed with surgical CSF diversion. For the majority, IIH is a chronic condition with disabling headaches that need active management. Fluctuations in weight may be reflected in changes in ICP and visual function. Poor visual prognosis is associated with male patients, severe papilloedema, decreased visual acuity at pres- entation, and diagnostic delay. MRI features are not predictive of visual outcome (Fig. 24.10.5.1). FURTHER READING Ball AK, et al. (2011). A randomised controlled trial of treatment for idiopathic intracranial hypertension. J Neurology, 258, 874–​81. Lee AG, et al. (2005). The use of acetazolamide in idiopathic intra- cranial hypertension during pregnancy. Am J Ophthalmol, 139, 855–​9. Mollan SP, Davis B, Silver NC, Shaw S, Malucci C, Wakerley BR, Krishnan A, Chavda S, Ramalingam S, Edwards J, Hemmings K, Williamson M, Burdon MA, Hassan-Smith G, Digre K, Liu GT, Jensen RH, Sinclair AJ (2018). Idiopathic intracranial hypertension: consensus guidelines on management. JNNP, pii: jnnp-2017–317440. Mollan S, Ali F, Hassan-Smith G, Botfield H, Mollan S, Friedman D, Sinclair AJ (2016). Evolving evidence in adult idiopathic intracra- nial hypertension: pathophysiology and management. JNNP, 87(9), 982–92. Markey K, et al. (2016). Understanding idiopathic intracranial hyper- tension:  mechanisms, management and future directions. Lancet Neurol, 15, 78–​91. Mollan SP, et al. (2014). A practical approach to, diagnosis, assessment and management of idiopathic intracranial hypertension. Pract Neurol, 14, 380–​90. Piper RJ et al. (2015). Interventions for idiopathic intracranial hyper- tension. Cochrane Database Syst Rev, 8, CD003434. Sinclair A, et  al. (2010). Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study. BMJ, 7, 341. Sinclair AJ, et  al. (2011). Is cerebrospinal fluid shunting in idio- pathic intracranial hypertension worthwhile? A  10-​year review. Cephalalgia, 31, 1627–​33. Whiteley W, et al. (2006). CSF opening pressure: reference interval and the effect of body mass index. Neurology, 67, 1690–​1. Yri HM, Jensen RH (2015). Idiopathic intracranial hypertension: clinical nosography and field-​testing of the ICHD diagnostic cri- teria. A case-​control study. Cephalalgia, 35, 553–​62. 24.11 Infections of the central nervous system 606 24.11 Infections of the central nervous system 6060 24.11.1 Bacterial infections 6060 Diederik van de Beek and Guy E. Thwaites 24.11 Infections of the central nervous system CONTENTS 24.11.1 Bacterial infections  6060 Diederik van de Beek and Guy E. Thwaites 24.11.2 Viral infections  6082 Fiona McGill, Jeremy Farrar, Bridget Wills, Menno De Jong, David A. Warrell, and Tom Solomon 24.11.3 Intracranial abscesses  6097 Tim Lawrence and Richard S.C. Kerr 24.11.4 Neurosyphilis and neuro-​AIDS  6100 Hadi Manji 24.11.5 Human prion diseases  6109 Simon Mead and R.G. Will 24.11.1  Bacterial infections Diederik van de Beek and Guy E. Thwaites ESSENTIALS Bacterial meningitis occurs in many clinical situations, including spontaneous (the most important category), post-​traumatic, and device-​associated (relating to cerebrospinal fluid shunts and drains). Each of these is associated with a particular pattern of infecting organisms, clinical presentation, and outcome, but overall there is high morbidity and mortality. Aetiology (1) Adult spontaneous community-​acquired meningitis—​80–​85% of cases are caused by Neisseria meningitidis or Streptococcus pneumoniae in most countries, with Listeria monocytogenes, aerobic Gram-​negative bacilli (e.g. Escherichia coli), Haemophilus influenzae, and Staphylococcus aureus causing most of the others. Streptococcus suis serotype 2 is an im- portant cause in Asia. (2) Post-​traumatic meningitis—​most hospital-​ acquired infections are caused by aerobic Gram-​negative bacilli; S. pneumoniae causes most community-​acquired disease. (3) Device-​ associated meningitis—​most infections are nosocomial and caused by coagulase-​negative staphylococci or Staph. aureus. Patients with recurrent meningitis frequently have an underlying anatomical or immunological defect (particularly hypogammaglobulinaemia or complement deficiencies). In some parts of the world, HIV infection has altered the pattern of aetio- logical agents (and presentation and outcome of meningitis), with Mycobacterium tuberculosis increasingly common. Clinical features (1) Community-​acquired meningitis—​the classic triad of fever, nu- chal rigidity, and altered mental status is present in just under 50% of patients. Other manifestations include rashes (particularly with men- ingococcal disease), seizures, and focal neurological signs. Clinical tests of ‘meningeal irritation’ (e.g. Kernig’s sign, Brudzinski’s signs, and nuchal rigidity) are unreliable to rule out meningitis. Tuberculous, cryptococcal, and other fungal meningitides usually develop more slowly than pyogenic bacterial disease. (2) Post-​traumatic bacterial meningitis—​often indistinguishable clinically from spontaneous meningitis. (3)  Device-​associated meningitis—​usual presentation is insidious, with features of shunt blockage such as headache, vomiting, fever, and a decreasing level of consciousness. Investigation and treatment Speed is of the essence—​the first step in the management of acute bacterial meningitis is to obtain blood cultures and start antimicro- bial therapy and (when indicated) adjunctive dexamethasone, along with providing any necessary supportive care. In the United Kingdom, family doctors are advised to give parenteral antibiotics before trans- ferring the patient to hospital if meningococcal meningitis is suspected. Lumbar puncture—​this is the diagnostic procedure of choice if the diagnosis of bacterial meningitis cannot be ruled out, and can be safely performed without a preceding cranial CT scan to detect brain shift and evidence of herniation provided that the patient does not have any of the following: (1) signs suggesting a space-​occupying lesions—​papilloedema or focal neurological signs, excluding cranial nerve palsy, (2) new-​onset seizure, (3) moderate-​to-​severe impair- ment of consciousness, or (4) an immunocompromised state. The cerebrospinal fluid—​the opening pressure is usually raised. Frank turbidity instantly suggests the diagnosis of pyogenic meningitis. On microscopic examination the white blood cell count is typic- ally over 1000 cells/​μl, and over 100 cells/​µl in over 90% of cases, with neutrophils usually predominant, and organisms may be seen after Gram or acridine orange staining. Elevated protein and de- pressed glucose concentrations aid in distinction from viral menin- gitis. Culture of organisms has a sensitivity of about 80% in untreated 24.11.1  Bacterial infections 6061 cases, but this is much reduced in those who have been partially treated, when lumbar puncture results must be interpreted with par- ticular care when attempting to differentiate viral, tuberculous, and bacterial disease. Rapid bacterial antigen tests and tests based on the polymerase chain reaction for bacterial DNA are increasingly used. Antimicrobial therapy—​the choice of initial treatment is based on knowledge of which bacteria most commonly cause the disease, based on age and/​or clinical circumstances, and on local antimicro- bial susceptibility patterns. Adults with community-​acquired disease would typically receive initial treatment with (1) vancomycin, with (2) ceftriaxone or cefotaxime, with (if age >50 years, alcoholism, or altered immune status) (3) ampicillin, which would then be modified based on cerebrospinal fluid culture results and in vitro susceptibility testing. Dexamethasone—​this appears to be beneficial in HIV-​negative adults with confirmed bacterial meningitis, but there is no evidence for a beneficial effect in those who are HIV-​positive and not on antiretroviral drugs. Complications—​these include systemic compromise, stroke, and raised intracranial pressure. Various adjunctive therapies have been described to improve outcome in such patients, including anti-​ inflammatory agents, anticoagulants, and strategies to reduce intra- cranial pressure, but there are few randomized clinical studies with which to judge whether they are effective. Prevention The incidence of bacterial meningitis can be reduced by (1)  vaccination—​this is available against H.  influenzae type b, pneumococcal and meningococcal disease; (2) chemoprophylaxis—​ given to close adult contacts of meningococcal disease (and children of <4 years exposed to H. influenzae type b). Introduction The association of headache and tinnitus with lethal inflammation of the brain was described by Hippocrates. It was not until the 19th century that lumbar puncture was introduced as a diagnostic pro- cedure. Most important in the treatment of bacterial meningitis was the introduction of penicillin in 1940, which reduced the mortality rates of bacterial meningitis to an overall fatality rate of approxi- mately 20%. Despite advances in medical care, the introduction of cranial CT and improvements in intensive care support, the mor- tality from bacterial meningitis remains high. The global spread of multidrug-​resistant bacteria has further complicated the treatment of patients with bacterial meningitis. Aetiology, genetics, pathogenesis, and pathology Aetiology Bacterial meningitis occurs in many clinical situations, each of which is associated with a particular pattern of infecting organisms, clinical presentation, and outcome. Spontaneous meningitis is the most important category. It can be divided into neonatal menin- gitis and meningitis of childhood and adulthood. Post-​traumatic meningitis follows neurosurgery or fractures of the skull. Device-​ associated meningitis complicates the use of cerebrospinal fluid shunts and drains. Infection may also be considered as community acquired or nosocomial (hospital acquired or physician associated). The bacterial species that cause meningitis vary by geographical re- gion and according to the categories (Table 24.11.1.1). Age and local social conditions influence the attack rate and mortality of spontan- eous meningitis. Neonatal meningitis is usually caused by three species: group B streptococci (Streptococcus agalactiae), Escherichia coli, and Listeria monocytogenes. Many other organisms have been reported to cause the disease. Infection mostly occurs in the postpartum period, but can occur as late as six weeks after birth. Prolonged rupture of mem- branes and low birth weight are important risk factors. Spontaneous community-​acquired meningitis in children (under 14 years of age) is usually caused by Neisseria meningitidis or Strep. pneumoniae. The national implementation of conjugated Haemophilus influenzae type b (Hib) capsular vaccine immunization programmes by many countries during the 1990s has dramatically reduced, or almost eliminated, Hib meningitis; however, meningitis caused by H. influenzae remains common in countries that have not yet implemented a national immunization programme. In most countries, 80–​85% of cases of spontaneous community-​ acquired meningitis in adults are caused by Strep. pneumoniae and N.  meningitidis. L.  monocytogenes, aerobic Gram-​negative bacilli (such as E.  coli), H.  influenzae, and Staphylococcus aureus cause most of the remaining cases. Strep. suis (group R haemolytic streptococcus) serotype 2 is an important cause of meningitis (and rarely infective endocarditis and septicaemia) in Asia. Hong Kong, Thailand, China, and Vietnam all report Strep. suis as a major cause of adult meningitis. Post-​traumatic meningitis occurs in patients with skull or spinal injuries (i.e. skull fractures) or in those who have undergone head and neck or spinal surgery. It usually arises in association with a cerebrospinal fluid leak and soon after injury, but may occur many years after the trauma. In these patients, the risk of developing men- ingitis is as high as 25% with a clinically apparent cerebrospinal fluid leak. The aetiology depends on whether the infection is acquired nosocomially or in the community. Most hospital-​acquired infec- tions are caused by aerobic Gram-​negative bacilli, such as E. coli, Klebsiella pneumoniae, other Enterobacteriaceae, Acinetobacter spp., and Pseudomonas spp. Less commonly, Strep. pneumoniae, H. influ- enzae, Staph. aureus, and other normal upper respiratory tract flora cause meningitis in patients in hospital. Post-​traumatic meningitis acquired in the community is caused mainly by Strep. pneumoniae. Device-​associated meningitis is a well-​recognized entity occurring in patients with cerebrospinal fluid drains and shunts. Most infec- tions are nosocomial and caused by coagulase-​negative staphylo- cocci (50–​60%) and Staph. aureus (15–​30%). Aerobic Gram-​negative bacilli, streptococci, Corynebacterium spp., and Propionibacterium acnes are encountered. These infections usually present within a few months of inserting the device. Occasionally, Strep. pneumoniae, N. meningitidis, and H. influenzae are responsible. Recurrent meningitis is an unusual (5–​10% of meningitis) but well-​recognized clinical category (see Chapter 24.11.2). Such cases Acknowledgement: The authors and editors acknowledge the inclusion of material from the chapter by DA Warrell, JJ Farrar, and DWM Crook in the 4th edition of the Oxford textbook of medicine. section 24  Neurological disorders 6062 frequently have either an underlying anatomical or an underlying immunological defect. The immune deficiencies that most often predispose to recurrent meningitis are hypogammaglobulinaemia and complement deficiencies. Consideration should be given to im- munizing such patients against the most common pathogens. Genetics Adoption studies have shown that the risk of acquiring bacterial infections is strongly heritable, as is the risk of dying from an in- fection. In recent years there is a growing interest in genetic vari- ation in the host immune system related to susceptibility or severity of infection. For meningococcal diseases, a genome-​wide asso- ciation study showed single nucleotide polymorphisms (SNPs) within complement factor H (CFH) to be associated with increased susceptibility to disease. For pneumococcal meningitis, SNPs in complement factor 3 (C3) were associated with reduced suscepti- bility to meningitis. For outcome on bacterial meningitis, a SNP in complement factor 5 (C5) was associated with outcome. In these patients, cerebrospinal fluid levels of C5a and sC5b-​9 were sig- nificantly associated with outcome as well. Mice lacking the C5a receptor showed decreased disease severity, and treatment with C5-​antibodies completely prevented mortality in a treatment model of pneumococcal meningitis in mice. Bacterial meningitis is a complex disorder in which injury is caused, in part, by the causative organism and, in part, by the host’s own inflammatory response. Particular subgroups of patients with a genetic predis- position to more severe illness, potentially mediated through their innate immune response, is possible, and further work in this area may help design rationale adjunct therapy. Pathogenesis The acquisition of infection and mode of invasion of the cerebro- spinal fluid vary with the type of meningitis. However, once infec- tion is established, the inflammatory injury and pathophysiology are similar in all types of bacterial meningitis. The organisms that cause neonatal meningitis are acquired by the baby from the vagina and perineum during delivery or from the en- vironment soon after birth. The three main infecting species, Strep. agalactiae (group B streptococci), E.  coli, and L.  monocytogenes, invade the host and cause septicaemia and meningitis. An unusual feature of E. coli and many Strep. agalactiae strains (capsular types K1 and III, respectively) is that their capsules consist of polysialic acid. The association of this unusual type of capsule with two viru- lent strains suggests a role in the pathogenesis of neonatal meningitis. Causative organisms of spontaneous meningitis, Strep. pneumo- niae and N. meningitidis, are acquired by person-​to-​person spread (see Chapters 8.6.3 and 8.6.5). Nasopharyngeal colonization by bac- teria generally leads to asymptomatic carriage. Invasion of the host is particularly likely to occur early after acquisition of the organism, before the host has developed protective immunity. Carriage is suf- ficient to produce immunity and resistance to disease. The greatest risk of disease, therefore, is in the first few years of life, at a time when the non​immune host first encounters these pathogens. The precise anatomical site of invasion is not known for these patho- gens. In response to the local generation of inflammatory factors, however, as seen in the presence of viral infections, the compos- ition of surface components on target epithelial and endothelial cells changes. Binding of bacteria to up-​regulated receptors (e.g. platelet-​ activating-​factor receptors) promotes migration through the re- spiratory epithelium and vascular endothelium, resulting in invasive disease. Once the bacterium invades the bloodstream, the host can react with massive activation of inflammatory cascades. The main cascade pathways that are involved are the complement system, in- flammatory response, and coagulation and fibrinolysis pathways. These pathways do not act independently but are able to interact. Genetic polymorphisms among components of these pathways (e.g. complement deficiencies and defects in sensing or opsonophagocytic pathways) are involved in the susceptibility to infection, as well as to severity of disease and outcome. Cytokines coordinate a wide var- iety of inflammatory reactions and play an important role in the Table 24.11.1.1  Causative organisms in community-​acquired adult meningitis in the Netherlands, Malawi, and Vietnam Organism Nationwide study, the Netherlands, 2006–2014 (n = 1412) Queen Elizabeth Central Hospital, Blantyre, Malawi, 1997–​1999 (n = 351) Centre for Tropical Diseases, Ho Chi Minh City, Vietnam, 1998–​2001 (n = 500) No. % No. % No. % Streptococcus pneumoniae 1017 72 88 25 38 8 Strep. suis 7 <1 –​ –​ 65 13 Gram-​negative bacilli 13 1 22 6 11 2 Neisseria meningitidis 150 11 64 18 9 2 Streptococcus spp. 80 7 6 2 11 2 Staphylococcus aureus 21 1 –​ –​ 3 1 Listeria monocytogenes 74 5 –​ –​ –​ –​ Haemophilus influenzae 47 3 –​ –​ 7 1 Mycobacterium tuberculosis culture confirmed –​ –​ –​ –​ 46 9 Probable tuberculous meningitis –​ –​ 44 13 210 42 Other probable bacterial meningitis –​ –​ 59 17 5 1 No confirmation of bacteria –​ –​ 68 19 90 19 24.11.1  Bacterial infections 6063 initiation, maintenance, and termination of inflammatory reactions. Prominent proinflammatory cytokines include TNFα, IL-​1, and IL-​ 6. Essential parts of the inflammatory response include activation of coagulation and fibrin deposition, shifting the haemostatic balance towards thrombosis. Pathogens can enter the central nervous system (CNS) via the bloodstream and via the blood–​brain barrier, or by direct invasion through the external barrier (e.g. invade the cerebrospinal fluid dir- ectly through an anatomical defect). Shunt-​associated meningitis is caused mainly by organisms that colonize the skin and contaminate the surgical wound and prosthetic material at the time of surgery. The infected shunt becomes coated with a film of adherent bacteria, commonly referred to as a ‘biofilm’, which is not susceptible to clin- ically achievable levels of antibiotic. Such infections are usually in- curable unless the foreign material is removed. The blood–​brain barrier is formed by cerebral microvascular endothelial cells that restrict blood-​borne pathogen invasion. Cytokines stimulate cell-​surface expression of receptors, which allows binding to activated endothelial cells and invasion of bac- teria into the subarachnoid space. Physiologically, concentrations of leucocytes, antibodies, and complement components in the sub- arachnoid space are low. This condition facilitates multiplication of bacteria, which undergo autolysis under conditions such as growth to stationary phase or exposure to antibiotics. Lysis of bacteria leads to the release of immunostimulatory and/​or toxic bacterial products. Bacterial cell-​wall products (e.g. lipopolysaccharide and lipoteichoic acid), bacterial toxins (e.g. pneumolysin), and bacterial DNA induce a severe inflammatory response via binding to Toll-​like receptors (TLRs). TLRs play a key role in innate immunity by their capacity to recognize conserved molecular patterns shared by sev- eral microorganisms. Once engaged, TLRs transmit the activating signal into the cell and thereby initiate the induction of genes, such as costimulatory molecules and inflammatory cytokines. Thus far, 11 members of the TLR family have been identified in mammals. Whereas TLR2 is considered the key receptor for pneumococci and other Gram-​positive bacteria, TLR4 seems to play an important role in meningococcal and other Gram-​negative bacterial infec- tions. TLR-​mediated signalling pathways are now being elucidated. Studies in experimental pneumococcal meningitis have demon- strated that the key pathway is dependent on myeloid differenti- ation factor 88, which induces early phase activation of NF-​κB. The inflammatory cascade induces various pathophysiological al- terations, such as migration of leucocytes across the blood–​brain barrier (leading to cerebrospinal fluid pleocytosis) and increased blood–​brain barrier permeability. TNF​α and IL-​1β stimulate the expression of chemokines and adhesion molecules, which play an important role in the influx of leucocytes from the circulation to the cerebrospinal fluid. Although Fas (CD95) and Fas ligand (FasL, CD95L) have been implicated as being involved in the acute in- flammatory response by attracting neutrophils and regulating their survival, animal studies in pneumococcal meningitis have shown that they are not essential in the regulation of the acute inflamma- tory response during this disease. On stimulation with bacterial components, leucocytes release a broad range of potentially tissue-​ destructive agents that contribute to vasospasm and vasculitis, including oxidants (e.g. peroxynitrite) and proteolytic enzymes such as matrix metalloproteases. Evidence in animal studies of meningitis suggests that multiple types of programmed cell death play a central role in the complex balance among invading bacteria, the immune system, and host cells, leading to inflammation and tissue damage in infections. In addition, animal studies demon- strated that loss of ependymal cells and ciliary function expose the underlying neuronal milieu to host and bacterial cytotoxins which are likely to contribute to the neuropathology commonly observed in meningitis. The cell walls of Gram-​positive bacteria and lipo- polysaccharides of Gram-​negative bacteria cause inflammatory change, thereby increasing vascular permeability and leading to the development of cerebral oedema. The inflammatory reaction in meningitis is associated with several severe alterations in the normal physiology of the CNS (Fig. 24.11.1.1). (1)  Permeability of the blood–​brain barrier in- creases, which is best measured by the increased penetration of the cerebrospinal fluid by albumin. Also, antibiotic penetration of the cerebrospinal fluid is enhanced. (2)  Increased intracranial pres- sure results from cerebral oedema secondary to an accumulation of interstitial fluid, and communicating hydrocephalus is caused by decreased cerebrospinal fluid reabsorption and cellular swelling sec- ondary to cell injury. (3) A vasculitis may affect mainly the large ves- sels traversing the subarachnoid space. This vascular injury may not only disrupt the normal autoregulation of cerebral blood flow, but, in severe cases, the vessel may become obstructed with thrombus, causing a cerebral infarct. The major impact of increased intracra- nial pressure and vasculitis is decreased cerebral perfusion, causing general hypoxic brain injury. Pathology There is diffuse acute inflammation of the pia arachnoid, with mi- gration of neutrophil leucocytes and exudation of fibrin into the cerebrospinal fluid. Pus accumulates over the surface of the brain, especially around its base and the emerging cranial nerves, and around the spinal cord. The meningeal vessels are dilated and con- gested and may be surrounded by pus (see Fig. 24.11.1.1). Pus and fibrin are found in the ventricles and there is ventriculitis, with loss of ependymal lining and subependymal gliosis. Within the sub- arachnoid space and intraventricular system, infection may produce blockages of cerebrospinal fluid circulation, especially at the various foramina or in the aqueduct, causing obstructive hydrocephalus or spinal block. If reabsorption of cerebrospinal fluid across the sub- arachnoid granulations is prevented by a subarachnoid haematoma or empyema or thrombosis of the intracranial veins and venous sinuses, communicating hydrocephalus will result. In patients with meningitis, intracranial hypertension may be the result of cerebral oedema, the ventricular dilatation of hydrocephalus, or subdural or epidural collections of pus. Cerebrovascular complications occur in 15–​20% of patients with bacterial meningitis (see Fig. 24.11.1.1). In patients with pneumo- coccal meningitis, brain infarction is the cause of death in 14% of fatal episodes. Other abnormalities include subdural effusion or empyema, septic thrombosis of the cerebral venous sinuses, sub- arachnoid haematomas, compression of intracranial structures as a result of intracranial hypertension, and herniation of the temporal lobes or cerebellum. Gross changes, such as pressure coning, which would provide an obvious cause of death, are rarely found. In some cases death may be attributable to related septicaemia, although the familiar finding of bilateral adrenal haemorrhage (Waterhouse–​ Friederichsen syndrome) may well be a terminal phenomenon section 24  Neurological disorders 6064 rather than a cause of fatal adrenal insufficiency as was once im- agined. Patients with meningococcal septicaemia may develop acute pulmonary oedema. Myocarditis was a common finding in some series of patients. Epidemiology The attack rate of endemic meningitis caused by N. meningitidis is usually low (1–​5 cases/​105 persons per year), but occasionally the Fig. 24.11.1.1  Multiple complications in a patient with pneumococcal meningitis. (a) proton-​density T2-​weighted MRI of the brain shows a transverse view of a hyperintense signal in the basal ganglia that indicates bilateral oedema. (b) A postmortem view of the brain of the same patient shows yellowish-​coloured meninges as a result of extensive inflammation. (c) Confirmation of the bilateral infarction of the basal ganglia. The microscopic substrate in the same patient shows a meningeal artery with (d) lymphocytic infiltration in and around the vessel wall, (e) extensive subpial necrotizing cortical inflammation, and (f) oedema in the white matter. Published previously by van de Beek et al. (2006). Nature Clin Pract Neurol, 2(9), 504–​16. 24.11.1  Bacterial infections 6065 incidence of the infection may increase and even reach epidemic proportions (e.g. >300 cases/​105 persons per year). Crowding is thought to play a role in the epidemics occurring in military re- cruits, South African miners, and other groups of people crowded together in closed environments. The attack rate of N. meningiti- dis disease may increase secondarily to epidemics of influenza A. However, the precise origin of the major epidemics affecting re- gions such as sub-​Saharan Africa remains unexplained. The bac- terial capsule plays a role in determining the pattern of invasive disease caused by N. meningitidis. Meningococcal virulence is re- lated to capsule expression, expression of other surface structures, and underlying genotype. The attack rate of Strep. pneumoniae meningitis (1–​2 cases/​105 persons per year) is remarkably constant around the world. The highest attack rate of all three bacterial species is in children under 1 year of age and falls off rapidly with increasing age. The decrease in susceptibility with increasing age results from the acquisition of protective immunity, mainly as a result of nasopharyngeal car- riage. It increases in patients aged over 50 years. A high propor- tion of pneumococcal cases exhibit an associated infective focus. Otitis media or sinusitis is found in approximately 30% of cases and pneumonia in up to 25%. Hypogammaglobulinaemia (primary or secondary, e.g. in nephrotic syndrome and chronic lymphocytic leukaemia), sickle cell disease, splenic dysfunction or splenec- tomy, and previous trauma to the skull (see next) are risk factors for developing pneumococcal meningitis. Strep. suis (group R haemolytic streptococci) serotype 2 infection is related to occupational contact with pigs or pork, but the pre- cise epidemiology remains poorly understood. In the Netherlands the incidence of S.  suis meningitis among abattoir workers and pig breeders was 3/​100 000 per year. It is reported to be the most common cause of adult pyogenic meningitis in Vietnam. Possible routes of entry include skin abrasions, found in 40% of patients, and upper respiratory and gastrointestinal tracts. Splenectomized pa- tients are particularly at risk, as with other capsulated Gram-​positive organisms. Although rarely fatal, Strep. suis is commonly associated with bilateral permanent deafness. Worldwide, L. monocytogenes accounts for few cases of menin- gitis, with an attack rate of approximately 0.2 to 0.4 cases/​105 per- sons per year or 1–​5% of the cases of meningitis. Increased attack rates have been associated with contaminated foods such as un- pasteurized soft cheeses, pâté, and poorly refrigerated precooked chicken. Meningitis due to L. monocytogenes is a disease that oc- curs among immunocompromised patients (e.g. attributable to immunosuppressive therapy, immunosenescence, diabetes, or ma- lignancies) and older people. Staph. aureus causes 1–​5% of the cases of spontaneous meningitis and usually occurs in association with infective endocarditis. Spontaneous cases of H. influenzae menin- gitis, both capsulate type b and non​capsulate strains, account for up to 5% of adult cases of meningitis. Aerobic Gram-​negative (i.e. E. coli) meningitis occurs especially in aged, debilitated, and dia- betic people. The source in these infections is usually thought to be the renal tract. The increasing incidence of HIV infection has altered the presen- tation and pattern of aetiological agents causing meningitis. A large series of adult patients with meningitis who presented to the Queen Elizabeth Central Hospital in Blantyre, Malawi, was reported in 1975. At that time, meningitis comprised 2.5% of medical admissions, the most common pathogens being N. meningitidis and Strep. pneumo- niae. Since then, the population of Malawi has been severely affected by the AIDS pandemic, and the HIV seroprevalence of antenatal women has climbed steadily through the 1980s to the present level of more than 30%. The changed overall pattern in this series is prob- ably due to the influence of HIV infection; in a survey of 153 pa- tients with invasive pneumococcal disease, HIV seroprevalence was 95%. In South Africa, HIV-​infected children have more antibiotic-​ resistant isolates and a different clinical presentation compared with HIV-​uninfected children. In adults, the HIV epidemic was found to be responsible for increasing chronic infections such as tuberculous and cryptococcal meningitides. The roll out of antiretroviral therapy is expected to modify this considerably. Another epidemiological trend is emerging of antibiotic-​resistant strains of Strep. pneumoniae. Pneumococci resistance to penicillin, due to changes in its penicillin-​binding proteins, was first reported in 1965. The prevalence of such resistance was limited until an epi- demic of highly resistant pneumococci occurred in South Africa in 1977. Since then, resistance has developed worldwide and in some regions it occurs in a frequency up to 70%. Reports of reduced sus- ceptibility of pneumococci to several antibiotics, including broad-​ spectrum cephalosporins, have also been published. In response to this epidemiological trend, recommendations for suspected and confirmed bacterial meningitis have necessarily evolved. Prevention Immunization Vaccines to the three major pathogens causing community-​acquired meningitis are available. H.  influenzae type b capsular conjugate (Hib) vaccines are now routinely given in the developed world and there has been a dramatic reduction in the incidence of H. influenzae type b meningitis in these countries and invasive disease has been essentially eliminated (see Chapter 8.6.13). However, it remains an important cause of meningitis in mostof the world where vaccine programmes have not been implemented. Current pneumococcal vaccines elicit immune responses to cell-​ wall polysaccharides of pneumococci (Chapter 8.6.3). The current 23-​valent pneumococcal polysaccharide vaccine contains capsular polysaccharides of 23 serotypes responsible for about 90% of inva- sive pneumococcal infections. In the United States of America, the vaccine is recommended for all people aged 65 years and older and for those aged between 2 and 64 years who are at increased risk for invasive pneumococcal disease because of underlying illnesses, such as asplenia or immunodeficiency (e.g. infection with HIV or use of immunosuppressive drugs), or renal failure. However, the vaccine is poorly immunogenic in certain groups at high risk for invasive pneumococcal infection, especially children younger than 2 years old (with relatively immature B cells), older people, and immuno- compromised patients. The immune response in infants and young children can be improved by conjugation of pneumococcal polysac- charides to carrier proteins that enable activation of T cells, thereby enhancing antibody production and immunological memory. The pneumococcal conjugate vaccines (PCV) consists of seven, ten, or thirteen capsular polysaccharides that are among the most prevalent in children aged 6 months to 2 years, include most antibiotic-​resistant types, and are highly represented in section 24  Neurological disorders 6066 immunocompromised and older patients. In the United States of America, the use of four doses of PCV is recommended for all children aged 23 months and younger and those aged 24–​ 59 months with chronic illnesses, including sickle cell disease, immunocompromising conditions, and cochlear implants. The introduction of PCV in the United States of America has reduced the burden of invasive pneumococcal disease in children as well as in older age groups through herd immunity. As a consequence, bacterial meningitis has become a disease predominantly of adults rather than of infants and children. Routine vaccination with PCV7 initially decreased the amount of multidrug-​resistant pneumococcal strains, but this effect was only temporary. A decline in the incidence of pneumococcal meningitis has been observed in other studies that did not show evidence of an emergence of disease caused by serotype replacement. However, multiple other studies did observe an emergence of all invasive pneumococcal disease caused by serotypes not in the heptavalent vaccine, emphasizing the need for continued surveillance and the development of vaccines with efficacy against these other serotypes; 10-​valent and 13-​valent vaccines have been developed and may prove efficacious against these emerging serotypes. Patients with anatomical defects leading to an increased risk of invasive pneumo- coccal disease (i.e. previous trauma to the skull) may be at risk of unusual pneumococcal serotypes not commonly associated with invasive disease. In the developing world, invasive pneumococcal disease (including meningitis) remains a leading cause of morbidity and mortality. Since 1905, major epidemics of meningococcal meningitis have occurred in sub-​Saharan Africa every few years (see Chapter 8.6.5). For epidemic meningitis control in sub-​Saharan Africa, the World Health Organization recommends a strategy of emergency im- munization with meningococcal A/​C polysaccharide vaccine when epidemic thresholds are exceeded. Given the relatively poor routine immunization coverage in this region, current strategies of immunization campaigns that achieve higher coverage would generally be more effective and less costly than model routine-​ scheduled programmes, assuming that campaigns can be rapidly implemented. Routine vaccination also offers herd immunity for the un- vaccinated population. The most illustrative example of such a major impact is the introduction of meningococcal conjugate vaccines. Vaccination against serogroup A  in Africa and sero- group C in Europe have decreased its incidence by 95% or more. More recently, a four-​component, recombinant, meningococcal serogroup B vaccine was shown to be immunogenic and safe in two randomized controlled trials testing infants and children. Implementation of this vaccine may further decrease invasive meningococcal disease, but decreasing rates of penicillin suscep- tibility and the possible resurgence of the disease remain a public health threat. Immunization should be considered in all patients with recur- rent meningitis or traumatic head injury, and in splenectomized patients. Chemoprophylaxis The attack rate of meningitis is higher in the immediate contacts of an index case of meningococcal (up to 1000-​fold) or H. influenzae type b meningitis (500-​fold only in children under 4 years of age) than in the population at large. The administration of rifampicin or ciprofloxacin eliminates the carrier state and is assumed to eliminate the risk of secondary cases of meningitis (see Table 24.11.1.3). Close adult contacts of meningococcal disease are given either rifampicin (300 mg every 12 h for 2 days) or a single oral dose of ciprofloxacin (750 mg). Doctors, nurses, and other healthcare workers need not be given chemoprophylaxis unless they have given mouth-​to-​mouth resuscitation. There is no evidence of benefit of antibiotics administered prophylactically to patients with skull fractures and/​or cerebro- spinal fluid leakage. Surgical closure of the leak is the only effective means of preventing meningitis in such cases. The prevention of device-​associated meningitis relies on rigorous infection con- trol. Ventricular and lumbar drains should be removed as soon as possible. Shunt insertion should be performed while adhering to strict aseptic techniques, and surgical antibiotic prophylaxis may also help to reduce shunt infection. Clinical features Community-​acquired bacterial meningitis Early diagnosis and rapid initiation of appropriate therapy are vital in the treatment of patients with bacterial meningitis. A re- cent study provided a systematic assessment of the sequence and development of early symptoms in children and adolescents with meningococcal disease (encompassing the spectrum of disease from sepsis to meningitis) before admission to the hospital. Classic symptoms of rash, meningismus, and impaired consciousness de- velop late in the prehospital illness, if at all. Early signs before ad- mission in adolescents with meningococcal disease were leg pain and cold hands and feet. Bacterial meningitis is often considered but may be difficult to recognize. The clinical presentation of a patient with bacterial men- ingitis may vary depending on age, underlying conditions, and se- verity of illness. Clinical findings of meningitis in young children are often minimal. In childhood bacterial meningitis, and in older patients, classic symptoms such as headache, fever, nuchal rigidity, and altered mental status may be less common than in younger and middle-​aged adults. Infants may become irritable or lethargic or stop feeding, and are found to have a bulging fontanelle, separation of the cranial sutures, meningism, and opisthotonos, and they may develop convulsions. These findings are uncommon in neonates, who sometimes present with respiratory distress, diarrhoea, or jaundice. In a prospective study of adults with bacterial meningitis, the classic triad of signs and symptoms consisting of fever, nuchal rigidity, and altered mental status was present in only 44% of the patients. Certain clinical features may predict the bacterial cause of meningitis. Predisposing conditions such as ear or sinus infec- tions, pneumonia, immunocompromise, and dural fistulae are estimated to be present in 68–​92% of adults with pneumococcal meningitis. Rashes occur more frequently in patients with menin- gococcal meningitis, with reported sensitivities of 63–​80% and with specificities of 83–​92%. Rash is occasionally seen in patients with echovirus type 9, leptospirosis, Staph. aureus, Strep. pneu- moniae, Strep. suis, H.  influenzae, Salmonella enterica Serovar Typhi, and other infections, especially in those associated with 24.11.1  Bacterial infections 6067 infective endocarditis. The brownish or reddish geometrical, vasculitic rash of fulminant meningococcaemia is unmistak- able and, characteristically, the toes and fingers become necrotic (Fig. 24.11.1.2). Seizures before admission occur in 5–​9% of all cases, and 15–​23% of patients develop seizures during their clinical course. Cranial nerve palsy is relatively rare; most commonly affected are cranial nerves VIII (6%), III (4%), IV (3%), and VII (2%). Focal cerebral findings (aphasia, hemiparesis, and monoparesis) on admission occur in approximately 15–​23% of patients. Papilloedema is un- common in patients with acute bacterial meningitis (3–​4% of patients; however, in most studies the results of fundoscopic exam- ination were not recorded). Systemic manifestations, such as hypo- tension and tachycardia, occur frequently in community-​acquired bacterial meningitis. Bilateral sensorineural deafness develops early, two to nine days after the start of symptoms, in most patients with Strep. suis type 2 meningitis. Initially associated with tinnitus this may progress to complete deafness within 24 h. Bacteria probably invade the cochlea via the cochlear aqueduct from the subarachnoid space to produce suppurative labyrinthitis and acute deafness. Associated clinical fea- tures of Strep. suis meningitis include III nerve palsy, septic arth- ritis, and purpuric skin lesions. Arthritis occurs in 7% of adults with bacterial meningitis, most commonly in meningococcal meningitis, but is also seen in 5% of patients with Strep. suis. Recognition of con- current arthritis is important because prolonged antibiotic therapy is necessary. The presence or absence of meningeal signs such as Kernig’s sign, Brudzinski’s signs, and nuchal rigidity are physical examination findings often documented when evaluating a patient for possible meningitis. Kernig’s sign was first described in the 1880s and was originally done with the patient in the sitting position, but today is frequently done in the supine position. This test involves flexing the hip and extending the knee and a positive result is recorded when pain is elicited in the back and legs. Brudzinski’s neck sign is typically done in the supine position where the head is passively flexed and is interpreted as positive when flexion at the hips to lift the legs is elicited in response. Nuchal rigidity is a clinical determination of severe neck stiffness and inability to passively flex and extend the head in a normal fashion. Local causes of neck stiffness, such as local sepsis (i.e. in the nuchal muscles or cervical lymph nodes), cervical spondylitis (particularly common in older people), temporoman- dibular arthritis, dental problems, and pharyngeal lesions, should be considered. A prospective study of 297 adults evaluated Kernig’s sign, Brudzinski’s sign, and nuchal rigidity and their relationship to men- ingitis diagnosed by lumbar puncture. This study found that none of these signs accurately identified patients with meningitis. There was no correlation with moderate meningeal inflammation or with microbial evidence of infection (such as positive Gram stain or posi- tive cultures), and Kernig’s and Brudzinski’s signs were found to have poor sensitivity (5%) with high specificity (95%). In this study population, 80 of 297 patients had meningitis, but only 24 had nu- chal rigidity (sensitivity, 30%). Nuchal rigidity was absent in 148 of the 217 patients without meningitis (specificity, 68%). Notably, only 3 of the 297 patients had bacterial meningitis by cerebro- spinal fluid culture, and nuchal rigidity failed to identify 2 of these 3 patients with bacterial meningitis. Post-​traumatic bacterial meningitis This is often indistinguishable clinically from spontaneous men- ingitis. However, in obtunded or unconscious patients who have suffered a recent or previous head injury, few clinical signs may be present. A fever and deterioration in the level of consciousness or loss of vital functions may be the only signs of meningitis. Finding a cerebrospinal fluid leak adds support to the possibility of meningitis in such patients, but this is undetectable in most cases. The range of bacteria causing meningitis in these patients is broad and con- sideration should be given to broad-​spectrum antibiotics including metronidazole for anaerobic pathogens. Fig. 24.11.1.2  Rashes in a patient with meningococcal meningitis. section 24  Neurological disorders 6068 Infections of cerebrospinal fluid shunts Patients may present with clinical features typical of spontan- eous meningitis, especially if virulent organisms are involved. The more usual presentation is insidious, with features of shunt blockage such as headache, vomiting, fever, and a decreasing level of consciousness. Fever is a helpful sign, but is not a con- stant feature and may be present in as few as 20% of cases. Shunts can be infected without causing meningitis, in which event the features of the infection will be determined by where the shunt drains. Infection of shunts draining into the venous system produces a disease similar to chronic right-​sided infective endo- carditis together with glomerulonephritis (shunt nephritis), whereas infection of shunts draining into the peritoneal cavity produces peritonitis. Differential diagnosis When a patient presents to an emergency department physician, primary care doctor, neurologist, or infectious disease specialist for an emergent evaluation, the patient history can help to estimate the probability of meningitis. A wide variety of patient complaints may be elicited from patients with meningitis, and a meta-​analysis that included 845 patients over a 30-​year period showed poor sen- sitivity and specificity for symptoms such as headache, nausea, and vomiting for the diagnosis of meningitis. This is not surprising since such non​specific symptoms are found in many patients with a wide variety of clinical conditions. Viral meningitis is important in the differential diagnosis. Meningeal irritation is seen in many acute febrile conditions, especially in children. Local infections of the nasopharynx, cervical lymph nodes, muscles, and spine may produce convincing neck stiffness. Tetanus may be easily confused with meningitis if the persisting rigidity and recurrent spasms go unnoticed. In all these conditions the cerebrospinal fluid will be normal. Subarachnoid haemorrhage can present with sudden headache, neck stiffness, and deteriorating consciousness, and a less dramatic progression of symptoms is seen in patients with some intracranial tumours. Tuberculous and cryptococcal and other fungal meningitides usually develop more slowly than pyogenic bacterial menin- gitis. They may be distinguished by examining cerebrospinal fluid. Cryptococci and free-​living amoebae may be mistaken for lymphocytes in the cerebrospinal fluid unless an India-​ink preparation is examined to reveal the cryptococcal capsule and the characteristic movements of amoebae. Aseptic meningitis comprises many conditions, many of them caused by viruses, in which there are clinical signs of meningism and the cerebrospinal fluid is found to be abnormal (see Chapter 24.11.2). This group includes partially treated bacterial meningitis and the chemical meningitides, resulting from the introduction of irritants into the subarachnoid space (contrast media, antimicrobial agents, and contaminants of lumbar puncture and spinal anaesthesia). The cerebrospinal fluid glucose concentration may be very low. Discharge of a tuberculoma may produce a sterile tuberculin reac- tion, and the discharge of the contents of a craniopharyngioma or epidermoid cyst into the cerebrospinal fluid can also cause chem- ical meningitis. Clinical investigations Lumbar puncture Once an initial patient evaluation has been completed with history and physical findings, lumbar puncture is the diagnostic procedure of choice if the diagnosis of bacterial meningitis cannot be ruled out. Characteristic findings in the cerebrospinal fluid are typically used to make the diagnosis of meningitis. Indications for CT scan before lumbar puncture In view of the urgent nature of this testing to make the diagnosis of meningitis, one of the issues that physicians are faced with in the hospital emergency department is whether neuroimaging—​either CT or MRI—​is required before lumbar puncture. Patients with ex- panding masses (e.g. subdural empyema, brain abscess, or necrotic temporal lobe in herpes simplex virus encephalitis) may present with symptoms that appear to be identical with those of bacterial meningitis. In these patients, lumbar puncture may be complicated by brain herniation. The withdrawal of cerebrospinal fluid reduces counterpressure from below, thereby adding to the effect of com- pression from above, increasing the brain shift that may already be present. In patients with suspected bacterial meningitis the inter- pretation of cranial imaging should be focused on brain shift and space around the brainstem, which may result from the pressure effects of a focal space-​occupying lesion or severe diffuse brain swelling as illustrated in Fig. 24.11.1.3. Recommendations for cranial CT and fears of herniation are based on the observed clinical deterioration of a few patients in the several to many hours after lumbar puncture and the perceived tem- poral relationship of lumbar puncture and herniation, but as pre- viously mentioned proving a cause-​and-​effect association is very difficult based on the available data. Therefore, it is reasonable to proceed with lumbar puncture without a CT scan if the patient does not meet any of the following criteria: patients who have new-​onset seizures, an immunocompromised state, signs suggestive of space-​ occupying lesions (papilloedema or focal neurological signs—​not including cranial nerve palsy), or moderate-​to-​severe impairment of consciousness. Other contraindications to lumbar puncture in- clude local skin sepsis at the site of puncture, a clinically unstable pa- tient, and any clinical suspicion of spinal cord compression. Lumbar puncture may also be harmful in patients with coagulopathy, be- cause of the chance of needle-​induced subarachnoid haemorrhage or of the development of spinal subdural and epidural haematomas. Contraindications for (immediate) lumbar puncture are provided in Box 24.11.1.1. Examination of cerebrospinal fluid (See Chapter 24.3.1.) In patients with bacterial meningitis, the cerebrospinal fluid opening pressure is usually raised (>200 mmCSF), and occasionally it is markedly raised (>500 mmCSF). Frank turbidity of cerebro- spinal fluid instantly suggests the diagnosis of pyogenic meningitis. Microscopic examination of cerebrospinal fluid for white cells, red cells, and organisms, the measurement of glucose and protein, and culture are important investigations in a case of possible menin- gitis. Classically described, the white blood cell count in bacterial meningitis is typically greater than 1000 cells/​μl, although in viral 24.11.1  Bacterial infections 6069 meningitis it is less than 300 cells/​μl—​although considerable overlap exists in these categories. The neutrophil count is typically elevated in bacterial meningitis compared with viral meningitis. A raised cerebrospinal fluid white blood cell (WBC) count is pre- sent in most patients with bacterial meningitis but, rarely, the count may be normal (fewer than 6 WBC/​µl, all lymphocytes) but the cerebrospinal fluid may still appear turbid because of the vast num- bers of bacteria. Most cases (more than 90%) present with a count exceeding 100 WBC/​µl. The measurement of protein and glucose is an important aspect of cerebrospinal fluid analysis to comple- ment the cell counts because abnormal protein and glucose levels are typically found in bacterial disease but are relatively normal in many cases of viral meningitis. Gram or acridine orange stain of cerebrospinal fluid samples, although having reported sensitivities of only 50–​90% can certainly help to make the diagnosis of bac- terial disease with a specificity approaching 100%. Care should be taken in assessment of the cerebrospinal fluid in patients who have been partially treated with antibiotics before being seen. In this case the cerebrospinal fluid may be very difficult to interpret and the cerebrospinal fluid from partially treated pyogenic meningitis and tuberculosis (TB) meningitis can be extremely difficult. An algo- rithm based on readily available clinical and laboratory tests can be useful in deciding whether the patient has pyogenic meningitis or TB meningitis. Culture of organisms has a sensitivity of approximately 80% in untreated cases, and is aided by the culture of good volumes of cerebrospinal fluid and minimizing the delay between the lumbar puncture and setting up of the culture. Organisms are recovered much less often from partially treated cases. Isolation of an or- ganism is not only helpful in establishing the diagnosis, but al- lows the identification and susceptibility testing of the aetiological agent. The culture result can also be used to decide on the need for antibiotic prophylaxis, contact tracing, and other public health control measures. A range of rapid bacterial antigen tests may be helpful in detect­ ing the presence of bacterial capsular polysaccharide antigens of pneumococci, meningococci, H. influenzae, and group B strepto- cocci. These tests may reach a sensitivity and specificity of 90% or greater for detecting specific causes of bacterial meningitis. However, in our experience these tests seldom add to the diagnostic yield of a good Gram or acridine orange stain performed on an ad- equate volume of cerebrospinal fluid. New molecular techniques for detecting bacteria in the cerebrospinal fluid by polymerase chain re- action (PCR) methods have emerged as powerful tools in the diag- nosis of patients with negative cultures of cerebrospinal fluid; such tools have high sensitivity and specificity. Recurrent bacterial meningitis (See Chapter 24.11.2.) In patients with no apparent cause of recurrent meningitis or known history of head trauma, the high prevalence of remote head injury and cerebrospinal fluid leakage justifies an active search for anatomical defects and cerebrospinal fluid leakage in a patient with recurrent bacterial meningitis. Detection of β2-​transferrin in nasal (a) (b) (c) Fig. 24.11.1.3  Cranial imaging to evaluate potential contraindications for lumbar puncture should be focused on identifying signs of a focal space-​occupying lesion, evidence of brain shift, and/​or signs of severe diffuse brain swelling. (a) Normal brain, (b) meningitis-​associated cerebral infarct causing pronounced brain shift, and (c) diffuse brain swelling associated with severe infection. Initial lumbar puncture should not be done when CT findings of significant brain shift are found, and empirical therapy for meningitis should be continued in such patients. Reprinted from Fitch and van de Beek (2007). Lancet Infect Dis, 7(3), 191–​200, Copyright 2007, with permission from Elsevier. Box 24.11.1.1  Contraindications for immediate lumbar puncture Neuroimaging before lumbar puncture to detect brain shift • Signs of brain shift — Papilloedema — Focal neurological signs, not including cranial nerve palsy • Glasgow Coma Score less than 10 • Severe immunocompromised state • New-​onset seizures Other contraindications for lumbar puncture • Serious skin infection at site lumbar puncture • Septic shock • Spinal cord compression • Anticoagulant therapy or severe coagulopathy section 24  Neurological disorders 6070 discharge in cases of rhinorrhoea is a sensitive and specific method to confirm the presence of a cerebrospinal fluid leak. Optimum imaging is done by thin-​slice CT of the skull base and is also the ini- tial imaging of choice. It is important to take into account that small bone defects on CT do not prove cerebrospinal fluid leakage. T2-​ weighted MRI may detect a small cerebrospinal fluid leak, but lacks fine bone detail. As cerebrospinal fluid leaks are often intermittent, the administration of intrathecal contrast will not be more accurate to prove leakage and depends on the timing of imaging. Anatomical defects and cerebrospinal fluid leakage might require consultation of a neurosurgeon or otolaryngologist to evaluate the necessity of surgical repair, which has an overall high success rate and a low mor- tality and morbidity. Emergency management Management algorithm Although some guidelines propose an arbitrary time-​based goal for antibiotic administration, others focus on disease severity and immediate antibiotic administration once the diagnosis has been considered. No prospective clinical data have determined the rela- tionship between the timing of antimicrobial treatment and clinical outcome in patients with bacterial meningitis. However, delayed treatment is associated with a bad outcome. A retrospective study in adults with acute bacterial meningitis showed that delayed antibiotic treatment (resulting from cranial imaging or hospital transfer) con- tributed significantly to mortality. Another retrospective study of adults with community-​acquired bacterial meningitis also identi- fied delay in treatment with adverse outcome in patients who had deteriorated to the highest stage of prognostic severity before the first dose of antibiotics was administered. A recent prospective study of patients with pneumococcal meningitis who were admitted to the intensive care unit showed that a delay of more than 3 h between hospital admission and initiation of antimicrobial therapy was as- sociated with an increased 3-​month mortality. In patients with sus- pected bacterial meningitis whose lumbar puncture is postponed because of coagulopathy (e.g. disseminated intravascular coagu- lation), severe septic shock, or the need for cranial imaging (see Box 24.11.1.1), antimicrobial therapy should be started immedi- ately (Fig. 24.11.1.4). In those who deteriorate clinically or who have cloudy cerebrospinal fluid (suggestive of bacterial meningitis), antibiotic treatment should be started directly after lumbar puncture whereas in those who are clinically stable and whose cerebrospinal fluid is not cloudy treatment can be delayed until cerebrospinal fluid analysis confirms the diagnosis. In the United Kingdom, family doctors are advised to give (paren- teral) antibiotics before transferring the patient to hospital if men- ingococcal meningitis is suspected. However, it may be difficult to identify patients with meningococcal meningitis and to determine whether they will benefit from such prehospital treatment. Several retrospective studies have shown conflicting results. Some patients with bacterial meningitis are unconscious and should be managed accordingly. Their airway should be maintained and they may need intubation to protect the airway and maintain ventilation. Monitoring in a neurological–​neurosurgical intensive care unit is recommended in order to recognize changes in level of consciousness and the development of new neurological signs, monitor for subtle seizures, and effectively treat severe agitation. A urethral catheter should be inserted. Bacterial meningitis may be associated with septic shock, which is an important predictor of outcome. Patients with meningitis and septic shock may require insertion of a Swan–​Ganz catheter, to measure cardiac output, the cardiac index, systemic vascular resist- ance, and pulmonary wedge pressures in order to assess intravas- cular volume and cardiac function. Care should be taken to estimate and replace imperceptible fluid loss through the skin and lungs in patients who are febrile. Patients with bacterial meningitis are at risk of acute hyponatraemia, although most cases are mild. This may result from cerebral salt wasting, the syndrome of inappropriate antidiuretic hormone secretion, or ex- acerbation by aggressive fluid resuscitation. Uncertainty about the mechanism creates a clinical dilemma about whether intravenous fluids should be restricted in bacterial meningitis. In children with bacterial meningitis, fluid restriction does not improve either brain oedema or outcome. It seems reasonable to maintain adult patients with meningitis in a normovolaemic state. Patients whose core tem- peratures exceed 40°C should be cooled using physical methods or an antipyretic to avoid brain damage and excessive fluid loss through sweating. Antipyretic treatments are often administered in severely ill patients, but randomized controlled trials (RCTs) of 723 children with bacterial meningitis in Luanda, Angola, and 360 children in Malawi, showed that paracetamol did not increase survival. Case series reported favourable effects of moderate hypothermia in bac- terial meningitis, but one RCT showed that moderate hypothermia did not improve outcome in patients with severe meningitis, and even suggested harm. Antimicrobial treatment The choice of initial antimicrobial therapy is based on which bac- teria most commonly cause the disease, based on age, clinical cir- cumstances, and prevailing antimicrobial susceptibility patterns (Table 24.11.1.2). Once the pathogen has been isolated, specific treatment based on the susceptibility of the isolate can be substi- tuted for the empirical regimen (Table 24.11.1.3). The pharmacokinetics and pharmacodynamics dynamics of anti- microbial agents are highly relevant. Penetration of the blood–​brain barrier to reach the subarachnoid space is of paramount import- ance in clearing bacteria from the cerebrospinal fluid. Penetration is affected by lipophilicity, molecular weight, structure, and protein-​ bound fraction. Bacterial meningitis is a dynamic process and cerebrospinal fluid penetration of antimicrobials is highly de- pendent on the breakdown of blood–​brain barrier permeability. Anti-​inflammatory drugs such as dexamethasone might influence permeability and thereby interfere with cerebrospinal fluid pene- tration of antimicrobial agents. The activity of antimicrobial drugs in infected purulent cere- brospinal fluid depends on their activity in a low pH environment, protein-​bound fraction, bacterial growth rate and density, and clear- ance from the cerebrospinal fluid. Antibiotics target the bacterial cell wall, the bacterial cell membrane, and biosynthetic processes. Bacteriostatic antibiotics merely inhibit growth of microorganisms, whereas bactericidal agents kill the bacteria. Antibiotic-​induced lysis of bacteria leads to the release of immunostimulatory cell-​wall components and toxic bacterial products, which induce a severe inflammatory response through binding to TLRs. 24.11.1  Bacterial infections 6071 NO NO Assess severity Ventilation Circulation Neurologic examination Stabilization and/or correction coagulopathy Indications for imaging before lumbar puncture? CSF consistent with bacterial meningitis? CSF consistent with bacterial meningitis? Bacterial meningitis Bacterial meningitis: DXM and empiric therapy DXM and empiric antimicrobial therapy DXM and empiric antimicrobial therapy Cloudy CSF or apparent progress of disease? Shock and/or Coagulopathy? Anticoagulant-use Disseminated intravascular coagulation DXM and empiric antimicrobial therapy Start investigations Blood cultures Blood gases Serum laboratory investigations Chest X-ray Rash: skin biopsy NO Lumbar puncture Indications for imaging before lumbar puncture? Lumbar puncture No lumbar puncture CT/MRI scan brain Significant space- occupying lesion? Reconsider diagnosis Suspicion for bacterial meningitis Typical signs may be absent, prior antibiotics may mask severity of illness YES YES YES YES YES NO YES NO NO NO YES Fig. 24.11.1.4  Algorithm for the management of patients with suspected community-​acquired bacterial meningitis. CSF, cerebrospinal fluid. This material was previously published as part of an online supplementary appendix to van de Beek, et al. (2006). N Engl J Med, 354(1), 44–​53. Copyright 2006 Massachusetts Medical Society. All rights reserved. section 24  Neurological disorders 6072 Neonatal meningitis This is largely caused by group B streptococci, E.  coli, and L.  monocytogenes. Initial treatment should, therefore, consist of penicillin or ampicillin plus a third-​generation cephalosporin, pref- erably cefotaxime or ceftriaxone, or penicillin, or ampicillin and an aminoglycoside. Childhood meningitis In the community, children are at risk of meningitis caused by N.  meningitidis and Strep. pneumoniae, and, rarely in Hib-​ immunized children, H.  influenzae. Antimicrobial resistance has emerged among the three major bacterial pathogens causing meningitis. Although intermediate penicillin resistance is common in some countries, the clinical importance of penicillin resistance in the meningococcus has yet to be established. Adult meningitis Spontaneous meningitis in adults is usually caused by Strep. pneumo- niae or N. meningitidis. Due to the worldwide emerge of multidrug-​ resistant strains of Strep. pneumoniae, some experts recommend addition of vancomycin to the initial empirical antimicrobial regimen in adult patients. Although no clinical data on the efficacy of rifampicin in patients with pneumococcal meningitis are currently available, some experts would recommend the use of this agent in combin- ation with a third-​generation cephalosporin, with or without vanco- mycin, in patients with pneumococcal meningitis caused by bacterial strains that, on the basis of local epidemiology, are likely to be highly resistant to penicillin or cephalosporin. Strep. suis remains sensitive to the β-​lactams and should be treated with penicillin, cefotaxime, or ceftriaxone. Fluoroquinolones may be an alternative. In patients aged over 50 years, ampicillin should be added to the aforementioned anti- biotic regimen for additional coverage of L. monocytogenes, which is more prevalent among this age group. Nosocomial post-​traumatic meningitis This is caused mainly by multiresistant hospital-​acquired organ- isms such as K.  pneumoniae, E.  coli, P.  aeruginosa, and Staph. aureus. Depending on the pattern of susceptibility in a given hos- pital unit, ceftazidime (2 g intravenously, every 8 h), cefotaxime, ceftriaxone, or meropenem should be chosen. If P. aeruginosa in- fection seems likely, ceftazidime or meropenem are the preferred antibiotics. Device-​ and shunt-​associated meningitis This is caused by a wide range of organisms, including meticillin-​ resistant staphylococci (mostly coagulase-​negative staphylococci) and multiresistant aerobic bacilli. Cases with shunts and an insidious onset are probably caused by organisms of low pathogenicity, and empirical therapy is a less urgent requirement. For postoperative meningitis the first-​line empirical therapy should be cefotaxime, ceftriaxone, or meropenem. If the patient has received broad-​ spectrum antibiotics recently or if P.  aeruginosa is suspected, ceftazidime or meropenem should be given. Meropenem should be used if an extended-​spectrum, β-​lactamase organism is sus- pected, and flucloxacillin or vancomycin if Staph. aureus is likely. The infected shunt or drain will almost certainly have to be removed urgently. Definitive antibiotic treatment Once the aetiological agent has been isolated and its suscepti- bilities determined, the empirical treatment should be changed, if necessary, to an agent or agents specific for the isolate (see Table 24.11.1.3). The optimal duration of treatment has not been determined by rigorous scientific investigation; however, treat- ment regimens that are probably substantially in excess of the min- imum necessary to achieve cure have been arrived at through wide clinical experience. Table 24.11.1.2  Recommendations for empirical antimicrobial therapy in suspected community-​acquired bacterial meningitis Predisposing factor Common bacterial pathogens Initial intravenous antibiotic therapy Age <1 month Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes Ampicillin plus cefotaxime or an aminoglycoside 1–​3 months Strep. pneumoniae, Neisseria meningitidis, Strep. agalactiae, Haemophilus influenzae, E. coli, L. monocytogenes Ampicillin plus vancomycin plus ceftriaxone or cefotaximea 3–​23 months Strep. pneumoniae, N. meningitidis, Strep. agalactiae, H. influenzae, E. coli Vancomycin plus ceftriaxone or cefotaximea 2–​50 years N. meningitidis, Strep. pneumoniae Vancomycin plus ceftriaxone or cefotaximea 50 years N. meningitidis, Strep. pneumoniae, L. monocytogenes, aerobic Gram-​negative bacilli Vancomycin plus ceftriaxone or cefotaxime plus ampicillinb With risk factor presentc Strep. pneumoniae, L. monocytogenes, H. influenza Vancomycin plus ceftriaxone or cefotaxime plus ampicillin Post-​traumatic Strep. pneumoniae, H. influenzae Vancomycin plus ceftriaxone or cefotaxime plus ampicillin Postneurosurgery Coagulase-​negative staphylococci, Staph. aureus, aerobic Gram-​negative bacilli (including Pseudomonas aeruginosa) Vancomycin plus ceftazidime Cerebrospinal fluid shunt Coagulase-​negative staphylococci, Staph. aureus, aerobic Gram-​negative bacilli (including P. aeruginosa), Propionibacterium acnes Vancomycin plus ceftazidime General recommendations for intravenous empirical antibiotic treatment have included penicillin 2 MU every 4 h; amoxicillin or ampicillin 2 g every 4 h; vancomycin, 15 mg/​kg every 8 h; third-​generation cephalosporin: ceftriaxone 2 g every 12 h or cefotaxime 2 g every 4–​6 h; ceftazidime 2 g every 8 h. a In areas with very low penicillin resistance rates monotherapy, penicillin may be considered. b In areas with very low rates of penicillin resistance and cephalosporin resistance, combination therapy of amoxicillin and third-​generation cephalosporin may be considered. c Alcoholism, altered immune status. Adapted from van de Beek D, et al. (2006). N Engl J Med, 354(1), 44–​53. Copyright 2006 Massachusetts Medical Society. All rights reserved. 24.11.1  Bacterial infections 6073 General recommendations for empirical antibiotic treatment have included ceftriaxone administered intravenously every 12 h or intravenous cefotaxime every 4 to 6 h, and/​or ampicillin at 4-​h intervals, or benzylpenicillin every 4 h. There are no randomized comparative clinical studies of the various dosing regimens. In gen- eral, 7 days of antimicrobial therapy are given for meningitis caused by N. meningitidis and H. influenzae, 10–​14 days for Strep. pneu- moniae or Strep. suis, and at least 21 days for L. monocytogenes. As these guidelines are not standardized, it must be emphasized that the duration of therapy may need to be individualized on the basis of the patient’s response Adjunctive dexamethasone treatment Animal models of bacterial meningitis showed that bacterial lysis, induced by antibiotic therapy, leads to inflammation in the sub- arachnoid space. The severity of this inflammatory response is associated with outcome and can be attenuated by treatment with steroids. On the basis of experimental meningitis studies, several clinical trials have been undertaken to determine the effects of ad- junctive steroids in children and adults with bacterial meningitis. Of several corticosteroids, the use of dexamethasone in bacterial meningitis has been investigated most extensively. Dexamethasone is a glucocorticosteroid with anti-​inflammatory as well as im- munosuppressive properties. It has excellent penetration into the cerebrospinal fluid. In a meta-​analysis of randomized trials since 1988, adjunctive dexamethasone was shown to reduce meningitis-​ associated hearing loss in children with meningitis due to H. influ- enzae type b. As the design of most available studies on adjunctive dexa- methasone therapy in adults with bacterial meningitis was flawed, its value in adults was long debated. In 2002, results of a European randomized placebo-​controlled trial showed that Table 24.11.1.3  Specific antimicrobial therapy in community-​acquired bacterial meningitis based on cerebrospinal fluid (cerebrospinal fluid) culture results and in vitro susceptibility testing; this material was previously published as part of an online supplementary appendix to reference Microorganism, susceptibility Standard therapy Alternative therapies Streptococcus pneumoniae   Penicillin MIC   < 0.1 mg/​l Benzylpenicillin or ampicillin Cefotaxime or ceftriaxone, chloramphenicol   0.1–​1.0 mg/​l Cefotaxime or ceftriaxone Cefepime, meropenem   ≥ 2.0 mg/​l Vancomycin + cefotaxime or ceftriaxonea Fluoroquinolonea   Cefotaxime or ceftriaxone MIC   ≥1.0 mg/​l Vancomycin plus cefotaxime or ceftriaxoneb Fluoroquinolonec Neisseria meningitidis   Penicillin MIC   <0.1 mg/​l Benzylpenicillin or ampicillin Cefotaxime or ceftriaxone, chloramphenicol   0.1–​1.0 mg/​l Cefotaxime or ceftriaxone Chloramphenicol, fluoroquinolone, meropenem Listeria monocytogenes Benzylpenicillin or ampicillind Trimethoprim–​sulfamethoxazole, meropenem Group B streptococci Benzylpenicillin or ampicillind Cefotaxime or ceftriaxone Escherichia coli and other Enterobacteriaceae Cefotaxime or ceftriaxoned Aztreonam,d fluoroquinolone, meropenem,d trimethoprim–​sulfamethoxazole, ampicillind Pseudomonas aeruginosa Ceftazidimed or cefepimed Aztreonam,d ciprofloxacin,d meropenemd Haemophilus influenzae   β-​Lactamase negative Ampicillin Cefotaxime or ceftriaxone, cefepime, chloramphenicol, fluoroquinolone   β-​Lactamase positive Cefotaxime or ceftriaxone Cefepime, chloramphenicol, fluoroquinolone Chemoprophylaxise N. meningitidis Rifampicin, ceftriaxone, ciprofloxacin, azithromycin a Consider addition of rifampicin if dexamethasone is given. b Consider addition of rifampicin if the MIC (minimum inhibitory concentration) of ceftriaxone is ≥2 mg/​litre. c Gatifloxacin or moxifloxacin; no clinical data on use in patients with bacterial meningitis. d Consider addition of an aminoglycoside. e Prophylaxis is indicated for close contacts, who are defined as those with intimate contact, which covers those eating and sleeping in the same dwelling as well as those having close social and kissing contacts; or healthcare workers who perform mouth-​to-​mouth resuscitation, endotracheal intubation, or endotracheal tube management. Patients with meningococcal meningitis who are treated with monotherapy of penicillin or amoxicillin (ampicillin) should also receive chemoprophylaxis, because carriage is not reliably eradicated by these drugs. fGeneral recommendations for intravenous empirical antibiotic treatment have included penicillin 2 MU every 4 h; amoxicillin or ampicillin 2 g every 4 h; vancomycin 15 mg/​ kg every 8 h; third-​generation cephalosporin: ceftriaxone 2 g every 12 h or cefotaxime 2 g every 4–​6 h; cefepime 2 g every 8 h; ceftazidime 2 g every 8 h; meropenem 2 g every 8 h; chloramphenicol 1–​1.5 g every 6 h; fluoroquinolone: gatifloxacin 400 mg every 24 h or moxifloxacin 400 mg every 24 h, although no data on optimal dose needed in patients with bacterial meningitis; trimethoprim–​sulfamethoxazole 5 mg/​kg every 6–​12 h; aztreonam 2 g every 6–​8 h; ciprofloxacin 400 mg every 8–​12 h; rifampicin 600 mg every 12–​24 h; aminoglycoside: gentamicin 1.7 mg/​kg every 8 h. The preferred dose for chemoprophylaxis: rifampicin 600 mg orally twice daily for 2 days; ceftriaxone 250 mg intramuscular; ciprofloxacin 750 mg orally; azithromycin 500 mg orally. Adapted from van de Beek, et al. (2006). N Engl J Med, 354(1), 44–​53. Copyright 2006 Massachusetts Medical Society. All rights reserved. section 24  Neurological disorders 6074 adjunctive treatment with dexamethasone, given before or with the first dose of antimicrobial therapy, improved the outcome of adult bacterial meningitis (relative risk (RR) 0.59; 95% con- fidence interval (CI) 0.37–​0.94) and reduced its mortality (RR 0.48; 95%CI 0.24–​0.96). This beneficial effect was most apparent in patients with pneumococcal meningitis, in whom the mortality rate was decreased from 34% to 14%. The benefits of adjunctive dexamethasone therapy were not undermined by an increase of severe neurological disability in patients who survived or by any corticosteroid-​induced complication. In a post-​hoc analysis, including only patients with pneumococcal meningitis who died within 14 days of admission, the mortality benefit of dexametha- sone therapy was due entirely to reduced mortality from systemic causes such as septic shock, pneumonia, or acute respiratory dis- tress syndrome; there was no significant reduction in mortality due to neurological causes. Results of a subsequent quantitative review of this topic in adults, which included five clinical trials, confirmed that treatment with corticosteroids was associated with a significant reduction in mor- tality (RR 0.6; 95% CI 0.4–​0.8) and in neurological sequelae (RR 0.6; 95% CI 0.4–​1). The reduction in case fatality in patients with pneumococcal meningitis was 21% (RR 0.5; 95% CI 0.3–​0.8). In meningococcal meningitis, in which the number of events was smaller, there were favourable point estimates for preventing mor- tality (RR 0.9; 95% CI 0.3–​2.1) and neurological sequelae (RR 0.5; 95% CI 0.1–​1.7), but these effects did not reach statistical signifi- cance. Adverse events were equally divided between the treatment and placebo groups. Treatment with adjunctive dexamethasone did not worsen long-​term cognitive outcome in adults after bacterial meningitis. Since the publication of these results, adjunctive dexa- methasone has become routine therapy in most adults with sus- pected bacterial meningitis. In 2007, an updated Cochrane analysis was published on the effi- cacy and safety of adjunctive corticosteroids, including 20 random- ized clinical trials involving 2750 people. In this analysis, adjuvant corticosteroids were associated with lower case fatality (RR 0.83; 95% CI 0.71–​0.99), lower rates of severe hearing loss (RR 0.65; 95% CI 0.47 to 0.91), and long-​term neurological sequelae (RR 0.67; 95% CI 0.45–​1.00). Again, the effect of corticosteroids was evident in adults with bacterial meningitis. In children the beneficial effect was less convincing, although there was a trend towards a beneficial ef- fect on hearing loss in non-​H. influenzae meningitis. In the Cochrane meta-​analysis, there was a difference in effi- cacy of corticosteroids between high-​ and low-​income countries. For children with bacterial meningitis admitted in high-​income countries, corticosteroids showed a protective effect against se- vere hearing loss (RR 0.61; 95% CI 0.41–​0.90), favourable point es- timates for severe hearing loss associated with non-​H. influenzae meningitis (RR 0.51; 95% CI 0.23–​1.13), and short-​term neuro- logical sequelae (RR 0.72; 95% CI 0.39–​1.33). For children in low-​ income countries, the use of corticosteroids was not associated with benefit. This difference was mainly caused by inclusion of the Malawian study, which included children in whom treatment began later, children who were more likely to be malnourished, and some HIV-​1 positive children. There may be several reasons for the dif- ference in efficacy of corticosteroids, such as delayed presentation, clinical severity, underlying anaemia, malnutrition, the antibiotic used and HIV-​1 positivity. A recent study compared characteristics of children with culture-​positive bacterial meningitis treated in the Royal Liverpool Children’s Hospital and the Children’s Unit, Queen Elizabeth Central Hospital, Blantyre, Malawi; the two cohort studies were derived from time periods before the introduction of vaccines. Children in Malawi presented later and were more often comatose and malnourished, compared with children in Britain. The mortality rate from bacterial meningitis in children in Malawi was much higher than in children in Britain (41% vs. 7%), even when infected with the same organisms. Randomized studies in adults with pyogenic meningitis from Malawi and Vietnam have also been published. In the Malawi study, dexamethasone was not associated with any significant benefit, whereas in Vietnam a significant benefit in mortality (RR 0.43; 95% CI 0.2–​0.94) was seen in patients with confirmed pyogenic menin- gitis. These conflicting results are difficult to interpret and further large studies in developing countries may be needed. Despite these encouraging results, the use of adjunctive dexa- methasone in bacterial meningitis remains controversial. Recently a meta-​analysis with individual patient data from 2029 adults and children from Malawi, Europe, Chile, and Vietnam was com- pleted. HIV infection was confirmed or likely in approximately a third of all patients and a diagnosis of bacterial meningitis was microbiologically confirmed in 80%, most frequently with Strep. pneumoniae. Dexamethasone was not associated with a significant reduction in deaths (dexamethasone 270/​1019 (27%) vs. placebo 275/​1010 (27%); odds ratio or OR 1.0; 95% CI 0.8–​1.2), death or severe neurological sequelae or bilateral severe hearing loss (dexa- methasone 43% vs. placebo 44%; OR 0.9; 95% CI 0.8–​1.1), death or any neurological sequelae or any hearing loss (dexamethasone 54% vs. placebo 57%; OR 0.9; 95% CI 0.7–​1.1), and death or severe bi- lateral hearing loss (dexamethasone 54% vs. placebo 57%; OR 0.9; 95% CI 0.8–​1.1). However, there was a suggestion that dexametha- sone may reduce hearing loss among survivors (dexamethasone 24% vs. placebo 30%; OR 0.8; 95% CI 0.6–​1.0; p  =  0.04). There was no effect in any prespecified subgroups including specific causative organisms, pre-​dexamethasone antibiotic treatment, HIV status, or age. Pooling of mortality results with all other published trials did not change the conclusions. The use of adjunctive dexametha- sone treatment was not associated with an increased risk of adverse events. Adjunctive dexamethasone in the treatment of acute bac- terial meningitis does not appear to reduce deaths or neurological disability or to produce harm. There were no significant treatment effects in any of the prespecified subgroups. A post-​hoc analysis showed that dexamethasone adjuvant therapy may reduce hearing loss in survivors. By reducing permeability of the blood–​brain barrier, steroids can impede penetration of antibiotics into the cerebrospinal fluid. This was shown for vancomycin in animal studies and can lead to treatment failures, especially in patients with meningitis caused by drug-​resistant pneumococci in whom antibiotic regimens often include vancomycin. However, in a recent observational study, which included 14 adult patients admitted to the intensive care unit because of suspected pneumococcal meningitis, appropriate concentrations of vancomycin in the cerebrospinal fluid were obtained even when concomitant steroids were used. The dose of vancomycin used in this study was 60 mg/​kg per day. Although these results suggest that dexamethasone can be used without fear of impeding vancomycin penetration into the cerebrospinal fluid 24.11.1  Bacterial infections 6075 of patients with pneumococcal meningitis (provided that vanco- mycin dosage is adequate), it is recommended that patients with bacterial meningitis due to non​susceptible strains, treated with adjunctive dexamethasone, are carefully monitored throughout treatment. Treatment of complications The management of adults with bacterial meningitis can be com- plex and common complications are meningoencephalitis, systemic compromise, stroke, and raised intracranial pressure (ICP) (see Fig. 24.11.1.1). Various adjunctive therapies have been described to improve outcome in such patients, including anti-​inflammatory agents, anticoagulant therapies, and strategies to reduce ICP. Few randomized clinical studies are available for other adjunctive ther- apies in adults with bacterial meningitis. The inflammatory response in the CNS results in blood–​brain bar- rier permeability, cerebral oedema, and increased ICP. Classically, there are two types of brain oedema: vasogenic due to blood–​brain barrier disruption, resulting in extracellular water accumulation, and cytotoxic or cellular oedema due to sustained intracellular water collection. A third type, osmotic brain oedema, results from osmotic imbalances between blood and tissue. A Dutch cohort study evaluated the effects of complications on mortality in patients with pneumococcal meningitis and com- pared these findings among different age groups. In older patients (≥ 60 years), death was usually a result of systemic complications, whereas death in younger patients (< 60 years) was predomin- antly due to neurological complications such as brain herniation. This observation may be explained by age-​related cerebral atrophy, which allows older patients to tolerate brain swelling. These find- ings suggest that supportive treatments that aim to reduce ICP could be most beneficial in younger adults with pneumococcal menin- gitis. Methods available to reduce intracranial pressure range from simple (e.g. elevation of the head of the bed to 30°) to aggressive strategies (e.g. ‘Lund concept’), although there is no evidence that ICP monitoring and treatment of increased ICP are beneficial in pa- tients with bacterial meningitis. Some have advocated early intra- cranial pressure monitoring, aggressive treatment of brain oedema with high doses of corticosteroids, osmotic diuretics, decompressive craniectomy, and ventriculostomy when there is hydrocephalus, but there is no conclusive evidence of improved outcome except in anecdotal cases. In bacterial meningitis, as blood–​brain barrier permeability has been increased, the effect of mannitol is uncertain. There is little in- formation from clinical and experimental studies concerning the use of mannitol in bacterial meningitis. A single dose of mannitol re- duced ICP for approximately 3 h in a meningitis model. Continued intravenous infusion of mannitol attenuated the increases of re- gional coronary blood flow (CBF), brain water content, and ICP in a pneumococcal meningitis model. Initial RCTs suggested that gly- cerol could reduce hearing loss and neurologic sequelae in children with bacterial meningitis. However, an RCT in Malawian adults with bacterial meningitis was stopped early because of higher mortality in the glycerol-​treated patients as compared to placebo. A subsequent study from Malawi, including 360 children with bacterial menin- gitis, also showed no benefit of glycerol with comparable mortality, rates of hearing loss, and sequelae in glycerol-​ and placebo-​treated patients. Prognosis In Europe and North America, the overall mortality rate of patients with meningitis caused by N. meningitidis is about 7–​14%, by Strep. pneumoniae 15 to 40%, and by group B streptococci and L. monocy- togenes meningitis above 20%. The mortality is much higher in very young and old people, and in patients with debilitating illnesses. A study in Zaria, Nigeria demonstrated that the mortality rate of pneumococcal meningitis was 32% in patients who were fully con- scious on admission, 40% in those who were confused, 54% in semiconscious patients, and 94% in those who were comatose. In Vietnam, in a prospective study of 250 cases of adult bacterial men- ingitis, the overall mortality rate was 13%. Permanent neurological sequelae include intellectual impairment, deafness and other cranial nerve deficits, and hydrocephalus. The re- ported incidence of sensorineural deafness after meningitis ranges from 5% to 40%. A large proportion of patients recover within a few months. N. meningitidis and H. influenzae are the main causes of this complication. Permanent deafness occurs in more than 50% of patients with Strep. suis meningitis. It may be bilateral, complete, and associated with vestibular involvement. Even in patients with apparently good recovery, cognitive impair- ment occurs frequently. In a prospective study, cognitive impair- ment was detected in 27% of adults who made a good recovery from pneumococcal meningitis. Results of a more recent study showed that about a third of adult survivors of bacterial meningitis experi- ence subtle long-​term cognitive impairment, which consists mainly of slight mental slowness. In this study the prevalence of cognitive impairment in patients after pneumococcal and meningococcal meningitis was similar. Tuberculous meningitis Epidemiology Tuberculous meningitis (TBM) kills or disables half those who have the condition and is the most dangerous form of infection with Mycobacterium tuberculosis. Fortunately, it is a relatively uncommon manifestation of TB and represents around 1% of all forms of the disease. In Western countries, its incidence has fallen in parallel with TB as a whole, but for those in the less developed world TBM re- mains a common cause of bacterial meningitis, particularly in popu- lations with a high prevalence of HIV infection. Before the arrival of HIV, most cases of TBM were in young chil- dren and occurred as a complication of primary infection. Now an increased proportion of cases occur in adults with HIV coinfection. HIV infection greatly increases the risk of all forms of TB, but in particular the extrapulmonary forms such as TBM, and the risk in- creases as the CD4 count declines. Pathogenesis Understanding of the pathogenesis of TBM has progressed little since the studies of Rich and McCordock in the 1920s and 1930s. They demonstrated, through post-​mortem examinations of chil- dren and experiments on rabbits, that the pathogenesis of TBM requires two steps. During the first step the meninges and brain parenchyma are seeded by blood-​borne bacteria with the formation section 24  Neurological disorders 6076 of small subpial or subependymal foci of infection (or the Rich foci). In children the bacteraemia usually occurs during primary pulmonary infection and may be subclinical, whereas in adults this step may occur after new pulmonary infection or reactivation of old foci. The second step requires the rupture of a Rich focus with re- lease of bacteria into the subarachnoid space. This heralds the onset of meningitis, which, if left untreated, will result in severe and ir- reversible neurological pathology. In 75% of children the onset of TBM is less than 12 months after the primary infection. Pathology Three processes are responsible for the neurological pathology of TBM. An adhesive exudate develops around the basal cisterns and can obstruct cerebrospinal fluid causing hydrocephalus and com- promise efferent cranial nerves (Fig. 24.11.1.5). Granulomas can coalesce to form tuberculomas, or an abscess in unusual cases, causing diverse clinical consequences dependent on their anatom- ical location (Fig. 24.11.1.6). And an obliterative vasculitis can cause infarction and stroke syndromes, commonly involving the basal ganglia, internal capsule, and territory of the middle cerebral artery (Fig. 24.11.1.7). The severity of these complications is believed to depend on the intracerebral inflammatory response and strongly predicts outcome. Spinal cord involvement occurs in around 10% of patients and is often overlooked. Clinical manifestations include very high cerebrospinal fluid protein concentrations, limb weakness, and pain. Vertebral tuberculosis (Pott’s disease) accounts for around a quarter of cases (Fig. 24.11.1.8) and may be associated with fusiform paravertebral abscesses (Fig. 24.11.1.9) or a gibbus (Fig. 24.11.1.10). Extradural cord tuberculomas cause more than 60% of cases of non-​ osseous paraplegia, although tuberculomas can occur in any part of the cord (Fig. 24.11.1.11). Tuberculous radiculomyelitis is a rare accompaniment to TBM, characterized by a subacute paraparesis, radicular pain, and bladder dysfunction. MRI reveals loculation and obliteration of the spinal subarachnoid space with nodular intradural enhancement (Fig. 24.11.1.12). Fig. 24.11.1.5  CT scan of the head with contrast showing intense basal meningeal enhancement and dilated ventricles. Fig. 24.11.1.6  CT of the head with contrast showing gross hydrocephalus and multiple ring-​enhancing tuberculomas. Fig. 24.11.1.7  MRI of the brain with contrast, showing intense basal enhancement with large left middle cerebral artery territory infarction and mass effect. Fig. 24.11.1.8  MRI of the spine showing destruction of vertebrae and displacement of the cord. 24.11.1  Bacterial infections 6077 Clinical features If left untreated, TBM follows a slowly progressive course that leads to death in almost all cases. The first symptoms are non​specific and unlikely to raise the suspicion of TBM. Infants may become irrit- able or go off their feeds, whereas older patients may complain of malaise, insomnia, lethargy, anorexia, and gradually worsening headache. These prodromal symptoms can last from 2 weeks to 8 weeks until the classic features of meningitis become more ap- parent. Patients commonly present to hospital at this stage, when the infection is well established. They will usually complain of headache and vomiting; many will present confused or comatose. Examination reveals neck stiffness in most, although it is rarely as marked as in acute pyogenic bacterial meningitis. Cranial nerve palsies are found in 25% of patients, with nerves VI, III, and VII being most commonly affected. Ten per cent of patients will present with a mono-​ or hemiparesis. Fundoscopy reveals papilloedema in half of patients and, occasionally, choroidal tubercles. Rarely, TBM presents as an acute meningoencephalitis that can be difficult to distinguish from pyogenic bacterial or viral meningitis. Seizures are rare in adults with TBM, but more common in children. HIV infection does not appear to alter the clinical presentation of TBM, although evidence of other extrapulmonary disease is more likely in HIV-​infected patients (Fig. 24.11.1.13). Coma occurs in advanced disease and is strongly correlated with outcome. It is usually caused by raised ICP as a result of cerebro- spinal fluid obstruction and cerebral oedema. Hydrocephalus is found in 90% of children at diagnosis and 50% of adults, and is strongly associated with delayed treatment and prolonged coma. Reduced conscious level may also be caused by metabolic disturb- ance. Hyponatraemia affects more than 50% of patients with TBM, although why it occurs is uncertain. Some patients have a classic syndrome of inappropriate antidiuretic hormone secretion (SIADH) but many others have reduced plasma volumes and persistent natri- uresis with normal concentrations of antidiuretic hormone. Indeed, some have suggested that ‘hyponatraemic natriuretic syndrome’ is a better descriptive term for this common complication of TBM. Unusual neurological manifestations of TBM are well described, particularly in the older literature. Movement disorders may follow Fig. 24.11.1.9  MRI of the spine showing vertebral destruction and large, bilateral, paravertebral abscesses. Fig. 24.11.1.10  Spinal deformity or ‘gibbus’ in patient with vertebral tuberculosis. Fig. 24.11.1.11  MRI of the spine with contrast showing cavitating cervical tuberculoma. Fig. 24.11.1.12  MRI of the spine from patient with tuberculous radiculomyelitis showing meningeal thickening. section 24  Neurological disorders 6078 basal ganglia infarction: tremor is the most common problem, but chorea, ballismus, and myoclonus are all reported. Tuberculomas can affect the hypothalamus and pituitary and cause disordered tem- perature regulation, diabetes insipidus, and panhypopituitarism on rare occasions. More controversial are cases that present with evi- dence of diffuse cerebral involvement but without clinical or cere- brospinal fluid signs of meningitis. ‘Tuberculous encephalopathy’ was first described in Indian children with disseminated TB and was characterized by coma, convulsions, involuntary movements, and pyramidal signs but with normal cerebrospinal fluid examin- ation. It has not been reported in adults. Post-​mortem examinations revealed diffuse cerebral oedema, demyelination, and sometimes haemorrhage—​features more typical of a postinfectious allergic dis- seminated encephalomyelitis. Diagnosis The diagnosis and treatment of TBM before the onset of coma are the greatest contribution that a physician can make to improve out- come. However, making the diagnosis is challenging because the clinical features of the disease are non​specific, small numbers of ­bacteria in the cerebrospinal fluid reduce the sensitivity of conven- tional bacteriology, and alternative diagnostic methods are incom- pletely assessed. The presenting clinical features of TBM are insufficiently specific to enable the diagnosis to be made on the history and examination alone. Recall of recent exposure to TB may be helpful, particularly in children, as may evidence of active extrameningeal TB on examin- ation. Chest radiography reveals active or previous TB infection in 50%; the appearance of miliary TB is particularly useful as it strongly suggests multiorgan involvement. Skin testing with the purified pro- tein derivative of M. tuberculosis is probably of limited value, except in infants. Examination of the cerebrospinal fluid is an essential part of diagnosing TBM and is a safe procedure for most patients with TBM. Hydrocephalus is not a contraindication to lumbar punc- ture. Cerebrospinal fluid pressures are usually raised (mean 30 cmH2O) and the cerebrospinal fluid is typically clear and slightly xanthochromic. Much is made in the older literature of the formation of a spider’s web clot in the cerebrospinal fluid from pa- tients with TBM but the diagnostic utility of this phenomenon has never been systematically tested and is probably exaggerated. The total number of white cells in the cerebrospinal fluid varies from fewer than 5/​µl to 1500/​µl. Most patients will have 300 to 500 cells/​ µl cerebrospinal fluid but older and immunosuppressed people may have low or even normal counts. The cells are a mixture of neutrophils and lymphocytes, although lymphocytes usually form 70–​90% of the total. Occasionally, TBM can present with a short history with 1500–​2500 WBCs/​µl in the cerebrospinal fluid, most of which are neutrophils. Cerebrospinal fluid total protein concen- trations are raised in 95%, typically between 1 and 2 g/​l; concen- trations of more than 3 g/​l suggest spinal involvement and possibly spinal block. The ratio cerebrospinal fluid:blood glucose concen- tration is less than 0.5 in 95% and is a useful way of distinguishing TBM from other lymphocytic meningitides, especially viral men- ingitis, in which cerebrospinal fluid:blood glucose is usually more than 0.5. Attempts have been made to identify the clinical and cerebro- spinal fluid findings predictive of TBM. In children, a history longer than 6 days, optic atrophy, focal neurological deficit, abnormal movements, and neutrophils forming less than half the total cere- brospinal fluid leucocytes were independently associated with TBM. A diagnostic rule developed in Vietnamese adults to distin- guish TBM from bacterial meningitis calculated weighted scores for the variables predictive of TBM (score in brackets): age less than 36 years (0), 36 years or more (+ 2); peripheral blood white cell count fewer than 15 000 × 103/​ml (0), 15 000 × 103/​ml or more (+ 4); dur- ation of symptoms more than 6 days (− 5), 6 days or less (0); cerebro- spinal fluid white cells fewer than 900/​µl (0), 900/​µl or more (+ 3); and cerebrospinal fluid neutrophils less than 75% of total cells (0), 75% or more (+ 4). A total score of less than 4 indicated TBM, and a score of 4 or more indicated bacterial meningitis; when applied pro- spectively the rule was 86% sensitive and 79% specific. However, the performance differs where TB prevalence is lower and HIV preva- lence higher than in Vietnam. CT and MRI of the brain provide diagnostic information, but there are few data to indicate whether the findings can help discrim- inate TBM from other cerebral disorders. Basal meningeal enhance- ment, hydrocephalus, tuberculoma, and infarction are the cardinal neuroradiological features of TBM (see Figs. 24.11.1.1–​24.11.1.3). Indeed, the presence of basal meningeal enhancement, tuberculoma, or both, was 89% sensitive and 100% specific for the diagnosis of TBM in one study. Pre-​contrast hyperdensity in the basal cisterns may be a highly specific radiological sign of TBM in children. Cranial MRI is better at defining brainstem and cerebellum pathology, tuberculomas, infarcts, and the extent of inflammatory exudates, but there are no data to suggest that MRI is better than CT in discriminating TBM from other disorders. Cryptococcal meningitis, viral encephalitis, sarcoidosis, meningeal metastases, and lymphoma may all produce similar radiographic findings. The major role of neuroradiology has been in the management and follow-​up of the complications of TBM requiring neurosurgery. The culture of M. tuberculosis from the cerebrospinal fluid is the gold standard diagnostic test for TBM, but takes 2–​6 weeks and is therefore too slow to aid clinical decision-​making. Demonstrating acid-​fast bacilli of M. tuberculosis in the cerebrospinal fluid after Ziehl–​Neelsen staining is the oldest and most widely available rapid diagnostic test (Fig. 24.11.1.14), but the performance varies widely depending upon the volume of cerebrospinal fluid examined, the Fig. 24.11.1.13  Tuberculous, suppurating, inguinal lymphadenopathy with sinus tract formation in an HIV-​infected woman with tuberculous meningitis. 24.11.1  Bacterial infections 6079 duration of microscopy, and the skill of the operator. Most labora- tories find acid-​fast bacilli in the cerebrospinal fluid of only 10–​20% of those with TBM. Meticulous microscopy and the examination of large (>5 ml) volumes of cerebrospinal fluid can improve the sensi- tivity of both staining and culture to more than 60% and 80%, re- spectively. HIV infection is also associated with better performance of bacteriology because there are higher concentrations of bacteria in the cerebrospinal fluid. Commercial nucleic acid amplification tests, such as those based on PCR, have helped improve TBM diagnosis, but have important limitations. The GeneXpert MTB/​RIF assay is now widely avail- able worldwide, utilizing a cartridge-​based real-​time PCR to detect Mycobacterium tuberculosis, and the genetic mutations which confer rifampicin resistance, within 3 hours. Several studies from different settings indicate it has high diagnostic specificity (approaching 100%), but sensitivity is 50–​60% when used on cerebrospinal fluid for the diagnosis of TBM. Therefore, it can be used to ‘rule in’ the diagnosis of TBM, and gives very useful information on likely rifam- picin susceptibility, but cannot be used to ‘rule out’ the diagnosis. Unfortunately, there is still no single test that will allow the physician to confidently rule out TBM and empirical therapy, based on clinical features alone, is often required. Many other approaches to the diagnosis of TBM have been at- tempted and shown preliminary promise, but none has proved suffi- ciently reproducible, sensitive, specific, and practical for widespread clinical use. Commercial immunological assays based on the produc- tion of interferon-​γ after stimulation with M. tuberculosis-​specific antigens (ESAT6 and CFP10)—​the T-​SPOT and QuantiFERON-​TB assays—​have been a major advance in the diagnosis of latent TB infection, but their potential role in TBM diagnosis has not been established. Current data suggest these assays have reasonable specificity (80–​100%) when used on cerebrospinal fluid for TBM diagnosis, but they lack sensitivity. Unless additional data become available, these assays cannot be recommended for the routine la- boratory diagnosis of TBM. In summary, a high index of clinical suspicion is required to diag- nose TBM and, given the fatal consequences of delayed treatment, clinicians should be encouraged to initiate ‘empirical’ therapy in the setting of compatible clinical, epidemiological, and laboratory findings. Differential diagnosis TBM usually presents as a subacute lymphocytic meningitis and the differential diagnosis will depend on the age of the patient, geographical location, and immune status. In immunocompetent individuals the major differential diagnoses are partially treated pyo- genic bacterial meningitis and viral meningoencephalitis. Various neoplastic infiltrations of the meninges (e.g. carcinomas, leukae- mias, and lymphomas) may be more common at the extremes of age. Neurosarcoidosis can be very difficult to distinguish from TBM, as may neurosyphilis. Geographical region can suggest specific alter- native diagnoses, for example, meningitis caused by Angiostrongylus cantonensis or Gnathostoma spinigerum in south-​east Asia, or by Coccidioides spp., Histoplasma spp., or cysticercosis in the Americas, can all mimic TBM. The immunosuppressed patient represents an important group often at high risk for diseases caused by mycobac- teria, fungi, and herpesviruses. Cryptococcal meningitis is the major differential diagnosis of TBM in HIV-​infected patients but can usu- ally be distinguished on the basis of a cerebrospinal fluid Indian ink stain, fungal culture, or a cryptococcal antigen test. Cerebral toxo- plasmosis can be difficult to differentiate from cerebral tuberculosis, especially when multiple tuberculomas are present, and cyto- megalovirus (CMV) and herpes simplex virus (HSV) 1 and 2 men- ingoencephalitis can also cause diagnostic confusion with TBM. In most of these cases careful microbiological examination of the cere- brospinal fluid (for fungi and mycobacteria, in particular), selected use of nucleic acid amplification assays (M. tuberculosis, Toxoplamsa gondii, CMV, and HSV), and serological tests (syphilis) will allow a diagnosis to be made. Treatment The treatment of TBM follows the model of a short course of chemo- therapy for pulmonary TB: an ‘intensive phase’ of treatment with four drugs, followed by a prolonged ‘continuation phase’ with two drugs. The first two months of treatment should be with isoniazid, rifam- picin, pyrazinamide, and streptomycin, ethambutol, or ethionamide. The British Thoracic Society (BTS) and the Infectious Disease Society of America (IDSA) favour ethambutol as the fourth drug, al- though they acknowledge the lack of evidence from controlled trials. Others, particularly in South Africa, advocate ethionamide, which penetrates healthy and inflamed meninges more effectively than eth- ambutol or streptomycin, but can cause severe nausea and vomiting. In adults, daily single doses of 300 mg isoniazid, 600 mg rifampicin, and 2000 mg pyrazinamide probably provide adequate levels in the sera and cerebrospinal fluid of patients with TBM. There is some evidence higher dose rifampicin given intravenously may increase survival, but a large trial that compared the standard regimen with orally administered higher dose rifampicin (15 mg/​kg), in addition to levofloxacin as a fifth drug for the first 2 months of treatment, found no benefit. Higher drug doses are recommended in young children, and have been used with success, notably in South Africa, but this approach cannot yet be recommended in adults. Unlike the treatment of pulmonary TB, interruptions in anti-​TB chemotherapy are an independent risk factor for death from TBM. British and American guidelines suggest between 9 and 12 months of total anti-​TB treatment for TBM, although a systematic review concluded that 6 months might be sufficient provided that the likelihood of drug resistance is low. Isoniazid and rifampicin are Fig. 24.11.1.14  Acid-​fast bacilli of Mycobacterium tuberculosis stained by Ziehl–​Neelsen stain in cerebrospinal fluid. section 24  Neurological disorders 6080 considered mandatory in the continuation phase and the BTS sug- gests that therapy should be extended to 18 months in those unable to tolerate pyrazinamide in the intensive phase. Others recommend that pyrazinamide be given throughout treatment because of its ex- cellent penetration across the blood–​brain barrier, although there is no supporting evidence from controlled trials. TBM caused by M.  tuberculosis resistant to one or more first-​ line anti-​TB drugs is an increasingly common problem. Isoniazid resistance alone does not appear to have a major impact on out- come from TBM, except in HIV-​infected individuals. However, the combination of rifampicin and isoniazid resistance (multidrug re- sistance) has a major impact such that most patients will die un- less second-​line therapy is started early. Detecting TBM caused by multidrug-​resistant organisms is difficult: patients are likely to be dead before the results of conventional susceptibility tests (which take 6–​8 weeks) are available. The rapid molecular detection of ri- fampicin resistant Mycobacterium tuberculosis in cerebrospinal fluid (CSF) by GeneXpert MTB/​RIF has proved very useful, although the limited sensitivity of the assay (50–​60%) means a high clinical sus- picion is still required. Furthermore, the best combination, dose, and duration of second-​line agents for the treatment of multidrug-​ resistant TBM are not known. Until more data become available the treatment of multidrug-​resistant TBM should follow the prin- ciples of treating drug-​resistant pulmonary disease:  never add a single agent to a failing regimen; use at least three previously unused drugs, one of which should be a fluoroquinolone and the other an injectable agent (e.g. amikacin or capreomycin); and treat for at least 18 months. Adjunctive corticosteroids The use of adjunctive corticosteroids has been controversial ever since they were first suggested for the management of TBM more than 50 years ago. A meta-​analysis and systematic review of all con- trolled trials published before 2000 concluded that corticosteroids probably improved survival in children, but small trial sizes, poor treatment allocation concealment, and possible publication bias did not support clear treatment recommendations. In 2004, a con- trolled trial of adjunctive dexamethasone in 545 Vietnamese adults with TBM revealed that dexamethasone treatment was strongly as- sociated with a reduced risk of death after 9 months of treatment (RR 0.69, 95% CI 0.52–​0.92, p =  0.01), but did not prevent severe disability in the survivors. The effect of dexamethasone was con- sistent across all grades of disease severity, dispelling a previously held belief that corticosteroids benefited only those with more se- vere disease, but did not demonstrate a significant effect on death or disability in those infected with HIV. Current evidence suggests that all HIV-​uninfected patients with TBM should be given dexametha- sone, regardless of age or disease severity. A clear benefit of dexa- methasone in HIV-​infected patients has not been demonstrated, but the trial in Vietnam suggested that it was safe and might improve survival. There are no data from controlled trials comparing different cor- ticosteroid regimens, so the choice of regimen should be based on those used in the published controlled trials. In adults, the following regimen was shown to improve outcome in Vietnam: those with a Glasgow Coma Scale (GCS) score of less than 15 or focal neuro- logical deficit at the start of treatment received intravenous drug for 4 weeks (0.4 mg/​kg per 24 h week 1, 0.3 mg/​kg per 24 h week 2, 0.2 mg/​kg per 24 h week 3, and 0.1 mg/​kg per 24 h week 4) followed by 4 mg total oral drug, reducing each week by 1 mg until 0. Those without coma or neurological signs received intravenous drug for 2 weeks (0.2 mg/​kg per 24 h week 1, 0.1 mg/​kg per h week 2), fol- lowed by the same oral reducing course just described. In children, the South African trial demonstrated improved survival with 4 mg/​kg per day of prednisolone for the first month of treatment. Response to therapy and treatment of complications Ninety per cent of deaths from TBM occur in the first month of treatment. The response to therapy is slow and can follow a fluc- tuant course. Indeed, a rapid and sustained response over a few days suggests an alternative diagnosis. Headache is often present for many weeks, even in uncomplicated cases. Fever rarely disap- pears within a week, and pyrexia is often observed for 6–​8 weeks. The degree of neck rigidity at presentation varies considerably and can take 4–​6 weeks to resolve. The cerebrospinal fluid mirrors the slow clinical response: cell counts remain elevated for 1–​2 months, cerebrospinal fluid glucose remains low for a similar duration, and total cerebrospinal fluid protein can rise before falling slowly over many months. Transient episodes of high fever, worsening headache, and increased nuchal rigidity can occur during the first 2 months of treatment, particularly in those with more severe dis- ease. Distinguishing self-​limiting events from the onset of more serious complications is difficult. New focal neurological signs, or a fall in conscious level, rarely accompanies these transient deterior- ations. Cranial imaging should be arranged urgently if new clinical signs develop during treatment. Hydrocephalus, cerebral infarc- tion, the expansion of intracranial tuberculoma, hyponatraemia, and poor adherence to therapy are the foremost reasons for severe acute deterioration. The expansion of intracranial tuberculoma after the start of treatment is a widely reported complication and frequently labelled as a ‘paradoxical’ treatment reaction. Recent data suggest that 75% with TBM develop tuberculomas during therapy but only small proportions are symptomatic. Most au- thors suggest treatment with prolonged high-​dose corticosteroids if the tuberculoma causes clinical deterioration, although there are no controlled trials to support these recommendations. There are case reports to suggest that adjunctive thalidomide may help in the management of symptomatic expanding tuberculomas. Rarely, tuberculomas coalesce to form an abscess and neurosurgical drainage may be indicated. Hydrocephalus is a common and serious complication of TBM and can be treated with diuretics (furosemide and/​or acetazolamide), serial lumbar punctures, or ventriculoperitoneal/​ atrial shunting. There are no data from controlled trials that de- termine which method of treatment is best. Some advocate early shunting in all patients with hydrocephalus, whereas others recom- mend shunting only for patients with non​communicating hydro- cephalus. External ventricular drainage has been used to predict response to ventriculoperitoneal shunting but without success; others suggest that monitoring lumbar cerebrospinal fluid pressure can predict response to medical treatment. Without clear evidence physicians must balance possible benefit with the resources and ex- perience of their surgical unit and the significant complications of shunt surgery. Severe hyponatraemia is a common and often overlooked cause of deterioration on therapy. With the pathogenesis unclear, the 24.11.1  Bacterial infections 6081 best way of correcting the plasma sodium is uncertain. Sodium and fluid replacement are probably indicated in hypovolaemic hyponatraemia, whereas fluid restriction may be more appro- priate in those who are euvolaemic with evidence of SIADH. There is anecdotal evidence to suggest that fludrocortisone replacement therapy and demeclocycline may be useful. Prognosis and sequelae TBM kills or severely disables half of the people who have the con- dition. Outcome is even worse in those coinfected with HIV as more than half die. Whether highly active antiretroviral therapy can im- prove survival is uncertain. A  recent trial comparing immediate versus 2-​month delayed antiretroviral therapy found no difference in survival between the treatment arms. The immediate treatment arm had more drug-​related adverse events, therefore delayed treat- ment is currently recommended. The severity of TBM has been divided into three grades, a cat- egorization that takes its name and definitions from the 1948 British Medical Research Council (MRC) study of streptomycin in TBM treatment (Table 24.11.1.4). The grades are still used because they are good predictors of outcome: less than 10% of patients die with grade I disease, whereas 50% with grade III will not survive. Indeed, extremes of age, high MRC grade, HIV in- fection, and multidrug resistance have all been confirmed as the strongest independent predictors of death from TBM in nu- merous studies. Permanent sequelae occur in 10–​30% of survivors: intellectual impairment is common in infants and young children and a quarter of all patients will have cranial nerve deficits, including blindness, deafness, and squints. Ten per cent (10%) will have permanent mono-​, hemi-​, or paraparesis. Prevention (See Chapter 8.6.26.) Although the efficacy of Bacillus Calmette–​Guérin (BCG) im- munization to prevent pulmonary TB is controversial, its ability to prevent disseminated TB (including TBM) in young children is widely accepted. Meta-​analyses have shown that BCG immuniza- tion at birth prevents around 70% of all cases of childhood TBM and is a highly cost-​effective intervention in settings with a high prevalence of TB. Whether the protection lasts into adulthood is uncertain. TBM can also be prevented by treating the household contacts of newly diagnosed cases of pulmonary TB. The BTS recommend either 6 months of isoniazid or 3 months of isoniazid and rifam- picin for Mantoux-​positive contacts to prevent progression to active disease. Possible future developments Immunization Widespread introduction of vaccines, especially where disease burden is greatest, is likely to further decrease the global burden of acute bacterial meningitis. The efficacy of the 23-​valent pneumo- coccal polysaccharide vaccine has been extensively studied and, in a meta-​analysis, its efficacy was estimated to be 38–​53% for the prevention of invasive pneumococcal disease in adults. Although PCV are highly effective in children, the high costs of this vaccine limit its implementation in healthcare in less devel- oped countries. A possible alternative or complementary approach is to develop vaccines directed against non​capsular antigens common to all pneumococcal species. Potential targets for future pneumococcal protein vaccines are neuraminidase, autolysin, pneumolysin, pneumococcal surface protein, and pneumococcal surface adhesion A. The high variability of N. meningitidis emphasizes the need for a permanent global follow-​up, so that public health decision-​makers and vaccine manufacturers can plan the most relevant vaccine strategies and development according to the most recent epidemio- logical trends, while taking into account the cost and logistical hur- dles that are the major limitations for the less developed world. Genetic factors Large prospective multinational studies have been performed to determine the role of genetic factors contributing to suscep- tibility and outcome in bacterial and tuberculous meningitis. Findings may have several implications for therapy and preven- tion. Existence of subgroups of patients with genetic variations (e.g. leukotriene A4 hydrolase gene and TBM susceptibility and treatment response) or deficiencies in innate immunity that es- pecially benefits from immunomodulatory therapy is likely. In addition, genotypes may be used to identify patients at high risk for the development of disease and those with high risk for com- plications. Physicians may, in the future, be able to use genetic information to dedicate immune-​based therapy to modulate the response in a given patient. Randomized clinical trials Large trials of adjuvant dexamethasone in adults and children with acute bacterial meningitis are still needed and randomized comparative studies of various treatment regimens should be per- formed. The role of adjunctive dexamethasone for HIV-​infected patients with TBM also needs defining by large trials. New adjunctive therapies The growing emergence of drug resistance as well as shifts in sero- type incidence is fuelling further development of novel antibiotic and adjuvant treatment strategies. In addition to the widespread introduction of dexamethasone, other options for adjuvant drugs may lie in modulating ROS/​RNS-​mediated damage, in caspase in- hibition, or in drugs targeting specific mediators in the inflamma- tory, complement, or coagulation cascades. Potentially, the efficacy of therapeutic interventions may be enhanced by simultaneous intervention at several levels of the inflammatory cascade. Despite the benefits of these strategies in experimental models, clinical trials Table 24.11.1.4  The British Medical Research Council disease severity grades for tuberculous meningitis Grade Clinical criteria I Alert and oriented without focal neurological deficit II GCS score 14–​10 with or without focal neurological deficit or GCS 15 with focal neurological deficit III GCS score <10 with or without focal neurological deficit GCS, Glasgow Coma Scale. 24.11.2 Viral infections 6082 Fiona McGill, Jeremy 24.11.2 Viral infections 6082 Fiona McGill, Jeremy Farrar, Bridget Wills, Menno De Jong, David A. Warrell, and Tom Solomon section 24  Neurological disorders 6082 are needed to assess their efficacy in patients with bacterial menin- gitis. There is still an urgent need for new treatment options and refinement of emergency and neurocritical care. Trials are needed to assess treatment modalities such as intracranial pressure man- agement and specific monoclonal antibodies. However, the greatest effect on the burden of illness due to bacterial meningitis is likely to be achieved through widespread use of vaccinations. FURTHER READING British Medical Research Council (1948). Streptomycin treatment of tuberculous meningitis. Br Med J, i, 582–​97. Brouwer MC, et  al. (2012). Dilemmas in the diagnosis of acute community-​acquired bacterial meningitis. Lancet, 380, 1684–​92. Dastur DK, et al. (1995). Pathology and pathogenetic mechanisms in neurotuberculosis. Radiol Clin North Am, 33, 733–​52. Heemskerk D, et al. (2016). Intensified anti-​tuberculosis therapy of adults with tuberculous meningitis. N Eng J Med 374, 124–​34. Klugman KP, et al. (2003). A trial of a 9-​valent pneumococcal conju- gate vaccine in children with and those without HIV infection. N Engl J Med, 349, 1341–​8. McIntyre PB, et al. (2012). Effect of vaccines on bacterial meningitis worldwide. Lancet, 380, 1703–​11. Molyneux E, Riordan FA, Walsh A (2006). Acute bacterial meningitis in children presenting to the Royal Liverpool Children’s Hospital, Liverpool, UK and the Queen Elizabeth Central Hospital in Blantyre, Malawi: a world of difference. Ann Trop Paediatr, 26, 29–​37. Mook-​Kanamori BB, et al. (2011). Pathogenesis and pathophysiology of pneumococcal meningitis. Clin Microbiol Rev, 24, 557–​91. Nguyen Thi Hoang Mai, et al. (2007). A randomized controlled trial of dexamethasone for Vietnamese adolescents and adults with bac- terial meningitis. N Engl J Med, 357, 2431–​40. Rich AR, McCordock HA (1933). The pathogenesis of tuberculous meningitis. Bull John Hopkins Hosp, 52, 5–​37. Ruslami R, et al. (2013). Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-​label, random- ised controlled phase 2 trial. Lancet Infect Dis, 13, 27–​35. Scarborough M, et al. (2007). Corticosteroids for bacterial meningitis in adults in sub-​Saharan Africa. N Engl J Med, 357, 2441–​50. Stephens DS, Greenwood B, Brandtzaeg P (2007). Epidemic menin- gitis, meningococcaemia, and Neisseria meningitidis. Lancet, 369, 2196–​210. Stewart SM (1953). The bacteriological diagnosis of tuberculous men- ingitis. J Clin Pathol, 6, 241–​2. Thompson MJ, et al. (2006). Clinical recognition of meningococcal disease in children and adolescents. Lancet, 367, 397–​403. Thwaites G, et al. (2002). A clinical diagnostic rule for adults with tu- berculous meningitis. Lancet, 360, 1287–​92. Thwaites G, et  al. (2004). A randomized, double blind, placebo-​ controlled trial of dexamethasone for the treatment of adults with tuberculous meningitis. N Engl J Med, 351, 1741–​51. Thwaites G, et al. (2013). Tuberculous meningitis: more questions, still too few answers. Lancet Neurology, 12, 999–​1010. Torok ME, et al. (2011). Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)—​associated tuberculous meningitis. Clin Infect Dis, 52, 1374–​83. van de Beek D, et al. (2007). Corticosteroids for acute bacterial menin- gitis. Cochrane Database Syst Rev, 1, CD004405. van de Beek D, et al. (2012). Advances in treatment of bacterial menin- gitis. Lancet, 380, 1693–​702. 24.11.2  Viral infections Fiona McGill, Jeremy Farrar, Bridget Wills, Menno De Jong, David A. Warrell, and Tom Solomon ESSENTIALS Meningitis Enteroviruses are responsible for most cases of viral meningitis where a pathogen is identified; many other viruses can also cause meningitis with considerable geographical and seasonal variation. Clinical features and prognosis—​typical presentation is with sudden onset of fever, headache, neck stiffness, and photophobia. There is no change in conscious level. Prognosis is generally good, though recent data suggest not always. Encephalitis Japanese encephalitis virus is the most common cause of enceph- alitis in Asia:  other causes—​with considerable geographical and seasonal variation—​include rabies, herpes simplex virus, tick-​borne encephalitis virus, dengue viruses, chikungunya virus, enteroviruses including EV71, Nipah virus, West Nile virus, measles, and mumps. Clinical features and prognosis—​most patients present with a febrile illness followed by altered consciousness, convulsions, and some- times focal neurological signs, or signs of raised intracranial pressure; psychiatric presentations can also occur. Some manifestations sug- gest particular viruses (e.g. hydrophobia in rabies; Parkinsonian and extrapyramidal features in Japanese encephalitis, and temporal lobe features in herpes simplex encephalitis). Mortality and morbidity vary according to cause, but are high (e.g. mortality 10–​25% in Japanese en- cephalitis), with neurological sequelae in more than half of survivors. Myelitis Viral ‘anterior horn’ cell myelitis is classically caused by poliovirus, which has now been eliminated from much of the world: other causes—​ with considerable geographical and seasonal variation—​include other enteroviruses, Japanese encephalitis virus, and West Nile virus. Clinical features—​following a non​specific episode of influenza-​ like symptoms, patients presents with meningism preceding or ac- companying the development of lower motor neurone (flaccid) paralysis. Respiratory and bulbar paralysis is life-​threatening. Mortality in adults is more than 20%. Investigation The most important investigation is lumbar puncture to allow examination of the cerebrospinal fluid, with typical findings of (1)  pleocytosis—​ranging from tens to thousands of cells/​µl, with lymphocytes usually predominating; (2) modest increase in protein concentration; (3) normal or mildly low glucose concentration. Some viruses can be isolated from the cerebrospinal fluid, and viruses can sometimes be cultured from distant sites, but polymerase chain re- action technology is now used routinely for diagnosis of viral central nervous system infection. Treatment Aciclovir is effective in treating herpes simplex encephalitis, but there is no effective specific treatment for most viral infections 24.11.2  Viral infections 6083 of the central nervous system. The focus is therefore on sup- portive care. Prevention Prophylactic vaccination is available against poliomyelitis, Japanese encephalitis, tick-​borne encephalitis, mumps, measles, rubella, and rabies. Postexposure rabies vaccination is effective in preventing ra- bies encephalitis. Hyperimmune immunoglobulin has been used for prophylaxis of measles, herpes zoster virus, rabies, and some other infections in high-​risk groups. Other neurological disorders in which viruses may play a role These include (1) Reye’s syndrome—​an acute encephalopathy with liver impairment affecting children aged 2–​16 years, associated with use of salicylates and a preceding viral illness. (2) Progressive ru- bella panencephalitis and subacute sclerosing panencephalitis  —​ typically occur several years after the initial illness with rubella virus and measles virus, respectively, and are characterized by intellec- tual impairment and behavioural change. (3) Progressive multifocal leucoencephalopathy—​caused by papovaviruses, most often in the immunocompromized; onset is usually with progressive evidence of a focal lesion of one cerebral hemisphere, before gradual develop- ment of more widespread signs; there is no effective treatment apart from restoration of immune function. (4) Guillain–​Barré syndrome is a post-​ or parainfectious condition which can follow Epstein–​ Barr virus, cytomegalovirus, and other viral infections, including the mosquito-​borne Zika virus. Introduction Viruses invade and damage the central nervous system in two ways:  directly, by infecting the leptomeninges, brain, and spinal cord; and, indirectly, by inducing an immunological reaction re- sulting in para-​ and postinfectious diseases. In both cases, the terms ‘meningitis’, ‘encephalitis’, and ‘myelitis’ are used alone or in com- bination. Meningitis implies inflammation of the meninges without alteration of consciousness, convulsions, or the production of focal neurological abnormalities; in encephalitis there is impairment of cerebral function, usually with an altered state of consciousness and often with convulsions and focal neurological signs; myelitis indi- cates involvement of the spinal cord resulting in varying degrees of limb weakness with or without sensory disturbance. Retroviral dis- eases of the central nervous system and prions are dealt with else- where (Chapter 8.5.23 and Chapter 24.11.5). Aetiology There is considerable geographical and seasonal variation in the kinds of viruses causing meningitis, encephalitis, and myelitis. Vulnerability varies with age and immunocompetence. Some of the most important causes are zoonotic viruses (i.e. they circulate natur- ally among animals, occasionally spilling over into humans). Often arthropods, such as insect or ticks, are the means of transmission, making them arboviruses (arthropod-​borne viruses). Meningitis Enteroviruses are responsible for most cases of viral meningitis glo- bally, where a virus is identified. Almost all serotypes have been implicated both in sporadic cases, and in outbreaks. The second commonest causes of viral meningitis are the herpes simplex virus (HSV) type 2, and varicella zoster virus (VZV). Adenoviruses and Epstein–​Barr virus (EBV) are also important causes found glo- bally, as are mumps and measles, although their incidence depends on the extent of vaccination. The importance of arthropod-​borne viruses (arboviruses) varies according to geographical location, season, and for some, the extent of vaccinations; although several of these viruses are named for the dramatic encephalitis they cause; they also important causes of meningitis. Tick-​borne encephalitis virus occurs across large swathes of northern Europe and Asia; the mosquito-​borne Toscana virus is important in Italy in the summer months. In the Americas the flaviviruses (West Nile, and St Louis encephalitis virus) and the alphaviruses (Eastern and Western equine encephalitis viruses) cause meningitis, as do bunyaviruses, such as California (La Crosse) encephalitis viruses. Throughout the tropics dengue, though better known as a cause of rash and haemor- rhage, also causes meningitis. In many cases of presumed viral meningitis, a pathogen is never identified. The term aseptic meningitis is often used to describe the syndrome of meningitis with lymphocyte predominance, whether or not a virus is identified. Myelitis Poliovirus was considered previously the major cause of viral acute flaccid paralysis globally, but has now been eliminated from much of the world. It remains a problem in a handful of coun- tries in the African and eastern Mediterranean regions, with only two countries in the world still having endemic disease at the end of 2015. Enterovirus 71 is now the leading cause of acute flaccid paralysis. In 2014 a worrying increase in acute flaccid paralysis was seen in the United States which coincided with an outbreak of enterovirus 68. Other enteroviruses, such as coxsackie viruses A and B, and echoviruses have all been implicated as causes of flaccid paralysis. Flaviviruses which attack the anterior horn cells of the spinal cord can also cause a polio-​like paralysis, including Japanese encephalitis virus, West Nile virus, Tick-​borne enceph- alitis virus, and Zika virus. Other potential viral causes of myelitis include rabies virus, VZV, EBV, and herpesvirus simiae (B virus). HSV-​2 can cause lumbosacral myeloradiculitis. HTLV-​1 causes a spastic paraparesis often called tropical spastic paraparesis (TSP) or HTLV-​1-​associated myelopathy (HAM). Encephalitis Viral causes of encephalitis vary from country to country. Japanese encephalitis virus is the major cause in Asia. It is estimated that there are around 68 000 cases of Japanese encephalitis annually, with approximately 17 000 deaths. Dengue viruses have also been implicated as a cause of encephalitis in both south-​east Asia and Latin America. Rabies remains an important cause of fatal enceph- alomyelitis, especially in the Asian subcontinent and Africa (see Chapter 8.5.10). In 1999 an outbreak of an encephalitic illness among pig farm and abattoir workers in Singapore and Malaysia heralded the arrival of section 24  Neurological disorders 6084 Nipah virus as an important cause of central nervous system (CNS) infection. It has also caused outbreaks in Singapore, Bangladesh, and India. The closely related Hendra virus, which also causes encephal- itis in horses and occasionally humans, has not been seen outside of Australia (see Chapter 8.5.7). In North America and other Western countries HSV is the most common cause of sporadic viral encephalitis. Herpetic encephalitis accounted for 74–​81% of cases of encephalitis in the United States where a pathogen was found. In the United Kingdom it has an es- timated incidence of 2.3 per million population each year; HSV-​ 1 accounts for 95% of cases, whereas HSV-​2 causes encephalitis mainly in neonates and those who are immunosuppressed. Since 1999 when West Nile virus was first identified in New York, it has spread to become the third most common cause of viral en- cephalitis in the United States. It has been known to cause enceph- alitis in Africa and the Middle East, as well as southern and Eastern Europe. Zika virus, which has spread in recent years, and is best known as a cause of congenital defects and Guillain-Barre syn- drome, can also cause encephalitis. In the United Kingdom, HSV-​1 is also the most frequently diag- nosed cause of viral encephalitis. Other causes include varicella zoster virus, enteroviruses, EBV, and HHV-​6. Louping ill is the only indigenous arthropod (tick)-​borne encephalitis in the United Kingdom but rarely causes disease in humans. Parechovirus is emerging as an important cause of encephalitis in young children, especially those under 3 months of age. In northern Europe and the former Soviet Union, tick-​borne en- cephalitis virus is endemic. In many developing countries rabies is also an important cause of encephalitis. Other regional causes are Rift Valley fever virus in Africa and the Middle East, arenaviruses (Junin, Guanarito, Sabiá, Lassa, and Machupo) in Latin America and Africa, Marburg and Ebola viruses in Africa, Colorado tick fever virus in North America, and Murray Valley encephalitis and Hendra viruses in Australia. Zika virus, which from 2015 caused large out- breaks in South America also appears to cause encephalitis. Postinfectious encephalomyelitis most commonly follows measles, vaccinia, varicella, rubella, mumps, and influenza. Guillain–​Barré syndrome, a sensorimotor polyneuropathy (see Chapter 24.16), has been associated with infections by EBV, cytomegalovirus (CMV), coxsackievirus B, VZV, and recently Zika virus. The decreasingly used nervous tissue vaccines for rabies may give rise to postvaccinal encephalomyelitis, whereas immunization against influenza, rabies, hepatitis B, measles, and poliomyelitis have all been complicated by Guillain–​Barré syndrome. Immunocompromized patients are particularly vulnerable to some viral infections. Those with depressed cell-​mediated immunity may de- velop VZV encephalitis, and CMV may cause a subacute encephalitis in patients with advanced HIV disease. JC virus also causes neurological damage in the form of progressive multifocal leucoencephalopathy in immunodeficient patients, especially those with advanced HIV or pa- tients on immunosuppressive drugs, such as natulizimab, used in the treatment of multiple sclerosis. This is described in more detail later in this chapter. In children or adults with hypogammaglobulinaemia, enteroviruses, including live-​attenuated polio vaccine, may produce a progressive and fatal meningoencephalitis. An acute meningoenceph- alitis can be part of primary HIV infection; the virus may also cause subacute chronic encephalopathies and dementia in patients with AIDS (see Chapter 8.5.23). HHV-​6B causes encephalitis in young children following stem cell transplantation. It is most common in Japan. Epidemiology Many viral infections of the CNS occur in seasonal peaks or as epidemics, for example, enteroviral disease and Japanese enceph- alitis; others, such as herpes simplex virus encephalitis, are spor- adic. Epidemics of Japanese encephalitis (see Chapter 8.5.14) occur in the summer or rainy season in northern India, Nepal, northern Thailand, Vietnam, Korea, Taiwan, and China. However, in southern Vietnam, Indonesia, Malaysia, southern India, and the Philippines the disease can occur the year round, although the peak occurs at the start of the rainy season. This variation in the incidence of dis- ease is an important consideration when recommending immun- ization. In endemic areas Japanese encephalitis is mostly a disease of children, but as the disease spreads to new regions, or if non-​ immune travellers visit endemic regions, adults are also affected. The major vector, Culex tritaeniorhynchus mosquito, is infected by feeding on the bird or mammal reservoir species. West Nile virus is a mosquito-​borne flavivirus closely related to Japanese encephal- itis, that occurs in both epidemics and sporadically across Africa, southern Europe, and the Americas. Tick-​borne encephalitis (see Chapter 8.5.14) occurs in spring and early summer when the ticks are most active, but can also be ac- quired by drinking the unpasteurized products of infected dairy ani- mals, especially goat’s milk. Mumps encephalitis is most common in the late winter or early spring, whereas enterovirus infections occur most often in the summer and early autumn. Rodent-​related encephalitides, such as the arenaviruses, occur typically when the rodent population is at its peak, either in the fields (Machupo and Junin viruses) or around the home (lymphocytic choriomeningitis virus). Rift Valley fever, survives periods of cold weather, during which the invertebrate–​vertebrate cycle is suspended by the virus ‘overwintering’ in its arthropod vectors (e.g. in the bottom of dried-​ up ponds) or hibernating invertebrate reservoirs. Rabies occurs sporadically or in microepidemics (see Chapter 8.5.10). Infections by many neurotropic viruses are most frequent and severe in children and older people. Herpes simplex encephal- itis affects all age groups but shows peaks of incidence in those aged between 5 and 30 years and those over 50 years, it is normally due to HSV-​1. When HSV-​2 invades the CNS, it is most likely to cause a non​fatal meningitis in adults, but can produce a severe encephalitis in neonates. Enteroviruses and parechoviruses can also cause severe encephalitis and sepsis-​like syndromes in young babies. Among the mosquito-​borne epidemic encephalitides, California encephalitis, and Japanese encephalitis are most common in children, St Louis and West Nile encephalitis occur more commonly in older people, whereas Eastern and Western equine encephalitis affect both very young and older people. Postinfectious encephalitis is most frequent in children, because it complicates the common childhood exanthematous viral infec- tions; it can take the form of acute disseminated encephalomy- elitis (ADEM). Emerging viral infections of the CNS Almost all of the new and emerging pathogens are viruses, and many have neurological sequelae. Nipah virus encephalitis is a zoo- nosis infecting pigs and flying foxes (Pteropus spp). The closely re- lated Hendra virus has caused a few cases of equine and human encephalitis, with a human fatality in Brisbane, Australia in 2008 (see 24.11.2  Viral infections 6085 Chapter 8.5.7). Zika virus, a flavivirus, has caused a significant out- break in South and Central America in 2015/​2016. There has been an associated increase in the number of cases of microcephaly, although the exact causal relationship remains to be established. Currently there is no treatment or vaccine. Usutu, another flavivirus, has been isolated in birds in Austria and has caused a handful of human cases in Europe. Ebolavirus has been associated with several neurological presentations, including cases of meningitis and encephalitis. Pathogenesis Having entered the body via the skin, mucous membranes, respira- tory or gastrointestinal most viruses multiply in the blood stream be- fore crossing the blood brain barrier to enter the CNS. Rabies virus is different, however, and enters peripheral nerves through acetyl- choline and other receptors and travels to the CNS in axoplasm, employing the microtubular dynein motor system. HSV is throught to travel up the trigeminal nerve and lay dormant in the trigeminal ganglion. Viruses inoculated through the skin include those trans- mitted by arthropods, as well as rabies virus. Arthropod-​borne vir- uses are presumed to replicate in local lymph nodes, then the vascular endothelium, and macrophages, in order to sustain viraemia (detect- able virus in the blood). Rabies virus may multiply locally in the cyto- plasm of muscle cells before entering peripheral nerves. Viruses that enter through the respiratory tract (e.g. measles, mumps, varicella) or gut (enteroviruses) multiply in local lymphoid tissue before entering the bloodstream. Viraemia is a feature of most viral infections, yet invasion of the CNS is rare in most cases. The explanation for this is not known, but the CNS has several intrinsic physical barriers to infectious agents, including viruses. These include the blood–​brain barrier with its ‘tight junctions’, virus-​resistant cells, and the absence of lymphatic drainage. In the case of rabies, HSV and VZV, the virus enters the CNS through the peripheral nerves. Although the sub- arachnoid space surrounding the olfactory nerves projects through the cribriform plate and is directly beneath the nasal mucosa, this route of infection seems to be extremely rare in humans and has been proven only in a few cases of inhaled rabies virus infection and herpes simplex encephalitis. Viruses have accidentally been inoculated dir- ectly into the CNS by infected corneal transplant grafts (rabies). Herpes simplex encephalitis may complicate primary HSV infection in children and young adults, but in most cases of herpes simplex en- cephalitis the cause is thought to be reactivation of latent virus (HSV-​ in the trigeminal nerve, autonomic nerve roots, or brain. HSV-​2 and VZV can also cause neurological disease, either as a result of pri- mary infection or reactivation following latency. In the case of VZV, disease can also occur following vaccination. Different neural cells are selectively vulnerable to invasion by dif- ferent neurotropic viruses. Examples are the predilection of polio- viruses for lower motor neurons of the anterior horns of the spinal cord, and of rabies for neurons of the limbic system and cerebellar Purkinje cells. HSV-​1 primarily causes infection of the brain paren- chyma (encephalitis) and HSV-​2 is normally associated with men- ingeal infection. The pathological effects of viral infections on the CNS include: • destruction and phagocytosis of neurons (neuronophagia) as a result of either viral invasion itself or immune lysis • demyelination • inflammatory oedema with the compressive effects of raised intracranial pressure • vascular lesions, in some cases In rabies, a universally fatal encephalitis, neuronolysis is relatively mild. However, the virus may interfere with neurotransmission at central and peripheral synapses. It also produces severe systemic effects, following its centrifugal spread (e.g. myocarditis and car- diac arrhythmias) and focal effects on vasomotor and respiratory centres in the brainstem and in the temporal lobes and amygdala (see Chapter 8.5.10). The host’s immune responses to viruses play a crucial role in combating infection. They may be directed against either the virus particle or the virus-​infected cell, and may be humoral or cell me- diated. An important local immune response at infected surfaces is provided by IgA antibody, which is present in secretions in the gut, saliva, and respiratory tract. This is important, for example, in the early stages of poliovirus infection where the antibody neutralizes the virus by combining with viral surface proteins. The systemic viral infection may also be limited by means of circulating IgG and IgM antibodies, which can neutralize the virus in a variety of dif- ferent ways. Immune responses may also occur locally within the CNS, where local synthesis of immunoglobulins in response to virus infection, sometimes in an oligoclonal pattern, may be evident. Such antibody elevations may be of considerable diagnostic value. Sometimes the immune responses to the viruses themselves may result in immunopathological processes leading to disease. This may occur in several different ways, such as through the deposition in blood vessels of immune complexes formed between an antiviral antibody and viral antigen. In other cases, such as lymphocytic choriomeningitis virus infection, the induction of virus-​specific cytotoxic T lymphocytes is itself responsible for the production of encephalitis. In Japanese encephalitis there is evidence of cytokine mediated apoptosis of non​infected cells. Pathology Meningitis Viral meningitis is mostly a non​fatal disease and, as a result, less is known about the pathology. The basal leptomeninges, ependyma, and choroid plexus are infiltrated with mononuclear cells, but the parenchyma is normal. In mumps meningitis there may be exfoli- ation of ependymal cells. HSV-​2 meningitis often occurs following reactivation. HSV-​2 preferentially lies latent in the sacral ganglia, as opposed to HSV-​1 which preferentially has latency in the trigeminal ganglia. This dif- ference may account for the fact the HSV-​2 predominantly causes meningitis and HSV-​1, encephalitis. HSV-​2 is primarily transmitted sexually and is much more common in women than men, hence HSV-​2 meningitis also predominantly occurs in women. Enteroviruses predominantly cause meningitis in older children and young adults, but can also lead to a polio-​like illness (especially EV71 and EV68) and encephalitis which can be fatal in young chil- dren. Enteroviral meningitis normally occurs following a primary infection, acquired via the faeco-​oral route, and probably occurs section 24  Neurological disorders 6086 following haematogenous spread. Enterovirus can be detected in the blood in some cases. VZV meningitis can, and often does, occur in the absence of a rash—​either following primary infection or reactivation. It often oc- curs in older adults, possibly as a result of immunosenescence that is also associated with an increased risk of shingles in that age group. Cerebellar ataxia is an uncommon complication following primary VZV infection in children. Poliomyelitis In poliomyelitis the virus is distributed widely throughout the brain and spinal cord, possibly even in non​paralytic cases, but usually the only cells to suffer chromatolysis and phagocytosis are motor neurons in the anterior horns of the spinal cord, medulla, and grey matter of the precentral gyrus. Encephalitis Most viral encephalitides are characterized by infiltration of the meninges and perivascular cuffing (in the Virchow–​Robin spaces) in the cortex and underlying white matter, by lymphocytes, plasma cells, histiocytes, and some neutrophils. There is also proliferation of microglia with the formation of glial nodules. Neuronolysis and demyelination are variable in their degree and location. Infected neurons may show characteristic inclusion bodies in their nuclei (measles, HSV and adenoviruses) or cytoplasm (Negri’s bodies in rabies). Microhaemorrhages and foci of necrosis may be found. Herpes simplex encephalitis Characteristic features of herpes simplex encephalitis are cerebral oedema and a severe haemorrhagic, necrotizing encephalitis. The disease is often asymmetrically localized to the inferior and medial parts of the temporal lobe, the insula, and the orbital part of the frontal lobe. Histological sections show eosinophilic Cowdry type A intranuclear inclusions with margination of chromatin in neurons, oligodendrocytes and astrocytes, inflammatory and haemorrhagic perivascular reactions, but no demyelination. Cowdry type A in- clusions are also found in VZV and CMV encephalitis. The unique cerebral localization of herpes simplex encephalitis has not been sat- isfactorily explained, but is probably the result of viral spread along specific neural pathways rather than a differential susceptibility of particular cell populations. A popular idea is that HSV spreads along olfactory pathways to the base of the brain and temporal lobes, but it is also possible that virus may spread from the trigeminal ganglia through sensory fibres innervating the dura near these regions. This latter mechanism is consistent with the discovery of latent HSV-​1 in the trigeminal, superior cervical and vagal ganglia in a high pro- portion of normal individuals, irrespective of whether they have a history of mucocutaneous herpes infections (‘cold sores’). Latent HSV-​1 might be reactivated by a variety of stimuli, such as sun- light, fever, trauma, and stress; however, the actual mechanisms underlying its latency and reactivation in the nervous system are not yet fully understood. If herpes simplex encephalitis is caused by the reactivation of latent virus, its rarity, despite ubiquitous asymptom- atic infection in humans, is hard to explain. Japanese encephalitis Microscopic appearances are typical of other viral encephalitides: there is oedema, congestion, focal haemorrhages of the brain and meninges, perivascular cuffing, neuronophagia, and glial nodules of the brain parenchyma. There may also be punched out necrotic lesions giving a ‘Swiss cheese’ appearance, which is characteristic of Japanese encephalitis. Neuronolysis and neuronophagia are un- usually widespread in the thalamus, basal ganglia, brainstem, cere- bellum (where there is marked destruction of Purkinje’s cells) and the spinal cord. Viral antigen is localized to neurons, especially in the brainstem, thalamus, and basal ganglia. West Nile virus encephalitis Pathological changes include varying degrees of neuronal necrosis in the grey matter, with infiltrates of microglia and polymorpho- nuclear leucocytes, perivascular cuffing, neuronal degeneration, and neuronophagia. Viral antigens have been demonstrated in neurons and in areas of necrosis. No antigen has been detected in other major organs, including lung, liver, spleen, and kidney. The major patho- logical lesions are seen in the brainstem and spinal cord. Nipah virus encephalitis Pathological studies on the brains of fatal cases demonstrated that the endothelium of small blood vessels in the CNS was par- ticularly susceptible to infection. This led to disseminated endo- thelial damage and syncytium formation, vasculitis, thrombosis, ischaemia, and microinfarction. There was also evidence of neur- onal infection by the virus that may have contributed to neuro- logical dysfunction. Enterovirus 71 There is severe perivascular cuffing, parenchymal inflammation, and neuronophagia in the spinal cord, brainstem, and diencephalon, and in focal areas in the cerebellum and cerebrum. Although no viral inclusions have been detected, immunohistochemistry showed viral antigen in the neuronal cytoplasm. Inflammation was often more extensive than neuronal infection, suggesting that other indirect fac- tors may be involved in tissue damage in addition to the effects of direct viral invasion. Clinical features Meningitis Symptoms include fever, headache, photophobia, and a stiff neck, but no symptoms are pathognomonic and symptoms alone cannot differentiate between bacterial and viral meningitis or indeed be- tween meningitis and other illnesses mimicking meningitis (e.g. upper respiratory tract infections and simple viral illnesses such as influenza), hence the need for lumbar puncture if there is any suspicion. Other non​specific symptoms such as nausea, anorexia, vomiting, abdominal pain, myalgia, and sore throat are common, particularly in enteroviral meningitis. Myalgia is particularly se- vere with coxsackievirus B infections. As in acute bacterial men- ingitis, infants with viral meningitis usually present with vague irritability and a tense fontanelle, and young children with fever and irritability or lethargy. Conjunctival injection, pharyngitis, and cervical lymphadenopathy may be found. Macular or pe- techial exanthems or enanthemas are seen with coxsackievirus A and B and echovirus infections (especially echovirus 9). Vesicles 24.11.2  Viral infections 6087 on the hands, feet, and mouth occur with coxsackievirus A16 and enterovirus 71 infections. By definition, the level of consciousness is normal in viral meningitis. If there is a reduction in conscious level or change in personality then alternative diagnoses should be considered such as viral encephalitis or bacterial meningitis. A prodromal influenza-​like illness, followed by a brief remission of symptoms, is typical of lymphocytic choriomeningitis viral in- fection or tick-​borne encephalitis, but in most cases of viral men- ingitis symptoms start suddenly. Occasionally genital or rectal vesicles associated with HSV-​2 or VZV skin lesions may occur. Other extraneurological features that may indicate a specific cause include: swelling in the parotid region (mumps, and occasionally coxsackie, lymphocytic choriomeningitis, and EBV), orchitis (mumps and lymphocytic choriomeningitis virus) and arthritis (lymphocytic choriomeningitis virus). Recurrent lymphocytic meningitis Most cases of recurrent viral meningitis are due to HSV-​2, al- though there have been case reports of recurrences with most viruses. Recurrent lymphocytic meningitis is often called by the eponymous term Mollaret’s meningitis, although in the original described condition the predominant cells in the cerebrospinal fluid (CSF) were polymorphs. In Mollaret’s meningitis there is complete spontaneous recovery and symptom-​free intervals lasting from a few days to years. Large monocytes (Mollaret’s) cells are occasionally seen. Other causes of recurrent meningitis include Behçet’s syndrome, CSF leak, Vogt–​Koyanagi–​Harada syndrome, sarcoidosis, and sys- temic lupus erythematosus. Myelitis Polioviruses (see Chapter  8.5.8) are acquired by droplet spread from the respiratory tract or by the faecal–​oral route. A ‘minor illness’, coinciding with viraemia, is a non​specific episode of influenza-​like symptoms—​fever, headache, sore throat, malaise, and mild gastrointestinal symptoms—​which resolves in a few days. Most of those infected have no further symptoms but, in a minority, a ‘major illness’ follows, sometimes after a few days’ re- mission of symptoms. The features of muscle pain, spasms, and sensory disturbances may precede or accompany the development of lower motor neuron (flaccid) paralysis. Some may also have fea- tures of meningeal irritation such as neck stiffness, photophobia, or encephalitis. Any combination of motor unit deficits may be seen. Respiratory and bulbar paralysis is life-​threatening. The most common causes of death are aspiration and airway obstruction, re- sulting from bulbar paralysis and paralysis of respiratory muscles. Disturbances of respiratory and cardiac rhythm, thought to be the result of damage to medullary vasomotor and respiratory centres, are extremely uncommon. Other complications include impaired control of body temperature and blood pressure, gastrointestinal haemorrhage, aspiration pneumonia, and paralysis of the bladder and bowel. Other enteroviruses that cause myelitis demonstrate a similar clinical picture; EV71 is the most important of these. A small single centre study of children with acute flaccid paralysis thought to be due to EV68 had proximal and asymmetric flaccid limb weakness. Most children in this series had involvement of the upper limbs and cranial nerve dysfunction which is dissimilar to poliovirus infections. HTLV-​1 causes a spastic paraparesis characterized by weak- ness of the lower limbs, associated gait disturbance, and urinary bladder dysfunction. Around 50% of cases may have a sensory disturbance. Encephalitis Most patients with viral encephalitis present with the symptoms of fever, headache, seizures, lethargy, and personality or behavioural changes. In children irritability may be an important symptom. Focal neurology is present in approximately a third of patients. Herpes simplex encephalitis As well as the usual clinical features of severe viral encephalitis, pa- tients with herpes simplex encephalitis have symptoms related to the focal nature of the encephalitis (frontal and temporal cortex and limbic system) (Fig. 24.11.2.1). These include behavioural abnor- malities, olfactory and gustatory hallucinations, anosmia, amnesia, expressive aphasia, and temporal lobe seizures. Most deaths occur within the first 2 weeks. Measles encephalitis Measles virus can cause encephalitis in several different ways. It can cause primary measles encephalitis which occurs at the same time as the rash. This occurs in about 1 in a 1000 people who have measles. There is also an immune mediated encephalitis that oc- curs in the immediate period after an acute measles infection. This postmeasles encephalitis is associated with brain swelling and should be treated with steroids. Measles inclusion body en- cephalitis occurs mostly in immunodeficient children within one year of infection or vaccination, and finally subacute sclerosing panencephalitis (SSPE) can occur several years after the acute mea- sles infection. There are characteristic electroencephalographic (EEG) changes in SSPE (Fig. 24.11.2.2) and very high levels of measles IgG are found in the CSF. The risk of SSPE seems to be greater if measles is contracted at an early age. Japanese encephalitis (See Chapter 8.5.14.) After an incubation period of 7–​14 days, patients develop non-​ specific prodromal symptoms (fever, headache, malaise, and nausea) lasting 2 to 3 days. Neurological symptoms begin with a deteriorating level of consciousness, and often generalized con- vulsions, especially in children, which may lead to status epilep- ticus. Parkinsonian and extrapyramidal features occur frequently and choreoathetoid movement disorders or severe dystonias can last for many months (Fig. 24.11.2.3). The case fatality rate is 20% in those admitted to hospital. Most deaths occur in the first 7–​10 days from respiratory failure, aspiration pneumonias, intra- cranial hypertension, or uncontrolled seizures. Up to 50% of sur- vivors suffer from intellectual impairment, psychiatric problems, persistent epilepsy, or a vegetative state (Fig.  24.11.2.4a) with spastic quadraparesis or evidence of basal ganglia involvement (Fig. 24.11.2.5), such as dystonia of the limbs and trunk, rigidity, and tremor (Fig. 24.11.2.4b). Nipah virus encephalitis (See Chapter 8.5.7.) (b) (a) Fig. 24.11.2.1  (a, b) Magnetic resonance (MR) scans of herpes simplex encephalitis in two Vietnamese patients showing the characteristic bilateral and extensive damage particularly to the temporal lobes but often extending to other parts of the cerebral cortex. Fig. 24.11.2.2  EEG changes in subacute sclerosing panencephalitis showing periodic complexes approximately one every 3 seconds. 24.11.2  Viral infections 6089 The main clinical features of Nipah virus encephalitis are fever, headache, dizziness, reduced consciousness, and prominent brainstem dysfunction. Distinctive signs included myoclonus, areflexia, hypotonia, hypertension, and tachycardia, suggesting extensive brainstem and spinal cord involvement. MRI during the acute illness shows widespread focal lesions in subcortical and deep white matter and, to a lesser extent, in grey matter on T2-​weighted sequences (Fig. 24.11.2.6). Long-​term sequelae are common. West Nile virus encephalitis West Nile virus infections can present either as a simple febrile illness—​West Nile fever—​meningitis or encephalitis. Encephalitis is the rarest of these but the most severe. In endemic areas, infection with West Nile virus is usually asymptomatic or associated with a mild flu-​like illness. When the virus is introduced into a naïve population as it was in the United States of America in 2001, the incidence of encephal- itis rises particularly in older people. An erythematous rash of the neck, trunk and limbs is present in 20% of cases. Extrapyramidal symptoms are common. Muscle weakness, areflexia, and diffuse flaccid paralysis in association with an axonal polyneuropathy are also reported. Tick-​borne encephalitis (See Chapter 8.5.14.) A feverish illness accompanied by myalgia, headache and fa- tigue develops 4–​28 days after the tick bite. Between 1 and 33 days later, about one-​third of the patients will develop meningitis, meningoencephalomyelitis, myelitis, or meningoradiculitis. Enterovirus 71 As the goal of poliomyelitis eradication appears more achiev- able, another enterovirus is emerging as a significant cause of acute neurological disease in Asia. EV71 was first recognized in 1969 and is responsible for a variety of clinical manifestations, including:  hand, foot, and mouth disease; aseptic meningitis; meningoencephalitis; and acute flaccid paralysis. In contrast to other enteroviruses, the encephalitis associated with EV71 nor- mally affects the brainstem and is associated with cardiovascular instability—​possibly due to neurogenic pulmonary oedema. Myoclonic jerks are also more common in EV71 encephalitis. (a) (b) (c) (e) (d) Fig. 24.11.2.3  Japanese encephalitis in Anuradhapura, Sri Lanka. (a) Comatose female patient showing symmetrical chorioathetotic movements of the upper limbs. (b) Comatose child showing dystonic movements of the upper and lower limbs. (c) Convalescent child, conscious but with residual dystonia of all four limbs. (d) Convalescent child with floppy head and involuntary movements of all four limbs. (e) Convalescent boy with residual weakness of the neck flexors. Courtesy of Dr D T D J Abeysekera. section 24  Neurological disorders 6090 Most patients with neurological infection due to EV71 will also have features of hand, foot, and mouth disease—​a common mani- festation of EV71. Postinfectious encephalomyelitis Encephalomyelitis also occurs as a rare complication of other fe- brile illnesses. Sudden convulsions, coma, fever, or pareses appear 10–​14 days after infection with varicella, rubella, mumps, or influ- enza. In the case of varicella and rubella, encephalitic symptoms develop 2–​12 days after the rash has appeared, and in mumps before or after parotid swelling. Involuntary movements, cranial nerve le- sions (VII and III), pupillary abnormalities, nystagmus, ataxia, and upper motor neuron signs are common. Imaging usually shows an acute disseminated encephalomyelitis with demyelinating lesions in the white matter. A similar syndrome also occurs very rarely as a complication of immunisation. (a) (b) Fig. 24.11.2.6  MRI of two patients with Nipah virus encephalitis. Acute Nipah virus encephalitis in a 57-​year-​old pig farmer showing multiple focal lesions in the grey–​white matter junction. These are areas of infarction secondary to vasculitis. (a) courtesy of Drs B J Abdullah and Sazilah Sarj, Kuala Lumpur, Malaysia. (a) (b) Fig. 24.11.2.4  (a) Vietnamese patient in a vegetative state after Japanese encephalitis. (b) Thai patient with severe neurological sequelae after Japanese encephalitis. (a) copyright DA Warrell; (b) courtesy of the late Professor Prida Phuapradit. Fig. 24.11.2.5  MRI evidence of inflammation in the basal ganglia, cerebellar peduncles, and substantia nigra in Japanese encephalitis. 24.11.2  Viral infections 6091 Diagnosis Clinical and epidemiological features such as the season, known current epidemics, the patient’s age, occupation, animal con- tacts, and countries or areas visited recently may give some clues to the specific aetiology. However, in most cases laboratory tests and/​or imaging will be needed to confirm the diagnosis. A spe- cific diagnosis may be suggested by distinctive clinical features of the illness such as hydrophobia in rabies and temporal lobe features in herpes simplex encephalitis, or features of the asso- ciated infection (e.g. mumps parotitis, measles rash, skin and mucosal lesions of herpesviruses and gastrointestinal symptoms associated with enteroviral infections), but often these features are not present. Laboratory investigations The aim of any investigations should be to confirm the syndromic diagnosis and to demonstrate a specific aetiological agent (par- ticularly important for the potentially treatable herpesvirus in- fections) or to exclude potentially treatable non​viral causes of meningitis or encephalomyelitis (Table 24.11.2.1). The most important investigation is examination of the cerebrospinal fluid. Contraindications to lumbar puncture are the same as for acute bacterial meningitis (see Chapters 24.3.1 and 24.11.01). If there are lateralizing neurological signs or evidence of brain shift, a CT or MRI scan should be performed to exclude an intracranial mass lesion before contemplating a lumbar puncture. Initial CSF investigations The opening pressure is useful as a pointer to certain diagnoses. It is likely to be normal in viral meningitis, but is increased in encephalitis where there is intense cerebral oedema. Pleocytosis ranges from tens to thousands of cells per microlitre. Lymphocytes and other mononuclear cells normally predominate. The cerebro- spinal fluid contains erythrocytes or is xanthochromic in haem- orrhagic encephalitides, such as herpes simplex encephalitis or VZV meningitis, which is often accompanied by a vasculopathy. Protein concentration is usually increased in the range of 50–​ 150 mg/​dl with an increasing proportion of IgG as the disease progresses. Leakage of serum IgG into the cerebrospinal fluid and intrathecal IgG synthesis, indicated by a monoclonal band, are responsible. A blood glucose should be taken at the same time Table 24.11.2.1  Causes of aseptic meningitis,a with or without encephalitis or myelitis, other than viruses and postinfectious/​ postvaccinal syndromes Cause Diagnostic clinical feature or investigation Bacteria Acute bacterial meningitis (partially treated) Blood cultures CSF PCR (either specific target e.g. Neisseria meningitidis or Streptococcus pneumoniae or 16S ribosomal DNA PCR), Antigen detection (CIE, LA) Intracranial/​spinal abscess or empyema (parameningeal infections) Blood cultures Physical examination (exclude otitis media, trauma, dermoid sinus, and so on), radiographs, CT/​MRI, myelogram Brucella spp. CSF culture on serum-​dextrose agar, blood culture, serology, PCR Cat-​scratch disease bacillus Warthin–​Starry stain of skin and lymph nodes, skin test Mycobacteria CSF microscopy, culture; Mantoux test, chest radiograph, PCR Mycoplasma spp. CSF and serum IgM (IFA) Spirochaetes Leptospira spp. Serology Relapsing fevers Blood smear, mouse inoculation Lyme disease Serology (EIA, IFA), culture, CSF IgG (EIA IFT) Syphilis Serology (FTA-​abs test) serum and CSF Spirillum minus Microscopy of wound or lymph node aspirates, mouse inoculation Rickettsiae (Rocky Mountain spotted fever, murine, epidemic, scrub typhus) Serology (Weil–​Felix), skin biopsy IFT (RMSF) Fungi Blastomyces spp. CSF culture, EIA, demonstration at other sites, lung, skin, biopsy Candida spp. CSF culture (repeated) Coccidioides spp. CSF CFT, culture, microscopy Cryptococcus spp. CSF India ink, LA—​beware false positive with surface condensate on agar Histoplasma spp. CSF culture (repeated), demonstration at other sites, blood smear (buffy coat) serum, urine, CSF antigen detection (RIA) (continued) section 24  Neurological disorders 6092 as the CSF the lumbar puncture to allow comparison. The CSF to blood glucose ratio is usually normal or mildly decreased in viral brain infections. Lower levels are occasionally reported, es- pecially in mumps and lymphocytic choriomeningitis virus in- fections. Cerebrospinal fluid examination may be normal if it is performed very early in the illness, or there may be a predom- inantly neutrophil pleocytosis (e.g. in early in enteroviral men- ingitis or herpes simplex encephalitis); occasionally the glucose concentration is low. Virology Full laboratory resources allow a specific virus to be implicated in 60–​70% of cases of lymphocytic meningitis and in 20–​60% of patients with encephalitis (Table 24.11.2.2). Polymerase chain reaction on cerebrospinal fluid (CSF PCR) is now the mainstay of diagnosis for most viral causes of meningitis or encephalitis. Multiplex PCR has allowed the possibility to test for multiple pathogens at once—​this has proven to be cost effective and improve sensitivity. PCR is limited in many cases by the low viral load in the CSF. Identification of virus from a distant site is useful and suggestive, although not definitive of causation, in enteroviral disease (throat and stool samples by PCR). For some viruses detec- tion in the CSF is not diagnostic, for example, EBV and CMV may be found merely as a result of inflammation but may not necessarily be the cause of the illness. Specific viral IgM can be detected in serum for mumps, EBV, CMV, or measles, or using an IgM capture technique in the cerebrospinal fluid for Japanese encephalitis virus. This method is being used increasingly to detect IgM to other vir- uses. Serological evidence of disease does not necessarily confirm the cause of the neurological illness, as some peripheral infections can have prolonged periods of IgM positivity (e.g. West Nile virus). IgM may remain positive for up to one year and hence in areas of high endemicity may not be that useful. Seroconversion between acute and convalescent samples taken 2–​4 weeks apart or detecting higher IgM antibody levels in CSF than in blood can provide stronger evidence of causality. Avidity testing has also proven useful Cause Diagnostic clinical feature or investigation Protozoa Amoeba (Acanthamoeba spp., Naegleria spp., Balamuthia spp.) CSF microscopy (fresh wet preparation + India ink), culture Malaria (cerebral) Blood smears Toxoplasma spp. (Immunocompromized patients—​AIDS) CSF animal inoculation, serology, brain biopsy Trypanosomiasis (African and South American) Blood smear (buffy coat), lymph node aspirate, CSF microscopy, and IgM, serology, xenodiagnosis Helminths Angiostrongylus cantonensis CSF larvae, eosinophilia Cysticercosis CT/​MRI, radiographs, examination for subcutaneous cysts, CSF CFT, histology Gnathostoma spinigerum Cutaneous migratory swelling, CSF eosinophilia Hydatid disease Casoni test, serology, CT/​MR scan, radiographs Paragonimus spp. CSF ova, eosinophils, serology, CT/​MR scan or skull radiograph, histology Schistosomiasis Low transverse myelitis, ova in urine or stool, CT/​MRI, CSF eosinophilia, myelogram, histology Sparganosis Histology, CT/​MR scan Strongyloides stercoralis (Immunocompromized patients) larvae, ova in stool, duodenal fluid, and so on Other Behçet’s syndrome Clinical syndrome Carcinomas, cysts, leukaemias, lymphomas CSF cytology, evidence of condition elsewhere Chemical Recent lumbar puncture, spinal anaesthesia, myelography, isotope cisternography Drugs Non​steroidal anti-​inflammatory agents, immunomodulators, antimicrobials (e.g. trimethoprim) Kawasaki’s disease Clinical features, echocardiography, coronary angiography, and so on Lead encephalopathy Blood lead, blood smear, urinary coproporphyrins Sarcoidosis Histology, Kveim’s test, Mantoux test, serum Ca2+, ACE Systemic lupus erythematosus and other collagen/​vascular diseases Antinuclear antibodies, DNA antibodies, lupus erythematosus cells Vogt–​Koyanagi–​Harada syndrome Clinical syndrome Whipple’s disease Clinical features, jejunal histology ACE, angiotensin-​converting enzyme; CFT, complement fixation test; CIE, countercurrent immunoelectrophoresis; CSF, cerebrospinal fluid; EIA, enzyme immunoassay; FTA-​abs, fixed treponema antibody absorption test; HSV, herpes simplex virus; IFA, immunofluorescent antibody; LA, latex agglutination; PCR, polymerase chain reaction; RIA, radioimmunoassay; RMSF, Rocky Mountain spotted fever. a Aseptic meningitis: CSF pleocytosis but no bacteria stainable by Gram’s method and no growth on standard bacterial culture media. Table 24.11.2.1  Continued 24.11.2  Viral infections 6093 for some pathogens (e.g. CMV, West Nile virus, VZV, and mumps). The viraemia associated with Japanese encephalitis is very brief and isolation of the virus from cerebrospinal fluid is difficult. Virus can occasionally be isolated from post-​mortem material. Imaging of the brain and spinal cord The use of neuroimaging before a lumbar puncture (LP) has gen- erated considerable debate with some recommending cerebral imaging is performed before LP for all patients with suspected neurological infection. However, this can lead to unnecessary delays in treatment and LP, which reduces the likelihood of identifying a pathogen and potentially increasing mortality. The reason for neuroimaging is to detect cerebral herniation syn- dromes, or shift of brain compartments. If these are present and a LP is performed, there is a theoretical concern that a reduc- tion in pressure caused by the LP can precipitate a further brain shift which may lead to fatal herniation. Neuroimaging should be performed on patients who have clinical signs which may sug- gest brain shift and, if shift of brain compartments or herniation is found, LP should be delayed. Indications that brain shift might be present include focal neurological signs and reduced level of consciousness. Table 24.11.2.2  Specimens for the virological diagnosis of acute meningitis or meningoencephalomyelitis Virus Microbiological investigations CSF PCR Stool PCR Throat PCR Blood PCR Virus culture Acute serology Convalescent serology Intrathecal antibodies Avidity testing Other investigations Picornaviruses Polioviruses + + + –​ ++ from stool + + Other enteroviruses ++ + + + + + Parechoviruses ++ Herpesviruses Cytomegalovirus + –​ –​ –​ ++ Epstein–​Barr + –​ –​ –​ + Herpes simplex type 1 ++ –​ –​ –​ + –​ –​ + –​ Herpes simplex type 2 ++ –​ –​ –​ + –​ –​ + –​ HHV-​6b ++a –​ –​ –​ + –​ –​ –​ + Herpes B virus –​ –​ –​ ++ Herpes varicella zoster ++ –​ –​ –​ + Flaviviruses Japanese encephalitis virus + –​ –​ –​ + + ++ West Nile virus + –​ –​ –​ + + ++ + Tick-​borne encephalitis virus –​b –​ –​ +c + + + Bunyaviruses Toscana virus ++ –​ –​ –​ + + La Crosse –​ –​ –​ –​ –​ ++ ++ Other viruses Adenovirus ++ Mumps ++ + + Rabies + + ++ Nuchal skin biopsy Salivary PCR Lymphocytic choriomeningitis ++ + + HTLV-​1 + ++ ++ CSF, cerebrospinal fluid; HTLV, human T-​lymphotropic virus; PCR, polymerase chain reaction, TBE, tick-​borne encephalitis. ++ = first line investigations; + = useful adjunctive tests; –​ = not useful. a ​quantitative PCR can be useful in differentiating active replicating infection from chromosomally integrated virus. b ​may be positive in the rare cases of chronically progressive TBE disease (Siberian form). c ​unlikely to be positive in the second phase of the biphasic infection. section 24  Neurological disorders 6094 MRI, if available, is more sensitive that CT. As well as identifying any brain shift it is also useful for the diagnosis of the site, nature, and extent of any mass lesions, any associated oedema, sub-​ and epi- dural empyemas, hydrocephalus, demyelination, and other anatom- ical abnormalities (see Chapter 24.3.3). Few conditions will pathognomonic radiological appearances. Imaging will be very rarely needed in cases of straight forward viral meningitis. Herpes encephalitis may show classical temporal lobe involvement, 94% of patients have high-​signal T2-​hyperintense le- sions in the medial and inferior temporal regions, although this can occur in other conditions as well. MRI of the brain in West Nile en- cephalitis and other flaviviruses characteristically shows bilateral abnormalities in the basal ganglia and thalami. Leptomeningeal en- hancement is also commonly seen. Rabies encephalitis involves pre- dominantly the grey matter of the basal ganglia, thalamus, midbrain, and the pons. More discrete high-​signal intensity 2-​ to 7-​mm lesions, particularly in the subcortical and deep white matter of the cerebral hemispheres, have been associated with Nipah virus infection. Differential diagnosis Viral infections of the CNS must be distinguished from the many other conditions that produce similar clinical features and cere- brospinal fluid abnormalities. The differential diagnoses of viral meningitis are shown in Table 24.11.2.1. Viral myelitides must be distinguished from other causes of transverse myelitis and the Brown–​Séquard syndrome. These include spinal compression by tumours, abscesses, helminths or their ova, or vertebral disease. The differential diagnosis of viral myelitis includes: postinfectious and other immunopathic polyneuroradiculopathies, such as Guillain–​Barré syndrome; metabolic neuropathies such as acute porphyria; paralytic rabies; neoplastic polyradiculopathies; and rarities, such as tick paralysis and herpesvirus simiae (B virus) in- fection. The lack of objective sensory loss in poliomyelitis usually distinguishes it from these other entities. The differential diagnosis of viral encephalitis includes other in- fective encephalopathies:  bacterial, fungal, protozoal, and para- sitic; intracranial abscesses and neoplasms, and toxic and metabolic encephalopathies. Treatment Meningitis There is no specific antiviral treatment for almost all forms of viral meningitis. Aciclovir, which has proven anti-herpes activity, has never been trialled acutely in herpes meningitis. There is no consensus on its efficacy, resulting in a wide range of clinical practices with some who advocate no treatment and others who give up to 3 weeks of intra- venous aciclovir. A randomized trial of its pro-drug, valaciclovir (0.5 g twice daily) in recurrent HSV-​2 meningitis failed to show any benefit. Encephalitis Aciclovir (10 mg per kg three times daily for 2-3 weeks) is effective in treating herpes simplex encephalitis. This subject is also discussed in Chapter 8.5.2. Therapy with aciclovir should be started imme- diately on suspicion of encephalitis. Aciclovir is also the treatment for CNS associated VZV infections (usually at 15-20 mg/kg three times daily) and the rare, but very dangerous, encephalomyelitis caused by herpesvirus simiae B. For CMV infections, ganciclovir or foscarnet should be considered. Ribavirin is effective against some RNA viruses which occasionally cause encephalitis, such as those causing Lassa fever, haemorrhagic fever with renal syndrome, Congo Crimean haemorrhagic fever and possibly Argentine haem- orrhagic fever, and Rift Valley fever. Interferons have been used by intravenous, intrathecal, or intraventricular routes in the treatment of Japanese encephalitis, rabies, VZV, and other herpesvirus encephalitides, but have not proved effective in clinical trials. Hyperimmune plasma given within 8 days of the start of symp- toms has reduced the mortality rate of Argentine haemorrhagic fever (Junin virus) from between 20% and 30% to 1% and 3%. Intravenous immunoglobulin has proved effective in the treatment of Congo Crimean haemorrhagic fever. It is also widely used in Asia for the treatment of enterovirus 71, although evidence from randomized controlled trials is lacking. It has been reported favourably in case reports or feasibility studies in many other of the encephalitides, including Japanese encephalitis and West Nile virus. Myelitis There is currently no proven treatment for enteroviral disease. In the 2014 EV68 outbreak in the United States various treatment strat- egies were employed including combinations of steroids, intravenous immunoglobulin, plasmapheresis, and an experimental drug—​ pocapavir. None of these seemed to give any proven benefit, although numbers were small. Although most enteroviral infections are mild, given the propensity for some serotypes to cause serious life-​ and limb-​ altering disease there is a need to develop treatments and vaccines. Supportive treatment Corticosteroids have been used in the treatment of most of the viral encephalomyelitides, both in an attempt to combat cerebral oedema (especially in herpes simplex encephalitis) and for their other anti-​inflammatory effects. Convincing evidence of benefit from controlled trials is lacking, but the immunosuppressive ef- fects of corticosteroids have not led to obvious clinical deterioration. Corticosteroids (or adrenocorticotropic hormones) have also been used for postinfectious and postvaccinal encephalomyelitides, but the evidence for their efficacy is not convincing and, as they may ex- acerbate latent rabies in experimental animals, should be used only in life-​threatening cases of rabies postvaccinal encephalomyelitis. Severe intracranial hypertension should be treated with intravenous mannitol or mechanical hyperventilation. Nursing and general care are the same as for acute bacterial meningitis and tuberculous men- ingitis. Seizures should be treated but there is currently no evidence for prophylaxis, respiratory failure treated by mechanical ventila- tion, and attention given to fluid, electrolyte, and acid-​base balance. Prognosis and sequelae Viral meningitis generally has an excellent prognosis, but some pa- tients with HSV-​2 infection can have recurrent attacks. Additionally, there are increasing reports of neurocognitive problems following viral meningitis. Viral encephalitis and myelitis however can carry a significant mortality. Case fatality rates of some are as follows: rabies 100%; 24.11.2  Viral infections 6095 herpes simplex encephalitis (untreated) 40 to more than 75% (highest in neonates and those over 30 years old); Eastern equine en- cephalitis 50%; Japanese encephalitis 10–​40%; West Nile Virus 10%, measles 10–​20%; varicella 10–​30%; Western equine encephalitis 8%; St Louis encephalitis 3%; California encephalitis, Venezuelan en- cephalitis, and mumps less than 1%. The mortality rate of paralytic poliomyelitis increases from 5% in young children to more than 20% in adults. Postinfectious and postvaccinal encephalomyelitides carry case fatality rates of 15–​40%. Neurological sequelae are found in 5–​75% of survivors of Japanese encephalitis and herpes simplex encephalitis, and are common in infants. They include intellectual impairment, loss of memory, speech abnormalities (including subtle expressive aphasias), hemi- paresis, ataxia, dystonic brainstem and cranial nerve lesions, re- current convulsions, and various behavioural and personality disturbances. Sequelae are common with postinfectious enceph- alomyelitis. Post-polio syndrome is an unusual sequel to paralytic poliomyelitis developing after an interval of many years; it is a con- dition characterized by progressive muscle weakness and wasting, attributable to depletion of anterior horn cells, which has some similarities to motor neuron disease. Prevention Prophylactic immunization against poliomyelitis and measles has virtually eradicated encephalitides caused by these viruses in many communities. Pre-​ and postexposure rabies immunization has also proved effective in preventing rabies encephalitis. Vaccines are also available for Japanese encephalitis, tick-​borne encephalitis, mumps, and varicella. Some countries have been more successful than others in eliminating Japanese encephalitis; this is principally due to the extent of vaccine coverage for the disease. There is one live attenuated vaccine licensed for dengue virus, and a range of other vaccines are in various stages of development. Since the outbreak of West Nile infection in the United States of America, several vaccine candidates have been identified. Immune protection against infection was demonstrated in animal models and early human trials have shown good immunogenicity and toler- ability. Nipah virus vaccines are beginning to be assessed in animal models. Hyperimmune immunoglobulin has been used for passive im- munization following exposure to measles, cutaneous VZV, and rabies. Interferons have been used with some success to prevent herpesvirus infections (e.g. CMV in high-​risk groups such as renal transplant recipients). However, the evidence does not yet justify their routine recommendation. Prevention of neonatal HSV-​2 encephalitis can be attempted by treating any pregnant woman with signs and symptoms of genital herpes, followed by daily suppressive therapy with aciclovir. If a woman develops her first episode of genital herpes in the third tri- mester caesarean section is the recommended mode of delivery. Arthropod-​borne viral encephalitides can, to some extent, be prevented by avoiding or controlling the arthropod vectors (e.g. by the use of mosquito nets, insect repellents, insecticides), by at- tempting to control the numbers of wild vertebrate reservoir species, or by immunizing domestic animals, such as horses (Eastern and Western equine encephalitides). To control rabies, the principal wild mammalian vectors can be immunized (e.g. wild foxes, racoons, and black-​backed jackals have been immunized by distributing oral vaccine in bait). Domestic dogs and cats should be immunized. To prevent the viral encephalitides transmissible from laboratory animals (e.g. lymphocytic choriomeningitis from mice and rats, herpesvirus simiae B from monkeys) their screening, quarantine, handling, and housing should be strictly controlled. Other viral infections or disorders in which viruses play a role in the pathogenesis of neurological disease Reye’s syndrome Reye’s syndrome is an acute encephalopathy affecting children be- tween the ages of 2 and 16 years. The exact aetiology is not under- stood but it normally follows a viral illness and there is a strong association with aspirin use. It is a diagnosis of exclusion, but is rapidly fatal in 10 to 40% of cases. The defining characteris- tics are sudden impairment of consciousness, increase in serum aminotransferase concentrations (or, if a biopsy is done, a fatty liver). Symptoms develop a few days after varicella or an upper respiratory tract or gastrointestinal illness. Clusters of cases (me- dian age 11 years) have been associated with influenza B epidemics. Since the warnings regarding the use of aspirin the incidence has markedly decreased with only a handful of cases a year in both the United Kingdom and the United States. There is no specific treatment, but mortality can be reduced by treating hypoglycaemia, cerebral oedema, respiratory failure, fluid and electrolyte disturbances, and other complications. These meas- ures are also considered in Chapter 24.11.1. Progressive multifocal leucoencephalopathy (See Chapters 8.5.19, 8.5.23, and 24.11.4.) This disease is caused by opportunistic infection by papova- viruses, most commonly JC virus and the simian virus SV40. A high proportion of normal adults have antibodies to the former and the agent appears to be ubiquitous. Progressive multifocal leucoencephalopathy occurs in patients affected by lympho-​ or myeloproliferative diseases, sarcoidosis, other chronic granulomatous diseases, advanced HIV, and those who are therapeutically immunosuppressed. In patients with mul- tiple sclerosis, the monoclonal antibody natiluzimab, a and other immunosuppressives, have has led to an increase in patients with progressive multifocal leucoencephalopathy. Pathology JC virus particularly invades the nuclei of the oligodendroglia leading to demyelination of the white matter. The cerebellum and brain- stem are less often involved and the spinal cord is spared. Abnormal giant forms of oligodendrocytes with eosinophilic inclusions are seen microscopically, and arrays of intranuclear virus particles can often be identified by electron microscopy. JC virus antigen can be identified by immunofluorescence or immunohistochemistry. DNA probing has revealed unintegrated virus in oligodendrocytes, astro- cytes, endothelial cells, and extraneural organs such as kidney, liver, lung, spleen, and lymph nodes. section 24  Neurological disorders 6096 Clinical features The onset is usually with progressive signs of a focal lesion of one cerebral hemisphere, limb weakness, aphasia, or visual field defects such as homonymous hemianopia. More widespread signs gradually develop, leading to personality changes, intellectual deterioration, dysarthria or fluent aphasia, and bilateral weakness. Fits are rare. There is no systemic evidence of infection. Spontaneous temporary arrest or partial remission is common but eventual progression causes death in 6–​12 months, although far more chronic cases are on record, with survival, exceptionally, to 5 years. Investigation The cerebrospinal fluid is normal apart from occasionally a mild ele- vation of protein and slight pleocytosis, and is not under increased pressure. The EEG shows a bilateral excess of slow activity. The CT scan may at first show little abnormality, but eventually large, non-​ enhancing, low-​density lesions appear in the cerebral white matter. MRI is more sensitive. CSF can be tested by PCR for JC virus. If there is doubt the diagnosis can be confirmed by cerebral biopsy, but it is essential that white matter be included in the specimen. This may be important to distinguish lymphoma and, rarely, herpes simplex encephalitis involving white matter. Treatment In patients with progressive multifocal leucoencephalopathy asso- ciated with HIV the only treatment is to commence antiretrovirals, although there may still be significant sequelae. In patients on im- munosuppressive treatment reduction or removal of that treatment, if possible, can also help the outcome. There remains a need to iden- tify a specific antiviral treatment for this disease. Progressive rubella panencephalitis This extremely rare disorder (see Chapter 8.5.13) may follow con- genital rubella or rubella in early childhood. It evolves insidiously some 10 years after the original illness, similar to subacute sclerosing panencephalitis due to measles virus and is characterized by pro- gressive intellectual impairment with behaviour changes, fits, ataxia, spasticity, optic atrophy, and macular degeneration. Pathological changes are those of encephalitis with perivascular infiltration. The cerebrospinal fluid may show a slight rise in white cell and protein content, elevation of γ-globulin, and of antirubella antibodies to an extent greater than the rise in the serum level, suggesting local pro- duction of antibody within the CNS. The EEG may show changes similar to those seen in subacute sclerosing panencephalitis. The mechanism responsible for the appearance of this disorder is un- known and there is no effective treatment. Vogt–​Koyanagi–​Harada syndrome The cause of this rare syndrome is thought to be an inflammatory autoimmune reaction to an unidentified viral infection. The disorder affects tissues having a common embryological origin, the uvea and leptomeninges and the melanoblasts, ocular pigments, and auditory labyrinth pigments originating from the neural crest. The dermato- logical features consist of patchy whitening of eyelashes, eyebrows and scalp hair, alopecia, and vitiligo. Neurological manifestations include meningoencephalitis, raised intracranial pressure, neurosensory deafness, tinnitus, nystagmus, ataxia, ocular palsies, and focal cerebral deficits. Ocular features are those of uveitis with pain and photophobia, more generalized inflammation of the eye, retinopathy, and impaired visual acuity. The condition tends to be self-​limiting but may result in serious permanent ocular and neurological deficits. Steroids and immunosuppressive drugs have been used and are said to arrest the progression of at least some features of the disorder. EBV-​related neurological disease EBV, as well as occasionally causing meningitis and encephal- itis, can be responsible for other neurological conditions espe- cially in immunosuppressed patients. It is an oncogenic virus and is the cause of both primary CNS lymphoma and posttransplant lymphoproliferative disorder. Again, reduction of immunosup- pression, if possible, is important in these conditions and rituximab plays an important role in the treatment. Other neurological conditions where viruses may be involved Cerebrovascular disease and herpes zoster VZV infection is well known to cause a vasculopathy and has long been associated with the development of cerebrovascular disease. A cohort study has = shown it is an independent risk factor for vas- cular disease, especially cerebrovascular disease in young adults under the age of 40. HIV also increases the risk of cerebrovascular accidents. Immune mediated encephalitis Immune mediated encephalitis is increasingly being recognized as a cause of encephalitis in both children and adults. It includes acute disseminated encephalomyelitis which is considered else- where in Chapter 24.10.2, and autoimmune encephalitis which can account for around 10% of cases of encephalitis, and is associated with a range of anti-neuronal antibodies, including those directed against N-methyl-D-aspartate (NMDA), Leucine-rich, glioma inacti- vated 1 (LGI-1) and myelin oligodendrocyte glycoprotein (MOG). Autoimmune encephalitis may sometimes follow HSV encephalitis. FURTHER READING Aurelius E, et al. (2012). Long-​term valaciclovir suppressive treatment after herpes simplex virus type 2 meningitis: a double-​blind, ran- domized controlled trial. Clin Infect Dis, 54, 1304–​13. Baringer JR (2008). Herpes simplex infections of the nervous system. Neurol Clin, 26, 657–​74, viii. Campbell GL (2011). Estimating global incidence of Japanese Ence­ phalitis: a systematic review. Bull World Health Organ, 89, 766–​774E. Dayan GH (2012). Phase II dose ranging study of the safety and im- munogenicity of single dose West Nile vaccine in healthy adults ≥50 years of age. Vaccine, 30, 6656–​64. De Jong MD, et al. (2005). Japanese encephalitis-​a pathological and clinical perspective. PLoS Negl Trop Dis, 3, e437. De Ory F (2013). Viral infections of the CNS in Spain: a prospective study. J Med Virol, 85, 554–​62. JID Suppl 1 Nov 2014. Ellul MA (2016). Anti-​N-​methyl-​d-​aspartate receptor encephalitis in a young child with histological evidence on brain biopsy of co-​existent herpes simplex virus type 1 infection. Pediatr Infect Dis J, 35, 347–​9. Gaensbauer JT (2014). Neuroinvasive arboviral diseases in the United States 2003–​2012. Pediatrics, 134, e642–​50. 24.11.3 Intracranial abscesses 6097 Tim Lawrence a 24.11.3 Intracranial abscesses 6097 Tim Lawrence and Richard S.C. Kerr 24.11.3  Intracranial abscesses 6097 Goh KJ, et  al. (2000). Clinical features of Nipah virus encephalitis among pig farmers in Malaysia. N Engl J Med, 342, 1229–​35. Granerod (2010). Causes of encephalitis and differences in their clin- ical presentations in England: a multicentre, population-​based pro- spective study. Lancet Infect Dis, 10, 835–​44. Gyure KA (2009). West Nile virus infections. J Neuropathol Exp Neurol, 68, 1053–​60. John CC (2015). Global research priorities for infections that affect the nervous system. Nature, 527, S178–​86. Landry (2009). Herpes simplex type 2 meningitis: presentation and lack of standardised therapy. Am J Med 122, 688–​91. Mansfield KL, et al. (2009). Tick-​borne encephalitis virus—​a review of an emerging zoonosis. J Gen Virol, 90, 1781–​94. McGill F, Griffiths MJ, Bonnett L, Geretti AM, Michael BD, Beeching NJ, McKee D, Scarlett P, Hart IJ, Mutton K, Jung A, Adan G, Gummery A, Sulaiman WAW, Ennis K, Martin A, Haycox A, Miller A, Solomon T, on behalf of the UK Meningitis Study Investigators. Viral meningitis in UK adults - a multicentre prospective observational cohort study of incidence, aetiology and sequelae. Lancet Infect Dis (2018) In Press. Messacar K (2015). A cluster of acute flaccid paralysis and cranial nerve dysfunction temporally associated with an outbreak of enterovirus D68 in children in Colorado, USA. Lancet 385, 1662–​71. Muñoz LS, Barreras P, Pardo CA (2016). Zika Virus-Associated Neurological Disease in the Adult: Guillain-Barré Syndrome, Encephalitis, and Myelitis. Semin Reprod Med, 34(5), 273–79. Epub 2016 Sep 9. Ooi MH, et  al. (2007). Human enterovirus 71 disease in Sarawak, Malaysia:  a prospective clinical, virological, and molecular epi- demiological study. Clin Infect Dis, 44, 646–​56. Schuler Faccini L (2016). Possible association between zika virus infection and microcephaly—​Brazil 2015. MMWR, 65, 59–​62. Sejvar JJ, et al. (2007). Long-​term neurological and functional outcome in Nipah virus infection. Ann Neurol, 62, 235–​42. Shalabi M (2006). Benign recurrent lymphocytic meningitis. Clin Infect Dis, 43, 1194–​7. Solomon T (2004). Flavivirus encephalitis. N Engl J Med, 351, 370–​8. Solomon T, Baylis M, Brown D (2016). Zika virus and neurological disease-​approaches to the unknown. Lancet Infect Dis, 16, 402–​4. Turtle L, Solomon T (2018). Japanese encephalitis—the prospects for new treatments. Nat Rev Neurol, 14, 298–33. Tyler, K L (2018). Acute viral encephalitis, N Engl J Med, 379(6), 557–66. Vora NM (2014). Burden of encephalitis associated hospitalisations in the United States 1998–​2010. Neurology, 82, 443–​51. Weber T (2008). Progressive multifocal leucoencephalopathy. Neurol Clin, 26, 833–​54, x–​xi. 24.11.3  Intracranial abscesses Tim Lawrence and Richard S.C. Kerr ESSENTIALS An intracranial abscess is a life-​threatening condition. Although the incidence is low in countries where antimicrobial treatment for infec- tions is widespread, they remain frequent causes of space-​occupying masses in developing countries and, therefore, an important cause of death and disability. Early diagnosis and intervention is vital in redu- cing potential subsequent sequelae. Intracranial abscesses can be broadly divided into three categories based on their anatomical location:  extradural, subdural, and intraparenchymal. Aetiology—​frequently brain abscesses occur in at ‘risk patients’, such as the immunocompromised, those suffering from HIV/​AIDS and those in whom the anatomical barriers to infection have been disrupted (trauma, surgical intervention, mastoiditis, and so on). However, intracranial abscesses are often seen in healthy individuals with no risk factors, and in such individuals it may be difficult to iden- tify an underlying cause. In general abscesses may be classified by: (1) Route of transmission, including (a) direct—​from a local source of in- fection (e.g. otitis media); (b) haematogenous—​from a distant source (e.g. endocarditis, bronchiectasis, other septic lung conditions); or (c) following cranial surgery or fracture and: (2) Microbiology—​the most common organisms are aerobic, anaerobic, and micro-​ aerophilic streptococci, Staphylococcus aureus, and Bacteroides, but up to 25% of abscesses are sterile. Clinical features and investigation—​typical presentations include headache, focal neurological symptoms/​signs, seizures, meningism/​ meningitis, and signs of raised intracranial pressure. The investiga- tions of choice are either CT scanning, with and without contrast, or MRI. Confirmation of diagnosis, usually by culture, follows aspir- ation/​excision. Treatment and prognosis—​aside from supportive care and (where possible) identification and treatment of any underlying cause, treat- ment requires (1) abscess drainage by image-​guided surgical aspir- ation or excision by craniotomy, and (2)  long-​term antimicrobial therapy. Early intervention offers the best chance of recovery. Without intervention, intracranial abscesses are fatal. With appropriate treat- ment overall mortality is between 6.6% and 12.7%, depending on the surgical method used (aspiration compared with craniotomy, re- spectively). Long-​term complications from neurological deficit and epilepsy remain frequent in survivors. Introduction Intracranial abscesses, although less common since the introduction of antibiotics and improved treatment of systemic infections, still cause significant morbidity and mortality. The exact incidence and prevalence of intracranial abscesses is difficult to establish in the ab- sence of a comprehensive international study; however, small limited, population surveys suggest an incidence of approximately 0.4–​0.9 per 100 000 people in countries such as the United States, and greater in developing countries where intracranial abscesses account for up to 8% of all intracranial space-​occupying lesions, compared with 2% in developed countries. The use of modern imaging techniques and a combination of antibiotics and image-​guided surgery has resulted in a reduction in morbidity and mortality in these patients. Intracranial abscesses can be categorized according to their ana- tomical location, occurring in the extradural space, subdural space, or intraparenchyma. Occasionally, abscesses exist in more than one tissue plane. Intracerebral and subdural abscesses may rupture into the subarachnoid space and be accompanied by meningitis. Intracerebral pus may rupture into the ventricular system and pro- duce ventriculitis. section 24  Neurological disorders 6098 Aetiology The aetiology can be divided according to the route of transmission: • Direct—​microorganisms spreading from a local source of infec- tion such as otitis media, mastoiditis, paranasal sinusitis, or dental infection. • Haematogenous—​microorganisms spreading from a distant source such as a right-​to-​left shunt secondary to cyanotic con- genital heart disease in children, or subacute endocarditis, bron- chiectasis, and lung abscesses in adults. Abscesses can also form after intracranial surgery or cranial trauma. Immunodeficient patients are at increased risk of developing ab- scesses, either secondary to conditions such as AIDS or leukaemia. It is also thought that ischaemic brain tissue may encourage bac- terial invasion and, therefore, abscesses can develop in closed head injuries and following cerebral infarcts, although this is rare. The most common intracranial abscess is found within the intracerebral compartment, with about 60% related to middle-​ear infection and 20% to frontal sinusitis. In about 10% of cases no pri- mary source of infection can be identified. Owing to their strong connection with sinus and middle-​ear disease, most intracerebral abscesses are found within the frontal or temporal lobes, or within the cerebellum. Infection disseminated through the bloodstream from more distant sites may result in multiple abscesses in any part of the brain. Microbiology The most common organisms associated with intracranial ab- scesses are aerobic, anaerobic, and microaerophilic streptococci, Staphylococcus aureus, and Bacteroides. However, up to 25% of cul- ture samples are sterile. Cerebral abscesses associated with otitis media, mastoiditis, and nasal sinusitis usually show a mixed growth of anaerobic and aerobic organisms including anaerobic and microaerophilic streptococci and Bacteroides, Strep. Viridans, and Staph. aureus are also frequently seen. Listeria tend to produce areas of focal cerebritis rather than true abscesses. Abscesses associated with frontoethmoidal sinusitis are usually due to Strep. milleri and Strep. angiosus. With trauma the organism is often Staph. aureus or one of the Enterobacteriaceae. Pathology There are four distinct histological stages in the pathogenesis of intracranial abscesses. Spread of microorganisms, either direct or haematogenous, causes parenchymal damage after occlusion of the small vessels. The initial stage is early cerebritis (days 0–​3) char- acterized by a local inflammatory response with perivascular and parenchymal neutrophil infiltration. During late cerebritis (days 3–​9) a central necrotic area forms with macrophage infiltration. A  reticulin network forms around the necrotic area in the early capsular stage (up to day 14)  with parenchymal oedema. This is followed by the formation of a collagen capsule with distinct zones of neovascularization during the late capsular stage (after day 14). Perilesional cerebral oedema continues, and gliosis takes place. The areas of oedematous brain may exert considerable mass effect. In the case of direct spread, infection within an accessory air sinus or the petrous bone may cause an area of localized osteitis just above the dura. This can then spread intracranially. Initially it may be en- tirely confined to the extradural space, but will eventually penetrate the dura and spread subdurally. If the adjacent arachnoid is stuck to the inflamed patch of dura then it may spread into the subarach- noid space to give meningitis. If the subarachnoid space has been obliterated, it may penetrate the brain to produce initially a focal cerebritis. Large intracerebral abscesses can rupture into the ven- tricular system, producing a ventriculitis. Clinical features Presentation depends upon the site, size, and number of lesions, and the involvement of neighbouring structures such as the cerebral ventricles and the venous sinuses. The signs are, therefore, legion but the diagnosis should be considered in any case where there is an ob- vious primary source of infection associated with evidence of raised intracranial pressure, focal neurological signs, headache, seizures, or meningeal irritation. Extradural abscess may be difficult to detect clinically, but can sometimes manifest as severe, unremitting, localized headache in association with sinusitis or mastoiditis. Patients with subdural empyema frequently appear toxic, with a swinging pyrexia, severe headache, a depressed level of consciousness, contralateral hemipar- esis, papilloedema, meningeal irritation, and seizures. There is often an accompanying frontal sinusitis with tenderness of the forehead, erythema, and swelling of the eyelids. Diagnosis If a brain abscess is suspected, predisposing sources of infec- tion, including possible distant sites, should be carefully sought. Intracranial abscesses derived from haematogenous spread are often more fulminating in their course than those associated with direct spread. CT scans of the skull base, including views of the mastoids and other skull sinuses, should be performed. The investigations of choice for all forms of suspected intracranial abscess are either CT scanning, with and without contrast, or MRI (with and without enhancement). CT will normally demonstrate both extradural and subdural empyema and show intracerebral abscesses as ring-​enhancing lesions with low-​attenuation centres (Fig. 24.11.3.1). The CT and MRI appearances correlate closely with the pathogenesis. During the early stages of cerebritis areas of hypodensity may be very subtle with minimal contrast enhance- ment. At this stage MRI may reveal oedema and some ring enhance- ment not evident on CT. Subdural empyema may initially be thinly spread over the cerebral cortex, producing relatively little midline shift, appearing virtually isodense with brain on CT. Under such circumstances, contrast-​enhanced MRI (particularly with coronal views) is of great value. Diffusion-​weighted imaging with MRI can help differentiate a pyogenic abscess from other ring-​enhancing le- sions. Proton MR spectroscopy can be used to show peaks of lactate and cytosolic amino acids present in abscesses. 24.11.3  Intracranial abscesses 6099 The principal differential diagnoses in an intracranial abscess are meningitis, subdural haematoma, and intracranial tumour. It is not always possible to differentiate between intracerebral abscess and tu- mour on a CT scan, particularly when there is an appearance of ring enhancement, and it is largely for this reason that the biopsy of sus- pected cerebral tumour is advocated in nearly all such cases. MRI, however, tends to show a low-​signal capsule on T2-​weighted images and may be helpful in making this differentiation. One obvious concern is to differentiate between bacterial menin- gitis and intracerebral abscess. Both may present with pyrexia, neck stiffness, and some focal signs, but if there is any evidence of raised intracranial pressure, or any other supportive evidence of cerebral abscess, a lumbar puncture should be strictly avoided until a neuro- surgical opinion has been sought. Lumbar puncture in the presence of cerebral abscess can lead to tonsillar or tentorial herniation. The cerebrospinal fluid can be entirely normal in intracranial abscesses. Management Treatment includes identifying and treating the underlying cause and image-​guided surgical aspiration or excision of the abscess by craniotomy combined with long-​term antibiotics. Selected pa- tients can be managed without surgical intervention. This tends to be limited to those who have multiple or inaccessible abscesses and those in whom surgery is contraindicated due to poor general med- ical condition. However, without biopsy the diagnosis cannot be confirmed and the pathogens cannot be identified. Therefore, tissue should be obtained if at all possible. Early diagnosis and treatment are essential for good outcomes. The damaging effect of abscesses results from parenchymal dis- placement and oedema rather than destruction of tissue, so neurological deficits may be reversible. Treatment is aimed at identifying the causative organism, obtaining antibiotic sensitiv- ities, and reducing mass effect. Early management includes the fol- lowing steps: culturing blood and any extracranial infective lesion, obtaining tissue and starting appropriate intravenous antibiotics, administration of anticonvulsant agents, and, in cases of grossly depressed level of consciousness and massive cerebral oedema seen on a CT scan, giving intravenous dexamethasone. Steroids decrease cerebral oedema but are also thought to prevent antibiotic penetration. Therefore, they should only be used in patients with mass effect on CT. Pus from the suspected primary site of infection should be col- lected immediately and both aerobic and anaerobic cultures obtained. The intracranial pus must be similarly cultured. High dose intravenous empirical antibiotics should be commenced im- mediately without waiting for the culture report, and subsequently changed in the light of the sensitivity findings. The antimicrobial regimen should include metronidazole and, usually, a β-​lactam such as ceftriaxone, depending on the likely source of infection and the infective agent. Meropenem is an alternative. Although antibiotics have good penetration into cerebrospinal fluid, the acidic environ- ment of the abscess means that the efficacy of the antibiotic may be reduced. Intravenous antibiotics should be continued for sev- eral weeks before reverting to oral medication. Infection specialists should be involved in decisions regarding length and nature of anti- biotic treatment. Most supratentorial abscesses can be treated by aspiration through a burr hole. Aspiration is often repeated several times, but in about 30% of cases a single aspiration will suffice. Once the abscess is sterile, the capsule will shrink and finally form an irregular gliotic scar within the brain. Shrinkage of the abscess must be checked by serial CT or MRI scans. Subdural empyema should be evacuated through a craniotomy rather than burr holes, as very frequently the pus can spread widely, particularly alongside the falx cerebri. Extradural empyema is evacuated through a burr hole, or through a craniotomy for larger collections to allow complete excision of the abscess. Advances in image-​guided surgery have resulted in far more accurate and safe targeting of all intracranial lesions including ab- scesses and should be used to aid any surgical intervention. Cerebellar abscesses, when diagnosed early, may be aspirated through a burr hole, but immediate total excision is often recom- mended because the small volume of the posterior cranial fossa leaves little latitude in terms of tonsillar herniation and death. Prognosis The mortality rate from intracranial abscesses has been reduced from 40–​60% to around 10% since the introduction of CT scanners. The main problems remain those of late diagnosis and resistant bac- teria. Epilepsy and permanent disability still occur in up to 50% of cases. Temporal lobe abscess, subdural empyema, and abscesses that rupture into the ventricles have a worse prognosis. Fungal abscesses can occur in immunosuppressed individuals and carry a much higher mortality rate. FURTHER READING Helweg-​Larsen J, et al. (2012). Pyogenic brain abscess, a 5-​year survey. BMC Infect Dis, 12, 332. Kao PT, et al. (2003). Brain abscesses: clinical analysis of 53 cases. J Microbiol Immunol Infect, 36, 129–​36. Kastrup O, Wanke I, Maschke M (2008). Neuroimaging of infections of the central nervous system. Semin Neurol, 28, 511–​22. Fig. 24.11.3.1  Contrast CT scan showing large frontal cerebral abscess (A) with surrounding oedema (B) and ventricular compression (C). 24.11.4 Neurosyphilis and neuro- AIDS 6100 Hadi Ma 24.11.4 Neurosyphilis and neuro- AIDS 6100 Hadi Manji section 24  Neurological disorders 6100 Lorber B (1997). Listeriosis. Clin Infect Dis, 24, 1–​9. Mathisen GE, Johnson JP (1997). Brain abscess. Clin Infect Dis, 25, 763–​79. Matthijs BC, et al. (2014). Brain abscess. N Engl J Med, 371, 447–​56. Ratnaike TE, et al. (2011). A review of brain abscess surgical treatment—​ 78 years: aspiration versus excision. World Neurosurgery, 76, 431–​6. Report of the Quality Standards Subcommittee of the American Academy of Neurology (1998). Evaluation and management of intracranial mass lesions in AIDS. Neurology, 50, 21–​6. Sharma R, Mohandas K, Cooke RPD (2009). Intracranial ab- scesses: changes in epidemiology and management over five decades in Merseyside. Infection, 37, 39–​43. 24.11.4  Neurosyphilis and neuro-​AIDS Hadi Manji ESSENTIALS Neurosyphilis Invasion of the central nervous system occurs early in the course of syphilis infection. Neurosyphilis causes a meningitis, a myeloradiculopathy due to pachymeningitis, gummatous (granu- lomatous) cord and brain lesions; endarteritis may cause infarction and a low-​grade meningoencephalitis affecting the brain results in dementia (general paralysis of the insane) and in the spinal cord, a sensory ataxic syndrome (tabes dorsalis). Clinical features—​these are protean: neurosyphilis should always be considered in the diagnosis of neurological disorders without a convincing explanation, including (1)  stroke—​especially in young patients; (2)  ocular abnormalities (e.g. optic neuritis/​neuropathy, choroidoretinitis, pupillary abnormalities); (3)  unexplained cranial nerve disease, especially sensorineural deafness and vertigo; (4) de- mentia (5) a sensory ataxia caused by pathology within the dorsal roots and ganglia and the posterior columns (tabes dorsalis). Diagnosis, treatment, and prognosis—​diagnosis requires specific serological tests and examination of the cerebrospinal fluid (see Chapter 8.6.37). Treatment with antimicrobials is often curative in patients with meningitic or meningovascular disease, but is only partially effective in those with late forms of dementia or tabes. Follow-​up after treatment should include repeat examinations of the cerebrospinal fluid until the cell count is restored to normal limits. Neurological complications of HIV infection The neurological consequences of HIV infection include (1) op- portunistic infections—​toxoplasma encephalitis, cryptococcal meningitis, tuberculous meningitis, cytomegalovirus retinitis and encephalitis and John Cunningham virus infection causing pro- gressive multifocal leucoencephalopathy; (2)  neoplasms—​primary central nervous system lymphoma; (3) HIV itself can also affect the central and peripheral nervous systems causing HIV-​associated neurocognitive disorders which, in its most severe form, manifests as a subcortical dementia, a vacuolar myelopathy, and a peripheral neuropathy. The introduction of highly active antiretroviral therapies has greatly reduced the frequency of these complications in patients with access to these treatments. However, newer complications are now increasingly recognized such as a neurological immune reconstitution inflammatory syndrome, a compartmentalization syndrome (cerebrospinal fluid escape). There is a suggestion that some patients may continue to decline cognitively despite having an undetectable plasma viral load. the aetiology of which may be multifactorial including drug toxicity, poor cerebrospinal fluid penetration of some antiretroviral drugs, a low-​grade HIV-​related immune reconstitution inflammatory syndrome, cerebrovascular disease, and an accelerated ageing processes. Neurosyphilis The incidence of primary and secondary syphilis in the United Kingdom (excluding Scotland) increased from 2500 cases in 2008 to 6000 in 2016. In 2012 there were 5.6 million new cases world- wide. Syphilis, similar to other ulcerating genital infections such as herpes and chancroid, increases by a factor of three the risk for the acquisition and transmission of infection with the HIV, so disease has once again come under scrutiny. T. pallidum has been isolated from the cerebrospinal fluid of up to 40% of neurologic- ally asymptomatic patients with untreated primary and secondary syphilis. Despite this, cohort studies of untreated patients with late syphilis documented an incidence of clinical neurosyphilis of 9.4%. Thus, it would seem as if, at least in the immunocompetent patient, T. pallidum has a low virulence for the central nervous system (CNS). Clinical features (See Table 24.11.4.1.) Acquired syphilis is divided into: (a) an early, infectious stage (this includes primary, secondary, and early latent syphilis in asymptomatic patients where less than 2 years have elapsed since infection (World Health Organization definition)) and (b) the late, non​infectious stage includes late, latent syphilis where in asymp- tomatic patients more than 2 years have elapsed; gummatous (granulomatous) disease which can affect the skin, viscera, men- inges and also the brain parenchma, cardiovascular syphilis, and GPI/tabes). Although there is a rough time course to the develop- ment of the various neurological syndromes, there is considerable overlap; these syndromes are, in reality, part of the spectrum of disease. The broad term ‘neurosyphilis’ includes meningitis (acute and chronic), a myeloradiculopathy due to a pachymeningitis, and granulomatous lesions (gummas) that present as space-​occupying lesions within the brain, spinal cord, or epidural space, causing com- pression; meningovascular syphilis, which can occur in both early and late phases of the infection, involves the small-​ and medium-​ sized arteries, typically causing an endarteritis (Heubner’s endarter- itis obliterans), results in infarction. The so-​called late manifestations 24.11.4  Neurosyphilis and neuro-AIDS 6101 of neurosyphilis result from a low-​grade meningoencephalitis. In patients with general paralysis (also called general paralysis of the insane or dementia paralytica), the focus is on the frontotemporal cortex. Therefore, during the early stages, vague symptoms may include personality and mood changes, with impaired faculties of concentration and attention being the presenting features; memory difficulties develop later. In tabes dorsalis (taboparesis), which may coexist with general paralysis, the clinical presentation results from involvement of the dorsal roots and ganglia as well as the posterior columns within the spinal cord, with the clinical presentation of mainly a sensory ataxia. Diabetes can produce a similar clinical pic- ture with a sensory neuropathy and pupillary abnormalities (dia- betic pseudotabes). The optic nerve can be involved with or without other evidence of neurosyphilis, but must always be treated as if it were part of a systemic infection. Uveitis, chorioretinitis, optic neuritis, papillitis, and optic atrophy have all been reported at different stages of the disease. Extraocular presentations include nerve palsies involving the eye muscles and a superior orbital fissure syndrome. Although the Argyll Robertson pupil may occur in any form of the disease, it is generally encountered in tabes dorsalis. The pupils are small and irregular, being unreactive to light, but constrict normally to ac- commodation and convergence. Unilateral involvement is rare. The light/​near dissociation is the result of gliosis in the periaqueductal grey midbrain tegmentum, which may also account for the bilateral ptosis seen in some individuals. Diagnosis Neurosyphilis has a myriad of neurological manifestations and, therefore, the diagnosis enters the differential of most neurological conditions (see Table 24.11.4.1). Treatment in the early stages of the disease (i.e. of the meningitic and meningovascular syndromes) may well result in recovery, whereas the late forms—​with general paralysis and tabes dorsalis—​may cease to progress with only par- tial recovery. These neurological presentations include stroke, and should enter the differential diagnosis especially in younger patients, chorioretinitis, optic neuropathy of unknown cause, and single or multiple cranial neuropathies, particularly those involving cranial nerve VIII with vertigo and sensorineural deafness. Syphilis ser- ology should be performed routinely in patients with dementia and psychiatric illnesses. The non​treponemal serum reaginic tests, Venereal Diseases Research Laboratory (VDRL) test and rapid plasma reagin test (RPR), are almost always positive in secondary syphilis when the first neurological complications may be encountered. However, a false-​negative result may occur due to the prozone phenomenon if undiluted serum is used. This occurs in 1 to 2% of cases of secondary syphilis and is due to blockage of agglutination caused by the satur- ation of antigenic sites by excess antibody. The specific serological tests—​T. pallidum haemagglutination test (TPHA), T. pallidum par- ticle agglutination test (TPPA), fluorescent treponemal antibody ab- sorption test (FTA-​abs), and the treponemal enzyme immunoassay (EIA)—​are invariably positive. In late syphilis (meningovascular syphilis, gummatous, general paralysis, and tabes dorsalis), the serum VDRL/​RPR tests are nega- tive in 30% of untreated cases. All the specific tests have a sensitivity approaching 100%, so that a negative treponemal antigen test has an extremely high predictive value for excluding neurosyphilis. It is recommended that all patients with positive syphilis ser- ology who have ocular and/​or neurological symptoms and signs should undergo cerebrospinal fluid examination, as should pa- tients with latent infection of unknown duration. In order for these tests to be correctly interpreted, it is important that the cerebro- spinal fluid is not significantly (macroscopically) contaminated with blood. In patients with neurosyphilis there is usually a lymphocytic pleocytosis (>5 cells/​µl), with an elevated protein (>0.4 g/​l). In the late stages, particularly in tabes, the cerebrospinal fluid may be qui- escent. A reactive cerebrospinal fluid (CSF) VDRL establishes the diagnosis of active neurosyphilis, but a non​reactive test does not ex- clude it. The sensitivity of the CSF VDRL is 50%, with a specificity of 100%. A non​reactive CSF FTA-​abs or TPHA excludes the diagnosis. However, a reactive CSF FTA-​abs or TPHA does not establish the diagnosis because the presence of treponemal antibodies in the cere- brospinal fluid could result from passive transfer from the blood, or from a previous episode of treated syphilis. The sensitivity for the CSF FTA-​abs is 100%, with a specificity of 30%. The role of the polymerase chain reaction (PCR) in the diagnosis of neurosyphilis is unclear at present, because the technique cannot discriminate between viable and nonviable organisms. T. pallidum DNA has been detected in cerebrospinal fluid up to 3 years after intravenous treatment with penicillin. Table 24.11.4.1  Clinical features of neurosyphilis Syphilitic meningitis Meningovascular General paralysis Tabes dorsalis Time course Acute Within first year during secondary syphilis syndrome (rash, fever, lymphadenopathy, hepatitis, arthritis, glomerulonephritis) Months to years after infection, average 7 years 15–​20 years 20–​25 years Clinical features Cranial nerve palsies (III, VI, VII, VIII), hydrocephalus Stroke (hemiparesis, dysphasia), seizures, cranial nerve palsies, encephalitic syndrome, anterior spinal artery syndrome, myelitis Frontal–​temporal dementia, psychiatric symptoms (delusions, apathy), personality change, seizures, dysarthria, tremor (tongue, face, hands), optic atrophy Lightning pains (limbs, viscera); loss of pain and temperature (Charcot’s joints), joint position (sensory ataxia, positive Romberg’s sign), areflexia, Argyll Robertson pupils autonomic and sphincter dysfunction Chronic Myeloradiculopathy due to pachymeningitis section 24  Neurological disorders 6102 Treatment In patients with symptomatic neurosyphilis or ocular disease, the World Health Organization/​United Nations Programme on HIV/​ AIDS (WHO/​UNAIDS) and the European guideline on the man- agement of syphilis recommend treatment with benzylpenicillin (3–​4 million units intravenously every 4 h for 14 days). An alternative is procaine penicillin (1.2–​2.4 million IU intramuscularly once daily, plus probenecid 500 mg by mouth four times daily, for 17–​21 days). In patients with a history of penicillin allergy, one option is to per- form skin testing to confirm the allergy and to then consider desen- sitization. The other is to treat with doxycycline 200 mg by mouth twice daily for 28 days. After treatment of neurosyphilis, a repeat lumbar puncture should be performed at 6-​monthly intervals until the cell count is normal. The cell count should have decreased by 6 months and be entirely normal by 2 years. Syphilis in the era of HIV Since the onset of the AIDS epidemic there have been anecdotal re- ports of an accelerated course of syphilis and of treatment failures in patients who are dually infected. As cell-​mediated immunity, which is necessary to eradicate T. pallidum, may be impaired in HIV in- fection, this seems plausible. As a result of altered B-​cell function there has also been concern about the validity of the serological tests; however, the current consensus is that there is no difference between HIV-​infected and non​infected individuals clinically or serologically. A CSF examination is only recommended in early syphilis if pa- tients have neurological, ocular, or audiological symptoms, as in the non-​HIV group. In late syphilis some specialists recommend a CSF examination to exclude asymptomatic neurosyphilis, especially if the CD4 count is less than 350 cells/​mm3 and /​or the VDRL/​RPR titre is more than 1:32, however, there are no data to support this recommendation. Neuro-​AIDS (the neurological complications of HIV infection) Soon after the onset of the AIDS epidemic, it became clear that the nervous system was frequently involved. However, opportunistic in- fections, such as toxoplasmosis and cryptococcal meningitis, as well as neoplasms (such as primary central nervous system lymphoma, PCNSL) accounted for only 30% of the neurological problems en- countered. It also became evident that, in the later stages of the AIDS illness, patients developed neurological complications due to the HIV itself (Box 24.1.4.1). This included a progressive decline in cognitive function in association with motor abnormalities—​the AIDS—​Dementia Complex (ADC) or, as it is now known, HIV-​ associated neurocognitive disorder (HAND), a vacuolar myelop- athy, and a painful distal sensory peripheral neuropathy. With the introduction of highly active antiretroviral therapy (HAART) in 1996, there has been a dramatic decline in the incidence of neurological opportunistic infections, as well as HIV-​related dis- orders such as HIV–​dementia. The downside has been an increase in the peripheral nerve complications of some of the antiretroviral drugs, but also newer increasingly recognized syndromes such as neurological immune reconstitution inflammatory syndrome (IRIS) and HIV compartmentalization (or CSF escape). There is also concern regarding the continued high prevalence of milder forms of cognitive dysfunction in cohorts (20%) as well as a suggestion that some patients may continue to decline cognitively despite having an undetectable plasma viral load. The aetiology maybe multifactorial including drug toxicity, poor CNS penetration of antiretroviral drugs, a low-​grade HIV-​related IRIS, cerebrovascular disease, and an accelerated ageing processes. Clinical approach All areas of the neuraxis are vulnerable in individuals infected with HIV. Differing pathological processes occur simultaneously in various parts of the nervous system. Thus, Occam’s razor—​the principle of diagnostic parsimony, often used in medicine—​does not always apply. Another aspect to be considered is the possibility of simultaneous infection with more than one organism (e.g. men- ingitis due to Mycobacterium tuberculosis and Cryptococcus neo- formans). Mass lesions in the brain, with some not responding to antitoxoplasma therapy, could be due to lymphoma or another in- fective cause, such as a tuberculoma. The nervous system is involved early in the course of primary HIV infection, as evidenced by neurological seroconversion illnesses (Box 24.11.4.2). Furthermore, during the asymptomatic phase of the illness (i.e. when patients are well), the cerebrospinal fluid shows abnormalities in up to 60% of cases. This may be a lymphocytic pleo- cytosis of up to 50 cells/​mm3, an elevated protein, or the presence of oligoclonal bands. The cerebrospinal fluid glucose level is usually Box 24.11.4.1  Neurological complications in HIV infection Opportunistic infections • Toxoplasma gondii—​abscesses and encephalitis • Cryptococcus neoformans—​meningitis • JC virus (John Cunningham) ​progressive multifocal leucoencephalopathy (PML) • Cytomegalovirus—​retinitis, encephalitis, cauda equina syndrome, vasculitic neuropathy • Mycobacteriun tuberculosis—​meningitis, abscesses Tumours • Primary CNS lymphoma (PCNSL) • Metastatic systemic lymphoma HIV-​related disorders • HIV-​associated neurocognitive disorder (HAND) • Vacuolar myelopathy • Distal sensory peripheral neuropathy • Polymyositis Drug-​induced complications • Neuropathy (didanosine, stavudine, isoniazid) • Myalgia, mitochondrial myopathy (NRTIs) • Cognitive dysfunction (efavirenz) Immune reconstitution syndrome • Cryptococcus neorformans • PML • M. Tuberculosis • HIV (brain and peripheral nerves) CSF compartmentalization syndrome (CSF escape) 24.11.4  Neurosyphilis and neuro-AIDS 6103 normal. Therefore, these cytobiochemical markers are unhelpful in making a diagnosis of a meningitic or encephalitic illness. Reliance is, therefore, placed on specific markers such as the cryptococcal antigen or antibody tests such as the CSF VDRL or TPHA tests. As a result of the impaired immune response, a rise in anti- body titres to specific infections may not occur, especially during the later stages of HIV infection. Furthermore, the typical clinical picture—​the presentation of which, at least in some infections, such as meningitis, is the result of a brisk inflammatory response such as fever—​may not occur. In cryptococcal meningitis, only a third of patients exhibit the classic signs of meningism (i.e. neck stiffness, photophobia, and positive Kernig’s sign). The specific type of opportunistic complications encountered depends on several factors, including the degree of immunosup- pression. During the early stages when individuals are relatively im- munocompetent, with CD4 counts above 500/​mm3, autoimmune disorders such as demyelinating neuropathies may occur. With CD4 counts of between 200 and 500/​mm3, multidermatomal herpes zoster infections and tuberculosis (TB) may present. Once the level declines below 200/​mm3, patients are vulnerable to all the major opportunistic infections and the complications due to HIV itself. Symptomatic infection with cytomegalovirus (CMV) tends to occur at very low levels below 50/​mm3. With the introduction of antiretro- viral therapy (ART), these guidelines are less robust because, despite immunoreconstitution, pathogen-​specific memory T-​cell clones may not have been fully restored. Opportunistic infections Toxoplasmosis Toxoplasma gondii, whose definitive host includes members of the cat family with humans as the intermediate hosts, is an obligate intracellular protozoan. Human infection occurs through the inges- tion of tissue cysts in undercooked meat. Variations in dietary habits therefore explain the differing seroprevalence rates worldwide—​ 90% in French adults compared with 50% of residents in the United Kingdom. Symptomatic toxoplasmosis is usually due to a reacti- vation of latent infection in individuals with HIV. The risk of an HIV-​infected patient who is seropositive for IgG T. gondii antibody developing toxoplasmosis is around 25%. Toxoplasmosis is the most common cause of mass lesions in the brains of patients with HIV infection, including those in areas where TB is endemic. The clinical presentation is variable, but headache, confusion, seizures, and focal neurological deficits such as hemi- plegia, dysphasia, and visual field defects are the most common. Other presentations described include:  a variety of movement disorders (choreoathetosis, dystonia, and hemiparkinsonism); psychiatric illness such as depression; brainstem syndromes; and a rapidly progressive diffuse encephalitis. Rarely, the spinal cord may be involved with myelitis or cauda equina syndrome. A definitive diagnosis of toxoplasma encephalitis can be made only by brain biopsy. With increasing experience and pragmatism, it is now standard practice to treat any HIV-​infected individual who has a low CD4 count and multiple lesions on imaging with antitoxoplasma therapy (Fig. 24.11.4.1). A response, clinically and radiologically, con- firms the diagnosis. Although a negative blood toxoplasma serology result makes the diagnosis less likely, this may occur in up to 17% of cases. This loss of seropositivity may be the result of impaired anti- body synthesis with increasing immunosuppression. It is, therefore, useful to document an individual’s toxoplasma serostatus when HIV is diagnosed. For similar reasons, the expected rise in IgM and IgG levels does not occur. A single lesion on MRI is most likely to be due to lymphoma. A single lesion on CT should, if possible, be followed by MRI, which is a more sensitive method of detecting other lesions, particularly in the posterior fossa (Fig. 24.11.4.2). Box 24.11.4.2  Neurological HIV syndromes in Primary Infection Aseptic meningitis Meningoencephalitis Acute disseminated encephalopmyelitis Transverse myelitis Cauda Equina syndrome Acute demyelinating polyradiculopathy (Guillain–​Barré syndrome) Brachial neuritis (Parsonage–​Turner syndrome) Mononeuritis multiplex (vasculitis) Acute polymyositis CT/MRI Single lesion Multiple lesions Treatment for toxoplasmosis Positive Improvement (clinical and radiological) Negative Yes BIOPSY Continue for 4–6 weeks followed by prophylaxis Notes: (i) MRI may detect lesions not apparent on CT; (ii) In patients with significant mass effect and danger of herniation additional treatment with a reducing course of dexamathsone is necessary. Any deterioration subsequently on reduction of the steroids requires consideration of a biopsy. Blood toxoplasma serology No Fig. 24.11.4.1  Management of mass lesions in AIDS. Fig. 24.11.4.2  Cranial CT: multiple lesions with mass effect and cerebral oedema due to toxoplasmosis. section 24  Neurological disorders 6104 The main differential diagnosis is that of primary CNS lymphoma, which presents at similar CD4 counts and has a similar presentation both clinically and on imaging studies (Box 24.11.4.3). A clinical response is seen in 90% of patients by the second week of treatment (Table 24.11.4.2). It is necessary to reimage 2 weeks after treatment even if there is clinical evidence of improvement, because occasionally some lesions improve but others due to, for example, Mycobacterium tuberculosis, continue to enlarge, which then makes it necessary to consider a biopsy. The radiological improvement gen- erally lags behind the clinical improvement. Corticosteroids are only indicated in patients with significant mass effect and should be used for short periods only, as it makes it difficult to interpret the trial of anti—​toxoplasma treatment. Secondary prophylaxis is required after resolution of the acute episode. Patients infected with HIV who are seropositive for IgG against T.  gondii should be offered primary prophylaxis with 980 mg co-​trimoxazole (trimethoprim and sulfamethoxazole) if their CD4 count is below 200/​mm3. This also provides prophylaxis against Pneumocystis jirovecii pneumonia. After the initiation of HAART, primary prophylaxis maybe discontinued after successful suppres- sion of HIV viral replication and the CD4 counts exceed 200 cells/​ mm3 for 3 months. Secondary prophylaxis after an episode of toxo- plasmosis can be discontinued after 6 months of successful suppres- sion of HIV viral replication and a CD4 more than 200 cells/​mm3. Cryptococcus neoformans This encapsulated yeast is a ubiquitous organism in the environ- ment acquired by humans through inhalation. Although dissemin- ated infection can involve the skin, bones, lungs, eyes, and prostate, Box 24.11.4.3  Focal neurological syndromes Infections • Toxoplasma gondii (abscesses, encephalitis)* • JC virus (PML)* • Mycobacterium tuberculosis (tuberculoma)* • Fungal microabscesses (Cryptococcus neoformans, • Cytomegalovirus (brain stem syndrome) Neoplasms • Primary CNS lymphoma* • Metastatic tumours (non-​Hodgkin’s lymphoma, Kaposi’s sarcoma) Cerebrovascular • Ischaemic stroke (coagulopathies) • Embolic stroke (bacterial and non​bacterial endocarditis) • Vasculitis (meningovascular syphilis, herpes zoster) Most common. Table 24.11.4.2  Treatment of neurological opportunistic infections Infection Drug Dose Duration Side effects Notes Toxoplasmosis Acute Pyrimethamine + Loading dose of 200 mg, then 75 mg orally 4–​6 weeks Myelosuppression Sulfadiazine + 6–​8 g/​day orally or intravenously 4–​6 weeks Nephrotoxicity, renal calculi, crystalluria Clindamycin 2.4 g/​day oral or intravenously is an alternative to sulfadiazine. Side effect pseudomembranous colitis Folinic acid 15 mg/​day orally 4–​6 weeks To counteract the myelosuppressive effects of pyrimethamine Maintenance Pyrimethamine + 25–​50 mg/​day orally Until CD4 count >200 cells/​mm3 + undectable viral load for >6 months Sulfadiazine + 2 g/​day orally Clindamycin 1.2 g/​day Folinic acid 15 mg/​day orally Primary prophylaxis Co-​trimoxazole 480 mg/​day orally Nausea, Stevens–​ Johnson syndrome, thrombocytopenia CD4 count <200/​µl and toxoplasma serology positive Cryptococcal meningitis Acute (induction) Amphotericin B + 1.0 mg/​kg per day intravenously Combination of amphotericin + flucytosine for one week. Followed by one week of fluconazole 1200mg/day for adults, 12 mg/kg/day for children and adolescents up to maximum oif 800mg daily Hypokalaemia, renal failure, anaemia Via central line because of thrombophlebitis. Pre- emptive hydration, electrolyte replacement and toxicity monitoring necessary with amphotericin and flucytosine regimens. Alternative regimens: two weeks of fluconazole 1200mg for adults, 12 mg/kg/day for children flucytosine 100mg/kg/day, divided into four doses per day. Consolidation phase: fluconazole 800mg daily for adults, 6 - 12 mg/kg/day for children upto maximum of 800mg daily) for eight weeks following induction phase of two weeks 5-​Flucytosine 100 mg/​kg per day in four divided doses Myelosuppression Maintenance Fluconazole 200 mg daily for adults, 6 mg/kg/ day for children Until CD4 count 100 cells/​mm3 and undetectable viral load for >3 months Nausea, vomiting, abnormal liver function tests Amphotericin 1 mg/​kg per week if intolerant or relapse on fluconazole 24.11.4  Neurosyphilis and neuro-AIDS 6105 symptomatic infection with C. neoformans most often presents as meningitis. Cryptococcal infection is the most common infectious cause of meningitis in patients with AIDS (Box 24.11.4.4). Although the presentation may be acute, it is usually subacute with symp- toms of malaise, headache, fever, and vomiting. The classic signs of meningism—​neck stiffness, photophobia, and Kernig’s sign—​are present in only one-​third of patients. Other, less common symptoms include altered mental status, seizures, and focal neurological signs. The last are the result of parenchymal cryptococcal abscesses. Brain imaging is usually normal, although the basal meningitis may result in hydrocephalus or sometimes, particularly on MRI, small abscesses—​cryptococcomas—​may be evident. Cerebrospinal fluid examination is essential for the diagnosis, with culture of the fungus being the ‘gold standard’. The cytochemical markers in the cerebrospinal fluid may be normal. India ink staining of the cerebrospinal fluid will reveal the fungal hyphae in 70 to 80% of cases. Immunoassays (latex agglutination or ELISA) measuring cryptococcal antigen (CRAG) in CSF are rapid and have a sensitivity and specificity of more than 95%. Serum antigen measurements should also be measured, since in early disease (cryptococcaemia) these may be positive and CSF negative. Treatment with amphotericin B plus 5-​flucytosine is the com- bination of choice for the treatment during the induction phase of cryptococcal meningitis for a minimum of two weeks with evidence of clinical improvement and sterile CSF. Liposomal amphotericin is less toxic but more expensive. The consolidation phase for 8 weeks is with fluconazole 400 mg/​day and then maintenance fluconazole 200 mg for 12 months. The mortality rate still remains around 10%. Features that have been identified with a poor outcome include a relapsed infection, abnormal mental status, cerebrospinal fluid cryptoccal antigen titre greater than 1:1024, cerebrospinal fluid white cell count less than 20 cells/​mm3, positive India ink staining, hyponatraemia, and positive culture from an extrameningeal site. A cerebrospinal fluid opening pressure of more than 250 mm H2O is also a marker of poor prognosis. In milder cases, where none of these features is present, oral fluconazole may be used. A specific complication that requires close monitoring is the development of raised intracranial pressure due to obstruction of the arachnoid villi and cerebral oedema. This should be managed with repeated lumbar puncture or, if necessary, by the insertion of a lumbar or ventricular drain. Maintenance therapy is essential, with relapse rates approaching 100% if secondary prophylaxis with oral fluconazole is not adhered to. The serum cryptococcal antigen titre is not useful in predicting relapse. The timing for the initiation of ART after an episode of men- ingitis is controversial due to the risk of precipitation of the immune reconstitution syndrome (IRIS). Current opinion suggests starting between two and ten weeks after starting antifungal treatment with evidence of a sterile CSF. The patients at greatest risk of IRIS are those patients who are retroviral drug naïve with a high HIV RNA load and those with a poor CSF inflammatory response. Once the viral load has been fully suppressed and the CD4 count has risen above 200 cells/​mm3 for 3 months, secondary prophylaxis can be discontinued. JC virus (John Cunningham) Progressive multifocal leucoencephalopathy (PML) is caused by the reactivation of latent John Cunningham virus. This polyomavirus in- fection is acquired by most of the population during childhood as a banal upper respiratory infection. The virus is frequently found in the urine of healthy individuals. Before the AIDS epidemic, progressive multifocal leucoencephalopathy was a rare condition encountered in patients immunosuppressed as a result of haematological malig- nancies, drugs used in the treatment of post-​transplant recipients, autoimmune disorders such as systemic lupus erythematosus, and granulomatous disorders such as sarcoidosis. Nowadays, underlying HIV infection accounts for 85% cases, but the infection has also been highlighted following cases developing after immunomodulatory treatment in multiple sclerosis with drugs such as natalizumab. Before the introduction of HAART, the incidence of progressive multifocal leucoencephalopathy was 4%. The clinical presentation is subacute, with progressive focal neurological deficits such as a hemi- paresis, visual field defects, and a cerebellar syndrome. The disorder is not restricted to the white matter because patients may also de- velop dysphasia and seizures. Occasional patients may present with a progressive dementia with focal neurological signs. MRI characteristically shows multiple areas of high signal on T1-​weighted images and a low signal on T2-​weighted ones (Fig. 24.11.4.3). There is little or no enhancement, with no mass effect or oedema around the lesions. Serological testing is un- helpful because 80% of the general population is seropositive. It is possible to confirm the diagnosis of progressive multifocal leucoencephalopathy by detecting JC viral DNA in cerebrospinal fluid by PCR techniques. This has a sensitivity of 75% with a spe- cificity of 95%. In PCR-​negative cases it may be necessary either to repeat the cerebrospinal fluid examination or to perform a brain bi- opsy. The typical histological features show areas of focal demyelin- ation, bizarre enlarged astrocytes, and abnormal oligodendrocytes with inclusion bodies that stain for J viral antigens. Box 24.11.4.4  Meningitis in HIV infection Infections • Cryptococcus neoformans • Mycobacterium tuberculosis • Listeria monocytogenes • Treponema pallidum Neoplasms • Non-​Hodgkin’s lymphoma Fig. 24.11.4.3  T2-​weighted MRI in a patient with progressive multifocal leucoencephalopathy. section 24  Neurological disorders 6106 There is, to date, no specific treatment for progressive multifocal leucoencephalopathy. However, improving immune function with ART improves survival. Recently, there have been anecdotal data sug- gesting that the antidepressant mirtazipine may have some benefi- cial effects. Adequate trial results are awaited. Progressive multifocal leucoencephalopathy IRIS is not an infrequent complication—​this is treated with corticosteroids and continuation of ART. Cytomegalovirus The neurological complications from this herpesvirus result from reactivation in severely immunocompromised patients. Almost all patients infected with HIV are seropositive for CMV. Postmortem studies of the brains of patients who died from AIDS show evidence of CMV in 25% of cases. However, clinical CMV disease, apart from CMV retinitis, is rare. CMV retinitis is the most common manifestation of CMV dis- ease and can affect up to 20% of patients with AIDS. The slowly pro- gressive necrotizing retinitis results in characteristic white irregular lesions with central necrosis and haemorrhages—​the ‘cheese and tomato ketchup’ appearance. Retinal detachment may occur in pa- tients with extensive retinal involvement. The retinitis presents with symptoms of reduced visual acuity, floaters, and loss of peripheral vision. As the condition may be asymptomatic in the early stages, regular ophthalmological screening is recommended for high-​risk patients with CD4 counts below 50 cells/​mm3. A necrotizing ventriculoencephalitis has been described, usually in patients with evidence of CMV disease elsewhere (Box 24.11.4.5). The onset is subacute over a period of days or weeks with confusion, seizures, and brainstem signs such as internuclear ophthalmoplegia, ataxia, and cranial nerve palsies. Imaging studies typically show periventricular enhancement. CMV polyradiculopathy presents over a period of days with back pain, leg weakness, sensory impairment, and sphincter disturbance. The differential diagnosis includes syphilitic polyradiculopathy and infiltration with lymphoma. The cerebrospinal fluid reveals a poly- morphonuclear leucocytosis which is unusual for a viral infection. Early recognition and treatment are necessary to stabilize and, in some cases, improve the neurological impairment. Drugs licensed for the treatment of CMV disease include ganciclovir, cidofovir, and foscarnet. Oral ganciclovir is prescribed for secondary prophylaxis. Opportunistic tumours Primary CNS lymphoma (PCNSL) is the second most common cause of mass lesions after toxoplasmosis in adults, and the most common in children with AIDS. Histologically, this is a high-​grade, non-​Hodgkin’s, B-​cell lymphoma. The Epstein–​Barr virus is causally linked to PCNSL, with the identification of the viral DNA incorpor- ated into that of the neoplastic cells. The common presenting symptoms are those of headache with focal neurological deficits, altered level of consciousness, and seizures. Brain imaging reveals enhancing mass lesions with surrounding oedema and mass effect. These are similar to those found in toxo- plasmosis. PCNSL is more likely to present as a single mass lesion than toxoplasmosis and is also more likely to invade the ventricular walls. Recent studies using thallium-​201 single photon emission computed tomography (SPECT) suggest that it may be possible to differentiate between an abscess and a tumour, with the former having little uptake compared with the high uptake of the mitotically active lymphoma. There is no effective treatment for PCNSL. Whole-​brain radio- therapy provides, at best, only a modest benefit, with most patients succumbing within 2 months. Current evidence suggests that ART may improve survival in this group of patients. HIV-​associated neurological disorder (HAND) (Previously known as AIDS–​dementia complex) Before the introduction of ART (and in areas of the world where these drugs are still unavailable) approximately 15 to 20% of indi- viduals infected with HIV developed a variably progressive de- mentia with associated motor deficits. HAND is now classified to three degrees—​asymptomatic neurocognitive disorder (ANI), mild neurocognitive impairment (MND) with only mild functional ef- fects and HIV dementia (HAD) where there is marked functional impairment. In children, a similar HIV-​1-​associated progressive encephalopathy occurs more frequently than with opportunistic in- fections. This usually occurs within the context of severe immuno- suppression in those with a CD4 count of less than 200/​mm3. In around 3% of cases, HIV–​dementia is the AIDS-​defining illness. Large cohort studies, using clinical, MRI, and neuropsychological methods, have largely discounted the early reports of evidence of cognitive changes in asymptomatic HIV-​positive patients. The risk factors for the development of HAND are shown in Box 24.11.4.6. The clinical presentation in the early stages is with vague symp- toms of apathy, mood changes, and difficulty with memory and concentration. These are features of a subcortical dementia with no features of cortical involvement such as language, visuospatial, or calculation difficulties. This picture may be mimicked by de- pression, metabolic encephalopathy, and drugs, both therapeutic and recreational. At this stage, there may be few physical signs apart from brisk reflexes, impaired fine finger movements, and unsteady gait. Box 24.11.4.5  Encephalitis in HIV Virus • Cytomegalovirus • Herpes simplex • Herpes zoster • Human herpesvirus 6? Protozoa • Toxoplasmosis Box 24.11.4.6  Risk factors for HIV-​associated dementia • Nadir CD4 count (so-​called HAND legacy) • Increasing age • Systemic features—​anaemia, low body weight, systemic symptoms • substance abuse • Host genetic factors—​E4 isoform of apolipoprotein E; polymorphisms in TNF-α promoter and CCR2 • Coinfection with other viruses (e.g. hepatitis C) • Viral clade subtypes 24.11.4  Neurosyphilis and neuro-AIDS 6107 Later, the memory impairments are obvious, as is the psycho- motor retardation—​which may progress to frank mutism and a global dementia. Some patients develop seizures. The motor signs, due to the associated vacuolar myelopathy with a spastic paraparesis and sphincter disturbances are also present in a significant number of patients (Box 24.11.4.7). In addition, some patients will have HIV-​related distal sensory peripheral neuropathy. Thus, this group will have absent ankle jerks and extensor plantar responses. The diagnosis of the HIV–​dementia is made by clinical assessment—​there are usually no focal signs and the tempo of the disorder is an insidious one (Table 24.11.4.3). Investigations are performed to exclude other infective or neoplastic pathologies and, therefore, necessitate imaging, preferably with MRI, and a cere- brospinal fluid examination. MRI may show evidence of cerebral atrophy with compensatory ventricular dilatation, a diffuse white-​ matter high signal on T2-​weighted images with no enhancement. A cerebrospinal fluid examination may be non​specifically abnormal with a pleocytosis, elevated protein level, and oligoclonal bands. It important to exclude cryptococcal and tuberculous meningitis, pro- gressive multifocal leucoencephalopathy, and neurosyphilis. The HIV RNA viral load in cerebrospinal fluid correlates with the se- verity of clinical dementia, but there is too much overlap between non​demented and demented patients for the measurement to be of use as a diagnostic aid. There is no correlation between the plasma HIV RNA viral load and dementia. The pathological hallmark of HIV encephalitis is the pres- ence of multinucleated giant cells. These conglomerates of in- fected and uninfected microglia/​macrophages are indicative of productive HIV infection. Other pathological findings include a leucoencephalopathy and atrophy as a result of dendritic, synaptic, and axonal loss. There is no clear correlation between the clinical and pathological findings. One hypothesis for the entry of the virus into the CNS is the ‘Trojan horse’ theory, with invasion occurring by infected peripheral blood macrophages penetrating the blood–​brain barrier that has been disrupted by damage to the capillary endo- thelial cells. Although neuronal cells are rarely invaded by HIV, neuropathogenesis is driven by productive infection of endogenous microglial cells and astrocytes. Neuronal injury, which may be par- tially reversible, occurs as a consequence of the release of txic viral gene products such as Tat and gp41 as well as proinflamatory cyto- kines including tumour necrosis factor (TNF), quinolinic acid, and platelet-​activating factor. After the introduction of the first antiretroviral agent, zidovu- dine, and especially after HAART, the incidence of HAD has de- clined dramatically. Neurocognitive profiles of individual patients also improved while on ART. However, more recent studies have revealed a high prevalence of neurocognitive impairment, albeit mild, in 20%. There are concerns that as a result of poor CNS drug penetration, there may be continuing low-​grade viral persistence in the brain parenchyma. As a result, the CNS penetration effect- iveness score has been proposed. This is an arbitrary score based on pharmacokinetic data and drug properties. Some, but not all, studies have suggested beneficial effects on neurocognitive func- tioning when ART regimens with higher scores are used. Other possible causes of the high level of neurocognitive impairment in- clude drug toxicity and a persistent low-​grade chronic inflamma- tion and immune activation. Between 3% and 10% may develop a CSF viral escape or com- partmentalization syndrome. This is the discordance in viral load between plasma and CSF. Usually the plasma viral load is undetect- able or may show a blip in titres, with CSF loads being significantly higher. The clinical presentation includes an acute or subacute en- cephalitis, myelitis, and/​or a meningitis. Modification of ART leads to improvement. All patients with good virological control who present with neurological symptoms should have the CSF viral load measured. HIV-​associated neuropathy The most common neurological complication encountered in pa- tients infected with HIV is a distal sensory polyneuropathy, which may occur in 30% of those with AIDS (Box 24.11.4.8). It is a signifi- cant cause of morbidity. Typically, patients complain of numb, burning feet, with shooting stabbing pains and hyperaesthesia developing over a period of months. There is little or no weakness. The hands are infrequently involved. Since this is mainly a small fibre neuropathy the ankle jerks may be retained, Sensory testing reveals impaired pain and Box 24.11.4.7  Myelopathy in HIV Infections • HIV-​associated vacuolar myelopathy* • Herpes zoster* • Cytomegalovirus • HTLV-​1 (coinfection) • Treponema pallidum • Toxoplasmosis • Epidural abscess Neoplasm • Metastatic non-​Hodgkin’s lymphoma Other causes • Vitamin B12 HTLV-​1, human T-​cell leukaemia/​lymphoma virus-​1. Most common. Table 24.11.4.3  Clinical neurological features of HIV-​associated dementia Early symptoms Apathy, depression Poor concentration Poor short-​term memory Agitation, mania Early signs Tremor Hyperreflexia Impaired fine finger movements Late features Global dementia Frontal release signs Cerebellar signs Myelopathy Neuropathy Seizures Parkinsonism section 24  Neurological disorders 6108 temperature perception, with joint position and vibration sensation affected later. Further investigations are usually unnecessary in a patient with a CD4 count below 200 cells/​mm3 and showing the typical clin- ical picture, but it is always worth checking a fasting blood sugar, vitamin B12 level, and syphilis serology. It is important to enquire about alcohol intake and nutrition. Neurophysiological studies may reveal abnormal thermal thresholds initially with axonal involve- ment of large fibres on standard nerve conduction tests later in the course of the disease. If there is significant weakness, such as a foot drop, other diagnostic possibilities including vasculitis, malignant infiltration, and diffuse inflammatory lymphocytic syndrome need to be considered. As antiretroviral therapy has no therapeutic benefit, treatment is symptomatic with drugs used for the management of diabetic neuropathy, which it resembles. Drugs used include the tricyclic antidepressants and anticonvulsant drugs such as gabapentin, pregabalin, and also duloxetine. The nucleoside analogues didanosine (ddI), zalcitabine (ddC), and stavudine (d4T) cause a dose-​dependent sensory neuropathy that may be indistinguishable from distal sensory peripheral neur- opathy. Clues to this drug-​induced neuropathy include the shorter history of weeks rather than months, it is more painful than distal sensory peripheral neuropathy and improves on stopping the offending drug. However, there may be a continued worsening of symptoms for a period of 4 to 8 weeks after stopping—​the phenom- enon of ‘coasting’. The underlying mechanism appears to be the im- pairment of mitochondrial protein synthesis. A significant number of patients will improve on stopping the drug, but others are left with neuropathic symptoms due to the unmasking of an underlying distal sensory peripheral neuropathy. Fortunately, these older drugs are rarely, if ever, used these days. Neurological immune reconstitution inflammatory syndrome (IRIS) The introduction of ART results in the recovery of CD4 T lympho- cytes, including memory T-​cells. This may result in the ‘paradoxical deterioration’ of clinical or laboratory markers, including imaging studies, despite a favourable response in the viral load and CD4 count. This may be due to treatment of an overzealous CD8+ lymphocyte cytotoxic inflammatory response against antigens of the infective agent. Sometimes the IRIS occurs because unrecognized pathogens are ‘unmasked’ and the immune reaction leads to symptomatic dis- ease. The onset ranges from a few days to a few months but usually within the first 8 weeks. Risk factors for IRIS include a low baseline CD4 count, a greater than 2 log drop in viral load, a greater than 50 cell increase in CD4 count and antiretroviral drug naivety (Box 24.11.4.9). Neurological immune reconstitution inflammatory syndrome has now been described with Mycobacterium tuberculosis causing men- ingitis and brain abscesses, cryptococcal meningitis, CMV with the development of vitritis, uveitis, and cystoid macular oedema, and progressive multifocal leucoencephalopathy with MRI showing en- hancement and oedema which is usual in progressive multifocal leucoencephalopathy. An aggressive form of IRIS with a high mor- tality rate directed against HIV itself has been described. Brain biop- sies reveal extensive infiltrates of CD8 + cytotoxic lymphocytes The management in such cases is difficult, and although cor- ticosteroids are often used, there are no controlled trials. In life-​ threatening situations stopping the ART may be necessary. FURTHER READING Bruce JB (ed) (2018). Handbook of Clinical Neurology 3rd Series 152. The Neurology of HIV Infection. Elsevier. Centner CM, et al. (2013). Manifestations of HIV infection in the per- ipheral nervous system. Lancet Neurol, 12, 295–​309. Clifford D (2015). Neurological immune reconstitution inflammatory syndrome: riding the tide of immune recovery. Current Opin Neurol, 28, 295–​301. Janier M, et al. (2014). 2014 European guideline on the management of syphilis. J Euro Acad of Dermatol Venereol, 28, 1581–​93. Manji H, et al. (2013). HIV, dementia and antiretroviral drugs: 30 years of an epidemic. J Neurol Neurosurg Psychiatry, 84, 1126–​37. Rogstad K (ed) (2011). ABC of sexually transmitted infections, 6th edi- tion. Wiley-​Blackwell, Oxford. Box 24.11.4.8  Peripheral nerve complications in HIV infection HIV related • Axonal neuropathy (distal sensory peripheral neuropathy)*—​small fibre predominance. • Demyelinating neuropathy—​acute (Guillain–​Barré syndrome), chronic (chronic inflammatory demyelinating neuropathy) • Vasculitic (mononeuritis multiplex) • Diffuse inflammatory lymphocytic syndrome • Lower motor neuron syndrome (resembling motor neuron disease) Drugs • Antiretrovirals (ddI, ddC, d4T) • Isoniazid • Thalidomide • Dapsone • Metronidazole (high dose) • Vincristine CMV related • Vasculitic (mononeuritis multiplex) • Lumbosacral polyradiculopathy Others • Syphilis (polyradiculopathy) • Metastatic non-​Hodgkin’s lymphoma (polyradiculopathy) • Ganglioneuritis • Autonomic neuropathy Most common. Box 24.11.4.9  Neurological IRIS syndromes Opportunist Infection associated • PML • M. tuberculosis (meningitis, tuberculoma) • C. neoformans (meningitis, intracranial cryptococcomas) • Herpes viruses (VZV, CMV, HSV)—​(encephalitis, cerebral vasculitis, retinitis) • T. gondii (encephalitis) HIV associated • Subacute generalized encephalopathy (altered mental status, seizures, coma). MRI:  Multifocal diffuse high signal on T2 weighted images. Histopathology—​massive CD8 infiltration on brain biopsy. • Acute inflammatory demyelinating encephalitis (ADEM) • CNS vasculitis • Chronic low-​grade HIV IRIS causing HAND 24.11.5 Human prion diseases 6109 Simon Mead and R 24.11.5 Human prion diseases 6109 Simon Mead and R.G. Will 24.11.5  Human prion diseases 6109 Stoll M, Schmidt RE (2003). Immune restoration inflammatory syndromes:  the dark side of successful antiretroviral treatment. Curr Infect Dis Rep, 5, 266–​76. Swartz MN, Healy BP, Musher DM (1999). Late syphilis. In: Holmes KK, et al. (eds) Sexually transmitted diseases, pp. 487–​509. McGraw-​Hill, New York, NY. Tan IL, et al. (2012). HIV-​associated opportunistic infections of the CNS. Lancet Neurol, 11, 605–​17. 24.11.5  Human prion diseases Simon Mead and R.G. Will ESSENTIALS Prion (for proteinacious infectious particle) protein is a membrane-​ associated glycoprotein present in all mammalian species. Its normal function is unknown, but in prion diseases (also known as transmis- sible spongiform encephalopathies) a misfolded polymer form of the protein, partially resistant to protease digestion, is deposited in the brain and associated—​typically after long incubation periods—​with neuronal dysfunction and death. Prion disease aetiologies and clinical syndromes Several forms are recognized: (1) Sporadic prion diseases, principally, (a) Creutzfeldt–​Jakob disease—​a rare condition typically presenting in late middle age with a rapidly progressive dementia associated with a range of neurological signs, most commonly myoclonus of the limbs, cerebellar ataxia, and rigidity. Few patients survive for more than 2 years. Also, (b) variably protease sensitive prionopathy—​a seem- ingly rare type of sporadic prion disease associated with psychiatric signs, language output impairment, and ataxia. (2)  Inherited prion disease—​dominant pattern of inheritance; heterogeneous condition; in many cases age at clinical onset is younger and clinical duration is longer than sporadic disease; can be indistinguishable from sporadic Creutzfeldt–​Jakob disease. (3) Acquired forms including (a) iatrogenic Creutzfeldt–​Jakob disease—​exposures in or adjacent to the nervous system (e.g. neurosurgical instruments, dura mater grafts, corneal transplants) typically present in a similar manner to sporadic disease; peripheral exposure to infection (pituitary hormones) usually mani- fests with progressive cerebellar ataxia; can have very long incuba- tion times. (b) Variant Creutzfeldt–​Jakob disease—​bovine spongiform encephalopathy was identified in 1986 as a prion disease in cattle, with the favoured hypothesis being that contamination of feed, prob- ably with tissues from the central nervous system of affected animals. Variant Creutzfeldt–​Jakob disease is caused by transmission of bovine spongiform encephalopathy to humans. Typical presentation is with psychiatric symptoms, followed after a period of months by progres- sive ataxia, dementia, and choreiform or dystonic involuntary move- ments which often evolve into myoclonus. By 2018 there were 178 deaths from variant Creutzfeldt–​Jakob disease in the United Kingdom, with the most recent death occurring in 2016. (c) Kuru—​in Papua New Guinea this disease was transmitted by ritual cannibalism, which ceased by 1960, hence there have been no cases in people born after 1959. Typical presentation was with headache and limb pain, progressing to a cerebellar syndrome, with eventual dementia and immobility. Investigation, treatment, and prevention Investigation—​suspicion of the disorder depends on the recognition of clinical characteristics, then supported by (1) electroencephalography—​ periodic triphasic complexes may be seen in 60–​70% of cases of spor- adic Creutzfeldt–​Jakob disease and in some cases of its iatrogenic variant; (2) cerebrospinal fluid analysis—​elevation of 14-​3-​3 protein in the cerebrospinal fluid is about 90% sensitive and specific for sporadic Creutzfeldt–​Jakob disease, but less useful for its variant version; protein amplification technologies such as rt-​QUIC are increasingly useful and are over 90% sensitive and almost 100% specific; (3) MRI—​diffusion-​ weighted imaging protocols usually show abnormalities in the caudate nucleus, putamen, thalamus and cortex in sporadic Creutzfeldt–​Jakob disease, and the pulvinar region of the posterior thalamus in variant Creutzfeldt–​Jakob disease; (4) tissue biopsy of brain or tonsil. Treatment and prevention—​there is nothing that influences the clinical course of human prion diseases, nor any treatment to pre- vent the development of neurological disease after infection. Several symptomatic therapies may be helpful. Introduction Prion diseases, also known as transmissible spongiform encephal- opathies, are fatal disorders of the central nervous system affecting both humans and animals. The clinical features and patterns of oc- currence of these diseases vary, but they are linked by several charac- teristics including experimental and natural transmissibility, shared neuropathological features, prolonged incubation periods meas- ured in years, and the deposition of prion protein in the brain of the host. Prion diseases have become the subject of intense scien- tific and public interest because they are caused by a biologically dis- tinct disease mechanism and because of the implications for public health following the identification of a new human prion disease, variant Creutzfeldt–​Jakob disease (vCJD), and the evidence that it is caused by the transmission to humans of a cattle prion disease, bovine spongiform encephalopathy (BSE). There have been remarkable scientific advances in the under- standing of prion diseases and it is hoped that this may lead to improved diagnostic tests in life for the presence of infection and to therapies to prevent the development of disease. Human prion diseases have attained a public notoriety disproportionate to the overall burden of disease caused by these rare conditions. However, the transmission of an animal prion disease to humans has been a tragedy and the prolonged incubation periods characteristic of this group of diseases indicate that the eventual consequences of BSE for public health both in the United Kingdom and in other countries remain unpredictable. Historical perspective Scrapie was first transmitted experimentally from sheep to sheep in 1936 and to laboratory mice in 1961, but laboratory transmission of section 24  Neurological disorders 6110 human prion diseases was not achieved until 1966 (kuru) and 1968 (CJD). The seminal discovery that neurodegenerative diseases were transmissible stimulated extensive research into the nature of the infectious agent and attempts to identify the source of infection in CJD. Table 24.11.5.1 sets out the principal prion diseases known to affect humans and animals. Aetiology, genetics, pathogenesis, and pathology No bacterium or virus has been isolated in these diseases and there is no immunological response to infection. In 1982 Prusiner proposed that the protein deposited in the central nervous system (CNS) in these diseases was itself the causal agent. Purified infectious fractions of brain contain ‘prion’ protein, which is the major, and possibly the only, component of the infectious agent. Prions are remarkably re- sistant to inactivation procedures, including those that disrupt nu- cleic acids. Prion protein is a membrane-​anchored glycoprotein, and is present in all mammalian species (Fig. 24.11.5.1a). The normal function of prion protein is unknown. In prion diseases, a misfolded and multimeric form of the protein, partially resistant to protease digestion, is deposited in the brain and is associated with neuronal dysfunction and death. Prions propagate by a process of seeded polymerization whereby the normal cellular form of prion protein is misfolded on binding with the disease form (Fig. 24.11.5.1b). There is a range of experimental evidence supporting the hypoth- esis that the disease-​associated form of prion protein is the causal agent in prion diseases, most notably a series of elegant studies in transgenic rodents. Cellular expression of prion protein is neces- sary for the development of the neuropathological changes and the disease. Hereditary forms of human prion disease, which can be shown to be associated with prion infection of brain tissue, are caused by mutations of the prion protein gene. The occurrence of multiple strains of the infectious agent and the stability of the trans- mission characteristics of the bovine spongiform encephalopathy (BSE) agent in the laboratory after cross-​species transmission was seen by some as a challenge to the prion hypothesis. Most now hold the view that the multiple strains of prions disease are encoded by the structure of the disease-​associated form. The phenotype of dif- ferent clinicopathological subtypes of CJD is strongly determined by prion strain. In experimental transmission of prion diseases there are several key determinants of the efficiency of transmission, as judged by the incubation periods in recipient animals and the proportion of these animals that develop disease. The intracerebral route is the most effi- cient. Intravenous, intraperitoneal, and oral routes are decreasingly efficient. The incubation period is inversely related to the infective dose, while the strain of the infectious agent influences both the incubation period and whether recipient animals develop disease. Table 24.11.5.1  The prion diseases or spongiform encephalopathies Disorder Species Sporadic Creutzfeldt–​Jakob disease Human Inherited prion disease (includes Gerstmann–​Straussler–​Scheinker, fatal familial insomnia, and PrP systemic amyloidosis) Human Iatrogenic Creutzfeldt–​Jakob disease Human Kuru Human Variant Creutzfeldt–​Jakob diseasea Human Variably protease sensitive prionopathy Human Scrapie Sheep/​goat/​moufflon Transmissible mink encephalopathy Mink Chronic wasting disease Deer/​elk/moose/reindeer Bovine spongiform encephalopathya Cattle Feline spongiform encephalopathya Cat/​cheetah/​puma/​ocelot/​tiger Spongiform encephalopathy of captive exotic ungulatesa Kudu/​nyala/​oryx/​gemsbok/​eland a These disorders are associated with the same infectious agent (bovine spongiform encephalopathy). glycans Monomers (a) (b) Seed Fibre Fragmentation Clearance helix 1 helix 2 membrane anchor Fig. 24.11.5.1  (a) The structure of the normal cell-​surface prion protein (PrP). (b) A model of prion replication invoking seeded protein polymerization. In this model the normal prion protein binds to the end of a prion protein ‘seed’ (a ‘prion’), as a result the normal protein is misfolded into the abnormal conformation. The model also envisages that prion seeds can both fragment to generate more seeds, or be cleared. In CJD, the fragmentation (propagation) pathway overwhelms clearance. 24.11.5  Human prion diseases 6111 In some transmission studies (e.g. transmission of BSE to hamsters), recipient animals do not develop disease even after intracerebral in- oculation of high levels of infectivity. Within-​species transmission is generally more efficient than cross-​species transmission and this ‘barrier’ to transmission is influenced by characteristics of both the host and the infective agent. The relative homology of amino acid sequences of prion proteins between species is crucial, but is not the only determinant of the transmission barrier. After oral exposure, prions may replicate in the lymphoreticular system, including the spleen and lymph nodes, before entering the thoracic spinal cord or brainstem, probably via the autonomic ner- vous system, and then spreading caudally to the brain. Moderate levels of infectivity plateau in the lymphoreticular system and are not associated with organ dysfunction, while in the spinal cord and brain high levels of infectivity develop (e.g. 1012 infectious units per gram of brain in one model of hamster scrapie), leading to neuronal death and clinical disease. In some experimental and natural prion diseases, infectivity in the lymphoreticular system can be detected at about a third of the total incubation period by inoculation of tissues of the lymphoreticular system, such as spleen, into recipient ani- mals. The implication is that animals or humans incubating a prion disease may harbour significant infectivity in peripheral organs or tissues for long periods, if not lifelong. This has important implica- tions for the control and public health implications of prion diseases. Human prion diseases Human prion diseases may be classified as sporadic, inherited, or acquired (Table 24.11.5.2). Sporadic CJD Epidemiology Sporadic CJD is a rare disease, with an annual incidence of about 1–​2 cases per million population and a lifetime risk of 1:5000. The disease occurs worldwide and the cause is unknown, with no con- vincing evidence of an environmental source of infection and in par- ticular no proven link with the animal prion diseases. The regional clusters of cases identified in some countries are unusual and may reflect the chance aggregation of a rare phenomenon. Overall the geographical and temporal distribution of cases of sporadic CJD ap- pear to be random and case–​control studies have demonstrated no consistent risk factors for the development of disease, with no good evidence of an increased risk through occupation, dietary factors, or animal contact. The currently favoured hypotheses are that sporadic CJD is caused by a spontaneous mutation of prion protein to the abnormal form, which acts as a template for protein self-​replication and eventual disease, or alternatively there is a mutation of the prion protein gene in somatic cell(s) leading to the expression of mutant prion protein predisposed to convert into an abnormal form. It is also plausible that a small proportion of sporadic CJD is an unrecog- nized zoonotic or iatrogenic condition. Clinical features Clinically, sporadic CJD presents with a rapidly progressive de- mentia associated with a range of neurological signs, most com- monly myoclonus of the limbs, cerebellar ataxia, and rigidity. Less common features include dysphasia, pyramidal or extrapyramidal signs, primitive reflexes, cortical blindness, and lower motor neuron signs. Despite the predominantly cortical neuropathology epilepsy is rare. The rapidity of the progression of neurological deficits and cog- nitive decline is distinct from most other causes of dementia and the mean survival is only about 4 months from clinical onset, although in about 10% of cases the illness is more prolonged and a small minority of patients survive for 2 years or more (Fig. 24.11.5.2). Terminally there is often a state of akinetic mutism. Although the clinical presentation in sporadic CJD is relatively stereotyped, a minority of cases present atypically (e.g. acutely mimicking stroke), with cortical blindness, or with an initially pure cerebellar syndrome. The neuropathological characteristics of sporadic CJD include spongiform change, neuronal loss, and astrocytosis in the cerebral and cerebellar cortex, in accordance with the neurological signs seen in life. Neuropathological changes are widespread and deposition of prion protein can be detected with immunocytochemical tech- niques. In about 10% of cases there are cortical deposits of prion protein in the form of amyloid plaques. There is heterogeneity in the distribution and morphology of the neuropathological changes, which correlate in part with the clinical phenotype and with types of prion protein that can be distinguished on Western blot of brain tissue (Fig. 24.11.5.3 and Fig. 24.11.5.4). Sporadic CJD is mainly a disease of late middle age (Fig. 24.11.5.5) with a mean age at death of 67 years. In most systematic studies males and females are affected with equal frequency. The human prion protein gene is situated on chromosome 20 and contains a polymorphic nucleotide at codon 129, which expresses ei- ther methionine or valine. Homozygosity (MM or VV) at codon 129 increases susceptibility to sporadic CJD. The genotype distribution in sporadic cases in the United Kingdom is MM 70%, valine homo- zygous (VV) 17%, and heterozygous (MV) 13% in contrast to the genotype distribution in the healthy UK population (MM 40%, MV 49%, and VV 11%). There is accumulating evidence that the disease phenotype in sporadic CJD, as well as susceptibility, is influenced by an interplay between the codon 129 genotype and the prion protein strain type. The most rapidly progressive forms of CJD are associ- ated with the MM genotype, followed by the VV genotype, with the slowest progression associated with the MV genotype. Inherited prion diseases Epidemiology Familial occurrence of prion disease accounts for about 10% of all cases with a dominant pattern of inheritance. The paradox of a transmissible disease that is also inherited was clarified by the Table 24.11.5.2  Human prion diseases Sporadic Creutzfeldt–​Jakob disease Variably protease sensitive prionopathy Inherited Familial Creutzfeldt–​Jakob disease Gerstmann–​Straussler–​Scheinker syndrome Fatal familial insomnia PrP systemic amyloidosis Acquired Iatrogenic Creutzfeldt–​Jakob disease Variant Creutzfeldt–​Jakob disease Kuru section 24  Neurological disorders 6112 identification of an insertional mutation of six extra octapeptide re- peats and a missense mutation at codon 102 of the prion protein gene in families affected by the Gerstmann–​Straussler–​Scheinker syndrome, a condition known to be a human prion disease on the basis of the neuropathology and laboratory transmissibility. More than 60 prion protein gene mutations, including point and insertional mutations, have now been identified in inherited prion disease (Fig. 24.11.5.6). All clearly familial cases are associated with PRNP mutations. Fatal familial insomnia was first identified as a prion disease following the identification of a mutation at codon 178 of the prion protein gene in affected family members, and it was only later that transmission in the laboratory confirmed the status of fatal familial insomnia as a prion disease. PrP systemic amyloid- osis was first described in 2014 and does not seem to be trans- missible. The current hypothesis is that mutations of the prion protein gene predispose the protein to adopt the prion disease-​ associated form. Several inherited prion diseases, typically those which cause a CJD like phenotype show evidence of partial pene- trance in old age. The incidence of CJD in localized areas of Slovakia and in Libyan-​ born Israelis was discovered many years ago to be 60 to 100 times greater than expected. Following the identification of the mutations of prion protein in human disease, genetic studies have shown that in both clusters there is a high population frequency of mutations at codon 200 of the prion protein gene, and that the excess of cases of CJD is due to an excess of familial cases, with an expected back- ground incidence of sporadic cases. Clinical features Clinical presentation, age of clinical onset, and clinical dur- ation are highly variable. With some mutations, notably the most common worldwide, E200K, the clinical course is similar to spor- adic CJD, but cases of inherited prion disease may present with ataxia (e.g. Gerstmann–​Straussler–​Scheinker syndrome), or with a 0.15 0.16 0.14 0.12 0.1 0.08 0.06 0.04 0.02 0 0 0–30 30–60 60–90 90–120 120–150 Clinical duration from first symptom (days) Clinical duration of sporadic CJD Proportion 150–180 180–210 210–240 240–270 270–300 300–330 330–360 360–720 720 Fig. 24.11.5.2  Survival of patients with sporadic Creutzfeldt–​Jakob disease recruited in the National Prion Monitoring Cohort 2008–​2015. alternative classification 1 1 2A sCJD kDa 36 30 16 1 2 3 4 London PrPSc type vCJD 2B Fig. 24.11.5.3  Western blot of brain tissue showing multiple types of disease-​associated prion protein (termed PrPSc). The three bands in each lane represent different glycosylation states of PrP, either unglycosylated (bottom band, lowest molecular weight), monoglycosylated, or diglycosylated. Lanes 1–​3 are sporadic Creutzfeldt–​Jakob disease, whereas lane 4 is variant CJD. Two classifications are in use, the ‘London classification’ and an alternative system with fewer types. Types are distinguished in both systems by the mobility and the relative predominance of different bands. Differing mobility of types of sporadic CJD is thought to be related to the access of protease to the N-​terminal amino acids of PrPSc and is thought to correlate with prion strains. 24.11.5  Human prion diseases 6113 highly atypical phenotype such as fatal familial insomnia in which the early clinical features include dysautonomia and insomnia. PrP systemic amyloidosis causes a syndrome of diarrhoea and hereditary sensory and autonomic neuropathy with onset ranging from ages 25–​60. There may be variation in the clinical and patho- logical phenotype both within and between families even if these are associated with the same underlying mutation in the prion protein gene. Fig. 24.11.5.4  Examples of prion disease pathology. (a) spongiform change in sCJD (H&E), (b) gliosis and spongiform change in sCJD (GFAP), (c) kuru-like plaques in sCJD (ICSM35), (d) perineuronal PrP staining in sCJD (ICSM35), (e) perivacuolar PrP staining in sCJD (ICSM35), (f) synpatic PrP staining in sCJD (ICSM35), (g, h) florid plaques in vCJD (H&E, ICSM35), (i) PrP deposition in a tonsillar biopsy specimen in vCJD (ICSM35). Images were provided by Professor Sebastian Brandner, UCL Institute of Neurology and UCLH NHS Foundation Trust. 0.5 0.4 0.3 0.2 0.1 0 20–30 30–40 40–50 50–60 60–70 70–80 80–90 90–100 Age at clinical onset (years) Age at clinical onset in sporadic CJD Proportion 100–110 Fig. 24.11.5.5  Age-​distribution of sporadic Creutzfeldt–​Jakob disease recruited in the National Prion Monitoring Cohort 2008–​2015. section 24  Neurological disorders 6114 Iatrogenic CJD Epidemiology CJD has been transmitted accidentally in the course of medical treatment by neurosurgical instruments, corneal grafts, cadav- eric dura mater grafts, and human pituitary-​derived hormones (Table 24.11.5.3). The presumption is that infection from individ- uals with CJD was transmitted to uninfected individuals via these procedures and there is strong circumstantial evidence that this has occurred. In the two transmissions by corneal grafts the donors died of sporadic CJD, and in the neurosurgical transmissions there was a clear temporal link between surgical procedures on CJD cases and patients operated on using the same instruments who subsequently developed CJD. It is presumed that some human dura mater grafts and human pituitary hormones came from individuals with CJD and there may have been cross-​contamination in the production process, leading to dissemination of infection. Infection via human pituitary growth hormone has been demonstrated in laboratory 5- 0PRI 8- 0PRI 4- OPRI P102L P105L G114V G131V Y145X Q160X D178N E196K D202N Q217R Y218N V210I Y226X Q227X A117V Y163X T183A H187R E200K E211Q F198S P105T P84S P105S S132I R148H D178DEL2BP E211D V203I D202G A133V 2-0PRD S39L S17T P39S G54S 1-0PRI H85Y G142S G127V M129V E219K M154I N171S G195R V209M P238S 1-0PRD T188M M232T 3-0PRI R25H S97V 2-0PRI D167N F198V Q212P T188K T188A D167G T193I T188R T201SS I215V R208H R208C E196A V180I M232R E200D 129INSLGGLGGYV 6- 0PRI 9- 0PRI Definite Probable Possible Risk factor Polymorphism Resistance 7- 0PRI 12- 0PRI Fig. 24.11.5.6  Inherited prion diseases—​mutations of the prion protein gene. Over 60 definite, probable, or possibly causal mutations of the prion protein gene are known. There are also variants with increase or reduce the risk of sporadic prion disease, and variants which appear to confer no alteration of risk. Table 24.11.5.3  Iatrogenic Creutzfeldt–​Jakob disease worldwide Mode of infection No. of patients Mean incubation period (years) Clinical signs on presentation Neurosurgery 4 1.4 Visual/​dementia/​cerebellar Depth electrodes 2 1.3, 1.7 Dementia Corneal transplant 2 1.5, 27 Dementia Dura mater graft 228 12 Visual/​cerebellar/​dementia Growth hormone 226 17 Cerebellar Gonadotrophin 4 13.5 Cerebellar Packed red blood cellsa 3 6.5, 7.8, 8.3 Psychiatric, sensory, dementia, cerebellar a An additional asymptomatic but infected red-​cell recipient died of an unrelated illness: another asymptomatic infected haemophilia patient who had been exposed to potentially contaminated factor VIII also died of an unrelated illness (neither is included in the table). 24.11.5  Human prion diseases 6115 transmission studies. All cases of iatrogenic transmission of spor- adic CJD have involved surgical instruments, grafts, or hormonal products potentially contaminated by CNS tissue and, by implica- tion, high levels of infectivity. Clinical features There is a distinction between the clinical features in iatrogenic CJD which depends on the route of inoculation. In exposures in or adja- cent to the nervous system (neurosurgical instruments, dura mater grafts, and corneal transplants) most cases present with a progres- sive dementia similar to sporadic CJD. With a peripheral route of exposure to infection (cadaver derived human growth hormone, c-​ hGH) there is a progressive cerebellar ataxia and cognitive impair- ment develops late in the clinical course, if at all. The incubation period also varies according to the route of ex- posure to infection. With central exposure the mean incubation period ranges from about 18 months, similar to the incubation periods in primates after experimental intracerebral inoculation, to 12 years with dura mater grafts. With a peripheral route of ex- posure, the mean incubation period may extend to over 30 years, which is similar to the extended incubation periods in kuru, a human prion disease also caused by a peripheral route of exposure to infection. The polymorphism at PRNP codon 129 is a strong modifier of the incubation time of iatrogenic CJD; however, the experiences differ related to different exposures. For example, in c-​hGH iatrogenic CJD in France, individuals with an MM genotype have a shorter mean incubation time than those with genotype MV, whereas in the United Kingdom, those with the shortest mean incubation time are genotype VV, with MV and MM having longer incubations. These differences probably relate to the strain of prion which contamin- ated the c-​hGH. Despite incubation times approaching 40 years in the United Kingdom, those with iCJD related to c-​hGH and geno- type MM have rapid clinical courses. Measures to reduce the risk of iatrogenic transmission of CJD have been introduced in many countries. There are strict selection criteria for obtaining corneal grafts, recombinant growth hormone replaced human growth hormone in 1985, and human dura mater grafts have not been licensed in the United Kingdom since the early 1990s. Variant CJD Epidemiology Bovine spongiform encephalopathy was identified in 1986 as a novel prion disease in cattle in the United Kingdom, and is thought to have been caused by feeding cattle material contaminated with sheep scrapie or, perhaps, a previously unrecognized endemic prion disease of cattle. Bovine-​to-​bovine recycling of infection through cattle feed amplified the epidemic and there have now been over 180 000 documented cases of BSE in the United Kingdom. Small numbers of cases of BSE have been identified in other countries, mainly in Europe. In 1996, 10 cases of a novel form of human prion disease, variant Creutzfeldt–​Jakob disease (vCJD), were identified in the United Kingdom and a causal link with BSE was proposed as this was a new disease occurring only in the United Kingdom, the country with the greatest potential human exposure to BSE. Up to August 2015 there have been 174 primary cases of vCJD in the United Kingdom, 27 in France, and a limited number of cases in some other coun- tries. The mean age at death in vCJD is 30 years (range 14–​75 years) contrasting with a mean age at death in sporadic CJD of 67 years. The hypothesis that vCJD is caused by the BSE agent has been sup- ported by the consistent disease phenotype and, in particular, the neuropathology which is distinct from other human prion diseases, the failure to identify similar cases in the past either in the United Kingdom or elsewhere, and laboratory transmission studies that have shown a remarkable similarity between the transmission char- acteristics of BSE and vCJD in mice. Cases of vCJD have been identified from throughout the United Kingdom, and risk factors include residence in the United Kingdom and an MM genotype at codon 129 of the prion protein gene. All the United Kingdom cases and some of the cases in other countries had been resident in the United Kingdom during the 1980s to early 1990s, when human exposure to BSE was likely to have been max- imal. However, many of the cases outside the United Kingdom had never visited the United Kingdom, implying that exposure to BSE must have occurred in the country of origin to indigenous BSE or export from the United Kingdom of cattle or food products. The favoured hypothesis is that transmission of BSE to humans was through contamination of food, probably with tissues from the CNS such as brain or spinal cord which are known to contain high levels of infectivity in cattle infected with BSE. All tested cases of definite or probable vCJD to date have been MM homozygotes at codon 129 of the prion protein gene. This genotype is also present in about 70% of cases of sporadic CJD and may represent a sus- ceptibility factor for the development of vCJD. Variation at this locus can, however, influence the incubation period and disease phenotype and it is possible that cases of human infection with BSE may yet be identified in individuals with a VV or MV genetic back- ground. Indeed, a possible UK case of variant CJD with an MV gen- etic background was described in 2009. The potential future number of cases of vCJD is unknown, but the outbreak in the United Kingdom peaked in 1999/​2000 with a subsequent decrease in the annual number of deaths. Early pre- dictions estimated a total of 100 to over 136 000 cases of vCJD in the United Kingdom, but recent estimates are more conservative, predicting a maximum of no more than a few hundred cases There are, however, several uncertainties that make accurate predic- tion problematic, including the mean incubation period of BSE in humans, the level of the species barrier between bovines and hu- mans, and the possibility of future cases in a non-​MM genetic background. The identification of three cases of vCJD and one sub- clinical infection caused by transmission of the infectious agent through blood transfusion has raised concerns about the possibility of other routes of secondary transmission (e.g. through contamin- ated surgical instruments). Clinical features Presentation of vCJD is with behavioural and psychiatric disturb- ances and, in some cases, sensory disturbance. Initial referral is often to a psychiatrist with depression, anxiety, withdrawal, and behavioural change. Suicidal ideation is, however, infrequent and response to antidepressants poor. Delusions, which are complex and unsustained, are common. Other features include emotional la- bility, aggression, insomnia, and auditory and visual hallucinations. section 24  Neurological disorders 6116 Dysaesthesiae, or pain in the limbs or face, which was persistent ra- ther than intermittent and unrelated to anxiety levels is a frequent early feature. Typically, a progressive cerebellar syndrome then de- velops with gait and limb ataxia followed with dementia and pro- gression to akinetic mutism. Myoclonus is frequent, and may be preceded by chorea. Cortical blindness develops in a minority of pa- tients in late disease. Upgaze paresis, an uncommon feature of clas- sical CJD, has been noted in some patients. Kuru Epidemiology The transmissibility of human prion diseases was first demon- strated in 1966 with the transmission of a spongiform encephalop- athy to chimpanzees 18–​21 months after intracerebral inoculation of a brain extract from a patient who had died of kuru. This sem- inal experiment followed years of clinical, epidemiological, and anthropological research in the Fore region of Papua New Guinea where kuru was endemic. In the early 1960s kuru caused over half of all deaths in the affected population and there have been more than 3000 deaths from kuru in the at-​risk population of 30 000 people. Kuru predominantly affected women and children. The disease was transmitted at cannibalistic feasts where tissues with the greatest concentration of prions, principally the brain, were preferentially eaten by the children and females, the males older than 7 consuming predominantly muscle. The disease is a progressive ataxia and subsequent dementia developing over one to two years the patient ultimately becoming moribund. There is often a prodrome of headache. Banning canni- balistic practices has resulted in a dramatic decline in the prevalence of kuru, although a few cases may still occur. Interestingly, while the early cases were predominantly 129MM and 129VV, in the most re- cent analysis heterozygotes are the majority some with extremely long incubation times (over 50 years). As a result of the extreme selection pressures caused by the severity of the kuru epidemic, the Fore population show evidence of a population genetic evolutionary response. Survivors of the kuru epidemic, who were alive at the time of cannibalistic feasts, show marked Hardy-​Weinberg diserquilibrium at codon 129, with a pre- dominance of the resistant MV genotype. Remarkably, some elderly women who attended cannibalistic feasts but did not get kuru pos- sess a novel genetic resistance factor, G127V, unique to the Fore. In transgenic mice, this human gene variant in the homozygous state confers complete resistance to all prion diseases. The diagnosis of human prion diseases Human prion diseases are rare, but the high public profile of CJD and vCJD has resulted in an increase in the number of cases in which the diagnosis of one of these diseases is suspected. Accurate diag- nosis of any condition, including patients suffering from a human prion disease, is essential but the exclusion of a diagnosis is also im- portant, particularly for a fatal and untreatable condition. Although symptomatic treatment (e.g. for involuntary movements), can be helpful in human prion diseases, there is currently no available treat- ment that influences the clinical course or any treatment to prevent the development of neurological disease after infection. An im- portant objective is to improve diagnostic accuracy in human prion diseases and in particular to allow early diagnosis. In the absence of a test for the presence of the infectious agent, diagnosis depends on the recognition of the clinical characteristics of human prion dis- eases supported by a range of investigations, some of which have been developed in recent years. Diagnostic criteria for sporadic, iatrogenic, familial, and vCJD have been formulated and validated (Tables 24.11.5.4 and 24.11.5.5). In all human prion diseases, a def- inite diagnosis can be made only by the examination of tissue sam- ples, usually post-​mortem. In most cases of sporadic CJD, the diagnosis is suspected in life because of the multifocal neurological deficits, the development of myoclonus, and in particular the rapidity in the progression of cognitive impairment. The clinical picture is usually distinct from more common forms of dementia. In forms of sporadic CJD with early focal neurological features, such as a cerebellar syndrome, the rapid evolution of other neurological deficits and dementia suggests the diagnosis of CJD. Diagnosis may not be suspected in cases of sporadic CJD with atypical features such as long duration of illness, and/​or those with only or predominantly cognitive features. MRI, particularly with diffusion-​weighted and fluid-​attenuated inversion recovery (FLAIR) imaging, which in more than 90% shows specific high signal abnormalities in sporadic CJD, is now the key initial diagnostic investigation. Inherited prion diseases are often suspected because of a family history of a similar disorder, but in a significant proportion of cases of CJD associated with a prion protein gene mutation there is a family history of another neurodegenerative disorder or no relevant family history. The gradual clinical progression in many forms of hereditary human prion disease makes accurate diagnosis difficult and the diagnosis may be recognized in life only after prion protein gene analysis. Genetic testing should be carried only out with fully informed consent. Table 24.11.5.4  Diagnostic criteria for sporadic Creutzfeldt–​Jakob disease I Rapidly progressive dementia IIA Myoclonus IIB Visual or cerebellar problems IIC Pyramidal or extrapyramidal features IID Akinetic mutism III Typical electroencephalogram IV High signal in caudate/​putamen on MRI brain scan Definite Neuropathologically/​immunocytochemically confirmed Probable I + two of II + III or I + two of II + IV or I + two of II + positive 14-​3-​3 or Progressive neurological syndrome and positive RT-QuIC in CSF or other tissues Possible I + two of II + duration less than 2 years 24.11.5  Human prion diseases 6117 The diagnosis of iatrogenic CJD depends on the identification of a relevant risk factor (e.g. previous treatment with human growth hormones), and an assessment of the neurological presentation. Most patients with growth hormone-​related CJD present with a cerebellar syndrome, whereas after central iatrogenic exposure to infection the clinical picture is usually similar to that of sporadic CJD. The utility of specialist investigation in iatrogenic CJD is un- certain because of their rarity, but positive findings on MRI of the brain and/​or the 14-​3-​3 cerebrospinal fluid (CSF) test may support the diagnosis. The clinical picture in the later stages of vCJD is similar to that of sporadic CJD and, although the recognition of the diagnosis in the first cases of this new disease was difficult, the clinical pheno- type is now well known and the diagnosis is usually apparent after neurological signs develop, often in young patients in an age group in which dementia is very unusual. Diagnosis in the early stages is, however, difficult as there is a period of many months in which the clinical picture is dominated by psychiatric symptoms, including de- pression, anxiety, and withdrawal. Clues to the possibility of vCJD include cognitive impairment, subtle gait ataxia, and persistent painful sensory symptoms in combination with the psychiatric symptoms. The clinical features of sporadic and vCJD are compared in Table 24.11.5.6. Investigations in human prion disease Many of the investigations carried out in suspected cases of human prion disease do not show any specific disease-​related abnormality, but help to exclude other diagnoses, some potentially treatable. The interpretation of the results of investigations depends on the clinical picture because the sensitivity and specificity of surrogate markers for prion disease, such as 14-​3-​3 CSF analysis (see next), depend on clearly defining the characteristics of the patients in which the test has been carried out. Routine haematological and biochemical tests are usually normal. About a third of cases of sporadic or vCJD may have minor abnor- malities in liver function tests. The electroencephalogram (EEG) shows periodic triphasic com- plexes at about 1/​s in 60–​70% of cases of sporadic CJD (Fig. 24.11.5.7) and in some cases of iatrogenic CJD after central exposure to infec- tion. These EEG changes are relatively specific, but similar appear- ances can be seen in hepatic encephalopathy, lithium, or metrizamide toxicity, metabolic disturbance, and rarely in other forms of dementia such as Alzheimer’s disease. There is no CSF pleocytosis in any form of human prion disease, but CSF protein is elevated in about a third of cases. Elevation of the 14-​3-​3 CSF protein, a marker for neuronal damage, has a sen- sitivity and specificity of about 90% in the diagnosis of sporadic CJD, but is less useful in the diagnosis of vCJD. A new test has become available in recent years termed the real-​time quaking induced conversion assay (rtQUIC). This assay detects prion seeds by using cycles of shaking and incubation of a CSF sample in an excess of recombinant prion protein. The recombinant prion protein binds the seed, in a similar way to what is thought to happen during prion propagation, and misfolds, generating prion protein aggregates. Shaking (or ‘quaking’) then breaks up Table 24.11.5.5  Diagnostic criteria for variant Creutzfeldt–​Jakob disease IA Progressive neuropsychiatric disorder IB Duration of illness more than 6 months IC Routine investigations do not suggest an alternative diagnosis ID No history of potential iatrogenic exposure IE No evidence of a familial form of transmissible spongiform encephalopathy (TSE) IIA Early psychiatric symptomsa IIB Persistent painful sensory symptomsb IIC Ataxia IID Myoclonus or chorea or dystonia IIE Dementia IIIA EEG does not show the typical appearance of sporadic Creutzfeldt–​Jakob diseasec (or no EEG performed)c IIIB Bilateral pulvinar high signal on MRI scan IVA Positive tonsil biopsyd Definite IA + neuropathological confirmation of variant Creutzfeldt–​ Jakob diseasee Probable I + four out of five of II + IIIA + IIIB Probable I + IVAd Possible I + four out of five of II + IIIA a Depression, anxiety, apathy, withdrawal, delusions. b This includes both frank pain and/​or unpleasant dysaesthesia. c The typical appearance of the EEG in sporadic CJD consists of generalized triphasic periodic complexes at approximately one per second. These may occasionally been seen in the late stages of vCJD. d Tonsil biopsy is not recommended routinely, nor in cases with EEG appearances typical of sporadic CJD, but may be useful in suspect cases in which the clinical features are compatible with vCJD and MRI does not show bilateral pulvinar high signal. e Spongiform change and extensive deposition of prion protein with florid plaques, throughout the cerebrum and cerebellum. Table 24.11.5.6  Clinical features of sporadic and variant Creutzfeldt–​Jakob disease Feature Sporadic CJD Variant CJD Mean age at death 67 years 30 years Median illness duration 4 months 14 months Symptoms at onset: Cognitive impairment 70% 10% Psychiatric (depression, anxiety, and so on) <5% 70% Painful sensory symptoms <1% 20% Signs during clinical course: Dementia 100% 100% Ataxia 80% 100% Involuntary movements: Myoclonus 95% 70% Chorea <5% 50% Dystonia <5% 25% section 24  Neurological disorders 6118 the aggregates to generate more seeds for the reaction. The aggre- gates generated in this way can be labelled with the fluorescent thioflavin T. In some laboratories the rtQUIC test is more than 90% sensitive with sporadic CJD CSF samples, and is extremely specific (close to 100%). The test is particularly useful in atyp- ical clinical and imaging cases. rtQUIC is not at present opti- mized for variant CJD. Amplification assays using urine and/​or nasal mucosa have shown promising initial results, but further research is needed. MRI is the most useful modality of imaging in CJD (Fig. 24.11.5.8). High signal return from grey matter is characteristic of CJD and is usually most apparent on diffusion-​weighted images, less so on FLAIR, and least on T2 weighted images. Diffusion-​ weighted imaging can be done at various b-​values but conven- tionally 1000 s/​mm2. Apparent diffusion coefficient maps should be calculated to confirm true restricted diffusion and remove T2-​weighted ‘shine through’. Enhancement with gadolinium does not occur in any type of CJD. The distribution of the abnormal signal varies between different types of CJD. In sporadic CJD there is high signal return from the basal ganglia, typically the caudate and anterior putamen in around 70%. This may be asymmetrical. In addition, thalamic signal is often abnormal and can be focal, patchy, or diffuse. The abnormality can include the posterior complex, leading to consideration of variant CJD, but in sporadic CJD the thalamic signal is less intense than that from the caudate nuclei. Cortical ‘ribboning’ is found in many patients usually in addition to the basal ganglia abnormality. This is best seen on diffusion-​weighted imaging and apparent diffusion coefficient maps. The distri- bution can be focal involving any part of the cortex; care must be taken in determining abnormality in areas of allocortex par- ticularly the anterior cingulate and insula with 3T scanning and with frontal cortex adjacent to the frontal sinuses. Nevertheless, the cingulate abnormality often extends caudally and can be the sole abnormal cortical region. The cortical signal abnormality is usually asymmetrical. In a few patients cortical ribboning is the only abnormality. Taken together with the subcortical changes, the MRI signal is abnormal in over 90% of patients with sporadic CJD. In vCJD about 90% of patients in a prospective series have high signal return from the pulvinar and medial areas of the thalamus particularly adjacent to the ventricle, the so called ‘hockey stick’ sign. This is apparent on FLAIR and diffusion-​weighted imaging in most cases. However, it is unclear when this sign develops and it is not infrequent that the initial scan is reported as normal, but be- comes clearly abnormal over a few months. Brain biopsy can allow the confirmation of the diagnosis of a human prion disease in life, but this investigation has risks and is mainly carried out when there is a realistic possibility of an alterna- tive diagnosis. Tonsil biopsy in vCJD is a more accessible procedure for tissue diagnosis and may be important for the relatives of the patient and for clinicians. Fig. 24.11.5.7  Typical electroencephalogram in sporadic Creutzfeldt–​Jakob disease. Image was provided by Dr Tim Wehner of UCLH NHS Foundation Trust. 24.11.5  Human prion diseases 6119 FURTHER READING Atarashi R, et al. (2011). Ultrasensitive human prion detection in cerebrospinal fluid by real-​time quaking-​induced conversion. Nat Med, 17, 175–​8. Bradley R, et al. (2006). Variant CJD (vCJD) and bovine spongiform encephalopathy (BSE): 10 and 20 years on: part 1. Folia Neuropathol, 44, 93–​101. Brown P (2008). Transmissible spongiform encephalopathy in the 21st century. Neurology, 70, 713–​22. Cali I, et al. (2006). Classification of sporadic Creutzfeldt–​Jakob dis- ease revisited. Brain, 129, 2266–​77. Collee JG, et al. (2006). Variant CJD (vCJD) and bovine spongiform encephalopathy (BSE): 10 and 20 years on: part 2. Folia Neuropathol, 44, 102–​10. Collinge J, et al. (2006). Kuru in the 21st century—​an acquired human prion disease with very long incubation periods. Lancet, 367, 2068–​74. Collins SJ, et  al. (2006). Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt–​ Jakob disease. Brain, 129, 2278–​87. de Armond SJ, et  al. (2003). Perspectives on prion biology, prion disease pathogenesis, and pharmacologic approaches to treatment. Clin Lab Med, 23, 1–​41. Mead S, et al. (2009). A novel protective prion protein variant that colocalizes with kuru exposure. N Engl J Med, 361, 2056–​65. Wadsworth JDF, et  al. (2007). Update on human prion disease. Biochim Biophys Acta, 1772, 598–​609. Fig. 24.11.5.8  MR image of sporadic Creutzfeldt–​Jakob disease showing (a) ‘cortical ribbon’ on diffusion-​weighted images, (b) high signal from the caudate, putamen, thalamus, and cortex on FLAIR images, (c) high signal from caudate, putamen and less so the thalamus on diffusion-​weighted images, and (d) ‘pulvinar’ sign in variant CJD on FLAIR images. Images were provided by Dr Harpreet Hyare of the National Prion Clinic and UCLH NHS Foundation Trust. 24.12 Disorders of cranial nerves 6120 Robert D.M. 24.12 Disorders of cranial nerves 6120 Robert D.M. Hadden ESSENTIALS The 12 cranial nerves are peripheral nerves except for the olfactory and optic nerves which are central nervous system tracts. Disorders of particular note include the following: olfactory (I) nerve—​anosmia is most commonly encountered as a sequel to head injury. Eye movements—​third, fourth, and sixth cranial nerves—​complete lesions lead to the following deficits (a) third nerve—​a dilated and un- reactive pupil, complete ptosis, and loss of upward, downward and medial movement of the eye; (b) fourth nerve—​extorsion of the eye when the patient looks outwards, with diplopia when gaze is directed downwards and medially; (c)  sixth nerve—​convergent strabismus, with inability to abduct the affected eye and diplopia maximal on lateral gaze to the affected side. The third, fourth, and sixth nerves may be affected singly or in combination: in older patients the most common cause is vascular disease of the nerves themselves or their nuclei in the brainstem. Other causes of lesions include (a) false lo- calizing signs—​third or sixth nerve palsies related to displacement of the brainstem produced by supratentorial space-​occupying lesions; (b)  intracavernous aneurysm of the internal carotid artery—​third, fourth, and sixth nerve lesions. Lesions of these nerves can be mim- icked by myasthenia gravis or myopathies. Pupillary abnormalities—​these include (a)  constriction (miosis)—​ due to paralysis of the sympathetic innervation (Horner’s syndrome); (b) dilatation—​due to lesions of the third nerve. Trigeminal nerve—​pathology causes numbness and tingling of the side of the face and scalp back to the vertex, loss of the corneal re- flex and deviation of the jaw to the affected side. May be affected by intramedullary lesions, during the intracranial part of its course, and extracranially. Trigeminal neuralgia is usually due to compression of the nerve by aberrant vessels in the posterior fossa. It is characterized by paroxysms of intense pain strictly confined to the nerve’s distribu- tion and often responsive to carbamazepine. Facial nerve—​in upper (but not lower) motor neuron lesions there is relative preservation of power in the upper facial muscles. In Bell’s palsy, onset is rapid and frequently heralded or accompanied by aching pain in or around the ear: treatment with prednisolone with an antiviral agent improves the prognosis. Hemifacial spasm is characterized by irregular clonic or simultaneous twitching move- ments of the facial muscles, usually of insidious onset; injections of botulinum toxin may be helpful. Glossopharyngeal nerve—​rarely affected in isolation, when it is very difficult to detect any neurological deficit; usually affected in combination with the vagus nerve. Vagus nerve—​important symptoms of damage relate to pharyn- geal and laryngeal innervation producing a bulbar palsy with dys- phonia, dysarthria, and dysphagia. Causes include brainstem stroke, motor neuron disease, malignant infiltration anywhere along the course of the nerve and cranial polyneuropathy. Spinal accessory nerve—​may be affected by lesions, often neo- plastic, in the region of the jugular foramen, but more commonly by injuries to the neck or by operations for the removal of cervical lymph nodes. Hypoglossal nerve—​may be affected by tumours in the region of the anterior condyloid foramen, or by tumours or penetrating in- juries in the neck. The most common cause of bilateral lesions is the progressive bulbar palsy variant of motor neuron disease. Multiple cranial neuropathies (cranial polyneuropathy) might be due to inflammatory conditions (such as Guillain–​Barré syndrome, (Miller) Fisher syndrome, vasculitis, granulomatosis with polyangiitis (Wegener’s), sarcoidosis); infections (basal meningitis such as tu- berculosis, Lyme borreliosis, fungi); diabetes mellitus; meningeal carcinomatosis or lymphomatosis; or might be mimicked by my- asthenia gravis, motor neuron disease, botulism, or myopathies. Cranial MRI (with contrast) and cerebrospinal fluid analysis are the key investigations. Bulbar palsy is the syndrome of abnormality of cranial nerves arising from the medulla oblongata (nerves IX, X, XI, and XII). Tongue wasting and fasciculations, absent jaw jerk, absent gag reflex (unreliable unless unilateral), and flaccid dysarthria with nasal regurgitation distinguish this lower motor neuron syndrome from pseudobulbar palsy which is an upper motor neuron lesion of the medulla. A unilateral lesion of nerves V, VII, and VIII sug- gests pathology in the cerebellopontine angle such as vestibular schwannoma. 24.12 Disorders of cranial nerves Robert D.M. Hadden1 1  This chapter is adapted from earlier editions written by Professors P. K. Thomas (deceased) and Richard Hughes. 24.12  Disorders of cranial nerves 6121 The olfactory nerve (I) Loss of the sense of smell (anosmia) is most commonly encoun- tered as a sequel to head injury and is probably related to sever- ance of the central processes of the olfactory neurons as they pass through the cribriform plate to the olfactory bulb. It is usually per- manent. Distortion of olfaction (parosmia) may occur and can be persistent. The sense of smell is occasionally congenitally absent or may be acutely and permanently lost after a coryzal infection. Bilateral anosmia is frequently accompanied by impairment of taste related to reduced detection of the volatile substances that impart flavours to foods. Unilateral anosmia may occur in olfactory groove meningiomas or other subfrontal tumours. This is usually not de- tected by the patient. The central connections of the olfactory pathways are complex and include projections to the temporal lobes, hypothalamus, septal region, and amygdaloid nuclei. Olfactory hallucinations occur as a manifestation of temporal lobe epilepsy. Identification of odours may be impaired after bilateral medial temporal lesions and may be defective in multiple sclerosis, possibly as the result of demye- lination in the olfactory tracts. Reduced sense of smell occurs as an early symptom of some neurodegenerative disorders, including Alzheimer’s disease and idiopathic Parkinson’s disease. Complaints of hypersensitivity of the sense of smell commonly have a psycho- neurotic or migrainous basis and persistent olfactory hallucinations may be reported by psychotic patients. Persistent parosmia is some- times produced by lesions of the temporal lobe. Third, fourth, and sixth cranial nerves The third, or oculomotor, nerve supplies all the external ocular muscles with the exception of the superior oblique and lateral rectus. It also carries the parasympathetic innervation of the preganglionic pupilloconstrictor fibres of the iris. A complete third nerve lesion produces a dilated and unreactive pupil, complete ptosis, and loss of upward, downward, and medial movement of the eye. The eye becomes deviated laterally and slightly downwards. Diplopia is only experienced when the lid is lifted. The fourth or trochlear nerve supplies the superior oblique muscle. Following a lesion of this nerve, there is extorsion of the eye when the patient looks outwards. When the patient looks down- wards and medially, diplopia is experienced. This is particularly disturbing because looking downwards is important for walking and especially when descending stairs. The patient may compensate for this by tilting the head to the opposite side. The sixth or abducent nerve supplies the lateral rectus. A lesion of this nerve causes convergent strabismus, inability to abduct the affected eye, and diplopia which is maximal on lateral gaze to the affected side. The third, fourth, and sixth nerves may be affected singly or in combination, and the paralysis may be complete or partial. In some instances, the lesion is within the brainstem, where it may affect ei- ther the nuclei or the intramedullary portions of the nerve fibres. In older patients, the most common cause of single nerve lesions is microvascular ischaemia which typically spontaneously recovers in a few months. Extramedullary lesions of the third, fourth, and sixth nerves may occur at any point along their course, either intracranially or within the orbit. A third nerve palsy may develop in the region of the tentorial hiatus as a false localizing sign related to displacement of the brainstem produced by supratentorial space-​occupying lesions. Unilateral or bilateral sixth nerve palsies may also arise as a con- sequence of raised intracranial pressure, probably caused by trac- tion, again secondary to brainstem displacement. These nerves can be involved singly or together in conditions such as chronic basal meningitis or carcinoma of the skull base. Gradenigo’s syndrome comprises a sixth nerve palsy and pain of trigeminal distribution. It is produced by a lesion at the apex of the petrous temporal bone. As this syndrome was most commonly infective in origin and related to chronic middle ear disease, it is now much less frequent. The third, fourth, and sixth nerves traverse the cavernous sinus, as do the first and second divisions of the trigeminal nerve. In this situation, they are most commonly damaged by an intracavernous aneurysm of the internal carotid artery. The third nerve is affected more often than the fourth or sixth. The consequent internal and external ophthalmoplegia is frequently accompanied by pain, and sometimes sensory loss and paraesthesiae in the corresponding frontal region related to compression of the first division of the tri- geminal nerve. Sometimes pain occurs in the cheek from damage to the maxillary division. In the superior orbital fissure syndrome, caused for example by a tumour invading the fissure, a total oph- thalmoplegia may result, associated with pain and sensory loss in the distribution of the first division of the trigeminal nerve. The eye is often proptosed because of obstruction of the ophthalmic vein. The Tolosa–​Hunt syndrome consists of a painful external ophthal- moplegia related to a granulomatous angiitis. Within the orbit, the third, fourth, and sixth nerves may be affected by conditions such as tumours and granulomas. They may be damaged as a result of trauma at any point along their course and may be affected singly or as part of multiple cranial neuropathies, of which diabetes, the (Miller) Fisher syndrome, Lyme disease, vasculitis, and sarcoidosis are the most important causes. Internal and external ophthalmoplegias are common and this list of nerve lesions causing the syndrome is by no means exhaustive. Complex external ophthalmoplegia may also be caused by myasthenia or myopathy. Pupillary abnormalities Constriction of the pupil (miosis) occurs as a result of paralysis of the sympathetic innervation of the pupillodilator fibres of the iris and may be accompanied by the other features of Horner’s syn- drome; mild ptosis and vasodilatation and anhidrosis of the face on the same side. The ocular manifestations may be encountered alone if the damage is restricted to the intracranial portion of the sympa- thetic plexus around the carotid artery such as in carotid dissection. Raeder’s syndrome consists of these components of Horner’s syn- drome together with involvement of the first division of the trigem- inal nerve. It may be caused by tumours of the skull base. Miosis may also be produced by the local action of cholinergic drugs and by morphine and related compounds. Pupillary dilatation may be caused by lesions of the third nerve. The isolated third nerve palsies of presumed microvascular origin that can occur in diabetes mellitus characteristically spare the pupil. section 24  Neurological disorders 6122 In contradistinction, compressive lesions of the nerve, for instance by an aneurysm or transtentorial brain herniation, involve the pupil prominently and early. Anticholinergic drugs, such as atropine and related substances, and cocaine also cause pupillary dilatation. The Argyll–​Robertson pupil is small, fails to react to light, but constricts on ocular convergence, and, if bilateral, the pupils are fre- quently unequal in size (anisocoria). The pupil may be irregular in outline and does not dilate fully in response to mydriatics. Argyll–​ Robertson pupils are often related to neurosyphilis but somewhat similar pupils are occasionally encountered in diabetic neuropathy, in some hereditary neuropathies, and following the use of atropine-​ like eyedrops. The Adie’s tonic pupil reacts abnormally slowly both to light and on convergence, but particularly so for the response to illumination. A very bright light may be required to demonstrate any slow pu- pillary constriction. If the patient remains in a dark room for some minutes, the pupil slowly dilates. The condition may be unilateral or bilateral and is commoner in women than men. It causes minimal symptoms and requires no treatment. Tonic pupils may be associ- ated with absence or depression of the tendon reflexes (Holmes–​ Adie syndrome) and occasionally with anhidrosis in the limbs. Trigeminal nerve (V) The fifth cranial nerve is predominantly sensory in function, but also innervates the muscles of mastication. It emerges from the pons and runs forwards to the Gasserian (trigeminal) ganglion which is situated in Meckel’s cave near the apex of the petrous tem- poral bone. The three sensory divisions of the nerve run anteriorly from the ganglion. The first or frontal division passes through the cavernous sinus and the superior orbital fissure. Its branches supply sensation to the anterior part of the scalp, the forehead, and the eye, including the conjunctiva and cornea. The second or maxillary division leaves the skull through the foramen rotundum, traverses the infraorbital canal, and supplies the cheek. The mandibular div- ision emerges from the skull through the foramen ovale to reach the infratemporal fossa with the motor root with which it unites to form a single trunk. It is distributed to the lower lip, chin, and the lower part of the cheek, and its auriculotemporal branch sup- plies the tragus of the ear and temple. It also supplies the inner aspect of the cheek and the anterior two-​thirds of the tongue, and its lingual branch carries taste fibres from the anterior two-​thirds of the tongue which leave it in the chorda tympani to join the fa- cial nerve. The skin over the angle of the jaw is supplied from the second cervical nerve root, not the trigeminal nerve, which may be useful in distinguishing non​organic loss of sensation on the face, which usually follows the angle of the jaw. The motor root innerv- ates temporalis, masseter, pterygoids, mylohyoid, the anterior belly of the digastric and tensor tympani, and tensor palati muscles. With unilateral paralysis of the masticatory muscles, the jaw is pushed towards the affected side on opening by the unopposed external pterygoid on the unaffected side. The trigeminal nerve may be affected by intramedullary lesions. It may also be damaged during the intracranial part of its course. Its branches may be compromised extracranially. A  vestibular schwannoma or other space-​occupying lesion in the cerebellopontine angle may compress the nerve in the posterior fossa or the nucleus of its descending root in the brainstem. Loss of corneal sensation (tested by the corneal reflex) is usually the earliest feature. Reference has already been made to involvement of the nerve in association with damage to the sixth nerve at the apex of the petrous temporal bone (Gradenigo’s syndrome), as has involvement of the first and second divisions in the cavernous sinus, or the first division in the superior orbital fissure. Fluctuating facial numbness is a common functional symptom, typically sparing inside the mouth, not conforming to anatomical boundaries, and without objective sensory loss on examination. Fluctuating facial pain or dysaesthesia is commonly due to a variant of migraine, typically around one eye, often changing sides over time. Bilateral numbness around the mouth may be of brainstem origin. Isolated trigeminal neuropathy Rarely, a slowly progressive, isolated unilateral or bilateral affection of the trigeminal nerve causing numbness and/​or pain may occur as a manifestation of Sjögren’s syndrome, connective tissue disease, progressive systemic sclerosis, or amyloidosis. Most cases are idio- pathic. It may start in the chin as ‘mental numbness’. Trigeminal neuralgia Symptoms This condition is characterized by brief paroxysms of intense pain strictly confined to the distribution of the trigeminal nerve. It is generally encountered in individuals over the age of 50 years. It is commonly caused by the impingement of a vascular loop on the tri- geminal nerve root entry zone in the posterior fossa, though vascular loops are often asymptomatic. It may be idiopathic, or symptom- atic of underlying pathology such as multiple sclerosis, especially in younger patients, or compression/​infiltration of the nerve, for ex- ample by tumours in the cerebellopontine angle, to which a clue may be sensory loss. The pain is usually unilateral (never switching sides) and is felt either within the territory of one division of the nerve only, or may involve two adjacent divisions or affect the whole territory of the nerve. The distribution is usually in the second or third divisions of the nerve or both. The first division is rarely affected primarily, but pain may spread into it from the second division. Pain often starts in a tooth and fails to improve after dental extraction. Less commonly, it is bilateral. The pain occurs in brief searing paroxysms, each attack lasting only seconds, but repeated many times per day. The pain is often described as piercing, knife-​like, or electrical. Its intense quality may cause the patient to screw up their face in agony, hence the use of the term ‘tic doloureux’. The paroxysms may be spontaneous or pro- voked by movements of the face and jaw, by touching the skin, or by draughts of cold air on the face. Eating and speaking may become extremely difficult. ‘Trigger spots’ on the skin of the face may be present, the touching of which provokes the paroxysms. The attacks may be followed by less severe pain of a dull, boring character, and by tenderness of the skin in the affected area. The attacks usually cease at night. 24.12  Disorders of cranial nerves 6123 The timing and triggering of the pain is characteristic, and when trigeminal neuralgia is present the diagnosis is not usually missed. The usual mistake is to regard as trigeminal neuralgia pain that which is due to some other cause. Pain of continuous character is not trigeminal neuralgia. Absence of provocation by touching or moving the face or mouth also makes the diagnosis unlikely. Other causes of facial pain include migraine (often giving pain in, behind, or around one eye), cluster headache, atypical facial pain, or trigem- inal neuropathy. In the early stages, remissions lasting for months or years are usual, but in older patients’ remissions, if they occur, are likely to be brief. In all cases the remissions tend to become shorter as time goes on, and without treatment the condition persists for the rest of the patient’s life. Treatment The introduction of carbamazepine revolutionized treatment of this distressing condition. In most patients, pain a can be abolished or reduced. It is best to start with a low dose of 100 mg once or twice a day and increase by 100 mg every 2–​7 days until control is achieved (usually at 300–​800 mg per day, sometimes higher). Slow release preparations are preferred. The rate of increase and maximum dose may be titrated to minimize adverse effects of ataxia and drowsi- ness. In a pain crisis, the dose may be increased as fast as the pa- tient can tolerate; dosing three or four times daily gives more stable serum levels. Reduce the dose again when pain improves. Patients should be warned to stop the drug if an allergic rash occurs, because of the danger of exfoliative dermatitis. Hyponatraemia is common but usually mild and asymptomatic. Bone marrow suppression is very rare. Oxcarbazepine, a metabolite of carbamazepine, is an alternative first line treatment: it is probably equally effective and may have fewer adverse effects, but has a shorter serum half-​life. If these are not effective or not tolerated, baclofen, lamotrigine, pregabalin, gabapentin, or topiramate, may be tried, although the evidence base is weaker. In an acute pain crisis, small case series suggest short term benefit from topical lidocaine, intravenous phenytoin loading, or subcutaneous sumatriptan. If medical treatment is inadequate, the patient should be re- ferred for a neurosurgical opinion. Microvascular decompression of a vessel, shown on MRI to be impinging on the nerve, requires open craniotomy but usually gives a good long-​term outcome and is often curative. Patients unsuitable for this often benefit from destructive procedures of the trigeminal ganglion (gamma knife radiosurgery or percutaneous lesioning by heat, balloon compres- sion or chemical injection) which are less invasive procedures but have a lower chance of long-​term benefit, and a risk of persistent analgesia and sometimes painful dysaesthesiae, called ‘anaes- thesia dolorosa’, which may be more troublesome than the original condition. Ophthalmic herpes zoster The fifth nerve is prone to involvement in herpes zoster, usually in elderly individuals. The first division is most vulnerable, giving rise to the distressing condition of ophthalmic herpes. The clinical fea- tures and treatment of herpes zoster are considered elsewhere (see Chapter 8.5.2). An unfortunate sequel may be visual impairment from residual corneal scarring. Postherpetic neuralgia may give rise to persistent and unre- mitting spontaneous pain associated with cutaneous hyperaes- thesia in the affected area. Treatment of neuralgia should start with standard medication for neuropathic pain (tricyclic antidepres- sants, gabapentin or pregabalin) or perhaps the topical lidocaine 5% patch (but not ideal in this location). Alternatives could include duloxetine, carbamazepine, opioids, or tramadol. Facial nerve (VII) The seventh cranial nerve is largely motor. The nerve traverses the facial canal in the petrous temporal bone in close relationship to the middle ear and emerges at the stylomastoid foramen. Its branches pass forwards through the parotid gland to be distributed to the muscles of the face and the platysma. Within the petrous bone, a branch is given to the stapedius muscle. The chorda tympani, carrying the taste fibres from the anterior two-​thirds of the tongue, joins the nerve within the facial canal and a small branch supplies cutaneous sensation to the external auditory meatus. (The symptom of loss of taste is more commonly due to abnormality of the sense of smell.) The nerve also carries preganglionic parasympathetic fibres destined for the lacrimal gland. The distinction between upper and lower motor neuron lesions of the facial muscles is usually easy. In general, with upper motor neuron lesions (such as a stroke) there is relative preservation of power in the upper facial muscles, because these have a represen- tation in both cerebral hemispheres. There is no loss of tone with upper motor neuron lesions, so that the sagging of the face that is an unsightly feature of lower motor neuron palsy does not occur. In common with the trigeminal nerve, the facial nerve may be affected by tumours in the cerebellopontine angle. In the past, it was often involved in middle ear infections. It may be involved in meningeal carcinomatosis, fractures, and tumours of the skull base, in a variety of cranial neuropathies, and cephalic herpes zoster, but the most common lesion by far is Bell’s palsy. More peripherally, the nerve may be compromised in tumours of the parotid gland. Bell’s (idiopathic facial) palsy This is usually unilateral facial paralysis of rapid onset due to in- flammation of the nerve within the facial canal. Taste may also be affected. It has an annual incidence of 20–​32 per 100 000 and may develop at any age, most commonly between 20 and 50 years, and affects both sexes equally. There is some, but inconclusive, evidence that it is a manifestation of herpes simplex infection. In the acute stage, the nerve is swollen and compression within the facial canal may contribute to the damage to the nerve fibres. The onset is rapid and is frequently heralded or accompanied by aching pain below the ear or in the mastoid region. This clears within a few days and is not present in every case. The paralysis usually reaches its maximum severity after 1 or 2 days. Complete paralysis may occur. This may cause a mild dysarthria and some difficulty in eating because of food collecting between the gums and the inner sides of the cheek and the escape of fluid when drinking. The face sags, and the mouth may be drawn across to the unaffected side (which may give the false impression of tongue deviation). Paralysis of orbicularis oculi may render voluntary eye section 24  Neurological disorders 6124 closure impossible and, particularly in the older subject, ectropion develops. This can result in conjunctival injury from foreign bodies or drying (‘exposure keratitis’). The patient may complain of facial numbness due to altered movement, although objective sensory examination is normal and the trigeminal nerve is not involved. In more severe cases, loss of taste over the anterior two-​thirds of the tongue may be present, and paralysis of the stapedius muscle may result in a lack of tolerance for high-​pitched or loud sounds, called hyperacusis. Diagnostic tests are not usually required in typical cases, but in atypical cases the following may be considered. Selective lesions of the facial nerve within the brainstem do not affect taste, but almost always cause fifth or sixth nerves palsies and long tract symptoms or signs as well. With respect to peripheral lesions, middle ear disease requires exclusion. Facial paralysis may also be caused by herpes zoster as described next. A lesion of the facial nerve may be part of a more generalized disorder of which diabetes, Lyme disease, and sarcoidosis are the most important. Bell’s palsy is rarely bilateral and bilateral facial paralysis would raise the possibility of another dis- order, such as sarcoidosis, a Guillain–​Barré syndrome variant (‘fa- cial diplegia with paraesthesiae’), or Lyme. In approximately 85% of patients with Bell’s palsy, especially those with mild weakness, the paralysis is the result of a local conduction block within the facial canal without axonal degeneration. The con- duction block is presumably the consequence of segmental demye- lination. Provided that such cases do not progress to more severe weakness, remyelination is rapid, and most recover fully within a few weeks. In cases where there is total paralysis, axonal degeneration is likely to have occurred so that recovery has to take place by axonal re- generation, which is slow and incomplete. Evidence of reinnervation does not appear in under 3 months and the ultimate recovery is often incomplete or may fail to occur altogether. After reinnervation the regenerated axons may form inappropriate connections, causing synkinesis and ‘crocodile tears’. In synkinesis, blinking results in a simultaneous twitch of the angle of the mouth. ‘Crocodile tears’ are caused by aberrant parasympathetic reinnervation so that food elicits weeping instead of salivation. Axons remain excitable distal to the lesion for 3 or 4 days after interruption. It is, therefore, not possible to be certain from electrodiagnostic tests whether axonal degeneration has taken place until later. After that stage, electrical stimulation of the facial nerve at the stylomastoid foramen will still elicit a muscle contraction if the paralysis is due to conduction block, whereas none will be obtained if axonal degeneration has taken place. Treatment Oral corticosteroids and antivirals should be started as soon as possible, preferably within 3  days from onset. In a large high-​ quality trial, the percentage of patients with complete recovery after 9 months was significantly increased from 82% without to 94% with prednisolone, 25 mg twice daily for 10 days. Another trial obtained similar results with prednisolone 60 mg daily for 5 days and then a reducing dose for the next 5 days. In the Cochrane review of seven trials, the proportion of patients with incomplete recovery after six months was reduced by corticosteroids from 33% to 23%, and there was reduction in motor synkinesis but surprisingly not in cos- metically disabling sequelae after six months. Antiviral medication (acyclovir or valaciclovir) provides additional benefit. Hyperbaric oxygen was beneficial in an unblinded study. Patients with se- vere palsy, with inability to close the eye, should use moisturizing eye ointment and eye protection to protect the eye from exposure keratitis (some may require stitching of the lateral parts of the eye- lids, lateral tarsorrhaphy). Tailored facial exercises may help to im- prove facial function in people with moderate chronic weakness and perhaps in acute cases. Stretching exercises of the ipsilateral upper eyelid and contralateral mouth help to prevent contractures. Electrical stimulation of the paralysed facial muscles does not help long-​term outcome. If regeneration is inadequate after waiting at least a year, cosmetic operations may be considered to counteract the facial deformity. The angle of the mouth may be elevated by a fascial sling attached to the temporalis fascia, but the result is never highly satisfactory. Restoration of facial tone may be achieved by anastomosis of the hypoglossal to the facial nerve, but at the expense of denervation of the tongue on that side. Facial paralysis related to ‘geniculate’ herpes zoster (Ramsay–​Hunt syndrome) Very rarely facial palsy is due to zoster infection. If typical vesicles are detected in the ear and ulceration in the fauces, or anywhere on the head, then it is reasonable to give antiviral agents as well as corticosteroids, although evidence is lacking. Occasionally there is concomitant vertigo, tinnitus, and deafness due to involvement of the eighth nerve. Hemifacial spasm This consists of a unilateral disturbance affecting the facial muscles, producing irregular twitching movements of the facial muscles, usually of insidious onset. All affected parts of the face twitch syn- chronously. It most commonly occurs in middle-​aged women. Facial power is usually normal or there may be mild facial weakness. Usually no underlying cause is demonstrable. The condition select- ively affects the facial nerve, within the brainstem or in the posterior fossa. Hemifacial spasm is painless. If it is associated with pain, there may be a lesion in the cerebellopontine angle compressing both the trigeminal and facial nerves. It begins with intermittent twitching of the facial muscles such as around the eye, in the cheek, or at the angle of the mouth. These movements gradually become more frequent and extend to involve the rest of the facial muscles, over the course of some years. If they become severe, the face is contorted by irregular clonic spasms which may keep the eye closed for prolonged periods. The facial dis- tortion is often a considerable embarrassment to the patient, who finds that the spasms tend to be aggravated by emotional stress. It does not switch sides and is only rarely bilateral. Injections of botulinum toxin are usually helpful, but have to be repeated every 3 months. Neurosurgical intervention to relieve com- pression of the facial nerve by aberrant vessels in the posterior fossa may help selected cases. Clonazapam may help. The condition must be distinguished from the very common be- nign fasciculations of the face, usually periorbital, related to fatigue or emotional tension, and from facial myokymia that is occasionally encountered as a manifestation of multiple sclerosis. The latter con- sists of a persisting irregular rippling movement of the facial muscles that usually subsides after a week or two. These conditions can be distinguished by electromyography (see Chapter 24.3.2). 24.12  Disorders of cranial nerves 6125 Glossopharyngeal nerve (IX) The ninth cranial nerve leaves the skull through the jugular foramen, closely related to the tenth nerve. It supplies the stylopharyngeus muscle and the constrictor muscles of the pharynx. Parasympathetic fibres are supplied to the parotid gland. Sensory fibres are carried from the posterior third of the tongue, the ear, the fauces, and the nasopharynx, and chemoreceptor and baroreceptor afferents from the carotid sinus. The glossopharyngeal nerve is rarely affected in isolation. If it is affected alone, it is very difficult to detect the deficits expected from its anatomical distribution. Lesions usually occur in conjunc- tion with involvement of the vagus and give rise to some dysphagia, impaired pharyngeal sensation, and loss of taste over the posterior third of the tongue. It may be affected in the jugular foramen syn- drome, along with the tenth and eleventh nerves, of which glomus tumours or metastatic carcinomas are the commonest causes. The nerve may also be involved in diphtheritic neuropathy, Fisher syn- drome, and in cranial polyneuropathy. Glossopharyngeal neuralgia is rare and resembles trigeminal neuralgia but with symptoms in the distribution of the glossopha- ryngeal nerve. As with trigeminal neuralgia, it is most often en- countered in elderly subjects, and the pain may initially be confined to individual branches. Thus, it may be felt deep in the ear, related to the tympanic branch, or in the throat, related to the pharyngeal branches. It usually responds to treatment with carbamazepine. If that and other antiepileptic drugs fail, surgical treatment, usually section of the nerve, may be required. Vagus nerve (X) The tenth cranial nerve is structurally complex. Within the skull it is joined by the cranial portion of the eleventh nerve. It leaves the skull through the jugular foramen. Motor fibres supply the striated musculature of the palate and pharynx and, through the internal, external, and recurrent laryngeal nerves, the muscles of the larynx. Cutaneous sensory fibres are carried from the external ear and vis- ceral afferent fibres are carried from the pharynx, larynx, trachea, oe- sophagus, and the thoracic and abdominal viscera. Parasympathetic fibres innervate the parotid gland (through the glossopharyngeal nerve), the heart, and the abdominal viscera. Neurostimulation of the vagus nerve is a treatment for refractory epilepsy mediated by autonomic afferent fibres. The important symptoms of damage to the vagus nerve are those relating to pharyngeal and laryngeal innervation, causing dysphonia and dysarthria; a weak or bovine cough is probably the earliest sign of a mild lesion. The cells of origin in the nucleus ambiguus of the medulla may be damaged in the lateral medullary syndrome, motor neuron disease, and acute bulbar poliomyelitis, leading to dysphagia and dysphonia. Involvement along with the glossopharyngeal nerve in the jugular foramen syndrome has already been mentioned. The recurrent laryngeal nerve may be damaged during operations on the thyroid gland or by tumours within the neck, or within the thorax, usually due to carcinoma of the bronchus. The nerve on the left is vulnerable to damage by an aneurysm of the aortic arch. Isolated and unexplained lesions of the recurrent laryngeal nerve are not uncommon. Nuclear or high vagal lesions, as well as involving the larynx, cause palatal and pharyngeal paralysis. If unilateral, there are few symp- toms from palatopharyngeal paralysis. The uvula is pulled up to the opposite side on phonation and pharyngeal sensation is impaired on the affected side. The gag reflex is a reliable indicator if asym- metric, but is bilaterally absent in some normal people. With bilat- eral paralysis, the palate is paretic leading to nasality of the voice and nasal regurgitation of liquids on attempts at swallowing. Bilateral palatopharyngeal paralysis may be encountered in motor neuron disease, bulbar poliomyelitis, diphtheritic neuropathy, and cranial polyneuropathy. Intrinsic laryngeal paralysis from lesions of the recurrent laryn- geal nerve, if unilateral, may be asymptomatic or give rise to hoarse- ness of the voice. If the superior laryngeal nerve is also involved leading to paralysis of the cricothyroid muscle, the affected cord lies in a paramedian or cadaveric position. The effects of bilateral lesions of the recurrent laryngeal nerves depend upon the degree of approximation of the vocal cords. Lesions of insidious onset give rise to dysphonia and also to stridor on exertion. In partial lesions, close approximation of the cords may result from selective paralysis of the abductor muscles, giving rise to limitation of the airway and sometimes necessitating tracheostomy. With bilateral lesions involving both the recurrent and superior laryngeal nerves, both cords are paralysed and in the cadaveric position. Phonation is impossible. Spinal accessory nerve (XI) The spinal accessory portion of the eleventh cranial nerve arises from the upper cervical cord and the lower medulla. The nerve enters the foramen magnum and briefly joins the cranial portion (functionally part of the vagus nerve) before emerging from the skull through the jugular foramen. The spinal accessory nerve then separates and supplies the sternomastoid and trapezius muscles, the latter also receiving an innervation from the cervical plexus. The nerve may be affected by lesions, often neoplastic, in the region of the jugular foramen, but more commonly it is damaged by injuries to the neck or by operations for the removal of cervical lymph nodes, particularly as it crosses the posterior triangle of the neck. Isolated and unexplained lesions of the nerve are occasion- ally encountered. Unilateral paralysis of the sternomastoid usually passes un- noticed by the patient. The muscle does not stand out when the head is turned to the opposite side. Paralysis of the trapezius, on the other hand, causes difficulty in lifting the arm above the horizontal, in shrugging the shoulder, and in approximating the scapula to the midline and therefore also in carrying the extended arm backwards. The shoulder droops when the arm is hanging at the side and there is moderate winging of the scapula which is accentuated when the patient attempts to elevate the arm laterally. Hypoglossal nerve (XII) The twelfth cranial nerve supplies all the muscles of the tongue, both intrinsic and extrinsic. It leaves the skull through the anterior section 24  Neurological disorders 6126 condyloid foramen. A unilateral lesion of the hypoglossal nerve causes weakness, wasting, and fasciculations of the tongue on the affected side. The protruded tongue may deviate to the affected side if weakness is severe, but this is often misdiagnosed when not truly present. Articulation is unaffected. The nerve may be affected by tumours in the region of the anterior condyloid foramen, or by tumours or penetrating injuries in the neck, or by complications of carotid endarterectomy. If damage is the result of a unilateral lower brainstem lesion, it is usually combined with a contralateral hemiplegia. Bilateral lesions give rise to generalized wasting of the tongue. Wasting of the tongue is usually accompanied by fasciculation which is best detected with the tongue at rest. Protrusion becomes impossible and articulation is disturbed. The most common cause is the progressive bulbar palsy variant of motor neuron disease. Many normal people have irregular involuntary twitching or writhing movements of the tongue at rest, but the lack of wasting helps to distinguish this from pathological fasciculations. FURTHER READING Asbury AK, et  al. (1970). Oculomotor palsy in diabetic mellitus:  a clinicopathological study. Brain, 93, 555–​66. Brodal A (1965). The cranial nerves, 2nd edition. Blackwell Scientific, Oxford. Dyck PJ, Thomas PK (2005). Peripheral neuropathy, 4th edition. Elsevier Saunders, Philadelphia, PA. Gagyor I, et al. (2015). Antiviral treatment for Bell’s palsy (idiopathic facial paralysis). Cochrane Database Syst Rev, 11, CD001869. Kennard C (2007). How to examine eye movements. Practical Neurol, 7, 326–​30. Leigh JR, Zee DS (2006). The neurology of eye movements. Oxford University Press, New York, NY. Sullivan F, et al. (2007). Early treatment with prednisolone or acyclovir in Bell’s palsy. N Engl J Med, 357, 1598–​607. Younge BR (1966). Paralysis of cranial nerves III, IV and VI: causes and prognosis of 1000 cases. Arch Ophthalmol, 99, 76–​89. 24.13 Disorders of the spinal cord 6127 24.13.1 Di 24.13 Disorders of the spinal cord 6127 24.13.1 Diseases of the spinal cord 6127 Anu Jacob and Andrew J. Larner 24.13 Disorders of the spinal cord CONTENTS 24.13.1 Diseases of the spinal cord  6127 Anu Jacob and Andrew J. Larner 24.13.2 Spinal cord injury and its management  6135 Wagih El Masri(y) and Michael Barnes 24.13.1  Diseases of the spinal cord Anu Jacob and Andrew J. Larner ESSENTIALS The spinal cord is subject to numerous pathological processes which may be intrinsic (intramedullary) and/​or extrinsic (extramedullary) to the cord. Clinical features Symptoms and signs suggestive of spinal cord disease include (1) motor—​weakness and alteration in tone; acute cord lesions produce flaccidity (‘spinal shock’) whereas chronic processes pro- duce spasticity, with hyperreflexia, clonus, and upgoing (extensor) plantar responses; pathological processes affecting lower motor neurons in the anterior horns typically produce early muscle wasting and fasciculation; (2) sensory—​including numbness, loss of sensation, tingling, sensory ataxia; the demonstration of a sen- sory level and analysis of specific sensory deficit patterns are of particular importance in localizing the site, and therefore the likely cause, of a spinal cord lesion; and (3) autonomic—​sphincter dysfunction, most commonly affecting bladder function. Other clinical features may give clues to the cause of spinal cord dis- ease (e.g. multiple sclerosis, systemic lupus erythematosus, neurofibromatosis). Investigation Intramedullary and extramedullary pathologies may produce distin- guishable symptom profiles, but the clinical distinction can only ever be probabilistic. If there is acute onset of myelopathy, and/​or struc- tural disease is suspected, imaging of the cord is mandatory, with MRI the investigation of choice. Once structural lesions are excluded, further investigation depends on suspected cause (e.g. neurogenetic testing for some hereditary spastic paraplegias and spinocerebellar ataxias), and on geographical location or travel history (e.g. schisto­ some ova in faeces). Examination of the cerebrospinal fluid may be required. Particular conditions affecting the spinal cord Many diseases can affect the spinal cord. Those of particular note include (1)  spondylotic myelopathy—​the most common cause of progressive myelopathy due to cord compression; (2)  mul- tiple sclerosis—​may present as an isolated cord syndrome, usually partial rather than complete; (3) transverse myelitis—​most com- monly affects the thoracic cord; there may be a preceding his- tory of infection, and cerebrospinal fluid analysis may disclose an infective agent; (4)  subacute combined degeneration of the cord—​demyelination of the posterior and lateral columns due to vitamin B12 deficiency; neurological features may occur in the absence of haematological abnormality; (5)  genetic disorders—​ hereditary spastic paraplegia is usually an autosomal dominant disorder; causative mutations have been described in several genes; (6) vascular disorders—​anterior spinal artery occlusion can infarct whole or part of the anterior two-​thirds of the cord; (7) syr- ingomyelia; (8)  injury/​trauma—​see Chapter  24.13.2; (9)  motor neuron disease—​see Chapter 24.15; (10) cancer—​most common spinal cord tumours are metastasis, astrocytoma, ependymoma, lymphoma. Treatment and prognosis Specific medical and surgical treatments are determined by the particular cause of myelopathy. These may arrest progression, but function that has been lost may not recover fully. Prognosis of acute cord compression is directly related to the time delay between symptom onset and relief of compression. Chronic dis- ability as a consequence of spinal cord disease requires intensive neurorehabilitation. Introduction Disease within the substance of the spinal cord, intramedullary myelopathy, may result from a wide variety of pathological causes. Myelopathy may also result from pathology located outside the spinal cord (extramedullary) but within structures section 24  Neurological disorders 6128 immediately adjacent to the cord, either intradural or extradural, affecting normal cord function. Clinical features may some- times give clues to both the pathological nature and anatomical location of disease, but these have been greatly augmented with the development of magnetic resonance imaging studies of the spinal cord. Aetiology and pathogenesis The spinal cord and its addenda may be affected by structural, inflammatory, demyelinating, metabolic, infective, neoplastic, and paraneoplastic, genetic, vascular, and iatrogenic disorders (Table 24.13.1.1). Chronic progressive myelopathy should al- ways prompt consideration of a structural lesion such as a tu- mour, intrinsic or extrinsic, but cervical spondylotic change with osteophyte formation, with or without concurrent interverte- bral disc degeneration and prolapse, is the most common cause of progressive cord compression. Hyperacute cord syndromes (evolving over minutes) may result from trauma or vascular path- ology, and infective or inflammatory disorders (myelitis) may develop acutely (hours to days) or subacutely (days to weeks), although sometimes present in a chronic progressive fashion (over months). Table 24.13.1.1  Overview of causes of myelopathy Pathological process (NB not necessarily mutually exclusive) Intramedullary Extramedullary Structural: developmental Syringomyelia related to Chiari malformation Spina bifida, spinal dysraphism, diastematomyelia Chiari malformation Tethered cord syndrome Platybasia/​basilar invagination Arteriovenous malformations (AVM) Arachnoid cysts (e.g. in Marfan syndrome) Achondroplasia Structural: acquired/​ traumatic Cord transection Contusion/​haematoma Haematomyelia Central cord syndrome (hyperextension injury) Whiplash (hyperextension/​flexion injury) Spinal cord injury without radiologic abnormality (SCIWORA) Intervertebral disc prolapse +/​-​ osteophytes +/​-​ spinal stenosis Vertebral fracture (e.g. wedge fracture with vertebral metastasis) Atlanto-​axial subluxation (e.g. rheumatoid arthritis) Ossification of the posterior longitudinal ligament Dural herniation of the spinal cord (e.g. neuroenteric cyst) Epidural lipomatosis Structural: neoplastic Astrocytoma/​glioma Ependymoma Lymphoma Medulloblastoma Metastases Intradural: meningioma; neurofibroma; lipoma (+/​-​ spina bifida) Extradural: myeloma, lymphoma, sarcoma, haemangioblastoma, chordoma Metastases Leukaemic meningeal infiltration Demyelinating disease Multiple sclerosis Acute disseminated encephalomyelitis (ADEM) Neuromyelitis optica (NMO) and NMO spectrum disease Solitary sclerosis (Not applicable) Inflammatory and/​or immunological Transverse myelitis (idiopathic > clinically isolated syndrome) Sarcoidosis Systemic lupus erythematosus (SLE) Sjögren’s syndrome Behçet’s disease Giant cell arteritis Paraneoplastic myelitis Necrotizing myelitis (Foix–​Alajouanine syndrome) Eales’ myelopathy Arachnoiditis (e.g. related to radiological contrast media, ankylosing spondylitis) Discitis Infection Viral (e.g. poliomyelitis, HIV, HTLV-​1 [tropical spastic paraparesis], enterovirus, herpes simplex 1 and 2, herpes zoster, EBV, CMV, HHV6, HHV7) Spirochaetal: neurosyphilis (tabes dorsalis) Bacterial (e.g. brucellosis, tuberculoma) Parasitic (e.g. schistosomiasis) ‘Atypicals’ (e.g. mycoplasma) Spinal abscess: epidural, subdural Empyema Osteomyelitis (e.g. staphylococcal) Osteitis (e.g. tuberculosis [Pott’s disease], syphilis) Parasitic cysts (e.g. echinococcus) Metabolic and nutritional disorders Vitamin B12 deficiency (subacute combined degeneration of the cord) Copper deficiency associated myelopathy ‘Hepatic myelopathy’ Adrenomyeloneuropathy Vitamin E deficiency Lathyrism Konzo Krabbe’s globoid cell leukodystrophy Paget’s disease (‘osteitis deformans’) (continued) 24.13.1  Diseases of the spinal cord 6129 Clinical features The clinical features of spinal cord disease, the symptoms and signs, and their temporal progression, may give clues to disease localiza- tion (Tables 24.13.1.2 and 24.13.1.3) and pathogenesis. Symptoms and signs suggestive of spinal cord disease may be motor (weakness, spasticity), sensory (numbness, loss of sensation, tingling, sensory ataxia), and autonomic (sphincter and sexual dys- function). Acute and chronic pathologies may result in differing pat- terns of symptoms and signs, the former sometimes evolving to the latter. Involvement of specific spinal cord pathways may be inferred from the clinical features. Motor symptoms Weakness may affect all limbs (quadriparesis) or only the legs (paraparesis). The most severe presentation, for example, after traumatic cord transection, is with complete absence of power (quadriplegia, paraplegia). Exceptionally with extramedullary cer- vical cord lesions a triparesis may be seen, sometimes evolving in a sequential (‘round the clock’) pattern: arm, then ipsilateral leg, then contralateral leg. Alterations in tone often accompany weakness: in acute lesions flaccidity (‘spinal shock’) but with more chronic processes spasti- city with clonus, along with pathological accentuation of myotatic (tendon, phasic) reflexes (hyperreflexia), loss of cutaneous reflexes, and upgoing (extensor) plantar responses (Babinski’s sign). Tonic spasms, abrupt and painful spasm of limbs on one side that last seconds to less than a minute, and often occurring multiple times in a day, are often seen in neuromyelitis optica. They respond exceptionally well to carbamazepine. Muscle wasting is a late sign with upper motor neurone path- ology. Concurrent radiculopathy or neuropathy may however modulate the typical upper motor neurone signs, for example the absent ankle jerks with upgoing plantars sometimes seen in sub- acute combined degeneration of the cord in which there is concur- rent neuropathy, or in motor neuron disease with both upper and lower motor neurone involvement, or the segmental reflex depres- sion in a compressive cervical myeloradiculopathy. Inversion of re- flexes (i.e. movement opposite to that usually seen, such as elbow Pathological process (NB not necessarily mutually exclusive) Intramedullary Extramedullary Neuronal degeneration and hereditary disorders Motor neuron disease Other motor neuron diseases: spinal muscular atrophies, Hirayama disease Hereditary spastic paraplegias (HSP) Spinocerebellar ataxias Familial Alzheimer’s disease with presenilin-​1 gene deletion Familial British dementia (Worster–​Drought syndrome) (Not applicable) Vascular Cord infarction (e.g. anterior spinal artery syndrome) Cord ischaemia (e.g. ‘surfer’s myelopathy’) Aortic aneurysm Fibrocartilaginous embolism Decompression sickness Haematomyelia/​haematoma: into metastasis or vascular malformation, primary coagulation disorder Vascular malformations: dural arteriovenous fistula, arteriovenous malformations, cavernous angioma Iatrogenic Surgery of aortic aneurysm: anterior spinal artery syndrome Lumbar puncture: direct trauma to cord Radiation myelopathy (acute, delayed) Vaccination-​related myelopathy Drugs: anticoagulants (bleed into cord); heroin; subacute myelo-​ optic neuropathy with clioquinol Lumbar puncture: spinal subdural haematoma Medically unexplained ‘Hysterical paraplegia’ Table 24.13.1.2  Clinical clues to differentiation of intramedullary from extramedullary myelopathy Symptoms/​Signs Intramedullary Extramedullary Sensory Central (funicular) distribution of pain may occur. Patterns of sensory loss may be: dissociated (spinothalamic > dorsal column modalities, or vice versa) including classic Brown–​Séquard syndrome; suspended (cape-​like, cuirasse); sacral sparing. Vibratory sensibility more often affected than proprioception. Pain may be radicular or vertebral in distribution. Sensory signs not usually marked until the later stages and all modalities often involved. Brown–​Séquard syndrome may be more common with extrinsic than intrinsic pathologies. Motor Lower motor neurone signs at the level of the lesion(s) may be prominent and diffuse; upper motor neurone signs of spastic paraparesis below the level of the lesion tend to occur late. Combination of upper and lower motor neurone signs more likely to reflect intrinsic than extrinsic pathology. Sequential spastic paraparesis below the level of the lesion. Upper motor neurone signs occur early; lower motor neurone signs unusual and if present typically have segmental (radicular) distribution. Autonomic Bladder involvement common, often early symptom; slow to recover. Later involvement than in intramedullary lesions. section 24  Neurological disorders 6130 extension when eliciting the supinator reflex) may occur when pathology affects both the local reflex arc and segments higher in the cord. High spinal cord lesions may affect segments innerv- ating the diaphragm (C3–​5) with subsequent respiratory com- promise, particularly acute lesions, hence the need for respiratory monitoring in these circumstances. The root values of abnormal myotatic and cutaneous reflexes help to localize the lesion. Pathological processes targeting lower motor neurones in the an- terior horns of the spinal cord typically produce early muscle wasting and fasciculation. Motor neuron disease is the most common cause of these signs, sometimes in isolation (‘progressive muscular at- rophy’), but they may also occur following certain viral infections (poliomyelitis, enterovirus 71, flaviviruses such as Japanese enceph- alitis virus). A subacute motor neuronopathy is also described in association with underlying lymphoma. Sensory symptoms Spinal cord pathologies are often accompanied by a localizing sensory level, which may be defined clinically as the spinal seg- ment below which sensation is altered and above which it is in- tact. Because pain fibres forming the spinothalamic tracts ascend in the posterior horns for two or three segments prior to decussa- tion through the ventral commissure, contralateral loss or reduction of pain and temperature sensation may be associated with a level two or three segments above the site of pathology. The deficit asso- ciated with a sensory level may be complete, affecting all modalities, for example in cord transection (‘sawn off’) or complete transverse myelopathies, but more often is partial. Specific patterns of sensory deficit have particular localizing im- plications (Table 24.13.1.3). Because of the anatomical separation within the cord of the pathways subserving the sensory modal- ities of pain and temperature (spinothalamic) and proprioception (dorsal column), dissociated sensory loss may occur. Central cord pathologies such as syringomyelia selectively involve decussating spinothalamic pathways within the ventral commissure resulting in impaired pain and temperature sensation, often in a suspended (‘cape-​like’, cuirasse, ‘bathing suit’) distribution, dependent on the exact level of the syrinx. Osteoarthropathy (Charcot joints) due to loss of pain fibres may also occur in syringomyelia. Anterior spinal artery syndrome also spares the dorsal (posterior) columns. Conversely, the dorsal columns are preferentially affected in dis- orders such as subacute combined degeneration of the cord. Focal cervical cord pathology, most typically demyelination, may be ac- companied by Lhermitte’s sign, tingling paraesthesia radiating like an electric shock into the arms and legs on neck flexion; rarely there may be a motor equivalent, increased limb weakness on neck flexion (McArdle’s sign). Both signs reflect mechanosensitivity and impaired impulse transmission in demyelinated axons. Preservation of pain and temperature sensation in sacral dermatomes (‘sacral sparing’) below a sensory level may be seen with intramedullary lesions as a result of the topographical lamination of fibres in the spinothalamic tracts, the ventrolateral fibres of sacral origin being most external and hence later involved with expanding intramedullary lesions. Although ataxia is sometimes thought of as a motor symptom, it may also be a consequence of sensory dysfunction, specific- ally when afferent proprioceptive information is degraded or lost. Sensory ataxia, as distinct from cerebellar or optic ataxia, results in falling or markedly increased sway when standing with the eyes closed (Romberg’s sign) and impaired heel-​toe (tandem) walking (‘dynamic Romberg’s sign’). Pseudoathetosis, involuntary move- ments in the outstretched hands (‘piano-​playing fingers’), may also be seen. Dorsal column pathologies are particularly associated with sensory ataxia, classically the tabes dorsalis form of neurosyphilis, also sometimes known as locomotor ataxia. Table 24.13.1.3  Clinical presentations of intramedullary myelopathies Lesion type Tracts involved Clinical signs Examples Complete All Motor, sensory, and autonomic dysfunction below lesion Traumatic cord transection, acute necrotizing viral myelitis Brown–​Séquard (hemicord) syndrome Ipsilateral corticospinal and dorsal columns, contralateral spinothalamic columns Ipsilateral pyramidal weakens and dorsal cord sensory loss, contralateral spinothalamic loss Multiple sclerosis Anterior cord syndrome Bilateral anterior horn cells, corticospinal tracts, spinothalamic and autonomic Acute bilateral flaccid weakness, loss of pain/​ temperature, sphincter/​autonomic dysfunction, preserved dorsal column function Anterior spinal artery occlusion Dorsal (posterior) cord syndrome Bilateral dorsal columns Bilateral loss of proprioception, vibration sensation Vitamin B12 deficiency, copper deficiency, tabes dorsalis, AIDS-​associated vacuolar myelopathy Central cord Crossing spinothalamic, corticospinal, and autonomic fibres Dissociated sensory loss: pain and temperature impaired with preserved vibration and proprioception. May have pyramidal weakness and autonomic dysfunction below lesion Syringomyelia Conus medullaris Autonomic outflow and sacral spinal cord segments Early sphincter dysfunction, sacral sensory loss; mild (proximal) leg weakness L1 central disc prolapse, postviral myelitis Cauda equina syndrome Spinal nerve roots of the cauda equina Early flaccid leg weakness, often asymmetric, sensory loss in root distribution, followed by autonomic dysfunction Compression, acute cytomegalovirus polyradiculitis Tractopathies Selective tract involvement Selective pyramidal or dorsal column involvement Vitamin B12 deficiency, paraneoplastic myelopathy 24.13.1  Diseases of the spinal cord 6131 Autonomic symptoms Autonomic symptoms associated with spinal cord pathology are most typically those related to sphincter, particularly bladder, func- tion. Acute spinal cord lesions may result in urinary retention, for example cauda equina compression with central L1 disc prolapse, although sometimes the pathology may be many segments rostral to the clinical signs. Inflammatory and chronic lesions, for example multiple sclerosis, may be associated with urinary frequency, ur- gency and urge incontinence with urodynamic evidence of detrusor muscle hyperreflexia and detrusor sphincter dyssynergia (i.e. in- ability of the sphincter to relax while the detrusor contracts). Loss of awareness of bladder fullness with urinary retention and overflow (atonic bladder) may result from direct damage to the sacral cord. Cord damage may also result in constipation or faecal urgency or incontinence, and sexual (e.g. erectile) dysfunction. Loss of or ex- cessive sweating may be observed in syringomyelia. Horner’s syn- drome may be associated with cord pathology since the sympathetic afferents originate there, for example, isolated Horner’s syndrome has been reported with syringomyelia. Autonomic dysreflexia is a life-​threatening situation when sympa- thetic overactivity below the lesion, which cannot be countered by descending inhibitory spinal cord pathways due to the cord lesion, leads to severe hypertension. It occurs typically in complete trans- verse myelitis above T6 level and is triggered by visceral stimuli like a full bladder. Intramedullary versus extramedullary myelopathy Intramedullary and extramedullary pathologies may produce dis- tinguishable symptom profiles (Table 24.13.1.2) but the clinical dis- tinction can only ever be probabilistic, and further investigation by means of spinal cord imaging, ideally with MRI, is indicated. The syndrome originally described by Brown–​Séquard in the context of traumatic cord hemisection consists of ipsilateral spastic weakness with or without segmental lower motor neurone signs at the level of the lesion, with dissociated sensory loss comprising ipsilateral pro- prioceptive loss and contralateral pain and temperature loss below the level of the lesion. This pattern may occur with various patholo- gies including prolapsed disc, intra-​ and extramedullary tumours, and multiple sclerosis. Other clinical features may give clues to the aetiological diag- nosis of myelopathy. A  history of hindbrain headache may indi- cate a Chiari malformation. Likewise, other clinical signs may be informative: a segmental rash may be seen acutely with varicella zoster, and clinical stigmata may point to diagnoses such as systemic lupus erythematosus (SLE), neurofibromatosis, Paget’s disease, and rheumatoid arthritis. False localizing signs Although the 2–​3 segment mismatch between a clinically defined pain sensory level and the location of cord pathology is easily ex- plicable based on the known anatomy of spinal cord connections, other clinical signs distant from pathology are less easy to explain. Such false localizing signs in the cord include the association of for- amen magnum or upper cervical cord lesions with paraesthesia in the hands, intrinsic hand muscle wasting (‘remote atrophy’) and distal upper limb areflexia, a gestalt more suggestive of lower cer- vical myeloradiculopathy. Similarly, a midthoracic sensory level (described as a tight band, squeeze, or ‘girdle sensation’) with spastic paraparesis may occur with lower cervical or upper thoracic com- pressive pathology. Differential diagnosis The particular pattern of symptoms and signs may allow differenti- ation of myelopathy from disorders of nerve roots (radiculopathy), although because of their close proximity to the cord simultaneous segmental involvement is not uncommon (radiculomyelopathy) particularly with cervical spinal lesions; likewise, peripheral nerves (neuropathy), although certain disease processes may simultan- eously affect both (myeloneuropathy, e.g. subacute combined de- generation). Isolated lesions of the conus typically present with numbness in the lowest dermatomes (perianal) with bladdder and bowel involvement without weakness, but may soon progress to in- volve higher levels of cord causing motor symptoms. It may however be difficult to differentiate it from the cauda equina syndrome of multiple radiculopathies, although often both are present. Clinical investigations If there is acute onset of myelopathy, and/​or structural disease is sus- pected, imaging of the cord is mandatory and MRI the investigation of choice, usually requiring axial and sagittal sequences with T1-​ and T2-​weighting, with or without gadolinium contrast. Appearances may diagnose structural abnormalities such as spondylotic compres- sion, disc prolapse, intrinsic or extrinsic tumours, syringomyelia, Chiari malformations, abscess, or haematoma. Arteriovenous mal- formations may be seen, although it remains the case that on occa- sion myelography will reveal vascular anomalies not seen on MRI. Further definition of these vascular lesions with selective spinal angiography or magnetic resonance angiography may be helpful in planning appropriate treatment. Neurosurgical biopsy of mass le- sions may on occasion be required. Intrinsic cord disease may have characteristic appearances on MR imaging. Typical demyelinating lesions of multiple sclerosis usually extend for no more than two vertebral segments and may be mul- tiple, whereas more extensive lesions (‘longitudinal myelitis’) sug- gest neuromyelitis optica (NMO), or other infective, postinfectious, or vascular disease. These lesions may be associated with enhance- ment on postcontrast scans. Certain viral myelitides, such as polio- myelitis or enterovirus 71, may produce signal change confined to the anterior horns, consistent with a purely motor syndrome. T2-​ weighted hyperintensity in the grey matter of the anterior horns (‘snake-​eyes’) may also be seen in Hirayama disease/​O’Sullivan-​ McLeod syndrome, or paraneoplasia. Magnetic resonance spectros- copy of cord lesions may prove difficult because of partial volume effects in selected voxels. Once structural lesions are excluded, further investigation of myel- opathy will depend on the suspected cause. Blood tests may include haematological parameters such as full blood count and film, ESR, and vitamin B12 level. Biochemical analyses are seldom helpful other than for specific entities, such as angiotensin converting enzyme for sarcoidosis, and very long chain fatty acids for adrenoleukodystrophy which may be associated with the typical electrolyte changes of Addison’s disease. Raised alkaline phosphatase may alert to a possible section 24  Neurological disorders 6132 diagnosis of Paget’s disease. Serology for the venereal diseases re- search laboratory, autoantibodies including double-​stranded DNA, antiphospholipid antibodies, and gastric parietal cell antibodies may be required if specific diseases are suspected. NMO is associated with serum aquaporin-​4 immunoglobulin G antibodies (AQP4-​IgG). Serology for infective agents may encompass viral (HIV, HTLV-​1, enterovirus 71, EBV, CMV, varicella zoster, coxsackievirus, polio- virus), bacterial (brucella, tuberculosis), spirochaetal (syphilis) and parasitic (schistosomiasis) causes of myelopathy. In the appropriate geographical distribution or with positive travel history, a search for schistosome ova in faeces may be undertaken. Neurogenetic testing, following appropriate genetic counselling, is available for some of the many genetic loci which have been de- fined for the hereditary spastic paraplegias and spinocerebellar ataxias. Adrenoleukodystrophy has been linked to over 500 different mutations in the ATP-binding cassette ABCD1 gene. Examination of the cerebrospinal fluid may be required. Depending on the clinical scenario, this may require analysis for cell count, protein, glucose, xanthochromia, oligoclonal bands, serology, cytology, angiotensin converting enzyme and polymerase chain reaction for infective agents such as viruses and tuberculosis (see Chapter 24.3.1). Neurophysiological investigations (electromyography, nerve con- duction studies) have little direct role in the diagnosis of cord syn- dromes, although electromyography may be diagnostic for motor neuron disease, but may help to define concurrent radiculopathies or neuropathies which may focus differential diagnostic consider- ations. Somatosensory evoked potential studies may confirm a clin- ically defined spinal cord lesion, or provide evidence of a subclinical lesion, for example in multiple sclerosis, as may visual evoked poten- tial studies. However, MRI is more sensitive in this regard. Central motor conduction times to muscles in lower (e.g. tibialis anterior) or upper limb (e.g. abductor digiti minimi) may indicate cord path- ology, often being abnormal in transverse myelopathies, but this in- vestigation is not widely available. Criteria for diagnosis Clinical features of some of the more common causes of myelopathy (Table 24.13.1.1) are briefly presented. Structural disorders A syrinx is a fluid-​filled cavity within the spinal cord (syringomyelia) or brainstem (syringobulbia) which may be connected to a dilated central canal or separate from it. Most are associated with Chiari type hindbrain anomalies, sometimes with concurrent hydroceph- alus, but there are also associations with spinal trauma, spinal tu- mours, arachnoiditis, and inflammatory/​demyelinating disorders of the spinal cord such as multiple sclerosis and NMO. Demyelinating diseases The spinal cord is one the sites of predilection for demyelinating diseases. Multiple sclerosis (MS; see Chapter 24.10.2) may present as an isolated cord syndrome, usually partial rather than complete. Clues to the diagnosis may be typical MRI features in the cord, con- current demyelination on brain MRI, and cerebrospinal fluid (CSF) with oligoclonal bands. Distinct from this acute presentation is a progressive myelopathy, either following (secondary progressive MS) or without prior relapsing episodes (primary progressive MS). Neuromyelitis optica (NMO), also known as Devic’s syndrome, is an inflammatory disorder, an autoimmune astrocytopathy, with a predilection for optic nerves and spinal cord, causing typic- ally a long myelitis usually greater than three vertebral segments, associated with AQP4-​IgG. The phenotype has broadened with increasing availability of serological testing, with classification now encompassing NMO spectrum disorder (NMOSD). Further anti- bodies have been described in NMO (e.g. myelin oligodendrocyte), but as yet lack the specificity of AQP4-​IgG. Solitary sclerosis is a progressive neurological syndrome resulting from a single demyelinating lesion in the lower brainstem or upper cervical spinal cord, but not fulfilling diagnostic criteria for MS or NMOSD. Some patients have CSF oligoclonal bands suggesting that in some instances solitary sclerosis might be a spatially isolated, forme fruste, of MS. Acute disseminated encephalomyelitis (ADEM) is a monophasic inflammatory disorder of brain and spinal cord, more commonly seen in children than adults, and sometimes following infection or vaccination. Acute haemorrhagic leukoencephalitis (or Hurst’s disease) is probably related. The clinical picture is heterogeneous, with encephalopathy, focal neurological signs, and even psychosis being the presenting features. Multiphasic and recurrent variants have occasionally been described, and it may be difficult to differ- entiate ADEM from a first episode of MS. Clinical and radiological findings said to be more common in ADEM than MS include pre- ceding infectious disease, polysymptomatic presentation, pyram- idal signs, encephalopathy, bilateral optic neuritis, and epileptic seizures. Inflammatory and infective diseases Transverse myelitis most commonly affects the thoracic cord. If complete, there is paralysis, sensory loss, and incontinence, often with an acute flaccid paraparesis or paraplegia. There may be a preceding history of infection. MR imaging often reveals exten- sive longitudinal abnormal signal over several contiguous spinal segments, unlike the pattern typical of MS. Differential diag- nosis of such ‘longitudinal myelitis’ includes NMOSD, infective (viral), postinfectious, and postvaccination myelitides, and col- lagen vascular diseases. CSF analysis may disclose an infective agent, including coxsackieviruses, polioviruses, enterovirus 71, flaviviruses (Japanese encephalitis, West Nile virus), some of which have a predilection for the anterior horn cells producing a largely or exclusively motor picture and MR signal change confined to the anterior horns. HTLV-​1 more typically produces a chronic spastic paraparesis, also known as HTLV-​1-​associated myelopathy (HAM), and was probably the agent responsible for ‘tropical spastic parapar- esis’. The vacuolar myelopathy associated with HIV infection may be overlooked clinically because of other neurological involvement and is often defined only at post-​mortem. Postinfectious myelitis may be a variant of ADEM, hence the term ‘acute postinfectious encephalomyelitis’ has been suggested. Collagen vascular dis- eases such as SLE, with or without antiphospholipid antibodies, may be associated, and sometimes presents, with an acute myelitis which, as in the case of postinfectious myelitis, is associated with raised CSF cell count and protein but without oligoclonal bands. A depressed CSF glucose level has sometimes been reported in 24.13.1  Diseases of the spinal cord 6133 SLE transverse myelitis. However, much of the literature on SLE, Sjögren’s syndrome, or other connective tissue associated mye- litis predates the discovery of aquaporin-​4 IgG, which has been increasingly identified in such myelitides, suggesting that NMO rather than the connective tissue disease was responsible for the myelitis. Other multisystem inflammatory disorders like sarcoidosis and Behçet’s disease can affect the spinal cord and present typically as intramedullary single or multiple, short or long, contrast-​enhancing lesions that respond to steroids. Careful history, systemic examin- ation, and non​invasive tests will avoid misdiagnosis and spinal cord biopsy. A syndrome of acute necrotizing myelitis, sometimes known as Foix–​Alajouanine syndrome, may merge with the severe end of the transverse myelitis spectrum. This condition may be asso- ciated with vascular pathologies (see next), or haematological or lung neoplasms, and hence represent a paraneoplastic syndrome, although more usually these latter manifest as an encephalomy- elitis. A  progressive encephalomyelitis with rigidity and myo- clonus may occur as a paraneoplastic syndrome associated with antibodies directed against glutamic acid decarboxylase or gly- cine receptors. Some episodes of transverse myelitis resist all diagnostic efforts to define their aetiology and hence by a process of exclusion may be classified as idiopathic transverse myelitis. Metabolic and nutritional disorders In subacute combined degeneration of the cord due to vitamin B12 (cobalamin) deficiency, myelopathy is due to demyelination of spinal cord white matter tracts, specifically the posterior and lat- eral columns. MRI of the cervical spinal cord may show evidence of posterior column high signal intensity extending over several segments, unlike the appearances of MS, which may resolve or im- prove with vitamin B12 repletion. Although vitamin B12 deficiency may occur in the context of pernicious anaemia, myelopathy may also occur in the absence of haematological abnormality. A Schilling test to examine B12 absorption may be required. Elevated serum levels of homocysteine and methylmalonic acid, the substrates for cobalamin-​dependent enzymes, may be helpful when there is diag- nostic uncertainty and vitamin B12 levels are borderline. A concur- rent peripheral neuropathy, usually of axonal type, may be clinically and/​or neurophysiologically evident. Overuse of nitrous oxide analgesia may produce a similar clinical syndrome, due to functional B12 deficiency, as may acquired copper deficiency, often in the context of intestinal resection or dietary zinc excess. This disorder is associated with low serum copper and caeruloplasmin levels and increased signal in the dorsal columns on MRI. It may be the human equivalent of swayback disease seen in ruminants with copper deficiency. Vitamin E deficiency may be acquired, in the context of intestinal fat malabsorption, including patients with cystic fibrosis, or result from an autosomal recessive genetic disorder due to mutations in the α-​tocopherol gene. Ataxia is both cerebellar and spinal in these disorders and may respond to vitamin E supplements. Hepatic myelopathy has been described, in association with chronic liver disease and portal hypertension, without cord imaging abnormalities. This diagnosis of exclusion should be evident from the clinical context. Hereditary disorders Hereditary spastic paraplegia is a heterogeneous group of motor system disorders typified by lower limb spasticity which greatly predominates over weakness. There may, in addition, be mild dim- inution of lower limb vibration and proprioception, and in compli- cated cases there may be additional clinical features such as epileptic seizures, cognitive impairment or frank dementia, peripheral neur- opathy, amyotrophy, or extrapyramidal features. Most instances are inherited as autosomal dominant disorders although recessive and X-​linked variants are described, with over 70 genetic loci (heredi- tary spastic paraplegias) defined and over 50 genes harbouring de- terministic mutations, encoding proteins such as spastin, atlastin, paraplegin, spartin, and strumpellin. Adrenoleukodystrophy is an X-​linked recessive peroxisomal disorder with variable clinical phenotype related to age. Whereas children and adolescents have a cerebral presentation with per- sonality and intellectual changes leading to dementia, young adult males often present with a progressive spastic paraparesis with a mild distal polyneuropathy, adrenomyeloneuropathy, with de- layed cerebral involvement. There may be additional adrenal in- sufficiency. Positive family history may alert clinicians to the diagnosis. Some female heterozygotes (carriers) may manifest an adrenomyeloneuropathy-​like syndrome with mild spastic parapar- esis. Cord imaging in adrenomyeloneuropathy may show atrophy but no signal abnormality. Friedreich’s ataxia, the most common autosomal recessive cere- bellar ataxia, may present with a spastic paraparesis with extensor plantars, accompanied by absent ankle jerks due to the concur- rent axonal sensory polyneuropathy. The autosomal dominant spinocerebellar ataxias form a heterogeneous group, linked to over 30 different genetic loci, many associated with trinucleotide repeat expansions. The phenotype is of a progressive cerebellar syndrome with or without additional neurological features which may include spastic paraparesis. Although typically an exclusively cognitive disorder, variants of Alzheimer’s disease with spastic paraparesis have been described in association with mutations in the presenilin-​1 gene, most par- ticularly the exon 9 deletion. These patients also manifest a patho- logical phenotype, cotton wool plaques of amyloid protein, which although not absolutely specific are seldom seen in other cases. Familial British dementia, originally described as Worster–​Drought syndrome and now characterized as one of the hereditary cerebral amyloid angiopathies, resulting from stop codon mutations in the A-​Bri gene, typically presents with presenile dementia which is later complicated by cerebellar ataxia and spastic paraparesis. Vascular disorders of the spinal cord Vascular disorders of the spinal cord encompass both arterial infarction and haemorrhage or venous hypertension; venous in- farction is uncommon. Cord ischaemia has been postulated to contribute to spondylotic myelopathy and delayed radiation myelopathy. Arterial infarction is most commonly due to anterior spinal ar- tery occlusion; for example, during thoraco-​abdominal aneurysm repair. In this syndrome, because of the respective watersheds of an- terior and posterior spinal arteries, the whole or part of the anterior two-​thirds of the cord may be infarcted with loss of descending section 24  Neurological disorders 6134 motor and ascending sensory pathway integrity but with preserva- tion of dorsal column function. Hypoperfusion of the cord may be responsible for the myelopathies associated with fibrocartilaginous embolism, often associated with back injury, and with air embolism in decompression sickness (Caisson disease). A syndrome in novice surfers of low back pain, bilateral leg numbness and paralysis for 10–​60 min in association with restricted diffusion on MR imaging (‘surfer’s myelopathy’), may reflect cord ischaemia. Haemorrhage and/​or venous hypertension may occur with spinal vascular malformations, which may broadly be divided into dural arteriovenous fistulas, usually acquired, and arteriovenous malfor- mations, usually of developmental origin. Spinal dural arteriovenous fistulas typically present in middle age and beyond, most commonly in men, with a progressive myelopathy. Venous hypertension re- sults in cord hypoxia which may progress to irreversible necrosis (Foix–​Alajouanine syndrome; subacute necrotizing myelopathy). Stepwise progression may occur. In contrast, spinal arteriovenous malformations tend to present at a younger age than arteriovenous fistulas, with a mean age at onset in the third decade but sometimes in childhood. Arteriovenous malformations may be at any cord level, on the surface, within the parenchyma, or both. High flow lesions may also have arterial aneurysms on the supplying vessels. Spinal haemorrhage is the typical clinical manifestation, presenting with acute painful paraplegia, back pain, sciatica, with or without meningism and disturbance of consciousness; blood may track intracranially and simulate subarachnoid haemorrhage. Progressive neurological dysfunction is less often seen with arteriovenous mal- formations than with arteriovenous fistulas. The presence of a spinal bruit and/​or segmentally related cutaneous malformations may give a clue to the presence of an intradural arteriovenous malforma- tion. Spinal vascular malformations may occur in association with similar lesions in other organs or cutaneous angiomas; for example, in neurofibromatosis, with haemangioblastomas or cerebral aneur- ysms, and in specific syndromes (Cobb, Klippel-​Trénaunay-​Weber). Cavernous malformations may also occur in the spinal cord. Treatment and prognosis Treatment of myelopathy is, of course, dependent on establishing the precise aetiology. Structural lesions may require neurosurgical inter- vention, sometimes acutely to save or salvage cord function. With acute compressive lesions, prognosis is directly related to the time delay between symptom onset and relief of compression. Infective mass lesions may require debridement and systemic antibiotics. Foramen magnum decompression may be undertaken for syringo- myelia associated with Chiari malformation. Certain spinal cord vascular malformations may be amenable to endovascular treat- ment, or targeted (stereotactic) radiotherapy to shrink lesion size and reduce haemorrhagic risk. Radiotherapy of vertebral metastases causing malignant spinal cord compression is often undertaken. Specific treatment is sometimes available. Vitamin B12 myelop- athy may remit with vitamin repletion, although it is well recognized that there is an inverse relationship between duration of deficiency and extent of recovery following repletion. Dysaesthesia and pro- prioceptive deficits often persist, although these may be related in part to concurrent peripheral nerve involvement. Likewise with copper deficiency myelopathy, neurological decline is halted but seldom reversed by copper repletion. Cord compression with Paget’s disease may respond to specific treatment (bisphosphonates). Steroids are often prescribed for non​infectious inflammatory and necrotizing myelitides, sometimes with clinical improvement, al- though this may simply be a hastening of recovery which would have occurred anyway. Severe steroid unresponsive cases often improve following plasma exchange, which may be effective even many weeks after reaching clinical nadir. More specific immunosuppressive re- gimes (azathioprine, mycophenolate, rituximab) may be required in relapsing disorders such as NMOSD and SLE. Anticoagulation is in- dicated in the antiphospholipid antibody syndrome. Multiple scler- osis now has many effective disease-​modifying agents that reduce relapse rates and slow the accumulation of disability. Residual or progressive deficits in sensorimotor and sphincter function resulting from myelopathy may benefit from targeted symptomatic and neurorehabilitation strategies, including physio- therapy and occupational therapy. Symptom management may in- clude agents for spasticity (oral baclofen, tizanidine, dantrolene; focal injections of botulinum toxin; intrathecal baclofen), pain (antineuropathic pain medications such as pregabalin, gabapentin; duloxetine; spinal cord stimulators), bladder dysfunction (anti- cholinergic medications, clean intermittent self-​catheterization, suprapubic catheterization), and erectile dysfunction (sildenafil). FURTHER READING Jacob A, Weinshenker BG (2008). An approach to the diagnosis of acute transverse myelitis. Semin Neurol, 28, 105–​20. Jaiser SR, Winston GP (2010). Copper deficiency myelopathy. J Neurol, 257, 869–​81. Krupp LB, et  al. (2013). International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-​ mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler, 19, 1261–​7. Larner AJ (2016). A dictionary of neurological signs, 4th edition. Springer, London. Lo Giudice T, et  al. (2014). Hereditary spastic paraplegia:  clinical-​ genetic characteristics and evolving molecular mechanisms. Exp Neurol, 261, 518–​39. Lohre ET, et al. (2012). Radiation therapy in malignant spinal cord com- pression: what is the current knowledge on fractionation schedules? A systematic literature review. BMJ Support Palliat Care, 2, 51–​6. Mariano R, et al. (2018). A practical approach to the diagnosis of spinal cord lesions. Pract Neurol, 18, 187–200. Polman CH, et al. (2011). Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol, 69, 292–​302. Rathnasabapathi D, et al. (2015). Solitary sclerosis: progressive neuro- logical deficit from a spatially isolated demyelinating lesion: a fur- ther report. J Spinal Cord Med, 38, 551–​5. Transverse Myelitis Consortium Working Group (2002). Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology, 59, 499–​505. Wingerchuk DM, et  al. (2015). International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology, 85, 1–​13. Wong SH, et al. (2008). Myelopathy, but normal MRI: where next? Pract Neurol, 8, 90–​102. 24.13.2 Spinal cord injury and its management 6135 24.13.2 Spinal cord injury and its management 6135 Wagih El Masri(y) and Michael Barnes 24.13.2  Spinal cord injury and its management 6135 24.13.2  Spinal cord injury and its management Wagih El Masri(y) and Michael Barnes ESSENTIALS Traumatic spinal cord injury most commonly affects young men as a consequence of road traffic accidents, violence, and sports injuries. The incidence is increasing in older people, mainly due to falls. Early acute management Appropriate management of the individual at the scene of an accident is vital to avoid unnecessary worsening of a spinal cord injury. Those who are unconscious should be assumed to have a cervical spine injury, with the head and neck held firmly in a neu- tral position using a semi-​rigid collar, and transportation on a spinal board with a head immobilizer. Investigation—​spinal cord injury cannot be determined solely by examination, hence radiological investigation is essential. MRI is the best imaging technique. Treatment—​injuries to the cervical spine will usually receive skel- etal traction applied through skull calipers; thoracic and lumbar in- juries require simple support of the patient in the correct posture. Surgery may sometime be required (e.g. fusion and internal fixation, anterior or posterior decompression). Steroids are no longer admin- istered routinely. Management in the spinal cord injury centre In the neurologically intact patient, surgery allows the individual to be mobilized and discharged quickly. In the neurologically impaired patient with a multi-system physiological impairment and malfunction the injured cord is physiologically unstable and unable to protect itself from further non​mechanical damage by complications such as hypoxia, hypo- tension, hypertension, ischaemic events, sepsis, or hypothermia, all of which can easily occur due to the sudden autonomic and sensory-​motor impairment and loss of blood–​brain barrier. There are no studies to demonstrate that surgical intervention followed by early mobilization is as good as conservative management in terms of short and long-​term clinical outcomes (achieving uneventful early mobilization; days spent in recumbence throughout admission; in- cidence of pressure sores, respiratory infections, urinary infections, and other urinary complications; time from injury to completion of particular end points of rehabilitation; incidence of chronic neck or back pain; achieving and maintaining a good painless range of movement of the spine; level of independence and quality of life on discharge) or healthcare costs (days spent in intensive care; period of total hospitalization from injury to first discharge; frequency of readmission and total period of hospitalization during the first five years following first discharge to treat complications). Medical problems during the acute stage include (1) Paralytic Ileus— withhold oral intake until bowel sounds return. (2) Respiratory—​regular and frequent chest physiotherapy is vital. (3) Pressure sores—​should be preventable. (4) Bladder—​residual urine can predispose to infection or stone formation and contributes to impairment of renal function; failure of bladder emptying requires mechanical drainage, preferably by intermittent clean catheterization; detrusor hyperreflexia is treated with anticholinergics. (5)  Bowel care—​in the period of spinal shock the bowel remains flaccid and should not be allowed to overdistend. (6) Autonomic dysreflexia—​management consists of trying to avoid com- plications and use of antihypertensive agents. (7) Spasticity and con- tractures—​passive stretching of the spastic muscles and regular standing regimes can be helpful; antispasticity medication should be used with care because they induce significant tiredness and weakness. (8) Pain and dysaesthesia—​usually respond to the use of carbamazepine, tri- cyclic antidepressants, gabapentin, or pregabalin. (9) Risk of venous thromboembolism—​prophylactic anticoagulation is advisable. Rehabilitation—​a coordinated multidisciplinary team can improve functional outcome, a key element being the setting of realistic goals. Long-​term issues A very wide range of medical, physical, emotional, and social issues may need to be addressed. Later medical complications include pressure sores, pathological fractures, vesical and renal complica- tions, post-​traumatic syringomyelia and (in those with high cervical cord lesions) respiratory compromise. Prognosis With appropriate management, initial mortality from spinal cord injury is less than 5%. In the acute phase, with expert active physio- logical conservative management (APCM) of the cord injury and all its effects, over 70% of patients presenting with incomplete som- atosensory loss and about 7% of those presenting with complete somatosensory loss will recover to regain ambulation. Most of those with complete somatosensory loss will recover up to three myotomes below the level of the injury, and with ongoing support are able to lead dignified, healthy, fulfilling, enjoyable, productive, and often competitive lives. Life expectancy in paraplegia is modestly reduced, although in- dividuals with tetraplegia still die prematurely, in particular from re- spiratory infection, generalised sepsis and (occasionally) renal failure. Introduction Spinal cord injuries (SCI) are potentially devastating, paralysing life changing events. Below the site of injury, the various systems of the body no longer function normally and become significantly dependent on the reflex activity of the distal spinal cord segments. Function will differ at various stages following injury, especially be- tween the stage of spinal shock and gradual return of reflex activity. Reflex activity can be erratic in the long term, markedly disturbing function further, hence the functioning of the various systems of the body is likely to vary throughout the patient’s life, requiring con- tinued and frequent reviews and intervention. For example, during the stage of spinal shock, poor detrusor activity will cause retention of urine necessitating drainage with catheters. Following the return of reflex activity, the patient will be incontinent of urine and at risk of many complications, including hydronephrosis, renal failure, and autonomic dysreflexia. Management to contain urinary incon- tinence should also ensure safety to the upper urinary tract and to autonomic functions. section 24  Neurological disorders 6136 The multisystem dynamic physiological impairment and mal- function presents ongoing lifelong challenges to patients and clin- icians. Each of the affected systems of the body becomes a source of disability and a potential source of a wide range of complications. Complications during the first few weeks of injury, when the injured spinal cord is physiologically unstable and vulnerable, can cause fur- ther neurological deterioration. The associated sensory impairment presents ongoing risks to patients and a diagnostic challenge to clin- icians. Conventional symptoms and signs to diagnose associated in- juries or intra-​abdominal pathology cannot be relied upon. Pressure sores, fractures of long bones, and burns can remain unnoticed for several days. Mortality because of undiagnosed acute abdominal pathology can occur. The loss of coordinating and modulating influences from the brain usually results in cascading intersystem effects that are rarely seen in other medical conditions. For example, severe constipation in a tetraplegic or high paraplegic patient can result in excess spasti- city, which can involve the pelvic floor muscles causing retention of urine, urinary infections and/​or autonomic dysreflexia. The psychological, social, emotional, vocational, financial, envir- onmental, and relationship challenges to the patient, partner and family members are usually at least as devastating as the paralysis and the impairment of bodily functions. Almost all complications following SCI can be prevented or their effects minimized. Coordinated, multidisciplinary holistic care has significantly improved neurological outcome, quality of life, and life expectancy of tetraplegic and paraplegic patients. With expert treatment (Fig. 24.13.2.1) from the first few hours or days of injury, most patients with incomplete SCI recover ambulation. Patients with complete cord injuries who do not recover are able to live dig- nified, enjoyable, productive, and often competitive lives. Epidemiology The annual incidence of traumatic spinal cord injury varies and is reported to be up to 50 cases per million population per annum, but in the United Kingdom the incidence is 10–​15/​million population/​ year. Most injuries occur in males (around 80%), and the commonest cause is road traffic accidents (around 40%) (Table 24.13.2.1). There seems to be a steady increase in the incidence of elderly people who sustain spinal injuries during falls, mainly at home. About 10–​20% of spinal injuries are sustained during sporting activities such as diving and rugby. Regrettably, spinal cord injury from violence (ei- ther self-​harm or criminal assault) is increasing, and military con- flict is a cause of SCI in some parts of the world. Alcohol intake is a contributing factor to a significant number of spinal injuries from all causes. There is some evidence in the last decade that the incidence of traumatic spinal injury has reached a plateau. However, due to the significant increase in survival and life expectancy, the preva- lence has steadily increased in the last five decades, with a cur- rent estimate of 40 000 paraplegic and tetraplegic patients in the United Kingdom. W.E.M. BRITISH MODEL OF HEALTHCARE MANAGEMENT IN SPINAL CORD INJURIES Healthy Patient Lavyers Nurses Doctors Psychologist Social Worker Physiotherapist Back-up Team Occupational Therapist Soft landing in the community Maintenance of health & independence Outpatients Co-ordinators S.I.C. Hospital CONSULTANT ACUTE CARE POST DISCHARGE Community Rehab Specialists CONSULTANT S O C I A L W O R K E R O T S P I N A L I N J U R I E S C E N T R E C O N S G P N U R S E S P H Y S I O Fig. 24.13.2.1  Model of service delivery in the United Kingdom (author’s representation). 24.13.2  Spinal cord injury and its management 6137 Pathophysiology of spinal cord injury Spinal cord injury results in loss of auto-​regulatory mechanisms and disruption of the blood brain barrier. Ischaemia or further bleed­ ing within the cord can easily develop and cause further damage. Secondary changes (vascular, cellular, electrophysiological, enzym- atic, electrolytic, and metabolic) also occur in and around the in- jured site in the spinal cord. It is therefore not surprising that during the first few weeks of injury, the spinal cord is ‘physiologically un- stable’ and unable to protect itself from non​mechanical damage, such as severe hypotension, hypertension, severe anaemia, electro- lyte imbalance, hypoxia, hypothermia, and sepsis. Oedema of the cord at the site of the injury usually reaches its peak volume at 48–​72 hours from injury and can be associated with tem- porary neurological deterioration. Scientists and clinicians have, for several decades, tried to manipulate the post-​traumatic changes of the spinal cord in both the laboratory animal and in humans in the hope of improving the neurological outcome. Some improvement following decompression of the spinal cord can be demonstrated in the laboratory animal, when the impact of injury is of subthreshold magnitude and when decompression is carried out within minutes or few hours of injury. Such improvement is difficult to demonstrate in the laboratory above threshold impact or after four hours of in- jury. In the clinical situation decompressive surgery, steroids and a variety of pharmacological agents have been tried and have failed to demonstrate credible evidence of short or long term equality or su- periority of outcomes over that which can be obtained with APCM and without these interventions. Not all injuries to the spine are grossly unstable to the degree that this might cause further mechanical damage. However, once the structure of the bony spine has been disrupted, some degree of micromovement or microinstability is likely to be present at the site of injury, no matter how stable the injury is, and this could be an- other source of pain at the site of the fracture. Bony healing will occur between six to twelve weeks following injury, irrespective of the treatment being conservative or surgical, in most cases of vertebral fracture. In other words, biomechanical instability is time related and the most biomechanically unstable spinal column injuries are likely to become stable within six to twelve weeks of injury. Management at the scene of the accident and in the emergency department The appropriate management of the individual at the scene of an acci- dent is vital in order to avoid unnecessary worsening of neurological damage. If the individual is unconscious, then it should be assumed there is an injury to the cervical spine until proven otherwise. Until this diagnosis can be ruled out, the head and neck should, as far as possible, be held firmly in a neutral position except for patients with ankylosing spondylitis. This is normally achieved at the scene of an accident by immobilization in a semi-​rigid collar, but if this is not available alternative improvised methods of stabilizing the head and neck should be initiated. The individual should not be placed in the coma position as this will rotate the cervical spine, but is best placed—​if their other injuries allow—​in a lateral position with the head kept in line with the spine by the underlying arm. If any move- ment is necessary, the person should be ‘log rolled’ to ensure that the spine is kept in a straight and neutral position at all times. Usually transportation is on a spinal board with a head immobilizer. Patients with SCIs become poikilothermic and can easily de- velop hypothermia or hyperthermia, depending on the ambient temperature. This is due to the loss of the sympathetically medi- ated thermoregulatory mechanisms. Prevention of hypothermia can save lives since hypothermia can exaggerate the bradycardia, leading to cardiac standstill. Cardiac arrest also readily occurs with hypoxia, especially in patients with cervical cord injuries. The speed of evacuation is important, particularly if there are other life-​threatening injuries. The individual with a SCI should preferably be transferred to a specialist spinal injuries centre, but obviously resuscitation and other life-​threatening injuries may need treatment at the nearest trauma centre or emergency department. Diagnosis in the conscious patient Following significant trauma, impairment or loss of motor power and of sensation together with absent reflexes are usually the give- away signs of damage to the spinal cord and/​or nerve roots. In the absence of neurological signs; pain, tenderness, bruises, or swelling in the region of the cervical, thoracic, or lumbar spine and limitation of range of movement are likely to be indicative of bony or soft tissue damage of the spinal axis. In patients with SCI, the incidence of associated injuries is re- ported to be up to 40%, hence a thorough general examination is essential to exclude associated injuries, some of which can be life-​ threatening. It is also important to note that up to 20% of patients with spinal injuries are reported to have other non​contiguous in- juries of the spinal axis. The biomechanical stability of the spine requires thorough assess- ment prior to mobilization because neurological deterioration oc- curs mostly when neurologically intact or neurologically impaired patients are sat up in bed or mobilized prematurely, and this often leads to litigation. In the neurologically intact, deterioration is usu- ally caused by mechanical damage caused by an undiagnosed bio- mechanically unstable injury. The spinal cord of the neurologically impaired patient is also physiologically unstable. It cannot protect itself from non​mechanical damage. Neurological deterioration or lack of recovery can occur due to severe postural hypotension, hypertension, hypoxia, and sepsis. Diagnosis in the semi-​conscious and unconscious patient Unconscious or semi-​conscious patients with head injuries and/​or intoxication present particular challenges to the clinician. Delays in diagnosis can have major consequences. It is therefore para- mount that following a significant traumatic event such patients are Table 24.13.2.1  Causes of spinal cord injury—​comparison of causes in the United Kingdom and the United States of America Cause UK (%) USA (%) Road traffic accidents 35 43 Violence 7 19 Sports injuries 21 11 Falls (domestic and industrial) 36 19 Other 1 8 section 24  Neurological disorders 6138 managed with the assumption that they have sustained a spinal in- jury until proven otherwise, clinically and radiologically. Further damage to the spinal cord causing further neurological deterior- ation rarely occurs in recumbence, hence it is important that the patient remains in recumbence until a spinal injury has been ruled out. Clear written instructions to keep the patient in recumbence until an injury to the spine and/​or the spinal cord has been excluded is likely to prevent neurological deterioration, as well as minimize the risk of litigation. Accurate clinical diagnosis cannot be made until the patient be- comes conscious. The general examination of the semi-​conscious and unconscious patient can, however, yield clinical signs which, in combination, can help the clinician detect a neurological im- pairment of spinal cord origin. Things to look for include the following: • Facial or scalp lacerations and bruises—​their site can also be in- dicative of whether the cervical injury has occurred in flexion or extension. • Bruising or swelling over the spine—​may be apparent at an early stage, but their absence does not rule out an injury to the cervical spine. • Cardiovascular—​the combination of hypotension and brady- cardia due to the early loss of sympathetic reflexes and unopposed vagal tone is rarely seen in patients without cervical or upper thoracic spinal cord injury; engorgement of the distal peripheral veins in a hypotensive patient following trauma is one of the most helpful signs of cord damage. • Miosis of one or both pupil(s)—​occurs in cervical cord injuries due to the interruption of the sympathetic outflow. • Diaphragmatic breathing (absence of chest expansion during in- spiration associated with increasing abdominal girth and retrac- tion of intercostal muscles)—​this is a very useful sign, which in the absence of ankylosing spondylitis is almost diagnostic of a spinal cord injury in the cervical or upper thoracic spine. • Limbs—​absence of spontaneous movement in the limbs of a semi-​conscious irritable patient; absent tendon reflexes; spon- taneous movement of the upper limbs but not the lower limbs is likely to be caused by a thoracic or thoracolumbar injury; spon- taneous movement of the lower limbs but not the upper limbs is likely to be indicative of a central cord syndrome or a brachial plexus injury; the difference in the response to painful stimuli by pressure over bony prominences, the difference in muscle tone and in tendon reflexes between the upper and lower limbs are also likely to help towards locating a level of neural tissue injury. • Priapism. Radiological investigations All patients with suspected or clinically confirmed spinal injuries will require radiological investigation, but it is important to remember that spinal movement must be minimal during any procedures. Plain X-​rays have limited value in the lower cervical and upper thoracic spine. CT scan is the investigation of choice to demonstrate the bony spine longitudinally and cross-​sectionally. MRI is the in- vestigation of choice for the neural tissues as well as soft tissues. Most patients who sustain traumatic injuries of the spinal cord and cauda equina therefore require both a CT scan and an MRI scan. Injury to the spinal cord can occur in the presence of normal X-​rays and CT scans. SCI without radiological abnormality (SCIWORA) can occur in children and may only become apparent on an MRI scan. This can also occur in older people with underlying cervical spondylosis, when tetraplegia can result from hyperextension injury without fracture or dislocation. Pitfalls in neurological assessment and initial management One of the most common problems encountered is the mis-​diagnosis of the level of injury. A neurological examination is essential to de- termine the level and density of the cord lesion, indeed neurological examination and documentation is at least as important clinic- ally and medicolegally as the radiological examination in patients with suspected traumatic spinal cord injury. Fig. 24.13.2.2 illus- trates the myotomes, dermatomes, and reflexes as an aide memoire. Until the diagnosis has been established, and if a biomechanically unstable spinal column injury has been diagnosed, the patient will need to be log rolled with head and neck support during turning, which requires a minimum of four individuals. Cervical injuries have been erroneously diagnosed initially as upper thoracic injuries, even when the patient has been fully con- scious, alert, and cooperative. It is important to remember that the sensory innervation of the subclavicular area is from the fourth cer- vical dermatomes through the supraclavicular nerves, rather than the third and fourth thoracic dermatomes. It is therefore advisable to assess sensation in the upper trunk along the mid-​axillary line rather than in the mid-​clavicular line of the chest. In a busy emergency department, it is easy to mistake passive movements for active movements. For example, a patient with a C5 lesion in spinal shock will be able to actively move the deltoid and biceps muscles, resulting in active abduction of the shoulder and flexion of the elbow. This active movement will invariably result in passive movement of the wrist and fingers. If active voluntary and reproducible wrist and finger movements cannot be demonstrated, such movements should not be interpreted as normal movements. The same applies to active movements around the hips resulting in passive movement in knees and ankles. An apparently normal plantar response can be seen in patients with complete and incomplete SCI for several days or weeks fol- lowing injury, hence plantar and multisynaptic reflexes should not be relied upon for diagnostic or prognostic purposes in the early stages following injury. A positive bulbocavernosus reflex (internal/​external anal sphincter contraction in response to squeezing the glans penis or clitoris) without preservation of sensation and/​or voluntary anal contrac- tion cannot be relied upon as indicative of an incomplete lesion. The bulbocavernosous reflex is often found to be positive in complete cord injuries from a very early stage of injury. Weakness or absence of a voluntary anal squeeze is likely to be indicative of a spinal injury in a conscious patient. The presence of anal tone or a positive anal reflex does not exclude a spinal cord injury, as it can be due to early return of sacral reflexes. Reflex detrusor activity is likely to be absent during the acute stage of SCI. Unlike the patient with head injury who is likely to be in- continent of urine on presentation, a patient with spinal cord injury with or without concomitant head injury is likely to be dry and have a distended bladder before developing overflow incontinence. 24.13.2  Spinal cord injury and its management 6139 Although bowel sounds can often be heard in the first few hours of injury, the patient is very likely to develop a paralytic ileus which can last for up to a week and possibly longer. Neurogenic ileus can be aggravated by a retroperitoneal haematoma in patients with thoracolumbar injuries. Oral hydration and feeding should be withheld for at least 24 hours and until the bowel sounds are heard. Ruling out an associated intra-​abdominal injury is also paramount before oral intake is commenced. A paralytic ileus usually results in significant abdominal distension: this can interfere with the dia- phragmatic excursion, cause respiratory embarrassment, and has resulted in death of tetraplegic and high paraplegic patients. Patients with SCIs become poikilothermic and can easily develop hypothermia or hyperthermia depending on the ambient tempera- ture. This is due to the loss of the sympathetically mediated thermo- regulatory mechanisms. Prevention of hypothermia can save lives as hypothermia can exaggerate the bradycardia and cause cardiac standstill in patients with spinal cord injury. Further management General aims Initial management will consist of resuscitation, treatment of as- sociated injuries, containment of the biomechanical instability of the injured bony spine by either conservative or by surgical means and containment of the physiological instability of the injured cord. Whenever possible, treatment should be carried out in a specialized spinal injury centre as soon as possible. The ultimate goals of management are to ensure maximum neuro- logical recovery; maximum independence in activities of daily living, personal care, and hygiene; a biomechanically stable, pain-​free, flexible spine with a good range of movement; safe and convenient functioning of the various systems of the body; and prevention of complications at all stages during the lifetime of the patient. It is equally important to enable patients to make informed choices about treatment, regain assertiveness, take control of their own lives, re-​engage in employment and/​or any activity of their choice, and whenever possible compete in some sphere of life. The importance of education in the condition and ongoing supervision of all the ef- fects of paralysis and support of the patient to maintain health and independence following discharge cannot be overemphasized. There is clear evidence that outcome is maximized medically, physically, and psychologically, if individuals are managed in spinal injury centres as opposed to a fragmented, less coordinated, and less experienced approach in general hospital settings. The ultimate goals of these centres is to softly land healthy well-​functioning pa- tients in the community, maintain their health and maximum level of independence, minimize the cost of living in the community, and minimize the need for rehospitalization with medical and non-​ medical complications. The aims of active physiological conservative management (APCM) and of surgical management are to prevent neurological deterioration from further mechanical and non​mechanical damage of the neural tissue, allow maximum neurological recovery, prevent or minimize chronic pain, and preserve the range of movement at the site of the fracture. Reduction of the period of hospitalization and a reduction of cost is becoming increasingly necessary. There is, unfortunately, no evidence to suggest that any treatment (vaso-​pressor medication, surgical, biological, pharmacological, cellular, or other) can improve neurological recovery in humans or reduce cost of treatment. The favourable natural history of neurological recovery following spinal cord injury is sadly poorly appreciated and grossly under- rated. Most patients who present with incomplete injury in the first 72 hours of injury will recover sufficiently neurologically to walk again. Most patients with a complete spinal cord injury will exhibit some recovery for up to four dermatomes and myotomes below the initial level of injury (zone of partial preservation). Such outcomes are achieved when the injured cord is protected from further mech- anical damage as well as from non​mechanical damage by hypoxia, C8 Myotomes Muscle group Diaphragm Shoulder abductors Elbow flexors Supinators/pronators Wrist extensors Wrist flexors Elbow extensors Finger extensors Finger flexors Intrinsic hand muscles Hip flexors Hip adductors Knee extensors Ankle dorsiflexors Toe extensors Knee flexors Ankle plantar flexors Toe flexors Anal sphincter Reflexes Nerve supply C(3), 4 (5) C5 C5, 6 C6 C6 C7 C7 C7 C8 T1 L1, 2 L2, 3 L3, 4 L4, 5 L5 L4, 5 S1 S1, 2 S1, 2 S2, 3, 4 Biceps jerk C5, 6 Supinator jerk C6 Triceps jerk C7 Abdominal reflex T8-12 Knee jerk L3,4 Ankle jerk S1, 2 Bulbocavernosus reflex S3, 4 Anal reflex S5 Plantar reflex L2 S2 S3 C7 S5 C2 T2 T1 C4 T7 C6 T10 T4 T2 T1 T12 L1 C7 L2 L3 L4 S1 L5 C5 S4 Fig. 24.13.2.2  An aide memoire to examination—​summary of the dermatomes, myotomes, and associated reflexes. section 24  Neurological disorders 6140 marked hypotension, marked hypertension, severe anaemia, sepsis, marked electrolyte imbalance, and hypothermia, all of which can easily occur. In other words, both the physiological instability of the spinal cord and the biomechanical instability of the spinal column will require ‘containment’ during management, until biomechanical stability of the bony injury and physiological stability of the spinal cord are achieved. Several classifications have been developed in the last few decades to assess the mechanism and severity of the biomechanical instability in the acute stage, and to help orientate the spinal surgeon to an op- timum surgical approach. Some classifications are more popular than others, and some are more elaborate and more time consuming to use. Surgeons differ in their choice of classification, but what is common to all is that none of these classifications has been validated as to its predictive value in assessing instability once natural healing occurs following APCM. The classifications are rarely used by those who manage patients with APCM as the most unstable fractures of the spine can be contained with APCM and become stable without surgical intervention. Active physiological conservative management Up to the early 1980s, APCM had been the standard of care of pa- tients with SCI. It had been established that there was no correlation between the severity of the vertebral injuries on X-​rays and the neurological picture on presentation to the emergency department or the neurological outcome. Improvement of radiological imaging with the introduction of CT & MRI, improvement in the design of instrumentation and the increasing safety of anaesthesia, have all resulted in a change of standard of care, unfortunately without evi- dence of equality or superiority of outcomes, or reduction in cost. The rationale of APCM is based on observations made over the last seven decades and on the published excellent outcomes for neuro- logical and functional recovery. Further arguments for APCM are: • The complications that can cause non​mechanical damage of the spinal cord are easier to prevent with APCM than with surgery. • The risk of these complications is higher with surgery and postoperatively than with APCM. • The biomechanical instability of the injured spine can be con- tained easily and safely by non​surgical means in recumbence for 4–​6 weeks followed by bracing for a further 6 weeks. • The natural fusion at the site of the fracture leads to the shortest length of fusion that maintains the architectural segmentation of the spine, prevents the spine becoming rigid and prevents poten- tial instability above and/​or below a longer rigid fusion. • Further damage to soft tissue, including nerve endings is pre- vented by avoiding surgery. The great majority of patients treated with APCM will have a painless spine with good range of movement. Most importantly, with APCM spinal canal encroachment, cord compression and malalignment re- sulting from trauma do not correlate with the degree of neurological deficit and do not prevent neurological recovery. Most patients who present within the first 72 hours from injury with incomplete spinal cord injury and are treated with APCM will make a signifi- cant neurological recovery to ambulate, irrespective of the degree of malalignment, canal encroachment, or cord compression (please see online case 24.13.2.1, 24.13.2.2, 24.13.2.3). A period of 4–​6 weeks in recumbence is required with APCM. During this period simultaneous management of the injured spine and each of the impaired systems of the body will be carried out, ensuring prevention of further damage to soft tissues and complica- tions. Tilt table studies are carried out prior to mobilization to en- sure safety. Following mobilization, the patient is likely to require a cervical collar or a brace for a further period of 4–​6 weeks. Non​surgical management without an adequate period of immo- bilization in recumbence has often been erroneously described as conservative management and its outcomes compared with the out- comes of surgical management, leading to understandable conclu- sions. Adequately designed studies to compare outcomes of good APCM with good surgical management are long overdue. Outcome and prognostic indicators of recovery with active physiological conservative management In the late 1960s, Frankel et al. demonstrated at Stoke Mandeville Hospital that most patients with incomplete injuries of the spinal cord and cauda equina will recover significantly to ambulate without surgical or any other intervention (Table 24.13.2.2a). Between 5.9% and 8.9% of patients with complete cord injury will recover to ambulate. Many more will recover motor power and sen- sation within their grade or improve in grade, but not enough for ambulation (Table 24.13.2.2b). These results have been repeatedly confirmed by other groups, irrespective of the degree of canal sten- osis, canal encroachment, malalignment, or cord compression. The prognostic value of pin-​prick sensory sparing in the 48–​72 hours from injury was established in the late eighties and con- firmed by other groups. With optimum APCM, over 70% of pa- tients who present 48–​72 hours from injury with no motor power, but with preservation of pin-​prick sensation down in the S2/​S3 dermatomes (Frankel B), will recover to walk again within a year from injury. Patients with any distal flicker of movement (how- ever weak and/​or patchy) in the first 72 hours from injury have an even better chance of recovery. This recovery is achieved irre- spective of the degree of canal encroachment, cord compression, or severity of malalignment, and without any vasomotor medica- tion, surgical, pharmacological, cellular, or other intervention on the spinal cord. Patients with complete cord injury (Frankel A) and pin-​prick sen- sory sparing in the zone of partial preservation where no movement is detected will recover useful motor power in the equivalent myo- tomes without intervention. A neurological level higher than the bony level of the fracture is another good prognostic indicator of zonal recovery. Over two hundred individuals with various degrees of biomech- anical instability, cord compression and initial paralysis who were treated with APCM and who recovered to walk irrespective of the radiological presentation have given their consent to have their clin- ical, radiological, photographic documentation and videos available to study. The debate about early mobilization Early mobilization of the neurologically impaired is regarded by some as potentially hazardous, indeed early mobilization during the stage of spinal shock is usually associated with significant postural hypotension. The sympathetic nervous system fails to maintain the 24.13.2  Spinal cord injury and its management 6141 blood pressure, and a drop of BP can result in reduction of spinal cord perfusion pressure and possibly further cord damage from is- chaemia. Temporary neurological deterioration in association with postural hypotension has been reported, with recovery occurring as soon as the patient is back to recumbence. Close monitoring of neurological state during tilt table studies prior to mobilization re- vealed an incidence of about 8% in our population. Early mobilization of patients with complete cervical and upper thoracic cord injuries also causes reduction in vital capacity, and an associated drop of oxygen saturation can further impair cord func- tions and result in neurological deterioration or limited recovery. The incidence of patients who deteriorate permanently and those with a potential for recovery who do not recover when mobilized during the stage of spinal shock, the so-​called ‘silent deterioration’, is not known and is poorly documented in the literature. Pooling of the blood in the lower limbs is more marked during the stage of spinal shock due to sympathetic areflexia. Patients who are mobilized early are likely to be at higher risk of developing deep venous thrombosis and pulmonary emboli. The risk of ischial and sacrococcygeal sores is high during early mobilization because of the poor perfusion of the insensate skin during the stage of spinal shock and the loading of the weight of the patient on the ischial tuberosities and sacrococcygeal bony area. It remains to be proven that patients with paralysis, postural hypotension, and reduced vital capacity can benefit psychologically and otherwise from early mobilization. These patients usually feel weak, easily tire, and exhibit even lower mood. Often the patient has to go back to bed because of feeling faint and unwell. Surgical approaches Stabilization Surgical stabilization is most beneficial for patients with injuries to the spine without spinal cord damage. The spinal cord is physio- logically stable and unlikely to be damaged by non​mechanical ­insults. The patient does not require multisystem management or rehabilitation and can, therefore, be discharged home within days of surgery. Pure ligamentous injuries with displacement without bony injury to the vertebrae are unlikely to stabilize before 6–​8 months following injury and are likely to require surgery. The surgical ap- proach depends on the mechanism of injury, the source of spinal compression (front or back), and the preference of the surgeon. The belief by some that in humans surgical stabilization and/​or de- compression of the neurologically impaired is likely to improve the biological changes (vascular, cellular, electrophysiological, enzym- atic, electrolytic, and metabolic) thus improving neurology is not supported by clinical evidence. The injured spinal cord is at risk of sustaining further mechanical and non​mechanical damage during anaesthesia, the surgical procedure and postoperatively, with the reported incidence of complications from surgery and parasurgical procedures being about 3%. Complications, including neurological deterioration, following surgery are believed to be underreported. The commonly claimed benefits of surgical stabilization of pa- tients with cord injury are psychological benefit from early mobil- ization, earlier completion of rehabilitation, shorter hospitalization, and a reduction of the cost of treatment. Some surgeons also believe that surgical stabilization of the patient facilitates nursing. Some claim that the incidence of post-​traumatic syringomyelia is reduced following surgery. However, there is no evidence that early mobil- ization of patients with cord injury following surgery reduces the incidence of complications, number of days the patient spends in bed, or that equal end points of rehabilitation are achieved within a similar period or earlier, or that the total period of hospitalization from injury to discharge home with equal levels of independence, safety and convenience of bodily functions is shortened. Indeed, a significant number of unventilated patients with cervical spinal cord injury may require postoperative ventilation for days or weeks, cannot be mobilized early, and have their rehabilitation delayed and hospitalization prolonged. There is no evidence to suggest that sur- gery makes nursing easier, nor is there evidence to support equal or lower incidence of short-​ and long-​term pain following surgery. It is hoped that data collected nationally from all spinal injury Table 24.13.2.2  (a) Percentages of patients in Frankel gradesa A—​C improving to Frankel grades D or E (able to walk again) Site of cord lesion Cervical T1–​T10 T11–​12-​L1 Lumbar Frankel A   8.9%   5.9%   7.9% 44.4% Frankel B 57.6% 46.7% 70.8% 66.7% Frankel C 76.2% 50.0% 80.0% 75.0% (b)  Percentage of patients improving to Frankel Grade C (improved but not functionally useful for ambulation) Cervical T1–​T10 T11–​12-​L1 Lumbar Frankel A 25%   9.6% 11.1% 11% Frankel B   6% 13.3%   8.3% 33.3% a Description of the neurological sparing of patients in the various Frankel grades: Complete (A). ‘This means that the lesion was found to be complete, both motor and sensory, below the segmental level marked.’ Sensory only (B). ‘This implies that there was some sensation present below the level of lesion but that the motor paralysis was complete below that level.’ Motor useless (C). ‘This implies that there was some motor power present below the lesion, but it was of no practical use to the patient.’ Motor useful (D). ‘This implies that there was useful motor power below the level of the lesion. Patients in this group could move the lower limbs and many could walk, with or without aids.’ Recovery (E). ‘This implies that the patient was free of neurological symptoms, i.e. no weakness, no sensory loss, no sphincter disturbance. Abnormal reflexes may have been present.’ After Frankel HL, et al. (1969) The value of postural reduction in the initial management of closed injuries of the spine with paraplegia and tetraplegia. Paraplegia 7, 179–​92. section 24  Neurological disorders 6142 Centres in the United Kingdom will shed some light on this debate, but for now the benefits of surgical stabilization for early mobiliza- tion (before 4–​6 weeks) of injury remain to be proven. Decompression Opinion is divided among surgeons about the value of surgical decom- pression, which is not carried out routinely when the injured spine is surgically stabilized. However, patients who exhibit clinical signs of neurological deterioration with evidence of further mechanical neural tissue compression may benefit from spinal decompression. Claims were made in the early 1980s that early decompression was necessary to prevent neurological deterioration and enhance neuro- logical recovery. However, studies since the early 1990s to determine the significance of canal encroachment have revealed no correlation between the magnitude of canal encroachment, the neurological deficit, and the degree of neurological recovery. The majority of patients who present within 48–72 hours of injury with incomplete cord and cauda equina injuries and canal encroachment recover neurologically sufficiently to walk without surgical decompression or any other intervention. A recent multicentre study suggested that surgical decompression in the first 24 hours from injury resulted in relatively better neurological outcomes than decompression car- ried out after 24 hours, but unfortunately there was no comparison with APCM. Furthermore to date no attempts have been made to compare the incidence of complications including pain, the range of movement at the site of injury, or the quality of neurological re- covery, between patients who are surgically managed and those who are treated with APCM and in recumbence for 4–​6 weeks. Complications and their management Respiratory problems Paresis or paralysis of the intercostal muscles results in a reduc- tion of vital capacity. Paresis or paralysis of the abdominal muscles results in poor forced expiratory volume and impairment of the patient’s ability to cough. The higher the level of cord injury, the lower is the vital capacity and the poorer the ability to cough and expectorate especially during the stage of spinal shock. In the early hours and days following injury, respiratory function should be monitored carefully. Ventilation is likely to be required in patients with C3 cord lesions and above, but with adequate respira- tory management those with lesions at C4 and below are unlikely to require ventilation unless they have associated chest injury or a history of chronic chest disease. Regular chest physiotherapy to in- clude deep breathing exercises, vibration and percussion of the chest wall to loosen secretions, postural drainage and assisted coughing is vital since the most common cause of a decline in respiratory function is the retention of secretions. Assisted coughing with the patient in recumbence and head of the bed tilted down 10–​15o is likely to be necessary to get rid of bronchial secretions effectively. Assisted coughing against gravity during the stage of spinal shock, when the abdominal muscles are flaccid, is more effort-​consuming and less effective. With the return of reflex contractions of the ab- dominal muscles, forced vital capacity and the ability to generate a reasonably good cough by triggering a spasm of the abdominal muscles improve significantly. Cardiovascular problems The loss of sympathetic activity is likely to result in hypotension and bradycardia due to an unopposed vagal tone, both of which are more marked during the stage of spinal shock and with higher levels of cord injury. Patients cannot increase their heart rate in response to a drop of blood pressure such as will invariably occur during mobil- ization of the tetraplegic and high paraplegic patient in the stage of spinal shock. Tracheal suction, hypoxia, and hypothermia can also result in drop of heart rate and cardiac standstill. Atropine is often life-​saving and should always be readily available to administer to tetraplegic or high paraplegic patients when the heart rate drops below 45 beats/​minute. Although vasopressor drugs are often administered to raise the blood pressure, there is no convincing evidence of benefit in terms of neurological benefit or otherwise. It is also possible that raising the blood pressure when spinal cord auto-​regulatory mechanisms are impaired could lead to further bleeding in the spinal cord to the detriment of neural tissues and neural function. Venous thromboembolism Pooling of blood occurs in the lower limbs particularly during the stage of spinal shock. This is due to loss of vasomotor sympathetic reflexes and the absence of pumping muscle action. It is advis- able to keep the legs elevated to 10–​15o during the stage of spinal shock to minimize such pooling. Deep venous thrombosis (DVT) remains a significant complication after spinal injury, and the in- cidence of death from pulmonary embolism (PE) in patients who are not prophylactically anticoagulated is about 15%. The risk of PE is highest in the first three weeks after cord injury, and low mo- lecular weight heparin or warfarin are usually used for prophylaxis for about 12 weeks following injury. Some centres also use external pneumatic calf compression in addition to prophylactic anticoagu- lants. With the return of sympathetic and motor reflex activity the risk of DVT is slightly reduced. Autonomic dysreflexia Autonomic dysreflexia is a potentially fatal problem if inadequately managed. It is most commonly seen in those with cervical cord in- juries above the sympathetic outflow, but can occur in those with thoracic lesions above T6. It is characterized by an exaggerated autonomic response to a stimulus below the level of the lesion. Stimuli can include distension of the pelvic organs such as bladder, colon, and rectum, which induces sympathetic activity resulting in vasoconstriction and hypertension. Other stimuli include cath- eterization, urinary infections, sexual intercourse, discitis, pressure sores and even tight clothing, and surgical procedures can also induce autonomic dysreflexia. The problem occurs in around 50–​80% of those at risk, typically beginning 2–​12 months after injury and persisting long term. Patients with incomplete lesions are at less risk of developing this complica- tion. Symptoms and signs include anxiety, severe pounding head- aches, nasal obstruction; sweating, vasodilatation, and flushing above the level of the lesion; paraesthesia and significant hypertension. Good education and awareness of the patient, together with regular follow up to prevent and detect early and/​or treat complications that can trigger autonomic dysreflexia, are paramount to minimize the occurrence of this complication. Once automonic dysreflexia 24.13.2  Spinal cord injury and its management 6143 occurs, attention is directed to the reduction of the blood pressure. Sitting the person upright is usually helpful. Sublingual nifedipine can be used or, in more severe cases, parenteral antihypertensives. Hydrallazine, chlorpromazine, nitroprusside, and diazoxide have all been used. Occasionally the sympathetic reflex activity may have to be blocked by spinal epidural anaesthetic. All these are temporary measures until the precipitating cause is found and treated. Pressure sores Regrettably, the development of pressure sores still occurs, but really ought to be preventable. The patient is at highest risk during the stage of spinal shock when skin perfusion is at its poorest. The risk, however, persists for life. Sores are commonest where there are bony prominences near the skin such as the scapula, ischial tuber- osity, greater trochanter, sacrum, heel, and at the back of the head. A key to prevention is awareness of the potential problem, vigilance, and regular changes of position in bed and regular lifting in the wheelchair. There are many commercial mattresses and wheelchair cushions that help distribute the patient’s mass over a wide area of the skin. When lifting or positioning, shear forces should be avoided as far as possible, and the injured person should never be dragged over sheets or from the wheelchair. The skin should be kept clean (but not with alcohol), and particular care should be taken to avoid any urine or faecal soiling. If a sore does occur, the area must be kept clean and any dead tissue removed. There should be complete relief of pressure from that area until it is fully healed. Occasionally surgery is indicated for larger or deeply infected sores which otherwise will take too long to heal. Primary excision and direct closure remains the preferred surgical method of covering a sore when required. This allows the anatomy of the vascular supply to remain intact and hence repeated surgical closure can be carried out with good results if and when required. Education of the injured patients and their family is essential. Pressure sores are likely to cause excess spasticity, anaemia, higher risk of urinary infections, septicaemia, low mood and problems with relationships. The management of pressure sores should also include assessment of the level of haemoglobin, plasma protein, and zinc, as the patient may require replacement therapy. Bladder problems Before the Second World War, renal failure from infections, hydronephrosis, and stag horn calculi were the main causes of death within two years of those patients who survived a SCI. The develop- ment of dedicated spinal injury centres led to better understanding and management of the neurogenic bladder. The work of Sir Ludwig Guttmann and Hans Frankel in the middle of the last century is rele- vant to this day, having demonstrated that death from renal causes can be prevented, although unfortunately it remains a significant cause of mortality in developing countries. Early management In the period of spinal shock the bladder is usually non​contractile, and during the first 48–​72 hours after injury, when oliguria is ex- pected, a fine bore indwelling urethral catheter (g14) should be in- serted to monitor urine output. However, urethral catheterization beyond 72 hours is likely to result in colonialization of the bladder with bacteria, hence it is important that the indwelling catheter is removed, and intermittent catheterization commenced by a nurse or other trained assistant. The patient is likely to develop polyuria a few days later, and restriction of fluids below two litres/​day is likely to be required to avoid bladder distension. During this period the frequency of intermittent catheterization may have to be increased. Alternatively, a fine bore urethral catheter may be inserted for a few hours at a time during the period of the day or night when max- imum polyuria occurs. Later management Detrusor hyperreflexia often develops when the period of spinal shock wears off. This usually gives rise to frequent passage of small quantities of urine. Detrusor sphincter dyssynergia, with simultan- eous reflex contraction of the detrusor and sphincter muscles, occurs in most patients with suprasacral lesions of the spinal cord and can result in hydronephrosis and renal embarrassment if unmonitored. Detrusor hyporeflexia will tend to occur when there is damage to the sacral nerves S2, 3, and 4. A urodynamic study is recommended prior to discharge from hospital to determine the exact nature of the underlying bladder and sphincter functions. The management of urinary system following the acute stage of in- jury should not restrict the paralysed individual’s ability to socialize, work, and pursue hobbies. Four-​hourly intermittent catheterization remains the preferred method of drainage throughout the patient’s life, as it is associated with minimal risk of recurrent infections, vesical calculi, bladder autonomic dysreflexia, urethral strictures, and bladder cancer. Patients who can self-​catheterize should be en- couraged to do so: tetraplegic male and female patients may or may not wish to depend on an attendant to catheterize them every four hours. Occasionally anticholinergic drugs such as propantheline, oxybutynin, or imipramine may help to reduce detrusor activity and incontinence between intermittent catheterizations. Injection of botulinum toxin into the detrusor muscle of the bladder is effective when oral medication fails and has revolutionized the management of the overactive neurogenic bladder and neurogenic incontinence, minimizing the need for surgical intervention. Male patients who void reflexly must be closely monitored to ex- clude poor drainage (residual more than 100 ml), recurrent urinary infections, recurrent attacks of autonomic dysreflexia, or early signs of upper tract dilatation. Should they present with any of these symptoms and signs they will require repeat urodynamic studies, as some who wish to continue to void reflexly may require α-blockers or bladder outlet surgery (sphincterotomy) to minimize resistance from the bladder outlet, enhance drainage, and reduce vesical pres- sure during voiding. Following sphincteroromy reflex erections may be affected. Unfortunately, botulinum toxin injections in the sphincter muscles of the bladder have not always been successful in significantly reducing resistance to urine flow. Male tetraplegic patients should be able to void reflexly in an in- continence appliance consisting of a penile sheath attached to a leg bag, and some paraplegic male patients may also prefer to void re- flexly rather than be catheterized. Tetraplegic female patients who do not wish to be dependent on someone to catheterize them should be given an informed choice between absorbent pads or the inser- tion of a suprapubic catheter. Advice from a specially trained con- tinence nurse should be sought if absorbent pads are chosen to discuss the risks of skin irritation, inflammation, and pressure sores. Suprapubic catheters are much preferable to indwelling urethral section 24  Neurological disorders 6144 catheters because of less contamination from the perineum, as well as mitigating the risk of urethral strictures and fistulas. Cystoscopy and other surgical procedures Cystoscopy may be required in patients who complain of recurrent urinary infections. Regular cystoscopic surveillance of patients with suprapubic and urethral indwelling catheters is not generally re- garded as necessary. Advocates of cystoscopic surveillance quote the increased incidence of radiolucent urinary calculi and mucus ma- terial (which often block the catheter and cause urinary infections and autonomic dysreflexia), the increased incidence of metaplastic changes and cancer of the bladder, and the absence of sensation to alert the patient and the clinician, as legitimate reasons for a regular procedure. In the long term, in paraplegia and tetraplegia, bladder augmen- tation with an ileocystoplasty can be useful to increase bladder capacity. Artificial urinary sphincters can be inserted for the treat- ment of neuropathic incontinence, but caution should be exercised in patients with sensory loss due to the high rate of complications in such cases. Sacral anterior nerve root stimulators can be con- sidered in some individuals with suprasacral cord lesions: a radio-​ linked implant is inserted to stimulate the S2, S3, and S4 anterior nerve roots, and by activating the implant the bladder can be emp- tied. Often the same implant can also be used to assist in defecation and in obtaining penile erection. Urinary diversion procedures are, fortunately, now needed less frequently. Follow-​up Long-​term follow-​up and timely intervention are essential for sig- nificant reduction in long-​term risks and maintenance of a good quality of life. All patients with neurogenic bladder from SCI require annual clinical follow up, an ultrasound scan of their urinary tract with or without a plain abdominal X-​ray, blood tests including cre- atinine (eGFR), as well as urine culture and sensitivity, irrespective of the method of management of the urinary tract. This is to ensure adequate drainage with a residual urine of less than 100 ml in the patients who void reflexly, as well as good renal function free from urinary tract infections, urinary calculi, and upper urinary tract dilatation. Residual urine can predispose to infection, stone forma- tion, and contributes to impairment of renal function. The risk of these complications developing is particularly high if the failure to empty is associated with high intravesical pressure and back pres- sure to the kidneys. Bowel care In the initial period of spinal shock, the bowel remains flaccid and should not be allowed to overdistend with the risk of constipation and overflow incontinence. Manual evacuation is usually carried out until bowel activity returns. Eventually reflex emptying can occur in those with predominant upper motor neurone lesions, or the bowel can remain flaccid in those with lower motor neurone in- volvement. In the former, bowel evacuation can usually be triggered by glycerine suppository and/​or by anal digital stimulation. In those with flaccid bowel there is a continuing need to evacuate manually or by straining using abdominal muscles. Advice on a proper diet is also required. Natural aperients, such as senna, and a good quality high-​fibre diet together with a high fluid intake are recommended. Colostomy should be considered as a last resort because, in the absence of sensation, the potential skin problems around the stoma and the diagnosis of acute abdomen is more difficult to manage than in the neurologically intact. Spasticity and contractures Spasticity can occur in an upper motor lesion with intact spinal reflex arcs below the level of the lesion. It is usually worse in those with incomplete lesions. Spasms can be functionally useful and the individual can sometimes use flexor or extension spasms as an aid to standing transfers and dressing. Acute excess spasticity in pa- tients with complete cord injury should be regarded as a symptom of an underlying irritating factor or pathology. Excess spasticity usually produces functional problems as well as causing pain, and in the long term there is a significant risk of muscle contractures, hence aggressive early management of spasticity is important to maximize the use of any neurological recovery and prevent un- necessary complications. Initial management focuses on removing any unnecessary exacerbating factors such as pressure sores, constipation, tight cath- eter leg bags, or urinary infection. Treatment should always involve the use of an expert neurological physiotherapist who will advise on appropriate positioning and seating. In the early stages, passive stretching of the spastic muscles and regular standing regimes can be helpful, and in the longer term these can often be carried out by the disabled person and their carers. Antispastic drugs should always be used with care as they induce significant tiredness and weakness, but they can provide some useful background antispastic effect. Baclofen, dantrium, and tizanidine are the most commonly prescribed. Oral cannabis (or at least 50:50 ratio of tetrahydrocannabinol (THC) and cannabidiol—​Sativex) may also be helpful, and positive trials have been undertaken, but the agent is not yet licensed (except in Canada for neuropathic pain management). Nerve blocks with phenol and alcohol can be used, but intra- muscular botulinum toxin is probably most useful. This is injected directly into the muscle and blocks the release of acetylcholine from the nerve endings, producing muscle relaxation over three or four days which lasts about three months. Occasionally more severe spasticity will need other measures, such as intrathecal baclofen. If contractures have resulted, then surgical correction by tenotomy, tendon lengthening, or muscle division is often the only method that will get the limb back into a functionally useful position. Heterotopic ossification The term heterotopic ossification is used when calcification develops in an abnormal anatomical position in soft tissues. Its prevalence in spinal cord injury is reported to vary between 5 and 50%. The patho- genesis is not entirely known, but there is some evidence that it may be due to excessive stretching of muscle fibres, resulting in bleeding and calcification within the muscle. It commonly occurs around the hips and knees and can mimic an abscess in the acute stage of its development, causing a decreased range of movement as well as lo- calized swelling and joint effusion. Treatment is difficult: etidronate disodium (Didronel) is probably most useful. In severe cases sur- gical intervention can be required, but is usually unsatisfactory. Some centres now use prophylactic etidronate disodium for about a year, although this is not universally accepted. 24.13.2  Spinal cord injury and its management 6145 Pain and dysaesthesia Localized pain is quite common in the early weeks after injury. Peripheral burning pain can also develop and continue for some months. This usually responds reasonably well to the use of carba- mazepine, tricyclic antidepressants, gabapentin, or pregabalin. Pain from other sources such as osteoarthritis or nerve root compression can also occur. It should be remembered that individuals with spinal cord injury do not always appreciate pain, which is often manifested in different ways, such as autonomic dysreflexia or worsening of spasticity. Adequate pain relief during the acute stage of spinal injuries is essential to minimize long-​term chronic pain. Transcutaneous nerve stimulation, acupuncture, and psychological techniques, such as relaxation and hypnotherapy, or alleviation of depressive illness can help in some cases. Spinal cord stimulation or dorsal root entry zone radiofrequency coagulation can also be used, with variable outcomes. Rehabilitation Rehabilitation is an active and dynamic process that requires a con- centrated effort in addressing the pathophysiological, psychological, social, physical, vocational, and related effects of cord damage sim- ultaneously and effectively. Rehabilitation enables the individual to minimize the effects of impairment and maximize functional ac- tivity and participation. Psychological support is necessary throughout the period of hospitalization and often beyond. The great majority of patients with spinal cord injury will experience anxiety, low mood, resent- ment, and anger. Some will exhibit signs of reactive depression. Psychological support is also necessary to help a neurologically im- paired patient with a low energy level cope with a demanding en- ergy and effort consuming rehabilitation process. This support is best provided by trained members of staff with whom the patient feels most comfortable. There is ample evidence that a coordinated multidisciplinary, patient-​oriented, and goal-​oriented effort by a knowledgeable, well-​ trained, and experienced team can minimize medical, physical, and psychosocial complications of paralysis and improve functional outcome, participation, and quality of life for the individual with SCI. It is essential that the rehabilitation process commences in the first few hours or days after injury, and equally important that the team ensures functional outcomes are maintained throughout the individual’s life. This can be achieved by regular monitoring and oc- casional timely intervention. Acute stage following injury During the resuscitation period and for the first 4–​6 weeks following injury, the purpose of rehabilitation is to prevent complications that can easily develop in patients with SCI. Regular and frequent vibra- tion and percussion of the chest wall, together with assisted coughing by an experienced member of staff is required to prevent chest infec- tions. Regular and frequent passive movements of paralysed muscles and splinting can prevent contractures of paralysed muscles. The choice of an adequate mattress and regular turning of the patient in bed will prevent pressure sores. Prophylactic anticoagulation, with or without external pneumatic calf compression, reduces the risk of DVT and PE. Retraining the reflex activity of the physiologically impaired and malfunctioning systems of the body to function safely and conveni- ently should commence from the first few days of injury. This is an essential component of the rehabilitation process for individuals with SCI. Failure to do this, and/​or allowing complications such as pressure sores, contractures of muscles, constipation, DVT, recur- rent urinary or chest infections to develop, will probably prolong the subsequent stages of rehabilitation, prolong hospitalization, and in- crease the cost of treatment. Moreover, inadequate prevention or in- adequate management is likely to significantly limit the outcomes of physical, psychological, vocational, and social rehabilitation, as well as the quality of life of the paralysed individual. Fortunately, most of the complications following spinal injury are preventable, and when complications occur their effects can be minimized and limited. Collection of relevant information about the patient in terms of past medical history, education, employment, marital status, ac- commodation, hobbies, and personal habits should start from an early stage to enable the team to plan for the subsequent stages of rehabilitation. Reassurance and support to the patient and the family members is paramount for building trust for the subsequent stages of rehabilitation. Carefully selected and supervised peer support is of immense value to the newly injured. Subacute stage until discharge Safe mobilization Following the acute stage of injury, it is important to ensure that mo- bilization of the patient is safe, particularly to the vertical position. Tilt table studies should be carried out by a trained physiotherapist, who measures the blood pressure and monitors the neurological condition of the patient with every 10° increment of head-​up tilt. Should there be neurological deterioration in association with a drop of blood pres- sure, then the process should be aborted. Repeated tilting in bed and monitoring to the safe angle previously achieved and cautiously be- yond, with further increments of 10°, will eventually result in safe mo- bilization without neurological loss. Elastic stockings and abdominal binders may have to be used to prevent severe postural hypotension. Education Before embarking on the all-​consuming rehabilitation process, the clinician should impart accurate information and advice, give guid- ance on prognosis and natural history, and help the individual estab- lish realistic goals in an appropriate social context. Education of the patient to become expert in all aspects of his/​her condition, in the absence of cognitive or behavioural difficulties, is likely to facilitate the rehabilitation process, help maximize outcomes, and prevent complications in the short, medium, and long term. Table 24.13.2.3 describes the expected residual functional ability according to the level of the spinal cord lesion. Planning Adequate planning of the rehabilitation process, with agreement on the short and long-​term goals to be achieved, is undertaken with active involvement of the patient. What can be achieved will depend on a multitude of factors that include the level and completeness of the injury (Table 24.13.2.3), age, pre-​accident state of health and section 24  Neurological disorders 6146 level of activity, pre-​ accident education, employment, accommoda- tion, and personal habits. A psychological assessment of cognitive functions is likely to save unnecessary expenditure of time and effort in pursuing unachiev- able goals. Psychological support through the periods of anxiety, low mood, resentment, and anger is essential to buffer the impact of a demanding energy and effort consuming rehabilitation process. Goal-​oriented patient-​centred rehabilitation Active physical and locomotor rehabilitation will commence once the patient has achieved safe mobilization. A  series of multidis- ciplinary goal setting meetings that include the patient and (pref- erably) also a family member is necessary to achieve incrementally what is realistically possible, without overwhelming the patient. The goals set in each of these meetings should be Specific, Measurable, Achievable, Relevant and Time limited (SMART). Training in skills of independence within the level of disability, self-​care of bladder and bowels, dressing, undressing, balancing, safe transfers, use of assistive devices, wheelchair mobility, standing, and ambulating with or without orthoses, will all need to be addressed physically, psychologically, and emotionally by the patient. Supervised peer support from a patient with similar level of in- jury and disability who has succeeded in returning to a useful life has immense value. Demonstration by a peer that there is ‘light at the end of the tunnel’ is likely to be as valuable as the support given by members of staff. It is essential that the patient’s worries about the practicalities of life are minimized if energy and concentration are to be devoted to the rehabilitation process. The Spinal Cord Independence Measure is a validated tool to assess and document the progress made by the patient in self-​care, respiratory and sphincter management, as well as mobility. It is used in many spinal injury centres as an outcome measure throughout the goal-​oriented rehabilitation process, on discharge and at follow-​up reviews. Liaison with the community services from an early stage is im- portant if suitable accommodation and adequate care support in the community are to be ready at the time of discharge. Brief trial home visits are usually carried out before discharge and are particularly important to ensure that accommodation is appropriately adapted. Interim placement in a half-​way house or a residential home is sometimes necessary. Counselling Patients may not express their concerns about the effects of the spinal injury on their sexuality, fertility, employment, accommo- dation, partner, and family members, and about coping outside the hospital set-​up. These are nevertheless important issues that cause anxiety to almost all patients. Ongoing counselling by the clinician from the first few days of injury, enhanced by education of the pa- tient and reinforced by peer support, is an essential component of the rehabilitation process, helping to minimize anxiety and gen- erate confidence and realistic hope. Counselling and support of the partner is equally important, considering it is usually the partner who must deal with the brunt of the practicalities of life, certainly while the patient is in hospital and often beyond. Sexuality and fertility Self-​image and self-​confidence can be severely affected. Individuals should be counselled about the totality of sexuality as there is a tendency for discussions to focus on penetrative sexual intercourse. In both sexes, absence of genital sensation can be compensated for by use of other erogenous zones such as the breasts, neck, and mouth. Orgasm has been reported, even in complete spinal cord lesions. Table 24.13.2.3  Expected residual functional ability according to the level of spinal cord lesion Level of injury—​complete lesions Lesion below C3 Dependent on others for all care Diaphragm paralysed, needs permanent ventilation or diaphragm pacing Chin-​, head-​, or breath-​controlled electric wheelchair Lesion below C4 Dependent on others for all care Can breathe independently using diaphragm Can shrug shoulders Can use electric wheelchair with chin control Can type/​use computer with a mouth stick Environmental control system operated by shoulder shrug or mouthpiece Lesion below C5 Can move shoulders and flex elbows Can eat with a feeding strap/​universal cuff Can wash face, comb hair, clean teeth—​using feeding strap/​ universal cuff Can write using individually designed splint and wrist support Can help in dressing upper half of body Can push manual wheelchair short distances on the flat provided that pushing gloves are used with capstan rims on the wheels May be able to transfer across level surfaces using sliding board and a helper Electric wheelchair needed for functional mobility Lesion below C6 Can extend wrists Still needs strap to eat and for self-​care Can write using individually designed splint but may not need wrist support Can dress upper half of body unaided Can help in dressing lower half of body Can propel wheelchair up gentle slopes Can be independent in bed, car, and toilet transfers Can drive with hand controls Lesion below C7 Full wrist movement and some hand function, but no finger flexion or fine hand movements Can do all transfers, eat, and dress independently Can drive with hand controls Lesion below C8 All hand muscles; expect intrinsics preserved Wheelchair independent, but difficulty in going up and down kerbs Can drive with hand controls Lesion below T1 Complete innervation of arms Totally independent wheelchair life Can drive with hand controls 24.13.2  Spinal cord injury and its management 6147 In men there are various techniques and devices to restore erectile capacity. Most individuals with complete upper motor neurone lesions will have reflex but not psychogenic erections, but these are often not sustained or strong enough for intercourse. In those with parasympathetic sacral lesions reflex erections are usually not possible. Satisfactory erection can often be achieved by the use of intracavernosal drugs or mechanical means such as vacuum erec- tion aids and compressive retainer rings, although the introduction of sildenafil and similar pharmacological agents has reduced the need for mechanical or injected assistance. External ejaculation is rare following spinal cord injury. Retrograde ejaculation occurs in some patients. External ejaculation can be in- duced by vibro-​ejaculation or by electro-​ejaculation. Caution should be exercised during vibro-​ejaculation in patients with injuries above T6 as they are at risk of developing autonomic dysreflexia during the procedure. Patients who have sparing of sensation will require a gen- eral anaesthetic during electro-​ejaculation. Fertility is generally re- duced in men who have low sperm counts with diminished motility, but this has improved significantly in the last two decades with the introduction of the modern assistive conception techniques such as in vitro fertilization and intracytoplasmic sperm injection. In women problems can result from lack of vaginal lubrication. Fertility is not reduced, although some can go through a period of amenorrhoea after SCI. Women with SCI who become pregnant re- quire monitoring throughout pregnancy. Their ability to transfer may be affected by a gravid uterus, and they may require the use of a transfer board. The management of their bladder may need to change, and their kidneys may be at higher risk. They may develop autonomic dysreflexia during labour, but spinal cord injury is not by itself an indication for caesarean section. Tetraplegic and paraplegic women will usually give birth to healthy babies. Employment Overall, between 25 to 35% of people with spinal cord injuries re- turn to work, either in their original occupation or after a period of retraining into a new job. The chances of employment are higher in younger patients and in those who already had a job at the time of injury. There is also positive correlation with the number of years in education. Employment should become more prevalent as the ability to work at home becomes more readily achievable. The process of re-​employment or vocational retraining is usually started while the patient is in hospital. It is good practice for there to be a supported meeting (e.g. organized by the patient’s occupational therapist) with the patient and their employer to discuss the possi- bility of the individual resuming employment in the same or a dif- ferent capacity, the alterations that may need to be made to facilitate access, and to inform the employer about the statutory help and sup- port that can be obtained (in some countries) by re-​employing the patient. Where available, a disablement employment advisor should be involved, providing further advice and help about return to work, or—​in other instances—​careers advice, including discussion of fur- ther education or retraining to obtain new qualifications. Leisure pursuits A wide variety of leisure pursuits are possible for those with spinal cord injury. Integration into able-​bodied clubs and pursuits is ob- viously to be encouraged, but there are also a reasonable range of sports and other clubs for those with spinal injuries. Wheelchair skills can be finely tuned to develop expertise in a variety of sports. Slowly, physical access is improving to leisure and social outlets. Recent legislation, such as the Disability Discrimination Act in the United Kingdom, should further improve the situation. Driving Access to a motor vehicle is almost essential in modern society. Driving should be entirely possible for people with C5 spinal cord in- jury and below. Automatic transmission is needed and hand controls are usually necessary, enabling the individual to control the acceler- ator and brake functions from a lever or other device near the steering wheel. A variety of infra-​red devices to control secondary functions such as windscreen wipers, lights, and horn are now available. Very light power steering makes life easier for those with a weak grip. There are several techniques to stow wheelchairs safely for those with paraplegia, and for those with higher lesions there are several mechanical wheelchair stowage devices. It is also possible to adapt a suitable vehicle to enable people to drive from their wheelchair. Advice is often required on the range and type of suitable vehicles and adaptations, and on financial costs. Holidays Travelling on holiday, both inland and overseas, is now possible for individuals with all levels of injury. The Spinal Injury Association has a good database to provide advice about suitable and accessible accommodation in most holiday resorts. Information A key to independence is access to good quality information. In most countries there are now voluntary organizations that can pro- vide this. These can also act as pressure groups, and many have been instrumental in promoting increased awareness better accesss and improved legislation for disabled people. The internet now provides an excellent source of information and advice. Training in computer literacy should certainly be encouraged by the rehabilitation team. Discharge and post discharge Liaison with the community services is essential prior to discharge to ensure accessibility of the patient to their own home or other suit- able accommodation as well as adequate support. Most spinal injury centres in the UK provide an ongoing monitoring service for individ- uals with SCI following discharge. A one stop full outpatient review of the neurological, medical, psychological, social, and physical status is offered to the individual with SCI annually, or on alternate years. Some blood and urine investigations and an ultrasound scan of the urinary tract are carried out during the same outpatient review. This is to ensure continuing safe and convenient functioning of the various systems of the body, absence, or early detection of established compli- cations of which the sensory impaired patient is unlikely to be aware, and maintenance of the level of independence. A full neurological examination annually and an MRI of the spinal cord every 3–5 years are important to rule out clinically manifest and clinically silent post-​ traumatic syringomyelia, which can cause neurological deterioration. Most problems detected during outpatient review can be attended to during the same appointment, and such a patient-​centred service is believed to significantly minimize the time spent by the patient at- tending different clinics on different days, address any problem and its effects holistically in a coordinated manner, reduce frequency of hospitalization, and reduce the cost of living to the paraplegic and tetraplegic patient. section 24  Neurological disorders 6148 Access by phone or in person to the spinal injury centre following discharge is offered to most individuals with spinal cord injury in the United Kingdom, whereby patients who have a crisis can seek advice from the members of the team. Liaison with the local Rehabilitation Centre and with the community services is often necessary when top up rehabilitation is required and a psychological or social crisis occurs. If medical complications develop while the patient is in the community, the patient is usually readmitted to the spinal injury centre for investigations and treatment. This reduces the burden on district general hospitals, which are not equipped to deal with the spinal injury patient. It also reduces the cost of management since all the information about the patient is available at the spinal injury centre. Patients who require a specialist expertise that is not avail- able in the spinal injury centre should be managed in the appropriate specialist centre with an outreach input from the spinal injury centre to advise about prevention of potential complications that can occur because of the paralysis, and methods of prevention. Equipment Equipment and assistive devices should be provided following dis- cussion with the team in the spinal injury service. Environmental control equipment will enable an individual to control simple aspects of life around the house, such as a door intercom, turning lights on and off, turning the pages of a book, controlling the televi- sion and telephone, and using a computer. These devices can now be controlled, even by those with high tetraplegia, using mouth sticks or breath control. The occupational therapist will often be involved in such advice, particularly at the time of discharge back into the home environment. Conclusion and future prospects Spinal cord injury presents a range of challenges to patients, family members, and the multidisciplinary rehabilitation team. A holistic approach to the various medical and non​medical effects, from the early hours or days of injury through to liaison with the commu- nity, has demonstrated success in generating good outcomes at a relatively low cost. There is a current tendency to fragment the man- agement of the patient, with an overemphasis on the management of the injured spine surgically at the expense of all other effects of the injury. Evidence that resources are being targeted appropriately is still awaited. Considering the relatively low incidence of the condi- tion and its high complexity, and considering the increasing claims that new treatments improve outcomes, it is vital that patients with spinal cord injury are managed by experienced teams able to provide a fit for purpose service, and also able to adequately and objectively assess the added value of new interventions. At the present time we cannot repair the injured spinal cord in clinical practice, but developments in basic neuroscience are begin- ning to translate. Repair of the spinal cord, for example by transplant of glial cells cultured from stem cells or the adult olfactory system, may be possible in the near future. There is also progress in the use of neuroprotective agents in the acute phase. Other modalities, such as the use of anti-​NOGO monoclonal antibodies to augment plas- ticity and regeneration, chondroitinase and other pharmocological agents may also have a role to play in the future. It is therefore para- mount that the management of the spinal injury does not hinder the assessment of cord tissue regeneration using advanced radiological techniques such as PET scan and Tractography. However, our cur- rent inability to influence neuronal recovery should certainly not in- hibit active and dynamic rehabilitation in order for the spinal cord injured person to resume as normal a life as possible. Significant im- provements to overall survival and quality of life have been achieved in the last seven decades with the application of a knowledge based holistic coordinated approach to management that includes expert rehabilitation, as well as greater social awareness and understanding. FURTHER READING Bedbrook GM (1981). The care and management of spinal injuries. Springer-​Verlag, New York, NY. Bickenbach J, et al. (2013). International perspectives on spinal cord injury. World Health Organization & ISCoS, WHO Cataloguing-​in-​ publication Data. http://​apps.who.int/​iris/​bitstream/​10665/​94190/​ 1/​9789241564663_​eng.pdf Blackwell TL, et al. (2000). Spinal cord injury desk reference: guide- lines for life care planning and case management. Demos Medical Publishing, New York, NY. Bluvshtein V, et al. (2011). A new grading for easy and concise descrip- tion of functional status after spinal cord lesions. Spinal Cord, 49, 1–​9. Bromley I (2006). Tetraplegia and paraplegia: a guide for physiothera- pists. Churchill Livingstone Elsevier, London. Chhabra HS (2015). ISCOS textbook of comprehensive management of spinal cord injuries. Wolters Kluwer, New Delhi. Ditunno JF (1999). Predicting recovery after spinal cord injury: a re- habilitation imperative. Arch Phys Med Rehabil, 80, 361–​3. El Masry WS (1993). Physiological instability of the injured spinal cord. Paraplegia, 31, 273–​5. El Masry WS (2006). Traumatic spinal cord injury: the relationship be- tween pathology and clinical implications. Trauma, 8, 29–​46. El Masri WS, Kumar N (2017). Active physiological conservative management in traumatic spinal cord injuries—​an evidence-​based approach. Trauma, 19, 10–​22. El Masri WS (2010). Management of Traumatic Spinal Cord Injuries, current standard of care revisited. ACNR, 10(1), 37–40. Fehlings MG, et al. (2012). Early versus delayed decompression for traumatic cervical spinal cord injury: results of the surgical timing in acute spinal cord injury study (STASCIS). PLoS One, 7, e32037. Folman Y, el Masri WS (1989). Spinal cord injury: prognostic indica- tors. Injury, 20, 92–​3. Frankel HL, et al. (1969). The value of postural reduction in the ini- tial management of closed injuries of the spine with paraplegia and tetraplegia. Paraplegia, 7, 179–​92. Frankel HL (ed) (1992). Handbook of clinical neurology, vol. 17 (61): spinal cord trauma. Elsevier Science Publishers, Amsterdam. Glass CA (1999). Spinal cord injury: impact and coping. The British Psychology Society, London. Glass CA, et al. (2009). Spinal cord independence measure, version III: applicability to the UK spinal cord injured population. J Rehabil Med, 41, 723–​8. Grant R (1988). Physical therapy of the cervical and thoracic spine. Churchill Livingstone, London. Groah SL (2005). Managing spinal cord injury: a guide to living well with spinal cord injury. NRH Press, Washington, DC. Guttmann L (1976). Spinal cord injuries: comprehensive management and research, 2nd edition. Blackwell, Oxford. Hongyun Huang et al. (2018). Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017). Cell Transplantation, 27(2), 310–24. 24.13.2  Spinal cord injury and its management 6149 Harrison P ( 2007). Managing Spinal Cord Injury: The first 48 hours Published by the Spinal Injury Association 2007. Katoh S, El Masri(y) WS (1994). Neurological recovery after conserva- tive treatment of cervical cord injuries. JBJS, 76b, 225–​8. Katoh S, El Masri WS et al. (1996). Neurological outcome in conser- vatively treated patients with incomplete closed traumatic cervical spinal cord injuries. Spine, 21, 2345–​51. Ko H-​Y, et al. (2012). Factors associated with early onset post-​traumatic syringomyelia. Spinal Cord, 50, 695–​8. Kwon BK, Curt A, Belanger LM (2009). Intrathecal pressure moni- toring and cerebrospinal fluid drainage in acute spinal cord injury: a prospective randomized trial. J Neurosurg Spine, 10, 181–93. Rosenberg N, et  al. (1996). Neurological deficit in a consecutive series of vertebral fractures patients with bony fragments within the spinal canal. Spinal Cord, 35, 92–​5. Silver JR (2003). History of the treatment of spinal injuries. Kluwer Academic/​Plenum Publishers, New York, NY. Sisto S, Druin E, Macht-​Sliwinski M (2008). Spinal cord injuries: management and rehabilitation. Mosby, St Louis, MO. Smith M (1999). Making the difference:  efficacy of specialist versus non-​specialist management of spinal cord injury. Spinal Injuries Association, DESA Ltd, Milton Keynes. Stover SL, DeLisa JA, Whiteneck GG (1995). Spinal cord injury: clinical outcomes from the model system. Aspen Publishers, Gaithersburg, MD. Tator C (1982). Early management of acute spinal cord injury. Raven Press Books, New York, NY. Trieschmann RB (1988). Spinal cord injuries—​psychological, social and vocational rehabilitation, 2nd edition. Demos Publications, New York, NY. Vinken PJ, Bruyn GW (eds) (1976). Handbook of clinical neurology, vol. 25: injuries of the spine and spinal cord, part 1. Elsevier Science Publishers, Amsterdam. Vogel LC, et al. (2014). Spinal cord injury in the child and young adult. Mac Keith Press, London. Wade DT (1992) Measurement in neurological rehabilitation. Oxford University Press, Oxford. Useful addresses Spinal Injuries Association, SIA House, 2 Trueman Place, Oldbrook, Milton Keynes MK6 2HH Web: https://​www.spinal.co.uk The association for spinal cord injured people—​a good source of fur- ther information and advice. 24.14 Diseases of the autonomic nervous system 615 24.14 Diseases of the autonomic nervous system 6150 Christopher J. Mathias and David A. Low ESSENTIALS The autonomic nervous system innervates all organs, producing predominantly involuntary and automatic actions that are medi- ated by two principal efferent pathways, the sympathetic and para- sympathetic, which are neurochemically and anatomically distinct. Numerous synaptic relays and neurotransmitters allow the auto- nomic control of organ function at local and central levels to be inte- grated with the requirements of the whole body. The peripheral and central components of the autonomic ner- vous system are frequently affected by diseases, conditions, or toxins. Autonomic disorders are described as (1)  primary—​without de- fined cause, including multiple system atrophy and acute/​subacute dysautonomias; or (2) secondary—​with specific defects or as a con- sequence of other conditions, including diabetes mellitus, Riley–​Day syndrome, amyloid neuropathy, dopamine β-​hydroxylase deficiency, spinal cord injury, and many drugs. Clinical features Failure of the autonomic nervous system—​manifestations may be (1)  sympathetic—​adrenergic failure causes postural (orthostatic) hypotension and (in men) disturbed ejaculation; cholinergic disturb- ances interfere with sweating; (2) parasympathetic—​causing a fixed heart rate, erectile failure, and disturbed emptying of the urinary bladder and large intestine. Overactivity of the autonomic nervous system—​manifestations may be (1) sympathetic—​characterized by hypertension, tachycardia, and excessive sweating; (2)  parasympathetic—​leading to bradycardia. Mixed effects, peripherally and centrally, lead to complex clinical manifestations. Investigation Autonomic screening tests include (1)  cardiovascular—​(a) physio- logical (e.g. head-​up tilt, heart rate responses), (b) biochemical (e.g. plasma noradrenaline, adrenaline, and dopamine levels), (c) pharma- cological (e.g. clonidine growth hormone stimulation); (2) sweating (e.g. thermoregulatory response to increasing core temperature by 1°C). Autonomic dysfunction may also be suggested by a wide var- iety of other tests, including those of gastrointestinal, urinary/​renal, sexual, respiratory, and eye function. Treatment Symptomatic—​(1) Orthostatic hypotension—​management requires an approach combining (a)  non​pharmacological measures (e.g. avoidance of sudden standing, high salt intake); and (b) pharmaco- logical measures (e.g. fludrocortisone, sympathomimetics, such as ephedrine or midodrine). (2) Other symptoms—​combined pharma- cological and physical interventions can improve urinary incontin- ence, gastrointestinal motility disorders, and sexual dysfunction. Care is required to manipulate autonomic activity in patients with parkin- sonian manifestations because the autonomic aspects are frequently exacerbated by antiparkinsonian agents. Specific—​some causes of autonomic dysfunction are treatable (e.g. infusions of immunoglobulin and plasmapheresis for immune-​ mediated neuropathy); hepatic transplantation in familial amyloid polyneuropathy. Introduction The autonomic nervous system has two principal efferent path- ways, sympathetic and parasympathetic, that innervate and influ- ence every organ in the body (Fig. 24.14.1). Autonomic actions are predominantly involuntary and automatic, as indicated by the term ‘autonomic’ first proposed by Langley in 1898. The structure of the autonomic system, with numerous synapses centrally and periph- erally, as well as multiple neurotransmitters, provides flexible con- trol of organ function locally and in an integrated manner—​as in the maintenance of systemic blood pressure and body temperature. Disease of the autonomic nervous system may cause local or sys- temic effects. Basic principles The autonomic nervous system is primarily a visceromotor system, in which each efferent pathway is influenced in a variety of ways. Feedback and central integration are important and virtually every sensory pathway can influence its activity. For example, in spinal cord lesions, activation of visceral, skin, and muscle receptors below the level of the lesion influences autonomic activity and blood pres- sure through the spinal pathways, while heart rate responses to 24.14 Diseases of the autonomic nervous system Christopher J. Mathias and David A. Low 24.14  Diseases of the autonomic nervous system 6151 classic afferent baroreceptor pathways are retained. Key cerebral autonomic centres are in the hypothalamus, midbrain (Edinger–​ Westphal nucleus and locus ceruleus), and brain stem (nucleus tractus solitarius and vagal nuclei), and through intracerebral con- nections. Many other areas affect autonomic activity. Examples are the insular cortex, anterior cingulate gyrus, and amygdala, which are important in processing emotion and autonomic effects. Parasympathetic efferent pathways are craniosacral and sympathetic efferents are thoracolumbar; each has pre-​ and postganglionic fibres. The sympathetic ganglia are placed further from target organs than the parasympathetic ganglia. Autonomic nerve terminals at target organs vary in complexity; they have the capacity to synthesize neurotransmitters and a host of mechanisms affects uptake and interaction with local or blood-​ borne chemicals (Fig. 24.14.2). There are differences between or- gans, especially the gastrointestinal system, in which the enteric nervous system is considered as a third autonomic division. The multiplicity of neural pathways, transmitters, and modulators re- sults in selective control of responses in specific vascular territories and organs, making it a highly complex but precisely regulated and integrated system. Classification Diseases of the autonomic nervous system may result in central or peripheral damage or derangement; these may be primary with no known cause or secondary with specific abnormalities (dopamine β-​hydroxylase deficiency), or strong associations with other diseases (Holmes–​Adie syndrome or diabetes mellitus) (Table 24.14.1). Intermittent autonomic dysfunction may cause cardiovascular or sudomotor abnormalities (autonomic (neurally) mediated syn- cope or primary hyperhidrosis) (Box 24.14.1). Drugs are a common cause of autonomic dysfunction (Box 24.14.2). Classification can be considered in various ways. Dysfunction may be localized (Box 24.14.3) or widespread. Diseases may re- sult from lesions that are central (multiple system atrophy), spinal (spinal cord transection), or peripheral (pure autonomic failure), or from a highly specific biochemical deficit (dopamine β-​hydroxylase deficiency). Some are age related, with presentation at birth (Riley–​ Day syndrome), second decade (autonomic mediated syncope), or adulthood (familial amyloid polyneuropathy). Autonomic failure commonly causes underactivity, but the reverse, overactivity, can cause various manifestations, for example, paroxysmal hyperten- sion during autonomic dysreflexia in high spinal cord injuries. In autonomic mediated syncope there may be a combination of vagal overactivity and/​or sympathetic withdrawal. Clinical features Sympathetic adrenergic failure causes orthostatic hypotension and ejaculatory failure in men, while sympathetic cholinergic failure causes anhidrosis. Parasympathetic failure results in a fixed heart Sympathetic nervous system Mesen- cephalon Pons Superior cervical ganglion Stellate ganglion Coeliac ganglion Sympathetic trunk Superior mesenteric ganglion Inferior mesenteric ganglion Tear and salivary glands Liver Eye Lung Heart Stomach Pancreas Small intestine Large intestine rectum Bladder Reproductive organs Parasympathetic nervous system Vagus n. Cervical Thoracic Lumbar Sacral III IX.VII X Medulla obl. Fig. 24.14.1  Sympathetic (thoracolumbar) and parasympathetic (cranial and sacral) pathways that innervate a variety of organs. From Schmidt RF, Lang F (eds) (2007). Physiologie des Menschen, 30th edition. Springer-​Verlag, Heidelberg. Copyright © 2007, Springer Medizin Verlag Heidelberg, with permission of Springer. section 24  Neurological disorders 6152 Table 24.14.1  Classification of disorders resulting in autonomic dysfunction Primary (aetiology unknown) Acute/​subacute dysautonomias Pure pandysautonomia Pandysautonomia with neurological features Pure cholinergic dysautonomia Chronic autonomic failure syndromes Pure autonomic failure Multiple system atrophy (Shy–​Drager syndrome) Autonomic failure with Parkinson’s disease Secondary Congenital Nerve growth factor deficiency Hereditary Autosomal dominant trait Familial amyloid neuropathy Porphyria Autosomal recessive trait Familial dysautonomia (Riley–​Day syndrome) Dopamine β-​hydroxylase deficiency Aromatic l-​amino acid decarboxylase deficiency X-​linked recessive Fabry’s disease Metabolic diseases Diabetes mellitus Chronic renal failure Chronic liver disease Vitamin B12 deficiency Alcohol induced Inflammatory Guillain–​Barré syndrome Transverse myelitis Infections Bacterial Tetanus, leprosy Viral HIV infection Parasitic Chagas’ disease Prion Fatal familial insomnia Neoplasia Brain tumours—​especially of the third ventricle or posterior fossa Paraneoplastic, to include adenocarcinomas of lung and pancreas, and Lambert–​Eaton syndrome Connective tissue disorders Rheumatoid arthritis Systemic lupus erythematosus Mixed connective tissue disease Surgery Regional sympathectomy—​upper limbs, splanchnic denervation Vagotomy and drainage procedures—​‘dumping syndrome’ Organ transplantation—​heart, kidney Trauma Spinal cord transection Miscellaneous Subarachnoid haemorrhage Syringobulbia and syringomyelia Intermittent autonomic dysfunction See Box 24.14.1 Drugs See Box 24.14.2 From Mathias (2009). (a) Sympathetic nerve terminal Effector cell COMT Tyrosine Synaptic cleft Uptake 2 Uptake 1 TH DOPA DDC DA NA MAO + − D H D H (b) Ganglia Parasympathetic Sympathetic ACh-n ACh-m (VIP) NA (NPY) Glands Smooth muscle Heart ACh-m Blood vessels Heart Sweat glands DA − + NA Sympathetic ACh-n ACh-n NA − Target organ 2 1 Fig. 24.14.2  Schema of some pathways in the formation, release, and metabolism of noradrenaline from sympathetic nerve terminals. Tyrosine is converted into dihydroxyphenylalanine (dopa) by tyrosine hydroxylase (TH). Dopa is converted into dopamine (DA) by dopa-​decarboxylase (DDC). In the vesicles, dopamine is converted into noradrenaline (NA) by dopamine β-​hydroxylase. Nerve impulses release both dopamine β-​hydroxylase and noradrenaline into the synaptic cleft by exocytosis. Noradrenaline acts predominantly on α1-​adrenoceptors but has actions on β-​adrenoceptors on the effector cell of target organs. It also has presynaptic adrenoceptor effects. Those acting on α2-​adrenoceptors inhibit noradrenaline release and those on β-​adrenoceptors stimulate noradrenaline release. Noradrenaline may be taken up by a neuronal process (uptake 1) into the cytosol, where it may inhibit further formation of dopa through the rate-​limiting enzyme tyrosine hydroxylase. Noradrenaline may be taken into vesicles or metabolized by monoamine oxidase (MAO) in the mitochondria. Noradrenaline may be taken up by a higher-​capacity, but lower-​affinity, extraneuronal process (uptake 2) into peripheral tissues, such as vascular and cardiac muscle and certain glands. Noradrenaline is also metabolized by catechol-​O-​methyl transferase (COMT). Thus, noradrenaline measured in plasma is the overspill not affected by these numerous processes. (b) Outline of the major transmitters at autonomic ganglia and postganglionic sites on target organs supplied by the parasympathetic and sympathetic efferent pathways. The acetylcholine (ACh) receptor at all ganglia is of the nicotinic subtype (ACh-​n). Ganglionic blockers such as hexamethonium thus prevent both parasympathetic and sympathetic activation. Atropine, however, acts only on the muscarinic (ACh-​m) receptors at postganglionic parasympathetic and sympathetic cholinergic sites. The cotransmitters, along with the primary transmitters, are also indicated. NPY, neuropeptide Y; VIP, vasoactive intestinal peptide. (a) From Mathias CJ (2004). Disorders of the autonomic nervous system. In: Bradley WG, Daroff RB, Fenichel GM, Jancovich J (eds) Neurology in Clinical Practice, 4th edition. Butterworth-​Heinemann, Boston, USA, 2403–​40. (b) From Mathias CJ (1998). Autonomic disorders. In: Bogousslavsky J, Fisher M (eds) Textbook of Neurology. Butterworth-​Heinemann, Massachusetts, pp. 519–​45. 24.14  Diseases of the autonomic nervous system 6153 rate, a sluggish urinary bladder and large bowel, and, in men, erectile dysfunction. With overactivity there may be hypertension, tachy- cardia, and hyperhidrosis, although parasympathetic overactivity causes bradycardia. In autonomic disorders there are many clinical manifestations, which may cause diagnostic difficulties, especially when the disorder is generalized. The presenting complaints often provide clues. Palmar hyper­ hidrosis or gustatory sweating may indicate a localized disorder, or be a harbinger of widespread autonomic impairment, as the latter may complicate diabetes mellitus. A  cardinal feature is orthostatic hypotension (defined as a decrease in systolic blood pressure of more than 20 mm Hg and/or in diastolic pressure of more than 10 mm Hg on standing or head-​up tilt—​Fig. 24.14.3); this impairs perfusion of vital organs such as the brain. The symp- toms vary from fainting (syncope, loss of consciousness), some- times with ensuing injury, to fatigue and lethargy. Numerous factors in daily life enhance or reduce hypotension (Box 24.14.4). Some patients recognize these, with the self-​introduction of cor- rective measures. Large meals, refined carbohydrate, and alcohol, which enhance postprandial hypotension, are avoided. Many sit down, lie flat, or assume curious postures, such as squatting or stooping, which now are recognized as raising blood pressure (Fig. 24.14.4). With time, symptoms of orthostatic hypotension wane, for reasons such as improved cerebrovascular autoregula­ tion. In autonomic mediated syncope, venepuncture, or pain (in vasovagal syncope) or cervical movements and pressure (in carotid sinus hypersensitivity) cause hypotension and bradycardia. A his- tory of impaired sweating and temperature intolerance, urinary disturbances, sexual dysfunction (in men), and gastrointestinal derangement (constipation), especially together with orthostatic hypotension, should suggest a generalized autonomic disorder (Table 24.14.2). In the Riley–​Day syndrome (familial dysautonomia) there is a his- tory of consanguinity, usually in the Ashkenazi Jewish population. A family history is often elicited in the vasovagal form of autonomic mediated syncope and expected in familial amyloid polyneuropathy. A drug history, including exposure to chemicals, toxins, and poi- sons, is important. Box 24.14.1  Intermittent autonomic dysfunction • Autonomic (neurally) mediated syncope — Vasovagal syncope — Carotid sinus hypersensitivity — Situational syncope — Micturition syncope — Swallow syncope — With glossopharyngeal neuralgia — Defecation syncope — Laughter-​induced syncope • Postural tachycardia syndrome • Initial orthostatic hypotension • Primary or essential hyperhidrosis Box 24.14.2  Drugs, chemicals, poisons, and toxins causing autonomic dysfunction Decreasing sympathetic activity Centrally acting • Clonidine • Methyldopa • Moxonodine • Reserpine • Barbiturates • Anaesthetics Peripherally acting • Sympathetic nerve endings (guanethidine, bethanidine) • α-​Adrenoceptor blockade (phenoxybenzamine) • β-​Adrenoceptor blockade (propranolol) Increasing sympathetic activity • Amphetamines • Releasing noradrenaline (tyramine) • Uptake blockers (imipramine) • Monoamine oxidase A inhibitors (tranylcypromine) • β-​Adrenoceptor stimulants (isoprenaline) Decreasing parasympathetic activity • Antidepressants (imipramine) • Tranquillizers (phenothiazines) • Antidysrhythmics (disopyramide) • Anticholinergics (atropine, probanthine, benzatropine) • Toxins (botulinum) Increasing parasympathetic activity • Cholinomimetics (carbachol, bethanechol, pilocarpine, mushroom poisoning) • Anticholinesterases • Reversible carbamate inhibitors (pyridostigmine, neostigmine) • Organophosphorus inhibitors (parathion, sarin) Miscellaneous • Alcohol, thiamine (vitamin B deficiency) • Vincristine, perhexiline maleate • Thallium, arsenic, mercury • Mercury poisoning (‘pink’ disease) • Ciguatera toxicity • Jellyfish and marine animal venoms • First-​dose effects of drugs (prazosin, captopril) • Withdrawal of chronically used drugs (opiates, clonidine, alcohol) Adapted from Mathias (2009). Box 24.14.3  Examples of localized autonomic disorders • Holmes–​Adie pupil • Horner’s syndrome • Crocodile tears (Bogorad’s syndrome) • Gustatory sweating (Frey’s syndrome) • Reflex sympathetic dystrophy • Idiopathic palmar/​axillary hyperhidrosis • Chagas’ diseasea Surgical proceduresb • Sympathectomy—​regional • Vagotomy and gastric drainage procedures in ‘dumping syndrome’ • Organ transplantation—​heart, lungs a Listed here because it targets intrinsic cholinergic plexus in the heart and gut. b Surgery may cause some of the disorders listed here such as Frey’s syndrome after parotid surgery. From Mathias (2009). section 24  Neurological disorders 6154 A detailed clinical examination is necessary. Pupillary and as- sociated ocular abnormalities occur in Horner’s syndrome. To as- sess orthostatic hypotension, blood pressure should be measured with the patient lying flat, and after standing (or sitting, if not possible). A fall in systolic blood pressure of less than 20 mm Hg in the presence of appropriate symptoms does not exclude auto- nomic failure. Indeed, orthostatic hypotension may be unmasked, or enhanced, by factors such as ingestion of food and/​or exercise. Furthermore, in the presence of vascular disease (such as carotid artery stenosis) even a small fall in blood pressure results in cere- bral ischaemia. Lack of additional neurological features favours pure autonomic failure (with a good prognosis), while associated parkinsonism or cerebellar dysfunction suggests multiple system atrophy. Several disorders causing a peripheral neuropathy result in autonomic impairment. Basic bedside testing for glycosuria (in diabetes mellitus) or proteinuria (in systemic amyloidosis) provides important information. Investigations When an autonomic disorder is suspected, the first step is to de- termine if autonomic function is normal or abnormal. Autonomic screening tests (Box 24.14.5) have their value, but also their 160 (a) (b) (c) 140 120 100 80 60 40 20 200 150 100 50 160 140 120 100 80 60 40 20 200 150 100 160 140 120 100 80 60 40 20 200 150 100 50 0 16:00 20:00 24:00 04:00 08:00 12:00 16:00 Blood Pressure (mm Hg) Heart Rate (beat min–1) Blood Pressure (mm Hg) Heart Rate (beat min–1) Blood Pressure (mm Hg) Heart Rate (beat min–1) 0 50 0 0 0 0 Box 24.14.4  Factors influencing orthostatic hypotension • Speed of positional change • Time of day (worse in the morning) • Prolonged recumbency • Warm environment (hot weather, central heating, hot bath) • Raising intrathoracic pressure: micturition, defecation, or coughing • Food and alcohol ingestion • Water ingestiona • Physical exertion • Manoeuvres and positions (bending forward, abdominal com- pression, leg crossing, squatting, activating calf muscle pump)b (Fig. 24.14.5) • Drugs with vasoactive properties (including dopaminergic agents) a Raises supine blood pressure in chronic autonomic failure. b These manoeuvres usually reduce the postural fall in blood pressure, unlike the others. Adapted from Mathias et al. (2013). Fig. 24.14.3  Twenty-​four hour non​invasive ambulatory blood pressure profiles, showing systolic and diastolic blood pressure and heart rate at intervals through the day and night (the black bars indicate periods when the patient was in bed). (a) The changes in a normal subject with no postural fall in blood pressure; there was a fall in blood pressure at night while asleep, with a rise in blood pressure on waking. (b) The marked variability in heart rate in a patient with the postural tachycardia syndrome. The profile indicates episodes of profound tachycardia without hypotension. (c) The marked fluctuations in blood pressure in a patient with pure autonomic failure. The marked falls in blood pressure are usually the result of postural changes, either sitting or standing. Supine blood pressure, particularly at night, is elevated. Getting up to micturate causes a marked fall in blood pressure (at 03:00 hours). There is a reversal of the diurnal changes in blood pressure. There are relatively small changes in heart rate, considering the marked changes in blood pressure. 24.14  Diseases of the autonomic nervous system 6155 limitations. The majority are directed towards cardiovascular as- sessment and exclusion of autonomic underactivity. Tests of other systems are increasingly being made available. Normal screening results do not necessarily exclude an autonomic disorder, because, on the basis of the history and clinical examination, additional tests, such as carotid sinus massage may be needed in patients with syncope. If autonomic tests are abnormal, further evaluation will determine the site and extent of the autonomic lesion, the func- tional deficit, and whether it results from a primary or secondary disorder, because an accurate diagnosis is essential for prognosis and appropriate management. A  24-​h ambulatory blood pres- sure and heart rate profile using the autonomic protocol that in- cludes the effects of stimuli in daily life (such as food and exercise; Fig. 24.14.3) help in the evaluation and management of disorders 60° HEAD-UP TILT Normal Blood pressure (a) (b) (c) mmHg Heart rate bpm 60° Head up tilt Heart rate bpm 180 150 Blood pressure mmHg Autonomic failure 60° HEAD-UP TILT 150 180 0 0 0 0 Heart rate bpm Blood pressure mmHg Spinal injury 3 MIN OF 60° HEAD-UP TILT 150 180 0 0 Fig. 24.14.4  (a) Continuous blood pressure and heart rate recorded noninvasively before, during, and after head-​up tilt in a normal individual (upper panel), and (b) in a patient with autonomic failure and (c) in a patient with a high cervical spinal cord lesion. In the normal individual there is no fall in blood pressure during head-​up tilt, unlike a patient with autonomic failure in whom blood pressure falls promptly and remains low with a blood pressure overshoot on return to the horizontal. In this patient there is only a minimal change in heart rate despite the marked blood pressure fall. In the patient with spinal cord injury there is a fall in blood pressure because of impairment of the sympathetic outflow disrupted in the cervical spine. Heart rate rises because of withdrawal of vagal activity in response to the rise in pressure. (a) Adapted from Mathias CJ (2015). Orthostatic hypotension and orthostatic intolerance. In: De Groot JL, Jameson LJ (eds) Endocrinology, 7th edition. Elsevier, Philadelphia, PA. (b) From Mathias CJ (2015). Orthostatic hypotension and orthostatic intolerance. In: De Groot JL, Jameson LJ (eds) Endocrinology, 7th edition, Elsevier, Philadelphia, PA. section 24  Neurological disorders 6156 such as orthostatic hypotension and postural tachycardia syn- drome. Plasma catecholamine (noradrenaline and adrenaline, and in rare disorders such as dopamine β-​hydroxylase deficiency, dopamine) measurements (Fig. 24.14.6) and the clonidine growth hormone stimulation test may separate out the different auto- nomic failure syndromes. Investigations may be needed to diag- nose underlying diseases, and include neuroimaging studies (MRI or CT, MNR angiogram), serum amyloid protein scans, sural nerve Table 24.14.2  Some of the clinical manifestations and possible presentations in primary chronic autonomic failure syndromesa Cardiovascular Orthostatic hypotension Sudomotor Anhidrosis, heat intolerance Gastrointestinal Constipation, occasionally diarrhoea, oropharyngeal dysphagia Renal and urinary bladder Nocturia, frequency, urgency, incontinence, retention Sexual Erectile and ejaculatory failure in men Ocular Aniscoria, Horner’s syndrome Respiratory Stridor, involuntary inspiratory gasps, apnoeic episodes Other neurological deficits Parkinsonian and cerebellar/​pyramidal features a Certain features, such as oropharyngeal dysphagia and respiratory abnormalities (including those resulting from laryngeal fold paresis), occur in multiple system atrophy rather than in pure autonomic failure. From Mathias (2009). Box 24.14.5  Autonomic disorders considered under prognosis and response to intervention • Fixed and irreversible—​pure autonomic failure (PAF), spinal cord injury • Progressive and irreversible—​multiple system atrophy (MSA) • Progressive but stoppable—​familial amyloid polyneuropathy, dia- betes mellitus • Reversible—​immune-​mediated autonomic neuropathy 200 0 200 0 200 0 0 120 Time (sec) 0 0 120 60 Time (sec) Time (sec) BP (mmHg) 200 0 0 120 Time (sec) BP (mmHg) BP (mmHg) BP (mmHg) Fig. 24.14.5  Physical countermanoeuvres using isometric contractions of the lower limbs and abdominal compression. The effects of leg crossing in standing and sitting position, placing a foot on a chair and squatting on finger arterial blood pressure in a 54-​year-​ old man with pure autonomic failure and incapacitating orthostatic hypotension. The patient was standing (sitting) quietly prior to the manoeuvres. Bars indicate the duration of the manoeuvres. Note the increase in blood pressure and pulse pressure during the manoeuvres. From Wieling W et al. (2004). Non-​pharmacological treatment of reflex syncope. Clin Auton Res, 14 (Suppl 1), 62–​70. Copyright © 2004, Steinkopff Verlag, with permission of Springer. 24.14  Diseases of the autonomic nervous system 6157 biopsy (with specific staining with monoclonal antibodies), de- tection of antibodies to specific receptors (such as the nicotinic acetylcholine receptor), and genetic testing. These tests should be combined with non​neurological investigations, depending on the suspected diagnosis. Treatment This varies depending on the autonomic disease, the systems af- fected and the functional autonomic deficit, and whether the disorder is primary or secondary. Treatment should consider the underlying condition (e.g. in parkinsonian syndromes), where autonomic features may be worsened by antiparkinsonian therapy. In some diseases simple intervention is effective, such as unblocking a urinary catheter to resolve autonomic dysreflexia in high spinal cord lesions. In some, immunological therapy (intravenous γ-globulin, plasma exchange) can reverse the auto- nomic neuropathy. Complex procedures such as liver trans- plantation are needed to reduce variant transthyretin levels in familial amyloid polyneuropathy. Multidisciplinary expertise may be needed, as in the Riley–​Day syndrome and multiple system atrophy, to prevent complications, enhance survival, and improve quality of life. A combined approach is needed to reduce orthostatic hypotension, overcome urinary incontin- ence, alleviate gastrointestinal disturbances, and treat sexual dysfunction. The management of orthostatic hypotension is outlined in Box 24.14.6 and Table 24.14.3; in individual disorders, modifi­ cation is needed. In intermittent autonomic disorders the treatment varies, depend­ ing on the pathophysiological processes. Advances in the recognition, understanding of the patho- physiological changes, and treatment of autonomic disorders continue to progress. This relates also to disorders resulting in damage to the autonomic nervous system, examples of which are provided next and considered under prognosis based on the natural history of the disorder and/​or possible interventional measures (Box 24.14.4). In spinal cord injury, the possibility of reversal has recently been raised, unlike pure autonomic failure and mul- tiple system atrophy. Autonomic involvement in familial amyloid polyneuropathy is usually relentless but can be halted by liver transplantation and possibly drugs, as can autonomic neur- opathy in diabetes mellitus. Autonomic deficits can be substanti­ ally reversed in some with an immune-​mediated autonomic neuropathy. 0 Noradrenaline (pg/ml) Adrenaline (pg/ml) SUPINE 500 400 600 200 100 Dopamine (pg/ml) TILT 300 600 500 400 300 200 100 0 600 500 400 300 200 100 0 DBH defn-2 DBH defn-1 PAF MSA Controls DBH defn-2 DBH defn-1 PAF MSA Controls DBH defn-2 DBH defn-1 PAF MSA Controls * * * * Fig. 24.14.6  Plasma noradrenaline, adrenaline, and dopamine concentrations (measured by high-​performance liquid chromatography) in normal individuals (controls), patients with multiple system atrophy (MSA), patients with pure autonomic failure (PAF), and two individual patients with dopamine β-​hydroxylase deficiency (DβH defn) while supine and after head-​up tilt to 45° for 10 min. The asterisk indicates levels below the detection limits for the assay, which are less than 5 pg/​ml for noradrenaline and adrenaline and less than 20 pg/​ml for dopamine. Bars indicate ± standard error of the mean. Adapted from Mathias CJ, Low DA, Bannister R (2013). Investigation of autonomic disorders. In: Mathias CJ, Bannister R (eds) A Textbook of Clinical Disorders of the Autonomic Nervous System, 5th edition. Oxford University Press, Oxford. Box 24.14.6  Outline of non​pharmacological and pharmacological measures in the management of postural hypotension due to neurogenic failure Non​pharmacological measures To be avoided • Sudden head-​up postural change (especially on waking) • Prolonged recumbency • Straining during micturition and defecation • High environmental temperature (including hot baths) • ‘Severe’ exertion • Large meals (especially with refined carbohydrate) • Alcohol • Drugs with vasodepressor properties To be introduced • Head-​up tilt during sleep • Small, frequent meals • High salt intake • Judicious exercise (including swimming) • Body positions and manoeuvres To be considered • Water ingestion • Elastic stockings • Abdominal binders Pharmacological measures • Starter drug—​fludrocortisone • Sympathomimetics—​ephedrine, midodrine or DL-​DOPS/​L-​DOPS • Specific targeting—​octreotide, desmopression, or erythropoietin Adapted from Mathias et al. (2013). section 24  Neurological disorders 6158 Individual autonomic disorders Primary autonomic failure The onset is usually slow and insidious in chronic autonomic failure, unlike the acute/​subacute dysautonomias. Chronic autonomic failure The most common of these disorders is multiple system atrophy where there is additional neurological disease, unlike pure auto- nomic failure. Patients are usually middle-​aged at presentation, although with increasing awareness, it is being diagnosed in younger patients. In pure autonomic failure, diagnosis is usually considered be- cause of orthostatic hypotension. Nocturia (rather than incon- tinence) is frequent, presumably because fluid shifts from the peripheral to the central compartment, elevates blood pressure and improves renal perfusion. Constipation often occurs. In temperate climates, hypohidrosis may not be recognized, unlike tropical areas where heat intolerance and collapse may occur. In men, impotence is common. The clinical and laboratory findings indicate wide- spread sympathetic failure, usually with parasympathetic deficits. Physiological and biochemical tests, along with limited neuropatho- logical data, indicate a peripheral autonomic lesion. Management is directed predominantly towards reducing orthostatic hypotension. Although recovery does not occur, the overall prognosis in pure autonomic failure is good. Multiple system atrophy is a non​familial and sporadic disorder with autonomic features and additional neurological (parkinsonian, cerebellar, and pyramidal) features (see Box 24.14.7) that occur at any stage and in any combination, in an unpredictable manner. Thus, patients may initially consult a range of specialists. It is ran- domly progressive, which adds to difficulty in diagnosis. It is syn- onymous with Shy–​Drager syndrome, the former name. In multiple system atrophy, the additional neurological fea- tures are predominantly parkinsonian; in a smaller number they are cerebellar and, as the disease advances, there is usually a mix- ture of features (Fig. 24.14.7). The neuropathological findings include striatonigral degeneration in multiple system atrophy (parkinsonian) and olivopontocerebellar degeneration in multiple system atrophy (cerebellar), with both changes often seen in ei- ther form. There is cell loss in various brain-​stem nuclei (including the vagal nuclei), in the intermediolateral cell mass in the thoracic and lumbar spinal cord, and in Onuf’s nucleus in the sacral spinal cord, which accounts for the various autonomic and allied abnor- malities. The paravertebral ganglia and visceral (enteric) plexus are spared. A specific feature is the presence of intracytoplasmic, argyrophilic, oligodendrocyte inclusion bodies, within the brain and spinal cord. Many patients with multiple system atrophy have parkinsonian features and distinguishing multiple system atrophy Table 24.14.3  Drugs used in the treatment of orthostatic hypotension Site of action Drugs Predominant action Plasma volume: expansion Fludrocortisone Mineralocorticoid effects—​increased plasma volume Sensitization of α-​adrenoreceptors Kidney: reducing diuresis Desmopressin Vasopressin2-​receptors on renal tubules Vessels: vasoconstriction (adrenoceptor mediated) Ephedrine Indirectly acting sympathomimetic Resistance vessels Midodrine,a phenylephrine, methylphenidate Directly acting sympathomimetics Tyramine Release of noradrenaline Clonidine Postsynaptic α2-​adrenoceptor agonist Yohimibine Presynaptic α2-​adrenoceptor antagonist DL-​DOPS and L-​DOPS Prodrug resulting in formation of noradrenaline Capacitance vessels Dihydroergotamine Direct action on α-​adrenoceptors Vessels: vasoconstriction (non​adrenoceptor mediated) Triglycyl-​lysine-​vasopressin (glypressin) Vasopressin1-​receptors on blood vessels Vessels: prevention of vasodilatation Propranolol Blockade of β2-​adrenoceptors Indomethacin Prevents prostaglandin synthesis Metoclopramide Blockade of dopamine receptors Vessels: prevention of postprandial hypotension Caffeine Blockade of adenosine receptors Octreotide Inhibits release of vasodilator gut/​pancreatic peptides Acarbose, voglibose Intestinal α-​glucosidase inhibitors Enhancing sympathetic ganglionic transmission Pyridostigmine Acetylcholine esterase inhibition Heart: stimulation action Pindolol, xamoterol Intrinsic sympathomimetic Red cell mass: increase Erythropoietin Stimulates red cell production a Through its active metabolite. Adapted from Mathias CJ, Iodice V, Low DA, Bannister R (2013). Clinical features and evaluation of the primary chronic autonomic failure syndromes. In: Mathias CJ, Bannister R (eds) A Textbook of Clinical Disorders of the Autonomic Nervous System, 5th edition. Oxford University Press, Oxford. 24.14  Diseases of the autonomic nervous system 6159 from idiopathic Parkinson’s disease, especially in the early stages, is difficult. Thus, the true prevalence and incidence of multiple system atrophy are not known. At post-​mortem examination, up to a quarter of patients previously considered to have Parkinson’s disease have the characteristic neuropathological features of multiple system atrophy. In multiple system atrophy (parkinsonian), bradykinesia and rigidity are often bilateral, with minimal or no tremor, unlike Parkinson’s disease; however, this may not be a useful discrimin- ator in an individual. Lack of a motor response to l-​dopa is not indicative of multiple system atrophy, because two-​thirds respond initially, although refractoriness and side effects eventually reduce the benefit. The presence of autonomic failure (especially ortho- static hypotension) and unexplained genitourinary symptoms with sphincter disturbance should alert one to the possibility of mul- tiple system atrophy in patients with parkinsonian or cerebellar signs. Oropharyngeal dysphagia and respiratory abnormalities fa- vour multiple system atrophy, although these often occur later. The combination of cardiovascular autonomic failure and an abnormal urethral/​anal sphincter electromyogram, with characteristic clin- ical features, are virtually confirmatory of multiple system atrophy. Additional evaluation includes neuroimaging studies using MRI, positron emission tomography, and proton magnetic resonance spectroscopy of the basal ganglia, which are abnormal, at least in established cases. Clonidine growth hormone testing, based on α2-​adrenoceptor stimulation of the hypothalamus with release of human growth hormone-​releasing factor, distinguishes central from peripheral autonomic failure and separates Parkinson’s dis- ease from multiple system atrophy (Fig. 24.14.8); whether this is the case in the early stages of parkinsonism and in patients on dopaminergic agents (which are growth hormone secretagogues) remains to be resolved. The prognosis in multiple system atrophy is poor compared with idiopathic Parkinson’s disease and pure autonomic failure. Akinesia and rigidity often worsen, with increasing refractoriness and side effects (including orthostatic hypotension) from antiparkinsonian therapy. As the disease advances there is often considerable immo- bility and difficulty in communication. In multiple system atrophy (cerebellar), worsening truncal ataxia causes falls and an inability to stand upright; orthostatic hypotension compounds the disabilities. Box 24.14.7  Investigations in autonomic failure Cardiovascular Physiological • Head-​up tilt, standing; Valsalva manoeuvre • Pressor stimuli: isometric exercise, cutaneous cold, mental arithmetic • Heart rate responses:  deep breathing, hyperventilation, standing, head-​up tilt • Liquid meal challenge • Exercise testing • Carotid sinus massage • Situational orthostasis—​cervical and head movements, arm movements • 24-​h ambulatory blood pressure and heart rate monitoring using the autonomic protocol Biochemical • Basal plasma noradrenaline, adrenaline, and dopamine levels • Plasma noradrenaline: supine and standing • Urinary catecholamines Pharmacological • Noradrenaline—​α-​adrenoceptors, vascular • Isoprenaline—​β-​adrenoceptors, vascular and cardiac • Tyramine—​pressor and noradrenaline response • Edrophonium—​noradrenaline response • Clonidine—​stimulation (for growth hormone response) and suppres- sion (of plasma noradrenaline and adrenaline) • Atropine—​heart rate response Sweating • Thermoregulatory: increase core temperature by 1 °C • Sweat gland response to intradermal acetylcholine • Sympathetic skin response Gastrointestinal • Barium studies, videocinefluoroscopy, endoscopy, gastric-​emptying studies, anal sphincter electromyography Renal function and urinary tract • Day and night urine volumes and sodium/​potassium excretion • Urodynamic studies, intravenous urography, ultrasound examination, urethral sphincter electromyography Sexual function • Penile plethysmography • Intracavernosal papaverine • Ultrasound examination Respiratory • Laryngoscopy • Sleep studies to assess apnoea/​oxygen desaturation Eye • Lacrimal function: Schirmer’s test • Pupillary function: pharmacological and physiological From Mathias and Bannister (2013). P C M PAF PD PD+AF PSP LBD Autonomic Parkinsonian Cerebellar/ Pyramidal Dementia MSA Fig. 24.14.7  The major clinical features in parkinsonian syndromes and in allied disorders with autonomic failure. These include the three major neurological forms of multiple system atrophy—​the parkinsonian form (MSA-​P, also called striatonigral degeneration), the cerebellar form (MSA-​ C, also called olivopontocerebellar atrophy), and the multiple or mixed form (MSA-​M, which has features of both other forms)—​pure autonomic failure (PAF), idiopathic Parkinson’s disease (IPD), Parkinson’s disease with autonomic failure (PD + AF), progressive supranuclear palsy (PSP), and diffuse Lewy body disease (LBD). Adapted from Bannister R, Iodice V, Vichayanrat E, Mathias CJ (2013). Clinical features and evaluation of the primary chronic autonomic failure syndromes. In: Mathias CJ, Bannister R (eds) A Textbook of Clinical Disorders of the Autonomic Nervous System, 5th edition. Oxford University Press, Oxford, and Iodice V, Low DA, Vichayanrat E, Mathias CJ (2012). Cardiovascular autonomic dysfunction in Parkinson’s disease and parkinsonian syndromes. In: Ebadi M, Pfeiffer RF, Wszolek ZK (eds) Parkinson’s Disease, 3rd edition. CRC Press, Florida. section 24  Neurological disorders 6160 Incoordination of the upper limbs, speech defects, and nystagmus result in further disabilities. Respiratory complications include obstructive apnoea (caused by laryngeal abductor cord paresis), and central apnoea may necessi- tate tracheostomy. Oropharyngeal dysphagia enhances the risk of aspiration, especially when vocal fold paresis is present; a percutan- eous feeding gastrostomy may be needed. Urinary bladder dysfunc- tion is distressing, and its management, together with management of constipation and, if appropriate, treatment of sexual dysfunc- tion is important in improving quality of life. There is often a need for specialist therapists, including speech and language therapists, physiotherapists, dietitians, and occupational therapists. As the neurological decline is inexorable, supportive therapy is crucial in management of multiple system atrophy, and should incorporate the family, carers, and community along with the primary care medical practitioner and therapists. Orthostatic hypotension and other features of autonomic failure appear more common in Parkinson’s disease than previously thought. A current hypothesis places non​motor lesions in the ol- factory and brain-​stem areas, including vagal nuclei, before onset of parkinsonian features. In Parkinson’s disease the autonomic lesions appear peripheral and thus similar to pure autonomic failure. This is based on low basal plasma noradrenaline levels, and radionuclide and positron emission tomography studies, which indicate cardiac postganglionic sympathetic denervation. This is distinct from mul- tiple system atrophy where the lesions are preganglionic. Orthostatic hypotension and autonomic failure may precede the motor and cog- nitive decline in diffuse Lewy body disease. Acute/​subacute dysautonomias These disorders are relatively rare and consist of three main var- ieties: pure pandysautonomia (with features of both sympathetic and parasympathetic failure); pandysautonomia with additional neuro- logical features usually indicative of a peripheral neuropathy; and pure cholinergic dysautonomia. The prognosis in pandysautonomias is variable, with substantial recovery in some. Recovery after im- munoglobulin therapy favours an immunological basis, and the pos- sibility of a Guillain–​Barré syndrome variant. In pure cholinergic dysautonomia, described mainly in children and young adults, there is widespread parasympathetic failure with blurred vision, dry eyes, xerostomia, dysphagia with middle and lower oesophagus involve- ment, severe constipation, and urinary retention. Clinical findings include dilated pupils, an elevated heart rate, dry and warm skin, a distended abdomen, and a palpable urinary bladder. Anhidrosis may result in hyperthermia. The term ‘cholinergic’ is used because both parasympathetic and cholinergic sympathetic pathways (to sweat glands) are affected. Sympathetic vasoconstrictor function is preserved and orthostatic hypotension does not occur. Recovery is poor, but the prognosis is good if the condition is de- tected early. Management includes supportive therapy and adequate fluid and nutrient replacement of losses due to gastrointestinal and sudomotor failure. Barium studies should be avoided because contrast medium accumulates in the atonic colon. The differential diagnosis includes exposure to drugs, poisons, and toxins with anti- cholinergic effects. Similar autonomic features occur in thorn apple (Datura stramonium) seed poisoning; the poisoning is associated with hallucinations, hyperreflexia, and clonic jerking movements, and recovery occurs in a few days. Botulism B affects cholinergic systems but spares motor systems, and substantial recovery is ex- pected within 3 months of exposure. Secondary disorders Many disorders are associated with autonomic failure; a few are described here. Riley–​Day syndrome (familial dysautonomia) This is a recessive genetic defect characterized by absent lingual fungiform papillae, lack of corneal reflexes, absence of overflow emotional tears, decreased deep tendon reflexes, and a diminished response to pain and temperature; the disease occurs typically in children of Ashkenazi Jewish extraction. An abnormal intradermal histamine skin test (absent axon flare) and pupillary hypersensitivity to cholinomimetics provide diagnostic confirmation. Prenatal diag- nosis is possible with the genetic markers linked to chromosome 9 (b) 6 Growth hormone (mU/l) 22 20 18 16 14 Time (min) 12 10 8 4 2 0 12 11 10 9 8 7 6 5 4 3 2 1 0 Growth hormone (mU/l) −10 15 30 45 60 0 –10 15 30 45 60 0 Time (min) IPD (n = 14) MSA-C (n = 16) Parkinsonian MSA (n = 15) Controls (n = 27) PAF (n = 19) MSA (n = 31) (a) Fig. 24.14.8  (a) Serum growth hormone (GH) concentrations before (0) and at 15-​min intervals for 60 min after clonidine (2 µg/​kg per min) in normal individuals (controls), and in patients with pure autonomic failure (PAF) and multiple system atrophy (MSA). GH concentrations rise in controls and in patients with PAF with a peripheral lesion; there is no rise in patients with MSA with a central lesion. (b) Lack of serum GH response to clonidine in MSA (the cerebellar form and the parkinsonian forms) in contrast to patients with idiopathic Parkinson’s disease with no autonomic deficit (IPD), in whom there is a significant rise in GH levels. (a) From Thomaides T et al. (1992). The growth hormone response to clonidine in central and peripheral primary autonomic failure. Lancet 340, 263–​6. Copyright © 1992, with permission from Elsevier. (b) From Kimber JR, Watson L, Mathias CJ (1997). Distinction of idiopathic Parkinson’s disease from multiple system atrophy by stimulation of growth hormone release with clonidine. Lancet 349, 1877–​81. Copyright © 1997, with permission from Elsevier. 24.14  Diseases of the autonomic nervous system 6161 (q31). Autonomic underactivity and overactivity include lability of blood pressure (hypertension and orthostatic hypotension), inter- mittent hyperhidrosis, periodic vomiting, dysphagia, constipation, and diarrhoea. The neurological abnormalities include emotional and behavioural disturbances, and sensory deficits that result in in- jury to skin and joints. Skeletal problems (scoliosis), and respira- tory (aspiration) and renal failure contribute to a poor prognosis. Anticipation of complications and adequate therapy have extended survival into adulthood. Amyloid neuropathy Deposition of amyloid into autonomic nerves can occur in reactive systemic (AA) amyloidosis (in chronic inflammatory disorders) or in immunoglobulin light chain (AL) amyloidosis (with lymphomas). In familial amyloid polyneuropathy the sensory, motor, and autonomic abnormalities result from deposition in peripheral nerves of mu- tated variant transthyretin, produced mainly in the liver. Symptoms of a sensory and motor neuropathy often begin in adulthood in the lower limbs in Portuguese, Japanese, and Swedish forms (familial amyloid polyneuropathy I), and in the upper limbs in Indian/​Swiss and German/​Maryland forms (familial amyloid polyneuropathy II). These and other forms are now classified by the chemical and molecular nature of abnormal fibrillary protein, immunologically related to transthyretin. The most common is based on the first point mutations in the transthyretin gene associated with familial amyloid polyneuropathy—​methionine-​30 in the Portuguese form. The cardiovascular, gastrointestinal, and urinary systems are af- fected at variable stages, with the disease progressing relentlessly. Autonomic symptoms and signs may be dissociated, leading to underrecognition of the autonomic deficit. Liver transplantation re- duces variant transthyretin levels and prevents progression of neur- opathy. Its ability to reverse neuropathy is unclear, emphasizing the need for intervention before nerve damage occurs. Dopamine β-​hydroxylase deficiency This rare disorder (with 14 patients reported, 2 of whom are siblings) was recognized in the mid-​1980s. Enzymatic deficiency probably occurs at birth but presentation is often in childhood. Orthostatic hypotension has been the clue to recognition. The clinical features indicate sympathetic adrenergic failure, with sparing of sympathetic cholinergic and parasympathetic function; thus, sweating is pre- served, and urinary bladder and bowel functions appear normal. In men, erection is possible but ejaculation difficult to achieve. Basal levels of plasma noradrenaline and adrenaline are undetectable but dopamine is abnormally elevated. Sympathetic nerve terminals, ex- cept for the enzymatic and functional defect, are otherwise intact, as demonstrated by electron microscopy, immunohistochemistry, and sympathetic microneurography. Effective treatment is with the prodrug l-​dihydroxyphenylserine (l-​DOPS), which is given by mouth. It has a structure similar to noradrenaline and is con- verted by the enzyme dopa-​decarboxylase (abundantly present in extraneuronal tissue such as liver and kidneys) to noradrenaline, thus bypassing the dopamine β-​hydroxylase deficiency and re- placing the deficient neurotransmitter (see Fig. 24.14.2a). L-​DOPS has been successfully used in such patients and has transformed their lives. It has also been used successfully in orthostatic hyper- tension due to pure autonomic failure, multiple system atrophy, and Parkinson’s disease. Diabetes mellitus In patients with long-​standing diabetes, especially those on insulin, there is a high incidence of peripheral and autonomic neuropathy. Vagal denervation occurs earlier, impairing heart rate variability. Reduced sympathetic activity (e.g. in the feet), may increase blood flow substantially at an early stage before detection of neuropathy. Orthostatic hypotension may be enhanced by insulin. There may be sweating abnormalities (gustatory sweating), delayed stomach emptying (gastroparesis diabeticorum), impaired urinary bladder function (diabetic cystopathy), and impotence. Diarrhoea may be extremely distressing. Spinal cord injuries Autonomic dysfunction affecting many systems occurs in spinal injuries, depending on the lesion level and the degree of complete- ness. Cardiovascular dysfunction may be life-​threatening, espe- cially in high lesions in the acute phase of spinal shock, because lack of sympathetic activity with increased vagal tone may cause bradycardia and cardiac arrest (Fig. 24.14.9). After a few weeks, spinal shock passes and isolated spinal reflex activity returns; in cervical and high thoracic lesions, abnormal spinal activation re- sults in the syndrome of autonomic dysreflexia. This is induced by cutaneous, skeletal muscle, or visceral stimuli (not necessarily nox- ious) below the level of the lesion. Thus, severe muscle spasms, an anal fissure, or a blocked urethral catheter can result in paroxysmal hypertension (due to increased spinal sympathetic nerve activity, independent of normal cerebral pathways) with associated brady- cardia (because of preserved baroreceptor afferents and vagal ef- ferent pathways—​Fig. 24.14.10). Patients with lesions below T6 are typically spared. Patients with high lesions are also prone to ortho- static hypotension, which compounds difficulties in management, especially shortly after injury. Drugs Dysfunction may result from an autonomic neuropathy (as in- duced by alcohol, vincristine, and perhexiline maleate) or through pharmacological effects. The latter may be expected with the sym- patholytic agents, or may be a minor unexpected effect in suscep- tible individuals. An example is the anticholinergic bladder effects of disopyramide, which may cause urinary retention in patients with prostatic hyperplasia. A  variety of toxins and poisons, including mushroom toxicity and botulism, as well as nerve gases such as sarin, affect the autonomic nervous system. The first-​dose effect of angiotensin-​converting enzyme inhibitors and prazosin may be mediated by the Jarisch–​Bezold reflex. Autonomic overactivity may occur during withdrawal of clonidine, alcohol, and opiates. Intermittent autonomic dysfunction There is usually no damage to autonomic nerves and autonomic dys- function is often short-​lived. Autonomic (neurally) mediated syncope Syncope (fainting, loss of consciousness) may result from an inter- mittent and transient abnormality with increased cardiac parasympa- thetic (causing severe bradycardia, cardioinhibition) and/​or possibly sympathetic withdrawal (causing hypotensive vasodepression). The episodes may be cardioinhibitory, vasodepressor, or mixed section 24  Neurological disorders 6162 (Fig. 24.14.11). There are three major groups: vasovagal syncope, carotid sinus hypersensitivity, and situational syncope. Between epi- sodes, screening autonomic tests usually reveal no abnormalities. The most common disorder is vasovagal syncope. This is often fa- milial and more likely in females; it may present in the early teenage years and is induced by stimuli such as the sight of blood, pain, nee- dles, and at times even discussion of venepuncture. Hypotension is more likely in the upright position and may occur while standing still, especially in warm weather, and with salt and fluid depletion. Testing includes head-​up tilt, which sometimes may need to be prolonged for about 45 minutes, or with introduction of a provoca- tive stimulus such as venepuncture, cervical or arm movements, ideally during head-​up tilt. A variety of physiological (head-​up tilt plus lower body negative pressure) or pharmacological (isopren- aline infusions or glyceryl trinitrate) stimuli have been used to un- mask an episode, but may result in false-​positive results. Cardiac conduction disorders and other causes of syncope (neurological or metabolic) should be excluded. Treatment includes reducing or preventing exposure to precipitating causes and behavioural psy- chotherapy in patients with phobias. Added salt, fluid repletion, and physical conditioning are often useful. Techniques to increase sympathetic activity and maintain or raise blood pressure (such as sustained hand grip) and to prevent pooling (calf muscle activation) are helpful, especially in patients who have a warning window of symptoms before syncope. Sitting down, or lying flat, with the legs raised should prevent most episodes. Drugs such as fludrocortisone and vasopressor agents (ephedrine and midodrine) can be benefi- cial. Antidepressants such as the serotonin selective reuptake inhibi- tors (SSRIs) have been used with equivocal results. β-​Adrenergic blockers provide no benefit for younger patients in most cases. The long-​term prognosis is favourable. In older people, carotid sinus hypersensitivity is increasingly rec- ognized, especially in those with falls of otherwise unknown cause (Fig. 24.14.12). A classic history of syncope induced by head move- ments or collar tightening may be provided, although in many the precipitating factors are unclear. Carotid sinus massage should be performed in the laboratory with the requisite precautions, ideally using continuous blood pressure and heart rate recordings, with the patient also tilted head up, because hypotension is more likely to occur when sympathetic activation is needed. Treatment, especially of the cardioinhibitory forms, includes a cardiac demand pace- maker; vasodepressor forms may require pressor agents. Surgical denervation of the carotid sinus has been used successfully, espe- cially where unilateral hypersensitivity occurs. A variety of other stimuli, acting through short-​lived autonomic mechanisms, can also cause syncope, considered under situational BP (mmHg) HR (beats/min) Plasma NA and A (ng/ml) Time (min) IVP (mmHg) 200 0 100 0 100 0 0.20 0.00 Bladder stimulation Fig. 24.14.10  Blood pressure (BP), heart rate (HR), intravesical pressure (IVP), and plasma noradrenaline (NA) and adrenaline (A) concentrations in a tetraplegic patient before, during, and after bladder stimulation induced by suprapubic percussion of the anterior abdominal wall. The rise in BP is accompanied by a fall in heart rate as a result of increased vagal activity in response to the rise in blood pressure. The level of plasma noradrenaline (open histograms), but not adrenaline (filled histograms), rises, suggesting an increase in sympathetic neural activity independent of adrenomedullary activation. From Mathias CJ, Frankel HL (1986). The neurological and hormonal control of blood vessels and heart in spinal man. J Autonom Nervous Syst Suppl, 457–​64. (a) BP (mm Hg) Time (min) HR (beats/min) 200 0 100 6 h post atropine (0.6 mg IV) Off respirator Atropine 0.6 mg IV (b) 20 min post atropine (0.6 mg IV) Off respirator for suction 0 Time (min) BP (mm Hg) HR (beats/min) 200 0 0 100 Fig. 24.14.9  (a) The effect of disconnecting the respirator (as required for aspirating the airways) on the blood pressure (BP) and heart rate (HR) of a recently injured tetraplegic patient (C4–​5 lesion) in spinal shock, 6 h after the last dose of intravenous atropine. Sinus bradycardia and cardiac arrest (also observed on the electrocardiogram) were reversed by reconnection, intravenous atropine, and external cardiac massage. (b) The effect of tracheal suction 20 min after atropine. Disconnection from the respirator and tracheal suction did not lower either heart rate or blood pressure. (a) From Frankel HL, Mathias CJ, Spalding JMK (1975). Mechanisms of reflex cardiac arrest in tetraplegic patients. Lancet 2, 1183–​5. Copyright © 1975, with permission from Elsevier. (b) From Mathias CJ (1976). Bradycardia and cardiac arrest during tracheal suction—​mechanisms in tetraplegic patients. European Journal of Intensive Care Medicine 2, 147–​56. Copyright © 1976, Springer-​Verlag, with permission of Springer. 24.14  Diseases of the autonomic nervous system 6163 0 140 0 160 VENEPUNCTURE Blood pressure (a) (b) (c) mm Hg Heart rate bpm 60° HEAD-UP TILT Blood pressure mm Hg 60° HEAD-UP TILT START OF PRE-SYNCOPAL SYMPTOMS 0 140 0 160 Heart rate bpm 0 120 0 110 Heart rate bpm Blood pressure mm Hg 60° HEAD-UP TILT Fig. 24.14.11  Blood pressure and heart rate with continuous recordings in (a) a patient with the mixed (cardioinhibitory and vasodepressor) form of vasovagal syncope. (b) in a patient with the predominantly vasodepressor form of vasovagal syncope. (c) in a patient with the cardioinhibitory form of vasovagal syncope. In: Jameson JL, De Groot LJ (eds) (2015). Endocrinology, 7th edition, Elsevier, Philadelphia, PA. Copyright © 2016, with permission from Elsevier. section 24  Neurological disorders 6164 syncope. This may be together with factors such as heat or drugs that cause vasodilatation or reduce intravascular volume, thus increasing the tendency to hypotension and syncope. Examples include syn- cope associated with glossopharyngeal neuralgia (caused by swal- lowing), or induced by micturition, defecation, coughing, laughing, and playing wind instruments. Postural tachycardia syndrome Postural tachycardia syndrome is a poorly understood but important cause of orthostatic intolerance resulting from cardiovascular autonomic dysfunction. The onset might be linked to infection, trauma, surgery, or stress. Symptoms, which usually occur when standing and can be exacerbated by common stimuli in daily life, including modest exertion, food ingestion, heat, and time of day (morning), and appear to disrupt lives almost disproportionately. There is a substantial rise in heart rate (over 30 beats/​min or to 120 beats/​min or higher) without orthostatic hypotension, hence the term ‘postural (orthostatic) tachycardia syndrome’, or pos- tural tachycardia syndrome (Fig. 24.14.13). Syncope may occur. Cognitive dysfunction can occur. Proposed pathophysiological Left carotid sinus hypersensitivity Blood pressure mm Hg Heart rate bpm 160 0 LEFT CAROTID SINUS MASSAGE 120 0 Fig. 24.14.12  Continuous blood pressure and heart rate measured non​invasively in a patient with falls of unknown aetiology. Left carotid sinus massage caused a fall in both heart rate and blood pressure. The findings indicate the mixed (cardioinhibitory and vasodepressor) form of carotid sinus hypersensitivity. 0 200 0 140 0 200 0 140 10 MIN OF 60° HEAD UP TILT 10 MIN OF 60° HEAD UP TILT PoTS Normal Heart rate bpm Blood pressure mm Hg Heart rate bpm Blood pressure mm Hg Fig. 24.14.13  Blood pressure and heart rate measured continuously before, during, and after 60° head-​up tilt in a normal person (upper panel), and in a patient with the postural tachycardia syndrome (PoTS) (lower panel). Adapted from Mathias et al. (2012). 24.14  Diseases of the autonomic nervous system 6165 mechanisms include alterations in neural control, humoral factors, vascular properties, and intravascular volume, as well as physical deconditioning. Associated disorders include a partial autonomic neuropathy, chronic fatigue syndrome, mitral valve prolapse, mast cell activation disorder, and hyperventilation. A  rare gen- etic noradrenaline transporter deficit, or drugs, may be causative. A common association is with some of the classifications of Ehlers- Danlos syndromes, e.g., Hypermobile EDS (type 3 hEDS). The rela- tionship of postural tachycardia syndrome to previously considered psychosomatic disorders, such as soldier’s heart or da Costa’s syn- drome, remains unclear. Investigation should include evaluating potential causes and asso- ciated factors, which is an integral part of determining the patho- physiological processes involved to aid management. A multifactorial and individualized treatment strategy that includes pharmacological agents as well as non​pharmacological measures and interventions is often required. Other factors, including underlying and associated disorders, are also essential to consider. Non​pharmacological meas- ures include those as used in autonomic mediated syncope, such as salt and fluid repletion and graded exercise. In those with a low supine blood pressure, drugs to raise blood pressure may be used. These may include fludrocortisone, ideally in low doses to avoid adverse effects, such as a low plasma potassium level. It should not be used in patients with a tendency to retain fluid. A vasoconstrictor such as midodrine is often of value. Vasoconstrictors that increase heart rate, such as ephedrine, must be avoided. Cardioselective β-​adrenergic blockers have a role, but not when the tachycardia is in response to vascular pooling when upright. The selective sinus node blocker, ivabradine, may have a role in reducing tachycardia. In patients with postural tachycardia syndrome who have a normal or elevated supine blood pressure, fludrocortisone and midodrine should not be used. In patients who experience marked postprandial features, especially those in whom other treat- ments have been ineffective, subcutaneous octreotide can be bene- ficial in small doses. SSRIs have been used with mixed results. With appropriate management, the prognosis of postural tachycardia syn- drome is favourable. Spontaneous recovery may occur in some. Initial orthostatic hypotension Initial orthostatic hypotension is defined as a transient fall in blood pressure (>40 and >20 mm Hg systolic and diastolic, respectively) within 15 s after standing, accompanied by symptoms of cerebral hypoperfusion. This phenomenon is separated from orthostatic hypotension by its short duration—​between 20 and 30 s—​and a subsequent recovery of blood pressure to preorthostatic levels; it may cause a variety of posturally induced symptoms and even syncope or presyncope. The pathophysiological mechanisms in- clude a mismatch between cardiac output and vascular resistance resulting from an impaired calf muscle pump, rapid vasodilation, or activation of cardiopulmonary mechanoreceptors in response to increasing right atrial pressure leading to sudden sympathetic neural withdrawal. Management should include advice on non-​ pharmacological measures, including techniques to enhance sym- pathetic activity to raise blood pressure and prevent pooling, such as the use of isometric hand exercise, leg crossing, and tensing of lower limb muscles prior to and during the assumption of the up- right posture (Fig. 24.14.4). Primary or essential hyperhidrosis Excessive sweating without an underlying cause (such as hyperthy- roidism, infection, etc.) may be familial or sporadic, and it may be lo- calized, involving areas such as the palms, axillae, soles of the feet, or the face. In some there is widespread sweating. It can be distressing and socially destructive. Factors that provoke sweating include stress, heat, and exercise. In primary hyperhidrosis, investigation reveals no underlying pathology or autonomic deficit. Treatment options include percutaneous surgical sympathectomy for upper limb and facial sweating; in some, after surgery a complication is compensatory hyperhidrosis in the innervated areas, which some find worse than the original problem; treatment is with low doses of clonidine and anticholinergics (such as probanthine), iontophor- esis for palmar and plantar sweating, and botulinum toxin injections for localized areas. Cognitive behavioural therapy and anxiolytics, including SSRIs, have a role. FURTHER READING Low PA, Bennarroch EE (eds) (2008). Clinical autonomic disorders, 3rd edition. Lippincott Williams & Wilkins, Baltimore, MD. Mathias CJ (2009). Autonomic dysfunction. In:  Clarke C, et  al. Neurology: a queen square textbook. pp. 871–​982. Wiley-​Blackwell, Oxford. Mathias CJ, Bannister R (2013). Autonomic failure:  a textbook of clinical disorders of the autonomic nervous system, 5th edition. Oxford University Press, Oxford. Mathias CJ, et al. (2012). Postural tachycardia syndrome—​current experience and concepts. Nat Rev Neurol, 8, 22–​34. Mathias CJ, et al. (2013). Autonomic dysfunction: recognition, diagno­ sis, investigation, management, and autonomic neurorehabilitation. Handb Clin Neurol, 110, 239–​53. Robertson D, et al. (2012). Primer on the autonomic nervous system, 3rd edition. Elsevier, Waltham, MA. 24.15 The motor neuron diseases 6166 Tom Jenkins, 24.15 The motor neuron diseases 6166 Tom Jenkins, Alice Brockington, and Pamela J. Shaw ESSENTIALS The motor neuron diseases can be considered an extended family of conditions with pathology affecting the lower and/​or upper motor neurons, leading to clinical features of limb and/​or bulbar weakness. Accurate diagnosis is essential to guide management, in particular, treatment options, any genetic implications, and prognosis. Amyotrophic lateral sclerosis is the family prototype and is a dif- fuse neurodegenerative disorder characterized by both upper and lower motor neuron cell death, causing progressive paralysis of limb, bulbar (speech and swallowing) and respiratory muscles, and re- sulting in death from respiratory failure. The cardinal clinical feature of combined upper and lower motor neuron signs in various body regions (bulbar, arms, trunk, legs) forms the basis for diagnostic cri- teria. There is no cure and the disease progresses relentlessly, with few patients surviving beyond 5 years from symptom onset. Several rarer motor neuron diseases affect either lower or upper motor neurons exclusively. The lower motor neuron syndromes include progressive muscular atrophy (a pure lower motor neuron variant of amyotrophic lateral sclerosis), various inherited spinal muscular atrophies, Kennedy’s disease (X-​linked recessive bulbospinal neuronopathy), Hirayama disease and, importantly, multifocal motor neuropathy with conduction block, which is treatable with intravenous immunoglobulin therapy. Upper motor neuron syndromes are the rarest forms of motor neuron disease and include primary lateral sclerosis (a pure upper motor neuron variant of amyotrophic lateral sclerosis), hereditary spastic para- paresis, and, especially in the developing world, the dietary spastic parapareses lathyrism and konzo. Diagnosis of motor neuron diseases is clinical, supported by electrophysiological examination and, in the case of amyotrophic lateral sclerosis, exclusion of mimics. Age of onset, family history, and rate of deterioration are important diagnostic clues. While most motor neuron diseases are incurable, many of the symptoms are treatable and optimally managed in a multidisciplinary clinic setting. In amyotrophic lateral sclerosis, recent discoveries, such as insights into TDP-​43 pathology and the identification of the C9orf72 gene are helping decipher the incompletely understood pathogenesis, leading to prospects of better therapies in the future. Introduction Motor neuron diseases result from death and dysfunction of lower motor neurons in the anterior horns of the spinal cord and brainstem and/​or upper motor neurons in the cerebral cortex and descending corticospinal tracts, leading to weakness of voluntary muscles in the bulbar region, limbs, and trunk. Clinical signs of lower motor neuron involvement are muscle wasting, fasciculation, and flaccid weakness; upper motor neuron dysfunction produces spasticity, clonus, hyperreflexia, extensor plantar responses, and a pyramidal pattern of weakness. The nomenclature can be confusing; the term ‘motor neuron dis- eases’ describes a family of related disorders within which there is an extensive differential diagnosis (Table 24.15.1), as outlined in this chapter. In the United Kingdom, the term ‘motor neuron dis- ease (MND)’ is used as an umbrella term to describe collectively amyotrophic lateral sclerosis (ALS) (with clinical evidence of both upper motor neuron (UMN) and lower motor neuron (LMN) in- volvement) and its rarer variants, progressive muscular atrophy, and primary lateral sclerosis. In the United States, the term ALS, or sometimes Lou Gehrig’s disease, often refers to motor neuron disease in general (i.e. encompassing ALS, progressive muscular at- rophy, and primary lateral sclerosis). In this chapter, we will use the UK term ‘MND’ to refer to the prototypical motor neuron disorder encompassing ALS, progressive muscular atrophy, and primary lat- eral sclerosis. Progressive bulbar palsy is used variably to refer to a subgroup of patients with MND with isolated bulbar symptoms, usually of pure LMN phenotype. Pseudobulbar palsy describes UMN bulbar weakness, often associated with emotional lability; it is seen in primary lateral sclerosis, ALS, and other conditions and does not imply a specific aetiology. Monomelic amyotrophy refers to a clinical syndrome of LMN arm weakness; aetiology should not be implied by this term, but it has been used interchangeably to refer to both Hirayama disease (discussed next) and ‘flail arm’ MND in the literature. ‘Flail leg’ MND is also described, a LMN-​ predominant syndrome restricted to the legs, and is also referred to as ‘pseudopolyneuritic variant’ in older literature. Diagnosis of the motor neuron diseases is predominantly clin- ical, and centred on the identification of upper and/​or lower motor neuron signs in various body regions. Electrophysiology is the 24.15 The motor neuron diseases Tom Jenkins, Alice Brockington, and Pamela J. Shaw 24.15  The motor neuron diseases 6167 most important supportive investigation; electromyography can be used to identify subclinical LMN involvement in MND (and contributes to diagnostic criteria), or to identify conduction block in demyelinating motor neuropathies, such as multifocal motor neuropathy with conduction block. Genetic testing is available for Kennedy’s disease, some forms of spinal muscular atrophy, her- editary spastic paraparesis, and familial MND. Motor neuron dis- eases are generally incurable but symptomatic treatment for many clinical features is available. Respiratory muscle weakness can now be treated with non​invasive intermittent positive pressure ventila- tion and has been shown to improve survival and quality of life in MND. In diseases with bulbar features, malnutrition can be treated by feeding via nasogastric or gastrostomy tube. Spasticity can be managed with baclofen, tizanidine, gabapentin, diazepam, or dantrolene, while walking aids, wheelchairs and arm supports can address inadequate limb function. Electronic communication de- vices have advanced significantly, and eye tracking software is now available for those with advanced disease. Citalopram, amitrip- tyline, and dextromethorphan/​quinidine may help with emotional lability, often a feature in patients with pseudobulbar palsy. Housing and workplace modifications can allow patients to maintain inde- pendence despite worsening disability. The motor neuron diseases, particularly MND, are a focus of in- tensive neuroscience research. Therapeutic discoveries from animal models and clinical research raise the prospect for new treatments in the foreseeable future. Table 24.15.1  Classification of the motor neuron diseases Disease Clinical features Aetiology Amyotrophic lateral sclerosis and its variants (collectively MND) Amyotrophic lateral sclerosis (ALS) UMN and LMN disease affecting limbs, trunk, and bulbar muscles 90–​95% sporadic; 5–​10% familial, usually AD: Causative genes include C9ORF72, SOD1, TDP43, FUS (and rarely, VAPB, DNCT1, ANG, CHMP2B, VCP, Alsin, SETX plus others outlined in Table 24.15.2) Progressive muscular atrophy (PMA) Pure LMN variant of ALS Primary lateral sclerosis (PLS) Pure UMN variant of ALS ALS–​FTD ALS associated with frontotemporal dementia Lower motor neuron syndromes Autosomal recessive spinal muscular atrophy (SMA) Proximal weakness with variable age of onset. Type I (Werdnig–​Hoffman) presents in infancy, type II (intermediate) in early childhood, type III (Kugelberg–​Welander) in late childhood, type IV: is adult onset AR inheritance due to mutations in SMN1 gene. Variable levels of expression of a similar gene (SMN2) influence age of onset and clinical severity Autosomal dominant SMA Rare adult-​onset proximal SMA with AD inheritance in a few Brazilian families AD inheritance due to mutations in the VAPB gene (this gene can also rarely cause typical and atypical ALS) Acute infantile SMA without SMN mutations Resembles SMN-​related disease, but with additional features (e.g. arthrogryphosis, contractures) Causative genes unknown Distal SMAs Group of disorders comprising distal weakness with diverse patterns of muscle involvement (e.g. upper limb predominant, lower limb predominant, scapuloperoneal, vocal cord paralysis) Genetically diverse: causative genes identified are GARS, BSCL2, IGHMBP2, HSP22, HSP27 X-​linked spinobulbar muscular atrophy (Kennedy’s disease) Slowly progressive LMN disease affecting limbs and bulbar muscles, usually in men, associated with gynaecomastia, testicular atrophy, and diabetes X-​linked inheritance, due to triplet repeat expansion of the androgen receptor gene Hereditary bulbar palsy of infancy and childhood Brown–​Vialetto–​van Laere syndrome is a progressive pontobulbar palsy with deafness; Fazio–​Londe syndrome is part of the same disease spectrum, without deafness AR disease due to mutations in C20ORF54, a homologue of the rat riboflavin transporter gene Hirayama disease Weakness and wasting of one or both arms (rarely legs reported too), usually affecting young men, without generalized weakness Sporadic, may be acquired Post-​polio syndrome Delayed progressive weakness in a limb previously affected by poliomyelitis Acquired Multifocal motor neuropathy with conduction block Multifocal slowly progressive muscle weakness, with minimal wasting, and conduction block on electrophysiology which responds to intravenous immunoglobulin Immune-​mediated acquired Upper motor neuron syndromes Hereditary spastic paraparesis Slowly progressive spastic paraparesis that may be pure, or complicated by other neurological features, such as epilepsy, dementia, amyotrophy, or peripheral neuropathy Genetically diverse; usually AD inheritance, but may be AR or X-​linked. Spastin mutations account for 40% of cases Dietary spastic parapareses Lathyrism and konzo are spastic parapareses caused respectively by consumption of chickling peas, and unprocessed cassava Acquired AD, autosomal dominant; ALS, amyotrophic lateral sclerosis; ANG, angiogenin; AR, autosomal recessive; BSCL2, Berardinelli–​Seip congenital lipodystrophy 2; CHMP2B, charged multivesicular body protein 2b; DNCT1, dynactin; FTD, frontotemporal dementia; FUS, fused in sarcoma; GARS, glycyl tRNA synthetase; HSP, heat shock protein; IGHMBP2, immunoglobulin mu-​binding protein 2; LMN, lower motor neuron; ORF, open reading frame; PLS, primary lateral sclerosis; PMA, progressive muscular atrophy; SETX, senataxin; SMA, spinal muscular atrophy; SMN, survival motor neuron; SOD1, superoxide dismutase 1; TDP43, TAR DNA binding protein-​43; UMN, upper motor neuron; VAPB, vesicle-​associated membrane protein-​associated protein B; VCP, valosin-​containing protein. section 24  Neurological disorders 6168 Amyotrophic lateral sclerosis ALS occurs worldwide, with an incidence of approximately 2/​100 000 population and a prevalence of 6/​100 000. It is more common in men and the incidence increases with advancing age, peaking at 64–​74 years. A family history of ALS is present in 5–​10% of pa- tients, with an autosomal dominant inheritance pattern in most fa- milial cases. Although familial disease presents on average a decade earlier, in individuals, it is indistinguishable clinically from sporadic ALS. There have been major recent advances in the understanding of the genetic basis of familial ALS (Table 24.15.2). The discovery of in- tronic hexanucleotide (GGGGCC) expansions in the C9ORF72 gene is of major significance as it accounts for up to 50% of cases of fa- milial ALS and approximately 7% of apparently sporadic cases (10% of ALS as a whole), by far the most prevalent gene to date, and has Table 24.15.2  Genetic subtypes of amyotrophic lateral sclerosis Common causes of adult-​onset autosomal dominant ALS Mutation Chromosome C9ORF72 Hexanucleotide repeat as an intronic expansion in chromosome 9 open reading frame 72 9p Discovered in 2011, and accounts for 40–​50% of familial cases. Patients with C9ORF72-​related ALS have a higher prevalence of frontotemporal dementia and the genotype also causes frontotemporal dementia without ALS. The function of this gene is currently unknown, though the encoded protein has been shown to be involved in the initiation of autophagy. SOD1 Missense mutations in Cu/​Zn superoxide dismutase 1 21q Discovered in 1993, and accounts for 20% of familial cases. SOD1 catalyses conversion of toxic superoxide anion radicals to hydrogen peroxide. SOD1 mutations damage cells by toxic gain of function with dysregulation of multiple cellular processes. The well-​characterized SOD1 mouse model has enhanced understanding of ALS, but SOD1 ALS has important differences to sporadic disease and most other familial forms, notably the absence of TDP-​43 cytoplasmic inclusions. TDP43 Missense mutations in TAR DNA binding protein-​43 1p Discovered in 2008, and accounts for about 3–​5% of familial cases. TDP43 is involved in multiple elements of RNA processing. FUS Missense mutations in fused in sarcoma 16q Discovered in 2009, and accounts for about 3% of familial cases. FUS also plays a role in RNA processing. Rare genetic causes of adult-​onset ALS • Mutations in the vesicle trafficking protein VAPB have been described in phenotypically variable ALS in Brazilian families. • The motor protein DCTN1 has shown mutations in a family with a lower motor neuron disease with vocal cord paralysis, and in some patients with ALS and frontotemporal dementia. • ANG is a hypoxia-​response protein that stimulates angiogenesis. Mutations in the ANG gene have been demonstrated in patients with ALS, largely with Scottish or Irish ancestry. • CHMP2B is a vesicle sorting protein originally identified in patients with frontotemporal dementia, and subsequently found in patients with ALS without dementia, who had a predominantly LMN phenotype. • VCP mutations were originally described in families with an unusual disorder—​inclusion body myopathy with early-​onset Paget’s disease and frontotemporal dementia—​and have recently been identified in an exome sequencing study, in 1–​2% of cases of familial ALS. • OPTN1, a causative gene in primary open angle glaucoma, interacts with NFKB. Two homozygous mutations in OPTN1 have been described in consanguineous families with ALS in Japan, and a third heterozygous mutation subsequently identified in non​consanguineous Japanese families with ALS. It has also rarely been identified in patients of European descent. • UBQLN2 mutations were identified in a large pedigree with an X-​linked dominant pattern of inheritance of ALS, and also in four further families. • SQSTM1 (p62) mutations were identified in 15 patients with familial and sporadic ALS, in a candidate gene screening study of 546 ALS patients. These variants were not found in normal controls, but linkage with the disease was not established. • FIG4 Screening of FALS and SALS cases initially identified nine variants, with six showing impaired function in yeast models. • ATXN2 Intermediate CAG repeats of 27–​33 in this gene show a strong association with MND. • SIGMAR1 Using homozygosity mapping, a missense mutation in this gene was found to cause autosomal recessive MND in a large consanguineous family. • PFN1 Exome sequencing initially identified two multigenerational families with mutations in this gene and further rare cases have subsequently been identified. • MATR3 Mutations in this gene which encodes an RNA/​DNA binding protein have been identifies in a few families with MND. • TUBA4A Exome sequencing has identified mutations in several families with ALS/​MND. Mutations lead to disrupted microtubule assembly and stability. • CHCHD10 Exome sequencing initially identified a mutation in a family with MND, FTD, ataxia, and myopathy. Subsequently several mutations were identified in FALS cases. The encoded protein localizes to mitochondria, but its function is unknown. • TBK1 encodes a protein which has a role in innate immunity, autophagy, and NFKB signalling. Mutations have been found in families with ALS, ALS–​FTD, and FTD. • ERBB4 Rare mutations have been described in Japanese and Canadian families. • hnRNPA1 A mutation has been identified in a single FALS case. Rare genetic causes of juvenile-​onset ALS • Slowly progressive juvenile-​onset ALS is inherited in a recessive manner in a few large consanguinous families in Northern Africa and the Middle East. Some of these cases are due to mutations in Alsin, a putative GTPase regulator. • A rare autosomal dominant juvenile-​onset ALS with slowly progressive amyotrophy and pyramidal signs is caused by missense mutations in SETX, a DNA/​RNA helicase. • SPG11 Mutations in spatacsin are a known cause of hereditary spastic paraparesis. Several families with autosomal recessive juvenile-​onset ALS have been identified with mutations in this gene. ALS, amyotrophic lateral sclerosis; ANG, angiogenin; ATXN2, ataxin 2; CAG, cytosine–​adenine–​guanine; CHCDHD10, coiled-​coil helix coiled-​coil helix domain containing protein 10; CHMP2B, charged multivesicular body protein 2b; DNCT1, dynactin; ERBB4, erb-​b2 receptor tyrosine kinase 4; FIG4, phosphoinositide 5-​phosphatase; FUS, fused in sarcoma; hnRNPA1, heterogeneous nuclear ribonuclear protein A1; LMN, lower motor neuron; MATR3, matrin 3; NFKB, nuclear factor kappa β; OPTN, optineurin; ORF, open reading frame; PFN1, profiling 1; SALS, sporadic amyotrophic lateral sclerosis; SETX, senataxin; SOD1, superoxide dismutase 1; SIGMAR1, sigma non​opioid intracellular receptor 1; SPG11, spastic paraplegia gene 11, spatacsin; SQSTM, sequestosome; TBK1, TANK-​binding kinase; TDP43, TAR DNA binding protein-​43; TUBA4A, tubulin-α 4 A; UBQLN, ubiquilin; VAPB V, vesicle-​ associated membrane protein-​associated protein B; VCP, valosin-​containing protein. 24.15  The motor neuron diseases 6169 sparked intense research into the normal function of the gene, as a po- tential clue to pathophysiology. The C9ORF72 mutation can also cause frontotemporal dementia (FTD), highlighting pathophysiological overlap between the two conditions. Genetic testing for C9ORF72, TDP-​43, FUS, and SOD1 mutations, which together account for ap- proximately 70% of familial cases of ALS, is now available in the clin- ical setting. The cause of ALS in the remainder of apparently sporadic cases is largely unknown. Several pathogenic processes have been im- plicated. The discovery of C9ORF72 suggests that genetic factors may play an important role even in apparently sporadic disease, and the pre- vious discovery of mutations in the ribonucleic acid (RNA) processing genes TDP43 and FUS in patients with familial ALS has focused at- tention on the importance of RNA splicing and processing to motor neuron survival. Motor neurons are large cells with high metabolic requirements, and mitochondrial dysfunction and oxidative stress are likely to be involved in their susceptibility to degeneration. They have numerous glutamatergic inputs, and are therefore vulnerable to excitotoxicity. Riluzole, the only effective disease-​modifying drug in ALS, has antiglutamate effects, supporting this hypothesis. Motor neurons have the longest axons of any human cell and some evidence suggests that the disease process begins at the distal axon, perhaps due to perturbed axonal transport and disruption of the cytoskeleton. Intracellular protein aggregation is a notable pathological feature of the disease, although it is not known whether this is damaging to the cell. A major component of the aggregated protein within motor neurons is TDP-​43 (except in SOD1 cases), which becomes mislocalized from its normal nuclear location into the cytoplasm. There has also been recent interest in the role of the interactions between motor neurons and glial cells and inflammatory events in the pathogenesis of the disease. Epidemiological studies designed to determine the effect of occupational exposures and lifestyle factors on the risk of developing ALS have often given inconsistent results. Cigarette smoking has been associated with a significantly increased risk of ALS. Many high-​ profile sportsmen have been afflicted by ALS, most notably the base- ball player Lou Gehrig, and most clinicians would recognize the slim, sporty phenotype of the ‘typical’ patient. There is increasing evidence from case-​control studies to support physical activity as a risk factor in susceptible individuals, but further population-​based studies are needed, and it remains unclear whether any associations are causative or co-​occur with an as-​yet uncharacterized risk profile. The current in- complete understanding of ALS pathophysiology represents the main barrier to developing effective treatment and is the focus of intense re- search interest worldwide. Pathology Lower motor neurons degenerate in clinically affected areas of the spinal cord and brain stem, and associated diffuse astrocytic gliosis occurs. Surviving neurons show intracellular inclusion bodies; ubiquitinated inclusions within which the mislocalized protein TDP-​43 is a major component are the most frequent and specific (Fig. 24.15.1). Other inclusion bodies, such as eosinophilic Bunina bodies and accumulations of neurofilaments, are also seen. Axonal loss and gliosis in the descending motor pathways gives rise to the lateral sclerosis, most prominent in the medulla and cervical spinal cord, which gives the disease its name. Changes in motor cortex are more variable, but, in cases with severe UMN involvement, Betz cells are depleted. There is relative sparing of Onuf’s nucleus in the sacral spinal cord, and the brainstem oculomotor nuclei, which explains why sphincter dysfunction and ophthalmoparesis, respectively, are not generally observed clinical features. It is now recognized that (a) (b) (c) Fig. 24.15.1  TDP43 immunostaining of the anterior horn of the spinal cord. (a) Normal motor neuron where TDP-​ 43 staining is predominantly in the nucleus. (b) Pathological motor neuron in a case of motor neuron disease. There is depletion of TDP-​43 from the nucleus and aggregation as a compact inclusion in the cytoplasm of the cell. (c) Skein-​like TDP-​43 inclusion in the cytoplasm of a spinal motor neuron from a case of motor neuron disease. section 24  Neurological disorders 6170 other populations of neurons can also degenerate in motor neuron disease even though this is not usually evident clinically. For example, changes in the cerebellum, basal ganglia and sensory areas have been identified in imaging studies and abnormalities of central and per- ipheral sensory pathways described in electrophysiological studies. However, for practical purposes of clinical diagnosis at least early on, ALS can still be considered a motor syndrome, sometimes with asso- ciated cognitive manifestations; up to 10% of patients develop overt frontotemporal dementia. More subtle cognitive impairment is evi- dent on detailed neuropsychological testing in a much higher pro- portion of patients. In the few patients who are treated with invasive ventilation after the onset of respiratory failure, the disease may be prolonged by many years and, in these patients, the ‘total manifest- ations’ of ALS are seen, with widespread pathological changes, dif- fuse cerebral atrophy, EEG slowing, and the end-​stage of a locked-​in syndrome. The lesson from these patients is that ALS is a generalized neurodegenerative disorder, in which the motor neurons are particu- larly vulnerable. A subgroup of patients with isolated frontotemporal dementia (FTD), without motor neuron degeneration, also demon- strate cortical ubiquitin-​only neuropathology (FTD-​U). The idea that this reflects a shared pathogenesis is supported by the identi- fication of mutations in several genes (in particular C9ORF72; also TDP43, CHMP2B, DCN1, VCP) in families with cosegregation of ALS and FTD. Pure ALS, ALS with cognitive impairment, ALS–​FTD, and pure FTD may therefore represent a continuous spectrum of ubiquitin-​associated neurodegenerative disease. Clinical features ALS typically begins focally, but then spreads to contiguous regions ‘like a bush fire’. Patients tend to present with symptoms in a single body region, bulbar, arm or leg in approximate thirds and respiratory in approximately 1%. With time, the disease usually generalizes and symptoms in multiple regions become apparent. The Awaji Shima and El Escorial research diagnostic criteria for ALS require evidence of both UMN and LMN signs in three of the four body regions for a definite diagnosis, with less extensive involvement categorized as probable or possible ALS. In routine clinical practice, most diagnoses are made at these earlier, incomplete stages. The spinal forms of ALS usually present with weakness of one limb, often evident as intrinsic hand muscle weakness or foot drop (Figs. 24.15.2 and 24.15.3). Asymptomatic involvement of other limbs, especially fascicula- tions, is often evident on examination. Wasted, fasciculating muscles with brisk or even retained reflexes are an ominous finding, espe- cially if present in the bulbar region or more than one body region. With progressive disease, patients become wheelchair or bed-​bound, or unable to use their arms for activities of daily living. Despite en- forced recumbency, curiously, pressure sores are relatively unusual. Bulbar involvement leads to weakness of the tongue, pharynx, and larynx and results in dysarthria, which almost invariably precedes dysphagia, with risk of aspiration pneumonia (Fig. 24.15.4). The tongue may exhibit LMN features of bulbar palsy (wasting, weak- ness, and fasciculations), UMN features of pseudobulbar palsy (spasticity, immobility with ‘hot potato’ speech, and a brisk jaw jerk) Fig. 24.15.3  Wasting of the lower limbs in a patient with amyotrophic lateral sclerosis. Involvement of tibialis anterior causing footdrop is typical. Fig. 24.15.4  Appearance of the tongue in a patient with bulbar-​onset amyotrophic lateral sclerosis. The tongue is wasted and spastic (this is the maximal extent of protrusion). Fig. 24.15.2  Wasting of the hands in a patient with amyotrophic lateral sclerosis. Prominent involvement of the first dorsal interosseus muscle is typical. 24.15  The motor neuron diseases 6171 or both. The presence of pseudobulbar palsy is associated with ‘emo- tional incontinence’; evidence of uncontrollable crying or laughter may be evident in clinic and is generally distinguishable as different from the understandable upset relating to diagnosis. Palatal move- ments are reduced. There may be weakness of neck extensors leading to ‘head-​drop’ and mild facial weakness. With progression of bulbar disease, patients may become anarthric. Some people choose tube feeding to prevent an intolerable situation of hunger that cannot be alleviated due to inadequate bulbar function. The cough becomes weak because of vocal cord paresis and weakness of expiratory muscles and this further increases aspiration risk. Weight loss is a common feature, can partly be attributed to bulbar dysfunction and muscle loss but also appears to reflect a direct hypermetabolic effect of the disease process. Weakness of the diaphragm and intercostal muscles almost invariably develops as the disease progresses. With the onset of respiratory failure, patients may complain of dyspnoea or orthopnoea, but more subtle symptoms are often earlier mani- festations, such as fragmented sleep, daytime somnolence, anorexia, and morning headaches due to nocturnal carbon dioxide retention. These symptoms may not be volunteered by patients and should be specifically sought, as they are treatable with non​invasive ventila- tion. However, eventually respiratory failure worsens and is the usual mode of death, at a median of 2–​3 years from first symptom onset. Clinical variants Although combined upper and lower motor neuron degeneration is the hallmark of classical ALS, a pure LMN variant—​progressive mus- cular atrophy—​and a pure UMN variant—​primary lateral sclerosis—​ are considered part of the same disease spectrum (i.e. MND) because they all demonstrate ubiquitinated pathology at autopsy. With disease progression, many of these patients will acquire clinical features of classical ALS. Patients that retain a pure LMN or, especially, UMN phenotype have a favourable prognosis compared with ALS. Prognosis ALS progresses relentlessly and is invariably fatal. Death com- monly results from ventilatory respiratory failure or aspiration pneumonia. Weight loss and malnutrition confer a worse prog- nosis. Median survival from first symptom onset in bulbar-​onset disease is 20 months and, in limb-​onset disease, 29 months. Fifteen per cent (15%) of patients with limb-​onset disease survive longer than 5 years. Occasional patients survive much longer. Prolonged survival is more unusual in bulbar-​onset disease. Differential diagnosis and investigation The diagnosis of ALS is usually evident on clinical grounds at presentation, which is often delayed, due to the insidious nature of onset. Electrophysiology is performed to confirm active and chronic denervation in multiple regions and to exclude poten- tially treatable mimics, such as demyelinating neuropathy, myop- athy, or myaesthenia gravis (the latter especially in patients with bulbar onset). Cranial and cervical imaging may be used to exclude structural brainstem pathology or coexistent myeloradiculopathy causing mixed UMN and LMN signs, but these are infrequently viable differential diagnoses in practice. We have seen patients with both tongue and laryngeal carcinoma masquerading as bulbar-​onset MND; such differentials can be identified on imaging but there are usually additional clinical clues. Sometimes UMN involvement is not clinically demonstrable; for example, patients may have ab- sent Babinski’s responses due to severely denervated toe extensor muscles. In these circumstances, diagnosis is more challenging, and generally patients with pure UMN or LMN syndromes require more extensive investigation. Unfortunately, electrophysiological central motor conduction studies are a less reliable marker of UMN in- volvement in such cases than had been anticipated, but assessment of cortical hyperexcitability on specialized transcranial magnetic stimulation protocols (Short Interval intraCortical Inhibition, SICI) shows promise. The usual diagnostic problem lies in differentiating ALS from other motor neuron diseases, In addition to pure LMN or UMN phenotype, other red flags for alternative diagnoses include a young age of onset, unusually slow progression, parental consan- guinity, or dysphagia preceding dysarthria. Fasciculations can be normal in athletes and benign cramp-​ fasciculation syndromes without evidence of weakness or de- nervation, usually affecting middle-​aged adults, do not evolve into motor neuron disease. It is usual to exclude hyperthyroidism, hypercalcaemia, and other metabolic derangements that can cause fasciculations in the work-​up of ALS. Multifocal motor neuropathy is an important differential of progressive muscular atrophy because it is treatable. There may be marked weakness but little wasting, pre- dominantly affecting the arms. Proximal conduction block can be difficult to identify on electrophysiology and lumbar puncture and a trial of intravenous immunoglobulin may be warranted in suspected cases. Kennedy’s disease, occurring in males is much more slowly progressive than ALS and causes a pure LMN syndrome, often asso- ciated with gynaecomastia. Chin fasciculations can be a clue. Genetic analysis of the androgen receptor gene should be performed in sus- pected cases. Inclusion body myositis can present with wasting and weakness, which is usually more symmetrical than in ALS. Finger flexors are often weak (in contrast they are often relatively spared in ALS) and creatine kinase (CK) levels may be elevated (although modest elevation in CK up to 1000 IU/​litre is not uncommon in ALS due to denervation). ALS as a paraneoplastic syndrome is highly controversial. Hexosaminidase deficiency (autosomal recessive GM2 gangliosidosis) can present a variable neurological picture, oc- casionally as a motor syndrome with LMN and, rarely, also UMN involvement. More commonly, there are additional features such as cerebellar ataxia or dementia. Hexosaminidase assays should be re- served for young and/​or atypical patients, particularly in those of Ashkenazi Jewish extraction. Giving the diagnosis Time is required because the news is devastating and patients and their families often have many difficult questions. A skilled clinician will convey the necessary hard truths about implications and prog- nosis while providing support and maintaining hope. Ongoing and active support following diagnosis is very important, and can be most effectively provided in specialist centres by a multidisciplinary team. Patients may also benefit from contact with specialist char- ities, such as the Motor Neurone Disease Association (MNDA) in the United Kingdom. Treatment Disease-​modifying therapy There is no cure for ALS. Riluzole, an antiglutamatergic agent, re- mains the only conclusively proven disease-​modifying therapy. section 24  Neurological disorders 6172 Pooled analysis of the four trials, including 974 riluzole-​treated pa- tients and 503 placebo-​treated patients, showed that 50 mg twice a day increased median survival from 11.8 to 14.8 months (p = 0.046). There were small beneficial effects on both bulbar and limb func- tion, but not on muscle strength. Riluzole is generally well tolerated by patients; nausea, gastrointestinal upset, and raised transaminase enzyme levels may occur but are often transient and self-​limiting. Clinical trials of many different agents including branched-​chain amino acids, dextromethorphan, total lymphoid irradiation, the free radical scavenger acetylcysteine, gabapentin, creatine, vitamin E, lithium, coenzyme Q10, olesoxime, pentoxyfilline, glatiramer acetate, dexpramipexole have all proven negative to date. Edaravone, a free radical scavenger, is approved in Japan and the USA, based on a small reduction in rate of deterioration of ALS functional rating scale scores in a selected patient sub-group. There was no effect on survival and the medication is not currently licensed for use in Europe. Symptomatic therapy In contrast to the limited disease-​modifying therapeutic options, much can be done to address symptoms, disability, and distress. A  multidisciplinary setting appears to improve survival in obser- vational studies and usually includes a neurologist, specialist nurse, respiratory, anaesthetic and gastroenterology expertise (for non​in- vasive ventilation and gastrostomy insertion), speech and language therapist, physiotherapist, occupational therapist, social worker, and links to palliative care medicine. Charities, such as the Motor Neuron Disease Association in the United Kingdom, are often able to facilitate equipment provision. Respiratory function can be monitored clin- ically, and through forced/slow vital capacity, noninvasive random capnography and capillary blood gases, and augmented by over- night oximetry and capnometry when necessary. Non​invasive ven- tilation (NIV), usually delivered overnight initially, has been shown to prolong survival by a median of 205 days, and to improve quality of life in ALS, at least in patients without severe bulbar dysfunction. Diaphragm pacing was evaluated in a recent clinical trial but proved inferior to NIV. Cough assist devices are used to help clear respiratory secretions, and have hypothetical advantages in preventing aspiration pneumonia; a clinical trial is required to assess whether there is any survival benefit. Decisions about invasive ventilation pose complex practical and ethical dilemmas. Many patients prefer, and many clin- icians advise, to avoid endotracheal intubation in a disease causing such widespread and irreversible weakness, as a locked-​in syndrome is the end result. At earlier stages of disease, secretion management is important. Excess salivation can be a significant problem, especially for patients with bulbar disease, and can be effectively treated using anticholinergics, such as hyoscine patches, sublingual atropine drops, glycopyrronium, amitriptyline tablets, or botulinum toxin injection to the salivary glands. Carbocisteine is used to thin viscous secre- tions and facilitate expectoration. Early swallowing problems may be addressed by simple measures such as a chin tuck, attention to food consistency, and nutritional supplements. Later, more severe dysphagia can be treated with a gastrostomy tube inserted either under endoscopic or radiological guidance. Some centres now per- form a hybrid technique, which allows a larger diameter, more secure tube to be placed without conscious sedation, and in the presence of non​invasive ventilation, an important consideration as gastrostomy insertion becomes more risky with respiratory weakness, especially when forced vital capacity falls below 50%. Patients and clinicians may consider gastrostomy in the presence of significant weight loss, recurrent aspiration pneumonia, or when frequent choking or dys- phagia makes mealtimes prolonged or intolerable. Gastrostomy tube insertion has been shown to stabilize weight in ALS; while weight loss is an adverse prognostic factor, any survival and quality of life bene- fits remain to be determined in trials. The aims are to avoid a hungry, dysphagic patient unable to fulfil their nutritional requirements and to facilitate discharge home. Speech failure can be treated using a Lightwriter device in patients with adequate hand function, or by computer-​assisted communication devices operated through pres- sure, blowing, head nodding, blinking or eye tracking, depending on an individual’s capabilities. Lower motor neuron syndromes These forms of motor neuron disease generally follow a more benign course than ALS. Young age of onset and positive family history may suggest an inherited disorder. The pattern of weakness can also help differentiation. Progressive muscular atrophy The progressive muscular atrophy variant represents 5–​10% of MND. A proportion of these patients will develop UMN signs later in the disease course, and are then referred to as LMN-​predominant ALS. Patients with pure progressive muscular atrophy tend to have longer survival than those with classical ALS. The absence of UMN signs should prompt consideration of other motor neuron diseases, such as multifocal neuropathy with conduction block, spinal mus- cular atrophy, Hirayama disease or Kennedy’s disease. Multifocal motor neuropathy with conduction block Patients may present at any stage of adult life with multifocal and slowly progressive muscle weakness over as much as 20 years. The clinical picture is immensely variable. Distal limb muscles are mainly involved, often notably asymmetrically. The first symptoms and most severe weakness usually affect the arms. A third present with drop of an individual finger. Characteristically, severely weakened muscles show little or no wasting. Reflex loss is generally restricted to markedly affected muscles. The condition is neurophysiologically heterogeneous, ranging from isolated muscle denervation changes on electromyography through classical multifocal conduction block in motor nerves on nerve conduction studies, and occasionally a dif- fuse demyelinating, pure, motor peripheral neuropathy. There may be no electrophysiological abnormality in early cases or if conduc- tion block is proximal. Serum antibodies to GM1 gangliosides are detectable in one-​third of cases, but are of no proven pathogenic sig- nificance, and lack specificity for the condition (these antibodies can be seen in ALS too). The condition progresses insidiously, sometimes in a stepwise manner. Spontaneous remissions occur only occasion- ally, and usually in the subacute subgroup. High-​dose intravenous human immunoglobulin (IvIg) therapy can produce dramatic im- provement lasting 6–​8 weeks and repeat administration is the main- stay of treatment in symptomatic patients. With IvIg administered sufficiently regularly to prevent end-​of-​dose deterioration, pro- gressive motor axonal loss can be largely or completely prevented. Steroid therapy does not improve multifocal motor neuropathy, and may precipitate further deterioration. 24.15  The motor neuron diseases 6173 Spinal muscular atrophy Classical spinal muscular atrophy comprises a group of autosomal recessive inherited LMN degenerative disorders that affect prox- imal muscles, and are associated with deletions at 5q13 of the SMN1 survival motor neuron gene. The precise role of SMN has not been elucidated, but ribonucleoprotein or gene-​splicing regulation is a likely function. Type I  acute infantile spinal muscular atrophy (Werdnig–​ Hoffman disease) is one of the most common fatal autosomal reces- sive disorders of children. The disease frequency of approximately 1 in 25 000 in England results from a gene frequency of 1 in 160. Before the age of 6 months, babies become inactive, weak, and hypo- tonic, feed poorly, and are slow to attain motor milestones. They may be born with limb deformities and, in retrospect, fetal movements may have been sparse. The tongue is weak and may fasciculate. Head control is poor with proximally wasted areflexic limbs that tend to assume a frog-​like position. Sadly, half of these infants die by 6 months, and almost all have succumbed by 18 months, usually to respiratory complications. Patients with types II, III, and IV spinal muscular atrophy have increasing levels of expression of SMN pro- tein, due to differences in copy number of an almost identical gene, SMN2. In type II (intermediate form), muscle weakness occurs be- fore 18 months; children can sit but not walk, and usually die in ado- lescence. Type III (chronic childhood form, Kugelberg–​Welander disease) develops at any time after the age of 18 months to the early teens. Clinical features initially resemble Werdnig–​Hoffmann dis- ease if the onset is early, but then follow a more benign course. More than 90% of patients can walk or sit unsupported at some time, al- though these abilities are often eventually lost. Tongue involvement occurs in approximately 50%, but significant dysphagia is unusual. Some patients develop respiratory insufficiency as a result of inter- costal muscle involvement. Proximal limb weakness and wasting are usually slowly progressive, but may sometimes stabilize spon- taneously. Those with severe early weakness may develop secondary spinal and joint deformities. The prognosis varies, but survival into middle age is usual. Type IV is the unusual adult-​onset form of prox- imal spinal muscular atrophy, which starts between 15 to 60 years of age, usually in the fourth decade. The presentation is with slowly progressive proximal limb weakness and significant walking dis- ability does not usually occur until the sixth or seventh decade. Life expectancy is only slightly reduced. Distal muscles can also be in- volved and the tendon reflexes are usually lost. Bulbar involvement is uncommon. This type can be confused with progressive muscular atrophy; the lack of bulbar involvement, and indolent progression are helpful distinguishing features. In a few families from Brazil, adult-​onset proximal spinal mus- cular atrophy was found to be inherited in an autosomal dominant manner, due to mutations in VAPB, and both typical and atypical ALS were also seen in the same families. Acute infantile proximal spinal muscular atrophy is pathologically distinct and unrelated to SMN protein. These disorders are associated with additional fea- tures, such as pontocerebellar hypoplasia, arthrogryposis, bone fractures, and lethal congenital contractures. Distal spinal muscular atrophies The distal spinal muscular atrophies (also called hereditary motor neuropathies or neuronopathies) are a phenotypically and genetic- ally diverse group of rare motor neuron diseases. Spinal muscular atrophy with respiratory distress presents with severe respiratory dis- tress, in infants without a mutation in SMN, and with a distal pattern of weakness. Other forms of the disease present either with upper limb predominant, lower limb predominant, or a scapuloperoneal distribution of weakness, resembling muscular dystrophy. Adult-​ onset variants exist. Distal spinal muscular atrophy with vocal cord paralysis has been described in two Welsh families. Genetic testing is complicated because of the large number of subtypes, some with as-​yet unidentified mutations. X-​linked recessive bulbospinal neuronopathy (Kennedy’s disease) This disorder almost always occurs in men, although rare cases of female manifesting carriers have been reported. Onset is usually in the third to fifth decades of life. Kennedy’s disease is caused by a mutation within the androgen receptor gene causing extra cytosine–​ adenine–​guanine repeat sequences. Weakness usually first affects hand or pelvic girdle muscles and bulbar symptoms tend to develop later, sometimes up to 20 years after disease onset. Cramps are prom- inent and fasciculations are usually visible in the limb, tongue, and facial muscles. Characteristically, muscle contractions around the chin are induced by pursing the lips or grimacing. The disorder is slowly progressive and most patients survive into their seventh or eighth decade, except when bulbar involvement is unusually severe. The disorder is often misdiagnosed as MND until the unusually slow deterioration is questioned. Unlike MND, patients may have gynae- comastia, testicular atrophy, diabetes mellitus, and absent sensory nerve action potentials on electrophysiology. Hereditary bulbar palsy of infancy and childhood Brown–​Vialetto–​van Laere syndrome is a rare neurological disorder characterized by progressive pontobulbar palsy and bilateral sen- sorineural hearing loss, with variable age of onset. Deafness often precedes the development of VII, IX, X, XI, and XII cranial nerve palsies, which then develop relatively rapidly. With disease progres- sion, limb and respiratory weakness, UMN signs, cerebellar ataxia, and upper cranial nerve palsies develop. The same clinical presen- tation without deafness is known as Fazio–​Londe disease; the two eponymous syndromes are now considered variants of a single dis- ease entity. A causative mutation was recently identified in C20orf54, a homologue of the rat riboflavin transporter protein, and promising early studies suggest that high-​dose riboflavin may be beneficial. Hirayama disease This disorder is most commonly described in Asia, especially Japan and India, but can present in any population. It is usually sporadic and affects young men. The pathology has been hypothesized to in- volve microcirculatory changes induced by repeated or sustained neck flexion, but this is controversial and mechanisms remain in- completely understood. Hirayama disease presents with distal wasting and weakness of one hand or forearm, which progresses steadily for the first 2 years before either stabilizing or settling to a slow rate of subsequent progression. Characteristically, there is sparing of brachioradialis. The other arm can sometimes be affected later. Initially, there is often concern that the symptoms may rep- resent MND, but the expected UMN and bulbar involvement fails to materialize, and spread to the legs is unusual (although is de- scribed especially in Indian patients). Nerve conduction studies help section 24  Neurological disorders 6174 exclude MND, focal entrapment neuropathies, or multifocal motor neuropathy with conduction block. MRI of the cervical spine will exclude syringomyelia or other spinal cord disease and should be performed on flexion and with contrast; a characteristic enhancing epidural crescent may be seen, which enlarges on flexion. Post-​polio syndrome After two or more decades, very slowly progressive weakness may affect muscles previously involved by acute paralytic poliomyelitis. Although this predominantly affects the limbs, approximately 50% of the cases also have mild choking or dysphagia and weakness of the respiratory muscles, which may lead to hypercapnic respiratory failure. The sluggish deterioration, lack of UMN involvement, and previous history help distinguish post-​polio syndrome from ALS. Electromyography reveals giant motor units typical of extensive reinnervation. The mechanisms are somewhat controversial; at least equally commonly, late deterioration after polio is due to secondary degenerative arthritis or fibromyalgia. Upper motor neuron syndromes The pure UMN syndromes are the rarest forms of motor neuron dis- ease. Imaging is mandatory to exclude structural or demyelinating disease of the spinal cord, foramen magnum, or brain. Deficiencies of vitamins B12 and copper need to be considered along with dopa-​ responsive dystonia and adrenomyeloneuropathy. Rarely, syphilis and HTLV-​I (human T-​lymphocytic virus type I) infections can cause a pure UMN syndrome. Management of spasticity is im- portant, but can be challenging. Primary lateral sclerosis The primary lateral sclerosis variant of MND is a rare sporadic dis- ease (2% of cases) with an average age of onset of 50 years, and slow progression over an average of 15 years. The clinical features are all attributable to symmetrical degeneration of upper motor neurons destined for the spinal cord and bulbar region. A rare, even more slowly progressive hemiparetic variant also exists (Mills syndrome). Spasticity and weakness usually start insidiously in the legs and as- cend to involve the bulbar muscles later. Less commonly, patients present with pseudobulbar palsy. The associated emotional lability is often distressing for these patients but responds well to citalopram or amitriptyline. In the United States, dextromethorphan/​quini- dine is used for emotional lability. Bladder function is generally well preserved, but dysfunction can occur late in the disease course. Electromyography does not reveal the muscle denervation expected in UMN-​predominant forms of ALS, although some patients evolve to that condition. MRI may reveal atrophy of the precentral gyrus motor cortex, reflecting loss of the Betz cells from which the pyr- amidal tract originates. Central motor studies following electromag- netic stimulation of the motor cortex show delayed conduction. Hereditary spastic paraparesis Various forms of slowly progressive, symmetrical, spastic parapar- esis may be inherited, with onset often in the fourth to sixth dec- ades. The degree of leg spasticity often outweighs the severity of the weakness. Bulbar involvement is very rare, and arm function may be well preserved despite severe leg involvement. The condition is slowly progressive. It may remain asymptomatic in family members who are gene carriers. Urinary urgency and erectile dysfunction may occur. To date 56 loci have been identified, with pathogenic mutations identified in 41 genes. Clinically, the hereditary spastic parapareses are most conveniently divided into ‘pure’ and ‘compli- cated’ forms, the latter involving various additional features such as distal amyotrophy (termed Silver syndrome if early hand wasting), intellectual impairment, dementia, pigmentary retinopathy, optic atrophy, extrapyramidal features, sensory neuropathy, ataxia, or epilepsy. Inheritance is most commonly autosomal dominant, and these disorders are usually ‘pure’ and comprise abnormalities of various genes for proteins involved in intra-​axonal trafficking, such as spastin, atlastin, or KIF5A, while other genetic mutations involve receptor accessory protein 1 (REEP-​1), heat shock protein 60, and seipin. The less common autosomal recessive forms often produce ‘complicated’ phenotypes and mutations include those for paraplegin, spartin, and maspardin. X-​linked mutations are rarer still and generally present in childhood with ‘complicated’ phenotypes. Lathyrism Neurolathyrism is a spastic paraparesis caused by regular con- sumption of the chickling pea (Lathyrus sativus) for some months. It is endemic in parts of India and outbreaks have occurred in China, Africa, and central Europe at times of famine. Patients, usually young men, present either subacutely or chronically with a spastic paraparesis and a characteristic scissoring gait in which the balls of the feet take most of the weight. Once it has developed, neurolathyrism is usually not progressive, but little or no recovery occurs even after chickling pea consumption ceases. A  plant-​ derived excitotoxic amino acid, β-​N-​oxalyl-​amino-​L-​alanine (BOAA), a glutamate analogue, is considered pathogenic. Konzo Konzo is a form of tropical myelopathy that can occur in epidemics at times of famine in sub-​Saharan Africa. It appears to be due to dietary cyanogen consumption, resulting from insufficient soaking of the cassava roots used to produce flour. There is an abrupt onset of symmetrical spastic paraparesis, which is non​progressive but per- manent. Blood cyanide levels are raised at the onset of disease. FURTHER READING Al Sultan A, et al. (2016). The genetics of amyotrophic lateral scler- osis: current insights. Degenerative Neurological and Neuromuscular Diseases, 6, 49–​64. Bosch AM, et  al. (2011). Brown–​Vialetto–​Van Laere and Fazio–​ Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with po- tential treatment. J Inherit Metab Dis, 34, 159–​64. Cooper-​Knock J, et al. (2012). Clinico-​pathological features in amyo- trophic lateral sclerosis with expansions in C9ORF72. Brain, 135, 751–​64. Ferraiuolo L, et al. (2011). Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat Rev Neurol, 7, 616–​30. Gourie-​Devi M, Nalini A (2003). Long-​term follow-​up of 44 patients with brachial monomelic amyotrophy. Acta Neurol Scand, 107, 215–​20. 24.15  The motor neuron diseases 6175 Greenland KJ, Zajac JD (2004). Kennedy’s disease: pathogenesis and clinical approaches. Intern Med J, 34, 279–​86. Hardiman O, et  al. (2011). Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol, 7, 639–​49. Ince PG, et al. (2011). Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology. Acta Neuropathol, 122, 657–​71. Jenkins TM, et al. (2014). The evidence for symptomatic treatments in amyotrophic lateral sclerosis. Curr Opin Neurol, 27, 524–​31. Kiernan MC, et al. (2011). Amyotrophic lateral sclerosis. Lancet, 377, 942–​55. Ludolph AC, et al. (1987). Studies on the aetiology and pathogenesis of motor neuron diseases. 1. Lathyrism: clinical findings in established cases. Brain, 110, 149–​66. Markowitz JA, et al. (2012). Spinal muscular atrophy: a clinical and research update. Pediatr Neurol, 46, 1–​12. Miller RG, et  al. (2012). Riluzole for amyotrophic lateral sclerosis (ALS)/​motor neuron disease (MND). Cochrane Database Syst Rev, 3, CD001447. Phukan J, et  al. (2012). The syndrome of cognitive impairment in amyotrophic lateral sclerosis:  a population-​based study. J Neurol Neurosurg Psychiatry, 83, 102–​8. Rosen DR, et al. (1993). Mutations in Cu-​Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 362, 59–​62. Rossor AM, et al. (2012). The distal hereditary motor neuropathies. J Neurol Neurosurg Psychiatry, 83, 6–​14. Schüle R, Schöls L (2011). Genetics of hereditary spastic paraplegias. Semin Neurol, 31, 484–​93. Shaw PJ (2009). The motor neuron disorders. In: Donaghy M (ed) Brain’s diseases of the nervous system, 12th edition. Oxford University Press, Oxford. Singer MA, et al. (2007). Primary lateral sclerosis. Muscle Nerve, 35, 291–​302. Slee M, et  al. (2007). Multifocal motor neuropathy:  the diagnostic spectrum and response to treatment. Neurology, 69, 1680–​7. Trojan DA, Cashman NR (2005). Post-​poliomyelitis syndrome. Muscle Nerve, 31, 6–​19. Turner MR, et al. (2013). Mimics and chameleons in motor neurone disease. Pract Neurol, 13, 153–​64. Tylleskär T, et  al. (1992). Cassava cyanogens and Konzo, an upper motor neuron disease found in Africa. Lancet, 339, 208–​11. Vlam L, et al. (2012). Multifocal motor neuropathy: diagnosis, patho- genesis and treatment strategies. Nat Rev Neurol, 8, 48–​58. 24.16 Diseases of the peripheral nerves 6176 Rober 24.16 Diseases of the peripheral nerves 6176 Robert D.M. Hadden ESSENTIALS Disorders of peripheral nerve function can be categorized in terms of the site of the primary disturbance. (1) Neuronopathies (sensory or autonomic neuronopathies are also known as ganglionopathies)—​conditions causing death of the neuron cell bodies which then leads to degeneration of axons; (2)  Axonal neuropathies—​conditions that affect axons; (3)  Demyelinating neuropathies—​conditions in which the myelin sheaths or sup- porting Schwann cells are damaged and the axons are relatively preserved. Combinations of axonal and demyelinating pathology are common. (4)  Interstitial neuropathies—​conditions in which there is infiltration of the endoneurium; for instance, by granu- loma or amyloid. Clinical pattern Peripheral neuropathy characteristically causes predomin- antly distal weakness (with or without atrophy), sensory changes and/​or autonomic malfunction, either alone or in combin- ation. These occur in an anatomical distribution appropriate to the nerve or nerves affected, with three broad categories recog- nized:  (1) mononeuropathy—​a lesion of an isolated peripheral nerve; (2)  multifocal neuropathy (multiple mononeuropathies or ‘mononeuritis multiplex’); and (3) polyneuropathy—​diffuse and bilaterally symmetrical disturbance of function, typically length dependent (affecting nerves in proportion to their length). Investigation The diagnosis can usually be made from the history and examin- ation. Presence of both localized and generalized neuropathies may be confirmed by nerve conduction studies. Simple blood tests for diabetes mellitus, B12 deficiency, and common medical causes are sufficient for the diagnosis of many cases. Cerebrospinal fluid examination may be useful—​especially in suspected inflammatory demyelinating polyradiculopathy. When the diagnosis is not re- vealed by simple tests an extensive range of investigations for rare causes may be needed. Causes of peripheral neuropathies Mononeuropathies—​common conditions include median nerve en- trapment due to carpal tunnel syndrome, and compression of the ulnar nerve at the elbow and the common peroneal nerve at the fibular head. Generalized neuropathies—​causes include (1) diabetes mellitus—​ most commonly producing a symmetrical sensory polyneuropathy; autonomic neuropathy may be debilitating; (2)  alcohol—​usu- ally in association with thiamine deficiency; (3) other metabolic/​ endocrine disorders (e.g. amyloidosis, uraemia, hypothyroidism, acromegaly, critical illness polyneuropathy); (4)  toxic—​including industrial/​environmental substances (e.g. acrylamide, lead, thal- lium) and drugs (e.g. phenytoin, cisplatin, isoniazid, vincristine, thalidomide); (5) deficiencies (e.g. thiamine, vitamin B12); (6) in- flammatory (e.g. Guillain–​Barré syndrome, chronic inflamma- tory demyelinating polyradiculoneuropathy), multifocal motor neuropathy, paraprotein-​associated neuropathy; (7)  infection related—​leprosy, Lyme disease, HIV infection; (8)  granuloma- tous—​sarcoidosis; (9)  vasculitic disorders; (10) neoplastic and paraneoplastic—​most often with bronchial or ovarian malignancy; (11) genetic conditions (e.g. Charcot–​Marie–​Tooth disease; her- editary motor and sensory neuropathy), hereditary neuropathy with liability to pressure palsies, and multisystem conditions including familial amyloid polyneuropathy; and (12) chronic idio- pathic axonal polyneuropathy—​the cause of about 25% of cases of late-​onset symmetrical polyneuropathy remains unknown despite extensive investigation. General principles Structure of peripheral nerves The peripheral nerves consist of bundles (fascicles) of unmyelinated and myelinated axons that have their cell bodies in the anterior horns of the spinal cord (motor), dorsal root ganglia (sensory), or autonomic ganglia. Each fascicle is surrounded by a lamellated cel- lular sheath, the perineurium, which provides a diffusion barrier that separates the endoneurial compartment from the extracellular 24.16 Diseases of the peripheral nerves Robert D.M. Hadden1 1  This chapter is adapted from earlier editions written by Professors P. K. Thomas and Richard Hughes. 24.16  Diseases of the peripheral nerves 6177 tissues. Peripheral nerve trunks usually consist of several fascicles bound together by the mainly collagenous epineurial connective tissue. The nutrient vessels connect with a longitudinal anastomotic network of arterioles and venules in the epineurium. This, in turn, communicates through perforating vessels with a longitudinal, intrafascicular, capillary anastomotic network. This anastomotic system is extremely efficient: experimentally it is very difficult to produce ischaemia of nerve trunks by ligation of nutrient vessels. The occurrence of an ischaemic neuropathy therefore implies wide- spread vascular insufficiency. A blood–​nerve barrier, comparable to the blood–​brain barrier, exists in peripheral nerves (except in the sensory and autonomic ganglia and at motor nerve terminals). This, together with the diffusion barrier provided by the perineurium, regulates the composition of the endoneurial connective tissue fluid and thus the ionic environment of the nerve fibres. Normal physiology All peripheral nerve fibres, whether myelinated or unmyelinated, are located closely adjacent to Schwann cells. These may provide metabolic support for the axons, which often extend for very con- siderable distances from their perikarya. In myelinated fibres, the myelin segments are derived by the spiralling of the surface mem- brane of Schwann cells around the axons. The axon is exposed at the nodes of Ranvier, which represent the gaps between adjacent myelin segments. Conduction in unmyelinated axons takes place by the spread of a continuous wave of depolarization, the action potential, which migrates along the axolemma. In myelinated fibres, because of the high electrical resistance of the lipid in the myelin lamellae, the generation of the action potential is restricted to the nodes of Ranvier. Conduction is therefore saltatory, jumping from one node to the next by local currents that traverse the axon and the extra- cellular tissue fluid. By this means, conduction velocity is increased from about 1 m/​s in unmyelinated axons to 60 to 70 m/​s in the lar- gest myelinated fibres. Most of the synthetic mechanisms in neurons are sited in the cell bodies. Synthesized materials are then transported down the axons to the termination of the fibres by an active transport system. This involves a fast system with a rate of about 400 mm/​day, and a slow system, in which the structural proteins travel at 1 to 2 mm/​day. The system is bidirectional: there is also a retrograde system transporting materials, including neurotrophic factors, back from the periphery to the cell body. The retrograde system may be involved in the regu- lation of protein synthesis in the cell body and probably carries the signal for chromatolysis, which follows transection. Peripheral nerve pathology Disorders of peripheral nerve function can be categorized in terms of the site of the primary disturbance. Conditions that lead to the death of the neuron as a whole, with the loss of the cell body and the axon, are categorized as neuronopathies. Conditions that have a selective effect on axons are termed ‘axonal neuropathies’. Focal axonal lesions occur as a result of insults such as trauma or is- chaemia. Axonal interruption leads to wallerian-​type degeneration below the site of injury. Recovery must take place by axonal regen- eration which is a slow process: the rate of axonal regeneration is about 1–​2 mm/​day. A selective block of axonal conduction, without degeneration, may be caused by blockage of sodium channels at the nodes, by antibodies (e.g. some patients with axonal Guillain–​Barré syndrome) or toxins (e.g. tetrodotoxin). Generalized axonal neuropathies often lead to a selective de- generation of the distal portion of the fibres, which then extends proximally. The axons are said to ‘die back’ towards the cell bodies. This pattern is seen in many toxic neuropathies and neuropathies due to nutritional deficiency. In these conditions, the axonal break- down may result either from interference with enzymes involved in glycolysis which provide the metabolic energy for axonal trans- port mechanisms, or from cofactor deficiency or inactivation. As the enzymes are synthesized in the cell bodies and then transported down the axons, the further the distance from the cell body the greater the likelihood of metabolic insufficiency occurring. This probably accounts for the length-​dependent (distal) distribution of many such neuropathies, because longer axons will be more vul- nerable. Again, recovery must take place by axonal regeneration. In many distal axonal neuropathies that involve the peripheral ner- vous system, not only does the degeneration affect the distal parts of the motor and sensory axons in the periphery, but also the ter- minal parts of the centrally directed axons derived from the dorsal root ganglion cells. Thus, degeneration may be found in the ros- tral portions of the posterior columns in the spinal cord. This pro- cess has been referred to as central–​peripheral distal axonopathy. Neuropathy from iminodipropionitrile blocks the slow axonal transport system and leads to large swellings in the proximal parts of the axons that contain aggregations of neurofilaments (proximal axonopathy). Other neuropathies primarily affect the myelin, either directly, or through interference with Schwann cell function. The conse- quence is a selective demyelination with relative preservation of axonal integrity. This may be restricted to the region of the nodes of Ranvier (paranodal demyelination) or involve whole internodal segments (segmental demyelination), with consequent conduc- tion block. Selective myelin damage may occur, for example, as the result of a cell-​mediated attack on myelin by sensitized mono- nuclear cells, which is a possible explanation for the acute inflam- matory demyelinating polyradiculoneuropathy (AIDP) form of Guillain–​Barré syndrome. Another instance is in diphtheritic neuropathy where the demyelination is secondary to an interfer- ence with Schwann cell protein metabolism. Local compression by a tourniquet also gives rise to selective damage to myelin through mechanical effects, although more severe pressure causes axonal interruption. In diffuse demyelinating neuropathies, the distribu- tion of the clinical effects, as for distal axonal neuropathies, is often maximal peripherally. Presumably, this is a statistical effect:  the longer the nerve fibre, the more likely it is to include a region of demyelinating conduction block. Recovery after paranodal or segmental demyelination occurs by remyelination. Initially, the newly formed myelin segments are short and thin, which results in an abnormally slow conduction vel- ocity. Such reductions in conduction velocity may be focal (e.g. in relation to localized myelin damage in entrapment neuropathies), or widespread as in most inherited demyelinating neuropathies. In the latter, motor nerve conduction velocity is sometimes reduced to 10 m/​s or less. Finally, in other neuropathies the nerve fibres may be secondarily damaged by processes that primarily affect the connective tissues of section 24  Neurological disorders 6178 nerves or of the vessels (vasa nervorum). Usually a combination of demyelination and axonal loss occurs. Symptomatology Weakness or sensory loss may be due to either conduction block or axonal degeneration, but isolated conduction slowing is gener- ally asymptomatic. Conduction block is related to demyelination with preservation of axonal continuity (neurapraxia). Recovery may occur by remyelination and may be rapid and complete. This can be the situation in localized nerve lesions (e.g. ‘Saturday night’ palsy of the radial nerve), or in more widespread polyneuropathies, such as in the AIDP form of Guillain–​Barré syndrome (see next). If axonal interruption takes place, axonal degeneration occurs below the site of interruption. The muscle weakness is accompanied by at- rophy and electromyographic signs of denervation. If the interrup- tion is reversible, recovery has to take place by axonal regeneration which is often slow and incomplete. An important recovery mech- anism in conditions in which muscles become partially denervated is reinnervation of denervated muscle fibres by collateral sprouting from the remaining intact axons. Motor symptoms. In generalized symmetrical polyneuropathies, the muscle weakness and wasting are usually distal so begin in the lower limbs. This results in bilateral foot drop and a high stepping gait to avoid catching the toes on the ground. Involvement of the upper limbs begins with weakness and wasting of the small hand muscles, and usually weakness of the finger and wrist extensors, before the forearm flexor muscles. Proximal limb weakness sug- gests root involvement, especially inflammatory demyelinating polyradiculoneuropathy. Fasciculation due to spontaneous con- traction of isolated motor units is a feature of anterior horn cell (motor neuron) disease but may be encountered in peripheral neuropathies, as may muscle cramps. However, benign fascicula- tions are very common and distinguished by the lack of weakness and typically greater prominence in the history than the examin- ation. Neuropathic postural tremor, mainly affecting the upper limbs and resembling essential tremor, may be seen in patients with chronic demyelinating polyneuropathies, either genetic, inflam- matory, or associated with IgM paraprotein. A rare manifestation of peripheral neuropathy is the occurrence of continuous repetitive discharges in motor nerve fibres, leading to generalized muscular ri- gidity or ‘neuromyotonia’ (Isaacs’ syndrome, continuous motor unit activity syndrome). Loss of the tendon reflexes is a frequent accompaniment of a per- ipheral neuropathy, and usually first affects the ankle jerks; absence of all tendon reflexes suggests a demyelinating neuropathy. Sensory symptoms and sensory loss in symmetrical polyneuro­ pathies are usually distal (‘length dependent’) in distribution, giving rise to the ‘glove-​and-​stocking’ pattern of involvement. Only rarely is a proximal pattern encountered, suggestive of radiculoplexus neuropathy or ganglionopathy. The sensory loss typically affects all modalities, but sometimes is restricted to one of two broad patterns. In the first, the impairment predominantly affects the sensations of joint position, vibration, and light touch, corresponding to a predominant loss of function in the larger mye- linated nerve fibres. Loss of joint position sensation may cause sen- sory ataxia of gait or limbs, which can resemble that in cerebellar disease. When very severe it may also cause ‘pseudoathetosis’, involuntary movements of the fingers and hands with arms outstretched and the eyes closed. In the second pattern of selective sensory loss, known as small fibre neuropathy, pain and tempera- ture sensibility are predominantly affected, often with loss of auto- nomic function, corresponding to a predominant loss of small myelinated and unmyelinated axons. Typically, there is spontan- eous ‘burning’ pain; in more severe cases the loss of the protective effect of pain sensation may lead to persistent ulceration or more extensive tissue loss, most commonly in the feet, and neuropathic joint degeneration (Charcot’s joints). Positive sensory symptoms are frequent in peripheral neuropathy, due to excessive spontaneous action potentials. They are usually of a tingling nature (‘pins and needles’), but in small fibre neuropathies cause burning hot or cold sensations and pain. These may be aggra- vated by touching or stroking the skin. The International Association for the Study of Pain (2012 online update) defines the following terms, all of which may be caused by neuropathy. An abnormal sensation, whether spontaneous or evoked, is termed dysesthesia if unpleasant or paraesthesia if not. Neuropathic pain is pain caused by a lesion or disease of the som- atosensory nervous system. Hyperalgesia is increased pain from a stimulus that normally provokes pain. Allodynia is pain due to a stimulus that does not normally provoke pain. Hyperpathia is a syn- drome of pain characterized by an abnormally (increased) painful reaction to a stimulus (whether normally painful or not), especially a repetitive stimulus, as well as (paradoxically) an increased threshold; there may be faulty identification and localization of the stimulus, delay, explosive character, radiating sensation, and aftersensation. Sensitization is increased responsiveness of nociceptive (peripheral or central) neurons to their normal input, and/​or recruitment of a response to normally subthreshold inputs. Spontaneous pains of an aching or lancinating character may complicate several generalized polyneuropathies. Severe parox- ysms of lancinating pain occur in trigeminal neuralgia in which the lesion is at or close to the point of entry of the sensory roots into the pons. Following a traumatic lesion of peripheral nerve or plexus, sometimes complex regional pain syndrome type 2 (causalgia) develops, characterized by sustained burning pain, allodynia, and hyperpathia, often with vasomotor and sudomotor dysfunction and later trophic changes. Sympathectomy relieves some cases. Restless legs syndrome (voluntary movements of the legs to re- lieve unpleasant sensations, usually when resting or in bed) may be idiopathic or secondary to neuropathy, often a painful small fibre neuropathy, for example, due to renal failure. Dopamine agonists or pregabalin may help. Intermittent sensory symptoms without evidence of organic neuropathy are common but not well understood. They may arise in the peripheral nerves (from causes including compression, ec- topic action potentials, or hyperexcitability), cutaneous sensory re- ceptors, or central nervous system disturbances including anxiety, migraine sensory aura, and central sensitization. Disturbances of autonomic function are occasionally the predom- inant abnormality in a peripheral neuropathy, as in rare syndromes of primary autoimmune autonomic neuropathy/​ganglionopathy and familial dysautonomia. More commonly they accompany other manifestations, either with localized peripheral nerve lesions and/​ or with generalized neuropathies, such as AIDP, diabetic or amyloid polyneuropathy. 24.16  Diseases of the peripheral nerves 6179 Clinical phenotypes of neuropathy Neuropathies may be classified in several dimensions, firstly by distribution. Lesions of isolated peripheral nerves or nerve roots are termed ‘mononeuropathy’ or ‘radiculopathy’; multiple iso- lated lesions are termed multiple mononeuropathies, mononeuritis multiplex, or multifocal neuropathy. The lesions in a widespread multifocal neuropathy may summate to produce a symmetrical disturbance, but the history or a careful examination may indicate asymmetry or involvement of individual nerves. Isolated or multi- focal peripheral nerve lesions arise from conditions that produce localized damage, such as mechanical injury, nerve entrapment, vascular causes especially vasculitis, thermal, electrical, or radi- ation injury, granulomatous, neoplastic, or other infiltrations, and nerve tumours. Alternatively, there may be a diffuse, length-​dependent, and bilat- erally symmetrical disturbance of function termed polyneuropathy. When this affects the spinal roots as well as the peripheral nerves, the term ‘polyradiculoneuropathy’ is more appropriate. In general terms, polyneuropathies result from conditions that act diffusely on the peripheral nervous system, such as metabolic disturbances, toxic agents, deficiency states, and some autoimmune disorders. Isolated nerve lesions may sometimes be superimposed on a symmetrical polyneuropathy, as a consequence, for example, of pressure lesions in a patient confined to bed. In certain peripheral nerve disorders, there is an abnormal susceptibility to pressure lesions. Further dimensions include the timing which may be acute, sub- acute or chronic; and axonal or demyelinating neuropathy may be suggested by nerve conduction studies. The symptomatology (see earlier) suggests whether the predominant type of fibres involved are motor, sensory, or autonomic, and if the predominant sensory involvement is large fibre (touch and movement) or small fibre (pain and temperature), with positive (tingling/​pain) or negative (numb- ness) sensory symptoms. In practice this gives several typical clinical phenotypes: • Distal sensory polyneuropathy, the most common type, also known as length dependent. The increased vulnerability of the longer axons gives the typical stocking and glove distribution. • Painful small fibre sensory neuropathy (often with autonomic neuropathy). • Mononeuropathy (usually due to local compression or trauma). • Multifocal/​asymmetric neuropathy (suggesting an inflammatory cause). • Sensory ataxic neuropathy (sometimes coexists with pathology of the dorsal columns of the spinal cord). • Motor and sensory neuropathy. • Demyelinating neuropathy (clinical clues are proximal weakness and absence of all tendon reflexes). Formulation of the clinical phenotype is an important first step towards narrowing the differential diagnosis and selecting appro- priate investigations. The Washington University neuromuscular website is a useful advanced reference tool (http://​neuromuscular. wustl.edu). Diagnosis and investigation A screen of blood tests should be done for the most common causes. The American Academy of Neurology practice parameter recommended the most useful blood tests to be glucose, vitamin B12 with B12-​metabolites (methylmalonic acid with or without homo- cysteine), and serum protein immunofixation electrophoresis. Glucose tolerance testing and HbA1c should be considered, par- ticularly in overweight patients. Most neurologists would also test renal, liver, and thyroid function, folic acid, FBC, ESR, and HIV. A careful history assessing risk factors for neuropathy may guide further investigation. The history and physical examination are usually sufficient to in- dicate that the patient has a peripheral neuropathy. If confirmation is required, this may usually be obtained by nerve conduction studies. Conduction may be examined in motor and sensory nerve fibres, and can give evidence of both localized and generalized neuropathies. Although axonal and demyelinating neuropathy can usually be dis- tinguished, mildly reduced conduction velocity may also occur in regenerating axons following axonal degeneration. Somatosensory evoked potentials are most useful if the patient has sensory deficit with areflexia yet paradoxically normal sensory nerve conduction, to show preganglionic disease, such as chronic immune sensory polyradiculopathy. Cerebrospinal fluid examination may be helpful, particularly where there is proximal involvement of nerve roots (polyradicu­ loneuropathy). In symmetrical axonal neuropathy, the cerebrospinal fluid protein is usually normal or only slightly increased. In chronic inflammatory demyelinating polyradiculoneuropathy, the protein concentration is usually markedly increased, often to more than 1000 mg/​litre. The protein concentration is also usually increased in Guillain–​Barré syndrome, especially after the first week, whereas the cell count remains normal or only shows a few lymphocytes. The cell count is usually increased in neuropathies associated with Lyme dis- ease and some other infections. Imaging of peripheral nerves by magnetic resonance neurography or ultrasound has improved technically in recent years, allowing diagnostic utility in conditions with enlargement, compression, or inflammation of nerves, such as demyelinating neuropathies (in- flammatory or genetic), nerve tumours, or leprosy. This requires specialist expertise and equipment. Ultrasound is useful in diagnosis of entrapment/​compression where the nerve is close to the skin, for example, in carpal tunnel syndrome; paradoxically a chronically compressed nerve actually becomes thickened not thinned. MRI is also useful for excluding lumbar spinal canal stenosis and central nervous system disease. Nerve biopsy is useful in only a few situations, especially multi- focal neuropathy to show vasculitis or other inflammatory disorders, and in amyloidosis. It is best performed in centres with expertise in nerve biopsy to minimize the high risk of artefact from suboptimal surgical or laboratory technique. Treatment of neuropathies in general The following may benefit even neuropathies lacking a specific treat- ment. Patients with significant sensory loss should be advised on foot care: to inspect their feet regularly for early signs of injury or blistering that may lead to ulceration, to take extra care with new shoes, to limit walking barefoot to avoid injury, and to see a podia- trist early for any problems. Neuropathic pain may be helped by tricyclic antidepressants, gabapentin (standard or extended release), pregabalin, duloxetine, or venlafaxine as first-​line treatment; further treatment may section 24  Neurological disorders 6180 include carbamazepine, tramadol or strong opioids (including sustained-​release oxycodone, transdermal buprenorphine, or tapentadol). Fewer than one in three patients gets acceptable benefit from any drug, but the most common avoidable cause of failure is inadequate titration of the dose to the maximum toler- ated. Those with pain localized to a small area (including the feet), especially with allodynia or touch-​sensitive dysaesthesia, may benefit from 5% lidocaine plasters, capsaicin (either 0.075% cream, or the much more effective 8% patch which must be applied by trained specialists every three months), or botulinum toxin. Rehabilitation. Patients with foot drop may benefit from one of many different types of ankle-​foot orthosis, which must fit well. Patients with abnormal foot posture or deformity (especially those with Charcot–​Marie–​Tooth disease) should see an orthotist or biomechanical podiatrist. Physiotherapy may benefit those with weakness or abnormal gait, but excessive strength training may be detrimental to severely weak muscles. Weight loss eases the burden on weak legs, but the best form of aerobic exercise is usually not walking or running which overstrains weak ankles. Mononeuropathies Phrenic nerve (C2–​4) This nerve innervates the diaphragm. When the diaphragm is to- tally paralysed, breathlessness is worse when lying flat or swimming. Examination shows loss of the normal protrusion of the upper abdomen during inspiration (especially during rapid sniff), or re- placement by retraction (paradoxical movement). Radiographically, paralysis may be detected by unilateral or bilateral elevation of the diaphragm in a chest radiograph and its failure to descend on inspir- ation. The phrenic nerve may be involved in its course through the neck or thorax by wounds or tumours such as bronchial carcinoma, and it is sometimes affected in idiopathic brachial plexus neuropathy (neuralgic amyotrophy) and in some rare forms of Charcot–​Marie–​ Tooth disease. Nerve to serratus anterior (C5–​7) The serratus anterior acts as a fixator of the scapula, holding the scapula against the chest wall when forwards pressure is exerted by the arm. It is involved in forwards movement of the shoulder, as in a rapier thrust, and in elevation of the arm, when it rotates the scapula. When serratus anterior is paralysed in isolation, the position of the scapula is almost normal at rest but, if the extended arm is pushed forwards against resistance, ‘winging’ of the scapula becomes more evident. The vertebral border, particularly in its lower portion, stands away from the chest wall. The nerve to serratus anterior may be involved in penetrating wounds, but usually in association with damage to the brachial plexus. It may be injured by forcible de- pression of the shoulder. Serratus anterior weakness is a common component of idiopathic brachial plexus neuropathy (neuralgic amyotrophy) and it is frequently encountered as an isolated and un- explained lesion. Brachial plexus The brachial plexus may be affected by intrinsic lesions, neo- plastic infiltration, penetrating wounds of the neck, in fractures and dislocations of the shoulder and clavicle, as a result of traction on the arm, or by pressure from an aneurysm or a cervical rib or fibrous band. Idiopathic brachial plexus neuropathy This condition is also known as ‘neuralgic amyotrophy’ and ‘brachial neuritis’. It is likely an immune-​mediated disorder, with a probable underlying genetic predisposition (unidentified in sporadic cases) and susceptibility to mechanical injury of the brachial plexus. It may follow immunization, surgery, or infections (including hepatitis E), or occur without a recognizable antecedent event. Some cases occur as an autosomal dominant disorder, hereditary neuralgic amyot- rophy, with variable penetrance, which is genetically heterogenous but often caused by mutations in the SEPT9 gene. It develops acutely with intense pain in the shoulder region which lasts days or weeks. Paralysis of the muscles of the shoulder girdle becomes evident within a day or two of the onset of the pain, some- times also of the arms or of the diaphragm. It may be unilateral or bilateral, usually without much sensory loss. More distal upper limb muscles may be affected (such as variants affecting predominantly the anterior or posterior interosseous nerves), as may the phrenic nerve and, occasionally, the recurrent laryngeal nerve. The cerebro- spinal fluid is consistently normal. There is often prominent wasting of scapular muscles with electromyographic evidence of denerv- ation. Recovery is variable over 1 to 2 years but may ultimately be satisfactory. Not all cases recover fully and recurrences can occur. A comparable disorder can affect the lumbosacral plexus (idiopathic lumbosacral plexopathy). The pattern of muscle involvement suggests a patchy process, al- lowing distinction from a root lesion because of selective involve- ment of some but not all muscles innervated by the same root. An immune reaction is assumed but not established. In a retrospective observational study oral prednisone given in the first month after onset shortened the duration of the initial pain and led to earlier re- covery in some patients, but there are no randomized trials. Postirradiation brachial plexopathy Brachial plexus damage may occur as a sequel to radiotherapy for breast carcinoma or tumours in the neck. The onset of symptoms is usually several years after treatment, but may be within months. It can be difficult to distinguish from tumour recurrence but is less likely to be painful. MRI, and especially positron emission tomog- raphy, may be helpful in diagnosis. It does not improve and treat- ment is supportive only. Traction lesions of the brachial plexus Traction on the arm may result in damage to the plexus itself or may lead to avulsion of the spinal roots from the cord. If the roots are avulsed, sensory nerve action potentials from affected fingers will be preserved despite total anaesthesia, and the histamine flare re- sponse will be preserved in anaesthetized skin. This follows from the fact that the nerve fibres are interrupted proximal to the dorsal root ganglia and therefore the peripheral sensory axons do not degenerate. In severe traction lesions, commonly encountered in current medical practice as a result of motorcycle accidents, the whole of the plexus may be damaged. With forcible downward displacement of the shoulder, as when someone is thrown forwards and the shoulder strikes against an obstacle, only the upper part of the plexus, involving 24.16  Diseases of the peripheral nerves 6181 the contribution from the fifth and sixth cervical nerve roots, may be damaged. This may also be encountered as a birth injury from traction on the head, or on the trunk in a breech presentation (Erb’s palsy), and rarely in anaesthetized patients during surgery or in indi- viduals carrying heavy rucksacks. Selective injury to the lower part of the plexus involving the contributions from the eighth cervical and first thoracic nerve roots occurs as a result of traction with the arm extended, as when an individual falls from a height and tries to save himself by hanging on to a ledge. It may also occur as a birth in- jury following traction with the arm extended (Klumpke’s paralysis), but is less common than upper plexus damage. Selective damage to the upper portion of the plexus (C5 and C6 roots or upper trunk) results in paralysis of deltoid, biceps, brachialis, brachioradialis, and sometimes supraspinatus, infraspinatus, and subscapularis. If the roots are avulsed from the cord, the rhomb- oids, serratus anterior, levator scapulae, and the scalene muscles will be affected. The arm hangs at the side, internally rotated at the shoulder, with the elbow extended and the forearm pronated in the ‘waiter’s tip’ position. Abduction at the shoulder and flexion at the elbow are not possible. The biceps and brachioradialis jerks are lost. Sensory loss affects the lateral aspect of the shoulder and upper arm and the radial border of the forearm. Selective paralysis of the lower brachial plexus (C8, T1) results in paralysis of all the intrinsic hand muscles and a consequent claw-​hand deformity, weakness of the medial finger and wrist flexors, and sensory loss along the medial border of the forearm and hand and over the medial two fingers. Cervical sympathetic paralysis, giving rise to Horner’s syndrome, is frequently associated. When the spinal roots are avulsed from the cord, regeneration is impossible and intractable spontaneous pain may be a highly troublesome sequel. Where the injury is distal to the dorsal root ganglia, lesions of the upper portion of the brachial plexus recover more satisfactorily than lower plexus lesions. The value of surgical repair is still a controversial issue. In Erb’s form of birth injury, weak- ness of abduction at the shoulder and flexion at the elbow often per- sist, although there may be little residual sensory loss. Full recovery takes place in about a third of cases. It is less likely to occur with lower plexus injuries or if the whole plexus is involved. Early recog- nition and the application of measures to reduce the risk of joint con- tractures are important. Surgical treatment may be considered soon after the injury in cases where the nerve roots have been avulsed. Thoracic outlet syndromes The contribution of the eighth cervical and first thoracic roots to the brachial plexus may be damaged by angulation over a cervical rib or, more usually, a fibrous band arising from the seventh cervical ver- tebra and attached to the first rib. Numbness, pain, and paraesthesiae occur along the medial (ulnar) border of the forearm and hand, extending into the medial two fin- gers. The pain tends to be provoked by carrying heavy articles with the hand on the affected side. Damage to the lower part of the brachial plexus leads to weakness and wasting of the small hand muscles, and of the medial forearm wrist and finger flexors. Occasionally, there is selective wasting of the thenar muscles in the hand, mimicking me- dian nerve involvement. Horner’s syndrome may be a feature. Nerve conduction studies are helpful for distinguishing from a lesion of the ulnar or median nerves. Standard MRI may miss a small lesion. Surgical removal of the rib or fibrous band often leads to abolition of the pain and paraesthesiae, but may not improve wasted muscles. The subclavian artery may be affected by cervical ribs, giving rise to aneurysmal dilatation and vascular symptoms such as Raynaud’s phenomenon and embolic phenomena, but the simultaneous occur- rence of both neural and vascular phenomena is rare. Neoplastic involvement Tumours may arise locally in the brachial plexus, such as a nerve sheath tumour in neurofibromatosis type I, or the plexus may be in- vaded by tumours arising in other structures. The most common are invasion of the lower part of the plexus by an apical carcinoma of the lung (Pancoast’s tumour) or by breast carcinoma, which give rise to wasting and weakness of the small hand muscles and of the medial forearm wrist and finger flexors, with prominent pain and sensory loss affecting the medial border of the forearm and hand, and cer- vical sympathetic paralysis. Radial nerve (C5–​8) The long course of the radial nerve and its position in relation to the humerus make this nerve unusually susceptible to external com- pression. It is a continuation of the posterior cord of the brachial plexus. In the upper arm, it supplies triceps and anconeus, and the posterior cutaneous nerve of the arm, and more distally the lower lateral brachial cutaneous branch and the posterior cutaneous nerve of the forearm. Muscular branches of the radial nerve innervate brachioradialis and extensor carpi radialis longus and brevis. The superficial radial nerve descends along the radial border of the forearm and supplies the skin over the dorsum of the hand and the thumb, index, and middle fingers. The deep branch forms the pos- terior interosseous nerve which winds around the lateral aspect of the radius, passes through supinator, which it supplies, and in- nervates extensor digitorum, extensor digiti minimi, extensor carpi ulnaris, and often extensor carpi radialis brevis, abductor pollicis longus, extensor pollicis longus and brevis, and extensor indicis. The nerve may be injured in wounds of the axilla so that the par- alysis includes triceps, resulting in loss of extension at the elbow. The most frequent type of injury is compression of the nerve in the middle third of the arm against the humerus, as in ‘Saturday night palsy’ in which an individual falls asleep when intoxicated with the upper arm over the arm of a chair. Triceps is spared, but brachioradialis, supinator, and all the forearm extensor muscles are paralysed including weakness of finger and wrist extension. Sensory impairment is limited to the dorsum of the hand. Commonly the le- sion consists of a localized conduction block so that muscle wasting does not occur and a muscle response can be obtained on electrical stimulation of the nerve below the level of the lesion. Recovery may be complete within a matter of weeks. At times, there is some associ- ated axonal degeneration so that electromyographic evidence of de- nervation is detectable and full recovery is correspondingly delayed. Many muscles not supplied by the radial nerve work at a disad- vantage when the wrist and finger extensors are paralysed. These defects must not be mistaken for signs of injury to other nerves. Owing to the flexed position of the wrist, gripping is impaired, but, if the power of the wrist and finger flexors is tested with the wrist extended, it can be shown to be normal. The action of the interossei in abducting and adducting the fingers is also feeble when the fin- gers are flexed, but full power is demonstrable if these muscles are tested with the hand resting flat on a table so that the fingers are section 24  Neurological disorders 6182 maintained in extension. This explains the benefit of a wrist exten- sion splint while recovery is awaited. A lesion of the posterior interosseous nerve gives rise to weak- ness confined to extension of the fingers and wrist (extensor carpi ulnaris), and extension and the long abductor of the thumb. Supinator is spared, together with brachioradialis and the radial wrist extensors, and there is no sensory loss. The nerve may be com- pressed, usually under the arcade of Frohse (a sharp band of fibrous tissue, which binds together the superficial and deep heads of the supinator muscle as they arise from the lateral epicondyle of the hu- merus and lateral border of the radius). A similar pattern of weak- ness may be caused by multifocal motor neuropathy (typically with differing weakness in different fingers) or idiopathic brachial plexus neuropathy, so NCS/​EMG and MRI or ultrasound are needed before considering surgical exploration and decompression. Axillary nerve (C5, C6) This is a branch of the posterior cord of the brachial plexus. It sup- plies deltoid and teres minor and the skin over deltoid through the upper lateral brachial cutaneous nerve. It may be damaged in in- juries to the shoulder and the chief symptom is an almost complete inability to abduct the arm at the shoulder. Musculocutaneous nerve (C5, C6) This nerve is rarely damaged alone, but may be involved in injuries to the brachial plexus. It supplies coracobrachialis, biceps, and brachialis, and the lateral cutaneous nerve of the forearm. Flexion at the elbow is still possible by brachioradialis, but is weak. Median nerve (C6–​8, T1) The median nerve arises from the medial and lateral cords of the brachial plexus and descends with the brachial artery through the upper arm, entering the forearm deep to the bicipital aponeurosis. It has no muscular branches above the elbow. It supplies all the muscles in the anterior aspect of the forearm except flexor carpi ulnaris and the medial half of flexor digitorum profundus. The main trunk of the nerve supplies pronator teres, flexor carpi radialis, palmaris longus, and flexor digitorum superficialis. Through the anterior inter- osseous branch, it also supplies the lateral aspect of flexor digitorum profundus, flexor pollicis longus, and pronator quadratus. The main trunk passes deep to the flexor retinaculum of the wrist and its re- current muscular branch supplies abductor pollicis brevis and op- ponens pollicis, and contributes to the innervation of flexor pollicis brevis. It also supplies the lateral two lumbrical muscles, the skin of the lateral aspect of the palm, and the lateral three and a half digits over their palmar aspects and terminal parts of their dorsal aspects. Median nerve lesions in the forearm The median nerve may be injured in the region of the elbow or compressed at the level of the pronator teres muscle. Entrapment neuropathies in the upper forearm are, however, uncommon. Occasionally the anterior interosseous branch is involved in isolation. Complete lesions of the median nerve at the elbow give rise to par- alysis of pronator teres, the radial flexor of the wrist, the long finger flexors except the ulnar half of the deep flexor, most of the muscles of the thenar eminence, and the two radial lumbricals. In brief, there is an inability to flex the index finger and the distal phalanx of the thumb, flexion of the middle finger is weak, and opposition of the thumb is defective. The appearance of the hand has been described as simian; it shows ulnar deviation, the index and middle fingers are more extended than normal, and the thumb lies in the same plane as the fingers. In more detail, pronation is incomplete and defective. The pa- tient attempts to overcome this by rotating the whole limb at the shoulder. Paralysis of the wrist flexors is evident when attempts are made to flex against resistance. The tendon of flexor carpi ulnaris stands out alone and the hand goes into ulnar deviation. Flexion of the fingers is good in the ulnar two fingers, although weaker than normal. The index finger cannot be flexed and the middle finger only incompletely. Flexion at the metacarpophalangeal joints is possible in all fingers, including the index, and flexion at these joints with extension at the interphalangeal joints is accomplished by interossei and the lumbricals. If the proximal phalanx of the thumb is immo- bilized, it will be found that flexion of the terminal phalanx is abol- ished because of paralysis of flexor pollicis longus. Paralysis of the thenar muscles gives rise to defective abduction and opposition of the thumb. By means of the adductor, the thumb can be drawn into the palm, but, as the radial fingers cannot be flexed or the thumb opposed, it is impossible to place the tip of the thumb on the fingers. Sensory loss is evident over the lateral three and a half digits and the lateral aspect of the palm, although individual variations occur. There is anaesthesia over the two terminal phalanges of the index and middle fingers. This degree of sensory loss, combined with the motor deficit, renders the thumb and index fingers almost useless and makes paralysis of the median the most serious single nerve lesion in the upper limb. Vasomotor and trophic changes often ensue: the skin, nails, and finger pulp tend to become atrophic. After a total transection of the nerve in the region of the elbow, even with a satisfactory surgical repair, recovery is slow and rarely complete, particularly with respect to the innervation of the hand. With partial lesions of the median nerve in the arm or forearm, complex regional pain syndrome (causalgia) may be a troublesome consequence. The pain develops hours to weeks after the injury. The pain is severe and unremitting, and frequently has a burning or smarting quality. Upon this may be superimposed severe paroxysms of pain (allodynia) provoked by touching the limb or emotional dis- tress. The skin usually becomes dry and scaly, but excessive sweating may be a feature. Immobility may lead to contractures of the joints. Treatment is difficult but sympathectomy may help. Carpal tunnel syndrome Much the most common median nerve lesion is the carpal tunnel syndrome, in which the median nerve is compressed at the wrist as it passes deep to the flexor retinaculum. The usual presentation is with intermittent acroparaesthesiae, which consist of numbness, tingling, and burning sensations felt in the hand and fingers; the pain sometimes extends up the forearm as far as the elbow or even as high as the shoulder or root of the neck. The paraesthesiae are sometimes restricted to the radial 3½ digits, but may affect all the digits because some fibres from the median nerve are distributed to the little finger through communication with the ulnar nerve in the palm. The attacks of pain and paraesthesiae are most common at night and often wake the patient from sleep. The hand tends to feel numb and useless on waking. Symptoms are then relieved within minutes by shaking the hand. The symptoms may recur during the day when the hand is used, gripping a steering wheel, or immobile 24.16  Diseases of the peripheral nerves 6183 in certain positions. Intermittent acroparaesthesiae may persist for years without the appearance of constant sensory loss or weakness. Examination is usually normal, but a minority develop weakness and wasting of the thenar muscles, particularly of abduction of the thumb (Fig. 24.16.1), or sensory loss over the tips of the me- dian-​innervated fingers. Occasionally patients present with symp- toms or signs of median nerve deficit in the hand without attacks of acroparaesthesiae having occurred, particularly in older individuals. The symptoms are usually characteristic, with abnormal signs not being found except in advanced cases. At times percussion over the carpal tunnel may elicit Tinel’s sign, or symptoms may be provoked by hyperextension of the wrist or sustained flexion (Phalen’s sign). Neither sign is very specific or sensitive. Confirmation can usually be obtained by nerve conduction studies (except these are normal in 5% of cases). Carpal tunnel syndrome is more common in women than men and its lifetime prevalence is 10%. It is commonly associated with excessive use of the hands. It may develop as a consequence of wrist joint abnormality from rheumatoid arthritis, osteoarthritis, or an old fracture. Predisposing causes include pregnancy, obesity, myx- oedema, acromegaly, and amyloidosis, but most cases are idiopathic so screening for underlying causes is not recommended. A  twin study has shown a strong genetic component. The superficial situ- ation of the median nerve at the wrist also renders it liable to injury as a result of lacerations or suicide attempts. Fluctuation of symptoms is common and spontaneous recovery occurs in about 20% of patients. A conservative approach to treat- ment is appropriate initially, with weight loss and avoidance of pro- voking activities. Splinting of the wrist in a neutral position during the day and/​or night may also be useful. The preferred treatment for milder cases is local corticosteroid in- jection at the wrist, shown in short-​term randomized trials as more efficacious than placebo or oral corticosteroids. About half of pa- tients obtain satisfactory relief from corticosteroid injection alone but symptoms may recur, so injection can be repeated if necessary. Oral steroids, splinting, ultrasound, yoga, and carpal bone mobil- ization are also efficacious. Surgical carpal tunnel release (dividing the flexor retinaculum) is recommended for more severe cases, or those with persistent weakness or numbness, or refractory to steroid injection or splinting. Surgery and steroid injection have not been directly compared in a randomized trial. The average success rate from surgery is about 75%, but it is more inconvenient and may be complicated by a painful scar. About 7% of patients report that their hands are worse after the operation than before. Symptoms that were previously intermittent usually recover completely but permanent symptoms may not. Ulnar nerve (C7, C8, T1) The ulnar nerve arises from the medial cord of the plexus, usually with a contribution from the lateral cord. It descends in the medial side of the upper arm, passes around the elbow in the ulnar groove between the olecranon process of the ulna and the medial epicon- dyle of the humerus, and enters the forearm under an aponeurotic band between the humeral and ulnar heads of flexor carpi ulnaris. It then runs superficial to flexor digitorum profundus to the wrist and enters the hand between the pisiform bone and the hook of the hamate, superficial to flexor retinaculum. After penetrating the hypothenar muscles, its deep branch crosses the palm and ends in flexor pollicis brevis. In the upper arm, branches arise that supply flexor carpi ulnaris and the medial part of flexor digitorum profundus. In the forearm, the dorsal branch arises, winds around the ulna and supplies the skin over the dorsal aspect of the hand and the medial one and a half fingers. In the hand, a superficial branch supplies palmaris brevis and the skin over the medial aspect of the palm and the medial one and half fingers. The deep branch, after supplying the hypothenar muscles, innervates interossei, the third and fourth lumbricals, ad- ductor pollicis, and part of flexor pollicis brevis. Ulnar nerve lesions at the elbow Total paralysis from lesions at this level, including the branches to flexor carpi ulnaris and flexor digitorum profundus, gives rise to wasting along the medial side of the forearm flexor muscles. There is weakness of flexion of the fourth and fifth fingers. If the proximal portions of these fingers are held immobilized, flexion of the terminal phalanges is not possible. When the hand is flexed to the ulnar side against resistance, the tendon of flexor carpi ulnaris is not palpable. Paralysis of the hypothenar muscles abol- ishes abduction of the fifth finger. Paralysis of interossei and the medial two lumbricals gives rise to the ‘claw-​hand’ deformity (Fig. 24.16.2). The action of these muscles is to flex the fingers at the metacarpophalangeal joints with the fingers extended at the interphalangeal joints. In a claw hand, the posture of the fingers is opposite to this, namely extension of the metacarpophalangeal joints with flexion at the interphalangeal joints. Although all the interossei are paralysed, the defect is seen mainly in the ulnar fin- gers because the lumbricals supplied by the median nerve are still active. The long extensors of the fingers, being unopposed, overex- tend the proximal joints, and flexor digitorum superficialis flexes the proximal interphalangeal joints. Fig. 24.16.1  Thenar wasting in a patient with a severe median nerve lesion. section 24  Neurological disorders 6184 In the hand, there is wasting of the hypothenar muscles, interossei, and the medial part of the thenar eminence. Movements of abduc- tion and adduction of the fingers are weak, as is adduction of the extended thumb against the palm. Sensory loss affects the dorsal and palmar aspects of the medial side of the hand and the medial one and a half fingers. The ulnar nerve may be damaged by dislocations or fracture dis- locations at the elbow and is sometimes compressed in individuals who habitually lean on their elbows. This is most likely to happen in those performing heavy manual work or if there is an excessive carrying angle at the elbow, as may occur after a previous malunited supracondylar fracture of the humerus (‘tardy ulnar palsy’). In this case, the ulnar nerve is often palpably enlarged in the ulnar groove and for a short distance proximally. Ulnar nerve lesions are not in- frequent in leprosy when the enlargement of the nerve tends to be maximal at a little distance above the elbow. Entrapment may also occur in the cubital tunnel which is formed by an aponeurotic band between the two heads of flexor carpi ulnaris under which the nerve passes. Distinguishing between lesions at the ulnar groove and at the cubital tunnel aponeurosis is difficult and may require detailed neurophysiological assessment and imaging. Education of the patient about the mechanism of damage to the ulnar nerve and avoidance of leaning on the elbow reduced symp- toms in a small randomized controlled trial (RCT) in mild disease. Night splinting to avoid excessive elbow flexion is often recom- mended but did not offer extra benefit in one trial. In severe progres- sive cases lasting more than three months surgery may be considered, although many improve spontaneously or remain mild, and surgery has never been compared in a RCT to conservative treatment alone. The lesion should first be confirmed by nerve conduction studies and imaging with ultrasound or MRI. The alternative operations are transposition of the nerve from behind to in front of the medial epicondyle, decompression of the nerve where it passes through the cubital tunnel, or medial epicondylectomy. Meta-​analysis suggests that simple decompression and decompression with transposition are equally effective in idiopathic ulnar neuropathy at the elbow, including when the nerve impairment is severe, each giving im- provement in about 70% of patients. The operation performed will depend on the experience of the surgeon and intraoperative findings. Lesions at the wrist or in the hand Damage to the ulnar nerve at the wrist will spare the dorsal branch, so that cutaneous sensation over the dorsum of the hand and fingers is spared. A lesion just proximal to the wrist will give rise to sen- sory impairment on the palmar aspect of the hand and fingers alone, and weakness of all the ulnar-​innervated intrinsic hand muscles. A slightly more distal lesion spares the superficial branch of the nerve and therefore produces no sensory deficit. Finally, damage to the deep palmar branch spares the hypothenar muscles, but causes weak- ness of the other ulnar-​innervated small hand muscles. Lesions at the wrist or in the hand are usually the result of compression by ganglia or by repeated occupational trauma. Damage to the deep palmar branch, for example, may be caused by firm pressure in the palm from a screwdriver or drill or bicycle handlebars. If occupational pressure is the cause, recovery follows cessation of the precipitating cause. Should improvement fail to occur after an appropriate interval, sur- gical exploration to establish whether a ganglion is present is merited. It is not always easy on clinical grounds to decide whether the lesion is at the elbow or the wrist. Compression of the nerve in the cubital tunnel, for example, may spare the branches to flexor carpi ulnaris and flexor digitorum profundus. In these circum- stances, nerve conduction studies may be helpful, as they may in distinguishing between lesions of the ulnar nerve and damage to the eighth cervical and first thoracic spinal roots. MRI or ultrasound is also helpful to localize the lesion site. Lumbosacral plexus Lesions of the lumbosacral plexus are not common. The plexus may be involved in pelvic malignancy, such as from carcinoma of the uterine cervix, bladder, prostate, or rectum, or be the site of a local neural tumour. It may be compressed by a haematoma in pa- tients receiving anticoagulant therapy or who have haemophilia, or be involved in fractures of the pelvis. The lumbosacral plexus may be compressed against the rim of the pelvis by the fetal head during parturition, with consequent weakness of the anterior tibial and peroneal muscles, and sensory impairment in the distribution of the fourth and fifth lumbar dermatomes. The superior gluteal nerve may also be affected. Recovery is initially good but may not be com- plete. The plexus may be affected in diabetic (or rarely non​diabetic) lumbosacral radiculoplexus neuropathy (diabetic amyotrophy). Femoral nerve (L2–​4) This nerve arises from the lumbar plexus, crosses the iliac fossa be- tween psoas and iliacus, and enters the thigh deep to the middle of the inguinal ligament. In the iliac fossa it supplies iliacus and, in the thigh, pectineus, sartorius, and quadriceps femoris, and anterior cu- taneous branches to the front of the thigh. The continuation of the femoral nerve is the saphenous nerve, which supplies the skin over the medial aspect of the lower leg as far as the medial malleolus. Fig. 24.16.2  ‘Claw-​hand’ deformity in a patient with an ulnar nerve lesion. 24.16  Diseases of the peripheral nerves 6185 Damage to the femoral nerve causes weakness of knee extension, wasting of quadriceps, loss of the knee reflex, and sensory impair- ment over the anterior thigh and in the distribution of the saphe- nous nerve in the medial calf. With a proximal lesion, there may also be weakness of hip flexion from paralysis of iliacus. The femoral nerve may be injured in fractures of the pelvis or femur, in dislocations of the hip, in childbirth, and at times during operations on the pelvis or hip. It may be involved by psoas abscesses or tumours, or in wounds of the thigh. It is commonly involved in large psoas muscle haematomas in individuals with haemophilia and in diabetic radiculoplexus neuropathy, but sometimes no cause is found. There is usually gradual recovery. Owing to the rapid disper- sion of the branches in the thigh, partial lesions are common from wounds at this site. The nerve to quadriceps is most often injured, and the resulting paralysis causes considerable difficulty in walking because the knee cannot be locked in extension and gives way, es- pecially when descending stairs. The saphenous nerve is sometimes damaged in surgery for the treatment of varicose veins. Obturator nerve (L2–​4) The nerve emerges from the lateral border of psoas, crosses the lat- eral wall of the pelvis, and enters the thigh through the obturator foramen where it supplies gracilis, adductor longus and brevis, ad- ductor magnus, obturator externus, and sometimes also pectineus, and the skin over the lower medial aspect of the thigh. Damage to the obturator nerve results in weakness of adduction and internal rotation at the hip, pain in the groin, and sensory im- pairment on the medial part of the thigh. The nerve may be involved in pelvic fractures, hip and pelvic surgery, and neoplastic infiltration, and can be damaged by the fetal head or forceps during parturition. Lateral cutaneous nerve of the thigh (L2, L3) This nerve arises from the lumbar plexus, passes obliquely across the iliacus, and enters the thigh under the lateral part of the inguinal liga- ment. It supplies the skin over the anterolateral aspect of the thigh. Meralgia paraesthetica is a common pure sensory entrapment neuropathy resulting from compression of this nerve usually as it passes under the inguinal ligament. It is more common in men and obese individuals, or may occur in pregnancy or childbirth, and may be unilateral or bilateral. The symptoms consist of numbness in the territory of the nerve, combined with tingling or burning paraes- thesiae provoked by prolonged standing or after excessive walking. Neurophysiology is diagnostically unhelpful. Treatment is not usually required. Weight loss may be helpful, and in many instances the condition subsides spontaneously. Rare cases with troublesome pain may benefit from lidocaine plasters or cap- saicin cream. Occasionally local corticosteroid injection or surgical decompression are tried, without good evidence that they are better than conservative treatment. Sciatic nerve (L4, L5, S1–​3) The sciatic nerve enters the thigh through the sciatic notch. It is com- posed of the tibial and peroneal divisions which are usually bound together within a common sheath, the tibial division lying medially. It descends through the posterior aspect of the thigh, initially deep to gluteus maximus, and supplies semitendinosus, semimembranosus, and the long head of biceps through its peroneal division. It separ- ates into the tibial and common peroneal nerves in the lower thigh, which supply all the muscles below the knee, and both nerves con- tribute to the formation of the sural nerve. Partial lesions often affect the peroneal division more severely than the tibial. Total interruption of the sciatic nerve gives rise to foot drop. Walking is possible, but the patient cannot stand on the toes or the heel of the affected foot and the ankle is unstable. All movement below the knee is paralysed. If the injury is in the upper thigh, flexion of the knee is also weak. The skin is anaesthetized (with absent sweating) over the entire foot except for the medial border which is supplied by the saphenous nerve. Pressure sores may develop. The anaesthesia extends upwards on the posterolateral aspect of the calf in its lower two-​thirds. Beyond this area of complete anaesthesia, there is a wide zone in which sensibility may be diminished. The ankle reflex is lost but the knee reflex is retained. The sciatic nerve may be involved in pelvic tumours and can be injured by fractures of the pelvis or femur, during hip replacement operations, or by intramuscular injection to the buttock in locations other than the recommended upper outer quadrant. After the radial and ulnar, it is implicated in gunshot wounds more frequently than any other nerve. Incomplete lesions of the nerve may be caused by pressure of the nerve against the hard edge of a chair in individ- uals who fall asleep while intoxicated. Similar lesions may occur in people with diabetes, in whom the peripheral nerves are more sus- ceptible to pressure neuropathy. The syndrome of root pain and sciatica is considered in Chapter 19.4. Tibial nerve (L4, L5, S1–​3) After separating from the peroneal division of the sciatic nerve in the lower thigh, this nerve passes through the popliteal fossa and enters the calf deep to gastrocnemius through the fibrous arch of soleus. It descends through the calf to the medial side of the ankle, passes beneath the flexor retinaculum, and divides into the medial and lateral plantar nerves. It supplies popliteus, all the muscles of the calf, and, through the plantar nerves, the small muscles of the sole of the foot and sensation to the sole. When the nerve is interrupted, the patient is unable to plantarflex or invert the foot, flex the toes, or stand on the ball of the foot. Paralysis of interossei leads to a claw-​like deformity of the toes. Sensation is lost over the sole. Causalgia may arise after partial lesions. Injury to the distal portion of the nerve by a penetrating injury or deep wound of the calf gives rise to paralysis of the in- trinsic muscles of the foot but spares the muscles acting at the ankle. Sensation is lost on the sole of the foot and this may be accompanied by pain. If the injury is distal to the origin of the branches to flexor hallucis longus and flexor digitorum longus, the lesion may escape detection because paralysis of the small foot muscles and sensory loss over the sole may be overlooked. The tibial nerve is very rarely compressed under the flexor retinaculum (tarsal tunnel syndrome), usually precipitated by osteoarthritis or post-​traumatic deformities at the ankle, or teno- synovitis. Burning pain and tingling paraesthesiae occur in the sole, usually after prolonged standing or walking. The condition is gen- erally unilateral. Careful examination may demonstrate wasting of the intrinsic muscles in the medial aspect of the foot, and sensory impairment over the sole. Nerve conduction studies may be helpful diagnostically. Treatment is by surgical section of flexor retinaculum. Morton’s metatarsalgia (also known as intermetatarsal neuroma) is a syndrome of lancinating pain, numbness, or paraesthesiae, section 24  Neurological disorders 6186 usually in one of the web spaces at the base of the toes, especially the third web space. The pain occurs especially on weight-​bearing. Removing the shoe and massaging the foot or manipulating the toes may bring relief. It is not a neoplasm but probably perineural fibrous tissue provoked by chronic compression of a plantar nerve branch. Ultrasound is useful in diagnosis. Treatments include orthoses, ultrasound-​guided injection of corticosteroids or sclerosing alcohol, radiofrequency ablation, or neurectomy surgery. Common peroneal nerve (L4, L5, S1, S2) After separating from the tibial division of the sciatic nerve in the lower part of the thigh, the common peroneal nerve descends through the popliteal fossa, winds around the neck of the fibula, and divides into its superficial and deep branches. The superficial peroneal nerve passes down in front of the fibula, supplies peroneus longus and brevis, and emerges in the lower leg, supplying the skin on the lateral aspect of the lower leg. It crosses the extensor retinaculum and supplies the skin on the dorsum of the foot and the second to fifth toes. The deep peroneal branch continues to wind around the fibula, pierces the anterior intermuscular septum, and descends on the anterior inter- osseous membrane. It innervates tibialis anterior, extensor digitorum longus, extensor hallucis longus, and peroneus tertius. It passes deep to the extensor retinaculum after which it supplies extensor digitorum brevis and the skin of the adjacent sides of the first and second toes. Damage to the common peroneal nerve is more frequent than in- jury to its two branches because of its vulnerable superficial pos- ition at the neck of the fibula. It gives rise to foot drop, with paralysis both of dorsiflexion and eversion at the ankle and of toe extension. Cutaneous sensation is impaired over the lateral aspect of the lower leg and ankle, and on the dorsum of the foot. It is distinguished from an L5 root lesion by preservation of ankle inversion power. The common peroneal nerve may be compressed at the neck of the fibula by habitually sitting with the legs crossed, prolonged squatting or kneeling, pressure during sleep or while anaesthetized, and various other events. It can be damaged by traction caused by fractures of the tibia and fibula, and is sometimes damaged by ischaemia in the anterior tibial compartment syndrome. Paralysis caused by external pressure frequently gives rise to a local conduction block usually with satisfac- tory recovery within weeks. A foot-​drop orthosis may be helpful while recovery is awaited. Rare progressive cases require imaging. Sural nerve (L5, S1–​2) This arises from the sciatic nerve and descends to the back of the calf, winds around to the lateral side of the ankle, and supplies the skin of the lateral border of the foot. Sensory impairment occasion- ally results from pressure on the nerve in the back of the calf, for example, by tight ski boots. This nerve is the one most commonly chosen on the rare occasions when a nerve biopsy is needed. Generalized neuropathies Neuropathies related to metabolic and endocrine disorders Diabetes mellitus A significant degree of peripheral neuropathy develops in about 15% of patients with diabetes, although many more have either minor symptoms without signs, or asymptomatic neuropathy on examination or nerve conduction study. The most common type is distal sensory polyneuropathy of metabolic aetiology, and fewer patients have (multi)focal neuropathy due to ischaemia or microvasculitis. The most common form is a chronic slowly progressive symmet- rical distal (length-​dependent) sensory polyneuropathy, causing numbness and tingling paraesthesiae in the toes and feet, and less often in the fingers. Aching or lancinating pains in the feet and legs, particularly at night, may be a troublesome feature. Examination may reveal loss of vibration sense in the feet, depression of the ankle jerks, and distal cutaneous sensory impairment. Loss of the sense of pain may result in foot ulcers or Charcot’s osteo-​neuro-​ arthropathy; impaired sensation may give an ataxic gait. Some pa- tients have a pure small fibre neuropathy with spontaneous burning pain, and reduced sensation to temperature and pinprick, but normal reflexes and preserved sensation to vibration, light touch, and position. Infrequently there is an acute onset of painful diabetic polyneuropathy, associated with either poor diabetic control and precipitate weight loss (‘diabetic neuropathic cachexia’), or a rapid improvement in glycaemic control (‘insulin-​triggered acute painful neuropathy’). Autonomic neuropathy frequently accompanies the sensory neuropathy and may be the predominant manifestation. It rarely oc- curs in isolation. Symptoms referable to the alimentary tract include dysphagia from oesophageal involvement, episodes of vomiting re- lated to gastric atony (gastroparesis), and episodic nocturnal diar- rhoea, often alternating with periods of constipation. Those related to the genitourinary system include erectile dysfunction, retrograde ejaculation, bladder atony with difficulty in voiding, and urinary re- tention with overflow. Vascular sympathetic denervation sometimes results in orthostatic hypotension, and cardiac parasympathetic de- nervation may cause an elevated resting heart rate and the absence of beat-​to-​beat variation with deep breathing. Pupillary disturbances usually take the form of a reduced response to light. Gustatory facial sweating provoked by the smell and taste of food can be trouble- some. Anhidrosis may occur distally in the limbs; if it is extensive and also affects the trunk, heat intolerance can result. Mononeuropathies tend to occur more commonly in older people with diabetes. They may develop insidiously or have an abrupt onset with pain. Of the cranial nerves, the nerves to the external ocular muscles, particularly the third and sixth, and also the facial nerve, are affected most often. Unlike the effects of compression of the third nerve by an aneurysm, pupillary reflexes are often spared. On the trunk, isolated radiculopathies may occur. The likely cause of all these is microvascular ischaemia and most patients make a good spontaneous recovery in a few months. In the limbs, the lesions tend to occur at the common sites of compression or entrapment. It seems likely that the nerves of people with diabetes exhibit an exces- sive vulnerability to damage from pressure. Diabetic lumbosacral radiculoplexus neuropathy (also known as diabetic amyotrophy or diabetic proximal neuropathy) is an uncommon severe multifocal neuropathy typically affecting older obese individuals with type 2 diabetes associated with profound subacute weight loss. It consists of severe asymmetrical proximal and distal weakness. Less commonly it is symmetrical. The onset is over days to months, often with severe pain, but with little sensory loss. The knee jerks are usually depressed or absent. Inflammatory 24.16  Diseases of the peripheral nerves 6187 lesions including microvasculitis have been demonstrated in nerve biopsies, leading to trials of pulsed corticosteroids, which may re- duce pain but have not been proven to benefit weakness. Most pa- tients improve spontaneously over a year or two. A rare variant of this is the syndrome of ‘painless diabetic motor neuropathy’ that may cause weakness of all limbs developing over months with par- tial spontaneous improvement. The causation of diabetic neuropathy is uncertain. It tends to occur more often in people with poorly controlled diabetes, but the correlation is not close. In type 2 diabetes it may be the presenting symptom or occur for the first time on initiation of treatment with insulin. There is evidence to suggest that diabetic microangiopathy is important in the genesis of isolated nerve lesions. Metabolic fac- tors are probably more important in the origin of the symmetrical polyneuropathies, but their nature is uncertain. An increased con- centration of sorbitol in nerves secondary to hyperglycaemia may be involved in causing nerve fibre dysfunction. People with diabetes are more at risk of developing some other neuropathies including entrapment neuropathies and chemotherapy-​induced neuropathy. Diabetes is the most common cause of neuropathy in the Western world, but cannot reliably be excluded by a normal fasting blood glucose: if suspected, HbA1c and/​or an oral glucose tolerance test should be done. Some studies suggest patients with prediabetes (impaired glucose tolerance or impaired fasting glycaemia) may also have an increased risk of neuropathy, even if they do not have diabetes. Treatment. Enhanced blood glucose control reduces the risk of development of clinical neuropathy in type 1 and probably type 2 diabetes, and reduces nerve conduction and vibration threshold ab- normalities in both types, but at the expense of an increased risk of severe hypoglycaemic episodes. Acute-​onset neuropathies usu- ally recover adequately over months, but chronic sensory (and autonomic) polyneuropathy usually persists and progresses slowly even with enhanced glycaemic control. There are no other specific treatments of proven benefit. Care of the feet is vitally important in diabetic sensory neuropathy, to prevent the development of chronic ulceration. Medication for neuropathic pain is described in the section ‘Treatment of neuropathies in general’. Postural hypotension can be improved by raising the head of the bed at night, high fluid and salt intake, and compression stockings; more severe cases may require treatment with the α-​agonist midodrine and fludrocortisone. Gastroparesis may respond to metoclopramide, domperidone, or erythromycin. In extreme cases, persistent vomiting may necessitate a roux-​en-​Y gastroenterostomy. Diabetic diarrhoea can be helped by low-​dose tetracycline or diphenoxylate, loperamide, or codeine phosphate. An atonic bladder can be managed in the earlier stages by regular voiding, lower abdominal compression, and straining. More severe cases should undergo urodynamic studies and are usu- ally best managed by intermittent self-​catheterization. Urinary tract infections should be treated promptly. Bladder neck resection can be useful in carefully selected cases. Erectile dysfunction may be treated with one of the phosphodiesterase inhibitors, sildenafil, tadalafil, or vardenafil, or intrapenile injections of alprostadil (prostaglandin E1) for resistant cases. Uraemia Uraemic neuropathy occurs in patients with severe chronic renal failure especially those on long-​term haemodialysis. The symptoms are usually predominantly sensory, with numbness and tingling paraesthesiae, and burning in the feet. Restless legs syndrome and cramps are often conspicuous (see Section 24.21). A distal motor neuropathy may be associated and occasional cases are purely motor. The condition is not necessarily improved by increased haemodialysis but does improve after kidney transplantation. Failure to clear ‘middle molecules’ that are toxic to axons has been proposed but not proved to be the mechanism. The nerve trunks in the arm and forearm are at risk during surgery for placing an arterio- venous fistula for dialysis. Symptoms may be produced by surgical damage, ischaemia, sometimes partly attributable to shunting, and compression. Hypothyroidism Compression of the median nerve in the carpal tunnel in hypothyroidism has already been discussed. Rarely a generalized mixed motor and sensory neuropathy develops. This improves on treatment of the hypothyroidism. The slow contraction and relax- ation observed in the tendon reflexes is due not to a disturbance of peripheral nerve function, but to an alteration in the contractile mechanism of the muscle fibres. Acromegaly In addition to carpal tunnel syndrome, acromegaly may cause a sensory and motor polyneuropathy. The peripheral nerves may be thickened because of an overgrowth of endoneurial and perineurial connective tissue. A similar neuropathy is occasionally observed in pituitary gigantism. Critical illness polyneuropathy A generalized polyneuropathy involving widespread axonal degen- eration may develop in patients with prolonged stays in intensive care units with sepsis, systemic inflammatory response syndrome, and multiple organ failure. The neuropathy is discovered when the patient is too weak to wean from the ventilator. It is difficult to distin- guish from critical illness myopathy and often both occur together. The precise cause is unknown. It is particularly likely to occur after the use of prolonged neuromuscular junction blockade, hypergly- caemia, and high-​dose corticosteroids. Intensive insulin therapy is proven to reduce the incidence and severity of neuromyopathy, and early rehabilitation is beneficial. There is no specific treatment but the neuropathy usually improves slowly over a year or so and satis- factory recovery may occur. Other metabolic disorders Symmetrical sensory and autonomic polyneuropathy probably does occur with cirrhosis but most cases are the result of the al- coholism that is its most common cause. A mild, painful, sensory neuropathy is occasionally encountered in primary biliary cir- rhosis, sometimes related to xanthomatous deposits in the cuta- neous nerve trunks. Toxic neuropathies Industrial and environmental Alcohol See ‘Deficiency neuropathies’. section 24  Neurological disorders 6188 Acrylamide Acrylamide monomer was formerly a cause of peripheral neur- opathy because it was absorbed through the skin by workers manufacturing the non​toxic polymers used in waterproofing and other industries. It caused a distal sensory and motor neuropathy with prominent numbness and disequilibrium. Distal axonal de- generation occurred and slow improvement followed cessation of exposure. With proper safety precautions this neuropathy should not occur. Arsenic Arsenical poisoning is occasionally seen as a result of accidental or homicidal ingestion of insecticides containing arsenic, or from indi- genous medicines in India. Gastrointestinal symptoms develop after acute ingestion, followed by a mixed sensory and motor neuropathy after one to three weeks. Desquamation of the skin of the feet and hands takes place after about six weeks, and white lines (Mees’ lines) appear in the nails. There is a systemic illness with anaemia and ab- normal liver function. The skin may become generally pigmented or show focal ‘raindrop’ pigmentation, and hyperkeratosis of the palms of the hands and soles of the feet may appear. Slow recovery from the neuropathy occurs with removal from exposure. Chelating agents are of value in treating the non​neurological complications, but it is uncertain whether they are effective for the neuropathy. Lead Lead neuropathy is now rare in the United Kingdom, although it was encountered as a consequence of the contamination of drinking water by lead pipes in old buildings. Subclinical neuropathy may be detectable in lead workers. It remains a hazard in certain parts of the world from the use of lead glazes in pottery. Lead poisoning usu- ally causes a triad of abdominal pain with constipation, anaemia, and neuropathy. The neuropathy may be predominantly motor and affect the upper much more than the lower limbs. It is frequently asymmetrical and typically produces weakness of first the finger and then the wrist extensors. The ‘lead colic’ that may occur is probably a manifestation of autonomic involvement. Severe chronic lead poi- soning causes bluish discoloration of the gums just below the teeth, especially if they are carious. The neuropathy improves on cessation of lead intake. Chelating agents accelerate removal of lead but it is uncertain which of dimercaprol, edetate, penicillamine, and 2,3-​ dimercaptosuccinic acid (DMSA) is the best. Mercury Exposure to inorganic mercury salts and organic mercurial com- pounds may lead to neurological damage. There was as an outbreak of poisoning in Minamata Bay, Japan, related to the consumption of fish contaminated by organic mercury. Dementia, cortical blindness, and ataxia occur, together with paraesthesiae, the last due perhaps to involvement of the dorsal root ganglia. Peripheral neuropathy was also a component of ‘pink disease’ in infants, consisting of anaemia, light sensitivity, skin rash, weight loss, and hypotonia. It was caused by the inorganic mercury in teething powders. Thallium This is present in certain pesticides and rodent poisons, and was formerly used as a depilatory agent. Accidental or homicidal poisoning is occasionally encountered. Acute ingestion causes nausea, vomiting, and diarrhoea. In severe cases coma develops rap- idly. In milder cases there are central nervous symptoms including anxiety and choreoathetosis, and the development of a progressive, very painful, sensory, and motor neuropathy. Alopecia is charac- teristic and develops later, after about two or three weeks, and renal damage may occur. Both Prussian blue to bind thallium in the gut and chelating agents to clear thallium from the body have been used as treatment. Organophosphates Organophosphates, especially tri-​ortho-​cresylphosphate, have been widely used as lubricants, insecticide crop sprays, antiparasitic sheep dip, and in chemical warfare. The original description of organo- phosphate poisoning was in relation to illegal liquor distillation in the United States of America during the prohibition era (ginger jake paralysis). A large outbreak occurred in Morocco from contamin- ated cooking oil. Accidental or suicidal acute poisoning with high doses causes an acute muscarinic syndrome with diarrhoea, sweating, salivation, and miosis. After 12 hours to 4 days, patients develop generalized weakness, possibly due to neuromuscular blockade, confusion, and even coma. Recovery from this begins after 1 or 2 weeks. However, between 1 and 3 weeks after the acute exposure, some patients develop a subacute predominantly motor neuropathy—​ ‘organophosphate-​induced delayed polyneuropathy’. Recovery is slow and often incomplete. Chronic low-​dose exposure to organo- phosphates (at doses insufficient to cause acute symptoms) does not cause neuropathy. Other industrial substances Carbon disulphide, used in the manufacture of rayon, occasionally gives rise to a mild sensory neuropathy. Neuropathy may occur as a result of industrial exposure to the organic solvents n-​hexane and methyl-​n-​butyl ketone. The former is also encountered as a conse- quence of solvent abuse (‘glue sniffing’); n-​hexane, which has an in- toxicant action, has been used as a solvent in certain glues. Other industrial agents causing neuropathy are ethylene oxide and methyl bromide. Trichlorethylene (or an impurity) has caused trigeminal neuropathy. Drug induced Bortezomib The proteasome inhibitor bortezomib, an antineoplastic agent used for multiple myeloma, frequently causes a painful subacute sensory axonal neuropathy, and rarely a more acute sensory-​motor neur- opathy that can resemble Guillain–​Barré syndrome. Isoniazid A mixed motor and sensory neuropathy may be produced by iso- niazid and is more likely to occur in individuals who acetylate the drug slowly. The neuropathy is related to interference with pyridoxine metabolism. Axonal degeneration occurs in the per- ipheral nerves. The neuropathy recovers slowly when the patient stops taking the drug; this may be prevented by giving pyridoxine, which does not interfere with the antituberculosis action of the isoniazid. 24.16  Diseases of the peripheral nerves 6189 Nitrofurantoin Excessively high blood levels of nitofurantoin as may occur in pa- tients with reduced renal function, can cause a rapid-​onset mixed motor and sensory neuropathy, which may be confused with Guillain–​Barré syndrome. Nucleoside analogue reverse transcriptase inhibitors in HIV The nucleoside analogue reverse transcriptase inhibitors (zalcita- bine, didanosine, and stavudine) cause a dose-​dependent, subacute, painful, sensory axonal neuropathy, for which reason these drugs are now rarely used. The neuropathy continues to progress for some weeks after the patient stops taking the drug but this eventually im- proves. It may be difficult to distinguish from the painful neuropathy caused by HIV itself without withdrawal of the drug. Painful neur- opathy in a patient on most modern anti-​HIV drugs is much more likely to be due to the HIV disease than to the drugs. Phenytoin After taking phenytoin for years, patients may report symptoms of a mild sensory neuropathy. More commonly the neuropathy is asymptomatic but detectable on clinical and especially neurophysio- logical examination. Platinum Oxaliplatin, cisplatin, and carboplatin chemotherapy may cause a painful predominantly sensory neuropathy after taking several courses. Recovery from the neuropathy is variable and often limited. Ototoxicity is more frequent, causing high-​tone deafness and tin- nitus. Oxaliplatin also causes an acute cold-​sensitive dysaesthesia, which improves quickly. Despite much research, no substance has yet been found to prevent this neurotoxicity. Pyridoxine Pyridoxine, if taken in large doses as ‘megavitamin therapy’, causes a severe sensory neuropathy with numbness of the feet and an un- steady gait. It is disputed whether chronic doses as low as 100 mg daily cause neuropathy, the daily requirement being only 2 mg. Taxanes The taxanes, paclitaxel and docetaxel, used in cancer treatment, cause a dose-​dependent, predominantly sensory axonal neuropathy. It presents with numbness and paraesthesiae in the feet and worsens with each dose. With high doses weakness develops. If the drug is stopped, the neuropathy worsens for some weeks before improving, a phenomenon called ‘coasting’. Thalidomide Thalidomide, used in the treatment of some vasculitides and mul- tiple myeloma, also causes a dose-​dependent, predominantly sen- sory neuropathy. It presents with painful paraesthesiae and cramps in the legs. It may be associated with palmar erythema, brittle nails, and tremor. It improves if the drug is stopped. Vincristine Vincristine produces a dose-​dependent axonal neuropathy, and its therapeutic use in neoplasia is limited by this side effect. Patients first develop distal paraesthesiae and lose their ankle reflexes. If the drug is continued, they gradually develop distal sensory loss and may eventually develop weakness that comes on quite rapidly. The neuropathy improves satisfactorily if the drug is withdrawn. Other substances Other drugs that may give rise to neuropathy are doxorubicin, amiodarone, chloroquine (with myopathy), dapsone, disulfiram, ethambutol, gold, metronidazole, misonidazole, nitrous oxide (with a myelopathy), podophyllin, suramin, and zimeldine. This list is not exhaustive and if a patient with an unexplained neuropathy is taking drugs of any sort, it is worth checking whether any of the drugs is reported to cause neuropathy. Deficiency neuropathies Alcoholic neuropathy This usually occurs on a background of nutritional deficiency. The dietary intake of the person abusing alcohol is high in carbohydrates and low in vitamins. Moreover, such individuals are known to have a reduced capacity to absorb thiamine. A direct toxic effect of alcohol on peripheral nerves may also be involved. The clinical features of alcoholic neuropathy are similar to those of thiamine deficiency (see next), sometimes with coexistent alcohol-​induced cerebellar ataxia or myopathy. Other deficiency states may coexist, such as the Wernicke–​Korsakoff syndrome. Improvement may take place with B vitamin (especially thiamine or benfotiamine) replacement and reduced alcohol intake, but it is beset with the usual difficulties met in treating patients with alcohol problems. Vitamin B12 deficiency Vitamin B12 deficiency, from whatever cause, is a common cause of a distal sensory neuropathy, with sensory ataxia, sensory loss, and paraesthesiae, either in isolation or with a myelopathy or other cen- tral nervous system manifestations. Haematological changes are not always present. The peripheral neuropathy improves more satisfac- torily with treatment than the central disturbances. This condition is considered in detail in Chapter 22.6.6. Vitamin B12 blood levels are unreliable: a mildly low level (>140 pg/​ml) cannot necessarily be assumed to be the cause of a neuropathy, but increased serum methylmalonic acid and homocysteine are useful markers of sig- nificant B12 deficiency which may occur even at low normal serum levels (<350 pg/​ml). A peripheral neuropathy is one component of Nigerian ataxic neuropathy, in which the other features are posterior column degen- eration, sensorineural deafness, and optic atrophy. It has been sug- gested that an interference with vitamin B12 metabolism by cyanide derived from cassava in the diet, combined with nutritional defi- ciency, is responsible. Coeliac disease There is an association between coeliac disease and some neuro- logical syndromes including cerebellar ataxia and peripheral neuropathy. In patients with malnutrition or vitamin B12 or folate deficiency, this is easily explained. Most patients with neurological manifestations experience preceding gastrointestinal symptoms be- fore developing peripheral neuropathy. Nevertheless, some patients do develop a peripheral neuropathy, usually a symmetrical, distal, sensory axonal neuropathy, in their absence. This now justifies at section 24  Neurological disorders 6190 least screening for antibodies associated with coeliac disease in pa- tients with otherwise unexplained axonal neuropathy. Whether the associated neuropathy is caused by subtle nutritional deficiency or an unidentified toxic factor is not known. Regardless of this, im- provement after institution of a gluten-​free diet has been reported. Thiamine deficiency (See also Chapter 11.2.) Thiamine deficiency is the cause of dry beri-​beri which occurs in severely malnourished communities, especially those subsisting on diets largely made up of polished rice, and medical conditions that reduce thiamine intake, most commonly chronic alcohol abuse, hyperemesis of pregnancy, and after gastric surgery. Initial symp- toms of fatigue, irritability, and cramps are followed by the devel- opment of a painful sensory neuropathy, sometimes with sensory ataxia. In severe cases, involvement of the recurrent laryngeal nerves may lead to hoarseness of the voice. The neuropathy may be associ- ated with cardiomyopathy (‘wet beri-​beri’). The diagnosis may be supported by a reduced activity of erythrocyte transketolase, which requires thiamine as a cofactor. Distal axonal degeneration occurs in the peripheral nerves and slow recovery ensues with vitamin replacement. Strachan’s syndrome Strachan’s syndrome, originally described in Jamaica but also ob- served in other parts of the world under conditions of nutritional deprivation, is characterized by the combination of a painful sen- sory neuropathy, optic neuropathy, and deafness, in association with orogenital dermatitis. There may also be features of a myelopathy. It is assumed to be due to deficiency of the B vitamins, but the precise deficit has not been identified. It may improve with B vitamin and folate supplementation. Pyridoxine deficiency As well as high doses of pyridoxine causing neuropathy, as described earlier, pyridoxine deficiency may contribute to the neuropathy that occurs in nutritional deficiency states. Isoniazid neuropathy is re- lated to an interference with pyridoxine metabolism. Vitamin E deficiency Vitamin E deficiency occurs in some hereditary disorders and in hepatobiliary and bowel disorders that impair its absorption. It pro- duces a multisystem neurological disorder in which cerebellar ataxia is the most prominent problem but peripheral neuropathy also oc- curs. It may be diagnosed by measuring plasma concentrations of α-​tocopherol, the most active form of vitamin E. Inflammatory and postinfective neuropathies Leprosy Peripheral nerve involvement in leprosy is considered in Chapter 8.6.28. Guillain–​Barré syndrome Guillain–​Barré syndrome is the most common cause of acute neuro- muscular paralysis in developed countries. Its annual incidence is about 1 per 100 000 throughout the world, being more common in men and older people. It consists of weakness of two or more limbs developing over a few days, with extremes of a few hours to up to 4 weeks. The tendon reflexes are usually (but not always) reduced or absent in weak limbs. The illness often, but not necessarily, causes paraesthesiae, pain, and sensory loss. There are no signs of central nervous involvement. In two-​thirds of cases there has been an in- fective illness between 1 and 6 weeks, most commonly 1 or 2 weeks, earlier. The infection is most commonly an uncharacterized upper respiratory tract infection but alternatively gastroenteritis. About 25% of cases are due to preceding Campylobacter jejuni infection, but 15% result from a preceding cytomegalovirus infection, 5–​10% from Epstein–​Barr virus, and 1–​5% from mycoplasma. Many other associated infections have been reported but not proved by large-​ scale epidemiological studies. The onset is usually with the simultaneous development of weak- ness of the limbs, paraesthesiae, and numbness. Pain, including back or root pain, may be a prominent feature and may precede the weak- ness. Weakness may be proximal, distal, or generalized in distribu- tion, but is usually fairly symmetrical. The facial and bulbar muscles are commonly involved and sometimes the ocular muscles. About 25% of patients develop such severe respiratory muscle weakness for which they need intubation and artificial ventilation. Rarely a com- plete ‘locked-​in’ state may develop. Autonomic disturbances include tachycardia, hypertension, and then later postural hypotension, bladder atony, and ileus. Papilloedema sometimes develops. This same clinical picture may be caused by any of three patho- logical entities. In Europe and North America, acute inflammatory demyelinating polyradiculoneuropathy is the underlying pathology in more than 90% of cases. Its pathogenesis is unclear but the hy- pothesis that it is due to a T-​cell-​mediated autoimmune response to one of several peripheral nerve myelin proteins is giving way to the idea that it is caused by a complement-​fixing antibody directed against an unidentified ganglioside or combination of gangliosides. In China, Japan, and Mexico most cases are caused by acute motor axonal neuropathy. In such cases preceding Campylobacter jejuni in- fection is common and antibodies to the ganglioside GM1, GD1a, or both are usually present in the serum. Epitopes resembling the terminal sugars of these gangliosides are present in the bacterial walls of the Campylobacter jejuni strains, which induce acute motor axonal neuropathy. The antibodies probably produce the neuropathy by reacting with gangliosides on the axolemma or at the motor nerve terminals, then blocking nerve conduction or inducing axonal de- generation. There is also a less common acute motor and sensory axonal neuropathy. Diagnosis is largely clinical, often supported by neurophysio- logical and cerebrospinal fluid findings, but sometimes all investiga- tions are normal. In AIDP, nerve conduction studies typically show motor nerve conduction block, slowing of motor nerve conduction, often multifocal, and reduced sensory nerve action potential amp- litudes. In the axonal forms of the disease, the changes are those of an axonal neuropathy. During the first week, routine neurophysio- logical tests may be normal. Accurate identification of the neuro- physiological type may require serial studies. The cerebrospinal fluid usually has an increased protein concentration (but often normal in the first week), and normal or sometimes slightly increased leuco- cyte count (rarely more than 10 and by definition not more than 50/​µl), predominantly lymphocytes. Antibodies to gangliosides, especially GM1, may be present, especially in the axonal forms. The differential diagnoses are acute muscle dysfunction (including 24.16  Diseases of the peripheral nerves 6191 hypo-​ or hyperkalaemia), neuromuscular junction disorders, other causes of neuropathy (including drugs, toxins, and vasculitis), and cauda equina, cord, and brain-​stem causes of paralysis. A worse outcome is predicted by older age, preceding diarrhoea and more severe weakness. About a quarter of patients have a be- nign course, never losing the ability to walk. About a quarter re- quire artificial ventilation, accounting for most of the 5% who die, and 20% are left with persistent disability so severe that they need help walking. Of the remainder, most are able to walk with help by 1 month and without aid by 3 months, and return to work or their usual activities by 6 months. Some patients have persistent fatigue. The mainstays of management are careful monitoring for the development of respiratory failure (by forced vital capacity) and cardiac arrhythmia, venous thromboembolism prophylaxis, and excellent intensive care. Plasma exchange or intravenous immuno- globulin (2 g/​kg) improve the rate and extent of recovery if given within the first two, and perhaps four weeks; a repeat course is often given to those not improving (RCT in progress). Corticosteroids are not beneficial. Pain may be a significant problem (see ‘Treatment of neuropathies in general’). Careful positioning and physiotherapy are important to avoid pressure sores and contractures. Exercise programmes are probably useful for fatigue. Deterioration within nine weeks from onset is usually a ‘treatment-​related fluctu- ation’ requiring a repeat course of immunoglobulin, but later re- lapse usually indicates the development of chronic inflammatory demyelinating polyradiculoneuropathy. Neurophysiology does not assist this distinction. Fisher syndrome A syndrome of ophthalmoplegia, ataxia, and loss of the tendon re- flexes was described by Miller Fisher in 1956. Similar to Guillain–​ Barré syndrome, it commonly follows an infection, progresses for a few days, and then plateaus and eventually improves. As in Guillain–​ Barré syndrome, the cerebrospinal fluid protein concentration is usu- ally increased. Facial and bulbar palsies also occur and are accepted as part of the syndrome, but patients with associated limb weakness are regarded as having an overlap with Guillain–​Barré syndrome. In the pure cases, motor nerve conduction remains normal but sensory action potentials disappear. The prognosis is excellent even without immunotherapy. The diagnosis is usually straightforward, but con- fusion with botulism and diphtheritic neuropathy may arise. In most patients with Fisher syndrome, antibodies to ganglioside GQ1b are present in the serum and are probably important in causing terminal nerve damage. Formes frustes of Fisher syndrome, with only some of the features, are sometimes encountered. Bickerstaff’s brain-​stem encephalitis is similar to Fisher syn- drome with additional signs of central nervous system involvement, including altered consciousness and extensor plantar responses. In addition there may be an increased cerebrospinal fluid cell count and abnormalities in the brain stem visible on MRI. Chronic inflammatory demyelinating polyradiculoneuropathy Chronic inflammatory demyelinating polyradiculoneuropathy is a chronic progressive or relapsing disorder with weakness and sensory changes in the limbs developing over more than 8 weeks. Patients whose symptoms stabilize in less than 4 weeks are regarded as having the AIDP form of Guillain–​Barré syndrome (or acute-​onset chronic inflammatory demyelinating polyradiculoneuropathy), whereas those whose symptoms progress over 4–​8 weeks are considered to have subacute inflammatory demyelinating polyradiculoneuropathy. The three disorders probably constitute a spectrum. Chronic inflam- matory demyelinating polyradiculoneuropathy is as an important treatable form of chronic neuropathy which should be distinguished from the many less treatable causes of chronic axonal neuropathy. Its prevalence has ranged from 2 to 9 per 100 000 in different studies. Clinical features suggestive of chronic inflammatory demyelinating polyradiculoneuropathy are proximal and distal weakness of all limbs, loss of all tendon reflexes without much muscle wasting, and raised cerebrospinal fluid (CSF) protein. There may or may not be significant sensory loss. Nerve conduction studies are key to making the diagnosis, and should be repeated if the diagnosis is uncertain. The hallmarks of chronic inflammatory demyelinating polyradiculoneuropathy are multifocal slowing of motor nerve con- duction, often with partial conduction blocks, and prolonged dur- ation of compound muscle action potentials. Sensory nerve action potentials are often reduced or absent. Raised CSF protein, and thickened nerves on imaging, are supportive but not always pre- sent. In typical cases, the clinical features are symmetrical but about 10% of patients have an asymmetric or multifocal disorder called the Lewis–​Sumner syndrome or ‘multifocal acquired demyelinating sensory and motor neuropathy’. There are also pure motor, pure sen- sory, and focal variants. The first-​line treatment is either corticosteroids (daily prednis- olone reducing from 60 mg, or monthly pulses of dexamethasone or methylprednisolone); or intravenous immunoglobulin (initially 2 g/​ kg). Treatment usually needs to be continued for months or longer. Compared with immunoglobulin, corticosteroids have a lower re- sponse rate but are much cheaper and more likely to induce a longer remission. There is no consensus on the regime for long-​term im- munoglobulin, but the largest trial used 1 g/​kg every 3 weeks, and the dose and interval may be adjusted according to the response, which should be assessed by formal outcome measures. Many pa- tients choose to switch to subcutaneous immunoglobulin which may be more convenient with fewer adverse effects. Most patients improve, but those failing to respond should be referred to a spe- cialist to confirm the diagnosis, and to consider further treatments including plasma exchange, azathioprine, or cyclophosphamide. Multifocal motor neuropathy Multifocal motor neuropathy typically causes chronic distal asym- metric weakness in the upper limbs without sensory loss, often associated with IgM antibodies to ganglioside GM1. The diag- nosis depends on nerve conduction studies identifying multiple regions of motor nerve conduction block with preserved sensory nerve conduction through the same nerve segment. Rare patients have no identified conduction block. The only proven treatment is intravenous immunoglobulin (as for chronic inflammatory demyelinating polyradiculoneuropathy, mentioned earlier) but this needs to be repeated approximately every month. Multifocal motor neuropathy may be worsened by corticosteroids. Lyme disease Lyme disease is a multisystem disease caused by tick-​borne spirochaetes belonging to the genus Borrelia (see Chapter 8.6.33). About 3 months after infection and without necessarily having had a preceding rash or arthritis, a small proportion of infected patients section 24  Neurological disorders 6192 develop lymphocytic meningitis, facial palsy, painful radicular symptoms, and/​or rarely a more severe generalized asymmetrical polyradiculoneuropathy. Some develop peripheral nerve lesions without ever having symptomatic meningitis. Serum antibodies to Borrelia are helpful in diagnosis but are common in endemic areas. In a hospital setting measurement of serum/​cerebrospinal fluid anti- body index is very specific but does not detect all cases. Nerve bi- opsies are not usually needed to make the diagnosis but may show extensive inflammatory infiltrates although the spirochaetes are not identifiable. Treatment is usually given in the form of paren- teral ceftriaxone but oral doxycycline is a possible alternative for mild cases. HIV infection A variety of neuropathies may be related to HIV-​1 infec- tion, particularly types tending to occur in different phases of the disease. At the time of seroconversion or soon afterwards, Guillain–​Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, or multifocal vasculitic neuropathy may develop and precede other features of HIV infection. In the later AIDS phase, a distal symmetrical polyneuropathy is common. It is a slowly progressive disorder predominantly affecting small sen- sory fibres that may be painful and similar to the toxic neuropathy produced by reverse transcriptase inhibitors mentioned earlier. In advanced cases an aggressive lumbosacral polyradiculoneuropathy from cytomegalovirus infection is encountered. HIV infection and its treatment are discussed in Chapter 8.5.23. Herpes zoster Varicella-​zoster virus commonly causes ‘shingles’:  neuropathic pain/​itching/​paraesthesiae in the distribution of a sensory derma- tome, with (or without) a vesicular rash. Less commonly there is involvement of more than one dermatome, plexopathy, motor radiculopathy, facial palsy, myelopathy, or meningoencephalitis. Acute antiviral treatment is recommended. Aciclovir does not pre- vent postherpetic neuralgia, which may be treated with standard medications for neuropathic pain (see ‘Treatment of neuropathies in general’) or locally with lidocaine plasters or capsaicin cream. Sarcoid neuropathy Facial palsy is the most common peripheral nerve manifestation of sarcoidosis (see Chapter 18.12). It may be bilateral and accompanied by uveitis and parotitis. Less commonly subacute or fluctuating multiple cranial nerve palsies occur. More rarely, almost any pat- tern of peripheral neuropathy has been seen, including multiple mononeuropathy and a Guillain–​Barré syndrome-​like picture, al- beit usually more subacute. Other manifestations of sarcoidosis, such as erythema nodosum, arthritis, enlarged lymph nodes, uve- itis, and abnormal chest radiographs, are not always present and the diagnosis has to be considered in a variety of neuropathies. The cerebrospinal fluid is abnormal in about half the patients with per- ipheral nerve sarcoidosis. If an accessible nerve can be biopsied, sar- coid granulomas may clinch the diagnosis. Corticosteroids are the mainstay of treatment. Diphtheritic polyneuropathy Diphtheria (Chapter 8.6.1) used to be a serious, even fatal, disease of children. It was almost completely prevented in children by the advent of immunization. As immunity wanes, occasional cases are now seen in adults. It most commonly causes infection of the pharynx (often with a visible grey pseudomembrane), or occa- sionally post-​traumatic cutaneous ulcers. Peripheral neuropathy is caused by the release of an exotoxin that interferes with Schwann cell function, probably by affecting protein synthesis, and produces segmental demyelination. The nerves are not invaded by the bac- terium. Between 1 and 7 weeks after pharyngeal infection, patients may develop numbness of the tongue and face and a bulbar palsy. The bulbar palsy and respiratory involvement may be so severe as to require artificial ventilation. Paralysis of accommodation and some- times of the external ocular muscles may occur. Weakness and sen- sory loss may develop in the limbs, sometimes as the bulbar palsy is beginning to improve. Neuropathy may progress for many weeks, often with a biphasic time course. The disease also causes myocar- ditis. Nerve conduction studies show slowing of motor nerve con- duction. The cerebrospinal fluid protein concentration becomes increased and the cell count may be raised. In particular in those cases with a normal cell count, there is a possibility of confusion with Guillain–​Barré syndrome. Diagnosis can be made by culturing Corynebacterium diphtheriae from the throat, or identifying its toxin or DNA in throat swabs. Treatment is supportive; antitoxin seems beneficial only if given within two days of onset of pharyngitis. Vasculitic peripheral neuropathy Vasculitic peripheral neuropathy usually presents as a painful rap- idly progressive multifocal or asymmetric neuropathy, or sometimes as multiple mononeuropathies or symmetrical polyneuropathy, and sometimes without pain. The neuropathy is typically distal, lower limb predominant, sensory or sensory-​motor, with a stepwise time course. It may precede or follow systemic manifestations of vasculitis. It is caused by many types of systemic vasculitis, most commonly ANCA-​ associated small vessel vasculitides, but also polyarteritis nodosa, in- fections including hepatitis C virus-​associated cryoglobulinaemia, lupus, drug induced, or paraneoplastic. In rheumatoid arthritis, carpal tunnel syndrome and ulnar nerve lesions due to joint derangement are the most common peripheral nerve manifestations, but rheuma- toid vasculitis may cause florid multiple mononeuropathies or some- times a slowly progressive distal sensory neuropathy, or one restricted to the digital nerves. Sometimes vasculitis exclusively affects periph- eral nerves, called non​systemic vasculitic neuropathy, which includes some diabetic syndromes. Diagnosis may be confirmed by biopsy of an affected tissue, including peripheral nerve, muscle, or skin, showing vascular damage and mural inflammation. This is one of the principal indi- cations for nerve biopsy, which should preferably be done in a spe- cialist centre to minimize surgical and laboratory artefact. Treatment of vasculitic neuropathy is the same as the treatment for the underlying disorder. Corticosteroids (usually oral prednisolone) are the mainstay of treatment. In many, especially severe cases, an immunosuppressive agent is also given. Pulsed intravenous (or oral) cyclophosphamide for 3 months followed by azathioprine is com- monly used. Patients may require treatment of neuropathic pain and neurorehabilitation including ankle-​foot orthoses. The neuropathy usually greatly improves over 1–​2 years. Sjögren’s syndrome may cause several types of neuropathy, including vasculitic neuropathy, sensory ataxic neuronopathy 24.16  Diseases of the peripheral nerves 6193 related to dorsal root ganglionitis, or a painful small fibre neur- opathy (see next). Sometimes the trigeminal ganglion is affected in isolation. Neoplastic and paraneoplastic neuropathy Direct invasion of cranial nerves or spinal roots may occur in malig- nant infiltration of the meninges and of the brachial and lumbosacral plexus from local malignancies. Malignant infiltration is usually painful. Infiltration of peripheral nerves is most commonly from malignant lymphomas. Rarely, generalized infiltration may occur to produce multifocal neuropathy or even an acute neuropathy resem- bling Guillain–​Barré syndrome. CSF cytology requires at least 5 ml of fresh CSF and may need to be repeated as sensitivity for detection of malignant cells is low. Paraneoplastic neuropathy may develop as a non​metastatic, autoimmune complication of carcinoma, most often bronchial or gastric, and occasionally with lymphoma. The underlying neo- plasm often pursues an unusually indolent course, suggesting that the autoimmune process is holding the neoplasm in check, but may be identified by positron emission tomography scanning. The neuropathy may antedate the discovery of the carcinoma by up to 3 years. A wide variety of clinical pictures has been reported. The most common syndrome is the subacute sensory neuronopathy (dorsal root ganglionopathy) usually associated with a small cell lung carcinoma and anti-​Hu antibodies. This presents with a se- vere sensory ataxia and areflexia, often worse in upper limbs and with autonomic disturbance, or sometimes burning pain. Sensory neuronopathy may also be idiopathic or caused by Sjögren’s syn- drome or HIV. Other paraneoplastic neuropathies include potas- sium channel antibody-​associated neuromyotonia, or vasculitis. Carcinoma of the bronchus is associated with other types of neur- opathy, including a slowly progressive mixed sensory and motor neuropathy. Paraneoplastic neurological syndromes often occur in combinations. Gynaecological cancers are particularly associ- ated with a cerebellar syndrome and antibodies to Purkinje cells (anti-​Yo antibodies). Peripheral neuropathy may be part of this syndrome. Paraneoplastic neuropathies may stabilize after removal of the underlying tumour, but rarely improve and immunotherapy is rarely beneficial. Paraprotein-​associated neuropathy Both peripheral neuropathy and monoclonal gammopathy of undetermined significance (MGUS) become more common with advancing age, so the association is not necessarily causa- tive. In a demyelinating neuropathy, an IgM paraprotein is usu- ally causative, but the presence of an IgG or IgA MGUS is usually coincidental as these patients (and some with IgM MGUS) be- have in every respect like patients with chronic inflammatory demyelinating polyradiculoneuropathy without a paraprotein. In an axonal neuropathy, the presence of any paraprotein is probably coincidental unless there is amyloidosis or a malignant plasma cell dyscrasia. The most common syndrome is an IgM paraprotein-​associated demyelinating neuropathy, half of whom have antibodies to myelin-​ associated glycoprotein. The characteristic features are of a slowly progressive distal, predominantly sensory, demyelinating neur- opathy, often with a postural tremor and ataxia. Neurophysiology shows characteristic predominantly distal motor slowing. Nerve biopsy may show widely spaced myelin lamellae. Most patients have MGUS, but bone marrow biopsy and CT body scan are recom- mended to identify the minority of patients with identical neuro- logical features who have Waldenström’s macroglobulinaemia. About one-​third of patients respond to intravenous immuno- globulin, rituximab, cyclophosphamide, bendamustine, or combinations. In the rare CANOMAD syndrome (chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialo- syl antibodies), antibodies are present against gangliosides GQ1b or GD1b. Other rare syndromes of MGUS-​associated neuropathies are likely due to as-​yet unidentified antibody properties of their paraproteins. Malignant plasma cell dyscrasias may affect the peripheral ner- vous system. Multiple myeloma deposits may compress spinal nerve roots, causing pain and radicular symptoms as well as cord compres- sion, but does not usually cause a neuropathy except as an adverse effect of treatments such as bortezomib or thalidomide. The mixed cryoglobulins in essential cryoglobulinaemia, some- times associated with hepatitis C infection, cause a vasculitic mul- tiple mononeuropathy. The treatment is that of the underlying condition. The POEMS syndrome (polyneuropathy, organomegaly, oedema, monoclonal protein, and skin changes) is a multisystem paraneoplastic disorder with osteosclerotic myeloma (or solitary plasmacytoma or Castleman’s disease), usually IgG or IgA lambda paraprotein, very high serum concentration of vascular endothelial growth factor, and a mixed axonal and demyelinating neuropathy, often painful. Not all the features in the name are required; papilloedema and thrombocytosis may occur. Sclerotic bone lesions should be sought by CT or PET of spine, pelvis or whole body. Treatment may be by irradiation, melphalan-​based chemotherapy, or peripheral blood stem cell transplantation. Amyloidosis The various forms of amyloid disease are described in Chapter  12.12.3. The peripheral nerves may be involved in pri- mary amyloid light-​chain amyloidosis (due to plasma cell dyscrasia such as myeloma, typically with lambda light chains), or in familial amyloid polyneuropathy (see Genetic neuropathies), but not in secondary amyloidosis due to chronic inflammation. The clinical features are similar, typically with a painful sensory (predomin- antly small fibre) polyneuropathy with early prominent autonomic dysfunction (as described earlier for diabetes). Carpal tunnel syn- drome is common, because of deposits in the flexor retinaculum. Large fibre sensory and motor involvement occur later. Sometimes the neuropathy is asymmetric or multifocal. Amyloid deposits are present in the peripheral nerve trunks, which may be enlarged, and in the dorsal root and sympathetic ganglia. Carpal tunnel syndrome (without generalized neuropathy) is also frequent in patients with amyloidosis due to wild-​type transthyretin, or to β2-​microglobulin in long-​term haemodialysis. Diagnosis is by biopsy of an affected tissue, with measurement of serum free light chains or serum and urine electrophoresis (Bence-​ Jones protein). Amyloid light-​chain amyloidosis may respond to chemotherapy or peripheral blood stem cell transplantation. Pain and autonomic symptoms may require treatment as described here earlier for diabetic neuropathy. section 24  Neurological disorders 6194 Genetic neuropathies Charcot–​Marie–​Tooth disease and related disorders Charcot–​Marie–​Tooth disease (CMT, a hereditary motor and sen- sory neuropathy) usually presents during childhood or adolescence (sometimes much later) with difficulty in walking or because of foot deformity. There are over 60 causative genes, so patients are grouped into phenotypic types. Charcot–​Marie–​Tooth disease type 1 (CMT1) is caused by a demyelinating neuropathy with markedly slowed conduction velocities (upper limb motor conduction vel- ocity <38 m/​s). Charcot–​Marie–​Tooth disease type 2 (CMT2) is due to an axonal neuropathy with relatively preserved conduction vel- ocities. Most types are dominantly inherited, but a family history may be absent. The clinical pictures of most forms of CMT are similar. Foot de- formity is common and consists of a high arch, or pes cavus, and clawing of the toes, sometimes with an equinovarus deformity, often causing mechanical pain. (A high arch without bony deformity is not specific for CMT and may be due to foot muscle wasting from any severe axonal neuropathy). Muscle weakness tends to affect distal leg muscles, sometimes with an ‘inverted champagne bottle’ leg appearance (Fig. 24.16.3), and may give bilateral foot drop with a high stepping gait. Weakness and wasting of the small hand muscles may appear later. The tendon reflexes become depressed or lost, and there is a variable degree of distal sensory loss. Sensory action poten- tials are paradoxically often severely affected despite minimal or no sensory symptoms or signs. Progress of the disease is slow and cases with little disability or that are asymptomatic are common. The most common form is CMT1a, accounting for 70% of all cases. It is caused by duplication of the gene for peripheral myelin protein 22 (PMP22). The onset is most frequently in the first decade. Foot deformity and scoliosis occur more often than in CMT2, sen- sory loss and ataxia tend to be greater, and generalized tendon areflexia is usual. The peripheral nerves may be palpably thickened. The next most common is a mutation in GJB1 (coding for connexin-​32) causing X-​linked CMT; women may be asymptom- atic or only mildly affected by an axonal neuropathy, whereas men usually have a somewhat multifocal demyelinating neuropathy which may be confused with chronic inflammatory demyelinating polyradiculoneuropathy on neurophysiology or have intermediate conduction velocity. Typically the abductor pollicis brevis muscle is disproportionately weaker than the first dorsal interosseous. The third most common is a mutation in myelin protein zero. The genetic diagnosis of CMT is developing rapidly. If first-​line single gene tests are negative then next-​generation sequencing can simultaneously test a panel of multiple genes but is expensive and still identifies only a quarter of patients with axonal neuropathy. An appropriate diagnostic strategy in suspected genetic neuropathy is first to assess whether axonal or demyelinating by neurophysiology. If demyelinating, test PMP22 duplication first, then GJB1 if no male–​ male transmission, then a gene panel. If axonal, classify clinically into one of three phenotypes for which gene panels are available: sensory predominant (hereditary sensory neuropathy), motor predominant (hereditary motor neuropathy), or mixed motor-​sensory (CMT2). Rare forms cause severe early-​onset demyelinating neuropathy pre- senting in infancy, or tremor. Affected individuals may be helped by advice on foot care per- haps from a podiatrist, the use of orthotic appliances which improve mechanical pain and gait, and sometimes by surgical correction of foot deformity or tendon transfer. As yet, there are no disease modi- fying therapies for any type. Hereditary neuropathy with liability to pressure palsies This is a common, relatively mild, autosomal dominant disorder, usually caused by a deletion of the same PMP22 gene which is du- plicated in CMT1a. It is typically diagnosed when a patient has evidence of several nerve entrapments (especially carpal tunnel syndrome and/​or ulnar neuropathy) together with a mild general- ized demyelinating neuropathy shown on nerve conduction studies. Many patients are asymptomatic and a few have pain. Treatment is by decompression of any symptomatic entrapments. Distal hereditary motor neuropathies Hereditary motor neuropathies resemble CMT but lack significant sensory involvement. There are multiple causative genes, but even modern gene panels identify only a minority of patients. Some types have upper limb predominance (such as GARS or BSCL2) and some have upper motor neuron signs. Distal wasting and weakness are sometimes instead due to a distal myopathy, a distinction that can be difficult even with electromyography. Hereditary sensory (and autonomic) neuropathies Hereditary sensory and autonomic neuropathies are much less common than CMT. As the name implies they are usually predom- inantly sensory and autonomic but motor involvement does occur, leading sometimes to overlap with the phenotype of CMT. They pre- dominantly affect the small sensory nerve fibres subserving pain and temperature. As the autonomic abnormalities are generally milder Fig. 24.16.3  Patient with Charcot–​Marie–​Tooth disease type 1 (CMT1) showing symmetrical distal lower limb muscle wasting. 24.16  Diseases of the peripheral nerves 6195 than the sensory abnormalities, they may be called hereditary sen- sory neuropathies. The sensory loss often leads to a mutilating acropathy, with neuropathic joint degeneration (Charcot joints) and chronic cutaneous ulceration, particularly of the feet (Fig. 24.16.4). Neuropathy as part of multisystem genetic diseases (See also Section 12.) Neuropathy may be one manifestation of the many forms of hereditary ataxia, spastic paraplegia, mitochondrial disease, dis- orders of lipid metabolism, or of DNA repair. For example, per- ipheral nerve involvement occurs in metachromatic and globoid cell leucodystrophy, adrenomyeloneuropathy, Fabry’s disease (pre- dominantly small fibre), hereditary high-​density lipoprotein de- ficiency (Tangier disease), hereditary abetalipoproteinaemia, and cholestanolosis. Giant axonal neuropathy is a rare, childhood-​onset, autosomal recessive disorder characterized by segmental axonal enlargements containing accumulations of neurofilaments due to a mutation in the gigaxonin gene. Affected children usually have abnormally curly kinky hair and may have central nervous system abnormalities. Porphyria (See also Chapter 12.5.) A predominantly motor neuropathy may complicate acute severe attacks in the rare autosomal dominant disorders of acute inter- mittent and variegated porphyria and hereditary coproporphyria, and in the recessively inherited δ-​aminolaevulinic acid dehydratase deficiency. The neuropathy is usually preceded by colicky abdom- inal pain and mental disturbances including confusion, psychosis, and epilepsy. The neuropathy develops acutely during an acute at- tack of porphyria and resembles Guillain–​Barré syndrome. It is often predominantly proximal, affects the motor more than sensory nerves and may affect the cranial nerves. Autonomic features in- clude tachycardia, hypertension, pupillary dilatation, constipation, and sweating. The best diagnostic screening test is measurement of urine porphyrins during an acute attack. Acute attacks should be treated with intravenous glucose and haem arginate to reduce the formation of porphyrin precursors. Familial amyloid polyneuropathy A painful axonal polyneuropathy similar to amyloid light-​chain amyloidosis may be caused by several genetic conditions. The most common are those related to point mutations in the gene for transthyretin. The neuropathy begins with the involvement of small nerve fibres, leading to a distal loss of pain and tempera- ture sensation and autonomic failure; occasionally the neuropathy is demyelinating. Spontaneous pain is often a feature and a muti- lating acropathy may develop. The onset is commonly in the fourth or fifth decade and the disorder is slowly progressive, leading to death within about 10 years. Transthyretin is produced mainly in the liver and liver transplantation may halt progression of the dis- ease (see Chapter 12.12.3). Amyloid stabilizers such as tafamidis and diflunisal may slow progression, but highly effective gene silencing therapies are becoming available. Hereditary amyloid neuropathy can also be caused by mutations in the gene for other proteins which have differing clinical features. In the Iowa form, the amyloid is de- rived from a mutated form of apolipoprotein A1 and causes a painful predominantly sensory neuropathy. In the Finnish form, there is a mutation in the gene for the plasma protein gelsolin, and the neur- opathy affects the cranial nerves and is associated with a corneal lat- tice dystrophy. Refsum’s disease Refsum’s disease is a rare, autosomal recessive, progressive multisystem disorder causing features including demyelinating motor-​sensory polyneuropathy, ataxia, pigmentary retinal degeneration, anosmia, deafness, cardiomyopathy, and ichthyosis. The presentation is usu- ally with night blindness during adolescence. The disorder is usually due to mutations in the PHYH gene. The best diagnostic test is raised serum phytanic acid. Treatment is with a diet low in phytanic acid, and sometimes plasma exchange for acute exacerbations. Chronic idiopathic axonal polyneuropathy Despite extensive investigation, the cause of about one-​quarter of cases of late-​onset symmetrical polyneuropathy remains unknown. Such cases are probably heterogeneous and may reflect undiagnosed alcohol abuse, carcinoma, or forms of CMT2. For those in whom no cause can be found the term ‘chronic idiopathic axonal poly- neuropathy’ is often used. This is a syndrome of slowly progressive, predominantly sensory neuropathy in older people. Numbness and paraesthesiae, often painful, spread from the toes up the legs and become associated with unsteadiness. It progresses very slowly over years and rarely becomes seriously disabling, although the pain may be distressing and require treatment (see ‘Treatment of neuropathies in general’). In some patients, there is evidence of impaired glucose or lipid metabolism, and it is likely that in some the underlying cause is related to the metabolic syndrome. Fig. 24.16.4  Chronic foot ulceration and deformity in a case of hereditary sensory neuropathy. section 24  Neurological disorders 6196 Small fibre neuropathy This is an abnormality predominantly of the small sensory (Aδ and C) nerve fibres affecting pain, temperature, and autonomic function. Typical symptoms are chronic painful paraesthesiae, often feeling burning hot or cold, starting distally in the feet. On sensory exam- ination, some patients have hypersensitivity with hyperalgesia and distortion of sensation so that normally non​painful stimuli appear painful (allodynia), and others have reduced sensitivity to pinprick and temperature. Large-​diameter nerve fibre functions remain rela- tively normal, including power, coordination, reflexes, and sensa- tion to light touch, vibration, and joint position. Conventional clinical neurophysiological tests are normal because the sensory nerve action potentials derive from the large, not the small, nerve fibres. Various investigations are used in some specialist centres to support the diagnosis which otherwise has to be made on clinical grounds. Probably the most reliable test is skin biopsy to assess reduction of intraepidermal nerve fibre density, though this correlates poorly with pain. Alternatives include quantitative sen- sory testing of temperature thresholds, corneal confocal microscopy, contact heat-​ or laser-​evoked potentials, sympathetic skin response, laser Doppler imaging of flare response, or microneurography. There are many possible underlying causes, some treatable, most commonly diabetes or prediabetes, but also dyslipidaemia, chronic kidney disease, alcohol, HIV, hepatitis C, vitamin B12 deficiency, coeliac disease, Sjögren’s syndrome, amyloidosis, drug-​induced (especially chemotherapy), paraneoplastic, various genetic causes (including sodium channelopathies), and many cases are idiopathic. Treatment is of the underlying cause, but there are rare acute steroid-​responsive cases. Some cases of fibromyalgia are due to small fibre neuropathy. The syndrome with erythema of the feet during exacerbations of pain is termed erythromelalgia. Symptomatic treatment is with drugs for neuropathic pain such as amitriptyline, pregabalin, and duloxetine, or local treatment with capsaicin cream 0.075% or lidocaine 5% medicated plasters. FURTHER READING Birch R, Bonney C, Wynn Parry CB (1998). Surgical disorders of the peripheral nerves. Churchill Livingstone, Edinburgh. Collins MP, et al. (2010). Peripheral Nerve Society Guideline on the classification, diagnosis, investigation, and immunosuppressive therapy of non-​systemic vasculitic neuropathy. J Peripher Nerv Syst, 15, 176–​84. Dyck PJ, Thomas PK (2005). Peripheral neuropathy, 4th edition. W B Saunders, Philadelphia, PA. England JD, et  al. (2009). Practice parameter:  evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-​based review). Report of the AAN, AANEM and AAPMR. Neurology, 72, 185–​92. Hughes RAC, et al. (2005). Supportive care for Guillain–​Barré syn- drome. Arch Neurol, 62, 1194–​8. Joint Task Force of the EFNS and the PNS (2010). European Federation of Neurological Societies/​Peripheral Nerve Society Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force—​first revision. J Peripher Nerv Syst, 15, 185–​95. Latov N (2014). Diagnosis and treatment of chronic acquired demyelinating polyneuropathies. Nat Rev Neurol, 10, 435–​46. O’Brien MD (2010). Aids to examination of the peripheral nervous system, 5th edition. W.B. Saunders, Philadelphia, PA. Rossor AM, Evans MRB, Reilly MM (2015). A practical approach to the genetic neuropathies. Pract Neurol, 15, 187–​98. Stewart JD (2000). Focal peripheral neuropathies, 3rd edition. Lippincott, Williams & Wilkins, Philadelphia, PA. van den Berg B, et  al. (2014). Guillain–​Barré syndrome: patho- genesis, diagnosis, treatment and prognosis. Nat Rev Neurol, 10, 469–​82. van den Bergh P, et al. (2010). European Federation of Neurological Societies/​Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy:  re- port of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—​first revision. Eur J Neurol, 17, 356–​63. van Schaik IN, et al. (2010). European Federation of Neurological Societies/​Peripheral Nerve Society guideline on management of multifocal motor neuropathy. In: European handbook of neu- rological management, 2nd edition, vol. 1, pp. 343–​50. Wiley, Chichester. Websites Cochrane Library. http://​www.cochranelibrary.com/​ National Center for Biotechnology Information. Online Mendelian Inheritance in Man (OMIM). http://​www.ncbi.nlm.nih.gov/​sites/​ entrez?db=omim Washington University School of Medicine in St Louis. WU Neuromuscular. http://​neuromuscular.wustl.edu/​naltbrain.html 24.17 Inherited neurodegenerative diseases 6197 Sw 24.17 Inherited neurodegenerative diseases 6197 Swati Sathe ESSENTIALS Many disorders of the nervous system, especially the degenerative conditions, have a genetic basis, which is usually due to a mutated gene resulting in decreased production of a critical structural or regu- latory protein. When evaluating a patient with a possible neurodegenerative condition, the following are critical; (1) asking the question, is this a sporadic or inherited condition? (2) taking a detailed family history; (3) establishing an accurate age of onset and history of progression; (4) concentration on the first clinical manifestations of disease, which may give critical clues to diagnosis; (5) conducting a careful general examination, looking for signs outside the nervous system; (6) logical investigation, remembering the key point that, while a clinical diag- nosis of a genetic disorder can be confirmed by the identification of a potentially pathogenic gene mutation in a patient with signs and symptoms consistent with that disorder for whom alternative or coexisting disorders have been excluded, much less diagnostic cer- tainty is provided when genetic testing identifies a gene variant of un- known clinical significance, or when a potentially pathogenic gene variation is discovered in a patient whose clinical syndrome does not conform to the genetic condition. This chapter reviews and provides a guideline for inherited neurodegenerative disease. It is organized in a manner that a good neurological examination would be organized (i.e. systemic dis- orders followed by neurological disorders), discussed in a top-​down manner (i.e. from cortex to muscle). Discussion of individual dis- orders starts with the molecular genetics, followed by molecular pathology, histology, clinical features, investigational findings, and management. The disorders are grouped in 12 sections: Neurocutaneous syndromes (phakomatoses)—​disorders that pre- sent with skin and brain as their primary organs of affection. Defects in DNA repair—​for example, xeroderma pigmentosum, ataxia-​telangiectasia, and Cockayne’s syndrome, which present with a variety of abnormalities, including in many conditions a propensity to various cancers and skin abnormalities. Metabolic disorders with neurological system as the primary organ of affection, including (1) Leucodystrophies—​these are dis- orders which have a genetic basis, a progressive clinical course, primary involvement of white matter, and a demonstrable bio- chemical or molecular defect. The primary leukodystrophies can be classified into three subgroups: (a) classic dysmyelinative disorders (e.g. X-​linked adrenoleukodystrophy, metachrom- atic leukodystrophy); (b)  hypomyelinative with delayed or decreased myelin production (e.g. Pelizaeus–​Merzbacher dis- ease); and (c) vacuolating myelinopathies (e.g. Canavan’s dis- ease). (2) Metabolic disorders (e.g. various mitochondrial and lysosomal storage diseases, amino and organic acidemias, some glycogen storage diseases). 4. Dementing disorders—​the genetic basis of common and gen- erally sporadic disorders is discussed, including Alzheimer dis- ease, frontotemporal dementia, Lewy body dementia, and prion diseases. 5. Inherited epilepsy syndromes—​these are often caused by defects in genes regulating voltage-​ or ligand-​gated ion channels, but epi- lepsy is also a feature of several lysosomal storage diseases and many other inborn metabolic disorders. 6. Headache disorders—​with focus on inherited small vessel disease presenting as migraine, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). 7. Movement disorders—​basal ganglia pathology is a principal feature of these conditions, which include Wilson disease, Huntington disease, Parkinson’s disease, neuroacanthocytosis, neurodegeneration with brain iron accumulation, and heredi- tary dystonias. 8. Hereditary ataxias—​these can be grouped as autosomal dominant ataxias, X-​linked and autososmal recessive (e.g. Friedreich ataxia) ataxias, rare but treatable ataxias, and epi- sodic ataxias. Pathology involves primarily the cerebellum and/​ or spinocerebellar tracts. 9. Hereditary spastic paraplegias—​the pyramidal tracts of the spinal cord are a major site of pathology in this group of conditions, which have extremely wide clinical variability in age of onset, se- verity, course, presence and degree of weakness, and occurrence of other neurologic signs. 10. Motor neuron diseases—​including spinal muscular atrophy and amyotrophic lateral sclerosis. 24.17 Inherited neurodegenerative diseases Swati Sathe section 24  Neurological disorders 6198 11. Disorders of the peripheral nerve—​these include autosomal dom- inant demyelinating genetic neuropathies, hereditary sensory, and motor neuropathies, hereditary motor neuropathies. 12. Muscle disorders—​these include dystrophinopathies (Duchenne and Becker muscular dystrophy), myotonic dystrophies, limb-​ girdle muscular dystrophies, distal myopathies, hereditary in- clusion body myopathies, congenital muscular dystrophies, and congenital myopathies. Introduction It is increasingly recognized that numerous disorders of the ner- vous system, especially the degenerative conditions, have a genetic basis. Even so, these disorders may be difficult to recognize as such because of dearth of specific signs, slow progression of symptoms, and lack of definite family history. Inherited neurodegenerative dis- orders present an enormous challenge because of the complexity of the nervous system, the broad clinical and genetic heterogeneity characteristic of these diseases, and the progressive and generally ir- reversible nature of their neuropathology. A mutated gene is gener- ally at fault, often resulting in decreased production of a structural or regulatory protein important for the development or normal func- tioning of a special part of the nervous system. Neurogenetics combines studies in the fields of Neurosciences and Genetics to understand the role of genes in the development, maintenance, and preservation of function of the nervous system. Unprecedented expansion of knowledge and techniques in the field of molecular genetics has led to great advances in our understanding of the basis of inherited neurological disease. This translates in to the clinical field as availability of a range of molecular, cytogenetic, and biochemical tests, which brings with it the need for a systematic approach to narrow diagnostic possibilities to facilitate judicious use of these tests. This chapter aims to equip the general physician to be able to recognize signs and symptoms of an inherited neurologic disease and initiate work-​up. Clinical approach Several factors should be considered in evaluation of a patient pre- senting with a possible neurodegenerative disease. Is the patient’s condition sporadic or inherited? Several seemingly sporadic disorders are now known to be late-​ onset forms of inherited disorders. Very often, especially in cases of lysosomal disorders or enzyme deficiencies, where residual en- zyme activity dictates the phenotype of the disease, late-​onset forms with higher residual activity may manifest in a completely different manner. For example, late-​onset Tay–​Sachs disease presents as a motor neuron and cerebellar disease and thus lacks classic features of infantile Tay–​Sachs, namely cognitive decline, seizures, or cherry red spot. Similarly, a divergent mutation, unlike the one known to cause the classic manifestation of a disorder, may modify the pheno- type significantly (e.g. shorter expansion of the trinucleotide repeat presents as adult-​onset tremor-​ataxia syndrome in case of Fragile X syndrome, quite unlike the mental retardation phenotype seen in young boys with longer repeats). Similarly, late-​onset forms an autosomal recessive of disease are very likely to be interpreted as sporadic (e.g. in case of very late-​onset Friedreich ataxia, where a presentation as such after the age 40 would otherwise be considered unlikely). Consistent loss of neurological function, involvement of more than one neurological pathways and lack of an obvious ac- quired aetiology should be prompt clinicians to consider the possi- bility of an inherited neurodegenerative disease. Family history A detailed three-​generation family history should be obtained with emphasis on any related neurological symptoms, keeping in mind that genetic disorders have variable expression and penetrance. This leads to intrafamilial variability in clinical presentation. In CADASIL, for example, families are described where younger indi- viduals were severely disabled while their senior relatives were much less impaired. Family history may be lacking in autosomal recessive disease or in situations where the index case is adopted. Knowledge of consanguinity is helpful with respect to recessive conditions, and a maternal inheritance pattern, which is especially common in neurological diseases, is consistent with mitochondrial gene dis- order. The clinician interested in neurogenetics should also be- come familiar with other disease-​causing genetic mechanisms such as the effects of genetic imprinting (parent-​of-​origin effect), uniparental disomy, chromosomal disorders, and the effects of spontaneously occurring major rearrangements within and be- tween chromosomes. Modifier genes may also have a profound effect on penetrance (i.e. whether a disease-​causing gene is ex- pressed or remains silent). Age of onset and progression Elucidation of the molecular defects in classic forms of neurogenetic disorders has permitted an expansion of the phenotypic spectrum to include both earlier onset of more severe variants as well as later, adult-​onset forms of disease. Thus, a practitioner experienced in geriatrics cannot ignore the possibility of a typical childhood-​onset disorder first appearing in late adult life, nor can the paediatrician discount the likelihood of a classic adult-​onset condition presenting in childhood. The age at which a patient reports that their symp- toms began may not be true age of onset (e.g. patients may report that they became unable to walk in their twenties in some congenital muscular dystrophies or myopathies, but there is often history of hypotonia, delayed motor milestones, congenital dislocation of hip, or pulmonary infections in infancy). Additionally, in their teens and young adulthood they may have had difficulty keeping up with their peers in sports. This indicates a ‘congenital’ onset rather than ‘late’ onset form of the disease. How did the disease begin? The earliest clinical signs in most inherited diseases of the nervous system refer to one neuroanatomical region or pathology specific to that disease. It may be the cortex as in dementias, the underlying white matter as in many leucodystrophies, the pyramidal tract as in the hereditary spastic paraplegias, the extrapyramidal system affected in various movement disorders, or cerebellar–​spinal pathways typical of the spinocerebellar degenerations. It there- fore behoves the clinician to take note of the earliest signs and 24.17  Inherited neurodegenerative diseases 6199 symptoms, and to extract from the examination an indication of the principal anatomical system(s) involved. Delineating and enumerating at the end of the evaluation each subsystem of the nervous system is a good technique (i.e. observe for signs of cor- tical, subcortical, basal ganglia, brain stem, cerebellar, spinal cord, peripheral nerves, neuromuscular junction, or muscle involve- ment), and then consider a disorder or a syndrome that encom- passes those specific pathways. General examination and investigation The presence of extraneural clues such as specific signs involving the eyes, skin, connective tissues, or visceral organs may point towards certain inborn errors of metabolism. Important find- ings that are of particular significance include corneal clouding or cataracts, abnormalities in skin pigmentation, musculoskeletal abnormalities, dysmorphic features, or enlargement of the liver and/​or spleen. Important diagnostic clues come from investigations that indicate disorders of pathways involving amino acids, organic acids, lipids, carbohydrates, purines, and pyrimidines, heavy metals, porphy- rins, and vitamins. Based on clinical picture and biochemical tests of urine and blood, it is possible to localize the abnormality to par- ticular subcellular elements such as the mitochondria, lysosome, or peroxisome. Although ultimately DNA analysis will lead to a specific diag- nosis, there are many tools to assist the clinician in obtaining the correct clinical diagnosis. These include various neuroimaging tech- niques, neurophysiology studies, microscopic studies of blood cells and tissue biopsies, and biochemical analyses of blood, urine, cere- brospinal fluid, and cultured skin cells. Judicious choices of confirmatory studies need thoughtful con- sideration of the history, clinical findings, and family history, often in consultation with a neurometabolic disease specialist. A  cau- tionary remark regarding DNA testing is appropriate. The clinical diagnosis of a genetic disorder can be confirmed by the identifica- tion of a potentially pathogenic gene mutation in a patient with signs and symptoms consistent with that disorder for whom alternative or coexisting disorders have been excluded. Much less diagnostic certainty is provided when genetic testing identifies a gene variant of unknown clinical significance, or when a potentially pathogenic gene variation is discovered in a patient whose clinical syndrome does not conform to the genetic condition. This is extremely im- portant given the increasing availability of testing with large (and expensive) multigene panels. Management Inherited diseases of the nervous system, particularly as seen in adults, present in a slow progressive manner after a prolonged pre-​ symptomatic or pauci-​symptomatic period of several decades. This creates difficulties in therapeutic attempts to reverse a pathological process that is advanced and already associated with significant cell loss, as well as in counselling and preventing further cases within the same family. Hence, where there are therapies, prospects for new- born screening are being considered. In cases of disorders with se- vere morbidity and/​or mortality that are as yet untreatable, prenatal diagnosis, often using pre-​implantation testing, is considered. Use of this technology pre-​supposes knowledge of a specific genetic marker within a family for the disease in question. Section I: Neurocutaneous syndromes (phacomatoses) The phakomatoses are disorders affecting mainly the skin along with the central and peripheral nervous systems, characterized by multiple hamartomas and other congenital malformations. Four classical neurocutaneous syndromes include neurofibromatosis, tu- berous sclerosis, Sturge–​Weber syndrome, and von Hippel disease. Over the years, more than 60 neurocutaneous syndromes have been described. Affected individuals often have an increased genetic sus- ceptibility to develop malignancies as these diseases involve defects in tumour-​suppressor genes. Neurofibromatosis 1 Neurofibromatosis 1 (NF1) (MIM 162200), also called von Recklinghausen’s disease, is the commonest of the phacomatoses and one of the most common autosomal dominant disorder, with an in- cidence of 1 in 4000 live births and prevalence of 1 in 5000 without any predilection for ethnicity or gender. It is often inherited from a more mildly affected parent; random somatic mutation of the one re- maining functional NF1 gene is believed to be required for tumour formation. The NF1 gene that maps to chromosome 17q11.2, codes for neurofibromin. Diverse functions of protein neurofibromin are impli- cated in the breadth of clinical and imaging manifestations seen in pa- tients with NF-​1. The functions of the NF1 gene include: (1) Tumour suppression via negative regulation of the p21 RAS proto-​oncogene. (2) Regulation of neural stem cell proliferation, survival and astroglial differentiation, and neuroglial progenitor function. (3) Maintenance of the vascular wall. (4) Normal myelination by Schwann cells: the gene for oligodendrocyte myelin glycoprotein, a major myelin protein, is em- bedded within intron 27b of the NF1 gene. (5) Bone formation and re- modelling. Thus, alteration in the function of neurofibromin leads to abnormalities of brain formation (especially myelination), tumours, vascular lesions and osseous abnormalities/​skeletal dysplasias. NF1 may be suspected in early childhood but will not develop into the full-​blown condition for several years. The first feature to appear are café-​au-​lait macules, which may be present as early as at birth or appear during the first few months of life. There must be six or more café-​au-​lait spots to meet diagnostic criteria. Freckling in areas not exposed to sun such as the axilla occurs next, usually by school age, followed by development of Lisch’s nodules, which are melanotic hamartomas of the iris that can be seen as whitish, yellow, or brown spots on visual inspection in patients with light-​coloured irises, but often require slit-​lamp examination. Dermal neurofibromas ranging from a few millimetres to a centimetre or more appear at puberty, which are made of Schwann cells, fibroblasts, and mast cells. They are flesh coloured; when pressed, they invaginate through the skin (‘button-​holing’). Patients may have only a few or may have thou- sands of these ‘mollusca fibrosa’. These tumours may be cutaneous or subcutaneous, or extend into multiple nerves forming plexi- form neurofibromas (Fig. 24.17.1) producing diffuse enlargement of major nerve trunks. About 40% of patients develop plexiform neurofibromas, which have a 5–​10% risk of malignant transform- ation with poor overall survival rate. A small percentage of patients develop optic pathway gliomas, which do not appear to cause any ophthalmological symptoms. Scoliosis occurs in 21% of patients and may be dystrophic or non​dystrophic; the latter is characteristic of section 24  Neurological disorders 6200 NF1, is rapidly progressive, and has a worse prognosis (Fig. 24.17.2). Phaeochromocytoma, renal artery stenosis, and precocious pu- berty are also encountered. Learning disabilities, attention deficit disorder, intellectual impairment, seizure disorder, and psychi- atric manifestations may appear in a small percentage of patients. Pilocytic astrocytomas also develop most commonly in the optic nerve, chiasma, and tract. Focal neurologic signs may be caused by dumbbell shaped neurofibromas arising from nerve roots with extraspinal and intraspinal components. Patients may therefore present with signs and symptoms of spinal cord compression or cauda equina syndrome. Diagnostic criteria for NF1 are enumer- ated in Box 24.17.1. Segmental NF is described in individuals with the mosaic form of NF1 with features usually limited to one or more regions of the body. A somatic mutation that occurs late in embryonic develop- ment can result in disease localized to a segment. Patients are still susceptible to NF complications or transmission to offspring. Brain magnetic resonance imaging (MRI) T2-​weighted images re- veal high-​intensity, non​enhancing lesions, most often found in the brainstem, thalamus, cerebellum, and basal ganglia but not in sub cortical white matter. These tend to disappear by late adolescence or early adulthood. Optic pathway gliomas involving the optic nerves, chiasm and frequently the optic tracts are seen in about 20% of NF1 patients almost always before the age of six years (Fig. 24.17.3). Common vascular abnormalities seen on imaging include stenoses, occlusions, ectasia, moyamoya disease, and fusiform aneurysm for- mation. Skeletal changes associated with mesodermal dysplasia in- clude posterior vertebral body scalloping; thinning of the pedicles, transverse processes, and lamina; foraminal enlargement; sphenoid wing dysplasia and cortical thinning; periosteal proliferation; scler- osis; and bowing of the long bones (Fig. 24.17.2). The goals of evaluation and follow-​up are to confirm the diagnosis of NF, provide genetic counselling, detect emergence of treatable complications, and optimize quality of life. Plexiform neurofibromas causing pressure symptoms may necessitate excision and others may merit removal for cosmetic reasons; they often recur. Rapid expan- sion of a tumour, the development of pain, and loss of neural func- tion suggest malignant change, and this occurs most often during adolescence or in young adults. Early treatment with wide surgical resection, with or without adjuvant chemotherapy or radiotherapy is indicated. Development of hypertension will require investigation for phaeochromocytoma, and spinal deformity may need ortho- paedic attention. Follow-​up annually in a multidisciplinary neuro- fibromatosis clinic is advisable. Neurofibromatosis 2 Neurofibromatosis 2 (NF2) (MIM 101000) is also autosomal dom- inant but is much less common than NF1 with a frequency of 1 in 40 000 live births and prevalence of 1 in 200 000. The NF2 gene is located on the long arm of chromosome 22 and encodes merlin or schwannomin, a protein expressed in neurons, the lens of the eye, blood vessels, leptomeningeal cells, astrocytes, gonadal tissue, and Schwann cells. As in the case of neurofibromin, merlin mediates growth suppression, and the development of NF2 requires a second hit to the remaining normal NF2 gene. The loss of NF2 expression is also seen in 30–​70% of sporadic meningiomas and almost all sporadic schwannomas. NF2 has minimal cutaneous and no skel- etal abnormalities. The principal manifestation is bilateral vestibular schwannomas associated with multiple meningiomas, cranial nerve tumours, optic gliomas, and spinal tumours (Fig. 24.17.4). Diagnostic criteria for NF2 are listed in Box 24.17.1. Patients who meet some of the criteria of NF2 but not enough to confirm the diag- nosis should receive regular follow-​up. They may eventually develop other manifestations, thus confirming the diagnosis. Adults present with unilateral hearing loss often associated with tinnitus. The Wishart form, usually associated with a truncating mu- tation, presents earlier with faster progression of lesions leading to deafness, cataracts, and focal neurological deficits. The milder or Gardner form presents later in life with relatively stable tumours over years. Recommended diagnostic testing includes brain MRI with at- tention to internal auditory canal and spinal MRI to assess for tu- mours. In cases of bilateral hearing loss, a cochlear implant may be beneficial. Surgical treatment remains a cornerstone of manage- ment for symptomatic and progressive vestibular schwannomas, meningiomas, and spinal tumours. Vascular endothelial growth factor inhibitors have shown promising results for in delaying sur- gery for vestibular schwannomas, and other targeted molecular therapies are investigational options. Tuberous Sclerosis Complex (Bourneville’s disease) Tuberous sclerosis complex (TSC) (MIM 191100)  is a disorder of cellular differentiation and proliferation that affects the brain, skin, kidneys, heart, and other organs. The disorder is domin- antly inherited with a birth incidence of 1:6000–​9000, but may be transmitted by individuals who are asymptomatic or show only minimal clinical evidence of the disease. Isolated cases are fre- quent, making up as many as 80 or 90% of index cases; two thirds may represent new mutations. Genetic heterogeneity has now been established, with separate loci on chromosomes 9q34 (TSC1) and 16p13.3 (TSC2). The TSC1 gene product hamartin and the Fig. 24.17.1  Internal plexiform neurofibroma. Coronal MRI shows an extensive neurofibroma (asterisk) in an eight-​year-​old boy with neurofibromatosis type 1. Reprinted from The Lancet 13(8), Hirbe AC and Gutmann DH, Neurofibromatosis type 1: a multidisciplinary approach to care, pages 834–​43, Copyright © 2014, with permission from Elsevier. 24.17  Inherited neurodegenerative diseases 6201 TSC2-​derived protein tuberin form a functional heterodimer that results in downstream inhibition of mTOR (mammalian target of rapamycin), a serine-​threonine kinase implicated in the activa- tion of translation regulators involved in the expression of many proteins in cell proliferation and growth (Fig. 24.17.5). Tuberin also binds p27, which has been implicated in regulating cell cycle progression. Glutamatergic and GABAergic neurotransmission abnormalities have been demonstrated in the tubers, which may underlie epilepsy and intellectual disability seen in tuberous scler- osis (TS). Mutations are identified in 85% of patients with TS, 85% of those are in TSC2. Those with TSC1 mutation have a less severe disease phenotype. Many clinical features of TSC result from hamartomas, but true neoplasms also occur, particularly in the kidney and brain. Impaired cellular interaction causes disruption of neuronal migration along radial glial fibres and abnormal proliferation of glial elements; ab- normal neuronal migration plays a major role in neurological dys- function. Neuropathological lesions include subependymal nodules (SENs), cortical and subcortical hamartomas (tubers), areas of focal cortical hypoplasia, and heterotopic grey matter. SENs com- monly arise from germinal matrix progenitors and can grow over time, but eventually calcify by adolescence. These may enlarge and transform into subependymal giant cell astrocytomas (SEGAs) (Fig. 24.17.6). Tubers develop between 14 to 16 weeks of gestation Fig. 24.17.2  Skeletal abnormalities in individuals with neurofibromatosis type 1. Plain film radiographs showing: (a) dystrophic scoliosis (asterisk) in an 11-​year-​old girl; (b) tibial bowing (asterisk) in a 10-​month-​old baby girl; (c) tibial pseudarthrosis (asterisk) in a nine-​month-​old baby girl; and (d) tibial pseudarthrosis after insertion of an internal rod (asterisk) in a nine-​year-​old boy. Reprinted from The Lancet 13(8), Hirbe AC and Gutmann DH, Neurofibromatosis type 1: a multidisciplinary approach to care, pages 834–​43, Copyright © 2014, with permission from Elsevier. section 24  Neurological disorders 6202 and frequently extend as linear or wedge-​shaped lesions from ven- tricle wall to the cortical surface. Thus, the tuber load is established before birth. Focal cortical malformations (Fig. 24.17.7) involve one gyrus at a time, but more diffuse involvement may lead to hemimegalencephaly. Histologically, these areas demonstrate disor- ganized cortical lamination, abnormal myelination, and indistinct grey/​white differentiation. Classic clinical features of tuberous sclerosis are intellectual impairment, infantile spasms, epilepsy, occurrence of retinal hamartomas, and characteristic skin lesions (Table 24.17.2). The earliest cutaneous lesions are irregular foliate areas of depigmentation, hypomelanotic macules or ash leaf spots, over the trunk. These patches are readily identified when viewed under ultraviolet (UV) illumination using Woods’ lamp. Presence of three or more patches is required for diagnosis as these may be seen in normal individ- uals. Facial angiofibromas (‘adenoma sebaceum’) (Fig. 24.17.8) are another type of skin lesions that develop over the cheeks in a ‘butterfly’ distribution and on the forehead with multiple small warty elevations. Finally, a ‘shagreen patch’ may be present over the lower back. This consists of an area of elevated roughened skin with a yellowish tinge, which has been likened to sharkskin. An ungual or periungual fibroma is present after puberty and in adult life. The cerebral malformations give rise to intellectual impair- ment, which is evident in early life and may be static or involve a slowly progressive cognitive decline, often complicated by a be- havioural disorder. Common neurological manifestations of TSC are mental retardation, seizures, and behavioural abnormalities. Milder forms of the disease with little or no neurological impair- ment are common even in parents of affected children. Seizures develop during first year of life and are of various types; recur- rent generalized or focal seizures occur in 80% to 90% of patients; one-​third of children with TSC develop infantile spasms. Infantile spasms are indicative of more cortical lesions and worse cognitive impairment. In addition to intellectual disability, many children with TSC have serious behavioural disorders such as autistic be- haviour, hyperkinesis, aggressiveness, and frank psychosis. The prevalence of autistic spectrum disorders is 25% to 50% in pa- tients with TSC. SEGAs develop in 6% to 14% of patients with TSC. When enlarged, they cause symptoms of increased intracra- nial pressure due to an obstructive hydrocephalus, which mani- fests as new focal neurological deficits, behaviour change, or worsening seizures. Box 24.17.1  Diagnostic criteria for NF1 and NF2 Diagnostic criteria for NF1: • The patient must have two or more of the following: 1 Six or more café-​au-​lait macules measuring 1.5 cm or larger in a postpubertal or 0.5 cm or larger in a prepubertal patient 2 Two or more neurofibromas or one or more plexiform neurofibromas 3 Skinfold freckling in the axilla or groin 4 Optic nerve glioma 5 Two or more iris hamartomas (Lisch nodules) 6 A distinctive bony lesion such as dysplasia of the sphenoid bone or thinning of a long-​bone cortex (pseudarthrosis) 7 A first-​degree relative (i.e. parent, sibling, or offspring) with NF1 diagnosed by the above criteria Diagnostic criteria for NF2: • The patient must have either of the following: — Bilateral VS — A first-​degree relative with NF 2 and either unilateral VS at age younger than 30 years; or any 2 of the following: meningioma, schwannoma, glioma, juvenile posterior subcapsular lenticular opacity Fig. 24.17.3  Low-​grade glial neoplasms. (a) MRI showing an optic glioma in the left optic nerve (asterisk) of a four-​year-​old boy with neurofibromatosis type 1. (b) MRI showing a brainstem glioma (asterisk) in a nine-​year-​old boy with neurofibromatosis type 1. Reprinted from The Lancet 13(8), Hirbe AC and Gutmann DH, Neurofibromatosis type 1: a multidisciplinary approach to care, pages 834–​43, Copyright © 2014, with permission from Elsevier. 24.17  Inherited neurodegenerative diseases 6203 Fig. 24.17.4  Bilateral vestibular schwannomas are characteristic of NF2. (a) Small bilateral vestibular schwannomas. (b) Medium-​sized vestibular schwannomas that are compressing the brainstem. (c) Giant bilateral vestibular schwannomas that are compressing the brainstem and causing hydrocephalus. Reprinted from Otolaryngologic Clinics of North America 48(3), Slattery WH, Neurofibromatosis Type 2, pages 443–​60, Copyright © 2015, with permission from Elsevier. RAPTOR TBC1D7 GTP Rheb ATP, amino acid and lipid production Glucose metabolism Nucleotide synthesis Lysosomal biogenesis Mitochondrial biogenesis Autophagy mLST8 PRAS40 mTOR mTORC1 Rheb GDP Rapamycin and other mTORC1 inhibitors DEPTOR Protein synthesis Tsc protein complex TSC1 TSC2 p p Fig. 24.17.5  TSC protein complex and mTOR signalling. Reprinted from Pediatric Clinics of North America 62(3), DiMario FJ, Sahin M and Ebrahimi-​Fakhari D, Tuberous Sclerosis Complex, pages 633–​48, Copyright © 2015, with permission from Elsevier. section 24  Neurological disorders 6204 Computed tomography (CT) best demonstrates the calcified SENs of TSC. SENs may extend into the ventricles to produce an appearance that was considered to resemble ‘candle guttering’. Gliomas sometimes arise in these lesions. Brain MRI shows evi- dence of abnormal neuronal migration as high-​signal linear lesions running perpendicular to the cortex. Retinal tumours, termed phacomas or hamartomas (Fig. 24.17.9), may be present, and cardiac rhabdomyomas occasionally arise as well as hamartomas of the lungs and kidneys. Renal angio­myolipomas presenting by age of 10 years may occur in up to three-​fourths of patients with TSC. Most of these lesions are benign with varying amounts of vascular tissue, fat, and smooth muscle; they may be bi- lateral. Polycystic disease of the kidneys may also be associated. Treatment goals in TSC are to control epilepsy and maximize cognitive function and learning. Periodic evaluation to monitor emerging symptoms and signs is needed. Two approved treatments for infantile spasms are oral vigabatrin and injectable adrenocortico- tropic hormone (ACTH) preparation. Broad-​spectrum antiepileptic agents are usually necessary for ongoing treatment of epilepsy in patients. Corpus callosotomy is an option in young children with refractory seizures as is resective epilepsy surgery in individuals with seizures localizing to a single tuber. Temporal lobectomy or hemispherectomy may be considered in patients with medically re- fractory epilepsy. Vagal nerve stimulator implant may be beneficial for patients with refractory partial seizures. Although not specific for TSC, behavioural and learning disabilities such as attention deficit hyperactivity disorder and autism spectrum Fig. 24.17.6  Subependymal giant cell astrocytoma. Reprinted from Pediatric Clinics of North America 62(3), DiMario FJ, Sahin M and Ebrahimi-​Fakhari D, Tuberous Sclerosis Complex, pages 633–​48, Copyright © 2015, with permission from Elsevier. Fig. 24.17.7  Cortical dysplasias (dysplasia, tubers, and migration lines). Reprinted from Pediatric Clinics of North America 62(3), DiMario FJ, Sahin M and Ebrahimi-​Fakhari D, Tuberous Sclerosis Complex, pages 633–​48, Copyright © 2015, with permission from Elsevier. Fig. 24.17.8  Facial angiofibromas. Reprinted from Pediatric Clinics of North America 62(3), DiMario FJ, Sahin M and Ebrahimi-​Fakhari D, Tuberous Sclerosis Complex, pages 633–​48, Copyright © 2015, with permission from Elsevier. Fig. 24.17.9  Retinal hamartoma. Reprinted from Pediatric Clinics of North America 62(3), DiMario FJ, Sahin M and Ebrahimi-​Fakhari D, Tuberous Sclerosis Complex, pages 633–​48, Copyright © 2015, with permission from Elsevier. 24.17  Inherited neurodegenerative diseases 6205 disorders require educational assistance as well as psychotropic and stimulant medications. SEGAs may require surgical removal if they are growing or symptomatic. Newer option of stereotactic radio- therapy (SRT) is available. TSC1 or TSC2 gene products are involved in the inhibition of the mammalian target of rapamycin pathway (mTOR), which regulates cell growth and proliferation. Loss of TSC1 or TSC2 leads to overactivation of mTOR and uncontrolled cellular proliferation. Everolimus is an allosteric mTOR inhibitor approved for use in subependymal giant cell astrocytoma. Renal tumours require resection or arterial embolization therapy if there is bleeding, pain, or malignant transformation. Facial angiofibromas have been successfully treated by laser ablation especially when rapidly growing, bleeding, or crusting; however, they may  recur (Box 24.17.2). Von Hippel–​Lindau disease The von Hippel–​Lindau (VHL) disease (MIM 193300) is an auto- somal dominant disorder caused by heterozygous mutations in the VHL tumour-​suppressor gene (3p25.3, which encodes a 232-​amino-​ acid protein (pVHL). pVHL plays a key role in cellular oxygen sensing through ubiquitylation and proteasomal degradation of its targets hypoxia-​inducible factor (HIF)–​1 and HIF-​2. In turn, this affects the upregulation of vascular endothelial growth factor (VEGF), platelet-​derived growth factor-β (PDGF-β), transforming growth factor alpha (TGF-α), and erythropoietin substances. VHL lesions obey the classic Knudson 2-​hit hypothesis in which sec- ondary inactivation of the non​mutated pVHL allele leads to loss of pVHL function. This results in failure of polyubiquitination and proteasomal degradation of HIF, which is central for the patho- genesis of the disease. The resulting high levels of HIF create a state of pseudohypoxia leading to transcriptional activation of genes linked to erythropoiesis, angiogenesis, and cell metabolism. This proves conducible to the development of highly vascularized tu- mours typical of VHL and the commonly observed erythrocytosis in affected patients. Most recently, HIF-​independent pVHL functions have also been uncovered that may play a role in VHL tumorigenesis. Those include apoptosis regulation, cell senes- cence control, microtubule stabilization and maintenance of the primary cilium, and regulation of extracellular matrix forma- tion and cell–​cell adhesion. Some sporadic renal cell carcinomas, hemangioblastomas, and pheochromocytomas also harbour VHL biallelic inactivation, thus corroborating the role of pVHL func- tion loss in development of tumours. The VHL syndrome, thus, is associated with an increased risk of developing various benign and malignant tumours including retinal capillary haemangioblastomas (RCH) or retinal angioma and central nervous system haemangioblastomas (CNS HB), hem- angiomas of the adrenal gland, liver, and lung, paragangliomas, phaeochromocytomas (PHEO), renal cysts and clear cell renal cell carcinomas (ccRCC), endolymphatic sac tumours (ELST) as well as pancreatic cysts, pancreatic neuroendocrine tumours (PNET) and cystadenomas of the epididymis and the broad liga- ment (Table 24.17.1, Fig. 24.17.10, pictures 1–​7). Box 24.17.2  Diagnostic criteria for tuberous sclerosis complex Major Features 1 Facial angiofibromas or forehead plaque 2 Non​traumatic ungual or periungual fibroma 3 Hypomelanotic macules (more than three) 4 Shagreen patch (connective tissue nevus) 5 Multiple retinal nodular hamartomas 6 Cortical tuber* When cerebral cortical dysplasias and cerebral white-​matter migration tracts occur together, they should be counted as one rather than two features of tuberous sclerosis. 1 Subependymal nodule 2 Subependymal giant cell astrocytoma 3 Cardiac rhabdomyoma, single or multiple 4 Lymphangiomyomatosis† † When both lymphangiomyomatosis and renal angiomyolipomas are pre- sent, other features of tuberous sclerosis should be present before a definite diagnosis is assigned. 1 Renal angiomyolipoma† Minor Features 2 Multiple randomly distributed pits in dental enamel 3 Hamartomatous rectal polyps‡ ‡ Histological confirmation is suggested. 4 Bone cysts§ § Radiographical confirmation is sufficient. 5 Cerebral white-​matter radial migration lines*, †, ‖ ‖ One panel member felt strongly that three or more radial migration lines should constitute a major sign 6 Gingival fibromas 7 Non​renal hamartoma‡ 8 Retinal achromic patch 9 Confetti skin lesions 10 Multiple renal cysts‡ — Definite tuberous sclerosis complex: either two major features or one major feature plus two minor features. — Probable tuberous sclerosis complex: one major plus one minor feature. — Possible tuberous sclerosis complex: either one major feature or two or more minor features. Reprinted with permission from Roach, E.S., Gomez, M.R., Northrup, H., 1998. Tuberous sclerosis consensus conference: revised clinical diagnostic criteria. J Child Neurol 13, 624–​8, Copyright © 1998, SAGE Publications. Table 24.17.1  Von Hippel–​Lindau (VHL)-​associated tumours Location Tumour Central nervous system haemangioblastomas (HB) Eyes retinal capillary haemangioblastomas (RCH) Petrosal bone endolymphatic sac tumours (ELST) Pancreas pancreatic cysts, neuendocrine tumours (PNET) Kidney renal cysts, clear cell renal cell carcinomas (ccRCC) Adrenal glands phaeochromocytomas (PHEO) Epididymis, broad ligament cystadenomas Reprinted from Schmidt S et al. (2014) Management of von Hippel–​Lindau Disease: An Interdisciplinary Review. Oncol Res Treat 37, 761–​71. section 24  Neurological disorders 6206 This tumour predisposition syndrome has an incidence of 1:36 000 newborns and estimated prevalence in Europe is about 1–​9/​100 000. Age dependent penetrance reaches approximately 95% by age 65 years. De novo mutations occur in about 20% of the cases. In patients with positive family history, clinical diagnosis of VHL disease can be made based on finding a single VHL-​associated tumor and in cases that lack a positive family history, presence of at least 2 VHL-​associated tumours is required for the diagnosis. Suspected cases should be referred for genetic screening of the VHL gene for mutations. Of note, homozygous mutations result in familial erythrocytosis-​2 (ECYT2; 263400). Clinical classification is based on the genotype phenotype correl- ation. Type 1 is generally caused by whole or partial gene deletion or nonsense mutation; pheochromocytoma is not one of its features. In type 2 variant is associated with missense mutations and is charac- terized by pheochromocytomas. Type 2 disease is subdivided type 2A (low risk of renal cell carcinoma), type 2B (high risk of renal cell carcinoma), and type 2C (pheochromocytoma only). Common pancreatic lesions include benign cystic disease including microcystic or serous adenomas, which occur in up to 70% of patients with VHL and are often discovered incidentally during abdominal imaging screening. Pancreatic NETs, though non​functioning, can ­occasionally present with abdominal pain, nausea, or diarrhoea. These lesions may cause compression of the main pancreatic duct, pancrea- titis, and compression, or invasion of adjacent organs. The mean age at diagnosis in patients with VHL disease is lower than in sporadic cases (35 versus 58 years), which is probably related to periodic screening. Pheochromocytomas occur only in type 2 VHL disease and are adrenal or extra adrenal, bilateral, and asymptomatic. Similar to pan- creatic NETs, pheochromocytomas also tend to be diagnosed approxi- mately 20 years earlier in familial than in sporadic cases. Malignant disease is relatively rare. The retinal lesions consist of angiomatous vascular malformations. The cerebellar lesion is a haemangioblastoma, often cystic, which may slowly expand and require surgical treat- ment. Such tumours may be associated with polycythaemia. VHL: screening for affected or at-​risk individuals: Careful ophthalmic examinations every 12 months beginning in infancy or early childhood MRI scans of the head (±spine) every 12–​36 months beginning in adolescence to detect presence of CNS hemangioblastomas MRI scans of the abdomen every 12 months from age 16 years for renal cell carcinoma Retinal haemangio- blastomas, see picture 3 and 4 Phaeochromocytomas, see picture 5 Pancreatic cysts, pancreatic neuroendocrine tumours (=PNET) Cystadenoma of the epididymis and the broad ligament Renal cysts and clear cell carcinomas (=ccRCC), see picture 7 A–C Endolymphatic sac tumours (=ELST), see picture 6 A and B CNS and spinal Haemangioblastomas, see picture 1, 2 A and B Picture 1 Picture 2 Picture 3 Picture 4 Picture 5 Picture 6 Picture 6 Fig. 24.17.10  Picture 1: T1-​weighted image of the cerebellum with bilateral cystic haemangioblastomas (HB). Picture 2: Sagittal magnetic resonance imaging (MRI) of the cervical spine shows four small HB at the fourth ventricle, medulla oblongata, and cervical cord (white arrows in (B)). No tumour-​associated cysts or syringomyelia are present. Minimal oedema of one tumour can be seen on T2-​weighted images (black arrow in A). (A) T2-​weighted, (B) enhanced T1-​weighted MRI, sagittal view. Pictures 3 and 4: Fundus photography (3) and fluorescein angiography (4) of a retinal capillary haemangioblastoma (RCH). Picture 5: A small strong enhancing phaeochromocytoma of the left adrenal gland can be identified after the application of gadolinium (arrow). Enhanced T1-​weighted MRI in arterial phase, coronal view. Picture 6: Endolymphatic sac tumour of the left side (thick arrows) with typical destruction of the posterior wall of the petrosal bone. At the posterior margin of and contralateral to the tumour, parts of the sigmoid sinus are visible after gadolinium application (thin arrows). AT2-​weighted, B enhanced T1-​weighted MRI, axial view. Picture 7: Clear cell renal cell carcinoma (ccRCC) in two different patients. A small early and strong enhancing carcinoma can be seen in the upper part of the left kidney (white arrow in (A)), showing similar contrast to the normal kidney during parenchymal phase (white arrow in (B)). Simple kidney cysts can be depicted best during parenchymal phase (open arrows (A) and (B)). (C) shows multifocal ccRCC of the lower part of the left kidney with inhomogeneous contrast enhancement (white arrows in (C)). Note multiple pancreatic cysts in the same image (open arrow in C). (A) and (C) Enhanced T1-​weighted MRI, arterial phase, (B) enhanced T1-​weighted MRI, parenchymal phase, coronal view. Reprinted from Schmidt S et al. (2014) Management of von Hippel–​Lindau Disease: An Interdisciplinary Review. Oncol Res Treat 37, 761–​71. Fig. 24.17.10  Continued 24.17  Inherited neurodegenerative diseases 6207 4. Yearly screening for phaeochromocytoma beginning in early childhood:  24-​h urine studies to measure catecholamine me- tabolites and measurement of plasma normetanephrine levels; the latter is reported to be the most sensitive test for detecting phaeochromocytoma. Patients with VHL require imaging of the CNS and spinal cord, monitoring of blood pressure and catecholamine metabolites, and an annual eye examination. Surgical removal is required for symp- tomatic tumours. Although, primary treatment of all VHL-​related tumours is local, systemic therapy is warranted when there are re- peated local interventions at multiple sites or repeated recurrences in one area or progression of inoperable and previously irradiated tumours. Sunitinib, a multi-​target tyrosine kinase inhibitor, is being investigated in a phase II trial in patients with VHL. Multiple other agents are currently under clinical investigation as potential treat- ments for hemangioblastoma. VEGF-​targeting agents are a reason- able choice in keeping with the pathophysiology in most tumours. Bevacizumab is a humanized monoclonal antibody that binds to the soluble VEGF and inhibits its interaction with the VEGF re- ceptor. It has been demonstrated to be efficacious in patients with hemangioblastoma and renal cell carcinoma. Oral anti-​VEGF agent, PTK787/​ZK222584 which targets all known VEGF receptor tyrosine kinases and TKI-​538, an anti-​angiogenic multikinase inhibitor, are currently under investigation in phase II trials for the treatment of hemangioblastoma in patients with VHL, while histone deacetylase (HDAC) inhibitor vorinostat is also in phase I clinical trial. Given enormous lifelong impact on quality of life, early molecular genetic testing of the children of an affected VHL parent is strongly recommended. A  comprehensive paediatric-​screening programme to detect tumours should be started as early as possible. VHL dis- ease is a challenging systemic disease that has better outcomes with continuous medical surveillance and treatment is best approached in an interdisciplinary fashion. This chronic unpredictable disease has major implications on various important matters like career and em- ployment, health insurance, and family planning. Psychological stress and insecurity should not be underestimated and properly managed. Sturge–​Weber syndrome Sturge–​Weber Syndrome (SWS, also known as encephalofacial angiomatosis, MIM 185300) is a sporadic congenital condition caused by a somatic activating mutation in GNAQ. The classic manifestation is a capillary malformation of the skin, port-​wine birthmark, also known as port-​wine stain/​nevus, in the V1 distribution of the face (forehead and/​or eyelid); V2 and V3 distributions may be involved. This may be associated with cerebral venous malformations (leptomeningeal angiomatosis), and ocular capillary venous vascular malformations causing glaucoma. Venous angioma containing dilated and tortuous deep cerebral veins is confined to the piamater. Chronic venous stasis forms the basis of progressive calcification of underlying brain paren- chyma starting with deep cortical layers spreading to the upper layers. Progressive brain atrophy succeeds the calcification. Bilateral port-​ wine nevus is associated with a higher risk of brain involvement. Epilepsy, owing to the brain calcification and atrophy, is the most frequent neurological feature in 75–​80% of patients, followed by intel- lectual impairment, migraine, stroke-​like episodes, and focal neuro- logical deficits are frequent. All seizure types may occur; however, Complex partial seizures are frequently encountered. Stroke-​like epi- sodes marked by transient hemiparesis or visual field deficits, diffi- cult to distinguish from postictal Todd’s paresis, are described in SWS. However, the stroke-​like episodes are more prolonged than a postictal paresis and may last days, weeks, or months, or become permanent. It has been suggested that SWS patients may have regional cerebral hypoperfusion with brain areas at risk for sustained ischaemia. Neuroimaging is of prognostic value since most children with facial port-​wine stains without an intracranial involvement would develop normally. Plain radiographs of the skull, although now in- creasingly obsolete, may detect intracranial calcifications following the gyral patern, revealing the classic ‘tram line’ appearance; however, calcifications are often not present before age 2 yr. Brain MRI with gadolinium contrast demonstrates the presence of the leptomenin- geal angioma and involvement of other brain structures, if present (Fig. 24.17.11). CT of the brain reveals calcifications in the involved leptomeningeal vessels. Fig. 24.17.11  MRI and FDG PET images for a three-​year-​old boy with bilateral facial PWS, left sided hemiparesis and seizures; (a). (b). axial and coronal T1 weighted MRI with gadolinium contrast respectively showing assymetric leptomeningeal enhancement, prominent choroidal vessels, and right-​sided atrophy; (c). FDG PET showing right-​sided hypometabolism most prominent in the right frontal region. Reprinted from European Journal of Paediatric Neurology 18(3), Sudarsanam A and Ardern-​Holmes SL, Sturge–​Weber syndrome: from the past to the present, pages 257–​66, Copyright © 2014, with permission from Elsevier. section 24  Neurological disorders 6208 No specific treatment exists for SWS. Port-​wine stains can be treated by selective photothermolysis with a pulsed-​dye laser. The best response to laser treatment occurs in smaller lesions and in younger children (<1 yr), probably related to development of ectasias in older children. Complications include scarring and transient hyperpigmentation. Ophthalmologic evaluation is es- sential in the neonatal period for assessment of congenital glau- coma; further recommendations are quarterly ophthalmologic evaluations for first two years of life followed by at least yearly evaluations if the examination remains normal. Glaucoma is treated with topical medications as indicated. Surgical therapy is required when the intraocular oressure does not normalize. Seizure management may be difficult in SWS. Management of seizures in SWS often is difficult and medical management may not always achieve adequate seizure control. Carbamazepine is the recommended antiepileptic of choice. In refractory cases, sur- gical options are hemispherectomy, or limited surgical resection of epileptogenic tissue. Cowden syndrome Cowden syndrome, or multiple hamartoma syndrome (MIM 158350), an autosomal dominant condition, is a subtype of PTEN hamartoma tumour syndrome. It manifests as multiple hamartomas in a variety of tissues along with dermatologic changes and an in- creased risk of developing several types of systemic cancers at a young age. It has an estimated prevalence of 1 in 200 000 people. It is caused by more than 300 known mutations in the PTEN gene or phosphatase and tensin homologue, a tumour suppressor gene located on chromosome 10q23.3. Twenty-​five to 34% of patients with Cowden syndrome have germline mutations in the PTEN (phosphatase and tensin) homologue gene that negatively regulates the PI3K/​AKT/​mTOR signalling pathway. Thus, loss of PTEN re- sults in activation of the pathway, which is critical in carcinogenesis. Germline mutations in PIK3CA and AKT1 have also been reported in patients with Cowden syndrome and in individuals without a germline PTEN mutation. Patients with Cowden syndrome usually present with mucocu­ taneous or extra-​cutaneous hamartomatous tumours involving multiple organs along with an increased lifetime cumulative risk of developing breast cancer, thyroid cancer, endometrial cancer, colorectal cancer, renal cancer, and melanoma. Lhermitte-​Duclos disease, now recognized as part of CD, is a very rare condition char- acterized by dysplastic gangliocytoma of the cerebellum known to present with headaches, cerebellar ataxia and cranial neuropathies, and may cause increased intracranial pressure. Management of Cowden syndrome is multifaceted, including periodic surveillance with screening for malignancies and treatment of benign and malignant manifestations with medical or surgical therapy. Although no therapies have been approved for patients with Cowden syndrome, clinical trials evaluating the role of PIK3CA/​ mTOR inhibitors such as sirolimus are underway. Proteus and Proteus-​like syndrome Proteus syndrome (MIM 176920) is a rare disorder comprising ir- regular, progressive postnatal overgrowth, and malformations of skin, connective tissue, fat, brain, and other tissues. Proteus syn- drome is associated, through a somatic activating mutation in the AKT1 oncogene, with AKT kinase activation, which regulates cell proliferation and apoptosis. Cutaneous capillary and venous mal- formations also occur. Proteus syndrome is also associated with monomorphic adenoma of the parotid glands and bilateral ovarian cystadenoma. Unilateral cystadenoma and meningioma have also been reported in patients with Proteus syndrome. Clinical recogni- tion and diagnosis is often difficult owing to overlap with other over- growth syndromes. The role of AKT inhibitors and mTOR inhibitors for the treatment of Proteus syndrome needs further exploration. Bannayan–​Riley–​Ruvalcaba syndrome Bannayan–​Riley–​Ruvalcaba syndrome (BRRS, MIM 153480)  is one of the PTEN hamartoma tumour syndrome along with Cowden syndrome and Proteus-​like syndrome. Germline mutations in the PTEN (phosphatase tensin) are found in two-​thirds of individuals with BRRS; although autosomal dominant in nature, spontaneous mutations are also described. PTEN, a tumour-​suppressor gene, has been mapped to chromosome 10q23.3. Mutations in the gene lead to unregulated proliferation of the three embryonic germ layer cells causing ectodermal, mesodermal, and endodermal hamartomas. This rare autosomal dominant disorder is characterized by macro- cephaly, intestinal hamartomatous polyps, lipomas, pigmented maculae of the glans penis, developmental delay, and intellectual im- pairment. Vascular malformations, such as arteriolovenous shunts, arteriovenous anomalies, and arteriovenous fistulas, are described in a subset of BRRS patients. Section II: Defects in DNA repair As in the phacomatoses, the diseases involving defects in DNA repair cause skin abnormalities, neurological manifestations, and tumours, although the tumours are outside the CNS. Xeroderma pigmentosum Xeroderma pigmentosum (XP) is a recessively inherited disorder with 100% penetrance and an estimated incidence of 1 in 100 000 to 1 in 1000 000. Eight different causative genes (XPA, XPB, XPC, XPD, XPE, XPF, or XPG) have been mapped, all of which are in- volved in either nucleotide excision repair or post-​DNA replication translation synthesis. Mutations result in cellular hypersensitivity to the damaging effects of ultraviolet radiation (UV) resulting in a 10 000-​fold increased risk of skin cancers. In the most severely af- fected form, the XP-​A gene, mapped to chromosome 9q34.1, is de- fective. The protein product of this gene has a much higher affinity for UV-​damaged DNA than undamaged DNA, indicating a role for this protein in damage recognition. XP, defined by extreme sensitivity to sunlight, resulting in sun- burn, pigment changes in the skin, and a greatly elevated incidence of skin cancer, begins in childhood. Neurological manifestations occur in 20 to 30% of patients. Severely affected children are symp- tomatic at age of 2 years often with loss of reflexes as the initial sign ((De Santis–​Cacchione syndrome). Further neurological deteri- oration causes progressive mental deterioration, cerebral atrophy, sensorineural deafness, choreoathetosis, cerebellar ataxia, periph- eral neuropathy, and growth retardation. Median age at death in XP patients with neurodegeneration (29 years) is significantly younger than those without neurodegeneration (37 years). Ocular signs are 24.17  Inherited neurodegenerative diseases 6209 restricted to the anterior, UV-​exposed structures of the eye (lids, cornea, and conjunctiva) and include photophobia, conjunctival erythema, keratitis, and tumours. Frequent dermatological evaluation, total protection from sun ex- posure and UV-​emitting lamps is employed. Pre-​malignant lesions are treated with cryotherapy, liquid nitrogen, topical 5-​fluorouracil (5-​FU) or topical imiquimod. Although there were significant side effects, oral isotretinoin is effective in decreasing the number of new non​melanoma skin cancers. Early and adequate treatment of skin cancers is extremely important; all suspected tumours should be biopsied and removed. Ataxia-​telangiectasia Ataxia-​telangiectasia (MIM 208900) is an autosomal recessive dis- order is caused by mutations in the ATM (for AT mutated) gene located on chromosome 11q22–​23. The gene product, which is ex- pressed in all tissues, encodes a large protein that is a member of the phosphatidylinositol-​3 kinases that serve as a regulators of the cell cycle checkpoint in response to breaks in double-​stranded DNA. Defective or missing product delays accumulation of the tumour-​ suppressor p53 in response to DNA damage, thereby increasing the risk for cancer. Cells are susceptible to damage by ionizing radi- ation or chemotherapeutic agents that cause double-​stranded DNA breakages. Ataxia-​telangiectasia (AT) presents in early childhood with un- steady gait and truncal instability. Infants’ meet major milestones until age 1; however, by age 2 to 3 years, staggering gait (ataxia) appears. Oculomotor apraxia (inability to follow an object to command) and dysarthria occur early but are difficult to evaluate in young children. Gaze initiation failure, choreoathetosis, and recurrent infections develop, followed by ocular telangiectasias between age 4 and 7 years. Later, cutaneous telangiectasias appear on the face, hands, and feet, the hair becomes prematurely grey, and lymph nodes are atrophic. Sexual infantilism, hepatic dys- function, and insulin-​resistant diabetes develop in older patients. Speech becomes incomprehensible, mental functioning declines, and, by teens, the child has lost the ability to walk. Affected chil- dren generally become wheelchair bound by age 10 to 15 years. Cancer develops in 38%, mainly in the form of lymphoreticular tumours and acute T-​cell leukaemias. Older patients develop epi- thelial tumours in various organs. There is also an increase in the incidence of cancer in heterozygotes, especially breast cancer in women. Death occurs in the second decade. Late-​onset forms, with onset as late as third or fourth decade and milder phenotype, have been described. Laboratory tests reveal an elevated serum α-​fetoprotein, low levels of IgA and IgG2, poor responsiveness to common antigens, and an increased sensitivity of the patient’s chromosomes to irradiation. On neuropathological examination there is a degeneration of the Purkinje and granule cells of the cerebellum, loss of anterior horn cells and dorsal root ganglion cells of the spinal cord, and loss of medullated fibres in peripheral nerves of some cases. General path- ology studies show absence or abnormal development of the thymus and all lymphoid system elements. Management of patients with ataxia-​telangiectasia involves the control of infections with antibiotics, monitoring for early signs of malignancy, the avoidance of multiple X-​ray exposures, and the use of antitumour drugs rather than radiation therapy. Cockayne’s syndrome Cockayne syndrome (CS, MIM 216400) is a progressive devastating multisystem disorder with a minimal incidence of 2.7 cases per million births, evaluated in Western Europe. Autosomal recessive mutations in ERCC6 (CSB) cause most (65%) cases of Cockayne syndrome whereas mutations in ERCC8 (CSA) account for the re- mainder (35%) cases. Both proteins are involved in DNA repair after ultraviolet damage and mutations lead to a specific cellular defect in transcription-​coupled nucleotide excision repair. CS phenotypic spectrum ranges from ‘classical’ more severe type I; type II, overlapping with cerebral-​oculo-​facialskeletal syndrome (COFS); and a milder type III. Initially, COFS and UV-​sensitive syn- drome were described independently from CS but eventually proved to be allelic to canonical Cockayne patients. Some rare patients show a very severe phenotype with combined features of CS and XP. In the classic form of this rare, autosomal recessive, multisystem, degenerative disease, symptoms start at the end of the first year or beginning of the second year. There is progressive growth failure and worsening post-​natal microcephaly, constantly below three standard deviations in all forms of the disease. Psychomotor development is retarded with profound intellectual disability. Overall, the severity of the developmental delay is usually correlated with the overall severity of the disease. Loss of subcutaneous and orbital fat gives the characteristic facial appearance with enophthalmia. The face as- sumes a wizened, progeria-​like appearance with sunken orbits, large beak-​like nose, prominent ears, and narrow mouth and chin. The hair is sparse and the skin thin and photosensitive, but skin cancer does not occur. Eye signs include photophobia, decreased lacrima- tion, cataracts, retinal pigmentary degeneration, optic atrophy, stra- bismus, and nystagmus. Most CS patients show a unique combination of pyramidal, extra-​ pyramidal, cerebellar, and peripheral signs. Limb hypertonia and spasticity are early features associated with brisk of tendon reflexes. Almost all CS patients show cerebellar involvement with gait ataxia, action tremor, and dysarthria. Late-​onset forms often present with cerebellar ataxia. Sensorineural deafness is a constant feature. Death occurs in the second or third decade. White matter loss and ventricle enlargement may be the earliest sign on brain imaging present in all clinical subtypes. Brain MRI shows progressive cerebral and cerebellar atrophy, brain calcifica- tions, and T2 white matter hyperintensities due to hypomyelination and in some cases secondary demyelination. Calcifications are seen in the basal ganglia, in the dentate nuclei and the subcortical white matter. There is no specific treatment for CS. Symptomatic management of neurological issues is provided as necessary. Section III: Metabolic disorders Leucodystrophies The term ‘leucodystrophy’ is generally applied to those diseases that have a genetic basis, a progressive clinical course, primary involve- ment of white matter, and a demonstrable/​ presumed biochem- ical or molecular defect. In contrast, the leucoencephalopathies are those disorders of white matter that lack the genetic, progres- sive, or other qualities of the leucodystrophies, generally caused section 24  Neurological disorders 6210 by acquired conditions such trauma, toxicity, or insult (e.g. peri- ventricular leukomalacia secondary to premature birth or white matter abnormalities caused by chemotherapy or meningitis). Most recent population-​based estimate for leukodystrophies shows an incidence of 1 in 7500 live births; however, fewer than half of patients receive a specific diagnosis. Primary leucodystrophies are those inherited diseases with principal white matter involvement whereas, in secondary leucodystrophies, the involvement white matter is in associ- ation with other neurological structures and or organs and may lead to destruction of both axons and myelin by a more dif- fuse process. The primary leucodystrophies can be classified into three subgroups:  (1) classic dysmyelinative disorders (e.g. X-​linked adrenoleukodystrophy, metachromatic leukodystrophy); (2)  hypomyelinative with delayed or decreased myelin produc- tion (e.g. Pelizaeus–​Merzbacher disease); and (3)  vacuolating myelinopathies (e.g. Canavan’s disease). Most vacuolating leocodystrophies lead to demyelination. Within the category of the secondary leucodystrophies are metabolic, mitochondrial, and muscular dystrophy, and various syndromic (genetic) disorders. Myelin development Myelin development requires complex developmental orchestration of genes, proteins, and different cell types such as oligodendrocytes, the glial cells that produce myelin and the myelin sheath, and inter- actions with other cell types, particularly neurons. It begins during fetal life and continues through adulthood. In addition to the pri- mary myelin function of accelerated action potential propagation, myelin is vital for maintenance of axonal health, and nutritional sup- port of axons. Oligodendrocytes or oligodendroglia arise from oligodendrocyte precursor cells during fetal and postnatal life. Each oligodendrocyte extends numerous myelin sheet-​forming processes that envelope more than one axonal projection. Myelin, composed of proteins (30%) and lipids (70%), is produced in a highly energy-​dependent manner. The most abundant protein components are myelin basic protein (MBP) and proteolipid protein (PLP). The lipid compo- nents of myelin are cholesterol, phospholipids, and glycolipids, mostly glycosphingolipids such as galactocerebrosides. Neuron-​ oligodendrocyte interactions are necessary for normal myelination and oligodendrocytes migration; extent of myelination is affected by neuronal activity. Myelination begins in the fourth month of gesta- tion with deep structures and proceeds in an inside–​outside, dorsal-​ to-​ventral, and caudal-​to-​rostral fashion. Essentially all areas of the brain are myelinated by the second year of life. Leucodystrophy could be caused by a large number of insults or processes that affect not only myelin development or myelin turn- over but also neurons or other glia such as astrocytes. On one hand, mutations in the intrinsic myelin protein PLP1 lead to Pelizaeus–​ Merzbacher disease, whereas mutations in the ubiquitously ex- pressed translation initiation factor subunits EIF2B1–​5 cause vanishing white matter disease. Management A comprehensive team that includes specialists in neurology, physical medicine, orthopaedics, pulmonary medicine, and gastroenterology is often required to administer medical, social, and supportive care for most leukodystrophy patients and families. Medications may include antiepileptic drugs for seizures and medi- cations to reduce spasticity (baclofen, diazepam, tizanidine, botu- linum toxin). Proper physical therapy, exercise, and orthotics may be helpful in management of spasticity and gait disorder. Surgery may be indicated for contractures and scoliosis. Gastrostomy may be required in advanced disease to maintain nutrition in individ- uals who have severe dysphagia. Special education is usually ne- cessary for children with appropriate assistive communication devices. Genetic counselling is of utmost importance. Carrier status in parents, possibility of siblings being affected or carriers and risk of developing the disease in subsequent pregnancies should be expli- citly explained. Screening other family members for carrier state is recommended when making reproductive decisions. Classic dysmyelinative leucodystrophies Adrenoleucodystrophy X-​linked adrenoleucodystrophy (X-​ALD. MIM 300100), caused by a defect in the gene ABCD1, is the most common peroxisomal disorder with a pan-​ethnic disease incidence of 1 in 20 000 males. ABCD1, which maps to Xq28, encodes for peroxisomal transporter ATP-​binding cassette subfamily D member 1 (ABCD1, formerly ALDP) membrane protein that is a member of the ATP-​binding cas- sette transporter superfamily. The protein mediates the import of very long-​chain fatty acid (VLCFA) CoA esters across the peroxi- somal membrane. The dysfunction of ABCD1 results in impaired degradation of VLCFAs in peroxisomes. This leads to accumulation in all tissues and body fluids of saturated very-​long-​chain fatty acids (VLCFAs), particularly hexacosaenoic (C26:0) and tetracosaenoic (C24:0) acid. While accumulation of VLCFAs is incriminated in the demyelinating pathology in AMN, the exact molecular mechanism by which VLCFAs are involved in the onset or progression of in- flammation in cerebral ALD is still not understood. Six-​hundred and ninety-​five (695) non​recurrent mutations have been described in the X-​ALD database, out of which 343 are missense mutations. Mutations such as deletions, frameshifts, and nonsense mutations generate truncated proteins; missense mutations often lead to un- stable proteins. Initially, de novo mutation rates of around 5% were described; however, recent studies report a higher de novo mutation rate of at least 19%. Pathologically, ballooning of cytoplasm with the presence of lamellar cytoplasmic inclusions is seen initially, most prominently in the zona fasciculata, followed by cytolytic cell death at a later stage. Although manifestations of X-​ALD range from childhood to late adulthood, two predominant phenotypes are: adrenomyeloneuro­ pathy (AMN) and the cerebral form of X-​ALD (CALD). CALD presents usually as childhood-​onset condition, but occasionally adolescent-​, and adult-​onset, rapidly progressive cerebral form, are seen in affected males. AMN presents as adult-​onset, slowly progres- sive myeloneuropathic form in males and upto 50% of carrier fe- males. Varying degrees of primary adrenal insufficiency (Addison’s disease) are invariably found in affected males whereas this endo- crine disorder very rarely appears in females. Addison’s only form is also known. The childhood cerebral form usually presents between 4 and 8 years of age, never before the age of 2.5 years, with behavioural 24.17  Inherited neurodegenerative diseases 6211 symptoms. The child becomes withdrawn and less verbal, and has difficulty with auditory and visual discrimination. Spastic parapar- esis, incontinence, seizures, and feeding difficulties ensue with rapid progression to a vegetative state. Adults with adrenomyeloneuropathy (AMN) present with a slowly progressive paraparesis, together with sensory and sphincter disturbances. It is associated with a non​inflammatory distal axonopathy involving the dorsal column and corticospinal tract in the lower thoracic and lumbar regions, as well as more proximal seg- ments of the corticospinal tracts in the internal capsule. In 30 to 40% of all male patients with AMN, there is inflammatory cerebral in- volvement detectable at the earlier stages of presentation or several years later. MRI often shows no abnormalities in the AMN pheno- type, apart from infrequent spinal cord atrophy and T2-​weighted hyperintensity. Of males affected by X-​ALD 70% have Addison’s dis- ease, in most instances associated with cerebral ALD or AMN; how- ever, a smaller proportion of patients may have an ‘Addison-​only’ phenotype of X-​ALD, which is indistinguishable from Addison’s disease attributable to other causes. Therefore, plasma VLCFA assay should be performed in all patients with idiopathic Addison’s dis- ease, especially males. MRI of the brain in the childhood form shows a characteristic pattern of demyelination, found in approximately 80% of cases, involving confluent T2-​weighted hyperintensity and Tl-​weighted prolongation of the deep parieto-​occipital white matter, which progresses in a centrifugal manner within a caudorostral direction (Fig. 24.17.12). There is gadolinium enhancement on T1-​weighted imaging at the periphery of the involved white matter corres- ponding to regions of active demyelination and inflammation. A reverse pattern with frontal involvement is seen in another 15% of cases. Definitive diagnosis is established in males by demonstration of elevated levels of VLCFAs, which show abnormally high con- centrations of C26:0 as well as high ratios of C24:0 and C26:0 to C22:0. As the test results for VLCFAs may be falsely negative or equivocal in 10 to 15% of heterozygous women, mutation ana- lysis of the ABCD1 gene is recommended to confirm diagnosis or carrier state. Treatment includes general supportive care and symptomatic treatment for the patient. Adrenal hormone replacement therapy can be lifesaving; so all male patients should be adequately moni- tored for adrenal insufficiency. Haematopoietic stem cell transplant- ation (HSCT) provides the most favourable outcome in children at the early stage of the illness with five-​year survival rates of 92%, mortality rates of less than 5 % and a superior neurological and functional status compared with the group that have not received a transplant. Early stage is usually defined as a good clinical condition (e.g. performance IQ of 80 or higher) and few lesions on brain MRI (e.g. Loes score of 9 or less). Stabilization of the disease usually oc- curs about 6 months after the transplantation. Initially HSCT may accelerate the rate of progression, it is therefore, contraindicated in patients with advanced cerebral involvement. There is no disease-​modifying treatment to prevent the onset or slow the progression of the chronic myelopathy of X-​ALD. Lorenzo’s oil, which is a 4:1 mixture of glyceryl trioleate and gly- ceryl trierucate, combined with moderate reduction of fat in the diet, normalizes or significantly lowers the levels of plasma VLCFAs, although it does not significantly alter the rate of progression in symptomatic individuals. Lorenzo’s oil was proven to be ineffective in halting progression in several open-​label trials; a placebo-​ controlled trial to determine if there is an effect on the rate of dis- ease progression was discontinued before completion and was not published. Lorenzo’s oil may provide a preventive benefit in asymp- tomatic boys aged between 18 months and 8 years who are at the greatest risk for the development of the cerebral form of X-​ALD and in whom the brain MRI is normal. Other approaches, including antioxidants are under investi- gation. Recently, transplantation with autologous bone marrow transfected in vitro with ABCD1 has been performed with success. A new method for newborn screening by determination of C26:0 lysophosphatidylcholine (C26:0-​LPC) from dried blood spots may impact the detection, monitoring, and treatment of X-​ALD. As X-​ALD poses a significant burden to patients and families, pro- fessional genetic counselling is recommended. X-​ALD heterozy- gous screening for women, together with prenatal diagnosis and preimplantation diagnosis, is available for families at risk. Fig. 24.17.12  (a) Brain MRI (axial images; FLAIR sequence) showing abnormally increased signal in the splenium of the corpus callosum, the parieto-​occipital white matter, the visual pathways (optic radiations and lateral geniculate bodies), as well as the medial geniculate bodies of auditory pathway and the posterior limbs of the internal capsules. The demyelinating lesions are extensive and correspond to an advanced disease stage. (b) Brain MRI (axial images; FLAIR sequence) showing abnormally increased signal involving the posterior and anterior limbs of the left and right internal capsule. Reprinted from Biochimica et Biophysica Acta 1822(9), Kemp S, Berger J and Aubourg P, X-​linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects, pages 1465–​74, Copyright © 2012, with permission from Elsevier. section 24  Neurological disorders 6212 Metachromatic leucodystrophy Metachromatic leucodystrophy (MLD, MIM 250100)  is a sulphatide lipidosis caused by a deficiency of the lysosomal enzyme sulphatidase (arylsulphatase A, ASA), which catalyses the first step in the degradation of the sulphatide, 3-​O-​sulphogalactosyl-​ ceramide (cerebroside sulphate), or, in a few rare instances, a de- ficiency of cofactor saposin B (Sap-​B). There is another distinct clinical form of ASA deficiency, multiple sulphatase deficiency, in which at least seven different sulphatases are defective due to an abnormality in their processing and functional maturation. MLD is an autosomal recessive disorder with an estimated frequency of 1 in 121 000, ranging between 1 in 40 000 and 1 in 300 000. Some genotypic–​phenotypic correlation is possible:  homozygosity of null alleles usually causes a late-​infantile form of the disease, a combination of null allele and an allele with residual activity is as- sociated with juvenile onset, whereas two alleles with residual ac- tivity results in adult-​ or juvenile-​onset disease. Deficiency of ASA results in the accumulation of the substrate, cerebroside sulphate forming lysosomal storage deposits, in the white matter of the CNS and peripheral nervous system, which when stained with cresyl violet or toluidene blue reveal a brownish or reddish birefringence (metachromasia). Sulphatides are most abundant sphingolipids in myelin, accounting for 4% of its composition. Sulphatides accumu- late in the oligodendrocytes, Schwann cells, phagocytes, astrocytes, and also neurons. It has been shown in vitro that sulphatide loading triggers inflammatory cytokines involved in apoptosis. Exact mech- anism through which accumulation of sulphatides leads to demye- lination is not known. Most patients are equally divided between late-​infantile and ju- venile onset, and about 20% of patients have an onset in adolescence or later. In the late-​infantile form, the clinical signs begin between 15 months and 2 years, with frequent falls followed by the inability to walk, flaccid weakness, and peripheral neuropathy. The ability to sit without support is lost between 2 and 3 years of age. Speech becomes slow and indistinct, truncal titubation develops, optic atrophy be- comes apparent, and deep tendon reflexes are initially diminished and then lost. Spasticity develops in the legs but the arms remain hypotonic. Spinal root and peripheral nerve involvement cause ex- quisite sensitivity to touch. Electrophysiological testing shows slowing of the motor and sen- sory nerve conduction velocities. The cerebrospinal fluid protein level is elevated. Brain MRI T2-​weighted images reveal centrifu- gally expanding, progressive, confluent, symmetrical white matter disease, with posteroanterior gradient. In the later stages of late-​ infantile MLD children are quadriplegic and spastic, with decere- brate, decorticate, or dystonic posturing, in association with loss of speech, seizures, hypertonic fits, bulbar palsy, and blindness. Death occurs 1–​7 years after the onset of symptoms. Juvenile MLD presents between age 2.5 and 16 years, with poor school performance and gait imbalance, followed by confusion and inability to follow directions. The speech becomes slurred; spasticity and inability to walk ensue. Tremor, tonic spasms, and seizures may also occur. There is visual failure. Peripheral neuropathy is common but not invariable. Most patients with juvenile MLD do not live into adulthood. Adult MLD presents insidiously in late adolescence or early adult life with deterioration in school performance, disorganized thinking, poor memory, and a schizophrenia-​like psychosis. The gait is ataxic with pyramidal signs such as hypertonia and hyperreflexia. Peripheral neuropathy may or may not be associated with the adult-​ onset variant of MLD. Incontinence can develop relatively early. Despite the presence of optic atrophy, vision, and the patient’s aware- ness of his or her environment are preserved until the end-​stage of the disease. The progression is usually slower than in the early onset disease with spastic quadriparesis, decorticate posturing, and pathological reflexes noted after 5 to 10 years, but survival for several decades is possible. The widespread use of MRI, which shows pref- erential involvement of the subcortical white matter in the frontal regions in the adult-​onset form, has improved recognition of this variant in psychiatric patients. Diagnosis is based on demonstration of low ASA activity levels in the peripheral blood leucocytes or skin fibroblasts. About 10% of the general population has a pseudodeficiency of ASA (i.e. low activity on testing in vitro due to the presence of a polymorphism but with no clinical neurological disease). This needs to be excluded before a conclusive diagnosis of MLD is made. Increased excretion of urinary sulphatides is indicative of true ASA deficiency, whereas urinary sulphatides are normal in pseudodeficiency. Similarly in saposin B deficiency, in vitro ASA levels may be normal as they are performed in the laboratory with water-​soluble artificial substrate, but urinary sulphatide excretion is high. Brain MRI (Fig. 24.17.13) changes occur in the form of bilateral symmetric abnormal T2 signal hyperintensity starting in the corpus callosum and then involving the periventricular white matter. In the infantile form, the disease usually starts in the splenium of the corpus callosum and the parieto-​occipital white matter, in the adult form, in the rostrum and frontal white matter. The subcortical fibres are usu- ally spared. With disease progression, there is involvement of the pro- jection fibres, cerebellar white matter, basal ganglia and thalami with decreased signal intensity on T2-​weighted images, probably as a result of accumulation of metal or other breakdown products in the brain. Typical for MLD the ‘tigroid pattern’ pattern which shows radiating stripes of normal signal intensity within the abnormal white matter. A scoring system based on MRI abnormalities combined with clinical parameters can be used as a measure of disease severity. Extent and severity of abnormal white matter signal, involvement of projection fibres, and basal ganglia atrophy is staged as mild, moderate, or se- vere. A low N-​acetylasparate (NAA) level due to the diffuse neuronal loss and elevated myo-​inositol due to to reactive gliosis characterize proton magnetic resonance spectroscopy (H MRS) in MLD. Progression of MLD may be slowed or halted when bone marrow transplantation or umbilical cord stem cell transplantation is under- taken in presymptomatic patients or early in the course of the dis- ease when neuropsychological signs are not advanced. Monocytic cells of bone marrow cross the blood–​brain barrier then differentiate into microglial cells and deliver enzymes to oligodendrocytes and neurons to correct the enzyme deficiency. Since replacement of the resident microglia is slow, it can take 12–​24 months until the dis- ease stabilizes. HSCT is therefore, ineffective for patients with overt neurological symptoms or for those with the aggressive infantile onset. In MLD, enzyme replacement therapy (ERT) administered intravenously is ineffective, due to the inability of the enzyme to cross the blood–​brain barrier. Intracerebral agent delivery is cur- rently under investigation. 24.17  Inherited neurodegenerative diseases 6213 In gene therapy, the goal is to genetically modify autologous haematopoietic stem cells (HSC) to express or overexpress the ARSA gene. In a small study with three presymptomatic infantile MLD patients were treated with autologous HSCs transduced ex vivo with ARSA encoding lentiviruses and reinfused after the pa- tients had been treated with a myeloablative regimen. One year after reinfusion, functional ASA was isolated from cerebrospinal fluid and disease manifestation was halted for the follow-​up times, ran- ging from 18 to 24 months. Multiple sulphatase deficiency (Austin’s disease) Mutations in SUMF1, which encodes a protein (the human C(α)-​ formylglycine-​generating enzyme) involved in the processing of the catalytic site of all sulphatases, lead to a defective post-​translational modification of several sulphatases and a neurovisceral disorder, mul- tiple sulphatase deficiency (MSD, MIM 272200). It is characterized by tissue accumulation of sulphatides, glycosaminoglycans (muco- polysaccharides), and cholesteryl sulphate. The clinical features of MSD overlap between the neurological findings of early infantile MLD and the dysmorphic facial features and skeletal deformities (i.e. dysostosis multiplex) seen with mucopolysaccharidosis (MPS). Urinary excretion of sulphatides, heparan sulphate, and dermatan sulphate is high. Clinical features include ichthyosis in young in- fants with psychomotor retardation, hepatosplenomegaly, deafness, and peripheral neuropathy. Diagnosis of MSD is based on charac- teristic clinical manifestations and demonstration of deficiencies of the arylsulphatases A, B (N-​acetylgalactosamine-​4-​sulphate sulphatase), and C (steroid sulphatase), and four other sulphatases involved in the degradation of specific glycosaminoglycans. Globoid cell leucodystrophy (Krabbe disease) Collier and Greenfield described unusual ‘globoid’ cells in the white matter of patients with acute infantile diffuse ‘sclerosis’, a condi- tion reported initially in two siblings by Knud Haraldsen Krabbe, a Danish neurologist, in 1916. This condition, now termed Krabbe disease (MIM 245200), is caused by deficiency of galactocerebroside β-​galactosidase (β-​GALC; galactosylceramidase), which nor- mally cleaves galactosylceramide into ceramide and galactose. Pathologically, there is rapid destruction of myelin and myelin-​ forming cells (i.e. oligodendrocytes and Schwann cells) with Fig. 24.17.13  Axial T2 weighted (a, b, d, e, g, h) and sagittal T1-​weighted (c, f, i) MR images of three patients with MLD. (a–​c) A 2-​year-​old patient with late-​infantile MLD. Involvement of the periventricular white matter and centrum semiovale with parieto-​occipital predominance and involvement of the splenium. U-​fibres are spared. (d–​f) A seven-​ year-​old patient with juvenile MLD. (f) Shows the typical pattern of radiating stripes with bands of normal signal intensity in between. U-​fibres are spared. (g–​i): 28-​year-​old patient with adult MLD. In addition to the white matter signal abnormalities with frontal predominance, there is mild supratentorial atrophy (g, h). Reprinted from Best Practice & Research Clinical Endocrinology & Metabolism 29(2), van Rappard DF, Boelens JJ and Wolf NI, Metachromatic leukodystrophy: Disease spectrum and approaches for treatment, pages 261–​73, Copyright © 2015, with permission from Elsevier. section 24  Neurological disorders 6214 reactive astrocytic gliosis and tissue infiltration by multinucleated macrophages, that is, globoid cells filled with PAS (periodic acid–​ Schiff)-​positive materials. Psychosine (galactosylsphingosine), a toxic metabolite that accumulates in the brain, is considered to be detrimental to the myelin-​forming cells. Disease incidence in the general population is estimated at 1 in 100 000. There are at least 130 reported mutations in the β-​GALC gene that cause Krabbe’s disease. Eighty to 95% of known cases, present as an early infantile form, with onset between 3 and 6 months of life. They have marked irrit- ability, rapidly progressive generalized rigidity, and tonic spasms. Clenched fists and myoclonic jerks may be the earliest noted signs. Blindness and optic atrophy with pendular nystagmus develop later. The earliest objective findings in Krabbe disease are abnormalities of the brainstem auditory-​evoked response (ABR) as well as the visual-​ evoked potential. Brain MRI shows symmetrical T2-​weighted signal abnormalities in the periventricular region of the posterior cerebral hemispheres. Nerve conduction studies reveal markedly reduced nerve conduction velocities, while cerebrospinal fluid protein is ele- vated. Visceral organs as well as the skeletal system are unaffected. Death occurs between the ages of 1 and 2 years secondary to respira- tory difficulties and/​or bronchopneumonia. About 10 to 15% of patients present with the late-​infantile or juvenile form of the disease at approximately 5 years of age. They have a progressive gait disorder, spastic paraparesis, and cerebellar ataxia. Dystonia and visual failure may be associated. Behavioural changes and intellectual impairment may be the presenting features in juvenile-​onset patients. The diagnosis of Krabbe disease is made based on deficient β-​ GALC activity in peripheral leucocytes or cultured skin fibroblasts. Gene sequencing further confirms the diagnosis. Mutation analysis is helpful for screening of siblings as well as other carriers in the family and prenatal diagnosis of any subsequent pregnancies. There is no definitive treatment for Krabbe disease. HSCT, using umbilical cord blood, is effective in modifying the clinical course and improving the neurological status of infantile Krabbe’s disease; however, it is most effective if performed in the presymptomatic stages. Substrate reduction and chemical chaperone therapies are being considered. New-​born screening (NBS) was instituted in the State of New  York in United States in 2006. Early infantile variant has been detected in only 1:400 000 New York babies during the first 8 years of NBS, with late-​onset variants being more frequent. The false-​positive rate and positive predictive value of New York’s MS/​ MS-​based enzyme assay, as reported in the Advisory Committee on Heritable Disorders in New borns and Children (ACHDNC) evidence review, were 0.004% and 8%, respectively. Several other states in the United States through legislative action have mandated newborn screening for lysosomal storage disorders. There are pilot projects undertaken in other states in the United States as well as across the world. Alexander disease Alexander disease (MIM 203450), a sporadic autosomal dominant condition first reported by WS Alexander in 1949, is an unusual form of leucodystrophy presenting clinically and pathologically with white matter dysfunction but caused by mutations in the rod domain of the glial fibrillary acidic protein (GFAP) gene, resulting primarily in astrocytic dysfunction. A pathological hallmark of Alexander dis- ease is the presence in the astrocytes of eosinophilic, refractile, often rod-​shaped, cytoplasmic inclusions termed ‘Rosenthal fibres’, which contain the intermediate filament protein GFAP in association with αβ-​crystalline, small heat-​shock proteins. These are predominantly distributed in the subependymal, subpial, and perivascular regions, in the basal ganglia and thalamus, and in the brainstem. There is widespread myelin deficiency in infantile cases associated frequently with cystic degeneration and cavitation. The arcuate fibres as well as occipital lobes and cerebellum are spared. In the juvenile-​onset form, the white matter degenerates whereas adult-​onset disease may have only patchy zones of myelin pallor or cavitation. The most common infantile form, with age of onset between birth and 2 years, is a relentlessly progressive lethal condition presenting as megalencephaly, seizures, hydrocephalus, and psychomotor re- tardation, and progressing to spastic quadriplegia. Survival varies from a few weeks to several years, but rarely beyond the early teens. Juvenile-​onset Alexander disease between ages of 4 and 10 years presents with slowly progressive ataxia, spasticity, and bulbar signs, including speech and swallowing difficulties with relatively preserved intellect. Adult-​onset presentation, increasingly recognized and no longer considered a very rare form of the disease, is often character- ized by pseudo-​bulbar signs, ataxia, and spasticity, associated with atrophy of the medulla and upper cervical cord on neuroimaging. Clinical variability ranges from a presentation similar to juvenile-​ onset Alexander disease, progressive spastic paraplegia, slowly progressive dementia to relapsing–​remitting neurological symp- toms mimicking multiple sclerosis that becomes recognizable as Alexander’s disease upon neuropathological examination. Recently, Alexander disease is divided into 2 groups: type I was characterized by early onset seizures, megalencephaly, and typical MRI features, and type II with a later age at onset characterized by brainstem fea- tures and atypical MRI findings. Classic MRI features for the infantile variant include frontal white matter changes, a periventricular rim with high T1 and low T2 signal and T2 hyperintensity involving the basal ganglia, thalamus, and brainstem (Fig. 24.17.14). There is contrast enhancement of peri- ventricular grey and white matter structures such as ventricular lining, periventricular rim of tissue, white matter of the frontal lobes, optic chiasm, fornix, basal ganglia, thalamus, dentate nu- cleus, and brainstem. Periventricular structures may appear swollen and cystic giving rise to a suspicion of tumour. Finding Rosenthal fibres on pathology may further complicate the issue. Atrophy and signal change of the medulla and spinal cord dominate in late-​onset Alexander disease. Middle cerebellar peduncle abnormalities have been described. Alexander disease should be entertained in the dif- ferential diagnosis, especially in juvenile or adult cases, when brain MRI shows predominant or isolated involvement of posterior fossa structures, multifocal, tumour-​like brainstem lesions and brainstem atrophy, diffuse signal changes involving the basal ganglia, thalamus, or both, with contrast enhancement, as well as a garland-​like appear- ance of the ventricular wall. Management of patients with Alexander disease is symptomatic. Seizure management in children can be challenging. In late-​onset cases, supportive measures include treatment for spasticity and aids for ambulation. 24.17  Inherited neurodegenerative diseases 6215 Hypomyelinative leucodystrophies Pelizaeus–​Merzbacher disease Pelizaeus–​Merzbacher disease (PMD, MIM 312080), the proto- typical X-​linked recessive hypomyelinating disorder, is caused by alterations in the proteolipid protein (PLP) gene (PLP), which in oligodentrocytes encodes two major CNS myelin proteins: PLP and its spliced isoform DM20. The phenotypic spectrum of PMD ranges from PMD type II (connatal form) to PMD type III (transitional form) to PMD type I (classic form) to spastic paraplegia type 2 (SPG2; complicated form, to SPG2 (pure form), and is closely related to the genotype. Missense mutations in the highly conserved region of the DM20-​related protein family cause the most severe forms, whereas Fig. 24.17.14  (a) Axial, (b) coronal, and (c) sagittal T2-​weighted images show abnormally hyperintense white matter in both frontal lobes, with involvement of subcortical fibres. There also is a radial arrangement of hypointense stripes within abnormally hyperintense posterior white matter (arrows). Note the subcortical white matter is spared in these regions. (d) Magnified axial inversion recovery image shows details of the hypointense radial stripes (arrows), constituting a typical tigroid pattern. Note: Tigroid pattern on MRI: Tigroid pattern is evident on T2 weighted MR imaging. It is a peculiar arrangement of radially oriented T2-​hypointense stripes within the abnormally hyperintense deep parieto-​occipital white matter. The stripes are thought to represent relatively preserved perivascular myelin within the abnormal white matter. Although it was first reported in Pelizaeus–​Merzbacher disease and it is considered to be a hallmark of metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD). It is rarely described in other lysosomal storage disorders such as infantile GM1 gangliosidosis (GM1) and leukodystrophies such as Alexander disease. It is not invariably present in all affected patients. Reprinted with permission from Biancheri R et al. (2013) Magnetic Resonance Imaging ‘Tigroid Pattern’ in Alexander Disease. Neuropediatrics 44(3), 174–​6, Copyright © 2013, Georg Thieme Verlag KG. section 24  Neurological disorders 6216 substitutions of less conserved amino acids, as well as gene alterations that do not affect the DM20 isoform such as truncations, or dele- tions, cause less severe forms of PMD and SPG2. Large duplications including the entire PLP gene are the most frequently encountered mutations, which cause the classic phenotype; triplications cause a more severe phenotype. Seitelberger delineated the neuropatho- logical characteristics in PMD, which correlate well with the severity of the clinical presentation. The common pathological characteristics include lack or reduction of myelin sheaths in large areas of the white matter, with a patchy appearance of relatively conserved thin myelin islets, resulting in a ‘tigroid’ pattern. The structure of neurons and their processes including axons is well preserved. The typical early manifestations of classic PMD as described by Pelizaeus and Merzbacher, include hypotonia, nystagmus, and de- layed motor development within the first year of life, followed by spasticity, cerebellar dysfunction, dystonia, and choreoathetotic movements and then disappearance of the nystagmus. Seizures may or may not be present. Patients often show slow development in the first decade of life; up to 45% of patients may be able to assume a sitting posture and some may be able to walk and acquire language capabilities. Slow deterioration begins in the second decade until death in mid-​adulthood. In the connatal form there is congenital psy- chomotor developmental arrest with feeding problems, stridor, and spasticity, leading to progressive contracture of extremities, often ac- companied by seizures. Death occurs in the first decade of life. Spastic paraplegia type 2 (SPG2) is allelic to PMD based on partial overlap of clinical manifestations with PMD and the discovery of PLP1 mutations in SPG2. In SPG2 normal motor development oc- curs in the first year of life, but progressive weakness and spasticity of the lower limbs develop between the ages of 2 and 10. In addition some clinical features seen in PMD, such as nystagmus, optic at- rophy, ataxia, dysarthria, and intellectual impairment, although less prominent, may be present. Later-​onset spastic diplegia with no add- itional neurological complications (the pure form of SPG2) has also been reported. Most female carriers of PLP mutations are asymp- tomatic; however, in rare families, including the family described by Pelizaeus, manifestations ranging from mild spastic diplegia to pro- gressive leucodystrophy with dementia have been reported. Female carriers for PLP mutations causing a mild phenotype in males tend to be symptomatic, whereas those carrying mutations causing severe phenotypes in males are usually asymptomatic in female carriers. This may be related to a skewed pattern of X inactivation in cells in which a severe mutation favours preferential inactivation whereas a milder mutation may not confer the selectivity or to the elimination of oligodendrocytes expressing severe mutations during early mye- lination, unlike those expressing milder mutations that persist. The fact that PMD is characterized by delay in myelination and not by demyelination is reflected in T2-​weighted images on brain MRI as diffuse hyperintensity, which typically involves all the white matter including cerebral hemispheres, cerebellum, and brainstem, unlike many other demyelinating leucodystrophies, where abnormalities are often confined to specific regions (Fig. 24.17.15). Additionally, T1-​weighted signals from white matter in PMD are usually normal or isointense, unlike other demyelinating or dysmyelinating con- ditions where the T1 signal is hypointense. Thinning of the corpus callosum and atrophy of the cerebral hemispheres may be seen in se- vere PMD cases. Sparing of the corticospinal tracts can occur in clas- sical PMD. Patients with the PLP null phenotype have milder diffuse abnormalities of the white matter whereas milder SPG2 phenotype may have patchy areas of hypomyelination on MRI. Definite MRI abnormalities may not be apparent until age two. Extensive but non-​ progressive abnormalities of multimodal evoked potentials are ob- served in PMD. Electromyogram and nerve conduction studies are normal. Diagnosis of PMD/​SPG2 is made based on clinical presentation, X-​linked inheritance pattern, MRI indicative of hypomyelination, and molecular testing confirming duplication or other mutation of the PLP1 gene. Currently, there is no definitive therapy for PMD. Symptomatic management of spasticity, feeding difficulties, and dystonia is recommended. 18q− syndrome 18q− syndrome, one of the most common chromosomal deletion syndromes, was first described by DeGrouchy in 1964. The clinical picture is distinguished by several dysmorphic features including short stature, microcephaly, midface hypoplasia, malformed ears, stenotic ear canals, flat philtrum, carp-​shaped mouth, prognathism, tapered fingers, proximal thumbs, and prominent fingerprint whirls, as well as numerous neurological deficiencies such as hypotonia, hearing loss, nystagmus, and intellectual impairment. The deleted 2-​Mb region of 18q22–​23 contains seven known genes, one of which Fig. 24.17.15  Brain magnetic resonance images of a two-​year-​old boy with PLP1 deletion. (a) T1-​weighted axonal images are nearly normal. (b) T2-​weighted axonal images show diffuse hypomyelination with some myelination still present in the posterior limbs of the internal capsule, corpus callosum, brainstem, and cerebellar peduncles. Reprinted from Brain and Development 34(10), Torisu H et al., Clinical and genetic characterization of a 2-​year-​old boy with complete PLP1 deletion, pages 852–​6, Copyright © 2012 The Japanese Society of Child Neurology, with permission from Elsevier. 24.17  Inherited neurodegenerative diseases 6217 encodes for myelin basic protein (MBP), which is a key structural protein of CNS myelin. As the deletion most often involves the distal portion of the long arm of chromosome 18 from q21 to qter, haploinsufficiency of MBP is implicated in the delayed or incom- plete development of myelin seen on brain MRI; however, proton MR spectroscopy (MRS) studies suggest the possibility of active de- myelination or increased myelin turnover. The characteristic pattern of dysmyelination on brain MRI T2-​weighted images, which shows low grey matter–​white matter contrast, persists in individuals with 18q–​ beyond their first decade. The severity of dysmyelination ap- pears to correlate with the severity of other features of the 18q syn- drome, implicating the role of other deleted genes more proximal to the MBP locus in defective myelination in these patients. Pelizaeus–​Merzbacher-​like disease Uhlenberg et  al. in 2004 reported children with Pelizaeus–​ Merzbacher-​like disease (PMLD) with mutations in GJA12 (gap junction protein, α-​12 gene), now known as gap junction pro- tein, γ-​2 gene (GJC2, MIM 608803). Only 8% of PMLD cases are caused by mutations in GJC2. GJC2 encodes a member of a large family of connexin proteins, called connexin 47 (Cx47) or connexin 46.6 (Cx46.6), which is a 4-​pass transmembrane protein highly ex- pressed in oligodendrocytes. PMLD caused by GJC2 mutations, called PMLD1 (MIM 608804), or leukodystrophy hypomyelinating 2 (HDL2), has an autosomal recessive mode of inheritance with missense, nonsense, frameshift, and indel mutations reported. Patients with PMLD and GJA12 mutations show the character- istic clinical symptoms such as nystagmus and impaired motor development in infancy, followed by ataxia, choreoathetotic move- ments, dysarthria, and progressive spasticity. Up to 70% of these patients have been reported to acquire walking capability; their intellectual functions were well preserved compared with their motor impairment. Epileptic seizures and peripheral neuropathy have been reported in a few cases. In patients with GJA12 pro- gression of mutations is slower, their cognition is better preserved, and there is partial myelination of pyramidal tracts compared with classic PMD. Brain MRI is similar to that of PMD with high T2-​weighted signal throughout the cerebral white matter and pyr- amidal tracts. Severe hypomyelination associated with increased N-​ acetylaspartylglutamate in the cerebrospinal fluid. A rare disorder that must be considered in the differential diag- nosis of connatal forms of PMD has been reported in two unrelated girls with almost complete absence of myelin on cerebral MRI, as shown by a homogeneous high signal of white matter on T2-​weighted images and a low signal on T1-​weighted images in association with highly elevated concentrations of N-​acetylaspartylglutamate (NAAG) in their cerebrospinal fluid. Clinical features include |rota- tory nystagmus within the first 2 months, epilepsy, feeding difficulty, and acquired microcephaly. Initial pyramidal signs were followed by hypotonia and loss of reflexes secondary to peripheral neuropathy. No mutation could be found in the gene encoding the NAAG-​ degrading enzyme. No further reports have appeared in literarture since first description in 2004. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-​ABC) In 2002, van der Knaap et al. described seven unrelated patients with unidentified leucodystrophy. MRI picture was characteristic of diffuse myelin deficiency in the central white matter and at- rophy of the neostriatum (caudate and putamen) and cerebellum (vermis greater than hemispheres). This condition was labelled as hypomyelination with atrophy of the basal ganglia and cerebellum (H-​ABC). Subsequently these cased were found to have a heterozy- gous c.745G. A mutation in TUBB4A, encoding for tubulin β 4A. At least 23 additional patients have been described. Presenting fea- tures are usually motor in the form of oculomotor symptoms, speech complaints, gait instability, or hypotonia. All patients had spasticity and majority had ataxia, movement disorder choreoathetosis or dystonia, rigidity, and dysarthria. Two thirds of patients described thus far are male, two thirds had symptom onset before age 2 and two thirds had delayed motor development. Half of the patients had tremors, microcephaly, and short stature. On MRI, there was diffuse myelin deficiency with high signal intensity on T2-​weighted images in the cerebral white matter including the corpus callosum, internal capsule, and pyramidal tracts in the midbrain and pons. With pro- gression of the disease there was dilatation of the lateral ventricles and atrophy of the caudate nucleus, putamen, and cerebellum. Hypomyelination and congenital cataract Hypomyelination and congenital cataract is a rare autosomal re- cessive hypomyelinating leucodystrophy, described by Zara et al. in 2006, caused by deficiency of hyccin, a membrane protein implicated in both central and peripheral myelination. The FAM126A gene lo- cated on chromosome 7p21.3-​p15.3 encodes it. Other features are progressive neurological impairment and congenital cataract. Most patients have cataract surgery within their first few months and in- tellectual impairment and developmental delay are evident by 1 year. Almost all achieve the ability to walk in the second year with support but lose this ability by the end of first decade to become wheel chair bound due to slowly progressive pyramidal and cerebellar dysfunc- tion, as well as peripheral neuropathy manifesting as lower-​limb muscle weakness and wasting. Neurological findings include dys- arthria, truncal hypotonia, brisk tendon reflexes, and bilateral ex- tensor plantar responses along with cerebellar signs, such as truncal titubation and intention tremor. Recently milder phenotypes have been described. Subsequent studies have described milder pheno- types such as delayed cataract and ability to walk without support. Brain MRI shows diffuse cerebral hypomyelination with increased white matter water content and progressive white matter atrophy with preservation of the cortex and deep grey matter structures. Electrophysiological studies show evidence of demyelination as well as axonal pathology in most patients. 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy/​ Leucoencephalopathy with ataxia, hypodontia, and hypomyelination Wolf et al. in 2005 described four patients with early onset progres- sive ataxia, short stature, and a distinctive pattern of hypodontia, hypomyelination, and cerebellar atrophy with ataxia. Motor devel- opment was normal or slightly delayed and mental development was mildly retarded. Four adult patients with milder neurologic signs and hypogonadotropic hypogonadism were described shortly there- after. Subsequently, mutations in POLR3A, coding for the largest subunit of RNA polymerase III and POLR3B, encoding another sub- unit of this polymerase, have shown to cause 4H, as well as 2 other entities: ‘hypomyelination with cerebellar atrophy and hypoplasia section 24  Neurological disorders 6218 of the corpus callosum’, and ‘leukodystrophy with oligodontia’. In general, patients with POLR3A mutations are more severely affected than patients with POLR3Bmutations with faster regression and shorter life expectancy. 4H leukodystrophy has a spectrum of disease severity. At the se- vere end, affected children do not achieve independent walking and have mild-​to-​moderate intellectual disability. At the milder end of the spectrum, patients present after age 5 years with learning diffi- culties and motor clumsiness. About 10% cases present late, after age 10 years. Developmental delay is noted in half the patients between the age of 1 and 2 years. Unsupported walking if achieved was usu- ally before age 2 years; about a fifth are never able to walk independ- ently. Majority of patients have severe intention tremor, dysmetria and/​or gait ataxia. Abnormal smooth pursuit and gaze-​evoked nys- tagmus is present in most patients. Speech and swallow deteriorate slowly as well. Epilepsy, pyramidal signs and extrapyramidal signs, including dystonia, are less common. Wheelchair dependence oc- curs by the end of the first decade, but several patients may still be ambulatory in adulthood. Learning difficulties or mild-​to-​moderate intellectual disability in present in most. Cognition usually deteri- orates slowly in the second decade. Acute neurologic deterioration with infections is known with not all children regaining their pre- vious level. Hypodontia and dental abnormalities are prominent with natal teeth, delayed dentition with abnormal order of deciduous tooth eruption and upper median incisors erupting late or not at all. However, dental abnormalities may be seen only in two thirds of pa- tients and as such are not required to make the diagnosis. Delayed puberty secondary to hypogonadotrophic hypogonadism, is seen in three fourths of cases. Growth hormone deficiency is also reported in some patients. Another noteworthy feature is pronounced and progressive myopia. Pathological examination in one case of a 14-​year-​old girl showed diffuse white matter atrophy with thin corpus callosum, enlarged lateral ventricles, and non​homogeneous discoloration of the white matter. Histologic analysis revealed variable white matter rarefac- tion, lack of myelin, and reduced numbers of oligodendrocytes with better preservation of the perivascular myelin in the centrum semiovale. Foamy macrophages were seen clustering around small blood vessels. The cerebellar folia were mildly atrophic and there was non​homogeneous lack of myelin in the deeper cerebellar white matter. Brain MRI invariably showed hypomyelination (i.e. T2-​ weighted images show a diffusely hyperintense signal and a normal hyperintense signal on T1-​weighted images with myelination of the optic radiation and small T2 hypointense dot in the posterior limb of the internal capsule). A thin corpus callosum is evident by adult- hood. Cerebellar atrophy, particularly in the vermis, is also noted. Vacuolating leucoencephalopathies Canavan’s disease Canavan’s disease, an autosomal recessive disorder caused by defi- ciency of aspartoacylase, leads to a build-​up of NAA in the brain, as well as to NAA acidaemia and NAA aciduria. Canavan’s disease is pan-​ethnic but there is a high prevalence of the carrier state, es- timated at 1 in 37 to 1 in 50, in the Ashkenazi Jewish community. Two point mutations (at positions 693C and 854A in the coding sequence) are responsible for 97% of mutant alleles in Ashkenazi Jews, whereas C914A is the most common mutation among non-​ Jews, found in 30–​60% of mutant alleles. Aspartoacylase, a zinc carboxypeptidase enzyme expressed exclusively in the CNS in oligodendrocytes, normally hydrolyses NAA, which is derived from neurons to aspartic acid and acetate. The free acetate moiety is con- verted to acetyl-​CoA by acetyl-​CoA synthetase and presumably further utilized as a building block for myelin lipids. Pathologically, intermyelinic oedema, widespread vacuolation in the lower layers of the cerebral cortex, and subcortical white matter and lack of myelin occur, along with astrocytic swelling and mitochondrial changes re- sulting in spongy degeneration of the brain white matter. Most cases present early in infancy but a few milder cases with a later onset have been encountered. Three clinically distinct groups of Canavan disease have been identified: (i) the congenital form with severe symptoms in the first few weeks of life; (ii) the infantile form, the most common form in which the disease is apparent by 6 months of age; and (iii) the juvenile form, in which the disease is apparent by the age of 4 or 5 years. Infants with Canavan’s dis- ease appear normal at birth, but developmental delay and hypo- tonia, including head lag, are evident between 2 and 6 months of age followed by macrocephaly and severe impairment of motor development by 1 year. Other features include ataxia, inadequate visual tracking, and poor sucking ability. Optic atrophy, spasticity, and seizures soon ensue. In spite of profound delays, Canavan dis- ease patients can sometimes interact with others, smile, and reach for objects. Eventually, affected children become increasingly de- bilitated with age, and unable to move voluntarily or to swallow. Death typically occurs before adolescence. Mild/​juvenile Canavan disease can go unrecognized due to mild phenotype and normal head circumference. Urine organic acid screen showing elevation of urine NAA, often more than 100-​fold compared to normal individuals, is often the first diagnostic clue in evaluation of patients with Canavan’s dis- ease. Diffuse loss of white matter including the subcortical U-​fibres, which are usually spared in most other forms of leucodystrophy, is evident on brain MRI. There is a marked increase in the NAA peak in brain white matter on MRS. The deficiency in aspartoacylase ac- tivity can be confirmed in cultured skin fibroblasts from patients but enzyme determinations in cultured amniotic fluid cells are not reliable. Although not required for diagnosis, gene sequencing will reveal pathogenic mutations; this provides the necessary genetic in- formation for pre-​natal testing of subsequent pregnancies. Calcium acetate has been tried in Canavan’s disease to replace the deficient acetate and acetazolamide has been used to slow the pace of macrocephaly (Fig. 24.17.16). A  long-​term follow-​up of gene therapy with an adeno-​associated viral (AAV) vector carrying the ASPA gene (AAV2-​ASPA) in 13 Canavan disease patients re- ported that the gene therapy was tolerable, no severe long-​term ad- verse effects were noted, elevated NAA in the brain was reduced, the progression of brain atrophy was slowed, and improvements were observed in the frequency of seizures. Moreover, neurological examination showed significant improvement in motor functions in younger cohorts of treated CD patients, indicating the possible advantage of early therapeutic interventions. Prevention strategies have included testing for carriers in Ashkenazi Jewish couples and prenatal diagnosis in at-​risk pregnancies using NAA quantification in amniotic fluid and molecular analyses of chorionic villous cells and amniocytes. 24.17  Inherited neurodegenerative diseases 6219 Megalencephalic leucoencephalopathy with subcortical cysts Megalencephalic leucoencephalopathy with subcortical cysts (MLSC) is an autosomal recessive disorder caused by alteration in the gene MLC1, mapped to chromosome 22qtel, which encodes a membrane protein that is expressed almost exclusively in the brain, especially in astrocytes, and leucocytes. Based on the pattern of localization it is speculated that the MLC1 protein is involved in astrocytic regulation and/​or transport of ions or other substances. MLC1 mutations all disrupt the membrane localization of the MLC1 protein. Mutations in HEPACAM, coding for hepatic and glial cell adhesion molecule GlialCAM, also cause MLC. GLIALCAM mutations also disrupt the localization of MLC1 indicating that MLC1 is central in the pathophysiology of MLC. At least 50 mu- tations have been found thus far in MLC1; however, members of the Agarwal ethnic group of northern India, in whom the disease is more prevalent, share a common homozygous mutation, 320insC, suggesting a founder effect. Histopathology shows a spongiform leucoencephalopathy in the subcortical white matter without cor- tical involvement. The outermost lamellae of myelin sheaths contain countless vacuoles with sparing the middle or inner parts of myelin sheaths. Although most vacuoles are covered by single myelin la- mellae, some vacuoles were partially covered by multi-​lamellar myelin sheaths or oligodendroglial cell extensions. MLSC is characterized clinically by macrocephaly noted within the first year or at birth, slow progressive decline in motor functions including ataxia and spastic paraparesis several years later, leading to inability to walk, and seizures in about 60% of patients. Cognitive functions are only mildly impaired with some decline in the second decade. Characteristic MRI findings that distinguish MLSC from other megalencephalic leucodystrophies include diffusely abnormal and swollen cortical cerebral white matter and bilateral cystic changes, the appearance of which resembles that of cerebrospinal fluid in all sequences, especially in the temporal lobes, occasionally in the frontoparietal regions but sparing the occipital lobes. In addition, the cerebellar white matter may exhibit mildly abnormal T2 signal but there is no swelling. Eventually the swelling resolves and cortical atrophy de- velops. The number and size of the cysts progressively increase, such that they eventually occupy a significant portion of the frontoparietal cortex. The EEG shows multifocal epileptiform discharges. Supportive treatment, including treatment of seizures, is recommended. Vanishing white-​matter disease (childhood ataxia with CNS hypomyelination) Childhood ataxia with CNS hypomyelination (CACH), a pan-​ ethnic autosomal recessive disease, also described as vanishing white matter disease (VWM) or myelinopathia centralis diffusa, was first identified in 1997. Astute application of molecular genetics in a population of a limited geographical region in the eastern part of the Netherlands led to the discovery that mutations in any one of the five subunits of eukaryotic translation initiation factor 2B (eIF2B) cause CACH/​VWM and the recognition of a wider clinical spec- trum. The eIF2B protein complex has a key regulatory role in protein synthesis through initiation of translation. Regulation of the activity of eIF2 is a protective mechanism for cells in response to stress. Mutated eIF2B could impair the ability of cells to regulate protein synthesis, resulting in increased susceptibility to various physio- logical stress conditions. On gross examination of the brain, the cor- tical grey matter is of normal consistency in marked contrast to the white matter of the centrum semiovale which is softened, atrophic, and gelatinous. There is rarefaction with moderate-​to-​severe vacu- olation of the white matter with relative sparing of axons and sub- cortical U-​fibres. The distinguishing feature of CACH/​VWM is the presence of foamy oligodendrocytes, which on ultrastructural ana- lysis show abnormal abundant cytoplasm containing membranous (a) (b) 1 2 Fig. 24.17.16  (a) T2 weighted image of MRI brain showing 1 characteristic symmetric white matter hyperintensities of subcortical U-​fibres, and 2 symmetric white matter hyperintensities of brainstem and cerebellum. (b) Magnetic resonance spectroscopy showing a high peak of N-​acetyl aspartate which is the characteristic feature of Canavan disease. Reprinted from Sreenivasan P and Purushothaman KK. Radiological Clue to Diagnosis of Canavan Disease. Indian J Pediatr (2013) 80: 75, Copyright © 2012, Dr K C Chaudhuri Foundation, with permission of Springer. section 24  Neurological disorders 6220 structures and numerically increased and morphologically ab- normal mitochondria. Abnormally shaped coarse astrocytes and gliosis are present. In the severe forms, there is a reduction of the number of astrocytes and possibly astrocyte progenitors, but not of oligodendrocyte progenitors. Clinically, early development and head circumference are normal, while some patients may present with speech and cognitive delay. The most common initial presentation is new-​onset ataxia between ages of one and five years. The disorder may be heralded by coma or a dysmetric tremor following mild head trauma or a febrile illness and apparently, even after an acute fright, can occur spontaneously. Subsequent deterioration is generally progressive with gait diffi- culty, cerebellar signs, pyramidal signs, dysarthria, and seizures. The course is often remitting–​relapsing and patients may remain stable for years at any phase of the illness. Dysphagia and optic atrophy are seen late in the disease; the peripheral nervous system is usually un- affected. Death typically occurs during the first or second decade of life. There is a wide phenotypic spectrum which includes congenital forms with manifestations in organs besides the brain, a rapidly as well as a subacutely fatal infantile form, a slowly progressive form with onset after age 5 years that is often associated with ovarian insuf- ficiency (dysgenesis), termed ‘ovarioleucodystrophy syndrome’, and an adult-​onset disease variant. Brain MRI shows symmetrically and diffusely abnormal subcortical white matter with hypointense signal on T1-​weighted MRI and hyperintense signal intensity on T2 im- ages with sparing of the cortex. Cystic degeneration with a radiating stripe-​like pattern or cavitation within the white matter is best seen on proton density or FLAIR sequences; there is no gadolinium en- hancement of these lesions on post-​contrast T1-​weighted MRI. Early and selective involvement of the inner rim of the corpus callosum (septo-​callosal surface) is recently described as a distinguishing sign from other leucodystrophies. Supportive management such as avoidance of stress situations, use of antipyretics and antibiotics, physical therapy for motor dis- abilities, and carbamazepine for seizures is recommended. In fam- ilies with a known mutation prenatal diagnosis can be offered. Progressive cavitatory leucoencephalopathy Progressive cavitatory leucoencephalopathy (PCL) was initially reported in 2005 by Naidu et  al. as childhood-​onset progressive cavitatory leucoencephalopathy associated with an increase in lactate in brain, blood, and cerebrospinal fluid. There may be subtle devel- opmental delay followed by acute onset of irritability or neurological deficits occurring after 2 years of age, followed by steady or intermit- tent clinical deterioration with death between 11 months and 14 years of life. Brain MRI shows irregular asymmetrical patchy areas of white matter abnormality that evolved to multicystic degeneration. MRS shows elevated lactate in the affected structures. PCL appears to be a distinct genetic entity, possibly involving mitochondrial dysfunction, but the exact molecular basis is yet to be elucidated. Secondary inherited leucoencephalopathies Amino acidaemias Neurological manifestations including leucoencephalopathy are frequently present in the amino and organic acidaemias. MSUD is an autosomal recessive disorder caused by deficiency in a sub- unit of the branched-​chain α-ketoacid dehydrogenase complex, which is required for the oxidative decarboxylation of branched-​ chain ketoacids. MSUD-​associated metabolites initiate a process leading to the proteolytic degradation of myelin proteins, thereby producing abnormal myelin sheaths. Patients with MSUD after a relaxed treatment protocol were reported to have myelin abnormal- ities demonstrated on T2-​weighted brain MRI as increased signal in the mesencephalon and/​or brainstem (cerebral peduncles and dorsal brainstem), less so in the basal ganglia–​thalamus and globus pallidus, and less prominent areas of decreased signal intensity in T1-​ weighted images. More severely involved patients had supratentorial changes, especially in the occipital periventricular and cerebellar white matter. The myelin abnormality may be due to chronic ex- posure of the brain to branched-​chain amino acids or to a deficit of essential large neutral amino acids, the transport of which across the blood–​brain barrier is impaired by an excess of the branched-​chain amino acids. In phenylketonuria (PKU), white matter changes on MRI are typ- ical of the adolescent and adult with PKU. However, the distribution of MRI signal abnormality is most marked in supratentorial regions and only in more severe cases does it extend into the basal ganglia, brainstem, or cerebellum. Organic acidaemias Cerebral MRI has revealed bilateral white matter changes in sev- eral organic acidopathies, including l-​2-​hydroxyglutaric aciduria, 2-​methyl-​3-​hydroxybutyryl-​CoA dehydrogenase deficiency, and 3-​ hydroxy-​3-​methylglutaryl-​CoA lyase deficiency. Glutaric aciduria type 1 Glutaric aciduria type 1 (GA1) is an autosomal recessive disorder due to a deficiency of mitochondrial enzyme glutaryl-​CoA dehydro- genase (GCDH) resulting in the accumulation of glutaric acid and 3-​hydroxyglutaric acid in the blood, urine, and CSF. Macrocephaly is present at birth or within the first few weeks of life. Most chil- dren present with an acute encephalopathic crisis between 3 and 24 months of age in the setting of an infection or illness with de- hydration. Early myelinating tracts are usually spared white matter changes in GA1 primarily involve the periventricular white matter. Other characteristic MRI findings of GA1 include widening of the Sylvian fissure, decreased opercularization of the insula, and acute striatal necrosis. L-​2-​Hydroxyglutaric Aciduria L-​2-​hydroxyglutaric aciduria is caused by mutations in both alleles of the L2HDGH gene resulting in deficiency of L-​2-​hydroxyglutarate dehydrogenase, which is FAD-​linked mitochondrial enzyme that converts L-​2 hydroxyglutarate to α-​ketoglutarate. Clinically, L-​2 hydroxyglutaric aciduria presents with variable degrees of psy- chomotor and speech delay followed by a slowly progressive neurodegenerative disorder presenting as cerebellar, pryamidal, and extrapyramidal signs with cognitive decline. MRI findings are char- acteristic showing initial patchy and eventual confluent low signal on T1-​weighted images and increased signal on T2-​weighted images in the subcortical white matter bilaterally with frontal predomin- ance. Cerebellar and brainstem white matter is not involved. 24.17  Inherited neurodegenerative diseases 6221 Methylmalonic aciduria MMA is a heterogeneous autosomal recessive group of disorders characterized by accumulation of methylmalonic acid due to a de- fect in intracellular cobalamin metabolism (coenzyme deficiency). MMA typically presents fairly early in infancy with a history of poor feeding, vomiting, progressive lethargy, floppiness, and muscular weakness. Brain MRI scan typically demonstrate involvement of basal ganglia and white matter with the globus pallidus being se- lectively affected. Demyelination of corticospinal tracts in a pattern that resembles B12 deficiency of combined systems degeneration is also seen. Glycogen storage disease type IV/​adult polyglucosan body storage disease Glycogen storage disease type IV (GSD IV), an autosomal recessive disorder, results from deficient activity of the branching enzyme 1,4-​glucan-​6-​glucosyltransferase mapped to chromosome 3p14. It presents in infancy with severe liver disease, causing cirrhosis, portal hypertension, and early death. A fatal neonatal neuromuscular form and a milder non​progressive hepatic form are known. A late-​onset variant, referred to as adult polyglucosan storage disease (APBD), first described in 1971. There is a predilection for Ashkenazi Jesish ancestry, although it has been described in all eth- nicities. Not all patients with APBD have deficiency of the glycogen-​ branching enzyme; however, when present levels are reduced to less than 25% of normal. ABD is characterized by onset in by the fifth of neurogenic bladder, which may precede other symptoms by a decade. Neurogenic bladder, spastic paraplegia, and axonal neuropathy are cardinal signs of the disease and present in 90% of the patients. Cognitive decline consisting of mild attention and memory deficit may also affect up to 50% of patients with APBD. Neurophysiological studies reveal an axonal sensorimotor peripheral neuropathy. The MRI shows extensive, non​enhancing, bilateral, symmetrical, peri- ventricular and subcortical white matter changes with the T2 signal abnormality extending to the posterior limb of internal capsule, external capsule caudally to pons and cervicomedullary junction, involving usually in the pyramidal tracts and the medial lemniscus. There is consistent and progressive atrophy of the brainstem (me- dulla) and spinal cord. Sural nerve biopsy, which can be diagnostic, shows frequent enlargements of myelinated fibres that stain posi- tive with PAS. PAS-​positive inclusions are also found within skeletal muscle fibres and the apocrine gland cells of the skin. Sjögren–​Larsson syndrome Sjögren–​Larsson syndrome (SLS) is an autosomal recessive dis- order resulting from mutations in the gene for the microsomal enzyme fatty aldehyde dehydrogenase (FALDH), first described in 1957 by Sjögren and Larsson in a consanguineous cohort of 28 patients from the county of Vasterbotten in northern Sweden. The worldwide prevalence of this pan-​ethnic disorder is probably less than 0.4 per 100 000. FALDH catalyses the oxidation of medium-​ and long-​chain fatty aldehydes to the corresponding carboxylic acids. Deficiency in FALDH leads to elevation of free fatty alcohols in the plasma and leukotriene B4 (LTB4) in the urine. The accu- mulation of fatty alcohols or aldehyde-​modified marcromolecules disrupts the integrity of multilamellar membranes in skin and myelin. Neuropathologically, there is reduction in myelinated nerve fibres in cerebral and cerebellar white matter, loss of neurons in the cortex and basal ganglia, and deposition of pigments. PAS-​ positive lipoid substances are found in the subpial, subependymal, and perivascular glial layers as well as in cerebral and cerebellar white matter, and there are perivascular macrophages containing lipofuscin-​like pigments and spheroid bodies in the neuropili of several brainstem nuclei. Babies with the condition may be born preterm with ichthyosis, which is generalized brownish-​yellow in colour and associated with a severe pruritus. Developmental delay and spasticity are apparent by the first or second year, leading to contractures in the lower ex- tremities and wheelchair dependency in adolescence. Cognition is impaired in most patients. Pseudobulbar dysarthria, delayed speech, and seizures are common. Ophthalmological abnormalities include photophobia, macular dystrophy, and decreased visual acuity. After several years, glistening white dots surround the macular region of the retina, form of crystalline maculopathy. EEG shows sym- metrical slow background activity with no epileptiform pattern. Cerebral MRI studies reveal multifocal areas of delayed myelin- ation, hyperintense signal abnormality in the periventricular zone, and mild ventricular enlargement in the oldest patients. On MRS of the cerebral white matter and basal ganglia, there is a distinct diag- nostic sharp lipid peak, believed to arise from the accumulation of long-​chain fatty alcohols or aldehydes. Treatment has been attempted with a low-​fat diet supplemented with medium-​chain fatty acids but was not successful. Beneficial effects have been described using the LTB4 synthesis inhibitor Zileuton. The accumulation of leukotrienes due to FALDH-​ dependent deficient degradation is presumed to play an important part in the inflammatory reactions seen in the skin of SLS patients. The hypolipidaemic drug, bezafibrate, has been shown to induce residual FALDH activity in patient fibroblasts and may be a thera- peutic option. Cerebrotendinous xanthomatosis This rare but underdiagnosed disorder should always be con- sidered in the differential diagnosis of a leucodystrophy, because it is a treatable condition. Among Moroccan Jews the incidence of cerebrotendinous xanthomatosis (CTX) is 1 in 108 and in the gen- eral US population its prevalence is estimated to be 3 to 5 in 100 000. The 5α-​dihydro-​derivative of cholesterol, cholestanol, is increased 10-​ to100-​fold in CTX. It is present in the diet but its accumula- tion in the nervous system apparently results from increased en- dogenous production and impairment to its egress as a result of the blood–​brain barrier. Mutations in the sterol 27-​hydroxylase gene (CYP27) cause a block in bile acid synthesis, leading to absence of chenodeoxycholic acid in the bile and excretion of bile alcohols (bile acid precursors) in the bile and urine. Absence of chenodeoxycholic acid leads to upregulation of endogenous bile acid synthesis. Brain atrophy with multiple yellowish deposits in the plexus choroideus and in brain white matter are evident on autopsy. Microscopically, multiple dispersed lipid crystal clefts and granu- lomatous lesions in the cerebellar hemispheres, demyelination and perivascular accumulation of foamy macrophages in the globus pallidus, and extracellular deposition of homogeneous myelin-​ like material in periventricular areas are evident. Examination of spinal cord may show demyelination, gliosis, and involvement of the long tracts. Nerve biopsy reveals primary axonal degeneration, section 24  Neurological disorders 6222 demyelination, and remyelination. Xanthomas are an accumulation of xanthoma cells and multiple, dispersed lipid crystal clefts. Symptoms commonly appear in childhood or during the second decade, but patients may present in the neonatal period or in middle age. Patients with CTX have an average age of 35 years at the time of diagnosis and a diagnostic delay of 16 years. There may be difficulty in school due to slowly progressive intellectual impairment, behav- ioural difficulties, and psychiatric symptoms. Neurological findings almost invariably develop and include cerebellar and pyramidal tract signs, peripheral neuropathy, and seizures. The neurological manifestations may be classified into two main clinical subgroups, the classic form (cerebellar and supratentorial symptoms) and the spinal form (chronic myelopathy). Other manifestations include cataracts, tendon and tuberous xanthomas (especially of the Achilles tendon), diarrhoea, osteo- porosis, and bone fractures. Within the neonatal period, prolonged cholestatic jaundice may be observed. Eye signs in addition to cata- racts include optic disc pallor, premature retinal senescence, palpe- bral xanthelasmas, corneal lipoid arcus, and proptosis. Premature atherosclerosis and cardiovascular disease have been reported among the multiple clinical manifestations of CTX. The biochemical abnormalities in CTX include a plasma cholestanol concentration 5-​ to 10-​fold greater than normal (330 ± 30 μg/​dl), a urine bile alcohol concentration of 14 000 ± 3500 nmol/​litre, and a plasma bile alcohol concentration more than 500-​ to 1000-​fold greater than normal (8.48 ± 3.67 nmol/​litre). Imaging studies dis- close cerebellar and spinal cord atrophy, symmetric hyperintensities in the dentate nuclei and brain white matter hypodensity. The cere- bellar white matter is especially involved and there is hypersensitivity of the dentate nuclei bilaterally on the FLAIR sequence. A mainly spinal cord syndrome can occur with white matter abnormalities in the lateral and dorsal columns of the spinal cord. Long-​term oral therapy with chenodeoxycholic acid (750 mg/​ day), most effective in presymptomatic individuals, has been shown to suppress the abnormal bile acid synthesis, correct the biochemical abnormalities, and reverse the progression of CTX. Although HMG-​ CoA (hydroxymethylglutaryl coenzyme A) reductase inhibitors re- duce serum cholesterol levels, caution is exercised because they can exacerbate the mitochondrial impairment. Although cholic acid can normalize plasma cholestanol and improve non​neurological symp- toms, only CDCA can improve the neurological symptoms in pa- tients with CTX. Long-​term replacement therapy with CDCA can increase bone mineral content. Combination therapy with CDCA (300 mg/​d) and pravastatin (10 mg/​d) can improve lipoprotein me- tabolism, inhibit cholesterol synthesis, and reduce plasma levels of cholestanol and plant sterols. Lysosomal diseases Lysosomal storage disorders (LSDs) are a heterogeneous group of conditions mostly related to failure of degradation of one or more macromolecules which results in their accumulation within tis- sues (Table 24.17.2). Together these disorders, numbering over 50, have an incidence of 1 in 5000 to 7000 births. Two thirds of these conditions are enzyme deficiencies wherein the un-​metabolized or partially metabolized substrate accumulates. The stored materials are by products of the cellular turnover of complex glycoproteins, glycolipids, glycosaminoglycans (mucopolysaccharides), and oligosaccharides. Whereas lysosomal enzymes are ubiquitously expressed, the sub- strate on which they act may be confined to a single organ or system, as in Krabbe disease, or distributed more widely causing multi-​ systemic manifestations, as in Gaucher disease. Signs of disease manifestations may become evident prenatally, at birth, or at any time from infancy to adulthood. Here LSDs that involve the central and/​or peripheral nervous system are considered. Clinical genetics Most LSDs are inherited in an autosomal recessive manner, some are X-​linked. The LSDs that affect the nervous system are neurodegenerative in nature with onset of clinical neurological symptoms usually following some period of normal development. This characteristic feature allows recognition of a storage disease on clinical evaluation. The age of onset and course of the disease is often dictated by the residual enzyme activity which in turn depends on the severity of the mutation. Homozygous or compound heterozy- gous null and/​or severe deleterious mutations often lead to absent or almost absent residual enzyme along with the classic infantile or late-​infantile presentation and a rapidly progressive and often fatal disease course. Most LSDs were originally described in this classic form and bear the name of the physician(s) who identified them. However, homozygous or compound heterozygous milder missense mutations usually allow some residual enzyme activity. Very often, this leads to later-​onset and relatively slowly progres- sive disease. In addition, there is a remarkable change in phenotypic expression such that often the organ involvement or the clinical feature that is considered hallmark of the infantile presentation is no longer evident. A striking example of this may be late-​onset Tay–​Sachs disease, which does not present with cherry red spot, seizures, cognitive decline, or macrocephaly. Instead it is a anterior horn cell and cerebellar disease with variable psychiatric features. Or late-​onset forms of Pompe disease where there is no significant cardiac involvement. This unexpected and unanticipated change in phenotype as well as the likelihood that the late-​onset forms mimic other common dis- orders (e.g. limb-​girdle muscular dystrophy and late-​onset Pompe disease, leads to under significant delayed diagnosis and misdiag- nosis). The diagnostic delay in late-​onset forms of LSDs is consid- erable mostly related to lack of awareness among physicians about the wide spectrum of phenotypic expression and true prevalence of LSDs. This is compounded by the perception that since most of these disorders do not have definitive therapies, lack of accurate diagnosis may not change medical management in an individual pa- tient. However, newer therapies are rapidly being developed. Also, accurate diagnosis permits appropriate genetic counselling for the patient and family and allows apt prognostication. Among Ashkenazi Jews, the frequency of the carrier state for cer- tain of the lysosomal storage diseases (LSDs) is higher than in the general population. For this reason, screening couples before con- ception or in the early stages of a pregnancy is done to determine their carrier status for these disorders, which include Tay–​Sachs dis- ease, Niemann–​Pick disease types A and B, and mucolipidosis IV. In each pregnancy of a couple in which both partners are carriers of the same recessive trait, there is a 25% risk of an affected fetus. Monitoring of their pregnancies by amniocentesis or chronic villous 24.17  Inherited neurodegenerative diseases 6223 Table 24.17.2  Lysosomal storage diseases Stored substrate Disease Enzyme/​protein deficiency Gene locus Sphingolipids GM2 gangliosides, glycolipids, globoside oligosaccharides Tay–​Sachs disease α Subunit of β-​hexoaminidase 15q23–​24 GM2 gangliosides (three types) Sandhoff’s disease β Subunit of β-​hexoaminidase 5q13 GM2 gangliosides GM2 activator 5q32–​33 GM2 gangliosides, AB variant GM1 gangliosides, oligosaccharides, keratin sulphate, glycolipids GM1 gangliosides (three types) β-​Galactosidase 3p21-​3pter Sulphatides Metachromatic leucodystrophy Arylsulphatase A (galactose-​3-​sulphatase) 22q13.31-​qter GM1 gangliosides, sphingomyelin, glycolipids, sulphatide Metachromatic leucodystrophy variant Saposin B activator 10q21 Galactosylceramides Krabbe’s disease Galactocerebrosidase 14q31 α-​Galactosylsphingolipids, oligosaccharides Fabry’s disease α-​Galactosidase A Xq22 Glucosylceramide, globosides Gaucher’s disease (three types)a β-​Glucosidase 1q21 Glucosylceramide, globosides Gaucher’s disease (variant) Saposin C 10q21 Ceramide Farber’s disease (seven types) Acid ceramidase 8p22–​21.2 Sphingomyelin Niemann–​Pick disease types A and B Sphingomyelinase 11p15.1–​15.4 Mucopolysaccharides (glycosaminoglycans) Dermatan sulphate and heparin sulphate MPS I, Hurler–​Scheie α-​l-​Iduronidase 4p16.3 Heparan sulphate MPS IIIA, Sanfilippo A Sulphamidase 17q25.3 MPS IIIB, Sanfilippo B α-​N-​Acetylglucosaminidase 17q21.1 MPS IIIC, Sanfilippo C Acetyl-​CoA:α-​glucosaminide-​N-​ acetyltransferase MPS IIID, Sanfilippo D N-​acetylglucosamine-​6-​sulphatase 12q14 Keratan sulphate MPS IVA, Morquio A Galactosamine-​6-​sulphatase 16q24.3 MPS IVB, Morquio B β-​d-​Galactosidase 3p21.33 Dermatan sulphate MPS VI, Maroteaux–​Lamy N-​Acetylgalactosamine-​4-​sulphatase 5q13–​14 Dermatan sulphate and heparan sulphate MPS VII, sly Hyaluronidase 7q21.1–​22 Hyaluronan MPS IX β-​d-​Glucuronidase 3p21.3 Glycogen Glycogen Pompe’s disease, glycogen storage disease type IIA α-​d-​Glucosidase 17q25 Glycogen Danon’s disease Lysosomal associated membrane protein-​2 (LAMP-​2) Xq24 Oligosaccharides/​glycopeptides α-​Mannoside α-​Mannosidosis α-​Mannosidase 19p13.2–​q12 β-​Mannoside β-​Mannosidosis β-​Mannosidase 4q22-​25 α-​Fucosides, glycolipids α-​Fucosidosis α-​Fucosidase 1p34.1–​36.1 α-​N-​Acetylgalactosaminide Schindler–​Kanzaki disease α-​N-​Acetylgalactosaminidase 22q13.1–​13 Sialyloligosaccharides Sialidosis α-​Neuraminidase 6p21.3 Aspartylglucosamine Aspartylglucosaminuria Aspartylglucosaminidase 4q34-​35 Multiple enzyme deficiencies Glycolipids, oligosaccharides Mucolipidosis II (I-​cell disease); mucolipidosis III (pseudo-​Hurler’s polydystrophy)—​three complementation groups) N-​Acetylglucosamine-​1-​phosphotransferase 4q21–​q23 Mucolipidosis III subtype C γ subunit mutations on 16p Galactosialidosis Protective protein/​cathepsin A 20 (continued) section 24  Neurological disorders 6224 biopsy permits interruption at an early stage. The birth incidence of several of these disorders has decreased in this ethnic community due to couple screening and counselling. Another type of preven- tion programme, popular among the Orthodox Jewish population, involves non​stigmatizing premarital testing permitting marriages to be arranged that avoid the possibility of two carriers for the same disease trait marrying. Families, with affected previous child, can access prenatal testing of the subsequent conceptus using either information on the mu- tations present in the family or through testing of enzyme activity in the chorionic villous cells or the cultured amniotic fluid cells. Newborn screening is also being developed for those LSDs in which an intervention, such as umbilical cord stem cell transplantation (e.g. Krabbe disease) or enzyme replacement therapy (e.g. Pompe disease), may be done in the early newborn period to prevent dis- ease progression. The application of multiplex systems that measure the activities of several lysosomal enzymes simultaneously either by immunofluorescent probing or by tandem mass spectroscopy, with novel substrates, are exciting new developments that make neonatal screening possible. In all cases in which a diagnosis of an LSD is made, family members should be offered genetic counselling and should be encouraged to inform relatives of their increased risk of carrying the trait for the disease. Sphingolipidoses The sphingolipidoses are characterized by abnormalities in the me- tabolism of various glycolipid substrates that are present within membranes of nerve cells and myelin. Most of these disorders are neurodegenerative in nature. Glycosphingolipids (GSLs) undergo degradation within lysosomes through the sequential action of spe- cific acid hydrolases with the assistance of non​enzymatic glycopro- tein cofactors, so-​called sphingolipid activator proteins (or saposins [SAPs]). Ultrastructural studies of tissues from patients with GSL storage diseases typically reveal the presence of characteristic inclu- sions such as the membranous cytoplasmic bodies present in pa- tients with GM1 and GM2 gangliosidoses. Gangliosidoses The carbohydrate moieties of the glycocalyx (‘sweet husk’) that sur- rounds cells are involved in diverse functions such as (i) cell differ- entiation, (ii) cell–​cell interactions, and (iii) signal transduction. Cells in the CNS express an abundance of cell surface glycosylated proteins and lipids. Lipid rafts, which are sites of signal transduction, are enriched in glycosphingolipids (GSLs). A  group of sialylated phosphorus-​free GSLs, known as gangliosides, are essential for normal neural development and function. The gangliosides com- prise of a ceramide backbone, to which glycans are attached through a single glycosidic linkage at the 1-​hydroxyl position. The glycan chains contain one to four (and unusually up to 7) sialic residues. Svennerholm, based on the placement of their sialic acid residues and their distinct chromatographic mobility, assigned the nomen- clature of these ganglioside substrates. Thus G denotes ganglioside, M/​D/​T/​Q (mono-​/​di-​/​tri-​/​tetra-​, and so on) indicate the number of sialic acid residues, with an assigned number being originally based on the migration order of the gangliosides on thin layer chromatog- raphy (e.g. GM3 > GM2 > GM1). Catabolism of the carbohydrate portion of gangliosides occurs in the lysosomes where removal of glycosyl residues is catalysed by specific glycosidases. While present in most tissues including peripheral neurons, gan- gliosides are found in greatest concentration in the grey matter of the brain. Disorders of ganglioside metabolism are classified according to the specific enzyme deficiency and the resultant accumulation of its substrates. Each disorder is further categorized by age of onset into classic (early or late) infantile or later-​onset (juvenile or adult) forms. Age of onset and degree of disease expression are influenced, in part, by the degree of residual enzyme activity. Secondary gan- glioside accumulation occurs in other LSDs such as the MPSs and Niemann–​Pick disease type C. GM1 gangliosidosis GM1 gangliosidosis is an autosomal recessive LSD caused by defi- ciency of the enzyme β-​galactosidase (β-​Gal, GLB1) with estimated incidence of 1:100 000–​200 000 live births. The GLB1 protein is Stored substrate Disease Enzyme/​protein deficiency Gene locus Sulphatides, glycolipids, glycosaminoglycans Multiple sulphatases SUMF-​1 3p26 Lipids Cholesterol esters Wolman’s disease, cholesteryl ester storage disease Acid lipase 10q23.2–​q23.3 Cholesterol, sphingomyelin Niemann–​Pick disease type C NPC1; HE1 18q11–​12; 14124.3 Monosaccharides/​amino acid monomers Sialic acid, glucuronic acid Salla’s disease, infantile free sialic acid storage disease Sialin 6q14–​15 Cystine Cystinosis Cystinosis 17p13 Peptides Bone proteins Pyknodysostosis Cathepsin K 1q21 S-​Acylated proteins Palmitoylated proteins Infantile neuronal ceroid lipofuscinosis Palmitoyl-​protein thioesterase 1p32 Pepstatin-​insensitive lyosomal peptidase Late-​infantile neuronal ceroid lipofuscinosis Pepstatin-​insensitive lysosomal peptidase 11p15 Table 24.17.2  Continued 24.17  Inherited neurodegenerative diseases 6225 encoded by the GLB1 gene (MIM 230500), mapped on the 3p21.33 chromosome. To date more than 130 mutations have been described. It is associated with the neuronal storage of the monosialoganglioside GM1. Normally 20% of all gangliosides found in the brain and 80% of gangliosides in myelin are the monosialoganglioside GM1. Several other substrates of β-​galactosidase, including lactosylceramide, asialofetuin, oligosaccharides carrying terminal β-​linked galactose and keratan sulphate, also accumulate and this may explain the pres- ence of dysmorphic facial features reminiscent of the MPS disorders in the early infantile form of GM1 gangliosidosis. Morquio B syn- drome is an alleilic disorders where GLB1 is defective with respect to keratan sulphate. Primary neurological involvement is not known in Morquio B syndrome. Histological examination of the brain in infantile GM1 gangliosidosis shows neurons and glial cells with distended cytoplasm and eccen- trically placed pyknotic nuclei. The nerve cell bodies of the neurons are ballooned. Foam cells with highly vacuolated cytoplasm was noted in visceral organs including liver, spleen, bone marrow, lung, adrenal medulla, and thyroid. Electron microscopy shows concen- trically arranged inclusion bodies, which largely replace normal cytoplasmic constituents. In later-​onset forms marked GM1 ganglio- side storage is seen in the basal ganglia. Three main clinical forms have been identified: type I (infantile), type II (late-​infantile/​juvenile), and type III (adult) with overlapping manifestations. Early infantile GM1 gangliosidosis presents with hypotonia, feeding difficulties, and failure to thrive in the first weeks to 6 months of life. A macular cherry red spot is found in about 50% of cases, and there is a startle response similar to that seen in Tay–​ Sachs disease. Cherry red spot represents the normal ganglion cell-​ free region of fovea which appears bright red against the abnormally pale retina, where lipid-​laden ganglion cells produce a white ring or halo. Dysmorphic facial features such as frontal bossing, wide depressed nasal bridge, gingival hypertrophy, or thickened alveolar ridges are prominent. Hepatosplenomegaly as well as bone deform- ities referred to as dysostosis multiplex, similar to those found in the MPS disorders, including hypoplasia and anterior beaking of the thoracolumbar vertebrae and widening of the diaphysis of long bone, are also noted. Cardiac complications include enlargement of the heart with thickening of the heart valves and endocardial fibroelastosis, leading to valvular incompetence and cardiac failure. Hydrops fetalis may be the presenting feature at birth in 6% of cases. The course is relentlessly progressive leading to spasticity, tonic spasms, and pyramidal signs with decerebrate rigidity by the second year with or without seizures. Respiratory failure and bronchopneu- monia lead to death, usually by 2 years. The late-​infantile form has an onset usually between 7 and 36 months, often with walking difficulty and frequent falls. Facial dysmorphism, skeletal deformities, and organomegaly are less prominent. Progression of the disease leads to seizures, spastic quadriparesis, and pseudobulbar signs such as drooling and dys- phagia. Death occurs between the ages of 3 and 10 years. The late-​onset form, with onset beyond three years of age, is a protracted illness with dysarthria, dystonia, and mild-​to-​moderate intellectual impairment, usually developing in late childhood or adolescence, but signs and symptoms may be delayed until the third or fourth decade of life. There is vacuolation of periph- eral blood lymphocytes, and the presence of galactose-​containing oligosaccharides and keratan sulphate in urine, findings that help to distinguish GM1 gangliosidosis from mucolipidosis II (I-​cell dis- ease), because both can present with dysmorphic facial features and hepatosplenomegaly. Diagnosis is established by assay of β-​Gal activity in peripheral blood leucocytes and cultured skin fibroblasts, or prenatally using cultured chorionic villous sample (CVS) or amniocytes. Only symp- tomatic treatment is available. In animal studies, oral administra- tion of bicyclic 1-​deoxygalactonojirimycin derivative (6S-​NBI-​DGJ) ameliorated the brain pathology of GM1 gangliosidosis mouse model. Systemic AAV9 gene transfer in adult mice with GM1 gangliosidosis reduces lysosomal storage in CNS and extends lifespan. GM2 gangliosidoses The GM2 gangliosidoses are a group of heterogeneous clinical variants associated with the neuronal storage of the monosialoganglioside GM2, caused by mutations in genes encoding α or β subunit of hexosaminidase A (Hex-​A) or the GM2 activator protein. The three major forms of GM2 gangliosidoses are (1) Tay–​Sachs disease, caused by mutations of HEXA that result in a deficiency of HEXA but normal HEXB activity (2) Sandhoff disease, caused by mutations of HEXB that result in a deficiency of both isoenzymes HEXA and HEXB and (3) the AB variant, caused by mutations in GM2A that lead to an inability to form a functional ganglioside GM2/​GM2A complex. The Hex-​A enzyme, with molecular mass of approximately 100 kDa, is a trimer consisting of one α-​ and two β-​subunits, encoded by genes situated on different chromosomes. Mutations in the β-​subunit lead to deficiency of Hex-​B as well, which is a tetrameric homopolymer of β subunits. The B1 variant of GM2 gangliosidosis, which has a high incidence in Portugal, results from altered substrate specificity of Hex-​A. In this variant the mutated enzyme retains the ability to de- grade the artificial substrate used in diagnostic assays, but not the natural substrate in vivo or the sulphated artificial substrate. Ultrastructural examination in GM2 gangliosidosis reveals neur- onal GM2 ganglioside storage throughout the cortex and the deep grey nuclei, the spinal cord, and the autonomic ganglia. Characteristic pathological features are axonal hillock enlargement, known as meganeurite formation, and sprouting of new synapse-​covered den- dritic neurites at the axon hillock termed ‘ectopic dendritogenesis’, as well as axonal spheroid formation or neuroaxonal dystrophy. Spheroids are focal enlargements of various sizes distributed along myelinated and unmyelinated axons in the grey and white matter, consisting of multivesicular and dense bodies, mitochondria, and other organelles. This suggests that there is defective endocytic trafficking within axons. The incidence in the general population has been estimated at 1 in 112 000 live births, although the disease was highly prevalent among Ashkenazi Jews (1 in 3900 live births). Successful implementation of carrier screening programmes for at-​ risk couples has remedied this situation. The ‘classic’ infantile form of Tay–​Sachs disease (TSD) is named after a British ophthalmologist, Warren Tay, and an American neur- ologist, Bernard Sachs. It presents in infancy with psychomotor de- terioration, poor head control, easy startle, axial hypotonia, bilateral pyramidal signs, and cortical blindness (pupillary responses are pre- served). A characteristic hallmark of the disease is the presence of a macular cherry red spot. In the second year of life, brain enlarge- ment (not hydrocephalus) leads to progressive megalencephaly; however, with further loss of the neurons and gliosis, the ventricles dilate. Progressive neurological deterioration leads to a spastic state section 24  Neurological disorders 6226 and cachexia. Generalized tonic-​clonic and simple motor seizures that occur in later stages necessitate multiple anticonvulsant medi- cations and are often the focus of clinical care. Death usually occurs between 3 and 5 years of age. The AB variant, caused by deficiency of the GM2 activator, has a phenotype that is indistinguishable from the infantile form; however may present somewhat later than the classic infantile form. This diagnosis is suspected when the labora- tory test results for assays of Hex-​A and -​B enzyme activity using artificial substrates are normal and the clinical presentation suggests gangliosidoses. The later-​onset forms of GM2 gangliosidosis follow a protracted course and there is no ethnic predilection. Differences in the age of onset and disease progression, presumably determined by the severity of the underlying mutation, distinguish the childhood form, which has an onset between ages 3 and 6 years (chronic GM2 gangliosidosis) from the adult-​onset variant or late-​onset TSD (LOTS), appearing in the teens or early adulthood. The pheno- type of the B1 variant is similar to that of the childhood-​onset form. Affected children develop dysarthria and gait difficulty, due to spastic paraparesis, which may be accompanied by tonic-​clonic or myoclonic seizures. Cerebellar atrophy is common. Psychiatric disturbances and neuropathy is more prevalent in patients with the Sandhoff variant than in those with the Tay–​Sachs variant. Disease progression is marked by spasticity, rigidity, and dementia, ending in a vegetative state leading to death by the age of 15 years. LOTS primarily presents as a very slowly progressive disorder with anterior horn cell and cerebellar degeneration. Proximal muscle weakness, ataxia with cerebellar atrophy, and fascicula- tions are prominent in the later-​onset forms, often leading to a wheelchair-​dependent state over several years of disease duration. Age of onset is variable from teens to the fourties. Psychiatric dis- turbances, including frank psychosis, may be the initial manifest- ation of disease, particularly among younger patients. Vision and optic fundi are normal, although some cognitive decline is fre- quently encountered. The adult-​onset phenotype this carries none of signature characteristics of infantile Tay–​Sachs disease namely cognitive decline, visual failure with cherry red spot, seizures, or macrocephaly. Therefore, it has a significantly high risk of delayed or missed diagnosis. Late-​onset GM2 gangliosidosis should be con- sidered in the differential diagnosis of adult patients with signs of lower motor neuron and cerebellar dysfunction. Some adult-​onset patients may live into their 50s or 60s. Sandhoff’s disease (SD), a pan-​ethnic disorder, is caused by mutations in the β-​subunit of Hex-​A and -​B. Although the age of onset and clinical course are similar to TSD, organomegaly, N-​ acetylglucosamine-​containing oligosaccharides in urine, and oc- casional cardiomyopathy are distinguishing features. Dysesthetic peripheral neuropathy may predominate in late-​onset forms of Sandoff along with anterior horn cell and cerebellar features. The diagnosis is ascertained by assays of total hexosaminidase and Hex-​A activity in leucocytes, and cultured skin fibroblasts comple- mented by analysis of the underlying Hex-​A gene mutations. Prenatal diagnosis of the GM2 gangliosidoses is available. Biochemical and/​or molecular tests are preformed on cultured cells obtained by CVS or amniocentesis. There is no definitive therapy for GM2 gangliosidoses. Substrate reduction therapy, based on the inhibition of glucosylceramide synthesis using the iminosugar miglustat, was not beneficial in ameliorating the disease course in LOTS. There have been prelim- inary studies involving pyrimethamine as a chaperone to HexA enzyme enhancement for LOTS; further studies are necessary to determine the efficacy. Gene therapy is under intense investigation. Jacob sheep, a naturally occurring animal model of Tay–​Sachs dis- ease offers promise as a means for trials of gene therapy. Fabry disease (see Chapter 12.8) Fabry Disease (FD, OMIM 301500)  or Angiokeratoma corporis diffusum was originally described by Anderson and Fabry in 1898. FD is a slowly progressive X-​linked lysosomal disorder characterized by storage of glycolipids consisting mainly of globotriasoylceramide, as a result of a-​galactosidase A  deficiency. The storage occurs mainly in the myocardial muscle cells, glomerular and tubular epi- thelia of the kidney, and vascular smooth muscle cells and endo- thelia leading to progressive organ failure. The reported incidence ranges from 1:40 000 to 1:117 000 worldwide. The disease is caused by mainly missense and nonsense mutations, but also small and large deletions. There is significant inter and intrafamilial variability. However, mutations leading to a complete loss of function are asso- ciated with the ‘classical disease phenotype’, with childhood onset in boys. Conversely, residual enzyme activity might lead to slow pro- gression of the disease leading to the cardiac or renal variants with delayed onset. The primary cause of morbidity and mortality in FD is kidney and heart involvement. Prior to dialysis and ERT, average age of death in men with FD was 41 years. Neurological manifestations of FD are discussed here. Although storage of lipid is described in certain nuclei such as the amygdaloid body, subiculum, and dorsal vagus nucleus of the medulla oblongata FD is not considered to be a neurodegenerative disease. The central nervous system manifest- ations are primarily related to small and large vessel disease. There are several distinct and unusual symptoms associated with the classic phenotype of FD which is seen in young boys starting in the pre-​teen to adolescent years, usually between 6–​8 years. The most striking feature of classic FD is neuropathic pain in the distal extremities with Fabry crisis presenting as acute episodic pain typ- ically beginning in hands and feet and may radiate proximally, often precipitated by stress, heat, exercise, or fever. Patients also suffer a chronic burning or tingling pain in extremities, acroparesthesias. Pain is one of the most disabling symptom in FD. In addition to painful neuropathy, patients sometimes have arthralgias of un- known origin. Dysautonomic features due to involvement of the autonomic nervous system especially the A ∂ fibres such as hypo or anhidrosis, reduced salivation, and lachrymation, gastrointes- tinal dysmotility, cardiac dysrhythmia, and reduced cutaneous flare after histamine injections are common manifestations of FD. Gastrointestinal symptoms in the form of abdominal discomfort, nausea, vomiting, and diarrhoea occur. Angiokeratomas develop in virtually all patients in childhood or adolescence characteristically described below the umbilicus in the genital areas, buttocks, and thighs along with palms of hands, which increase in number and distribution over years. The most common eye finding in patients with FD is cornea verticillata. Despite a myriad of pathognomonic clinical findings FD is significantly underdiagnosed especially in young boys and men. Neurological examination usually reveals loss of temperature sen- sation in hands and feet and a reduced tolerance to low temperature 24.17  Inherited neurodegenerative diseases 6227 exposure. Nerve conduction studies, which assess only large myelin- ated fibres, are generally normal. Sophisticated techniques to assess the small fibre involvement such as quantitative sensory test (QST), a biophysical method based on computerized automated sensory testing to measure detection thresholds for warm and cold in the feet and hands, revealed significantly elevated detection thresholds for warm and cold stimuli in the foot and for cold in the hands of FD patients compared to controls. Intraepidermal nerve fibre density (IENFD) is positively correlated in males with Glomerular filtration rate (GFR). The classic phenotype of FD is rarely seen in heterozygous women, however many of the carriers have isolated or multiple manifestations of the disease. The process of lyonization, random X-​chromosomal inactivation during embryogenesis, results in varying proportion of cells carrying the normal or the abnormal X-​ chromosome with the α-gal mutation. Apart from the episodic and chronic pain, cerebrovascular dis- ease remains the major cause of morbidity and early mortality in patients with FD. Various factors have been implicated in the patho- genesis of cerebrovascular disease in FD. Intracranial small arteries and arterioles show accumulation of Gb-​3 within endothelial cells causing narrowing and may lead to ischaemia. There is evidence for endothelial dysfunction as well as a procoagulant state with in- creased platelet aggregation. There have been numerous studies demonstrating ectasia and dilatation of large vessels especially in the posterior circulation, stenosis and thickening of small vessels, and altered cerebral blood flow. There is increased risk of ischaemic small and large vessel strokes in men and women with FD with up to 25 % of the patients suffering cerebrovascular events over their life course. Chronic occlusive small vessel disease leads to leukoaraiosis whereas cardioembolic phenomenon contributes to territorial is- chaemic strokes. Studies show the mean age of stroke in men and women to be 39 and 46 respectively; thus FD represents an im- portant cause of cryptogenic stroke. Hyperintensities of the thalamic posterior region or the pulvinar sign on MRI T1-​weighted images are noted by the third decade in about one fourth of patients and frequency increased with age. Corresponding images on CT scan show increased density likely due to calcification. Arterial spin tagging (AST) MRI images and positron emission tomographic (PET) studies reveal increased cerebral blood flow in the posterior circulation suggesting that hyperperfusion may have induced dystrophic posterior thalamic cal- cification, with a selective vulnerability of the putamen. Impairment of the vasoreactivity and autoregulation in the posterior circulation, probably due to pericytes, endothelial cells, or nitric oxide pathway dysfunction result in hyperperfusion followed by increasing capil- lary leakage. An increased basilar diameter has been shown to rep- resent another radiological finding suggestive of FD. Patients with FD require intensive pain management. Pain is often refractyory to several medications as well as other modalities of treatment. Patients are often prescribed antiplatelet therapy for prevention of cardiac and cerebrovascular disease. ERT for FD was approved in 2001 in Europe and 2003 in the United States. Success with ERT has been limited. ERT in more advanced stages of FD does not halt disease progression especially in patients with decreased renal function. Males with less advanced disease (e.g. relatively pre- served renal function or absence of LVH at start of therapy), also demonstrate disease progression despite ERT. However, in males with a GFR less than 60 ml/​min/​1.73 m2 treated with ERT, decline of renal function is less pronounced when compared to the untreated group. ERT did have a beneficial effect on the course of LV mass when compared to untreated groups. It is known that new WMLs develop despite ERT. In 2015, chaperone therapy, migalastat, was ap- proved for FD in Europe. No data on efficacy of chaperone therapy for CNS involvement in FD are available. Gaucher disease Gaucher disease, the most common lysosomal storage dis- order with an estimated frequency of about 1 in 50 000, is caused by the deficiency of the lysosomal enzyme glucocerebrosidase (acid β-​glucosidase), leading to the accumulation of its substrate, glucocerebroside (glucosylceramide) within cells of monocyte/​ macrophage lineage. The three major clinical subtypes are delin- eated based on the presence or absence of neurological involvement as well as the age of onset, rapidity of disease progression, and the rate and severity of neurological deterioration, when present. In contrast to the large amount of lipid stored in the liver and spleen, there is no significant accumulation of glucocerebroside in the brain. Severe glucocerebrosidase deficiency leads to produc- tion of glucosylsphingosine (psychosine), an alternative neurotoxic metabolic by product, which could play a contributory role in the pri- mary neurological involvement seen in certain subtypes of Gaucher disease. Neuropathological studies reveal lipid-​filled cells in the perivascular Virchow–​Robin spaces and neuronophagic microglial nodules in several regions of the brain (e.g. cortex, thalamus, basal ganglia, brainstem, and cerebellum) and in the spinal cord. Type I Gaucher disease, a pan-​ethnic disorder with high preva- lence among the Ashkenazi Jewish population (carrier frequency about 1 in 20), usually refers to the non​neuropathic disease asso- ciated with hepatosplenomegaly, anaemia, thrombocytopenia, and pulmonary involvement. There are six to eight common mutations described of which N370S is the commonest mutation. Having at least one allele with this mutation confers significantly decreased or no possibility of neuronopathic disease. There is a wide spectrum of age of onset and severity of disease ranging from early onset sever disease to late adult forms with minimal hepatosplenomegaly even within individuals who are hiomozygous for N370S mutations. Being affected with type I Gaucher disease or even being a carrier in- creases the risk of developing Parkinson’s disease by about five fold. The onset of Parkinson’s disease is consistently earlier in these pa- tients with higher cognitive involvement, although there is no other phenotypic or pathological distinction from idiopathic Parkinson’s disease noted. In type II Gaucher disease, disease onset is before 12 months of age. In this acute neuropathic form, infants develop spasticity with head retraction (opisthotonus), dysphagia, and a rapidly fatal course; death usually occurs between 2 and 3 years of age. Laryngeal stridor, trismus, seizures, and aspiration pneumonia are frequent complications. Type III Gaucher disease, found in about 5% of patients with Gaucher disease, is a chronic disorder with variable age of onset, usually before the age of 10 years. Neurological features include gaze initiation failure, tonic-​clonic and myoclonic seizures ataxia, and extrapyramidal rigidity. Severe pulmonary involvement is often pre- sent. The Norbottnian variant of type III Gaucher disease presents with neurological problems which may be restricted to supranuclear section 24  Neurological disorders 6228 horizontal gaze palsy despite the presence of significant extra-​ neurological systemic problems. ERT is now the mainstay of treatment for Gaucher disease, al- though it does not alter the course of neurological deterioration in patients with type II or type III Gaucher disease. Substrate reduc- tion therapy (SRT) with both miglustat and eliglustat tartrate has been shown to be effective in ameliorating several clinical features of Gaucher disease and was approved for use in type I Gaucher pa- tients, although role of substrate reduction therapy in neuropathic Gaucher disease still has to be elucidated. Niemann–​Pick disease Niemann–​Pick disease (NPD) represents a group of auto- somal recessive disorders associated with mutations of the acid sphingomyelinase (ASM) gene, resulting in primary deficiency of sphingomyelinase causing progressive storage of sphingomyelin (phosphorylcholine) in the reticuloendothelial system. NPD sub- types A (infantile neuropathic) and B (later-​onset non​neuropathic) represent the spectrum of allelic variants. NPD subtypes C and D are also allelic disorders due to mutations of either the NPC1 or the NPC2 gene, which may be associated with mild secondary ASM de- ficiency. Mutations in NPC1 or -​2 leads to disruption in the traf- ficking and/​or metabolism of cholesterol and sphingolipid. Early infantile neuronopathic NPD type A presents within the first few weeks or months with failure to thrive and hepatomegaly; over time the liver and spleen become massive. This is followed by neurological regression and the appearance of the macular cherry red spot; psychomotor development progresses no further than the 12-​month level, after which neurologic deterioration is relentless. Interstitial lung disease caused by storage of sphingomyelin in pul- monary macrophages results in frequent respiratory infections and often respiratory failure. This ultimately leads to liver failure with ascites and jaundice, cachexia, rigidity, and opisthotonus. Death occurs in the second or third year of life. NPD type B is later in onset and milder in manifestations than NPD type A, character- ized by hepatosplenomegaly with progressive hypersplenism and stable liver dysfunction, gradual deterioration in pulmonary func- tion, osteopenia, and atherogenic lipid profile. Progressive and/​or clinically significant neurologic manifestations occur infrequently. Survival to adulthood can occur. There are vacuoles within periph- eral lymphocytes and monocytes, as well as foam cells in the bone marrow. Deficient ASM activity in leucocytes or cultured skin fibro- blasts confirms the diagnosis of NPD types A and B. NPD type C has an estimated incidence of 1 in 150 000. Mutations in the gene NPC1, which encodes a large transmembrane glyco- protein localized primarily in the late endosomes, causes approxi- mately 95% of cases, whereas a smaller group of patients has been shown to have a defect of the NPC2 gene, which encodes a small soluble lysosomal protein with cholesterol-​binding properties. It is a neurovisceral lipid storage disorder neuropathologically charac- terized by axonal spheroids, intraneuronal cytoplasmic inclusions, and neuronal loss. About 50 to 60% of cases are considered to have the classic pres- entation with a benign, self-​limiting jaundice in early infancy, followed by normal initial development. Between the ages of 3 and 8 years these children develop hepatosplenomegaly, clumsi- ness, ataxia, and supranuclear vertical gaze palsy, accompanied by blinking or head thrusting, eventually progressing to dysarthria, dysphagia, and cognitive decline. Characteristic neurological manifestations include saccadic eye movement abnormalities or vertical supranuclear gaze palsy, cerebellar signs, and gelastic cataplexy. Seizures and dystonia are also common. Neurological deterioration is relentless leading to a bed bound state and even- tually death by late second or third decade. Late-​onset forms are increasingly recognized with typical as well as atypical features such as psychiatric presentations, mimicking depression or schizo- phrenia, with few or subtle neurologic signs, beginning in adoles- cence or adulthood. A severe form of NPD type C presents at birth with ascites, jaundice, and a rapidly progressive fatal course. NPD type D was described among the French Acadians in Nova Scotia (Canada) with a disease onset usually between age 2 and 4 years. A founder mutation in NPC1 has subsequently been described in this population. MRI of the brain is usually normal until the late stages of the illness. Eventually marked atrophy of the superior/​anterior cere- bellar vermis, thinning of the corpus callosum, and mild cerebral atrophy is seen. Increased signal in the periatrial white matter, re- flecting secondary demyelination, may also occur. Management of patients with NPD type C is primarily symptom- atic. Medical management of seizures, dystonia, and cataplexy is in- dicated. If disordered sleep is identified, a nocturnal sedative may be used. Supportive care includes chest physical therapy with aggres- sive bronchodilation, antibiotic therapy for intercurrent infection, physical therapy, and a regular bowel programme to prevent severe constipation, which may present as increased seizure frequency or increased spasticity. Swallowing must be monitored to allow con- sideration of gastrostomy tube placement when aspiration or nutri- tional compromise is imminent. Clinical studies have supported a role of iminogugar miglustat, n-​butyldeoxynojirimycin, in stabilizing NPC. The agent has been approved for the management of neurologic manifestations of NPC in several countries, not including the United States. Preliminary studies of neurosteroid replacement therapy or the active agent which was the vehicle, hydroxypropyl β-cyclodextrin have shown some promise. Metachromatic leucodystrophy (sulphatide lipidosis) See ‘Leucodystrophies’, this chapter. Krabbe disease (globoid cell leucodystrophy) See ‘Leucodystrophies’, this chapter. Mucopolysaccharidoses (for individual discussion see Chapter 12.8) The MPSs are a group of heterogeneous disorders resulting from deficiency of lysosomal glycosidases and sulphatases involved in the sequential degradation of glycosaminoglycans (GAGs). Each follows an autosomal recessive inheritance pattern except MPS II, which is X-​linked. Their collective incidence is estimated at about 1 in 25 000 to 1 in 50 000. Incomplete hydrolysis and accumulation of GAGs leads to deposition of different types of intralysosomal in- clusion bodies in tissues, the most characteristic of which are the zebra bodies. Increased urinary excretion of the substrates dermatan sulphate, heparan sulphate, keratan sulphate, and chondroitin sul- phate is often used as a screening test for MPS in suspected cases; however, a definitive diagnosis of a particular MPS subtype is based 24.17  Inherited neurodegenerative diseases 6229 on specific enzyme assays using plasma, leucocytes, or cultured skin fibroblasts. Despite being aetiologically distinct, several non​neurological clinical features are shared by MPSs, mainly coarse facial features and dysostosis multiplex. The latter refers to the typical skeletal and radiographic findings (e.g. bullet-​shaped phalanges), and flattening and anterior beaking of the vertebral bodies. Ophthalmic compli- cations include corneal opacity, pigmentary retinal degeneration, optic atrophy, and glaucoma. Developmental regression is noted in several MPS subtypes. Hydrocephalus can result from the de- position of GAGs and histiocytic infiltration in the meninges (i.e. pachymeningitis). GAG storage at various sites may lead to nerve compression syndromes such as carpal tunnel syndrome and spinal cord compression. Following clinical suspicion, the first step in diagnosis a MPS dis- order is to measure urinary glycosaminoglycans. Neither the quan- titative nor the qualitative method can diagnose a specific lysosomal enzyme deficiency, including MPS I; however, an abnormality de- tected by either or both methods indicates the likely presence of an MPS disorder. Diagnosis is confirmed by identification of biallelic pathogenic variants in respective genes by molecular sequencing or detection of deficient activity of the respective lysosomal enzyme in fibroblasts, leucocytes, or plasma. Children and adults with MPS invariably require intensive multi- disciplinary management which includes disciplines of genetics, neurology, cardiology, pulmonology and sleep medicine, ENT, Ophthalmology, surgery, orthopaedics, physical therapy, occupa- tional therapy, and speech therapy. Mucopolysaccaridosis I (MPS I) Mucopolysaccharidosis type I (MPS I), a progressive multisystem disorder caused by biallelic pathogenic mutations in IDUA leading to deficient activity of the lysosomal enzyme α-​L-​iduronidase. Clinical features range over a wide continuum, with affected individuals best described as having either severe or attenuated MPS I, a distinction that influences therapeutic options. The greatest variability is ob- served in individuals with attenuated MPS I. MPS I is seen in all ethnicities at a frequency of approximately 1:100 000 for the severe form and 1:500 000 for the attenuated form. Neurological features are consistent with severe MPS I (Hurler syndrome) whereas they are mild or absent in attenuated MPS I (Scheie syndrome). Deficiency of α-​L-​iduronidase removes non​reducing terminal α-​ L-​iduronide residues during the lysosomal degradation of the glyco- saminoglycans heparan sulphate and dermatan sulphate. Heparan sulphate is found in abundance in the brain as part of the extracel- lular matrix. In MPS I, the accumulation of glycosaminoglycan in the lysosomes of neurons and secondary deposits of glycolipids that form zebra bodies presumably lead to severe intellectual disability and hydrocephalus. In severe MPS I, infants appear normal at birth but may have in- guinal or umbilical hernias. The mean age of diagnosis for severe MPS I is approximately nine months. Death is caused by cardio- respiratory failure usually within the first ten years of life. Systemic features include coarsening of facial features, hepatosplnomegaly, progressive skeletal dysplasia (dysostosis multiplex), corneal clouding, hearing loss and cardiac involvement with thickening and stiffening of the valve leaflets can lead to mitral and aortic re- gurgitation. Chronic recurrent rhinitis and persistent copious nasal discharge without obvious infection are common. Noisy breathing and obstructive sleep apnoea is caused by storage of GAGs that is associated with enlargement of the tongue, tonsils, and adenoids, narrowed trachea, and thickened vocal cords. Normal early neurological development is followed develop- mental delay, usually obvious by 18 months. A measurable decrease in intellectual capacity occurs thereafter. Language skills are limited due to the triad of intellectual decline, hearing loss, and large tongue. Children may plateau for several years followed by a slow decline in intellectual capabilities. By the time of death at age 8–​10 years, most children are severely intellectually disabled. Communication hydro- cephalus is common. Definitive therapy with haematopoietic stem cell transplant (HSCT) is considered standard of care for children with severe MPS I. Outcome from HSCT is significantly influenced by disease burden at the time of diagnosis. It is generally recommended that HSCT be performed before age two years to maximize benefit. In children undergoing HSCT before evidence of significant developmental delay (i.e. usually between ages 12 and 18 months), HSCT appears to slow the course of cognitive decline. Children showing significant cognitive impairment prior to undergoing HSCT do not show cor- rection of existing impairment. Although an approved ERT exists for MPS I, it does not cross the blood–​brain barrier and thus is not ex- pected to influence the CNS disease in severely affected individuals. Mucopolysaccaridosis II (MPS II) Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is an X-​linked multisystem disorder characterized by deficiency if iduronate 2-​sulphatase (I2S) leading to glycosamino- glycans (GAG) accumulation in several organs and consequently varied clinical presentations related to these organs. CNS involvement is significant in the group of children labelled as ‘early progressive’ disease, manifesting primarily as progressive cognitive deterioration. Cognitive decline, combined with the pro- gressive airway and cardiac disease, usually results in death in the first or second decade of life. In the slowly progressive form, the CNS is minimally affected, if at all. Survival into the early adult years with normal intelligence is common in this group. The appearance of newborns with MPS II is normal. Coarsening of facial features and macroglossia generally manifests between ages 18 months and four years in the early progressive form and about two years later in the slowly progressive form. CNS manifestation is inexorable, usually resulting in developmental regression between ages six and eight years. Chronic communicating and seizures may also occur. Growth in the first five years of life may be above average fol- lowed by growth lags and eventual short stature. Macrocephaly is universal. Ivory-​coloured skin lesions on the upper back and sides of the upper arms are pathognomonic of Hunter syndrome. Hypertrophic adenoids and tonsils and ankylosis of the temporo- mandibular joint limits opening of the mouth and may lead to pro- gressive swallowing impairment. Hoarse voice, irregularly shaped teeth, overgrown gingival tissue, painful dentigenous cysts, and conductive and sensorineural hearing loss, complicated by recur- rent ear infections, occur in most affected individuals. Joint contrac- tures, particularly of the phalangeal joints, causing significant loss of joint mobility are one of the earliest noteworthy diagnostic clues. Hip dysplasia is the most common long-​term orthopaedic problem section 24  Neurological disorders 6230 and can become a significant disability with early onset arthritis if not treated. Respiratory involvement hasis multifactorial: frequent upper-​respiratory infections, airway obstruction, thickof respiratory secretions, and stiffness of the chest wall. Progressive obstructive airway disease results in sleep apnoea, the need for positive pressure assistance and eventually tracheostomy. Valvular heart disease is common; cardiomyopathy, hypertension, and rhythm disorder are seen occasionally. Hepatomegaly and/​or splenomegaly and umbil- ical/​inguinal hernia are frequent findings. A recombinant form of human iduronate 2-​sulphatase that has been approved in the United States and the European Union for the treatment of MPS II and has shown efficacy in ameliorating some systemic manifestations of MPS II. However, it does not cross the blood–​brain barrier and therefore, CNS manifestations are unchanged. Mucopolysaccaridosis III (MPS III) MPS III or Sanfilippo syndrome is due to an abnormal accumula- tion of heparan sulphate secondary to defective degradation within the cell. MPS III is divided into the following five subtypes based on the different enzyme deficiencies:  (1) MPS IIIA (heparan-​N-​ sulphatase), (2)  MPS IIIB (α-​N-​acetylglucosaminidase), (3)  MPS IIIC (acetyl-​coenzyme A:  α-​glucosaminide acetyltransferase), (4) MPS IIID (N-​acetylglucosamine-​6-​sulphatase) and (5) currently putative MPS IIIE (N-​glucosamine 3-​O-​sulphatase, arylsulfatase G or ARSG). The incidence of MPS III or Sanfilippo syndrome ranges from 0.29/​100 000 to 1.89/​100 000 live births. Systemic features are similar to other MPS disorders such as coarse facial features, skeletal pathology, stunted growth, hepatosplenomegaly, macrocrania, and hearing loss. However, the primary characteristic feature of MPS III is de- generative CNS disease resulting in mental retardation and hyper- activity, typically commencing during childhood. Pre-​natal and early stages of post-​natal development are usually normal. The ini- tial stages of disease may begin between the ages of 1 and 3 years, which manifest as delayed cognitive development and/​or aggressive behavioural problems such as hyperactivity with violent destructive behaviours and sleep disturbances, as well as hindered speech devel- opment which may become increasingly severe between the ages of 3 and 5 years. Patients may plateau between 5 to 10 years of age fol- lowed by neuroregression with a progressive and severe loss of intel- lectual processes and motor functions. MPS III patients ultimately regress to a vegetative state until death, which can occur anywhere between the early teens to late adulthood. Glycoproteinoses Deficiency of lysosomal exoglycosidases involved in the hydrolysis of the carbohydrate side chains attached to the peptide backbone of glycoproteins by the N-​glycosidic asparagine links leads to dis- orders of glycoprotein degradation termed the ‘glycoproteinoses’. All are sautosomal recessive in inheritance. The clinical features of glycoproteinoses are similar to the MPS disorders, such as coars- ening of facial features, dysostosis multiplex, intellectual impair- ment, and hepatosplenomegaly. Patients with glycoproteinoses have excessive urinary excretion of oligosaccharides; however, identifi- cation of the underlying enzyme deficiency requires assays use of leucocytes or cultured skin fibroblasts. Mannosidosis Mannosidosis results from a deficiency of either α-​ or β-​ mannosidase. MAN2B1 is the only gene known to be associated with α-​mannosidosis. Glycoproteins are digested by proteinases and glycosidases within the lysosomes into small fragments to be excreted or transported to the cytosol for reuse. Lack of lysosomal α-​mannosidase, results in the multisystemic accumulation of un- digested oligosaccharides in the lysosomes. Three clinical forms of α-​mannosidosis are distinguished based on the age of onset. The more severe infantile form (type III) is associated with severe mental deterioration, facial dysmorphism, dysostosis multiplex, and hepatosplenomegaly, with death occurring usually between the ages of 3 and 10 years often due to infection. In the relatively milder type II form intellectual impairment is evident by 2 or 3 years of age with delayed speech and poor motor performance. There are superficial corneal opacities, spoke-​like posterior lens opacities, deafness, subtle facial dysmorphism, and skeletal abnormalities on radiographs. The clinical course is protracted, extending into adulthood. Late neurological complications include hydroceph- alus and spastic quadriplegia. Widening of the diploic space with underdevelopment of the sinuses and prominent periventricular Virchow–​Robin spaces are seen on MRI of the brain. Destructive arthropathy due to storage of oligosaccharides may be seen in chil- dren and adults. A mild form (type I) is recognized after age ten years with absence of skeletal abnormalities, myopathy, and slow progression. The lysosomal enzyme β-​mannosidase cleaves the β-​linked man- nose residue present in all types of N-​glycosylprotein glycans. Clinical spectrum is variable and given the low incidence of the disease a de- fined phenotype is difficult to establish. However, β-​Mannosidosis presents with a range of neurological features including severe psy- chomotor retardation, hearing loss, seizures, peripheral neuropathy. The diagnosis of mannosidosis relies measurement of respective mannosidase enzyme activity in peripheral blood leukocytes or other nucleated cells such as fibroblasts. Gene sequencing helps demonstrate two pathogenic mutations. No definitive therapy is available. Fucosidosis Deficiency of α-​fucosidase leads to accumulation of fucose-​ containing oligosaccharides, glycopeptides, and, to a lesser extent, mucopolysaccharides and glycolipids in tissues associated with their excessive urinary excretion. There is prominent neurological dys- function in all subtypes. The early onset severe infantile form (type I) with neurological deterioration between 6 and 18 months of age rapidly progresses to a decerebrate state. Associated features are coarse facies, growth retardation, recurrent infections, dysostosis multiplex, angiokeratoma. The later-​onset form is relatively slowly progressive (type 2); neurological regression occurs in the second or third year of life. Death usually occurs between the ages of 4 and 6 years in both subtypes. A third group of patients may show slowly progressive neurological deterioration into adolescence or adult- hood. Brain MRI shows extensive and progressive changes in the signal intensity of the white matter and the internal medullary lam- inae of the thalami, as well as high signal intensity on T1-​weighted images and low signal intensity on T2-​weighted and FLAIR images in the globus pallidus and substantia nigra. The diagnosis is based 24.17  Inherited neurodegenerative diseases 6231 on demonstration of decreased α-​fucosidase activity in leucocytes or cultured skin fibroblasts. Aspartylglucosaminuria Aspartylglucosaminuria is described largely in Finland and results from a deficiency of aspartylglucosaminidase (AGA). This enzyme cleaves the bond between asparagine and N-​acetylglucosamine of N-​linked glycoproteins. Speech problems and severe behavioural abnormalities, with alternating periods of hyperactivity and ap- athy, are predominant in the clinical picture. Recurrent infections and diarrhoea are common in the early months and years of life. Insidious motor and mental deterioration, often with seizures, de- velop between the ages of 5 and 15 years. Mild coarsening of the fa- cial features and skeletal abnormalities such as deformities of the vertebrae, periosteal thickening of the long bones, and thickening of the calvarium are evident by adolescence. Increased aspartylglucosamine in urine and decreased AGA ac- tivity in plasma, leucocytes, or cultured skin fibroblasts confirm the diagnosis. Sialidosis Sialidosis types I and II are clinical variants associated with the defi- ciency of α-​neuraminidase (sialidase, NEU1) and increased urinary excretion of sialyloligosaccharides. A  few vacuolated lympho- cytes and histiocytes may be present in peripheral blood and bone marrow smears, respectively. At the ultrastructural level swollen lysosome are visible in bone marrow cells and in Kupffer cells of the liver. Increased high molecular weight sialylated oligosaccharides are found in the urine. In sialidosis type I (cherry red spot–​myoclonus syndrome) pro- gressive visual loss with a typical eye finding of a macular cherry red spot, myoclonus, and seizures develop in late childhood or ado- lescence, usually by the second or third decade. Typically, these patients have no obvious physical defects, and their intelligence is normal or only slightly impaired. Most prominent clinical finding is irregular myoclonic jerks. They are precipitated by action, sensory stimuli, emotional upset, menstruation, and smoking. The visual loss is progressive and is associated with bilateral macular cherry red spots that may fade later in the course of the disease. The progres- sive nature of the disease leads to difficulties with speech, walking, and feeding, followed by blindness, optic atrophy, and intellectual deterioration. Brain imaging shows cerebral and cerebellar atrophy. In sialidosis type II, also known as mucolipidosis type I has an in- cidence of 0.02/​100 000 live births. There are neurological, visceral, and skeletal abnormalities including dysostosis multiplex, a Hurler-​ like phenotype, intellectual impairment, and hepatosplenomegaly. There are three sub types: the congenital form, with onset in utero, is associated with non​immune hydrops fetalis, ascites, facial oedema, inguinal hernias, and hepatosplenomegaly. They are stillborn or die shortly after birth with a systemic and fulminant condition. Both the infantile patients with longer survival and the juvenile cases de- velop macular cherry red spots and myoclonus, and may also have hearing loss and angiokeratoma. The diagnosis is based on deficient α-​neuraminidase activity, preferably in cultured skin fibroblasts or leucocytes. Galactosialidosis results from the combined deficiency of α-​ neuraminidase and β-​galactosidase, due to defects in the protein cathepsin A (PPCA), which offers protection against rapid proteo- lytic degradation. It is clinically characterized by cerebellar ataxia, myoclonus, and visual failure in late childhood or adolescence. Additional features include the cherry red macular spot, dysmorphic facial features, hepatomegaly, and skeletal changes. The diagnosis of galactosialidosis is based on deficient activity of both α-​neuraminidase and β-​Gal in leucocytes or cultured skin fibroblasts, and/​or mutations in the gene encoding the PPCA. Galactosialidosis can be distinguished from GM1 gangliosidosis by normal β-​Gal activity in serum or plasma, unlike GM1 gangliosidosis. Schindler’s/​Kanzaki’s disease (a-​N-​ acetylgalactosaminidase deficiency) This rare disorder, initially described by D Schindler, is a form of neuroaxonal dystrophy, which results from deficiency of a glycosyl-​ hydrolase, α-​N-​acetylgalactosaminidase (NAGA). Progressive motor and mental deterioration, with myoclonic seizures, pyram- idal signs with hyperreflexia, hypotonia, and optic atrophy were described in two brothers who were bedridden by age 4 years. Subsequently, in 1989, Kanzaki and colleagues described a group of adult Japanese patients, without overt neurological manifest- ations and diffuse angiokeratoma, who had NAGA deficiency and increased urinary excretion of several glycopeptides. Mucolipidoses The mucolipidoses feature the combined tissue storage of GAGs and sphingolipids and are a group of disorders with clinical fea- tures similar to MPSs, except for the absence of urinary excretion of GAGs. Mucolipidosis type I or sialidosis type II This condition is described under ‘Sialidosis’, this chapter. Mucolipidosis type II and type III Mucolipidosis type II (I-​cell disease) and type III (pseudo-​Hurler’s polydystrophy) are caused by is caused by a mutation in the N-​acetylglucosamine-​1-​phoshate transferase, α/​β subunits (GNPTAB) gene. This results in abnormal transport of newly synthesized enzymes to the lysosome due lysosomal acid hydrolase enzymes lacking a normal recognition phosphate group and abnormally accumulating in the extracellular space rather than the lysosome. Mucolipidosis II has autosomal recessive inheritance, with a world- wide prevalence of 0.15/​100 000 live births. I-​cell disease manifests with progressive severe psychomotor retardation, dysmorphic facial features, gingival hypertrophy, and dysostosis multiplex. Cardiorespiratory abnormalities are similar to those seen in MPS I  (Hurler syndrome), including cardiac valve problems, thick- ening of the airways, and thoracic cage stiffening. ML-​III has a similar clinical picture; in addition to stiffness of the fingers and shoulder, a ‘claw-​hand’ deformity, short stature, and scoliosis may be noted. Mild coarsening of the face, corneal clouding, and ret- inopathy with progressive bone and cardiac valve involvement are also commonly seen. The diagnosis of ML-​II and -​III is based on a demonstration of markedly increased lysosomal enzyme activities in the plasma while the corresponding activities in leucocytes and cultured skin fibroblasts are markedly decreased. section 24  Neurological disorders 6232 Mucolipidosis type IV Mucolipidosis IV (ML-​IV) is caused by mutations in the gene MCOLN1, mapped to chromosome 19p13.3–​13.2. It encodes pro- tein called mucolipin, which normally functions as a calcium (Ca2+)-​ permeable cation channel but is also involved in lysosomal biogenesis and membrane trafficking. ML-​IV is prevalent among the Ashkenazi Jewish population with two common mutations accounting for 95% of the alleles. However due to aggressive premarital couple screening, currently most affected individuals are non-​Ashkenazi Jewish. The disease has a protracted course characterized by early arrest in neurological development by the end of first year of life manifesting as absent speech, intellectual impairment, and motor retardation and slowly progressive visual impairment during the first decade as a result of a combination of corneal clouding and retinal degeneration. Achlorhydria is a consistent manifestation which may lead to iron deficiency and iron deficiency anaemia. Progressive renal failure has been recognized in recent years to be a feature of MLIV. There are no dysmorphic facial features, hepatosplenomegaly, or skeletal abnor- malities. Neurologic examination typically reveals severe dysarthria or anarthria, slow chewing, slow eating and swallowing, spasticity, and hyperactive tendon reflexes. Diagnosis may be based on electron microscopic examination of conjunctival and skin biopsies which show characteristic lysosomal inclusions as well as enlarged lysosomes in all cell types. However, molecular genetic analysis of common mutations is often used for diagnostic purposes. Speech therapy, physical therapy for spasticity and ataxia, ankle–​ foot orthotics (AFOs), antiepileptic drugs as needed, and surgical correction of strabismus are employed for supportive care. Eye care includes topical lubricating eye drops, artificial tears, gels, or oint- ments for ocular irritation. Glycogen storage disease type II (Pompe disease) Pompe disease, also known as (PD, OMIM 232300) glycogen storage disease type II and acid-​maltase deficiency, is a metabolic myopathy characterized by lysosomal glycogen storage caused by deficiency of the lysosomal enzyme acid α-​glucosidase. Pompe disease has a varied estimated frequency in different ethnicities of one in 40 000 in African-​American to 146 000 in Australian populations. The gene-​encoding acid α-​glucosidase (GAA) is mapped to chromosome 17q and contains 19 coding exons. Over 200 muta- tions have been reported, of which about 75% are pathogenic. When the acid α-​glucosidase activity decreases below critical, lysosomal glycogen begins to accumulate. This glycogen is not primarily util- ized for energy production and therefore common manifestations seen in other glycogen storage disorders of hypoglycaemia, ketosis, or lactic academia are not seen in PD. This threshold level of enzyme required to accumulate glycogen varies depending on the organ. Hypertrophic cardiomyopathy is a typical sign of classic infantile Pompe’s disease in which no residual acid α-​glucosidase activity is present, but is rarely seen in late-​onset forms with higher residual activity. Pathological changes in skeletal muscle, however, are prom- inent throughout the clinical spectrum. Pompe disease may present at any age, though the classic in- fantile form was first described by Pompe in 1932 and usually pre- sents in patients within the first months of life with median age of onset between 1.6 to 2.0 months. Presenting symptoms are feeding difficulties, failure to thrive, respiratory infections, hypotonia, and diminished spontaneous movements. The heart is characteristically affected with hypertrophic cardiomyopathy, thickening of the ven- tricular walls and septum that may lead to outflow tract obstruc- tion and cardiac failure. The electrocardiogram shows high voltages, repolarization disturbances, and frequently a short PR interval. Motor development is delayed and major motor milestones such as rolling over, sitting, or standing are usually not achieved. Patients show slipping through on vertical suspension and prom- inent head lag. Tendon reflexes are often diminished. There is en- largement of the tongue and the liver. Hearing deficit, osteoporosis and osteopenia are now noted as a features in children who survive longer following administration of enzyme replacement therapy. Prior to ERT mean age of death was 6.0–​8.7 months; patients with classic infantile Pompe’s disease rarely survive beyond 1 year of age. With onset beyond one year of age, cardiac involvement is much milder or absent. Symptoms of children and adults with a non-​ classic presentation are predominantly related to skeletal muscle dysfunction, resulting usually in reduced mobility followed by re- spiratory problems. Presenting symptoms are difficulty running, climbing stairs, rising from an armchair, and walking. Other first symptoms were fatigue and muscle cramps. Early involvement of the diaphragm leads to low vital capacities in the supine position al- though pulmonary function in the upright position is still adequate. This leads to sleep disordered breathing and patients learn to sleep with their head elevated. Patients may report morning headache as a symptom of hypoventilation during sleep causing hypercarbia. Use of accessory muscles such as sternocleidomastoid may be evident during clinical examination. Patients who are still ambulatory may need ventilation at night. Patients progress slowly but relentlessly to loss of ambulation and wheel chair use along with ventilator sup- port. Life expectancy is diminished in juvenile and adult patients with Pompe disease, usually related to pulmonary complications. Late-​onset forms of Pompe closely mimic limb-​girdle muscular dys- trophy in presentation and often may be diagnosed in that category. The average diagnostic delay ranges from 7 to 10 years; although nu- merous cases are known where diagnosis is delayed for decades. Very high index of suspicion is necessary to ensure timely and appropriate diagnosis, given that enzyme replacement therapy is now available. Diagnosis is confirmed by enzyme estimation in peripheral leuco- cytes or isolated lymphocytes. Several new methods use assays of acid α-​glucosidase activity in dried bloodspots which offers a convenient and reliable method for screening. Infants with classic Pompe dis- ease have less than 1% residual activity; children and adults have residual activity, but usually no more than 30% of average normal activity. Sequencing the GAA gene provides confirmation of diag- nosis by identifying the mutations as well providing family mutation for screening other family members for affected or carrier state. ERT was first approved in Europe and United States for infantile and late onset forms of PD in 2006. In infantile PD, ERT should be initi- ated as soon as the diagnosis of infantile Pompe disease is established. Infusion associated reactions are common, which can be modified by slowing the rate of infusion or administration of antipyretics, anti- histamines, or glucocorticoids. Majority of treated children develop IgG antibodies to ERT within the first three months of treatment. Affected individuals with high sustained IgG titers may have a poor clinical response to treatment. Infants who are CRIM (cross-​reactive immunogenic material) negative require immunomodulation very 24.17  Inherited neurodegenerative diseases 6233 early in the treatment course, optimally before the first infusion. Compared to an untreated cohort, when ERT is initiated before age six months and before the need for ventilatory assistance there is im- proved survival, improved ventilator-​independent survival, reduced cardiac mass, and significantly improved acquisition of motor skills. Treatment with alglucosidase alfa reduces the risk of mortality in late-​onset patients to close to a fifth of that experienced in the natural course. Patients on treatment demonstrate improved pulmonary function as documented by forced vital capacity (FVC) within the first few months, followed by a gradual return to baseline in con- trast to the consistent decline and earlier death seen in untreated pa- tients. Over time the difference in percentage predicted sitting FVC between treated and untreated patients increases. Improvements in the six minute walk test occur quickly and are sustained over time. Sialic acid storage disorders These autosomal recessive disorders, caused by mutations in the sialin gene, SLC17A5, encoding a protein involved in the transport of sialic acid (N-​acetylneuraminic acid), include the following allelic disorders: infantile free sialic acid storage disease (ISSD) and Salla’s disease (or the Finnish variant). The severe infantile form (ISSD) presents with non​immune hydrops, hypertrophic cardiomyopathy, ascites, hepatosplenomegaly, inguinal hernias, coarse facies, and dysotosis multiple, causing death in the first 2 years of life. Clinical features of the juvenile form include developmental delay and growth retardation, seen in early childhood with mild coarsening of the facial features, hepatomegaly, and psychomotor retardation. In Salla’s disease, named after a region in northeastern Finland, af- fected children manifest with mild coarsening of features, exotropia, hypotonia, ataxia, and learning disabilities during the first year of life without visceromegaly or skeletal abnormalities. Increased amounts of free sialic acid are found in the serum and urine, as well as in cultured skin fibroblasts and several tissues, including the brain. Neuronal ceroid lipofuscinoses (NCLs) The neuronal ceroid lipofuscinoses (NCLs) represent a group of childhood-​onset disorders with a combined prevalence of approxi- mately 1 in 12 500 births characterized by the intralysosomal aggre- gation of autofluorescent proteinaceous ageing pigments (i.e. ceroid and lipofuscin). Under the electron microscope, the accumulated material takes three different forms: granular osmiophilic deposits (GRODs), curvilinear profiles, and fingerprint bodies. The form that predominates in a particular patient correlates with the particular mutated gene. For example, in CLN1 only GRODs are seen and in CLN2 curvilinear profiles predominate, whereas CLN3 is distin- guished by a preponderance of fingerprint bodies. They share common clinical features that include epileptic seiz- ures, progressive psychomotor decline, visual failure, and premature death. There are eight major subtypes based on age at onset, pres- entation, and pathological findings (CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN8, and CLN10). Clinical progression varies among the different NCLs. There are an increasing number of ex- amples of different mutations in a single gene giving rise to quite dif- ferent diseases (e.g. a particular missense mutation in CLN2/​TPP1 is associated with spinocerebellar ataxia SCAR7, a slowly progressing but not life-​limiting disease with no ophthalmologic abnormalities or epilepsy, and absence of typical storage). Diagnosis is established by demonstration of the respective en- zyme deficiencies in peripheral leucocytes or cultured fibroblasts. Diagnosis is significantly aided by electron microscopy of a skin bi- opsy and observation of nerve endings that show the typical inclu- sions. It is recommended that skin biopsy be obtained from sensitive skin areas such as the axilla where the density of nerve endings may be higher. Molecular testing establishes the diagnosis with biallelic mutations detected. CLN1 The infantile form of NCL, caused by mutations in CLN1, the gene encoding the enzyme palmitoyl-​protein thioesterase 1 (PPT1), has the widest range of age of onset. PPT1 removes palmitate residues from proteins which accumulate in CLN1 as GRODs. Whichever the age of onset, all CLN1 patients will have GRODs on electron microscopy. Palmitoylation plays a critical role in neuronal vesicular transport and intracellular signalling. PPT1 is also found in non-​ lysosomal compartments in presynaptic terminals. These findings suggest that CLN1 is may not exclusively be a storage disorder. Most patients have infantile onset between 8 and 18 months of age with irritability, deceleration of head growth, muscular hypo- tonia, ataxia, motor clumsiness, irritability, sleep disturbance, and visual failure after a period of normal development during the first year. Rapid developmental deterioration occurs during the second year of life with loss of all motor abilities and social interest, blind- ness, and increasing spasticity, seizures, and myoclonus. Fine motor skills are affected with purposeless, characteristic hand movements (hyperkinesias) such as those seen in Rett’s syndrome. Death usually occurs in early childhood. Some patients may have late-​infantile, ju- venile, and even adult-​onset as late as 40 years of age. It is possible that most if not all Kuf’s disease (originally CLN4) cases are actually adult-​onset CLN1. CLN2 Cerliponase alfa was the first drug to be approved by US FDA in April 2017 for treatment of TPP1 deficiency in pediatric patients over three years of age. Clinical studies showed that intraventricular enzyme replacement therapy with recombinant TTP1 administered every other week slowed the loss of walking ability in treated pa- tients as compared with a natural historical cohort. Late-​infantile NCL, caused by mutations in CLN2, which encodes the enzyme tripeptidyl-​peptidase 1 (TPP). The enzyme removes tri- peptides from N-​termini of small proteins such as the subunit c of mitochondrial ATP synthase. In addition to the lysosome, TPP1 lo- calizes to the Golgi apparatus, lipid rafts, and endosomes, and inter- acts with CLN5, CLN3, and CLN8. Presence of pure curvilinear membrane-​bound lysosomal aggregates without clear lipid droplets is the hallmark for CLN2 mutation disease. Onset is between second and fourth year of life with unexpected delay of psychomotor development or epilepsy of sudden onset. Seizures are generalized tonic-​clonic or partial, frequently of a severe myoclonic type, which may soon become resistant to drug treatment. Gross and fine motor abilities, cognitive functions, and, later, vision are rapidly lost within 3 years of onset. Spasticity, truncal hypotonia, loss of head control, near-​continuous myoclonus, frequent seizures, and an extended vegetative state characterize the rest of the child’s life until death in early adolescence. Death is often due to aspiration pneumonia. Electroencephalography (EEG) includes characteristic section 24  Neurological disorders 6234 occipital spike responses to slow flash (1–​2 Hz) stimulation before the onset of seizures, which exaggerates as the disease progresses. Electroretinography is diminished even before noticeable visual loss. CLN3 Juvenile NCL, caused by mutations in CLN3. Ultrastructurally, CLN3 cases exhibit fingerprint profiles within the lysosomal re- sidual body, or in conjunction with curvilinear or rectilinear profiles, or as a small component within large membrane-​bound lysosomal vacuoles. CLN3 encodes a transmembrane protein that has been reported to localize to membrane lipid rafts in lysosomes, endosomes, synaptosomes, and the cell membrane, as well as in mitochondria. CLN3 has been implicated in antiapoptosis, pro- cessing of mitochondrial membrane proteins, regulation of lyso- somal pH, transport of basic amino acids into the lysosome, and lysosomal size. CLN3 presents with visual failure, noticed around the age of 5 to 10 years leading to blindness usually within a few years, gradual psychomotor deterioration during early school years, followed by seizures and psychosis. Ocular pathology is initially a pigmentary retinopathy often misdiagnosed as retinitis pigmentosa or cone dys- trophy. In adolescence, speech, mobility, and cognitive skills deteri- orate and seizures set in. Children have behavioural problems such as aggressiveness, psychosis, mood disturbance, and anxiety. Speech becomes dysarthric and dysfluent with echolalia. As the disease pro- gresses, myoclonic jerks and parkinsonian features and gait develop. This particular NCL is diagnosable through the identification of vacuolated blood lymphocytes. CLN5 Mutations in CLN5 cause the Finnish variant of late-​infantile NCL with onset between four and 7 years. CLN5 encodes a transmem- brane protein and is synthesized as four precursors, all directed to the lysosome. The longest form is associated with the lysosomal membrane and interacts with CLN2 and CLN3. Lipopigments are distributed in the central nervous system and extracerebrally, and include fingerprint bodies, curvilinear profiles, lamellar inclusions, and occasionally condensed fingerprint figures associated with lipid droplets. Characteristic clinical symptoms include developmental regres- sion, visual impairment, ataxia, and myoclonus epilepsy, similar to the other NCLs. Neurophysiologic examination shows giant visual-​evoked potentials, exaggerated somatosensory potentials, and occipital spikes in response to photic stimulation, similar to CLN2. CLN6 CLN6 encodes a protein of unknown function with seven trans- membrane domains localizing to the endoplasmic reticulum. Lipopigments include fingerprint, curvilinear, as well as rectilinear patterns. CLN6 is found in multiple ethnicitieswith age of onset ran- ging from 18 months to 8 years, with the majority between 3 and 5 years. Early features include gait and speech disturbance, seizures, and developmental delay. CLN7 The CLN7 gene product is a lysosomal integral membrane pro- tein with features suggestive of transport function. In CLN7 dense fingerprint profiles are present in the lymphocytes. Disease onset is between 2 and 7 years. Psychomotor regression or seizures can be the initial presenting signs. CLN8 The CLN8 protein appears to be an enzyme in the pathway of ceramide synthesis and localizes to the ER and the ER–​Golgi inter- mediate compartment. GROD, curvilinear, and fingerprint pro- files have been reported on electron microscopy, in various tissues, including lymphocytes. CLN8 has two forms based on the muta- tion:  childhood-​onset (5–​10  years) with intractable epilepsy fol- lowed by progressive cognitive decline or mild developmental delay in infancy followed by a florid progressive myoclonic epilepsies (PME) with progressive myoclonus, seizures, retinopathy, and psy- chomotor regression starting between three and six years. CLN10 CLN10 is a fulminant disease due to mutations in lysosomal pro- tease, cathepsin D, where complete loss-​of-​function mutation leads to a congenital form with encephalopathy, status epilepticus, and death due to respiratory insufficiency in the first days and weeks of life with massive GRODs in the central nervous system. Milder form with missense mutations in one patient is described with childhood-​onset neurodegenerative disease with ataxia, retinop- athy, severe cognitive decline, and no seizures at age 17. Section IV Dementia syndromes Almost all major dementia syndromes are disorders of abnormal protein aggregation. Both genetic and sporadic forms of each illness exist and overlap has been found with parkinsonian–​dementia syn- dromes. This section surveys the clinical genetics of dementia. See Chapter 24.4.2 for more detailed clinical account of the dementing disorders. Alzheimer’s disease Alzheimer’s disease accounts for about two-​thirds of cases of pro- gressive dementia. It begins with the insidious onset of loss of re- cent memory, increasing forgetfulness, disorientation, decreased abstraction ability, and word-​finding difficulty. Behavioural prob- lems arise including agitation, restlessness, insomnia, paranoia, and sometimes delusions or hallucinations. Depression is common. As the disease progresses the patient becomes increasingly immobile, incontinent, and mute with death occurring one to two decades after symptom onset. Pathological hallmarks, in both familial and sporadic cases, are extracellular plaques of amyloid-​β (Aβ) and intraneuronal inclu- sions of hyperphosphorylated tau within the cortex and subcor- tical nuclei. The neuritic plaques containing extracellular deposits of amyloid β-​protein (Aβ) are intimately associated with dystrophic neurites, activated microglia within the amyloid deposit, and re- active fibrillary astocytes surrounding the lesion. The tangles consist of masses of abnormal paired helical filaments (PHFs) and straight filaments in the perinuclear cytoplasm of selected neurons. The PHFs contain insoluble aggregates of the microtubule-​associated protein tau in a hyperphosphorylated, largely insoluble form, often conjugated with ubiquitin. Fibrillar Aβ deposits are also found in the 24.17  Inherited neurodegenerative diseases 6235 basement membranes of cerebral capillaries, arterioles, and small arteries. Clustering of early onset Alzheimer’s disease within families was observed as early as the 1930s. In the 1990s it was confirmed that the disease could be caused by autosomal dominantly inherited genetic mutations. Initially mutations were described in the amyloid pre- cursor protein (APP) gene on chromosome 21 and subsequently in presenilin (PSEN)1 on chromosome 14 and PSEN2 on chromo- some. Over 200 changes, including mutations, polymorphisms, and variants of unknown significance have now been described in these genes. Duplications of the APP gene as well as an extra copy as seen in Down’s syndrome or trisomy 21, have also been identified as an additional cause of familial Alzheimer’s diease (FAD). Mutations in PSEN1 account for most cases of FAD and collectively, FAD accounts for up to 0.5% of Alzheimer’s in general. Though the mechanisms are complex and variable, all three genes known to cause FAD ultimately result in the enhanced production and/​or deposition of Aβ. APP is a transmembrane protein that ap- pears to play a role in neural plasticity and the regulation of synapse formation. When APP is sequentially acted on by β-​ and γ-​secretase, β-​ secretase activity generates a soluble extracellular fragment and its transmembrane domain is cleaved γ-​secretase at a variety of different sites, generating a peptide from 39–​43 amino acids in length: the Aβ protein. PSEN1 forms part of the γ-​secretase complex. Aβ peptides, particularly Aβ42, may have toxic effects on neuronal and synaptic function intracellularly, and seed extracellularly to precipitate in the form of amyloid plaques. Most FAD-​causing mutations appear to ei- ther increase Aβ40 and Aβ42, or alter the ratio between them. Both FAD and sporadic Alheimer’s show a greater proportion of Aβ40 de- position in individuals who carry an ε4 allele. Additionally, possession of the APOε4 allele in FAD is associated with a decreased age at onset. Two distinct histopathological profiles identified in FAD caused by PSEN1 mutations are driven by the position of the mutation within the gene, although this is not absolute. Type 1 pathology, associated with mutations occurring before codon 200, closely resembles the pathology in sporadic Alzheimer’s disease, with many diffuse and cored plaques, and few white-​matter plaques. Amyloid angiopathy is mild to moderate, confined to leptomeningeal vessels. Mutations beyond codon 200 tend to have type-​2 pathology, which is more severe leptomeningeal and intraparenchymal amyloid angiopathy with large diffuse plaques concentrated around amyloidotic arteries. Independent of the APOE genotype Aβ40 deposition is increased in those with type 2 pathology. Individuals with type 1 pathology have a younger age at onset (on average 5 years earlier) and shorter dis- ease duration (c.2.5 years) than those with type 2 pathology. It has been suggested that in addition to increasing the produc- tion and deposition of Aβ42 some mutations affect Notch signalling, inducing breakdown of the vascular epithelium causing leakage of Aβ into brain tissue. Seeding of existing deposits of Aβ may produce larger plaques seen around vessels in type 2 pathology and promote development of amyloid angiopathy. Majority of the reported APP mutations lie in the vicinity of the β-​ and γ-​secretase cleavage sites. Families with mutations at these sites were found to have, in addition to early impairment of episodic memory, dyscalculia, lack of insight, and prominent myoclonus and seizures. Mutations found within the Aβ coding sequence, have spe- cific relation to amyloid angiopathy The ‘Dutch mutation’ in APP, a glutamic acid to glutamine substitution at position 693 (APPE693Q) gives rise to severe amyloid angiopathy leading to recurrent cerebral haemorrhage. Pathologically, although diffuse parenchymal deposits of Aβ are present, neuritic plaques and neurofibrillary tangles are ab- sent. Similar severe amyloid angiopathy is seen in patients with Iowa mutation (APP D694N) in addition to widespread neurofibrillary tangles and amyloid plaques, particularly abundant Aβ40 deposition. However, clinically patients presented with progressive cognitive impairment and not recurrent cerebrovascular events. Similarly, the ‘Arctic’ mutation APP E693G has a purely cognitive phenotype, despite the presence of marked amyloid angiopathy. Comparing the Arctic and Dutch mutations, which occur at exactly the same pos- ition (amino acid 693) but give rise to totally different phenotypes suggests that the polarity of the substituted amino acid influences the pathology. The Dutch mutation replaces glutamic acid with polar and hydrophilic glutamine, which may have a greater affinity for, and pro- pensity to disrupt, the vessel wall than the Artic mutation involves replacement with non​polar and hydrophobic glycine. APP duplications Copy number variation plays a role in Alzheimer’s disease patho- genesis as is well demonstrated by its association with Down’s syn- drome. Duplications of the APP gene can give rise to FAD with diverse phenotype even within a single family. Pathologically prom- inent amyloid angiopathy and clinically high frequency of seizures are characteristic. The size of the duplication does not appear to in- fluence the clinical presentation. The most striking feature of FAD is the younger age at onset com- pared to sporadic form:  families with PSEN1 mutations present within the range 35 to 55 years, APP mutations between 40 and 65 years and PSEN2 mutations between 40 and 70 years. Majority of individuals with FAD have clinical presentations similar to sporadic Alzheimer’s, comprising an early impairment of episodic memory with progressive involvement of multiple cognitive domains. However, several PSEN1 mutations have been reported to present with language impairment,. Posterior cortical atrophy described in sporadic Alzheimer’s disease, with marked visual processing deficits and relatively well preserved memory, to date, has not been observed in FAD. Myoclonus and seizures, which are typically late manifestations in sporadic Alzheimer’s, can be a particularly prom- inent and early sign in FAD. Spastic paraparesis, occurring simul- taneously with cognitive deficits or predating by several years, has been reported to occur in association with over 20 different PSEN1 mutations. Despite similar amounts of Aβ deposition in the cere- bellum, Purkinje cell loss and reactive astrocytosis are often more severe in FAD than sporadic Alzheimer’s disease; cerebellar signs may be absent clinically. Extrapyramidal signs, particularly those causing very early onset of the disease, have been reported with several PSEN1 mutations. Of note, new light was shed on the role of innate immunity and in- flammation in development and progression of Alzheimer’s disease when several groups reported a new pathogenic missense mutation in a gene coding for the triggering receptor expressed on myeloid-​ derived cells (TREM-​2) and subsequently in CD33. TREM-​2 is an innate immune receptor highly expressed on immature dendritic cells in the peripheral lymphatics, microglia, and osteoclasts. The receptor is normally involved in phagocytosis of neural debris in the brain and profoundly down-​regulates proinflammatory cyto- kine production. Homozygous loss-​of-​function TREM-​2 mutations section 24  Neurological disorders 6236 have been previously linked to an early onset of dementia coupled with bone abnormalities. A heterozygous TREM-​2 genetic variant is strongly associated with a significant increase in the risk of late-​ onset Alzheimer’s disease. The reduced function of TREM-​2 in blocking proinflammatory cytokine production is thought to impair innate immune regulation and may be a key to the pathogenic risk of Alzheimer’s disease. Frontotemporal dementia Frontotemporal dementia (FTD) is the second most common cause of presenile dementia, accounting for 12 to 25% of dementia cases with a prevalence estimated between 10 and 30 per 100 000 in indi- viduals between the ages of 45 and 65 years. Originally, the concept of FTD arose with the recognition of dementia with Pick’s bodies (silver-​staining intraneuronal inclusions) in the presence of circum- scribed atrophy of the frontotemporal regions. However, as Pick’s bodies are present in a minority of cases, this finding is no longer an essential component of FTD. Almost 50% of individuals with FTD have a positive family history, and 10 to 20% conform to an auto- somal dominant pattern of inheritance (familial frontotemporal lobar degeneration FTLD). FTD presents in the sixth decade in three subtypes. In the frontal variant, behavioural changes predominate (bvFTD). Patients with predominantly left hemisphere involvement experience progressive language deficits (progressive non​fluent aphasia, PNFA). In cases of left anterior lobe atrophy, there is progressive loss of the know- ledge of words and objects, difficulties in communicative speech and understanding the semantic content of language (semantic de- mentia, SD). However, patients ultimately progress to more global impairment in frontal and temporal lobe functions. Pathologically, FTD is a proteinopathy characterized by presence of abnormal, ubi- quitinated protein inclusions that reside in the cytoplasm and nu- cleus of neuronal and glial cells. It is now recognized that FTLD and amyotrophic lateral scler- osis (ALS) co-​occur on a spectrum of a disease complex. There is clustering of neurodegenerative diseases in relatives of patients with ALS. Up to half of ALS patients show some functional impairment in frontal lobe tests, and in 15% of cases it is severe enough to war- rant an official diagnosis of FTLD. On the other hand, around 40% of FTLD cases have measurable motor dysfunction with up to 15% meeting criteria for ALS diagnosis. Therefore, following terminology appropriately refers to patients as: (i) ALS with cognitive or behavioural impairment (ALS Ci/​ALS Bi): ALS patients who do not meet the criteria for FTLD, but do have behavioural or cognitive deficits (ii) familial frontotemporal lobar degeneration and motor neuron disease (FTLD-​MND or FTLD-​ MND-​like):  Patients with FTLD who show some motor neuron involvement clinically or on electromyography without actually developing ALS (iii) ALS-​FTLD or FTLD-​ALS: Those who fall at the midway point; the order is usually dependent on the clinical symp- toms that appeared first. Several genes are implicated in pure FTLD, FTLD-​ALS, and pure ALS. Microtubule-​associated protein Tau (MAPT) Originally FTLD families with autosomal dominant inheritance and clinical presentation of frontal disinhibition, dementia, parkin- sonism, and amyotrophy were linked genetically to chromosome 17q21, thus named FTDP-​17 cases. Most of these FTDP-​17 cases stained positive for inclusions of microtubule-​associated protein Tau (MAPT). Analysis of the MAPT gene on chromosome 17q21 iden- tified the first novel missense and splice-​site mutations in MAPT as- sociated with FTLD; subsequently 44 MAPT mutations have been reported that result are either missense mutation, interfere with al- ternative splicing, or disrupt the ratio of tau isoform. Mutations that disturb alternative splicing regulation lead to an increase in the four repeat (4R, sticky) form over three repeat (3R, non​sticky) form of tau, and along with missense mutations in exon 10 are associated with a tauopathy composed of 4R tau. Missense or splice-​site mu- tations affecting exon 10 cause neuronal and glial inclusions while mutations outside of exon 10 cause neuronal inclusions only com- prised of all six isoforms. Progranulin Discovery of FTDP-​17 families without MAPT mutations led to analysis of near-​by genes, showing a second gene, granulin (GRN), within the region of chromosome17q21, 1.7 Mb centromeric to MAPT, which had mutations. Neuronal inclusions in these cases did not show tau-​positive staining, but did stain for ubiquitin. GRN gene encodes a cysteine-​rich secreted glycoprotein, progranulin (PGRN), implicated in tissue repair, glucose sensing, and cancer. PGRN is proteolytically cleaved by enzymes such as elastase into small pep- tides, known as granulins. Most GRN mutations found to date cause disease due haploinsufficiency; nonsense mutations producing a premature termination of the coding sequence and a non​translated protein. FTLD-​ALS (also refer to ALS in Section X, Motor Neuron Disease) TDP-​43 Most FTLD cases who had tau-​negative inclusions but stained posi- tive for ubiquitin (known as FTLD-​U) were found to contain TAR DNA-​binding protein (TDP-​43 protein), as did ALS cases, both sporadic and some familial. This group of patents is labelled as FTLD-​TDP. TDP-​43 is a 414 amino acid nuclear protein, encoded by TARDBP, a chromosome 1 gene. TDP-​protein shuttles between the nucleus and the cytoplasm. In vitro, when its translocation to the nucleus is inhibited, TDP-​43 accumulates, and is sequestered as cytoplasmic aggregates. Missense and nonsense mutations in TARDBP cause FTLD-​ALS spectrum with a frequency of less than 1% in FTLD and around 1% in ALS. FTLD-​TDP cases are further sub classified as: FTLD-​TDP type A  is most often associated with progranulin mutations. Pathological highlights are numerous short dystrophic neurites (DN), crescentic or oval neuronal cytoplasmic inclusions (NCI), concentrated primarily in neocortical layer 2. and moderate number of lentiform neuronal intranuclear inclusions (NII). Repeat expansion mutation in the C9orf72 gene is also associated with FTLD_​TDP type A. FTLD-​TDP43 type B is associated with FTD-​ALS and bvFTD. Pathology also includes NCIs, but NIIs and DNs are rare. Males are more frequently affected and this group has the shortest life expect- ancy at just over five years on average. Hexanucleotide expansion mutation (GGGGCC) in the gene C9orf72 is associated with this sub type 24.17  Inherited neurodegenerative diseases 6237 FTLD-​TDP43 type C features long DN in superficial cortical layers, predominantly in layer II, and clinically presents with SD (and occasionally bvFTD). At this time, there is no linkage to any gene. FTLD-​TDP43 type D have few NCI and numerous NII and DN throughout all layers. This subtype is associated with valosin-​ containing protein (VCP) mutations, and is very rare at less than 1% of familial FTLD. Clinical presentation for type D is familial inclu- sion body myopathy with Paget Disease of Bone and frontotemporal dementia (IBMPFD). FUS Fused in sarcoma (FUS, also known as translocated in liposarcoma, TLS) codes for a 526 amino acid protein and is identified as a fu- sion oncogene causing human myxoid liposarcomas. The protein has several conserved domains, a transcriptional activation domain, multiple nucleic acid binding domains and a nuclear localization signal. It was. In the nucleus, FUS may be involved in regulation of transcription and pre-​mRNA splicing. Mutations in the FUS gene are identified as a cause of fALS in 2009, representing around 4% of fALS. The FUS protein was found to be deposited in cytoplasmic inclusions in these patients. VCP Valosin-​containing protein (VCP, also known as p97) is a conserved, multifunctional protein which comprises around 1% of total cellular protein and is a member of the class II AAA (ATPases associated with diverse cellular activities) family. It is known to paly diverse functions include ER and Golgi reassembly, nuclear envelope re- generation, proteolysis, spindle disassembly, chromosome conden- sation, DNA damage response, DNA replication, suppression of protein aggregation, autophagy, ER-​associated protein degradation, and sex determination. VCP mutations are an underlying cause of IBMPFD (inclusion body myopathy with Paget’s disease of bone and frontotemporal de- mentia). Most individuals with IBMPFD present with myopathy, occurring in 80–​90% of patients in adulthhood (c.44 years) with proximal and distal muscle weakness. Electromyography shows myopathic changes and biopsy shows myonuclear and sarcoplasmic inclusion bodies reactive with ubiquitin and TDP-​43. A  third of patients present with dementia a decade later with characteristic language and/​or behavioural dysfunction and FTLD-​TDP D type pathology. C9orf72 The C9orf72 gene encodes a protein of unknown function, but pre- dicted function of the gene product based its structure, is to regu- late membrane traffic in conjunction with Rab-​GTPase switches. A hexanucleotide repeat mutation with the sequence GGGGCC in the first intron of C9orf72 was found to be the most common genetic cause of cause of fALS and FTD, responsible for around 40% of fALS and 21% of FTD. Normal copy number ranges from zero-​30 copies to an excess of four thousand in mutation carriers. Pathologically, C9orf72 mutations are frequently categorized as FTLD_​TDP43 type B pathology, however, have a type A pathology in the outer layers of the cerebral cortex is also described. The hexanucleotide repeat in the non​coding region of the C9orf72 gene allows expression of mutant proteins made of dipeptide repeats (DPRs) via an interesting phenomenon known as repeat-​associated non-​ATG dependent translation (RAN translation). RAN transla- tion occurs in the absence of the ATG codon and from both strands. In addition to the aberrant proteins themselves, a ‘toxic RNA’ hy- pothesis due to the propensity of the RNA of C9orf72 to form highly stable guanine quadruplexes (G-​quadruplexes), and secondary structures formed from short tracts of G-​rich sequence associating together is postulated. P62/​sequestosome-​1 p62, encoded for by the SQSTM1 gene, is a stress-​inducible intracel- lular protein involved in the regulation of cell survival and death via regulation of cell signal transduction. Following the candidate gene approach identification of SQSTM1 mutation, it has been further re- ported in ALS and in FTLD. Ubiquilin 2 The UBQLN2 gene encodes ubiquilin-​2 (UBQLN2), a member of the ubiquilin (UBQLN) family that regulates degradation of ubiqui- tinated proteins. Mutations in this gene have been found in very rare cases of dominantly inherited chromosome-​X-​linked ALS (X-​ALS) and ALS with FTLD. Dementia with Lewy bodies Lewy body dementia (LBD) is distinguished by the presence of intracytoplasmic aggregates of α-​synuclein and other proteins within neurons, especially the CA2/​3 region of the hippocampus. LBD is a complex neurodegenerative disorder caused by the inter- action of genetic and environmental factors. Histologically, LBD is characterized by the presence of Lewy bodies, which are spherical intracytoplasmic deposits around the nucleus and along the den- drites of cortical and subcortical neurons. These inclusions, evident particularly in dopaminergic neurons, are mainly made up of fila- mentous α-​synuclein and ubiquitin proteins. The disease is mostly sporadic; however, there are rare cases of familial aggregation. Missense mutations in the α-​synuclein gene (SNCA) are demonstrated to be associated with the disease. Two different mutations (P123H and V70M) in two different families with LBD have been identified in the β-​synuclein gene (SNCB). Clinically picture of LBD may be difficult to differentiate from Alzheimer’s disease or Parkinson’s disease with dementia. LBD is characterized by progressive cognitive impairment, wide ‘fluctu- ations’ in attention and alertness, recurrent visual hallucinations, and parkinsonis. Additional features LBD include: REM sleep be- haviour disorder, severe sensitivity to neuroleptics, repeated falls and syncope, transient loss of consciousness, delirium, and non-​ visual hallucinations. Prion disorders Prion diseases, or transmissible spongiform encephalopathies, are fatal neurodegenerative disorders that affect humans and animals. Prion diseases have in common the accumulation of an abnormal isoform of the normal human protein PrP. Prion diseases cause a spongiform change within brains associated with astrogliosis and neuronal loss. The key mechanism in the pathogenesis of prion dis- eases is the conversion of the cellular prion protein (PrPC) into PrPSc. Most cases are sporadic but 15% have a familial basis and 1% are acquired iatrogenic. section 24  Neurological disorders 6238 PRNP is located on chromosome 20p12 in humans and codes for a 253 amino acid prion protein (PrP). To date, more than 30 muta- tions of PRNP found in the open reading frame of this gene are the only cause of familial prion diseases, which include familial CJD, GSS, and fatal familial insomnia (FFI). Mutations are autosomal dominant point mutations and insertion/​deletion mutations of octapeptide re- peats (OPRI/​OPRD). A codon 129 polymorphism with homozygosity for methionine or valine results in greater susceptibility for sporadic or iatrogenic CJD, whereas heterozygosity at this codon is protective. Methionine homozygosity at this codon results in increased suscepti- bility to vCJD. FFI is associated with a mutation at codon 178 plus me- thionine on the polymorphic codon 129. If a valine residue is present at the polymorphic codon 129, CJD results rather than FFI. Amino acid substitutions at several other codons cause GSS. Creutzfeldt–​Jakob disease (CJD) generally presents between ages 50 and 70 with dementia, myoclonus, and ataxia. It is rapidly pro- gressive with death usually within less than 1 year. The EEG of many of the patients contains 1-​ to 2-​Hz triphasic periodic sharp waves. On MRI, hyperintensity is detectable on FLAIR and diffusion-​weighted images in the neocortex, basal ganglia, thalamus, and cerebellum. A variant of CJD (vCJD), believed to be caused by transmission of bovine spongiform encephalopathy (BSE or ‘mad cow disease’) to humans, has been seen in young adults (average age 29 years). It presents with psychiatric symptoms, painful dysaesthesias, ataxia, dementia, and a movement disorder. The median survival is longer than in CJD (c.14.5 months). Diagnosis requires brain or tonsillar biopsy to demonstrate PrPSc. The pathology of vCJD is distinctive with diffuse vacuolization and PrP-​containing plaques surrounded by a halo of the spongiform change. Another variant, Gerstmann–​Sträussler–​Scheinker syndrome (GSS), is an inherited form that occurs at an earlier age than CJD and progresses more slowly, with death resulting in 2–​10 years. Signs include ataxia, decreased reflexes, and dementia. Amyotrophy and parkinsonian signs may also appear. EEG changes such as those in CJD are not present. Mild cerebral or cerebellar atrophy is present but there are fewer vacuolar changes than in CJD. There are extensive PrP-​amyloid plaques and in some cases also neurofibrillary tangles. In FFI, the insomnia is untreatable but cognitive function is spared until late in the disease. Other signs are ataxia, pyramidal and extrapyramidal dysfunction, and dysautonomia. Pathological exam- ination reveals almost no vacuolization but neuronal loss and gliosis are found in the thalamus, inferior olives, and to a lesser degree in the cerebellum. Section V: Epilepsy genetics Genetic factors account for about 40% of the aetiological causes of epi- lepsy, but only about 1% are monogenic (Mendelian), being caused by mutation(s) in a single gene, and termed ‘genetic epilepsies’. The risk of epilepsy in the offspring and siblings of patients with epilepsy of any cause is 2–​5%, with higher concordance in monozygotic compared to dizygotic twins. Genetic epilepsies may be ‘syndromic’, where epilepsy is a comorbid condition of another disorder or syndrome, or ‘non-​ syndromic’, where epilepsy is the core manifestations, and the latter are described in this section of this chapter. Genetic testing should be considered in any patient with epilepsy in whom there is a positive family history, or there are features such as developmental delay or abnormal neurologic examination that is not otherwise explained. Non​syndromic genetic epilepsies Consideration of non​syndromic genetic epilepsies can pragmatic- ally be based on age of onset of seizures. Epilepsies of neonatal onset Benign familial neonatal seizures (BFNS) This is an autosomal dominant syndrome characterized by multi- focal clonic or focal seizures, which typically begin on day 2 and spontaneously remit after a few weeks or months, recurring in later life in about 10% of cases. BFNS can be caused by mutations in the voltage-​gated potassium channel genes KCNQ2 and KCNQ3, and some mutations of KCNQ2 are associated with severe epileptic en- cephalopathy, in which the use of retigabine (a potassium channel activator) is being investigated. Benign familial neonatal infantile seizures (BFNIS) This is an autosomal dominant syndrome that presents as afebrile, partial seizures with secondary generalization between day 2 and 7 months of age, with spontaneous remission by 1 year. It is often caused by missense mutation of KCNQ2 (see Table 24.17.3). Neonatal epileptic encephalopathies These are severe neonatal and early infantile epilepsy syndromes in which recurrent clinical seizures are associated with impairment of cognitive, sensory and motor development (see Table 24.17.3). Mutations are often found in genes involved in a wide range of elements required for nerve function. Epilepsies of infantile onset Benign familial infantile seizures Benign familial infantile seizures is an autosomal dominant epi- lepsy with onset between 4 and 8 months of age. Seizures are par- tial, may cluster, with good response to treatment. Prognosis for remission is good. The syndrome is associated with multiple genes (Table 24.17.4). Dravet syndrome Dravet syndrome, also known as severe myoclonic epilepsy of in- fancy, was described first by Charlotte Dravet in 1978. In 2001, SCN1A gene mutations were found to be associated and more than 600 mutations have been described ever since. A  website http://​www.scn1a.info tracks new mutations. SCN1A encodes for the α-subunit of voltage-​gated sodium channels which regu- late the excitability of neurons and neuronal networks. De novo truncations in SCN1A are found in 85% of Dravet syndrome pa- tients but missense mutations may also occur. Other SCN1A gene mutations have been implicated in generalized epilepsy with fe- brile seizures plus syndrome as well as other epilepsy syndromes. Severe loss-​of-​function mutations corroborate with severe epi- lepsy syndromes. Clinically infants present at the age of 6 months, typically with prolonged generalized febrile seizures with subsequent evolution into other seizure types such as myoclonic, complex partial seizures, atypical absence seizures. Cognitive and behavioural deterioration 24.17  Inherited neurodegenerative diseases 6239 Table 24.17.3  Genetics of non​syndromic epilepsies of neonatal onset Epilepsy syndrome Epilepsy syndrome subgroup Inheritance Locus Gene Gene product Gene function BFNS BFNS AD 20q13.33 KCNQ2 Subunit voltage-​gated K channel Subunit voltage-​gated K channel activity AD 8q24.22 KCNQ3 Subunit voltage-​gated K channel Subunit voltage-​gated K channel activity BFNIS BFNIS AD 2q24.3 SCN2A α-subunit voltage-​gated Na channel Subunit voltage-​gated Na channel activity EIEE EIEE1 X-​linked recessive Xp21.3 ARX Aristaless-​related homeobox Homeobox transcription factor EIEE2 X-​linked dominant Xp22.13 CDKL5 Cyclin-​dependent kinase-​like 5 Regulation of other gene function (MECP2) EIEE3 AR 11p15.5 SLC25A22 Solute carrier family 25, member 22 Mitochondrial carrier of l-​glutamate EIEE4 AD 9q34.11 STXBP1 Syntaxin-​binding protein 1 Synaptic vesicles docking and fusion EIEE5 AD 9q34.11 SPTAN1 Spectrin, α, non​erythrocytic 1 Regulation of receptor binding and actin cross-​linking EIEE6/​Dravet syndrome AD 2q24.3 SCN1A SCN9A α-subunit voltage-​gated Na channel Subunit voltage-​gated Na channel activity AD 5q34 GABRG2 GABA-​A receptor, γ-​2 polypeptide GABA-​A receptor activity EIEE7 AD 20q13.33 KCNQ2 Subunit voltage-​gated K channel Subunit voltage-​gated K channel activity EIEE8 X-​linked recessive Xq11.1-​q11.2 ARHGEF9 Rho guanine nucleotide exchange factor 9 Formation of postsynaptic glycine and GABA receptor clusters EIEE9 X-​linked Xq22.1 PCDH19 Protocadherin 19 Cell signalling and adhesion EIEE10 AR 19q13.33 PNKP Polynucleotide kinase 3-​prime phosphatase DNA repair EIEE11 AD 2q24.3 SCN2A α-subunit voltage-​gated Na channel Subunit voltage-​gated Na channel activity EIEE12 AR 20p12.3 PLCB1 Phospholipase C, β-​1 Signal transduction EIEE13 AD 12q13.13 SCN8A α-subunit voltage-​gated Na channel Subunit voltage-​gated Na channel activity EIEE14 AD 9q34.3 KCNT1 (gain of function) Subunit voltage-​gated K channel Subunit voltage-​gated K channel activity EIEE15 AR 1p34.1 ST3GAL3 ST3 β-​galacstoside α-​2,3-​ sialyltransferase 3 Glycosylation of proteins EIEE16 AR 16p13.3 TBC1D24 Tre2-​Bub2-​Cdc16-​ domain family, member 24 Intracellular vesicular transport EIEE17 AD 16q12.2 GNAO1 Guanine nucleotide-​binding protein, α-​activating polypeptide O gene Signal transduction EIEE18 AR 1p34.2 SZT2 Mouse seizure threshold 2 gene Induction of superoxide dismutase EIEE19 —​ 5q34 GABRA1 GABA receptor, α-​1 GABA-​A receptor function EIEE20 X-​linked recessive Xp22.2 PIGA Phosphatidylinositol glycan, class A Anchoring proteins to cell surface EIEE 21 AR 12p13.31 NECAP1 NECAP Endocytosis-​associated protein 1 Clarthrin-​mediated endocystosis in synapses EIEE22 congenital disorder of glycosylation, type IIm X-​linked dominant Xp11.23 SLC35A2 Solute carrier family 35, member 2 UDP-​galactose transporter EIEE23 AR 1p31.3 DOCK7 Dedicator of cytokinesis 7 Guanine nucleotide exchange factor, role in neurogenesis EIEE24 AD 5p12 HCN1 Hyperpolarization-​activated cyclic nucleotide-​gated potassium channel 1 Function of this subset of K channels (continued) section 24  Neurological disorders 6240 tends to correlate with the frequency of seizures. Treatment of Dravet syndrome is challenging. Some benefit may be seen with the use of stiripentol, topiramate, valproate, clobazam, clonazepam, and levetiracetam, as well as a ketogenic diet. Certain anticonvulsants including lamotrigine and carbamazepine may exacerbate seizures in these patients. In June 2018, the US FDA approved oral Cannabidiol [CBD] for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, in patients two years of age and older. When compared with placebo, CBD was shown to be effective in reducing frequency of seizures in three randomized, double- blind, placebo-controlled clinical trials involving 516 patients with either Lennox-Gastaut syndrome or Dravet syndrome. West syndrome West syndrome is an infantile-​onset severe epileptic encephalopathy syndrome. It is recognized by a triad of infantile spasms, developmental delay or regression, and a characteristic electroencephalographic pattern called hypsarrhythmia. Several early infantile epileptic en- cephalopathy syndromes progress into a West syndrome phenotype especially those with mutations in ARX and CDKL5 genes, del 1p36 and inv dup (15). Traditional medications are adrenocorticotrophic hormone and vigabatrin; often ketogenic diet, topiramate, felbamate, zomisamide, and valproate may help. Generalized epilepsy with febrile seizures plus Seizures often first occur in early childhood in association with fever but continue after the age of six in the absence of fever. Seizures may be tonic-​clonic, myoclonic, atonic, or absence seizures, or even myoclonic-​astatic epilepsy; vary rarely focal temporal lobe epilepsy has been described. In most children, neurological development is normal and the seizures present by age 11. Sodium channel genes, encoding the α1, β1, and α2 subunits have been implicated: SCN1A encoded on chromosome 2q24, SCN1B located on 19q13.1, and SCN2A, also mapped to chromosome 2q24, respectively. Mutations in the γ-​aminobutyric acid (GABA) receptor γ-​subunit gene, GABRG2, located on chromosome 5q34 have also been found in the generalized epilepsy with febrile seizures plus (GEFS+) phenotype (Table 24.17.4). Epilepsy of infancy with migrating focal seizures Epilepsy of infancy with migrating focal seizures, also known as malignant migrating partial epilepsies in infancy, is a rare syn- drome characterized by onset in the first six months of life of several refractory seizure types independently migrating from one cortical area to another. Mutations in KCNT1 and other genes are implicated (Table 24.17.4). KCNT1 encodes for a sodium-​activated potassium channel highly expressed in neurons and cardiomyocytes. Mutations are typically gain-​of-​function mutations causing activation of the channel with pathologic potassium conductance. Although seizure frequency and severity typically improve with age, there remains severe degrees of developmental delay. Antiarrhythmic drugs like quinidine may provide a therapeutic target. Pyridoxine-​dependent seizures The seizures in neonatal-​onset epileptic encephalopathy are re- sistant to antiepileptic drugs but respond immediately to the administration of pyridoxine in greater than the normal physio- logical requirement. Plasma and urinary levels of δ1-​piperidine-​ 6-​carboxylate (P6C) and α-​aminoadipic semialdehyde (α-​AASA) are increased due to mutations in ALDHTAI, the gene-​encoding antiquitin, an α-​AASA dehydrogenase. The accumulating P6C in- activates pyridoxal-​5-​phosphate, which is needed for GABA pro- duction, a central inhibitory neurotransmitter. Failure to recognize and treat this condition early can lead to permanent brain damage and lifelong intellectual impairment. Glucose transporter 1 deficiency syndrome Clinical manifestations of this infantile-​onset disorder include se- vere seizures, intermittent ataxia, confusion, movement abnormal- ities, spasticity, sleep disturbances, and recurrent headaches. There is deceleration of head growth with acquired microcephaly, develop- mental delay, and cognitive impairments. Early appearance of epi- sodic eye movements simulating opsoclonus has led to work-​up for an occult neuroblastoma. The absolute level of cerebrospinal fluid glucose is low and cere- brospinal fluid lactate concentration is also reduced. The disorder is due to new heterozygous mutations in GLUTI, which encodes a glucose transporter that is highly expressed in brain and red blood cells. The diagnosis may be confirmed by measuring the uptake of 3-​O-​methyl-​d-​glucose into erythrocytes. The seizures are refractory to conventional anticonvulsant medications and are exacerbated by phenobarbital, but respond to a ketogenic diet. Benign myoclonic epilepsy of infancy Benign myoclonic epilepsy of infancy starts in infancy with myo- clonic seizures, reflex myoclonus, and photosensitivity. The aetiology Epilepsy syndrome Epilepsy syndrome subgroup Inheritance Locus Gene Gene product Gene function EIEE25 AR 17p13.1 SLC13A5 Solute carrier family 13, member 5 Sodium-​dependent citrate transporter SRGAP2-​ associated EIEE —​ 1q32.1 SRGAP2 Slit-​Robo Rho GTP-​ase activation protein 2 Neuronal migration and differentiation MEF2C-​ associated EIEE —​ 5q14.3 MEF2C MADs box transcription enhancer factor 2, polypeptide C Neuronal migration AD, autosomal dominant; AR, autosomal recessive; BFNIS, benign familial neonatal infantile seizures; BFNS, benign familial neonatal seizures; EIEE, early infantile epileptic encephalopathy; GABA, γ-​aminobutyric acid; UDP, uridine-​5-​prime-​diphosphate. Reprinted from Pediatric Clinics, Vol. 62, Hani AJ, Mikati HM and Mikati MA, Genetics of Pediatric Epilepsy, Pages 703–​22, Copyright © 2015, with permission from Elsevier. Originally adapted from OMIM database. Available at: http://​www.ncbi.nlm.nih.gov/​omim/​. Table 24.17.3  Continued 24.17  Inherited neurodegenerative diseases 6241 is not known but 50% of patients have family history of epilepsy or febrile seizures. Familial infantile myoclonic epilepsy Familial infantile myoclonic epilepsy starts in early infancy with myoclonic seizures, febrile seizures, and tonic-​clonic seizures; however, there is no psychomotor delay. Causative mutations are homozygous loss-​of-​function mutations in the TBC1D24, which regulates neurotransmitter release at the synaptic level (see Table 24.17.4). Epilepsies of childhood onset Early and late-​onset childhood occipital epilepsy The early onset childhood occipital epilepsy, also known as Panayiotopoulos syndrome, with the hallmark of autonomic seiz- ures including vomiting and late-​onset childhood occipital epilepsy (LOCOE) characterized by visual seizures are thought to be partly genetic given the increased incidence of epilepsy in first-​degree members of patients. Benign epilepsy with centrotemporal spikes Benign epilepsy with centrotemporal spikes (BECTS) is the most common benign focal epilepsy of childhood.. Genome wide analysis showed linkage to a region on chromosome 11p13. Some cases have also been linked to GRIN2A mutations and to DEPDC5 mutations. Seizures, occurring between ages of 7 to 10 years, are unilateral sen- sorimotor involving face with speech arrest and hypersalivation. Childhood absence epilepsy In childhood absence epilepsy, although considered polygenic, mu- tations in genes encoding the various subunits of the GABA-​A re- ceptor and mutations in the voltage-​gated calcium channel subunits may contribute (Table 24.17.5). Seizures are marked by brief alter- ation of consciousness for an average of 10 seconds followed by rapid return to baseline mental status within 2 to 3 seconds. Landau–​Kleffner syndrome Landau–​Kleffner syndrome (LKS) is a focal epilepsy with speech dis- order with or without mental retardation. It is marked by epileptic Table 24.17.4  Genetics of non​syndromic epilepsies of infantile onset Epilepsy syndrome Epilepsy syndrome Inheritance Locus Gene Gene name/​Product Gene function BFIS BFIS1 AD 19q BFIS1 Benign familial infantile seizure 1 —​ BFIS2 AD 16p11.2 PRRT2 Proline-​rich transmembrane protein 2 Transport of synaptic vesicles BFIS3 AD 2q24.3 SCN2A Sodium channel, voltage-​gated type II, α-subunit Sodium channel activity BFIS4 AD? 1p36.12-​p35.1 —​ —​ —​ Dravet Syndrome (EIEE6), SMEI Dravet syndrome AD 2q24.3 SCN1A SCN9A α-subunits of voltage-​gated Na channel Subunit voltage-​gated Na channel activity AD 5q34 GABRG2 GABA-​A receptor, γ-​2 polypeptide GABA-​A receptor activity West syndrome Please refer to EIEE section in Table 24.17.3 Generalized epilepsy with febrile seizures plus GEFSP, type 1 (GEFSP1) AD 19q13.2 SCN1B β-subunits of voltage-​gated Na channel Subunit voltage-​gated Na channel activity GEFSP2, AD 2q24.3 SCN1A α-subunits of voltage-​gated Na channel Subunit voltage-​gated Na channel activity GEFSP3 AD 5q34 GABRG2 GABA-​A receptor, γ-​2 polypeptide GABA-​A receptor activity GEFSP4 AD 2p24 —​ —​ —​ GEFSP5 AD 1p36.3 GABRD GABA receptor, δ-subunit GABA-​A receptor activity GEFSP6 AD 8p23-​p21 GEFSP7 AD 2q24.3 SCN9A α-subunits of voltage-​gated Na channel Subunit voltage-​gated Na channel activity GEFSP8 AD 6q16.3-​q22.31 EIMFS Please refer to EIEE6, EIEE16, and EIEE14 in Table 24.17.3 for possible causative genes. EIMFS AR 11p15.5 SLC25A22 Solute carrier family 25, member 22 Mitochondrial carrier of l-​glutamate EIMFS AR 20p12.3 PLCB1 Phospholipase C, β-​1 Signal transduction Familial infantile myoclonic epilepsy FIME AR 16p13.3 TBC1D24 Tre2-​Bub2-​Cdc16-​ domain family, member 24 Intracellular vesicular transport BFIS, benign familial infantile seizures; EIEE, early infantile epileptic encephalopathy; EIMFS, Epilepsy of infancy with migrating focal seizures; SMEI, severe myoclonic epilepsy of infancy. Reprinted from Pediatric Clinics, Vol. 62, Hani AJ, Mikati HM and Mikati MA, Genetics of Pediatric Epilepsy, Pages 703–​22, Copyright © 2015, with permission from Elsevier. Originally adapted from OMIM database. Available at: http://​www.ncbi.nlm.nih.gov/​omim/​. section 24  Neurological disorders 6242 aphasia. LKS and some cases of BECTS may be caused by mutations of GRIN2A gene. Mutations lead to increase in open time and de- crease in the closed time of NMDA channels. Epileptic encephalopathy with continuous spike-​and-​wave during sleep This condition, caused by heterozygous mutations in the GRIN2A, manifests with seizures, cognitive regression, and electroencephalo­ graphic pattern of continuous spike wave during non-​REM sleep. Epilepsies of adolescent onset Juvenile absence epilepsy This condition, which can be caused by mutations in several genes (Table 24.17.6), presents with absence seizures at about 12 years of age in association with generalized tonic-​clonic seizures in most cases. Juvenile myoclonic epilepsy This condition, caused by mutations of the GABRA1, CACNB4, GABRD, EFHC1, and CLCN2 genes (see Table 24.17.3), presents with myoclonic jerks, generalized tonic-​clonic seizures, and (some- times) absence seizures. Autosomal dominant nocturnal frontal lobe epilepsy This condition is typically caused by mutations in genes encoding various nicotinic acetylcholine receptor subunits. Severe forms can be caused by mutations in the KCNT1 gene, which encodes a calcium-​activated potassium channel. Autosomal dominant partial epilepsy with auditory features (ADPEAF) This condition is caused by mutations of the LGI1 l(eucine-​rich glioma-​inactivated 1) gene in 50% of cases. Clinical presentation is with focal seizures and predominant auditory auras, commencing between the second and fourth decades. Epilepsies of variable age of onset Familial focal epilepsy with variable foci This autosomal dominant epilepsy may be cuased by mutations in DEPDC5 (DEP domain-​containing protein 5 involved in G-​protein signalling pathways) gene. Clinical presentation is with daytime focal seizures, presenting before the age of 20 years, which arise from different foci in different family members (hence the name). Progressive myoclonic epilepsies (PME) These are mostly autosomal recessive disorders characterized by myoclonus, generalized tonic-​clonic seizures, and progressive neurologic deterioration, with eventual development of cerebellar signs and dementia. Causes include neuronal ceroid lipofuscinoses, neuronopathic Gaucher’s disease, the cherry red spot–​myoclonus epilepsy syndrome (all lysosomal storage diseases); myoclonus Table 24.17.5  Genetics of non​syndromic epilepsies of childhood onset Epilepsy syndrome Epilepsy syndrome Inheritance Locus Gene Gene product Gene function Early onset childhood occipital epilepsy Panayiatopoulos syndromea LOCOE LOCOE—​ described by Gastauta Benign epilepsy with centrotemporal spikes BECTS = Rolandic epilepsy AD 11p13 CAE CAE susceptibility gene 1 AD 8q24 CAE susceptibility gene 2 AD 5134 GABRG2 GABA-​A receptor, γ-​2 polypeptide GABA-​A receptor activity CAE susceptibility gene 5 AD 15q12 GABRB3 GABA-​A receptor, β-​3 polypeptide GABA-​A receptor activity CAE susceptibility gene 6 AD 16p13.3 CACNA1H α-​1-​subunit of voltage-​gated calcium channel Voltage-​gated Ca channel function CAE susceptibility gene 4 AD 5q34 GABRA1 GABA-​A receptor, α-​1 polypeptide GABA-​A receptor activity LKS: subset of focal epilepsy with speech disorder LKS AD 16p13.2 GRIN2A Glutamate receptor, ionotropic, NMDA, subunit 2A Regulates NMDA receptor excitatory properties Epilepsy with myoclonic-​ atonic seizures Possible association with GEFSP 1, 2, and 3 (see Table 24.17.4) Lennox–​Gastaut syndrome Please refer to EIEE genes in Table 24.17.3. Epileptic encephalopathy with continuous spike wave during sleep Please refer to LKS gene GRIN2A detailed above in this table BECTS, benign epilepsy with centrotemporal spikes; CAE, childhood absence epilepsy; LKS, Landau–​Kleffner syndrome; LOCOE, late-​onset childhood occipital epilepsy; NMDA, N-​methyl-​d-​aspartate. a These syndromes are presumed to have a genetic aetiology, but no definite mutations have been identified. Reprinted from Pediatric Clinics, Vol. 62, Hani AJ, Mikati HM and Mikati MA, Genetics of Pediatric Epilepsy, Pages 703–​22, Copyright © 2015, with permission from Elsevier. Originally adapted from OMIM database. Available at: http://​www.ncbi.nlm.nih.gov/​omim/​. 24.17  Inherited neurodegenerative diseases 6243 epilepsy with ragged red fibres (a mitochondrial disorder); and two other conditions, Lafora body disease and Unverricht–​Lundborg disease (Baltic myoclonus epilepsy syndrome). Familial PME can rarely be caused by mutations in other genes. Neuronal ceroid lipofuscinoses This class of hereditary neurodegenerative lysosomal storage dis- eases is a common cause of childhood-​onset seizures with an es- timated incidence of 1 in 25 000. Common features are decline in cognition and motor functions, and blindness. Autofluorescent lipopigment accumulates within neurons and inclusion bodies char- acteristic of each variant can be seen by electron microscopy (EM). Infantile neuronal ceroid lipofuscinosis (CLN1) is characterized by blindness before age 2, seizures, and marked cerebral atrophy. The ultrastructural appearance of the stored substance is predominantly granular, osmiophilic, dense material. Late-​infantile CLN2 patients present at age two to three with sleeplessness, seizures, and then visual loss. Curvilinear bodies are present on electron microscopy. The juvenile-​onset patients (CLN3) develop retinal pigmentary de- generation in mid to late childhood and then seizures, and, as teens, cerebellar and extrapyramidal signs appear. On electron microscopy a pattern of fingerprint bodies predominates. Death in infantile NCL (CLN1) occurs in childhood whereas survival into adoles- cence or adult life is the norm for the other variants. See section on lysososmal storage disorders for further details about the neuronal ceroid lipofuscinoses. Neuronopathic Gaucher’s disease Gaucher’s disease is characterized by lysosomal storage of the glycosphingolipid, glucocerebroside, within the reticuloendothelical system, involving principally the spleen, liver, and bone. It is due to deficiency of the hydrolytic enzyme, glucocerebroside β-​glucosidase, encoded on chromosome 1; in the most common type 1 patient it rarely causes CNS complications. However, patients with the rare type 2 form fail to develop neurologically, become cachectic, with multiple brainstem signs and seizures. In the type 2 patient, death usually occurs before the age of two from pneumonia. Approximately 5% of patients with Gaucher’s disease worldwide have, in addition to visceromegaly, slowly progressive neurological involvement which includes gaze initiation failure, strabismus, Table 24.17.6  Genetics of non​syndromic epilepsies of adolescent onset Epilepsy syndrome Epilepsy syndrome Inheritance Locus Gene Gene product Gene function JAE JAE susceptibility gene 1 AD 6p12.2 EFHC1 EF-​hand domain-​containing protein 1 Enhances calcium influx JAE susceptibility gene 2 AD 3q27.1 CLCN2 Chloride channel 2 Regulates activity of the chloride channel JME JME susceptibility gene 1 AD 6p12.2 EFHC1 EF-​hand domain-​containing protein 1 Enhances calcium influx JME susceptibility gene 3 AR 6p21 JME susceptibility gene 4 AD 5q12-​q14 JME susceptibility gene 5 AD 5q34 GABRA1 GABA-​A receptor, α-​1 polypeptide GABA-​A receptor activity JME susceptibility gene 6 AD 2q23.3 CACNB4 Voltage-​gated Ca channel, β-​4 subunit Voltage-​gated Ca channel activity JME susceptibility gene 7 AD 1p36.33 GABRD GABA receptor, δ-subunit GABA-​A receptor activity JME susceptibility gene 8 AD 3q27.1 CLCN2 Chloride channel 2 Regulates activity of the chloride channel JME susceptibility gene 9 AD 2q33-​q36 ADNFLE ADNFLE 1 AD 20q13.33 CHRNA4 α-​4 subunit of nAch receptor Regulates nAch receptor GABAergic inhibition ADNFLE 2 AD 15q24 ADNFLE 3 AD 1q21.3 CHRNB2 β-​2 nAch receptor Regulates nAch receptor GABAergic inhibition ADNFLE 4 AD 8p21.2 CHRNA2 α-​2 subunit of nAch receptor Regulates nAch receptor GABAergic inhibition ADNFLE 5 AD 9q34.3 KCNT1 subunit voltage-​gated K channel Subunit voltage-​gated K channel activity Autosomal dominant partial epilepsy with auditory features Also known as AD lateral temporal lobe epilepsy AD 10q23.33 LGI1 Leucine-​rich, glioma-​ inactivated protein Regulates glutamatergic synapse development Ach, acetylcholine; AD, autosomal dominant; ADNFLE, autosomal dominant nocturnal frontal lobe epilepsy; Ca, calcium; GABA, γ-​aminobutyric acid; JAE, juvenile absence epilepsy; JME, Juvenile myoclonic epilepsy; Na, sodium; nAch, nicotinic acetylcholine. Reprinted from Pediatric Clinics, Vol. 62, Hani AJ, Mikati HM and Mikati MA, Genetics of Pediatric Epilepsy, Pages 703–​22, Copyright © 2015, with permission from Elsevier. Originally adapted from OMIM database. Available at: http://​www.ncbi.nlm.nih.gov/​omim/​. section 24  Neurological disorders 6244 developmental delay, and, in a few patients, cardiac symptoms. Some develop myoclonic seizures, which progress in frequency and severity and become unresponsive to anticonvulsant therapy. Diagnosis of this autosomal recessive disease can be made by assay of blood β-​glucosidase activity. Enzyme replacement therapy is effective in correcting the haematological abnormalities (anaemia, thrombocytopenia), and promotes reduction in the size of the liver and spleen but has proved ineffective in halting the progression of the myoclonic encephalopathy. Cherry red spot–​myoclonus epilepsy syndrome (sialidosis type 1) This autosomal recessive lysosomal storage disease begins in late childhood or early adolescence with action myoclonus. Subsequently, generalized seizures and polymyoclonus develop. A cherry red spot may be seen in the macula early in the course of the disease, with blindness ensuing before significant cognitive de- cline occurs. Eventually the patient becomes bedridden and totally disabled by multiple myoclonic jerks. Vacuolated lymphocytes are present in peripheral blood and foamy histiocytes may be found in the bone marrow. Within urine, there is a marked increased in sialic acid-​containing oligosaccharides. The disorder is due to a deficiency of lysosomal α-​neuraminidase located on chromosome 6p21.3. Myoclonic epilepsy with ragged red fibres Patients with MERFF present in early adult life with short stature, myoclonus, seizures, ataxia, muscle weakness, and sensory neur- opathy. Subsequently, dementia, hearing loss, and optic atrophy occur. This is a lactic acidosis and ragged red fibres are seen on a muscle biopsy with Gomori’s trichrome stain. The principal neuro- pathological findings are degeneration of the dentate nuclei and superior cerebellar peduncles, the spinocerebellar tracts, and the posterior columns of the spinal cord. The cause in most cases is a point mutation at position 8,344 of the mitochondrial gene for tRNALys. Lafora’s body disease This autosomal recessive disease begins in late childhood or early adolescence and progresses to death within 5 years. Most patients have a mutation in the EPM2A gene located on chromosome 6q23–​ 25 coding for the protein laforin. A few patients have a mutation in EPM2B instead which codes for malin. Tonic-​clonic and myoclonic seizures, polymyoclonus, and pro- gressive mental deterioration occur. Cerebellar ataxia, optic atrophy, rigidity, and exaggerated reflexes develop later. On MRI there is moderate cerebellar atrophy and intracellular inclusion bodies com- posed of polyglucosan are present within neurons of the cerebral cortex, cerebellar dentate nuclei, liver, muscle, and axillary sweat glands. The last is a preferred site for a diagnostic biopsy. Unverricht–​Lundberg disease (Baltic myoclonus) This autosomal recessive progressive encephalopathy is particularly frequent in Finland and Estonia, hence the term ‘Baltic myoclonus’. This disorder is caused by a sequence alteration in the cystatin B gene (CSTB) on chromosome 21, which involves expansion of a dodecamer (CCCCGCCCCGCG) in the 5-​′flanking area of CSTB. A  few patients with point mutations have also been described. Onset is in childhood or adolescence and begins with generalized seizures. They are more frequent on awakening. Various stimuli will intensify the polymyoclonic activity. Cerebellar ataxia, dysarthria, pyramidal signs, distal muscle wasting, and over time mental de- terioration become evident. Nerve cell loss occurs in the cerebellar cortex, dentate nuclei, and thalami, and sometimes also in the basal ganglia, brainstem, and anterior horn cells of the spinal cord. Some patients have benefited from 5-​hydroxytryptophan, piracetam, or baclofen, but the condition may be worsened by phenytoin, which should be avoided. Syndromic genetic epilepsies Syndromic genetic epilepsies include disorders where epilepsy is part of a constellation of symptoms that determine the clinical phenotype. Table 24.17.7 summarizes some common syndromic epilepsy syndromes. Rett Syndrome De novo sporadic cases of X-​linked dominant Rett syndrome are more common (>99%) than familial cases (<1%); both caused in 9% of cases by loss-​of-​function mutations in the gene-​encoding methyl-​CpG-​binding protein 2 (MECP2) at Xq28. MeCP2 is widely expressed in many organs, and its highest expression is detected in brain, lung, and spleen. MeCP2 is a multifunctional protein that is involved in transcriptional regulation as well as modulating chro- matin structure. Mutations in the genes cyclin-​dependent kinase-​ like 5 and forkhead box protein G1 have been reported to cause Table 24.17.7  Genetics of some syndromic epilepsies Syndrome Genes Mode of inheritance Clinical features Rett syndrome MECP2 X-​linked dominant Ataxia, postnatal microcephaly, severe neurodevelopmental problems, especially with movement and absent or deficient speech, regression and breathing abnormalities Angelman syndrome UBE3A Uniparental disomy, maternal deletion Severe cognitive disability, absent speech, periods of inappropriate laughter, postnatal microcephaly, ataxic gait, jerky movements, and epilepsy Tuberous sclerosis TSC1 TSC2 Autosomal dominant Skin (i.e. hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, ungual fibromas), central nervous system (i.e. cortical tubers, subependymal nodules, subependymal giant cell astrocytoma), kidney (i.e. angiomyolipomas, cysts), and heart (i.e. rhabdomyomas, arrhythmias) Mowat–​Wilson syndrome ZEB2 Autosomal dominant Microcephaly, agenesis of the corpus callosum, cognitive disability with severe speech impairment, and seizures Pitt–​Hopkins syndrome MBD5 TCF4 Autosomal dominant Intellectual disability with severe speech impairment, motor incoordination, postnatal microcephaly, breathing anomalies, and seizures Data from Noh GJ, Jane Tavyev Asher Y, Graham JM Jr. Clinical review of genetic epileptic encephalopathies. Eur J Med Genet 2012; 55(5):281–​98. 24.17  Inherited neurodegenerative diseases 6245 atypical, variant, or congenital Rett syndrome. Reett syndrome oc- curs with a frequency of 1 in 10 000–​20 000 girls with no proclivity for a particular race or ethnic group. Dr Andreas Rett first described Rett syndrome in 22 girls with a progressive neurologic syndrome with seizures. Rett syndrome is characterized by early normal growth and development for at least six months of age with subsequent regression. Some early signs may be evident by 2–​4 months of age such as hypotonia, jerkiness in limb movement, and deceleration of head growth, before recognition of developmental regression. Arrested cognitive and motor develop- ment, loss of acquired verbal skills and stereotyped repetitive hand movements with loss of normal hand function occur beginning around 12–​18 months of age. This onset of this nascent develop- mental regression may be abrupt over a span of weeks to months associated with severe sleep disturbances, irritability, and poor eye contact that is occasionally mistaken for autism. A more indolent course of neurologic deterioration ensues often ending in significant motor disability and a wheel chair bound state. The disease even- tually reaches a plateau and patients may survive into their sixth or seventh decade. Four stages are identified following a normal pre- natal and postnatal development of about 5 months. Stage I is her- alded by an early onset of developmental stagnation at 6 months to 1.5 years of age. During this period, major RTT phenotypes such as microcephaly (reduced brain/​head size), reduced growth rate, loss of language and behavioural skills, and seizures start to appear. Stage II is mainly defined by rapid developmental regression with an onset of 1–​4 years of age. There is loss of already acquired skills in commu- nication and behaviour and show symptoms of mental retardation. Stage III is usually referred to as pseudo-​stationary or plateau period that lasts 4–​7 years following stage II, also referred to as wake-​up period because some patients are able to regain certain skills such as communication abilities. Nonetheless, there is progression of the re- spiratory problems, disturbed sleeping patterns, scoliosis (abnormal curvature of the spine), anxiety and hand apraxia/​dyspraxia. Stage IV marks later motor deterioration during which patients lose their ability to walk and become non​ambulatory. In more severe cases, patients may develop parkinsonian phenotype. The last stage may last from several years to decades. Epilepsy is very common in Rett syndrome with frequency ran- ging from approximately 50%-​90%; the course and severity of epi- lepsy is often variable. Most seizures appear between 2 to 5 years of age (median onset is 4 years), usually at clinical stages II-​III. Non-​ MECP2 mutations are more likely in patients with onset of seizures prior to one year of age. Although not established, it is suggested that early onset of seizures may be associated with more seizure types, more intractable epilepsy, and status epilepticus. All seizure types may be present in Rett syndrome including complex partial, gen- eralized tonic-​clonic, tonic, and myoclonic seizures, with absence and clonic seizures being less frequent. The severity of epilepsy often tends to decline after adolescence even in intractable cases. Myriad of other behaviours seen in Rett syndrome patients may be misidentified as seizures by parent including hand stereotypies, breath-​holding, and cyanosis, hyperventilation, staring, unusual eye movements (oculogyric movements, blinking episodes), oral fa- cial dyskinesias, unwarranted bouts of laughing or screaming, and motor abnormalities (tremor, dystonia, jerking, spasticity, and epi- sodic atonia). Chaotic breathing patterns in the waking state, but not during sleep, are common. EEG patterns can also be classified into four stages that parallel the clinical stages. At stage I EEG results tend to be normal. At stage II (18 months-​ 3 years) slow background activity is characteristic- ally seen during wakefulness. Rolandic spikes (focal spikes in the centrotemporal regions) may be seen as the first EEG abnormality, often continuing into stage III. With clinical progression, poorly de- veloped or absent sleep spindles with augmentation of epileptiform activity may be seen. During stage III (plateau 2–​10 years) seizure burden is prominent, sleep patterns continue to be abnormal and waking background activity remains slowed. During this period a unique pattern of bilaterally synchronous bursts of pseudo-​periodic δ activity and generalized rhythmic spike discharges are seen most prominently during sleep. In stage IV (late motor deterioration) slowing of the background activity is persistent epileptiform abnor- malities on EEG; however, clinical seizures are generally no longer a prominent feature. Choice of the ideal first anticonvulsant drug remains unclear. Moreover with up to 50% are intractable and require polytherapy for seizure control. Common drugs reported in clinical practice as first-​ or second-​line monotherapy for Rett syndrome include val- proate and lamotrigine. Medications like valproate, lamotrigine, and Topamax may address other behavioural comorbidities of Rett syn- drome such screaming episodes or mood stability. The consensus statement by the International Ketogenic Diet Study Group lists Rett syndrome as a condition in which the ketogenic diet has been reported as ‘probably’ particularly beneficial. Many children with Rett syndrome are fed with gastrostomy tubes, so they can be easily started on the ketogenic diet without compliance issues. Vagus nerve stimulation has demonstrated 50% reduction in seizure frequency in small patient series. Epileptic encephalopathy due to other inborn errors of metabolism Numerous hereditary metabolic encephalopathies other than those described earlier are associated with seizures. In the neonatal period and early infancy these include disorders of amino acids and or- ganic acids, urea cycle disorders, biotinidase deficiency, peroxi- somal and mitochondrial diseases, sulphite oxidase deficiency, and 3-​phosphoglycerate dehydrogenase deficiency. Seizures presenting in the late-​infantile and early childhood period may indicate a lyso- somal disorder, GABA transaminase deficiency, or creatine synthase deficiency. Disorders to consider when seizures present in later childhood or adolescence include, in addition to those listed earlier, acute intermittent porphyria and early onset Huntington’s disease. In all cases in which the diagnosis is obscure, routine work-​up should include a metabolic screen of blood and urine, plasma amino acids, total, free, and acylcarnitines, urine organic acids, brain CT or MRI, very-​long-​chain fatty acids for peroxisomal disease, blood lac- tate and pyruvate for mitochondrial disorders, and skin biopsy for electron microscopy to rule out a lysosomal disease. Alpers’ syndrome Progressive encephalopathy with intractable seizures, diffuse neur- onal degeneration, and cortical spongiosis with and without liver disease are features of Alpers’ disease. It usually affects infants and young children, but rare juvenile cases are also known. Development delay may precede the onset of seizures, which may start abruptly and consist of various types in individual patients including a section 24  Neurological disorders 6246 marked myoclonic component. Marked motor retardation and in- tellectual impairment with blindness ensue. Liver dysfunction with jaundice and hepatomegaly may develop. CT and MRI show pro- gressive cerebral atrophy. Mutations in the gene coding for the cata- lytic subunit of the mitochondrial DNA (mtDNA) polymerase γ (POLGI) have been found in a wide phenotypic spectrum of patients with this autosomal recessive disease. Menkes’ kinky hair disease The disease is caused by mutations in the ATP7A (MNK) gene en- coded on chromosome Xq13.3. This X-​linked disorder of copper transport causes profound neurological deterioration with the early onset of seizures, abnormal face and hair, hypothermia, skeletal abnormalities, and arterial degeneration. The scalp hair is sparse, stubby, and greyish in colour. Under a microscope, the hairs are seen to be twisted and display partial breaks. Seizures including myo- clonic jerks are almost constant and survival is generally less than 2 years. Serum copper and ceruloplasmin levels are very low, and brain copper is reduced due to poor absorption of copper from the intestine. Section VI: Headache Disorders In the current classification of headache disorders, headache at- tributable to genetic disorders is not classified separately. Genetic disorders that include headache as their primary, or one of their primary, manifestation are included in International Headache Classification-​II as secondary headaches included under ‘Headache attributed to cranial or cervical vascular disorder’. The classification thus implies that a vascular pathology causes headache in these gen- etic disorders. Migraine is one of the prominent presenting features of several genetic cerebral small vessel diseases, which include cere- bral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL); retinal vasculopathy with cere- bral leukodystrophy (RVCL); and hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopahty. The mech- anisms underlying the development of headache in these genetic vasculopathies are not yet well understood. CADASIL CADASIL is the most common autosomal dominant non​amyloid, non​inflammatory adult-​onset small vessel arteriopathy affecting the small-​sized arterioles. It is genetically caused by mutations in NOTCH3 located on chromosome 19p13.2-​p13.1. NOTCH3 protein is a heterodimeric receptor with an extracellular, ligand-​ binding domain, a transmembrane domain, and a cystoplastmic domain. The NOTCH3 gene belongs to the evolutionary conserved Notch receptors family and encodes a 2,321-​amino-​acid-​long single pass transmembrane protein, a cell surface receptor that, in human adult tissue, is solely expressed on vascular smooth muscle cells. The protein participates in signal transduction pathway, crit- ical for vascular development, homeostasis, and vascular smooth muscle cells (VSMC) differentiation and maintenance. Of the 33 exons, pathogenic missense mutations occur in exons 2–​24 in over 95% of cases. The exons encode the epidermal growth factor-​ like repeats (EGFR), each of the repeat has six cysteine residues. Invariably, mutations lead to an addition or deletion of cysteine, leaving behind an odd number of cysteine residues within a given EGFR. Histopathologically, there are diffuse lesions of the hemispheric deep white matter and multiple lacunar infarcts in the white and deep grey matter, as well as in the brain stem. Small arteries and arterioles show loss of smooth muscle cells, prominent thickening of the wall, and deposition of uncharacterized granular osmiophilic material (GOM), located extracellularly and close to the cell sur- face of smooth muscle cells and pericytes. Eventually, there is de- generation and disappearance of VSMCs. In addition, there is an abnormal accumulation of the extracellular domain of NOTCH3 protein (NOTCH3ECD) at the plasma membrane of vascular smooth muscle cells and brain pericytes in close vicinity to, and within, GOM deposits. A small study from Scotland provided an estimate of 4.15 cases/​ 100 000; however, the precise prevalence of CADASIL is unknown. CADASIL is characterized by four cardinal manifestations: (1) mi- graine with aura (MA) in 30–​40% of patients, with an average age of onset of 30 years; (2) ischaemic events in 60–​85% of patients, with an average age of first event of 49 years; (3) mood disturbances in 20% of patients; and (4) cognitive decline after the age of 50 years and dementia by the sixth to seventh decade of life. The cognitive deficit is mostly executive dysfunction and change in personality. Average age at diagnosis of CADASIL is between 40 and 50 years. Atypical migraine has been described in up to 50% of cases with prolonged aura, hemiplegia, or basilar migraine. Brain imaging in CADASIL highlights the leukoaraiosis seen as assymmetric areas of increased signal on T2-​weighted MRI located in deep and periven- tricular white matter. The white matter intensities may be. Lacunar infarcts, subcortical lacunar lesions, and microbleeds are seen on imaging later in life. CARASIL Although migraine is not a feature of CARASIL, it is included here for sake of organizational convenience. Analogous to CADASIL, CARASIL as implied by the name, an autosomal recessively dis- order. The gene defect is in a serine peptidase, HTRA1. HTRA1 belongs to the family of high-​temperature requirement A  serine proteases, which participates cell signalling and protein degradation (Fig. 24.17.17). The clinical features of CARASIL are in many respects similar to those in CADASIL. Half of the patients experience recurrent ischaemic lacunar strokes. There is a stepwise, progressive impair- ment of brain function leading to dementia, usually by the age of 30 to 40 years. Premature diffuse baldness is common especially in males. 80% of the patients suffer from disc herniation and degen- erative spondylosis at lower thoracic or upper lumbar levels causing back pain. Brain imaging is similar to CADASIL. Retinal vasculopathy with cerebral leukodystrophy RVCL was originally described in three families under three dif- ferent disease names: cerebroretinal vasculopathy (CRV), hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy, and stroke. Their allelic nature was established fol- lowing discovery of the disease-​causing gene, which encodes the 3ʹ-​5ʹexonuclease TREX1. Being 3ʹ-​5ʹexonuclease, it may play a role DNA editing and repair. Trex1 protein is part of the SET complex, which is involved in apoptosis induced by cytoxic T-​cells and killer 24.18 Disorders of the neuromuscular junction 6295 24.18 Disorders of the neuromuscular junction 6295 David Hilton- Jones and Jacqueline Palace ESSENTIALS Two fundamentally different pathological processes are associated with disease at the neuromuscular junction: (1) acquired disorders in which autoantibodies are directed against nerve or muscle receptor or ion channels; (2) rare inherited conditions in which the defect may be pre-​ or postsynaptic. Myasthenia gravis Aetiology and epidemiology—​the fundamental disorder is loss of func- tional acetylcholine receptors most frequently as a result of binding of antiacetylcholine receptor (anti-​AChR) antibodies. Incidence is about 10 per million population and prevalence about 8 per 100 000, with a marked female bias in cases aged under 40 years and male preponderance in those over 50 years. Thymomas occur in about 10% of cases. Clinical features and diagnosis—​the most characteristic feature is fatiguability, meaning demonstrable weakness (without muscle pain) precipitated by repeated or sustained muscular activity. In more than 50% cases this first manifests as diplopia and ptosis. For prac- tical purposes, a positive anti-​AChR or anti-​MuSK antibody test is confirmatory and no further diagnostic investigations are required; electromyography and the intravenous edrophonium test are helpful in seronegative patients. The presence of a thymoma can only be as- sessed by CT or MRI of the thorax. Treatment and prognosis—​thymomas require excision, but this in it- self will not improve myasthenia. Anticholinesterase drugs (e.g. pyri- dostigmine) give symptomatic improvement in most patients, and may be sufficient in those with very mild disease. Other manage- ment is determined by the type of disease: (1) ocular myasthenia—​ alternate-​day prednisolone with/​without steroid-​sparing agents (e.g. azathioprine); (2)  early-​onset seropositive disease—​some patients benefit from thymectomy, with prednisolone and azathioprine in- dicated for those who do not, and other immunosuppressants in those who are refractory; (3) late-​onset, anti-​MuSK, and seronega- tive diseases—​most respond to immunosuppression; (4) myasthenic crisis—​supportive care with intubation and assisted ventilation may be required; plasma exchange and intravenous immunoglobulin may both lead to rapid improvement. Overall prognosis is good, with over 90% achieving near-​normal functional recovery. Lambert–​Eaton myasthenic syndrome A presynaptic disorder, associated with small-​cell lung cancer in c.60% of cases, caused by the presence of antibodies that reduce the number of functional presynaptic P/​Q-​type voltage-​gated cal- cium channels. The condition is characterized by limb-​girdle weak- ness and symptoms of autonomic dysfunction. Pyridostigmine may offer some symptomatic benefit, but 3,4-​diaminopyridine is more effective and the drug of choice. For those with inadequate symp- tomatic benefit, immunosuppression, as for myasthenia gravis, is in- dicated. In cancer-​associated disease, removal of the tumour often leads to improvement; immunosuppression can be effective when an associated cancer is unlikely. Other conditions These include (1) congenital myasthenic syndromes—​usually auto- somal recessive; various forms include presynaptic, endplate acetyl- cholinesterase deficiency, and postsynaptic; (2) neuromyotonia—​may be idiopathic, but recognized associations include tumour and ac- quired demyelinating polyneuropathies; the main clinical features are muscle stiffness, cramps, and twitching; electromyography shows highly characteristic features; most patients gain symptomatic relief from carbamazepine, phenytoin, or lamotrigine. Neuromuscular transmission Anatomically there are three main components to the neuro- muscular junction (Fig. 24.18.1). The presynaptic component is the motor nerve terminal, which contains packages (quanta) of acetylcholine, each of which contains several thousand molecules of acetylcholine. This is separated from the postsynaptic acetyl- choline receptors, which sit atop the terminal expansions of the junctional folds of the muscle fibre membrane, by the synaptic space. The nerve fibre membrane contains voltage-​gated sodium, potassium, and calcium channels. Voltage-​gated sodium channels are also present postsynaptically, at the base of the clefts of the junctional folds. The nicotinic acetylcholine receptor is a pentameric structure composed of four different subunits—​α, β, γ, and δ in fetal muscle, 24.18 Disorders of the neuromuscular junction David Hilton-​Jones and Jacqueline Palace section 24  Neurological disorders 6296 and α, β, ε, and δ in adult muscle. It is configured to produce a cen- tral ion channel. Depolarization of the motor nerve terminal is dependent on voltage-​gated sodium channels. Repolarization is the result of in- activation of these sodium channels and opening of voltage-​gated potassium channels. During depolarization, voltage-​gated calcium channels open—​the influx of calcium ions into the nerve terminal triggers release (by exocytosis) of quanta of acetylcholine. The acetylcholine binds to the interfaces between the α and γ and α and ε subunits of the acetylcholine receptors. This alters the conformation of the channel, allowing cations (mainly sodium) to enter the muscle fibre. This influx generates the endplate poten- tial, which in turn activates voltage-​gated sodium channels. These trigger the action potential that is propagated away from the neuro- muscular junction, along the muscle fibre, and initiates contraction. Spontaneous release of individual quanta of acetylcholine, as op- posed to the multiple release triggered by a nerve action potential, gives rise to miniature endplate potentials, which can be recorded by a microelectrode inserted into the muscle fibre. These are of insufficient amplitude to trigger an action potential in the muscle fibre membrane. The action of acetylcholine on acetylcholine receptors is termin- ated by the hydrolysis of acetylcholine by the enzyme acetylcholin- esterase, which is anchored to the basal lamina by a collagen-​like molecule, ColQ (see Fig. 24.18.1). The acquired neuromuscular junction disorders are associated with antibodies directed against one of the ion channels (Table 24.18.1). The fact that there are three autoimmune disorders known to affect such a small region may be explained by the neuromuscular junction, unlike the peripheral nerve, not being contained within the blood–​ nerve barrier, which stops just short of the nerve terminal, and thus being potentially exposed to circulating humoral attack. The inherited disorders may affect presynaptic processes (acetylcholine resynthesis, packaging, or release), acetylcholinesterase binding, or postsynaptic function (acetylcholine receptor numbers or localization). Pathogenic mechanisms are considered in more detail when discussing individual disorders. Myasthenia gravis This is by far the most common of the conditions discussed in this chapter and it responds favourably to treatment. In general, over 90% of patients can be returned to normal function, although in most this represents a pharmacological remission and the patient remains dependent on treatment. Epidemiology All ethnic groups are affected. The annual incidence is about 10 per million population, and the prevalence about 8 per 100 000. All ages may be affected. There is a marked female bias in patients below age 40 years, who are often HLA B8-​DR3, whereas over the age of 50 years men predominate, and myasthenia is increasingly recognized in very elderly people. A rather different pattern is seen in people of Asian origin; prepubertal onset is very common, the disease is often purely ocular, and there is a strong association with HLA DRw9. Pathogenesis The fundamental disorder in myasthenia gravis is loss of functional acetylcholine receptors, which in most cases is a result of binding of anti-​acetylcholine receptor (anti-​AChR) antibodies. High-​ affinity immunoglobulin IgG class antibodies can be detected, by the standard assay used for diagnostic purposes, in 85% of patients with generalized myasthenia and about half of those with purely ocular myasthenia (so-​called seropositive cases). Antibodies bind to the main immunogenic region of the α subunits of the acetylcho- line receptor, and also to other sites on the surface of the receptor. δ α ε α β (b) Muscle fibre Acetylcholine receptors Nerve terminal Voltage-gated sodium channels Axon Voltage-gated potassium channels Acetylcholine Voltage-gated calcium channels (a) Fig. 24.18.1  (a) Diagrammatic representation of the neuromuscular junction demonstrating the molecules that are targets for autoimmune and genetic diseases. (b) Cartoon of the organization of the subunits of the nicotinic acetylcholine receptor. These subunits form a channel in the membrane (central hole), which opens when acetylcholine (ACh) binds. The adult form differs from the fetal form by substitution of the γ subunit with an ε subunit. Antibodies in myasthenia bind to both forms, often to the main immunogenic region on the α subunits. Antibodies in rare cases of fetal arthrogryposis bind to the γ subunit close to the ACh-​binding site. Table 24.18.1  Ion channels responsible for the different clinical disorders Ion channel Clinical disorder Acetylcholine receptor Myasthenia gravis Voltage-​gated calcium channel Lambert–​Eaton myasthenic syndrome Voltage-​gated potassium channel Acquired neuromyotonia 24.18  Disorders of the neuromuscular junction 6297 Patients who do not have antibodies detected by this assay are clas- sified as seronegative. However, there is overwhelming evidence even in these patients that their disease is immune mediated: their clinical characteristics are similar to those of seropositive patients, they respond to plasma exchange and immunosuppressant therapy, their plasma can induce neuromuscular transmission dysfunction when injected into animals, and the infants of such mothers may be born with neonatal myasthenia (see next), indicating transplacental transfer of a humoral component. The last decade has seen the iden- tification of other causative antibodies. In up to one-​half of so-​called seronegative cases there is an anti- body directed against muscle-​specific tyrosine kinase (MuSK) which has a role in receptor clustering (see Fig. 24.18.1). The exact pathogenic mechanism in these anti-​MuSK cases remains uncertain but, as noted next, such patients have a rather characteristic clin- ical presentation. It has been shown that low-​affinity anti-​AChR or MuSK antibodies, detectable with a cell-​based assay, may be present in those patients with neither AChR nor MuSK antibodies detect- able by the standard assay. The most recent antibody to be recog- nised, although its pathogenic significance is not yet established, is directed against low-​density lipoprotein 4 (Lrp4). Loss of functional acetylcholine receptors by antibody binding is due to complement-​mediated lysis, acceleration of internal- ization and degradation, and blocking of acetylcholine binding. Morphological consequences include widening of the synaptic cleft and a marked reduction of the postsynaptic folds of the muscle fibre membrane. Although the efferent limb of the immune response, described next, has been reasonably well characterized, numerous questions remain to be answered about the afferent limb. Susceptibility to my- asthenia gravis is associated with particular immune response genes with correlation to different haplotypes relating to the age of onset of the disease (particularly HLA B8-​DR3 in younger patients). These observations are not of immediate relevance to routine clinical prac- tice. In contrast, knowledge about involvement of the thymus is rele- vant to classification and management. The thymus has a key role in the process of inducing immune tol- erance, by removal of self-​antigen T-​cell clones, and it is not nor- mally a source of autoantibodies. The acetylcholine receptor is, however, expressed on thymic myoid cells and in early onset, anti-​ AChR antibody-​positive patients there is hyperplasia of the thymic medulla, with germinal centres surrounded by a T-​cell zone. In the germinal centres there is enrichment of acetylcholine receptor-​ specific T cells and B/​plasma cells. On the basis of these observa- tions, and the beneficial response to thymectomy, there seems little doubt that the thymus is involved in the pathogenesis of myasthenia gravis, but exactly how has yet to be elucidated. Identification of the mechanism may well be important in developing immune-​specific treatment. In late-​onset cases and anti-​AChR antibody-​negative patients, the thymus is typically much less abnormal or atrophic (which is normal in later life), although some pathological changes have been noted. In such cases there is no good evidence of benefit from thymectomy. Patients with anti-​MuSK antibodies show very little thymic path- ology and probably do not benefit from the operation. Thymomas occur in about 10% of cases. They are locally inva- sive (notably affecting the pleura and pericardium) and may seed within the pleural cavity. These patients are almost invariably anti-​ AChR antibody positive. Surgical excision is required because of local tumour invasiveness, but, in contrast to those patients with thymic hyperplasia, this does not usually ameliorate the myasthenic symptoms. Based on the presence or absence of antibodies detected by the routine clinical assay and the state of the thymus gland, five main subgroups of patients can be identified (Table 24.18.2)–​the fifth group being MuSK positive patient. Penicillamine-​induced myas- thenia, which generally recovers after drug withdrawal, is clinically similar to the idiopathic disease and the patients are anti-​AChR anti- body positive. Clinical features Myasthenia gravis causes skeletal muscle weakness, but the most characteristic feature is fatigability. The term ‘fatigue’ causes some confusion because it may have different meanings to a clinician, physiologist, and layperson. Thus, the fatigue of chronic fatigue syndrome is quite different from that of myasthenia. Simply put, fatigue in myasthenia gravis manifests itself by increasing demon- strable weakness, without muscle pain, precipitated by repeated or sustained muscular activity. Symptoms fluctuate from day to day and week to week, which may in part explain the common delay in diagnosis and suspicions as to its genuineness. Other factors that can exacerbate the weakness include heat, emotional factors, menstruation, intercurrent infections, and drugs that interfere with neuromuscular transmission (aminoglycoside antibiotics, quinine, quinidine, β-​blockers, procainamide, and neuromuscular-​blocking drugs related to anaesthesia). In over half of patients, the presenting symptoms relate to extraocular muscle weakness (diplopia and ptosis); these muscles will be involved in over 90% of patients at some stage during the disease. The next most frequent presentation is with limb-​girdle weakness. Typically, as the disease worsens, the weakness spreads from the extraocular muscles to the lower facial and bulbar muscles (causing dysarthria and dysphagia), to the neck, and then to the limbs. However, there are many variations on this theme. A rela- tively common presentation in older patients, typically men, is with selective weakness of neck extension—​as they walk the head drops forwards and they arrive in the clinic holding up the head with a hand under the chin. Relatively selective weakness of finger extension Table 24.18.2  The four main subgroups of myasthenia gravis Age of onset (years) Thymoma Sero-​negative <40 40 Thymus Hyperplasia Atrophy Thymoma ?Normal/​atrophy Anti-​AChR antibody titre High Low Intermediate Absent section 24  Neurological disorders 6298 and abduction is common. In patients with anti-​MuSK antibodies there is a female preponderance, prevalent oculobulbar involvement sometimes with facial muscle and tongue atrophy, often very limited limb involvement, and a high frequency of ventilatory insufficiency. On examination, weakness may or may not be evident—​fatigue can be demonstrated in limb muscles, but is often most striking around the eyes and with respect to bulbar muscles. Fatigable ptosis is a striking sign (Fig. 24.18.2). As the patients give their history, the fatigue of bulbar muscles may be revealed by increasing dys- arthria. A potentially misleading sign is ‘pseudo-​internuclear oph- thalmoplegia’, which may be bilateral—​failure of adduction due to weakness of the medial recti. Eye movements may show striking fatigue. With increasing severity, the weakness at rest may be so marked that it is difficult to demonstrate fatigue. Respiratory muscle weakness may be out of proportion to limb weakness; it is best as- sessed by measuring the forced vital capacity (not peak flow). A fall in blood oxygen saturation is a late sign and should not be used alone to monitor ventilatory function. Muscle wasting is seen only in undertreated patients with long-​established disease, although it is more common in patients with anti-​MuSK antibodies. The tendon reflexes are normal, and indeed often rather brisk. There are no ab- normal sensory signs. There is an increased incidence of other autoimmune diseases, particularly thyroid disease (about 3% of patients) and less fre- quently rheumatoid arthritis, systemic lupus erythematosus, poly- myositis, and acquired neuromyotonia. Coexistence of myasthenia and Lambert–​Eaton myasthenic syndrome has been reported. Natural course This is very variable. In some patients the disorder remains con- fined to the extraocular muscles (ocular myasthenia gravis). If that is the case for more than 2 years, and particularly if the patient is seronegative, the development of generalized disease is unlikely. Older studies, before the introduction of immunosuppressive ther- apies, suggest that the disease reaches maximum severity within 7 years. In one study, the interval between onset and the first episode of maximal weakness (‘myasthenic crisis’) was less than 36 months in over 80% of patients. Permanent spontaneous remis- sion occurs, but is rare—​of the order of 1% per annum. On the other hand, particularly early in the course of the disease, there may be protracted periods of spontaneous remission, sometimes lasting several years. Diagnosis This is based on the clinical picture, supported by appropriate la- boratory results. For practical purposes, a positive anti-​AChR or anti-​MuSK antibody test is confirmatory and no further diagnostic investigations are required. In seronegative patients, electromyog- raphy (EMG) and the intravenous edrophonium (Tensilon) test are helpful. Although the edrophonium test (demonstration of im- provement with a short-​acting cholinesterase inhibitor) has a long pedigree and sound pharmacological basis, there are concerns about its use, particularly by doctors who are inexperienced. The patient is given 600 µg atropine intravenously; this blocks the po- tentially unpleasant muscarinic effects of the edrophonium and also acts as a single-​blind placebo for the patient. The test dose of 2 mg edrophonium follows, which in some patients is sufficient to give a diagnostic response. If not, a further 8 mg edrophonium is given. There must be an easily assessable measure of improvement—​most commonly degree of ptosis. The test is therefore likely to be of most use in patients with purely ocular symptoms and signs. Rarely, car- diorespiratory collapse may occur. False-​negative and false-​positive results are not uncommon. The conventional EMG measure for diagnosing myasthenia gravis is the demonstration of a decremental response of the compound muscle action potential in response to repetitive nerve stimulation at 3 Hz. More sensitive, but not specific and only available in specialist centres, is the presence of increased jitter and blocking, as assessed by single-​fibre EMG. The presence of a thymoma can be assessed only by CT or MRI of the thorax. Differential diagnosis There are few difficulties in the presence of extraocular muscle in- volvement and readily demonstrable fatigue, although there can be confusion with Lambert–​Eaton myasthenic syndrome and con- genital myasthenic syndromes. Diagnostic difficulties can occur when, as occasionally happens, eye signs and fatigue are absent. Amyotrophic lateral sclerosis with little wasting may be suspected. Conversely, in long-​established myasthenia, muscle wasting may be misleading. More difficult is seronegative, purely ocular myas- thenia; the most important differential diagnosis is mitochondrial cytopathy, in which increased jitter may also occur. Other diagnoses to consider include oculopharyngeal muscular dystrophy and thy- roid ophthalmopathy. (a) (b) Fig. 24.18.2  (a, b) Fatigable ptosis in myasthenia gravis. 24.18  Disorders of the neuromuscular junction 6299 Botulism, caused by food poisoning, an infected wound, or clos- tridial overgrowth in the gastrointestinal tract in infants, may need to be considered. Features of autonomic malfunction are usually present. Treatment There is no universally agreed approach to treatment, but basic guidelines to help clinicians without extensive experience of managing myasthenia have been published recently. As noted, thymomas require excision, but this in itself will not im- prove the myasthenia. Subsequent management of the myasthenia in patients with thymic tumours is as for those with myasthenia without a thymoma. Anticholinesterase drugs, by reducing acetylcholine breakdown, give symptomatic improvement in most patients, and may be suffi- cient in those with very mild disease. Pyridostigmine is the drug of choice, given orally four or five times daily, starting at 30 mg/​dose and increasing if required to 60 mg/​dose with a maximum dose of 360 mg/​day. Abdominal cramping is a common side effect, relating to muscarinic overstimulation, and responds to propantheline, ideally taken 30 min before each dose of pyridostigmine. If an ad- equate response is not obtained at this dose of pyridostigmine, further increases should not be made and other forms of therapy should be considered. The management of ocular myasthenia differs somewhat from the generalized form of the disease, the latter also depending on age of onset and antibody status. Ocular myasthenia If anticholinesterase drugs have given an inadequate response, alternate-​day prednisolone therapy should be introduced. A suit- able starting daily dose is 5 mg, increasing by 5 mg every fourth dose (or weekly) until an adequate response has been obtained (often, for an adult, a dose of around 30 mg) or a maximum acceptable dose (around 0.75 mg/​kg body weight) has been reached. Once remis- sion has been achieved, the pyridostigmine can be withdrawn, and then the prednisolone reduced slowly—​initially by 5 mg/​month, but when down to 20 mg by as little as 1 mg/​month). Azathioprine (see next) may be added if there is an inadequate response or the min- imal effective dose of prednisolone is deemed to be unacceptably high. Ocular muscle surgery can be beneficial if there is a poor or in- complete response to treatment and if the defect appears to be fixed. Early-​onset seropositive myasthenia Many, but not all, of these patients benefit from thymectomy, as con- firmed in the recent international thymectomy trial. Up to one-​third enter remission, and a further one-​half improve if given immunosup- pressive treatments. These benefits are occasionally rapid, but more typically develop over the following 1–​2 years, possibly longer. The conventional approach was through a sternal split, but among the population most likely to be considered for surgery, young women, the cosmetic implications meant that many would not consider it. In most major centres, the preferred approach is now through video-​ assisted surgery, with or without a robot, including in some cases removal of a thymoma. The limited available evidence, but also con- siderable anecdotal experience, suggests that this ‘keyhole’ approach is as effective as the conventional approach, despite theoretical con- cerns that aberrant thymic tissue may be left behind by the less in- vasive approach. Thymectomy should only be performed in centres experienced in such surgery and with the support of appropriately trained anaesthetists and neurologists. For those patients who do not respond adequately to anticholinesterase drugs and thymectomy, immunosuppression is indicated. Introduction of prednisolone may exacerbate myasthenic weakness and should generally be done in hospital. The starting dose is 10 mg on alternate days, increasing by 10 mg/​dose until the patient reaches the target dose of 1.5 mg/​kg body weight per dose, or in an adult, a maximum dose of 100 mg on alternate days. When remission has been achieved the dose is slowly reduced, as for ocular myas- thenia, until the minimal effective dose has been established. A con- trolled trial has shown the benefits of the addition of azathioprine (2.5 mg/​kg body weight per day); the starting dose is 25 or 50 mg daily, increased by 25 or 50 mg daily, each week (or more rapidly as an inpatient) until the target dose is reached. During introduc- tion, weekly tests of full blood count and liver function are required. When established, testing can be reduced gradually to 3 monthly. When available, thiopurine methyltransferase (TPMT) activity ana- lysis may be used to identify those at risk of azathioprine toxicity, but even in low-​risk patients there should be regular haematological monitoring. Azathioprine takes more than 6 months to take max- imal effect, after which time it may be possible to reduce prednis- olone to a minimum. Some specialists introduce azathioprine at the same time as starting prednisolone in all patients with generalized disease, whereas others add it later if it is clear that the dose of pred- nisolone required to achieve admission is unacceptably high. For those who do not respond to, or are intolerant of, prednis- olone and/​or azathioprine, other immunosuppressant drugs, such as ciclosporin, methotrexate, mycophenolate mofetil, and cyclophos- phamide, may be used. Despite many anecdotal reports of benefit, the role of rituximab remains uncertain. Late-​onset myasthenia This form of myasthenia is increasingly recognized with many cases, of both sexes, presenting over the age of 70 years. Although not for- mally assessed, it appears that these patients do not benefit signifi- cantly from thymectomy. Most respond to the immunosuppressant regimen described earlier. Anti-​MuSK and seronegative myasthenia Patients with such a myasthenia do not appear to respond to thym- ectomy. Seronegative myasthenia generally responds well to the immunosuppressant regimen outlined earlier. Patients with anti-​ MuSK antibodies may be more resistant to anticholinesterases and immunosuppression than anti-​AChR-​positive patients, and other immunosuppressant drugs may be required. Treatment–​resistant myasthenia Some patients prove to be very resistant to prednisolone and con- ventional immunosuppressant drugs. Recent evidence has shown that some, but certainly not all, will respond to rituximab. This may be particularly true for anti-​MuSK myasthenia. There remains con- cern about possible long-​term side-​effects, including progressive multifocal leucoencephalopathy. Myasthenic crisis Intubation and assisted ventilation may be required. Plasma ex- change and intravenous immunoglobulin may both lead to a rapid section 24  Neurological disorders 6300 improvement (within 1–​2 weeks) in strength, but the beneficial effects start to wear off within about 8 weeks. However, this gives useful time in which to establish an immunosuppressant regimen, as discussed earlier. Plasma exchange and intravenous immunoglobulin are also useful in preparing myasthenic patients for thymectomy and may reduce the likelihood of deterioration consequent upon the intro- duction of prednisolone. Osteoporosis is an important concern in patients receiving long-​term, high-​dose prednisolone. Management guidelines differ depending upon age, sex, and coexistent morbidity. Local guidelines should be followed with respect to bone density scanning and use of calcium, vitamin D, and bisphosphonates and related drugs. Prognosis The outlook for most patients with myasthenia is good, with over 90% achieving near-​normal functional recovery. Death is most likely to occur during a myasthenic crisis early on in the course of the disease. The response to thymectomy has been noted. Unwanted effects relating to the immunosuppressant drugs may have an im- portant influence on the outcome. Myasthenia in pregnancy Recent ‘best practice’ guidelines have been published and should be of help to both clinicians and patients. Pregnancy has no significant long-​term effect on myasthenia, but relapse may be more common in the puerperium. Some 10% of infants born to myasthenic mothers have transient neonatal myasthenia due to transplacental passage of maternal anti-​AChR antibodies. Symptoms include feeding and respiratory difficulties, generalized weakness, and, less commonly, ptosis. They resolve within a few weeks. Immunosuppressive treatment with prednisolone or azathioprine, and probably ciclosporin, should be maintained during pregnancy to ensure good control of the mother’s myasthenia and to reduce the likelihood of neonatal weakness. There is no evidence of sig- nificant teratogenicity or other harmful effects on the fetus from these drugs, although appropriate preconception counselling is es- sential. Similarly, breastfeeding is not contraindicated for women taking these drugs. Methotrexate is contraindicated for women and men attempting to conceive. Recent evidence suggests that mycophenolate mofetil may be associated with a specific fetal malformations. Much more rarely, the infant is born with arthrogryposis multi- plex congenita, secondary to profound intrauterine weakness and lack of movement. This relates to maternal antibodies that target the fetal form of the acetylcholine receptor, which is present at the neuromuscular junction until the last weeks of pregnancy, and in some cases the mother herself has been asymptomatic. Future research This may provide a better understanding of the immune processes involved, and thus lead to the development of selective treat- ments that avoid generalized immune suppression or other un- wanted effects of the currently available drugs. Recently there have been many reports that rituximab may be of benefit in patients with myasthenia, including those resistant to more conventional immunosuppressant regimes and particularly those with MuSK myasthenia. However, on current evidence it cannot be recom- mended as first-​line treatment and further studies are required. Lambert–​Eaton myasthenic syndrome Lambert–​Eaton myasthenic syndrome is a presynaptic disorder, characterized by limb-​girdle weakness and symptoms of autonomic dysfunction, which is often associated with small-​cell lung cancer. Delayed diagnosis is common. Symptomatic and immunosuppres- sant therapies are available. Epidemiology Some 60% of patients have cancer-​associated Lambert–​Eaton myasthenic syndrome, usually caused by small-​cell lung cancer and much more rarely by other tumours; in these cases the peak pres- entation is in the fourth to sixth decades. The other 40% have non-​ cancer-​associated Lambert–​Eaton myasthenic syndrome and may present from childhood onwards. It is estimated that 3% of patients with small-​cell lung cancer develop Lambert–​Eaton myasthenic syn- drome, but that the diagnosis is frequently not made. The weakness is often attributed to non​specific cachectic effects and the disorder is neither suspected nor investigated. Lambert–​Eaton myasthenic syndrome, similar to many other paraneoplastic disorders (see Chapter  24.23), may predate the appearance of the cancer by as much as 5 years. Pathogenesis Both forms are associated with IgG class antibodies, which reduce the number of functional presynaptic P-​/​Q-​type voltage-​gated cal- cium channels by cross-​linking adjacent channels. This causes re- duced calcium influx and therefore reduced quantal release of acetylcholine. As in myasthenia, patients with Lambert–​Eaton myasthenic syndrome have an increased incidence of other forms of autoimmune disease, including a rare association with acquired myasthenia gravis. Small-​cell lung cancers express voltage-​gated calcium channelss and it is proposed that the tumour triggers an antibody response to those channels; the antibodies then cross-​react with the calcium channels at the neuromuscular junction, causing Lambert–​Eaton myasthenic syndrome. Clinical features Most patients present with an abnormality of gait and complain that their legs feel heavy or weak. Symptomatic upper limb weakness tends to present later. Autonomic dysfunction is common, but infre- quently volunteered, and includes dryness of the mouth and consti- pation. In men, impotence may predate limb weakness. Compared with myasthenia gravis, ocular symptoms are rarely severe or par- ticularly troublesome, and bulbar weakness is rare. On examination, mild ptosis and diplopia may be evident. The ab- normality of gait is often more striking than demonstrable weakness when testing on the examination couch. This is partly because of the phenomenon of postexertional potentiation. Physiologically, with sustained effort, there is mobilization of nerve calcium stores and consequently increased quantal release of acetylcholine. Clinically, this augmentation is apparent in two ways: first, strength increases after a few seconds of maximal effort; second, the tendon reflexes, 24.18  Disorders of the neuromuscular junction 6301 which are reduced or absent, increase or appear following 10–​15 s of maximal contraction of the relevant muscle. Sensory testing is normal. Diagnosis Single-​fibre electromyography, as in myasthenia gravis, shows in- creased jitter and blocking, and repetitive nerve stimulation studies show decrement at certain frequencies. However, the characteristic neurophysiological finding, which reflects the clinical observa- tions made earlier, is of a small-​amplitude compound muscle ac- tion potential that shows potentiation, sometimes enormous, 15 s after voluntary maximal contraction. Diagnosis is confirmed by demonstrating the presence of anti-​voltage-​gated calcium channels antibodies, which are detectable in up to 90% of cases. Treatment Pyridostigmine may offer some symptomatic benefit, but 3,4-​ diaminopyridine is generally more effective. 3,4-​Diaminopyridine blocks the voltage-​gated potassium channels (see Fig. 24.18.1), thereby prolonging the duration of the nerve action potential, re- sulting in a greater influx of calcium. The maximum dose of 3,4-​ diaminopyridine is 100 mg daily. If the symptomatic response is inadequate then treatment with alternate-​day prednisolone (up to 1.5 mg/​kg body weight per dose) and azathioprine (2.5 mg/​kg body weight per day), as in myasthenia gravis, can be highly effective cancer-​associated and non​cancer-​ associated Lambert–​Eaton myasthenic syndrome, but in the former group use of such drugs must be discussed with the oncologists. In a smoker in whom a cancer is not identified at presentation, it is prudent to repeat chest imaging (CT or MRI) yearly for 5 years. In cancer-​associated Lambert–​Eaton myasthenic syndrome, re- moval of the tumour often leads to symptomatic improvement. Plasma exchange and intravenous immunoglobulin both give short-​term benefit and can be used in cancer-​associated and non-​ cancer-​associated Lambert–​Eaton myasthenic syndrome. Prognosis In cancer-​associated Lambert–​Eaton myasthenic syndrome, the prognosis is largely determined by the tumour. In non​cancer-​ associated Lambert–​Eaton myasthenic syndrome many patients can be rendered asymptomatic, but some prove very resistant to treatment. Congenital myasthenic syndromes This is a rare group of conditions with an overall prevalence in the United Kingdom of around 1 in 200 000 people. However, some areas have a prevalence as high as 1 in 70 000, reflecting diagnostic variation as well as the effects of racial composition and familial clustering. Congenital myasthenic syndrome (CMS) is a genetic- ally determined (usually autosomal recessive—​so a history of con- sanguinity is common), non-​autoimmune disorder. Major clinical features include onset in infancy, fatigable weakness, a decremental response to repetitive nerve stimulation, and absence of AChR or MuSK antibodies. A significant exception to this generalization is the classic slow-​channel syndrome, which may present in infancy or adult life, and is inherited as an autosomal dominant trait. The syndromes may be classified on the basis of the site of the defect of neuromuscular transmission, but this is not always certain. A re- vised classification is evolving based on the molecular mechanisms identified. Diagnosis depends on electrophysiological tests, the clin- ical phenotype and response to treatment, and in around 80–​90% cases on identification of the specific genetic defect. Presynaptic disorders These are the least well characterized of the myasthenic disorders. They include disorders of acetylcholine resynthesis caused by cho- line acetyltransferase (ChAT) mutations resulting in reduced ACh release. ChAT CMS is characterized by episodic apnoeas in early life and symptoms respond to anticholinesterase drugs. Endplate acetylcholinesterase deficiency Mutations in the acetylcholinesterase collagen-​like tail subunit gene (COLQ), which is responsible for anchoring acetylcholinesterase to the basal lamina, affects the normal termination of neuromuscular transmission. The consequent prolonged endplate potentials lead to a desensitization of the AChRs and depolarization blockade and an additional secondary excitotoxic myopathy. Characteristic features such as a repetitive compound muscle action potential in response to a single stimulus and a slow pupillary response to light are re- ported in a minority. Severe and progressive muscle weakness is usually evident from birth or early infancy although milder pheno- types are reported. Anticholinesterase drugs, not surprisingly, are ineffective but ephedrine or oral salbutamol can improve symptoms. Postsynaptic disorders These disorders are associated with mutations in the genes that en- code the AChR subunits or associated AChR-​clustering proteins. They may affect the number of receptors, the receptor-​presenting area, or the kinetic properties of the central ion channel. The most common disorder in the United Kingdom is acetylcho- line receptor deficiency, which is most frequently caused by muta- tions in the ε-​subunit gene. Presentation is at birth or within the first few years of life. There is generalized weakness, delayed motor milestones, feeding difficulties, and extraocular muscle involve- ment. There is a good response to anticholinesterase drugs and 3,4-​diaminopyridine. The fast-​channel syndrome is phenotypically similar to acetyl- choline receptor deficiency and may be associated with α-​, δ-​, or ε-​subunit mutations. The mechanism is altered kinetics of the re- ceptor ion channel. The slow-​channel syndrome is also a kinetic disorder that can be associated with mutations in any of the adult AChR subunits. As in endplate acetylcholinesterase deficiency it causes a desensitiza- tion blockade and electromyography may show a repetitive response to a single nerve stimulus. This overstimulation of muscle and the prolonged endplate potentials lead to a secondary excitotoxic my- opathy. Slow-​channel disorder is an autosomal dominant condition with variable penetrance and may remain subclinical. In adult life it may present with progressive weakness, characteristically affecting finger extensors and thumb abductors. Anticholinesterase drugs are unhelpful, but quinidine or fluoxetine may be beneficial. Mutations in rapsyn, an AChR-​clustering protein, is associ- ated with a common mutation (N88K), thus aiding screening. The rapsyn defect leads to reduced numbers of clustered AChRs. This section 24  Neurological disorders 6302 condition usually presents in infancy and is characterized by squint without limitation of eye movements and mild resolving joint con- tractures. Such children often have unexplained and acute crises in muscle weakness, and bulbar and respiratory function, and the diagnosis is crucial because this phenotype responds so well to anticholinesterases. Occasionally adulthood-​onset cases are de- scribed with a very mild phenotype. DOK7 mutations have been recently described in cases of CMS with a limb-​girdle phenotype, and normal eye movements in most cases. DOK7 is a postsynaptic protein that interacts with MuSK. This disorder generally responds poorly to anticholinesterases, but over months often improves markedly when ephedrine or oral sal- butamol is given. Recently, mutations in glutamine-​fructose-​6-​phosphate transaminase 1 (GFPT1) and dolichyl-​phosphate (UDP-​N-​ acetylglucosamine) N-​acetylglucosaminephosphotransferase 1 (DPAGT1) genes have been identified in patients with a limb-​girdle CMS associated with tubular aggregates on muscle biopsy. These have relative sparing of ocular, facial, and bulbar muscles, tend to present after infancy (in early childhood), respond to anticholinesterases and 3,4-​DAP may give additional benefit. AChR deficiency syndromes caused by AChR ε-​subunit or rapsyn mutations and DOK7 mutations make up more than 75% of all gen- etically confirmed cases of CMS in the United Kingdom and thus initial diagnostic screening focuses on these three genes. Neuromyotonia This term describes a condition in which peripheral nerve over- activity leads to spontaneous muscle activity. It is thus quite different from classic myotonia, which relates to an abnormality of muscle fibre membrane activity. Neuromyotonia may be seen in association with a variety of inherited disorders (notably neuropathies and spinal muscular atrophy), but the most common form is acquired; this form may be idiopathic, but recognized associations include tumour (thymoma—​sometimes also in association with myas- thenia gravis; bronchial carcinoma) and acquired demyelinating polyneuropathies. Most acquired cases are autoimmune in origin and about 50% have antibodies directed against voltage-​gated potas- sium channels in the peripheral nerve (see Fig. 24.18.1), for which an assay is now available. As noted earlier, activation of these chan- nels is an important factor in nerve repolarization—​the symptoms of neuromyotonia can be understood in terms of reduced numbers of potassium channels, prolonged depolarization, and excessive re- lease of acetylcholine. The main clinical features are muscle stiffness, cramps, and twitching (myokymia), which may be localized or generalized. Voluntary muscle contraction may precipitate or exacerbate the abnormal activity. The myokymia persists during sleep and gen- eral anaesthesia. Additional symptoms include peripheral paraes- thesias and excess sweating, and, rarely, mood change, disturbed sleep, and hallucinations. These central symptoms are part of a con- dition called Morvan’s syndrome which is discussed elsewhere (see Chapter 24.24). Apart from the muscle twitching (which may be confused with the fasciculation of denervation), physical examination may be normal. Mild weakness may be evident, proximally or distally. In long-​standing cases, muscle hypertrophy (simply a form of work hypertrophy) may be present. Tendon reflexes may be reduced. Electromyography shows highly characteristic, and diagnostic, doublet, triplet, or multiplet motor unit discharges, or periods of continuous motor unit discharge, with a high (up to 300 Hz) intraburst frequency. Fibrillation and fasciculation potentials may also be seen. Further confirmation of the diagnosis comes from anti-​ voltage-​gated potassium channels antibody assay, which is positive in about 50% of cases using the currently available assay. Chest imaging should be considered to exclude thymoma and bronchial carcinoma. Most patients gain symptomatic relief from carbamazepine, phenytoin, or lamotrigine. If the benefit is insufficient, immunosup- pression with prednisolone and azathioprine is often helpful. FURTHER READING Neurobiology of myasthenic syndromes Vincent A (2007). Myasthenia gravis and myasthenic syndromes. In: Gilman S (ed) Neurobiology of disease. Elsevier Academic Press, Burlington, MA. Myasthenia gravis Benveniste O, Hilton-​Jones D (2010). The role of rituximab in the treatment of myasthenia gravis. European Neurological Review, 5, 95–​100. Evoli A, et  al. (2003). Clinical correlates with anti-​MuSK anti- bodies in generalized seronegative myasthenia gravis. Brain, 126, 2304–​11. Evoli A, et al. (2010). Autoimmune and inherited disorders of neuro- muscular transmission. In: Karpati G, et al. (eds) Disorders of volun- tary muscle. Cambridge University Press, Cambridge. Higuchi O, et al. (2011). Autoantibodies to low-​density lipoprotein receptor-​related protein 4 in myasthenia gravis. Ann Neurol, 69, 418–​22. Norwood F, et  al. (2014). Myasthenia in pregnancy:  Best practice guidelines from a UK multispeciality working group. J Neurol Neurosurg and Psych, 85, 538–​43. Sussman J, et  al. (2015). Myasthenia gravis:  Association of British Neurologists’ management guidelines. Pract Neurol, 15, 199–​206. Lambert–​Eaton syndrome Maddison P, Newsom-​Davis J (2005). Treatment for Lambert–​Eaton myasthenic syndrome. Cochrane Database Syst Rev, 2, CD003279. Titulaer MJ, et  al. (2011). Clinical Dutch–​English Lambert–​Eaton myasthenic syndrome (LEMS) tumor association prediction score accurately predicts small-​cell lung cancer in the LEMS. J Clin Oncol, 29, 902–​8. Wirtz PW, et al. (2002). Differences in clinical features between the Lambert–​Eaton myasthenic syndrome with and without cancer: an analysis of 227 published cases. Clin Neurol Neurosurg, 104, 359–​63. Wirtz PW, et al. (2005). Lambert–​Eaton myasthenic syndrome has a more progressive course in patients with lung cancer. Muscle Nerve, 32, 226–​9. Congenital myasthenic syndromes Burke G, et al. (2003). Rapsyn mutations in hereditary myasthenia: distinct early-​ and late-​onset phenotypes. Neurology, 61, 826–​8. 24.18  Disorders of the neuromuscular junction 6303 Chaouch A, et al. (2012). 186th ENMC International Workshop: con- genital myasthenic syndromes. Neuromuscul Disord, 22, 566–​76. Engel AG, Sine SM (2005). Current understanding of congenital myasthenic syndromes. Curr Opin Pharmacol, 5, 308–​21. Engel A, et al. (2015). Congenital myasthenic syndromes. Pathogenesis, diagnosis and treatment. Lancet Neurology, 14, 420–​34. Palace J, et al. (2007). Clinical features of the DOK7 neuromuscular junction synaptopathy. Brain, 130, 1507–​15. Neuromyotonia Hart IK, et al. (2002). Phenotypic variants of autoimmune peripheral nerve hyperexcitability. Brain, 125, 1887–​95. Maddison P (2006). Neuromyotonia. Clin Neurophysiol, 117, 2118–​27. 24.19 Disorders of muscle 6304 24.19.1 Structure a 24.19 Disorders of muscle 6304 24.19.1 Structure and function of muscle 6304 Michael G. Hanna and Enrico Bugiardini 24.19 Disorders of muscle CONTENTS 24.19.1 Structure and function of muscle  6304 Michael G. Hanna and Enrico Bugiardini 24.19.2 Muscular dystrophy  6310 Kate Bushby and Chiara Marini-Bettolo 24.19.3 Myotonia  6328 David Hilton-​Jones 24.19.4 Metabolic and endocrine disorders  6334 David Hilton-​Jones and Richard Edwards 24.19.5 Mitochondrial disease  6343 Patrick F. Chinnery and D.M. Turnbull 24.19.1  Structure and function of muscle Michael G. Hanna and Enrico Bugiardini ESSENTIALS The motor unit—​the final common pathway for all voluntary muscle activity—​is composed of an anterior horn cell, its peripheral axon, the axon terminal branches, the associated neuromuscular junctions, and the muscle fibres innervated. Muscle cells—​these are multinucleate units with unique structures adapted for response to metabolic, nervous, and autocrine signals. Their key elements being (1) sarcolemma—​complex structured pro- teins maintain the integrity of the muscle fibre membrane, which contains specialized regions (motor endplates) by which innervating nerves interact at synapses; (2) contractile components—​biochemical interactions between actin and myosin filaments are initiated by cal- cium ions released from the sarcoplasmic reticulum; contraction is powered by chemical energy released by the hydrolysis of adenosine triphosphate, in globular regions of myosin, after they form crosslinks with actin. Different types of motor units—​there are two biochemical variants (1) type 1—​rich in mitochondria and specialized for oxidative me- tabolism of fat; (2) type 2—​larger fibres with abundant glycogen that generate energy by glycosis and are critical for short-​lived muscle contraction. All muscles contain populations of both fibre types, but differ in their proportions and functions. Clinical perspective—​knowledge of the underlying molecular cell biology, neurophysiology, and biochemical energetics of muscle provides a useful basis for understanding the symptoms, signs, and pathogenesis of clinical disorders affecting the muscles. Mutations in sarcolemmal proteins, such as dystrophin, cause diseases with widespread effects on skeletal muscle function, the heart, and survival. Basic anatomy of skeletal muscle We possess more than 150 voluntary (skeletal) muscles, most of which are attached to the skeleton at both ends through tendons. Complex voluntary movements of the body are achieved by inte- grated activity of different skeletal muscle groups. To the naked eye a transverse section of any skeletal muscle reveals small units known as muscle fascicles. Each skeletal muscle fascicle is com- posed of many basic structural units known as muscle fibres (Fig. 24.19.1.1). Muscle fibres are cylindrical structures that may be several centimetres long and 50–​100 µm in diameter. A muscle fibre is a highly specialized cell. Similar to any other cell it has a mem- brane (the sarcolemma), contains cytoplasm (the sarcoplasm), and has an endoplasmic reticulum (the sarcoplasmic reticulum), as well as other subcellular organelles such as mitochondria. However, un- like cells from many other tissues, muscle cells are multinucleate. Typically, the nuclei are positioned at the edges of the muscle fibre. The sarcolemma of muscle fibres possesses specialized regions known as motor endplates. These endplate regions are the points at which the axon innervating a muscle fibre forms synapses. Release of acetylcholine from the presynaptic region trans- mits the axonal action potential to the muscle fibre membrane by binding to postsynaptic acetylcholine receptors located in the sarcolemma at the endplate. The sarcolemma is differentially per- meable to ions. This allows different concentrations of ions to be maintained inside and outside the membrane, and is critical in maintaining the resting membrane potential. A chain of important structural proteins maintains the integrity of the sarcolemma by linking intracellular muscle fibre cytoskeletal proteins to the extra- cellular matrix. These structural proteins include dystrophin (lo- cated in a subsarcolemmal distribution), the dystrophin-​associated glycoprotein complex (a trans-​sarcolemmal protein complex), and 24.19.1  Structure and function of muscle 6305 laminin (located extracellularly). These important proteins may be dysfunctional in certain forms of genetic muscle diseases (see Chapter 24.19.2). After staining, or if suitably illuminated, muscle fibres are seen to have regular cross-​striations that extend right across the inside of the fibre, dividing it up into sarcomeres (see Fig. 24.19.1.1). The parts of the cross-​striations are identified by letters:  the light I band is divided by the dark Z line and the dark A band has the lighter H zone in its centre. The region between two ad- jacent Z lines is called a sarcomere. The cross-​striations are due to the presence of the principal contractile filamentous proteins, actin, and myosin, in the sarcoplasm. These filamentous proteins are arranged in rod-​like structures known as myofibrils. A single myofibril contains many protein filaments. In life, myofibrils are transparent on routine light microscopy, but, if viewed with a po- larizing microscope, a typical pattern of cross-​striations can be seen within individual myofibrils. The correct understanding of the basic microscopic anatomy of this pattern of cross-​striations was critical to the discovery of the sliding filament theory of skel- etal muscle contraction. The sliding filament theory of skeletal muscle contraction The protein filaments contained within myofibrils are of two types: the thin filaments are composed of actin, tropomyosin, and troponin, and the thick filaments of myosin (Fig. 24.19.1.2). The thick filaments are approximately twice the diameter of the thin filaments. The thick filaments are lined up to form the A bands, whereas the array of thin filaments forms the less dense I bands. The lighter H bands in the centre of the A bands are the regions where, when the muscle is relaxed, the thin filaments do not overlap the thick fila- ments. The Z lines transect the myofibrils and connect to the thin filaments. If a transverse section through the A band is examined under the electron microscope, each thick filament is found to be surrounded by six thin filaments in a regular hexagonal array (see Fig. 24.19.1.2). The myosin molecules have large globular heads at their C-​terminal portions (Fig. 24.19.1.3), and the heads contain an actin-​binding site that hydrolyses adenosine triphosphate (ATP). During muscle contraction, cross-​linkages occur between the heads of the myosin and the actin molecules (Fig. 24.19.1.3). The thin filaments are composed of two chains of actin that form a long double helix. Tropomyosin molecules are long filaments lo- cated in the groove between the two chains of actin. Troponin molecules are small globular units located at intervals along the tropomyosin molecules. Troponin has three components: troponin T, responsible for binding to tropomyosin; troponin I, which in- hibits the interaction of actin and myosin; and troponin C, which contains the binding sites for the Ca2+ ions that initiate contraction (see Fig. 24.19.1.3). The process by which shortening of the contractile elements of muscle is brought about is sliding of the thin filaments over the thick filaments. The width of the A band is constant, whereas the Z lines move closer together when the muscle contracts and further (a) Tendon 50–100 µm 1–2 µm 0–8 µm 1–5 µm 0–8 µm Muscle fibre Tendon Whole muscle (b) Muscle fibre Fibrils (c) Isolated myofibril (d) I band A band I band Z line H zone Z line Myofibril showing band-pattern at resting length Diameter 50 Å (5 nm) Diameter 100 Å (10 nm) (e) Muscle filaments on same scale at myofibril in (d) Fig. 24.19.1.1  The dimensions and arrangement of the contractile components in a muscle. The whole muscle (a) is made up of fibres (b) that contain cross-​striated myofibrils (c, d). These are constructed of two types of protein filaments (e), put together as shown in Fig. 24.19.1.2. I Z I Z A H Fig. 24.19.1.2  Diagram illustrating the arrangement of the different kinds of protein filament (thick filaments: myosin; thin filaments: actin) in a myofibril. At the top are three sarcomeres drawn as they would appear in longitudinal section. Below are transverse sections through the H zone and other parts of the A band where the thick and thin filaments interdigitate. The plane of section determines whether, in electron micrographs, there seem to be one or two thin (actin) filaments between two thick (myosin) ones. Reprinted from Huxley and Hanson (1972), Copyright © 1972 Academic Press Inc., with permission from Elsevier. section 24  Neurological disorders 6306 apart when it is stretched. The sliding during muscle contraction is produced by breaking and reforming the cross-​linkages between actin and myosin. The immediate source of energy for contraction is hydrolysis of ATP localized to the myosin head. Neural activation of muscle fibres—​the motor unit The motor unit is the final common pathway for all voluntary muscle activity. It is composed of an anterior horn cell (located within the spinal cord), its peripheral axon, the axon terminal branches, the associated neuromuscular junctions, and the muscle fibres innerv- ated. The muscle fibres of a single motor unit are spatially dispersed throughout a muscle and only a few fibres innervated by the same anterior horn cell are contiguous. The number of motor units varies greatly between muscles, from approximately 1000 in leg muscles to 100 in intrinsic hand muscles. The number of muscle fibres per motor unit also varies greatly, and motor units differ in physiological and biochemical characteristics. Two main types of motor units are recognized, each composed of a single muscle fibre type. Type 1 muscle fibres contain many mitochondria and are slightly smaller than type 2 muscle fibres because they contain myofibrils, which are more slender. Type 1 fibres contain a high concentration of oxida- tive enzymes and more fat; type 2 fibres are larger, contain fewer mitochondria, but have a higher concentration of glycogen and en- zymes involved in anaerobic metabolism such as myophosphorylase. All skeletal muscles contain a mixture of both fibre types, typically in a chequerboard pattern when stained appropriately (with the myofibrillar ATPase reaction) and visualized under light micros- copy (Fig. 24.19.1.4). Type 1 fibres are also known as slow fibres because they contract and relax slowly and are abundant in muscles concerned mainly with maintaining posture. In contrast, type 2 fibres contract and relax quickly and are also known as twitch fibres. Type 2 fibres can be further subdivided into type 2a and 2b based on their intensity of staining with myofibrillar ATPase reaction at different pH values (Table 24.19.1.1). Normally muscle fibres do not contract in isolation; rather the muscle fibres that comprise the motor unit contract together in re- sponse to depolarization of an anterior horn cell. Such depolariza- tion is transmitted along the axon until it invades the nerve terminal. This results in opening of voltage-​gated calcium channels located in the presynaptic membrane. Calcium enters the nerve terminal down an electrochemical gradient. The resulting increase in presynaptic calcium concentration promotes fusion of acetylcholine-​containing vesicles normally present in the nerve terminal with the presynaptic membrane. Quanta of acetylcholine are released into the synaptic cleft and diffuse to the postsynaptic membrane to bind to and acti- vate acetylcholine receptors. Acetylcholine binding causes opening of its receptor channel, allowing cations to enter the muscle fibre in the endplate region. This cation flux depolarizes the postsynaptic membrane, resulting in a mini-​endplate potential. The summation of endplate potentials results in the excitation of the postsynaptic membrane, which is then conducted along the muscle fibre mem- brane. The excitation is transmitted into the muscle fibre by invagin- ations of the sarcolemma known as the T-​tubule system. Activation of calcium channels in the T-​tubule system membrane results in opening of calcium channels in the sarcoplasmic reticulum. Calcium is then released into the muscle fibre cytoplasm, initiating muscle contraction. Myosin I Cross-bridge Tropomyosin Troponin C T Actin ADP + Pi Ca2+ ATP Ca2+ Ca2+ Ca2+ Myosin I C T Fig. 24.19.1.3  Initiation of muscle contraction by Ca2+ ions. The cross-​bridges (heads of myosin molecules) attach to binding sites on actin (striped areas) and swivel when tropomyosin is displaced laterally by binding of Ca2+ ions to troponin C. Source data from Katz AM, 1975, Congestive heart failure. New England Journal of Medicine 293, 1184; 1184–1191. Fig. 24.19.1.4  A transverse section of human skeletal muscle obtained by biopsy from a patient with spinal muscular atrophy stained for the myofibrillar ATPase reaction after preincubation at pH 4.6. There is extensive evidence of fibre type grouping, particularly of the type 1 fibres, resulting from reinnervation. Magnification ×150. Kindly supplied by Dr Margaret Johnson. 24.19.1  Structure and function of muscle 6307 Energy production in skeletal muscle Resting skeletal muscle requires remarkably little energy, but the need for energy production may increase dramatically in response to ex- ercise, because energy is required for muscle contraction. ATP is the main source of energy in muscle. It is required for shortening of the contractile filaments and for the active reuptake of calcium into the sarcoplasmic reticulum after each muscle contraction. Maintenance of electrochemical gradients across the sarcolemma also requires ATP. Resynthesis of ATP from adenosine diphosphate (ADP) is es- sential for normal muscle function. The two main energy-​producing pathways in muscle are glycolysis in the sarcoplasm and oxidative phosphorylation in the mitochondria. Resynthesis of ATP from ADP is also aided by phosphocreatine and the creatine kinase reaction. Creatine kinase catalyses the transfer of high-​energy phosphate from phosphocreatine to ADP in circumstances in which ATP demand may outstrip ATP production (e.g. at the very start of exercise be- fore oxidative phosphorylation or glycolysis is activated). Glycolysis is the main pathway of ATP synthesis in anaerobic conditions and results in the generation of lactate. Oxidative phosphorylation is the major ATP-​generating pathway in aerobic conditions. The main fuel sources in skeletal muscle are glucose, glycogen, and fatty acids. In anaerobic conditions, glycogen is the main energy source. In aerobic exercise, glycogen and glucose are utilized initially, but, after approxi- mately 30 min, fatty acids are the main energy source. In resting aer- obic muscle, fatty acids provide the principal source of fuel. Several muscle diseases are recognized in which energy metabolism is im- paired; these are known as the metabolic myopathies. Diseases of human skeletal muscle: overview Human muscle diseases may be conveniently divided into those that are genetically determined and those that are acquired (Box 24.19.1.1). The clinical history in muscle diseases Although a muscle biopsy is usually needed to determine the exact type of muscle disease, the clinical history and examination are usu- ally sufficient to determine whether a muscle disease is present or absent. As many muscle diseases are genetically determined, it is particularly important to consider the family history. A careful drug history is also essential. Although many diseases may affect skeletal muscle (see Box 24.19.1.1), there are three main symptoms with which patients may present: muscular pain, muscular weakness, and fatigability. A further important but less common symptom is darkening of the urine (pigmenturia) due to release of myoglobin from damaged muscle, which occurs particularly in the metabolic myopathies. Unless pigmenturia has been dramatic, patients may not volun- teer this symptom. Muscle pain is a common symptom, but in only about a third of patients presenting with this symptom will an underlying muscle disease be identified. In those without a defin- able muscle disease, many are considered to have a psychogenic Table 24.19.1.1  Histochemical and physiological characteristics of the three major types of muscle fibre Fibre type 1 2A 2B Enzyme reactions NADH–​tetrazolium reductase and SDH +++ ++ + Myofibrillar ATPase: pH 9.4 + +++ +++ pH 4.6 +++ –​ +++ pH 4.3 +++ –​ –​ Phosphorylase + +++ +++ Physiological properties Twitch speeds Slow Fast Fast Fatigue resistance +++ ++ + Nomenclature Peter et al. (1972) Slow twitch Fast twitch Fast twitch Oxidative Oxidative–​glycolytic Glycolytic Burle et al. (1971) S (slow contracting) FR (fast contracting, fatigue resistant) FF (fast contracting, fast fatigue) From Walton JN, Mastaglia FL (1980). Box 24.19.1.1  A simple classification of human muscle diseases Genetically determined muscle diseases • Muscular dystrophies, such as Duchenne/​Becker • Congenital myopathies, such as nemaline • Muscle ion channel disorders, such as hyper-​/​hypokalaemic periodic paralysis • Metabolic myopathies, such as McArdle’s disease (myophosphorylase deficiency) and mitchondrial myopathies Acquired muscle diseases • Inflammatory muscle diseases, such as polymyositis/​dermatomyositis • Degenerative muscle diseases, such as inclusion body myositis • Endocrine muscle diseases, such as hyper-​/​hypothyroid myopathies • Toxic and drug-​induced muscle diseases, due to alcohol/​corticosteroids section 24  Neurological disorders 6308 cause for their muscle pain, although some may have as yet un- defined disorders of muscle metabolism. Sometimes it can be difficult for the patient and the phys- ician to distinguish between pain originating in muscle and that originating in joints or bones. Certain rheumatological diseases may result in joint pain as well as muscle pain (e.g. systemic lupus erythematosus may cause arthritis and polymyositis). Muscle pains may take the form of cramps, which are involuntary con- tractions of muscle groups. Simple muscle cramps are not un- common in older people and frequently occur at night. There is usually no underlying muscle disease but drugs such as diuretics (which induce hypokalaemia) may be implicated. In younger pa- tients, muscle cramps may be the presenting feature of a metabolic muscle disease such as McArdle’s disease. Muscle pain brought on by exertion is a particular feature of the metabolic muscle dis- eases. Muscle contractures may also be a source of muscle pain in patients with metabolic myopathies. Patients experience a pain similar to a cramp, but, unlike a cramp, electromyography reveals that a contracture is electrically silent. Muscle weakness is a common feature of muscle diseases and the distribution of weakness in most of these diseases is in the prox- imal limb muscles. Patients may complain of difficulty performing tasks that involve lifting their arms up to or above the head, such as brushing hair. Proximal lower limb muscle weakness causes diffi- culties getting out of low chairs and in climbing stairs. Muscle dis- eases often affect the limb musculature symmetrically, although there are important exceptions to this (e.g. one of the common autosomal dominant muscular dystrophies), fascioscapulohumeral muscular dystrophy, often affects the limb muscles in an asymmet- rical fashion. Some muscle diseases may affect the facial muscu- lature as well as that of the limb. Symptoms may include difficulty in whistling, closing the eyes, or articulating. Respiratory muscle disease may cause breathlessness. It is important to determine the natural history of muscle weakness. In most genetically determined muscle diseases, weakness progresses slowly over years; occasionally patients may experience attacks of weakness separated by periods when they seem to have normal strength, as in the periodic par- alyses. The muscle weakness in the inflammatory muscle diseases usually develops more rapidly. Fatigability is defined as an increase in weakness with exer- cise. Patients may say that they can start a particular physical ac- tivity but the longer they continue the weaker they become. They may also complain that they become weaker as the day goes on. Myasthenia gravis, a disorder of neuromuscular transmission, is the principal cause of fatigability. In patients with myasthenia gravis, fatigability can usually be demonstrated at the bedside. Patients with metabolic muscle diseases may also experience fatigability. The physical examination in muscle disease The examination may be broadly divided into two aspects:  first, an examination is made to establish whether there are any clues to the cause of the muscle disease. In this context, the general phys- ical examination is very important. Particular attention is paid to eliciting signs that might indicate an underlying endocrine or rheumatological disorder (e.g. signs of hyper-​/​hypothyroidism, Cushing’s syndrome, or rheumatological disorders such as systemic lupus erythematosus). Inspection of the skin may reveal the appear- ances of dermatomyositis. The second part of the examination in- volves examining the muscular system to determine the extent and severity of the condition; this may also give further clues to the aeti- ology. The muscles are inspected for any atrophy or hypertrophy (as occurs in some muscular dystrophies) or for any spontaneous ac- tivity of the muscle fibres (such as fasciculation, which might indi- cate an anterior horn cell disorder). The muscles should be palpated for any tenderness or swelling, which may occur in inflammatory muscle diseases. Myotonia is a delayed relaxation of muscle after contraction, and may be ob- served by asking the patient to clench the fist and then open it rap- idly. A patient with myotonia is unable to open the clenched fist rapidly due to an inability to relax the contracted muscles quickly. Myotonia may also be evident on percussion of muscle. The exam- ination of muscle power is carried out systematically, starting with the cranial musculature before proceeding to the arms and legs. The degree of weakness is assessed with reference to the Medical Research Council grading scale (0 to 5). The distribution of weak- ness is also noted, because different muscle diseases have charac- teristic patterns of weakness. Bedside assessment of respiratory muscles including the diaphragm is also important, although detailed assessment of these muscles requires formal spirometry. Finally, the tendon reflexes are elicited. These are generally pre- served in acquired muscle diseases, except when there is advanced weakness; however, they may be lost relatively early in the course of dystrophies. Investigating the patient with muscle disease Investigations are generally instituted only when the history and examination have provided clear evidence that the patient has symp- toms and/​or signs of muscle disease. The investigations are aimed primarily at determining the exact type of muscle disease because it is essential to establish whether the patient has a treatable muscle disease, such as an inflammatory myopathy. Many investigations of increasing complexity and invasiveness are available. Simple blood tests allow an assessment of the endocrine and nutritional status of the patient (such as thyroid function, the consumption of excess alcohol, or the presence of vitamin D de- ficiency). Measurement of blood creatine kinase is important be- cause this can be an indicator of the degree of muscle fibre damage or necrosis. Creatine kinase is generally elevated in inflammatory muscle diseases and in many of the muscular dystrophies. Increasingly, DNA-​based testing is available from simple blood samples. This can be particularly helpful and in some situations may obviate the need for further more invasive tests, such as a muscle biopsy (e.g. if analysis of the dystrophin gene on the X chromosome identifies a pathogenic mutation known to associate with Duchenne muscular dystrophy, the diagnosis is confirmed). The expanding use of the genetic techniques has revealed that gen- etic muscle disorders are heterogeneous and several genes may be associated with the same disease. For example, congenital myop- athies are caused by mutations of more than 20 genes. To face this genetic heterogeneity it is now possible to test simultaneously all the genes associated with a specific phenotype (‘genetic panel’) allowing a quick and cost-​effective approach to several genetic muscle diseases. 24.19.1  Structure and function of muscle 6309 The diagnosis of metabolic muscle diseases may be achieved by specific dynamic tests (e.g. McArdle’s disease can be diagnosed using the ischaemic lactate test), and mitochondrial disease may be suspected on the basis of subanaerobic exercise tests (both these tests are described in the relevant section). Detailed nerve conduction studies and electromyography (EMG) are useful in determining whether a patient has a neuropathy, a de- fect in neuromuscular junction transmission, or a myopathy. EMG is useful in characterizing any spontaneous activity of muscle, such as fasciculations or myotonia. Although EMG is generally useful in confirming the presence of a myopathy, it is less useful in determining the cause. Muscle MRI is increasingly being recognized as a diagnostic tool in muscle diseases. MRI detects inflammatory and dystrophic changes and may reveal specific pattern of muscle involvement nar- rowing the differential diagnosis. Furthermore, quantitative MRI methods may be used as a marker of disease progression. Muscle biopsy allows a detailed analysis of the internal archi- tecture of muscle and is an extremely valuable and safe investiga- tion in carefully selected patients. Using a range of histochemical stains, histochemical enzyme reactions, and immunological tech- niques on frozen muscle biopsy sections, much information of diagnostic use can be obtained. Different muscle diseases often reveal characteristic patterns of abnormalities, which are usually identified by light microscopic techniques. Using basic histochem- ical stains, the features of different muscular dystrophies are gen- erally similar, the most common features being marked variations in fibre diameter, internal nuclei, fibre splitting, fibre necrosis and regeneration, and increase in connective tissue. However, a more precise diagnosis of the type of muscular dystrophy can now be obtained by immunostaining techniques. Antibodies that are raised against specific membrane proteins allow quantitative ana- lysis (e.g. staining using antibodies directed against dystrophin re- veals no or very little dystrophin in cases of Duchenne muscular dystrophy). Prominent inflammatory infiltrates are typically seen in muscle sections from patients with inflammatory myopathies. Figs. 24.19.1.5, 24.19.1.6 and 24.19.1.7 show the muscle biopsy features of some of the metabolic myopathies. In some cases, the changes seen on the biopsy clearly indicate a myopathic process, but it is not possible to be more specific in the absence of typical immunological, inflammatory, or metabolic changes. Fig. 24.19.1.5  A transverse section of human skeletal muscle obtained from a patient with carnitine deficiency and stained with Sudan black B. The massive accumulation of neutral fat, especially with the type 1 fibres, is evident. Magnification ×196. Fig. 24.19.1.6  A transverse section of skeletal muscle obtained from a patient with mitochondrial myopathy, stained for the MADH-​TR reaction. The type 1 fibres are darkly stained and show the typical reticulated appearance of so-​called ‘ragged-​red fibres’ with massive mitochondria, particularly in many fibres just deep to the sarcolemma. Magnification ×384. Kindly supplied by Dr Margaret Johnson. Fig. 24.19.1.7  A transverse section of a biopsy specimen obtained from one quadriceps muscle in a patient with mitochondrial myopathy, showing arrays of paracrystalline inclusions in the damaged mitochondria. Bar = 1 µm. Kindly supplied by Dr Michael Cullen. 24.19.2 Muscular dystrophy 6310 Kate Bushby and Ch 24.19.2 Muscular dystrophy 6310 Kate Bushby and Chiara Marini- Bettolo section 24  Neurological disorders 6310 FURTHER READING Hughes BW, Kusner LL, Kaminski HJ (2006). Molecular architecture of the neuromuscular junction. Muscle Nerve, 33, 445–​61. Huxley HE, Hanson J (1972). The molecular basis of contraction. In: Bourne GH (ed). The structure and function of muscle, Vol 1, 2nd edition. Academic Press, New York, NY. Larsson L, et al. (1991). MHC composition and enzyme-​histochemical and physiological properties of a novel fast-​twitch motor unit type. Am J Physiol, 261, 93–​101. Smerdu V, Karsch-​Mizrachi I, Campione M (1994). Type IIx myosin heavy chain transcripts are expressed in type IIb fibers of human skeletal muscle. Am J Physiol, 267, C1723–​8. Walton JN, Mastaglia FL (1980). The molecular basis of muscle dis- ease. In: Thompson RHS, Davison AN (eds) The molecular basis of neuropathology. Edward Arnold, London. Wattjes MP, Kley RA, Fischer D (2010). Neuromuscular imaging in inherited muscle diseases. Eur Radiol, 20, 2447–​60. 24.19.2  Muscular dystrophy Kate Bushby and Chiara Marini-Bettolo ESSENTIALS Muscular dystrophies are primary, genetically determined disorders of muscle. All cause muscle weakness, which is usually progressive. They are challenging to classify, but clinical characteristics can be combined with genetic and molecular information to obtain a useful operational nomenclature for prognosis and family counselling. In general, diagnosis is guided by the age at which clinical manifest- ations appear, the distribution of weakness, and the rate at which muscle function is lost, but unusual features such as muscle pain and rhabdomyolysis may also contribute to the identification of a par- ticular hereditary muscle disorder. Congenital muscular dystrophies Congenital muscular dystrophies are defined by their very early childhood onset and dystrophic features on the muscle biopsy. Clinically patients present with early onset of muscle weakness and hypotonia, and contractures are common. Respiratory and car- diac involvement is common and can be severe. In some cases, the congenital muscular dystrophies can have overlapping genetic and clinical features with the congenital myopathies. Molecularly based subclassification allows the recognition of various subgroups including those associated with mutations in/​causing: (1) laminin A2 (LAMA2), (2)  α-​dystroglycan and glycosyltransferase enzymes (FKRP, FKTN, POMT1, POMT2, POMGnT1, LARGE, ISPD, GTDC2, DAG1, TMEME5, B3GALNT2, B3GNT1, GMPPB, SGK196, DPM1, DPM2, DPM3, DOLK) (3) collagen VI (COL6A1, COL6A2, COL6A3)—​, (4) lamin A/​C (LMNA), (5) selenoprotein 1 (SEPN1), (6) ryanodine receptor 1 (RYR1), (7) integrin A7 and A9 (ITGA7, ITGA9) (8) nesprin 1 (SYNE1) (9) choline kinase beta (CHKB), and (10) other congenital muscular dystrophies with no genetic diagnosis but compatible clinical and histological features. Table 24.19.2.1 gives an overview on the congenital muscular dystrophy classification including no- menclature, gene, phenotype, relative frequency in the UK popula- tion and diagnostic test. Dystrophin deficiency Mutations (mostly deletions) in the dystrophin gene result in defi- ciency of dystrophin protein and cause variable phenotypes ran- ging from the more severe form, Duchenne muscular dystrophy to the milder form, Becker muscular dystrophy. Despite these being X-​linked diseases female carriers can also manifest the disorders. Cardiomyopathy can occur in conjunction with the skeletal muscle weakness, but also in the absence of overt weakness as X-​linked di- lated cardiomyopathy. Clinical features—​(1) Duchenne muscular dystrophy—​all affected boys are symptomatic within the first 3 years of life, although diag- nosis is frequently delayed beyond this; motor milestones and speech are frequently delayed; there is a pronounced waddling gait on attempting to run. Hypertrophy of the calf muscles is al- most universal. (2) Becker muscular dystrophy—​mean age at onset is 11 years; typically manifests with difficulty with high steps and climbing hills; may suffer muscle pain after exercise; frequently have hypertrophy involving the same muscle groups as seen in Duchenne muscular dystrophy. (3) About 10% of female carriers can also pre- sent with variable skeletal and/​or cardiac muscle involvement. Exercise induced muscle pain is common as well as calf hyper- trophy. (4) X-​linked dilated cardiomyopathy (XL-​dCMP)—​a distinct dystrophinopathy phenotype characterized by dilated cardiomyop- athy and absence of overt skeletal muscle weakness. Treatment is similar to dilated cardiomyopathy and surgery may be necessary for refractory heart failure. Investigation, diagnosis, and prevention—​serum creatine kinase is always massively elevated, but the level does not distinguish the severity of the disease. Molecular confirmation of the diagnosis is essential to assist in defining prognosis and allow provision of appro- priate genetic counselling. Prognosis and complications—​the prognosis of ‘dystrophinopathies’ is highly variable, especially among Becker MD and manifesting car- riers. Untreated patients with Duchenne muscular dystrophy lose the ability to walk by the age of 12, but corticosteroids delay deteri- oration. Scoliosis, respiratory failure, and cardiomyopathy develop during the teenage years. With appropriate multidisciplinary sup- portive care, survival into or beyond the late twenties and thirties is becoming more common. Novel therapeutics directed to the muta- tions in the dystrophin gene or the downstream effects of dystrophin deficiency are a prospect for treatments in the future and are cur- rently being tested in trials, with likely availability of these new drugs on the market in the coming years. At the time of writing, conditional marketing approval in Europe only has been granted for ataluren, though access remains restricted. Other muscular dystrophies Facioscapulohumeral muscular dystrophy is an autosomal dom- inant disease sometimes arising as the result of a new dominant mutation. Affected individuals manifest early symptoms, typically including facial weakness, shoulder girdle weakness, and foot-​ drop, often by their teens or twenties. Serum creatine kinase may be normal or mildly elevated. Diagnosis can be confirmed in 95% 24.19.2  Muscular dystrophy 6311 of cases by demonstration of a deletion close to the telomere of chromosome 4q: more complex analysis is required for the other cases. The condition is usually slowly progressive; complications rarely include scoliosis and respiratory failure. Emery–​Dreifuss muscular dystrophy—​caused by mutation of any one of several genes encoding components of the nuclear envelope (e.g. emerin, lamin A/​C). This may present at any age, with contrac- tures of the ankles and elbows and rigidity of the spine often pre- dating any clear weakness. Prognosis is determined by ability to manage life-​threatening cardiac arrhythmias and varies depending on the exact gene involved. Limb-​girdle muscular dystrophies—​these comprise a range of dis- orders that cause weakness of the proximal musculature. Important considerations in any case are (1) could it be a dominant disease? (e.g. limb-​girdle muscular dystrophy 1B; allelic with autosomal dom- inant Emery–​Dreifuss muscular dystrophy), Bethlem myopathy; (2) age of presentation and of rate of progression—​these give im- portant clues to likely diagnosis; (3) investigations—​creatine kinase is greatly elevated in all forms of autosomal recessive limb-​girdle mus- cular dystrophy; electromyography confirms a primary myopathic process; muscle biopsy shows dystrophic changes on standard analysis, with more specialized testing for diagnosis of, for example, sarcoglycanopathies, calpainopathy, or dysferlinopathy. Oculopharyngeal muscular dystrophy —​typically presents in the sixth decade with ptosis, dysphagia to solids, and dysphonia. Associated with an expanded triplet repeat in the gene for poly(A) binding protein 2. Introduction Muscular dystrophy is not a single disease. Many different types of muscular dystrophy can be recognized: all are primary, genet- ically determined disorders of muscle and all cause muscle weak- ness and wasting, which is usually progressive. The various types of muscular dystrophy share several characteristic findings on muscle biopsy, most notably a variation of fibre size, evidence of muscle fibre necrosis, and usually replacement of muscle tissue by fat and fibrous tissue. These pathological findings are often, but not always, accompanied by elevation of the serum creatine kinase. Although the key clinical sign in muscular dystrophy is muscle weakness, the distribution of that weakness and the asso- ciation with other features such as wasting, hypertrophy, and joint contractures are the most helpful defining features in making a clinical diagnosis, together with age at presentation and rate of progression. Unusual presenting manifestations of muscular dys- trophy are muscle pain, rhabdomyolysis, myoglobinuria, and cardiomyopathy. Complications may include cardiac and respiratory failure or an- aesthetic problems. These complications may be relatively specific to particular types of muscular dystrophy. Taken together with the clinical findings in any patient, precise diagnostic tests (through ei- ther DNA analysis or protein analysis of a muscle biopsy sample) are available for most of these disorders, as knowledge of the underlying mechanism of disease for each of these entities has increased. Confirmation of the type of muscular dystrophy in any individual patient is critical to the provision of appropriate management, prognostic advice, and genetic counselling. No form of muscular dystrophy is currently curable, although various experimental therapeutic procedures are under investigation. Classification of the muscular dystrophies Various classifications of the muscular dystrophies have been pro- posed, reflecting historical advances in the understanding of this group of diseases (Box 24.19.2.1). The current basis for classifi- cation combines an appreciation of the clinical features with the ability to determine the molecular basis for the disease. Therefore, the eponymous names (e.g. Duchenne muscular dystrophy) still in common usage reflect the detailed clinical descriptions pro- vided by early clinicians; other disease names reflect the recog- nized pattern of muscle involvement in a particular condition (e.g. fascioscapulohumeral muscular dystrophy). Disease designations based on the genetic or protein defect in a particular disorder (e.g. dystrophinopathy) are becoming more widely used, reflecting the fact that some disorders previously believed to be clinically dis- tinct actually represent different manifestations of lesions at the same locus. Genetic analysis has also revealed an unsuspected level of heterogeneity with different genetic causes for disorders that show superficial clinical similarities. This can be seen most strik- ingly within the ‘limb-​girdle’ and congenital groups of muscular dystrophies. The pathophysiology of the muscular dystrophies Biochemical and physiological experiments failed to shed any light on the mechanisms by which muscular dystrophy could arise, and it has only been since the identification of the dystrophin gene (DMD) in 1987 that progress has been made. It is now quite clear that proteins involved in several different functions within the muscle cell can, when altered or absent, cause muscle damage and account for the pathological and clinical features of a muscular dys- trophy. Some of these proteins are components of the membrane of the muscle fibre that may have a structural or signalling role, others are components of the nuclear envelope or muscle-​specific enzymes (Fig. 24.19.2.1). General points on the diagnosis of muscular dystrophy Box 24.19.2.2 summarizes some of the major considerations for arriving at the correct diagnosis of a muscular dystrophy. History taking at the time of presentation (Box 24.19.2.3) may be par- ticularly informative. The clinical history may be pathognomonic. Detailed diagnostic information is given in the following text re- lating to specific diseases. The main tools for specific diagnosis in muscular dystrophy are the use of antibodies for immunolabelling of muscle biopsy sections and/​or the application of specific DNA-​ based genetic analysis. Muscle MRI can also be helpful in achieving a diagnosis as it can show selective patterns of muscle involvement Box 24.19.2.1  Basis of the classification of muscular dystrophies • Clinical description • Genetics (autosomal dominant/​recessive/​X-​linked) • Underlying gene/​protein defect • Localization or function of the protein involved section 24  Neurological disorders 6312 specific to various forms of muscular dystrophy and these specific patterns are increasingly well defined. General points on the management of the muscular dystrophies Despite the fact that no cures for muscular dystrophy have been es- tablished, there are many management issues that may be important or specific to the various types. However, as yet there is little system- atic or comprehensive clinical research into management and ran- domized trials of management regimens are few and far between. It is nevertheless appropriate, where possible, that patients with a diag- nosis or a suspected diagnosis of muscular dystrophy should be re- ferred to a specialist clinic with access to the full range of specialists, who need to be involved in the coordinated care of these patients depending on their diagnosis and stage of disease. The multidiscip- linary approach of these clinics ensures that patients have access to the full range of diagnostic facilities, are able to obtain specialized multidisciplinary care (including physiotherapy advice), and can obtain accurate genetic counselling where this is required. Access to patient support organizations and their staff is also of paramount im- portance. Patients should also be informed and offered the option to sign on to disease specific patient registries, as these are a powerful tool to collect information to gather better understanding of these rare conditions and help develop standards of care, identify partici- pants for clinical trials, and update patients with relevant information to their condition. The diagnosis of any kind of muscular dystrophy, in that it inevitably implies a progressive and incurable disease, pos- sibly with implications for children or other relatives, is a consider- able burden and one that needs to be recognized and supported. The congenital muscular dystrophies The congenital muscular dystrophies (CMDs) are defined by their very early childhood onset. They comprise several disorders with different molecular pathological bases for the diseases. For their presentation, see Box 24.19.2.4. Extracellular matrix: Plasma membrane Cytoplasm Nuclear envelope Extracellular matrix Cytoplasm: Nuclear envelope: Plasma membrane: Collagen Laminin Fukutin FKRP POMGnt LARGE Myotilin Emerin Dystrophin Integrins Caveolin Dysferlin Sarcoglycans Nesprins Lamin A/C Actin Telethonin TRIM32 Titin Calpain 3 Ab-crystallin Desmin Fig. 24.19.2.1  Schematic diagram to show localization within the muscle fibre (where known) of some of the proteins involved in producing a dystrophic phenotype. Box 24.19.2.2  Diagnosis of muscular dystrophy • History (especially motor milestones, age at onset, physical prowess as a child). • Age of patient (congenital/​childhood/​teenage/​adult presentation). • Pattern of muscle involvement on examination (predominantly prox- imal/​distal, upper limb/​lower limb, symmetrical/​asymmetrical). • Pattern of associated features on examination (contractures, muscle wasting, hypertrophy). • Level of serum creatine kinase in active disease (massive elevation in dystrophinopathy, sarcoglycanopathy, dysferlinopathy, calpainopathy, congenital muscular dystrophy (some); moderate elevation in facioscapulohumeral muscular dystrophy, Emery–​Dreifuss muscular dystrophy, congenital muscular dystrophy (some); normal to mild elevation in autosomal dominant limb-​girdle muscular dystrophy, facioscapulohumeral muscular dystrophy (some)). • Electromyography (to exclude neurogenic causes of weakness and congenital myasthenias, especially if serum creatine kinase is not markedly elevated). • Muscle imaging (ultrasound scans can confirm muscle involvement, but to confirm pattern of muscle involvement need MRI/​CT). • Muscle biopsy, histology, and storage of frozen biopsy material for fur- ther analysis. • Specialized analysis of muscle biopsy (immunocytochemistry, immunoblotting, electron microscopy). • DNA analysis is now the gold standard for diagnosis. Box 24.19.2.3  History taking in muscle disease • Question in detail about early motor development. • Elicit what actually were the first symptoms experienced by a patient; this may be difficult but is important in highlighting the initial pattern of muscle involvement—​lower limb vs. upper limb/​ proximal vs. distal musculature. • Ask ‘When were you at your fastest?’; this may be informative in determining age of peak motor performance. • Ask about performance at school sports. • Particularly useful indicators in that respect are the ability to climb ropes (upper girdle weakness), muscle pain on running, a tendency to spend all the time in goal at football(!). • Do not assume that difficulty climbing stairs always indicates proximal muscle weakness—​it may reflect an inability to push up on the toes. • Ask specifically about the ability to stand on tiptoe/​stand on heels. The need to wear heels on shoes at all times may indicate Achilles tendon contractures. • Patients who had early Achilles tendon contractures may have had them operated on before being referred for diagnosis. Ask about this. 24.19.2  Muscular dystrophy 6313 Differential diagnosis In the neonatal and early childhood presentation the main clinical diagnostic confusion (after excluding central causes of hypotonia) may be with spinal muscular atrophy (check SMN gene for char- acteristic deletions), congenital myotonic dystrophy (facial weak- ness is usually more pronounced and diagnosis can be excluded on genetic testing), and congenital myopathy (may be distinguished on muscle biopsy). In all of these conditions, serum creatine kinase is either normal or much lower than seen in many congenital muscular dystrophies. With later childhood presentation the differential diagnosis is as already mentioned, plus Duchenne muscular dystrophy (though calf hypertrophy is usually more pronounced and serum creatine kinase is typically higher—​biopsy will exclude the diagnosis) or childhood presentation of a limb-​girdle type of muscular dystrophy. Classification There are several recognized forms of congenital muscular dys- trophy and, as there is considerable heterogeneity in the group that remains, additional entities are ultimately likely to be distinguished at the genetic level. The diagnostic classification of this group of diseases was previously very clinically based, but is moving in- creasingly into a molecularly based. This allows the recognition of various subgroups of CMD: laminin α2 (LAMA2) associated CMD (MDC1A), the types of CMD involving abnormal glycosylation of α-​dystroglycan (where there is frequent eye and/​or brain involve- ment as well as muscle weakness), CMD associated with collagen VI mutations (Ullrich congenital muscular dystrophy or UCMD), and rigid spine muscular dystrophy-​1 (RSMD1) due to mutations in the selenoprotein-​1 gene (Table 24.19.2.1). Cases of CMD due to mu- tations in genes also causing other types of muscular dystrophy are also increasingly recognized, for example with mutations in lamin A/​C. Rare cases of CMD, mental retardation, and abnormal mito- chondria (CMDmt) have been described associated with mutations in choline kinase beta (CHKB). Establishing the diagnosis Serum creatine kinase may, in some forms of congenital muscular dystrophy, be normal, but is typically elevated at least twofold, and up to twentyfold or more in the laminin A2-​deficient group and the α-​dystroglycanopathies. Muscle biopsy shows dystrophic changes and allows examination for LAMA2, α-​dystroglycans, and collagen VI in muscle; skin is also used to distinguish cases with normal and abnormal or absent protein. MRI of the brain is a useful adjunct to diagnosis because it will confirm the presence of white matter changes, which are always present after age 6 months in pri- mary LAMA2 deficiency, and the characteristic brain malforma- tions in the types of CMD associated with α-​dystroglycanopathy (see Table 24.19.2.1). Prognosis and management The overall prognosis depends on the type of CMD and individual severity in the patient because there can be major variability even within the different subgroups. Children with the most severe forms are at risk of dying in early childhood. If they survive this period, with appropriate management of feeding problems, and respiratory and (in a minority) cardiac complications, survival into adult life is the norm. The muscle weakness in congenital muscular dystrophy may be relatively static, but the complications of that weakness can be severe, and vary according to the precise diagnosis. The degree of muscle weakness is quite variable. In primary laminin A2-​deficient CMD, the severity of the disease correlates roughly with the abun- dance of laminin A2 in the muscle, with children completely lacking laminin A2 rarely achieving independent ambulation. Others may Box 24.19.2.4  Presentation of congenital muscular dystrophies Neonatal presentation • Hypotonia, which may be prenatal • Feeding problems (usually mild) • Joint contractures, especially knees, hips, and ankles (Fig. 24.19.2.2) • Joint laxity that may coexist with contractures at other joints Early childhood presentation • Delayed motor milestones • Failure to thrive • Repeated respiratory infections Later childhood presentation (rare) • Mainly proximal muscle symptoms • History of delayed motor milestones • Rigid spine, contractures of ankles, hips, and knees (a) (c) (b) Fig. 24.19.2.2  (a) Typical clinical picture of a baby presenting with MDC1A (muscular dystrophy, congenital, type 1a). Note the hypotonic posture, and mild contractures of the hips, knees, and ankles. (b, c) Immunofluorescence picture of skin biopsy labelled with an antibody to laminin A2 (merosin), showing normal (b) and absent labelling (c) patterns. This investigation can be carried out on a variety of tissues including skin, muscle, and placenta. section 24  Neurological disorders 6314 Table 24.19.2.1  The congenital muscular dystrophies Disease and nomenclature Gene Relative frequency in the UK population (expressed as % of CMD clinic population) Diagnostic tests Phenotype Collagen VI related dystrophies (COL6-​RD) COL6A1, COL6A2, COL6A3 21% Frequent absence or abnormality of collagen VI immunolabelling in muscle or cultured fibroblasts. Mutation testing Characteristic pattern of joint hyperlaxity distally with proximal contractures. May be abnormal skin, including keloid scarring and hyperkeratosis Can present as: • Ullrich congenital muscular dystrophy (UCMD)–​ severe non​ambulant and transient ambulant. UCMD is typically autosomal recessive, de novo dominant mutations are increasingly recognized • Intermediate phenotype • Bethlem myopathy (BM, milder allelic form) CMD with abnormal glycosylation of α-​dystroglycan (a dystroglycan-​ related dystrophy, α-dystroglycanopathy, a DGpathy) fukutin, FKRP, LARGE, POMT1, POMT2 POMGnT1, DAG1, DPM2/​DPM3, GMPPB, ISPD, GTDC2, B3GNT1, SGK196, TMEM5, and others 15% Abnormal labelling of α-dystroglycans in muscle, mutation testing Very variable brain phenotype ranging from normal to severe lissencephaly. Eye phenotype is also variable from normal to micro-​opthalmia • Walker–​Warburg syndrome • Muscle–​eye–​brain disease; Fukuyama CMD; Fukuyama-​like CMD • CMD with cerebellar involvement; cerebellar abnormalities may include cysts, hypoplasia, and dysplasia • CMD with mental retardation and a structurally normal brain on imaging; (includes patients with isolated microcephaly or minor white matter changes on MRI) • CMD with no evidence of abnormal cognitive development Can present also as: • Limb-​girdle muscular dystrophy (LGMD) with mental retardation • LGMD without mental retardation MDC1A (muscular dystrophy congenital type1A, Laminin A2 deficiency LAMA2-​ related dystrophy, LAMA2-​CMD, merosin-​ deficient CMD) LAMA2 10% Absence of laminin A2 labelling in muscle and skin, mutation testing White matter radiolucency on MRI, approx 30% have epilepsy. May have restricted eye movements. Progressive development of severe contractures, scoliosis, feeding and respiratory problems require close follow-​up Congenital laminopathy (LMNA related dystrophy, LMNA-​CMD, LCMD, and Emery–​Dreifuss) LMNA 3% Mutation testing in LMNA Very heterogeneous phenotype Early onset axial weakness with absent or early loss of ambulation, dropped head syndrome, feeding difficulties, and respiratory involvement Milder phenotypes Cardiac phenotype: arrhythmogenic cardiomyopathy with conduction block and also ventricular tachyarrhythmias requiring use of an AICD Selenoprotein 1 related myopathy presenting as CMD (SEPN1 related myopathy, RSMD1) SEPN1 1% Immunolabelling in muscle is typically normal. Diagnosis established on mutation in SEPN1 Typical rigid and side sliding spine develops in first decade. Early respiratory failure while ambulation maintained. Selenoprotein 1 gene mutations are also responsible for multiminicore disease RYR1 related myopathy presenting as CMD (RYR1-​CMD) RYR1 n/​a Muscle biopsy shows central core, multiminicore, centronuclear and non​specific pathologies. which can assume CMD like characteristics Early scoliosis and absent or limited ambulation Others Various other causes of CMD have been described including mutations in integrin α-7 and α-9, nesprin 1, and CHKB ITGA7, ITGA9, SYNE1 CHKB n/​a Depends on causative gene which will need to be detected by protein and mutation testing Depends on causative gene: ITGA7 related CMD: delayed motor milestones, respiratory impairment, scoliosis ITGA9 related CMD: similar to UCMD but no protruding calcanei, no respiratory failure, and acquired ability to walk SYNE1-​related CMD: adducted thumbs, mental retardation, ophthalmoplegia CHKB-​related CMD: large appearing mitochondria, cognitive impairment (with normal brain MRI), acanthosis nigricans like lesions and intense pruritus 24.19.2  Muscular dystrophy 6315 learn to walk independently but this is usually much later than usual, and these children may later lose this ability. For all types of CMD, joint contractures and scoliosis are major complications of the disease and cause much additional disability, requiring careful management by physiotherapy, standing regimens, orthoses, and surgery where appropriate. Feeding problems may be intractable and lead to chronic malnutrition unless treated by naso- gastric or gastrostomy feeding. Malnutrition may contribute to sus- ceptibility to chest infections, which is also heightened by weakness of the respiratory muscles. These children are at risk of respiratory failure and their follow-​up should include monitoring for this com- plication, which can be effectively managed by the provision of noninvasive home nocturnal ventilation. Cardiac failure is a rela- tively rare complication in CMD but has been reported in MDC1A and the α-​dystroglycanopathies. Fukuyama congenital muscular dystrophy, muscle–​eye–​brain disease, Walker–​Warburg syndrome, and other diseases within the α-​dystroglycanopathy spectrum may be dominated by intellectual and visual impairment. In MDC1A, brain changes on MRI are typ- ically asymptomatic. In UCMD intellectual development is normal but respiratory failure is a major risk in the first decade. RSMD1 overall carries a generally much milder prognosis with respect to mobility, but this may mask a serious risk of respiratory failure and scoliosis, both generally necessitating intervention by the end of the first decade, often while still ambulant. Genetic counselling CMD are generally inherited in an autosomal recessive fashion, however dominant inheritance is possible and needs careful rec- ognition to provide correct genetic counselling. Indeed, collagen VI and lamin A/​C related disorders can be inherited in a recessive as well as a dominant pattern and these tend to be de novo mu- tations. It is, therefore, important to recognize dominant acting mutations—​segregation studies are needed to determine whether the mutation is de novo, but the possibility of somatic or germline mosaicism in de novo mutations should always be considered to provide correct counselling. As the molecular basis for these dis- orders has recently become much better established, specific diag- nosis should be attempted in all cases in order to allow proper direction of management, as well as prenatal and carrier testing where requested. Dystrophin deficiency This group, including two of the most common forms of muscular dystrophy—​Duchenne and Becker muscular dystrophy—​involve the same gene and protein. These are X-​linked diseases, caused by mutations, most of which are deletions, in the dystrophin gene (DMD). Presentation Duchenne muscular dystrophy (OMIM 300377) • All patients are symptomatic within the first 3 years of life, al- though the mean age at diagnosis is 51.7 months (4.3 years) with a range of 10–​91 months. • Motor milestones are often delayed (half the cases are not walking by 18 months). • Speech is also frequently delayed. • Patient is unable to run: there is a pronounced waddling gait on attempting to rush. • Patient is unable to jump with both feet together or to hop: there is no spring in the step. • ‘Climbs up legs’ on rising from the floor: Gower’s manoeuvre. • Can present with anaesthetic complications. Anaesthesia guide- lines can be found on http://​community.parentprojectmd.org/​ profiles/​blogs/​revised-​duchenne-​anesthesia-​recommendations- ​2015 Becker muscular dystrophy (OMIM 300376) • The mean age at onset of Becker muscular dystrophy is 11 years, although the range of age at presentation is extremely wide and the diagnosis may be made at any age, particularly if there is a family history. • A proportion will have had delayed motor milestones (this may correlate as much with reduction in IQ as with major motor prob- lems at that age). • Many describe being unable to keep up with peers at school. • There is difficulty with high steps and climbing hills. • Muscle pains after exercise are a common complaint, especially in teenagers (rarely myoglobinuria). Manifesting carriers of Duchenne muscular dystrophy/​Becker muscular dystrophy A highly variable group, which may occasionally be as severely af- fected as those with Duchenne muscular dystrophy or more or less mildly than those with Becker muscular dystrophy. Up to 10% may be at risk of cardiac complications of their carrier status. Dystrophin-​associated cardiomyopathy OMIM 302045 There are symptoms and signs of hypertrophy progressing to dilated cardiomyopathy in the absence of major muscle symptoms. Some patients have an elevated serum creatine kinase. Establishing the diagnosis The clinical presentation of Duchenne muscular dystrophy (DMD) is very characteristic. Hypertrophy of the calf muscles is almost universal (Fig.  24.19.2.3a), sometimes accompanied by muscle hypertrophy elsewhere, most frequently involving deltoid, parts of the quadriceps, the tongue, and masseters. Wasting of the pectoral and scapular muscles leads to hypotonia around the shoulders, de- tected as the child ‘slipping through the hands’ on being lifted. In the lower limbs, quadriceps power is weaker than that of the ham- strings. Formal examination of a small child may be difficult, and the main clinical tool is observation of walking, attempting to run, jump, and climb stairs, and to rise from the floor. It is imperative to give the child space to attempt to run, as this will bring out the lack of spring in the step and the lack of fluidity of the attempted running. Becker muscular dystrophy (BMD) has been described as a ‘slow motion version of Duchenne muscular dystrophy’, in that the pattern of muscle involvement in these two allelic disorders is essen- tially identical (Fig. 24.19.2.3c), but progresses at a much slower rate in BMD. Patients with BMD may be quite strong on formal muscle examination, but tend to show subtle signs of proximal muscle weakness on climbing stairs or running. They frequently section 24  Neurological disorders 6316 have hypertrophy involving the same muscle groups as seen in DMD. Some patients have pes cavus. Serum creatine kinase is always massively elevated, even to more than 200 times normal, but levels of serum creatine kinase do not distinguish the severity of the disease. Muscle biopsy and electro- myography are non​specifically but generally severely dystrophic. The muscle biopsy in BMD may also show some grouped fibre atrophy reminiscent of a ‘neurogenic’ pathology. Molecular confirmation of the diagnosis is essential to assist in defining prognosis and to pro- vide appropriate genetic counselling. In addition, current standards of diagnosis include detailed characterization of the mutation as it is essential in view of mutation-​specific drugs that are now available or being developed for use, so far, in clinical trials. Multiple ligation probe amplification is a technique that can detect copy number of every exon and confirm the diagnosis in the 60–​80% of patients in whom a deletion or duplication of the dystrophin gene is present, regardless whether the patient is a male or female—​this was not the case with previously used techniques like multiplex polymerase chain reaction. For patients in whom deletion and duplication ana- lysis are negative, testing for point mutations via direct sequencing techniques (Sanger sequencing or next-​generation sequencing) of the entire coding region is mandatory. In dubious cases of unknown pathogenicity of the variant identified or in patients with no detect- able mutation, it is useful to consider a muscle biopsy by which, in all patients, the diagnosis can be established by not finding or finding reduced dystrophin in the muscle biopsy (Fig. 24.19.2.3d). This ana- lysis also allows the distinction of dystrophinopathy from the much rarer (in most populations) limb-​girdle types of muscular dystrophy. Precision of the exact mutation is important for offering carrier testing to the mother and other family members (important to es- tablish the risk of any cardiac problems as well as to allow genetic advice for future pregnancies) and also to allow future access to the mutation-​specific treatments that are currently under development, such as antisense oligonucleotide-​mediated exon skipping and stop codon suppression. Prognosis Within the ‘dystrophinopathy’ group the prognosis is highly vari- able. By definition, untreated patients with DMD lose the ability to walk by the age of 12, though this definition is now difficult to apply as the widespread use of corticosteroids has delayed the loss of ambulation in many patients well into their teenage years. The development of scoliosis, respiratory failure and cardiomy- opathy (Box 24.19.2.5) are also delayed with the use of steroids, and improved overall management means that survival into or beyond the late 20s and 30s is becoming more common. Patients with BMD are ambulant beyond 16 years of age, and may remain able to walk independently into their fifth decade or later. These patients are susceptible to cardiac failure at any age from the teens onward and should be monitored for this complication on a regular basis (Box 24.19.2.5). Respiratory failure is a late com- plication in BMD and correlates with very late-​stage disease. The lifespan in BMD may be normal, or reduced in more severe dis- ease. An ‘intermediate’ group is also recognized, patients losing ambulation between age 12 and 16: their overall prognosis is also intermediate between DMD and BMD. Around 8% of carriers of (b) (a) (c) (d) Fig. 24.19.2.3  (a) Child with Duchenne muscular dystrophy at presentation, showing the marked calf and quadriceps hypertrophy and tendency to rise onto the toes. (b) Teenage boy in the later stages of the disease, showing the complications of marked immobility, scoliosis, and muscle wasting. This young man has now been maintained on home nocturnal ventilation successfully for more than 7 years. (c) Clinical pattern at presentation in a young man with Becker muscular dystrophy. Note hypertrophic muscles in calves and quadriceps and mild wasting around the shoulder girdle. (d) Immunocytochemical analysis of dystrophin in normal muscle, Becker muscular dystrophy muscle, and Duchenne muscular dystrophy muscle. In normal muscle, dystrophin labels evenly around the periphery of the muscle fibres. This labelling is typically patchy and reduced in Becker muscular dystrophy, and is either completely or almost completely absent in Duchenne muscular dystrophy. Box 24.19.2.5  Practice point: cardiac involvement in dystrophinopathy • All patients with dystrophinopathy are at risk of developing cardio- myopathy which progresses with age. It is frequently asymptomatic, and needs to be sought through full cardiac assessment including echocardiography, as treatment with antifailure medication may im- prove function and prognosis. • Cardiac transplantation has been used successfully in patients with Becker muscular dystrophy and manifesting carriers of dystrophinopathy. It may be more utilized in DMD as other manage- ment modalities improve. • Cardiac compromise is the major determinant of operative risk in boys with Duchenne muscular dystrophy, and all should have a full cardiac assessment in advance of any surgery at any age. 24.19.2  Muscular dystrophy 6317 DMD or BMD may develop some signs of the disease: rarely this is in a full-​blown form comparable to the disease in boys. In prac- tice, there is a continuum of severity with the highest incidence in the DMD group (birth incidence 1 in 3500 male live births), while the estimated incidence in the BMD group is at 1 in 18 518 male births. As the lifespan is so much longer in the BMD group, however, the prevalence of the two conditions is roughly similar (about 24 per million population in north-​east England). Over the whole group, there is a correlation between dystrophin abundance (as measured in a muscle biopsy sample) and se- verity: children with completely absent dystrophin tend to be con- fined to a wheelchair slightly earlier than children whose biopsies contain low levels of dystrophin. Patients with BMD have much higher levels of dystrophin (see Fig. 24.19.2.3). These dystrophin levels also correlate in most cases with the type of mutation found in the dystrophin gene—​in DMD most deletions are out of frame, not supporting the production of dystrophin, whereas BMD patients typically have in-​frame deletions, allowing the production of a re- duced amount of dystrophin of a slightly smaller size. Although these correlations are useful in a general sense, they are not absolutely predictive of outcome in an individual case, and must always be taken in the context of the clinical features of the patient. Indeed, the move towards genetic testing as the primary step in diag- nostics means that most patients now will not have a muscle biopsy routinely. They can be useful, however, in giving the best possible guide to prognosis, especially in those patients who present early with no clinical clues as to the severity of the disease, or who are identified by neonatal screening or the incidental finding of a high serum creatine kinase level. Management DMD is essentially a predictable disease with complications that need to be proactively sought and managed in different systems. Although, in the past, a nihilistic attitude to management in DMD was widespread, evidence of the benefits of proactive management is now available and all patients should have access to the highest possible care. The key to proper management is a team specializing in neuromuscular management, who can oversee the coordination of input from physiotherapy, orthopaedic, cardiac, respiratory and psychology specialists. Input from other specialties, including occu- pational therapy, educational psychology, gastrointestinal medicine, and palliative care, may also be required. Indeed, corticosteroids to- gether with multidisciplinary management of DMD boys have led to changes of the natural history of this condition, improvement of quality of life and prolonged survival with the possibility of life ex- pectancy into the late thirties. Duchenne muscular dystrophy: the early stages Proper management of a child with DMD starts with awareness of the possibility of the diagnosis in any boy who is not walking by the age of 18 months or whose mobility is poor compared with that of his peers. The current mean age at diagnosis has improved over the last decade dropping from almost 5 years to 4.3 years with a range of 10–​91 months, highlighting still unacceptable delays. The principal impetus to early diagnosis is currently the ability to offer parents the option of prenatal diagnosis in subsequent pregnancies. Early diagnosis is essential, as prompt management and interventions according to standards of care results in better outcomes. When specific treatments become available, there is likely also to be a need to implement such treatments before the disease is too advanced. Once the diagnosis has been considered, measurement of the serum creatine kinase will confirm the suspicion and ideally a re- ferral to a specialist unit should be made at this stage. The spe- cialist unit should have rapid-​track access to DNA diagnostic and, if needed, muscle biopsy facilities to confirm the diagnosis as quickly as possible. DMD is a devastating diagnosis, and should be given to the family following guidelines for the best practice for disclosure of bad news: the parents should be seen together wherever possible in complete privacy, they should have time to sit and ask questions, and have access to experienced staff for support and further information. Access to support groups and the relevant national charity is appro- priate. Supporting information should also be passed immediately to the GP, health visitor, and school who may never have looked after a child with this type of condition before. As DMD is an X-​linked condition, early access to genetic counsel- ling is also vital shortly after diagnosis (Box 24.19.2.6) and needs to be reinforced as the affected person and his siblings reach adulthood. Untreated, DMD has a rapidly progressive course with loss of am- bulation in the first decade of life and death before the age of 20. Thanks to the introduction of corticosteroids and multidisciplinary management in boys with DMD the life expectancy and disease course have changed substantially. As part of the multidisciplinary management, the introduction of nocturnal non​invasive ventilation and scoliosis surgery has been shown to have a positive impact on survival, in particular if combined. In addition, early cardiac treat- ment with angiotensin converting enzyme (ACE) inhibitors and β-​ blockers can delay the progression of dilated cardiomyopathy. From Box 24.19.2.6  Genetic counselling in dystrophinopathy Genetic counselling in dystrophinopathy is an essential part of the man- agement of any family where a diagnosis of dystrophinopathy has been made because the potential implications go far beyond the index case. • These are X-​linked diseases. • The new mutation rate in the dystrophin gene is high. • Most cases of Duchenne muscular dystrophy are born now in families with no prior history of the disease. • None the less, even in these families, other female relatives (through the maternal line) are at risk of being carriers. • The essential piece of information is the delineation of the dystrophin mutation in the affected child (easy to find in the 60% in whom the mutation is a deletion, but point mutation testing my sequencing re- quired in the remainder). • In the presence of a known mutation, female relatives can be offered testing directly to see if they are carriers or not. • They may choose to have prenatal diagnosis on the basis of that testing. • Even if mothers of boys with Duchenne muscular dystrophy can be shown not to be somatic carriers of the mutation in their son, they still may have a proportion of egg cells containing the mutation (a situation known as ‘germline mosaicism’). They therefore remain at a 10–​20% risk of having another affected child in a future pregnancy. • Boys with Duchenne muscular dystrophy are increasingly surviving to adulthood with some having the opportunity to have children, and men with Becker muscular dystrophy often do (overall fitness reduced to around 2/​3). All of their daughters are obligate carriers of Becker muscular dystrophy, but none of their sons are at risk. Genetic coun- selling is an important part of transition planning. section 24  Neurological disorders 6318 early stages physiotherapy management of ankle and hip contrac- tures with regular stretching exercises is fundamental for mainten- ance ambulation. Boys frequently develop a toe-​walking gait which partially compensates for their proximal muscle weakness—​walking splints or ankle–​foot orthoses are, therefore, not appropriate at this stage and any early Achilles tendon contractures are better man- aged through passive stretching and night-​time below-​knee splints. During the late ambulatory phase, at the point at which walking be- comes impossible independently, knee–​ankle–​foot orthoses can be introduced to prolong ambulation, but are not essential. Corticosteroids are at present the sole available treatment that has been proven to slow down the decline in muscle strength and prolong ambulation. It is recommended that corticosteroids (prednisolone or deflazacort) are started between the age of 2 and 5 years (when strength is plateauing or declining) for the preservation of strength. An increasing consensus has developed that use of daily corticoster- oids (prednisolone at a dose of 0.75 mg/​kg per day or deflazacort at a dose of 0.9 mg/​kg per day) is preferred to alternative regimes; how- ever, intermittent regimens are currently being tested in a double-​ blind randomized trial which may potentially lead to changes in these recommendations. Controlled trials show a clear benefit for strength and respiratory function for up to 18 months, and uncon- trolled long-​term cohort studies report a significant delay in loss of ambulation, a reduction in the development of scoliosis, and a pro- tective effect on respiratory and also cardiac function. Close moni- toring for the side effects of corticosteroids is, of course, indicated, and crucial to minimize the potentially harmful effects of the treat- ment. In DMD the most commonly reported side effects are weight gain (which can be addressed with careful attention to diet), reduc- tion in height, delayed puberty, and behavioural side effects, which may respond to a change in timing of dosage to evening instead of morning, as well as to standard psychological means to improve be- haviour management. A further concern is the development of sig- nificant osteoporosis, which is a risk in any case in boys with DMD, but which may be exacerbated, particularly in the lumbar spine, by steroid usage. The prophylactic use of bisphosphonates in this pa- tient group remains controversial, but intravenous bisphosphonate treatment is certainly indicated if there is a problem with symptom- atic fracture, and this need not be an indication for discontinuation of steroid treatment. Prophylactic cardiac treatment with ACE in- hibitors and β-​blockers is currently being investigated in a double-​ blind, randomized, multicentre, placebo-​controlled trial to assess whether this can prevent the development or delay the age of onset of cardiomyopathy in boys with normal left ventricular function on transthoracic echocardiography. Duchenne muscular dystrophy: after mobility is lost Despite optimal multidisciplinary management loss of ambulation inevitably occurs and interventions and adaptation should follow according to disease progression (early and late non​ambulatory phase). The prompt provision of a powered wheelchair with indoor and outdoor access is critical to the best possible maintenance of independence and access to wheelchair sports. In the early non-​ ambulatory phase provision of a manual wheelchair may also be ne- cessary, predominantly for indoor use and as a backup. With disease progression upper limb strength will inevitably decline and alterna- tive control devices need to be considered to maintain independ- ence. Regular assessment of the wheelchair, with particular attention to correct seating, promoting upright and symmetrical spine pos- ture, is fundamental to reduce scoliosis, as well as lower limb neutral posture to limit foot deformities. Scoliosis is seen in around 90% of patients with DMD who have not been treated with steroids, though corticosteroid use reduces this risk dramatically. For patients with progressive scoliosis, spinal surgery in an experienced setting is a good way to restore posture and comfort, and has an additive effect on survival. Physiotherapy priorities for all boys shift towards pos- tural support, the prevention and containment of contractures, and respiratory maintenance. Alongside progressive loss of ambulation, respiratory muscle strength declines, and respiratory management and prompt intervention become fundamental. Regular measuring of respiratory muscle function (forced vital capacity) in order to monitor the progression of the disease and identification of early signs of respiratory failure is required in order for timely interven- tion and to improve the quality of life and longevity in these patients, since respiratory failure is still among the main causes of death in patients affected by DMD. As forced vital capacity falls further, boys are at serious risk of chest infections and ultimately nocturnal respiratory failure. Respiratory care should begin early with prompt access to anti- biotics at the first sign of any infection, access to immunizations, support for and augmentation of coughing, and non​invasive venti- lation. Patients are at risk of hypercapnia, and oxygen should not be administered without proper monitoring of blood gases and a low threshold for initiating respiratory support. Symptoms of respira- tory failure may be extremely insidious and totally missed unless explicitly sought (Box 24.19.2.7). Routine overnight pulse oxim- etry (which can readily be carried out at home provided that the equipment is available) can show a trend of deteriorating overnight Box 24.19.2.7  Respiratory failure in neuromuscular disease Respiratory failure in neuromuscular disease is a complication which needs to be specifically sought. • It may be the result of intercostal muscle or diaphragmatic weakness or a combination of the two. The presence of a scoliosis or other spinal deformity may be an additional factor. • Nocturnal problems tend to dominate. • Frank symptoms of morning CO2 retention may be seen (poor colour, morning sickness, headaches, confusion) but these are late symptoms and the problem should be detected by investigation or careful history taking before this stage. • Increasing frequency of chest infections may indicate incipient respira- tory failure. • Subtle signs include loss of appetite and weight loss, loss of energy and enthusiasm. • Poor sleep, increasing wakefulness at night, inability to lie flat may also be seen together with a tendency to fall asleep during the day. • Difficulties swallowing and difficulty completing sentences may also be seen. • In many muscle diseases, the main risk of respiratory failure is when the patient is no longer able to walk independently and weakness is pro- nounced (for example Duchenne muscular dystrophy, Becker mus- cular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-​girdle muscular dystrophy, and so on). • In other muscle diseases, respiratory failure may be an earlier feature and present while the patient is still ambulant (for example multicore and other congenital myopathies, some forms of congenital muscular dystrophy). 24.19.2  Muscular dystrophy 6319 oxygenation and, together with the monitoring of symptoms, high- light the time at which elective nocturnal respiratory support, ideally at least through non​invasive ventilation initially, should be provided. Such respiratory support abolishes symptoms, reduces the tendency to chest infections and undoubtedly improves life- span, in particular if combined with spinal surgery, with a good quality of life. In the late stages of DMD, nutrition may be of concern. Loss of weight occurs in most boys as a result of dysphagia, slow eating due to chewing difficulties and low mood as the disease progresses, and issues of diet and the possibility of supplemental nutrition (possibly by gastrostomy) need to be addressed. Patients may need referral to Speech and Language therapy to assess their swallowing function as dysphagia can lead to aspiration pneumonia. Constipation is also frequently reported in DMD and can be se- vere; it may also contribute to reduced appetite. Constipation is usu- ally managed with laxatives or a combination of laxatives and rectal enemas; however, these should be used carefully as they can lead to a vasovagal reaction. DMD patients have an increased anaesthetic risk and pre-​an- aesthetic cardiac and respiratory assessment is important. When exposed to inhalational anaesthetics or muscle relaxants like succinylcholine, patients can develop rhabdomyolysis. Non-​de- polarizing neuromuscular blockers can be used safely instead of succinylcholine. Inhalational anaesthetics should be avoided if possible and intravenous anaesthetics should be used instead. DMD patients are exposed to increased fracture risk due to ster- oids. Early mobilization and rehabilitation is essential. Internal fixation should be taken into consideration to shorten immobiliza- tion. There is also a high risk of vertebral fractures, and these can sometimes be asymptomatic. Fat embolism syndrome is extremely rare, though a life-​threatening event, that usually presents following a fracture of long bones, but can present also after minor trauma. Signs and symptoms suspicious of fat embolism syndrome are shortness of breath and/​or neuro- logical symptoms following a fall or fractures. Respiratory function should be supported. A chest CT scan may be helpful to confirm the diagnosis. Thanks to improvements in care management life expectancy for patients with DMD has increased, and patients are now reaching adulthood with a relatively good quality of life. While this was not the case a few years ago, a young DMD man can now aim to reach higher education levels and also achieve independent living. Transition of care to adulthood needs timely planning, to allow care hand- over ideally to a multidisciplinary team, to monitor and promptly address care needs arising in an adult men with DMD in order to maximize health. While at present only few adult men with DMD achieve independent living, this is likely to become more common in future and represents a challenge for the patient and family; the team around the family should be able to provide adequate support to achieve this and overcome barriers. The actual cause and timing of death in DMD is hard to pre- dict. Some patients will die of a particularly severe chest infection. In others cardiomyopathy may be difficult to control or a cardiac arrhythmia may arise. Any medical intervention at the later stages should be carefully managed by an experienced team. Early onset of cardiomyopathy is a poor prognostic sign. Talking about death to these patients and their parents, helping them to prepare and also address their fears and uncertainties, is another important but easily neglected aspect of management. Education On average, children with DMD have an IQ around 1 standard de- viation below the normal mean; often a striking verbal performance deficit is observed and there is a deficit in number span. Learning problems are not progressive. Additional behavioural phenotypes may complicate the pattern of learning needs, including a tendency to behaviour in the autistic spectrum in some children. Schooling should offer the best possible environment for learning, taking into account the profile of needs of the individual child, and including full attention to information technology equipment, while sup- porting the very real physical needs of the child. Families and areas vary as to whether this will be best provided through mainstream or special schooling. With a good education and medical support, boys with DMD and the appropriate intellectual potential can go on to higher education, and should be encouraged to do so. Becker muscular dystrophy Management issues in BMD tend to cover the same broad areas as DMD, but with the deterioration in muscle function over a much longer timescale. Certain complications, such as scoliosis, are very unusual. Other complications, such as cramping muscle pains after exercise, which can be a particular problem in the teenage years, are more common. Despite the fact that BMD is much milder than DMD, it can represent a considerable and insurmountable dis- ability for the person who has it, and problems with adjustment, poor self-​esteem, and poor body image are all fairly common in this group. There are no hard data to define completely any intel- lectual problems in BMD, but on average it is likely that this group has a general reduction in IQ, although probably not to the ex- tent seen in DMD. Cardiac complications may occur at any age in BMD and require proactive surveillance and management (see Box 24.19.2.5): respiratory complications tend to be a feature of the late stages of the disease. Fascioscapulohumeral muscular dystrophy Fascioscapulohumeral muscular dystrophy (FSHD) is an example of a muscular dystrophy named for the most characteristic pattern of muscle involvement observed (that of involvement of the facial, scapular, and humeral muscles predominantly). However, other muscle groups usually become involved with time and may even be involved at onset. Presentation • Age at presentation is variable. Most affected individuals manifest some symptoms by their teens or twenties. Occasionally symp- toms may be very minor, even late in adult life. • Symptoms may, unusually for a muscular dystrophy, be very markedly asymmetrical. Early symptoms typically include facial weakness (inability to bury eyelashes or puff cheeks; this often goes unnoticed), shoulder girdle weakness manifesting as problems in reaching high shelves, chan- ging light bulbs, or climbing ropes, and foot-​drop. section 24  Neurological disorders 6320 An infantile form of FSHD is recognized with early childhood onset, extremely marked facial weakness, and progressive weakness of both the shoulder and pelvic girdle musculature. Lumbar lordosis may be profound. Hearing loss and retinal telangiectasia may be seen in any patient with FSHD but are particularly associated with this most severe form of the disease. Differential diagnosis The clinical pattern of FSHD can be very distinctive, and the asym- metry of muscle involvement is a major clue. However, facial weak- ness may be very variable and, if it is absent or subtle, confusion can arise with forms of limb-​girdle muscular dystrophy. Diagnostic investigations Serum creatine kinase may be normal or mildly elevated. Muscle biopsy and electromyography (EMG) provide supportive evidence for a muscular dystrophy; some inflammatory features are some- times also seen in the biopsy. Most cases (if not all) of FSHD are linked to altered expression of the DUX4 gene in the macrosatellite repeat D4Z4 region chromosome 4q35. A DNA-​based test is avail- able that can confirm the diagnosis in 95% of cases. This test involves the demonstration of a DNA deletion that is consistently associated with the disease and shows a shortening of the D4Z4 allele, which causes altered expression of the DUX4 gene. This common form of FSHD is known as FSHD1. A smaller percentage of patients (about 3–​5%) have epigenetic factors that alter the chromatin relaxation in the D4Z4 (DUX4 permissive allele) area, without a shortening of the D4Z4 allele; in this group of patients mutations have been identi- fied in the chromatin modifier SMCHD1. This group of patients is known as FSHD2. Prognosis and management Infantile FSHD is a progressive disease that leads to early con- finement to a wheelchair and the development of such complica- tions as scoliosis and respiratory failure. This condition is most frequently seen as a result of a new dominant mutation in cases with no family history, and these children often have particularly large DNA deletions on chromosome 4. The development of a lumbar lordosis, seen also in later-​onset fascioscapulohumeral muscular dystrophy, together with secondary hip flexion con- tractures, can be very disabling. Bracing may be partially suc- cessful at controlling the lordosis, but at the expense of some loss of mobility. More typically, FSHD is a slowly progressive disease. As the disease progresses it can involve the proximal as well as the distal lower limb muscles. Around 20% of patients with FSHD will become unable to walk independently, most when aged over 40. Involvement of the proximal lower limbs before the age of 20 years is a poor prognostic sign, indicating an increased like- lihood of wheelchair use. Some patients describe progression as being stepwise in nature, with periods of faster deterioration al- ternating with phases of plateauing of their symptoms. Foot-​drop is a common complaint, which can be helped by the provision of daytime ankle–​foot orthoses. A significant proportion of patients with FSHD complain of painful muscles, for which no cause can be found and for which pain relief may be difficult. Some pa- tients find swimming or a small dose of antidepressants useful for this symptom. More severely affected patients with FSHD may develop respiratory failure or swallowing problems, and these complications should be sought. Cardiomyopathy is rarely reported. Genetic counselling FSHD1 is an autosomal dominant disease and as such an affected person has a 50% chance of transmission to his or her offspring, regardless of sex. Use of the new DNA diagnostic techniques has shown that up to 30% of cases of FSHD may represent de novo dom- inant mutations. Germline mosaicism is also common. Genetic analysis has also shown a higher proportion of asymptomatic gene carriers than expected, with females overrepresented in this group. The availability of a relatively straightforward genetic test in this disorder has opened up the possibility of presymptomatic and pre- natal testing, which were previously impossible. However, despite an overall correlation between the size of the deletion found and the severity of the symptoms, the DNA test is not useful in predicting the severity of the disease—​people in individual families with appar- ently the same sized deletion may have a very variable experience of the disease (Fig. 24.19.2.4). FSHD2 is inherited in a digenic manner, meaning that SMCHD1 and DUX4-​permissive alleles segregate independently and each parent will carry either a SMCHD1 or a permissive DUX4 allele. Clinically, this means that heterozygous patients are asymptomatic. Putting this together, there is a risk to between 25 and 50% of the offsprings being affected, depending on the haplotypes in the wider Fig. 24.19.2.4  Mother and daughter with fascioscapulohumeral muscular dystrophy. The mother is extremely mildly affected and has minimal symptoms. By contrast the daughter was affected from early childhood and has been wheelchair dependent outside from her early teens. Note the daughter’s expressionless face and her posture—​she is leaning forward due to a combination of her marked lumbar lordosis, a major feature of the condition, and hip flexion contractures. 24.19.2  Muscular dystrophy 6321 family. As for FSHD1, there is variability in disease expression even within the same family. Emery–​Dreifuss muscular dystrophy (OMIM 300384) Classic Emery–​Dreifuss muscular dystrophy (EDMD) has a highly characteristic phenotype. X-​linked recessive, autosomal dominant, and (very rare) autosomal recessive forms are recognized, and the genes involved in these conditions encode proteins that are com- ponents of the nuclear envelope (Fig. 24.19.2.5). The gene involved in X-​linked EDMD is emerin (EMD), and that involved in auto- somal dominant and autosomal recessive EDMD2 and 3 is lamin A/​C (LMNA/​LMNC). Other genes have also been implicated in patients with an Emery–​Dreifuss phenotype, including nesprin 1 and 2 (SYNE1 and SYNE2), EDMD 4 and 5, four-​and-​a-​half-​ LIM protein 1 (FHL1) EDMD6 and transmembrane protein 43 (TMEM43) EDMD7. Presentation • Patients may present at any age, most typically in the early teens, although symptoms may be present much earlier than that. • Contractures of the ankles and elbows and rigidity of the spine often predate any clear weakness. • Consequently, these patients have frequently had Achilles tendon release before the diagnosis is suspected. • Weakness and wasting are typically humeroperoneal in distribution. A key part of these conditions, which may rarely be seen at pres- entation, is cardiac involvement, most typically arrhythmias (see next). Several alternative phenotypes (a form of congenital mus- cular dystrophy limb-​girdle muscular dystrophy 1B and a pure cardiac disease—​Box 24.19.2.8 and see Fig. 24.19.2.5) exist in com- bination with mutations in the same gene as autosomal dominant EDMD (lamin A/​C). Lamin A/​C mutations are also described in several diseases where there is no predominant muscle phenotype, including partial lipodystrophy, some forms of progeria syndromes, mandibuloacral dysplasia, and a form of peripheral neuropathy. Some patients may show overlapping features of these different syn- dromes. Laminopathy is much more phenotypically diverse than X-​linked EDMD and a high index of suspicion of this disorder is necessary, especially due to the almost inevitable life-​threatening cardiac complications. Confirming the diagnosis Serum creatine kinase is typically mildly elevated in EDMD. Muscle biopsy shows non​specific histological features: in X-​linked EDMD, emerin is absent in muscle and skin. Detection of mutation in the emerin gene is necessary to offer genetic counselling to female rela- tives at risk of being carriers. The involvement of lamin A/​C (the gene responsible for auto- somal dominant EDMD) cannot be determined by antibody analysis in muscle, but requires the demonstration of a lamin A/​C mutation. Many lamin A/​C mutations arise anew, and germline mosaicism is common. Use of specific genetic testing has shown that, in fact, in (a) (b) Fig. 24.19.2.5  Muscular dystrophy phenotypes characterized by prominent contractures. (a) This patient has autosomal dominant Emery–​Dreifuss muscular dystrophy, with a proven mutation in his lamin A/​C gene. The elbow and Achilles tendon contractures seen here, combined with his markedly rigid spine, are very similar to the pattern of contractures and weakness seen in the X-​linked form of the disease. (b) Bethlem myopathy in a woman with marked contractures of the elbows, ankles, and spine. In addition she has finger flexion contractures, demonstrated here by attempting to straighten the fingers with the wrist extended. Box 24.19.2.8  The skeletal muscle laminopathies • Forms of congenital muscular dystrophy, Emery–​Dreifuss muscular dystrophy and limb-​girdle muscular dystrophy are all caused my mutations in lamin A/​C, a component of the nuclear envelope. • The phenotype is variable, depending on age at onset and the presence or not of contractures as a major component of the phenotype. • Where contractures are present, these typically involve the elbows, Achilles tendons, and spine. In these patients, there is often a humeroperoneal pattern of muscle weakness as in X-​linked Emery–​ Dreifuss muscular dystrophy. • Where contractures are less of a feature, patients typically present with proximal muscle weakness. • In all groups, cardiac involvement is the most important complica- tion. Arrythmias may lead to sudden death and should be sought and treated appropriately. • A  phenotype with exclusively cardiac involvement has also been described. • New mutations and germline mosaicism is common in this group. section 24  Neurological disorders 6322 contradistinction to what had been previously reported, autosomal dominant EDMD is more frequent than the classically described X-​linked form. Differential diagnosis In addition to previously mentioned other genes (SYNE1, SYNE2, FHL1, TMEM43) that can give rise to Emery–​Dreifuss phenotype, other muscular dystrophies may present with contractures as an im- portant component (see Fig. 24.19.2.5). Some forms of CMD may be associated with contractures and a rigid spine. Bethlem myop- athy may present congenitally (often with torticollis) or in early childhood: here finger flexion contractures, elicited especially on wrist extension, are more prominent and cardiac involvement is not associated. Bethlem myopathy is itself genetically heterogeneous, involving mutations in any of the genes for collagen VI-​α1, -​α2, and -​α3. The condition is allelic to the much more severe CMD, UCMD. Unlike in UCMD, where examination of skin and muscle frequently shows an abnormality of collagen VI expression, in Bethlem myop- athy collagen VI labelling in muscle may be normal. Immunoanalysis of cultured fibroblasts may be a useful diagnostic tool before pro- ceeding to mutation analysis, which is time-​consuming due to the large size of the three genes to be screened and the presence of many polymorphisms. Muscle MRI demonstrates a very characteristic pattern of muscle involvement that can be used to help diagnosis and guide mutation testing. Patients with Bethlem myopathy may show skin abnormalities such as follicular hyperkeratosis and ab- normal scarring. In some cases, calpainopathy (limb-​girdle muscular dystrophy 2A) may be associated with contractures of the ankles, elbows, fin- gers, and paraspinal muscles. However, the associated weakness here is predominantly proximal and of a characteristic distribution (see next). These patients typically have a higher creatine kinase, absent calpain 3 on biopsy and CAPN3 mutations. Prognosis and management The prognosis in EDMD relates almost directly to the ability to manage the life-​threatening arrhythmias to which every patient with either the X-​linked or dominant form is susceptible. Severe arrhythmias are inevitable by the third decade. All patients with this diagnosis should, therefore, be under regular cardiological review, and once a rhythm disturbance has been detected cardiac pacing may be life saving. However, in autosomal dominant EDMD evi- dence suggests that the risk of ventricular arrhythmias necessitates the use of an implantable defibrillator. In this condition there is also a risk of cardiomyopathy, which may be less amenable to routine treatment. Management of the contractures in EDMD is the other main issue, and will involve close liaison with a physiotherapist. Operative treatment of contractures, especially at the Achilles ten- dons, is commonly performed, but, although such surgery does work in the short term, contractures often recur. With increasing age, however, contractures frequently stabilize. Muscle weak- ness may worsen but progression is usually very slow. Rigidity of the spine may complicate weakness of the respiratory muscles and nocturnal respiratory support may be needed. Monitoring should include regular assessment of forced vital capacity when sitting and lying, and symptom enquiry for any symptoms of re- spiratory impairment. The limb-​girdle muscular dystrophies The broad definition of the term ‘limb-​girdle muscular dystrophy’ comes from the classification of Walton and Nattrass in 1954, when the term was suggested to describe those patients with weakness of the proximal musculature who did not fulfil the criteria for either the X-​linked muscular dystrophies or fascioscapulohumeral mus- cular dystrophy. The term has always encompassed a heterogeneous group of disorders: now that many of them can be distinguished at the gene or protein level it is no longer sufficient to use it without qualification as to the specific type of disease (Table 24.19.2.2). The type of limb-​girdle muscular dystrophy may be suggested by the precise pattern of muscle involvement, with confirmation from a combination of genetic and protein analysis. The ability to provide a precise diagnosis in limb-​girdle muscular dystrophy has greatly im- proved the prognostic and genetic information that can be given to these patients. In recent years, thanks to the development and intro- duction of next-​generation sequencing techniques for diagnostic purposes, this particular field of limb-​girdle muscular dystrophies (LGMDs) has grown rapidly, and new genes have been identified as causative of LGMD, or known genes causative of other forms of muscular disorders were identified as responsible for the limb-​girdle phenotype. Careful attention is needed when counselling about these newly identified conditions and prognostic implications. The approach to diagnosis in limb-​girdle muscular dystrophy Could it be dominant disease? Autosomal dominant limb-​girdle muscular dystrophy (LGMD) represents only around 10% of the total LGMD population, and LGMD1A, -​1C, -​1D, and -​1E have been very rarely re- ported. In families with a dominant history the most likely diag- noses are fascioscapulohumeral muscular dystrophy (exclude fascioscapulohumeral muscular dystrophy on DNA analysis espe- cially if there is any suspicion of facial weakness), LGMD1B (al- lelic with autosomal dominant EDMD—​see Box 24.19.2.8), and Bethlem myopathy. New mutations are common, however, so, if the clinical features are suggestive of one of these disorders, the diag- nosis should be pursued even in the absence of a family history. Features that should raise the suspicion of dominant disease are less marked elevation of creatine kinase (typically normal to five times normal in dominant disease and much higher than this in active recessive disease), or the presence of early and prominent contractures. As knowledge of the disorders within the auto- somal dominant LGMD classification has grown, together with a greater understanding of the other phenotypes that have been identified in association with mutations in the same genes, a key feature of these diseases has clearly emerged as variability. So, for example, LGMD1A is due to mutations in myotilin, which is also responsible for a form of myofibrillar myopathy. Patients in this group may have mutations in a range of different genes and the phenotypes may be very variable, including both proximal and distal muscle weakness, and cardiac and respiratory complica- tions. LGMD1B or laminopathy has already been discussed in the section on EDMD—​a very high index of suspicion of this diagnosis is definitely required. Caveolin 3 mutations, respon- sible for LGMD1C, are also now recognized in a form of rippling 24.19.2  Muscular dystrophy 6323 Table 24.19.2.2  The more prevalent autosomal recessive types of limb-​girdle muscular dystrophy Type of muscular dystrophy (gene symbol) Calpainopathy (LGMD 2A) (CAPN3) Dysferlinopathy (LGMD 2B/​MM) (DYSF) Sarcoglycanopathies (LGMD 2C–​2F) (SGCA, SGCB, SGCC, SGCD) Dystroglycanopathies (LGMD 2I, 2K, 2M, 2N, 2O, 2P, 2T, 2U) (FKRP, POMT1, fukutin, POMT2, POMGnT1, DAG1, GMPPB, ISPD) LGMD2L (ANO5) Distribution Worldwide, some isolates (e.g. Reunion, Amish, Basque) Worldwide. Founder effect in Libyan Jewish population.?Others Worldwide. Regional differences in different types Worldwide. Founder mutation in Scandinavia for FKRP Worldwide. UK founder mutation Status of diagnosis Protein, mutations Protein, mutations Protein, mutations (may not be readily found in all patients) Abnormal glycosylation of α-​dystroglycan and laminin A2, mutations in FKRP, POMT1, fukutin, POMT2, POMGnT1, DAG1, GMPPB, ISPD Mutation in AN05 Protein Calpain 3 deficiency detectable by monoclonal antibody on blots Dysferlin deficiency detectable on sections and blots • Dystrophin may be mildly abnormal • γ and α: may see selective reduction • β and δ: mostly see depletion of all Secondary reduction in α-​ dystroglycan and laminin A2 in some muscle biopsies No protein test yet available: all antibody analysis normal Mutations Widely distributed, few recurrent. All types of mutation seen, large deletions rare. Changes may be non-​ pathogenic. Except in homozygotes, difficult to correlate mutation type with rate of progression Widely distributed, few so far recurrent • α R77C seen in 42% of chromosomes • γ two predominant mutations, N. African and gypsy. Otherwise mutations very heterogeneous • Missense mutations mainly in extracellular domain Depending on causative gene involved. FKRP common mutation (C826A) responsible for many cases Founder mutation in UK and other N. European groups Age at onset Typically 8–​15, may be from early childhood or adulthood Most present around 20 (± 5 years). Onset not in first decade α most variable—​may be from childhood to adulthood. γ, β, δ tend to be more severe. Majority of all types will present in first decade Congenital form may be very severe: ranges to very mild disease in LGMD group Typically late adulthood; males usually younger than females Mode of presentation and selective Muscle involvement Highly selective pattern of muscle involvement wasting post. compartment of thighs, scapular winging. Sparing of hip abductors. Relative involvement of muscle groups important Variable. May be: • lower limbs first • proximal alone, mixed proximal/​ distal alone • distal presentation most commonly posterior, may be anterior Weakness, toe walking, muscle pains/​cramps are typical presentations. Main muscles—​shoulder girdle involvement more prominent than DMD, scapular involvement, hamstrings more than quadriceps, lordosis, foot-​drop in some before loss of mobility Proximal muscle weakness Asymmetrical muscle atrophy, may be proximal or distal, clinically may resemble LGMD2B Early development Motor milestones normal; physical prowess in childhood may be less good than peers Normal—​good athletic prowess Motor milestones less delayed than DMD, even if later very severe Usually normal, but can be delayed in some forms Normal Rate of progression May not be linear—​can see rapid change with no gender effect. Otherwise gradual with time. Age at death probably typically in 60s Usually slow—​some more rapidly progressive Cases have similar age at onset Variability main feature: • poor correlation between age at onset/​ progression • rate of progression very variable • may be great intrafamilial variation, even with sibs Variable, usually mild Usually mild; typically maintain ambulation until old age, women may remain asymptomatic Age of confinement to wheelchair 20–​30+ Typically beyond 30s. Seems to be normal lifespan Earliest 9 years. Variability in mild cases very marked. Occasional asymptomatic cases in adult life (esp. α). Typically even most severe cases live to 30s In mild cases 40+, in severe forms <20 Late adulthood if at all (continued) section 24  Neurological disorders 6324 Atrophy Posterior compartment of thighs, latissimus dorsi Typically distal LL, biceps—​may be very selective. Atrophy of proximal deltoid, hypertrophy of distal Anterior and posterior thighs, shoulder girdle Proximal Patchy and may be assymetrical Hypertrophy Occasionally see calf hypertrophy Very rare—​a few cases have transient calf hypertrophy at presentation which may be painful Common in calves, also elsewhere. May be macroglossia Common in calf muscles May be seen in some muscle groups Contractures AT contractures common. Occasionally more widespread No AT contractures, lordosis, hip flexion contractures (may be problem in rehab.). Scoliosis less common than DMD even when WCB Not common in LGMD forms, reported in LGMDK, 2M, 2P Not common Facial involvement Mild facial weakness unusual. Also macroglossia very occasionally seen No facial weakness No facial weakness, may see macroglossia. In later stages typical transverse smile Mild facial weakness common No Cardiac status Normal Normal α usually not present (one Dutch patient). β, γ, δ may be important Cardiomyopathy significant complication Cardiomyopathy not reported to date Respiratory status Respiratory impairment may be significant in some Normal Common, may be at later stage than DMD Some cases require nocturnal ventilation Well-​preserved respiratory status Intellectual function Normal Normal Normal Normal or mildly impaired Normal Creatine kinase 10–​100 × normal May be low or mildly raised in young presymptomatic cases, rising to huge elevation by early teens. Very high in active phase of disease, falling with age 10–​100 × normal 10–​100 × normal 10–​100 × normal Biopsy Dystrophic Dystrophic plus inflammation, may be perivascular or more widespread Dystrophic Dystrophic Dystrophic Other Muscle imaging confirms highly selective pattern of muscle involvement Muscle imaging may reveal asymptomatic proximal changes in distal onset and vice versa. Phenotypes may vary with same mutation and between sibs Genotype–​phenotype correlations: α-​null tend to be more severe; β truncating very severe, huge variation with missense. Majority in γ are truncating mutations. δ mutations so far are rare Allelic with forms of congenital muscular dystrophy Muscle imaging can be quite specific Note Finnish anterior tibial MD homozygotes may show reduction of calpain on blots May have been misdiagnosed as polymyositis or distal myopathy Main differential diagnosis is with dystrophinopathy. Occasional cases may resemble calpainopathy. No clinical guidelines to distinguish subgroups, though very mild disease most likely to be α N/​K Females may remain asymptomatic with hyperCKaemia LGMD, limb-​girdle muscular dystrophy; DMD, Duchenne muscular dystrophy; WCB, wheelchair bound; N/​K, not known; LL, lower limbs; AT, Achilles tendon. Table 24.19.2.2  Continued 24.19.2  Muscular dystrophy 6325 muscle disease, as well as in patients presenting with myalgia or hypercalcaemia. Therefore, a broad level of knowledge about the possible diagnostic features in these different disorders is neces- sary when taking the family tree for these patients, as well as is in the individual clinical assessments required—​rippling, for ex- ample, may be seen only if specifically elicited. What is the age and nature of the presentation? Variability in the age of presentation and the rate of progression is usual in the various autosomal recessive types of LGMD. However, some broad conclusions can be helpful (Fig. 24.19.2.6). Childhood presentation is most common in sarcoglycanopathy, which may superficially resemble dystrophinopathy, with frequent calf (and other muscle) hypertrophy. Adult-​onset cases are less frequent and are essentially ‘Becker-​like’ in presentation. However, whatever the age at presentation, in sarcoglycanopathy, quadriceps is almost always stronger than the hamstrings. This is the reverse of the pattern seen in dys- trophin deficiency. Another important differential diagnosis in a ‘Becker-​like’ (including the presence of calf hypertrophy and cardiomyopathy) presentation is LGMD2I, which is the most common form of LGMD in northern Europe. Calpainopathy may present with early childhood symptoms, especially con- tractures of the Achilles tendons, but onset is most commonly between 8 and 15 years of age. Dysferlinopathy typically pre- sents in the late teens or early twenties, and early features may include proximal weakness or distal involvement (usually manifesting as difficulty standing on tiptoe). LGMD2L can re- semble dysferlinopathy in many ways. Which investigations should be performed? Serum creatine kinase is greatly elevated in all forms of autosomal recessive LGMD, but may be only marginally elevated or within the normal range in autosomal dominant LGMD. EMG confirms a primary myopathic process. Standard analysis of the muscle bi- opsy together with immunohistochemistry analysis has been so far necessary to confirm dystrophic changes (which, especially in dysferlinopathy, can be accompanied by evidence of inflamma- tion) and attempt to determine the type of LGMD together with the clinical features (Fig. 24.19.2.7). Gene analysis is required to confirm the diagnosis. However, if so far the muscle biopsy analysis together with the clinical picture were directing the targeted genetic testing, with the advent of novel sequencing techniques, allowing a simultaneous testing of multiple known genes causative of mus- cular dystrophy, genetic testing is going to replace some of the more invasive investigations (i.e. muscle biopsy). Nevertheless, muscle (a) (b) (c) (d) Fig. 24.19.2.6  Typical clinical pictures of patients with different types of autosomal recessive limb-​girdle muscular dystrophy (LGMD). (a) Calpainopathy or LGMD2A. Note the predominantly atrophic pattern of muscle involvement and Achilles tendon contractures. The stance is often wide based due to the imbalance of the hip abductors and adductors and tight Achilles tendon. (b) Dysferlin deficiency or LGMD2B. Note the wasting of the posterior calf muscles and flat-​footed stance. (c) Child with γ-​sarcoglycanopathy or LGMD2C. Note the lordotic posture and scapular winging, both of which may be more marked at presentation in sarcoglycanopathy than in dystrophin deficiency. (d) Adult with γ-​sarcoglycanopathy, to illustrate the variability in severity of sarcoglycan deficiencies and the muscular hypertrophy, which may be as marked or more marked than in dystrophin deficiency. Fig. 24.19.2.7  Multiplex western blotting as an approach to diagnosis in limb-​girdle muscular dystrophy. Two strips of a western blot of control human skeletal muscle protein extracts immunostained with a mixture of antibodies to the proteins indicated. Absence or reduced intensity of a particular species, compared with the other proteins labelled in the same lane, can indicate which gene and protein are implicated in that patient’s disease. Courtesy of Dr L V B Anderson, University of Newcastle upon Tyne. section 24  Neurological disorders 6326 biopsy and immunohistochemistry analysis may be still necessary and fundamental to interpret genetic variants of unknown clinical significance. Scheme for specialized investigations Do the clinical features or family history suggest a specific disorder (Boxes 24.19.2.9–​24.19.2.11)? If so, look for that first. The sarcoglycanopathies Dystrophin staining may be mildly abnormal in these pa- tients, reflecting the close and interdependent relationship between the proteins of the dystrophin-​associated complex; however, the predominant abnormality on immunolabelling or immunoblotting will be the absence or reduction of one or more of the sarcoglycans. The pattern of reduction of these proteins may give a clue as to the primary gene involvement. Detection of the mutation is necessary to offer prenatal diagnosis and specific genetic counselling. Calpainopathy Here the sarcoglycans are normal, as is dystrophin. Currently avail- able antibodies to calpain 3 do not work on tissue sections but need to be used on immunoblotting. Detection of reduced or ab- sent calpain on immunoblotting (see Fig. 24.19.2.7) indicates the need to search for calpain 3 mutations, which are highly variable, are generally non-​recurrent, and may involve any part of the large (24 exons) gene. Studies consistently report a level of around 20–​ 25% of non​detection of the second mutation in calpain 3, suggesting the presence of a significant number of mutations missed by cur- rent screening technologies. A secondary reduction in calpain 3 may be seen in some cases of dysferlin deficiency. The situation at the muscle biopsy level is also complicated by the fact that patients with mutations, especially in the autocatalytic domain of calpain 3, show normal protein expression on immunoblotting. A multidisciplinary approach to diagnosis in calpainopathy, including the recognition of often a very characteristic phenotype, together with protein and genetic testing, is still required. Interestingly and to add complexity to this field, recent reports suggest rare cases of dominant inherited calpain 3 mutations and further studies are in progress to better understand this new entity. Dysferlinopathy Here, all other proteins with the possible exception of calpain 3 are within the normal range, and deficiency of dysferlin can be demon- strated on tissue sections or immunoblotting. Decreased or absent dysferlin in muscle is an indication to proceed to mutation detec- tion. The dysferlin gene is very large (55 exons) and, as with the other forms of LGMD, mutations are highly variable. LGMD2I and other forms of LGMD with abnormal glycosylation of a dystroglycan It is increasingly recognized that mutations in the same genes, which can cause a congenital muscular dystrophy with abnormal glycosylation of α dystroglycan, can also cause a much milder lgmd phenotype. Indeed, mutations in the FKRP gene can give rise to a severe congenital muscular dystrophy (MDC1C) phenotype as well Box 24.19.2.9  Clinical features of sarcoglycanopathies • These most frequently present in childhood, but may present at any age. Intrafamilial variability is common. • These conditions are most closely related clinically to dystrophinopathy which will be the major differential diagnosis and have a similar spec- trum of severity. • Typically motor milestones are less delayed than in dystrophinopathy. • Muscle hypertrophy is common. • Intelligence is not affected. • Cardiomyopathy is an important complication, though not universal, and should be sought through careful surveillance. • Respiratory failure is an important late complication. • Scoliosis is seen in the most severely affected individuals. • Prognosis overall is typically better than dystrophinopathy presenting at a similar age. Box 24.19.2.10  Clinical features of calpainopathy • This is the most common form of limb-​girdle muscular dystrophy in most populations. • May present at any age but typically 8–​15 years. • Highly selective muscle involvement: posterior thigh weakness, and wasting; scapular winging common at onset. • Muscle hypertrophy rare—​tends to be predominantly atrophic pattern. • Preservation of hip abductor muscles even at late stages contributes to characteristic wide-​based stance. • Most have Achilles tendon contractures:  a subgroup presents with much more prominent contractures in an Emery–​Dreifuss muscular dystrophy-​like pattern. • Progression is variable but never as fast as Duchenne muscular dystrophy. • Cardiac involvement is not common but respiratory impairment may be seen in late stages. • Prognosis in all but the most severe and early onset cases is good. Box 24.19.2.11  Dysferlinopathy: clinical features • Presentation most commonly in late teens or early twenties. • Patients often report good muscle prowess before onset of disease. Serum creatine kinase may not be massively elevated in presymptomatic cases. • Occasional patients present with unilateral calf swelling which may be tender and lead to the clinical diagnosis of myositis. • Primary muscle involvement is always in the lower limbs, with absence of upper girdle involvement at onset. • Lower limb involvement may be of proximal muscles or distal muscles. The distal muscles involved first are typically posterior (leading to difficulty standing on tiptoe as an early feature) but may be anterior. • Progression is typically slow and life expectancy is not reduced. This is the usually mildest type of limb-​girdle muscular dystrophy. • Cardiomyopathy is not reported and respiratory involvement is usually mild and at a very late stage only. • The main differential diagnosis, especially in patients presenting with distal weakness, may be an alternative form of distal myopathy. Typically here the creatine kinase is not so high. Patients with ANO5 mutations (LGMD2L) can present in a very similar way, though pres- entation typically may be later and the pattern of muscle involvement may be more asymmetrical. 24.19.2  Muscular dystrophy 6327 as a much milder and common lgmd phenotype (LGMD2I). The phenotypic spectrum of disease is highly variable, and disease onset can range from the first to the fourth decade of life. This milder phenotype is actually the more common presentation with mu- tations in FKRP (LGMD2I), which is a relatively common cause of LGMD in northern Europe where there is a founder mutation. Respiratory failure and cardiomyopathy are common features, to- gether with muscle hypertrophy and myalgia. Creatine kinase levels can range from moderately raised to very high levels depending on the subtype. The diagnostic clue in these cases is abnormal α dystroglycan on muscle immunolabelling, sometimes associ- ated with a secondary reduction also in laminin A2 especially on immunoblotting. Other forms of limb-​girdle muscular dystrophy Additional rare forms of LGMD have also been described. LGMD2G is mainly seen in Brazil and is due to mutations in telethonin. LGMD2H is restricted mainly to the Hutterite popula- tion of Canada and is due to mutations in TRIM32. Homozygous titin mutations in Finland (where a distal myopathy due to titin mutations is relatively common) cause LGMD2J. LGMD2L is due to mutations in AN05 and mutations in this gene also cause a form of Miyoshi myopathy. The LGMD group is rapidly expanding; at present the LGMD classification is complex and 23 genes have been identified so far in the autosomal recessive group (LGMD2A-​ LGMD2W). The existence of families with an LGMD phenotype but no detectable mutations to date suggests that novel muscular dystrophy genes remain to be identified and this process is likely to be accelerated by the application of the rapid sequencing tech- nologies that are currently coming on line. With the introduction of next-​generation sequencing techniques, patients can now be screened using muscular dystrophy related gene panels, which al- lows simultaneous testing of multiple known genes causative of muscular dystrophy. Where targeted Sanger sequencing or panel gene screening fail to identify a causative gene, whole exome sequencing (WES) has the potential to identify novel causative genes. WES analysis can be performed as a panel analysis in first instance, screening for known genes first, but offers also the op- portunity to widen the screening in order to identify novel genes. These novel and powerful diagnostic techniques will likely reverse the diagnostic workout and approach from what was a phenotype-​ genotype correlation to a genotype–​phenotype correlation. And, if the muscle biopsy and other investigations were so far in most cases preceding the genetic test, this will likely be reversed and used as a tool to prove pathogenicity of variants identified by novel sequencing techniques. Limits of these sequencing methods have to be kept well in mind. Indeed, despite the genome coverage being wide; deletion and duplications, as well as repeat sequences are not always well spotted, and coverage of large genes can represent a challenge. In these cases, standard techniques offer a better diag- nostic approach. Management Once the diagnosis is secure, management should include moni- toring and treatment for the specific complications of the various subtypes. Attention needs to be given to the particular prevalence of cardiac or respiratory involvement and appropriate surveillance and treatment initiated. If a clear diagnosis is not possible (e.g. where appropriate samples are not available or where the diagnosis cannot be reached even after exhaustive investigation), the management should, as a minimum, include physiotherapy and regular cardiac and respiratory surveillance. Oculopharyngeal muscular dystrophy Oculopharyngeal muscular dystrophy is unusual in that it has an ex- ceptionally late presentation. It is another example, like FSHD, were the muscular dystrophy is named for the most characteristic pattern of muscle involvement observed. Presentation • Presentation is typically in the sixth decade. • It commonly presents with ptosis, dysphagia to solids, and dys- phonia, which may be as severe as in myotonic dystrophy. • Other features include ophthalmoparesis, facial weakness, and proximal muscle weakness. Diagnosis The muscle biopsy in oculopharyngeal muscular dystrophy typically shows the presence of rimmed vacuoles and intranuclear inclusions. DNA analysis confirms the presence of an expanded guanine–​ cytosine–​guanine repeat in the poly(A)-​binding protein 2 gene (PABPN1 gene; MIM 602279) on chromosome 14q11. Prognosis and management Ptosis can be managed surgically, but frequently recurs. Dysphagia may respond, at least partially, to surgical intervention with myotomy of the cricopharyngeal muscle and other annular muscle fibres. Potentially life-​threatening complications may include aspir- ation pneumonia and regurgitation. Progression of the limb muscle weakness is highly variable. Genetic counselling Oculopharyngeal muscular dystrophy is an autosomal dominant disorder. Genetic analysis offers the potential for presymptomatic testing if this is specifically sought. Prospects for specific treatment in  muscular dystrophy Drug treatments have a limited place in the treatment of muscular dystrophy at present, apart from the use of corticosteroids in DMD and cardiac medications in conditions where cardiomyopathy is a specific risk. Proactive and anticipator treatment for patients and their families based on knowledge on the likely course of specific diseases remains the mainstay of treatment at present, and this is likely to be the case at least for the current generation of patients. This treatment is ideally provided through a specialized multidis- ciplinary team, bringing together with the ‘myologist’ the skills of medical and associated colleagues from physiotherapy, occu- pational therapy, genetics, cardiology, respiratory medicine, and orthopaedics. Treatments to modify the underlying disease are 24.19.3 Myotonia 6328 David Hilton- Jones 24.19.3 Myotonia 6328 David Hilton- Jones section 24  Neurological disorders 6328 entering clinical trials. Gene transfer experiments in animal models have proved the general feasibility of this approach to these genetic diseases, at least on a small scale. Modification of mutations, either by drugs or by other means, is an area of research, as is the concept of up-​regulating the production of ancillary proteins. Novel and promising therapies arising from genetic manipulation concepts, targeting either DNA or RNA are currently undergoing clinical trials and may be licensed for treatment. In boys with DMD who have a nonsense mutation in the dystrophin gene, resulting in a premature stop codon, nonsense suppression therapies induce a readthrough of premature stop codons through insertion of an amino acid into the peptide chain allowing full translation. While in patients with a deletion resulting in disruption of the reading frame and absence of protein, exon skipping techniques are able to restore the reading frame and produce a shorter, though functional, protein. Other promising approaches include gene transfer through viral vectors. In view of these promising developments with mutation-​specific treatments, achieving a precise genetic diagnosis is fundamental, as is the possibility for these patients to be offered participation in clinical trials, when available. Participation in research is the way forward for better understanding of the disease, identifica- tion of early signs and markers of disease progression and contri- bution to the development of novel therapeutics. Patients should be informed and encouraged to sign on to patient disease specific registries, acting as a database for all patients diagnosed with a specific condition. On top of the need for databases to collect in- formation for better understanding of these rare conditions and help developing standards of care, registries offer the possibility to identify patients for clinical trial and keep patients updated with new developments in the field of muscular dystrophy. The list of registries is available at http://​www.treat-​nmd.eu/​resources/​ patient-​registries/​list/​. FURTHER READING With the rate of change, over the last few years, in the information available about genetically determined diseases, the most up-​to-​date reviews of the subject may be found on the internet rather than in traditional textbooks. Bushby K, et al. for the DMD Care Considerations Working Group (2010). Diagnosis and management of Duchenne muscular dys- trophy, part  1:  diagnosis, and pharmacological and psychosocial management. Lancet Neurol, 9, 77–​93. Bushby K, et al. for the DMD Care Considerations Working Group (2010). Diagnosis and management of Duchenne muscular dys- trophy, part  1:  diagnosis, and pharmacological and psychosocial management. Lancet Neurol, 9, 177–​89. Engel A (ed.) (2004). Myology, 3rd edition. McGraw Hill, New York, NY. Karpati G, et al. (eds) (2010). Disorders of Voluntary Muscle 8th edi- tion. Cambridge University Press, Cambridge. Murphy AP, Straub V (2015). The classification, natural history and treatment of the limb girdle muscular dystrophies. J Neuromuscul Dis, 2, S7–​S19. Nigro V, Savarese M (2014). Genetic basis of limb-​girdle muscular dystrophies: the 2014 update. Acta Myol, 33, 1–​12. Mercuri E, Muntoni F (2012). The ever-​expanding spectrum of con- genital muscular dystrophies. Ann Neurol, 72, 9–​17. Lemmers RJLF, Miller DG, van der Maarel SM (1999). Facioscapulohumeral muscular dystrophy. In:  Pagon RA, et  al. (eds) GeneReviews®. Websites Leiden University Medical Center. Leiden Muscular Dystrophy pages. http://​www.dmd.nl National Center for Biotechnology Information (NCBI). Online Mendelian Inheritance in Man (OMIM). http://​www.ncbi.nlm.nih. gov/​sites/​entrez?db=omim Neuromuscular Disorders Online gene table http://​www. musclegenetable.org/​ TREAT-​nmd network http://​www.treat-​nmd.eu/​ Washington University Neuromuscular Disease Centre. http://​neuro- muscular.wustl.edu/​ 24.19.3  Myotonia David Hilton-​Jones ESSENTIALS Myotonia is defined at an electrical level as repetitive discharge of the muscle fibre membrane after initial activation, which occurs due to dysfunction of the membrane’s ion channels, most commonly the chloride channel, less commonly the sodium channel. This manifests clinically as stiffness of the muscle and delayed relaxation after vol- untary contraction (e.g. difficulty relaxing the grip after clenching the fingers, and stiffness in the thigh muscles and difficulty walking on first moving after rest). Disabling myotonia may respond to carba- mazepine, phenytoin or, often most effectively, mexiletine, although supplies are now limited. Particular myotonic disorders Useful clinical distinction can be made between (1)  myotonic dystrophies—​multisystem disorders in which weakness is a signifi- cant feature, and (2) non​dystrophic myotonias. Myotonic dystrophy type 1 (Steinert’s disease)—​caused by ex- pansion of an unstable trinucleotide repeat in the myotonic dystrophy protein kinase (DMPK) gene, leading to myotonia through altered splicing of the chloride channel gene. There are four main patterns of disease: (1) congenital; (2) childhood onset; (3) classic or early adult onset; (4) late onset, asymptomatic, or oligosymptomatic. The classic form of the disease is the most frequent cause of myotonia and the most prevalent muscular dystrophy in adults (c.1 in 8000). In addition to myotonia and a characteristic pattern of weakness affecting the facial muscles and (unusually for a myopathic disorder) distal limbs, other fea- tures include premature male-​pattern balding, cataracts, central nervous system involvement (cognitive change, excessive daytime sleepiness), cardiac conduction abnormalities (which may lead to sudden death), gastroenterological involvement (dysphagia and irritable bowel syndrome), and respiratory problems. Recurrent chest infections are common due to the combination of muscular 24.19.3  Myotonia 6329 weakness and the tendency to aspirate, and death is often sec- ondary to pneumonia. The underlying trinucleotide repeat is unstable and increases in size during meiosis, giving rise to antici- pation in which the disease has an earlier onset in the offspring of affected individuals. Myotonic dystrophy type 2 (proximal myotonic myopathy)—​ caused by a quadruplet repeat expansion in the zinc finger 9 pro- tein (ZNF9) gene (also called CNBP) that leads to disruption of normal RNA processing and altered splicing patterns of numerous genes. Clinical features are similar to type 1, but with proximal (rather than distal) weakness and less evident anticipation. Non​dystrophic myotonias—​mutations affecting the skeletal muscle chloride channel (CLCN-​1) gene give rise to the rare condition myotonia congenita, which can be inherited as either an autosomal dominant or recessive trait. Myotonia is striking; leg stiffness causing difficulty walking is the major feature, but persistent weakness is uncommon. Introduction Myotonia can be considered as a symptom, a physical sign, or a neurophysiological phenomenon, but understanding is perhaps best served by discussing these in the reverse order. The basic neurophysiological finding is of repetitive muscle fibre action potentials following a stimulus, which may be voluntary con- traction or muscle percussion. The repetitive electrical activity causes muscle contraction, and thus myotonia is characterized by delayed muscle fibre relaxation after such a stimulus. Electromyography demonstrates the repetitive firing. Characteristically, the discharge gradually declines in amplitude and frequency, producing the so-​ called ‘dive-​bomber’ sound in the monitoring loudspeaker. The term ‘myotonia’, and apparently related terms such as ‘paramyotonia’ and ‘neuromyotonia’, cause much confusion. Various diseases accom- panied by myotonia have different molecular origins and many as- sociated symptoms and signs As a physical sign, myotonia is demonstrated either as de- layed muscle relaxation following voluntary contraction (e.g. grip myotonia—​Fig. 24.19.3.1), or as persistent muscle dimpling fol- lowing percussion (percussion myotonia—​Fig. 24.19.3.2). As a symptom, complaints relating to myotonia differ between pa- tients with myotonic dystrophy, which is by far the most common cause of myotonia, and those with myotonia congenita. In myotonic dystrophy, even when grip myotonia is readily evident on examin- ation, the patient may offer no symptoms. They are more likely to complain of hand weakness than of myotonia. When the myotonia is symptomatic, the patient complains of difficulty releasing objects after a tight grip. This is sometimes striking. One patient first noted grip myotonia in early adult life, when he was appointed as a teacher at a school—​as his future headmaster shook his hand to congratu- late him, he was embarrassingly unable to release his grip. In myo- tonic dystrophy, bulbar symptoms relating to myotonia are quite common—​patients complain of their tongue or jaw ‘locking’ when speaking or swallowing, and tongue myotonia on percussion may be demonstrated. By contrast, in myotonia congenita weakness is absent and the myotonia, which is generalized, is problematic, particularly in the lower limbs. Patients complain of stiffness that is most evident on trying to initiate movement after rest. Thus, the patient who has been sitting in the waiting room rises and walks with profound leg stiffness, somewhat reminiscent of spasticity, into the con- sulting room. A classic presentation is the soldier on the parade ground—​after a prolonged period ‘standing to attention’, the order to march results in his falling due to leg muscle stiffness. One such patient also demonstrated marked grip myotonia—​on an unfor- tunate occasion he alighted from a bus but, unable to release his grip from the handrail before the bus departed, was dragged along the road. (a) (b) (c) Fig. 24.19.3.1  Grip myotonia: the patient was asked to grip the examiner’s fingers tightly for 3 s, and then to release the grip as rapidly as possible. The two photographs were taken at 3-​s intervals. section 24  Neurological disorders 6330 In most disorders, myotonia lessens with repeated activity of the muscle. Thus, the sign becomes less striking with repeated percus- sion of the thenar eminence or attempts to demonstrate grip myo- tonia. As a symptom, for example, the leg stiffness in myotonia congenita lessens as the patient continues to walk. In paramyotonia the reverse is seen, with myotonia increasing with activity—​so-​ called paradoxical myotonia. Some, but by no means all, patients complain that their myotonia is worse in the cold. This is again a particular characteristic of paramyotonia. As the anecdotes described here indicate, severe myotonia—​ which is more common in myotonia congenita than the myotonic dystrophies—​can be very disabling. It may respond to phenytoin, but side-​effects can be problematic. Recent evidence favours the use of mexiletine, which is effective and generally well tolerated, with no adverse cardiac effects even in the myotonic dystrophies in which cardiac conduction defects are common. Classification of myotonic disorders As with many other inherited neuromuscular disorders, nomen- clature and classification are currently in a state of flux as mo- lecular mechanisms are being unravelled. For clinical purposes a useful distinction is between those multisystem disorders in which weakness is a significant feature, and which are therefore referred to as dystrophies, and the non​dystrophic myotonias (Table 24.19.3.1). Classic myotonic dystrophy was previously called dystrophia myotonica, which gave rise to the abbreviation DM. It shows no genetic heterogeneity, all cases being associated with a trinucleotide repeat expansion in the 3’-​untranslated region of a novel protein kinase gene (DMPK) on chromosome 19q. This locus and clinical disorder are referred to as DM1. A closely related condition, previ- ously called proximal myotonic myopathy (PROMM), is caused by a quadruplet repeat expansion in intron 1 of the zinc finger 9 protein gene (ZNF9), also called CNBP, on chromosome 3q and is referred to as DM2. The most common non​dystrophic myotonias are the autosomal dominant and recessive forms of myotonia congenita, both of which are caused by mutations of the skeletal muscle chloride channel gene (CLCN1). Different mutations of the skeletal muscle sodium channel gene (SCN4A) give rise to hyperkalaemic periodic paralysis and re- lated disorders, including paramyotonia congenita. These chloride and sodium channelopathies, together with the calcium channel dis- orders causing hypokalaemic periodic paralysis, are discussed fur- ther in Chapter 24.19.4. Schwartz–​Jampel syndrome is a very rare recessive dis- order of infantile onset, characterized by skeletal abnormalities (chondrodysplasia), abnormal facial appearance, and abnormal muscle electrical activity. Electromyography shows periods of con- tinuous electrical activity, which are probably neural in origin. It is caused by mutations in the HSPG2 gene, encoding the basement membrane protein perlecan. (a) (b) (c) Fig. 24.19.3.2  Percussion myotonia: following a sharp tap, the thenar eminence muscles contract and then relax slowly (photographs taken at 3-​s intervals). Table 24.19.3.1  Classification of myotonic disorders Myotonic dystrophies (multisystem myotonic myopathies) Non​dystrophic myotonias DM1: myotonic dystrophy type 1 (chromosome 19q) Chloride channelopathies: myotonia congenita (chromosome 7q) DM2: myotonic dystrophy type 2 (chromosome 3q) Sodium channelopathies: paramyotonia congenita (chromosome 17q) Schwartz–​Jampel syndrome: chondrodystrophic myotonia (chromosome 1p) 24.19.3  Myotonia 6331 Myotonic dystrophy type 1 (DM1) DM1 is the most frequent cause of myotonia and is also the most prevalent muscular dystrophy in adults. It is a multisystem dis- order that has very important (but sometimes rather neglected) manifestations other than skeletal muscle dysfunction, involving cardiac conduction tissues, smooth muscle, eyes, and the central nervous system. Clinical severity ranges from death in utero to a condition so mild that it may be asymptomatic and with no ab- normal physical signs in old age. The molecular basis is an expan- sion of an unstable trinucleotide repeat in a gene coding for a novel protein kinase, DMPK. There is strong evidence that the molecular mechanism in both DM1 and DM2 is disruption of normal RNA processing which causes altered splicing patterns of numerous genes, including the chloride channel gene (compare myotonia congenita)—​this explains the myotonia—​and the insulin receptor gene, causing insulin resistance. Myotonic dystrophy provides a dramatic example of the phenomenon of ‘anticipation’, by which succeeding generations may be much more severely affected than their predecessors, and this correlates with the size of the genetic expansion. Epidemiology The disease is seen worldwide, with a particularly high frequency in French Canadians in Quebec (originating from a single immigrant couple). Incidence and prevalence figures are unreliable, and prob- ably mostly underestimates, because of the difficulty in identifying asymptomatic individuals. A generally accepted prevalence value is 8/​100 000 population. Pathogenesis The molecular basis is the expansion of a trinucleotide (cytosine–​ thymine–​guanine, CTG) repeat sequence in the 3′-​untranslated region of the myotonic dystrophy protein kinase (DMPK) gene on chromosome 19q. In the normal population the size of the re- peat is in the range CTG5–​37, with a trimodal distribution of 5, 11 to 17, and 19 to 37 repeats. Expansions in the range CTG37–​49 are believed to represent premutations. Individuals with myotonic dys- trophy have repeats in the range CTG50–​5000 and, as noted next, there is a correlation between the size of the repeat and clinical severity, and an inverse correlation between repeat size and age of onset. Diagnostic studies are based on measurement of the expansion size in blood lymphocyte DNA. There is only a broad correlation be- tween lymphocyte expansion size and clinical severity, in large part because other tissues may have very different expansion sizes com- pared with lymphocytes. The expansion size in lymphocytes cannot therefore be used in any meaningful predictive fashion for clinical severity and because of misunderstandings relating to this, some la- boratories will only report ‘positive or negative’ for an expansion, without stating the size. A fundamental concept is that the expanded gene is unstable. It is mitotically unstable, and so the size of the gene increases with age. There is somatic mosaicism, so that the expansion is not the same size in different tissues. More important is intergenerational CTG-​repeat instability, which explains why the disease tends to increase in severity, and also show rather different clinical features, in subsequent generations. The gender of the parent of origin is important. In most trans- missions the allele size increases. However, there appears to be a threshold limit for sperm, and males never transmit the very large expansions associated with congenital myotonic dystrophy (see next), which occurs only when the mother is the gene carrier. There is some evidence of meiotic drive, which leads to preferred transmis- sion of the abnormal expanded allele. Clinical features From the previous discussion, it is apparent that there is a con- tinuous distribution of expanded allele size, and a relationship be- tween allele size and disease severity and between allele size and age of onset. While accepting that some patients will fall between these categories, for practical clinical purposes myotonic dystrophy can be considered to give rise to four main patterns of disease: • congenital • childhood onset • classic or early adult onset • late onset, asymptomatic, or oligosymptomatic As it is the best known, and illustrates the multifarious manifest- ations of myotonic dystrophy, the classic form is discussed first. Classic form Onset is in adolescence or early adult life. The principal manifest- ations are summarized in Table 24.19.3.2. Several rarer or clin- ically less important associations are also recognized, including reduced fertility, testicular atrophy, insulin resistance (but rarely overt diabetes), retinopathy, eye movement disorder, peripheral neuropathy, disturbed tests of endocrine function, hypotension, pilomatrixomas, and reduced levels of immunoglobulins and complement. Table 24.19.3.2  Main clinical features of myotonic dystrophy System Manifestations Neuromuscular Weakness Myotonia Ocular Cataract Central nervous system Excessive daytime sleepiness Low IQ Sensorineural deafness Cardiovascular Heart block Dysrhythmias Sudden death Respiratory Recurrent infections Sleep apnoea Hair Premature balding Gastrointestinal Dysphagia Irritable bowel syndrome Pseudo-​obstruction section 24  Neurological disorders 6332 Skeletal and smooth muscle The features of myotonia have already been discussed. The distribu- tion of muscle weakness is highly characteristic. Wasting and weak- ness of the facial muscles, combined with premature male-​pattern balding (in males much more apparent than females), give rise to the typical facial appearance of the condition (Fig. 24.19.3.3). The temporalis muscle is atrophic, giving a sunken appearance over the temples. There is ptosis. Eye closure is weak and in se- vere cases the sclera may remain visible. The jaw tends to hang down. Neck flexion is weak and in some, but not all, patients there is evident atrophy of the sternomastoid muscles. In the limbs, and in marked contrast to most other myopathic disorders, the weak- ness is predominantly distal. In the upper limbs there is weakness and wasting of the small hand muscles and of the long wrist, and finger flexor and extensor muscles in the forearm. There is often profound weakness of grip and the patient complains of difficulty with tasks such as wringing out a cloth and removing the lid from a bottle. A simple hand-​held dynamometer reveals the extent of the weakness—​whereas a normal woman would easily exceed 35 kg, patients of either sex may manage only 1 or 2 kg. In the lower limbs there is weakness of ankle dorsiflexion, presenting as tripping easily and foot-​drop. As the disease advances, weakness becomes evident more proximally, but the marked distal predilection re- mains throughout. Bulbar muscle weakness presents with dysarthria and dysphagia. Smooth muscle involvement contributes towards the dysphagia. Symptoms akin to those of irritable bowel syndrome are frequent. Constipation is also common and pseudo-​obstruction rare. There may be evidence of incoordinate uterine contraction in labour but there is little evidence that this is of any clinical significance and most women can deliver a pregnancy normally. Ocular Cataracts develop at an early age. The initial manifestation is multi- coloured opacities in the subcapsular regions, readily seen on slit-​ lamp examination. Identification of cataracts used to be important in screening asymptomatic family members for the disease, but that has now been replaced by DNA testing. In practice, the cataracts are managed as any other cataracts, being operated on when vision is significantly impaired. Early-​onset cataracts, even in the absence of any other suggestive features, should always raise the suspicion of myotonic dystrophy. Central nervous system Central nervous system disease is expressed in two main ways. As a group, patients with myotonic dystrophy have a lower intelligence than average, but many mildly affected patients have intelligence within the normal range. They are often perceived as apathetic or lacking self-​motivation. There is neuropsychological evidence of specific defects of frontal lobe functioning. The second principal feature is excessive daytime sleepiness, which affects over three-​ quarters of patients, some profoundly. This appears to be a central phenomenon and is only rarely attributable to obstructive sleep ap- noea/​nocturnal sleep disturbance. Cardiovascular Cardiovascular dysfunction is arguably the most important extramuscular manifestation of myotonic dystrophy and is prob- ably responsible for most of the not infrequently reported cases of sudden death. The most commonly recognized pattern is of pro- gressive conduction disturbance. Thus, in very early cases the ECG is normal. Subsequently, the PR interval gradually lengthens until first-​degree block is present. Left anterior hemiblock is particularly common. Later features include bundle-​branch and complete heart block. Tachyarrhythmias also occur, most frequently atrial flutter or fibrillation, but also ventricular arrhythmias, which may be fatal. Symptoms include palpitation, dizzy spells, and fainting. Prolonged ECG monitoring and sometimes intracardiac electrophysiological studies are indicated if such symptoms are reported, or the standard ECG shows significant change. All patients should have an ECG annually and be advised to report any cardiac symptoms immedi- ately. Rhythm disturbances precipitated by anaesthesia or surgery are common, as are respiratory problems. For these reasons, patients should carry a medical alert bracelet/​medallion and, for elective ad- missions for surgery, be reminded to inform the anaesthetist of their diagnosis. The latter is particularly important for asymptomatic in- dividuals diagnosed on the basis of DNA studies following family screening, because they may not consider themselves to be at risk; they are. Although there is some correlation between cardiac in- volvement and overall severity of the myotonic dystrophy, it is not absolute and individuals with minimal muscle involvement may have significant ECG changes. Heart muscle disease, as opposed to disordered cardiac con- ducting tissues, is not clinically significant and routine echocardi- ography is not required. Respiratory Recurrent chest infections are common and relate to respiratory muscle weakness and the tendency to aspirate. In advanced dis- ease, death is often secondary to pneumonia. Respiratory insuffi- ciency may become apparent following anaesthesia, with difficulty in weaning from the ventilator. Chronic hypoventilation and sleep fragmentation may cause excessive daytime sleepiness, but in prac- tice are much less common than the presumed central mechanism already mentioned. However, it must be considered and excluded (e.g. by overnight oximetry) if felt to be a possibility. Particular warning features would include a history of disturbed night-​time Fig. 24.19.3.3  Adult-​onset myotonic dystrophy: typical facial features (see text). 24.19.3  Myotonia 6333 sleep, snoring, waking with headaches, and the development of sec- ondary polycythaemia. Congenital form By definition, this form of myotonic dystrophy is evident at birth, but the spectrum of early-​onset myotonic dystrophy is much wider, as noted next. The exclusive (with only very rare exceptions) maternal transmission of congenital myotonic dystrophy has al- ready been discussed. Many fetuses carrying large expansions are aborted spontaneously in early pregnancy and there is a high rate of fetal wastage. As a result of the unstable nature of the CTG re- peat and the associated phenomenon of anticipation, it is not un- common for the mother to be unaware of her own diagnosis at the time of birth. In that situation, the diagnosis in the infant is not always immediately apparent, because there are no entirely specific clinical features. There is often a history of polyhydramnios and poor fetal move- ment in the pregnancy. The child is born hypotonic (‘floppy’) and talipes is present in about half. Respiratory and feeding difficulties may necessitate assisted ventilation or an oxygen tent, and feeding by nasogastric tube. Some die in the neonatal period from respira- tory complications, but, somewhat surprisingly, there are few fur- ther deaths in the survivors until the late teens and early adult life. There is generalized weakness, including the face—​the jaw hangs open and the mouth has a characteristic tented or carp-​like (as in fish) appearance. Myotonia is not evident clinically and even elec- tromyographically may not appear for several years. In those who survive, hypotonia resolves and motor function im- proves over the following few years, but during adolescence the fea- tures of the classic adult form of the disease appear (Fig. 24.19.3.4). Cognitive impairment is invariable and may be severe. Most re- quire special needs schooling. Bowel involvement is common, with faecal soiling and irregular bowel habit. Curiously, cataracts are rela- tively uncommon. The overall prognosis is poor. Some 25% die in the first 18 months of life, most in the neonatal period. Half survive into the mid-​30s, death most commonly resulting from respiratory involvement, but with a proportion of sudden deaths almost certainly due to cardiac conduction defects. Few achieve an independent adult life. Childhood-​onset form It is only recently that the specific problems of childhood-​onset disease have been recognized. By definition, such children do not have evidence of disease at birth. Motor milestones may be delayed. Problems are often first recognized around the start of schooling with evidence of cognitive delay and poor language development. Dysarthria is common. Fatigue and slowness of activities are often striking. Facial weakness is almost invariable, together with weak- ness of neck flexion. Late-​onset form This form is associated with a small CTG-​repeat expansion. It is typically asymptomatic or oligosymptomatic, and diagnosed during family studies or by an alert ophthalmologist when the patient presents with cataracts. Skeletal muscle disease may be absent, or confined to mild myotonia and weakness restricted to the hands. Balding may be a feature. It is not uncommon to see the parents of a patient with the classic adult form of the dis- ease and not be able to identify the transmitting parent on clinical examination. Importantly, even patients with such minimal symptoms may oc- casionally develop significant cardiac conduction problems and they should have annual electrocardiograms. Management The essential management issues in myotonic dystrophy are: • genetic counselling • annual electrocardiogram (ECG) • anaesthetic risks • physical therapies • cataract surgery A particular concern relates to the genetic phenomenon of antici- pation and the potential for an asymptomatic mother, ignorant of the diagnosis, to give birth to a congenitally affected child. When the diagnosis of myotonic dystrophy is established in a family member it is imperative that at-​risk relatives are offered screening. Reproductive options include prenatal diagnosis, by chorionic villus sampling, with termination of an affected fetus and, gradually be- coming more widely available, preimplantation genetic diagnosis. Annual ECG should be performed in all patients. They and their medical attendants must be aware of the cardiorespiratory compli- cations associated with anaesthesia. They should be encouraged to wear an appropriate medical alert bracelet or medallion. A few pa- tients require nocturnal positive-​pressure ventilation by facemask, but most excessive daytime sleepiness is not related to respiratory insufficiency. Recurrent chest infections are common. Annual influ- enza immunization should be advised. Pneumococcal immuniza- tion is also given but is of uncertain value. Physiotherapy, and occupational and speech and language therapy all have a role, as does the use of orthotic devices (e.g. for foot-​drop). Bowel problems in the congenital form require specific advice and counselling. Excessive daytime sleepiness may respond, sometimes dramatic- ally, to modafinil (but sleep-​related breathing abnormalities should be excluded). Cataract surgery is required when vision is significantly impaired. Fig. 24.19.3.4  Myotonic dystrophy: the affected mother’s two children have the congenital form of the disease. 24.19.5 Mitochondrial disease 6343 Patrick F. Chin 24.19.5 Mitochondrial disease 6343 Patrick F. Chinnery and D.M. Turnbull 24.19.5  Mitochondrial disease 6343 is failure of substrate utilization or supply when energy demands increase during exercise or starvation. In other disorders, there is disruption of the plasma membrane. Apparently idiopathic cases are probably due to an unidentified metabolic defect or infection. FURTHER READING Anderson L, et al. (2014). Effectiveness of enzyme replacement therapy in adults with late-​onset Pompe disease: results from the NCS-​LSD cohort study. Journal of Inherited Metabolic Disease, 37, 945–​52. Brini M (2004). Ryanodine receptor defects in muscle genetic diseases. Biochem Biophys Res Commun, 322, 1245–​55. Christopher-​Stine L (2006). Statin-​myopathy: an update. Curr Opin Rheumatol, 18, 647–​53. Engel AG, Franzini-​Armstrong C, eds (2004). Myology, 3rd edition. McGraw-​Hill, New York, NY. Hanna M (2006). Genetic neurological channelopathies. Nature Clin Pract Neurol, 2, 252–​63. Karpati G, Hilton-​Jones D, Griggs R (eds) (2001). Disorders of volun- tary muscle, 7th edition. Cambridge University Press, Cambridge. Mastaglia F (2006). Drug induced myopathies. Pract Neurol, 6, 4–​13. Mastaglia F, Hilton-​Jones D (2007). Handbook of neurology—​myopathies. Elsevier, Amsterdam. Padala S, Thompson PD (2012). Statins as a possible cause of inflam- matory and necrotizing myopathies. Atherosclerosis, 222, 15–​21. Wagenmakers AJM, Coakley JH, Edwards RHT (1988). The metabolic consequences of reduced habitual activities in patients with muscle pain and disease. Ergonomics, 31, 1519–​27. World Health Organization (1980). International classification of impairments, disabilities, and handicaps. WHO, Geneva. http://​apps. who.int/​iris/​bitstream/​10665/​41003/​1/​9241541261_​eng.pdf World Health Organization (2000). International classification of functioning and disability ICIDH-​2. WHO, Geneva. http://​www3. who.int/​icf/​icftemplate 24.19.5  Mitochondrial disease Patrick F. Chinnery and D.M. Turnbull ESSENTIALS Mitochondrial encephalomyopathies are caused by primary de- fects of the respiratory chain that lead to disturbed generation of adenosine triphosphate by aerobic metabolism. This characteristic- ally impairs the function of high-​demand tissues such as the brain, eye, cardiac, and skeletal muscle, as well as endocrine organs. The numerous proteins involved are encoded by genes in mitochon- drial or nuclear DNA. Mutations in these genes can lead to clinical disorders. Clinical features The clinical presentation of mitochondrial disease is highly vari- able: the same clinical syndrome can be caused by different gen- etic defects, and the same genetic defect may present in a variety of different ways. Several characteristic syndromes are described, including those produced by the following: Large-​scale single deletions of mitochondrial genome—​typically cause progressive ophthalmoplegia and ptosis, and limb muscles may be affected; can also cause an extended phenotype of cere- bellar ataxia, pigmentary retinopathy, sensorineural deafness, dia- betes mellitus, and heart block (Kearns–​Sayre syndrome). These are typically not inherited. Point mutations in the mitochondrial genome are a major cause of inherited visual loss, particularly in young adult males (Leber’s her- editary optic neuropathy). Other syndromes include mitochondrial encephalomyopathy with lactic acidosis and stroke-​like episodes and Leigh’s syndrome of subacute necrotizing encephalomyopathy, with characteristic lesions in basal ganglia, cerebellum, and brain- stem. These may be maternally inherited. Autosomal recessive nuclear genetic mutations cause a range of overlapping phenotypes from severe infantile encephalomyopathy through to ophthalmoplegia, ataxia, and encephalopathy presenting in middle age. Autosomal dominant ophthalmoplegia is also seen. Many patients do not fit precisely into one of these defined clin- ical syndromes and often have systemic involvement, which may be more prominent than the neurological features. Investigation and treatment Investigation—​aside from general investigations to characterize the pattern and nature of organ involvement, the diagnostic strategy depends on the clinical context: (1) Defined clinical syndrome—​in some patients it is possible to identify a specific clinical syndrome with a clear maternal family history suggestive of a mitochondrially inherited disorder. Under these circumstances it is appropriate (after counselling) to proceed directly to molecular genetic testing. (2) Cases not fitting a defined clinical syndrome —​the key investiga- tion is a biopsy of affected tissue (usually muscle) for biochemical studies of oxidative phosphorylation, leading on to molecular ana- lysis of mitochondrial and nuclear DNA before whole exome and whole genome sequencing. However, in consanguineous popula- tions whole-​exome sequencing before biopsy should be considered, especially in children. Treatment—​there is no definitive treatment for most patients with mitochondrial disease. Some very rare enzyme defects have specific treatments (e.g. Q10 biosynthesis disorders). Management is aimed at minimizing disability, preventing complications, and genetic coun- selling. Multidisciplinary expertise is needed to provide adequate nu- trition and physiotherapy, and to address endocrinological, cardiac and ophthalmic complications. Introduction Mitochondria are ubiquitous intracellular organelles that are involved in many different metabolic pathways. Disorders of intermediary metabolism (such as fatty acid β-​oxidation or tri- carboxylic acid cycle defects) involve mitochondrial enzymes, but the term ‘mitochondrial disease’ usually means a disease which is due to an abnormality of the final common pathway of energy metabolism—​the mitochondrial respiratory chain, which is linked to the production of adenosine triphosphate (ATP) by oxidative section 24  Neurological disorders 6344 phosphorylation. The respiratory chain is essential for aerobic metabolism, and respiratory chain defects characteristically af- fect tissues and organs that are heavily dependent upon oxidative metabolism (such as the central nervous system, the eye, skeletal muscle, myocardium, and endocrine organs). Although mitochondrial dysfunction has been demonstrated in many sporadic and inherited disorders, these are not primarily disorders of the mitochondrial respiratory chain and are not con- sidered further here. Biochemistry and genetics of the respiratory chain The intermediary metabolism of carbohydrates, amino acids, and fatty acids generates the reduced cofactors NADH, NADPH, and FADH2. These cofactors transfer electrons to the mitochondrial re- spiratory chain. As the electrons are passed through complexes I to IV of the respiratory chain along the inner mitochondrial mem- brane, protons are pumped out of the mitochondrial matrix into the intermembrane space. This creates an electrochemical gradient that is harnessed by complex V (ATP synthase) to generate ATP from adenosine diphosphate (ADP). Each respiratory chain complex con- tains many polypeptide subunits, some of which are coded by genes within the nucleus and some of which are encoded by the mitochon- drial genome (mtDNA). The mitochondrial genome encodes seven complex I  sub- units (NADH-​ubiquinone oxidoreductase), one of the complex III subunits (ubiquinol-​cytochrome c oxidoreductase), three of the complex IV (cytochrome c oxidase) subunits, and the ATPase 6 and ATPase 8 subunits of complex V. Interspaced between the protein-​encoding genes are two ribosomal RNA genes (12S and 16S rRNA), and 22 transfer RNA genes that provide the necessary RNA components for the mitochondrial translation machinery. The re- maining polypeptides, including all of the complex II subunits, are synthesized from nuclear gene transcripts within the cytosol. These are subsequently imported into the mitochondria through the inner and outer membrane translocation complexes. There are many additional proteins that are essential for the normal as- sembly and function of the mitochondrial respiratory chain. There are currently estimated to be more than 1000 nuclear encoded mitochondrial proteins. As a result, mitochondrial respiratory chain disorders can be due to mutations affecting both nuclear and mitochondrial genes. The classification and investigation of mitochondrial respiratory chain disorders has been revolutionized by the recent advances in our understanding of the underlying genetic defects affecting both mtDNA and nuclear DNA (Table 24.19.5.1). Basic mitochondrial genetics There are two main differences between nuclear DNA and mtDNA that are important for the expression and transmission of mitochon- drial genetic disease, as follows. Heteroplasmy and the threshold effect Each mammalian cell contains over 1000 copies of the small (16.5 kb) mitochondrial genome. Individuals with mtDNA disease often harbour a mixture of mutated and wild-​type (normal) mtDNA—​a situation known as heteroplasmy. Single cells only express a respira- tory chain defect when the proportion of mutated mtDNA exceeds a critical threshold with low levels of wild-​type mtDNA. Different organs, and even adjacent cells within the same organ, may con- tain different amounts of mutated mtDNA. This variability, coupled with tissue-​specific differences in the threshold and the varied de- pendence of different organs on oxidative metabolism, explains in part why certain tissues are preferentially affected in patients with mtDNA disease. In general, postmitotic (non​dividing) tissues such as neurons, skeletal and cardiac muscle, and endocrine organs har- bour much higher levels of mutated mtDNA and are often clinic- ally involved. In contrast, rapidly dividing tissues such as the bone marrow are only rarely clinically affected (one example is Pearson’s syndrome—​see next). Maternal inheritance and the transmission of heteroplasmy After fertilization of the oocyte, sperm mtDNA is actively degraded. Consequently, mtDNA is transmitted exclusively down the maternal line. This means that affected males with mtDNA disease cannot transmit the genetic defect. Deleted molecules are rarely transmitted from clinically affected females to their offspring (risk c.1 in 24). By contrast, a female harbouring a heteroplasmic mtDNA point mu- tation, or mtDNA duplications, may transmit a variable amount of mutated mtDNA to her children. Early during development of the female germ line, the number of mtDNA molecules within each oo- cyte is drastically reduced before being subsequently amplified to reach a final number of more than 100 000 in each mature oocyte. This restriction and amplification (also called the mitochondrial ‘genetic bottleneck’) contributes to the variability between indi- vidual oocytes, and the different levels of mutant mtDNA seen in the offspring of a single heteroplasmic female. Clinical presentation of respiratory chain disorders Mitochondrial disease is highly variable both clinically and at the genetic level. The same clinical syndrome can be caused by dif- ferent genetic defects (which may be within nuclear or mitochon- drial genes), but the same genetic defect may present in a variety of different ways. It is often possible to identify well-​defined clinical syndromes (Table 24.19.5.1), but many patients present with a col- lection of clinical features that are highly suggestive of respiratory chain disease but do not fit into a discrete clinical category. Defined clinical syndromes (See Table 24.19.5.1.) Large-​scale deletions can cause chronic progressive external oph- thalmoplegia and bilateral ptosis (PEO). Some of these patients have limited limb muscle involvement. In contrast, similar deletions may also cause chronic progressive external ophthalmoplegia with bilateral sensorineural deafness, cerebellar ataxia, pigmentary ret- inopathy, diabetes mellitus, and cardiac conduction defects leading to complete heart block. When this begins in teenage years and is associated with a raised cerebrospinal fluid protein, it is called the Kearns–​Sayre syndrome (KSS), which is a progressive neurological 24.19.5  Mitochondrial disease 6345 Table 24.19.5.1  Mitochondrial disease clinical syndromes due to mutations of mtDNA and nuclear DNA Clinical syndrome Clinical symptoms/​signs Age of onset Inheritance Genes Alpers–​Huttenlocher syndrome Seizures, developmental delay, hypotonia, hepatic failure Infancy/​childhood AR POLG Ataxia neuropathy syndromes (ANS): Including MIRAS, SCAE, SANDO) SANDO: PEO, dysarthria, sensory neuropathy, cerebellar ataxia. Other ANS: Sensory axonal neuropathy with variable degrees of sensory and cerebellar ataxia. Epilepsy, dysarthria, or myopathy are present in some Teenage or adult AR POLG, C10orf2, OPA1, SPG7 Autosomal dominant optic atrophy (DOA) Slowly progressive visual failure. 20% have deafness, PEO, ptosis, neuropathy, myopathy Childhood AD OPA1 Deafness sensorineural hearing loss Sensorineural hearing loss Childhood M mtDNA point mutations (eg. m.1095T>C, m.1555A>G, m.7445A>G) Kearns–​Sayre syndrome (KSS) PEO, ptosis, pigmentary retinopathy, cardiac conduction abnormality, ataxia, CSF elevated protein, diabetes mellitus, sensorineural hearing loss, myopathy <20 years S mtDNA single deletions Leber hereditary optic neuropathy (LHON) Subacutre sequential monocular visual loss. males:females 4:1 Adulthood M mtDNA point mutations (m.11778G>A, m.3460G>A, or m.14484T>C in 90%) Leigh syndrome Encephalopathy precipitated by illness, brainstem, and cerebellar dysfunction, neuropathy, cardiomyopathy Infancy AR, M, XLR mtDNA point mutations (usually MTATP6) Mutations in nDNA-​encoded respiratory chain components and assembly factors. PDH deficiency Maternally inherited diabetes and deafness (MIDD) Non​insulin-treated diabetes Sensorineural hearing loss Adulthood M mtDNA point mutations (m.3243A>G is the most common) Mohr-​Tranebjaerg Syndrome Deafness, dystonia Adulthood XLR TIMM8A Mitochondrial DNA depletion syndrome Diffuse myopathy, encephalomyopathy, or hepatocerebral syndrome Congenital or infantile presentation, with hypotonia, respiratory weakness, and death within few years of life AR DGUOK, TK2, C10orf2, POLG, RRM2B, SUCLA2, SUCLG1, MPV17 Mitochondrial cardiomyopathy Cardiomyopathy (hypertrophic or dilated). May be neutropenia (Barth Syndrome) Infancy, childhood, or adulthood M, AR, XLR mtDNA point mutations COX15, SLC25A3, TAZ Mitochondrial myopathy (isolated) Axial/​proximal myopathy. May have other features of mitochondrial disease (ataxia, polyneuropathy) Any age of onset S, M mtDNA point mutations mtDNA single large-​scale deletions Myoclonus, epilepsy, and ragged-​red fibres (MERRF) Stimulus sensitive myoclonus, generalized seizures, ataxia, cardiomyopathy. A minority of patients have PEO Childhood M mtDNA point mutations (m.8344A>G most common) POLG Myopathy, encephalopathy, lactic acidosis, stroke-​like episodes (MELAS) Stroke-​like episodes with encephalopathy, migraine, seizures. Variable presence of myopathy, cardiomyopathy, deafness, diabetes, ataxia. A minority of patients have PEO Typically <40 years of age but childhood more common M mtDNA point mutations (m.3243A>G in 80%) Myopathy, neurogastrointestinal encephalopathy (MNGIE) PEO, ptosis, gut dysmotility, proximal myopathy, axonal polyneuropathy, leukodystrophy Childhood to early adulthood AR TYMP Neurogenic weakness with ataxia and retinitis pigmentosa (NARP) Ataxia, pigmentary retinopathy, weakness Childhood M MTATP6 (usually at m.8993T>G/​C) Pearson syndrome Sideroblastic anaemia, pancreatic failure Infancy S, M Single large-​scale mtDNA deletions Progressive external ophthalmoplegia (PEO) Ptosis, ophthalmoparesis. Proximal myopathy and dysphagia Any age of onset. Typically more severe phenotype with younger onset S, M, AR, AD mtDNA deletions mtDNA point mutations POLG, POLG2, SLC25A4, C10orf2, RRM2B, TK2, OPA1, SPG7 Sengers syndrome Cataract, cardiomyopathy, myopathy, lactic acidosis AR AGK AGK Inheritance pattern: AD, autosomal dominant; AR, autosomal recessive; M, maternal/​mitochondrial; S, sporadic; XLR, X-​linked recessive. Other abbreviations: MIRAS, mitochondrial recessive ataxia syndrome; PEO, progressive external ophthalmoplegia; PDH, pyrivate dehydrogenase; SANDO, sensory ataxia neuropathy dysphagia and ophthalmoplega; SCAE, spinocerebellar ataxia with epilepsy. section 24  Neurological disorders 6346 disorder associated with severe disability. Hypoparathyroidism and hypothyroidism are well-​recognized features of KSS. These two syn- dromes (PEO and KSS) are the extremes of a spectrum of disease and many individuals lie somewhere between the pure extraocular muscle and severe central neurological phenotypes. Pearson’s syndrome of exocrine pancreatic failure, sideroblastic anaemia, and marrow panhypoplasia is usually due to a mtDNA deletion. Pearson’s syndrome also presents in infancy and many individuals who have survived into later childhood subsequently developed the Kearns–​Sayre phenotype. Although many patients with PEO and KSS are sporadic cases, PEO can also be inherited as either an autosomal dominant (adPEO) or recessive (arPEO) trait. These patients have multiple deletions of mtDNA in skeletal muscle, which arise due to a primary nuclear genetic defect. A high incidence of psychiatric disease, a parkin- sonian syndrome and primary gonadal failure have been docu- mented in some families with adPEO. Some arPEO cases have a profound peripheral neuropathy and ataxia (referred to as SANDO, sensory ataxic neuropathy with dysarthria and ophthalmoparesis), and some family members present with adult-​onset ataxia without ophthalmoplegia (also called mitochondrial recessive ataxia syn- drome, MIRAS) which is common in Scandinavia. Mutations in the gene encoding the mitochondrial polymerase (polγ, encoded by the nuclear gene POLG) are a major cause of adPEO and arPEO. adPEO can also be caused by mutations in PEO1 (which codes for the mtDNA helicase Twinkle), SLC25A4 (which codes for the adenine nucleotide translocase ANT1), POLG2 (which codes for the acces- sory subunit of polγ), and RRM2B. AdPEO and optic atrophy are caused by mutations in OPA1, and arPEO with a spastic paraparesis and ataxia is caused by mutations in SPG7. Pathogenic point mutations of mtDNA are more common than rearrangements. This is partly because mtDNA deletions cause sporadic disease, whereas many mtDNA point mutations are trans- mitted down the maternal line. The m.3243A>G mutation in the leucine tRNA gene was first described in a patient with mitochon- drial encephalomyopathy with lactic acidosis and stroke-​like epi- sodes. Different families harbouring the same genetic defect may have different phenotypes. For example, some families harbouring m.3243A>G have predominantly diabetes and deafness, some have chronic progressive external ophthalmoplegia, and some present with hypertrophic cardiomyopathy. It is currently not known why this is the case, but it is likely that additional nuclear genetic factors play an important role in modifying the expression of the primary mtDNA defect. This single mutation is important since it has been estimated that between 0.5 and 1.5% of cases of diabetes mellitus in the general population are associated with the m.3243A>G mutation and accounts for about a third of all adult mitochondrial disease. Patients may present with myoclonic epilepsy, ataxia, optic at- rophy, and have ragged-​red fibres in skeletal muscle (MERRF); this is usually due to a point mutation of mtDNA (e.g. m.8344A>G). mtDNA mutations are the major cause of visual loss in young adult males. About one-​half of all males who harbour one of three point mutations of mtDNA (m.11778G>A, m.14484T>C, m.3460G>A) develop bilateral sequential visual loss in the second or third decade—​a disorder known as Leber hereditary optic neur- opathy. Most individuals with these mutations are homoplasmic, harbouring only mutated mtDNA. It is not clear why the disease only affects approximately one-​half of the males and only 10% of females who inherit the primary mtDNA defect. Clinical penetrance is in- creased by cigarette smoking and a high alcohol intake. Additional, as yet unknown, nuclear genetic factors may also be important in modulating the phenotype. Leigh’s syndrome (subacute necrotizing encephalomyopathy) is a relapsing encephalopathy with prominent cerebellar and brain- stem signs that usually presents in childhood and is associated with characteristic neuroimaging abnormalities involving the basal ganglia. Leigh’s syndrome can be due to an X-​linked pyruvate de- hydrogenase deficiency or a defect of the mitochondrial respiratory chain. Complex I deficiency or cytochrome c oxidase deficiency are common findings in Leigh’s syndrome. In these patients it may be possible to identify recessive mutations in nuclear complex I genes, or genes involved in the assembly of the respiratory chain complexes (e.g. SURF1). Point mutations at position m.8993 in the ATPase 6 gene of mtDNA may cause neurogenic weakness with ataxia and retinitis pigmentosa. These particular mutations are also associated with some forms of childhood Leigh’s syndrome. Alpers–​Huttenlocher syndrome is a severe autosomal recessive hepatoencephalopathy with intractable seizures and visual failure which presents in early childhood and is associated with depletion (loss) of mtDNA in affected tissues. Mutations in POLG are a major cause of Alpers–​Huttenlocher syndrome. Sodium valproate precipi- tates fulminant liver failure in these patients and should not be used. Other causes of mtDNA depletion include mutations in MPV also cause liver disease, TK2 (encoding thymine kinase) which pre- sents with a progressive childhood myopathy or spinal muscular at- rophy, DGUOK (encoding dexyguanosine kinase) which presents in childhood with a myopathy and liver failure, and SUCLA2 (coding for ADP-​forming succinyl-​CoA synthase) which presents in early childhood with an encephalomyopathy. Cytochrome c oxidase deficiency may also present in childhood with an infantile myopathy and a severe lactic acidosis, which may also be associated with a cardiomyopathy and the Toni–​Fanconi–​ Debre syndrome. Despite maximal supportive intervention, this is usually a fatal disorder and a severe depletion of mtDNA occurs in a proportion of these cases. It is important to recognize that isolated myopathy and lactic acidosis may be self-​limiting, often with a sig- nificant improvement by 1 year of age and complete resolution by the age of 3 years. This is associated with the homoplasmic m.14674T>C mtDNA mutation. Other homoplasmic mtDNA mutations known to cause disease include m.1555A>G which causes non​syndromic deafness that may be precipitated by aminoglycosides; and m.1624T>C which can cause Leigh’s syndrome. Coenzyme Q10 deficiency can present in childhood with recurrent myoglobinuria, myopathy, and seizures. In some families it presents with an infantile encephalomyopathy with renal tubular defects. Finally, it may also present with ataxia and variable involvement of other regions of the central nervous system, peripheral nerve, and muscle. Mutations in genes coding for enzymes involved in the bio- synthesis of coenzyme Q10 have been found in some families (e.g. COQ2, ADCK3). Non​specific clinical presentations Many patients do not present with a characteristic phenotype. Children may present in the neonatal period with a metabolic en- cephalopathy and systemic lactic acidosis, often associated with 24.19.5  Mitochondrial disease 6347 hepatic and cardiac failure. This may be associated with depletion in the total amount of mtDNA within affected tissues (see earlier). This syndrome may be fatal. Childhood presentations may be even less specific, with neonatal hypotonia, feeding and respiratory difficulties, and failure to thrive. A respiratory chain defect should be considered in any patient who has a disease with multiple organ involvement, particularly if there are central neurological features (such as seiz- ures and dementia), a myopathy, cardiomyopathy, and endocrine abnormalities such as diabetes mellitus (Fig. 24.19.5.1). Bilateral sen- sorineural deafness and ocular features (retinopathy, optic atrophy, ptosis, and ophthalmoparesis) are common. Renal tubular defects, gastrointestinal hypomotility, cervical lipomatosis, and psychiatric features are also well described in patients with respiratory chain dis- ease. Patients with biochemical defects affecting multiple respiratory chain enzymes are common. These disorders can present from floppy infants with poor feeding at birth to myopathy and ophthalmoplegia in old age. Many are caused by mutations of mtDNA, but a vast array of autosomal recessive nuclear gene defects are also implicated, causing defective intramitochondrial protein synthesis. Investigation of respiratory chain disease The investigation of patients with a suspected mitochondrial encephalomyopathy involves the careful assimilation of clinical and laboratory data. In a significant proportion of cases (such as Leber’s hereditary optic neuropathy), it is possible to identify a specific clin- ical syndrome with a clear maternal family history. Under these cir- cumstances it is appropriate to carry out a molecular genetic test on a blood sample. In many situations, particularly in sporadic cases, this is not appropriate because the clinical features overlap with those of many other disorders. Even if the patient has a mitochondrial dis- order, numerous different genetic defects may be responsible, some of which will not be detectable by analysis of blood samples. Investigations fall into two main groups: clinical investigations used to characterize the pattern and nature of the different organs involved, and specific investigations to identify the biochemical or genetic abnormality. General clinical investigations It is essential to search for the more common features of respira- tory chain disease, especially those which are potentially treat- able. This includes cardiac assessment (ECG, echocardiography, and MRI) and endocrine assessment (oral glucose tolerance test, HbA1c, thyroid function tests, alkaline phosphatase, fasting cal- cium, and parathyroid hormone levels). The organic and amino acids in urine may be abnormal even in the absence of overt tubular disease. Measuring blood and cerebrospinal fluid lactate levels is more helpful in the investigation of children than adults. These measurements must be interpreted with caution because there are many causes of blood and cerebrospinal fluid lactic acidosis, including fever, sepsis, dehydration, seizures, and stroke. The cere- brospinal fluid protein may be elevated. The serum creatine kinase level may be raised but is often normal. Neurophysiological studies may identify a myopathy or neuropathy. Electroencephalography may reveal diffuse slow-​wave activity consistent with a subacute encephalopathy, or evidence of seizure activity. Cerebral imaging may be abnormal, showing lesions of the basal ganglia, high signal in the white matter on MRI or generalized cerebral atrophy. Specific investigations A skeletal muscle biopsy is invaluable in the investigation of respira- tory chain disease. Histochemical and biochemical investigations, in conjunction with the clinical assessment, often indicate where the underlying genetic abnormality must lie. Other clinically affected tissues may also be biopsied, and cultured skin fibroblasts may be investigated particularly in children. Histochemistry and biochemistry Histochemical analysis may reveal subsarcolemmal accumulation of mitochondria (so-​called ‘ragged-​red’ fibres), or cytochrome c oxidase deficiency. A mosaic of cytochrome c oxidase-​positive and Central nervous system Encephalopathy Stroke-like episodes Seizures and dementia Psychosis and depression Ataxia Migraine Cardiac Hypertrophic cardiomyopathy Dilated cardiomyopathy Heart block Pre-excitation syndrome Renal Renal tubular defects Toni-Fancomi Debre syndrome Gastrointestinal Dysphagia Pseudo-obstruction Constipation Hepatic failure Eye External ophthalmoplegia Ptosis Cateract Pigmentary retinopathy Optic atrophy Hearing Bilateral sensorineural deafness Endocrine and diabetes Diabetes mellitus Hypoparathyroidism Hypothyroidism Gonadal failure Peripheral nervous system Myopathy Axonal sensorimotor neuropathy CELL Nuclear subunits mtDNA subunits I II III IV V D-LOOP CYT b ND5 L (CUN) S (AGY) H ND4 ND4L ND3 COX III OL W ND2 M I ND1 16SrRNA 12SrRNA F T Q L (UUR) V P E ND6 OH Y C N A Nucleus The mitochondrial genome G R Mitochondrion ATPase8 ATPase6 S (UCN) COX II COX I D K Fig. 24.19.5.1  The clinical features and biochemical and molecular genetic basis of mitochondrial disease. section 24  Neurological disorders 6348 cytochrome c oxidase-​negative muscle fibres suggests an underlying primary mtDNA defect or a secondary defect of mtDNA as seen in patients with POLG mutations. Patients who have cytochrome c oxi- dase deficiency due to a nuclear genetic defect usually have a global deficiency of this enzyme affecting all muscle fibres. Electron micros- copy may identify paracrystalline inclusions in the intermembrane space, but these are non​specific and may be seen in other non-​ mitochondrial disorders. Respiratory chain complex assays can be carried out on various tissues. Measurement of the individual re- spiratory chain complexes determines whether an individual has multiple complex defects that would suggest an underlying mtDNA defect, involving either a tRNA gene or a large deletion, or a nuclear genetic defect affecting protein translation within mitochondria. Isolated complex defects may be due to mutations in either mito- chondrial or nuclear genes. Co-​enzyme Q10 can be measured dir- ectly in affected tissues. Molecular genetic investigations Under certain circumstances, the clinical and/​or biochemical features may point towards a specific genetic defect detected by targeted molecular genetic analysis in a blood sample (e.g. Leber hereditary optic neuropathy, or POLG diseases), or urinary epi- thelium for some mtDNA defects (e.g. m.3243A>G). In other pa- tients, the first step is to exclude a defect of mtDNA, testing for mtDNA deletions, depletion or point mutations by sequencing in an affected tissue (see next). In patients where the clinical and biochemical features implicate a nuclear genetic diagnosis (e.g. paternal transmission, or multiple deletions of mtDNA), or the mtDNA is normal, then nuclear genetic analysis is carried out. If there is one obvious candidate gene known to be a common cause of the clinical and biochemical phenotype (e.g. SURF1 in isolated COX deficiency), then it is appropriate to sequence a specific gene. In other patients, a long list of genes may be implicated. These may form part of a panel tested using next generation sequencing (e.g. in patients with complex I deficiency). If an obvious panel of genes is not indicated, then exome or whole genome sequencing should be performed. For some mtDNA defects (particularly mtDNA deletions and depletion) the abnormality is not detectable in a DNA sample extracted from blood, and the analysis of DNA extracted from muscle is essential to establish the diagnosis. Urinary epithe- lium can also be used in some circumstances. Many patients with mitochondrial disease have a previously unrecognized mtDNA defect and it is necessary to sequence directly the mitochondrial genome. Interpretation of the sequence data can be extremely dif- ficult. mtDNA is highly polymorphic and any two normal indi- viduals may differ by up to 60 base pairs. In the strictest sense, a mutation can only be considered to be pathogenic if it has arisen independently several times in the population, it is not seen in controls and it is associated with a potential disease mechanism. These stringent criteria depend upon a good knowledge of poly- morphic sites in the background population. If a novel base change is heteroplasmic, this suggests that it is of relatively recent onset. Family, tissue segregation and single cell studies may show that higher levels of the mutation are associated with mitochondrial dysfunction and disease, which strongly suggests that the muta- tion is causing the disease. Management There is currently no definitive treatment for patients with mito- chondrial disease, except for patients with deficiency of coenzyme Q10. Management is aimed at minimizing disability, preventing complications and genetic counselling. Supportive care and surveillance Many patients with mitochondrial disorders require follow-​up over many decades. An integrated approach is essential involving the primary physician, other specialist physicians (ophthalmology, diabetes, and cardiology), specialist nurses, physiotherapists, and speech therapists. Vigilant clinical monitoring over many years can prevent the development of complications, such as those secondary to cardiac and endocrine involvement. Specific procedures may be indicated at various stages of disease. These include cardiac pacing, ptosis correction, cataract surgery, percutaneous gastrostomy, and even transplantation for organ limited disease. Genetic counselling The detailed investigation of patients with respiratory chain disease usually leads to a specific molecular genetic diagnosis. This has pro- found implications on the counselling given to patients and their families. Similar clinical phenotypes can have very different gen- etic causes. For example, PEO can be maternally inherited (due to m.3243A>G), autosomal dominant (due to OPA1) or autosomal re- cessive (e.g. due to POLG). If it is possible to identify the causative mutations in both the offspring and parents, then this will allow con- fident genetic counselling for the whole family. If, as in some cases, it is not possible to identify the underlying gene defect, or the genetic defect in the affected child cannot be traced back to the parents, then counselling is less straightforward. If a causative primary mtDNA defect is identified, then the impli- cations for counselling are distinctly different. Males cannot transmit pathogenic mtDNA defects. Patients who carry mtDNA deletions rarely have a family history suggestive of mtDNA disease, and there is low risk that they will transmit the mtDNA defect to any offspring. Women harbouring heteroplasmic pathogenic mtDNA point muta- tions may transmit the genetic defect to their offspring. The mito- chondrial genetic ‘bottleneck’ leads to a variation in the proportion of mutated mtDNA that is transmitted to any offspring (see earlier). It is therefore possible for a female to have mildly affected as well as severely affected children. The risk of having affected offspring varies from mutation to mutation, and although there does appear to be a relationship between the level of mutated mtDNA in the mother and the risk of affected offspring, there are insufficient data from prospective studies to allow accurate risk prediction. Nuclear genetic defects follow well described inheritance patterns, but the clinical penetrance of many recently identified nuclear gene defects has yet to be established, creating uncertainty in the clinic. Prognosis In general, the prognosis depends upon the extent of central neuro- logical involvement. Patients with Leber’s hereditary optic neuropathy 24.19.5  Mitochondrial disease 6349 rarely have significant central neurological features and have a normal lifespan. The prospect for visual recovery varies. After the initial nadir, individuals harbouring the m.11778G >A mutation are the least likely to regain functional vision, while those harbouring the m.14484T >C mutation are the most likely to regain their sight. Children presenting with an encephalopathy have a poor prog- nosis. Although residual neurological deficits are common after re- peated childhood encephalopathic episodes, the disease may enter a more stable ‘chronic’ phase during teenage years and adulthood. A similar course may be seen in adults presenting with a relapsing encephalopathy. In contrast, a large proportion of adults with mtDNA defects and chronic progressive external ophthalmoplegia have very mild disease that may remain limited to the extraocular muscles for many decades. For specific mtDNA mutations, there also appears to be a relationship between the proportion of mutated mtDNA in skeletal muscle and the severity of the disease. Although the proportion of mutated mtDNA in muscle may give some guide to prognosis, there is insufficient information available to allow ac- curate prognostic counselling based upon these determinations. A significant proportion of patients have distinct phenotypes associ- ated with unique genetic defects and the prognosis must be guarded in these families. Pharmacological treatments and novel approaches under development No medicines are licenced for the treatment of mitochondrial dis- eases, and there is no objective evidence that any treatment is effective. Anecdotal reports describe benefits from ubiquinone (coenzyme Q10) in patients with disorders of coenzyme Q10 biogenesis, and some patients have a riboflavin-​responsive disorder. Several clinical trials are currently evaluating the effects of novel treatment approaches in patients with mitochondrial disease (https://​ClinicalTrials.gov), and idebenone shows promise as the first treatment for Leber hereditary optic neuropathy. Bone marrow transplantation is effective in pa- tients with very rare autosomal recessive enzyme defects (caused my mutations in TP). Dichloracetate can be used to reduce lactic acid levels but may cause an irreversible toxic neuropathy and is therefore not used in adults. Exercise is important for patients with mtDNA disease, and isometric muscle contraction may lead to an improve- ment in muscle strength. Finally, several centres are investigating methods for correcting the underlying mtDNA defect using targeted antigenomic molecules and gene therapy, and new approaches are being developed to prevent the transmission of mtDNA mutations through mitochondrial donation. FURTHER READING Anderson S, et al. (1981). Sequence and organization of the human mitochondrial genome. Nature, 290, 457–​65. Chinnery PF, et al. (2014). The challenges of mitochondrial replace- ment. PLoS Genet, 10, e1004315. Di Mauro S, et al. (2013). The clinical maze of mitochondrial neur- ology. Nat Rev Neurol, 9, 429–​44. Gorman GS, et al. (2015). Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Annals of Neurology, 77, 753–​9. Klopstock T, et  al. (2011). A randomized placebo-​controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain, 134, 2677–​86. Klopstock T, et  al. (2013). Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy. Brain, 136, e230. Koopman WJ, Willems PH, Smeitink JA (2012). Monogenic mito- chondrial disorders. N Engl J Med, 366, 1132–​41. Pfeffer G, et  al. (2012). Treatment for mitochondrial disorders. Cochrane Database Syst Rev, 4, CD004426. Pfeffer G, et al. (2013). New treatments for mitochondrial disease—​no time to drop our standards. Nat Rev Neurol, 9, 474–​81. Stewart JB, Chinnery PF (2015). The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat Rev Genet, 16, 530–​42. Taylor RW, et al. (2014). Use of whole-​exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain com- plex deficiencies. JAMA, 312, 68–​77. Vafai SB, Mootha VK (2013). Medicine: a common pathway for a rare disease? Science, 342, 1453–​4. 24.2 Mind and brain Building bridges between neuro 24.2 Mind and brain: Building bridges between neurology, psychiatry, and psychology 5778 Adam Zeman ‘The great regions of the mind correspond to the great regions of the brain’ Paul Broca ‘ . . . the master unsolved problem of biology: how the hundred million nerve cells of the brain work together to create consciousness . . . ’ E. O. Wilson. Consilience, 1998 ESSENTIALS Medicine is traditionally regarded as concerning itself with disorders of the body while psychiatry concerns itself with disorders of the mind—​and ‘never the twain shall meet’. But both everyday clinical experience and our growing understanding of the physical basis of mind challenge this view. Patients are always a compound of body and mind; discoveries relating to the mechanisms, phylogeny, on- togeny, and functions of the central nervous system are gradually traversing the mind-​body and mind-​brain divides. We should take a bio-​psycho-​social approach in every clinical encounter and seek theories that explain the emergence of mind from life much as life emerges from matter. Introduction Here is one view of the relationship between medicine and psych- iatry: physicians study, diagnose, and treat disorders of the body. Psychiatrists, by contrast, study, diagnose, and treat disorders of the mind. Medicine is concerned mainly with processes in objects—​ like the circulation of the kidney; psychiatrists concern themselves mainly with the experiences of subjects—​like auditory hallucin- ations. Medical disorders are ‘organic’, psychiatric disorders are ‘func- tional’. Medicine is mainly a science, psychiatry mainly an art. The brain, on this view, occupies an ambiguous position, poised between body and mind: it is an ambiguous intermediary, a skilful interpreter between the languages of mind and body. Nevertheless, disorders of body and mind can and should be rigorously distinguished. This chapter will examine, and question, these assumptions. They are not universally held but they are widespread and ten- acious. They have some practical importance, influencing the way that doctors approach patients and train students, and they underpin a deep theoretical problem in biology, the puzzling rela- tionship between body and mind. A century of research on the bio- logical basis of cognition, mood, personality, and behaviour, and much recent writing in philosophy, points to the need to rethink these time-​honoured beliefs. What is the mind? ‘Mind’ is not a scientific term and has no strict technical definition. We use it to refer, broadly, to the capacities that enable our cog- nition, mood, motivation, personality, and behaviour. ‘Cognition’ in turn, a word derived from the Latin ‘cognoscere’, to know, re- fers to our intellectual capacities: very broadly these allow us to gain and store knowledge of the world, including one another, and to use it to guide our actions. Cognition is currently subclassified into attention, memory, executive function (the ability to organize thought and behaviour), language, perception, and praxis (our capacity for skilled action). Cognition is closely related to—​but not identical with—​the other aspects of mind: mood and motiv- ation are self-​explanatory; personality refers to the more or less enduring traits that characterize our conduct of our lives and our approach to other people; behaviour is included among the elem- ents of mind to allow for instances—​like temper tantrums—​in which the outward manifestations of mental processes are their most striking feature. It is worth noting, in passing, that because the term ‘mind’ is col- loquial rather than technical, and because its workings are of great interest and importance to most of us, we tend to have preconcep- tions about its nature. These are strongly influenced by our religious and cultural backgrounds. There is, for example, a powerful human tendency, apparent across cultures and historical time, to believe that the mind can be prised apart from the body and survive its death. Whatever our own attitudes to these beliefs, they continue to exert a widespread influence. 24.2 Mind and brain: Building bridges between neurology, psychiatry, and psychology Adam Zeman 24.2  Mind and brain 5779 What is consciousness? Another complex capacity, consciousness, closely linked to mind, has attracted enormous interest over the past 30 years. The term ‘consciousness’ can be used to refer both to a state of arousal—​ wakefulness, for example, as opposed to sleep or coma—​and to the contents of our awareness—​for instance, ‘what it is like’ to be sitting and reading these words. Recent advances have allowed neuroscien- tists to investigate the physical basis of experiences like this, taking due account both of the rich texture of our awareness and the im- mense subtlety of the related processes occurring in the brain. The advances that have made this possible include the development of functional brain imaging techniques, which are constantly revealing exquisite correlations between features of experience and events in the brain; and discoveries in psychology showing that only a part of what happens in the brain ever reaches awareness, underwriting the concept of unconscious processes. But the fundamental explanation for the current, widespread, fascination with consciousness is that its science holds out the promise of healing the ancient rift between brain and mind. The biology of conscious and unconscious mind Mechanism The maintenance of wakefulness depends upon the integrity of a complex activating system located in the upper brain stem, thal- amus, hypothalamus, and basal forebrain which projects widely throughout the cerebral hemispheres to regulate conscious states. These are reflected in the rhythms of the brain’s electrical activity recorded from the scalp—​the electroencephalogram (EEG). The contents of awareness, by contrast, depend upon the transient acti- vation of widespread ‘neuronal assemblies’, interconnected groups of neurons distributed among cortical and subcortical regions. The recent discovery of the brain’s ‘resting state networks’ high- lights the underlying organization that gives rise to these transient assemblies. At any given moment, much of the potentially conscious activity in the brain occurs unconsciously—​you were probably not aware, before reading this, of the tension in your left elbow. What distin- guishes the neural activity of which we are aware? There are sev- eral candidates with some empirical support for each: the quantity of neural activity, related to its amplitude and duration; its quality, for example, the degree of synchronization among participating neurons; its location in the brain, for example, whether it is predom- inantly cortical or subcortical; its connectivity, for example, whether activity in early sensory areas does or does not propagate to cor- tical areas downstream. The two current leading theories of aware- ness, the global workspace model, and the integrated information approach, both emphasize the last of these four parameters. They propose that the distinctive feature of the neural activity ‘in con- sciousness’ is that it is both processed locally and communicated widely throughout the brain, gaining access, in particular, to the neural resources that control action and allow report. These theories are beginning to bear practical fruit, as in the recent development of a ‘perturbation complexity index’, which captures the complexity of conscious state and content in a single informative value. Phylogeny—​evolution of the mind The elements of the nervous system—​the neuron, its ion channels, and its chemical transmitters—​date back to the origins of multicel- lular life. In almost every complex organism these common elements have been exploited to create a signalling system that enables ani- mals to respond to events around them with appropriate actions, the earliest embodiment of mind. Some animals have invested heavily in this system, allowing a progressively richer range of perceptual distinctions and a more flexible repertoire of response. This process of ‘encephalization’ has been particularly striking in parts of the ver- tebrate lineage, including our own primate line. The rapid growth of the brain, out of proportion to change in body size, has been the most striking feature of the past five million years of hominid evo- lution. It occurred in parallel with—​probably both drove and was driven by—​the emergence of technology, language, and culture, with the implication that the most distinctive features of the human mind are integral to our biology. Ontogeny—​individual development of mind ‘Follow a child from its birth, and observe the alterations that time makes, and you shall find, as the mind by the senses comes to be more and more furnished with ideas, it comes to be more and more awake’, wrote the philosopher John Locke 300 years ago. Our cap- acity to learn, the prerequisite for the process Locke describes, is now thought to depend upon the plasticity of synapses: these are shaped by experience, which strengthens some and weakens others, creating neural assemblies that represent regularities in the world around us and in our behaviour. There is no shortage of material for this process: the human brain contains of the order of 1011 neurons, each receiving up to many thousands of synapses. The development of a human mind has another crucial dimension. The acquisition of a ‘theory of mind’ between the ages of around two and five—​the realization that we ourselves and those around us gain knowledge of the world from a fallible, limited, perspective, and are therefore liable to false belief—​may be the most distinctively human intellectual achievement. Function What is the biological purpose of the mind? Simple nervous sys- tems are networks of communication and control, designed to en- sure that the organism responds to events in the environment with appropriate actions. Complex nervous systems elaborate these pro- cesses, but the tailoring of behaviour to circumstance remains the fundamental function of the mind. The mind-​brain problem How then are mind and brain related? The relationship is clearly intimate, but also puzzling. Traditionally, physicalism claims that what passes through our mind is identical with what happens in our brains; behaviourism asserts that statements about mental events can be reduced to statements about behaviour; functionalism sug- gests that mental processes can be understood in terms of transform- ations of sensory inputs into motor outputs. The puzzle that troubles some thinkers about mind and brain is that, seemingly, one could know everything about an organism’s neural processes, behaviour, SECTION 24  Neurological disorders 5780 and functional design, and yet be ignorant about what it is like to be that creature. This inspires alternative ‘dualistic’ accounts of mind and brain, which posit an essential difference between mental and physical, subjective and objective, entities or properties. But these dualistic theories, in turn, get into difficulty when they try to explain the undoubted interactions between mind and brain. This ancient dilemma remains unresolved: it seems likely that the solution will involve some changes in our understanding of the nature of both matter and mind. A practical solution: A bio-​psycho-​social approach The mind-​brain problem impinges on clinical practice. As every practising doctor knows, interactions between mind, brain, and body are constantly on view. Here are some examples: (1) med- ical problems usually come to light by way of a complex set of intervening psychological processes that occur when someone notices, ponders and decides to present with a physical symptom; (2) psychological upset can manifest itself in physical symptoms, as for example in a panic attack or a somatoform disorder; (3) phys- ical diseases commonly cause secondary psychological reactions, such as anxiety and depression; (4) physical disease affecting the brain often gives rise directly to psychological manifestations, for example, memory loss. Given that the physical and mental are both constantly on show in the everyday practice of medicine, there is much to recommend taking a ‘bio-​psycho-​social’ approach to every patient. This acknow- ledges that people can’t be divided into ‘organic’ and ‘functional’ groups: we are all compounded of body and mind. In every clinical encounter—​whether in general practice, cardiology, neurology, or psychiatry—​we should aim to define its biological, psychological, and social dimensions. A theoretical solution: Matter, life, and mind In the 19th century many thinkers believed that ‘life’ was an irre- ducible phenomenon, the manifestation of an ‘élan vital’. The bio- chemical discoveries of the 20th century revealed that life simply is the set of processes that allow organisms to utilize energy from their surroundings to reproduce themselves—​and thereby made it clear how matter could give rise to life. It seems natural to ask whether mind might be explained in terms of the intelligent activities of living things, just as life has been explained in terms of the workings of organized matter. Is this a plausible ambition? As we have seen, attempts to ‘conjure’ mind from brain can be met with puzzlement: there seems to be no possibility of understanding how the ‘water of the brain’ gives rise to the ‘wine of experience’. But arguably the problem we run into here results from narrowing the frame of explanation too severely. Mind is not a mysterious eman- ation from the brain—​it is always the activity of a human being: an activity rooted in a brain and body; the product of a long, largely forgotten history of development; embedded in the context of a human culture; and usually engaged in interaction with its physical surroundings. The brain is not a magic lamp from which we conjure the genie of mind: it is instead a great enabler, a subtle instrument enabling us to apprehend, and engage with, the rich complexities of our social and physical environment. Conclusion Given what science and philosophy reveal about the nature of the mind, here is an alternative view of the relationship between medi- cine and psychiatry: physicians and psychiatrists study, diagnose, and treat illnesses. These are physical processes linked to human experiences, the outcome of disorders of structure or function occurring in organisms. Some, medical disorders, are more easily identified or understood at the level of bodily process, others, psy- chiatric disorders, at the level of subjective experience, but this distinction is extremely fluid, especially so in clinical neurology. Medicine must always draw on science, to understand the physical basis of disorders, and art, to appreciate the individual human com- plexities of the resulting predicaments. All our disorders affect our bodies and our minds. FURTHER READING Butler C, Zeman A (2005). Neurological syndromes which can be mistaken for psychiatric conditions. J Neurol Neurosurg Psychiatry, 76(Suppl 1), i31–​8. Cummings JL, Mega MS (2003). Neuropsychiatry and behavioural neu- roscience. Oxford University Press, Oxford. David AS, et al. (eds) (2009). Lishman’s organic psychiatry: a textbook of neuropsychiatry, 4th edition. Wiley-​Blackwell, Chichester. Gazzaniga MS, et al. (2013). Cognitive neuroscience: the biology of the mind, 4th edition. W.W. Norton & Company Ltd, New York, NY. Laureys S, Gosseries O, Tononi G (2016). The neurology of conscious- ness, 2nd edition. Academic Press, San Diego, CA. Zeman A (2002). Consciousness: a user’s guide. Yale University Press, New Haven, CT. Zeman A (2014). Neurology is psychiatry and vice versa. Pract Neurol, 14, 136–​44. 24.21 Acquired metabolic disorders and the nervous 24.21 Acquired metabolic disorders and the nervous system 6368 Neil Scolding ESSENTIALS Many systemic disorders of metabolism have neurological conse- quences. Conditions of particular note include the following: Major organ diseases Anoxic brain damage—​cardiac arrest is a relatively common cause of global cerebral anoxia; other causes include suffocation, anaesthetic catastrophes, drowning, or acute carbon monoxide poisoning. The consequences depend on the duration of anoxia: (1) brief—​manifests as syncope; (2) longer lasting (up to perhaps 5 min)—​there is rapid loss of consciousness, generalized fits, dilated pupils, and bilateral ex- tensor plantar responses; long-​term course and prognosis are unpre- dictable; (3) more sustained (longer than a few minutes)—​permanent or prolonged, but reversible brain damage. Other conditions—​these include (1) Hepatic encephalopathy—​acute hepatic coma and chronic hepatic encephalopathy; (2) respiratory disease—​chronic respiratory failure causing hypercarbic encephalop- athy; obstructive sleep apnoea; (3) renal failure—​neurological mani- festations include uraemic encephalopathy, symmetrical sensorimotor polyneuropathy, myopathy, dialysis disequilibrium syndrome, dialysis dementia; (4) critical illness polyneuropathy. Endocrine disorders Many endocrine disorders have neurological manifestations, including: (1) Phaeochromocytoma—​anxiety, headache; complica- tions of accelerated phase hypertension. (2)  Cushing’s syndrome—​ proximal myopathy, psychiatric disorders, direct consequences of pituitary tumour. (3) Adrenal insufficiency—​adrenal crisis may manifest with depressed consciousness and/​or neurological complications of hypoglycaemia or hyponatraemia. (4) Thyroid disease—​thyrotoxicosis can cause myopathy, chorea, and mania; hypothyroidism can present with a confusional state or coma and is often associated with a my- opathy. (5) Diabetes mellitus—​complications include mononeuritis, diabetic amyotrophy, peripheral neuropathy, autonomic neuropathy, and those due to hypoglycaemia. Ionic abnormalities (1) Hyponatraemia—​non​specific symptoms may appear when the plasma sodium drops below about 120 mmol/​litre; fits and coma are usually associated with plasma sodium values below 110 mmol/​litre. The condition and its treatment (see Chapter 21.2.1) can be associated with central pontine myelinolysis. (2) Hypernatraemia—​may cause drow- siness or (in severe cases) coma; (3) hypercalcaemia—​muscle weakness, lassitude, and a mild encephalopathy are common; (4) hypocalcaemia—​ causes neuromuscular irritability, tetany with a Chvostek’s sign, and mild encephalopathy; severe hypocalcaemia may cause fits, psychosis, and coma. Alcohol Effects of alcohol on the nervous system, aside from those that are acute and transient, include (1) delirium tremens—​an agitated confused state, with signs of sympathetic overactivity, that typically develops rapidly several days after ethanol abstinence in chronic abusers; (2) Wernicke–​Korsakoff syndrome—​classically manifesting with confusion, ophthalmoplegia and ataxia; treatment with thia- mine should be given on suspicion; (3)  peripheral neuropathy; (4) cerebellar degeneration; (5) dementia; (6) myopathy. Introduction There are various common prejudices concerning acquired meta- bolic diseases and their neurological complications: that they are uncommon; and that little, if anything, has changed on the subject for the past half century or so. They may indeed be uncommon amongst Neurology inpatients—but a brief foray into an Internal Medicine or a Care of the Elderly ward reveals a very different truth. And it is indeed true that that the descriptions of the clinical fea- tures of Wernicke’s and Korsakoff’s syndromes have not really been bettered (i.e. significantly altered) since these eponymous disorders were first identified. However, the dramatic, serious, and not un- common neurological picture of central pontine myelinolysis and its still uncertain metabolic cause(s); the emergence of new(-​ish) disorders such as superficial siderosis and E-​induced water intoxi- cation; the changing face and context of other disorders (e.g. iatro- genic Cushing’s syndrome, chemotherapy-​induced nutritional and metabolic disruption); all of these help to emphasize the import- ance and impact of acquired neuro-​metabolic diseases. This chapter aims to deal with these, or to point elsewhere in this text to where they are covered. 24.21 Acquired metabolic disorders and the nervous system Neil Scolding 24.21  Acquired metabolic disorders and the nervous system 6369 Metabolic complications of major organ disease Cardiovascular disease: anoxic brain damage Cerebral anoxia is caused by insufficient cerebral blood flow, re- duced oxygen availability, reduced oxygen carriage by the blood, or metabolic interference with the utilization of oxygen, alone or in combination. Thus, cardiac arrest is a relatively common cause of global cerebral anoxia; others as diverse as suffocation, anaesthetic catastrophes, drowning, or acute carbon monoxide poisoning can produce similar results. Brief global ischaemic anoxia causes syncope. If the episode is prolonged, myoclonic jerks or tonic–​clonic seizures may occur. Still more protracted insults may precipitate a period of confusion and residual amnesia. More lasting acute severe anoxia rapidly leads to loss of conscious- ness, generalized fits, dilated pupils, and bilateral extensor plantar responses. Periods of anoxia up to perhaps five minutes may cause transient coma with recovery of consciousness. Delayed postanoxic encephalopathy, characterized pathologically by demyelination in the hemispheres and in the basal ganglia, may follow within one to two weeks, often commencing with increasing irritability, apathy, and confusion. Frank dementia may emerge, or an amnesic syndrome in less severe cases, and there may also be pseudobulbar palsy and other pyramidal signs, gait ataxia, and in- continence, and/​or an akinetic–​rigid syndrome with or without dys- tonia. Some patients may be severely disabled by action myoclonus. The course and prognosis in prolonged cerebral anoxia are most unpredictable: residual deficits may be permanent; slow (months to years) but often considerable recovery may emerge; or the condition may progress occur over weeks to months. Yet more sustained oxygen deprivation—​more than a few minutes—​results in permanent or prolonged but reversible brain damage. Irreversible coma may be accompanied by flaccidity, loss of all reflex function except heart beat and tendon jerks, fixed, dilated pupils, and a flat electroencephalogram. (Drugs and hypothermia may cause a flat electroencephalogram, but recovery is possible.) Such patients are considered in some countries to have suffered irre- versible brain death if all signs of brainstem function are absent on repeated examination over 12 to 24 h. Other, less severely affected patients show partial recovery of brainstem reflex function, such as pupillary responses, reflex eye movements, and muscle tone, and may breathe spontaneously. However, no sign of consciousness or intelligent response to the external world occurs, and they may re- main in such a persistent vegetative state for months or years. Subacute or gradual anoxia may occur in severe anaemia, heart failure, pulmonary disease or exposure to high altitude (‘mountain sickness’). It produces inattentiveness, fatigue, headache, and intel- lectual deterioration, followed by memory difficulties and ataxia. Cerebral anoxia is also the main cause of neurological symptoms in several other systemic conditions. Disseminated intravascular coagu- lation (see Chapter 22.7.5), can produce headache and difficulty in concentration, vertigo, blurred vision, and speech difficulties. Such confusion and disorientation may progress to stupor and coma with focal or generalized signs of brain disturbance. Spontaneous bleeding is common, in the form of petechiae in the skin or optic fundus, purpura, and even intracranial haemorrhage. Cerebral malaria (see Chapter 8.8.2) should always be borne in mind as a cause of unexplained coma in patients living in, or recently returning from an endemic area area. Most patients describe chills and fever for a few days prior to the onset of lethargy, stupor, and finally coma. The diagnosis is established by finding the parasite in blood films. Cerebral anoxia as a consequence of sickle cell anaemia might also be considered in such individuals. Fat embolism follows (by some 12–​72  h, though sometimes longer) severe trauma, particularly to the limbs (perhaps up to 3–​4% of individuals with long bone fractures), but may also be a compli- cation of burns and other severe system disturbance. Multiple pul- monary microemboli of fat may lead to progressive hypoxia and respiratory failure. Multiple cerebral microemboli produce confu- sion, lethargy, stupor, and finally coma. Symptoms often begin hours to days after the original injury, and are accompanied by fever and hyperventilation. A characteristic petechial rash usually develops over the upper half of the body on the second to third day after in- jury. There may also be fundal haemorrhages. The respiratory fea- tures range from the appearance of linear streaks radiating from the hilar region, or patchy opacities on the chest to fully developed adult respiratory distress syndrome. Clotting abnormalities range from mild thrombocytopenia to acute disseminated intravascular coagu- lation. Urinary fat globules can be found. Management is largely supportive—​correcting both hypoxia and the coagulation disorder. Improvements in cardiac surgical techniques have greatly reduced neurological complications, but some patients still emerge from the anaesthetic with signs of diffuse or focal brain damage. If they sur- vive the acute episode, the prognosis usually is good. Hepatic encephalopathy (See also Chapter 15.21.4). Hepatic encephalopathy is defined as any type of brain disorder caused by the failure of liver function, either actual (from hepatocellular damage) or effective (as in porto-​systemic shunt). Its metabolic origins are complex and poorly understood. Hepatic encephalopathy may be acute or chronic. In either case, four stages of increasing severity are commonly recognized: stage 1—​impaired attention, disturbed sleep, behavioural changes (irritability, euphoria, or anxiety); psychomotor slowing; stage 2—​drowsiness, personality change, disorientation; stage 3: somnolence or semi-​stupor; stage 4: coma. Acute hepatic failure This occurs with massive liver necrosis due most commonly to se- vere hepatitis (viral or autoimmune) or poisons. In other patients, who may have relatively well-​preserved liver function but extensive portosystemic shunts, coma may be precipitated by a sudden intake of nitrogenous substances as occurs (in effect) with gastrointestinal bleeding, infections, or high-​protein diets. Not uncommonly, an acute encephalopathy is precipitated in an individual with chronic but stable liver disease (usually, cirrhosis) by a superimposed insult—​which may range from constipation to electrolyte disturb- ance, diuretic treatment, infection, or sedatives. Personality and cognitive changes progress, if unchecked, to con- fusion, apathy, and lack of concentration, or occasionally excite- ment requiring sedation, followed by stupor and coma in hours or days. Characteristic neurological findings are asterixis (‘liver flap’), in which the outstretched hands show postural lapses or negative myoclonus, and hepatic foetor. Chorea and pyramidal signs may appear as the patient lapses into coma. Decerebrate posturing is common at this stage, and focal deficits such as hemiplegia may section 24  Neurological disorders 6370 occur. Nystagmus, conjugate deviation of the eyes, skew deviation, and even disconjugate eye movements may be evident, but reflex eye movements and pupillary responses are preserved, until the patient becomes totally unresponsive and dies. Paroxysmal and later per- sistent high-​voltage triphasic slow waves are present in the electro- encephalogram until death is imminent. Many metabolic abnormalities may contribute to the cause of hepatic coma, including hyperammonaemia (more than 145 µmol/​ litre or 200 mg/​dl), hypoglycaemia and hyperventilation producing a respiratory alkalosis. Altered amino acids and neurotransmitters (especially γ-​aminobutyric acid), formation of toxic amines such as octopamine, and short-​chain fatty acids have also been incrimin- ated. Intravascular coagulation and other coagulation defects com- plicate damage to the brain. Glial oedema is seen; cerebral oedema can raise intracranial pressure seriously or even fatally. Hepatic coma carries a high mortality, but if the patient can be kept alive, liver regeneration with excellent hepatic and cerebral re- covery may occur. Early recourse to an intensive care unit setting is important; an electroencephalogram (EEG) is important, partly to exclude non​convulsive status epilepticus, and partly to monitor hepatic encephalopathy, often showing progressive slowing of base- line activity, followed by the characteristic bifrontal, synchronous, periodic triphasic waves (common in grade III encephalopathy). Treatment includes intensively seeking, and where possible ad- dressing the precipitant, sterilizing the bowel, correction of meta- bolic and bleeding abnormalities, the administration of lactulose (though there is evidence that polyethylene glycol may be superior), and haemoperfusion or other techniques to remove toxins. The benzodiazepine antagonist flumazenil may help. Intracranial pres- sure monitoring is fraught with hazards, not least the coagulopathy, but mannitol (though not dexamethasone) is of proven benefit in lowering intracranial pressure in this context. Liver transplantation has an increasing role. Chronic hepatic encephalopathy/​acquired hepatocerebral degeneration In chronic liver disease, particularly in patients with extensive portosystemic shunting, a more progressive neurological syn- drome may emerge, with cognitive decline accompanied by extra- pyramidal features—​including tremor or chorea, an akinetic–​rigid syndrome, and focal dystonia. Ataxia is often seen, and falls are common. The term acquired hepatocerebral degeneration is com- monly applied (for genetically determined hepatocerebral degen- eration, including Wilson’s disease, see Chapter 24.7.3). Again, the precise metabolic cause has not been established, though manga- nese accumulation is implicated. Characteristically, the disorder fluctuates, with episodes of marked confusion, excitement, or frank hepatic coma. Hepatic encephalopathy-​related treatments, such as a low-​protein diet, gut-​sterilizing antibacterials, and lactulose, are of limited value. L-​dopa preparations can help, while liver trans- plantation can reverse the deficits. A hepatic or portal-​systemic myelopathy is also described. Respiratory disease Hyperventilation causes hypocarbia and alkalosis, resulting in parasthaesia, especially perioral, light-​headedness, and unsteadi- ness, visual disturbances, and occasionally carpopedal spasm; syncope may follow. Chronic respiratory failure causes what is essentially a low-​grade chronic hypoxia and hypercarbic encephalopathy, with the defining features of confusion and headache accompanied by a myoclonic or asterictic tremor and papilloedema. Mechanical devices for delivering domiciliary oxygen have transformed the management of this disorder, and the quality of life of its sufferers. Obstructive sleep apnoea is characterized by conspicuous snoring and an often obese habitus. Early morning headache and inatten- tiveness or irritability with excessive daytime sleepiness occur. Renal failure Renal failure (see Chapter 21.6) is associated with a variety of neuro- logical complications. Uraemic encephalopathy is now uncommon, though still seen. Patients become progressively drowsy, stuporose, and finally comatose. Hyperventilation, multifocal myoclonus, tremor, asterixis, tetany, and generalized fits occur. Eye move- ments and pupillary reactions are not affected. Uraemia, metabolic acidosis, hyperkalaemia, disorders of calcium, sodium and water balance, and hypertensive encephalopathy all contribute to the clin- ical picture. Dialysis rapidly reverses the metabolic abnormalities of uraemia, but the encephalopathy may take days to clear. Other com- plications of chronic renal failure include myopathy due to chronic hypocalcaemia, and a symmetrical sensorimotor polyneuropathy, often subacutely progressive and disabling. It may be resistant to dia- lysis, but renal transplantation has been associated with a slow and sustained improvement. Iatrogenic disease in renal failure Some patients develop the dialysis disequilibrium syndrome during correction of their uraemic abnormalities. Rapid correction of the metabolic changes, primarily through creating a significant brain:plasma osmotic gradient, leads to the emergence of headache, asterixis, myoclonus, delirium, generalized convulsions, stupor, and even coma. Raised intracranial pressure with papilloedema may occur. Chronic dialysis—​perhaps three to seven years—​may pre- cipitate dialysis dementia if dialysate with a high aluminium con- tent has been used; this is now rare. Such patients begin to develop speech hesitancy and arrest, then intellectual and cognitive abnor- malities, convulsions, myoclonus, and sometimes focal neurological abnormalities. EEG shows multifocal bursts of profound slowing and spikes. Death follows within a year. Wernicke’s encephalopathy (see below) can occur in chronic dia- lysis without thiamine supplements. Patients with renal disease are particularly prone to develop toxic complications of drugs normally excreted in the urine—​peripheral neuropathy due to nitrofurantoin, labyrinthine damage due to streptomycin, or optic atrophy due to ethambutol. Metabolic disorders due to endocrine disease (See Section 13). Adrenal disease Phaeochromocytoma Phaeochromocytoma causes paroxysms of anxiety, tremor, head- ache, and palpitations—​combined with the serious consequences of malignant hypertension. The associations with von Hippel–​Lindau 24.21  Acquired metabolic disorders and the nervous system 6371 disease, multiple endocrine neoplasia syndromes, ataxia telangi- ectasia, and Sturge–​Weber syndrome should not be overlooked. Cushing’s syndrome Endogenous Cushing’s syndrome in two-​thirds of cases is due to a pituitary adrenocorticotropic hormone (ACTH)-​secreting adenoma—​conventionally termed Cushing’s disease. Ectopic ACTH-​secreting malignant neoplasms and ACTH-​independent adrenal tumours represent the other principal causes of en- dogenous disease; iatrogenic hyperadrenalism produces similar neurological symptoms. The systemic features are described in Chapter 13.2.1. Neurological complications include: (i) proximal myopathy, which can be severe and painful; (ii) psychiatric dis- orders, ranging from mild mood disturbance through moderate depression (common) to severe psychosis; (iii) a benign intracra- nial hypertension-​like picture; and (iv) direct consequences of a pituitary tumour, particularly optic chiasmal compression. Adrenal insufficiency Hypoadrenalism due to primary adrenal failure (Addison’s dis- ease) or ACTH deficiency (from pituitary disease or chronic steroid treatment) causes weakness, lassitude, nausea, and diar- rhoea; and stupor or coma may be precipitated by surgical pro- cedures or other acute illness. Hypotension (especially postural), hyponatraemia, hyperkalaemia and, often, hypoglycaemia (see Chapter 13.5.1) occur: each may be symptomatic—​indeed, attacks of hyperkalaemic periodic paralysis may occur. Amnesic deficits, depression, and impaired concentration progressing to confusion are relatively common. Addisonian crises may be accompanied by generalized convulsions, which are attributed to hyponatraemia and water intoxication. Benign intracranial hypertension with papilloedema and a proximal myopathy may also occur. X-​linked adrenoleukodystrophy Discussed in Section 24.17. Thyroid disease Thyroid disease carries metabolic complications, directly re- lated to abnormal thyroxine levels, and (with shared eponyms) neuroimmune features—​Hashimoto’s encephalopathy and Grave’s ophthalmopathy. Here only the former will be considered. Thyrotoxicosis The features of hyperthyroidism include anxiety, tremor, tachy- cardia, and insomnia. Chorea or mania may occur. A severe prox- imal myopathy is not uncommon, and rarely myasthenia gravis is seen. Thyroxine-​responsive hypokalaemic periodic paralysis is well-​reported. Myxoedema Hypothyroidism may present with lethargy progressing to a toxic confusional state or a subacute hypothermic, hypotensive coma. The latter (which may be provoked by infection, trauma, exposure to cold or sedation), together with the occasionally-seen psychosis or dementing illness (‘myxoedema madness’) responds to (judicious) thyroxine hormone replacement. Ataxia occurs in 5–​10% of patients with hypothyroidism, and improves with thyroxine replacement. Hypothyroid myopathy is characterized by proximal weakness with stiffness, aching and cramps, and pseudomyotonic delayed muscle relaxation evident on tapping tendons or muscle bellies (with percussion-​induced muscle ridging). Muscle hypertrophy (Hoffmann’s syndrome) is rare. Carpal tunnel syndrome may occur due to deposits of myxoedematous tissue around the median nerve of the wrist, and rarely this may cause a diffuse peripheral neuropathy. Diabetes mellitus Diabetes mellitus (Chapter 13.9.1) causes a wide variety of neuro- logical disturbances. Centrally, stupor or coma may be produced by hyperosmolality, ketoacidosis, lactic acidosis, spontaneous (prediabetic) or iatrogenic hypoglycaemia, uraemia, or hyperten- sive encephalopathy. Transient ischaemic attacks and stroke due to cerebral arteriosclerosis and hypertension are common in patients with diabetes. Peripherally, nerve damage may occur in patients with estab- lished diabetes, or may be the presenting feature of the illness; it is described in more detail in Chapter 24.16. The following syndromes are recognized: • Single painful nerve lesions (mononeuritis):  isolated cranial neuropathies (typically III, IV, VI, or VII), a lateral popliteal nerve palsy, or an intercostal neuropathy (or more likely, thoracic radiculopathy) are common and may result from haemorrhage or infarction of the nerve; • Carpal tunnel syndrome, an ulnar nerve palsy, or other compres- sion neuropathies may result from the undue susceptibility of peripheral nerves in diabetes to pressure; • Mononeuritis multiplex may occur, with a microvascular basis; • Diabetic amyotrophy is more accurately a lumbosacral radiculo­ plexopathy, causing the subacute weakness and wasting, often with pain, affecting quadriceps muscles, usually very asymmetric- ally. It is probably due to vasculitic ischaemia or infarction in the proximal nerve roots or lumbosacral plexus; • A distal symmetrical peripheral neuropathy in diabetes may take the form of a mild asymptomatic sensory neuropathy with loss of vibration sense in the feet and absent ankle jerks. Less commonly, there is severe and progressive sensorimotor neuropathy affecting the legs before the arms; • Autonomic neuropathy is common, producing impotence, diar- rhoea, loss of sweating, and abnormal pupils—​which may be irregular, and unreactive to light, mimicking Argyll Robertson pupils. Autonomic neuropathy causes orthostatic hypotension, syncope, and sometimes abrupt cardiac arrest in patients with diabetes. It should be recalled that diabetes may occur as a feature of several genetically determined neurological diseases, including Friedreich’s ataxia, X-​linked spinomuscular atrophy, mitochondrial cytopathies, myotonic dystrophy, and the Wolfram syndrome; it is also associ- ated with the stiff man syndrome. Hypoglycaemia Hypoglycaemic coma can be difficult to diagnose and is dangerous. In any case of coma, stupor, or confusion of unknown cause, and often in newly presenting status epilepticus, blood should be drawn for glucose analysis and insulin levels, and then 25 g of glucose (with section 24  Neurological disorders 6372 or following thiamine) should be administered intravenously. Such an injection can do no harm and may save lives. The most common cause of hypoglycaemia is insulin overdose, or excessive hypoglycaemic drug intake. Hyperinsulinism due to an adenoma of the islets of Langerhans in the pancreas is un- common, as is hypoglycaemia due to prediabetes or a retroperi- toneal sarcoma. Hypoglycaemia may also occur in alcoholism and liver disease, after gastric surgery and in a variety of rare metabolic conditions. Hypoglycaemia presents in four ways: (1) as a toxic confusional state, sleepy confusion, bizarre behaviour, or mania; (2)  as un- explained coma with brainstem dysfunction, including decere- brate spasms and neurogenic hyperventilation, but with preserved oculocephalic reflexes and pupillary responses; (3) as a (normally reversible) stroke-​like illness with focal (usually hemiparetic) deficit; and (4) as epilepsy. Hyperinsulinism, very rarely, also causes predominantly motor peripheral neuropathy. Hyperinsulinism is difficult to diagnose on occasion, but can be established by satisfying the criteria for Whipple’s triad, namely symptoms of hypoglycaemia, associated with a low blood sugar and a disproportionately high serum insulin, and clinical response to glucose replacement (see Chapter 13.9.2). Metabolic disorders due to ionic or acid–​base abnormalities Hyponatraemia or ‘water intoxication’ The normal serum osmolality is 290 ± 5 mosmol/​kg; serum osmo- lality below about 260 or above about 330 mosmol/​kg is likely to produce cerebral changes. Sodium is the most abundant serum cation, so that hyponatraemia is almost always the cause of hypo-​ osmolality. (Serum osmolality is approximately equal to double the serum sodium concentration plus 10, provided that glucose and urea levels are normal.) In hyponatraemia, body water is increased relative to solute, causing water excess in the brain. Rapid changes in serum sodium osmolality produce much greater neurological effects than chronic hyponatraemia. Hyponatraemia occurs in renal disease, as a result of excessive intravenous water infusions, due to excessive diarrhoea, vomiting, or sweating, or may result from the inappropriate secretion of antidiuretic hormone in bronchial carcinoma, focal hypothalamic damage due to neoplasm or infection or diffuse acute brain disease resulting from head in- jury, meningitis, or encephalitis, or subarachnoid haemorrhage. (It is, however, noteworthy that in the latter acute situations, salt-​ wasting may also cause hyponatraemia, in which circumstances fluid restriction exacerbates the problem:  hypovolaemia distin- guishes salt-​wasting from the eu-​ or hypervolaemia of vasopressin excess.) Patients with hyponatraemia become confused and restless, and can develop asterixis, multifocal myoclonus, generalized convul- sions, stupor, and coma. Symptoms may appear when the plasma sodium drops below about 120 mmol/​litre, and fits and coma usu- ally are associated with plasma sodium values below 110 mmol/​ litre. A few patients with chronic hyponatraemia may develop the syndrome of central pontine myelinolysis (see next). Treatment is by water restriction; infusions of hypertonic saline are not advised. Central pontine myelinolysis This was first described 60  years ago. It is often associated with hyponatraemia, and more particularly with rapid correction of serum sodium by parenteral hypertonic fluids: correction by no less than 1–​2  mmol/​litre/​hour, or 8–​12  mmol/​litre/​day, appears safe. Central pontine myelinolysis is also seen in alcoholics, in severe liver and renal disease, and in other metabolic disturbances—​some have suggested ‘osmotic demyelination syndrome’ as a better name. The disease is characterized by a rapidly progressive flaccid or spastic quadriplegia, with involvement of bulbar muscles producing dys- arthria and dysphagia. Consciousness and eye movement may re- main intact. At worst the patient may be unable to speak or swallow, or to move any muscle except those of the eyes. Death is common but remarkable recovery may occur. Extrapontine myelinolysis is also now well-​recognized. Hypernatraemia The common cause of hyperosmolality is diabetes, producing se- vere hyperglycaemia. Hyperosmolality due to hypernatraemia is rare, except in those who dehydrate in hot climates. Chronic un- compensated water loss in untreated diabetes insipidus may result in mild hypernatraemia, but such patients only develop severe hypernatraemia if they fail to drink. Patients with simple diabetes insipidus usually maintain thirst, but if intercurrent illness leads to excessive water loss and restricted water intake, they may be- come dehydrated, drowsy, stuporose, and unconscious. Simple diabetes insipidus may be due to pituitary surgery, trauma, or pi- tuitary tumours. If pathology extends into the hypothalamic re- gion, not only may secretion of vasopressin be deficient, but thirst regulation may also be abolished. Hypothalamic damage causing severe hypernatraemia may occur in large pituitary tumours, craniopharyngiomas, hypothalamic tumours, sarcoidosis, or Hand–​Schüller–​Christian disease. Loss of thirst in such patients often precipitates hypernatraemic coma with serum sodium rising above 160–​170 mmol/​litre. Hypernatraemia may also occur as a result of severe water depletion, particularly in children with in- tense diarrhoea. Hypercalcaemia (See Chapter 13.4). High serum calcium may be due to primary hyperparathyr- oidism, immobilization, sarcoidosis, vitamin D intoxication, or multiple bony metastases. Symptoms include anorexia, nausea, vomiting, intense thirst, polyuria, and polydipsia. Muscle weak- ness, lassitude, and a mild encephalopathy are common. The latter may produce delusions and changes in mood so that many such patients are initially treated for a psychiatric condition. A toxic confusional state with lethargy and stupor, sometimes with gener- alized or focal seizures and papilloedema, also may occur. A more severe syndrome with pyramidal signs, ataxia, and an internuclear ophthalmoplegia is also described. Hypocalcaemia (See Chapter 13.4). Reduced serum calcium concentration may be caused by para- thyroid or thyroid surgery, chronic renal failure, or chronic anti- convulsant drug treatment. It also occurs in primary idiopathic 24.21  Acquired metabolic disorders and the nervous system 6373 hypoparathyroidism (when the serum parathormone level is low), and in pseudohypoparathyroidism (in which the serum parathormone level is normal or high, and there is no response to parathyroid hormone; skeletal deformities and dysmorphism also are present). Pseudopseudohypoparathyroidism is a syn- drome with similar skeletal and dysmorphic abnormalities but normal serum calcium and parathormone levels. Hypocalcaemia causes neuromuscular irritability, tetany with a Chvostek’s sign, and mild encephalopathy. Severe hypocalcaemia leads to general- ized convulsions, psychosis, stupor, and coma. Raised intracranial pressure with papilloedema may occur in hypoparathyroidism. Hypocalcaemia is commonly misdiagnosed as mental retardation, dementia, or epilepsy. Skin changes and cataracts are character- istic. Calcification in basal ganglia on skull radiograph or CT scan may be evident. Rarely, basal ganglia calcification may be associ- ated with extrapyramidal disorders. Magnesium Renal disease may impair the ability to excrete magnesium, which is cardiotoxic. Hypomagnesaemia, due to inadequate intake or exces- sive renal or gastrointestinal loss, causes secondary hypocalcaemia; the former rarely occurs without the latter, and the neurological complications often attributed to low magnesium are precisely those of hypocalcaemia. Hypermagnesaemia may cause an encephalop- athy with decreased or absent tendon jerks; the latter may progress to a flaccid paralysis. Potassium Hypokalaemia, often caused by diuretics, causes myalgia and prox- imal myopathy; rhabdomyolysis can occur. Hyperkalaemia can pre- cipitate areflexic flaccid paralysis, which may be fully reversible with correction of the serum potassium. The periodic paralyses are dis- cussed in Chapter 24.19.4. Acid–​base disturbances Systemic acidosis and alkalosis (see Chapter 12.11) occur in many diseases causing metabolic coma, but of the four acid–​base balance disorders (respiratory or metabolic acidosis or alkal- osis), only respiratory acidosis directly causes stupor and coma. Hypoxia associated with respiratory acidosis may be important in producing neurological abnormalities. Metabolic acidosis, by itself, usually only causes delirium or, at most, drowsiness. Even severe disorders of acid–​base balance usually do not impair brain function, since the central nervous system (CNS) possesses a powerful acid–​base homeostatic armoury, including compensa- tory changes in respiratory rate and cerebral blood flow, and cel- lular buffering in nervous tissue. Coma in metabolic acidosis due to diabetic ketosis or hyperosmolality, lactic acidosis, uraemia, alcohol poisoning, or intake of ethylene glycol, methyl alcohol, or paraldehyde is usually due to associated metabolic abnormal- ities or direct effects of other toxins in these conditions. Severe respiratory acidosis produces a reduction in alertness parallel to the degree of acidosis. Respiratory alkalosis, although con- stricting cerebral arterioles and decreasing cerebral blood flow, rarely interferes with cerebral function. A patient in coma with respiratory alkalosis due to hyperventilation has some other con- dition such as sepsis, hepatic disease, pulmonary infarction, or salicylate overdose. Even severe metabolic alkalosis only produces a confusional state, rather than coma. Alcohol and the nervous system Alcohol damages the nervous system in many ways; some the re- sult of acute or chronic poisoning, others of associated vitamin deficiency. This section will mainly address the neurological conse- quences of chronic, excessive alcohol intake, not the acute transient effects of alcohol. Delirium tremens This develops several days after ethanol abstinence in chronic abusers. Usually rapid in onset, there is an agitated confused state, with signs of sympathetic overactivity. Circulatory collapse may con- tribute to the 5–​10% mortality. It is generally distinguished from the less severe alcohol withdrawal syndrome, characterized by broadly similar symptoms that occur sooner—​within hours of withdrawal—​ and are usually self-​limiting. Ethanol withdrawal seizures repre- sent a not uncommon cause of adult-​onset fits. Benzodiazepines have transformed the management of delirium tremens and the al- cohol withdrawal syndrome, and significantly reduced its mortality. (Intravenous thiamine must also be given.) The Wernicke–​Korsakoff syndrome Inadequate intake of thiamine, of whatever cause, may lead to foci of marked hyperaemia with multiple small haemorrhages affecting particularly the upper brainstem, hypothalamus, and thalamus adja- cent to the third ventricle, and the mammillary bodies. Histologically there is a proliferation of dilated capillaries with perivascular haem- orrhage. There may be associated alcohol-​induced damage to the cerebral cortex, cerebellum, and peripheral nerves. Such pathology can be produced in animals by a diet deficient in thiamine. Thiamine deficiency can be demonstrated in patients with the Wernicke–​Korsakoff syndrome, and administration of thiamine can reverse many of the symptoms and signs of this syn- drome. (Wernicke’s and Korsakoff’s syndromes probably represent the acute and chronic consequences of the same pathological pro- cess.) Thiamine and its pyrophosphate are cofactors to at least four enzymes: pyruvate decarboxylase, α-​ketoglutarate dehydrogenase, the branched-​chain ketoacid decarboxylase system, and transketo- lase. Thiamine deficiency results in reduced conversion of pyruvate to acetyl coenzyme A, causing elevated plasma and tissue pyruvate levels, with decreased flux through the Krebs cycle, reducing adeno- sine triphosphate (ATP) production, and impairing energy supply. Alcoholism combined with an inadequate diet is the most common cause of the Wernicke–​Korsakoff syndrome. Malnutrition in prisoners of war, or at times of famine, may also be responsible. Chronic vomiting, for example, during pregnancy or due to gastro- intestinal disease, systemic malignancy, prolonged intravenous feeding, and anorexia nervosa are well-​recognized causes. The onset may be insidious or subacute with increasing leth- argy and inattentiveness, which develops into a typical confusional state with disorientation in time and place, loss of memory, and al- tered consciousness. Ophthalmoplegia develops with diplopia. The most common eye signs are nystagmus on lateral or vertical gaze, section 24  Neurological disorders 6374 sixth-​nerve palsies, or defects of conjugate gaze. Retinal haem- orrhages may occur. Most patients who are alcoholics will also have signs of a peripheral neuropathy, and many exhibit ataxia. Hypothermia may appear. Wernicke’s encephalopathy is a medical emergency: untreated, the patient lapses into stupor and then coma, and dies—​the mortality untreated is 20%. In less acute cases, or in those recovering from the acute confusional phase, the characteristic features of the Korsakoff psychosis will appear. The patient has an often very severe gross am- nesic defect for recent events, such that new information cannot be retained for more than a matter of minutes or hours. The patient is disorientated in time and place, but alert. Despite the severe de- fect of recent memory, the remote past is usually accurately recalled. Gaps in memory are filled by imaginary and often graphic accounts (confabulation). The diagnosis is clinical. Formal diagnostic criteria have been commonly accepted-a clinical diagnosis of Wernicke’s encephal- opathy in alcoholics requires two of the following four features: (1) dietary deficiencies, (2) eye movement abnormalities, (3) cerebellar dysfunction, and (4) either an altered mental state or mild memory impairment. That said, the diagnosis must be at least considered in any individual with unexplained confusion, stupor, or coma, par- ticularly in the presence of eye signs, a peripheral neuropathy, or a history of alcoholism or excessive vomiting. The cerebrospinal fluid is usually normal, although the protein may be slightly raised. Brain scanning can be normal, although patients who are alco- holic (and fall often) may have subdural haematomata, or atrophy. Demonstration of reduced red cell transketolase activity, or of raised plasma pyruvate levels, is often invalidated by intake of food as soon as the patient comes under supervision. Thiamine should be given urgently to all such patients before any carbohydrate, (usually in the form of high-​potency intravenous Pabrinex®) to a dose of 200 mg thrice daily for several days, or until oral vitamin B complex preparations can be taken. A  particular problem arises commonly in the emergency department when pa- tients exhibiting stupor or coma of unknown cause are admitted. All such patients should be given high-​dose thiamine and glucose parenterally—​if glucose is given without thiamine to a patient with Wernicke–​Korsakoff syndrome, rapid deterioration and death can follow. Those who are thiamine deficient cannot handle the glucose load. Effective treatment will restore consciousness and reverse eye signs, the latter usually within hours, but unfortunately the Korsakoff amnesic syndrome frequently does not resolve. The earlier the treat- ment, the better the chances of recovery, hence treatment on suspi- cion as a medical emergency. Alcoholic peripheral neuropathy (See also Chapter 24.16). Although thiamine deficiency has long been considered respon- sible for the peripheral neuropathy associated with chronic alco- holism, a direct toxic effect has also been proposed. Pathologically, the picture of peripheral nerve damage is very similar to that seen in beriberi—​a predominantly axonal neuropathy of the ‘dying back’ type, affecting somatic and sometimes autonomic nerves. Alcoholic peripheral neuropathy predominantly involves sen- sory nerves, producing distal parasthesias in the feet, followed by the hands and, characteristically, pain. The last may be intense and agonizing. Squeezing the calves or scratching the soles of the feet may cause severe discomfort. At a later stage, weakness and wasting of the distal limb muscles follows, with areflexia. Evidence of auto- nomic neuropathy may be seen in abnormal pupillary reactions and tachycardia, although postural hypotension is rare, and the sphinc- ters are usually spared. Alcohol must be proscribed and high-​potency vitamin B is given parenterally for some 10 days and then orally. The prognosis de- pends on how early treatment is initiated. Symptoms may take weeks to subside, and in more severe cases recovery may take many months or may be incomplete. Alcoholic cerebellar degeneration Some patients who are alcoholic may develop a relatively pure syn- drome of midline cerebellar ataxia, with a progressive unsteadi- ness of gait and of leg movements, and little or no involvement of the arms. Dysarthria and nystagmus are not common. Many such patients also have evidence of alcoholic peripheral neuropathy. Pathologically there is degeneration of the cerebellar cortex, par- ticularly of the Purkinje cells, and also of the olivary nuclei. Changes in the cerebellum characteristically affect the anterior and superior parts of the vermis and hemispheres—​often visible on MR scans. This complication of alcoholism does not seem to be due to thia- mine deficiency—​though alcohol withdrawal and vitamin replace- ment can lead to recovery. Alcoholic dementia (See Section 26.) In the past, there has been debate over whether alcoholism pro- duces dementia, or whether the occasionally seen permanent cog- nitive deficits are rather the chronic consequences (or variants) of Wernicke–​Korsakoff syndrome. Certainly, a large proportion of those who habitually take exces- sive alcohol develop cognitive deficits varying from mild changes to severe diffuse global dementia, with atrophy of the cerebral cortex and enlargement of the cerebral ventricles. The dementia has the usual features of personality change, loss of memory, impairment of intellect, and emotional instability, with failure at work or in per- sonal relationships. The gradual drift into destitution is all too fa- miliar. Head injuries in alcoholic bouts and epilepsy may occur and contribute to the overall final picture. The fully developed case of the ‘down and out’ is an antisocial demented individual, with dysarthric speech, tremor, an ataxic gait, and a peripheral neuropathy, who still forlornly or aggressively clutches the bottle and a bag of residual belongings. Treatment by withdrawal of alcohol (if possible) and vitamin re- placement can lead to some improvement and occasionally to par- tial reversal of cerebral atrophy on scanning. However, the prognosis is generally poor, not least because of the difficulties of persuading those addicted to alcoholic to stop drinking. Marchiafava–​Bignami disease This rare disease was first described in Italian drinkers of crude red wine, but occurs in other alcohol abusers. It presents with sub- acute dementia, progressing rapidly to fits, spasticity or rigidity, and paralysis, culminating in coma and death within a few months. Pathologically there is widespread demyelination and axonal damage in the corpus callosum and the central white matter of 24.21  Acquired metabolic disorders and the nervous system 6375 the cerebral hemispheres (all of which may be readily disclosed by MRI), also involving the optic chiasma and middle cerebellar ped- uncles. Abstinence stabilizes but rarely reverses the syndrome. Alcoholic myopathy Acute alcohol poisoning can produce a dramatic toxic myopathy. There is severe pain, muscle tenderness, oedema, and weakness, which may be associated with myoglobinuria, renal damage, and hyperkalaemia. Arrhythmias may occur. The syndrome is reversible if the necessary intensive support is available. A subacute painless myopathy resolving after withdrawal of alcohol has also been de- scribed. Chronic alcoholism is associated commonly with a painless myopathy, occasionally with coexistent cardiomyopathy; again, ab- stinence can cure the disorder. Tobacco–​alcohol amblyopia Another uncommon complication of alcohol occurs in combination with strong tobacco. The patient develops painless sudden or sub- acute bilateral visual failure, associated with bilateral centrocaecal scotomas. The condition has been attributed to cyanide in tobacco causing a disorder of vitamin B12 metabolism. Visual failure and optic atrophy may occur in patients with pernicious anaemia, par- ticularly those who smoke. A related condition is tropical amblyopia, occurring in Africa. This has been related to excessive consumption of cassava root containing cyanide. Treatment of these conditions is with hydroxycobalamine injections. Ecstasy ‘Ecstasy’ (3,4-​methylenedioxymethamphetamine, MDMA) has been a widely used recreational drug for three decades or more. Fatalities have been reported, but more common neurological sequelae in- clude (1) hyperpyrexia and rhabdomyolysis with multiorgan failure; (2) hyponatraemia and its complications (largely caused by deliberate water self-​intoxication, possibly intentional, to avoid (1); (3) bruxism and trismus; (4) serotonin syndrome; (5) more direct and, it is sug- gested, lasting, toxic effects on glia, neurons, and/​or cerebral endothelia. Superficial siderosis of the CNS Superficial siderosis is an unusual nervous system disorder recog- nized relatively recently. The four principal clinical manifestations are: progressive ataxia; cranial polyneuropathy, particularly sensori- neural deafness; myelopathy causing a spastic tetraparesis; and pro- gressive dementia. Headaches occasionally feature. Cerebrospinal fluid examination reveals xanthochromia which, importantly, per- sists with repeated examination. MRI is diagnostic, with low signal intensity on T2-​weighted images apparent at the surface of the cere- bellum, cranial nerves, brainstem, spinal cord, and more deeply on the borders of the dentate and basal ganglia. Iron deposition can be shown by high-​strength MRI, corresponding to pathological descriptions of subpial siderotic deposits in the meninges. Repeated subarachnoid haemorrhage, cerebral tumours, or past surgery are recognized causes of this syndrome, but often none is historically evident; repeated subclinical haemorrhage is postulated but not proven. No treatments are of proven benefit. FURTHER READING Metabolic complications of major organ disease Baumgaertel MW, Kraemer M, Berlit P (2014). Neurologic complica- tions of acute and chronic renal disease. Handb Clin Neurol, 119, 383–​93. Bernal W, Wendon J (2013). Acute liver failure. N Engl J Med, 369, 2525–​34. Ferro JM, Oliveira S. (2014). Neurologic manifestations of gastrointes- tinal and liver diseases. Curr Neurol Neurosci Rep, 14(10), 487. Aboussouan LS. (2005). Respiratory disorders in neurologic diseases. Cleve Clin J Med, 72(6), 511–20. Tormoehlen LM (2011). Toxic leukoencephalopathies. Neurol Clin, 29, 591–​605. Vilstrup H, et al. (2014). Hepatic encephalopathy in chronic liver dis- ease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology, 60, 715–​35. Metabolic disorders due to endocrine disease Charnogursky GA, Emanuele NV, Emanuele MA (2014). Neurologic complications of diabetes. Curr Neurol Neurosci Rep, 14(7), 457. Wood-​Allum CA, Shaw PJ (2014). Thyroid disease and the nervous system. Handb Clin Neurol, 120, 703–​35. Metabolic disorders due to ionic or acid–​base abnormalities Agrawal L, Habib Z, Emanuele NV (2014). Neurologic disorders of mineral metabolism and parathyroid disease. Handb Clin Neurol, 120, 737–48. Singh TD, Fugate JE, Rabinstein AA (2014). Central pontine and extrapontine myelinolysis: a systematic review. Eur J Neurol., 12, 1443–50. Alcohol and the nervous system Harper C, Giles M, Finlay-​Jones R (1986). Clinical signs in the Wernicke–​Korsakoff complex: a retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry, 49, 341–​5. Planas-Ballvé A, Grau-López L, Morillas RM, Planas R (2017). Neurological manifestations of excessive alcohol consumption. Gastroenterol Hepatol., 40(10), 709–717. Schuckit MA (2014). Recognition and management of withdrawal delirium (delirium tremens). N Engl J Med, 371, 2109–​13. Miscellaneous metabolic and deficiency disorders of the nervous system Hall AP, Henry JA (2006). Acute toxic effects of ‘Ecstasy’ (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaes, 96, 678–​85. Kumar N (2007). Superficial siderosis: associations and therapeutic implications. Arch Neurol, 64, 491–​6. Young GB (1995). Neurologic complications of systemic critical illness. Neurologic Clinics, 13, 645–​58. 24.23 Paraneoplastic neurological syndromes 6384 J 24.23 Paraneoplastic neurological syndromes 6384 Jeremy Rees ESSENTIALS Paraneoplastic neurological syndromes are disorders caused by the presence of an underlying tumour, but not due to either direct or metastatic invasion, or to recognized metabolic or endocrine com- plications. They are thought to arise from an autoimmune response to ‘onconeural’ tumour antigens which are also expressed by cells of the central or peripheral nervous systems. Paraneoplastic neurological syndromes are rare but important be- cause (1) they often develop before the cancer has been identified, (2)  serological testing for specific antineuronal (onconeural) anti- bodies may identify a neurological disorder as paraneoplastic and the results may suggest the location of the underlying tumour and/​ or predicts its prognosis. In some cases, the identity of the antibody predicts an immunotherapy-​responsive disease. Epidemiology—​the most common tumours associated with paraneoplastic syndromes are lung (both small-​cell lung cancer and non-​small-​cell lung cancer), ovary, breast, thymus, lymph nodes (Hodgkin’s disease and non-​Hodgkin’s lymphoma) and testis. Treatment—​a few paraneoplastic syndromes respond to immuno- suppression or to treatment of the underlying cancer, particularly when they are associated with germ cell tumours and antibodies to neuronal cell-​surface proteins, but treatment is unrewarding for most. Patients with paraneoplastic neurological syndromes often re- main severely disabled even if the cancer is cured. Specific syndromes Brain—​(1) cerebellar degeneration—​most common with lung cancer (especially small-​cell lung cancer), breast, and gynaecological cancer, and Hodgkin’s disease; (2)  opsoclonus/​myoclonus; (3)  limbic en- cephalitis (see Chapter 24.24); (4) brainstem encephalitis; Spinal cord, dorsal root ganglia, and peripheral nerves—​(1) necro- tizing myelopathy; (2) motor neurone disease (some cases); (3) mye- litis; (4) sensory neuronopathy; (5) peripheral neuropathies. Neuromuscular junction and muscle (see also Chapter 24.18)—​(1) Lambert–​Eaton myasthenic syndrome—​typically associated with small-​ cell lung cancer; (2) myasthenia gravis—​occurs in 30% of patients with thymomas; (3) polymyositis/​dermatomyositis; (4) neuromyotonia. Incidence The most frequent paraneoplastic neurological syndrome (PNS) is Lambert–​Eaton myasthenic syndrome (LEMS), which affects about 2 to 3% of patients with small-​cell lung cancer (SCLC), and myasthenia gravis. This is most commonly autoimmune, but about 10% of patients have an associated thymoma (Chapter 24.18). By contrast, the PNS affecting the central nervous system are very rare, probably affecting fewer than 1% of patients with cancers of all types. In one series of almost 1500 patients with tumours, only three had paraneoplastic cerebellar degeneration, and none had subacute sensory neuronopathy. In a surveillance study of all PNS from the United Kingdom, 50 cases were iden- tified in one year; the female:male ratio was greater than 3:1, the median age of onset of PNS was 66 years and only 11% of patients were less than 50 years of age at presentation. The PNS preceded the diagnosis of cancer in 84% of patients. In a recent European multicentre study of almost 1000 patients, predominantly with central nervous system involvement, paraneoplastic cerebellar degeneration and sensory neuronopathy were the most fre- quent (24%), followed by limbic or brainstem encephalitis and encephalomyelitis (22%). Despite their low incidence, paraneoplastic syndromes are im- portant for several reasons. • About two-​thirds of cases develop before the cancer has been identified and so their presence may lead to the detection of small and potentially curable cancers. • The presence of specific antibodies in the serum of patients with a PNS identifies the neurological disorder as paraneoplastic and may strongly suggest the location of the underlying tumour. • The PNS is often more disabling than the cancer and, in some instances, may be the cause of death. • A PNS or an antibody associated with a PNS (see next) may pre- dict a less aggressive course for the cancer. • Paraneoplastic antibodies identify proteins normally restricted to neurones that are of importance in the development and maintenance of the nervous system (see ‘Further reading’). 24.23 Paraneoplastic neurological syndromes Jeremy Rees 24.23  Paraneoplastic neurological syndromes 6385 The syndromes The clinical syndromes may be focal or diffuse involving single or multiple parts of the nervous system. The most well-​characterized syndromes (termed ‘classical’ by Graus et al.) are those that should always arouse suspicion of an associated cancer, and are listed in Table 24.23.1. These syndromes are commonly, but not always, associated with antibodies to certain onconeural antigens which point to the most likely tumours (Table 24.23.2), and will be described in detail next. The exception is limbic encephalitis that is often non​paraneoplastic (Chapter 24.24) and treatable with immunomodulation. Onconeural antibodies These antibodies often confirm the syndrome as being paraneoplastic and may point to a specific underlying tumour. For example, a pa- tient with paraneoplastic cerebellar degeneration who has serum anti-​Yo antibodies will almost always have a breast, ovarian, or other gynaecological cancer. Patients with paraneoplastic cere- bellar degeneration associated with non​gynaecological cancers have other antibodies that react with Purkinje cells or do not have antibodies identifiable by current techniques. The main antigens (Table 24.23.2) are cytoplasmic or nuclear proteins, although some are membrane proteins that are accessible to circulating antibodies, Table 24.23.1  Classical paraneoplastic neurological syndromes Syndromes Anatomical region Encephalomyelitis Limbic system, brainstem, spinal cord Limbic encephalitis Limbic system Subacute cerebellar degeneration Cerebellum Opsoclonus–​myoclonus Brainstem Sensory neuronopathy Dorsal root ganglia Chronic gastrointestinal pseudo-​obstruction Myenteric plexus Lambert–​Eaton myasthenic syndrome Neuromuscular junction Dermatomyositis Muscle Table 24.23.2  Onconeural antibody-​associated paraneoplastic syndromes Antibody to Neuronal reactivity Cloned genes Tumour Clinical syndromes Hu Nucleus>cytoplasm (all neurones) HuD, HuC SCLC, neuroblastoma,, prostate PEM, PSN, PCD, gastrointestinal pseudo-​obstruction Yo Cytoplasm, Purkinje cells CDR34, CDR62 Ovary, breast, PCD Ri Nucleus>cytoplasm (CNS neurones) Nova Breast, gynaecological cancer, lung, bladder Brainstem encephalitis, opsoclonus–​myoclonus Tr Cytoplasm, Purkinje cells Not known Hodgkin’s disease PCD VGCC Presynaptic neuromuscular junction P/​Q-​type VGCC SCLC LEMS, PCD VGKC-​complex Presynaptic: neuromuscular junction and CNS neurones LGI1 (non​paraneoplastic) and CASPR2 (paraneoplastic) Thymoma, SCLC Neuromyotonia, antonomic, limbic encephalitis or combinations of these (Morvan’s syndrome) Retinal Photoreceptor, ganglion cells Recoverin and others SCLC, melanoma, gynaecological CAR, MAR Amphiphysin Presynaptic Amphiphysin Breast, SCLC Stiff person syndrome, PEM, myelopathy, and myoclonus CV2 (CRMP5) Oligodendrocytes cytoplasm CRMP5 (POP66) SCLC, thymoma PEM, PCD, chorea, sensory neuropathy, myelopathy, gastrointestinal pseudo-​obstruction Ma1 Neurones (subnucleus) Ma1 Lung, others Brainstem, PCD Ma2 Neurones (subnucleus) Ma2 Testis Limbic/​brainstem encephalitis NMDAR Surface membrane of hippocampal and other neurones NR1 subunit Ovarian teratoma Limbic encephalitis with prominent neuropsychiatric features progressing to movement disorders, fall in consciousness and autonomic instability AMPA receptor Surface of hippocampal and other neurones GluR1/​2 SCLC, breast, thymoma Limbic Encephalitis GABA(B) receptor Surface of hippocampal and other neurones GABA(B1) or GABA(B2) SCLC Limbic Encephalitis Glycine receptor Inhibitory synapses on neurones GlyRα1 and others Thymoma, lymphomas Stiff Person Syndrome often with dysautonomia and brainstem involvement mGluR5 Neuronal cell surface Metabotropic glutamate receptor Hodgkins disease (2 cases reported) Limbic encephalitis Ganglionic form of nAChR Ganglionic synapses Ganglionic AChR SCLC, thymoma autoimmune dysautonomia AChR, acetylcholine receptor; CAR, cancer-​associated retinopathy; CNS, central nervous system; PCD, paraneoplastic cerebellar degeneration; SCLC, small-​cell lung cancer; VGCC, voltage-​gated calcium channels; VGKC, voltage-​gated potassium channels; CRMP5 (collapsin response mediator protein). For other abbreviations, see text. section 24  Neurological disorders 6386 (e.g. voltage-​gated calcium channels and N-​methyl-​D-​aspartate (NMDA) receptors). Certain autoantibodies are associated with specific tumours but widely varying paraneoplastic syndromes. For example, the anti-​ Hu antibody (Fig. 24.23.1) is almost always associated with SCLC (occasionally neuroblastoma or prostate cancer), but may be found in several different clinical syndromes usually encompassed by the term ‘encephalomyelitis’. The clinical abnormalities include limbic encephalitis, paraneoplastic cerebellar degeneration, brainstem en- cephalitis, sensory neuronopathy, and autonomic failure. Some or all of these clinical abnormalities may be found in the same patient. Not all patients with a classical syndrome and associated tumour have onconeural antibodies. Thus, the absence of positive detect- able antibodies should not be taken as evidence that the patient has a non​paraneoplastic form of disease. In some conditions, there are no identified antibodies. A good example is opsoclonus–​myoclonus associated with neuroblastoma in children. This paraneoplastic disorder is probably immune-​mediated. The failure to find a disease-​ or tumour-​specific antibody does not mean that one is not present, only that current techniques have not identified it. As techniques improve, new antibodies are regularly being reported; of particular interest is the discovery of antibodies directed against N-​methyl-​D-​aspartate receptors (NMDAR) on hippocampal neur- ones in young female patients and children with a progressive en- cephalitis, many of which are associated with ovarian teratomas (see ‘Further reading’). Tumours associated with PNS The most common tumours associated with PNS are found in lung (both SCLC and non-​SCLC), ovary, breast, thymus, lymph nodes (both Hodgkin’s Disease and Non-​Hodgkin’s Lymphoma) and testis. In a recent European survey, other tumours were also identified sug- gesting that whole-​body scanning is appropriate in the diagnostic work-​up of patients with suspected PNS. Diagnosis Certain clinical clues suggest that a neurological disorder may be a PNS. The onset is subacute or even acute; in some cases, the symptoms develop over a few days so that a stroke is initially sus- pected. Most PNS are progressive initially then stabilize after weeks to months, although more slowly progressive syndromes may occur. Recovery is rare in most of the central nervous system syn- dromes, probably because of irreversible neuronal loss and degen- eration, although improvement after oncological treatment have been reported. The neurological disorders are usually moderate or severe. Most patients have substantial disability by the time they first come to medical attention. Mild or waxing and waning neurological symptoms are rarely paraneoplastic. For example, the patient with paraneoplastic cerebellar degeneration is usually unable to walk or sit unsupported because of truncal ataxia, unable to write and, sometimes, unable to read because of oscillopsia. The neurological findings are often characteristic. A subacutely developing pancerebellar disorder, the rapid development of opsoclonus, or the development of LEMS strongly suggests cancer as the underlying cause. However, none of these syndromes, even the most characteristic, is invariably associated with cancer. Thus, only about two-​thirds of patients with LEMS have cancer and only about 10% of patients with myasthenia gravis have a tumour (almost always thymoma). Probably about one-​half of the patients with subacute cerebellar degeneration have cancer. Limbic enceph- alitis can present as both a paraneoplastic and a more common non-​ paraneoplastic form (Chapter 24.24). Imaging in suspected PNS is often normal or non​specific. Indeed, one of the clues to the presence of a PNS is the relative normality of imaging in a patient with such severe clinical symptoms and signs. Occasionally MRI may show high signal within one or both medial temporal lobes (limbic encephalitis) or brainstem (brain- stem encephalitis), and very rarely diffuse oedema of the cerebellum (paraneoplastic cerebellar degeneration). The cerebrospinal fluid may show pleocytosis (30–​40 cells), elevated protein, increased IgG, and oligoclonal bands, particularly early on in the course of disease, which then settles within a few weeks of onset. The immunoglobulin abnormalities usually persist. In a patient with a known cancer, the diagnosis of PNS should usually only be made after exclusion of the more common neurological complications of cancer, particularly malignant meningitis or treatment toxicity (e.g. chemotherapy-​ induced peripheral neuropathy). In a patient without a known cancer, particularly when con- ventional imaging studies (radiography, CT, ultrasonography, and mammography) are negative, the appropriate use of whole-​body fluorodeoxyglucose positron emission tomography (FDG-​PET) may show a FDG-​avid ‘hot spot’ suggestive of an occult malignancy (Fig. 24.23.2). Blood tumour markers are rarely helpful in this clin- ical context. If an onconeural antibody is present and the search for an underlying cancer is negative, the physician is obliged to follow 35–40 kDa Fig. 24.23.1  Anti-​Hu antibodies: serum immunoreactivity with rat brainstem counterstained showing strong nuclear staining (solid arrow) and weaker cytoplasmic staining (dashed arrow) typical of anti-​Hu (anti ANNA 1) antibodies (DAB-​peroxidase counterstained with haematoxylin and eosin). Western blot shows a ‘ladder’ pattern of bands between 35 and 40 kDa. The patient was a woman with paraneoplastic cerebellar degeneration who was subsequently found to have lung cancer. Courtesy of Elizabeth Amyes Msc, University of Oxford. 24.23  Paraneoplastic neurological syndromes 6387 the patient carefully, searching periodically for a cancer. The recom- mended time for follow-​up is five years from presentation, except for LEMS which is 18 months. The difficulties of defining and hence diagnosing PND have been carefully considered by an international panel of neurological ex- perts who have established guidelines for more rigorous diagnostic criteria. The aim of these guidelines has been to facilitate diagnosis, classification, and collaborative research. They rely on the defin- ition of ‘classical’ paraneoplastic syndromes and ‘well-​characterized’ onconeural autoantibodies. On this basis a condition could be diag- nosed as paraneoplastic based on a descending hierarchy of fac- tors: (1) presence or absence of ‘classical’ syndrome; (2) presence or absence of cancer; (3) presence or absence of ‘well-​characterized’ antineuronal antibodies and (4) exclusion of other possible causes of a similar neurological syndrome. On the basis of combinations of these criteria, the diagnosis of a PND is now either ‘definite’ or ‘possible’. (See ‘Further reading’.) Pathogenesis Current evidence suggests that PNS result from an autoimmune reaction to ‘onconeural’ antigens in the tumour. These antigens are those that are normally restricted to the nervous system (or the testis, which is also an immunologically privileged site). The immune system therefore recognizes the antigen as foreign and some patients mount an immune response. The immune response may have the beneficial effect of slowing tumour growth, but it can also damage those parts of the nervous system that express the antigen. Although many PNS are associated with specific neuronal autoantibodies, there is limited evidence that those directed against cytoplasmic or nuclear antigens are pathogenic. T lymphocytes recognizing these or other onconeural antigens, and other cellular immune mechan- isms, are the likely pathogenic agents in these conditions. In contrast, antibodies directed against membrane ion channels or receptors for neurotransmitters (e.g. voltage-​gated calcium and potassium chan- nels, NMDA and AMPA forms of glutamate receptors) are patho- genic but are also often present in non​paraneoplastic forms of the disease. These antibodies recognize epitopes located at presynaptic or postsynaptic sites. Treatment Those PNS which are associated with antibodies to the neuronal surface proteins (NMDAR, AMPAR, GABA(B)R, CASPR2), such as LEMS, MG, and NMDAR encephalitis respond to immunosuppres- sion or to treatment of the underlying cancer (Table 24.23.3). Some syndromes, such as opsoclonus–​myoclonus, may remit spontan- eously, but for most PNS associated with antibodies to intracellular Fig. 24.23.2  Axial T2W MRI brain of patient with limbic encephalitis showing high signal in left medial temporal lobe (arrow). Table 24.23.3  Treatable paraneoplastic neurological syndromes Syndrome Treatment Completely responsive Lambert–​Eaton myasthenic syndrome (LEMS) Tumour therapy, plasma exchange, intravenous immunoglobulin, 3,4 diaminopyridine Myasthenia gravis Tumour therapy, plasma exchange, intravenous immunoglobulin, steroids, immunosuppressants, thymectomy, anticholinesterases Dermatomyositis Steroids, immunosuppressants, intravenous immunoglobulin Opsoclonus–​myoclonus (children) Steroids, ACTH, tumour therapy Limbic encephalitis or other syndromes with antibodies to cell-​surface antigens, e.g. VGKC, NMDAR, AMPAR, GABA(B)R, GlyR Tumour therapy, plasma exchange, intravenous immunoglobulin, immunosuppressants Neuromyotonia Antiepileptics, steroids, plasma exchange, tumour therapy Demyelinating neuropathy (osteosclerotic myeloma) Tumour therapy, radiation, bevacizumab Partially responsive Opsoclonus–​myoclonus (adults) Steroids, tumour therapy, clonazepam, diazepam, baclofen Paraneoplastic cerebellar ataxia (Hodgkin’s disease) Tumour therapy Opsoclonus/​ataxia (anti-​Ri) Steroids, cyclophosphamide section 24  Neurological disorders 6388 antigens, treatment is unrewarding, and the patient remains severely disabled even if the cancer is cured. Treatments usually involve im- munosuppression with plasma exchange, intravenous immuno- globulin, steroids, or cytotoxic agents (e.g. cyclophosphamide), particularly for those syndromes associated with onconeural auto- antibodies. It is possible that the rapid onset of the syndromes does not allow sufficient time for accurate early diagnosis and for treat- ment to begin before irreversible neuronal damage has occurred. With earlier diagnosis, therapy may be more successful. However, as mentioned already, several of the ‘classical’ paraneoplastic con- ditions appear to exist in non​paraneoplastic forms (e.g. limbic en- cephalitis with potassium channel antibodies) and may respond to immunotherapies; therefore, if onconeural antibodies are absent, and no cancer is found, a trial of immunotherapy should be con- sidered. There has been interest in rituximab (anti-​CD20 mono- clonal Ab) which has shown modest benefit in a small open trial of patients with PNS. Specific syndromes Brain and cranial nerves (See Box 24.23.1.) Paraneoplastic cerebellar degeneration Paraneoplastic cerebellar degeneration may complicate any ma- lignant tumour but is most common with lung cancer (especially SCLC), breast and gynaecological cancer, and Hodgkin’s disease. Males and females are both affected, and the age incidence reflects the age distribution of the underlying cancer. Neurological mani- festations precede detection of the associated tumour in over one-​ half of patients, rarely by more than five years, or paraneoplastic cerebellar degeneration may develop after diagnosis of the tumour. In some instances, the tumour is not found until autopsy. Typically, the disorder begins as gait ataxia that progresses over a few days to weeks to severe truncal and appendicular ataxia with dysarthria and nystagmus. The nystagmus is frequently downbeating. Vertigo with or without nausea and vomiting is common and many patients complain of diplopia. The cerebellar signs are bilateral but may be asymmetrical. The cerebellar deficit usually stabilizes but, by then, the patient is often incapacitated. Spontaneous improvement some- times occurs, particularly when associated with Hodgkin’s disease. Some patients will also be found to be mildly cognitively impaired and demonstrate extensor plantar reflexes or sensory changes sug- gesting a more widespread encephalomyelitis. The cerebrospinal fluid may be normal, but there is usually a pleocytosis within the first few months, and raised protein and oligoclonal bands may also be present. Cytological examination of the cerebrospinal fluid and contrast-​enhanced MRI of the brain are essential to rule out leptomeningeal metastases. MRI scans typically are normal early, but later show signs of progressive cerebellar at- rophy with prominent cerebellar folia and a dilated fourth ventricle. The pathological hallmark of paraneoplastic cerebellar degener- ation is loss of Purkinje cells, affecting all parts of the cerebellum. Less striking changes in the cerebellar cortex may include thinning of the molecular layer with microglial proliferation and astrocytic gliosis, proliferation of Bergmann glia, and slight thinning of the granular layer with decreased numbers of granule cells. When typical, the clinical picture of paraneoplastic cerebellar degeneration is almost pathognomonic. When atypical, the dis- order must be distinguished from a cerebellar tumour (primary or metastatic) and from leptomeningeal metastases (by MRI and cerebrospinal fluid examination, respectively), from late-​onset, non​paraneoplastic cerebellar degenerations, cerebellar haemor- rhage and infarction; prion diseases, cerebellar ataxia related to 5-​ fluorouracil, capecitabine or high-​dose cytarabine, and metabolic disorders, especially alcoholic cerebellar degeneration. There have been occasional reports of a partial or near-​complete remission of paraneoplastic cerebellar degeneration following treatment of the primary tumour. This is very unusual, however, and most patients do not improve even when treatment is begun early in the illness, before Purkinje cells are irreversibly dam- aged. Plasmapheresis, corticosteroids, immunosuppressive drugs, intravenous immunoglobulin, and rituximab have all been tried and may lead to mild symptomatic improvement in the ataxia. Paraneoplastic cerebellar degeneration may occasionally be as- sociated with LEMS, both associated with SCLC and antivoltage-​ gated calcium channels antibodies. Recognition and treatment of the peripheral symptoms can lead to overall clinical benefits. In the future, non​paraneoplastic potentially treatable forms may be identified. Opsoclonus–​myoclonus Opsoclonus is a disorder of eye movements consisting of almost continuous chaotic, multidirectional, involuntary, high-​amplitude conjugate saccades that are often accompanied by synchronous blinking of the lids. It is usually considered to be a paraneoplastic syndrome complicating 2% of childhood neuroblastoma (dancing eyes syndrome) or a variety of tumours in adults, particularly breast cancer and SCLC, but there are cases that are non​paraneoplastic and self-​limiting (see next). Opsoclonus may be an isolated neurological sign, but is often accompanied by myoclonus of the trunk, limbs, head, diaphragm, larynx, pharynx, and palate, and ataxia, hence the term opsoclonus–​ myoclonus or opsoclonus–​myoclonus ataxia. Neurological symp- toms precede identification of the neuroblastoma in at least 50% of patients, and the tumour may be missed by abdominal examination; thus, recognition of the neurological syndrome is an important clue to the presence of a neuroblastoma. There are reports of antibodies to neuroblastoma cell lines but no specific antigen has been defined. When a neuroblastoma is associated with opsoclonus–​myoclonus, there is a higher than expected incidence of intrathoracic tumours and of tumours with a benign histology. The prognosis of the neuro- blastoma is better if opsoclonus–​myoclonus is associated than when there is no neurological complication, an observation not explained by earlier diagnosis when neurological symptoms are present. The neurological disorder responds to adrenocorticotropic hormone (ACTH) and to intravenous immunoglobulin but not to prednisone. Box 24.23.1  Paraneoplastic syndromes affecting the brain • Subacute cerebellar degeneration • Opsoclonus–​myoclonus • Limbic encephalitis • Brainstem encephalitis 24.23  Paraneoplastic neurological syndromes 6389 However, most patients suffer residual neurological damage, usually cognitive. Opsoclonus–​myoclonus is less common in adults, and in younger adults is often non​paraneoplastic. Nevertheless, about 20% of adult patients reported with opsoclonus–​myoclonus have an underlying cancer. The neurological symptoms usually precede diagnosis of the tumour and commonly progress over several weeks, although more rapid or slower progression may be observed. The cerebrospinal fluid may show a mild pleocytosis and an elevated protein. The MRI is usually normal. Neuropathological findings have been variable. In some patients there are no identifiable abnormalities. In others, the changes resembled those of paraneoplastic cerebellar degeneration with a loss of Purkinje cells, inflammatory infiltrates in the brain- stem, Bergmann gliosis, and loss of cells from the granular layer of the cerebellum. The prognosis for recovery or partial remission of the neuro- logical disorder is better for opsoclonus–​myoclonus than it is for paraneoplastic cerebellar degeneration. Improvement may follow treatment of the underlying tumour, and spontaneous partial re- missions occur. Differential diagnosis includes non​paraneoplastic conditions such as viral infections, postinfectious encephalitis, hydrocephalus, thalamic haemorrhage, and toxic encephalopathies from thallium or lithium, amitriptyline overdose, and diabetic hyperosmolar coma. Limbic encephalitis Limbic encephalitis may occur as an isolated finding initially, but the paraneoplastic forms frequently progress to a more extensive encephalomyelitis. The neurological symptoms often precede diag- nosis of the tumour by up to 2 years; sometimes the cancer is not detected until autopsy. Symptoms usually progress over several weeks, but the course may be more insidious. Anxiety and depres- sion are common early symptoms, but the most striking feature is a severe impairment of episodic memory. Other manifestations in- clude agitation, confusion, hallucinations, and partial or generalized seizures. The symptoms may spread to include other brain func- tions (e.g. the hypothalamus), with changes in appetite or sleep (e.g. hypersomnia). Dementia usually occurs, but occasionally there may be a spontaneous remission; an increasing number of these cases are now known to be associated with antibodies to voltage-​gated potas- sium channel complex proteins. Indeed, this test should now be sent off in any patient presenting with a rapidly progressive amnesic syn- drome, as it is treatable. The cerebrospinal fluid commonly shows a pleocytosis and an elevated protein concentration in PNS cases. MR scans are usually normal but medial temporal abnormalities have been reported (Fig. 24.23.3). Inflammatory pathological changes affect the grey matter of the hippocampus, cingulate gyrus, pyriform cortex, orbital surfaces of the frontal lobes, insula, and the amygdala. No treatment has proved uniformly beneficial although spontaneous remissions have been reported and some patients have improved after treatment of the underlying tumour. If onconeural antibodies are negative and there is no evidence of a tumour, immunosuppression should be con- sidered as recent studies have identified antibodies against novel cell-​surface antigens (voltage-​gated potassium channel complex proteins, LGI1, CASPR2, or NMDARs) which are associated with a favourable prognosis. NMDAR antibody encephalitis This condition, relatively recently described, has proved to be common, particularly in younger adults and children. Patients present with neuropsychiatric features, sometimes following a viral illness, and progress rapidly to a severe encephalop- athy with seizures, movement disorders, autonomic instability, and reduced consciousness. Despite the severity of the disease, the MRI is often normal or changes non​specific, but the cere- brospinal fluid often shows pleocytosis during the first days. Oligoclonal bands tend to appear later. Ovarian teratomas or cysts are found in up to 50% of the adult females, but tumours are less common in males or the increasing number of children iden- tified, even within the first year of life. Removal of the ovary(s) and multiple symptomatic treatments are required, combined with immunotherapies with steroids, plasma exchange, and intravenous immunoglobulins; benefits may be evident within a few weeks but if not, rituximab and cyclophosphamide are recommended (see ‘Further reading’). Although many pa- tients require intensive care for weeks or months, the long-​term prognosis is positive with a proportion returning to normal life particularly if identified and treated early. The ovarian tu- mours express NMDARs. Experimental results suggest that the antibodies reduce the number of hippocampal NMDARs in a reversible manner. Fig. 24.23.3  Whole-​body FDG-​PET scan showing two hot spots in right middle lobe (arrow) from patient with cerebellar degeneration and anti-​Hu antibodies in whom chest radiography and CT of the thorax were both negative. Subsequent biopsy confirmed small-​cell lung cancer. section 24  Neurological disorders 6390 Brainstem encephalitis Paraneoplastic brainstem encephalitis is often associated with clin- ical and pathological evidence of encephalomyelitis elsewhere within the central and peripheral nervous systems, but may occur as the dominant or an isolated clinical finding. It is commonly associ- ated with SCLC, but an identical clinicopathological syndrome may be seen in the absence of a malignancy. The clinical features vary according to the brainstem structures involved in the pathological process. Common manifestations in- clude vertigo, ataxia, nystagmus, vomiting, bulbar palsy, oculomotor disorders, and corticospinal tract dysfunction. Less common clin- ical features include deafness, myoclonus of the palate, central al- veolar hypoventilation presenting with respiratory failure and jaw dystonia. Basal ganglia involvement produces movement disorders including chorea or Parkinson’s syndrome, these being more com- monly seen in patients with anti-​CV2 antibodies. Neurological symptoms may develop before or after discovery of the malignancy. The pathological changes are identical to those ob- served in other forms of paraneoplastic encephalomyelitis. Visual loss PNS can affect retinal photoreceptors, either rods or cones or both. They can cause a retinal vasculitis or optic neuropathy. Paraneoplastic retinal degeneration, also called cancer-​associated retinopathy, usu- ally occurs in association with SCLC, melanoma, and gynaecological tumours. Typically, the visual symptoms include episodic visual obscurations, night blindness, light-​induced glare, photosensitivity, and impaired colour vision. Visual symptoms usually precede the diagnosis of cancer. The symptoms progress to painless visual loss. They may begin unilaterally but usually become bilateral. Visual testing demonstrates peripheral and ring scotomas and loss of acuity. Fundoscopic examination may reveal arteriolar narrowing and ab- normal mottling of the retinal pigment epithelium. The electroretino- gram is abnormal. Cerebrospinal fluid is typically normal, although elevated immunoglobulin levels have been reported. Inflammatory cells are sometimes seen in the vitreous by slit-​lamp examination. Retinal antibodies (e.g. recoverin), although well recognized, are not routinely available in most countries. Pathologically, cancer-​associated retinopathy is associated with a loss of photoreceptors and ganglion cells with inflammatory infil- trates and macrophages. The other parts of the optic pathway are preserved, although a loss of myelin and lymphocytic infiltration of the optic nerve may occur. Treatment of cancer-​associated retinopathy is usually unsuc- cessful although a recent report describes improvement in some pa- tients with the use of intravenous immunoglobulin. The condition is not recognized very frequently, and there may be non​paraneoplastic forms that are difficult to distinguish. Spinal cord and dorsal root ganglia (See Box 24.23.2.) Necrotizing myelopathy This is an extremely rare PNS. The initial symptoms of muscle weak- ness and sensory loss in the arms and legs may be asymmetrical, but eventually signs become bilateral and symmetrical. Back or ra- dicular pain may precede other neurological signs. Cerebrospinal fluid abnormalities may include an elevated level of protein and a mild pleocytosis. Swelling of the spinal cord may be apparent on MRI. Typically, the neurological deficit progresses rapidly over days or a few weeks, ultimately leading to respiratory failure and death. There is no effective treatment. Pathologically, there is widespread necrosis of the spinal cord, often most marked in the thoracic segments. The necrosis involves all components of the spinal cord with white matter usually more affected than grey matter. Motor neuron disease (amyotrophic lateral sclerosis) There is controversy as to whether motor neuron disease can be re- garded as a classical PNS. It is likely to be paraneoplastic in three distinct groups of patients; the first with a rapidly progressive amyotrophic lateral sclerosis picture associated with anti-​Hu anti- bodies; the second with primary lateral sclerosis and breast cancer; and the third with a subacute motor neuronopathy associated with lymphoma. Classical motor neuron disease in a patient with a pre- vious history of cancer is probably not paraneoplastic, merely re- flecting the occurrence of two reasonably common diseases of older age in the same patient separated in time. Myelitis Paraneoplastic myelitis is usually a part of the encephalomyelitis syndrome with inflammatory lesions elsewhere in the brain and dorsal root ganglia as well as the spinal cord. The clinical picture is dominated by the radicular element of a myeloradiculitis and is characterized by patchy wasting and weakness of muscles, some- times combined with fasciculations. The upper extremities are often more severely affected than the legs, reflecting predominant involve- ment of the cervical spinal cord. There may be striking weakness of neck and intercostal muscles, resulting in respiratory failure. Sensory symptoms and autonomic dysfunction may be present. Sensory neuronopathy Paraneoplastic sensory neuronopathy is most commonly asso- ciated with SCLC. Symptoms typically begin before the cancer is identified, with dysaesthetic pain and numbness in the legs or occa- sionally in the arm(s), face, or trunk. The symptoms may be asym- metrical at onset but progress over days to several weeks to involve the limbs, trunk, and sometimes the face, causing a severe sensory ataxia. All sensory modalities are affected. Deep tendon reflexes are lost but motor function is preserved. Occasional patients have a mild and indolent neuropathy. The cerebrospinal fluid is typically inflammatory. Early pathological changes are limited mostly to the dorsal root ganglia, in which both a loss of neurones and the presence of lymphocytic inflammatory infiltrates are noted (Fig. 24.23.4). About 50% of patients with paraneoplastic sensory neuronopathy have pathological changes that may be clinically inapparent in other Box 24.23.2  Paraneoplastic syndromes affecting spinal cord and dorsal root ganglia • Sensory neuronopathy • Necrotizing myelopathy • Subacute motor neuronopathy • Motor neuron disease (primary lateral sclerosis) • Myelitis (as part of encephalomyelitis) 24.23  Paraneoplastic neurological syndromes 6391 regions of the nervous system. As with other PND, this disorder rarely responds to treatment. Peripheral nerves (See Box 24.23.3.) Sensory and sensorimotor neuropathy Peripheral neuropathies, particularly mild distal sensorimotor neuropathies, are common in patients with cancer and may be due to the metabolic or nutritional effects of late cancer, or associated with certain drugs (e.g. cisplatin). Some patients not known to have cancer, and who are not evi- dently systemically ill, present to the neurologist with a peripheral neuropathy that may be quite severe and disabling. It is estimated that about 10% of those patients whose initial evaluations do not reveal an obvious cause (such as vitamin B12 deficiency, alcohol, or diabetes), will eventually prove to have cancer as the underlying reason for the peripheral neuropathy. Paraneoplastic peripheral neuropathy may take several clinical and pathological forms. The most common is the distal, symmetrical, subacutely developing, sensory neuropathy which may be either axonal or demyelinating. A relatively pure sensory neuropathy, a mononeuritis multiplex due to microvasculitis, an acute polyradiculopathy, a focal neuropathy such as brachial neuritis, or an autonomic neuropathy may also be paraneoplastic. Most of these neuropathies are not associated with autoantibodies and the diagnosis is often one of exclusion. Neuromuscular junction and muscle (See Box 24.23.4.) Paraneoplastic disorders of the neuromuscular junction include the Lambert–​Eaton myasthenic syndrome, myasthenia gravis, and acquired neuromyotonia. These disorders have a common patho- genetic mechanism—​they are caused by antibodies against ion channels and, whether paraneoplastic or not, they respond to im- munological treatment. They are described in more detail in Chapter 24.18. Finally, because of its similarity to neuromyotonia, the stiff person syndrome is also included in this section. Whereas the more common non​paraneoplastic form is associated with antibodies to glutamic acid decarboxylase, the presence of amphiphysin or other onconeural antibodies should raise the suspicion of a tumour. Lambert–​Eaton myasthenic syndrome Lambert–​Eaton myasthenic syndrome (LEMS) results from a re- duced release of acetylcholine at presynaptic nerve terminals. The same P/​Q-​type voltage-​gated calcium channels are found in small-​cell lung cancers. Interestingly, the richest source of P/​Q-​ type voltage-​gated calcium channels is the cerebellum, perhaps explaining the occasional relationship of paraneoplastic cerebellar degeneration and LEMS. LEMS can be treated either by immune suppression or by treat- ment of the underlying cancer when present. Patients with SCLC associated with LEMS have a better prognosis than patients with SCLC who do not develop a paraneoplastic disorder, but this could be partly due to earlier diagnosis. Myasthenia gravis Myasthenia gravis occurs in 30% of patients with thymomas, and approximately 10% of patients with myasthenia gravis are found to have a thymoma. Usually the two are diagnosed synchronously but rarely myasthenia may develop many years after the thymoma, sometimes in association with other autoimmune diseases (e.g. red-​ cell aplasia). Polymyositis and dermatomyositis Only a minority of patients, usually older people, with polymyositis or dermatomyositis have an underlying malignancy as the cause. Dermatomyositis with typical cutaneous changes is more likely to be paraneoplastic than polymyositis. Females and males are affected in approximately equal numbers. Symptoms of proximal muscle weak- ness, with pain and high creatine kinase levels, generally precede Fig. 24.23.4  Sensory ganglionitis: dorsal root ganglion with hypercellular nodules marking the site of ganglion cell degeneration. Another ganglion cell (dashed arrow) is in the process of degenerating. A healthy ganglion cell is shown in the bottom left-​hand corner of the plate. Box 24.23.3  Paraneoplastic syndromes affecting peripheral nerves • Subacute or chronic sensorimotor peripheral neuropathy • Mononeuritis multiplex and microvasculitis of peripheral nerve • Brachial neuritis • Autonomic neuropathy (as part of anti-​Hu syndrome) • Demyelinating peripheral neuropathy (myeloma or plasmacytoma) Box 24.23.4  Paraneoplastic syndromes affecting neuromuscular junction and muscle • Lambert–​Eaton myasthenic syndrome • Myasthenia gravis • Dermatomyositis, polymyositis, acute necrotizing myopathy • Neuromyotonia section 24  Neurological disorders 6392 identification of the cancer. The tumour may be at any site, but breast, lung, ovarian, and gastric malignancies are the most common. Corticosteroids, cyclosporin, and other immunosuppressants have been used successfully. Other reports suggest that high-​dose intravenous immunoglobulin is useful in patients unresponsive to other forms of immunosuppression. Neuromyotonia and stiff person syndrome Muscle cramps are a common complication of cancer, sometimes re- lated to electrolyte imbalance or induced by chemotherapy. A much rarer but clinically significant PNS is acquired neuromyotonia. The disorder is characterized by muscle stiffness, cramps, and obvious rippling and twitching of muscles, sometimes leading to sustained abnormal postures. Relaxation after voluntary contraction is de- layed. Symptoms persist during sleep (and are abolished by curare). Sudden prolonged bursts of high-​frequency, involuntary, repetitive muscle action potentials are seen on electromyography. The muscle spasms and rigidity are sometimes precipitated by activity, forcing patients to become sedentary. The disorder arises from peripheral nerves and is sometimes a part of the encephalo- myelitis syndrome. The disorder is usually non​paraneoplastic, but may be associated with cancer including thymomas and SCLC. Antibodies against voltage-​gated potassium channels are often posi- tive (Chapter 24.24). Plasma exchange improves the patient’s condi- tion; but they often respond to anticonvulsants alone. Injection of IgG from affected patients into experimental animals can reproduce evidence of peripheral nerve hyperexcitability. Stiff person syndrome may superficially resemble neuromyotonia, but has a central origin and is usually not paraneoplastic. This rare disorder is clinically characterized by stiffness and rigidity, with epi- sodic spasms of axial muscles. A variant of the syndrome affects the limbs. Painful reflex spasms can occur in response to tactile stimuli or startle. Muscle action potentials are normal on electromyography but the activity is continuous and excessive and increased by volun- tary activity. The disorder is usually autoimmune, associated with antibodies against glutamic acid dehydroxylase; since this antibody is also important in type 1 diabetes, the assay is widely available. When paraneoplastic, it can be associated with lung or breast tu- mours, often with the appropriate onconeural antibody. Recently antibodies to glycine receptors have been recognized in patients with stiff person syndrome or a form of progressive encephalomy- elitis with rigidity and myoclonus. FURTHER READING Candler PM, et  al. (2004). A follow up study of patients with paraneoplastic neurological disease in the United Kingdom. J Neurol Neurosurg Psychiatry, 75, 1411–​15. Dalmau J, et al. (2011). Clinical experience and laboratory investi- gations in patients with anti-​NMDAR encephalitis. Lancet Neurol, 10, 63–​74. Giometto B, et al. (2010). Paraneoplastic neurologic syndromes in the PNS Euronetwork database: a European study from 20 centers. Arch Neurol, 67, 330–​35. Graus F, et  al. (2004). Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry, 75, 1135–​40. Höftberger R, Rosenfeld MR, Dalmau J (2015). Update on neuro- logical paraneoplastic syndromes. Curr Opin Oncol, 27, 489–​95. Kayser MS, et al. (2010). Psychiatric manifestations of paraneoplastic disorders. Am J Psychiatry, 167, 1039–​50. Rees JH (2004). Paraneoplastic syndromes: when to suspect, how to confirm and how to manage. J Neurol Neurosurg Psychiatry, 75 Suppl 2, ii43–​50. Vedeler CA, et al. (2006). Management of paraneoplastic neurological syndromes: report of an EFNS Task Force. Eur J Neurol, 13, 682–​90. 24.24 Autoimmune encephalitis and Morvan’s syndrom 24.24 Autoimmune encephalitis and Morvan’s syndrome 6393 Camilla Buckley and Angela Vincent ESSENTIALS Autoimmune limbic encephalitis—​typical presentation is with acute or subacute onset of short-​term memory loss, seizures, and dis- orientation. MRI characteristically shows striking abnormalities in the hippocampus. Antibodies against cell-​surface proteins that are components of voltage-​gated potassium channel complexes are found in a high proportion and are probably pathogenic. Aside from supportive care, treatment is with immunosuppression, often com- prising corticosteroids with intravenous immunoglobulin and/​or plasma exchange. Morvan’s syndrome—​a very rare condition presenting with varying degrees of neuromyotonia, memory loss, confusion, sleep disturb- ance, and autonomic features, also with antibodies to voltage-​gated potassium channel-​complex proteins, in about 90% of patients. Autoimmune encephalopathy with antibodies to N-​methyl-​D-​ aspartate receptor (NMDAR)—​a neuropsychiatric illness, often affecting young women who may have an associated ovarian tera- toma. Prompt treatment with immunosuppression can lead to good outcomes but there is a 5% mortality rate and delayed diagnosis is common in patients with less typical presentations. Autoimmune limbic encephalitis with VGKC-​complex antibodies Epidemiology Since its first recognition in 2001, hundreds of patients have been identified with autoimmune limbic encephalitis (LE) associated with antibodies that immunoprecipitate voltage-​gated potassium channel (VGKC)-​complex proteins. Preliminary epidemiology sug- gests that it is more common in men (2:1) and that the median age at onset is 65 years. The phenotype has been recognized mainly in patients over the age of 18 years at onset. Clinical features The classic presentation is with subacute onset of short-​term memory loss, seizures, disorientation, with psychological disturb- ance or hallucinations. Additional features that may occur are sleep disturbance, autonomic dysfunction, and neuromyotonia, but these would be more typical of Morvan’s syndrome (see next). The most striking feature on examination is the profound disorientation and memory loss, leading to poor performance on bedside cognitive tests such as the Mini-​Mental State Examination. Neuromyotonia (see Chapter 24.19.3) may be evident, but often the examination is otherwise unremarkable. Some patients develop only one aspect of the syndrome (e.g. isolated memory loss or isolated temporal or frontal seizures), but are otherwise similar to those with the full syndrome. Some patients report an influenza-​like illness one to two weeks earlier. Recently, an increasing number of patients with immunotherapy-​responsive brief frequent dystonic seizures (termed faciobrachial dystonic seizures), that often precede the limbic disturbance by days to months, have been recognized. Investigations Hyponatraemia is present in 80% of patients, usually accompanied by a low plasma and urine osmolarity. Other routine blood tests are normal. The cerebrospinal fluid is often normal but may show a mild pleocytosis. VGKC-​complex antibody titres are character- istically very high in these patients (more than 400 pmol/​litre and often more than 1000 pmol/​litre (normal range less than 100 pmol/​ litre)), and higher than the titres commonly found in patients with neuromyotonia (usually less than 400 pmol/​litre) (Fig.  24.24.1b). MRI shows striking abnormalities in 70% of patients and it is often these that lead the clinician to suspect the diagnosis and request the confirmatory serological test (Fig. 24.24.1a). The most classic change is high signal restricted to the hippocampus (either uni- laterally or bilaterally), best seen on T2-​weighted or FLAIR (fluid-​ attenuated inversion recovery) sequences, with associated swelling of the affected area. A few patients have more widespread areas of increased signal in the medial temporal lobes and amygdala. LE associated with VGKC antibodies can occasionally (<10%) be a paraneoplastic disorder and so all patients should undergo appro- priate imaging to detect any underlying malignancy (e.g. thymoma or small-​cell lung cancer). VGKC-​complexes are extracted from brain tissue and include the Kv1 shaker-​type VGKCs in a multiprotein complex that includes leucine-​rich glioma-​inactivated 1 (LGI1) and contactin-​associated protein-​like 2 (CASPR2). The antibodies can be identified by 24.24 Autoimmune encephalitis and Morvan’s syndrome Camilla Buckley and Angela Vincent section 24  Neurological disorders 6394 immunoprecipitation of VGKC-​complexes, or by binding to the individual proteins by cell-​based assays. In LE and faciobrachial dystonic seizures, they are most often directed to LGI1; CASPR2 antibodies are found in neuromyotonia and Morvan’s syndrome. However, VGKC-​complex antibodies without LGI1 or CASPR2 re- activity may not be helpful in achieving a diagnosis, and their sig- nificance needs further research. Treatment Initially patients often require fluid restriction to manage the hyponatraemia, antiepileptic drugs for their seizures, antipsychotic drugs to control paranoid ideation, and corticosteroids with plasma exchange or intravenous immunoglobulin for acute immuno- suppression. The choice of antiepileptics is complicated by the hyponatraemia, which can be profound. Often the seizures do not respond well to antiepileptics alone and do not start to reduce in fre- quency until immunosuppression has been established. There have been no randomized controlled trials to determine the most effective immunosuppressive regimens in these patients and currently the protocols are similar to those used to treat pa- tients with autoimmune disorders of the neuromuscular junction (see Chapter 24.18). Corticosteroids appear to be a particularly im- portant component because longer-​term follow-​up suggests that those treated with intravenous immunoglobulin alone respond less well than those treated with intravenous immunoglobulin and ster- oids. Although early treatment is recommended, as it appears to be associated with improved prognosis, even late introduction of ster- oids and other immunosuppression can be beneficial. Differential diagnosis Acutely, the differential diagnosis lies mainly with infectious causes of LE, the most common being herpes simplex encephalitis (HSE), and most patients will have a cerebrospinal fluid polymerase chain reaction for HSE performed on admission, particularly if they have a high fever and severe headache. Korsakoff’s pyschosis can present similarly and so an accurate alcohol history and suggestive blood tests, such as liver function tests and mean cell volume, should be performed. The other main differential lies with paraneoplastic LE, so all pa- tients need imaging to detect associated tumours and, in the right context, it may be appropriate to look for the particular antibodies seen with these disorders (see Chapter 24.23). Other forms of po- tentially immunotherapy-​responsive LE are now being recognized, some of which are associated with antibodies to other neuronal surface antigens (e.g. N-​methyl-​D-​aspartate receptor, see next and Chapter 24.23) and can be non​paraneoplastic. Table 24.24.1 sum- marizes the most useful antibodies and associated syndromes. Morvan’s syndrome, although very rare, can present similarly to LE but requires sleep disturbance (mainly insomnia) and is also distin- guished by additional peripheral and autonomic features (see next), that can go unrecognized. In addition (as with the autoimmune disorders of the neuromuscular junction), there are patients with a similar clinical phenotype who respond to immunomodulatory therapies, but in whom no antibody is detectable by current methods, although new diagnostic tests will undoubtedly emerge. Pathogenesis VGKC-​complex LE is probably an immune-​mediated disorder given the time course of patients’ clinical, serological, and radiological re- sponses to immunosuppression. VGKC is a transmembrane protein that is densely expressed in the hippocampus and elsewhere in the brain, where it is complexed with LGI1, CASPR2, and other proteins. Genetic mutations in VGKC can cause seizures both in mice and in humans and, as the channel is involved in stabilizing the membrane potential, its dysfunction will result in neuronal hyperexcitability. There is evidence that LGI1 antibodies are pathogenic; they disrupt the role of LGI1 in modulating VGKC function in hippocampal cul- tures. Less is known about CASPR2 antibodies. NMT LE −100 0 100 200 300 400 1000 2000 3000 4000 VGKC antibody (a) (b) Fig. 24.24.1  (a) T2-​weighted coronal MRI of the brain with the red circles highlighting the abnormal high signal bilaterally in the hippocampi of a patient with limbic encephalitis (LE) associated with voltage-​gated potassium channel (VGKC) complex antibodies. (b) VGKC-​complex antibody levels in patients with LE compared with those in patients with neuromyotonia. The horizontal line denotes the cut-​off for healthy individuals. LE patients with these antibodies usually have values more than 400 pmol/​litre, these are common and up to 1000 pM/​litre in the rare Morvan’s syndrome (not shown), whereas they tend to be lower titre and absent in >60% of patients with neuromyotonia. 24.24  Autoimmune encephalitis and Morvan’s syndrome 6395 Morvan’s syndrome This is a very rare condition in which patients present with varying degrees of neuromyotonia, central nervous system symptoms such as memory loss, confusion and sleep disturbance, and add- itional autonomic features such as constipation and cardiac ar- rhythmias. Few cases have been described, but the majority have VGKC-​complex antibodies, usually at levels intermediate between neuromyotonia and VGKC LE; these are directed more often to CASPR2 than to LGI1. Thymoma is more common than in VGKC LE or neuromyotonia (c.50%), and can be aggressive, but most pa- tients do well with thymectomy, if appropriate, and immunosup- pression, and some appear to have a self-​limiting disease. Autoimmune encephalopathy with NMDAR antibodies Epidemiology Patients with a neuropsychiatric disorder associated with antibodies that immunoprecipitate the NMDA receptor were first identified in 2007. Preliminary epidemiology suggests that it is more common in women (4:1) and that the median age at onset is 21 years. 25% of cases occur in children and the illness is uncommon in those over 45 years (<5%). It appears to be more common in Asian and African patients. Up to 40% of young women with the antibodies will have an ovarian teratoma which can be bilateral. Clinical features Patients can present with a wide variety of neuropsychiatric symp- toms, but prominent features usually include headache, movement disorders, behavioural disturbance, psychosis, seizures, catatonia, mutism, autonomic disturbance, and altered consciousness. Central hypoventilation, profound autonomic neuropathy, catatonia, and coma often necessitate management on the intensive care unit. The most striking feature on examination is the movement disorder which classically involves the perioral musculature but can affect any muscles, but it is not usually present at first presentation. In add- ition, there is often dystonic posturing and increased tone. Speech impairment is common and patients may become mute. Many cases presenting as a relapse following herpes simplex virus encephalitis have been described, particularly in children. Investigations Routine blood tests are usually normal. The cerebrospinal fluid often reveals a lymphocytosis, which can be marked (>400 cells/​ul), espe- cially in the early phase of the illness. NMDAR antibodies can be detected in serum and in cerebrospinal fluid, but titres are higher in serum. MRI may be normal in up to 50% of patients but there can be T2 hyperintensity in various brain regions, most commonly the brainstem or limbic areas. Some patients have white matter signal change which is unexplained. Electroencephalography frequently demonstrates profound slowing and there may be electrographic evidence of seizure activity. Treatment Initially patients require antiepileptic drugs for their seizures, anti- psychotic drugs for behaviour, benzodiazepines for catatonia, and corticosteroids with plasma exchange for acute immunosuppres- sion. Any associated teratoma should be promptly surgically re- moved. Second line immunosuppression is generally with rituximab or cyclophosphamide. The role of ‘steroid-​sparing agents’, such as azathioprine or mycophenolate, remains uncertain. Table 24.24.1  The most useful antibodies and their associated syndromes Antigen Demographics Most common clinical phenotypes/​tumours N-​methyl-​D-​Aspartate receptor (NMDAR) 80% females Age range: <12 months to 85 years (median 21 years) Whole brain encephalopathy (initial psychiatric symptoms, seizures, memory, and language deficits, followed by movement disorders, autonomic instability, and decreased level of consciousness); ovarian tumours in young adult women VGKC-​complex associated protein: leucine-​rich glioma-​inactivated 1 (LGI1) 65% males Age range: 30 to 80 years old (median 60 years) Limbic encephalitis. Faciobrachial dystonic seizures; thymus and lung rare. VGKC-​complex associated protein: contactin-​associated protein-​like 2 (CASPR2) 85% males Age range: 46 to 77 years (median 60 years) Limbic encephalitis Neuromyotonia. Morvan’s syndrome including insomnia, autonomic features, and neuromyotonia. Idiopathic ataxia; thymoma in up to 50% α-​amino-​3-​hydroxy-​5-​methyl-​4-​ isoxazolepropionic acid receptor (AMPAR) 75% females Age range: 23 to 87 years (median 60 years) Limbic encephalitis (prominent psychiatric manifestations); lung, thymoma, and breast tumours γ-​aminobutyric acid B receptor (GABAbR) 50% females Age range: 24 to 75 years (median 62 years) Limbic encephalitis (prominent seizures); small-​cell lung cancer most common γ-​aminobutyric acid A receptor (GABAaR) Not yet clear Age range wide Status epilepticus or limbic features without clear-​cut syndrome; no clear tumour association Glycine receptor (GlyR) 50% males Age range: wide Progressive encephalomyelitis with rigidity and myoclonus, stiff person syndrome, or related features; thymoma, lymphomas, breast <20% section 24  Neurological disorders 6396 Differential diagnosis Acutely the differential diagnosis includes limbic encephalitis (see earlier), systemic lupus erythematosus, a primary psychiatric dis- order, or metabolic causes including toxins. New central nervous system autoantibodies and associated clinical syndromes are continually being described and are proving clinically useful in identifying patients who may respond to immunomodu­ latory treatments (see Table 24.24.1). Guidelines for recognition of autoimmune forms of encephalitis have been published. FURTHER READING Buckley C, et al. (2001). Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol, 50, 73–​8. Graus F, et al. (2016). A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol, 15, 391–​404. Irani SR, et  al. (2010). Antibodies to Kv1 potassium channel-​ complex proteins leucine-​rich, glioma inactivated 1 protein and contactin-​associated protein-​2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain, 133, 2734–​48. Irani SR, et al. (2011). Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol, 69, 892–​900. Irani SR, et al. (2012). Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol, 72, 241–​55. Irani SR, et al. (2014). Cell-​surface central nervous system autoanti- bodies: clinical relevance and emerging paradigms. Ann Neurol, 76, 168–​84. Titulaer MJ, et  al. (2013). Treatment and prognostic factors for long-​term outcome in patients with anti-​NMDA receptor en- cephalitis:  an observational cohort study. Lancet Neurol, 12, 157–​65. Vincent A, et  al. (2004). Potassium channel antibody-​associated encephalopathy:  a potentially immunotherapy-​responsive form of limbic encephalitis. Brain, 127, 701–​12. Vincent A, et  al. (2011). Autoantibodies associated with diseases of the CNS:  new developments and future challenges. Lancet Neurol, 10, 759–​72. SECTION 25 Disorders of the eye Section editor: Christopher P. Conlon 25.1  The eye in general medicine   6399 Tasanee Braithwaite, Richard W.J. Lee, and Peng T. Khaw 24.3 Clinical investigation of neurological diseas 24.3 Clinical investigation of neurological disease 5781 24.3.1 Lumbar puncture 5781 R. Rhys Davies and Andrew J. Larner 24.3.1 Lumbar puncture 24.3.1 Lumbar puncture 24.3.2 Electrophysiology of the central and periph 24.3.2 Electrophysiology of the central and peripheral nervous systems 5785 Christian Krarup 24.3.3 Imaging in neurological diseases 5802 Andre 24.3.3 Imaging in neurological diseases 5802 Andrew J. Molyneux, Shelley Renowden, and Marcus Bradley 24.3.4 Investigation of central motor pathways Mag 24.3.4 Investigation of central motor pathways: Magnetic brain stimulation 5817 K.R. Mills 24.3.4  Investigation of central motor pathways: Magnetic brain stimulation 5817 represent a major revolution in the management of patients with aneurysmal SAH and other complex neurovascular conditions. FURTHER READING Atlas S (2008). Magnetic resonance imaging of the brain and spine, 4th edition. Lippincott Williams & Wilkins, Philadelphia, PA. Barkovich AJ, Raybaud C. (2011) Paediatric Neuroimaging, 5th edition. Lippincott Williams & Wilkins, Philadelphia, PA. Osborn AG (2012). Osborn’s brain: imaging, pathology and anatomy. Amirsys, Salt Lake City, UT. 24.3.4  Investigation of central motor pathways: Magnetic brain stimulation K.R. Mills ESSENTIALS The ability to stimulate percutaneously the central nervous system of conscious humans without causing pain has opened up new areas for neurophysiological investigation in the early diagnosis of neurological disease, and has furthered the understanding of normal and abnormal motor control. Magnetic stimulators are now available that can excite both upper and lower limb areas of the motor cortex, as well as cranial nerves, motor roots, and deeply sited peripheral nerves. Clinical applications—​these include: (1) measurement of central motor conduction time—​this is prolonged in some cases of mul- tiple sclerosis, the threshold is usually raised in motor neuron dis- ease, and the technique may be useful in cerebellar ataxia, including Friedrich’s ataxia; (2)  assessment of completeness of spinal cord injury; and possibly (3) evaluation of neurodevelopmental delay in children with neurodegenerative and other related diseases. The technique can be used serially to monitor progress of disease or after neurological injury or to examine the effects of drugs, and it can be used safely in neonates and children. Magnetic stimulators The magnetic stimulator is an essentially simple device: a brief pulse of electric current is passed through a coil which then generates an intense magnetic field permeating unattenuated into the sur- rounding media. Any electrical conductor, such as the brain, in the vicinity of the coil will have currents induced within it; these induced currents are capable of exciting cerebral neurons. Coils are placed on the scalp and may be plane circular, figure of eight, or double cone in geometry, the last being especially effective in exciting leg areas of the motor cortex. Some magnetic stimulators produce a predom- inantly monophasic field pulse, others multiphasic pulses; with the former, the side of the coil next to the scalp determines which hemi- sphere is predominantly excited, whereas with the latter both hemi- spheres are about equally excited. Physiology If a single electrical anodal shock is applied to the exposed cortex of a monkey and recordings are made from the pyramidal tract, it is seen that, if stimulus intensity is sufficient, an initial wave pro- duced by direct activation of pyramidal tract neurons (the D wave) is followed by a variable number of other waves produced by indirect trans-​synaptic activation (I waves) of the same pyramidal neurons. In humans a single weak magnetic stimulus to the scalp probably excites pyramidal tract cells trans-​synaptically; stronger stimuli may excite the cells directly. The effect of a single stimulus is to cause a high frequency (500–​1000 Hz) burst of impulses to descend in the fastest fibres of the pyramidal tract; the spinal motoneurons are en- gaged by these impulses and, if their excitability is high enough and there is sufficient temporal and spatial summation, the motoneurons fire, causing a muscle contraction. There is considerable conver- gence and divergence of pyramidal tract fibres within motoneuron pools: single spinal motoneurons receive many corticospinal inputs and, conversely, single pyramidal tract fibres branch to supply many spinal motoneurons. Intrinsic hand muscles are the most easily ex- cited by brain stimulation, but all voluntary muscles appear to be accessible via cortical stimulation. The amplitude of response of a muscle depends on the intensity of the stimulus, to a lesser extent on coil placement on the scalp, but most potently on the degree of voluntary preactivation of the muscle. Thus, the amplitude of response of an intrinsic hand muscle may be 20–​30 times greater if the individual performs a gentle (5–​ 10% maximum) voluntary contraction of the muscle. This facilita- tion is probably due to both cortical and spinal cord mechanisms, voluntary action increasing the effectiveness of the stimulus at the cortex, at the same time as the excitability of spinal motoneurons is increased by other pathways. The latter mechanism predominates in intrinsic hand muscles. Clearly, many factors, including mental set, affect the size of muscle response to the stimulus, and it should be emphasized that this phenomenon of response variability contrasts with the identical and reproducible responses obtained from max- imal electrical peripheral nerve shocks; central motor conduction studies should not be regarded simply as an extension of nerve con- duction measurements. Single scalp shocks also bring into play inhibitory mechanisms: if an individual maintains a steady voluntary muscle contraction, the initial excitation caused by the stimulus is followed by a silent period, due to the inhibition of voluntary action. Experiments with paired cortical stimuli have established short interval intracortical inhibition where a subthreshold conditioning stimulus reduces the effects of a subsequent test stimulus if the interstimulus interval is 1–​5 ms, and long interval intracortical inhibition, probably corres- ponding to the silent period (mentioned earlier) where the response SECTION 24  Neurological disorders 5818 to the second of a pair of equally intense stimuli is less if the interval between them in 50–​150 ms. A triple stimulation technique in which stimuli to the cortex, wrist, and Erb’s point are carefully timed to produce collisions, can directly quantify the degree of corticospinal tract excitation. This has proved clinically useful in serially moni- toring amyotrophic lateral sclerosis. Safety of magnetic stimulation Several studies have looked at the acute effects of magnetic stimuli on animals. It has been shown that magnetic stimuli have little de- tectable effect on the heart rate, arterial blood pressure, or cerebral blood flow in cats. Magnetic brain stimulation has no acute ef- fects on the human electroencephalogram or on the performance of simple cognitive tests. There have currently been no reports of adverse effects in healthy humans, but, clearly, workers in the field should remain vigilant, especially for long-​term effects. It has been calculated that the total amount of power dissipated in the brain during magnetic stimulation is 1.8 µJ/​cm3 per stimulus and, at the maximal rate of stimulation of 0.3 Hz, the average power dissipation is 53 µW, some five orders of magnitude below the basal metabolic rate of the brain. It was considered prudent for early users of magnetic stimulation to exclude patients who had a history of epilepsy from their studies. Since then, magnetic stimulation has actually been used to attempt to localize epileptic foci in patients with intractable seizures. Despite magnetic stimulation devices being used on many thousands of pa- tients, many of whom must have had a predilection for epilepsy, there have been only a few reports of a fit being related to single-​ pulse brain stimulation. Measurement of central motor conduction time The latency of muscle response has a central and a peripheral com- ponent and a delay due to synaptic transmission in the spinal cord. There is good evidence that, at least with limb muscle, the con- nection from the pyramidal tract to spinal motoneuron is mono- synaptic. The central component of conduction—​central motor conduction time—​can be estimated by subtracting from the cortex to muscle latency an estimate of the peripheral conduction time obtained either from F-​wave measurement (see Chapter 24.3.2) or from responses evoked by root stimulation. In healthy individuals, the mean latency (± standard deviation) of responses in intrinsic hand muscle is 19.7 ± 1.2 ms and the central motor conduction time is 6.1 ± 0.9 ms. The amplitude of responses from brain stimu- lation is usually compared with that obtained from maximal per- ipheral nerve stimulation; again, there is great variability, but in healthy individuals the response from cortical stimuli is usually at least 15% of that from nerve stimulation. As many factors can influence these values, each laboratory should develop its own nor- mative database. Motor roots may be excited by both electrical and magnetic stimu- lators. The former method is preferable because it is not possible to obtain maximal responses in all healthy individuals with mag- netic coils, even with optimal coil geometry, coil orientation, and coil position. Both devices activate motor roots at or just outside the intervertebral foramina, and so peripheral conduction time es- timated by this method omits conduction in the small segment of motor root within the spinal canal, and central motor conduction time is slightly overestimated. The method must be used, however, if F waves are unobtainable. Compound responses from muscle may be recorded with sur- face electrodes, or single motor unit responses may be recorded with needle electrodes; the former method is used clinically, the latter is useful in research. Several parameters of the surface-​ recorded response are useful: the maximum amplitude, the onset latency with the muscle relaxed or contracted, the threshold for evoking a response and the input:output relation giving a measure of cortical excitability or inhibitability. Prolongation of central motor conduction time has been reported in many conditions and is not specific. Delay can be produced by a variety of pathological processes: demyelination of central fibres can lead to slowing of impulse propagation in the central motor pathway; desynchronization of descending impulses can lead to loss of temporal summation at the motoneuron and delay in its firing; and loss of corticospinal axons can lead to impairment of spatial summation at motoneurons and can again delay firing. Multiple sclerosis In multiple sclerosis, central motor conduction time is prolonged in about 70% of cases when there are clear clinical signs of a pyr- amidal lesion in a particular limb (Fig. 24.3.4.1). The delay in some cases is very considerable: central motor conduction time may be up to five times longer than in controls. It is likely that, in these cases, demyelination of central fibres is the mechanism leading to delay. In other cases, delay is more modest, only a few milliseconds, Cortex Wrist 11.6 ms 11.8 ms 10 ms 5 mV 25.5 ms 19.2 ms 1 mV Right Left C7/T1 Fig. 24.3.4.1  Slowing of central motor conduction in multiple sclerosis. Compound muscle action potentials are recorded with surface electrodes over the left and right abductor digiti minimi muscles. Stimuli are given to the ulnar nerve at the wrist (left), the C7 to T1 motor roots (middle), and the motor cortex (right). Onset latencies are shown and the variability of responses from cortical stimulation can be seen. On the left, the central motor conduction time is 7.4 ms, but on the right is prolonged at 13.9 ms. 24.3.4  Investigation of central motor pathways: Magnetic brain stimulation 5819 and the mechanism is less certain. Abnormal central motor con- duction appears to correlate most closely with exaggerated reflexes and spasticity rather than with weakness or cerebellar signs in the limb. Abnormal central motor conduction time from leg areas of motor cortex also correlates with the finding of extensor plantar responses. Central motor conduction can, however, be abnormal even in the absence of clinical signs. In a large series, it was found that cen- tral conduction was abnormal in 20% of cases of multiple sclerosis with no motor signs in the particular limb. The technique can thus be used as a screening test for the disease, although it compares unfavourably with visual-​evoked potentials, which have a higher rate of abnormality in the absence of clinical signs. This may merely reflect the greater accuracy with which the motor system can be examined clinically. Central motor studies may also be helpful in deciding on the importance of equivocal motor signs, such as mild impairment of fine finger movements. Motor neuron disease In motor neuron disease, the most common abnormality is a raised threshold for excitation of the motor cortex, although in early cases the threshold may be reduced. In some cases, responses cannot be obtained even with the strongest stimuli applied in optimal condi- tions. Central motor conduction time may be prolonged, but usu- ally only modestly, and responses are often reduced in amplitude in comparison with responses evoked by maximal nerve stimulation. The more muscles that are examined, the greater is the likelihood of detecting an abnormality. The test can be used to confirm an upper motor neuron component to weakness when lower motor neuron signs predominate or for detecting an upper motor neuron lesion in a limb without clinical signs. Cerebrovascular disease In stroke, responses in an affected limb may be normal, delayed, or absent, with abnormality grossly paralleling the clinical abnor- mality. Central motor conduction studies have been used to predict outcome of stroke; if performed within the first 48 h after the ictus, a poor outcome at six months is predicted by absent responses and a favourable outcome by normal responses. Whether the prediction is superior to that made purely on clinical grounds is uncertain, but at least the method is quantitative and can be used serially to follow recovery. Movement disorders Most studies have shown central motor conduction to be normal in Parkinson’s disease, multiple system atrophy, Wilson’s disease, Huntington’s disease (including at-​risk relatives), dystonia, and progressive supranuclear palsy. In some cases of Wilson’s disease, central conduction delays have been found. In all these conditions, however, there may be subtle changes in motor cortex excitability detectable as a change in threshold or an abnormal inhibitory re- sponse to appropriately timed pairs of cortical stimuli. Degenerative neurological diseases Several rarer degenerative diseases have been investigated with the technique: Friedreich’s ataxia often shows delayed and dispersed re- sponses, as does early onset cerebellar ataxia with retained reflexes, the severity of the abnormalities reflecting disease duration. In late-​ onset cerebellar degeneration, on the other hand, the responses are normal in 62% of cases. In hereditary spastic paraparesis and tropical spastic paraparesis, responses from upper limb muscles are usually normal, whereas those from the lower limbs are delayed or absent. Abnormalities of central motor conduction have also been described in some cases of hereditary motor and sensory neur- opathy types I and II, the abnormalities being found especially in those patients with additional upper motor neuron signs. Central motor conduction abnormalities have also been described in a family with hereditary motor and sensory neuropathy with pyram- idal signs (HMSN type V). Spinal cord lesions Magnetic brain stimulation has been used to assess the complete- ness of spinal cord injury. A variety of facilitating techniques must be used; the modulation of flexion reflexes by brain stimuli has been shown to be useful in establishing whether injury is complete; in 4 of 26 patients evidence of incomplete lesions was found in patients with clinically complete spinal cord injuries. In compressive myel- opathy, by recording from a variety of upper limb muscles, central motor conduction time can be used to localize more accurately the compressed cord segment. This can prove useful to the neurosur- geon when there are multiple levels of compression on imaging. Paediatric applications The central conduction time in a group of 457 normal individuals between the ages of 32 weeks and 55 years has been determined. It was found that central conduction time decreases rapidly over the first two years of life and then remains constant at the adult value. In contrast, peripheral conduction increases in proportion to arm length after the age of five years. It is suggested that this constant central delay could be useful during the acquisition of motor skills. Central motor conduction has been studied in a range of neuro- logical diseases in children. For example, in 13 of 20 children with an upper motor neuron syndrome of varied aetiology, the central conduction time was abnormal, but magnetic resonance imaging and/​or computed tomography showed focal abnormalities in only seven. In cerebral palsy, responses are often absent. In 15 children with extrapyramidal syndromes, the central conduction time was normal. Use of brain stimulation for neurosurgical monitoring Although somatosensory motoring has been shown to be of use during neurosurgical procedures to alert the surgeon to the SECTION 24  Neurological disorders 5820 possibility of cord damage, the use of motor monitoring is far more relevant because paraplegia is one of the most feared, although rare, outcomes of surgery near the cord. Electrical brain stimulation and recording from the cord by epidural electrodes have been achieved; responses consist of a series of waves analogous to the D and I waves recordable in primates. Magnetic stimulation appears to produce I waves but the responses are very sensitive to anaesthetic agents and the depth of anaesthesia produced, especially nitrous oxide. Monitoring of motor tracts during surgery is best achieved using electrical brain stimulation and is often combined with somatosen- sory evoked potential monitoring. FURTHER READING Chen R, et al. (2008). The clinical diagnostic utility of transcranial mag- netic stimulation: report of an IFCN Committee. Clin Neurophysiol, 119, 504–​32. Magistris MR, et al. (1999). A clinical study of motor evoked poten- tials using a triple stimulation technique. Brain,122 (Pt 2), 265–​79. Mills KR (1999). Magnetic stimulation of the human nervous system. Oxford University Press, Oxford. Rothwell JC, et  al. (1991). Stimulation of the human motor cortex through the scalp. Exp Physiol, 76, 159–​200. 24.4 Higher cerebral function 5821 24.4.1 Disturba 24.4 Higher cerebral function 5821 24.4.1 Disturbances of higher cerebral function 5821 Peter J. Nestor CONTENTS 24.4.1 Disturbances of higher cerebral function  5821 Peter J. Nestor 24.4.2 Alzheimer’s disease and other dementias  5830 Jonathan M. Schott 24.4.1  Disturbances of higher cerebral function Peter J. Nestor ESSENTIALS Clinicopathological and imaging studies indicate strong associ- ations between particular disorders of cognition and focal disease in the brain, but not all focal lesions induce specific loss of higher functions. Neuropsychological research has deepened our under- standing by suggesting organizational frameworks for human cog- nitive faculties. Neurological basis for cognition The neocortex around the primary sensory and motor cortices is made up of unimodal association areas, which link to heteromodal association areas, with the linkage of topographical region to spe- cific functional attribute becoming progressively less tightly de- fined. Other areas of the brain that interact with these association areas in a critical way for cognition include (1)  limbic system—​ particularly in the domains of memory and emotion; (2) basal fore- brain nuclei—​important to the successful encoding of memory; (3)  basal ganglia—​relating to attention and speed of cognitive processing; (4)  brainstem reticular formation—​determining the level of arousal. Clinical testing of cognition Regardless of the suspected disorder, the clinician should always proceed in the following way:  (1) ensure adequate attention to undergo further testing—​if the patient has a profound attention deficit, then their cognition cannot be properly assessed; (2) assess language comprehension—​almost all tests are going to be presented with verbal instruction; (3)  leave tests of executive function and praxis to the end of the examination—​they often require adequate levels of function in all other cognitive domains; and (4) always ask, ‘can this apparent disorder be explained in terms of a more elem- ental deficit?’ Particular tests of cognitive function can aid clinical diagnosis of cerebral disease and monitor treatment. It may also be possible to define the specific needs and deficiencies for which supportive aids may assist the patient. Specific cognitive domains Disorders of the higher functions of the brain can be described in terms of the following specific domains: Attention—​the ability to attend to a specific sensory stimulus and to maintain attention is an obligatory first step to any further cogni- tive processing. Breakdown in attentional processing is the central deficit in delirium or acute confusional states. Language and related disorders—​numerous terms are used to describe aphasic syndromes, but the best approach is to consider language fluency and paraphasias in spontaneous conversation, comprehension, naming, and repetition. Particular types of language and related disorders may be associated with particular anatomical lesions. Visuospatial and perceptual disorders—​a dorsal occipitoparietal pathway is concerned with spatial information and preparation for reaching (‘where?’ and ‘how?’); a ventral occipitotemporal pathway is concerned with identifying visual stimuli (‘what?’). Striking neuro- psychological syndromes are seen following selective damage to one pathway. Memory—​(1) Implicit memory—​unconscious memory sys- tems, such as that responsible for conditioning as well as memory for motor tasks. (2)  Explicit memory—​the consciously appreciated memory, which is the category most relevant to clinical disease; div- ided into (a) episodic memory, referring to autobiographical recol- lection of personal events; typically impaired in Alzheimer’s disease and lesions of the limbic system; and (b) semantic memory, referring to factual knowledge and the store of objects and meanings; lesions of the temporal lobes cause loss of this memory, with a severe incap- acity to name objects and recall the meaning of words. Apraxia—​a loss of ability to carry out skilled motor tasks that cannot be explained in terms of an elementary disorder of motor control (weakness or ataxia), primary sensory disturbance, or a global impairment of cognition. Usually the result of damage to the left 24.4 Higher cerebral function SECTION 24  Neurological disorders 5822 (dominant) hemisphere, particularly the superior parietal lobule and the premotor area of the frontal lobe. Personality and behavioural change—​alterations in complex be- haviour, personality, and social comportment cannot be simply defined, but are broadly associated with frontal or anterior temporal lobe pathology. Introduction Modern scientific study of higher cerebral function began in the late 19th century with the case studies of Broca and Wernicke. Their observations of language disorders associated with damage to the left hemisphere gave rise to the notion that specific mental faculties could be dissociated from each other and localized to specific regions within the cerebral hemisphere. Since that time clinicopathological and, more recently, imaging studies have estab- lished associations between specific cognitive disorders and focal brain lesions; these studies also show that some lesions do not give rise to highly specific deficits. The field of neuropsychology has offered complementary insights into this area by providing con- cepts of how cognitive faculties are organized. The border between psychiatry and neurology is a medical con- struct rather than a real boundary; many patients with structural brain diseases have psychiatric symptoms, cognitive complaints are prominent in depression and schizophrenia, and in the dementias it is typical to find a combination of both neuropsychological (cog- nitive) deficits with a range of neuropsychiatric (behavioural and personality) alterations. Another critical area has been the study of anatomy: the finding that neocortical histology varies by region led to the development of cytoarchitectonic maps such as that of Brodmann. Brodmann’s map has become a shorthand way of discussing regional special- ization across the cortex. Meanwhile, anatomical studies of neural tracts have provided insights into how topographically distinct re- gions may interact. Handedness and hemispheric dominance The finding of asymmetrical functions in the human cerebral cortex led to the introduction of the term ‘hemispheric dominance’. Neuroscientists often refer to cognitive processes being a function of the ‘dominant’ or ‘non​dominant’ hemisphere; when such termin- ology is used, the ‘dominant’ hemisphere is synonymous with that which underpins language function. In right-​handed individuals, over 95% have left hemisphere dominance; only rarely does aphasia arise from right hemisphere damage, in which circumstance it is re- ferred to as ‘crossed aphasia’. In left-​handed individuals, dominance is more complex and language skills are more often shared between the hemispheres, although the left hemisphere is relatively dom- inant in about 70% of individuals. While the left hemisphere usually specializes in language, the non​dominant hemisphere plays an im- portant role in spatial cognition (with damage to the frontoparietal regions resulting in spatial neglect) and particularly in face pro- cessing (with damage to the right occipitotemporal junction produ- cing prosopagnosia). Primary sensory input and motor output Motor The primary motor area lies in the precentral gyrus, immediately ros- tral to the central sulcus. The body is represented ‘somatotopically’ along the precentral gyrus: the lower limb at the superomedial and the face at the inferolateral extremity, with the upper limb in be- tween. This is of clinical importance because the vascular supply of the superomedial region is from the anterior cerebral artery whereas the rest of the motor cortex is from the middle cerebral artery. Thus, middle cerebral artery territory infarction will affect face and upper limb with relative sparing of the lower limb, and the converse will be the case with anterior cerebral territory occlusions. Vision After passing from the retina, via optic nerves and tracts to the lateral geniculate body of the thalamus, visual information passes to the striate cortex of the occipital lobes (primary visual cortex) through the optic radiations (see Chapter 24.6.1). As images pre- sented to the right visual field are represented on the left retina and conveyed to the left occipital lobe, a lesion of the latter will cause a right homonymous hemianopia (and vice versa for right occipital lesions). Fibres in each optic radiation separate such that input from the superior half of the retina (inferior visual field) runs from lateral geniculate to the striate cortex via parietal white matter whereas that from the inferior retina (superior visual field) loops down into the temporal lobe. Consequently, a lesion of the parietal lobe can cause a contralesional inferior quadrantanopic field defect whereas a tem- poral lobe lesion can cause a contralesional superior quadrantanopia. Large temporoparietal lesions (e.g. due to middle cerebral artery oc- clusion) may also cause homonymous hemianopia, which can be distinguished from that resulting from an occipital lesion by pres- ervation of opticokinetic nystagmus in the latter but not the former. Bilateral lesions to the primary visual cortex lead to ‘cortical blind- ness’ in which vision is lost, but, unlike blindness secondary to ret- inal or optic nerve diseases, pupillary reflexes are preserved. Some cortically blind individuals deny that they have any visual disorder at all (namely visual anosagnosia)—​a condition known as Anton’s syndrome. These cases tend to have more extensive lesions involving both striate and adjacent visual association cortices. Somatosensory The primary somatosensory cortex occupies the postcentral gyrus of the parietal lobe with a somatotopic representation of the body analogous to that of the primary motor area. Sensory deficits due to lesions of the thalamus, or lower components of the sensory system, cause gross abnormalities in the appreciation of touch, pinprick, temperature, and other sensations, and must be excluded before comment can be made on higher sensory function. Parietal lesions cause specific impairment of ‘discriminative’ sensation, including joint position sense and two-​point discrimination. Parietal drift (the patient is asked, with eyes closed, to maintain the upper limbs outstretched in front of the trunk at 90°) is a sign of impairment of the former ability. It is considered specific for a contralateral par- ietal lesion when the drift is upward, because a downward drift may also be a consequence of subtle motor weakness. The normal sep- aration distance at which one can discriminate one point from two 24.4.1  Disturbances of higher cerebral function 5823 varies according to body region: fingertips 3 mm, palm 1 cm, and body surface 4–​7 cm. Other signs of parietal sensory impairment are an inability to name numbers traced on the palm of the hand (agraphaesthesia), and an inability to name small objects (such as keys and coins) placed in the patient’s hand (astereognosis). Obviously there is potential to confuse true astereognosis with a more general deficit of object naming such as that caused by loss of semantic know- ledge or aphasia (see next). However, ambiguous results on par- ietal sensory testing can largely be avoided if the examiner adopts a methodical approach of: (1) excluding a lesion below the parietal lobe by establishing that the patient can appreciate, for instance, a pinprick or light touch; and (2) examining from the suspected normal to abnormal side to exclude a more general impairment of cognitive faculties. Auditory Auditory information coming from the cochlear nuclei via the inferior colliculus and the medial geniculate nucleus of the thal- amus travels to the primary auditory cortex (Heschl’s gyrus) in the posterosuperior temporal lobe. Clinically apparent cortical hearing impairment is uncommon due to the bilateral representation of audi- tory material from each ear by the cerebral cortex. Bilateral lesions of this area (as a result of strokes, prolonged hypotension, or carbon monoxide poisoning) will cause ‘cortical deafness’, a rare disorder manifest by inability to understand spoken language or recognize sounds although presence or absence of noise can be determined. Unlike Wernicke’s aphasia (see next), individuals can understand written text and their language output is normal. Cognitive domains Beyond the primary sensory and motor cortices, the neocortex is made up of unimodal and heteromodal association areas. Unimodal association cortices lie adjacent to their respective primary modality whereas heteromodal association cortex is found in the prefrontal and temporoparietal regions. Moving from primary through uni- modal to heteromodal association cortex, the linkage of topograph- ical region to a specific functional attribute becomes progressively less tightly defined. Heteromodal association cortices, as the name implies, receive inputs from multiple unimodal areas, but also from non​neocortical areas. Anatomically, as the neocortex approaches the diencephalon, upon which the cerebral hemispheres sit, it trans- forms into a histologically distinct area: the limbic system. These areas also have critical roles in cognition, particularly in the do- mains of memory and emotion, and have reciprocal projections with heteromodal association cortices. Other brain regions that have important modulatory roles on cognition include: (1) the basal forebrain nuclei, which contain cho- linergic neurons that project extensively to limbic and neocortical regions and are known to be important to the successful encoding of memory; (2) the basal ganglia, which have reciprocal links to frontal association cortices and have important modulatory roles relating particularly to attention and speed of cognitive processing; and (3) brainstem reticular formation nuclei which project into the hemispheres via the thalami, the most clearly defined role for these projections being at the level of arousal. Although the remainder of this chapter discusses various dis- orders of higher mental function individually, one should not view these specific deficits as a random and independent collection of phenomena. It cannot be overemphasized that one should always follow a logical sequence in assessing cognitive function so as to avoid false-​positive diagnoses due to sequential effects. For example, tests of executive function that utilize analysis of complex verbal material would be beyond the grasp of a patient with Wernicke’s aphasia due to the fundamental disorder of language comprehen- sion without needing to implicate frontal lobe damage. Likewise, a patient with an acute delirium may be unable to perform even the most basic memory tasks as a consequence of the attention deficit and, therefore, ought not to be labelled amnesic. Therefore, regard- less of the suspected disorder, one should always bear the following sequence in mind: (1) ensure adequate attention to undergo further testing; (2) as almost all tests are going to be presented with verbal instruction, assess language comprehension; and (3) as tests of ex- ecutive function and praxis often require adequate levels of function in all other cognitive domains, these should be left to last. In sum- mary, always ask: ‘Can this apparent disorder be explained in terms of a more elemental deficit?’ Attention The ability to attend to a specific sensory stimulus, such as a human voice or passage of text, and to maintain attention is an obligatory first step to any further cognitive processing. Humans are continu- ously bombarded with sensory stimuli from both within and be- tween individual sensory input modalities; loss of ability to focus and sustain attention (or, alternatively, block out irrelevant ‘noise’) renders the individual incapable of following a specific sensory stimulus (such as a conversation) and at the same time vulnerable to random irrelevant environmental stimuli. Although disorders of the frontal lobes, basal ganglia, and ascending reticular for- mation are associated with poor attention, it is overly simplistic to consider attention as a localizable brain function. The most common causes of acute attention failure are diffuse brain insults such as a metabolic encephalopathy or closed head injury; break- down in attentional processing is the central deficit in delirium or acute confusional states, the main features of which are summar- ized in Table 24.4.1.1. Digit span is one of the most simple methods of assessing atten- tion, especially in the backward condition; normal individuals have a forward span of at least six digits and a reverse span one or two digits less. The digits must be presented as individual items (read the string to be repeated at a rate of one digit per second). A common pit- fall is to cluster digits as one does when reciting telephone numbers. This inflates span as each cluster becomes an individual item: com- pare repeating ‘6953–​8127’ with ‘6 . . . 9 . . . 5 . . . 3 . . . 8 . . . 1 . . . 2 . . . 7’. Ability to persevere at a given task is another way of considering at- tention, and can be tested by asking the patient to recite the months of the year in reverse order. Orientation is heavily dependent on attention and is assessed by questions of time and place. Testing personal orientation adds little, because only profoundly aphasic or hysterical patients are unable to relate their own name. A recent onset of profound disorienta- tion and attention deficit is typical of a delirium. It should be noted that many patients with episodic memory problems (such as early Alzheimer’s disease) remain well oriented. SECTION 24  Neurological disorders 5824 Language and related disorders Numerous terms are in use to describe aphasic syndromes, although some serve more to confuse than enlighten. The terms ‘expres- sive’ and ‘receptive’ particularly seem to mislead: on the one hand, all patients with aphasia have some form of difficulty ‘expressing’ themselves and, on the other, ‘receptive’ aphasia is often, errone- ously, taken to mean that patients have difficulty only with incoming language, but can produce their own language perfectly well. Less ambiguous terms for the two principal divisions of aphasia are ‘non​fluent’ and ‘fluent’, which correspond in classic aphasia nomen- clature to Broca’s and Wernicke’s aphasias. The classic aphasia syn- dromes are, however, rarely seen in the acute stages after stroke and do not characterize the language deficits found in the dementias. A  better approach is therefore to consider language fluency and paraphasias in spontaneous conversation, comprehension, naming, and repetition. Examining patients with aphasia Fluency and paraphasic errors Speech can be described as fluent if the patient is able to produce some well-​formed sentences or phrases even if empty or anomic (such as ‘Oh, you know, the thing you put the stuff in when you’re going somewhere and . . . ’). Non​fluent language, in contrast, is a consequence of breakdown of the language production and syn- tactic (grammatical) aspects of language, and is the hallmark of damage to Broca’s area and the left insula. Output is laboured or ‘telegraphic’, with often as few as two or three words per mi- nute; despite this, patients can convey meaning fairly successfully (e.g. ‘I . . . go . . . hospital’). Paraphasic errors are substitutions of a correct word for one re- lated in sound or meaning. The former, known as phonological or phonemic paraphasias, involve the substitution of related sound fragments (‘phonemes’) such as ‘dobble’ for ‘bottle’. Semantic para- phasic errors involve substitution of words of related meaning; the substituted word is typically a higher-​frequency example of the same semantic category (such as ‘dog’ for ‘fox’) or else of a superordinate category (such as ‘animal’ for ‘fox’). In more extreme circumstances, paraphasic substitutions may not be words at all (‘neologisms’); fluent output with virtually continuous neologisms is an utterly incomprehensible state sometimes referred to as ‘jargon aphasia’. Patients with lesions to Wernicke’s area invariably make a mixture of phonemic and semantic errors. Semantic errors are also very common in Alzheimer’s disease and semantic dementia. In Broca’s aphasia, phonological errors predominate. Comprehension Some degree of impairment of language comprehension can be de- tected in both fluent and non​fluent aphasia. Patients with fluent aphasia have more overtly impaired comprehension of word meaning (e.g. ordinary nouns). In mild cases this can be demonstrated with semantically complex language tasks (e.g. ‘Can you point to a source of artificial illumination?’) or by defining uncommon words (e.g. ‘What is an aubergine, accordion’, and so on). Comprehension of single nouns is preserved in patients with non​fluent aphasia, but comprehension—​in addition to production—​of complex grammar is impaired. This can be tested with reversible passive sentences (e.g. ‘The lion was eaten by the tiger; who survived?’) or by asking the patient to obey syntactically complex commands (e.g. ‘Touch the keys after touching the book’). Anomia Naming is a complex task that requires the integrity of three basic processes:  visual analysis, semantic knowledge (see ‘Memory’ section, later on), and word production (phonology). Virtually all patients with aphasia are anomic when tested using items of low fa- miliarity and late age of acquisition. The type of naming error and the ability to circumvent the deficit varies, however, according to the locus of damage. Patients with visuoperceptive deficits that produce visual errors (a ‘head’ for a ‘mushroom’, and so on) have retained tactile naming and can give correct responses when asked to put a name to a description (‘What do we call the large grey African animal with a trunk?’). A breakdown in the central semantic process causes impairment in naming from all modalities, whereas phonological deficits pro- duce phonological errors regardless of the mode of input. Repetition Lesions involving any of the perisylvian language structures are al- most always associated with impaired repetition, although this may not be apparent unless multisyllabic words (‘caterpillar’, ‘funda- mental’, and so on) and phrases (‘no ifs, ands, or buts’) are tested. Certain aphasic syndromes (see next) show either disproportionate impairment or preservation of repetition. Aphasic syndromes Broca’s aphasia This classic form of non​fluent aphasia is characterized by grossly ­distorted speech output with impaired production and comprehen- sion of syntax. Speech is typically halting and distorted by sound-​ based errors and simplification of grammar. There is great difficulty repeating words and phrases. It is associated with lesions to the left ventrolateral frontal lobe (Broca’s area); owing to its close proximity Table 24.4.1.1  The features of delirium Onset Usually acute/​subacute Course Fluctuating, nocturnal exacerbations Conscious state May be impaired, derangement of normal sleep–​wake cycle Cognitive profile Disoriented in time and place Severe impairment of attention (with knock-​on effects to other cognitive domains, i.e. due to poor registration) Psychiatric features Incoherent and perseverative Mood disorders: agitation, apathy Visual illusions and hallucinations Paranoid ideas common Physical signs Asterixis May be evidence of general medical illness (pyrexia, signs of hepatic failure, and so on) Reproduced from Hodges JR (ed.) (2001). Early onset dementia: a multidisciplinary approach. Oxford University Press with permission from Oxford University Press. 24.4.1  Disturbances of higher cerebral function 5825 to the motor cortex, when focal lesions (such as stroke or tu- mour) cause Broca’s aphasia, it is typically associated with a right hemiparesis. The distortion of language output, often described as speech apraxia, is thought to relate to concurrent damage to structures within the insula, which is almost always affected. Wernicke’s aphasia In Wernicke’s aphasia there is fluent, although vacuous, output with a mixture of semantic and phonological paraphasic errors and often neologisms. There is also impaired comprehension of word meanings and impaired repetition. In contrast to the fun- damental loss of word meaning seen in patients with semantic dementia and destruction of the left inferior temporal lobe after herpes simplex encephalitis, patients with Wernicke’s aphasia have breakdown in the mapping between speech and meaning systems. Lesions localize to the posterior portion of the left superior tem- poral gyrus—​known as Wernicke’s area. As this area overlies the optic radiation, the most common neighbourhood sign is a right homonymous hemianopia. Conduction aphasia This form of aphasia, as the name implies, is due to a disconnec- tion of the two principal language areas. Comprehension is relatively preserved and output is fluent, although phonological paraphasias occur. The striking abnormality is an impairment of repetition even for single syllable words such that attempts at repeating are laboured and contain phonological errors. Likewise, naming produces phono- logical errors even for high-​frequency items (such as for ‘cup’: ‘cah  . . . cab . . . cub’, and so on). Lesions producing conduction aphasia occur in the region of the supramarginal gyrus and, particularly, the underlying arcuate fasciculus, the tract linking the anterior and pos- terior language areas. Global aphasia In this devastating form of aphasia there is derangement of all aspects of language; patients with global aphasia are non​fluent and have impaired word comprehension, repetition, and naming. Language output is restricted to infrequent unintelligible noises or, at best, a single word or clichéd phrase. As the blood supply to both language areas is from the middle cerebral artery, global aphasia is not uncommon secondary to proximal occlusion of this vessel. Consequently, these patients are usually also hemiplegic and hemianopic. Aphasia in degenerative dementias Although the early hallmark of Alzheimer’s disease is typically memory impairment, aphasia becomes a universal feature as the disease progresses. It manifests predominantly with word-​wording difficulties in conversation. Underlying semantic knowledge also be- comes impaired, though the key early deficit is lexical retrieval (i.e. retrieving the word that corresponds to the semantic concept). This manifests as anomia in confrontation naming tasks but with rela- tively preserved performance when the patient is given a word and must define, or point to, it. A minority of patients with Alzheimer’s disease can actually present with this kind of aphasia, instead of the usual memory impairment. In other words, Alzheimer’s can occa- sionally present as a form of primary progressive aphasia in which case it is often given the syndromic label ‘logopenic’ primary pro- gressive aphasia. The other forms of progressive aphasia include semantic dementia (also called the semantic variant of progressive aphasia) and non-​ fluent progressive aphasia. The core deficit of semantic dementia is a loss of semantic knowledge (see ‘Semantic memory’ section) that, in turn, has a knock-​on effect on language in that one cannot name items if they do not recognize them in the first place (in contrast to word-​finding difficulties seen in early Alzheimer’s disease where the patient recognizes an item but just cannot produce its precise name). Conversation in semantic dementia may contain substitutions of higher-​frequency words (e.g. ‘at Christmas I cooked the big chicken’ instead of turkey), but often conversation can sound remarkably normal. This is, presumably, because they do not search for the names of items or concepts when they no longer have knowledge of such items. As such, there can be a striking discrepancy between fairly normal sounding patient-​initiated conversation and their be- wilderment when asked to define specific words. Non​fluent progressive aphasia, as the name suggests, causes slow, effortful speech that is typically easy to recognize in conversation. A difference to the classic Broca’s aphasia resulting from stroke is that the language is typically not telegraphic. Grammatical dysfunc- tion typically manifests with simplification of grammatical structure rather than overt grammatical errors. Dyslexia Patients with aphasia show dyslexic difficulties in keeping with their type of aphasia, so those with fluent aphasia will struggle to under- stand the meaning of words in printed form, whereas those with non​fluent aphasia have trouble with grammatical aspects of reading (particularly word endings: -​ed, -​ing, and so on). Within acquired dyslexia, however, dissociations have been defined for reading single words; these syndromes are known as deep and surface dyslexia. Deep dyslexia and surface dyslexia There may be a dissociation between ability to read orthograph- ically regular (pronounced as they are spelt) words such as ‘mint’, ‘flint’, and ‘hat’, and irregular words such as ‘pint’, ‘cellist’, and ‘island’. Difficulty reading the latter type is known as surface dyslexia and is one of the hallmarks of semantic dementia; for an irregular word such as ‘pint’ or ‘yacht’ to be read correctly, the reader must access knowledge of the word meaning because the graphical representa- tion of the word alone (i.e. its ‘surface’ structure) will not lead to cor- rect pronunciation. If the semantic knowledge base (located in the dominant temporal lobe) breaks down, the word can be pronounced only according to the rules of graphical-​to-​phonological translation and thus ‘pint’ will be pronounced like ‘mint’ (known as a ‘regular- ization’ error)—​in other words, analogous to how a normal person would pronounce a non​word, such as ‘rint’. A complementary syndrome is that of deep dyslexia in which pa- tients produce semantic paralexias when reading (reading ‘prison’ for ‘gaol’ or ‘beer’ for ‘pint’), are unable to read non​words, and have greater difficulty with abstract than with concrete words. This, sim- plistically, is thought to represent a loss of the grapheme-​to-​phoneme route with intact semantic knowledge (i.e. its ‘deep’ meaning). Deep SECTION 24  Neurological disorders 5826 dyslexia is typically seen in patients with extensive left hemisphere lesions and global aphasia. Alexia without agraphia This syndrome represents a classic disconnection syndrome of visual input from language areas due to a lesion in the left occipital lobe and adjacent splenium (disrupting input from the right occipital lobe); as such, although the right occipital cortex is capable of registering text, the information cannot be decoded by the language hemisphere. Patients are not aphasic and can write normally; they cannot read but can say words spelt out loud to them. Visual field testing shows a right homonymous hemianopia. Patients rapidly relearn how to read by identifying individual letters and reconstructing words by a laborious and slow letter-​by-​letter reading strategy. Agraphia Various acquired disorders of writing occur as homologues of other cognitive deficits, for example patients with aphasia make writing errors consistent with their aphasic syndrome (e.g. patients with Broca’s aphasia will make errors in writing syntax), deep and surface dysgraphias give rise to similar errors as deep and surface dyslexia, and ideomotor apraxia (see next) will cause a disorder in motor exe- cution such that writing will be of poor quality. Visuospatial and perceptual disorders The regions of the brain concerned with the higher-​order analysis of visual information can be divided into a dorsal (occipitoparietal) pathway concerned with spatial information and preparation for reaching, and a ventral (occipitotemporal) pathway concerned with identifying visual stimuli. In other words, the dorsal stream is involved in ‘where?’ and ‘how?’ and the ventral with ‘what?’ information for a given visual stimulus. Some of the most striking neuropsychological syndromes are seen following selective damage to one stream. The dorsal stream and Balint’s syndrome Constructional apraxia, an inability to draw or copy line drawings such as wire cubes and clock faces, is a common finding in par- ietal pathology, particularly with right-​sided lesions. More severe breakdown in spatial cognition, causing individuals to misreach for visually guided targets, trip on steps, or collide with furniture when walking, is seen with bilateral parietal diseases (such as watershed infarction, the ‘posterior cortical atrophy’ variant of Alzheimer’s dis- ease, and venous sinus thrombosis) and results clinically in Balint’s syndrome, the features of which are simultanagnosia, optic ataxia, and ocular apraxia. Simultanagnosia is the inability to integrate and make sense of an overall visual scene in spite of preservation in the ability to identify individual elements. Such patients are relatively better at identifying small objects; this can also be demonstrated by an inability to read vertically printed words although they can be read when printed normally. Ocular apraxia describes the inability to direct gaze to a novel visual stimulus, whereas optic ataxia is the inability to reach accurately for a visually guided target. Spatial neglect Although considered under the visuospatial heading, spatial neglect is really a cross-​modality disorder that typically involves the neglect of all sensory information (visual, tactile, auditory) from the side contralateral to the lesion. Chronic neglect virtually only occurs in the context of right parietal lobe damage. Right hemispatial neglect after an acute left parietal lesion can occur, but is usually less se- vere and tends to resolve within days. In addition to being a cross-​ modality disorder, it is not correct to define a ‘hemispatial field’ in purely retinotopic terms, for example, if a patient who exhibits neg- lect on visual field testing has the body turned to face the neglected extrapersonal hemispace (with head and eyes fixed in the original position), the neglected space is reduced. Visual neglect is best tested by cancellation (crossing off ‘A’s on a sheet of paper containing randomly arranged letters), drawing (clock, house, flower), or line bisection tasks. Patients with severe visual neglect may even appear to be hemianopic. A milder form of neglect can be elicited by ‘sensory extinction’ of the neglected side during bilateral sensory stimulation (visual and somatosensory at the bedside, although auditory neglect can be demonstrated experi- mentally). Patients often have associated hemiparesis, although as part of their neglect syndrome they may deny this impairment—​ a phenomenon known as anosagnosia. When presented with the hemiparetic limb they may even deny that it is their own. The ventral stream Lesions to the occipitotemporal pathway give rise to difficulty recognizing visual stimuli which is not a consequence of being unable to appreciate where an object is in space, as is the case in simultanagnosia. This deficit is known as visual object agnosia and has been divided further into aperceptual and associative var- ieties. In aperceptual agnosia, basic aspects of vision (acuity, fields, and contrast sensitivity) are intact, but patients cannot identify, or match, identical objects and have grave difficulty copying line drawings, although knowledge of these objects is intact if tested using other inputs such as describing from name. In contrast, as- sociative agnosia describes a state where loss of object knowledge occurs such that, although patients can copy line drawings well and match perceptually identical pictures, they cannot match non​perceptually identical images such as different angles of the same face or, for example, tell that two different types of clock are both clocks. Associative agnosia is a cross-​modality disorder such that knowledge of objects is impaired in non​visual modalities—​ in other words one component of generalized failure of semantic knowledge (see next). Differentiation of these agnosias requires the use of test material found only in neuropsychology labora- tories. One component of object knowledge is colour, loss of which (achromatopsia) usually accompanies occipitotemporal lesions and is more accessible to bedside evaluation. A restricted form of impaired object recognition relates to faces. Known as prosopagnosia, the person can no longer recognize previ- ously familiar faces but can recognize their voices and have access to knowledge from their names. Usually bilateral lesions of the inferior occipitotemporal junction are responsible, although cases with le- sions restricted to just the right side have been described. Memory Memory is divided by researchers into implicit and explicit sub- types (also known as non​declarative and declarative, respectively). 24.4.1  Disturbances of higher cerebral function 5827 Implicit memory refers to unconscious memory systems such as that responsible for conditioning as well as memory for motor tasks such as hitting a golf ball or playing a piece of music ‘by heart’. Explicit memory, in contrast, refers to consciously apprehended memory and is further divided into episodic and semantic memory. In clin- ical terms, when one refers to memory, it is only the explicit type of memory that is considered. When assessing memory complaints it is useful to apply a theoretically motivated approach to analysing symptoms according to the subcomponent of memory involved. In broad terms, memory subtypes can be considered under the fol- lowing headings. Working memory Working memory refers to the amount of information that can be held by the brain ‘online’ (such as reading a phone number then holding it as the object of one’s attention until the number can be dialled, or solving mathematical problems in the head); in the ab- sence of rehearsal, when the focus of one’s attention has moved to a novel topic for more than a few seconds, such items are lost. Working memory is also referred to as ‘short-​term’ memory by psychologists, although this latter term is often used by patients and their doctors to describe recently acquired episodic memory (see next); it also in- volves aspects of attention (see earlier) so, to avoid confusion, the term ‘working memory’ is preferable. Slips of working memory are often erroneously seen by patients as the harbinger of dementia and thus these individuals are commonly referred to memory clinics: these lapses of attention (such as forgetting why you opened the refrigerator door or went into the study, or immediately forget- ting a new telephone number) are common everyday phenomena which are increased with anxiety and depression, and also occur more commonly with advancing age. Complaints of this type are also common after head injury and in basal ganglia disorders. Semantic memory Semantic memory refers to the brain’s knowledge store of, for ex- ample, objects and word meanings; it is also the term applied to knowledge of facts, such as that Paris is the capital of France, can- aries are small yellow birds kept as pets, or Ronald Reagan was a president of the United States of America. Evidence from the study of semantic dementia suggests that the ventral region of the tem- poral lobes (particularly the rostral fusiform gyrus) are particularly critical to supporting semantic knowledge. The extent to which hemispheric specialization for different types of semantic know- ledge (words, objects, people, and so on) exists remains a subject for debate; loss of word knowledge appears to relate preferentially to left temporal damage whereas some visual material including faces may be more dependent on the right temporal lobe. Loss of memory for words is the usual complaint in patients with a primary disorder of semantic memory such as semantic dementia and after herpes simplex virus encephalitis. However, it is important to distinguish between the occasional word-​finding lapse, usually for proper nouns, which occurs normally (especially in later life), and the relentlessly progressive loss of vocabulary, which occurs in association with left temporal lobe pathology. Low-​frequency words are the most vulnerable and patients with semantic dementia often have some insight into this problem in the early stages (e.g. a car- penter may complain that he can no longer remember the names of tools). People with Alzheimer’s disease show a similar phenomenon, although it is usually a late feature compared to their profound early episodic memory deficit. Breakdown in semantic memory manifests as an inability to name objects or drawings with the production of broad superordinate re- sponses (such as ‘animal’ for ‘elephant’) and the inability to define the meaning of words. Category fluency (the ability to generate ex- emplars from a given semantic category such as types of animals, kitchen utensils, or birds) is another sensitive measure of semantic memory. Knowledge of famous people can be tested by identifying photographs and names, or asking the patient to list prime ministers in chronological order. Episodic memory Episodic memory refers to the event-​based memories unique to each individual, in other words our recollection of personally experi- enced episodes (indeed, it is sometimes termed ‘autobiographical’ memory). Difficulty with the acquisition of new event-​based mem- ories (such as inability to recall details of a television programme or conversation with a friend despite good attention at the time) is the hallmark of early Alzheimer’s disease and other causes of the am- nesic syndrome (Table 24.4.1.2). Lesions that give rise to amnesia involve the limbic system of the brain (especially the hippocampi and their connections—​Fig. 24.4.1.1). Although bilateral involve- ment is usually required to cause a full-​blown amnesic syndrome, neuropsychological testing can often reveal a selective deficit in verbal or non​verbal memory in cases of left-​ or right-​sided damage, respectively. Retrograde memory (established before the amnesic insult) is typically better than anterograde memory (established any time after) in amnesic syndromes and, within retrograde memory, very remote memory is classically (although not universally) better preserved than recent memory. On examination, patients with amnesia have a striking inability to relate anecdotes from their recent life, although in cases of basal forebrain amnesia they may offer confabulations. Amnesia can be assessed in the clinic by asking the patient to learn some information such as a new name and address; patients with amnesic syndromes (including early Alzheimer’s disease) typically repeat a name and address perfectly after two to three trials, but show very rapid for- getting and recall little or nothing after a delay of a few minutes of a distracting task. Amnesia may occur as a temporary state as is seen with tran- sient global amnesia (TGA), in which there is a sudden onset of se- vere amnesia that lasts several hours before resolution; afterwards the patient, characteristically elderly, is left with an islet of amnesia for the hours of the episode. TGA typically occurs as a solitary epi- sode; recurrent attacks of self-​limiting amnesia occasionally occur as a consequence of epileptic activity, hence the term ‘transient epi- leptic amnesia’ (TEA). Attacks of TEA are typically briefer than TGA (<1 h for TEA versus several hours for TGA) and frequently occur on waking. Apraxia Apraxia is defined as a loss of ability to carry out skilled motor tasks that cannot be explained in terms of an elementary disorder of motor control (weakness or ataxia), primary sensory disturbance, or a global impairment of cognition. In the early 20th century Liepmann SECTION 24  Neurological disorders 5828 distinguished three types of apraxia—​limb–​kinetic, ideomotor, and ideational—​and, although these terms have suffered from a lack of universally accepted definition, they are still widely used today. In an attempt to clear up ambiguity, the terms ‘production’ and ‘concep- tual’ apraxia are also now used to indicate ideomotor and ideational apraxia according to the definitions listed next. Limb–​kinetic apraxia refers to the loss of fine motor dexterity that can be seen, for instance, with mild pyramidal lesions (such as after recovery from stroke). In spite of apparently good strength and co- ordination, the person cannot manage tasks requiring fine motor control such as tying a shoelace or buttoning a shirt. As such, ac- cording to the aforementioned definition, this is not a ‘true’ apraxia but rather an artefact of the insensitivity of bedside tests of the motor system: in other words a primary motor deficit is unmasked only by tasks more demanding than routine tests of power and coordination. Ideomotor (production) apraxia refers to the inability to execute the motor programme for a given task (the temporal and spatial organization of movement) in spite of adequate comprehension, as demonstrated, for instance, by the ability to describe the cor- rect execution of the task (such as sharpening a pencil: ‘You put the pointed end of the pencil into the hole then turn it’) or to iden- tify correctly a task when done by someone else. Patients with ideomotor apraxia also have problems performing meaningless (non​symbolic) gestures. Ideational (conceptual) apraxia, in contrast, is a loss of know- ledge of actions: there is an inability to either perform or recognize a given motor task. There is also an inability to match tools correctly to their actions, so a person may select a screwdriver to hammer a nail. Unlike patients with ideomotor apraxia, they do not show disorders of the spatial and temporal aspects of action and thus their tool use, although incorrect, is fluent. To screen for apraxia, patients should be asked to perform skilled motor tasks to verbal instruction or to imitation including both meaningful and meaningless gestures. If deficits are un- covered, tests such as correctly identifying mimes performed by the examiner and matching tools to functions should be given. Subtle disorders of praxis may be evident only with low-​frequency tasks (such as using a vegetable peeler or a pencil sharpener as op- posed to a knife or a hairbrush). When asked to mime an action (such as hair combing or brushing teeth), ‘body part as tool’ errors are often cited as evidence for apraxia: the patient uses his or her hand as the tool (e.g. rubbing an extended index finger over the teeth as a toothbrush). It is, however, not uncommon for normal individuals to make these ‘body part as tool’ errors when asked to perform such tasks, hence it is essential when this type of error is committed to draw it to the person’s attention and reinstruct Table 24.4.1.2  Causes of the amnesic syndrome Type Common aetiologies Transient Transient global amnesia Transient epileptic amnesia Closed head injury (may be permanent) After electroconvulsive therapy Drugs (especially ethanol) Anatomically defined Hippocampus (and adjacent mesial temporal structures) Alzheimer’ s disease Herpes simplex encephalitis Limbic encephalitis (paraneoplastic; autoimmune with voltage-​gated potassium antibodies) Watershed infarction: cardiac arrest, CO poisoning, and so on Complicating epilepsy surgery Diencephalon (dorsomedial and anterior thalamus; mamillary bodies) Korsakoff’s psychosis Infarction (watershed, deep perforator occlusion, ‘top of the basilar’ syndrome) Basal forebrain Ruptured anterior communicating artery Aneurysm Fornix Complicating colloid cyst removal from third ventricle Retrosplenial/​posterior cingulate Various: tumour, haemorrhage, and so on Alzheimer’s disease? Psychogenic (non​organic) Thalamus Posterior cingulate Fornix Mammillary body Basal forebrain Hippocampus Fig. 24.4.1.1  Principal connections of structures critical to sustaining human memory. 24.4.1  Disturbances of higher cerebral function 5829 accordingly. Normal individuals are able to correct these errors, whereas those with apraxia cannot. In terms of the neural substrate for production (ideomotor) apraxia, the overwhelming majority of cases follow damage to the left (dominant) hemisphere. More specifically, there is evidence that a motor system incorporating the superior parietal lobule (Brodmann’s areas 5 and 7) and the premotor area of the left frontal lobe are particularly critical to the temporal and spatial organiza- tion of motor programmes. Conceptual apraxia is also indicative of left hemisphere dysfunction in most cases, although whether a more specific site can be identified is contentious. It is also important where a conceptual apraxia is suspected to ensure that it is not just one manifestation of a more generalized breakdown of semantic knowledge (see ‘Memory’, earlier). Buccofacial apraxia represents a specific form of apraxia in which patients are unable to perform tasks such as licking the lips or blowing out matches to command. It is particularly associated with non​fluent aphasia, presumably as the motor programming of articulation and non​linguistic buccofacial movements share a common pathway. Personality and behavioural change So far, disorders of higher mental function have been considered in quite discrete terms, in the sense of both the cognitive deficit and the cerebral location. Alterations in complex behaviour, personality, and social comportment cannot, however, be so simply defined, but are broadly associated with frontal or anterior temporal lobe pathology. The key to identifying such disorders is the presence of a sustained change from a previous state (thus differing from a lifelong eccentric personality), which cannot be explained by a primary psychiatric diagnosis. The only reliable way to confirm such changes is by taking a separate history from a partner or other close personal acquaint- ance with knowledge of the patient’s premorbid personality. Prefrontal syndromes The prefrontal cortex comprises that part of the frontal lobe rostral to the premotor area; it is classified as heteromodal association cortex and receives extensive inputs from unimodal association areas pos- terior to the central sulcus. The frontal lobes also have loop projec- tions running to the basal ganglia, then the thalamus, and back to the frontal lobes. Thus, lesions along this loop (as seen in conditions such as Huntington’s disease or progressive supranuclear palsy) may also share deficits in common with primary frontal lobe disorders. Anatomically, the prefrontal cortex can be divided into dorsolateral, orbital, and medial surfaces; although in many cases damage will not be restricted to just one of these regions, they provide a useful framework for considering prefrontal functions. Broadly, lesions to the dorsolateral surface are responsible for the frontal ‘dysexecutive’ syndrome, to the orbital surface for the classic frontal behavioural syndrome, and to the medial surface (anterior cingulate) for a pro- found amotivational state. The dysexecutive syndrome The term ‘executive’ refers to aspects of higher-​order brain func- tion, such as problem-​solving, reasoning, and mental abstraction, which rely on the dorsolateral prefrontal lobes. It is also associated with impulsivity, susceptibility to distraction, and failure to perse- vere with the task at hand. Various methods are available to measure these phenomena although no single test offers foolproof sensitivity in this domain, so one should apply as many as possible if the index of suspicion is high. The combination of letter-​ and category-​based verbal fluency pro- vides much useful information. In letter fluency, the patient is asked to generate as many words as they can think of beginning with a given letter in 1 min. They are instructed not to use proper nouns and not to just change the endings to create new exemplars (‘go, goes, going’, and so on). Neuropsychologists typically use the letters F, A, and S for this test, so it is best to choose another letter if it is likely that patients are also going to have a formal neuropsychological as- sessment. In category fluency, patients are asked to produce as many exemplars as possible from a given category in 1 min. Normal in- dividuals usually generate 15 or more words on letter fluency and do slightly better on the ‘animal’ category. Patients with executive deficits secondary to frontal (or the subcortical loop) pathology show an exaggeration of this relationship, doing poorly on category fluency but even worse on letter fluency (patients with semantic impairments related to temporal lobe diseases such as semantic de- mentia and Alzheimer’s disease typically show the reverse pattern of relatively worse performance on category fluency). The ‘go–​no go’ test offers a way of assessing impulsivity: the pa- tient is asked to tap the desk once if the examiner does so, but, if the examiner taps twice, he should not tap at all. Patients with frontal pathology are often unable to stop themselves from tapping in both conditions. Failure to abstract meaning from proverbs (‘What does ‘too many cooks spoil the broth’ mean?’) is a common test but is influenced by background intellectual ability and is culture bound. The so-​called ‘cognitive estimates’ test can be useful (‘What is the dis- tance from London to Paris?’ or ‘How fast does a racehorse gallop?’), as are ‘differences and similarities’ (‘What’s the difference between a child and a dwarf?’ or ‘In what way are a sculpture and a piece of music similar?’). Finally, the susceptibility to irrelevant stimuli mean that the tests of attention discussed here may also be impaired. It is important to note, however, that unlike cognitive neuro- psychological tests of, for instance, memory or language, executive function—​indeed cognitive functions ascribed to the frontal lobes in general—​is much more inconsistently related to pathology at an individual patient level. Abilities such as problem-​solving, mental flexibility, and abstraction overlap considerably with general intelli- gence, for example, a patient who responds that a racehorse gallops at 100 miles/​h, or, that London is 1000 miles from Paris, may simply have a poor knowledge of velocity and geography rather than being ‘dysexecutive’. On the other hand, patients with unequivocal frontal lobe pathology may sometimes be hard to fault on tests of executive function, in spite of problems in day-​to-​day life. This stands in con- trast to patients with, for example, Korsakoff’s psychosis who will display evidence of amnesia regardless of how one chooses to test memory. Orbitofrontal syndrome The striking changes in behaviour seen in patients with prefrontal lesions relate particularly to orbital (or ventral) surface damage. An important caveat to this locationist account is that most studies derive observations from either static lesions or frontotemporal dementia, in which damage usually extends beyond the orbital 24.4.2 Alzheimer’s disease and other dementias 583 24.4.2 Alzheimer’s disease and other dementias 5830 Jonathan M. Schott SECTION 24  Neurological disorders 5830 frontal cortex. Although devastating in their effects on social func- tion, such lesions are notoriously difficult to detect using standard psychometric tests. Patients lack empathy and emotional warmth (e.g. if confronted with something as serious as the admission to hospital of their partner, their primary concern may be that their mealtime routine will be disturbed). They are disinhibited and ob- livious to social mores such that they may be overly familiar with strangers, disregard personal space, and make inappropriate com- ments or gestures (often of a sexual nature). They often make rash and irresponsible decisions such as spending money above their means. They may develop stereotyped and ritualistic behaviours such as insisting on always taking a particular route when shop- ping or repetitively closing doors in the home: these behaviours can be so severe as to constitute a secondary obsessive–​compulsive disorder syndrome. A useful clue is often the presence of a change in eating behaviour. Patients may become fixated on one dish; often they develop a pref- erence for sweet foods. A lack of normal satiety means that they may overeat, often with secondary weight gain. Imitation and utilization behaviour are dramatic phenomena related to orbital frontal lobe damage. The patient with imita- tion behaviour unconsciously mimics the examiner’s posture and mannerisms regardless of how absurd they are: raising an arm in the air, placing a leg on the desk, or sitting on the floor. Utilization behaviour is even more striking:  patients will use any object placed in their grasp. The classic example is the patient offered multiple pairs of spectacles who attempts to wear them all, one on top of another. Amotivational states Medial frontal lesions are particularly associated with apathy. Patients lack spontaneity, they will not initiate conversation although they can reply to specific questions. In keeping with this observation, per- formance on tests such as the letter fluency task, described earlier, is severely impoverished. If left to their own devices, they may not spontaneously move, preferring to sit in a chair staring blankly into space. This apathy has also been termed ‘abulia’ in the past; in its most extreme form where the individual lies motionless with no speech, the term ‘akinetic mutism’ has also been applied. The cata- tonic phenomenon of maintaining postures when the limbs are moved by the examiner may also be seen. Patients with depression also show marked apathy, although it is accompanied by both the biological features of depression (anorexia, diurnal variation, and so on) and internal symptoms of mood disturbance (pessimism, suicidal thoughts, anhedonia, and so on). Temporal lobe syndromes In addition to the cognitive deficits that can occur with temporal lobe lesions such as amnesia and loss of semantic knowledge, be- havioural disturbances can also occur. The most severe, secondary to bilateral anterior temporal damage (including the amygdala), is the Klüver–​Bucy syndrome, which comprises three characteristic features:  placidity, even in threatening situations; indiscriminant hypersexuality; and oral exploration of objects. Other behaviours have been described in temporal lobe dysfunction, particularly, although not exclusively, in association with interictal temporal lobe epilepsy. These include preoccupation with religious or philo- sophical issues and a tendency to excessive writing. FURTHER READING Baddeley AD (1999). Essentials of human memory. Psychology Press, Hove. Berrios GE, Hodges JR (2000). Memory disorders in psychiatric prac- tice. Cambridge University Press, Cambridge. Brok P (2004). Into the silent land: travels in neuropsychology. Atlantic Books, London. Cappa SF, et  al. (2008). Cognitive neurology:  a clinical textbook. Cambridge University Press, Cambridge. Driver J, Mattingley JB (1998). Parietal neglect and visual awareness. Nat Neurosci, 1, 17–​22. Goodale MA, Westwood DA (2004). An evolving view of duplex vi- sion: separate but interacting cortical pathways for perception and action. Curr Opin Neurobiol, 14, 203–​11. Hodges JR (2007). Cognitive assessment for clinicians, 2nd edition. Oxford University Press, Oxford. McCarthy RA, Warrington EK (1990). Cognitive neuropsychology: a clinical introduction. Academic Press, San Diego, CA. Mesulam MM (1998). From sensation to cognition. Brain, 121, 1013–​52. Miller BL, Boeve BF (2009). The behavioural neurology of dementia. Cambridge University Press, Cambridge. Patterson K, Lambon-​Ralph MA (1999). Selective disorders of reading? Current Opin Neurobiol, 9, 235–​9. Patterson K, et al. (2007). Where do you know what you know? The representation of semantic knowledge in the human brain. Nat Rev Neurosci, 8, 976–​87. Rothi LJG, Heilman KM (eds) (1997). Apraxia: the neuropsychology of action. Psychology Press, Hove. Stuss DT, Alexander MP (2007). Is there a dysexecutive syndrome? Philos Trans R Soc B, 362, 901–​15. Tulving E, Craik FM (eds) (2000). The Oxford handbook of memory. Oxford University Press, New York, NY. 24.4.2  Alzheimer’s disease and other dementias Jonathan M. Schott ESSENTIALS Dementia is a syndrome of progressive impairment in memory and other cognitive deficits (aphasia, apraxia, agnosia, or disturb- ance in executive function) in the absence of another explanatory central nervous system disorder, depression, or delirium, sufficient to interfere with activities of daily living. In recent years there has been a move to consider and classify patients with less severe forms of cognitive impairment—​so-​called mild cognitive impairment—​ and non​memory presentations, with the latest DSM-​V criteria Acknowledgements: The author and editors gratefully acknowledge the inclusion in this chapter of material contributed to previous editions of the Oxford Textbook of Medicine by Professor John R. Hodges. 24.4.2  Alzheimer’s disease and other dementias 5831 identifying individuals with major or minor neurocognitive syn- dromes. Ongoing research using biomarkers suggest that there is a long presymptomatic phase for many causes of dementia. Epidemiology and classification Prevalence—​dementia is common, affecting about 7% of all people over 65 years, rising to over 20% of those over 85 years. It is esti- mated that there are over 35 million people with dementia world- wide, and that this will increase to over 65 million by the year 2030, and over 115 million by 2050. Classification—​dementia is a syndrome with many causative dis- eases. Most cases of dementia are due to neurodegenerative diseases—​ including Alzheimer’s disease, Lewy body diseases, frontotemporal dementia—​and/​or vascular syndromes. Some causes of dementia may be at least partially reversible, and these must always be considered and excluded. A very large number of rarer causes of dementia are rec- ognized, often presenting in younger individuals, and with additional, non​cognitive clinical features—​so-​called ‘dementia plus’. The various dementias Alzheimer’s disease—​the most common cause of dementia, is thought to be initiated by cerebral accumulation of the Aβ fragment of the amyloid precursor protein, followed by deposition and propa- gation of tau through vulnerable neural networks, inflammation, and ultimately irreversible neuronal and neurotransmitter loss. The typical initial cognitive deficit is impairment of episodic memory which is likely to reflect early medial temporal lobe involvement. Progression of disease is marked by failing memory, increasing dis- ability in managing complex day-​to-​day activities, mental inflex- ibility, and poor concentration, eventually leading to language and visuospatial impairments, apraxia, and failure of semantic memory. Non​memory presentations with primary language, visual, and be- havioural presentations are also seen, particularly in younger pa- tients. Neuropsychiatric symptoms are common, and behavioural problems can be prominent. Agitation, restlessness, wandering, and disinhibition cause considerable carer burden. Terminal stages are characterized by reduced speech, ambulatory difficulties, depend- ence, and incontinence. Diagnosis is based on clinical assessment increasingly supported by biomarkers, which allow both for more specific and earlier diagnosis. The mainstay of treatment is social sup- port and increasing assistance with day-​to-​day activities. Two classes of symptomatic medications—​the acetyl-​cholinesterase inhibitors and memantine—​generally achieve modest improvements in cog- nition in around 25–​50% of patients. Several disease-​modifying ap- proaches are currently undergoing clinical trials. Frontotemporal dementia—​is increasingly recognized as a common cause of dementia, particularly in younger patients. The pathology is usually accumulation of tau or 43 kDa TAR DNA-​ binding protein (TDP-​43) inclusions. Clinical presentation is with progressive changes in personality and behaviour, or with progres- sive aphasia. A significant proportion of patients, particularly with behavioural presentations, have a family history, with mutations in three genes (tau, progranulin, C9orf72) accounting for the majority of inherited forms. There are no specific treatments. Dementia with Lewy bodies—​is a common cause of dementia in older people. Typical presentation is with progressive cognitive de- cline, broadly similar to that seen in Alzheimer’s disease, but with several characteristic features including:  marked spontaneous fluctuations in cognitive abilities; visual hallucinations; and parkin- sonism. Patients may respond to treatment with cholinesterase in- hibitors, but neuroleptic drugs should be avoided whenever possible. Dementia with Lewy bodies is likely to be on the same spectrum as Parkinson’s disease dementia, where similar symptoms follow the emergence of motor problems. Vascular cognitive impairment—​a wide variety of vascular diseases of the brain can result in cognitive symptoms, the most important syndromes being large vessel infarction; and cerebral small vessel disease which encompasses several different entitites including small subcortical infarcts (lacunes), white matter hyperintensities, and cere- bral amyloid angiopathy. A range of rare genetic and inflammatory causes of vascular cognitive impairment are recognized. Particularly in older people, combinations of vascular cognitive impairment and Alzheimer’s disease or other neurodegenerative dementias are common—​so-​called ‘mixed dementia’. Treatment is that of the underlying vascular or inflammatory disease. Other neurodegenerative conditions associated with dementia in- clude: Huntington’s disease, progressive supranuclear palsy, and corticobasal degeneration. Prion diseases are rare but important causes of dementia which can occur on a sporadic, inherited or acquired basis, and are dis- cussed in Chapter 24.11.5. Potentially treatable causes of dementia include: hydrocephalus; chronic subdural haematomata; benign tumours; metabolic and endocrine disorders—​including hypothyroidism, Addison’s disease, and hypopitu- itarism; deficiency states—​including vitamin B12 deficiency; infections—​ including neurosyphilis and human immunodeficiency virus infection; transient epileptic amnesia; and inflammatory/​autoimmune disorders. Introduction Concepts of dementia have evolved considerably over time. Moving from an initial formulation as progressive global intellectual de- terioration, for many years the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-​IV) criteria prevailed, defining dementia as a syndrome consisting of progressive impairment in memory and at least one other cognitive deficit (aphasia, apraxia, agnosia, or disturbance in executive function) in the absence of an- other explanatory central nervous system disorder, depression, or delirium, resulting in symptoms sufficient to interfere with daily living. As researchers and clinicians became more aware of the spe- cific early cognitive profiles associated with different dementia syn- dromes, for example, that in early Alzheimer’s disease there may be isolated memory impairment many years before more widespread deficits develop, the concept of mild cognitive impairment was intro- duced, latterly refined to include amnestic and non​amnestic forms, and single and multidomain impairments. More recently, DSM-​V has proposed the use of the terms minor and major neurocognitive syndromes to reflect both the range of severity and causes of cogni- tive impairment. While still currently only within the research do- main, the advent of disease-​specific biomarkers has led to the field increasingly moving towards attempts to define individuals with prodromal or presymptomatic forms of dementia. For the purposes of this chapter, the term dementia will be used to discuss all causes of symptomatic cognitive decline. SECTION 24  Neurological disorders 5832 Importantly, dementia is not a diagnosis, but a syndrome that may result from many diseases. Some causes may be at least par- tially remediable, and therefore always warrant consideration and exclusion. However, most are due to neurodegenerative diseases, cerebrovascular disease, or combinations of both. While for most diseases post-​mortem brain examination is the only means of definitively determining the cause of an individual’s dementia, careful clinical assessment based on the pattern and progression of cognitive loss and allied clinical features, supplemented by investigations, allows for a specific diagnosis to be reached with a high degree of accuracy in most cases. This in turn allows for appropriate treatments to be instigated, bespoke care plans to be designed, and can guide prognostication. At the same time, advances in genetics, cellular biology and the development of novel biomarkers have greatly enhanced our understanding of the processes that lead to the development of specific dementia syn- dromes. These advances pave the way for rational treatments aiming to modify the underlying pathophysiology, with the ultimate aim of slowing, or ideally preventing, the development of cognitive impairment. Not least given the changes in definitions, the incidence of dementia is difficult to establish, but community prevalence studies suggest that about 7% of all people over 65 years of age suffer from dementia. This shows a marked increase with advancing age: between the ages of 65–​69 the prevalence is c.1.7%, approxi- mately doubling every five years such that more than 1/3 individ- uals over the age of 90 will be affected. While much rarer in younger patients, current estimates suggest that there are over 40 000 people in the United Kingdom with young onset dementia (onset before 65 years). Since dementia is predominantly a disorder of later life, the pro- jected increase in the older population, represents an increasing problem for individuals and society. In 2018 it was estimated that there were c.50 million people with dementia worldwide, and this would increase to c.152 million by 2015. This increase is predicted to be most marked in low or middle income countries who represent 58% of the total number of cases now, a figure predicted to rise to 71% by 2050. The annual costs of dementia are currently estimated to be $1 trillion dollars, rising to over $ 2 trillion by 2030. Causes of dementia The dementias can be classified in several ways, the most common being based on aetiology (Table 24.4.2.1). The most common causes of dementia before and after the age of 65 years (the arbi- trary cut-​off usually used to define late vs. young onset dementia) are shown in Fig. 24.4.2.1. The relative frequencies of causes of de- mentia differ depending on age, but it is notable that Alzheimer’s disease is the most common cause in both groups. The genetic forms of neurodegenerative dementias and other rarer causes are more common in the younger age group. Clinical assessment Accurate diagnosis of the dementias starts with a detailed clin- ical assessment. This should aim to determine if there is indeed evidence for cognitive impairment, and if so, whether it is life-​long Table 24.4.2.1  Causes of dementia Neurodegenerative diseases Alzheimer’s disease Frontotemporal dementia (behavioural variant and primary progressive aphasias)a Dementia with Lewy bodies Parkinson’s disease dementia Huntington’s disease and Huntington’s disease-​like syndromes 1–​3 Progressive supranuclear palsy Corticobasal degeneration Multiple system atrophy Primary age-​related tauopathy Argyrophilic grain disease Spinocerebellar ataxias (especially types 2, 12, 17) Fragile-​X tremor ataxia syndrome Familial British and Danish Dementia Dentato-​rubro pallidolusyian atrophy (DRPLA) Neurodegeneration with brain iron accumulation Vascular diseases Large vessel ischaemia Cerebral small vessel disease Hypertensive encephalopathy Vasculitides: •​ systemic lupus erythematosus •​ polyarteritis nodosa •​ Behçet’s disease •​ giant-​cell arteritis •​ primary CNS angiitis •​ cerebral amyloid angiopathy-​related inflammation Inherited vascular cognitive disorders: •​ CADASIL •​ cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy •​ retinal vasculopathy with cerebral leukodystrophy •​ hereditary cerebral amyloid angiopathies anoxia postcardiac arrest sickle-​cell disease superficial siderosis Infections HIV infection Progressive multifocal encephalopathy Cerebral toxoplasmosis Cryptococcal meningitis Neurosyphilis Subacute sclerosing panencephalitis Progressive rubella encephalitis Viral encephalitis Viral, bacterial, and fungal meningitides Whipple’s disease (continued) 24.4.2  Alzheimer’s disease and other dementias 5833 Prion diseases: •​ sporadic Creutzfeldt–​Jakob disease •​ familial prion diseases •​ iatrogenic prion disease •​ variant Creutzfeldt–​Jakob disease Neoplastic causes Primary intracerebral tumours: •​ frontal gliomas •​ posterior corpus callosal or midline tumours (thalamic, pineal, third ventricle) •​ cerebral lymphoma Extracerebral tumours: •​ frontal meningiomas •​ posterior fossa tumours (acoustic neuromas) Tumours causing hydrocephalus multiple cerebral metastases malignant meningitis Toxic causes Alcoholic dementia Heavy metals: •​ lead, mercury, manganese •​ carbon monoxide poisoning •​ drugs: illicit and prescribed Acquired metabolic disorders and deficiency states Chronic renal failure Dialysis dementia Porto-​systemic encephalopathy Hypothyroidism Cushing’s disease Addison’s disease Panhypopituitarism Hypoglycaemia (chronic or recurrent) Hypoparathyroidism Vitamin B12, B1, and folate deficiency Malabsorption syndromes Inherited metabolic disorders (that may present in adulthood) Wilson’s disease Porphyria Leucodystrophies: •​ adrenoleucodystrophy •​ metachromatic leucodystrophy •​ globoid-​cell leucodystrophy •​ Alexander’s disease •​ vanishing white matter disease •​ polyglucosan body disease Gangliosidoses Niemann–​Pick Type C Cerebrotendinous xanthomatosis Adult-​onset neuronal ceroid-​lipofuscinosis (Kuf’s disease) Mitochondrial cytopathies Subacute necrotizing encephalopathy (Leigh’s disease) Fabry’s disease Trauma Major head injury Subdural haematoma Dementia pugilistica Hydrocephalus: communicating and obstructive Inflammatory/​autoimmune Multiple sclerosis Sarcoidosis Acute disseminated encephalomyelitis Lgi1 and CASPR2 antibody mediated limbic encephalitis NMDA-​antibody associated encephalitis Paraneoplastic (limbic) encephalitis Miscellaneous Polycystic lipomembranous sclerosing leukoencephalopathy (Nasu Hakola disease) Neuroferritinopathy Hereditary diffuse leukoencephalopathy with spheroids Fragile-​X tremor ataxia syndrome Neuroacanthocytosis Giant axonal neuropathy Progressive myoclonic epilepsy syndromes a Several different underlying pathologies (see text). (a) Other 29% DLB 7% FTD 12% VaD 18% AD 34% (b) DLB 20% Other 5% VaD 20% AD 55% Fig. 24.4.2.1  Relative frequency of different causes of dementia (a) before 65 yrs and (b) after 65 yrs. DLB refers to all Lewy body dementia, and to pathologically confirmed rather than clinically diagnosed cases Table 24.4.2.1  Continued SECTION 24  Neurological disorders 5834 and non​progressive (i.e. not due to dementia) or acquired. It is im- portant to distinguish between dementia and delirium (see next) as they are associated with different causes, although commonly coexist. Exclusion of potentially treatable forms of cognitive im- pairment is vital, as is the identification of significant psychi- atric morbidity that can mimic or complicate organic forms of dementia. The history—​supplemented wherever possible by an informant—​should include ascertainment of the onset, progres- sion, and current cognitive impairments as well as prior medical, medication and family history, and use of illicit drugs, tobacco, and alcohol. The cognitive examination allows for the extent and focality of cognitive function to be assessed, which is diagnos- tically helpful as different dementia syndromes target different brain regions. Physical examination may reveal important clues to the diagnosis (e.g. the presence of parkinsonism in dementia with Lewy bodies, or patchy upper motor neuron signs in vas- cular cognitive impairment). This is particularly important in patients with younger onset or atypical dementias where the dif- ferential diagnosis is large, and any additional symptoms and signs—​so-​called ‘dementia plus’—​may provide important clues to the diagnosis. Investigation has historically focused on excluding ‘treatable’ causes of dementia, with a range of blood tests to exclude major metabolic, infectious, or inflammatory processes, and structural brain imaging to rule out lesions potentially amenable to neurosur- gery (e.g. tumours, subdural haematomata, and hydrocephalus). Increasingly, however, investigations are directed to determining dementia subtypes. Formal neuropsychology provides quantita- tive information about the extent and pattern of an individual’s performance relative to their expected cognitive performance and age-​related normative ranges, and can be very informative both in determining whether there is objective impairment, and in differ- ential diagnosis. Magnetic resonance imaging (MRI) allows for the assessment of specific patterns of brain atrophy which have posi- tive predictive pattern for many of the major neurodegenerative forms of dementia; the presence of white matter lesions can indi- cate cerebrovascular disease, inflammation, or suggest a range of rarer causes of dementia; and the diagnosis of prion diseases has been revolutionized by the advent of diffusion weighted imaging. In selected cases, cerebrospinal fluid examination may not only be helpful in excluding infection or inflammation in atypical cases, but also in making a positive diagnosis of Alzheimer’s disease and diagnosing prion disease. Molecular imaging can provide evidence for central dopaminergic depletion in Lewy body diseases and other conditions associated with parkinsonism; and the advent of specific positron emission tomography (PET) ligands binding fi- brillar amyloid allows for the demonstration of Alzheimer-​related pathology in vivo. In the appropriate clinical context, and with suitable counselling and consent, genetic testing—​increasingly performed using next generation sequencing which allows for multiple different genetic mutations to be assessed in parallel—​ may allow for autosomal dominant forms of dementia to be def- initely diagnosed during life. In unusual or atypical forms of dementia, a very wide range of investigations (Table 24.4.2.2), ranging from blood testing, advanced imaging, and tissue biopsy may be required to reach the diagnosis, with brain biopsy reserved for the very few individuals in whom a potentially treatable cause (e.g. central nervous system vasculitis) is possible, yet cannot be diagnosed by other means. Management of the demented patient depends on the cause, se- verity, and social situation. Specific medications are available for certain diseases (discussed next). Appropriate management of comorbidities (e.g. vascular risk factors and depression) is important. The extent to which additional care or other interventions are re- quired will depend on the individual patient and their circumstances, and needs to be re-​evaluated as the disease progresses over time. In the sections that follow, the main differential diagnostic alter- natives to dementia are considered; the major neurodegenerative causes of dementia and vascular cognitive impairment are reviewed; and other important and ‘treatable’ causes of dementia are discussed. Prion diseases are discussed in Chapter 24.11.5. Differential diagnosis of dementia Psychiatric causes of cognitive impairment A wide variety of psychiatric disorders are associated with cognitive symptoms. Cognitive symptoms are common in depression, particu- larly in the older population. The main complaints are of poor recent memory and concentration, and distractibility. There may be a lack of subjective feelings of depression, thereby making the diagnosis Table 24.4.2.2  Investigation of dementia Routine Full blood count and ESR Biochemical profile (urea and creatinine, electrolytes, calcium, liver function) Vitamin B12 and folate levels Thyroid function Chest radiography Structural brain imaging (MRI preferred over CT) Neuropsychological examination Other tests which may be indicated in certain cases Electroencephalography Fluorodeoxyglucose PET or SPECT Amyloid PET Whole body FDG-​PET CT CSF examination (including measures of Aβ1-​42 and tau) Screening for autoimmune/​inflammatory disease Screening for cardiac sources of emboli Slit-​lamp examination Specific blood and/​or urine tests for inherited metabolic disorders Screening for HIV and other infections Genetic testing –​ with suitable consents Sleep study Tissue biopsy Cerebral biopsy ESR, erythrocyte sedimentation rate; RBC, red blood cells; CT, computed tomography; EEG, electroencephalogram; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-​photon emission computed tomography; CSF, cerebrospinal fluid; HIV, human immunodeficiency virus. 24.4.2  Alzheimer’s disease and other dementias 5835 difficult. Although not always present, the so-​called biological fea- tures of depression include sleep disturbance, and loss of appetite and libido. Other common symptoms are low energy, lack of interest in hobbies and activities, and nihilism about the future. There may be a past personal or familial history of depression. The cognitive picture is typically of impaired attention and patchy performance on memory and frontal tasks. There may be some inconsistency in test perform- ance and often patients easily give up on testing. Language output may be sparse but individual words are usually pronounced normally. Even after detailed testing, it may on occasions be difficult to distinguish de- pression from dementia, noting that depression may coexist with, and is not an uncommon consequence of a diagnosis of dementia; and in some cases, late onset depression may be an early sign of a developing neurodegenerative disease. If doubt remains, a therapeutic trial of an antidepressant and or psychiatric assessment may be warranted, and the patient should be monitored to ensure there is no progression. A related group of patients who make up a significant proportion of referrals particularly to young onset dementia clinics are those anx- ious about their cognition in the absence of objective evidence for significant impairments—​sometimes referred to as the ‘worried well’, or as having subjective cognitive impairment. In contrast to patients with dementia, these individuals are often much more concerned about their symptoms than their friends or family members; appro- priate investigation and explanation is the mainstay of management. Patients with major psychiatric disorders, including schizophrenia, may have significant psychomotor retardation sufficient to mimic dementia. Long-​term use of antipsychotic drugs can produce par- kinsonian features resembling Lewy body disease; in these cases, a negative dopamine transporter scan may be helpful to exclude the latter. Finally, rarely patients may present with a rapid onset of memory and/​or intellectual impairment likely representing a form of conversion disorder. There is loss of personal identity and salient personal and life events, which is unlike most organic disorders of memory. There may be an obvious precipitant (such as marital problems, or trouble with the law) and a past psychiatric history is common. ‘Ganser’s syndrome’ is a name for the condition where the patient gives bizarrely wrong answers to questions, for example, when asked ‘How many legs does a horse have?’, they reply three or five. Even with such functional states, the examiner must be aware that some organic (e.g. autoimmune) conditions can present rap- idly and with unusual symptoms, and that concomitant organic dis- orders can exaggerate the psychiatric condition. Delirium This clinical syndrome may be caused by a range of disorders af- fecting the brain including intracranial infections, head trauma, epi- lepsy (postictal states and non​convulsive status), raised intracranial pressure, or subarachnoid haemorrhage, or secondary to many sys- temic illnesses or insults—​including infections, metabolic derange- ments, hypoxia, and drugs. The clinical features include the acute onset of attentional abnormalities and disturbance of consciousness (from clouding to coma), perceptual distortions, illusions, and hal- lucinations, psychomotor disturbance (hypo-​ or hyperactivity and rapid shifts between the two), disturbance of the sleep–​wake cycle, emotional lability, and marked fluctuations in performance and be- haviour. The most consistent abnormality is inattention, with a re- duced ability to maintain attention to external stimuli, leading to distractibility and difficulty answering questions, and to appropri- ately shift attention to new stimuli, leading to perseverations. The investigation and treatment need to be focused in each case on the likely precipitants, although in a proportion of older people no cause is found. Importantly, dementia and delirium commonly coexist, and unexplained rapid decline in cognition in a patient with an es- tablished dementia should prompt investigation to rule out causes of delirium. Although the course and prognosis depend on the underlying diagnosis, if there is resolution of the precipitant there is potential for cognitive improvement to the baseline state. Neurodegenerative causes of dementia Neurodegenerative diseases make up most causes of dementia. These disorders have several features in common. Most cases are sporadic, although for many diseases a proportion of cases occur on an autosomal dominant basis. Deposition of abnormally conformed proteins within the brain is thought to be a key initiating event, with subsequent propagation of abnormal proteins through neural net- works, neuroinflammation, synaptic and neurotransmitter loss and neuronal death, all of which precede the develop of symptoms, in the case of some diseases by many years. Each of the neurodegenerative diseases is associated with a specific abnormal protein species or combination of abnormal proteins, and it is the specific protein(s) that define the disorders pathologically. For reasons that are as yet unknown, different protein species have particular tropism for dif- ferent brains networks, which goes some way to explaining the fairly consistent clinical phenotypes associated with each of the disorders. However, in some cases the same protein abnormalities, and indeed the same genetic mutation, can cause a range of different symptoms; different neurodegenerative diseases can occur in combination; and particularly in elderly populations cerebrovascular disease is very common and is likely to influence phenotype. Alzheimer’s disease Overview Alzheimer’s disease is the most common cause of dementia. Of the 5–​10% of the population aged over 65 years who have some kind of cognitive decline, over 60% of cases will be due to Alzheimer’s dis- ease; and, although accounting for a smaller percentage of younger onset cases, Alzheimer’s disease is still the single largest cause. The initial disease description by Alois Alzheimer (1864–​1915) in 1907 was of a woman in her fifties with a progressive dementia and be- havioural disturbance, who was found to have neurofibrillary tan- gles and amyloid plaques throughout her cerebral cortex, latterly determined to be due to a mutation in the Presenilin 1 gene. The term ‘Alzheimer’s disease’ was then applied to similar cases with a presenile dementia, before it was determined that identical patho- logical changes were seen in most elderly demented patients. Histological diagnosis remains the ‘gold standard’, and aside from those patients with rare autosomal dominant mutations, there is no definitive diagnostic test available during life. While for many years Alzheimer’s disease was essentially a diagnosis of exclusion as reflected by the widely used NINCDS–​ADRDA criteria, these and SECTION 24  Neurological disorders 5836 other criteria have recently been updated to incorporate advances in biomarkers, allowing for the diagnosis to be made with increased confidence. Much recent research has focused on methods of early and accurate diagnosis, which is particularly important in view of the advent of potential disease-​modifying treatments. Updated biomarker-​supported clinical and research criteria from both the National Institute of Aging and International Working Group allow not only for patients with dementia due to Alzheimer’s disease to be diagnosed, but also for Alzheimer’s disease to be diagnosed in pa- tients with mild cognitive impairment (Table 24.4.2.3). While only currently of relevance for research, the finding that a substantial pro- portion of apparently healthy individuals have positive Alzheimer biomarkers has led to the concept of prodromal or presymptomatic forms of the disease with associated research criteria/frameworks, paving the way for trials aiming to prevent or delay symptom onset. Epidemiology and risk factors Familial Alzheimer’s disease While most cases of Alzheimer’s disease occur on an apparently sporadic basis, a very small proportion (<0.5%) arise due to muta- tions in the Presenilin 1 gene on chromosome 14, the amyloid pre- cursor protein (APP) gene on chromosome 21, or very rarely the Presenilin 2 gene on chromosome 1. In these families, disease onset is typically but not exclusively at an early age (35–​55 years), and is fairly consistent within families; as with Huntington’s disease, pene- trance is complete for Presenilin 1 and APP, but more variable for Presenilin 2. Individuals with Down’s syndrome (trisomy 21) de- velop Alzheimer’s disease during their third and fourth decades, likely due to having an extra copy of the APP gene. Sporadic Alzheimer’s disease For patients with sporadic Alzheimer’s disease, age is the most im- portant overall risk factor, with the prevalence approximately doubling every five years from 0.5% at the age of 60–​65, to more than 40% in those living beyond 90. From a genetic perspective, Apolipoprotein E (ApoE) has long been established as a risk factor for Alzheimer’s dis- ease and remains the single most common genetic determinant of sus- ceptibility to late onset disease. ApoE is a component of several classes of plasma and cerebrospinal fluid (CSF) lipoproteins. The brain is the most important site of ApoE production outside the liver, and ApoE is thought to be important in lipid homeostasis in the brain. There are three common alleles for the ApoE gene: ε2, ε3, and ε4. One or two ε4 alleles confer an increased risk of Alzheimer’s disease and lower the age of onset in a ‘dose-​dependent’ fashion. Recent advances in genetic technology have led to the identification of more than 20 other risk loci for Alzheimer’s disease. While each locus individually confers only a very small increased risk, their identification has provided evidence implicated cholesterol processing, inflammation, and endosomal traf- ficking in Alzheimer pathogenesis; and taken together, genetic factors are estimated to account for c.2/3 of the risk for Alzheimer’s disease. Many epidemiological studies have investigated medication, life- style, and related risk factors. Factors reported to reduce risk for Alzheimer’s disease include prior treatment with oestrogens, statins, antihypertensivs, and non​steroidal anti-​inflammatory drugs; exposure to folate, vitamins E and C, and coffee; cognitive activity, and moderate alcohol intake. Conversely, elevated homocysteine, depression, midlife cardiovascular risks, and low education may increase risk. Pathology The pathological hallmarks of Alzheimer’s disease are: (1) Deposition of amyloid-​β peptide (Aβ) in the cerebral cortex in the form of se- nile or neuritic plaques. Plaques range in size from 50 to 200 nm and consist of an amyloid core containing 40–​43 amino acid con- taining Aβ fragments, with a corona of argyrophilic axonal and dendritic processes, amyloid fibrils, and microglia. Aβ is also de- posited in small blood vessels in over 80% of cases, so-​called cere- bral amyloid angiopathy. (2) Neurofibrillary tangles, formed from bundles of paired helical filaments, replace the normal neuronal cytoskeleton. The central core of the paired helical filaments is the microtubule-​associated protein tau. Abnormal phosphorylation of the tau protein causes the microtubular abnormalities and the sub- sequent collapse of the cytoskeleton. The neurofibrillary tangles are seen as intensely staining intraneuronal inclusions with silver stains or specific anti-​tau immunochemistry. (3) Macroscopically, patients with Alzheimer’s disease have reduced brain weight, although there may be overlap with age-​matched controls. Focal neuronal loss, or atrophy, is particularly focused on medial temporal lobe structures including the entorhinal cortex, hippocampus, and parietotemporal association areas, with relative sparing of the primary sensory motor and visual cortices (Fig. 24.4.2.2). As well as protein deposition, loss of neurons, and synapses, neuroinflammation is increasingly recognized as a feature of Alzheimer pathology. Alzheimer’s disease is associated with re- duction in a range of neurotransmitters, including a marked cho- linergic deficit. One of the two classes of medications licensed for Alzheimer’s disease, the acetylcholinesterase inhibitors, acts by reducing enzymic breakdown of acetylcholine with the aim of improving cognitive function. The pathological diagnosis of Alzheimer’s disease requires the presence of both neuritic plaques and neurofibrillary tangles in the brain of an individual with dementia. The distribution of these pathologies each follows its own broadly consistent trajectory as the disease advances. Thal staging of amyloid plaque pathology fol- lows five distinct stages, starting in the neocortex (Stage 1) before spreading sequentially to allocortex (Stage 2), striatum, dienceph- alon, and basal forebrain (Stage 3), brainstem nuclei (Stage 4) and finally the cerebellum (Stage 5). Braak and Braak staging of neuro- fibrillary tangle distribution and severity follows a six-​stage pro- cess starting with deposition in the transentorhinal and entorhinal cortices (Stages 1 and 2), followed by involvement of hippocampus and other limbic structures (Stages 3 and 4), before the isocortex becomes involved (Stage 5 and 6). Contemporary pathological cri- teria combine these two criteria with the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuritic plaque-​score (none, sparse, moderate, or frequent), to produce an ‘ABC’ score from which an Alzheimer’s neuropathology likelihood level—​none, low, intermediate, or high—​is determined. Pathophysiology The dominant hypothesis to explain the mechanisms leading to Alzheimer’s disease is the amyloid cascade model, which proposes that the Aβ fragment of the APP gene plays an essential and up- stream role in the pathogenesis. APP may be processed to pro- duce non​toxic species, but when cleaved sequentially by β-​ and γ-​secretases, leads to the accumulation of toxic, short, forms 24.4.2  Alzheimer’s disease and other dementias 5837 Table 24.4.2.3  Prior (NINCDS–​ADRDA) and one of the current (IWG-​2) criteria for Alzheimer’s disease a. The NINCDS–​ADRDA criteria for Alzheimer’s disease Probable Alzheimer’s disease Dementia established by clinical examination, documented by the Mini-​Mental State Examination (MMSE) or similar and confirmed by neuropyschological tests Decline in memory and at least one non​memory intellectual function Decline from previous level and continuing progression Onset between 40 and 90 years of age No disturbance in consciousness Absence of systemic disorders or other brain diseases that in and of themselves could account for the progressive deficits in memory and cognition Definite Alzheimer’s disease Clinical criteria of probable AD Histopathological evidence of AD at post-​mortem or biopsy Possible Alzheimer’s disease Patient has dementia syndrome with no other cause but clinical variation from typical for AD Patient has second disorder that is sufficient to produce dementia but not considered the cause of the dementia Single gradually progressive cognitive deficit in absence of other cause NINCDS–​ADRDA, National Institute of Neurological and Communicative Disorders and Stroke–​Alzheimer’s Disease and Related Disorders Association b. International Working Group-​2 (IWG2) research criteria for Alzheimer’s disease IWG-​2 criteria for typical AD (A plus B at any stage) A—​Specific clinical phenotype Presence of an early and significant episodic memory impairment (isolated or associated with other cognitive or behavioural changes that are suggestive of a mild cognitive impairment or of a dementia syndrome) that includes the following features: B—​In vivo evidence of Alzheimer's pathology (one of the following) Gradual and progressive change in memory function reported by patient or informant over more than 6 months Objective evidence of an amnestic syndrome of the hippocampal type, based on significantly impaired performance on an episodic memory test with established specificity for AD, such as cued recall with control of encoding test B—​In vivo evidence of Alzheimer's pathology (one of the following) Decreased Aβ1–​42 together with increased T-​tau or P-​tau in CSF Increased tracer retention on amyloid PET AD autosomal dominant mutation present (in PSEN1, PSEN2, or APP) Exclusion criteria for typical AD Sudden onset Early occurrence of the following symptoms: gait disturbances, seizures, major and prevalent behavioural changes Focal neurological features Early extrapyramidal signs Early hallucinations Cognitive fluctuations Non-​AD dementia Major depression Cerebrovascular disease Toxic, inflammatory, and metabolic disorders, all of which may require specific investigations MRI FLAIR or T2 signal changes in the medial temporal lobe that are consistent with infectious or vascular insults IWG-​2 criteria for atypical AD (A plus B at any stage) A—​Specific clinical phenotype (one of the following) Posterior variant of AD (including): An occipitotemporal variant defined by the presence of an early, predominant, and progressive impairment of visuoperceptive functions or of visual identification of objects, symbols, words, or faces A biparietal variant defined by the presence of early, predominant, and progressive difficulty with visuospatial function, features of Gerstmann syndrome, or Balint syndrome, limb apraxia, or neglect (continued) SECTION 24  Neurological disorders 5838 of Aβ (in particular the Aβ1-​42 peptide) in the brain. Acting through mechanisms not fully understood, but likely to involve neuroinflammation and spread of pathology through vulnerable neural networks, this is proposed to initiate a cascade of events that ultimately leads to the accumulation of hyperphosphorylated tau, and neuronal dysfunction and cell death Figs. 24.4.2.3 and 24.4.2.4. The strongest argument supporting a causal role for β amyloid comes from the identification of mutations of the APP gene and the genes for Presenilin 1 and 2 responsible for the early onset forms of familial Alzheimer’s disease. These mutations modify the generation of Aβ peptides in such a way that the relative proportion of the highly amyloidogenic Aβ1-​42 form is increased. Conversely, a very rare APP mutation that reduces production of toxic forms of Aβ may protect against Alzheimer’s disease. In spor- adic Alzheimer’s disease, there is evidence for impaired clearance of toxic Aβ species. There is evidence that, rather than the highly aggregated Aβ species, soluble oligomeric forms of Aβ may repre- sent the most neurotoxic entity that causes synaptic dysfunction. Logopenic variant of AD defined by the presence of an early, predominant, and progressive impairment of single-​word retrieval and in repetition of sentences, in the context of spared semantic, syntactic, and motor speech abilities Frontal variant of AD defined by the presence of early, predominant, and progressive behavioural changes including association of primary apathy or behavioural disinhibition, or predominant executive dysfunction on cognitive testing Down's syndrome variant of AD defined by the occurrence of a dementia characterized by early behavioural changes and executive dysfunction in people with Down's syndrome B—​In vivo evidence of Alzheimer's pathology (one of the following) Decreased Aβ1–​42 together with increased T-​tau or P-​tau in CSF Increased tracer retention on amyloid PET Alzheimer's disease autosomal dominant mutation present (in PSEN1, PSEN2, or APP) Exclusion criteria for atypical AD Sudden onset Early and prevalent episodic memory disorders Major depression Cerebrovascular disease Toxic, inflammatory, or metabolic disorders IWG-​2 criteria for mixed AD (A plus B) A—​Clinical and biomarker evidence of AD (both are required) Amnestic syndrome of the hippocampal type or one of the clinical phenotypes of atypical AD Decreased Aβ1–​42 together with increased T-​tau or P-​tau in CSF, or increased tracer retention on amyloid PET B—​Clinical and biomarker evidence of mixed pathology For cerebrovascular disease (both are required) Documented history of stroke, or focal neurological features, or both MRI evidence of one or more of the following: corresponding vascular lesions, small vessel disease, strategic lacunar infarcts, or cerebral haemorrhages For Lewy body disease (both are required) One of the following: extrapyramidal signs, early hallucinations, or cognitive fluctuations Abnormal dopamine transporter PET scan IWG-​2 criteria for the preclinical states of AD IWG-​2 criteria for asymptomatic at risk for AD (A plus B) A—​Absence of specific clinical phenotype (both are required) Absence of amnestic syndrome of the hippocampal type Absence of any clinical phenotype of atypical AD B—​In vivo evidence of Alzheimer's pathology (one of the following) Decreased Aβ1–​42 together with increased T-​tau or P-​tau in CSF Increased retention on fibrillar amyloid PET IWG-​2 criteria for presymptomatic AD (A plus B) A—​Absence of specific clinical phenotype (both are required) Absence of amnestic syndrome of the hippocampal type Absence of any clinical phenotype of atypical AD B—​Proven AD autosomal dominant mutation in PSEN1, PSEN2, or APP, or other proven genes (including Down's syndrome trisomy 21) Table 24.4.2.3  Continued 24.4.2  Alzheimer’s disease and other dementias 5839 Importantly, while Aβ is necessary for Alzheimer’s disease to de- velop, it is not sufficient. Biomarker and autopsy studies suggest a significant proportion of older people—​perhaps a third of individ- uals in their seventies—​harbours significant Aβ pathology, in the absence cognitive symptoms; and it seems likely that the accumula- tion of tau pathology and atrophy are downstream processes both of which correlate more closely with, but still predate the development of, symptoms. Despite promising results in animal models, clinical trials of therapies aiming to clear Aβ pathology from the brain have not been successful in patients with established Alzheimer’s disease, most likely as by this stage the neurodegenerative cascade has al- ready been initiated and is too advanced. There is thus an increasing interest in applying such therapies to asymptomatic individuals with evidence for Aβ pathology, although this currently remains very much in the realm of research. Clinical features Amnestic Alzheimer’s disease As much as it is possible to consider a ‘typical’ form of Alzheimer’s disease, the most common earliest cognitive deficit is impairment of episodic memory (memories for events or episodes, including day-​ to-​day memory and new learning). This is thought to reflect that the earliest site of pathology is in the medial temporal lobe structures. As discussed earlier, ‘amnestic mild cognitive impairment’ (MCI) is a term increasingly used for people who are impaired on episodic memory tasks but who do not otherwise fit the criteria for a diagnosis of dementia. It is becoming clear that many, if not all, such people are in the predementia or early stages of Alzheimer’s disease. However, MCI can result from deficits in domains other than memory; may be caused by other diseases including depression; and is not always progressive, and when it is can take several years to develop a full-​ blown dementia syndrome. Recent studies indicate a conversion rate to dementia of around 10–​20% per annum. The main clinical fea- tures at this stage are severe forgetfulness, often with repetitive ques- tioning particularly concerning the retention of new information, which over time begins to result in impairments in social functioning or job performance. As the disease progresses to mild Alzheimer’s disease, memory function worsens, particularly affecting recall (e.g. forgetting recent visits or family events), with increasing problems managing complex day-​to-​day activities such as finances and shop- ping, mental inflexibility, and poor concentration, which reflects in- volvement of attentional and executive function. Insight is variably affected; often patients retain a partial awareness of their difficulties but underestimate the extent of the problem, but on occasions they can be remarkably unaware of their difficulties. Remote memory is typically reported to be relatively well preserved with a temporally graded pattern (i.e. sparing of most distant memories), although this may be difficult to confirm objectively. As the disease con- tinues to progress patients often develop impairments in language, most typically word finding difficulties, a shrinking vocabulary, and poor understanding of complex words and concepts. Visuospatial Fig. 24.4.2.2  Macroscopic and microscopic observations in Alzheimer’s disease (AD). Macroscopic observation of coronal slices shows dilatation of the ventricles (a, *) and reduction in bulk of the deep white matter and size of the hippocampus (a, arrow). Aβ immunohistochemistry shows numerous plaques both cored and diffuse in the frontal cortex (b); shown at higher magnification in (c) (cored plaque arrow; diffuse plaque double arrow). Cerebral amyloid angiopathy can be found in a proportion of AD cases, where Aβ deposits in blood vessels (d). Numerous neurofibrillary tangles and neuropil threads are highlighted with tau immunohistochemistry (e) in the Ca1 hippocampal subregion, shown at higher magnification in F. Bar in (b) represents 100 μm in (b) and (e); 50 μm in (d) and 20 μm in (c) and (f). Courtesy of Dr Tammaryn Lashley, UCL. SECTION 24  Neurological disorders 5840 impairments and apraxia, which may develop at this stage, are par- ticularly disabling, causing difficulty in dressing, cooking, and per- forming other daily activities. As the cognitive deficits progress there is worsening of language function and semantic memory, and behav- ioural problems can be prominent. Neuropsychiatric symptoms par- ticularly apathy, anxiety, and mood disturbance are common in the earliest stages of Alzheimer’s disease; in the later stages delusions and hallucinations occur in up to 50% and 30% of patients, respectively. Agitation, restlessness, wandering, and disinhibition can cause a considerable burden for carers. The final stages of the disease are characterized by reduced speech output (or mutism), ambulatory difficulties, dependence, and incontinence. Seizures and myoclonus can be late features. There is considerable variation in the time from presentation to death: individuals diagnosed in their late 60s to early 70s have a median lifespan of 7–​10 years, but this is reduced to three years when diagnosis is made in the 90s. Phase 1 Phase 2 Phase 3 Phase 5 Phase 4 A (a) B stage I transentorhinal region transentorhinal region peristriate region peristriate region parastriate area peristriate region calcarine fissure striate area striate area parastriate area parastriate area peristriate region entorhinal region entorhinal region occipito- temporal gyrus occipito-temporal gyrus Heschl’s gyrus Heschl’s gyrus occipito- temporal gyrus temporal neocortex transento- rhinal region allo- cortex rhinal sulcus rhinal sulcus superior temporal gyrus superior temporal gyrus superior temporal gyrus lingual gyrus collateral sulcus hippocampus hippocampus stage II stage III stage III stage IV stage V stage V stage VI stage VI (b) (e) (f) (h) (i) (c) (d) (g) Fig. 24.4.2.3  (A) Thal Aβ and (B) Braak and Braak tau staging in Alzheimer’s disease. (A) Phases of β-​amyloidosis. Phase 1 is characterized by exclusively neocortical Aβ deposits (Neocortex: black). Phase 2 shows additional allocortical Aβ deposits (red arrows), phase 3 additional Aβ deposits in diencephalic nuclei (red arrows) and the striatum (not shown), phase 4 additional Aβ deposits in distinct brainstem nuclei (red arrows), and phase 5 in the cerebellum and additional brainstem nuclei (red arrows). (B) Stages of cortical neurofibrillary pathology. Involvement starts in the transentorhinal area (Stage 1) before spreading sequentially to the entorhinal cortex and hippcomampus (Stage 2), association areas of the temporal neocortex (Stage 3), insular, neocortical high order sensory association cortex of the temporal lobe (Stage 4), superior temporal gyrus (Satge 5), occipital lobe, and finally sensory association areas and the primary areas of the occipital neocortex (Stage 6). (A) Reproduced with permission from Thal DT et al. (2002). Phases of Aβ-​deposition in the human brain and its relevance for the development of AD. Neurology 58(12), 1791−1800. (B) Reprinted from Braak H and Braak E (1995). Staging of Alzheimer’s disease-​related neurofibrillary changes. Neurobiology of Aging 16, 271–​84. Copyright © 1995, with permission from Elsevier. 24.4.2  Alzheimer’s disease and other dementias 5841 Neurological examination is unremarkable in the early stages, although increased tone (often frontal resistance, or gegenhalten, in type) and mild extrapyramidal features can occur as the dis- ease progresses. Reflex changes such as extensor plantar responses and—​in contrast to frontotemporal dementia—​primitive reflexes (e.g. grasping, occur late if at all). In the final stages, there can be greatly increased rigidity and joint contractures. Atypical Alzheimer’s disease Patients with autosomal dominant forms of Alzheimer’s disease typically present with amnestic deficits, but can have a range of other features including prominent myoclonus, early seizures, and a spastic paraparesis. Some patients with sporadic forms of Alzheimer’s—​typically, but not exclusively those with younger age at disease onset—​present with non​amnestic, ‘atypical’ presen- tations. These patients include those with prominent higher level visual problems, and with other deficits implicating parietal lobe dysfunction, with relative sparing of memory—​posterior cortical atrophy, sometimes referred to as the visual variant of Alzheimer’s disease; those with hesitant speech and prominent word finding difficulties—​logopaenic aphasia; and individuals with prom- inent early behaviour problems, sometimes sufficient to mimic frontotemporal dementia (see next)—​behavioural or frontal variant Alzheimer’s disease. Investigations The aims of neuropsychological, imaging, and laboratory inves- tigations in Alzheimer’s disease are, as discussed earlier, first to exclude other potentially reversible causes of, or contributors to, dementia; and second to provide positive evidence for a diagnosis of Alzheimer’s disease. The extent and nature of investigation obvi- ously need to be tailored to the individual, but European, UK, and US guidelines all recommend that patients should undergo a range of blood investigations and brain imaging. Neuropsychological assessment characteristically shows early impairment in delayed verbal recall of new material, followed by reduced category fluency (in which individuals are asked to generate exemplars from a given category, e.g. ‘animals’), impaired naming of low-​frequency words, and difficulty with complex visuospatial tasks such as copying complex figures. MRI of patients with Alzheimer’s disease in the earliest stages (including amnestic MCI) typically show evidence of symmetrical medial temporal lobe and in particular hippocampal volume loss (Fig. 24.4.2.5), which is now included in new diagnostic criteria. Familial Alzheimer’s disease Mutations result in increased production of abnormal forms of Aβ Sporadic Alzheimer’s disease Impaired clearance of abnormal Aβ forms results in accumulation Increase in Aβ oligomers Neurotransmitter deficits Cognitive impairment Tau misfolding propagation; synaptic dysfunction Deposition into Aβ plaques Inflammatory responses (?) Fig. 24.4.2.4  Alzheimer’s disease pathogenesis: the amyloid cascade hypothesis. The central event in AD pathogenesis is proposed to be imbalance between Aβ production and clearance, with increased Aβ production in familial AD and decreased Aβ clearance in sporadic AD. Aβ oligomers may directly impact on hippocampal and synapse function. Aβ deposition, inflammation, and oxidative stress leads to tau pathology with tangle formation and atrophy; these downstream events lead to and correlate with neuronal dysfunction and cognitive symptoms. Fig. 24.4.2.5  Imaging appearances in Alzheimer’s disease. (a) T1-​weighted MRI shows hippocampal atrophy; (b) Amyloid PET shows widespread cortical fibrillar amyloid deposition (hot colours). SECTION 24  Neurological disorders 5842 Generalized volume loss, and parietal lobe atrophy are also common. In mild cases brain imaging can appear within normal limits; in such cases, repeat scanning after an interval may be helpful as in Alzheimer’s disease, as well as other forms of neurodegeneration, progressive volume loss in excess of that seen in normal ageing is expected. T2 or FLAIR sequences often show a degree of white matter change reflecting cerebrovascular disease, which commonly accompanies Alzheimer’s disease, particularly in older people. Iron-​ specific MR sequences (T2* or DWI) may reveal the presence of cortical microbleeds, reflecting amyloid angiopathy, in a minority of patients. A variety of other MR sequences (diffusion tensor imaging, spectroscopy) may show other aspects of Alzheimer’s pathology, but are not in use in routine clinical practice. FDG-​PET or single-​ photon emission computed tomography (SPECT) scanning typic- ally shows temporoparietal hypoperfusion. PET scanning using ligands that bind fibrillar amyloid allows for the demonstration of amyloid pathology during life (Fig. 24.4.2.5), and several tracers are now licensed; cost and availability currently limit their widespread use. Very recently, it has become possible to image tau deposition in vivo using PET ligands that bind to certain forms of tau, but this remains a research tool. Use of CSF in the diagnosis of dementia varies very consider- ably between countries; importantly interpretation of the results requires that the samples are taken and processed appropriately. Reduction of Aβ1-​42 and elevation of total and phosphorylated tau in the CSF is the typical pattern seen in Alzheimer’s disease. Included in new diagnostic criteria, these CSF markers have posi- tive predictive value in determining which individuals with MCI will develop dementia. Genetic testing for mutations in the causative genes may be appro- priate in patients with young onset disease, particularly where there is a family history. Advances in genetic technology allow for several genes to be screened concurrently. Genetic testing should only be done with specific consent and following appropriate counselling, due to the implications for other family members. In contrast to testing for causative mutations, assessing genetic risk factors (e.g. ApoE status), is not currently recommended in clinical practice. Management and prognosis The management of a patient with Alzheimer’s disease involves many sensitive issues. It is crucial to provide medical and psychological support to patients as well as to their families and carers. During the progression of the disease there will be different goals at different stages, ranging from aiding failing cognitive function in the setting of independent living, to managing behavioural problems and ag- gression, and eventually to providing full supportive nursing care. There is great variation in the rate of progression, but depending on the age and stage of disease at diagnosis, on average, patients spend several years in the mild or minimal stages (although it can be as long as 5–​10 years), between 4 and 5 years in the moderate disease stages, and, depending on the quality of care in the dependent stages, a year or more requiring full nursing care. Non​pharmacological treatment The mainstay of treatment is social support and increasing assist- ance with day-​to-​day activities. Issues such as establishing fitness to drive, and financial planning while the patient has capacity to do so, are important and should be discussed early in the course of the disease. Depending on individual circumstances, symptoms, and disease stage, there may be different requirements for the support services listed next: • information and education • diet, exercise, mental activity • carer support groups • community dementia team, including home nursing and per- sonal care • community services (e.g. meals-​on-​wheels, community trans- port services) • access to dementia charities • sitter service • day centre • respite care • residential/​nursing home • palliative care Pharmacological treatment Two classes of drugs, the cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) and the N-​methyl–​d-​aspartate (NMDA) receptor antagonist, memantine, are licensed for use in the symptomatic treatment of Alzheimer’s disease. In clinical trials, the cholinesterase inhibitors consistently achieve modest improve- ments in cognitive function compared to placebo. There is no evi- dence that they alter the overall course of the disease, although withdrawal of treatment in moderate-​severe disease has been shown to worsen cognition and function and to increase the risk of nursing home placement. Memantine has usually been used in patients not tolerating cholinesterase inhibitors, or those with more advanced disease. There is some evidence that combined treat- ment with a cholinesterase inhibitor and memantine may provide benefit in some patients. There is less good evidence for how best to treat other aspects of the disease including depression, agitation, and psychotic phenomena; in such cases, input from a specialist psychiatrist is recommended. Environmental modification and ap- propriate nursing input should be considered prior to instigation of medication. While individual patients may respond, evidence that conventional antidepressants help in depression in the context of Alzheimer’s disease is weak at best. Atypical antipsychotic drugs can be useful for treating severe neuropsychiatric symptoms, and risperidone is licensed for the short-​term treatment of aggressive behaviour. However, these drugs are associated with an increased long-​term risk of mortality and stroke in demented individuals, and so should be used cautiously and only when the benefits outweigh the risks. As discussed previously, approaches to clearing β-​amyloid have so far proven unsuccessful, but are currently been trialled in patients with milder disease, and asymptomatic individuals at risk of Alzheimer’s disease. Several other approaches, targeting different aspects of the amyloid cascade, neuro-​inflammation, and tau path- ology, are in various stages of development/​implementation. Frontotemporal dementia Overview Frontotemporal dementia (FTD) is a clinico-​pathological syndrome encompassing a range of different clinical syndromes centred on progressive behavioural and/​or speech presentations. FTD is now 24.4.2  Alzheimer’s disease and other dementias 5843 preferred to the older term ‘Pick’s disease’ to describe patients with focal frontal and/​or temporal focal atrophy, reflecting that the underlying pathology of these syndromes is heterogeneous. Arnold Pick (1851–​1924) first described patients with both progressive aphasia and associated severe left temporal cortical atrophy post-​ mortem, and patients with behavioural disturbances associated with frontal lobe atrophy. In 1910, Alzheimer described the histological changes in patients with focal lobar degeneration as distinct from the syndrome that bears his name, describing both argyrophilic intracytoplasmic inclusions (Pick bodies) and diffusely staining bal- looned neurons (Pick cells). More recently it has become clear that the spectrum of pathology that accompanies the clinical syndromes within the frontotemporal dementia spectrum is much broader, with a range of distinct inclusions as described next. There is additionally very considerable heterogeneity in the clinical features within the FTD spectrum, including overlap between FTD and motor neuron disease (MND, also referred to as amyotrophic lateral sclerosis), and atypical parkinsonism. A significant proportion of cases—​and par- ticularly those with behavioural presentations—​are familial, with up to c.40% having an affected family member; three major and several minor causative genetic mutations are recognized. While there is no one-​to-​one match between clinical syndrome, pathology, and gen- etic mutation, some fairly consistent patterns are emerging which can be diagnostically useful (Fig. 24.4.2.6). Epidemiology FTD is increasingly recognized as a common cause of dementia, particularly in the younger age groups (see Fig. 24.4.2.1). The peak incidence of onset is 45–​65 years of age, but 10% or more may have onset after the age of 70. Men and women are equally affected. Pathology While FTD is used to describe the clinical syndromes, the term frontotemporal lobar degeneration (FTLD) is used to describe the pathology. The gross pathological appearance in typical cases is of selectively atrophied frontotemporal regions which may be so severe as to produce the so-​called knife-​edged gyri, and deep widened sulci. The histopathological hallmarks are widespread cortical and subcor- tical gliosis, loss of large cortical nerve cells, and microvacuolation. At a microstructural level, FTLD is classified on the basis of the spe- cific pathological intracellular protein inclusions (see Fig. 24.4.2.7). Approximately 40% of FTLD is underpinned by tau pathology (FTLD-​tau), which can be further subdivided based both on morph- ology and predominance of the number of micro-​tubule binding repeats: 4-​repeat tauopathies include corticobasal degeneration, pro- gressive supranuclear palsy, argyrophilic grain disease and globular glial tauopathy; 4- and 3-repeat tauopathies include some cases of frontotemporal dementia due to mutations in the microtubule-​ associated protein tau (MAPT) gene on chromosome 17; classical Pick’s disease is a 3-​repeat tauopathy. Approximately 50% of FTLD cases are associated with inclusions containing the 43 kDa TAR DNA-​binding protein (TDP-​43), that is, FTLD-​TDP. FTLD-​TDP can be further subdivided into four subtypes (A, B, C, and D). Rarer inclu- sions seen in FTLD include fused-​in-​sarcoma protein (FTLD-​Fus), which comprises three different, very rare, conditions, neurofilament inclusion body disease, atypical FTLD-​U (aFTLD-​U) and basophilic inclusion body disease; and FTLD-UPS due to CHMP2B mutations. Genetics About 40% of patients with FTD have a positive family history, al- though in not all cases will a causative mutation be detected. In those with a confirmed mutation (familial FTD), three causative gene mutations account for more than 90% of cases. The first mutation, found in the late 1990s, involves the MAPT gene on chromosome 17, and results in tau pathology. In 2006, the second major locus close to MAPT, the progranulin gene, was discovered and shown to result in TDP-​43 (type B) pathology. In 2011 a hexanucleotide repeat expansion on chromosome 9 (C9orf72) was identified as a cause of familial MND, familial MND, or combinations of both diseases; and with either TDP-​43 type A or B pathology. Very rare other genetic causes include mutations in transactive DNA-​binding protein (TARDBP), fused-​in-​sarcoma, valosin-​containing protein, chromatin-​modifying protein 2B (CHMP2B), Sequestosome-1 (SQSTM1), and TANK-binding kinase 1 (TBK1). FTD bvFTD PNFA SD CBS/ PSP MND/ ALS Tau Ubi Clinical syndromes Pathology Genetics TDP FUS UPS MAPT GRN C9ORF72 VCP, SQSTM1, TARDBP, TBK1 FUS CHMP2B Fig. 24.4.2.6  Autosomal dominant genetic causes (red), pathology (green) and clinical syndromes (blue) of frontotemporal dementia. bvFTD, behavioural variant frontotemporal dementia; PNFA, progressive non​fluent aphasia; SD, semantic dementia; CBS, corticobasal syndrome; PSP, progressive suprnuclear palsy; MND, motor neuron disease; ALS, amyotrophic lateral sclerosis; Ubi, Ubiquitin; TDP, Tar DNA-​binding protein; FUS, fused-​in-​sarcoma protein; UPS, ubiquitin proteosome system VCP. Courtesy of Dr Jonathan Rohrer, UCL. SECTION 24  Neurological disorders 5844 Clinical features While the presentation of FTD is variable, two broad syndromic groups are recognized, that is, patients presenting with a prom- inent behavioural syndrome (behavioural variant FTD, bvFTD); and those with primary disturbance of language, primary progres- sive aphasia. Primary progressive aphasia in turn can be subdiv- ided into progressive non​fluent aphasia, semantic dementia, and logopenic variants. Fig. 24.4.2.7  Microscopic observations in frontotemporal lobar degeneration. Tau immunohistochemistry highlights the pathological hallmarks in FTLD-​tau (a–​c). The cytoplasmic inclusion called ‘Pick Bodies’ are a prominent feature in the granule cell layer of the hippocampus in Pick’s disease (a); astrocytic plaques are a diagnostic hallmark in corticobasal degeneration (b) and a tufted astrocyte a hallmark of progressive supranuclear palsy (c). FTLD-​TDP is divided into four pathological subtypes (subtypes A, B, C, and D) all with characteristic pathological features. Subtypes A–​C show neuronal cytoplasmic inclusions in the granule cell layer of the hippocampus (d, arrows); FTLD-​TDPA is characterized by neuronal cytoplasmic inclusions (e, arrow) and short neuropil threads (e, double arrow); FTLD-​TDPB by granular cytoplasmic inclusions affecting all cortical layers (f, arrow) and FTLD-​TDPC by long twisted neurites (g). FTLD-​FUS contains neuronal cytoplasmic (h, arrow) and intranuclear inclusions (h, double arrow) in the granule cells of the hippocampus; neuronal cytoplasmic inclusions in the frontal cortex (i) and large cytoplasmic and intranucelar inclusions in lower motor neurons (j). Bar in (a) represents 50 μm in (a–​g); 40 μm in (h) and (i); 20 μm in (j). Courtesy of Dr Tammaryn Lashley, UCL. 24.4.2  Alzheimer’s disease and other dementias 5845 Behavioural variant FTD Patients present with insidious and progressive changes in person- ality and behaviour that reflect the early locus of pathology in orbital and medial parts of the frontal lobes. There is often impaired judge- ment, an indifference to domestic and professional responsibilities, and a lack of initiative and apathy. Social skills deteriorate and there can be socially inappropriate behaviour, fatuousness, jocularity, and abnormal sexual behaviour with disinhibition. Many patients are restless with an obsessive-​compulsive and ritualized pattern of behaviour, such as pacing or hoarding. Emotional lability, mood swings, and loss of empathy are common; psychiatric phenomena such as delusions and hallucinations are less common, although may be seen in some of the genetic forms, and in C9orf72 cases in par- ticular. Patients often become rigid and stereotyped in their daily routines and food choices. A  change in food preference towards sweet foods is characteristic. Patients may show changes in music preference and altered sensitivity to pain and temperature. Of im- portance is the fact that simple bedside cognitive screening tests such as the Mini-​Mental State Examination (MMSE) are insensitive at detecting frontal abnormalities. More detailed neuropsychological tests of frontal function (such as the Wisconsin Card Sorting Test or the Stroop Test) usually show abnormalities. Speech output can be reduced with word finding difficulties, anomia and sometimes echolalia (repeating the examiner’s last phrase). Memory is rela- tively spared in the early stages, although it deteriorates as the dis- ease advances. Visuospatial function typically remains unaffected. Primary motor and sensory functions remain normal. Primitive re- flexes such as grasping and utilization behaviour develop during the disease process. Fasciculations or wasting, particularly affecting the bulbar musculature, deltoids or tongue are suggestive of an FTD/​ MND cross-​over syndrome, which has a worse prognosis; such cases should prompt consideration of testing for an expansion in the C9orf72 gene; and if negative, a TBK-1 mutation. Primary progressive aphasia—​progressive non​fluent aphasia, semantic dementia, and logopenic aphasia In progressive non​fluent aphasia there is a gradual loss of expressive language abilities with impairments in motor speech impairment (apraxia of speech) and/​or grammatical aspects of language produc- tion. This leads to non​fluent, agrammatical, and poorly articulated speech with phonological errors (e.g. ‘sitter’ for ‘sister’ or ‘fencil’ for ‘pencil’). Repetition of multisyllabic words and phrases is impaired but, at least early in the disease, word comprehension and object recognition are well preserved. Orobuccal apraxia (e.g. inability to cough or yawn to command) is common, and some patients develop parkinsonism and limb apraxia. The pathology is most commonly tau, but can be variable. In semantic dementia there is a profound loss of conceptual knowledge (or semantic memory), causing anomia and impaired comprehension of words, objects, or faces. The patient may com- plain of ‘loss of memory for words’, commonly ask what words mean, and has fluent, empty speech with generic substitutions such as ‘thing’ and ‘one of those’; grammatical aspects are pre- served. Naming is impaired with semantically based errors (such as ‘animal’ or ‘horse’ for zebra). Patients are unable to understand less frequent words and fail on a range of semantically based tasks such as matching words to pictures and matching pictures according to their meaning. Repetition of words and phrases is normal even though patients may be unaware of their meaning. Patients make surface dyslexic or regularization errors when reading, pronouncing irregular words phonetically (‘sew’ pronounce ‘sue’). Unlike patients with Alzheimer’s disease, day-​to-​day memory (episodic memory) visuospatial skills and non​verbal problem-​solving abilities are rela- tively preserved, at least in the early stages. As the disease progresses behavioural changes often emerge, similar to bvFTD. The pathology is almost always TDP type C. Logopenic aphasia is characterized by word finding pauses, and anomia. Semantic knowledge is variably preserved, and while being able to pronounce individual words patients have grave difficulties repeating longer phrases or sentences, and show impaired working memory (e.g. reduced digit span). The underlying pathology is usu- ally that of Alzheimer’s disease. Diagnosis Diagnosis of FTD and its various subtypes is based on the clin- ical, neuropsychological, and imaging assessments. Consensus clinical criteria developed for bvFTD and the various forms of primary progressive aphasia are shown in Table 24.4.2.4. The dif- ferences between the various syndromes described earlier may be clear early in the disease, but there is increasing overlap between the temporal and frontal syndromes as the disease progresses. In contrast to Alzheimer’s disease, superadded neurological signs (par- kinsonism or motor neuron) are relatively common even in mild to moderate stage disease, particularly in bvFTD and progressive non​fluent aphasia. Neuropsychometry can confirm and quantify the deficits observed at the bedside. Imaging provides invaluable information in the diagnosis of FTD (Fig. 24.4.2.8). MRI findings suggestive of FTD instead of Alzheimer’s disease include anterior–​ posterior atrophy gradient, and asymmetric atrophy. Patients with bvFTD typically have frontal atrophy; semantic dementia is asso- ciated with highly asymmetric left anterior temporal lobe atrophy; patients with logopenic aphasia often have relatively mild asym- metric atrophy involving the dominant hemisphere but otherwise resembling Alzheimer’s disease; and the MRI in progressive non-​ fluent aphasia is often fairly unremarkable for the degree of symp- toms, bar some widening of the left Sylvian fissure (Fig. 24.4.2.8). Specific atrophy patterns in the correct clinical context may provide clues to a genetic cause: progranulin mutations are associated with often profound atrophy of one hemisphere, whereas mutations in tau are often associated with symmetrical inferior medial temporal atrophy. Functional imaging using FDG-​PET typically mirrors the structural imaging results, with reduced frontotemporal perfusion and hypometabolism, and is perhaps most valuable where the struc- tural imaging is normal or equivocal. Amyloid PET where available may be helpful in excluding Alzheimer’s disease; while not clinically available, the advent of tau PET imaging may in due course have utility in refining the molecular diagnosis further. CSF examination is principally performed to exclude infectious or inflammatory pro- cesses and Alzheimer’s disease. Newer CSF (e.g. neurofilament light chain) and blood markers (e.g. progranulin) may in due course help in distinguishing FTD subtypes and/​or guide prognosis, but are not yet used in routine clinical practice. Management and prognosis There is no curative treatment at present, so the general manage- ment of the person with dementia and their family, as discussed earlier, is of prime importance. Management of some of the behav- ioural aspects can be particularly challenging. Particular care should SECTION 24  Neurological disorders 5846 Table 24.4.2.4  Consensus criteria for behavioural variant frontotemporal dementia and primary progressive aphasia Criteria for behavioural variant frontotemporal dementia I. Neurodegenerative disease The following symptom must be present to meet criteria for bvFTD A. Shows progressive deterioration of behaviour and/​or cognition by observation or history (as provided by a knowledgeable informant). II. Possible bvFTD Three of the following behavioural/​cognitive symptoms (A–​F) must be present to meet criteria. Ascertainment requires that symptoms be persistent or recurrent, rather than single or rare events A. Earlya behavioural disinhibition [one of the following symptoms (A.1–​A.3) must be present]: A.1. Socially inappropriate behaviour A.2. Loss of manners or decorum A.3. Impulsive, rash, or careless actions B. Early apathy or inertia [one of the following symptoms (B.1–​B.2) must be present]: B.1. Apathy B.2. Inertia C. Early loss of sympathy or empathy [one of the following symptoms (C.1–​C.2) must be present]: C.1. Diminished response to other people’s needs and feelings C.2. Diminished social interest, interrelatedness or personal warmth D. Early perseverative, stereotyped or compulsive/​ritualistic behaviour [one of the following symptoms (D.1–​D.3) must be present]: D.1. Simple repetitive movements D.2. Complex, compulsive, or ritualistic behaviours D.3. Stereotypy of speech E. Hyperorality and dietary changes [one of the following symptoms (E.1–​E.3) must be present]: E.1. Altered food preferences E.2. Binge eating, increased consumption of alcohol or cigarettes E.3. Oral exploration or consumption of inedible objects F. Neuropsychological profile: executive/​generation deficits with relative sparing of memory and visuospatial functions [all of the following symptoms (F.1–​F.3) must be present]: F.1. Deficits in executive tasks F.2. Relative sparing of episodic memory F.3. Relative sparing of visuospatial skills III. Probable bvFTD All of the following symptoms (A–​C) must be present to meet criteria A. Meets criteria for possible bvFTD B. Exhibits significant functional decline (by caregiver report or as evidenced by Clinical Dementia Rating Scale or Functional Activities Questionnaire scores) C. Imaging results consistent with bvFTD [one of the following (C.1–​C.2) must be present]: C.1. Frontal and/​or anterior temporal atrophy on MRI or CT C.2. Frontal and/​or anterior temporal hypoperfusion or hypometabolism on PET or SPECT IV. Behavioural variant FTD with definite FTLD Pathology Criterion A and either criterion B or C must be present to meet criteria. A. Meets criteria for possible or probable bvFTD B. Histopathological evidence of FTLD on biopsy or at post-​mortem C. Presence of a known pathogenic mutation V. Exclusionary criteria for bvFTD Criteria A and B must be answered negatively for any bvFTD diagnosis. Criterion C can be positive for possible bvFTD but must be negative for probable bvFTD A. Pattern of deficits is better accounted for by other non​degenerative nervous system or medical disorders B. Behavioural disturbance is better accounted for by a psychiatric diagnosis C. Biomarkers strongly indicative of Alzheimer’s disease or other neurodegenerative process Criteria for primary progressive aphasia (PPA) Inclusion and exclusion criteria for the diagnosis of PPA Inclusion: criteria 1–​3 must be answered positively Most prominent clinical feature is difficulty with language These deficits are the principal cause of impaired daily living activities Aphasia should be the most prominent deficit at symptom onset and for the initial phases of the disease Exclusion: criteria 1–​4 must be answered negatively for a PPA diagnosis Pattern of deficits is better accounted for by other non​degenerative nervous system or medical disorders 24.4.2  Alzheimer’s disease and other dementias 5847 2. Cognitive disturbance is better accounted for by a psychiatric diagnosis 3. Prominent initial episodic memory, visual memory, and visuoperceptual impairments 4. Prominent, initial behavioural disturbance Diagnostic features for the non​fluent/​agrammatic variant PPA At least one of the following core features must be present: Agrammatism in language production Effortful, halting speech with inconsistent speech sound errors and distortions (apraxia of speech) At least 2 of 3 of the following other features must be present: Impaired comprehension of syntactically complex sentences Spared single-​word comprehension Spared object knowledge II. Imaging-​supported non​fluent/​agrammatic variant diagnosis Both of the following criteria must be present: Clinical diagnosis of non​fluent/​agrammatic variant PPA Imaging must show one or more of the following results: a. Predominant left posterior fronto-​insular atrophy on MRI or b. Predominant left posterior fronto-​insular hypoperfusion or hypometabolism on SPECT or PET III. Non​fluent/​agrammatic variant PPA with definite pathology Clinical diagnosis (criterion 1 below) and either criterion 2 or 3 must be present: Clinical diagnosis of non​fluent/​agrammatic variant PPA Histopathologic evidence of a specific neurodegenerative pathology (e.g. FTLD-​tau, FTLD-​TDP, AD, other) Presence of a known pathogenic mutation Diagnostic features for the semantic variant PPA Both of the following core features must be present: Impaired confrontation naming Impaired single-​word comprehension At least 3 of the following other diagnostic features must be present: Impaired object knowledge, particularly for low-​frequency or low-​familiarity items Surface dyslexia or dysgraphia Spared repetition Spared speech production (grammar and motor speech) II. Imaging-​supported semantic variant PPA diagnosis Both of the following criteria must be present: Clinical diagnosis of semantic variant PPA Imaging must show one or more of the following results: a. Predominant anterior temporal lobe atrophy b. Predominant anterior temporal hypoperfusion or hypometabolism on SPECT or PET III. Semantic variant PPA with definite pathology Clinical diagnosis (criterion 1 below) and either criterion 2 or 3 must be present: Clinical diagnosis of semantic variant PPA Histopathologic evidence of a specific neurodegenerative pathology (e.g. FTLD-​tau, FTLD-​TDP, AD, other) Presence of a known pathogenic mutation Diagnostic features for the logopenic variant PPA Both of the following core features must be present: Impaired single-​word retrieval in spontaneous speech and naming Impaired repetition of sentences and phrases At least 3 of the following other features must be present: Speech (phonologic) errors in spontaneous speech and naming Table 24.4.2.4  Continued (continued) SECTION 24  Neurological disorders 5848 2. Spared single-​word comprehension and object knowledge 3. Spared motor speech 4. Absence of frank agrammatism II. Imaging-​supported logopenic variant diagnosis Both criteria must be present: Clinical diagnosis of logopenic variant PPA Imaging must show at least one of the following results: a. Predominant left posterior perisylvian or parietal atrophy on MRI b. Predominant left posterior perisylvian or parietal hypoperfusion or hypometabolism on SPECT or PET III. Logopenic variant PPA with definite pathology Clinical diagnosis (criterion 1 below) and either criterion 2 or 3 must be present: Clinical diagnosis of logopenic variant PPA Histopathologic evidence of a specific neurodegenerative pathology (e.g. AD, FTLD-​tau, FTLD-​TDP, other) Presence of a known pathogenic mutation AD, Alzheimer’s disease; FTLD, frontotemporal lobar degeneration; PPA, primary progressive aphasia. a As a general guideline ‘early’ refers to symptom presentation within the first 3 years. Table reprinted from Rascovsky K, et al. (2011). Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain, 134(pt9), 2456−77, by permission of Oxford University Press. Table 24.4.2.4  Continued Fig. 24.4.2.8  MR imaging in frontotemporal dementia. Each T1-​weighted MR image is presented with the patient’s clinical diagnosis and pathological or genetic diagnosis in brackets, and in radiological convention (left = right). (a) Right–​left-​sided medial temporal lobe atrophy; (b) left-​sided atrophy in the temporal lobe predominantly affecting the posterior perisylvian and temporoparietal areas; (c) left-​sided posterior fronto-​insular atrophy, which may be limited to a subtle widening of the left Sylvian fissure; (d) left–​right-​sided anterior temporal atrophy, particularly involving the temporal pole, the amygdala, and the anterior hippocampus, with relative preservation of more posterior structures; (e) focal (and often severe) atrophy affecting the anteromedial temporal lobes with striking loss in the amygdala, parahippocampus, and hippocampal heads bilaterally; (f) gross frontoparietal atrophy extending into the temporal lobe, predominantly affecting a single hemisphere. AD, Alzheimer’s disease; bvFTD, behavioural variant frontotemporal dementia; PNFA, progressive non​fluent aphasia; SD, semantic dementia; PPA, primary progressive aphasia; LPA, logopaenic aphasia; TDP, Tar DNA-​binding protein; GRN, progranulin mutation; MAPT, tau mutation. Courtesy of Dr Lorna Harper, UCL. 24.4.2  Alzheimer’s disease and other dementias 5849 be taken to regularly assess swallowing function, particularly in pa- tients with non​fluent aphasia; and the clinician should be alert to the possibility of developing motor neuron disease or atypical par- kinsonism, which may require specific interventions. Patients with a family history of dementia should be considered for screening for tau, progranulin, or C9orf72 mutations after appropriate genetic counselling. The prognosis can be variable with different rates of progression between individuals. The disease is progressive and the average duration from diagnosis is around five to ten years, but is often much shorted in those with FTD/MND. Dementia with Lewy bodies and Parkinson’s disease dementia Definition Since the discovery in the 1960s that patients with Lewy bodies in the cortex have a distinctive pattern of dementia with features of both Parkinson’s and Alzheimer’s diseases, it has been increasingly recognized as an important cause of dementia. The terminology has been confusing, with multiple designations including: Lewy body dementia, dementia of Lewy body type, diffuse Lewy body disease, and cortical Lewy body disease, with ‘dementia with Lewy bodies’ (DLB), now preferred. There is however increasing recognition of an overlap between DLB and the dementia associated with Parkinson’s disease (Parkinson’s disease dementia or PDD), with most clinicians now considering the two to be on the same spectrum, termed Lewy body disease (Fig. 24.4.2.9). Consensus criteria arbitrarily suggest that DLB is diagnosed when cognitive symptoms predate the emer- gence of motor parkinsonism by a year or more, with PDD preferred when motor parkinsonism occurs prior to, or within one year of, the development of cognitive problems. Epidemiology DLB is a common cause of dementia in the older population, accounting for 15–​30% of cases in post-​mortem series. The pro- portions of individuals diagnosed during life varies considerably, with a significant proportion diagnosed with Alzheimer’s disease. Onset is usually between the ages of 60 and 80. A significant pro- portion of individuals with Parkinson’s disease (PD) have some degree of cognitive dysfunction, and, as with Alzheimer’s disease, the concept of mild cognitive impairment due to PD has been intro- duced in recent years. The incidence of dementia is c.2–​6 times that of age-​matched controls, with a prevalence of over 75% 10 years after a diagnosis of PD. The most established risk factors for developing dementia in PD are increasing age, duration of disease, and severity of motor symptoms. Pathology The cardinal pathological features of both DLB and PDD are the presence of cortical Lewy bodies and Lewy neurites. Lewy bodies are intracytoplasmic eosinophilic neural inclusions predomin- antly composed of α-​synuclein (Fig. 24.4.2.10). Brainstem-​type Lewy bodies are seen on standard (e.g. haematoxylin-​eosin) staining, but detection of cortical Lewy bodies and Lewy neurites requires immunohistochemistry with anti-​α-​synuclein antibodies. Consensus pathological criteria for DLB require the determination of distribution and severity of Lewy type α-​synuclein pathology in ten different brain regions, allowing for designation as neocor- tical (diffuse), limbic (transitional), or brainstem predominant. The degree of Alzheimer pathology present is also taken into account in establishing the likelihood that an individual patient’s dementia is due to Lewy body pathology. Alzheimer’s disease pathology also commonly accompanies PDD, with the combination of both Alzheimer’s disease and Lewy body pathology being most robust pathological predictor of dementia. More recently pathology guide- lines from the National Institute on Aging-​Alzheimer’s Association recommend the use of the overarching term ‘Lewy body disease’ for both DLB and PDD, and add a further designation of amygdala predominant Lewy bodies, the category most commonly associated with Alzheimer’s disease pathology. Macroscopically, there is typically pallor of the substantia nigra and locus coeruleus, and diffuse cerebral atrophy: prominent at- rophy of medial temporal lobe structures may indicate additional Alzheimer’s disease pathology. In DLB there is loss of cholinergic neurons in the nucleus basalis of Meynert, marked reduction in acetylcholine throughout the cortex, and severe dopamine depletion in the basal ganglia Clinical features In DLB, patients typically present with progressive cognitive de- cline, which can be broadly similar to Alzheimer’s disease, although typically more focused on executive and parietal lobe deficits with relatively less memory involvement. There are, however, three par- ticular characteristic and distinguishing features. First, there is a tendency to marked spontaneous fluctuations in cognitive abilities, particularly alertness and attention. These fluctuations occur in 50–​75% of patients, may be profound, and may last anywhere be- tween hours and several days. Second, visual hallucinations, illu- sions, and fleeting misidentification phenomena occur in at least two-​thirds of patients even at an early stage and without drug provo- cation. The hallucinations are typically well-​formed, silent, and are usually images of people or animals. In contrast to those seen in major psychiatric disease, these hallucinations are typically not threatening, and indeed may be reported as being comforting. In patients without frank hallucinations, close questioning may reveal a sense of ‘presence’, sometimes extending to the phantom boarder phenomenon (the conviction that there are others living in the house). In some cases, misidentification may lead to the Capgras phenomenon (the belief that someone close to them has been re- placed by an exact double). Many of these phenomena seem at least in part to relate to the marked cholinergic deficit seen in this PD-MCI Bradykinesia Rigidity Tremor Postural instability Dementia Fluctuations Visual hallucinations PD Motor features Cognitive features PDD DLB Fig. 24.4.2.9  The spectrum of Lewy body diseases. PD, Parkinson’s disease, PD-​MCI, Parkinson’s disease—​mild cognitive impairment, PDD, Parkinson’s disease dementia, DLB, dementia with Lewy bodies. SECTION 24  Neurological disorders 5850 condition. Third is the occurrence of parkinsonism seen in 70–​100% of cases, which is usually mild in the early stages. Rigidity, gait dis- turbance, and bradykinesia are all common, although in contrast to patients with Parkinson’s disease the tremor may be absent and when present is usually mild, atypical (with postural and action components), and symmetrical. Repeated falls also occur. In the later stages the akinetic rigid syndrome can cause severe disabilities in mobility and swallowing, and an increase in the number of falls. There is often an exquisite sensitivity to neuroleptic medication, which can in extreme cases precipitate the malignant neuroleptic syndrome (delirium, hyperpyrexia, muscle rigidity, massive eleva- tion of creatine phosphokinase, and renal failure). Other symptoms include vivid dreams, rapid eye movement (REM) sleep behaviour disturbance, and prominent daytime som- nolence; falls, syncope, and transient loss of consciousness are likely to reflect autonomic dysfunction. In PDD, the cognitive profile is similar with a dysexecutive syndrome with impairments of atten- tion, executive, and visuospatial function. Memory is often affected, but typically to a lesser extent than in Alzheimer’s disease. PDD is associated with neuropsychiatric symptoms broadly similar to those seen in DLB, including hallucinations, apathy, depression, and anx- iety. Hallucinations may be spontaneous but may be associated with, or exacerbated by, dopaminergic medication. As with DLB, daytime somnolence, REM sleep behaviour disturbance, and autonomic dis- turbances are common. While motor parkinsonism is a sine qua non, PDD is more associated with bradykinesia, rigidity, and pos- tural instability than with tremor-​dominant PD. Diagnosis In DLB, neuropsychology shows a mixture of subcortical and cortical features, with prominent cognitive slowing plus impair- ment of executive (planning and organizational) abilities and visuoperceptual abilities. Compared with patients with Alzheimer’s disease, those with DLB tend to have greater deficits in attention and visuospatial processing, and (usually) less prominent memory loss. There is no reliable molecular biomarker for DLB. MRI shows broadly similar changes to Alzheimer’s disease, although medial temporal lobe atrophy is often less pronounced. FDG-​PET and SPECT shows occipitoparietal hypoperfusion. Dopamine trans- porter typically shows decreased central dopaminergic availability (Fig. 24.4.2.11). Diagnostic criteria (Table 24.4.2.5) defines several core (fluctations, hallucinations, spontaneous parkinsonism, REM sleep behaviour disorder) and indicative biomarkers which in com- bination can be used to classify patients as having either probable or Fig. 24.4.2.10  Microscopic findings in Lewy body dementia. α-​synuclein immunohistochemistry highlights cortical Lewy bodies in the frontal cortex (a, arrows); Lewy neurites are also found in the frontal cortex (b); Lewy bodies are also observed in the dopaminergic neurons of the substantia nigra (c) and the hippocampus (d). Bar in (a) represents 200 μm; 50 μm in (c) and (d), and 20 μm in (b). Courtesy of Dr Tammaryn Lashley, UCL. 24.4.2  Alzheimer’s disease and other dementias 5851 possible DLB. Clinical criteria have also been proposed for the diag- nosis of PDD, and for mild cognitive impairment in PD (PD-​MCI). While there are some very rare genetic causes of Lewy body path- ology which can have cognitive impairment (duplications/​triplica- tions of the α-​synuclein gene, mutations in the glucocerebrosidase gene), there is not a role for routine genetic testing. Management The treatment of patients with Lewy body disorders requires con- sideration of non​pharmacological approaches; minimizing the use of medications that may worsen the condition; and striking a balance between treating motor symptoms that may worsen cog- nition, and treatment for cognitive symptoms that may impact on mobility. As well as general non​pharmacological management of dementia, attention to any coexistent vision and hearing problems is important; ensuring appropriate lighting, especially at night, may improve hallucinations. It is important to review the need for, and where appropriate minimize or discontinue use of, drugs with anticholinergic actions which may worsen cognitive symptoms and postural hypotension. Antipsychotic drugs should be avoided wherever possible; if absolutely necessary, atypical antipsychotics should be used at the lowest possible dose and for the shortest dur- ation possible. Patients with DLB may be very sensitive to the side effects of dopamine-​enhancing medications used for the treatment of their motor symptoms. However, although dramatic motor im- provements are not to be expected, a cautious medication trial is worth attempting if motor symptoms interfere with function. In patients with PDD where cognition, and hallucinations in par- ticular, are problematic, simplifying dopaminergic treatment re- gimes and avoiding dopamine agonists may be helpful. There is now good trial evidence that acetylcholinesterase inhibitors such as donepezil and rivastigmine provide symptomatic bene- fits in both DLB and PDD, in terms of attention, cognition, and behaviour. At least anecdotally, there are often marked improve- ments in hallucinations following treatment. While parkinsonian symptoms can worsen with cholinesterase inhibitors particularly in PDD, the effects are usually small and should not preclude a trial of treatment. There is some weaker evidence that memantine may provide benefits in these conditions. Vascular cognitive impairment Definition and epidemiology Recent years have seen significant changes in how we consider the impact that cerebrovascular disease may have on cognition. As it be- came clear that vascular pathologies other than large vessel disease cause cognitive impairment, the term multi-​infarct dementia was superseded by the concept of ‘vascular dementia’. However, as the cognitive deficits produced by cerebrovascular disease may be both mild (e.g. not fulfilling conventional criteria for dementia), and due to several different pathologies, the term ‘vascular cognitive impair- ment’ is now preferred to encompass both the spectrum of cognitive impairments presumed to be due to cerebrovascular disease, and its varying aetiologies (Table 24.4.2.6). In particular, disease of small perforating vessels (including not only lacunes in the basal ganglia and deep white matter, but also more diffuse lesions in the white matter, often termed leukoaraiosis) has emerged as a key mechanism of vascular cognitive impairment. Traditionally regarded as the second most common cause of dementia, it is difficult to estimate the true contribution of vas- cular disease to cognitive decline. This relates in part to changes in definitions earlier, but also to advances in MRI, which now allow for a range of vascular pathologies to be detected with ever increasing sensitivity. Furthermore, Alzheimer’s disease and cere- brovascular disease very commonly coexist—​and indeed may share common risk factors, including hypertension, diabetes, and hypercholesterolaemia—​and are likely to have synergistic impacts on cognitive function. Common causes of vascular cognitive impairment The varieties of vascular diseases that affect the brain are legion, but from both a clinical and radiological perspective the common vas- cular lesions can conveniently be divided into large and small vessel disease. Large vessel ischaemia Large vessel ischaemia typically resulting from thrombosis or em- bolism, usually results in acute stroke, and discrete cortical, cere- bellar, brainstem, or subcortical lesions on MRI. The cognitive picture is dependent on the site(s) of the lesions. There may be se- vere language impairment, visuospatial disturbance, amnesia, and dyspraxia related to lesions in the middle and posterior cerebral artery distributions. Specific syndromes can result from focal le- sions, for example, lesions of the left angular gyrus result in a fluent aphasia, agraphia, acalculia, right–​left disorientation and finger agnosia, known as Gerstmann’s syndrome. There is commonly a history of atherosclerotic risk factors (e.g. hypertension, smoking, and hypercholesterolaemia), other evidence of atherosclerotic cardiac or peripheral vascular disease, and neurological signs on Fig. 24.4.2.11  Abnormal dopamine active transporter (DAT) scan in dementia with Lewy bodies. Dopamine transporter imaging shows symmetrical reduced basal ganglia uptake (dot-​like, rather than comma-​like, in appearance) in a patient with clinically probable dementia with Lewy bodies. SECTION 24  Neurological disorders 5852 Table 24.4.2.5  Criteria for dementia with Lewy bodies and Parkinson’s disease dementia Probable Parkinson’s disease dementia (PDD) Diagnosis of Parkinson's disease according to Queen Square Brain Bank criteria AND A dementia syndrome with insidious onset and slow progression, developing within the context of established Parkinson's disease and diagnosed by history, clinical, and mental examination, defined as impairment in more than one cognitive domain; representing a decline from premorbid level. Deficits severe enough to impair daily life (social, occupational, or personal care), independent of the impairment ascribable to motor or autonomic symptoms AND Typical profile of cognitive deficits including impairment in at least two of the four core cognitive domains (impaired attention which may fluctuate, impaired executive functions, impairment in visuo-​spatial functions, and impaired free recall memory which usually improves with cueing). The presence of at least one behavioural symptom (apathy, depressed, or anxious mood, hallucinations, delusions, excessive daytime sleepiness) supports the diagnosis of Probable PD-​D, lack of behavioural symptoms, however, does not exclude the diagnosis. EXCLUSION CRITERIA: Coexistence of any other abnormality which may by itself cause cognitive impairment, but judged not to be the cause of dementia, e.g. presence of relevant vascular disease in imaging Time interval between the development of motor and cognitive symptoms not known Features suggesting other conditions or diseases as cause of mental impairment, which, when present make it impossible to reliably diagnose PD-​D Cognitive and behavioural symptoms appearing solely in the context of other conditions such as acute confusion due to Systemic diseases or abnormalities; Drug intoxication; major depression according to DSM-​IV; Features compatible with probable vascular dementia. Dementia with Lewy bodies (DLB) Dementia defined as progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function or with activities of normal living. A patient must have either developed dementia before, or within one year of the onset of parkinsonian syndromes. If more than a year passes before the onset of dementia following parkinsonism, a diagnosis of PDD is made. A “probable” DLB diagnosis requires at least two core features or one core feature and at leas one indicative biomarker. A “possible” DLB diagnosis requires one of the seven items from the list of core features or indicative biomarkers. Supportive biomarkers are helpful in making the diagnosis but their specificity for DLB is not clear. Core features: Recurrent visual hallucinations Fluctuating cognition Spontaneous features of parkinsonism Rapid eye movement (REM) sleep behaviour disturbance (RBD). Indicative biomarkers Polysomnography confirming RBD Abnormal dopamine transporter (DAT) imaging Abnormal (low uptake) MIBG myocardial scintigraphy And, on four separate lines: Supportive biomarkers Relative preservation of medial temporal lobe structures on CT/MRI Generalized low uptake on SPECT/ PET perfusion scan with reduced occipital activity with reduced occipital activity +/- posterior congulate island sign on FDG-PET Prrominent posterior slow-wave activity on EEG Mild cognitive impairment—Parkinson’s disease dementia (MCI-PDD) Diagnosis of Parkinson's disease as based on the UK PD Brain Bank Criteria Gradual decline, in the context of established PD, in cognitive ability reported by either the patient or informant, or observed by the clinician Cognitive deficits on either formal neuropsychological testing or a scale of global cognitive abilitiesa Cognitive deficits are not sufficient to interfere significantly with functional independence, although subtle difficulties on complex functional tasks may be present Exclusion criteria Diagnosis of PD dementia based on MDS Task Force proposed criteria Other primary explanations for cognitive impairment (e.g. delirium, stroke, major depression, metabolic abnormalities, adverse effects of medication, or head trauma) Other PD-​associated comorbid conditions (e.g. motor impairment or severe anxiety, depression, excessive daytime sleepiness, or psychosis) that, in the opinion of the clinician, significantly influence cognitive testing a Depending on the scales used and how comprehensive the neuropsychological battery, PD-​MCI can be classified as Level 1 (lesser diagnostic certainty) or Level 2 (higher diagnostic certainty); and for classifications within Level 2 as single or multiple domain PD-​MCI. Adapted from: Emre M, et al. (2007). Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Movement Disorders, 22, 1689–1707 (PMID: 17542011); McKeith IG, et al (2017). Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 89(1), 88-100 (PMID 28592453); Litvan I, et al. (2011). MDS Task Force on mild cognitive impairment in Parkinson’s disease: critical review of PD-MCI. Movement Disorders, 26(10), 1814−1824 (PMID: 21661055). 24.4.2  Alzheimer’s disease and other dementias 5853 Table 24.4.2.6  Criteria for vascular cognitive impairment The term VCI characterizes all forms of cognitive deficits from VaD to MCI of vascular origin. These criteria cannot be used for subjects who have an active diagnosis of drug or alcohol abuse/​dependence. Subjects must be free of any type of substance for at least 3 months. These criteria cannot be used for subjects with delirium. Dementia The diagnosis of dementia should be based on a decline in cognitive function from a prior baseline and a deficit in performance in ≥2 cognitive domains that are of sufficient severity to affect the subject's activities of daily living. The diagnosis of dementia must be based on cognitive testing, and a minimum of 4 cognitive domains should be assessed: executive/​attention, memory, language, and visuospatial functions. The deficits in activities of daily living are independent of the motor/​sensory sequelae of the vascular event. Probable VaD There is cognitive impairment and imaging evidence of cerebrovascular disease and a. There is a clear temporal relationship between a vascular event (e.g. clinical stroke) and onset of cognitive deficits, or b. There is a clear relationship in the severity and pattern of cognitive impairment and the presence of diffuse, subcortical cerebrovascular disease pathology (e.g. as in CADASIL). There is no history of gradually progressive cognitive deficits before or after the stroke that suggests the presence of a non​vascular neurodegenerative disorder. Possible VaD There is cognitive impairment and imaging evidence of cerebrovascular disease, but There is no clear relationship (temporal, severity, or cognitive pattern) between the vascular disease (e.g. silent infarcts, subcortical small vessel disease) and the cognitive impairment. There is insufficient information for the diagnosis of VaD (e.g. clinical symptoms suggest the presence of vascular disease, but no CT/​MRI studies are available). Severity of aphasia precludes proper cognitive assessment. However, patients with documented evidence of normal cognitive function (e.g. annual cognitive evaluations) before the clinical event that caused aphasia could be classified as having probable VaD. There is evidence of other neurodegenerative diseases or conditions in addition to cerebrovascular disease that may affect cognition, such as a. A history of other neurodegenerative disorders (e.g. Parkinson disease, progressive supranuclear palsy, dementia with Lewy bodies); b. The presence of Alzheimer disease biology is confirmed by biomarkers (e.g. PET, CSF, amyloid ligands) or genetic studies (e.g. PS1 mutation); or c. A history of active cancer or psychiatric or metabolic disorders that may affect cognitive function. VaMCI VaMCI includes the 4 subtypes proposed for the classification of MCI: amnestic, amnestic plus other domains, non​amnestic single domain, and non​amnestic multiple domain. The classification of VaMCI must be based on cognitive testing, and a minimum of 4 cognitive domains should be assessed: executive/​attention, memory, language, and visuospatial functions. The classification should be based on an assumption of decline in cognitive function from a prior baseline and impairment in at least 1 cognitive domain. Instrumental activities of daily living could be normal or mildly impaired, independent of the presence of motor/​sensory symptoms. Probable VaMCI There is cognitive impairment and imaging evidence of cerebrovascular disease and a. There is a clear temporal relationship between a vascular event (e.g. clinical stroke) and onset of cognitive deficits, or b. There is a clear relationship in the severity and pattern of cognitive impairment and the presence of diffuse, subcortical cerebrovascular disease pathology (e.g. as in CADASIL). There is no history of gradually progressive cognitive deficits before or after the stroke that suggests the presence of a non​vascular neurodegenerative disorder. Possible VaMCI There is cognitive impairment and imaging evidence of cerebrovascular disease, but There is no clear relationship (temporal, severity, or cognitive pattern) between the vascular disease (e.g. silent infarcts, subcortical small vessel disease) and onset of cognitive deficits. There is insufficient information for the diagnosis of VaMCI (e.g. clinical symptoms suggest the presence of vascular disease, but no CT/​MRI studies are available). Severity of aphasia precludes proper cognitive assessment. However, patients with documented evidence of normal cognitive function (e.g. annual cognitive evaluations) before the clinical event that caused aphasia could be classified as having probable VaMCI. There is evidence of other neurodegenerative diseases or conditions in addition to cerebrovascular disease that may affect cognition, such as: a. A history of other neurodegenerative disorders (e.g. Parkinson disease, progressive supranuclear palsy, dementia with Lewy bodies); (continued) SECTION 24  Neurological disorders 5854 examination (e.g. spasticity, hyperreflexia, extensor plantar re- sponses, and a pseudobulbar palsy). There are often asymmetric signs on neurological examination, and gait apraxia and/​or bladder dysfunction can be early features. Multiple sequential large vessel vascular events can produce the classical stepwise decline histor- ically associated with multi-​infarct dementia; however, such pres- entations are seen only in a small proportion of cases of vascular cognitive impairment, most of whom show insidious progressive decline. Cerebral small vessel disease Diseases of the small vessels and associated parenchymal lesions are collectively referred to as cerebral small vessel disease (SVD), and together are the commonest cause of vascular cognitive im- pairment. The pathology of SVD is diverse, and includes fibrinoid necrosis, microatheroma, lipohyalinosis, and cerebral amyloid angiopathy. On MRI, SVD may manifest as one or more of small subcortical infarcts, white matter hyperintensities, prominent peri- vascular spaces, and cerebral microbleeds, occurring very com- monly in combination. Small subcortical infarcts, often referred to as lacunes (when mature with cavitation on neuroimaging) are caused by occlusion in the deep penetrating arterial branches. The basal ganglia, thalamus, and deep white matter are common sites for these lesions, due to the nature of the arterial supply. Lacunes and larger infarcts may coexist contributing to a mixed picture. The typical presentation of SVD-​related vascular cognitive impair- ment is with a more subcortical syndrome causing markedly slow processing, impaired attention, and frontal/executive dysfunction, apathy, and emotional lability. Thalamic lacunes can result in a speech disorder and, if bilateral, in amnesia. Examination features of SVD may include rigidity, gait disturbance, and extrapyramidal and pyramidal signs. White matter hyperintensities best seen on T2-​ or FLAIR-​MRI are a common feature of ageing attributed to SVD-​related mechanisms (Fig.  24.4.12). While most commonly due to vascular disease, they are also seen in a range of other condi- tions, and notably multiple sclerosis and other inflammatory condi- tions, certain infections, secondary to toxins, or in leucodystrophies for which there are numerous different causes. On MRI, vas- cular white matter hyperintensities are commonly seen in a peri-​ ventricular distribution and/​or deep/​subcortical regions, and can be rated using simple scales, with increasing confluence reflecting increasing disease severity. White matter hyperintensities often coexist with subcortical infarcts, and are also associated with the cognitive and other neurological features of the small vessel disease syndrome outlined earlier. Cerebral microbleeds are small areas of signal void best seen on MRI sequences sensitive to paramagnetic material (e.g. T2* or susceptibility-​weighted sequences), and most often reflect small haemorrhages. Microbleeds in the brainstem, cerebellum or deep white matter structures are commonly seen with other manifestations of SVD, and in the context of hyperten- sion. Strictly lobar microbleeds are most commonly due to cere- bral amyloid angiopathy (i.e. deposition of amyloid within the walls of small vessels). MRI features of cerebral amyloid angiopathy are seen in 10–​20% of patients with Alzheimer’s disease, and some de- gree of cerebral amyloid angiopathy is an invariable pathological feature of Alzheimer’s disease. While the cognitive sequelae of cerebral amyloid angiopathy are often difficult to assess, cerebral amyloid angiopathy is a common cause of lobar haemorrhage in older people. Treatment of vascular dementia The treatment should be directed to the amelioration of any underlying cause of the vascular disorder, such as reducing cardiac embolism (with anticoagulation), large vessel thromboembolism or small vessel occlusion (with antiplatelet agents), and treating vasculitides and vascular risk factors including hypertension and hyperlipidaemia. Where there is evidence for both ischaemia and microbleeds, the risks/benefits of antiplatelet agents and anticoagu- lants in particular, need to be carefully considered. Symptomatic treatment (e.g. with cholinesterase inhibitors) may have modest benefits, particularly if there is coexisting Alzheimer’s disease. Rarer causes of vascular cognitive impairment Genetic causes Cerebral autosomal dominant arteriopathy with subcortical in- farcts and leucoencephalopathy (CADASIL) is a rare autosomal dominant disease due to mutations in the notch3 gene on chromo- some 19. While the phenotype is variable, classical features include migraine-​like headaches, stroke-​like episodes, and the development of a subcortical dementia syndrome in the fourth or fifth decade. The MRI findings typically show subcortical infarcts, microbleeds on iron-​sensitive sequences, and diffuse white matter signal change extending into the anterior temporal lobes. Pathologically there is a distinctive angiopathy of the leptomeningeal and perforating ar- teries of the brain, with eosinophilic granular substance replacing smooth muscle. Although CADASIL is the commonest mono- genic form of small vessel disease, other genetic disorders include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; and retinal vasculopathy with cerebral leukodystrophy. Several monogenic diseases may present with intracranial haemorrhage, notably the hereditary cerebral amyloid b. The presence of Alzheimer disease biology is confirmed by biomarkers (e.g. PET, CSF, amyloid ligands) or genetic studies (e.g. PS1 mutation); or c. A history of active cancer or psychiatric or metabolic disorders that may affect cognitive function. Unstable VaMCI Subjects with the diagnosis of probable or possible VaMCI whose symptoms revert to normal should be classified as having ‘unstable VaMCI’. VCI, vascular cognitive impairment; VaD, vascular dementia; MCI, mild cognitive impairment; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CT/​MRI, computed tomography/​magnetic resonance imaging; PET, positron emission tomography; CSF, cerebrospinal fluid; and VaMCI, vascular mild cognitive impairment. Reprinted with permission from Gorelick PB, et al. (2011). Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/​American Stroke Association. Stroke, 42, 2672–​713. Copyright © 2011, American Heart Association, Inc. Table 24.4.2.6  Continued 24.4.2  Alzheimer’s disease and other dementias 5855 angiopathies most, but not all, of which are due to mutations in the APP gene. Inflammatory vascular causes Cerebral vasculitis refers to inflammation of cerebral blood vessels, and can occur in the absence of systemic involvement—​so-​called primary cerebral vasculitis—​or secondary to one of the causes of systemic vasculitis. Primary cerebral vasculitis has two major causes. Cerebral amyloid angiopathy-​related inflammation occurs spontaneously in a small subset of patients with cerebral amyloid angiopathy, and has been observed in a proportion of patients with Alzheimer’s disease taking part in clinical trials of anti-amyloid immunotherapy. Patients present with subacute cognitive decline or behavioural changes, seizures, headache, and with white matter hyperintensities, oedema, and microbleeds on MRI; spontaneous remission or a response to immunosuppression (e.g. corticoster- oids) may be seen. Primary angiitis of the central nervous system is a rare sporadic inflammatory disorder of cerebral blood ves- sels which can present with a variety of clinical features including progressive dementia. The MRI is almost invariably abnormal showing infarction often with enhancement, and CSF examin- ation typically shows elevated protein and cell count. While an- cillary investigations including angiography may give important clues, brain biopsy may be required to obtain a definitive diagnosis. Treatment is with immune suppression, usually with corticoster- oids and cyclophosphamide. Subcortical dementias Despite shortcomings, the differentiation between cortical and sub- cortical dementias can be useful in clinical practice (Table 24.4.2.7). This classification highlights the fact that, although disease of diverse cerebral structures can result in dementia, the resultant patterns of cognitive deficits are typically different. Alzheimer’s disease is the prototypical cortical dementia; vascular syndromes can pre- sent with a spectrum of features from cortical to subcortical, as can the Lewy body spectrum of diseases. Purer forms of subcor- tical dementia result from pathology of the basal ganglia and its connections or white matter, the prototypical examples being Huntington’s disease and progressive supranuclear palsy. The typical cognitive pattern is that of attentional and executive dys- function with marked cognitive slowing (bradyphrenia), causing problems with mentation and information retrieval. Memory is moderately impaired due to reduced attention and poor regis- tration, but is not as severely impaired as in Alzheimer’s disease. Fig. 24.4.2.12  Imaging changes in vascular cognitive impairment. (a) Large vessel ischaemia—​FLAIR-​MRI shows right middle cerebral artery stroke; (b) Small subcortical infarction—​T1 volumetric MRI shows left thalamic infarct (arrow); (c) white matter hyperintenstities—​T2-​W MRI shows confluent white matter disease; (d) amyloid angiopathy—​susceptibility-​weighted MRI shows numerous microbleeds (peripheral black dots). SECTION 24  Neurological disorders 5856 There is often an associated personality change and mood dis- turbance with prominent apathy. Spontaneous speech is impov- erished and slow. Huntington’s disease Huntington’s disease is an autosomal dominant inherited disorder with an incidence of about 4–​10 per 100 000. The mutation is an expansion of the trinucleotide repeat in the IT-​15 gene on chromo- some 4, which encodes the polyglutamine protein, huntingtin. Mean age of onset is 40 years, but is related to the length of the tri- nucleotide repeat. Psychiatric symptoms, such as depression, irrit- ability, and personality changes, often precede the motor disorder, which is typically choreiform. Progressive cognitive changes, which can precede the motor features, are of a subcortical pat- tern, with deficits in attention and concentration, executive func- tion, and memory retrieval. Death is typically 15–​20 years after symptom onset. Progressive supranuclear palsy Progressive supranuclear palsy (PSP) is a rare, but increasingly rec- ognized disorder with an incidence of 5–​6 per 100 000. The motor deficits are symmetrical in onset, with severe rigidity in the axial muscle groups and bulbar symptoms. A supranuclear gaze palsy al- most invariably develops, but in the early stages may be absent, or the only feature may be slowing of fast vertical eye movement (sac- cadic slowing). Another common early feature is a marked tendency to (backwards) falls. While the cognitive symptoms are usually those of a subcortical dementia, as discussed earlier, it can present as a frontotemporal dementia, either with behavioural problems or a progressive non​fluent aphasia before the motor and other features become apparent. Pathologically, PSP is characterized by neuro- fibrillary tangles, neuropil threads containing four-​repeat tau, and neuronal loss and gliosis in the subthalamic nucleus, red and dentate nuclei, and substantia nigra. The main neurotransmitter deficit is in dopamine. Unlike Parkinson’s disease, PSP does not respond well to levodopa. The disease progresses rapidly with an average time course of around seven years. Corticobasal degeneration Corticobasal degeneration (CBD) is a rare cause of a dementia and motor signs. In its classical motor form, patients present with an asymmetrical akinetic rigid syndrome, together with limb apraxia, and the almost pathognomonic feature of alien limb phenom- enon in which the affected limb(s) acts as if ‘with a will of its own’. Myoclonus and dystonia also occur. While dementia was origin- ally an exclusion criterion, it is now recognized not only to be a common late feature, but that CBD can present with a large range of cognitive features including those of a frontotemporal dementia (behavioural or usually a progressive non​fluent aphasia) or a pos- terior cortical atrophy syndrome. In practice, where there is an overlap between cognitive symptoms and atypical parkinsonism, the term ‘corticobasal syndrome’ is preferred, reflecting the range of pathologies—​including CBD, PSP, Alzheimer’s disease, and other forms of frontotemporal lobar degeneration—​which can be difficult to distinguish during life. In common with PSP, CBD is a four-​repeat tauopathy, with the pathology focused in the frontal and parietal cortices as well as the substantia nigra, basal ganglia, and thalamus. Other important causes of dementia and cognitive impairment Hydrocephalus Hydrocephalus can present or be associated with a subcortical de- mentia with frontal features and psychomotor slowing. The gait dis- order is a dyspraxia and when asked to walk patients may appear ‘being stuck to the floor’, although there is an absence or paucity of signs when the patient is examined in the supine position. The condition may be secondary to a prior disturbance of CSF flow (re- sulting from, for example, head injury, meningitis, or subarachnoid haemorrhage), but often no cause is found in older people. The com- bination of idiopathic hydrocephalus, cognitive impairment, gait disturbance, and incontinence with ventricular enlargement dispro- portionate to the degree of cortical atrophy is often referred to as normal-​pressure hydrocephalus. While this remains a controversial entity, carefully selected cases where alternate diagnoses have been excluded may respond to neurosurgical CSF diversion. Chronic subdural haematomas This potentially treatable cause of dementia is usually caused by head trauma. It is common in individuals at risk of recur- rent head injuries from falls, such as older people, those with al- cohol problems, and people with epilepsy. Risk is also increased Table 24.4.2.7  Subcortical and cortical dementias Feature Cortical Subcortical Examples Alzheimer’s disease Parkinson’s and Huntington’s diseases Speed of mental processing Normal Slowed Memory Severely impaired Recognition and recall affected Forgetfulness Recognition better Language Aphasia common Normal Frontal ‘executive’ abilities Preserved in early stages Disproportionately impaired early in disease Visuospatial and perceptual abilities Impaired early Impaired late Personality Unconcerned Apathetic and inert Mood Usually normal Depression common 24.4.2  Alzheimer’s disease and other dementias 5857 by coagulation disorders, either pathological or iatrogenic. The clinical features are of a subacute dementia with fluctuating cog- nitive performance, focal neurological signs, and sometimes symptoms of raised intracranial pressure; diagnosis is confirmed by neuroimaging. The peripheral mass lesions may be of varying signal density on computed tomography (CT), depending on the age of the lesion(s). If the lesions are isodense with the brain tissue, the diagnosis can be easily overlooked. Treatment is by neurosur- gical evacuation, except in clinically insignificant collections. The outcome is variable, and in some cases patients have a recurrence that may require further drainage. Benign tumours Subfrontal meningiomas are the classic tumours that present with features of a frontal dementia. The onset is usually insidious with personality changes, apathy, cognitive slowing, and other frontal fea- tures. Besides the neuropsychological abnormalities there may be associated neurological signs, including anosmia, unilateral or bi- lateral visual failure, and optic atrophy. Other relatively benign mid- line tumours occasionally present with hydrocephalus and cognitive impairment secondary to this (e.g. colloid cysts of the third ventricle and non​secretory pituitary tumours). Metabolic and endocrine disorders Metabolic derangements typically give rise to acute/​subacute-​onset cognitive impairments, producing delirium rather than dementia. While rare at least in developed countries, chronic metabolic and endocrine disorders can cause or complicate a dementia syn- drome. Hypocalcaemia and recurrent hypoglycaemia can result in a dementia accompanied by ataxia and involuntary movements. Endocrine disorders including hypothyroidism, Addison’s disease, and hypopituitarism can present with dementia, with or without psychiatric features. The prominent complaints common to most disorders are mental slowing, apathy, and poor memory. Cushing’s disease can present with psychiatric features, although a dementia syndrome is rarer. Deficiency states Vitamin B12 deficiency can cause the classic picture of subacute combined degeneration of the spinal cord, and a dementia. The dementia can be variable in severity and it is unusual to present without some features of peripheral neurological disease, at least di- minished vibration sense in the lower limbs and/​or sensory ataxia. Although most patients have a macrocytic anaemia, neurological manifestations can occasionally occur in the absence of haemato- logical features. Severe thiamine (vitamin B1) deficiency results in the Wernicke–​Korsakoff syndrome, with delirium, ataxia, and oph- thalmoplegia. The most common causes are alcoholism and recur- rent prolonged vomiting, such as hyperemesis gravidarum. Prompt replacement is required as otherwise an irreversible chronic amnesic syndrome can develop. Infections Neurosyphilis, once a common cause of dementia, is now rare. The associated neurological features include pupillary abnormalities, optic atrophy, ataxia, and pyramidal signs. The diagnosis is con- firmed with serology and examination of CSF. Treatment with appro- priate antibiotics can result in some improvement. Those at increased risk are people inadequately treated for syphilis and those infected with the human immunodeficiency virus (HIV). HIV infection per se is a common cause of dementia in some parts of the world. HIV encephalopathy is characterized by psychomotor slowing, person- ality change, and other features of a subcortical dementia. However, it is now recognized that cognitive impairment is common even in HIV patients on retroviral therapies, and can have a much wider phenotype, now referred to as HIV-​associated neurocognitive syn- drome (HAND). (Fig. 24.4.2.13). Examination of the CSF may show a pleocytosis, increased protein, and oligoclonal bands. White matter changes are visible on neuroimaging. Not least as it is potentially treatable, the diagnosis—​which can be established through simple serological testing—​should be considered in all patients with young onset or atypical forms of dementia. Cognitive changes in patients with HIV may also be due to opportunistic infections such as cerebral toxoplasmosis and cryptococcal meningitis, and progressive multi- focal leucoencephalopathy, which all require specific treatment. Transient epileptic amnesia Frequent subclinical seizures affecting temporal lobe structures, so-​ called transient epileptiform amnesia, can cause memory impair- ments sufficient to be mistaken for a neurodegenerative dementia. Patients often report unusual symptoms including complete loss of memory for salient events such as holidays. Close questioning may HIV-associated neurocognitive disorders Mild cognitive impairment that does not interfere with activities of daily living Asymptomatic neurocognitive impairment Mild cognitive impairment that interferes with activities of daily living Mild neurocognitive disorder Marked cognitive impairment that produces marked interference with activities of daily living HIV-associated dementia Fig. 24.4.2.13  HIV-​associated neurocognitive disorders. Summary of the Frascati criteria for HIV-​associated neurocognitive disorder. Reprinted from The Lancet, 13(11), Nightingale S et al., Controversies in HIV-​associated neurocognitive disorders, 1139–​51. Copyright © 2014, with permission from Elsevier. SECTION 24  Neurological disorders 5858 elicit a history of prominent déja vu, episodes of abnormal smells or tastes, or staring episodes. The diagnosis may require prolonged electroencephalography recording and, when confirmed, causes of focal epilepsy should be excluded. Treatment with anticonvulsants typically improves symptoms but does not always result in complete recovery. Obstructive sleep apnoea Obstructive sleep apnoea is increasingly recognized as a cause of cognitive impairment, likely as a consequence both of day time somnolence and impaired attention, and impaired memory con- solidation during sleep. The diagnosis should be considered in the context of snoring and somnolence, and can be confirmed with a formal sleep study. Immune mediated disorders As well as the vasculitides discussed earlier, a range of other immune mediated disorders can cause cognitive impairment. Cognitive impairment and dementia are common sequelae of (usually advanced) multiple sclerosis. Other causes include systemic lupus erthythematosis, sarcoidosis, and Behçet’s syndrome. Paraneoplastic syndromes can produce often rapid onset cognitive impairment, and in particular a limbic encephalitis—​with features including amnesia, behavioural change, and seizures—​often with associ- ated limbic signal change and swelling on MRI. A variety of dif- ferent antibodies are associated with testicular, ovarian, and lung tumours; other manifestation may include eye movement abnor- malities, neuropathy, and cerebellar ataxia. Antibodies directed against the NMDA receptor cause an autoimmune encephalitis often accompanied by a hyperkinetic movement disorder. NMDA encephalitis may occur in the context of an ovarian teratoma or without an identifiable tumour, and often respond to tumour re- moval (where present) and/or immune suppression. Antibodies directed against components of the voltage-​gated potassium channel (Lgi1 and CASPR2) are an important cause of usually non-​ paraneoplastic limbic encephalitis in the middle-​aged and elderly. Presentation can be with brief jerks of the arm and face (faciobrachial dystonic seizures) that can mimic prion disease. There is typically a subacute onset of memory impairment, seizures, and personality change, sometime accompanied by hyponatraemia. While some cases may be self-​limiting or mild, prompt immune suppression can prevent the development of irreversible atrophy and cognitive impairment. FURTHER READING Albert MS, et al. (2011). The diagnosis of mild cognitive impairment due to Alzheimer’s disease:  recommendations from the National Institute on Aging–​Alzheimer’s Association workgroups on diag- nostic guidelines for Alzheimer’s disease. Alzheimers Dement, 7, 270–​9. American Psychiatric Association (1994). Diagnostic and statis- tical manual of mental disorders, 4th edition (DSM-​IV). American Psychiatric Association, Washington, DC. Armstrong MJ, et al. (2013). Criteria for the diagnosis of corticobasal degeneration. Neurology, 80, 496–​503. Bang J, et al. (2015). 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Royal College of Physicians of London, London. 24.5.2  Narcolepsy Matthew C. Walker ESSENTIALS Narcolepsy with cataplexy is a specific syndrome of daytime sleepi- ness, disrupted nocturnal sleep, and episodes of sudden loss of muscle tone—​provoked by the anticipation of emotions (particu- larly laughter)—​leading to a tendency to fall, mouth opening, dys- arthria or mutism, and facial muscle jerking. It is associated with loss of hypocretin (orexin) neurons in the hypothalamus, hypocretin concentrations in the cerebrospinal fluid below 110 pg/ml, and the human leukocyte antigen genotype DQ B10602. A less common form of narcolepsy without cataplexy probably has a different, as yet unknown, pathogenesis. Once established, narcolepsy is lifelong; spontaneous recovery does not occur. Symptomatic treat- ment—​which is essential for school performance, work, driving ability, and quality of life—​is with stimulant (e.g. amphetamine) and anticataplectic (e.g. clomipramine) drugs. More recently, sodium oxybate, an anaesthetic, has been used to induce deep sleep over- night, resulting in improvements in all symptoms. Introduction Narcolepsy has been recognized as a distinct condition since the latter part of the 19th century, when the term narcolepsy was first used by Gélineau, and it was clearly distinguished from epilepsy and psychogenic conditions. However, there continue to be substantial delays in diagnosis through a failure to recog- nize its archetypical symptoms. The condition is characterized by dysregulation of the normal sleep-​wake cycle with disrupted nocturnal sleep, daytime sleep attacks, and intrusion of rapid eye movement sleep (REM sleep—​the main ‘dream’ sleep) phe- nomena into wakefulness. Aetiology • Narcolepsy in humans is most likely an autoimmune condi- tion that occurs in people with an underlying genetically deter- mined propensity exposed to an environmental trigger (e.g. an infection). Narcolepsy is rarely familial in humans, with a clear Mendelian pattern of inheritance occurring in fewer than 5% of all those af- fected. However, there is evidence that genetic factors do play an important role in aetiology. The lifetime risk for developing nar- colepsy is increased in first-​degree relatives of people with narco- lepsy by 10–​20-​fold and monozygotic twin studies also report high concordance rates of c.30%. There is also a very strong association with the human leukocyte antigen (HLA) haplotype. The strongest association is with the HLA-​DQB10602 allele that is present in 95% of patients with narcolepsy with cataplexy, and 40% of pa- tients with narcolepsy without cataplexy compared to c.25% of the general population. Our current understanding is that, in most cases, genetic back- ground strongly influences the risk of developing narcolepsy but that environmental factors trigger the condition. About half the patients with narcolepsy recall a major event, usually trauma, infection, stress, or change in sleep pattern preceding the devel- opment of the condition, but this is confounded by recall bias. Nevertheless, there is increasing evidence that there can be an in- fectious trigger. There is an association of narcolepsy with high titres of antistreptolysin O antibodies and with H1N1 influenza infection and vaccination. In rare instances, narcolepsy has been associated with lesions af- fecting the posterior hypothalamus, including those due to tumours, strokes, encephalitis, multiple sclerosis, and neurodegenerative dis- eases. Narcolepsy-​type symptoms can develop with rare inherited conditions such as Niemann–​Pick type C disease, Norrie disease, Möbius syndrome, and Prader–​Willi syndrome. 24.5.2  Narcolepsy 5883 Epidemiology • Narcolepsy is a rare condition that can occur at any age but usu- ally occurs in adolescence. Most people with narcolepsy have cataplexy. Narcolepsy has a prevalence of 25–​50/​10 000. The prevalence is substantially lower in Israel and substantially higher in Japan. Its overall incidence has been estimated at 0.74 per 100 000 person-​ years. There is a seasonal variation in the incidence of narcolepsy, with highest incidence in spring and lowest incidence in winter. It can develop at any age, but the peak onset is at 15 years and then a second, smaller peak at 36 years; approximately half the patients have an onset prior to 18 years (Fig. 24.5.2.1). However, there is a mean delay to diagnosis of up to 15 years. Approximately 70% of people with narcolepsy have cataplexy. Pathogenesis/​Pathology • Narcolepsy with cataplexy is associated with loss of hypocretin secreting neurons from the hypothalamus. Narcolepsy without cataplexy is likely to have multiple pathophysiologies. Narcolepsy with and without cataplexy are likely to have different pathophysiologies. Narcolepsy with cataplexy is associated with abnormalities of the hypocretin (orexin) neurotransmitter system. This system is critical for regulating sleep but also plays a part in regulating appetite and metabolism. In dogs, but not in humans, mutations in the hypocretin receptor have been found. However, low or undetectable levels of cerebrospinal fluid hypocretin are found in most patients with narcolepsy with cataplexy. In con- trast, narcolepsy without cataplexy is associated with low-​normal hypocretin levels. Post-​mortem studies have revealed that there is a reduction in the number of neurons that produce hypocretin in people with narcolepsy with cataplexy (Fig. 24.5.2.1). Together with the observation of a likely autoimmune aetiology and the strong association with HLA type, the present hypothesis is that in most cases, narcolepsy results from autoimmune destruction of hypocretin secreting neurons. In very rare instances (fewer than 5%), narcolepsy may be associated with a genetic abnor- mality affecting hypocretin secretion or its receptors, and in some neurodegenerative conditions the hypocretin neurons seem to be particularly susceptible. The precise mechanisms underlying narcolepsy without cata- plexy (30% of all people with narcolepsy) are unclear, and there might be a range of pathophysiologies. Clinical features • The clinical features of narcolepsy are: excessive daytime somno- lence with sleep attacks, daytime microsleeps (automatic behav- iours), poor and disturbed night-​time sleep, and dysregulation of REM sleep phenomena including cataplexy, hypnic hallucin- ations, and sleep paralysis (Table 24.5.2.1). Fig. 24.5.2.1  Distribution of hypocretin cells in perifornical and dorsomedial hypothalamic regions of normal (a, c, e, g) and narcoleptic (b, d, f, h) humans. Calibration bar. = 100 μm in C&D, otherwise calibration bar = 25 μm. Reprinted from Thannickal TC et al. (2000). Reduced number of hypocretin neurons in human narcolepsy. Neuron 27(3), 469–​74, copyright © 2000, with permission from Elsevier. Table 24.5.2.1  Symptoms of narcolepsy Symptom Narcolepsy with cataplexy Other hypersomnolent patients(variety of causes) Normal population Sleep paralysis 50% 20% 5% Hallucinations 70% 30% 10% Automatic behaviours 50% 20% 0% Disrupted sleep 70% 70% 25% Violent behaviour in sleep 30% 10% 0% After Sturzenegger C, Bassetti CL. The clinical spectrum of narcolepsy with cataplexy: a reappraisal. J Sleep Res 2004;13:395–​406. section 24  Neurological disorders 5884 Dysregulation of sleep The main symptom is irresistible sleep attacks during the day, which can occur at inappropriate times (such as during meals or while speaking to people), but usually occur in situations that can make us all sleepy (e.g. car journeys, after lunch, watching television). These sleep attacks usually last seconds up to 20 minutes and result in relief of the feeling of sleepiness. People usually have vivid dreams during these sleep periods and occasionally muddle the dreams with reality (e.g. it is not unusual to believe that there is an intruder in the house). In addition to these naps, people with narcolepsy frequently have microsleeps, in which they may ‘sleep’ for a matter of seconds, re- sulting in short periods of automatic behaviour during daytime, during which people may carry out inappropriate or absent-​minded actions (e.g. putting socks in the fridge) or writing/​typing nonsense. Microsleeps have been misdiagnosed as absence seizures, but differ clinically in that absences are associated with complete loss of aware- ness and motor arrest. Also, as part of the sleep dysregulation, people with narcolepsy sleep poorly at night, waking frequently. In addition, there is a strong association between narcolepsy and other conditions that can dis- rupt nocturnal sleep, including obstructive sleep apnoea, periodic limb movement of sleep, night terrors/​sleep walking (non-​REM sleep parasomnia), and dream enactment (REM sleep behavioural disorder). Dysregulation of REM sleep phenomena These consist of cataplexy, sleep paralysis, and hypnic (hypnogogic/​ hypnopompic) hallucinations. The latter two symptoms are not un- common in the general population. Cataplexy is almost pathognomonic for narcolepsy and describes episodes of muscle weakness or paralysis. Cataplexy is precipitated by strong emotion, such as laughter, anger, or surprise, but not by fear. This is an example of REM sleep phenomena intruding into wakefulness, as usually REM sleep at night is accompanied by muscle paralysis (excluding respiratory muscles) in order to prevent dream enactment. Cataplexy ranges in severity. Its less severe form is characterized by transient drooping of eyelids, head nodding, fa- cial jerking, and slurred speech. However, cataplexy may be severe enough to lead to complete collapse. Cataplexy needs to be distin- guished from the physiological ‘feeling weak at the knees’ that can occur in anyone with anxiety or laughter. Usually cataplectic attacks occur sufficiently slowly, so that people can avoid injury. The epi- sodes are brief, lasting for seconds or minutes, but they may be fol- lowed by a sleep episode or occur recurrently (especially following sudden medication withdrawal). Cataplexy is present in over 70% of people who have narcolepsy and can predate (in c.5%) or, more commonly, follow the onset of other symptoms. Hypnogogic/​hypnopompic hallucinations are brief vivid dream-​ like episodes that occur at sleep onset or immediately before waking respectively, and are often frightening or disturbing in na- ture, and can be muddled with reality. They can also occur during daytime naps. Sleep paralysis is the inability to move on waking from sleep. The episode can last from a few seconds to minutes, but respiratory muscles are unaffected. It is caused by the persistence of REM sleep loss of muscle tone on waking. Sleep paralysis is often associated with hallucinations; usually frightening hallucinations of someone pressing on the chest or choking the person. In addition to the aforementioned symptoms, people with narco- lepsy have increased body mass index (BMI) that may relate to lower metabolic rates. Differential diagnosis Daytime sleepiness can result from anything that disturbs or dis- rupts nocturnal sleep. Commonly this is either behavioural (i.e. people who just do not sleep enough at night) or due to obstructive sleep apnoea or restless leg syndrome/​periodic limb movements of sleep (however, these conditions are more common in people with narcolepsy). Usually these conditions result in sleep attacks that are different during the day, such that they are longer, unrefreshing, lack dream sleep, and tend to occur later in the day. Idiopathic hypersomnolence is a rarer condition characterized by normal or excessive nocturnal sleep and then sleep attacks during the day that tend to be longer than those in narcolepsy and not usually associ- ated with dreaming—​this condition may need to be differentiated by polysomnography/​multiple sleep latency tests (see next). Lastly, psychogenic ‘cataplexy’ has been described and usually lacks the specific involvement of head and facial muscles early in the attack and presents as sudden collapses. In cases where there is diagnostic doubt, a cerebrospinal fluid hypocretin level can be helpful. Clinical investigations Diagnosis is predominantly clinical with people having the typical constellation of symptoms (Table 24.5.2.1). Cataplexy is a specific symptom, but can be misdiagnosed. Polysomnography (monitoring sleep overnight) is important in excluding other causes of excessive daytime somnolence due to disturbances of night-​time sleep. People with narcolepsy typically have early onset sleep (<10 minutes) and early onset REM sleep (<20 minutes). A further test to confirm the diagnosis of narcolepsy is the multiple sleep latency test (MSLT). During this test the patient is allowed to fall asleep 4–​5 times at 2-​ hourly intervals throughout the day and the latency to onset of sleep and REM sleep is measured. Occasionally HLA typing can also be helpful. There is a strong correlation between narcolepsy (with cataplexy) and the HLA HLA-​DQB1*06:02 variant, but this subtype is common in the gen- eral population (see earlier) and therefore the positive predictive value is low. Measurement of cerebrospinal fluid hypocretin levels is useful to confirm the diagnosis of narcolepsy with cataplexy when there may be some question about the cataplexy (i.e. uncertainty when that symptom is present). A low cerebrospinal fluid hypocretin is the test with the highest specificity (almost 100%) but is not uni- versally present (especially in people without cataplexy), but is now used to define the narcolepsy type (Table 24.5.2.2). Treatment At present, there is no cure for narcolepsy and treatment is there- fore symptomatic (Table 24.5.2.3). 24.5.2  Narcolepsy 5885 General management Regular nocturnal sleep habits and attention to sleep hygiene help to minimize daytime somnolence, and one to two planned naps (especially in the afternoon) can be used to optimize daytime performance. Sleepiness Excessive daytime sleepiness is reduced by amphetamine-​like stimulants (usually dexamfetamine or methylphenidate), and modafinil (and the R-​enantomer, armodafinil). These drugs have very different kinetics, requiring different dosing regimens (Table 24.5.2.3). The use of modafinil is supported by randomized con- trolled trials. Armodafinil may offer some pharmacokinetic ad- vantages over modafinil. Advantages of amphetamine-​like drugs include long experience, low cost, a possible action against cata- plexy and higher efficacy; modafinil has the advantage that toler- ance does not develop (which can occur with amphetamines) and a lower rate of side effects. Common side effects of amphetamine-​ like drugs include irritability and insomnia while modafinil may cause headache, nausea, and rhinitis, and can interact with the oral contraceptive pill. In addition, amphetamines, methylphenidate, and modafinil may cause cardiac arrhythmias and increased blood pressure. Amphetamines are not recommended during pregnancy and the safety of modafinil during pregnancy is unclear. Recently, pitolisant, a histamine H3-receptor inverse agonist, which in- creases histamine release, has been licensed for use in narcolepsy with or without cataplexy. Its stimulant properties are similar to modafinil but it possibly lacks the cardiovascular side-effects. It interacts with the contraceptive pill. However, another advantage is that it has anticataplectic effects. Other stimulants are being developed and are in clinical trials. Overall, approximately 80% have moderate to marked improvement with treatment. Cataplexy Cataplexy can be treated with tricyclic antidepressants (clomipramine) and the selective serotonin uptake inhibitors (flu- oxetine). Other antidepressants, such as venlafaxine, can also be useful. These have not been subjected to randomized control trials. These drugs also treat other narcolepsy symptoms (such as sleep paralysis and hypnic hallucinations). These drugs can result in cardiac side effects, dry mouth, constipation, gastrointestinal upset, low sex drive, and agitation. Selegiline can also be used to treat the cataplexy and excessive daytime sleep, probably because of its central amphetamine-​like effect. More recently, sodium oxybate has been shown in randomized control trials to be effective in cata- plexy and also improves daytime somnolence (and other symptoms Table 24.5.2.2  Narcolepsy classification in the International Classification of Sleep Disorders-​3 (ICSD-​3) Narcolepsy type 1 (with hypocretin deficiency)—​both of the following criteria must be met: The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep, occurring for at least 3 months. The presence of one or both of the following: a) Cataplexy and a mean sleep latency of at most 8 minutes and 2 or more sleep onset rapid eye movement periods (SOREMPs) on a multiple sleep latency test (MSLT) performed according to standard techniques. A SOREMP on the preceding nocturnal polsomnography (i.e. rapid eye movement sleep onset within 15 minutes of sleep onset) may replace one of the SOREMPs on the MSLT. b) Cerebrospinal fluid hypocretin-​1 concentration, measured by immunoreactivity, is either up to 110 picograms/​ml or <1/​3 of mean values obtained in normal subjects with the same standardized assay. Narcolepsy type 2 (without hypocretin deficiency)—​all 5 of the following criteria must be met: The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months. A mean sleep latency of ≤8 minutes and 2 or more sleep onset REM periods (SOREMPs) on a MSLT performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal polysomnography may replace one of the SOREMPs on the MSLT. Cataplexy is absent. Either cerebrospinal fluid hypocretin-​1 concentration has not been measured or cerebrospinal fluid hypocretin-​1 concentration measured by immunoreactivity is >110 picograms/​mL or >1/​3 of mean values obtained in normal subjects with the same standardized assay. The hypersomnolence and/​or MSLT findings are not better explained by other causes such as insufficient sleep, obstructive sleep apnoea, delayed sleep phase disorder, or the effect of medication or substances or their withdrawal. American Academy of Sleep Medicine. Table 24.5.2.3  Pharmacological treatment for narcolepsy Drug Indication Dose/​24 hr Comments Oxybate EDS and cataplexy 4.5–​9 g Given as divided doses at night (second dose is given 2.5–​4 hours after first). Pitolisant EDS and cataplexy 4.5–36 mg Given as a single dose. Interaction with oral contraceptive. Dexamfetamine EDS (cataplexy) 5–​60 mg Half-​life of about 10 hours. Often needs to be given 2–​3 times per day. Methylphenidate EDS (cataplexy) 5–​80 mg Very short half-​life (2–​4 hours) but it is available as a slow release formulation. Modafinil EDS 200–​400 mg Half-​life 12–​18 hours. Can be given once or twice a day. Interaction with oral contraceptive. Clomipramine Cataplexy 10–​150 mg Often best given at night. Avoid sudden withdrawal. Fluoxetine Cataplexy 20–​60 mg Best given in morning. Avoid sudden withdrawal. Venlafaxine Cataplexy 75–​375 mg Often used in refractory cataplexy. Avoid sudden withdrawal. EDS, excessive daytime somnolence. 24.5.3 Sleep disorders 5886 Paul J. Reading 24.5.3 Sleep disorders 5886 Paul J. Reading section 24  Neurological disorders 5886 of narcolepsy). This is taken at night and acts as an anaesthetic, resulting in very deep sleep. Side effects include bed wetting and nausea, and, due to the large salt load, hypertension. Prognosis Narcolepsy is a lifelong condition. However, it may evolve over the first few years, and there can be a delay from the onset of sleepi- ness to the occurrence of cataplexy. The cataplectic symptoms may become less prominent over the years as people are better able to control them. The sleepiness (independent of treatment) tends to remain unchanged but can deteriorate in late adulthood because of the occurrence of other sleep disorders (in particular, obstructive sleep apnoea). Morbidities and mortality Narcolepsy has a considerable impact on quality of life, despite therapy, and this is age dependent. At all ages excessive daytime somnolence can affect concentration and memory (e.g. working memory). Children with narcolepsy can have educational dif- ficulties, decreased general well-​being, and poorer self-​image. Adolescents with narcolepsy report fewer relationships with friend and fewer leisure activities than others their age. Adults with narco- lepsy can have problems with employment and driving. Both chil- dren and adults commonly suffer from depression. People with narcolepsy have a standardized mortality rate that is about 1.5 that of the general population. In addition, people with narcolepsy (perhaps due to higher body mass index) have in- creased rates of diabetes, obesity, back pain, and obstructive sleep apnoea. Future developments The increased understanding of the pathogenesis of narcolepsy and the regulation of sleep are likely to lead to future therapies. Drugs, gene therapies or cell therapies that target the hypocretin system would seem to be approaches that are most promising in order to develop a cure. A less ambitious aim, to improve present therapies, may be achieved through drugs that act on specific neurotrans- mitter systems (eg histaminergic system) or through understanding the mechanisms by which sodium oxybate works (GABA(B) and γ-hydroxybutyrate receptor systems). Lastly, immunotherapy has received mixed reports. Failure of immunomodulatory therapies may be due to late diagnosis, emphasizing the need for tests that may enable early diagnosis and perhaps more effective disease modifying treatment. FURTHER READING Billiard M, et al.; EFNS Task Force (2006). EFNS guidelines on man- agement of narcolepsy. Eur J Neurol, 13, 1035–​48. Dauvilliers Y, Arnulf I, Mignot E (2007). Narcolepsy with cataplexy. Lancet, 369, 499–​511. Liblau RS, Vassalli A, Seifinejad A, Tafti M (2015). Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy. Lancet Neurol, 14, 318–​28. Mahlios J, De la Herrán-​Arita AK, Mignot E (2013). The autoimmune basis of narcolepsy. Curr Opin Neurobiol, 23, 767–​73. Morgenthaler TI, et  al.; Standards of Practice Committee of the American Academy of Sleep Medicine (2007). Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep, 30, 1705–​11. Sturzenegger C, Bassetti CL (2004). The clinical spectrum of narco- lepsy with cataplexy: a reappraisal. J Sleep Res, 13, 395–​406. Thannickal TC, et al. (2000). Reduced number of hypocretin neurons in human narcolepsy. Neuron, 27, 469–​74. 24.5.3  Sleep disorders Paul J. Reading ESSENTIALS Dysfunctional sleep is an important cause of morbidity and is as- sociated with numerous long-​term health problems. Sleep-​related symptoms can loosely be divided into insomnias, disorders causing excessive daytime sleepiness, and parasomnias, with some condi- tions having elements of all three categories. Insomnia Chronic insomnia usually has a behavioural or psychological basis and responds best to cognitive or relaxation therapies, although secondary causes of insomnia such as restless legs syndrome may have specific therapies. Circadian rhythm disorders may also present as insomnia, and several neurological syndromes such as Parkinson’s disease are also associated with poor quality and fragmented sleep. Excessive daytime sleepiness This usually has a specific identifiable cause, with sleep fragmenta- tion or disruption due to sleep-​disordered breathing being the most common reason for severe cases (see Chapter 18.5.2). However, at least 2% of excessively sleepy subjects will have a primary sleep dis- order such as narcolepsy. Narcolepsy can be considered a primary disorder of sleep–​wake regulation. An inability to stay awake for more than a few hours is usually the most obvious symptom, often in association with cata- plexy, sleep paralysis, and hallucinations. Disturbed nocturnal sleep and a variety of parasomnias are also common (see Chapter 24.5.2). Parasomnias Non​rapid eye movement sleep parasomnias—​these are very common in children and rarely require investigation or treatment. Sleepwalking, confusional arousals, and night terrors occurring within 90 min of sleep form a spectrum of conditions reflecting ab- normal arousals from the deepest stages of sleep. Not infrequently, the phenomenon persists into adulthood and may sometimes 24.5.3  Sleep disorders 5887 require short courses of hypnotic agents or sedative antidepressant therapy to suppress the nocturnal disturbances. Parasomnias arising from rapid eye movement sleep—​these are most common in middle-​aged men and may be a harbinger of a neurodegenerative syndrome such as Parkinson’s disease. Rapid eye movement sleep behaviour disorder occurs when the mechanism to paralyse voluntary muscles during dreams in rapid eye move- ment sleep fails, with the subsequent dream enactment some- times causing significant physical injury. Most patients respond to clonazepam although melatonin is increasingly used. Circadian rhythm disorders Circadian rhythm disorders—​these are increasingly recognized. Most arise from jet lag or shift work; a few reflect abnormalities of the intrinsic clock mechanisms, of which delayed sleep phase syn- drome is commonest, especially in adolescents, usually presenting with severe difficulties arising from bed for morning activities. Treatments are partially effective and include low-​dose melatonin taken mid-​evening and phototherapy given in the early morning. Introduction The need to sleep is imperative, reflecting the fact that sleepiness, similar to hunger and thirst, is a true drive state. Although its func- tion remains largely elusive, disordered sleep can be associated with profound adverse effects on cognition, mental health, and physical well-​being. Moreover, sleep-​related symptoms are very common, with 25% of people reporting problems that significantly and regu- larly impact on daily activities. Advances in our understanding of the neurobiology of sleep have challenged the traditional view that sleep is a passive or necessarily restful process. By contrast, rather than simply reflecting the absence of wakefulness, sleep is actively orchestrated, with a highly reprodu- cible and complex internal architecture. A typical pattern seen in a healthy adult is shown in Fig. 24.5.3.1. Episodes of rapid eye move- ment (REM) and non-​REM sleep recur through the night in four or five discrete cycles. It should be recognized that occasional arousals from nocturnal sleep are normal and that seemingly random body movements or shifts in position occur regularly throughout the night. In REM sleep episodes, however, despite high levels of cere- bral metabolic activity that loosely correspond to dream mentation, general motor activity is profoundly suppressed and any observable movements are confined to occasional minor jerks. Defining disordered sleep can be difficult: most classifications are now symptom based. The recently revised International Classification of Sleep Disorders (ICSD-​3—​see ‘Further reading’) recognizes seven categories: 1 Insomnias 2 Sleep-​related breathing disorders 3 Central disorders of hypersomnolence 4 Circadian rhythm sleep–​wake disorders 5 Parasomnias 6 Sleep-​related movement disorders 7 Isolated symptoms, normal variants, and unresolved issues Insomnia Chronic insomnia is loosely defined as the perception of inadequate sleep for more than three nights a week for a period of more than 3 months despite an adequate opportunity and desire to sleep. To fulfil the diagnostic criteria, there also needs to be a significant ad- verse effect on daily functioning as a result of poor sleep. The inability to fall asleep or maintain continuous sleep is a common symptom and has several extrinsic or secondary causes (Table 24.5.3.1). It is rare for organic cerebral pathology to underlie primary insomnia, and persistently maladaptive attitudes or behaviours are usually responsible. An index event or illness can often be identified. The common forms of primary insomnia are probably best treated by behavioural modification, including a combination of cognitive–​ behavioural therapy and relaxation techniques. The intermittent use of short-​acting hypnotics may be helpful, although long-​term drug treatment is rarely beneficial. If symptoms of inadequate sleep date back to childhood, the term ‘idiopathic insomnia’ is sometimes used. Although its neurobiology remains obscure, at some level this disorder probably reflects a con- stitutionally impaired sleep drive such that the normal homoeostatic pressure to sleep is inadequate. The interplay between psychological distress and chronic in- somnia is complex, with each element potentially fuelling the other. Psychiatric input to treat any significant mood disorder can there- fore be helpful in attempting to resolve sleep-​related symptoms. Hypersomnia Significant excessive daytime sleepiness is reported by 5% of the population and is most often due to poor quality or diminished overnight sleep (Table 24.5.3.2). It is important to distinguish true sleepiness or drowsiness from fatigue and lethargy, which often have 1 2 3 4 5 6 7 Time (hours through night) WAKING REM sleep NREM sleep stage I II III IV Typical hypnogram of young adult REM REM REM REM Fig. 24.5.3.1  A typical hypnogram of a young adult showing four cycles of non​rapid eye movement (non-​REM) and REM sleep. Two brief awakenings are shown that can be considered normal. The proportion of deep non-​REM sleep (stages III and IV) is highest in the first few hours of sleep whereas REM sleep predominates towards the end of the sleep period. section 24  Neurological disorders 5888 different causes. Within the abnormally sleepy population, approxi- mately 2% have a primary sleep disorder in which the most striking complaint is an inability to stay awake appropriately despite the desire to do so. Narcolepsy Introduction and clinical features Narcolepsy is not a rare disorder, with an estimated prevalence of 1 per 2000 in white populations. However, differences in case as- certainment and the availability of sleep services have led to con- siderable variance in reported rates worldwide. Moreover, there is undoubtedly a spectrum of severity and many mildly affected indi- viduals are either undiagnosed or diagnosed only after many years of symptoms. It most often starts in adolescence, with a second minor peak in early middle age. Symptoms are generally life-​long, although most people with the condition develop coping strategies to min- imize the impact of the syndrome. Narcolepsy is important, not least because it is usually disabling, influencing every aspect of daily living. Many people with narco- lepsy feel a sense of underachievement, partly because treatment is frequently either delayed or only partially effective. A perceived lack of medical interest in the disease, together with the adverse effects on schooling, careers, and relationships, understandably produces frustration. Secondary mood disorders are seen in many patients. Rather than reflecting true hypersomnolence over a 24-​hour period, narcolepsy is best viewed as a primary disorder of sleep–​wake Table 24.5.3.1  Some causes of primary and secondary insomnia Causes Comments Primary insomnia Intrinsic sleep disorders Psychophysiological insomnia Paradoxical insomnia Sometimes called ‘conditioned insomnia’, formerly called ‘sleep–​wake misperception’ Idiopathic insomnia History dates back to childhood Extrinsic sleep disorders Poor sleep hygiene Environmental sleep disorder Examples include sleep-​disordered bed partners or pets interfering with sleep; usually results in daytime sleepiness Altitude insomnia Mild hypoxaemia produces poor sleep because of unstable respiratory control overnight Drug-​dependent insomnia Hypnotics, stimulants, or alcohol may be responsible Secondary insomnia Neurological conditions Restless legs syndrome An important and treatable cause of insomnia Parkinson’s disease Sleep fragmentation can be an integral part of the condition Morvan’s syndrome A rare paraneoplastic or autoimmune syndrome with neuromuscular hyperexcitability and severe insomnia as cardinal features Fatal familial insomnia A very rare familial prion disease with significant thalamic pathology as the presumed substrate for severe insomnia Medical disorders Asthma Gastro-​oesophageal reflux An important and often overlooked diagnosis Chronic pain syndromes including fibromyalgia A high percentage of light non-​REM sleep is often seen Psychiatric causes Secondary to medication Mood disorders including anxiety, depression, and mania REM, rapid eye movement. Table 24.5.3.2  Some extrinsic and intrinsic causes of excessive daytime sleepiness Intrinsic causes Extrinsic causes Primary causes Sleep deprivation or insufficient sleep Narcolepsy Drug-​related hypersomnia Idiopathic hypersomnia Environmental sleep disorder Kleine–​Levin syndrome (intermittent sleepiness) Shift-​work sleep disorder Causes secondary to a chronic disorder Jet lag Sleep-​disordered breathing Restless legs syndrome and periodic limb movement disorder Multiple sclerosis Head injuries Encephalitis 24.5.3  Sleep disorders 5889 regulation (Fig. 24.5.3.2), with an inability to stay awake for more than a few hours as the most obvious symptom. Indeed, excessive daytime sleepiness not explained by another disorder remains an essential diagnostic criterion. Many patients describe sudden and irresistible urges to sleep, often in public or inappropriate situations, invariably worse if they are unoccupied or bored. In contrast to most other sleep disorders, short naps lasting minutes can often be re- storative. A few people with the condition are relatively unaffected by excessive daytime sleepiness and other features of the syndrome predominate. Cataplexy Cataplexy is a curious phenomenon, highly specific to narcolepsy and present to varying degrees in two-​thirds of patients. It is par- ticularly important to identify typical cataplexy because its pres- ence in a person with excessive daytime sleepiness is practically diagnostic of narcolepsy. Full-​blown episodes reflect an intrusion of profound muscle paralysis that descends over a few seconds from head to the lower limbs, often causing collapse to the floor. Identifiable triggers usually have an emotional content. Laughter or other positive emotions such as a pleasant surprise are the most common precipitants, although frustration and anger can also reli- ably provoke episodes. In some individuals the mere thought or an- ticipation of an emotional event can cause collapse. Reassuringly, attacks are rare in dangerous situations and most patients report cataplexy only when relatively relaxed in familiar environments with friends. It is therefore very uncommon for doctors to wit- ness episodes, making a reliable history crucial for confident diag- nosis. Importantly, partial or focal attacks are common and can be subtle, perhaps confined to the jaw or neck. Occasionally, an inability to tell the punchline of a joke due to a stuttering dys- arthria may be the only manifestation. Facial twitching or head bobbing is very common as an episode starts and can lead to diag- nostic confusion. Crucially, awareness is preserved in cataplexy, although in rare instances, when attacks last more than a mi- nute or so, dream-​like intrusions and altered consciousness may intercede. Severely affected individuals may have over 20 attacks a day, often reporting that the amusement or frustration induced by the cataplectic episodes themselves can prolong the period of weakness. It is widely thought that cataplexy occurs because REM sleep paralysis intrudes inappropriately into the wakeful state. Indeed, as in REM sleep, a person is rendered temporarily areflexic during an episode as a result of descending inhibitory neural impulses from lower brainstem centres directly on to motor neurons. Some evi- dence suggests that this phenomenon may occur to a minor degree during emotion in control individuals, adding credibility to the adage ‘going weak with laughter’. Sleep paralysis and hallucinations Sleep paralysis and hallucinations around sleep–​wake transition are the other two components of the narcoleptic ‘tetrad’ first described in 1957. However, only 25% of patients have all four elements, and the presence of these other symptoms, particularly sleep paralysis, is not specific to narcolepsy. Sleep paralysis is usually frightening, primarily because of an inability to take deep breaths voluntarily. Most episodes occur at the point of waking, although people with narcolepsy may also report episodes at sleep onset. Accompanying sensations of being crushed, with or without vivid visual hallucin- ations, may add to the distress of the episodes. Similar to cataplexy, this phenomenon reflects the intrusion of REM sleep elements into the wakeful or drowsy state. Hallucinations occurring at sleep onset (hypnagogic) or as the person wakes (hypnopompic) are usually visual and can be MT Control Sleep stage Untreated narcoleptic Sleep stage W REM 1 2 3/4 MT 18.00 20.00 22.00 24.00 02.00 04.00 06.00 REM sleep REM Sleep Time of day Time of day 08.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 02.00 04.00 06.00 08.00 10.00 12.00 14.00 16.00 W REM 1 2 3/4 Fig. 24.5.3.2  Comparisons of typical hypnograms over 24 h in a control person and someone with untreated narcolepsy. In the narcoleptic trace, there is severe disruption of the usual pattern with numerous daytime naps containing REM sleep. Overnight, the usual sleep architecture is disorganized in the person with narcolepsy with several awakenings and associated movement. MT, significant movements; W, wake. section 24  Neurological disorders 5890 both vivid and disturbing, especially in children. They repre- sent fragments of dream mentation intruding into the conscious state, reinforcing the notion that people with narcolepsy cannot adequately maintain a consistent and stable state of wakefulness or sleep. When questioned, most people with narcolepsy have frag- mented nocturnal sleep. Although this may be due to the intrusion of a parasomnia or obstructed breathing, both of which are more common in people with narcolepsy, the primary problem is one of sleep regulation and maintenance. The notion that people with narcolepsy have problems sleeping at night is counterintuitive to some but is an important addition to the original descriptions of the syndrome. Other symptoms In addition to obvious naps, most people with narcolepsy will experience numerous ‘micro-​sleeps’ through the day, in which awareness during activities is compromised for a few seconds. The resulting lapses lead to automatic and inappropriate behaviours, with worrying consequences for complex and potentially dan- gerous tasks such as driving. Although difficult to characterize, many people with narcolepsy also report significant problems with memory and concentration as a result of their sleep–​wake diffi- culties. Furthermore, increasing evidence suggests abnormalities of appetite, particularly at night, with cravings for sweet foods. Moderate obesity is more common in narcolepsy and may have a metabolic explanation because there is no link with excessive food intake. Indeed, some evidence suggests that overweight people with narcolepsy eat less than average. Pathogenesis and diagnosis Since the discovery in 1984 that Japanese people with narcolepsy were extremely likely to carry the human leucocyte antigen (HLA) haplotype DR2, an autoimmune basis for the syndrome has been thought likely. The predisposing antigen has since been established to be DQ-​B10602, which is present in over 90% of people with narcolepsy and cataplexy and around 50% of those without cata- plexy, compared with a frequency of 20% in control populations. Of interest, homozygosity for DQ-​B10602 appears to confer an even greater risk for the syndrome. Direct evidence for auto- immunity, in the form of either serum markers or cerebrospinal fluid (CSF) abnormalities, remains elusive and narcolepsy is rarely associated with other manifestations of autoimmunity. A minority of patients studied close to disease onset appear to have increased titres of specific immunoglobulins such as antistreptolysin O, al- though the significance of this remains uncertain. Further possible support for an autoimmune aetiology comes from the observation in Finland and Sweden that a significant surge in childhood cases appeared to associate temporally with vaccination against pan- demic H1N1 influenza. This association has also been observed in Ireland and the United Kingdom but not in other European coun- tries and case-​control studies will be needed to clarify the potential link. However, of interest, a threefold increase in narcolepsy was reported in China in 2009 following the H1N1 pandemic in the absence of a significant vaccination programme. This may imply that any non​specific activation of the immune system may confer an increased risk of narcolepsy, potentially in those with a predis- position for the disease. A major breakthrough in understanding the neurobiology of narcolepsy occurred in 1999 when two groups independently demonstrated abnormalities of a recently described neuropep- tide, hypocretin (also called orexin), in separate animal models. The well-​established autosomal recessive Doberman model was shown to have dysfunctional hypocretin receptors, whereas a mouse hypocretin knockout model developed convincing clinical features of narcolepsy with cataplexy. Subsequently, it has been demon- strated that CSF hypocretin is virtually absent both in sporadic ca- nine models and in people with narcolepsy and cataplexy. Indeed, a CSF hypocretin level of less than 110 pg/​ml is now considered diagnostic. Postmortem evidence has confirmed that pathology in narcoleptic brains is confined specifically to hypocretin neurons, potentially supporting the theory that they are destroyed by an auto- immune process. Confusingly, however, in rare familial narcolepsy and in sporadic cases without typical cataplexy, hypocretin levels can be preserved, implying that there is more than one pathogenic mechanism for certain forms of the syndrome. Following the unexpected involvement of the hypocretin system in human narcolepsy, it has been intensely studied in intact animals. Around 30 000 neurons containing the peptide are confined to the lateral hypothalamus but innervate all the arousal systems in the brain. Levels of hypocretin rise towards the end of the waking day, especially in the presence of peptide hunger signals or if the person is expecting food. Activity of hypocretin neurons therefore appears to stabilize a state of wakefulness when the organism needs to be alert. In narcolepsy their absence leads to inappropriate switches be- tween sleep and wakefulness. Moreover, transitions between behav- ioural states may be incomplete, explaining the intrusion of REM sleep phenomena such as paralysis into wakefulness. The mech- anism by which emotional stimuli (in particular) trigger cataplexy remains elusive. However, recent evidence from functional brain imaging techniques suggests that narcoleptic patients may have ab- normal processing of emotional information. If typical cataplexy is absent and CSF hypocretin levels cannot easily be measured, a positive diagnosis of narcolepsy can be made following a multiple sleep latency test. This test measures the pro- pensity for a person to fall asleep by recording the average length of time to reach light sleep in a conducive environment over four or five nap opportunities between 9.00 am and 3.00 pm. If the mean sleep latency is less than 8 min and REM sleep is achieved within 15 min on at least two occasions, the criteria for narcolepsy are fulfilled. Reliable results depend on ensuring a reasonable night’s sleep pre- ceding the investigation, and the test also requires a strict protocol to avoid false-​negative results. Secondary narcolepsy Narcoleptic symptoms including cataplexy have been reported in other neurological conditions. Given the recent advances in the understanding the neurobiology of the primary syndrome, it is not surprising that pathology in the region of the hypothalamus such as tumours around the third ventricle can lead to secondary narco- lepsy, presumably by depletion of hypocretin-​containing neurons. However, the mechanism of severe sleepiness or sleep–​wake dysregulation after head injury or as components of other condi- tions such as multiple sclerosis and Parkinson’s disease can be diffi- cult to explain. The various subtypes of narcolepsy are shown in Table 24.5.3.3. 24.5.3  Sleep disorders 5891 Treatment Advice on lifestyle helps some people with narcolepsy. Planned naps, especially after meals, may improve wakefulness. Furthermore, the avoidance of large meals rich in refined carbohydrates is re- portedly beneficial to some. Most people with narcolepsy, how- ever, benefit from medication to improve daytime wakefulness (Table 24.5.3.4), although few are normalized. Modafinil is the most widely used wake-​promoting agent and has partly replaced traditional psychostimulants. Its mechanism of action remains ob- scure, but a direct effect on arousal centres in the hypothalamus is postulated. It has no definite positive effect on cataplexy. Side effects are rare and include headache or gastrointestinal upset. Interactions with the oral contraceptive pill and uncertainty over safety in pregnancy may limit its use in young women. In severe sleepiness or if modafinil is unsuccessful, central stimulants with a predominantly dopaminergic action, such as dexamfetamine, are helpful, especially if used flexibly. Despite pre- scriber concerns, it is rare for psychological addiction to occur in narcolepsy, although tolerance may require increasing doses with time. Cardiovascular side effects such as hypertension are rela- tively rare but necessitate caution in older people. Given the dif- ferent mechanisms of action, a combination of modafinil and a psychostimulant is appropriate. Additional use of caffeine and setting aside time for planned naps may reduce the need for medication. A further drug with a novel mode of action is also being used in patients who fail to respond adequately or who are intolerant to es- tablished wake-​promoting treatments. Pitolisant appears to act as an inverse histamine (H3) receptor agonist and effectively increases histamine release from the posterior hypothalamus to increase alertness. About a half of people with narcolepsy also require specific treatment for cataplexy. Although the evidence base is small, most antidepressants will suppress cataplexy by increasing cerebral monoaminergic activity and inhibiting the tendency to enter REM sleep, although the side-​effect profile of most antidepressant drugs, Table 24.5.3.3  Subtypes of narcolepsy and associated features Narcolepsy with cataplexy (sporadic) (%) Narcolepsy without cataplexy (sporadic) (%) Familial narcolepsy (%) Secondary (symptomatic) narcolepsy (%) REM sleep reached within 15 min on two or more occasions in MSLT 85 100% (by definition) Uncertain 75 HLA DQ-​B1*0602 positivity 85–​93 35–​56 65–​79 Uncertain Presence of low or undetectable CSF Hcrt-​1 levels 90 14 38 Variable Reported instances of very low levels in individual cases Proposed or presumed pathogenesis Autoimmune destruction of Hcrt-​synthesizing neurons Partial Hcrt deficiency Multiple genotypes Damage to Hcrt-​containing neurons in the lateral hypothalamus Unknown mechanism in many Hcrt system very rarely involved directly CSF, cerebrospinal fluid; HLA, human leucocyte antigen; Hcrt-​1, hypocretin-​1; MSLT, multiple sleep latency test; REM, rapid eye movement. Table 24.5.3.4  Commonly used drug treatments for the narcoleptic syndrome Drug Total 24-​h dose range (mg) Comments Excessive daytime sleepiness Modafinil 200–​600 Different mechanism of action to traditional psychostimulants Dexamfetamine 5–​60 Tolerance can develop but dependence rare Methylphenidate 10–​80 Similar to amphetamine but possibly smoother action; long-​acting preparation available Sodium oxybate 4.5–​9 g Taken through the night; may act synergistically with daytime stimulants Pitolisant 20–​40 A novel mode of action that produces increased histamine levels in the hypothalamus Cataplexy Venlafaxine 75–​225 Possibly the antidepressant with most anticataplectic properties Clomipramine 10–​150 Potent but side effects often limit use Fluoxetine 20–​40 Appropriate for mild cataplexy; few side effects Sodium oxybate 4.5–​9 g Taken at night; up to 90% of attacks may be abolished after 4 weeks of treatment Disturbed nocturnal sleep Clonazepam 0.5–​2 Sleep continuity improved but sleep quality not usually refreshing; intermittent rather than continuous use advisable Sodium oxybate 4.5–​9 g Deep non-​REM sleep increased; overall sleep quality improved REM, rapid eye movement. section 24  Neurological disorders 5892 particularly the tricyclics, may limit their usefulness. A  new ap- proach for troublesome cataplexy is to use sodium oxybate, and trial evidence suggests that this drug helps daytime sleepiness as well. It is a liquid preparation taken before bed and—​due to its short half-​ life—​once during the night if the person is awake. The effects on cataplexy are striking after several weeks of therapy, with almost 90% of attacks abolished. Inadvertent daytime naps, and objective and subjective measures of daytime sleepiness also improve. The agent appears to work, in part, by inducing deep restorative sleep early in the night, such that the sleep drive is effectively dissipated by the fol- lowing morning. The drug should be used with extreme caution in any patient living alone or with young children in case confusional episodes from deep sleep are provoked. However, if disturbed noc- turnal sleep is a major symptom, it appears a logical treatment given that standard benzodiazepine hypnotic agents rarely induce re- freshing sleep in narcolepsy. Following the recent findings that most people with narcolepsy are deficient in the neuropeptide hypocretin, an obvious therapeutic goal will be to develop replacement therapy. There appear to be clin- ical effects if hypocretin levels are increased in animal models by intracerebral infusion, hence the development of an oral analogue that penetrates the blood–​brain barrier is a current pharmacological goal for treatment in humans. In line with the theory that narcolepsy may have an autoimmune basis, several small open trials have examined various forms of immunomodulation in treatment, especially if it is diagnosed near disease onset. However, results have generally been disappointing and it is thought placebo effects on cataplexy, for example, may have been substantial. Idiopathic hypersomnia Idiopathic hypersomnia is a diagnosis of exclusion most often made when excessively sleepy patients do not completely fulfil the diag- nostic criteria for narcolepsy. Depending on precise definitions, it is probably 10 times less common than narcolepsy. Classic cases report difficulty waking in the morning followed by prolonged unrefreshing daytime naps despite long and deep nocturnal sleep. Low mood and frequent automatic behaviours are commonly re- ported. However, no specific narcoleptic features such as cataplexy are present, and CSF hypocretin levels are generally normal. Sleep investigations should confirm a shortened daytime sleep latency of less than 8 min, preceded by normal but prolonged nocturnal sleep. A  new category of idiopathic hypersomnia without pro- longed overnight sleep has been proposed, but this is controversial and distinction from atypical or monosymptomatic narcolepsy can be difficult. As in narcolepsy, although usually with less satisfactory results, the treatment of idiopathic hypersomnia consists of modafinil alone or in combination with traditional psychostimulants. Some prelim- inary evidence suggests that flumazenil, given orally, may benefit some patients. This finding is of great interest given the demonstra- tion of an endogenous benzodiazepine-​like substance in the cere- brospinal fluid of some patients. Kleine–​Levin syndrome Kleine–​Levin syndrome is a rare and poorly characterized sleep disorder most commonly seen in adolescents. The primary feature is periodic hypersomnia lasting days to weeks, recurring at inter- vals of weeks to months. During symptomatic periods the person is generally drowsy and usually displays abnormal behaviours. These include simple irritability, hallucinations, hypersexuality, and ab- normal appetite, producing hyperphagia. Investigations are gener- ally unhelpful, although an excess of REM sleep is occasionally seen during episodes. Intermittent hypothalamic dysfunction is a specu- lative but plausible mechanism to explain the symptom complex. Secondary causes are very rare and reportedly include a wide variety of neurological conditions, such as multiple sclerosis and Prader–​ Willi syndrome. Treatments are empirical and usually ineffective, although the syndrome tends to resolve spontaneously after several years. An amphetamine may help during episodes and lithium may be used as a prophylactic agent. Parasomnias and sleep-​related movement disorders Parasomnias are loosely defined as intermittent undesirable events arising from sleep that are not epileptic in nature. The spectrum is large, ranging from visual imagery at sleep onset to complex motor behaviours, occasionally with violent components. Family mem- bers and bed partners are usually more concerned than the indi- viduals themselves, who often remain oblivious to any nocturnal disturbance. Parasomnias are generally classified according to the sleep stage from which they arise, although some are not ‘state dependent’. A simple yet valid scheme to explain most parasomnias is shown in Fig. 24.5.3.3. The brain can function in three distinct and mu- tually exclusive states, namely wakefulness, non-​REM sleep, and REM sleep. The brain normally switches seamlessly and relatively quickly between these states through the sleep–​wake cycle. Most parasomnias result from abnormal state transitions such that elem- ents of one state intrude into another: a person can be considered ‘caught’ for a variable period of time in a separate abnormal state somewhere between wake and sleep. With the exception of certain REM sleep disorders, the neuroana- tomical basis of parasomnias remains obscure. The high prevalence of familial aggregation suggests genetic factors and predominance in childhood implies a maturational component, particularly in non-​ REM parasomnias. Parasomnias at the sleep–​wake transition It is an almost universal experience to have occasional unpleasant sensations of falling through space at the point of sleep onset, with resulting brief muscular contractions. In some individuals these hypnic jerks can regularly interfere with sleep onset and recur through the night. In others there are accompanying explosive sen- sory phenomena, sometimes with severe head pain as a component. Treatments with short-​acting benzodiazepines may be justified in severe cases. More complex and prolonged phenomena comprising a variety of rhythmical movements also tend to occur during extreme drowsi- ness just before sleep. Head banging is the most common manifest- ation in children. The problem tends to resolve with time, although can persist into adulthood and disturb bed partners. Various patterns 24.5.3  Sleep disorders 5893 of movement are seen, with the head, neck, and trunk most com- monly involved. The view that the movements are semi-​voluntary, as part of a sleep-​inducing habit, does not concord with the observa- tion that the phenomenon arises only from deep or even REM sleep in a few individuals. Parasomnias arising from deep non-​REM sleep Non-​REM parasomnias are characterized by sudden but partial arousals from deep sleep, usually stage 4, resulting in behaviours for which the person usually has no subsequent clear recollection. Based on clinical features, sleepwalking, confusional arousals, and night terrors are recognized as three separate phenomena, all due to abnormal arousal from deep sleep. Within this notional spectrum, however, there may be considerable overlap and the type of episodes may change with age. In sleepwalking the person will typically leave the bedroom and may well engage in complex behaviours such as cooking and eating. Communication is possible at a basic level, but it is usually clear to observers that the person is not fully alert or responsive. Concerns often arise when there are attempts to leave the house or if there are any violent elements to the episodes. Confusional arousals refer to brief episodes of disorientation in which the person may sit up in bed and survey the environment be- fore returning to sleep. Night terrors are dramatic episodes, often lasting for several min- utes, in which the person suddenly arouses from sleep, typically with a loud scream and extreme agitation. Motor and autonomic indications of extreme fear are usually alarming to parents and observers. All these arousal disorders tend to occur within an hour of sleep, when non-​REM sleep is at its deepest. It is rare for events to recur through the night. If there is any recall, it is usually vague and re- lated to a non​specific fear or urge to leave the bedroom in the case of night terrors. Particularly deep sleep after a period of deprivation or induced by drugs (including alcohol) may increase the likelihood of events. General stress, changes in schedule, and sleeping in a new environment are further recognized precipitants. Non-​REM parasomnias are common in the first decade of life, affecting at least 6% of children on a regular basis. Persistence into adulthood occurs in around 15% of these. A confident distinction between nocturnal epilepsy and parasomnias can usually be made from clinical features alone, although investigations and video ana- lysis may be required in some cases. Particularly in adults, overnight investigations may reveal an additional sleep disorder such as sleep apnoea or periodic leg movements that may partially arouse the person and help to trigger a parasomnia. It is rarely appropriate to treat non-​REM parasomnias with medication, especially in children. However, if disturbances are frequent or likely to cause danger, short courses of benzodiazep- ines such as low-​dose clonazepam before bed are usually helpful. In the absence of any substantial evidence, antidepressants such as paroxetine are also used to good effect, presumably by effects on sleep architecture. REM sleep parasomnias REM parasomnias include nightmares, REM sleep paralysis, and REM sleep behaviour disorder. Given the propensity for REM sleep to occur late in the night, these parasomnias are typically reported between 3.00 am and 6.00 am, in contrast to the earlier occurrences of arousal disorders from non-​REM sleep. Nightmares represent arousals from unpleasant dreams and are universal experiences. However, up to 4% of adults have frequent or intrusive nightmares, often in the context of psychological stress or substance abuse. Nightmares with recurring themes are a hallmark of post-​traumatic stress disorder. Some drugs (e.g. β blockers), can trigger nightmares, as may the sudden withdrawal of antidepressant agents that normally suppress REM sleep. Symptoms of sleep paralysis, seen in around 40% of people with narcolepsy, can also occur as an isolated phenomenon, occasionally with a familial pattern. As in narcolepsy, the profound paralysis is usually disturbing. Typically, prolonged episodes can be aborted by a tactile stimulus from a bed partner. If treatment is thought neces- sary, tricyclic antidepressants are usually helpful. An increasingly recognized REM parasomnia occurs when ab- normal motor activity intrudes into REM sleep, reflecting a fault in the normal mechanisms that render dreaming individuals com- pletely atonic. So-​called REM sleep behaviour disorder (RBD) is predominantly an affliction of middle-​aged or older men and has an intimate relationship to several neurodegenerative dis- eases, particularly parkinsonism. Over 70% of people free of any movement disorder during wakefulness at the onset of symp- toms will develop Parkinson’s disease within 10 years of follow-​ up. Increasing evidence suggests that RBD confers an increased Fig. 24.5.3.3  A graphical demonstration depicting the normal transitions of the mutually exclusive states of wakefulness, non​rapid eye movement (non-​REM), and REM sleep. The switch from REM sleep to wakefulness can occur directly and would normally lead to a dream experience. Most parasomnias occur because of abnormal or inefficient state transitions. Sleepwalking and related phenomena occur when a person arouses incompletely from deep non-​REM sleep. Hypnic jerks may occur when the brain fails to fall asleep in its entirety. The narcoleptic symptoms of sleep paralysis, cataplexy, and hallucinations at sleep–​wake transition occur when elements of REM sleep intrude into wakefulness. Parkinsonian hallucinations probably represent REM sleep imagery occurring in the drowsy wakeful state. Some individuals report the ability to control their dreams (lucid dreaming) which can be considered as wakeful consciousness intruding into the REM sleep state. In some people with narcolepsy or severe dementia, it can be very difficult to stage sleep accurately and ‘overlap’ syndromes producing ambiguous sleep can occur. DLB, dementia with Lewy bodies; PD, Parkinson’s disease. section 24  Neurological disorders 5894 risk for relatively complex forms of Parkinson’s disease, potentially with early cognitive impairment or neuropsychiatric manifest- ations. Indeed, if parkinsonism is present at the time RBD is recog- nized, prospective studies suggest that a significant proportion will develop early dementia. The nocturnal episodes of RBD are brief and generally explosive, usually involving the arms. There is often an apparently aggressive intent, but injuries to bed partners are incidental and violence is rarely directed. In mild cases, episodes are confined to vocalization or swearing with little observable movement. If awoken during an event, dream recall is the norm, although most remain oblivious to their behaviours if their sleep remains continuous. Intriguingly, pleasant dreams or those with a sexual content are very rare, whereas reports of being chased by aggressors or attacked by animals are typ- ical themes. It is often appropriate to treat this parasomnia on a long-​term basis to prevent injury either to the person with the condition or to the bed partner. Clonazepam in a dose range of 0.25–​2 mg is usually ef- fective, with melatonin used as a second-​line agent at doses between 2 and 6 mg. If there are suspicions of an additional breathing-​related sleep disorder, overnight investigations are warranted because, for example, clonazepam may worsen obstructive sleep apnoea. Periodic leg movements of sleep Periodic leg movements of sleep are characterized by stereotyped leg movements occurring in clusters every 30 s throughout sleep, especially in the light non-​REM stages. The movements them- selves tend to be fairly slow, evolving over 1 to 5 s and typically involving both legs, although one or the other may predominate. An episode tends to start with great toe extension and spreads to include ankle dorsiflexion, followed by knee and hip flexion in se- vere cases. It is relatively rare for individuals to be aware of the leg movements, but bed partners may complain. The phenomenon increases dramatically with age and is strongly associated with restless legs syndrome. If periodic leg movements of sleep are demonstrated after overnight investigation, it can be difficult to gauge their clinical significance, especially if there are no associated electroencephalography (EEG) arousals. Further complications may arise if there are other reasons for fragmented sleep such as obstructive sleep apnoea, in which case leg movements may be triggered as a secondary epiphenomenon. Treatments for restless legs syndrome also ameliorate periodic leg movements of sleep. Dopamine agonists are usually effective, al- though it is difficult to predict in advance whether any response will be clinically meaningful. Circadian rhythm disorders If both quality and quantity of sleep are normal over 24 h but a person is unable to sleep or stay awake at the desired or expected time, a circadian rhythm disorder may be diagnosed. Most com- monly this problem has a clear extrinsic cause such as shift work or long-​haul jet travel, but in some situations there is almost certainly dysfunction of the internal clock mechanism. Behavioural or motiv- ational factors may contribute to the generation of highly irregular sleep–​wake especially in younger individuals. In mammals the primary biological clock is sited in an area of the hypothalamus called the suprachiasmatic nucleus. The mechanism of the clock at a subcellular level has been extensively researched and appears very similar across all animal species, including hu- mans. In strict isolation with no external cues, the periodicity of the human clock is around 24.3 h. In real life this rhythm is entrained precisely to 24 h primarily by light cues acting on retinal cells that contain a newly discovered retinal pigment, melanopsin. A retinal tract to the hypothalamus allows this information to influence the clock mechanism. People who are blind from birth frequently re- port difficulty in adapting to a conventional sleep–​wake cycle be- cause their internal clocks run a little ‘slower’ than average without light entrainment. Very rarely, sighted individuals also have a similar non-​24-​h sleep–​wake disorder, the precise mechanism of which re- mains obscure. Delayed sleep phase syndrome People diagnosed with delayed sleep phase syndrome can be con- sidered as extreme ‘night owls’ such that they are simply unable to sleep before 2.00 am or later. The main concern is usually the sub- sequent inability to wake effectively for school or work. It is im- portant to exclude significant mood disorder as a driver for the abnormal cycle. Similarly, delayed sleep phase syndrome would not be diagnosed in those who simply prefer the solitude of night and avoid daytime interactions. Sleep diaries and wrist actigraphy can help confirm the diagnosis, which mostly affects adolescents with a prevalence estimated at 1%. Those with the condition and their families are very commonly frustrated by this sleep disorder and the relative lack of its recognition. Treatment is difficult and starts with a strict schedule and general sleep hygiene measures. Melatonin taken around 2 h before desired sleep-​onset time may help with sleep onset, but long-​term use of hypnotics is usually unsuccessful. Phototherapy from a light box on waking may also help ‘reset’ the internal clock. Advanced sleep phase syndrome This is an extremely rare disorder but of interest because a familial form has been identified and the relevant gene analysed. The point mutation occurs in a period gene (hPer2) such that the circadian sleep–​wake period is 23.3 h. This results in individuals sleeping and waking at least 4 h earlier than expected. Other indications of disturbed circadian rhythm include melatonin secretion and core temperature. Humans also generally show ‘phase advance’ with increasing age. Common experience suggests that many older people will fall asleep in the evening and wake early in the day, especially in in- stitutions where this may be encouraged as part of a convenient regimen. Shift-​work sleep disorder An increasing number of people are employed in jobs requiring shift work in a variety of patterns. Rotating shifts, in particular, do not allow circadian rhythms to adapt and frequently lead to difficul- ties, either in staying awake for employment or in sleeping effect- ively during daylight hours. Of potential concern are the secondary effects of sleep deprivation on cognitive performance in tasks demanding sustained attention or decision-​making, especially 24.5.3  Sleep disorders 5895 in occupations involving heavy industry or transportation. Most shift workers find it increasingly difficult to adapt their sleep–​wake cycle as they age. Moreover, additional sleep problems such as ob- structive sleep apnoea may worsen the situation. If shift work is causing significant symptoms and cannot be avoided, treatment is a challenging area if simple sleep hygiene advice fails to help. Planned naps may be beneficial, and shift pat- terns that rotate by delaying work time rather than advancing it are generally easier to cope with. Regular medication is controversial with concerns over dependency, especially with regard to hypnotic agents. Regular caffeine may be used, and wake-​promoting drugs such as modafinil have been licensed in severe shift-​work sleep disorder, although the concept of shift-​work sleep disorder as a problem requiring drug treatment lies uncomfortably with many doctors. The assessment of sleep symptoms In assessing a patient with a sleep disorder, the importance of a de- tailed history from the person and, ideally, a bed partner or close family member cannot be overemphasized. Together with a sleep diary, when appropriate, most diagnoses can be made with mod- erate confidence on history alone. With important exceptions, such as sleep apnoea, where quantification of the problem is important, it is relatively rare for investigations to add useful diagnostic informa- tion, but they can be invaluable if a reliable history is not available (e.g. in the case of a person who sleeps alone). The availability of fa- cilities for studying sleep varies dramatically throughout the world, often dependent on how the tests are financed. The following section is based on a British perspective, where sleep medicine is relatively under-​resourced. Insomnia Overnight tests are rarely useful when insomnia is an isolated symptom. In people who complain of extremely reduced overnight sleep, surrogate monitoring of sleep using wrist actigraphy may be useful in demonstrating paradoxical insomnia, in which there is a misperception of the amount of sleep obtained. An algorithm for assessing chronic insomnia is shown in Fig. 24.5.3.4. Chronic insomnia associated with daytime sleepiness and frequent naps is likely to have a secondary identifiable cause. Excessive daytime sleepiness If excessive daytime sleepiness is the primary complaint, it is nor- mally possible to identify an underlying cause, even if the answer is simply insufficient overnight sleep. Care should be taken in establishing that sleepiness itself is the symptom of concern and not lethargy or fatigue, which are more likely to have psychological or motivational substrates. An algorithm for assessing a sleepy person is shown in Fig. 24.5.3.5. Parasomnias Non-​REM parasomnias are difficult to investigate and rely on a good history to allow confident diagnosis. Capturing an event on over- night recording is rare and investigations on asymptomatic nights are usually unremarkable. Particularly in adults, an additional sleep disorder may sometimes be precipitating a parasomnia. If so, it is appropriate to perform overnight investigations to detect arousals secondary, for example, to apnoea or leg movements. Differentiating non-​REM parasomnias from nocturnal epilepsy can be difficult and video analysis—​ideally of several episodes—​can be crucial for diag- nosis. The provision of video recorders to patients’ families in order to capture events at home may be more productive and cost-​effective than formal overnight recording in a hospital setting. Subject complains of inadequate sleep Is subject trying to sleep? Is a formal sleep disorder likely such as sleep-wake transition disorder, RLS or OSA? Is there shift work or a primary circadian disorder? Other causes of insomnia? NO NO NO NO YES YES YES ADVISE LIFESTYLE CHANGES ADVICE AND CONSIDERATION OF TREATMENT FURTHER HISTORY; DIARY AND/OR ACTIGRAPHY Confirms insomnia CONSIDER INVESTIGATIONS AND TREAT CONSIDER PARADOXICAL INSOMNIA If sleep hygiene and environment largely responsible ADVICE AS APPROPRIATE If symptoms suggest conditioned insomnia CONSIDER PSYCHOPHYSIOLOGICAL INSOMNIA If insomnia is lifelong CONSIDER IDIOPATHIC INSOMNIA If anxiety and/or depression prominent factors CONSIDER PRIMARY PSYCHIATRIC ILLNESS YES YES Fig. 24.5.3.4  Algorithm for the assessment of a person with insomnia. OSA, obstructive sleep apnoea; RLS, restless legs syndrome. 24.5.4 Syncope 5896 Andrew J. Larner 24.5.4 Syncope 5896 Andrew J. Larner section 24  Neurological disorders 5896 FURTHER READING American Academy of Sleep Medicine (2014). The International Classi­ fication of Sleep Disorders, 3rd edition. AASM, Westchester, NY. Arnulf I, et al. (2005). Kleine–​Levin syndrome: a systematic review of 186 cases in the literature. Brain, 128, 2763–​76. Bassetti C, Aldrich MS (1997). Idiopathic hypersomnia: a series of 42 patients. Brain, 120, 1423–​35. Chemelli RM, et al. (1999). Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell, 98, 437–​51. Cappuccio FP, Miller MA (2017). Sleep and cardio-metabolic dis- ease. Curr Cardiol Rep, 19, 110. Dauvilliers Y, Arnulf I, Mignot E (2007). Narcolepsy with cataplexy. Lancet, 369, 499–​511. Frank MG (2006). The mystery of sleep function: current perspectives and future directions. Rev Neurosci, 17, 375–​92. Garcia-Borreguero D, et al. (2013). The long-term treatment of rest- less legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the Inter­ national Restless Legs Syndrome Study Group. Sleep Med, 14, 675–84. Harris CD (2005). Neurophysiology of sleep and wakefulness. Respir Care Clin, 11, 567–​86. Hattar S, et  al. (2003). Melanopsin and rod-​cone photoreceptive systems account for all major accessory visual functions in mice. Nature, 424, 75–​81. Lin L, et al. (1999). The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell, 98, 365–​76. Lu BS, Zee PC (2006). Circadian rhythm sleep disorders. Chest, 130, 1915–​23. Lu J, et al. (2006). A putative flip-​flop switch for control of REM sleep. Nature, 441, 589–​94. Mason TBA, Pack AI (2007). Paediatric parasomnias. Sleep, 30, 141–​51. Mignot E, Nishino S (2005). Emerging therapies in narcolepsy–​ cataplexy. Sleep, 28, 754–​63. Morin C, et al. (1999). Nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine review. Sleep, 22, 1134–​56. Nishino S, Kanbayashi T (2005). Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/​orexin system. Sleep Med Rev, 9, 269–​310. Olson, EJ, Boeve BF, Silber MH (2000). REM sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain, 123, 331–​9. Overeem S, et al. (2012). Narcolepsy. Sleep Med Clin, 7, 263–​81. Postuma RB, et al. (2012). Rapid eye movement sleep behavior dis- order and risk of dementia in Parkinson’s disease. Mov Disord, 27, 720–​6. Saper CB (2006). Staying awake for dinner: hypothalamic integration of sleep, feeding and circadian rhythms. Prog Brain Res, 153, 243–​52. Saper CB, Chou TC, Scammell TE (2001). The sleep switch: hypothal- amic control of sleep and wakefulness. Trends Neurosci, 24, 726–​31. Silber MH (2001). Controversies in sleep medicine:  periodic limb movements. Sleep, Med, 2, 367–​9. Thannickal TC, et al. (2000). Reduced number of hypocretin neurons in human narcolepsy. Neuron, 27, 469–​74. Turek FW (2004). Circadian rhythms: from the bench to the bedside and falling asleep. Sleep, 27, 1600–​2. 24.5.4  Syncope Andrew J. Larner ESSENTIALS Syncope is the most common identified cause of transient loss of consciousness, being ten times more frequent than epilepsy. It is a consequence of cerebral hypoperfusion due to reduced cardiac Subject complains of inappropriate naps during the day or if Epworth score more than 10 Is likely cause either insufficient sleep, shift work, or environmental factors? Is medication a likely cause? Is there a history of severe snoring or apnoea at night? Is typical cataplexy present? Are the legs restless and/or jerky at night? No clear diagnosis from history? Is there a likely underlying neurological cause such as Parkinson’s disease? NO NO NO NO NO NO YES YES YES YES YES YES ADVISE LIFESTYLE CHANGES ADJUST OXIMETRY AND/OR PSG CONSIDER MSLT OR CSF HCT ASSAY IF DOUBT CONSIDER EMPIRICAL TREATMENT TREAT CONSIDER PSG AND MSLT YES Fig. 24.5.3.5  Algorithm for the assessment of excessive daytime sleepiness. Most authorities regard a score of 10 or over on the subjective Epworth sleep scale as significant. Oximetry can usually be performed overnight in the patient’s home with a finger monitor. CSF, cerebrospinal fluid; HCT, hypocretin (also called orexin); MSLT, multiple sleep latency test; PSG, polysomnography. 24.5.4  Syncope 5897 output, often related to reduced venous return due to decreased peripheral vascular resistance with pooling of blood volume in de- pendent body parts. Causes These include (1)  neurally mediated—​vasovagal; situational (e.g. cough syncope; carotid sinus); (2)  orthostatic (postural) hypotension—​autonomic failure; drug-​induced; volume deple- tion; (3) cardiac arrhythmia; (4) cardiac/​vascular structural dis- ease (e.g. aortic stenosis). Diagnosis, prognosis, investigations, and treatment Diagnosis is clinical, based on history of the circumstances of the event obtained from the patient and reliable eyewitness(es). In most patients, particularly under 45 years of age, the condition is benign and self-​limiting, with an excellent prognosis, requiring little investigation beyond physical examination and electrocar- diogram to exclude heart disease. Cardiac causes of syncope may require specific treatment. Introduction Syncope can be defined as a transient loss of consciousness asso- ciated with loss of postural tone consequent upon acute reduction of cerebral blood flow. Presyncope is the term sometimes used for symptomatic episodes of cerebral hypoperfusion which do not pro- gress to transient loss of consciousness. Syncope and presyncope are among the most common problems seen in general neurological outpatient clinics, although the condition overlaps both neuro- logical and cardiological practice since syncope is a syndrome with various causes ranging from benign self-​limiting episodes with ex- cellent prognosis to recurrent and possibly life-​threatening attacks, the latter often associated with an underlying cardiac disorder. Correct diagnosis is therefore vital, since management will be de- pendent on cause. Differential diagnosis, most particularly from epi- lepsy, is often required. Pathogenesis The pathophysiology of syncope relates to cerebral hypoperfusion, perhaps most particularly affecting the hindbrain. This may follow reduced cardiac venous return, consequent upon reduced periph- eral vascular resistance with peripheral blood pooling, leading to reduced stroke volume and cardiac output, or to a primary cardiac disorder impairing cardiac output. Factors predisposing to and precipitating the pathophysiological changes causing syncope may be identifiable, but often the pathogenesis is multifactorial, particu- larly in elderly patients. Distinction may be made between two forms of syncope: vaso- vagal, also known as reflex, neurally mediated, or neurocardiogenic syncope; and cardiac or cardiogenic syncope. This dichotomization forms the basis of widely used classification systems for syncope (Table 24.5.4.1). Vasovagal syncope In vasovagal syncope, reduced peripheral vascular resistance al- lows pooling of blood in dependent body areas, most usually the lower limbs, hence reduced venous return and cardiac output with consequent cerebral hypoperfusion. This may be precipitated (‘triggered’) by activities such as standing from the sitting or lying posture or prolonged standing (i.e. orthostatic stress), or by pain, fear, or medical procedures (e.g. venepuncture). In the absence of an evident trigger, the term ‘atypical vasovagal syncope’ may be used. In vasovagal syncope there may be a paradoxical bradycardia (cardioinhibitory response), since standing normally induces a re- flex increase in heart rate. It was this observation that led investiga- tors to infer an increase in vagal tone and Sir Thomas Lewis to coin the term ‘vasovagal’. However, the pathophysiology may, at least in some cases, relate also to sympathetic withdrawal with hypotension (vasodepressor response). Despite hypotension and thoracic hypo- volaemia, a paradoxical cerebrovascular arteriolar vasoconstriction has been observed experimentally, sometimes without cardiovas- cular changes (‘cerebral syncope’). Table 24.5.4.1  Causes of syncope Neurally mediated (neurocardiogenic, reflex) syncope: Vasovagal syncope: Typical Atypical Exertion-​related Sleep syncope Situational syncope (e.g. cough, sneeze, swallow, defaecation, postexercise, postprandial) Spontaneous carotid sinus syncope Orthostatic (postural) hypotension: Autonomic failure: primary, secondary Drug-​induced Volume depletion Cardiac arrhythmias: Sinus node disease (e.g. sick sinus syndrome) Atrioventricular conduction disorders Paroxysmal supraventricular and ventricular tachycardias Inherited disorders: prolonged QT syndromes (Romano-​Ward syndrome, Jervell-​Lange-​Nielsen syndrome), Brugada syndrome Cardiac/​vascular structural disease: Cardiac valvular disease (e.g. aortic stenosis) Acute myocardial infarction, ischaemia Hypertrophic obstructive cardiomyopathy Atrial myxoma Pericardial disease Subclavian steal syndrome section 24  Neurological disorders 5898 Situational syncope, such as cough or post-​tussive syncope, mic- turition syncope, swallow syncope, and defaecation syncope, may be subsumed under the category of neurally mediated or reflex syncope. Pathophysiologically, these entities share similar mechanisms related to reduced venous return, sometimes associated with performance of the Valsalva manoeuvre. The latter may also be relevant in syncope asso- ciated with diverse activities such as weight-​lifting or trumpet playing. Spontaneous carotid sinus syncope, related to carotid sinus hypersensitivity, may be precipitated by pressure on the neck or head turning. This clinical scenario is uncommon, although sensitivity as judged by carotid sinus massage may be found in patients without these particular triggers and forms an integral part of clinical inves- tigation of atypical vasovagal syncope. Sleep syncope is a recently characterized form of vasovagal syn- cope with attacks in the supine position, typically when waking with abdominal discomfort and an urge to defaecate followed by tran- sient loss of consciousness, often with associated autonomic features (sweating, nausea, palpitations, feeling warm). Orthostatic (postural) hypotension of any cause, such as use of certain drugs or autonomic failure, pregnancy, or in association with anaemia or reduced circulating blood volume, may predispose to syncope by impairing peripheral vascular resistance, likewise large meals with resultant postprandial hypotension. Cardiac syncope Cardiac syncope results from a fall in cardiac output which may be associated with arrhythmias, both brady and tachyarrhythmias, per- haps related to ischaemic heart disease or to specific disorders such as Brugada’s syndrome, or with structural cardiac disease such as hypertrophic cardiomyopathy (subaortic stenosis) or valvular dis- ease such as aortic stenosis. Vascular steal syndromes such as sub- clavian steal may also be associated with syncope due to diversion of blood away from hindbrain structures. Categories of idiopathic syncope (‘syncope of unknown origin’) and psychogenic syncope (or, more correctly, pseudosyncope) are also described, but these are both diagnoses of exclusion. The former is a useful diagnostic category since it is associated with a better prognosis than cardiac syncope. Psychogenic syncope (feigned un- consciousness) may be associated with various psychiatric diag- noses including panic attack, somatization, factitious disorder, and frank malingering. Epidemiology No age group is immune from syncope, although the cause does vary with age. In neurological practice, the diagnosis is most commonly made in adolescents or young adults who typically have neurally mediated syncope, with a marked predominance of females, and in older people where the possibility of a cardiac cause or multiple fac- tors is higher. Community-​based epidemiological surveys suggest that many individuals suffering a single or few syncopal episodes do not seek medical advice. Clinical features The clinical history is of paramount importance in making the diag- nosis of syncope. In this context, since patients are almost invariably seen after the event, the opportunity to question a reliable eyewit- ness, if need be by telephone, may be the most important investiga- tion. Equally, the clinician should guard against too great a readiness to accept witness statements that what they saw was a ‘seizure’ or ‘convulsion’. Symptoms before, during, and after the ictus should be ascertained (Table 24.5.4.2). It is recognized that in older subjects with a higher risk of cardiac syncope, the yield of the medical his- tory is lower. The circumstances preceding the event must be inquired about, questioning which aims to ascertain any provoking factors, par- ticularly emotional distress and orthostatic stress. Emotional or physical trauma, pain (including period pain, and eyeball pain or pressure:  the oculocardiac syndrome), and fatigue may increase the risk of syncope, as may sleep deprivation, either situational or in the context of sleep-​related disorders such as obstructive sleep apnoea-​hypopnoea syndrome. The stuffy atmosphere of hot and crowded environments may also predispose. Attacks while in the dentist’s chair, during venesection, or at the sight of blood are classic. Likewise, attacks immediately on rising from a recumbent position, or after prolonged standing, or up to 90 minutes after a large meal are suggestive of neurally mediated syncope. Cardiac syncope may be triggered by exercise, whereas postexertional syncope is more likely to be neurally mediated. Patients may be able to recall some premonitory, presyncopal, symptoms (Table 24.5.4.2), sometimes prompting their own Table 24.5.4.2  Symptoms in typical vasovagal syncope and approximate frequencies Prodrome TLoC Recovery Pallor (87%) Awareness of fainting (69%) Sweating (43%) Palpitations (33%) Blurred vision (31%) Weakness (31%) Nausea (26%) Feeling cold (18%) Feeling warm (15%) Abdominal discomfort (13%) Vomiting (10%) Tremors (8%) Yawning (3%) Abnormal movements (13%) Incontinence of urine (3%) Pallor (61%) Sweating (59%) Weakness (46%) Feeling cold (36%) Confusion (33%) Nausea (26%) Abdominal discomfort (10%) Vomiting (5%) Feeling warm (3%) TLoC, transient loss of consciousness. 24.5.4  Syncope 5899 comment that they have had a ‘faint’ or a ‘blackout’. These may in- clude a sensation of light-​headedness, as though they were going to pass out. Sometimes this is described by patients as ‘dizziness’, which must be distinguished from the ‘spinny dizziness’ (illusion of move- ment: vertigo) often reported in vestibular disorders. Patients may recall commenting on not feeling well, or being asked by witnesses if they were feeling all right. Patients may report that sounds such as voices were audible and intelligible but increasingly distant, or there may be tinnitus. Vision may shrink or become black leaving just ‘tunnel vision’, sometimes described as a feeling of distance. Patients may feel weakness or tingling (paraesthesia), or that they ‘need air’, and indeed may take action to leave the room or go outside before collapsing. Evasive action such as sitting or lying may be possible if presyncopal symptoms last one to two minutes, as may occur in neurally mediated syncope. Nausea, sweating (diaphoresis), feeling both hot and cold may also be remarked upon, suggesting autonomic activation; skin may feel clammy (cold and sweaty) to the touch. An enquiry about premonitory palpitations, during or independent of attacks of loss of consciousness, should also be made. However, not all syncopal episodes have premonitory symp- toms, in which case the likelihood of the attack being either atyp- ical vasovagal syncope or cardiac syncope is increased (Table 24.5.4.3). In addition, elderly people may have retrograde amnesia for syncopal episodes, and present to clinical services simply with ‘unexplained falls’. For events during the syncopal episode, the clinician is dependent on eyewitness accounts. These may note that the patient gradually slumps to the ground and lies still. The duration of loss of conscious- ness is usually brief, around 20 seconds, although on occasion it can be as long as minutes. Facial pallor, loss of colour or ‘greyness’ may be remarked upon. There may be some irregular twitching jerky (myo- clonic) movements of the limbs, ascribed to tonic brainstem motor activity, but not the sustained regular alternating tonic–​clonic move- ments typical of a generalized epileptic seizure (unless syncope is com- plicated by a secondary anoxic seizure, particularly if well-​meaning but misguided bystanders try to keep the patient in the upright pos- ition). Nonetheless an untrained observer may mistake myoclonic jerks for a ‘convulsion’ or ‘seizure’. Incontinence of urine may occur even in the absence of an epileptic seizure, and some studies have found that incontinence is not a useful discriminator between seizure and syncope. A slow pulse may be detected, should any bystander be both sufficiently quick-​witted and knowledgeable to assess this. Patients should be questioned about the next thing they remember after the blackout. Since the period of loss of consciousness is brief, patients may recollect coming round in the same location where they were at the onset of prodromal symptoms. Orientation to surround- ings should be inquired about; generally, patients are ‘with it’ and rec- ognize their surroundings fairly promptly, within a minute or two of coming round, and may ask what is going on. They may recall crowds of people around them. Eyewitnesses may also attest to a rapid recovery, without a prolonged period of postictal confusion. Disorientation after a blackout increases the likelihood that it was due to a seizure, as does increasing age. Facial pallor may persist after recovery from syncope, as may skin clamminess, and nausea and vomiting. Historical features may also be helpful in differentiating neurally mediated from cardiac syncope with high sensitivity and specificity (Table 24.5.4.3). Presyncopal features may last longer in neurally mediated attacks, and indeed may be entirely absent in some forms of cardiac syncope. Syncope with onset during exercise or in the supine position should always prompt consideration of a cardiac cause. Differential diagnosis The most important differential diagnosis of syncope is seizure, ei- ther epileptic or non​epileptic attack disorder. Other conditions to consider may also include drop attacks, transient ischaemic attack, cataplexy, and hyperekplexia, even though transient loss of con- sciousness is not a feature of these conditions. Patients with syncope are not infrequently reported to have had a fit or a seizure by bystanders, comments prompted perhaps by ob- servation of the myoclonic jerks which may occur. Various histor- ical and clinical features may argue for syncope and against epilepsy (Table 24.5.4.4), although it should be remembered that secondary anoxic epileptic seizures may complicate otherwise benign syncopal attacks; for example, if a patient is supported by bystanders and not allowed to fall to the floor. Hence, the diagnoses of syncope and seizure are not necessarily mutually exclusive. Atonic seizures may present a particular diagnostic problem, although these most often occur in combination with other types of epileptic seizure. Features which should raise the clinical index of suspicion for an epileptic seizure include lack of obvious provoking factors, am- nesia for the attack, a prolonged period of loss of consciousness, an eyewitness account of typical tonic–​clonic movements, attacks Table 24.5.4.3  Clinical clues to the differentiation of neurally mediated syncope from cardiac syncope Neurally mediated syncope Cardiac syncope Onset often subacute, with prodromal symptoms: faintness, weakness, paraesthesia, nausea, sweating Onset often sudden: palpitations, chest pain, dyspnoea may be present Precipitating and predisposing factors: emotional upset, trauma, pain, fatigue, assumption of upright posture, prolonged standing, postexercise, postprandial, hot enclosed environments, pregnancy Onset often spontaneous; may occur during exercise; may be history of cardiac disorder Often standing or sitting at onset Onset may occur standing, sitting, or supine (latter should increase suspicion of cardiac syncope) Appearance: facial pallor; usually patients lie still but irregular myoclonic twitches may occur; urinary incontinence may occur. May feel clammy (cold and sweaty) to touch. Bradycardia may be detected Similar, but urinary incontinence uncommon. Heart rhythm abnormality may be detected Post ictus: rapid recovery of orientation. Further episodes of syncope may occur with attempted standing Similar, unless prolonged hypoxia section 24  Neurological disorders 5900 developing during sleep, prolonged postictal confusion, and the presence of physical injury sustained during the event (although in- juries such as bony fractures and subdural haematoma may be sus- tained during syncope). A simple point score of historical features may distinguish syncope from seizures with sensitivity and speci- ficity of over 90%. Various clinical features may prompt consider- ation of non​epileptic attack disorder in the differential diagnosis of blackout, including convulsive movements not typical of epileptic attacks, sometimes including pelvic thrusting; eye closure with re- sistance to eye opening; and superficial injuries such as carpet burns. Drop attacks, unexplained falls forward onto the knees, particu- larly in older people, are not associated with loss of consciousness, but since patients may have little recall of these events this clinical scenario should prompt consideration of syncope. Carotid transient ischaemic attacks are not associated with loss of consciousness, and vertebral transient ischaemic attacks seldom so, and the latter are invariably accompanied by other focal neurological signs (diplopia, vertigo). Cataplexy, loss of muscular tone leading to a brief fall in response to emotion such as laughter, may be a feature of the nar- coleptic syndrome or occur in isolation, but is not associated with transient loss of consciousness; likewise, hyperekplexia, the patho- logical exaggeration of the startle response which may provoke a fall. Postural orthostatic tachycardia syndrome is characterized by ex- cessive increase in heart rate on assumption of upright posture but without orthostatic hypotension, and the presyncopal symptoms may resemble vasovagal presyncope. Clinical investigation Clinical examination at the scene of the syncopal event is seldom possible, and delayed examination in a clinical setting may well be unremarkable. Signs of cardiac disease, arrhythmic or structural, should be sought. Checking the blood pressure in the lying and standing positions to look for orthostatic hypotension may be under- taken, but prolonged standing (minutes) may be necessary to ob- serve a drop in blood pressure. Standard 12-​lead electrocardiography (ECG) is indicated to exclude arrhythmias such as short PR interval, prolonged corrected QT interval (QTc), and Brugada syndrome (right bundle branch block with ST segment elevation in leads V1 to V3). If a standard ECG is normal, then no other investigations may be required, particularly in young and otherwise healthy individuals. In typical vasovagal syncope, diagnosis and management may be based on the history alone and require no additional investigation. Further investigation, if required, generally falls outwith the experience and expertise of neurologists. In suspected atypical vasovagal syncope, the key investigation is head-​upright tilt table testing, a continuous passive orthostatic stress, with or without additional carotid sinus massage, to reproduce syncope and/​or find evidence of cardioinhibitory (bradycardia, or asystole; ‘malignant syncope’) and vasodepressor (hypotensive) responses. Tilt table testing affords continuous ECG and blood pressure monitoring and is undertaken with resuscitation equipment to hand. Ambulatory ECG may be indicated if the clinical index of sus- picion for arrhythmia is high (e.g. history of palpitations, elderly patient, recurrent events), but is subject to limited specificity un- less rhythm disturbances are correlated with clinical symptoms. Monitoring of cardiac rhythm with loop recorders (external, implantable) may be considered, and may indicate the need for pacemaker insertion in some patients with recurrent syncope. Echocardiography may be performed when there is clinical suspi- cion of a valvular (e.g. aortic stenosis) or other cardiac structural abnormality (e.g. hypertrophic obstructive cardiomyopathy, atrial myxoma), or if there is a positive cardiac history or abnormal ECG, but it has no place in otherwise unexplained syncope. Blood tests to exclude anaemia and hyponatraemia may be ap- propriate. Biomarkers of syncope have yet to be identified, although some candidates have been reported (B-​type natriuretic peptides; copeptin, a stress hormone). Structural brain imaging (CT, MRI) and electroencephalogram (EEG) may be indicated if seizure seems more likely than syncope as the cause of loss of consciousness. Cognitive screening is sometimes advocated in patients with unex- plained falls. Recurrent syncope is listed as a supportive feature in diagnostic criteria for dementia with Lewy bodies. Treatment and prognosis Treatment should be individualized according to cause. Explanation and reassurance may be the only intervention required in young in- dividuals without heart disease and with a normal ECG since prog- nosis is excellent. Advice about avoiding recognized predisposing and precipitating factors of neurally mediated syncope may be appropriate, as may increasing fluid and salt intake. Physical counterpressure man- oeuvres, such as hand gripping or crossing legs, may be effective if prodromal symptoms last long enough to enact them. Prognosis is worse for cardiac syncope than neurally mediated syncope, and the presence of structural heart disease is a predictor Table 24.5.4.4  Clinical clues to the differentiation of syncope from seizure Syncope Seizure Subacute onset with prodromal features Sudden onset, sometimes preceded by symptoms of aura (e.g. olfactory hallucinations) Precipitating and predisposing factors often identifiable from history Onset often spontaneous; may be predisposing factors such as sleep deprivation, missing meals, or precipitating factors such as flashing lights Onset most often when standing or sitting Onset may occur standing, sitting, or supine Appearance: facial pallor; usually lie still but irregular myoclonic twitches may occur, likewise urinary incontinence May be cyanosed or flushed. Stertorous breathing. Stereotypic tonic–​clonic movements in generalized seizures. Urinary and faecal incontinence may occur. Tongue biting (sides > tip). Injury as a consequence of fall Recovery usually rapid, with prompt orientation to surroundings Recovery often delayed many minutes, and no recall of event. Residual neurological signs may be present (Todd’s paresis, aphasia) 24.5.5 The unconscious patient 5901 David Bates 24.5.5 The unconscious patient 5901 David Bates 24.5.5  The unconscious patient 5901 of mortality in patients with syncope. Specific treatment of cardiac arrhythmia, valvular, and other structural disorders may be re- quired. Cardiac pacing may be indicated for certain arrhythmias, and a last resort in patients with recurrent neurally mediated syn- cope (the decision is now often aided by evidence from implantable loop recorders). Orthostatic hypotension induced by drugs (e.g. vasodilators, diuretics, phenothiazines, tricyclic antidepressants, monoamine oxidase inhibitors) may be improved by drug cessation or substitution. Autonomic failure, either primary or secondary, may be ameliorated by various strategies (e.g. volume expansion, fludrocortisone, graduated compression stockings, midodrine), and these options may also be explored as prophylaxis for recurrent syncope of non​cardiac origin, although there is currently no clear evidence in favour of pharmacological treatment with the possible exception of midodrine. Selective serotonin reuptake inhibitors have been found helpful on occasion. A common issue after transient loss of consciousness due to syn- cope relates to driving. Different jurisdictions have differing rules with respect to fitness to drive, which may relate to both driver age and vehicle type (cars, motor cycles; lorries, buses). These stand- ards should be consulted by physicians before advising patients on driving. In the United Kingdom, the Driver and Vehicle Licensing Agency (DVLA) places no restrictions on patients suffering reflex vasovagal syncope, defined as episodes with definite provoking fac- tors, with associated prodromal symptoms, and which are unlikely to occur while sitting or lying. Even recurrent events evoke no sanc- tion provided the ‘3 Ps’ (provocation, prodrome, posture) apply on each occasion. However, if loss of consciousness is likely to be un- explained syncope, patients are debarred from driving for a vari- able period dependent on whether the risk of recurrence is deemed to be high or low, and the type of licence applied for. A licence is revoked or refused for one year for lorry/​bus drivers with unex- plained syncope with high risk of recurrence. There are, in add- ition, particular standards for cough syncope (driving to cease until liability to attacks successfully controlled) and for individuals with pacemakers (for further information, see https://​www.gov.uk/​gov- ernment/​uploads/​system/​uploads/​attachment_​data/​file/​435071/​ aagv1.pdf). FURTHER READING Alboni P, Furlan R (2015). Vasovagal syncope. Springer, Heidelberg. Bajpai A, Camm AJ (2013). Cardiac causes of syncope. In: Mathias CJ, Bannister R (eds) Autonomic failure: a textbook of clinical disorders of the autonomic nervous system, 5th edition, pp. 701–​13. Oxford University Press, Oxford. Berecki-​Gisolf J, et al. (2013). Identifying cardiac syncope based on clinical history: a literature-​based model tested in four independent datasets. PLos One, 8, e75255. European Heart Rhythm Association (EHRA), et al. (2009). Guidelines for the diagnosis and management of syncope (version 2009): the Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC). Eur Heart J, 30, 2631–​71. Hainsworth R, Claydon VE (2013). Syncope and fainting: classifica- tion and pathophysiological basis. In: Mathias CJ, Bannister R (eds) Autonomic failure: a textbook of clinical disorders of the autonomic nervous system, 5th edition, pp. 690–​700. Oxford University Press, Oxford. Kenny RA, Grubb B (2013). Syncope in the elderly. In: Mathias CJ, Bannister R (eds) Autonomic failure: a textbook of clinical disorders of the autonomic nervous system, 5th edition, pp. 722–​9. Oxford University Press, Oxford. Krediet CTP, Wieling W (2013). Situational syncope. In: Mathias CJ, Bannister R (eds) Autonomic failure: a textbook of clinical disorders of the autonomic nervous system, 5th edition, pp. 730–​46. Oxford University Press, Oxford. Lagi A, et al. (2013). Copeptin: a blood test marker of syncope. Int J Clin Pract, 67, 512–​5. Lempert T, Bauer M, Schmidt D (1994). Syncope:  a videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol, 36, 233–​7. Lewis T (1932). A lecture on vasovagal syncope and the carotid sinus mechanism:  with comments on Gower’s and Nothnagel’s syndrome. BMJ, 1, 873–​6. Moya A, Rivas N, Perez-​Rodon J (2013). Overview of the contribution of recent clinical trials to advancement of syncope management. Prog Cardiovasc Dis, 55, 396–​401. National Institute for Health and Care Excellence (NICE) (2010). Transient loss of consciousness (‘blackouts’) management in adults and young people. Clinical Guideline. https://​www.nice.org.uk/​guid- ance/​cg109 Sharpey-​Schafer EP (1956). Syncope. BMJ, 1, 506–​9. Sheldon RS, et al. (2011). Standardized approaches to the investiga- tion of syncope: Canadian Cardiovascular Society position paper. Can J Cardiol, 27, 246–​53. Soteriades ES, et  al. (2002). Incidence and prognosis of syncope. NEJM, 347, 878–​85. Sutton R, van Dijk N, Wieling W (2014). Clinical history in manage- ment of suspected syncope: a powerful diagnostic tool. Cardiol J, 21, 651–​7. 24.5.5  The unconscious patient David Bates ESSENTIALS Prolonged loss of consciousness (coma, defined as a Glasgow Coma Score of 8 or less) is seen commonly:  (1) following head injury, (2) after an overdose of sedating drugs, and (3) in the situation of ‘non​traumatic coma’, where there are many possible diagnoses, but the most common are postanoxic, postischaemic, systemic infec- tion, and metabolic derangement (e.g. hypoglycaemia). Clinical approach Urgent assessment is required to identify and, where possible, cor- rect the pathological cause, and protect the brain from the develop- ment of irreversible damage. Key issues are to (1) ensure adequate protection of the airway and adequate ventilation; (2) immediately exclude (and treat) rapidly reversible causes, in particular hypogly- caemia and opioid toxicity; and then (3) consider a variety of dif- ferential diagnoses—​even in ‘non​traumatic coma’ the patient may section 24  Neurological disorders 5902 be harbouring delayed effects of head injury such as subdural haematomas, or meningitis arising from a basal skull fracture. Investigations After performing resuscitation, obtaining a history (from a witness if necessary), physical examination and bedside tests (e.g. fingerprick blood glucose), further investigation depends on the clinical con- text: (1) coma with focal signs or evidence of head injury—​urgent brain imaging by CT or MRI; (2) coma with meningeal irritation but without focal signs—​urgent brain imaging and/​or lumbar puncture is required; treat before investigation if clinical suspicion of menin- gitis (for example) is high; (3) coma without focal lateralizing neuro- logical signs and without meningismus—​the probability of finding a focal abnormality is low; haematological/​biochemical tests or a toxin screen are most likely to provide the diagnosis. Prognosis Brainstem reflexes are the most important clinical signs in defining prognosis: in the absence of sedative drugs, the absence for 24 h of corneal or pupillary reflexes, or of oculovestibular responses, is al- most incompatible with recovery to independence, whatever the cause of coma. Treatment Specific treatment (if any) will depend upon the particular cause of coma, but—​whatever the cause—​long-​term attention is required to the patient’s respiration, skin, circulation, and bladder and bowel function, seizures must be controlled, and the level of consciousness should be regularly assessed and monitored. In patients in whom the prognosis is hopeless, the institution and continuation of resus- citative measures is inappropriate and will serve only to prolong the anguish of relatives and carers (see Chapter 17.10). Definition Normal consciousness Consciousness is the state of awareness of the self and the en- vironment when provided with adequate stimuli; normal consciousness is exhibited by those patients who are fully re- sponsive to stimuli and show appropriate behaviour and speech. Patients who are asleep can be roused and then perform normally. Normal consciousness depends on the integration of activity in the ascending reticular activating substance of the brainstem and the neuronal connections between areas of the cerebral cortex. The ascending reticular activating substance determines arousal, which is shown by awakening with eye opening, motor re- sponses, and verbal communication. The content of consciousness, which is the combination of psychological responses to feeling, emotions, and mental activity, is mediated by the cerebral cortex (Fig. 24.5.5.1). Coma Coma is a state of unrousable unconsciousness without any psy- chologically understandable response to external stimuli or inner need. The patient may appear to be asleep but is incapable of re- sponding normally to external stimuli other than by showing eye opening to pain, flexion or extension of the muscles in the limbs to pain, and occasionally grunting or groaning in response to painful stimuli. It occurs when there is damage to the ascending reticular activating substance or bilateral damage to areas of the cerebral hemispheres, or both (Figs. 24.5.5.2–​24.5.5.5). Confusion Patients are usually disoriented with lowered attention, an inability to express thoughts, drowsiness, and defects in memory. There is clouding of consciousness characterized by an impaired capacity to think, understand, respond to, and remember stimuli. It is im- portant to differentiate acute confusion from dysphasia, amnesia, acute psychosis, severe depression, or dementia. Confusion is most commonly seen as the result of toxic or metabolic disturbances, par- ticularly in older people. Delirium There is motor restlessness, hallucination, disorientation, and delusion. The patient is often frightened and irritable, and the state can be regarded as profound confusion; both states should alert the doctor to impending coma. Delirium is most commonly seen in patients with toxic or metabolic disorders, but can be mimicked by degenerative brain disease, acute psychosis, and hypomania. Cerebral hemisphere Content of consciousness Brainstem Arousal (on–off switch of consciousness) Cerebellum Fig. 24.5.5.1  Normal consciousness. Diencephalic herniation Uncal herniation- third nerve palsy Fig. 24.5.5.2  Supratentorial mass. 24.5.5  The unconscious patient 5903 Stupor The patient appears to be asleep and will show little or no spontan- eous activity, respond only to vigorous stimulation, and then lapse back into somnolence. It may be difficult to differentiate stupor from catatonic schizophrenia or severe retarded depression, but in stupor due to organic disease the electroencephalogram (EEG) will always be abnormal. The vegetative state The patient breathes spontaneously, has a stable circulation, and shows cycles of eye opening and eye closure that may simulate sleep and waking, but he or she is unaware of self and environment. It can be seen transiently in the recovery from coma or it may persist to death. This state is usually seen in patients with diffuse bilateral cere- bral hemisphere disturbance with an intact brainstem, although it can occur with bilateral damage to the most rostral part of the brain- stem. It is most commonly seen after head injury or as the result of hypoxic–​ischaemic damage after cardiac arrest. The patient appears to be awake but is unaware, a condition that frequently causes dis- tress to carers and relatives (Fig. 24.5.5.6). The locked-​in syndrome Damage to the ventral portion of the pons below the level of the third nerve nuclei causes total paralysis of the limbs and lower cra- nial nerves, but with intact consciousness (Fig. 24.5.5.7). The pa- tient can open, elevate, and depress the eyes but cannot move the eyes horizontally, and there is no voluntary movement or speech. The diagnosis is made when the doctor recognizes that the pa- tient is able to open the eyes voluntarily and allow them to close in response to command, and can therefore respond to verbal and sensory stimuli by blinking. The most common cause is infarction Destruction of cortex and hemispheres Intact ascending reticular activating substance Fig. 24.5.5.6  Vegetative state. Intact ascending reticular activating substance Damage to ventral pons Intact cortex Fig. 24.5.5.7  Locked-​in syndrome. Fig. 24.5.5.3  Brainstem lesion—​intrinsic. Tonsillar herniation Local brainstem pressure Fig. 24.5.5.4  Brainstem lesion—​local pressure. Diffuse cortical injury Fig. 24.5.5.5  Bihemispheric damage. section 24  Neurological disorders 5904 of the ventral pons, usually in a patient with hypertension, although it can also be seen with pontine tumours and multiple sclerosis, in central pontine myelinolysis after profound hyponatraemia, and after head injury. The prognosis is poor, although some patients re- cover, usually with residual spasticity. An EEG may help by showing an alert state, reactive to external stimuli, and neurophysiology can be used to exclude similar incapacities occurring in myasthenia gravis or the Guillain–​Barré syndrome. Psychogenic unresponsiveness The term ‘pseudo coma’ or psychogenic unresponsiveness is used for patients who appear to be unconscious and in a coma but who are not. The simplest way to identify this condition is to undertake oculovestibular testing (see next), which will reveal the presence of nystagmus and indicate that the patient has an intact brainstem and cortex. The management of the patient in a coma History Once the patient is stable it is important to obtain as much infor- mation as possible from those who accompanied the patient to hos- pital or who observed the onset of the coma. The circumstances in which consciousness was lost are of vital importance in helping to identify the diagnosis. Generally, coma is likely to present in one of three ways: the predictable progression of an underlying illness; an unpredictable event in a patient with a previously known disease; or a totally unexpected event. In the first category are patients who deteriorate after focal brainstem infarction or those with known intracranial mass lesions who show similar deterioration. In the second category are patients with recognized cardiac arrhythmia or a known risk factor for sepsis. In the final category, it is important to distinguish whether there has been a previous history of seiz- ures, trauma, febrile illness, or focal neurological disturbances. The history of a sudden collapse in the midst of a busy street or office indicates the need for different investigations from those required when the patient has been discovered at home in bed surrounded by empty bottles that previously contained sedative tablets. Where there is uncertainty, a telephone call to relatives and medical attend- ants may be useful. Clinical assessment and examination Estimation of the temperature, pulse, blood pressure, and respira- tory rate, and examination of the skin, cardiovascular system, chest, and abdomen may often yield important clues in establishing the cause of a loss of consciousness. Fever, although not diagnostic, will usually indicate the presence of a systemic infection, menin- gitis, encephalitis, or abscess; seizures increase the likelihood of the last two diagnoses. Hypothermia is most commonly seen after exposure to low environmental temperatures, intoxication with al- cohol or barbiturates, the presence of peripheral circulatory failure or profound myxoedema: tachy-​ or bradyarrhythmias, evidence for valvular heart disease, or peripheral emboli raise the possibility of a cardiogenic cause; bruits over the carotid vessels suggest cerebro- vascular disease; and splinter haemorrhages suggest endocarditis or collagen vascular disease. Hypotension raises the possibility of shock, myocardial infarction or septicaemia, and Addison’s disease should be considered. Hypertension is less helpful as a clinical sign because it may be seen both as the result of cerebral insult or as an indicator of hypertensive encephalopathy. The odour of the breath of an unconscious patient may indicate the presence of alcohol, a ketotic fetor raises the possibility of dia- betes, and the fetor of hepatic or renal failure provides important clues. Clubbing of the fingernails suggests the possibility of a re- spiratory or gastrointestinal abnormality, and evidence of tracheal deviation, fluid in the chest, or collapse of the lung suggests the pos- sibility of a respiratory cause. In the abdomen the finding of enlarge- ment of an organ might indicate portal hypertension, polycystic kidneys, and an associated subarachnoid haemorrhage, or abnor- mality in the blood-​forming organs. The general colour of the skin and mucous membranes might reveal anaemia, jaundice, cyanosis, or the pink discoloration of carbon monoxide poisoning. Purpura suggests a bleeding diathesis and bruising around the head indicates the possibility of trauma or a base-​of-​skull fracture. A rash may in- dicate an infective or inflammatory disease and hyperpigmentation raises the possibility of Addison’s disease. The presence of puncture wounds might identify an individual who is diabetic or a recre- ational drug user. Neurological examination This requires observation and an assessment of reflex responses. The position, posture, and spontaneous movements of the patient should be noted; the skull and spine should be examined with testing for neck stiffness and Kernig’s sign to identify meningeal irritation. Ophthalmoscopy will identify papilloedema, fundal haemorrhages, emboli, and subhyaloid haemorrhages; it must be remembered that the absence of papilloedema does not exclude raised intracranial pressure. The ears and oral cavity should be examined. Level of consciousness The level of consciousness must be documented by the initial ob- server and can then be monitored by medical and nursing staff to determine the progress of the patient and identify the need for fur- ther investigation, therapy, and decision. The most useful hierarch- ical grading scale to assess the level of consciousness is the Glasgow Coma Scale (GCS) in which the patient’s response to graded stimuli of eye opening, motor response, and verbal response are recorded (Table 24.5.5.1); all four limbs are observed for responses to pain and the best response is recorded, although asymmetry should be noted and may identify lateralization. The scale measures conscious- ness and it is possible to score gradations from the fully conscious patient (eye opening, 4; motor response, 6; verbal response, 5) to the totally unresponsive patient (eye opening, 1; motor response, 1; verbal response, 1). If the level of consciousness can be shown to be improving, then urgent decisions may be delayed, but if de- terioration occurs it is imperative that a decision be made about management. Brainstem function The brainstem reflexes identify those lesions that affect the reticular activating substance and determine the viability of the patient. Most of the reflexes involve the eyes and the pattern of respiration, 24.5.5  The unconscious patient 5905 although the latter may be compromised by requirements of ventilation. Pupillary reactions Unilateral dilatation of a pupil with lack of a light response suggests uncal herniation of the temporal lobe over the tentorium cerebrum entrapping the third nerve or due to distortion of the brainstem; it may also be seen with a posterior communicating artery aneurysm or other third nerve damage. Midbrain lesions typically cause loss of the light reflex with pupils in the midposition, lesions in the pons cause small pupils with retained light responses, and fixed dilata- tion of the pupils suggests significant brainstem damage but must be differentiated from the fixed dilatation caused by atropine-​like agents instilled by earlier observers. Horner’s syndrome may be seen with lesions in the hypothalamus or brainstem, but can also be seen with damage to the wall of the carotid artery. Small pupils that react briskly to light raise the possibility of metabolic causes of coma such as hepatic or renal failure; drug intoxications tend not to affect the pupillary light responses. Corneal responses The corneal reflex is usually retained until a very deep coma occurs; if absent in a patient who appears to be otherwise in a light coma, there is a distinct possibility that the cause may be drug intoxication. The loss of the corneal reflex in the absence of drug overdose is a poor prognostic indicator. Spontaneous eye movements Conjugate deviation of the eyes suggests a focal hemispheric or brainstem lesion, depression of the eyes is seen with damage to the midbrain at the level of the tectum, and skew deviation of the eyes suggests a lesion at the pontomedullary junction. Incoordinate eyes suggest damage to the ocular motor or abducent nerve in the brain- stem or pathways, but a minor degree of divergence of the eyes is normal in the unconscious patient. Patients in a light coma will often have normal roving eye movements, similar to those of sleep, which may be conjugate or dysconjugate. They cannot be mimicked and, when present, exclude the possibility of psychogenic unresponsive- ness, when eye movements are likely to be more jerky. Reflex eye movements are important in assessing brainstem ac- tivity. The oculocephalic response obtained by rotating the patient’s head from side to side and observing the position of the eyes is likely to show doll’s eye movements when the brainstem is intact, but the eyes will remain in the midposition of the head when the brainstem is depressed. Oculovestibular testing is undertaken by the installation of 50–​ 200 ml of ice-​cold water into an external audi- tory meatus. The conscious patient, and those in psychogenic coma, will develop nystagmus with the quick phase away from the side of the stimulation, indicating an active pons and intact corticopontine connections. A tonic response with conjugate movement of the eyes towards the stimulated side indicates an intact pons and suggests a supratentorial cause for the coma, whereas a dysconjugate response or no response at all implies a lesion within the brainstem. Respiration The techniques of ventilation limit the value of observation of res- piration in patients with coma, but, if testing is possible before res- piration is controlled, then deep breathing suggests acidosis, regular shallow breathing is consistent with drug overdose, long-​cycle Cheyne–​Stokes respiration suggests damage at the level of the di- encephalon, and short-​cycle Cheyne–​Stokes respiration damage at the level of the medulla. Central neurogenic hyperventilation oc- curs with lesions in the low midbrain and upper pons, and reflex responses such as yawning, vomiting, and hiccoughing may occur with brainstem disturbances. Motor function Motor function is assessed as part of the level of consciousness in the GCS, but lateralizing abnormalities are important and indicate the likelihood of a focal cause, although they may occasionally be seen in the context of hepatic encephalopathy or hypoglycaemia. The presence of generalized or focal seizures implies hemispheric damage and may help in lateralization; multifocal myoclonus sug- gests a metabolic or anoxic cause with diffuse cortical irritation. Table 24.5.5.1  Neurological observation and assessment Glasgow coma scale Score Eye opening Spontaneous 4 To speech 3 To pain 2 Nil 1 Verbal response Orientated 5 Confused conversation 4 Inappropriate words 3 Incomprehensible sounds 2 Nil 1 Best motor response Obeys 6 Localizes 5 Withdraws 4 Abnormal flexion 3 Extension response 2 Nil 1 Brainstem function Pupillary reactions Corneal responses Spontaneous eye movements Oculocephalic responses Oculovestribular responses Respiratory pattern Motor function Motor response Muscle tone Tendon reflexes Seizures section 24  Neurological disorders 5906 Investigation After performing the resuscitation, history, examination, and assess- ment, the doctor should identify one of the three following states Table 24.5.5.2). Coma with focal signs or evidence of head injury In such patients, whether the focal signs indicate a brainstem or supratentorial problem, a CT scan or MRI should be undertaken. A normal scan may be seen in patients with hypoglycaemia or hep- atic coma and the presence of structural pathology will be identified, allowing a decision to be made about the indications for surgery or other therapy. Coma with meningeal irritation but without focal signs Such patients most commonly have subarachnoid haemorrhage, acute meningitis, or meningoencephalitis as the cause of their coma. Brain imaging is the ideal investigation to identify the presence of subarachnoid blood and exclude the possibility of focal collections. Depending on the results of the scan, a lumbar puncture may be per- formed to provide diagnostic information. If the suspicion of men- ingitis is high, then treatment with antibiotics should be started and, in the absence of focal signs or papilloedema, lumbar puncture may precede imaging. Coma without focal lateralizing neurological signs and without meningismus Most patients will have suffered diffuse anoxic–​ischaemic disease, metabolic derangement, or drug insult. It may be necessary to undertake imaging techniques but the probability of finding a focal abnormality is low, and it is more likely that haematological or bio- chemical tests or a search for toxins in the blood will provide the diagnosis or help identify an episode of ischaemia or hypoxia in the past. There may occasionally be an indication to undertake a lumbar puncture in such patients to exclude an inflammatory or infective cause. Patients who are in a coma as the result of a drug overdose will usually be identified from the history and the circumstances of dis- covery, but the possibility of drug-​induced coma should always be considered in patients without focal signs and without meningismus. The discrepancy in marked depression of brainstem responses in a patient who appears to be in a relatively light coma suggests a drug-​ induced coma, the importance of which is that such patients have a good prognosis provided that they are given adequate respiratory and circulatory support during the coma. Prognosis The prognosis of individual patients depends on the aetiology, depth of coma, duration of coma, and certain clinical signs. Aetiology Following a head injury, prognosis depends on the presence of intra- cranial haematoma, the age of the patient, and the severity of the sys- temic injury and its effects. Patients in a coma after a drug overdose have, in general, a good prognosis provided that they are adequately resuscitated and protected. Patients who are in a coma as a result of causes other than head injury or drug overdose for a period of more than 6 h have only a 10% chance of making a good recovery. Those who have had a subarachnoid haemorrhage or stroke have a less than 5% chance of making such a recovery, and those with hypoxic Table 24.5.5.2  Investigations to identify the coma state Diagnostic category Investigations Causes Coma with focal signs ± Papilloedema CT scan or MRI Haematoma (extradural, subdural, parenchymal) Hemiparesis Chest radiograph Infarction Brainstem signs Tumour Focal seizures Abscess Rarely metabolic Coma with meningismus ± Fever ± Imaging Meningitis ± Fundal changes Lumbar puncture Encephalitis Blood tests Subarachnoid haemorrhage Diffuse head injury Cerebral malaria Hypertensive encephalopathy Coma alone History Blood tests Drug overdose Systemic signs ± Lumbar puncture Hypoxic ischaemia Electroencephalogram Metabolic (diabetes, hepatatic, renal, and so on) Toxic (alcohol, carbon monoxide) Epilepsy 24.5.5  The unconscious patient 5907 or ischaemic injury, typically after cardiac arrest, about 10% chance. Those with metabolic or infective causes have almost a 30% chance of making a good recovery. A vegetative state is most likely to occur after head injury or hypoxic–​ischaemic damage. Depth of coma Patients with no response to eye opening, no focal response to pain, and a poor response to pain have a poorer outcome than those who respond with eye opening, grunting, and flexion of the limbs. Duration of the coma When patients have been in a coma for 6 h about 12% may make a good recovery, those who remain in a coma for 24 h have only a 10% chance of recovery, and at the end of a week only 3% of patients can be expected to make a good recovery. In general, patients who remain in a coma for more than 7–​14 days either die or enter a con- tinuing vegetative state. Clinical signs Brainstem reflexes are the most important clinical signs in defining prognosis; the absence of corneal or pupillary reflexes or of oculovestibular responses for 24 h, in the absence of sedative drugs, is almost incompatible with recovery to independence whatever the cause of the coma. Most brainstem reflexes are useful indicators of a poor prognosis but some, such as the development of nystagmus and oculovestibular testing or vocalization of any recognizable word within 48 h, identify patients with a good chance of recovery. The value of investigations Although the bedside tests of eye opening, motor response, and brainstem reflexes proposed by Plum et al. and formulated by Levy (see Further reading) have been the mainstay of assessment of the patient in coma in the accident and emergency department and in- tensive care unit (ICU) for three decades, there is increasing evi- dence that biochemical values and neurophysiological tests have a role to play. Resting state EEG correlates with outcome early in coma but is relatively insensitive. The value of the N20 wave in somatosensory-​evoked potential recording (N20 SSEP) and meas- urement of neuron-​specific enolase (NSE) in peripheral blood at varying time intervals in coma have been shown to be prognostic in the PROPAC study in centres in the Netherlands. It is suggested that the bilateral absence of N20 SSEP, or the finding of NSE serum levels greater than 33 µg/​litre, have a higher positive likelihood ratio and a lower false-​positive rate than the clinical signs of absence of pupil- lary and corneal reflexes in predicting a poor outcome. There are reservations in accepting the conclusions reached from this study because only patients who remained unconscious at 24 h were included and ‘poor outcome’ was defined as death or remaining unconscious at 1 month, and it was assumed that the chance of re- covery of consciousness in patients remaining unconscious for 1 month was virtually nil. Nevertheless, there is logic in looking for biological parameters to identify prognosis in coma and, despite the difficulty in obtaining standardized measures of NSE and complex evoked potentials in the circumstances of most ICUs, there is the suggestion that the bilateral absence of N20 SSEP or the presence of serum NSE greater than 33 µg/​litre might be used to define fu- tility of the continuance of care. At present using such criteria would result in litigation. It is, nevertheless, evident that a reproducible and validated biological marker would improve decision-​making in the early management of the patient in a coma and avoid prolonging an insentient life. Further validation of such measures in large studies is warranted. Continuation of care The long-​term care of patients in a coma may be undertaken in an ICU, on a specialist ward, in a rehabilitation unit, or in a long-​stay hospital. It is important that those in whom prognosis is hopeless should not be permanently exposed to the rigors of intensive care medicine but should continue to receive basic care within routine hospital wards or a more long-​stay environment. So long as patients are considered to have a potential for recovery they should be looked after in an ICU or a specialist ward. Their respiration, skin, circula- tion, and bladder and bowel function need attention, seizures must be controlled, and the level of consciousness should be regularly as- sessed and monitored. It is important that the mobility of joints and circulation to pressure areas are maintained during the long-​term care of the patient, and the possibility of aspiration pneumonia, peptic ul- ceration, and other complications of long-​term intensive care needs to be avoided. Techniques such as mechanical ventilation and steroid therapy should not be used routinely in the management of coma- tose patients; they do not improve prognosis and may compromise recovery. Investigations are of little help in identifying long-​term prognosis because various types of EEG pattern have been recorded from patients in prolonged coma and CT scans simply show cortical atrophy with ventricular dilatation. Some somatosensory-​evoked re- sponses have been reported to show loss of the cortical component in long-​term unconsciousness and positron emission tomography (PET) is reported to show metabolic underactivity but, at present, neither test can provide decisive information as to prognosis. Several studies have demonstrated an important role for func- tional neuroimaging in the identification of residual cognitive func- tion in the persistent vegetative state. These studies may be useful where there is concern about the accuracy of the diagnosis and the possibility that residual cognitive function is undetected, but the tests are extremely complex and subject to methodological and theoret- ical difficulties. Standardization of such techniques, including those assessing residual auditory function with a combination of PET and functional MRI (fMRI), remains a research tool and is unlikely to have a clinical role in the near future. Some authors believe fMRI can demonstrate speech perception, emotional processing, and con- scious awareness in some patients who behaviourally meet all the criteria that define permanent vegetative state. At present it is im- possible to estimate precisely the sensitivity and specificity of EEG-​ and fMRI-​based technologies for the evaluation of consciousness. FURTHER READING Bates D (1991). Defining prognosis in medical coma. J Neurol Neurosurg Psychiatry, 54, 569–​71. Bates D (1993). The management of medical coma. J Neurol Neurosurg Psychiatry, 56, 589–​98. 24.5.6 Brainstem death and prolonged disorders of 24.5.6 Brainstem death and prolonged disorders of consciousness 5908 Ari Ercole, Peter J. Hutchinson, and John D. Pickard section 24  Neurological disorders 5908 Fisher CM (1969). The neurological examination of the comatose pa- tient. Acta Neurol Scand Suppl, 45, 1–​56. Kondziella D (2016). Preserved consciousness in vegetative and min- imal conscious states: systematic review and meta-​analysis. J Neurol Neurosurg Psychiatry, 87, 485–​92. Levy DE (1985). Predicting outcome from hypoxic–​ischaemic coma. JAMA, 253 1420–​6. Owen MO, Coleman MR (2008). Functional neuroimaging of the vegetative state. Nat Rev Neurosci, 9, 235–​43. Plum F, et al. (2007). Diagnosis of stupor and coma. Oxford University Press, Oxford. Teasdale G, Jennett WB (1974). Assessment of coma and impaired consciousness: a practical scale. Lancet, ii, 81–​4. Zanbergen EJG, et al. (2006). Prediction of poor outcome within the first three days of post-​anoxic coma. Neurology, 66, 62–​8. 24.5.6  Brainstem death and prolonged disorders of consciousness Ari Ercole, Peter J. Hutchinson, and John D. Pickard ESSENTIALS Advances in resuscitation and the advent of modern intensive care techniques to support the circulation challenge the simple definition of death in terms of loss of spontaneous circulation (‘cardiac death’). Instead, death is now better regarded as an irreversible loss of the capacity for consciousness combined with irreversible loss of the capacity to breathe. Since the brainstem is required for both con- sciousness and spontaneous breathing, irreversible loss of brainstem function (e.g. after trauma, haemorrhage, or hypoxia/​ischaemia) de- fines the state of ‘brainstem death’. Clinical criteria for the diagnosis of brainstem death have been published, but practice varies around the world. Several prolonged disorders of consciousness from coma (loss of wakefulness and awareness) through the vegetative state (wakeful- ness without awareness) to the minimally conscious state (wakeful- ness with some awareness) are now recognized. Brainstem death lies at the extreme end of this spectrum and is, by definition, permanent. Once potentially confounding conditions have been excluded, the secure diagnosis of vegetative state and minimally conscious state are based on expert, multidisciplinary observation that must take place over an extended period before permanence can be declared with sufficient certainty. Unlike those with brainstem death, patients with prolonged disorders of consciousness may survive for many years without physiological support. The care of such patients has huge social, societal, ethical, and economic implications. Introduction Advances in resuscitation and advanced physiological support make a robust definition of death more complicated than simply the absence of a spontaneous circulation. Instead, we must recognize death in terms of the irreversible loss of those functions that we con- sider essential for human existence. Consciousness is clearly a key aspect of human essence. But pro- longed or permanent loss of capacity for consciousness forms part of a continuum. Patients in a vegetative state show no evidence of awareness and this state may be permanent. However, these patients may display clear wakefulness and spontaneous behaviours and this may continue without advanced physiological support, essentially indefinitely. Thus, a self-​consistent definition of death must be a stronger statement: The irreversible loss of the capacity for conscious­ ness combined with the irreversible loss of the capacity to breathe. Brain death and brainstem death Since the brainstem is essential for consciousness and breathing, the irreversible cessation of brainstem function (‘brainstem death’), whether caused by a primary intracranial catastrophe (e.g. trauma, intracranial haemorrhage) or the result of extracranial cranial events (e.g. hypoxia or cardiac arrest), is the same as death of the patient. Despite advances in prehospital, accident and emergency, and intensive care management of neurological conditions, including cerebral trauma, haemorrhage, hypoxia and infarction, there remain many who succumb. The mechanism of death from these condi- tions may be sudden with cardiorespiratory decompensation and circulatory arrest, or the heart may continue to beat with respiration maintained by artificial ventilation but in the context of irreversible loss of brain function—​the state of ‘brain death’. It is important to distinguish between the definitions of brain death and brainstem death. The original term ‘brain death’ (US Harvard criteria 1968) implied complete death of the whole ner- vous system (flat electroencephalogram or EEG). This state is con- sistent with the notion of irreversibility, but islands of electrical activity may persist in the cortex and/​or spinal reflexes may per- sist. Irreversible loss of brainstem function results in failure of neural transmission caudally to maintain respiration and cranially to maintain activation of the cerebrum by the reticular activating system. Thus, death of the brainstem is the same as death of the patient. In the United Kingdom, the term ‘brainstem death’ (death resulting from irreversible cessation of brainstem function) is pre- ferred and legally recognized. In practice, many brainstem dead pa- tients will also be brain dead. Criteria for diagnosis and brainstem death testing Worldwide practice varies, however in the United Kingdom specific criteria for the diagnosis of brainstem death have been published (‘A code of practice for the diagnosis and confirmation of death’—​ see ‘Further reading’). Confirmation of brainstem death is made by formal brainstem death testing. This follows strict protocols com- prising several stages. Clinical prerequisites There should be no doubt that the patient’s condition is due to ir- remediable brain damage of known aetiology. This may be obvious with computed tomography (CT) confirmation of a severe head injury or spontaneous haemorrhage, but may be much more diffi- cult to establish (e.g. after cardiac arrest with an indefinite period of 24.5.6  Brainstem death and prolonged disorders of consciousness 5909 hypoxia). Continued observation and investigation may occasion- ally be required. The patient must be unconscious. Reversible causes such as pri- mary hypothermia and potentially reversible circulatory, metabolic, or endocrine causes must be excluded. Electrolyte disturbances, and disorders of sodium homeostasis in particular, are common after devastating neurological injury and must be excluded as a primary cause of unconsciousness and corrected as appropriate. A sufficient period of time must be allowed for the elimination of any hypnotic or narcotic drugs. Barbiturates such as thiopen- tone (used in the management of intractable intracranial hyperten- sion) present a particular difficulty due to their zero-​order kinetics and consequent slow elimination after prolonged infusion as well as causing mydriasis, which interferes with clinical assessment. Laboratory drug assays may be helpful if there is doubt. The patient will be maintained on a ventilator because spontaneous respiration has ceased. The effects of neuromuscular blocking drugs and other respiratory depressants must be excluded. Confirmation with a nerve stimulator is advisable. High spinal cord injury must similarly be recognized as a potential confounder. Reasonable physiological control must be maintained throughout the tests and this can on occasion be difficult. It may not be ethically appropriate to institute escalating invasive support in an otherwise moribund patient simply to facilitate brainstem testing, particularly if this is likely to be delayed. Conduct of the tests In the United Kingdom, the diagnosis of brainstem death should be made by at least two medically qualified practitioners who fulfil the following criteria: • Both must have been registered with the General Medical Council for more than five years and be competent in the conduct and in- terpretation of brainstem testing. • At least one must be a consultant. It is important that neither should have any perceived clinical con- flict of interest (in particular, they must not be members of any transplant team). Two complete sets of tests (see Box 24.5.6.1) must always be performed with both practitioners acting together. In the United Kingdom the second set of tests may immediately follow the first set at the discretion of the clinicians; there is no prescribed time that must elapse. Special considerations Role of ancillary tests In the United Kingdom, radiological or neurophysiological studies do not form a routine part of the criteria unless clinical tests alone cannot be relied on (e.g. multiple facial and orbital fractures or a high spinal cord injury). Under such circumstances, ancillary tests such including angiography, electroencephalography, or transcranial Doppler ultrasonography, may be carried out to reduce diagnostic uncertainty. However, such tests require specialist expertise and may not be universally available. False positives and negatives are both possible. CT angiography in increasingly available and promising as a technique that may be used to demonstrate absence of cerebral blood flow. However, the interpretation of such studies is not always straightforward (Fig. 24.5.6.1). Children The concept of brainstem death is valid in children and infants older than 37  months’ gestation; it should not be applied before this time. In older infants up to the age of two months, a diagnosis of death by neurological criteria is possible but may be difficult. In post-​asphyxia or post-​resuscitation patients, a period of at least 24 hours observation should be allowed as a precaution before testing as the possibility of residual sedative effects is greater. Furthermore, the respiratory system may be immature and a stronger hypercarbic stimulus is warranted in order to confidently determine irreversible apnoea. After the age of two months, testing may proceed in a similar manner as in adults. Action following brainstem death testing Brainstem death is confirmed after both sets of tests have been com- pleted with no evidence of reaction being found. The legal time of death is the time of completion of the first set of tests. Following confirmation of brainstem death, mechanical ventilation, and life support should be withdrawn. Depending on the known wishes of the patient, organ donation after brainstem death may be possible and this should be discussed with the next of kin. It is important to avoid unnecessary delay in either discontinuing physiological support or undertaking organ retrieval after com- pletion of the second set of tests on grounds of patient dignity. Expeditious retrieval of organs maintains their function, so it is im- portant when it is a recognized that a patient is a potential organ Box 24.5.6.1  Tests for the diagnosis of brainstem death in the United Kingdom 1 The pupils are fixed and are unreactive to sharp changes in incident light intensity.a 2 Absent corneal reflexes.a 3 Absent oculo-​vestibular reflexes on caloric testing.a • With the head at 30 degrees to the horizontal plane, at least 50 ml of ice-​cold water is injected into each external auditory meatus in turn over one minute while the eyes are examined for movement. • Patency of the external meatuses should first be confirmed by visu- alizing the tympanic membranes with an auroscope. 4 No motor response in the cranial nerve distribution in response to stimulation of any somatic area. • Spinal reflexes may occasionally be present in response to periph- eral (but not central) stimulation but this does not invalidate the test. 5 Absent gag reflex to stimulation of the posterior pharynx. 6 Absent cough reflex in response to bronchial suctioning. 7 Absent respiratory effort. • The patient is preoxygenated with 100% oxygen. • Ventilation is adjusted so that a starting PaCO2 is at least 6.0 kPa and the pH is less than 7.40 to ensure adequate respiratory drive. Higher targets may be required in patients with chronic CO2 retention. Excessive hypercapnia/​acidosis must be avoided however. • The patient is disconnected from the ventilator and 5 litre/​min O2 instilled by endotracheal catheter to maintain adequate arterial oxygen saturation. • The patient is observed for respiratory effort for five minutes after which it should be confirmed that the PaCO2 has risen by more than 0.5 kPa. • Haemodynamic stability should be maintained throughout. a Note that it may occasionally be impossible to test both sides due to unilat- eral disease. This does not invalidate these tests, but ancillary testing should be considered if neither side can be tested. section 24  Neurological disorders 5910 donor that the transplant coordinator is contacted as soon as possible and the stage that proceedings have reached is made clear. Careful counselling of family and friends is crucial throughout this process and they may or may not wish to be present for the testing process. Personal experience has shown that the specialist nurses in organ donation can provide strong and essential support to the relatives, irrespective of the decision of whether or not to donate. Prolonged disorders of consciousness Consciousness encompasses the state of wakefulness (where eyes are open and there is motor arousal) and awareness (the ability to experience external stimulus in some way). Acute loss of con- sciousness is a common consequence of severe brain injury from any aetiology. Such patients may transit through various states of unconsciousness during recovery. Sometimes such recovery may be very slow or incomplete, leaving patients with a prolonged disorder of consciousness. Prolonged disorder of consciousness encompasses a spectrum of disorders from ‘coma’ (where both wakefulness and awareness are absent), though the vegetative state (wakefulness without evidence of awareness) to the minimally con- scious state (wakefulness with some awareness). Unlike brainstem death, vegetative state and minimally con- scious state patients breathe spontaneously and are not venti- lator dependent. Thus, such patients can survive for many years if adequately fed and nursed. States of prolonged disorder of consciousness are by definition long-​term or permanent condi- tions with devastating impact on patients and their families as well as complex clinical, ethical, medicolegal, and socioeconomic ramifications. The vegetative and minimally conscious state The term ‘vegetative state’ was introduced in 1972 by Jennett and Plum to describe the clinical condition resulting from loss of func- tion in the cerebral cortex with a functioning brainstem (patients who are awake but not aware). Such patients have the capacity for Fig. 24.5.6.1  CT angiogram (a, b) of a patient with brainstem death after severe traumatic brain injury in whom extensive facial fractures prevented a full set of tests being carried out. Internal carotid arteries are opacified with contrast (a, arrows) but intracranial intravascular contrast is largely absent. Some opacification of the middle cerebral arteries (b, arrows) may nevertheless be seen due to pulsatile mixing of blood and this could be mistaken for blood flow demonstrating the need for caution in the interpretation of ancillary tests. However, a CT venogram (c) does not reveal contrast in the transverse or sigmoid sinuses (at black arrows) demonstrating complete absence of venous drainage. 24.5.6  Brainstem death and prolonged disorders of consciousness 5911 spontaneous or induced arousal, sleep-​wake cycles, and spontan- eous or reflexive behaviours. However, such patients fail to demon- strate evidence of awareness of themselves or their environment. By contrast, patients with minimally conscious state show reproducible (although variably inconsistent) responses to external stimulus or interaction with surroundings. The most common cause of prolonged disorder of consciousness after acute brain damage is severe head injury, the mechanism being severe diffuse axonal injury severing the subcortical connections over a wide area. Secondary hypoxic brain damage is a contributing factor in some traumatic cases. Most non​traumatic cases result from severe hypoxia–​ischaemia of the brain after a cardiac arrest, near drowning, or strangulation, while a few result from severe hypoglycaemia in people with dia- betes. Other causes are acute intracranial haemorrhage or infection. In adults the vegetative state can evolve gradually during the late stages of chronic dementing conditions and, in children, can result from severe congenital malformations of the brain or from progres- sive metabolic or chromosomal diseases affecting the brain. At post-​mortem examination after acute hypoxic insults, there is commonly a widespread loss of cortical neurons. After acute trau- matic and non​traumatic damage leading to vegetative survival, there is almost always severe bilateral thalamic damage, although the cortex may be relatively spared. There is also progressive degen- eration over many months of neurons, nerve fibres, and their myelin sheaths remote from the site of initial damage, which is reflected during life in progressive enlargement of the ventricles as visual- ized by CT or MRI. Findings on the EEG are variable, but there is often loss of evoked cortical responses to somatic stimuli. Positron emission tomography in hypoxic cases shows severe depression of glucose metabolism in cortical grey matter, to levels found only in experimental deep barbiturate narcosis. Diagnosis Diagnosis has important implications for best-​interest decision-​ making and end-​of-​life care. Unfortunately, there is no simple and reliable test for awareness and recovery may be very slow. As a result, the secure diagnosis of continuing vegetative state or continuing minimally conscious state necessarily involves observation by a multidisciplinary team of skilled observers over a prolonged period of at least four weeks. Furthermore, the confounding influence of medical instability must be ruled out, as must a diagnosis of widespread paralysis such as the locked-​in syndrome, caused by brainstem damage which results in full awareness but leaving the patient able to communi- cate only by a yes/​no code using the sole remaining motor power of blinking the eyelids or moving the eyes, which itself may be a hard to elicit and inconsistent finding due to fatigability. Diagnosis of vegetative state Patients may have long periods of spontaneous eye opening (hence the inappropriateness of calling this condition irreversible or pro- longed coma). However, the eyes or head will never track a moving object. There may be a startle reaction to a sudden noise, but this is at best transient. All four limbs are paralysed and usually spastic, although spontaneous purposeless movements and orofacial movements, including unprovoked smiles and grimaces or tearing, may occur. Reflex posturing is seen and compatible with the diagnosis, as are generalized arousal responses. Reflexive movements, such as facial grimacing or grasp reflexes, may be present. Groans may be heard but never words (rarely a single, inappropriate word may be gener- ated, and this is thought to reflect small disconnected areas of cor- tical survival). There is no psychologically meaningful response to external stimuli, anticipatory or learned behaviour—​no evidence of a working mind. It is concluded that, although awake, these patients are not aware and do not have any distress or pain. Misdiagnosis by non​experts is common, and care is needed to exclude the minimally conscious state in which there are very limited responses to indicate some re- turn of cognitive activity. Recent functional brain imaging and elec- trophysiological studies have revealed that a very few vegetative state patients can hear and understand before responses suggestive of minimally conscious state appear clinically. Diagnosis of minimally conscious state By contrast, patients with minimally conscious state may exhibit some awareness of themselves or external stimuli. Although repro- ducible, this will be inconsistent and may be very limited. Such re- sponses may also be highly fatigable. Patients with minimally conscious state may be able to follow simple commands or issue yes/​no responses, although these may not be accurate. There may be some verbalization or reaction to the lin- guistic content of verbal stimuli. Similarly, while smiling or crying is seen in patients with vegetative state, a minimally conscious state is distinguished by these behaviours being in reaction to the emotional content of stimuli. Prognosis It is not possible to make a diagnosis of a permanent disorder of consciousness with absolute certainty. Patients in a vegetative or minimally conscious state for some time can still make some re- covery, however the likelihood diminishes over time. Of patients in a vegetative state one month after an acute insult, about half of head-​injured individuals will regain some consciousness, but only a few of the non​traumatic cases do. The vegetative state may be de- clared to be permanent after six months for anoxic/​ischaemic/​in- fective/​inflammatory or metabolic causes, but this diagnosis should not be made until at least one year after traumatic causes according to UK criteria. However, in all cases this needs to be individualized and a further 6–​12 months of assessment may be needed if there is uncertainty. For minimally conscious state, emergence has rarely been docu- mented after up to four years but is extremely unlikely after five years, and so a secure diagnosis of permanent minimally con- scious state may take many years to establish. However, absolute time limits are not entirely helpful and need to be individualized. The severity of the initial injury, low levels of responsiveness, and limited clinical trajectory may all suggest that recovery is highly improbable. Most who recover consciousness remain very severely disabled and dependent, particularly if they have been in a vegetative state for several months. There is a high mortality in the first year but, once this period has been survived, patients can live for many years if tube feeding and good nursing care are maintained, and infective complications actively treated. section 24  Neurological disorders 5912 Action after permanence is declared In England and Wales, the Mental Capacity Act 2005 sets out the framework for how decisions should be made on behalf of adults who cannot decide for themselves, and equivalent legislation exists in Scotland. Patients with prolonged disorders of consciousness do not have the mental capacity to make decisions about their care. Usually their premorbid wishes may not be explicitly known and it becomes necessary to determine what actions are in the patient’s best interests, except in cases where some advance directive or ap- propriate lasting power of attorney exists. Those involved in caring for persons who lack capacity must act in their best interests and this extends to decisions surrounding the prolongation of that person’s life. There is now a consensus in many countries that survival in a per- manent vegetative state is of no benefit to the patient, and that it is therefore appropriate to withdraw life-​sustaining treatment once permanence is declared. However, such decisions are not uncontro- versial. Decisions regarding the withdrawal of life-​sustaining treat- ment in minimally conscious state is more contentious still due to the patient’s degree of awareness of and interaction with the environ- ment around them. Many courts in the United States of America and the United Kingdom have agreed that clinically assisted nutrition and hydration (CANH) is medical treatment that can be withdrawn if judged to be no longer in the best interests of the patient. Once this is done a peaceful death occurs in 8–​12 days, and the cause of death is regarded as the original brain damage. Until 2017 in the United Kingdom it was a rule of practice to seek approval from the Court of Protection before withdrawing CANH. However, in more recent case law this was ruled to be unnecessary provided the clinicians have followed Good Clinical Practice and the case is otherwise uncontentious (i.e. provided that there is no dispute with family, other concerned parties, or among the treating team). This position brings the withdrawal of CANH for patients in a persistent vegetative state and minimally con- scious state into line with the principles of withdrawing or with- holding other life-​sustaining therapies, and places the emphasis on acting in accordance with the patient’s best interests— ​considering whether the outcome would have been acceptable to them and the likely decisions they would have made had they not lost their capacity. FURTHER READING Academy of Medical Royal Colleges (2008). A code of practice for the diagnosis and confirmation of death. AoMRC, London. Jennett B (2002). The vegetative state: medical facts, ethical and legal dilemmas. Cambridge University Press, Cambridge. Laureys S, Owen AM, Schiff ND (2004). Brain function in coma, vege- tative state, and related disorders. Lancet Neurol, 3, 537–​46. Monti MM, et al. (2010). Willful modulation of brain activity in dis- orders of unconsciousness. N Eng J Med, 362, 579–​89. Royal College of Paediatrics and Child Health (2015). The diagnosis of death by neurological criteria in infants less than two months old. London, RCPCH. Royal College of Physicians (2013). Prolonged disorders of conscious­ ness: national clinical guidelines. London, RCP. Wijdicks EF (2002). Brain death worldwide: accepted fact but no con- sensus in diagnostic criteria. Neurology, 58, 20–​5. 24.6 Disorders of the special senses 5913 24.6.1 V 24.6 Disorders of the special senses 5913 24.6.1 Visual pathways 5913 Sara Ajina and Christopher Kennard 24.6 Disorders of the special senses CONTENTS 24.6.1 Visual pathways  5913 Sara Ajina and Christopher Kennard 24.6.2 Eye movements and balance  5922 Michael Strupp and Thomas Brandt 24.6.3 Hearing loss  5931 Linda Luxon 24.6.1  Visual pathways Sara Ajina and Christopher Kennard ESSENTIALS Visual disturbances may be caused by diseases of the optic disc, optic nerve, optic chiasm, optic tract, lateral geniculate nucleus, optic radiations, and occipital lobe of the brain, as well as other brain areas involved in complex visual processing. Diagnosis of disturbances of the visual pathways requires both knowledge of their anatomy and physiology, and the ability to carry out a thorough neuro-​ophthalmological examination which should enable (1) documentation of the character and extent of the visual disturbance, and (2) topographic localization of the lesion, so that the relevant investigative techniques, such as radiological imaging, can be appropriately requested. Visual disturbances typically produced by particular lesions (1) Retina—​peripheral field constriction as in retinitis pigmentosa and a central field defect as in age-​related macular degeneration. (2) Optic nerve—​‘relative afferent pupillary defect’; defect of colour vision; central scotoma or arcuate defect (lesions just prior to the chiasm produce a junctional scotoma). (3) Optic chiasm—​bitemporal hemi- anopia. (4) Optic tract—​incongruous hemianopic defects. (5) Lateral geniculate nucleus—​wedge-​shaped homonymous field defects. (6) Optic radiations—​homonymous quadrantinopia or hemianopia depending on the extent and location of the lesion (upper quadrant, temporal lobe; lower quadrant, parietal lobe). (7) Occipital lobe of the brain—​(a) striate cortex—​homonymous hemianopia, sometimes with macular sparing, particularly with vascular disturbances; (b) su- perior or inferior bank of the striate cortex—​inferior or superior alti- tudinal defects, respectively. (8) Extrastriate areas involved in higher visual processing—​can produce a wide variety of defects, including specific loss of a visual modality such as colour (achromatopsia) or movement (akinetopsia), or visual agnosia. Clinical evaluation of visual function Examination of visual function initially requires an accurate assess- ment of the visual acuity. Acuity should be tested separately in each eye using the Snellen or some other optotype chart, which contains rows of letters of diminishing size. If an impairment (>6/​6) is noted, the patient should be allowed to wear spectacles or alternatively to view the chart through a pinhole, which eliminates any significant refractive error or optic media distortion. If the acuity does not im- prove, it is necessary to try to distinguish media opacities and ret- inal abnormalities from optic nerve dysfunction using the swinging flashlight test. In a darkened room each eye is alternately stimulated with a bright light, which is moved rhythmically from one eye to the other. When the light is swung from the good eye on to the defective eye, dilatation of the pupil is termed a ‘relative afferent pupillary de- fect’, and signifies optic nerve dysfunction. Another good indicator of an optic nerve disturbance is a defect of colour vision, which may be tested using one of several available booklets of colour plates, such as the Ishihara pseudo-​isochromatic plates. The photostress test is a useful test to distinguish a maculopathy from optic nerve dysfunction. The retina of the ‘normal’ eye is bleached by shining a bright light at the pupil for 10 s, and measuring the time for normal acuity to be re-​established. The test is repeated in the ‘abnormal’ eye and, if the difference in recovery time between the two eyes is greater than 60 s, the test is considered abnormal, indicating that the impairment is retinal and not due to an optic nerve disturbance. Careful fundoscopic examination of the eye is essential to identify abnormalities of the optic media, retina, and optic nerve head. Finally, examination of the visual fields is essential for topo- graphic localization because, as a result of the invariate ordering of nerve fibres along the visual pathway, lesions at specific sites pro- duce field defects of specific shapes (Fig. 24.6.1.1). Simple confron- tation tests provide a qualitative method of investigating the visual fields. The examiner sits opposite the patient, maintaining a constant section 24  Neurological disorders 5914 distance, and each eye is tested separately. With the patient fixating on the examiner’s nose, he or she is asked to count stationary fingers presented on either side of the vertical meridian in each quadrant in turn. If the patient cannot identify the fingers in a particular area, they are gently wiggled, and the hand moved towards fixation until they are visible to the patient, so mapping out the field defect. To examine the central field a red 5-​ to 10-​mm hatpin is moved away from or towards the central point of fixation. The patient is asked to describe any changes in the perception of colour or brightness, and whether or not the object disappears at any point. Perimetry provides a quantitative technique for measuring the fields, but a full description is beyond the scope of this chapter. Abnormalities of the optic disc Optic disc anomalies Optic nerve hypoplasia Hypoplasia of the optic nerve can be mild or severe, unilateral or bi- lateral, and may be associated with normal or impaired visual func- tion. It can occur in isolation, or be associated with central nervous system anomalies, such as the absence of the septum pellucidum in De Morsier’s syndrome (septo-​optic dysplasia). If there is a clinical indication, such as an enlarged blind spot or arcuate defect despite a normal disc appearance, optical coherence tomography can be useful at detecting more subtle abnormalities. This non​invasive test will identify thinning of the inner retinal nerve fibre layer corres- ponding to the hypoplastic nerve. Optic nerve dysplasia Optic nerve dysplasia presents with a spectrum of abnormalities, including optic nerve colobomas, optic pits, and the morning glory syndrome, all considered to be associated with abnormal closure of the embryonic optic stalk and cup fissure. They are sometimes associated with basal encephaloceles and other fore- brain anomalies. Optic disc colobomas These are deeply evacuated nerve head anomalies with blood ves- sels exiting from the margins, which are associated with defects in the retinal nerve fibre layer, leading to an appropriate visual field loss. Optic pits Optic pits are crater-​like depressions in the optic disc with a dark-​ grey hue, usually situated in the temporal disc margin with an ac- companying nerve fibre layer defect. The morning glory syndrome In this condition, an enlarged dysplastic disc is associated with an elevated, centrally retained mass of glial, embryonic glial, and vas- cular material, which radiates outwards in a sunburst pattern. Tilted discs An asymmetrically shaped, tilted disc is produced when the optic nerve leaves the globe at an extremely oblique angle. It is often as- sociated with a crescentic zone of exposed sclera along one edge which results in elevation of the superior disc. The disc may appear hypoplastic and patients with this condition often have moderately high myopia and oblique astigmatism. Optic nerve drusen Drusen of the optic disc can give rise to an elevation of the optic nerve head. Drusen are intrapapillary, prelaminar, refractile con- cretions that arise from degenerating nerve fibres (Fig. 24.6.1.2e). Anomalous discs due to drusen are usually smaller than normal, have an absent central optic disc cup, and exhibit an aberrant branching pattern of the central retinal vessels. Initially the drusen are buried with simple elevation of the disc, but become more ap- parent in later years when they seem to give rise to a typical lumpy disc, with a scalloped margin. Myelinated nerve fibres In slightly less than 1% of the population some portions of retinal nerve fibres are myelinated, although normally optic nerve mye- lination stops at the lamina cribrosa. It appears on fundoscopy as a white area, usually adjacent to the disc, which has a centrifugal feathered edge (Fig. 24.6.1.2d). Optic disc swelling Although the terms ‘optic disc swelling’ and ‘papilloedema’ have in the past been used synonymously, it is now usual to refer only to papilloedema as optic disc swelling when it is associated with raised intracranial pressure. Other cases of optic disc swelling are due to either local abnormalities in the optic nerve or orbit, or congenital anomalies as described earlier. A Left eye B C D E F G H Right eye H G F E D C B A Fig. 24.6.1.1  Patterns of visual field loss due to lesions at different locations along the visual pathway: (A) optic nerve lesions result in a central scotoma or arcuate defect; (B) optic nerve lesions just before the chiasma produce a junctional scotoma due to ipsilateral optic nerve involvement with the inferior contralateral crossing fibres (dashed lines); (C) chiasmal lesions produce bitemporal hemianopia; (D) optic tract lesions result in incongruous hemianopic defects; (E, F) lesions of the optic radiation result in either homonymous quadrantanopia or hemianopia depending on the extent and location of the lesion (upper quadrant, temporal lobe; lower quadrant, parietal lobe); (G) lesions of the striate cortex produce a homonymous hemianopia, sometimes with macular sparing, particularly with vascular disturbances; (H) lesions of the superior or inferior bank of the striate cortex result in inferior or superior altitudinal defects, respectively. 24.6.1  Visual pathways 5915 Local causes of optic disc swelling are usually associated with impaired visual acuity and colour vision, central, arcuate, or alti- tudinal field defects, and often an afferent pupillary defect. This con- trasts with papilloedema when the acuity and colour vision remain normal, except in the final stages, and is usually bilateral. Papilloedema The evolution of the disc changes in papilloedema caused by raised intracranial pressure are usually classified into four stages:  early, fully developed, chronic, and atrophic. In early papilloedema there is disc hyperaemia, mild disc swelling with blurring of the striations of the fine peripapillary nerve fibre layer, dilatation of retinal veins with loss of spontaneous venous pulsations, and occasionally fine splinter haemorrhages at the disc margin (Fig. 24.6.1.2a). In fully developed papilloedema, disc elevation is moderate to marked, and there is increased venous distension and tortuosity, an increasing number of peripapillary haemorrhages, cotton wool spots, and dilated capillaries on the disc surface. The retinal blood vessels and disc margin become increasingly indistinct (Fig. 24.6.1.2b). In chronic papilloedema, there is resolution of the haemor- rhages and exudates leaving a dome-​shaped (‘champagne cork’) disc swelling, which often contains hard exudates. White refractile bodies may appear on the disc surface, known as corpora amylacea. As time goes on there is increasing nerve fibre attrition, leading to progressive visual field loss. Finally, there is postpapilloedema (consecutive) atrophy, in which the disc acquires a milky opalescence and the retinal vessels are sheathed. Clinical features Usually papilloedema is bilateral and there is an absence of visual symptoms. However, unilateral or bilateral transient visual obscurations may occur, which last a few seconds and are often associated with postural changes. Although it has been suggested that such obscurations herald permanent visual loss, there is no evi- dence to support this view. The longer the papilloedema persists, the more likely there is to be progressive visual field loss, which usually starts as a peripheral field constriction. Occasionally, sudden visual loss occurs in a patient with papilloedema due to ischaemic optic neuropathy. Pathogenesis Papilloedema is due to impairment of axonal transport in the ret- inal nerve fibres, leading to axonal distension, which is seen as disc swelling at the level of the prelaminar optic nerve. Aetiology There is a vast array of different causes leading to increased intracra- nial pressure, in particular space-​occupying lesions such as tumours (Table 24.6.1.1). Management Treatment primarily depends on the underlying cause of the raised intracranial pressure. If it is due to a mass lesion that cannot be Fig. 24.6.1.2  (a) Mild papilloedema: note several features of papilloedema including blurring of the optic disc margins, hyperaemia and elevation of the optic nerve head, and oedema of the retinal nerve fibre layer. (b) Severe papilloedema: the optic disc here is markedly swollen, with several surrounding splinter and flame haemorrhages present, as well as a few cotton wool spots representing nerve fibre layer infarcts. (c) Optic atrophy: in optic atrophy, the loss of capillaries in the connective tissues among the prelaminar nerve fibre layer accounts for the pale appearance of the optic disc. (d) Myelinated nerve fibres: the abnormal myelination of fibres in the peripapillary nerve fibre layer gives them an opaque, white appearance with feathery edges. Lesions are often continuous with the optic disc, and may be associated with retinal vascular abnormalities. (e) Optic nerve drusen: the optic disc is usually smaller than normal, with an absent central optic cup. The edge of the optic disc is also irregular and lumpy, and there is often an aberrant branching pattern of the central retinal vessels. Table 24.6.1.1  Causes of papilloedema Mass lesions: tumours, aneurysms, granulomas, parasitic cysts Intracranial haemorrhage: subdural haematoma, epidural haematoma, subarachnoid haemorrhage Arteriovenous malformations Intracranial infections: brain abscess, meningitis, encephalitis Obstructed cranial venous outflow: dural venous sinus thrombosis, dural venous sinus infiltration, jugular vein compression, dural venous sinus arteriovenous malformation Obstructive hydrocephalus Brain oedema following trauma Spinal cord tumours Idiopathic intracranial hypertension (i)  idiopathic (ii)  secondary to metabolic and endocrine disorders: Addison’s disease, diabetic ketoacidosis, thyrotoxicosis, hypoparathyroidism, chronic uraemia (iii)  secondary to toxic causes: tetracycline, nalidixic acid, steroid therapy, lithium, hypervitaminosis A Guillain–​Barré syndrome Craniostenoses Mucopolysaccharoidoses Systemic illness: Behçet’s syndrome, status epilepticus, Reye’s syndrome, Whipple’s disease, systemic lupus erythematosis, systemic hypertension, chronic respiratory insufficiency section 24  Neurological disorders 5916 completely removed, or a non​surgically remediable cause, a shunting procedure or medical measures (e.g. osmotic agents or diuretics), such as acetazolamide may be used. In idiopathic intracranial hyper- tension, initial management would also include weight loss. Ischaemic optic neuropathy Ischaemic optic neuropathy (Fig. 24.6.1.2c) is the result of infarc- tion of the optic nerve head, and can either be arteritic, as part of giant cell arteritis, or non​arteritic (idiopathic ischaemic neuropathy, anterior ischaemic optic neuropathy), which is the more common form of the condition. Non​arteritic anterior ischaemic optic neuropathy (NAION) This tends to occur in patients aged between 50 and 80 years, but 23% are under 50 years old. It is characterized by abrupt, painless, and generally non​progressive visual loss, associated with an arcuate or altitudinal visual field loss. Acuity may worsen over days or even weeks in 35% of patients. In almost all cases, there is optic disc oe- dema, often associated with one or more splinter haemorrhages at the disc margin. Although previously considered irreversible, as many as 40% of patients may show some improvement. There is a 40% chance of involvement of the fellow eye within five years and only a 5% risk of having a second event in the same eye. Optic atrophy rapidly ensues after the ischaemic event. The cause of non​arteritic anterior ischaemic optic neuropathy remains obscure but is thought to result from vascular insufficiency of the posterior ciliary circulation affecting the distal optic nerve. It is often presents on awakening in the morning, which has suggested that nocturnal hypotension, sometimes related to medication for hypertension, may be a risk factor. There is often a small cup-​to-​disc ratio. There is also increasing evidence for vascular risk factors playing a part, including diabetes mellitus, hypercholesterolemia, and hyperten- sion: 60% of patients with non​arteritic ischaemic optic neuropathy have at least one vascular risk factor. There is no treatment of proven benefit, with use of systemic steroids remaining controversial but probably the most common treatment tried, and low-​level evidence supporting secondary prevention with antiplatelet agents. The most important aspect of management is to exclude the possibility of the arteritic form, because in such cases the fellow eye is particularly vulnerable to similar involvement. Arteritic anterior ischaemic optic neuropathy (AION) The arteritic form of anterior ischaemic optic neuropathy usually oc- curs in giant cell (cranial, temporal) arteritis, but also occurs rarely in lupus and polyarteritis nodosa. Anyone with non​arteritic anterior ischaemic optic neuropathy over the age of 50 should be suspected of having giant cell arteritis. This often occurs in the context of head- ache, malaise, weight loss, anorexia, anaemia, proximal muscle ache or stiffness, temporal artery tenderness, jaw claudication, and fever. These symptoms and signs usually precede the visual loss. The disc infarction is similar to that seen in non​arteritic anterior ischaemic optic neuropathy. A high index of suspicion is required for giant cell arteritis and, if suspected in a patient with visual loss, an urgent erythrocyte sedi- mentation rate (ESR) and temporal artery biopsy should be arranged. At the same time as blood is taken for the ESR, the patient should be started on systemic steroids (3 daily doses of 1 g intravenous methylprednisolone, followed by oral 1 mg/​kg per day). The oral steroid dose should be slowly tapered to maintain a normal ESR and the patient asymptomatic, and treatment should be continued for at least 12 months. Bone protection and prophylactic proton pump in- hibitors should also be prescribed for gastrointestinal protection. If steroids are withdrawn too early, a relapse of symptoms is common. In most patients the ESR is markedly elevated, as is the C-​reactive pro- tein. Occasionally the ESR may be normal. A biopsy of the superficial temporal artery should be obtained as soon as possible after the diag- nosis has been considered. Histologically, the vasculitis is character- ized by mononuclear inflammation often involving the entire vessel wall, with giant cells usually present. The biopsy will not be affected by the use of corticosteroids for at least 48 h, and up to 14 days. A positive temporal artery biopsy confirms the diagnosis of giant cell arteritis, but in 25% of patients skip areas are found in biopsy specimens, and therefore a negative biopsy may sometimes be obtained. Optic atrophy Optic atrophy is the final result of a variety of disturbances to the optic nerve or retina. The disc appears pale, and there is an absence of disc vasculature and retinal nerve fibres (see Fig. 24.6.1.1). Optic atrophy occurs after any disease process that results in death of the retinal ganglion cells with a dying back of their nerve fibres. This can, therefore, be due to diseases that directly involve the ganglion cells themselves or from damage to the axons in the pregeniculate visual pathway, resulting in retrograde atrophy. The development of optic atrophy is usually slow, dependent on its cause. In most instances the optic atrophy is bilateral, the disc appearing chalky-​white in colour with clearly defined margins. The differential diagnosis of optic atrophy is considered in Table 24.6.1.2. Table 24.6.1.2  Causes of optic disc atrophy Deficiency states Thiamine (‘tobacco–​alcohol amblyopia’) B12 (pernicious anaemia, ‘tobacco amblyopia’?) Drugs/​toxins Ethambutol Chloramphenicol Streptomycin Isoniazid Chlorpropamide Digitalis Chloroquine Ethchlorvynol Disulfiram Heavy metals Hereditary optic atrophies Dominant (juvenile) Leber’s Associated heredodegenerative neurological syndromes Recessive, associated with juvenile diabetes Demyelination Graves’ disease Atypical glaucoma Macular dystrophies 24.6.1  Visual pathways 5917 Optic neuritis Optic neuritis is a term used to describe an optic neuropathy due to inflammation, usually due to demyelinating disease but may result from other inflammatory or infectious aetiologies. In most cases the optic disc is normal on ophthalmoscopy and the term ‘retrobulbar neuritis’ may be used. In those cases in which the optic disc is swollen, the terms ‘papillitis’ and ‘anterior optic neuritis’ may be used. Clinical features It is important to distinguish between those features of typical optic neuritis of idiopathic or demyelinating causation and those of atypical optic neuritis. It is more common in women (female:male ratio is 3:1), with an age of onset of 20–​50 years (mean age of 30–​35 years). In typ- ical optic neuritis there is usually acute unilateral loss of visual acuity and visual field, which may progress over hours or a few days, reaching its maximal effect within one week. Ninety per cent (90%) of patients complain of ocular pain, which is noted especially with eye movement, and which may precede the visual impairment by a few days. The visual loss may range from contrast defects with maintained acuity to no light perception with the associated signs of an optic neuropathy. The optic disc appears normal in about two-​thirds of patients and swollen in a third. The patient is usually aged under 40 years, although optic neuritis may occur at any age, and improvement takes place in most patients (90%) to normal or near normal visual acuity over several weeks com- mencing usually within 2–​3 weeks of onset. There may be persistent subtle residual defects of colour vision, depth perception, and contrast sensitivity, which may continue for several months. Subsequent disc pallor may occur, but does not correlate closely with the level of visual recovery. An afferent pupillary defect is present in over 90% of patients with acute optic neuritis. Although optic neuritis is generally associated with a central scotoma, a wide variety of field defects may be found, ran- ging from a central scotoma to altitudinal and nerve fibre layer defects. Atypical optic neuritis may involve unilateral or bilateral simultan- eous onset of optic neuritis in an adult patient. There is often a lack of pain and there may be other ocular findings suggestive of an inflam- matory process, such as an anterior uveitis. Other features include a worsening of visual function beyond 14 days of onset, in a patient out- side the 20-​ to 50-​year age span. They may also have evidence of other systemic conditions, particularly inflammatory or infectious diseases (Table 24.6.1.3). The evaluation of patients with optic neuritis rather depends on whether or not it is a typical or an atypical case. Typical optic neuritis probably does not necessitate any additional laboratory investiga- tions, although an abnormal MRI of the brain significantly increases the likelihood of developing multiple sclerosis from around 20% to over 60%. Furthermore, this risk is dependent on the number of lesions identified on MRI; hence it is necessary to take this into consideration when making a decision about commencing disease-​ modifying therapy. Those patients with atypical optic neuritis should have a chest radiograph, laboratory tests, including a blood count, biochemistry, tests for collagen and vascular disease, and for syphilis serology. Examination of the cerebrospinal fluid is probably justified in this group of patients. Neuromyelitis optica This is a rare but important cause of bilateral or recurrent optic neur- itis that is clinically and pathologically distinct from multiple scler- osis. There is autoantibody-​mediated loss of the aquaporin-​4 water channel protein on astrocytes, which may cause secondary demye- lination in the central nervous system, including the optic nerves. Antibody testing for neuromyelitis optica (NMO)-​IgG has 94% specificity, and sensitivity of diagnosis increases to 99% with the re- vised diagnostic criteria including MRI evidence of a spinal cord or brain white matter lesion. Classically, the disease affects the optic nerves and spinal cord, causing longitudinal extensive transverse myelitis. In general, there is a lower frequency of brain lesions in neuromyelitis optica compared to multiple sclerosis, especially early in the disease, although this is not always the case. The mainstay of treatment is to prevent relapses, and patients with seropositivity at initial presentation are at particularly high risk of developing future episodes of optic neuritis. Although there is little evidence for treat- ment, measures include use of corticosteroids and plasma exchange in an acute attack, and long-​term immunosuppression for mainten- ance therapy. Management In typical optic neuritis there is no evidence-​based treatment which alters outcome. Although prednisolone or intravenous methylprednisolone may lead to a more rapid visual recovery, at the end of six months the visual acuity is no better than with no treatment. Therefore, steroid treatment of patients with typical optic neuritis is unnecessary, unless there is severe ocular pain that cannot be managed with analgesics, or if there is already poor vision in the fellow eye due to some other disease process. The likelihood of developing multiple sclerosis after optic neuritis is approximately 50% after 13 years. This is strongly related to the presence of white matter lesions on a baseline brain MRI. Where such lesions are pre- sent the evidence on which to base a decision as to whether to raise the issue of disease-​modifying treatment is still unclear. Heredofamilial optic neuropathies The hereditary optic neuropathies can either be those that are auto- somal dominant or recessive or those that are due to point mutations in mitochondrial DNA. The autosomal conditions usually present in childhood with impaired vision and pale optic discs. Table 24.6.1.3  Causes of optic neuritis Unknown aetiology Multiple sclerosis Viral infections of childhood (measles, mumps, chicken pox) with or without encephalitis Viral encephalitides Postviral, paraviral infections Infectious mononucleosis Herpes zoster Contiguous inflammation of meninges, orbit, sinuses Granulomatous inflammations (syphilis, tuberculosis, cryptococcosis, sarcoidosis) Intraocular inflammations section 24  Neurological disorders 5918 Leber’s hereditary optic neuropathy This mitochondrial disorder develops primarily in men (approxi- mately 14% in women) in the second to third decades of life. It is characterized by an abrupt loss of central vision in one eye although vision may progressively worsen over days. Occasionally visual loss may occur simultaneously in the two eyes. There is no associated pain on eye movement, in contrast to acute optic neuritis, and the visual loss is usually permanent with optic atrophy and large ab- solute central scotomas. However, the fundoscopic picture in the acute phase often shows swelling of the papillary nerve fibre layer, circumpapillary telangiectatic microangiopathy, and tortuosity of the retinal vessels. In most cases, visual dysfunction is the only manifestation in Leber’s hereditary optic neuropathy, but rare associations with car- diac conduction abnormalities have been reported and it is appro- priate to recommend a routine ECG. There is a maternal pattern of inheritance and point mutations in mitochondrial DNA, particularly at the 11 778 nucleotide, and less frequently at 3460 and 14 484, have been identified. The significance of the point mutation at 14 484 is that a much higher percentage (37% as opposed to 4%) of patients show some visual recovery when compared with patients who have a defect at 11 778. Several sec- ondary mutations have also been identified. It is therefore appro- priate to carry out genetic testing in those individuals presenting with atypical optic neuritis of the appropriate sex and age, even if a positive family history is not available. It is also worth noting that there is incomplete penetrance of the disease, with only 50% of males and 10% of females with mutations developing the pheno- type. It is therefore thought that additional factors may play a role, with tobacco smoking and alcohol consumption identified as the two strongest risk factors. There is no effective treatment, although some studies suggest modest results with a derivative of coenzyme Q10, idebenone, which is a potent antioxidant and inhibitor of lipid peroxidation. Dominant optic atrophy Also known as Kjer’s optic neuropathy, this is an insidious, slowly progressive optic neuropathy with typical onset in the first decade of life. It is inherited in a dominant fashion. It has an estimated preva- lence of approximately 1:50 000. Patients often present with slowly progressive bilateral and symmetrical visual loss, frequently accom- panied by central or centrocecal scotomas. Dyschromatopsia almost always occurs, with blue–​yellow and red–​green disturbances being the most common. In 60% of cases, a mutation in the nuclear gene OPA1 was identified as the genetic basis (encoding a mitochon- drial dynamin-​related GTPase protein), with most cases mapped to chromosome 3q28-​q29. Spontaneous recovery does not usually occur, and there is currently no treatment. Nutritional and toxic optic neuropathies Bilateral, slowly progressive, central visual loss with centrocaecal scotomas, and usually normal or mild temporal atrophic optic discs, characterizes optic nerve failure due to either nutritional de- ficiency or a toxic cause. Once a family history of one of the heredi- tary familial diseases has been excluded, this condition should be considered, and is usually due to a combination of alcohol abuse, deficiencies within the B-​vitamin complex, and frequently a high to- bacco consumption. With treatment by abstinence of the likely toxic agents and vitamin supplementation, recovery of vision usually oc- curs, unless the condition is so long standing that optic atrophy has intervened. Recent epidemics of optic neuropathy in Cuba and West Africa have probably been related to multiple dietary deficiencies. Toxic optic neuropathy has been associated with ethambutol, chloramphenicol, amiodarone, linezolid, disulfiram, halogenated hydroxyquinolones, lead, isoniazid, and vincristine. Tumours of the optic nerve Optic nerve sheath meningiomas Although optic nerve sheath meningiomas may arise directly from the optic nerve sheath, usually in the orbital regions of the nerve, they frequently arise from the tuberculum sellae, sphenoid wing, and olfactory groove, leading to secondary invasion or compres- sion of the nerve. Primary optic nerve sheath meningiomas, which arise from the dural sheath of the intraorbital optic nerve, are most frequently found in middle-​aged women and are usually unilateral, but if bilateral raise the possibility of central neurofibromatosis type 2 (NF-​2). Although most patients will have mild (2–​4 mm) prop- tosis and may already have optic disc pallor at the time of their initial consultation, they complain of dimming of vision and de- creased colour vision. Visual loss progresses over years, with optic disc swelling gradually being supplanted by optic atrophy, with or without the evolution of optociliary venous (retinochoroidal anas- tomoses) shunt vessels. The computed tomography (CT) picture in patients with these tu- mours is most often one of diffuse narrow enlargement of the optic nerve, with bulbous swellings of the nerve in the region of the globe and orbital apex (Fig. 24.6.1.3). ‘Railroad-​track’ calcification of the optic nerve sheath in the orbit is a characteristic feature. Use of MRI has enabled optic nerve sheath meningiomas to be distinguished from optic nerve gliomas, where the former but not the latter show that the nerve is readily distinguished from the optic nerve sheath. Fig. 24.6.1.3  CT image revealing a benign left optic nerve glioma. There is classical fusiform expansion of the optic nerve, causing mild anterolateral displacement of the globe. 24.6.1  Visual pathways 5919 Management of patients with optic nerve sheath meningiomas is controversial. Although there is general agreement that nerve sheath tumours are most aggressive in children and become pro- gressively more indolent with advancing age, there is no con- sensus as to the best way to treat these lesions. Clinical resection, particularly when there is intracranial spread, is usually incom- plete. These patients rarely die from the meningioma and it is probably best just to observe. In some instances radiotherapy has been shown to result in some visual improvement, but should be reserved for those patients in whom there is clear evidence of progression. Optic nerve gliomas Optic nerve gliomas, which may also involve the chiasma, are of two distinct types. By far the more common is the benign glioma of childhood, the other being the malignant glioblastoma in adults. Approximately a quarter of cases occur in the setting of NF-​1, where there is a strong female predominence. Benign optic nerve gliomas usually present within the first two decades of life, with a peak incidence from 1 year to 6 years of age. They represent 3–​5% of childhood brain tumours. Almost all are histologically World Health Organization (WHO) grade I pilocytic astrocytomas. The usual presenting manifestations are proptosis and visual loss, which may be so mild as to be undetectable, although a profound reduction in acuity is more common. The fundus may show either papilloedema or optic atrophy. MRI is the preferred method of imaging optic nerve gliomas, which usually have a fusi- form appearance, and have an almost pathognomonic appearance, so biopsy is usually not warranted. The clinical course of childhood optic nerve gliomas is highly vari- able. In some, tumour enlargement proceeds very slowly for a time but then reaches a plateau, whereas in others the enlargement proceeds unabated. Optic nerve gliomas are generally managed conservatively with regular follow-​up, with evidence of any progression being an indicator for treatment. With evidence of progression some practi- tioners favour radiation therapy for lesions with chiasmal involve- ment and surgery for at least those tumours restricted to the orbit. Optic nerve gliomas of adulthood are malignant gliomas that usu- ally arise in men aged 40–​60 years. These patients often present with a rapid onset of visual failure, which on some occasions may mimic acute optic neuritis. The tumour rapidly progresses, and the patient usually dies within a short period. Other optic nerve tumours Metastatic cancer may lead to optic nerve involvement, either as a result of infiltration of the meninges, as occurs with cancer of the breast and lung, or by direct tumour infiltration, as with lymphoproliferative disorders and certain types of leukaemia and non-​Hodgkin’s lymphoma. Paraneoplastic optic neuropathy has also been described in patients with small cell carcinoma of the lung. Disorders of the optic chiasm Approximately 25% of all brain tumours occur in the chiasmal re- gion and, as half of these cases initially present with visual loss, an appreciation of the various field abnormalities is important. Although there are several other causes for the chiasmal syndrome, such as trauma and demyelination, these are rare. The neuro-​ ophthalmological signs of a compressive optic chiasmal lesion are primarily a field defect and deterioration of visual acuity, which de- pend on the relationship of the chiasma to the pituitary. The classic field defect of a chiasmal lesion is a bitemporal hemianopia. This may be complete or incomplete and may or may not be symmetrical. It is unusual to have a bitemporal hemianopia with no reduction in central visual acuity in at least one eye, because the optic nerve is usually compromised in addition to the chiasma. In large series of patients with pituitary tumours the most common field defect is a bitemporal hemianopia (67%); less common are junctional scotoma (29%), homonymous hemianopia (7%), and prechiasmal field loss (2%). Other signs include optic disc pallor, but its absence usually indicates that a virtually complete return of visual function will occur with successful decompression. Other causes of chiasmal compression, in addition to pitu- itary adenomas (50–​55%), include craniopharyngiomas (20–​ 25%), meningiomas (10%), and gliomas (7%). However, there are other, non​compressive, causes of bitemporal hemianopia, including empty sella syndrome, optochiasmal arachnoiditis, and radionecrosis. Optic tract and lateral geniculate nucleus lesions The optic tract is the first point in the visual pathways where the ip- silateral temporal and contralateral nasal retinal nerve fibres come together, and so the field defect is usually a partial or complete homonymous hemianopia. When partial, there is often gross in- congruity between the visual field defects found in each eye, which may also be found with lesions of the lateral geniculate nucleus and more rarely the optic radiations. The most frequently encountered lesions causing the optic tract syndrome are aneurysms, craniopharyngiomas, and pituitary tumours. Lesions of the lateral geniculate nucleus have been found to pro- duce incongruous wedge-​shaped homonymous field defects, but when the aetiology is ischaemic the defect is usually congruous. The optic radiations As the geniculostriate fibres leave the lateral geniculate nucleus, the ventral fibres (subserving the superior visual field) pass anteriorly around the temporal horn of the lateral ventricle to form Meyer’s loop. Lesions in this region usually result in a wedge-​shaped, con- gruous, homonymous field defect, mainly affecting the superior quadrant. The visual acuity and pupillary responses are both normal. Lesions involving the optic radiation may be due to vascular occlu- sion, tumours (intrinsic or metastatic), or abscesses. Anterior tem- poral lobe resection is a surgical treatment that may be considered in intractable temporal lobe epilepsy. In about 15% cases this re- sults in a postoperative visual field deficit due to optic radiation damage. On conventional MRI the anterior extent of the Meyer loop (which varies from person to person) is poorly localized and there- fore cannot be reliably used for surgical preplanning. In contrast, MRI diffusion tractography (DTI) is proving increasingly useful for section 24  Neurological disorders 5920 tracking individual optic radiation pathways before resection, thus avoiding postoperative visual field defects. Although lesions of the dorsal optic radiation in the parietal lobe may result in a homonymous hemianopia primarily affecting the lower fields, large lesions usually result in a complete homonymous hemianopia with macular splitting. Damage to the parietal or occipitoparietal cortex may result in the phenomenon in the contra- lateral visual field, called unilateral visual inattention or visual ex- tinction. A test object presented in this field is perceived normally, but, when an identical object is similarly presented equidistant from the fixation point in the ipsilateral visual field, the stimulus in the field contralateral to the parietal lobe lesion disappears. Occipital lobe On reaching the occipital lobe there is a high degree of order in the fibres of the optic radiation and lesions, which usually result from infarction, trauma, or tumour, produce homonymous congruent field defects. The only features of the field defect that help localize the lesion to the occipital lobe, rather than the anterior optic radi- ation, are the presence of sparing of the macula or temporal crescent areas in a homonymous hemianopia. In macula sparing there is preservation of the visual field within a region of 1–​2° up to 10° around the fixation point in the hemianopic field. In the more usual situation, the hemianopic field is split along the vertical meridian through the fixation point (macular splitting). Altitudinal (dorsal/​ventral) field defects involving either the upper or lower occipital poles may occur as a result of trauma or vascular lesions. Cortical blindness Cortical blindness usually indicates selective involvement of the oc- cipital visual cortex. The essential features are: (1) complete loss of all visual sensation; (2) loss of reflex lid closure to threat; (3) normal pupillary light reactions; and (4) normal retina and full extraocular eye movements. The most common aetiology is hypoxia of the striate cortex. Despite the perception of blindness, so-​called ‘blind- sight’ can sometimes be demonstrated in these patients. This is the ability of patients with clinically blind fields, due to damage to pri- mary visual cortex, to detect, localize, or even discriminate visual stimuli despite not being able to report seeing the stimulus at all. This effect appears particularly strong for highly salient moving or flashing objects. The pathways subserving this function are not clear, although they are believed to involve subthalamic projections via the superior colliculus, or direct pathways bypassing primary visual cortex between LGN and extrastriate areas. Hemianopia and driving In the United Kingdom, the Driver and Vehicle Licensing Agency (DVLA) issues guidelines for drivers with visual field impairments, and this must be consulted when advising people with visual field loss about driving. In general, the minimum visual field for safe driving is a field of vision of at least 120° on the horizontal meridian. There should also be no significant field defect in the binocular field which encroaches within 20° of fixation either above or below the horizontal meridian. By this means, homonymous or bitemporal defects that come within 20° of fixation, whether hemianopic or quadrantanopic, are not accepted as safe for driving. Isolated scotomata represented in the binocular field near to the central fixation area are also inconsistent with safe driving. Following a stroke, patients with homonymous hemianopia are recommended not to drive. They may, however, be able to apply to the DVLA after one year if they can prove that they have learned to compensate for the defect. Rehabilitation of hemianopia Hemianopia is notoriously difficult to treat, with spontaneous re- covery unlikely after six months. There are three main therapeutic aims: attempts to restore the deficit itself, enlarging the field of gaze through compensatory strategies including saccadic eye move- ments, and the use of orthotic devices to increase the angle of vi- sion in intact fields. In most cases such techniques are of limited benefit, although their evidence is arguably getting stronger. With all techniques, patients must practise for many hours to experience the benefits, perhaps with eye movement-​based therapies requiring the least amount of exposure. However, because visual field loss can be very debilitating, it is increasingly accepted that some form of visual rehabilitation should be offered to patients. Disorders of higher visual processing In the extrastriate cortex there is parallel processing of different aspects of visual information before an organized synthesis of the visual scene can be generated. Specific lesions in one or other of these areas might be expected to give rise to an appropriate specific loss of a visual modality such as colour (achromatopsia), movement (akinetopsia), or faces (prosopagnosia). Acquired disorders of colour vision due to lesions of the central nervous system are of two types. In one type there is an inability to see colours (dyschromatopsia or achromatopsia). These patients have lesions in the region of the lingual and fusiform gyri, which lie in the antero-​inferior region of the occipital lobe. They complain that they cannot see colours and that everything looks grey or various shades of black and white. They are unable to identify the figures on pseudo-​isochromatic test plates, although they are able to name the colours of brightly coloured objects correctly. Other functions such as visual acuity, object recognition, and depth perception are all normal, but there is often an associated visual field defect, usually a bilateral superior homonymous quadrantanopia. In the other type of disorder, the colour sense is normal, but the naming and recog- nition of colour are impaired. This can occur as part of an aphasia, such as Wernicke’s or anomic aphasia, in the syndrome of alexia without agraphia, or as one feature of visual agnosia (see next). Rare cases of patients, who exhibit a selective deficit of move- ment perception (akinetopsia) have been reported. The patients have bilateral lesions involving the lateral occipitoparietotemporal junction. Visuospatial and/​or visuoperceptual abnormalities can occur with neurodegenerative diseases such as posterior cortical at- rophy, with tumours, or after brain injury or stroke affecting the parieto-​occipital lobes. In posterior cortical atrophy, a less common form of Alzheimer’s disease, neuronal loss is initially focused on 24.6.1  Visual pathways 5921 the occipital and parietal lobes rather than the hippocampus and medial temporal lobes, although symptoms classically worsen and pathology becomes more global over time. Dyspraxia and visuoperceptual problems may lead to problems with reading des- pite preserved single-​letter visual acuity, as well as difficulty rec- ognizing faces. Detailed cognitive testing using the Addenbrooke’s Cognitive Examination (ACE-​R) or Queen Square Screening Test for Cognitive Deficits (‘green book’) should be carried out to assess the degree and localization of impairments. Visual agnosia The term ‘visual agnosia’ refers to a rare condition in which there is an inability to recognize, name, or demonstrate the use of an ob- ject presented visually, in the absence of a language deficit, general intellectual dysfunction, or attentional disturbances. The patient is, however, able to name the object when using other sensory modal- ities such as touch or sound. Impaired visual object recognition is the prototypical disorder of lesions in the ventral occipitotemporal pathway. When patients are able to copy and match to sample ob- jects that they fail to name or recognize visually, the agnosia is termed ‘associative’. If there is an inability to perform all these tasks, the agnosia is termed ‘apperceptive’. One classification depends on the specific category of visual ma- terial that cannot be recognized such as alexia, prosopagnosia, and achromotopsia. Alexia is a disturbance of recognition of words, and in the pure form can cause difficulty reading despite an ability to write, good acuity, and intact auditory and language skills. Almost all lesions are localized to the left hemisphere, mostly the medial and inferior occipitotemporal region. A disturbance of face recogni- tion (prosopagnosia) is a specific inability to recognize familiar faces despite a normal ability to recognize everyday objects and is, there- fore, different from visual agnosia. Most cases of prosopagnosia are associated with bilateral damage to the lingual and fusiform gyrus of the medial occipitotemporal cortex, and are due to infarction, head injury, or hypoxia. Absent colour perception (achromotopsia) may occur in isolation or in various combinations, with localiza- tion similar to that for prosopagnosia. The most common cause of achromotopsia is bilateral simultaneous or sequential infarction in the distribution of the posterior cerebral artery. Bálint’s syndrome This disorder of higher visual processing encompasses a classical triad of visuospatial dysfunction. These are: (1) an inability to in- terpret complex scenes despite intact perception of the individual elements (simultanagnosia); (2) a failure to accurately reach and grasp components corresponding to an object’s characteristics (optic ataxia); and (3) a difficulty initiating voluntary saccades to visual targets (ocular motor apraxia). Optic ataxia is distinguish- able from visual agnosia, as in the latter case patients may be able to perform simple reaches to an object, despite an inability to rec- ognize it. Bálint’s syndrome results from bilateral occipitoparietal damage. In particular, simultanagnosia is linked to lesions of the dorsal occipital lobes, whereas optic ataxia is more variably lo- calized, including premotor cortex and occipitoparietal regions. Acquired ocular motor apraxia requires bilateral lesions of the frontal eye fields, inferior parietal lobes, or both. The most common cause is ischaemic, in particular watershed infarcts or vasculitis. Other causes include neurodegenerative disorders or subacute sclerosing panencephalitis, and less commonly tumours, abscesses, and trauma. Visual illusions Visual illusions occur when the visually perceived target appears al- tered in size, shape, colour, position in space, and number of images. The illusory type of defects may occur in the entire field of vision, or affect only the object or the background. The term ‘dysmetropsia’ indicates the apparent smallness (micropsia), largeness (macropsia), or irregularity of shape (metamorphopsia) of objects. Dysmetropsia usually occurs as a result of retinal disease due to distortion of the relative distance between rods and cones. Visual hallucinations Visual hallucinations occur under many circumstances, most com- monly as impaired visual input which most frequently occurs in age-​ related macular degeneration. These hallucinations, known as the Charles Bonnet Syndrome, occur in up to 10% of patients with severe binocular visual loss. Other causes include drug withdrawal, anoxia, migraine, infection, and schizophrenia, in addition to those related to focal neurological disease in the occipital or temporal lobes. Those in the last category may be unformed, consisting of flashes of light (coloured or white), lines, or simple shapes, or they may be complex, highly organized hallucinations of people or objects. Palinopsia Palinopsia is a rare disorder in which there is persistence (persev- eration) or recurrence of visual images after the exciting stimulus has been removed. There are several potential aetiologies for palinopsia, including seizures, cerebrovascular diseases, brain neoplasms, and eye or optic nerve disease. There are also a small number of case reports suggesting a reversible pallinopsia induced by topiramate use. FURTHER READING Apple DJ, Rabb MF, Walsh PM (1982). Congenital anomalies of the optic disc. Surv Ophthalmol, 27, 3–​41. Beck RW, ONTT Study Group (1992). A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med, 326, 581–​8. Boghen DR, Glaser JS (1975). Ischaemic optic neuropathy: the clin- ical profile and natural history. Brain, 98, 689–​708. Chung SM, Selhorst JB (1992). Cancer associated retinopathy. Ophthalmol Clin North Am, 5, 587–​96. Cowey A (2010). The blindsight saga. Exp Brain Res, 200, 3–​24. de Renzi E (1997). Prosopagnosia. In:  Finberg TE, Farah MJ (eds) Behavioural neurology and neuropsychology, pp. 245–​55. McGraw-​Hill, New York, NY. Dutton JJ (1992). Optic nerve sheath meningiomas. Surv Ophthalmol, 37, 167–​83. Dutton JJ (1994). Gliomas of the anterior visual pathway. Surv Ophthalmol, 38, 427–​52. Horton JC, Hoyt WF (1991). The representation of the visual field in human striate cortex: a revision of the classic Holme’s map. Arch Ophthalmol, 109, 816–​24. Humphreys GW, Riddoch MJ (1993). Object agnosias. In: Kennard C (ed) Visual perceptual defects, pp. 339–​59. Baillière Tindall, London. 24.6.2 Eye movements and balance 5922 Michael Stru 24.6.2 Eye movements and balance 5922 Michael Strupp and Thomas Brandt section 24  Neurological disorders 5922 Kölmel HW (1993). Visual illusions and hallucinations. In: Kennard C (ed) Visual perceptual defects, pp. 243–​64. Baillière Tindall, London. Lehmann M, et al. (2012). Global gray matter changes in posterior cortical atrophy:  a serial imaging study. Alzheimers Dement, 8, 502–​12. Liu GT, et al. (1994). Visual morbidity in giant cell arteritis: clinical characteristics and prognosis for vision. Ophthalmology, 101, 1779–​85. Manford M, Anderman F (1998). Complex visual hallucinations: clinical and neurobiological insights. Brain, 121, 1819–​40. McDonald WI, Barnes D (1992). The ocular manifestations of mul- tiple sclerosis. I. Abnormalities of the afferent visual system. J Neurol Neurosurg Psychiatry, 55, 747–​52. Miller DH, et al. (2012). Clinically isolated syndromes. Lancet Neurol, 11, 157–​69. Miller NR, Arnold AC (2015). Current concepts in the diagnosis, pathogenesis and management of nonarteritic anterior ischaemic optic neuropathy. Eye (Lond), 29, 65–​79. Neetens A, Smets RM (1989). Papilloedema. Neuro-​Ophthalmology, 9, 81–​101. Powell H, et al. (2005). MR tractography predicts visual field defects following temporal lobe resection. Neurology, 65, 596–​9. Riddoch G (1917). Dissociation in visual perceptions due to occipital injuries, with special reference to appreciation of movement. Brain, 40, 15–​57. Riordan-​Eva P, et al. (1995). The clinical features of Leber’s hereditary optic neuropathy defined by the presence of a pathogenic mitochon- drial DNA mutation. Brain, 118, 319–​37. Rosenberg MA, Savino PJ, Glaser JS (1979). A clinical analysis of pseudo-​papilloedema:  I.  population, laterality, acuity, refractive error, ophthalmoscopic characteristics, and coincident disease. Arch Ophthalmol, 97, 65–​70. Sadun AA, et al. (1994). Epidemic optic neuropathy in Cuba: eye find- ings. Arch Ophthalmol, 112, 691–​9. Sugishita M, et al. (1993). The problem of macular sparing after uni- lateral occipital lesions. J Neurol, 241, 1–​9. Thompson HS (1966). Afferent pupillary defects. Am J Ophthalmol, 62, 860–​73. Zeki S (1993). A vision of the brain. Blackwell, Oxford. 24.6.2  Eye movements and balance Michael Strupp and Thomas Brandt ESSENTIALS Eye movements The major function of eye movements is to keep the image of the visual surroundings stable on the retina, even during eye movements or head and body movements. This is achieved by (1) conjugate eye movements (both eyeballs move in parallel)—​gaze-​holding, smooth pursuit, saccades, vestibulo-​ocular nystagmus, and optokinetic nys- tagmus; and (2)  disconjugate eye movements—​convergence and divergence. All of these different eye movements are reflexive movements except saccades and convergence/​divergence. Clinical examin- ation of eye movements should include tests of (1) eye position (latent or manifest strabismus, in particular vertical divergence/​ skew deviation); (2)  nystagmus (in particular peripheral ves- tibular spontaneous nystagmus or central fixation nystagmus); (3) gaze-​holding function (gaze-​evoked nystagmus, sustained or unsustained endpoint nystagmus); (4)  smooth pursuit (saccadic or smooth); and (5) saccades (velocity, accuracy, and conjugacy). Many abnormalities of eye movements and nystagmus are dis- tinctive and often indicate the site and the side of a lesion (mid- brain, pons, medulla or cerebellum), for example, vertical and torsional eye movements are generated and controlled in the mes- encephalon, whereas horizontal eye movements are generated and controlled in the pons: gaze-​evoked nystagmus in all direc- tions, saccadic smooth pursuit, downbeat or rebound nystagmus, as well as hypermetric saccades indicate a lesion of the cerebellum or cerebellar pathways. Dizziness and vertigo Vertigo, dizziness, and disequilibrium are common complaints of pa- tients of all ages, particularly older people, with a lifetime prevalence of about 30%. Although the anatomy and the physiology of the ves- tibular and ocular motor systems are complex, a correct diagnosis can be made in most patients on the basis of the patient history and the bedside examination. Vertigo syndromes are commonly characterized by a combin- ation of phenomena involving (1) vertigo itself—​resulting from a dis- turbance of cortical spatial orientation; (2) nystagmus—​caused by a direction-​specific peripheral or central imbalance in the vestibulo-​ ocular nystagmus, which activates brainstem neuronal circuitry; (3) postural imbalance—​caused by inappropriate or abnormal acti- vation of monosynaptic and polysynaptic vestibulospinal pathways; and (4) unpleasant autonomic responses of nausea, vomiting, and anxiety—​ascending and descending vestibulo-​autonomic pathways activate the medullary vomiting centre. Clinical approach—​the history is of special importance, with the patient’s symptoms giving an idea of the likely underlying cause and differentiating the different forms of peripheral, central or functional vestibular vertigo/​dizziness as well as non​vestibular causes. Patient history should focus on four aspects: (1) duration and onset of the symptoms (attacks lasting seconds, minutes, or hours; acute onset of symptoms lasting days; permanent symptoms (>3 months); (2) type of vertigo/​dizziness (spinning ver- tigo, dizziness or postural imbalance); (3) factors that provoke, in- crease or alleviate the symptoms (e.g. change of head or body position, walking, changes of pressure, certain social situations); and (4) accompanying symptoms (in particular, brainstem or cerebellar symptoms, symptoms arising from the ear, or symptoms typical for migraine). Careful and systematic combined bedside examination of the vestibular and ocular motor systems often allows an exact topo- graphic determination of the lesion. Additional laboratory investiga- tions often do not contribute materially to the diagnosis, except the video-​head-​impulse test and caloric irrigation. Particular causes—​more than 60% of all patients presenting with dizziness, vertigo or disequilibrium in a neurological dizziness unit will be suffering from one of the following: (1) benign paroxysmal 24.6.2  Eye movements and balance 5923 positional vertigo; (2) functional dizziness; (3) central vestibular dis- orders; (4) vestibular migraine; (5) Menière’s disease; (6) acute unilat- eral peripheral vestibulopathy. Prognosis and treatment—​many forms of vertigo have a be- nign cause and are characterized by spontaneous recovery of vestibular function or central compensation of a vestibular tone imbalance. Most forms of vertigo can be relieved by (1) pharmaco- logical treatment—​depending on the particular cause; for example, vestibular suppressants for symptomatic treatment, probably anti­ migraineous drugs for vestibular migraine, probably high dosage of β-histine dihydrochloride for Menière’s disease, corticoster- oids for acute unilateral vestibulopathy (one controlled trial), antiepileptic drugs for vestibular paroxysmia (one controlled trial), or aminopyridines for downbeat nystagmus and episodic ataxia type 2 (controlled trials); (2)  physical therapy—​liberatory man- oeuvres for benign paroxysmal positional vertigo (multiple con- trolled trials) or vestibular exercises and balance training—​for uni-​ or bilateral vestibular failure (few controlled trials) or central forms of vertigo; (3) psychotherapy—​in particular for functional dizziness; or (very rarely); (4) surgery for vestibular schwannoma or superior canal dehiscence syndrome. Introduction The disorders underlying vertigo and dizziness are often combined with disturbances of eye movements; reciprocal effects occur be- cause of the anatomical and functional overlap of the vestibular and ocular motor systems. Therefore, both systems must always be tested in patients complaining of vertigo and dizziness. Using a systematic approach, it is possible to make a correct diagnosis in more than 90% of patients. The history is of special importance and one should already have an idea, from the symptoms reported by the patient, what the underlying cause of the vertigo is in order to differentiate the different forms of peripheral, central, and functional vestibular vertigo/​dizziness and non​vestibular forms. A careful and systematic examination of the ocular motor and ves- tibular systems often allows an exact topographic determination of the lesion, in particular to differentiate between central and periph- eral lesions in patients with acute symptoms. Important additional laboratory examinations of the vestibular system are the video-​ head-​impulse test and caloric irrigation to test the function of the vestibulo-​ocular reflex (VOR) as well as in some cases vestibular evoked myogenic potentials to test the function of the otolith organs. Eye movements Different types of eye movements can be distinguished, each with particular functions, physiological properties, and specific anatom- ical substrates:  smooth pursuit, saccades, optokinetic nystagmus, vestibulo-​ocular nystagmus, and gaze-​holding (all of these are con- jugate eye movements, i.e. both eyeballs move in parallel) as well as disconjugate eye movements (convergence and divergence). The major function of eye movements is to keep the image of the visual surroundings stable on the retina, even during eye or head and body movements. Normal vision relies on eye movements in two essential ways: on the one hand, eye movements make it possible to shift the gaze and to view objects of interest and, on the other, when the head or body moves during locomotion, the eyes move in a direction op- posite to that of the head and compensate for these head movements, thereby preventing involuntary shifts of the visual images projected on to the retina. The retinal images are kept steady. Optimal func- tioning of the eye movements is ensured by cooperation between the optokinetic reflex and the VOR as well as by visual fixation suppres- sion of the VOR when combined movements of the head and the visual target occur. For anatomical reasons many abnormalities of eye movements are distinctive and often indicate the site and the side of a lesion (e.g. vertical and torsional eye movements are generated and con- trolled in the mesencephalon), whereas horizontal eye movements are generated and controlled in the pons. The role of the cerebellum in eye movements and a precise diagnosis on the basis of disturbed cerebellar eye movements is often neglected. Frequent oculomotor signs such as saccadic smooth pursuit, gaze-​holding deficit in all directions or dysmetric saccades are caused by an impairment of the flocculus/​paraflocculus, nodulus, vermis, or fastigial nucleus. All in all, a systematic examination of the ocular motor system is very useful for topographic diagnosis, a method that can still be superior to imaging techniques, in particular in the acute phase. It is therefore important that the doctor examines in detail all types of eye movements of patients with, for example, double or blurred vision, oscillopsia (apparent movement of the visual surroundings due to retinal slip), vertigo, dizziness, or postural imbalance be- cause they can, by this means, often differentiate between ‘periph- eral’ and ‘central’ ocular motor disorders and thereby also between peripheral and central vestibular disorders. In their excellent book Neurology of eye movements, Leigh and Zee correctly state that ‘an understanding of the properties of each functional class of eye movements will guide the physical examination; a knowledge of the neural substrate will aid topological diagnosis’. Here the clinical examination techniques of the ocular motor system and common pathological findings, as well as the typical fea- tures of the different forms of nystagmus, are summarized. Eye position, range of eye movements, nystagmus, and gaze-​holding function The following eye movements should be examined: fixation when looking straight ahead, gaze-​holding function, smooth pursuit, saccades, convergence, optokinetic nystagmus, and vestibular nys- tagmus. Clinical examination should begin with examination of the eyes in nine different positions (i.e. looking straight ahead, to the right, left, up, and down, as well as diagonally right up, right down, left up, and left down) to determine ocular alignment (e.g. a possible misalignment of the eye axes), which may be accompanied by a head tilt as in trochlear palsy, fixation deficits, spontaneous nystagmus, impaired range of movement, and disorders of gaze-​holding abil- ities. The examination can be performed with an object for fixation or a small rod-​shaped flashlight. In primary position one should look for a misalignment of the eye position, in particular for a latent strabism (‘phoria’) or a mani- fest strabism (‘tropia’) by means of the cover-​test (Fig. 24.6.2.1) and the alternating cover-​test which allows the maximal angle of eye section 24  Neurological disorders 5924 deviation to be determined. For the differentiation between acute central and peripheral vertigo it is important to look for a vertical divergence (‘skew deviation’) which indicates a central lesion as a component of the ocular tilt reaction. With their eyes in the primary position the patient should also be examined for periodic eye movements, in particular a spontan- eous nystagmus. The leading symptoms of patients with nystagmus are blurred vision, oscillopsia, and/​or reduced visual acuity. In most forms of nystagmus, the pathological eye movement is the slow drift (slow phase), followed by rapid corrective saccadic eye movement (quick phase) which brings the eyes back to the ‘central position’. The direction of a nystagmus, however, is given according to the quick phase. During this quick phase, cortical mechanisms suppress oscillopsia. The different forms of nystagmus can be differentiated by the direction and factors that provoke the nystagmus or modify its in- tensity. Clinically relevant examples are as follows: a horizontal–​ rotatory peripheral vestibular spontaneous nystagmus, which is typically suppressed by fixation as in acute unilateral vestibulopathy, or a central fixation nystagmus, which typically is not suppressed by visual fixation, such as downbeat or upbeat nystagmus. Downbeat nystagmus is most often caused by an im- paired function of the flocculus, upbeat nystagmus can be due to a lesion in the medullar or midbrain. Infantile nystagmus typically beats horizontally at various frequencies and amplitudes, and in- creases during fixation. Ocular flutter (intermittent rapid bursts of horizontal oscillations without an intersaccadic interval) or opsoclonus (combined horizontal, vertical, and torsional oscilla- tions) occurs in various disorders such as encephalitis, tumours of the brainstem or cerebellum, or paraneoplastic syndromes, or in intoxication (in a strict sense they are not a nystagmus). Square-​ wave jerks (small saccades—​0.5–​5°) that cause the eyes to oscillate around the primary position increasingly can occur in progressive supranuclear palsy or certain cerebellar syndromes. The examination of the eyes with Frenzel’s spectacles or M glasses (Fig. 24.6.2.2) which largely prevent visual fixation is a sensitive method for the differentiation of the two types of spon- taneous nystagmus: peripheral vestibular spontaneous nystagmus, which typically can be suppressed by visual fixation, versus central (a) ORTHOPHORIE ESOPHORIE (b) EXOPHORIE ORTHOPHORIE HYPOPHORIE HYPERPHORIE (c) Fig. 24.6.2.1  Cover-​test to look for the eye position. With the cover-​test in primary eye position (a) and in the eight other eye positions an ocular misalignment can be detected. The alternating cover-​test shows the maximum angle of eye deviation. Typical eye deviations indicating a latent strabismus are an esophoria or an exophoria (b). In patients with acute vertigo one should look in particular for a vertical misalignment (i.e. vertical divergence/​skew deviation) (c) because this indicates a central lesion. Skew deviation is one of the four possible components of the ocular tilt reaction. In contrast to trochlear palsy, which also leads to a vertical divergence, in skew deviation the angle of eye deviation does not depend very much on the eye position and patients typically do not complain of double vision because this is due to a central lesion of graviceptive pathways. (a) (b) Fig. 24.6.2.2  Clinical examination with Frenzel’s spectacles (a) or M glasses (b): the magnifying lenses (+16 D) prevent visual fixation, which could suppress peripheral vestibular spontaneous nystagmus. These devices also enable the clinician to observe spontaneous eye movements better. Examination should include spontaneous, head-​shaking nystagmus (instruct the patient to rotate the head about 20 times and observe eye movements after head-​shaking), positioning nystagmus as in benign paroxysmal positional nystagmus (BPPV) or central positional nystagmus, as well as hyperventilation-​induced nystagmus as in vestibular paroxysmia or vestibular schwannoma. 24.6.2  Eye movements and balance 5925 fixation nystagmus, which is often present although the patient is fixating a target. This is because in a central lesion the patient cannot use retinal slip as an error signal to suppress the nystagmus whereas in a pure peripheral lesion the patient is able to do so. However, pa- tients with acute brainstem lesions are sometimes able to suppress their nystagmus. First, in clinical practise simply the characteristics of the nystagmus and pathological eye movements should be de- scribed because in this way the various forms of nystagmus can be easily diagnosed even with no additional laboratory examination, since the classification is based on purely descriptive criteria. After checking for possible misalignment of the axes of the eyes and eye movements in the primary position, the examiner should then establish the range of eye movements monocularly and binocu- larly in the eight end-​positions. Use of a small rod-​shaped flashlight has the advantage that the corneal reflex images can be observed and thus ocular misalignments can be easily detected (note: it is important to observe the corneal reflex images from the direction of the illumination and to ensure that the patient attentively fixates the object of gaze). Deficits of the range of eye movements found can indicate: (a) extraocular muscle dysfunction (e.g. chronic pro- gressive external ophthalmoplegia often associated with bilateral palsy); (b) impaired neuromuscular transmission (as in myasthenia gravis typically affecting different eye muscles in both eyes with use-​dependent weakness and ptosis), cranial nerve palsy (N. III, IV, VI); (c) central lesions with a supranuclear gaze palsy (as in pro- gressive supranuclear gaze palsy or Niemann-Pick type C disease) or an internuclear opthalmoplegia with the pathognomonic clinical sign of an adduction deficit on the side of the lesion of the medial longitudinal fascicle. A gaze-​evoked nystagmus, indicating a gaze-​holding deficit, is de- termined by examining eccentric gaze position. An isolated vertical gaze-​evoked nystagmus is observed in midbrain lesions, indicating a lesion of the interstitial nucleus of Cajal, the neural integrator for vertical eye movements. An isolated horizontal gaze-​evoked nys- tagmus most often indicates a lesion in the lower brainstem affecting the nucleus prepositus hypoglossi and/​or vestibular nuclei. A gaze-​ evoked nystagmus in all directions indicates an impaired function of the cerebellar flocculus (i.e. the neural eye velocity to position integrator). The latter can be caused by alcohol or medication (in particular anticonvulsants and benzodiazepines) or cerebellar dis- orders. A dissociated horizontal gaze-​evoked nystagmus (greater in the abducting than the adducting eye) in combination with an ad- duction deficit points to internuclear ophthalmoplegia due to a defect of the medial longitudinal fascicle, ipsilateral to the adduction deficit (which is the clinical hallmark of internuclear opthalmoplegia). Downbeat nystagmus usually increases in eccentric gaze position and when looking down because it is combined with a gaze-​holding deficit. To examine for a so-​called rebound nystagmus the patient should gaze for at least 30 s to one side and then return the eyes to the primary position; this can cause a transient nystagmus to ap- pear with slow phases in the direction of the previous eye position. Rebound nystagmus also indicates cerebellar dysfunction (floc- culus) or damage to the cerebellar pathways. Downbeat nystagmus, one of the most frequent acquired persisting forms of nystagmus, typically increases when looking down and especially to the side. A nystagmus beating diagonally and downward is found in the side- ward gaze. The cause of downbeat nystagmus is generally a bilat- erally impaired function of the flocculus/​paraflocculus. Smooth pursuit The patient is asked to visually track an object moving slowly in horizontal and vertical directions (10–​20°/​s) while keeping the head stationary. The signal for smooth pursuit eye movements is ‘retinal slip’. During clinical examination corrective (catch-​up or back-​up) saccades are looked for; they indicate a smooth pursuit gain that is too low or (rarely) too high (ratio of eye movement velocity to object velocity). Many anatomical structures (visual cortex, motion-​sensitive areas MT, V5, frontal eye fields, dorso- lateral pontine nuclei, cerebellum, and vestibular and oculomotor nuclei) are involved in smooth pursuit eye movements, which keep the image of a moving object stable on the fovea. These eye movements are also influenced by alertness, various drugs, and age. Even healthy individuals exhibit a slightly saccadic smooth pursuit during vertical downward gaze. For these reasons a sac- cadic smooth pursuit does not as a rule allow either an exact topo- graphical or an aetiological classification. Marked asymmetries of smooth pursuit, however, indicate a structural lesion; strongly impaired smooth pursuit is observed in intoxication (anticon- vulsants, benzodiazepines, or alcohol) as well as degenerative disorders involving the cerebellum, in particular the flocculus/​ paraflocculus. A reversal of slow smooth pursuit eye movements during optokinetic stimulation is typical of infantile/​congenital nystagmus (see earlier). Saccades First, it is necessary to observe spontaneous saccades triggered by visual or auditory stimuli. Then the patient is asked to glance back and forth between two horizontal or between two vertical targets. The velocity, accuracy, and the conjugacy of the saccades should be noted. Normal individuals can immediately reach the target with a fast single movement with or without one small corrective saccade. Slowing of saccades—​often accompanied by hypometric saccades—​ occurs, for example, with intoxication (medication, especially anti- convulsants or benzodiazepines) or in neurodegenerative disorders. Isolated slowing of horizontal saccades is generally observed in pon- tine lesions, indicating a dysfunction of the ipsilateral paramedian pontine reticular formation. Slowing of vertical saccades only in- dicates a midbrain lesion in which the rostral interstitial nucleus of the medial longitudinal fascicle (riMLF) is involved, not only in ischaemic or inflammatory diseases, but also in neurodegenerative diseases, especially progressive supranuclear palsy. In Niemann-​ Pick type C there is typically first a slowing of vertical downward, then upward saccades and later also of horizontal saccades. Since the cerebellum is responsible for the accuracy and not the velocity of saccades a dysmetria typically indicates an impaired function of the cerebellum or cerebellar pathways. Hypermetric saccades, which can be identified by a corrective saccade back to the object, indicate lesions of the cerebellum (especially the fastigial nucleus) or the cerebellar pathways. Patients with Wallenberg’s syn- drome make hypermetric saccades towards the side of the lesion due to a dysfunction of the inferior cerebellar peduncle; conversely, de- fects of the superior cerebellar peduncle lead to contralateral hypo- metric saccades. Hypometric saccades in all directions indicate a dysfunction of the dorsal ocular motor vermis. A slowing of the adducting saccade ipsilateral to a defective medial longitudinal fascicle is pathognomonic of an internuclear section 24  Neurological disorders 5926 opthalmoplegia. Delayed-​onset saccades are mostly caused by supratentorial cortical disturbances (Balint’s syndrome). Vergence test and convergence reaction A target is moved from a distance of about 50  cm towards the patient’s eyes or the patient looks back and forth between a dis- tant and a near target. Looking at a near target causes vergence, ac- commodation and miosis (i.e. the convergence reaction). Neurons important for the convergence reaction are in the area of the mes- encephalic reticular formation and the oculomotor nucleus. This explains why the convergence reaction is disturbed in rostral mid- brain lesions and tumours of the pineal region and thalamus, and why abnormalities of vertical gaze are often associated with these defects. In certain neurodegenerative disorders such as progres- sive supranuclear palsy, convergence is also often impaired. Inborn defects of the convergence reaction also occur in some forms of strabismus. Convergence-​retraction nystagmus can be induced by having the patient look upward, having him make saccades verti- cally upward, or look at a moving optokinetic drum with its stripes going downward. Instead of vertical saccades, rapid, convergent eye movements result that are associated with retractions of the eyeball. The site of damage is the posterior commissure or in rare cases a bilateral disorder of the riMLF. As a general rule, most often it is necessary to combine the patho- logical clinical findings of the different eye movement systems to differentiate between a central and a peripheral vestibular disorder, and to make an exact topographical diagnosis within the brainstem and cerebellum. Dizziness and vertigo Vertigo, dizziness, and disequilibrium are common complaints of patients of all ages, particularly older people. The lifetime preva- lence of vertigo and dizziness is about 30%. The clinical spectrum of vertigo is broad, extending from vestibular rotatory vertigo with nausea and vomiting to postural imbalance, gait disorders, and presyncope light-​headedness, from drug intoxication to hypo- glycaemic dizziness, from visual vertigo to phobias and panic attacks, and from motion sickness to height vertigo. Appropriate preventions and treatments differ for the various types of dizziness and vertigo; they include drug therapy, physical therapy, psycho- therapy, and surgery. Vertigo usually implies a mismatch of the vestibular, visual, and somatosensory systems. These three sensory systems subserve both static and dynamic spatial orientation, locomotion, and control of posture by constantly providing reafferent cues. The sensory in- formation is partially redundant in that two or three senses may simultaneously provide similar information about the same action. Thanks to this overlap of their functional ranges, it is possible for one sense to substitute, at least in part, for deficiencies in the others. When information from two sensory sources conflicts, the inten- sity of the vertigo is a function of the degree of mismatch: it is in- creased if information from an intact sensory system is lost as, for example, in patients with pathological vestibular vertigo who close their eyes. The distressing sensorimotor consequences of the mis- match are frequently based on our earlier experiences with orienta- tion, balance, and locomotion (i.e. there is a mismatch between the expected and the actually perceived pattern of multisensory input). Vertigo may thus be induced by physiological stimulation of the intact sensorimotor systems (height vertigo, motion sickness) or by pathological dysfunction of any of the stabilizing sensory sys- tems, especially the vestibular system. The symptoms of vertigo in- clude sensory qualities identified as arising from vestibular, visual, and somatosensory sources. As distinct from one’s perception of self-​motion during natural locomotion, the experience of vertigo is linked to impaired perception of a stationary environment; this perception is mediated by central nervous system (CNS) processes known as ‘space constancy mechanisms’. Loss of the external sta- tionary reference system—​required for orientation and postural regulation—​contributes to the distressing mixture of self-​motion and surround motion. Physiological and clinical vertigo syndromes are commonly char- acterized by a combination of phenomena involving perceptual, ocular motor, postural, and autonomic manifestations: vertigo, nys- tagmus, ataxia, and nausea. These four manifestations correlate with different aspects of vestibular function and emanate from different sites within the CNS: 1 The vertigo itself results from a disturbance of cortical spatial orientation. 2 Nystagmus (see earlier) is caused by a direction-​specific imbal- ance in the VOR, which activates brainstem neuronal circuitry from the labyrinth to the eyes but also to the cerebellum and cortex. 3 Postural imbalance is caused by inappropriate or abnormal activation of monosynaptic and polysynaptic vestibulospinal pathways. 4 The unpleasant autonomic responses with nausea, vomiting, and anxiety travel along ascending and descending vestibuloautonomic pathways to activate the medullary vomiting centre. More than 50% of all patients presenting with dizziness, vertigo, or disequilibrium in a neurological dizziness unit will be suffering from one of the six following common syndromes (Table 24.6.2.1): Table 24.6.2.1  Frequency of different vertigo syndromes in 30682 patients seen in a outpatient dizziness unit Diagnosis Frequency n % Functional dizziness 4556 14.8 BPPV 4532 14.8 Central vestibular vertigo 4101 13.4 Vestibular migraine 3650 11.9 Menière’s disease 3028 9.9 Unilateral vestibulopathy 2797 9.1 Bilateral vestibulopathy 2081 6.8 Vestibular paroxysmia 1000 3.3 Psychogenic vertigo 776 2.5 Perilymph fistula/SCDS unknown vertigo syndromes other disorders 159 1352 2650 0.5 4.4 8.6 BPPV, benign paroxysmal positional vertigo. 24.6.2  Eye movements and balance 5927 benign paroxysmal positional vertigo (BPPV), functional, central vertigo, vestibular migraine, Menière’s disease, or acute unilateral vestibulopathy. Clinicians unfamiliar with patients complaining of dizziness can most effectively deepen their knowledge by acquainting them- selves with these six most frequently met and challenging condi- tions of vertigo. Diagnosis and management of vertigo syndromes always require interdisciplinary thinking, and history taking is still much more important than recordings of eye movements or brain imaging techniques. Although most clinicians welcome the attempts to develop computer interview systems for use with neuro-​otological patients, and expert systems as diagnostic aids in otoneurology, their application in a clinical setting is still quite limited. The sensation of spinning vertigo indicates a dysfunction of the labyrinth (specifically of the semicircular canals which sense ro- tary acceleration), the vestibular nerve, or the caudal brainstem, which contains the vestibular nuclei. Dizziness is more difficult to assess because of its subjective character and its variety of sensa- tions. The patient history is the key to the diagnosis. One should focus on four aspects, ‘the triple T A’s’: 1 Time course of the symptoms A) attacks:  sec–​min:  BPPV (<1 min), vestibular paroxysmia (<1 min), superior canal dehiscence syndrome; min–​hrs: vestibular migraine (5 min–​72 h), Menière’s disease (20 min–​12 h); B) acute onset, lasting days to weeks acute unilateral vestibulopathy (‘vestibular neuritis’), brainstem or cere- bellar infarction; C) persisting symptoms (>6 months) bilateral vestibulopathy, functional dizziness, neurodegenerative disorders. 2 Type/​form of vertigo, for example, spinning vertigo, dizziness, or postural imbalance. 3 Triggers, situations, and circumstances when the symptoms occur (e.g. changes of head or body position typical of BPPV, changes of pressure typical of superior canal dehiscence syn- drome), or improve (e.g. small amounts of alcohol or sports, typical of functional dizziness). 4 Accompanying symptoms (from the inner ear such hearing loss, pressure in the affected ear, or tinnitus typical of Menière’s disease; from the brainstem such as double vision, perioral par- aesthesia, facial weakness, or hemiparesis indicating a central lesion; or migraineous symptoms typical of vestibular migraine). Healthy control (1) L (2) (3) R Time Amplitude Head rotation Eye movement Lesion of the RIGHT labyrinth Saccade (b) (a) (3) (2) (1) (1) (2) (3) L R Head rotation Eye movement Eye position Fig. 24.6.2.3  Clinical bedside testing of the horizontal vestibulo-​ ocular reflex (VOR) by the Halmagyi–​Curthoys head-​impulse test. Fast 20–​30° rotations of the head towards the side of the lesion show the dynamic deficit of the horizontal VOR. In contrast to the healthy control (a), the patient is not able to generate a fast contraversive eye movement and has to perform a corrective (catch-​up) saccade to refixate the target (b). This is the clinical sign of the deficit of the VOR. It is important to instruct the patient to look carefully at the examiner’s nose and to apply brief, high-​acceleration head thrusts to detect a unilateral peripheral vestibular deficit (e.g. due to acute unilateral vestibulopathy or a vestibular schwannoma). Table 24.6.2.2  Pharmacological therapies for vertigo Therapy Type of vertigo/​dizziness Vestibular suppressants Symptomatic relief of nausea (in acute peripheral and central vestibular lesions), prevention of motion sickness; should not be given for more than a few days Antiepileptic drugs (carbamazepine/​oxcarbazepine) (limited evidence) Vestibular paroxysmia, epileptic vestibular aura (very rare), paroxysmal dysarthria or ataxia in multiple sclerosis, other central vestibular paroxysms, superior oblique myokymia β-​Receptor blockers, antiepileptic drugs (topiramate, valproic acid) (limited evidence) Vestibular migraine β-histine dihydrochloride, high dosage (≥96 mg three times daily) and long term (≥12 months) (limited evidence) Menière’s disease Ototoxic antibiotics (gentamicin, transtympanically; several controlled trials) Menière’s disease (Menière’s drop attacks—​‘Tumarkin’s otolithic crisis’) Corticosteroids (limited evidence) Acute unilateral vestibulopathy, autoimmune inner ear disease, in particular Cogan’s syndrome 4-​Aminopyridine (5 to 10 mg three times daily; two controlled trials) or its sustained-​release form (10 mg two times per day) Downbeat nystagmus 4-​Aminopyridine (5 mg three times daily; one controlled trial) or its sustained-​release form (10 mg two times per day) Episodic ataxia type 2 Selective serotonin reuptake inhibitors (limited evidence) Functional dizziness section 24  Neurological disorders 5928 History taking also allows the early differentiation of vertigo and disequilibrium disorders into seven categories that serve as a prac- tical guide for differential diagnosis: 1 Dizziness and light-​headedness (functional dizziness, presyncopal dizziness, or drug intoxication) 2 Spontaneous recurrent attacks of spinning vertigo (vestibular paroxysmia, Menière’s disease, vestibular migraine) 3 Spinning vertigo for many days (acute unilateral vestibulopathy, Wallenberg’s syndrome) 4 Positioning/​positional vertigo (BPPV, central positional vertigo) 5 Postural imbalance and gait disorder (typical of bilateral vestibulopathy) 6 Oscillopsia (apparent motion of the visual scene), acute unilat- eral vestibulopathy or downbeat nystagmus; it also occurs in bilateral vestibulopathy, but only when patients walk or turn their head 7 Vertigo associated with auditory dysfunction (Menière’s disease, Cogan’s syndrome) Every patient who has vertigo or dizziness has to be examined by six tests:  first, look for a spontaneous nystagmus with and without Frenzel’s spectacles or M glasses as described earlier. Second, apply the head-​impulse test for the VOR. The VOR holds images of the seen world steady on the retina during brief head rotations and locomotion. This important clinical bedside test of the horizontal VOR is illustrated in Fig. 24.6.2.3. This test allows the doctor to find out whether there is a unilateral or bilateral peripheral vestibular deficit. Third, the diagnostic pos- itional manoeuvre looks for a positioning nystagmus (i.e. BPPV). Fourth, determination of the subjective visual vertical which is tilted in more than 90% of all patients with an acute unilateral central or peripheral vestibular disorders. Fifth, the Romberg test with the eyes open and closed. Sixth, the earlier detailed examination of eye movements is also important, to differen- tiate between peripheral and central forms of vertigo because the latter are almost always associated with central ocular motor dysfunction. To differentiate between an acute peripheral and a central lesion one should look for ‘the big five’: (1) skew deviation/​vertical diver- gence; (2) peripheral vestibular spontaneous nystagmus versus cen- tral fixation nystagmus; (3) gaze-​evoked nystagmus contralateral to the spontaneous nystagmus; (4) whether the head-​impulse test is normal or pathological (if normal, this indicates a central lesion in acute vertigo) (5) patient not able to stand unaided. Management of the dizzy patient The prevailing good prognosis of vertigo should be emphasized be- cause of the following: • Many forms of vertigo have a benign cause and are characterized by spontaneous recovery of vestibular function or central com- pensation of a peripheral vestibular tone imbalance. • Most forms of vertigo can be effectively relieved by pharmaco- logical treatment (Table 24.6.2.2), physical therapy in the form of liberating manoeuvres for BPPV (Table 24.6.2.3) or vestibular exercises and balance training for uni-​ or bilateral vestibulo­ pathy or central forms of vertigo, psychotherapy, in particular for functional dizziness or—​more and more rarely—​surgery. There is, however, no common treatment, and vestibular suppressants provide only symptomatic relief of vertigo and nausea. A  specific therapeutic approach thus requires recog- nition of the numerous particular pathomechanisms involved. Such therapy can include causative, symptomatic, or preventive approaches. H A P UT H H Cup P A UT RE LE 195° H H UT A P UT Cup A P RE LE 105° H P H UT A P H A UT Cup LE RE H P H UT A P H Cup A UT RE LE 1 2 3 4 90° Fig. 24.6.2.4  Schematic drawing of the Semont liberatory manoeuvre in a patient with typical benign paroxysmal positioning vertigo (BPPV) of the left ear. Boxes from left to right: position of body and head, position of labyrinth in space, position, and movement of the clot in the posterior canal and resulting cupula deflection, and direction of the rotatory nystagmus. The clot is depicted as an open circle within the canal; a black circle represents the final resting position of the clot. (1) In the sitting position, the head is turned horizontally 45° to the unaffected ear. The clot, which is heavier than endolymph, settles at the base of the left posterior semicircular canal. (2) The patient is tilted approximately 105° towards the left (affected) ear. The change in head position, relative to gravity, causes the clot to gravitate to the lowermost part of the canal and the cupula to deflect downwards, inducing BPPV with rotatory nystagmus beating towards the undermost ear. The patient maintains this position for 1 min. (3) The patient is turned approximately 195° with the nose down, causing the clot to move towards the exit of the canal. The endolymphatic flow again deflects the cupula so that the nystagmus beats towards the left ear, now uppermost. The patient remains in this position for 1 min. (4) The patient is slowly moved to the sitting position; this causes the clot to enter the utricular cavity. A, P, and H: anterior, posterior, and horizontal semicircular canals; Cup, cupula; UT, utricular cavity; RE, right eye; LE, left eye. Brandt T, Steddin S, Daroff RB (1994). Therapy for benign paroxysmal positioning vertigo, revisited. Neurology, 44, 796–​800. Copyright © 1994, American Academy of Neurology. 24.6.2  Eye movements and balance 5929 The essential characteristics are given for benign paroxysmal pos- itional vertigo (Fig. 24.6.2.4, Box 24.6.2.1 and also see Table 24.6.2.3), Menière’s disease (Box 24.6.2.2), acute unilateral vestibulopathy (Box 24.6.2.3), bilateral vestibulopathy (Box 24.6.2.4), and vestibular migraine (Box 24.6.2.5). Table 24.6.2.3  Physical therapies for vertigo Therapy Type of vertigo Liberatory or repositioning manoeuvres Benign paroxysmal positional vertigo (BPPV) Vestibular exercises and balance training Vestibular rehabilitation, central compensation of acute vestibular loss, habituation for prevention of motion sickness, improvement of balance skills in unilateral or bilateral peripheral vestibular deficits and central vestibular deficits Box 24.6.2.1  Benign paroxysmal positional vertigo (typical posterior semicircular canal type, p-​BPPV) Clinical syndrome Brief recurrent attacks of rotational vertigo and concomitant vertical rota- tory nystagmus precipitated by rapid head-​trunk tilt towards the affected ear or by neck extension (when first lying down in bed, sitting up from a supine position, turning over in bed from one side to the other, extending the neck to look up): • Latency—​vertigo and nystagmus begin 1 s or more after head tilt • Duration—​attacks last less than 60 s • Nystagmus—​vertical rotatory, with the fast phase beating upwards with a clockwise or anticlockwise rotatory component • Reversal—​when the patient returns to the seated position, vertigo and nystagmus reoccur in the opposite direction • Fatigability—​repetition of the manoeuvres results in ever-​lessening symptoms Incidence/​age/​sex Most common cause of vestibular vertigo that manifests throughout life, particularly in older people. Lifetime prevalence: at least 3% with inci- dence peaking in the sixth and seventh decades. Pathomechanism ‘Canalolithiasis’ most often of the posterior semicircular canal; dislodged otoconia (degeneration, trauma) congeal to form a free-​floating ‘heavy’ clot, which always gravitates to the most dependent part of the canal during changes in head position, thereby causing push or pull forces on the cupula. Aetiology • ‘Idiopathic’ forms over 95% • Symptomatic forms due to head trauma (relatively often bilateral BPPV), after acute unilateral vestibulopathy, known other inner ear disorders, vestibular migraine, or prolonged bed rest Course/​prognosis Natural history is considered benign because it resolves spontaneously in 70% of the patients within weeks, persists in about 20–​30% when un- treated, and recurs in 30–​50% after variable periods of years. Management • Liberating/​repositioning manoeuvres to free the canal of the ‘heavy’ clot (Fig. 24.6.2.4): Semont’s manoeuvre or Epley’s manoeuvre (both are equally effective) These are successful in less than 95% of patients within days or weeks. Differential diagnosis Central positional vertigo/​nystagmus, BPPV of a horizontal canal, ves- tibular migraine with positioning or positional vertigo, vestibular paroxysmia, superior canal dehiscence syndrome. Based on Brandt T, Dieterich M, Strupp M (2012). Vertigo and dizziness—​ common complaints. 2nd edition Springer, London. Box 24.6.2.2  Menière’s disease Clinical syndrome • Recurrent attacks of vertigo, lasting 20 min to 12 hours • Hearing impairment (<2000 Hz, at least 30 dB, related to the attacks of vertigo) • Fluctuating tinnitus in the affected ear • Subjective fullness of affected ear • Rarely, vestibular drop attacks (Tumarkin’s otolith crisis) Monosymptomatic forms are possible at the beginning of the disease, with variable auditory and vestibular deficits in the intervals between attacks. Contrast-​enhanced high-​resolution MRI of the inner ear can show endolymphatic hydrops. Lifetime prevalence/​age/​sex • 0.5% • Affects mainly age group from 30 to 50 years • Incidence in males and females roughly equal • Rare in children Pathomechanism • Endolymphatic hydrops of the labyrinth due to insufficient endo- lymph reabsorption in the endolymphatic sac or blockage of longitu- dinal endolymph flow • Attacks: periodic leakage or ruptures of the endolymph membrane with potassium-​induced depolarization of the nerve • Intervals: persisting impaired vestibular and/​or audiological deficits Aetiology • Idiopathic (aetiology not known in more than 95%) • Acquired, ‘delayed endolymphatic hydrops’ (i.e. inflammation or trauma, infectious, autoimmunological, traumatic), rarely hereditary Course/​prognosis • Usually begins in one ear with increasing frequency of attacks and major auditory/​vestibular deficit occurring during the first years • After 5 years both ears are affected in 15% of the patients if not treated Management • Medical:  β-histine (e.g. β-histine dihydrochloride):  at least 96 mg three times daily for at least 12 months as a prophylactic treatment (limited evidence) • If treatment with β-histine 96 mg three times per day does not pre- vent attacks, the dosage can be increased to up to 1440 mg per day. Very rarely steroids or ototoxic antibiotics are indicated: gentamicin transtympanically in low dosages of 10 mg with long intervals of at least 4 weeks because of the delayed ototoxicity—​‘wait and see’. Differential diagnosis • Vertigo migraine • Superior canal dehiscence syndrome • Vestibular paroxysmia • Acute unilateral vestibulopathy • Transient ischaemic attacks • Cogan’s syndrome section 24  Neurological disorders 5930 Box 24.6.2.3  Acute unilateral vestibulopathy (‘vestibular neuritis’) Clinical syndrome Acute onset of sustained: • Spinning vertigo • Postural imbalance with falls towards the affected ear • Horizontal–​rotatory spontaneous nystagmus (towards the unaffected ear) • Nausea and vomiting • Pathological head-​impulse test • Unilateral hypo-​ or unresponsiveness in caloric testing Incidence/​age/​sex Third most common cause of peripheral vestibular vertigo that mani- fests throughout life (affects mainly ages 30–​60 years; rare in children) without preference of sex. Pathomechanism Acute partial unilateral loss of labyrinthine function (most often hori- zontal and anterior semicircular canal paresis only) with a vestibular tone imbalance in yaw and roll planes. Aetiology Most probably herpes simplex virus 1 infection of the superior division of the vestibular nerve trunk. Course/​prognosis Spontaneous recovery within 1–​6 weeks due to: • Peripheral restoration of labyrinthine function (incomplete in about 50%) • Central compensation of vestibular tone imbalance • (Contralateral) vestibular, somatosensory, and visual substitution of the vestibular deficit Management Medical treatment Corticosteroids (beginning, for instance, with 100 mg 6-​methylprednisolone per day within 3 days after symptoms, then taper every fourth day by 20 mg) (so far only one randomized controlled trial) Antivertiginous drugs (for instance dimenhydrinate, but just for up to three days) Physical therapy (vestibular exercises) Differential diagnosis • Acute central brainstem lesions at the root entry zone of nerve VIII and the vestibular nucleus (multiple sclerosis plaques, small pontomedullary infarcts): ‘vestibular pseudoneuritis’ • Midline cerebellar infarction • Peripheral labyrinthine and vestibular nerve disorders, such as vas- cular anterior inferior cerebellar artery infarcts or Menière’s disease which may begin monosymptomatically • Vestibular migraine Box 24.6.2.4  Bilateral vestibulopathy Clinical syndrome Symptoms • Postural imbalance with unsteadiness of gait (particularly in the dark or on unlevel ground); no symptoms when sitting or lying down • Oscillopsia associated with head movements or when walking (40%) • There may be episodes of vertigo early in the development of bilateral vestibular failure but not in chronic state • Impaired spatial memory Signs • Bilateral pathological head-​impulse test • Absent or markedly reduced vestibulo-​ocular reflex with bithermal caloric testing and/​or the video-​head-​impulse test • Increased postural sway with eyes closed and/​or standing on foam rubber • Subtype associated with cerebellar ocular signs (in particular down- beat nystagmus) and polyneuropathy (so-​called cerebellar ataxia, neuropathy, and vestibular areflexia syndrome—​CANVAS) Incidence/​age/​sex • Often overlooked condition, in particular in older people; most fre- quent cause of postural imbalance in elderly subjects • Without preference of sex Pathomechanism • Progressive loss of bilateral labyrinthine and/​or vestibular nerve func- tion due to various aetiologies with concurrent somatosensory and visual ‘compensation’ (substitution) of vestibular function for spatial orientation, ocular stabilization, and postural control Aetiologies • Unclear in 75% (idiopathic, neurodegenerative), ototoxicity (oto- toxic antibiotics), bilateral Menière’s disease, meningitis, associated with cerebellar degeneration and downbeat nystagmus, so-​called CANVAS, bilateral vestibular schwannomas in neurofibromatosis type 2, immune-​mediated inner ear disease, bilateral sequential vestibular neuritis, congenital malformations, familial vestibulopathy Course/​prognosis Bilateral vestibular failure may develop simultaneously or sequentially, take an abrupt or slowly progressive course, and be complete or incom- plete. Permanent loss of vestibular function is most frequent. Management • Explanation of the deficit to the patient often causes considerable relief • Prevention (very restrictive with the use ototoxic drugs, in particular gentamycin) • Causative treatment (Menière’s disease, autoimmune inner ear dis- eases, such as Cogan syndrome) • Vestibular rehabilitation/​balance training Differential diagnosis • Of the various disorders causing bilateral vestibulopathy • Of disorders similar in symptomatology (unsteadiness and oscillopsia): — Cerebellar ataxia and cerebellar ocular motor disorders without bilateral vestibular failure (e.g. downbeat nystagmus), which, how- ever, is often associated with bilateral vestibulopathy — Functional dizziness — Intoxication — Vestibular paroxysmia — Superior canal dehiscence syndrome — Orthostatic hypotension — Visual disorders — Unilateral vestibular loss 24.6.3 Hearing loss 5931 Linda Luxon 24.6.3 Hearing loss 5931 Linda Luxon 24.7 Disorders of movement 5937 24.7.1 Subcortical 24.7 Disorders of movement 5937 24.7.1 Subcortical structures: The cerebellum, basal ganglia, and thalamus 5937 Mark J. Edwards and Penelope Talelli 24.6.3  Hearing loss 5931 FURTHER READING Brandt T, Dieterich M, Strupp M (2013). Vertigo and dizziness—​ common complaints. 2nd edition. Springer, London. Brandt T, Dieterich M (2017). The dizzy patient: don't forget disorders of the central vestibular system. Nat Rev Neurol, 13, 352–62. Brandt T, Steddin S, Daroff RB (1994). Therapy for benign parox- ysmal positioning vertigo, revisited. Neurology, 44, 796–​800. Brandt T, Strupp M, Dieterich M (2015). Five keys for diagnosing most vertigo, dizziness, and imbalance syndromes:  an expert opinion. J Neurol, 261, 229–​31. Herdman, SJ, Clendaniel R (2014). Vestibular rehabilitation, 4th edi- tion. FA Davies, Philadelphia, PA. Leigh RJ, Zee DS (2015). Neurology of eye movements, 5th edition. FA Davies, Philadelphia, PA. Lempert T, et  al. (2012). Vestibular migraine:  diagnostic criteria. J Vestib Res, 22, 167–​72. Lopez-​Escamez JA, et al. (2015). Diagnostic criteria for Menière’s dis- ease. J Vestib Res, 25, 1–​7. Staab JP, Eckhardt-Henn A, Horii A et al. (2017). Diagnostic criteria for persistent postural-perceptual dizziness (PPPD): Consensus document of the committee for the Classification of Vestibular Disorders of the Barany Society. J Vestib Res, 27, 191–208. Strupp M, et al. (2014). Central ocular motor disorders, including gaze palsy and nystagmus. J Neurol, 261 Suppl 2, S542–​58. Strupp M, et  al. (2015). Pharmacotherapy of vestibular and cere- bellar disorders and downbeat nystagmus: translational and back-​ translational research. Ann N Y Acad Sci, 1343, 27–​36. Strupp M, Kim JS, Murofushi T et al. (2017). Bilateral vestibulopathy: Diagnostic criteria Consensus document of the Classification Committee of the Barany Society. J Vestib Res, 27, 177–89. Strupp M, Lopez-Escamez JA, Kim JS et  al. (2016). Vestibular paroxysmia: diagnostic criteria. J Vestib Res, 26, 409–15. von Brevern M, Bertholon P, Brandt T et al. (2015). Benign par- oxysmal positional vertigo: Diagnostic criteria. J Vestib Res, 25, 105–17. 24.6.3  Hearing loss Linda Luxon Our hearing is a choice and dainty sense, and hard to mend, yet soon it may be marred. Blows, falls and noise . . . all these . . . breed tingling in the ears and hurt our hearing. Physicians of the Medical School of Salerno ESSENTIALS The World Health Organization has estimated that 360 million people worldwide are affected by disabling hearing loss, making hearing impairment—​the hidden handicap frequently overlooked by all clinicians—​the most common sensory impairment. Most of those affected are in low-​ and middle-​income countries, but 17% of the adult population in the United Kingdom are affected, with three-​ quarters being over 60 years of age. Causes may relate to cochlear, neurological, general medical, or iatrogenic pathology, with half of all cases being preventable by primary prevention. Clinical examination includes visual inspection of the anatomy of the external ear and tympanic membrane, and tuning-​fork tests, which may distinguish conductive from sensorineural hearing loss. Audiological investigations will (1) identify impairment (i.e. quan- tify audiometric thresholds at each frequency) and (2) determine the site of pathology (i.e. differentiate conductive from sensorineural de- fects); differentiate cochlear from retrocochlear abnormality; define central auditory dysfunction in the brainstem, midbrain, or auditory cortex and identify non​organic loss. Epidemiology and causes—​(1) Prevalence in adults—​factors include age, gender, genetic susceptibility, occupational group, ototoxicity, smoking, drinking, obesity, head injury, and hazardous noise ex- posure. (2) Congenital hearing impairment in children—​over one-​ half of cases are explained by factors associated with admission to a neonatal intensive-​care unit, genetic factors, and craniofacial ab- normalities. (3) Acquired hearing impairment in children—​the com- monest cause is a conductive hearing loss due to chronic secretory otitis media; meningitis (particularly meningococcal) is the com- monest cause of acquired sensorineural hearing loss in the United Kingdom. (4) Many of the preventable causes of hearing impairment remain common in the developing world:  consanguineous mar- riages, birth trauma, childhood infections, noise exposure, and the unlicensed sale of ototoxic drugs. Treatment—​this may involve (1)  protection from noise hazards and ototoxic drugs and management of chronic secretory otitis media; (2)  auditory rehabilitation—​including environmental aids, Box 24.6.2.5  Vestibular migraine Clinical features • At least five attacks of vertigo/​dizziness, duration 5 min to 72 hours • Migraine or history of migraine • More than 50% of the attacks associated with migraineous symptoms Examination finding During the attack • Pathological spontaneous or positional nystagmus (about 70%) • Postural imbalance (about 90%) During the attack-​free interval • Central ocular motor signs (>60%) less severe than in the attack • Peripheral vestibular deficit (10–​20%) Incidence/​age/​sex • The most frequent cause of spontaneous recurrent attacks of vertigo • In children the most frequent cause of any vertigo and dizziness • Females are more often affected than males (about 2:1) Management of vestibular migraine • Treatment of attacks with aspirin (not in children) or other non​steroidal anti-​inflammatory drug (NSAID) and dimenhydrinate • Prophylactic treatment with β-​blocker, topiramate, or valproic acid, if patient has more than two attacks per month section 24  Neurological disorders 5932 instruction in communication skills, and (if accepted by the patient) hearing aids; (sometimes) (3) surgery—​restorative in some cases of conductive hearing loss; implantable devices for totally deafened adults and children; and (4)  psychological/​social support to ad- dress the increased prevalence of mental health disorders, isola- tion, and limited occupational choices associated with significant hearing loss. Tinnitus Defined as a noise in the head or ears lasting for more than five minutes and unrelated to an external stimulus. Tinnitus increases in frequency with age, affecting about 20% of people over 60 years, although only 4% complain of the symptoms. However, 1–​2% report severe impairment of quality of life. It can be associated with many conditions, frequently in association with hearing impairment. Management—​this is primarily medical, including the following interventions:  (1) psychological—​explanation of tinnitus mechan- isms, cognitive behavioural therapy, or tinnitus retraining therapy and, if necessary, treatment of anxiety/​depression; (2) prosthetic—​ provision of hearing aids, noise generators to ‘mask’ tinnitus with desirable environmental noise; and (rarely) (3)  pharmacological—​ intravenous lidocaine (lignocaine) can result in the disappearance or amelioration of tinnitus, but the short duration of the effect and the adverse reactions prevent its use. There is no evidence to support pharmacotherapy in reducing the severity and intrusiveness of tinnitus. Hearing loss Pathophysiology For clinical purposes the ear is separated into three parts: the ex- ternal, middle, and internal ear (Fig. 24.6.3.1). The external ear is important in funnelling sound to the tympanic membrane and in the localization of sound. The middle-​ear ossicles connect the tym- panic membrane to the oval window of the cochlea, such that sound waves cause displacement within the fluid-​filled compartment of the membranous labyrinth. Within the internal ear, the mechanical ac- tivity at the oval window is transduced into neural responses by the hair cells of the organ of Corti (Fig. 24.6.3.2). Disorders of the external and middle ear result in abnormalities of the mechanical transmission of sound from the environment to the internal ear, and give rise to a conductive hearing loss (i.e. bone-​conducted sounds are louder than air-​conducted sounds). Common examples include impacted wax, serous otitis media (glue ear), chronic otitis media, and disorders of the ossicular chain (e.g. otosclerosis, and traumatic discontinuity). Disorders of the internal ear and cranial nerve VIII characteristic- ally give rise to a sensorineural hearing loss, in which the perception of both bone-​ and air-​conducted sounds is reduced and the appreci- ation of the intensity of sound and the frequency resolution of com- plex sounds are impaired. Many conditions may affect the cochlea, ranging from inherited, congenital, or iatrogenic non​syndromal or syndromal malformations to ototoxic damage (aminoglycoside, antimalarial, loop diuretics, chemotherapeutic drugs), ischaemia including in the posterior circulation, vasculitides, infections (mumps, rubella, syphilis, cytomegalovirus), autoimmune dis- orders, degenerative disorders, trauma, and idiopathic conditions such as Menière’s disease. Much doubt has been cast on so-​called ‘presbyacusis’, which may merely reflect an accumulation of toxic/​ traumatic insults to the ear over many years, and recent advances in molecular biology and genetics have shown the role of genetic mutations/​deletions in late-​onset/​progressive hearing impairments. Sudden sensorineural hearing loss, usually of cochlear origin, most commonly results from viral, vascular, or autoimmune disease. Importantly, recent studies have emphasized auditory plasticity with tonotopic reorganization in the auditory cortex, following audi- tory stimulation both with hearing aids and cochlear implantation. Pathology of cranial nerve VIII leading to auditory neuropathy and hearing impairment may present as an isolated phenomenon, but has also been defined in genetic disorders, including spinocerebellar degenerations, trauma, cerebellopontine angle tumours, bony dis- orders such as Paget’s disease, infective disorders (meningitis) and inflammatory conditions (sarcoidosis). Central auditory disorders may be developmental or acquired in origin and present with difficulties hearing in background noise and discriminating degraded speech (e.g. over a loudspeaker), and with sound localization, often with a normal or near-​normal audiogram. Unilateral neurological pathology rarely gives rise to an audiometric hearing impairment as a consequence of bilateral representation of each cochlea at every level of the central auditory pathway above the cochlear nuclei. Rarely, bilateral brainstem pathology may present as a symmetrical sensorineural hearing loss, whereas bitemporal cor- tical pathology may give rise to cortical deafness or auditory agnosia. Clinical examination Clinical examination requires examination of the anatomy of the ex- ternal ear to define visible signs of congenital ear disease (pits, tags, nodules, or malformations) and evidence of other craniofacial fea- tures suggestive of syndromal hearing impairment. In addition, a detailed examination of the tympanic membrane is required to de- fine the presence of pathology within the middle ear. Wax or debris obstructing the external auditory meatus should be removed by or under the supervision of an experienced clinician. Syringing is External auditory meatus Pinna Tympanic membrane Eustachian tube Semicircular canals Ossicles Oval window Cochlea Vestible External ear ear Internal ear Eighth nerve Middle Fig. 24.6.3.1  Diagram to illustrate the anatomy of the peripheral auditory system. 24.6.3  Hearing loss 5933 contraindicated in the presence of an infection or possible tympanic membrane perforation. Tuning-​fork tests (Fig. 24.6.3.3) remain the most valuable clinical test of auditory function and frequently enable a clinician to distinguish a conductive from a sensorineural hearing loss. The tests are based on two physiological facts: first, the inner ear is normally more sensitive to sound conducted by air than to that conducted by bone; second, in the presence of a purely con- ductive hearing loss, the affected ear is subject to less air-​conducted environmental noise, making it more sensitive to bone-​conducted sound. A general medical and neurological examination is manda- tory to define syndromes and the plethora of general medical con- ditions associated with hearing impairment. A detailed vestibular assessment is also of value. Investigations A battery of audiological tests is required to: • quantify audiometric thresholds at each frequency • differentiate a conductive from a sensorineural hearing loss • differentiate a cochlear from a retrocochlear abnormality • identify central auditory dysfunction in the brainstem, midbrain, or auditory cortex • identify a non​organic component Tests can be defined as subjective or objective (i.e. dependent or in- dependent of patient cooperation) in terms of providing auditory data. Two pathophysiological phenomena are of importance in the dif- ferentiation of a cochlear, sensorineural hearing loss from a neural VIII nerve or cochlear nuclei dysfunction: • Loudness recruitment is defined as an abnormally rapid increase in loudness, with an increase in intensity of the stimulus, and is characteristic of disorders affecting the hair cells of the organ of Corti, but is absent in the pathology of nerve VIII. • Abnormal auditory adaptation is a decline in discharge frequency with time, observed after an initial burst of neural activity in re- sponse to an adequate continuing stimulus applied to the organ of Corti. This phenomenon is characteristic of nerve VIII and brain- stem auditory dysfunction. Pure-​tone audiometry is the most widely available, subjective, quan- titative test of auditory thresholds. Electronically generated pure tones are delivered by earphones and the individual is required to respond to the quietest tone, at given frequencies between 125 and 8000 Hz in each ear. The sound may be delivered by air con- duction or, if the tones are delivered by a bone vibrator on the mastoid process, by bone conduction. In the latter test condition, as the intra-​aural attenuation for a bone-​conducted sound is neg- ligible, masking of the ear not under test with narrow-​band noise is mandatory. Bone-​conduction thresholds significantly better than air-​conduction thresholds (Fig.  24.6.3.4a) indicate a conductive hearing loss, whereas similar bone-​conduction and air-​conduction thresholds (Fig. 24.6.3.4b) are characteristic of sensorineural (i.e. cochlear or neural hearing loss). Impedance studies. The middle ear stapedius muscle contracts bi- laterally in response to loud sound, directed into either ear. Using an impedance bridge, the minimum intensity of sound at a given fre- quency required to this response and thus a movement of the tym- panic membrane, can be measured (the acoustic reflex threshold). This objective measure enables recruitment and abnormal auditory adaptation to be measured, and allows assessment of middle ear, cochlear, nerve VIII, and brainstem auditory function. Scala vestibuli Reissner’s membrane Spiral limbus Inner sulcus Cochlear nerve fibres Osseous spiral lamina Habenula perforata Inner rod Tunnel of Corti Scala tympani Basilar membrane Spiral ligament Outer sulcus Stria vascularis Claudius’ cells Hensen’s cells Deiter’s cells Outer hair cells Reticular lamina Scala media Tectorial membrane Outer rod Inner hair cell Fig. 24.6.3.2  Diagram of the organ of Corti. (c) (b) (a) S S S Fig. 24.6.3.3  Diagram to illustrate the Weber tuning-​fork test in (a) a normal individual, (b) a case of unilateral sensorineural hearing loss, and (c) a case of unilateral conductive hearing loss, in which the sound is heard more effectively in the affected ear because of the lack of masking by environmental sounds. S, direction sound heard; o, tuning-​fork placement. section 24  Neurological disorders 5934 Otoacoustic emissions are weak signals that can be recorded in the ear canal and are the result of contractile properties of the outer hair cells of the cochlea. Measurement of otoacoustic emissions, thus provides objective information about cochlear function and has become the mainstay of universal neonatal hearing screening. Suppression of the otoacoustic emissions by delivery of sound to the contralateral ear allows a measure of efferent auditory function and is of particular diagnostic value in neurological diseases affecting auditory function. Speech audiometry is a subjective test requiring the individual to repeat standardized lists of words delivered at varying intensities through headphones. The responses are scored and provide an as- sessment of auditory discrimination. They are of particular value in assessing the efficacy of hearing-​aid provision. Electrophysiological tests provide the major objective means of assessing auditory function and siting pathology in the auditory system. Electrocochleography enables the measurement of the elec- trical output of the cochlea and cranial nerve VIII in response to an auditory stimulus, whereas brainstem auditory-​evoked responses are of particular value in discriminating between cochlear and nerve VIII cochlear nuclei dysfunction (Fig. 24.6.3.5). Recordings are obtained by averaging a series of time-​locked responses gen- erated by the major processing centres of the auditory system in response to a repetitive sound stimulus. Analysis of the waveform must be undertaken in conjunction with knowledge of the pure-​ tone thresholds to interpret the responses appropriately. Modifications of the test technique (e.g. use of 1000 Hz tone burst and binaural rapid rate stimulation) may facilitate clinical iden- tification or monitoring of intracranial lesions. Middle latency responses are generated in the thalamocortical pathway in the audi- tory cortex and, despite some practical difficulties, are deemed to be a valid objective test in the assessment of central auditory dys- function, although sleep and/​or sedation may affect the response. Cortical-​ or late-​evoked auditory responses are the most effective method of defining auditory threshold at each frequency in a pa- tient, who is unable or unwilling to cooperate and are essential in legal cases, in which a non​organic loss should always be excluded. Behavioural tests of central auditory function, include subjective tests of monaural low-​redundancy speech; pattern recognition, such as the frequency pattern test and duration pattern test, which rely primarily on right hemisphere function; auditory temporal reso- lution, such as the Gaps-​in-​Noise and dichotic speech, which relies on an intact corpus callosum to transfer information from the right to left hemisphere. Vestibular investigations and imaging are frequently required to confirm a diagnosis (e.g. congenital inner-​ear anomaly, Menière’s disease, and acoustic schwannoma), whereas cardiac, renal, gastro- intestinal, endocrine, and metabolic investigations may be highly relevant in specific cases (e.g. Jervell–​Lange–​Neilsen syndrome, aminglycoside ototoxicity, collagen vascular disease, ulcerative col- itis, Pendred syndrome, and autoimmune disorders). Right –20 –10 0 10 20 30 40 50 60 70 80 90 100 110 120 Hearing level (dBISO) 125 250 500 1000 2000 4000 6000 Frequency (Hz) Right Bone condition Left Masked Frequency (Hz) –20 –10 0 10 20 30 40 50 60 70 80 90 100 110 120 Hearing level (dBISO) 125 250 500 1000 2000 4000 6000 Left (a) (b) Fig. 24.6.3.4  Pure-​tone audiograms showing both air-​ and bone-​conduction thresholds and illustrating a right conductive hearing loss (a) and a left sensorineural hearing loss (b). 0 2 LL 0.3 V V III I V III II I RR 10 8 6 4 Fig. 24.6.3.5  Illustration of auditory-​evoked brainstem responses showing normal waves I, II, III, and V from the right ear (RR) and delayed waves III and V from the left ear (LL), in a case of a left acoustic neurinoma. 24.6.3  Hearing loss 5935 Management Appropriate management of both acute and chronic hearing loss re- quires a detailed history and examination to ensure both appropriate management of related general medical, neurological, and oto- logical conditions and protection from leisure (discothèques) and occupational noise hazards, and ototoxic drugs. Conductive hearing loss due to trauma, chronic middle-​ear disease, or otosclerosis may be surgically remediable, whereas recent animal studies have highlighted the possible future role of antioxidants in the ameli- oration of sensorineural hearing loss caused by chemotherapeutic agents, aminoglycoside antibiotics, and noise. Sudden sensorineural hearing loss is deemed to be a medical emergency, but there are no randomized controlled trials confirming the efficacy of the various therapeutic interventions advocated: steroids, antiviral agents, and haemodilution techniques. Auditory rehabilitation is a problem-​solving exercise centred on each individual patient, and depends on assessing both the audi- tory disability of the individual and the relevance of this to other important people in the patient’s life. Not only auditory impairment, but also communication skills, including lip-​reading ability, the use of visual cues, and the level of speech and language, together with psychological and sociological factors, must be considered. The remedial process may be straightforward in a highly motiv- ated patient in whom there is an uncomplicated hearing loss, al- though over-​the-​counter aids, without expert consultation, are in general less satisfactory than those prescribed following assessment. However, in the presence of a complicating factor, such as a hearing loss which is difficult to improve with a hearing aid (e.g. an audi- tory neuropathy or a patient with physical handicap (e.g. arthritis making hearing aid manipulation difficult), the particular problem must be addressed to ensure optimal support). In patients who have a negative view of hearing aids, environmental aids, and instruction in communication skills before the introduction of a hearing aid may facilitate long-​term rehabilitation. In general, the provision of a hearing aid is effective only when the patient themselves, rather than well-​meaning family members, wishes to get help. Although hearing aids play a pivotal role in audiological rehabili- tation, a detailed description of their provision and selection is out- side the scope of this chapter. For many patients, wearable hearing aids, which bring sound more effectively to the ear, are invaluable, but environmental aids (assisted-​listening devices such as amplification systems, alerting warning devices, e.g. flashing lights connected to a doorbell or an alarm clock) may be adequate. In addition, sensory substitution systems, for example, where visual signals are generated in response to auditory cues such as a telephone or doorbell ringing, or a baby crying, may be helpful to a hearing-​impaired person. The general principles of hearing-​aid provision include the fitting of a comfortable ear mould, which provides a secure mounting for the aid and a good acoustic connection between the aid and the ear canal. Hearing-​aid selection involves matching the amplification output of the aid at specific frequencies with that required by the user. A particular disability experienced in most hearing-​impaired people is that of hearing speech in a noisy environment and, although pro- grammable digital processing hearing aids are of some help in this situation, conventional aids provide selective amplification of the frequencies relevant to speech, with minimal amplification at the peak frequency of background noise. For patients with a markedly asymmetric sensorineural loss, the better hearing ear is usually amp- lified, while for patients with bilateral symmetrical loss, bilateral amplification generally results in better outcomes. Conventional aids may be divided into body-​worn and head-​worn aids, which can be in spectacles, behind the ear, in the ear, or in the canal in design. The major advantage of body-​worn aids is the very high gain and max- imum output that can be achieved, whereas the disadvantage is the unsightly nature of the device and the poor microphone placement. Cochlear implantation is one of the most significant advances in modern medicine, which transforms the life of patients with pro- found hearing loss. It carries a low major complication rate of ap- proximately 4%, although, usually transient, vestibular symptoms are common. Electronic devices convert sound into electrical cur- rent for the purpose of directly stimulating residual auditory nerve fibres to produce hearing sensations. The devices are implanted in the cochlea, usually with an electrode array, with an externally worn microphone and processor. Bilateral cochlear implants have been used, more effectively than unilateral implantation, in totally deafened adults and children with good results, and should be con- sidered in all cases of profound acquired hearing loss and in chil- dren in whom there is good evidence of auditory nerve preservation in both congenital and acquired hearing impairment. Recent ad- vances have demonstrated the benefit of cochlear implantation in single sided sensorineural hearing loss case, hearing preservation after cochlear implantation and the use of ‘short’ electrodes in iso- lated high frequency loss. Current work aims to develop a totally implantable device avoiding the use of an external microphone, pro- cessor, and transmitting coil. In the bilateral absence of a functional cranial nerve VIII (e.g. neurofibromatosis) brainstem implants have been shown to be of value. The value of counselling for the hearing-​impaired person by a skilled hearing therapist must be emphasized. Such simple hearing tactics as encouraging the individual to ensure that the light is al- ways on the speaker’s face, that he or she places himself so that the better ear is towards the speaker, and sitting close to the sound source thereby minimizing background noise, can greatly improve communication ability. For profoundly hearing-​impaired individ- uals, psychological problems associated with isolation and occu- pational handicaps are significant and it is therefore essential that psychological, medical, and social support are readily available. Tinnitus Tinnitus may be defined as a perception of sound that originates from within the head rather than from within the external world. Rarely, the sound may have an externally detectable component and is then termed ‘objective tinnitus’ as opposed to the more common ‘subjective tinnitus’. Less than 10% of tinnitus sufferers will report pulsatile tinnitus. The experience of tinnitus is universal, but the complaint of tinnitus is rare. Many conditions are associated with tinnitus, but it is frequently, although not always, associated with hearing impairment. The pro- posed pathophysiological mechanisms include: • decoupling of the stereocilia of the hair cells • misinterpretation of auditory neural activity by higher auditory centres section 24  Neurological disorders 5936 • self-​sustaining oscillation of the basilar membrane • spontaneous optoacoustic emissions • an abnormality of the spontaneous resting activity of primary audi- tory nerve fibres, either secondary to the hypo or hyperexcitability of damaged hair cells or as a direct consequence of the derange- ment of primary neurons themselves • damage to the myelin sheath between auditory nerve fibres, allowing ephaptic transmission (cross-​talk) between adjacent nerve fibres • derangement of efferent fibres of the vestibulocochlear nerve, pro- ducing aberrant auditory behaviour Several studies have demonstrated that tinnitus complaint does not correlate with psychoacoustic features of the tinnitus, but there is a significant correlation between tinnitus complaint and psycho- logical symptoms. Importantly, the onset of tinnitus complaint may be associated with negative life events such as retirement, redun- dancy, bereavement, and divorce. The assessment of tinnitus includes a detailed history, clinical examination, and audiometric investigation as outlined for hearing impairment. The most common causes of objective tinnitus include palatal myoclonus, temporomandibular joint abnormalities, vascular abnormalities such as an arteriovenous fistula, and vascular bruits. Rarely, a patulous auditory tube may give rise to tinnitus, in which the patient complains of a blowing sound associated with respiration. Bilateral subjective tinnitus with evidence of a cochlear hearing loss is associated most commonly with presbyacusis, endolymphatic hydrops, vascular labyrinthine lesions, and noise-​induced hearing loss. However, it is also common with head injury, whiplash injury, ototoxicity, barotrauma, surgical intervention, and after such simple clinical practices as syringing. Unilateral subjective tinnitus, with or without an associated sensorineural hearing loss, must be fully in- vestigated to exclude an underlying cerebellopontine angle lesion, in particular an acoustic neurinoma. Pulsatile tinnitus may be related to changes in blood flow with turbulence, or normal flow sounds, which are perceived more intensely, secondary to increased bone conduction or loss of the masking effect of environmental sounds. Despite detailed investigation, including imaging, up to 30% of cases remain undiagnosed. Management The primary management of tinnitus is medical, although surgical intervention is required for the correction of arterial stenosis, giving rise to bruits, for glomus jugulare tumour and arteriovenous mal- formations. Destructive surgery (e.g. labyrinthectomy or auditory nerve section), has no place in the management of tinnitus as there is no evidence that destruction of the peripheral cochlear elements brings about improvements in tinnitus complaint. The medical management of tinnitus can be divided into psy- chological, pharmacological, and prosthetic intervention. The psychological management includes an explanation of tinnitus, reassurance that the symptom will not progressively deteriorate or indeed remain unchanged, the exclusion of sinister pathology to allay fear, and, if necessary, the appropriate formal psychiatric management of depression/​anxiety. Cognitive behavioural therapy and mindfulness have both been demonstrated to be effective management strategies. In the presence of a hearing impairment, the provision of hearing aids to ‘mask’ tinnitus with desirable en- vironmental noise may be of value. In the absence of such a loss, tinnitus maskers and noise generators have been advocated to pro- mote ‘adaptation’, but there is no evidence that tinnitus maskers are superior to placebo devices. Pharmacologically, intravenous lidocaine has been shown to result in the disappearance or ameli- oration of tinnitus, but there is no evidence to support pharma- cotherapy in reducing the severity and intrusiveness of tinnitus. Psychiatric drugs may be required for psychological management, although no single drug has been shown to be uniformly effective. Tinnitus retraining therapy is a management strategy based on a neurophysiological model of tinnitus. The retraining is a com- bination of prosthetic and psychological intervention, which in essence provides a structured framework for the various well-​ established mechanisms of tinnitus management outlined earlier in this chapter. In conclusion, positive reassurance, appropriate psychiatric management, and prosthetic support remain the main- stays of the medical management of tinnitus. FURTHER READING Davies R, et al. (2016) Neuro-​otology: problems of dizziness, balance and hearing. In: Clarke C, et al. (eds) Neurology: a queen square textbook, 2nd edition. John Wiley and Sons Inc, New York, NY. Moller A (2012). Hearing: anatomy, physiology, and disorders of the auditory system. Plural Publishing. San Diego, CA. 24.7 Disorders of movement CONTENTS 24.7.1 Subcortical structures: The cerebellum, basal ganglia, and thalamus  5937 Mark J. Edwards and Penelope Talelli 24.7.2 Parkinsonism and other extrapyramidal diseases  5946 Elisaveta Sokolov, Vinod K. Metta, and K. Ray Chaudhuri 24.7.3 Movement disorders other than Parkinson’s disease  5956 Bettina Balint and Kailash Bhatia 24.7.4 Ataxic disorders  5976 Nicholas Wood 24.7.1  Subcortical structures: The cerebellum, basal ganglia, and thalamus Mark J. Edwards and Penelope Talelli ESSENTIALS Less is known of the function of the cerebellum, thalamus, and basal ganglia than of other structures in the brain, but there is an increasing appreciation of their complex role in motor and non​motor functions of the entire nervous system. These structures exercise functions that far exceed their previously assumed supporting parts as simple ‘relay stations’ between cortex and spinal cord. The subcortical structures receive massive different inputs from the cerebral cortex and peripheral sense organs and stretch receptors. Through recurrent feedback loops this information is integrated and shaped to provide output which contributes to scaling, sequencing, and timing of movement, as well as learning and automatization of motor and non​motor behaviours. Cerebellum Functional neuroanatomy—​the cerebellum can roughly be divided into (1) vestibulocerebellum—​integration of vestibular information; (2)  spinocerebellum—​integration of sensory information from the body; (3)  pontocerebellum—​integration of information from the cortex regarding planned or ongoing movement. Function—​these are proposed to be as follows: (1) a timing device for movement; (2) facilitation of motor learning; and (3) facilitation and correct scaling and harmonization of muscle activity. Clinical features of cerebellar lesions—​these include impairment of movement with dysmetria (‘past-​pointing’), dysdiadochokinesia, truncal and gait ataxia (in midline vermal lesions), dysarthria, and ab- normal eye movements (commonly nystagmus). Basal ganglia Functional neuroanatomy—​the basal ganglia participate in multiple parallel loops which take information from different (mainly cortical) areas and then feedback (mainly) to those same areas. Input is mainly from the striatum; output comes almost exclusively from either the globus pallidus interna or the substantia nigra pars reticulate, which send inhibitory projections to the thalamus; dopamine is the main neurotransmitter that regulates activity. Function—​four main roles are hypothesized: (1) release of desired movement from inhibitory control; (2) inhibition of undesired move- ment; (3)  facilitation of sequential automatic movements; (4)  in- tegration of attentional, reward, and emotional information into movement and learning. Clinical features of basal ganglia lesions—​these include rigidity, akinesia, and dystonia. Thalamus Functional neuroanatomy—​the thalamus receives afferent input from the special senses, basal ganglia, cerebellum, cortex, and brainstem reticular formation; efferent output is mainly directed to cortical areas and striatum. Function—​the main thalamic functions are thought to include (1)  modulation of sensory information by integration of brain- stem (in particular reticular activating complex) and relevant cortical information; and (2)  modulation of cortical activity via cortico-​thalamocortical loops. Clinical features of thalamic lesions—​these include (1)  sensory abnormalities—​ranging from loss to deep-​seated, severe pain; (2) motor disorders (e.g. hemiplegia); and (3) movement abnormal- ities (e.g. myoclonus, dystonia) usually in the context of lesions also involving the basal ganglia. section 24  Neurological disorders 5938 Cerebellum Gross anatomy The cerebellum is located in the posterior fossa, bordered above by the tentorium cerebri and below by the foramen magnum. Anteriorly it borders the lower pons and medulla, separated from them by the fourth ventricle. The cerebellum is connected to the pons and medulla by the superior, middle, and inferior cerebellar peduncles. Afferents to the cerebellum enter largely through the in- ferior and middle peduncles, whereas most of the cerebellar effer- ents exit through the superior cerebellar peduncle. The cerebellum receives its blood supply from the posterior circulation via (rostrally to caudally) the superior, anteroinferior, and posteroinferior cere- bellar arteries. The anatomical divisions of the cerebellum (as is the case for the other subcortical structures discussed here, particularly the thal- amus) are complicated by several overlapping classifications. The simplest anatomical division of the cerebellum is into the two cere- bellar hemispheres and the midline structure called the vermis. A further division is into the flocculonodular lobe, comprising a nodular structure at the base of the cerebellum and an adjacent area of the hemisphere, the anterior lobe—​the part of the cerebellum rostral to the primary fissure—​and the posterior lobe—​the part of the cerebellum caudal to the primary fissure. This division is in line with the proposed evolutionary development of the cerebellum, something that underlies an alternative classification scheme dividing the cerebellum into archicerebellum (flocculonodular lobe, receiving mainly vestibular input), paleocerebellum (anterior lobe, receiving mainly spinal cord input), and neocerebellum (pos- terior lobe, receiving mainly cerebral cortical input via the pons). Deep within the cerebellum are the cerebellar nuclei, which both re- ceive input and produce output from the cerebellum. These nuclei, medially to laterally, are called the fastigial, globose, emboliform, and dentate nuclei. Cytoarchitecture The cellular architecture of the cerebellum is complex but remark- ably uniform (Fig. 24.7.1.1). It comprises five cellular types: Purkinje cells, granule cells, basket cells, Golgi cells, and stellate cells. These are arranged in three distinct cortical layers. These are, from the out- side in, the molecular layer (layer 1), the Purkinje cell layer (layer 2), and the granule cell layer (layer 3). Afferent input arrives at the cerebellum in the form of mossy fibres and climbing fibres. These are excitatory neurons arising from the input structures to the cere- bellum. Only the inferior olivary complex sends mossy fibres to the cerebellum, with the rest of the input structures sending climbing fibres. These fibres may synapse on cerebellar nuclei or ascend into the cerebellar cortex directly. The only efferents from the cerebellum are the axons of Purkinje cells. Mossy fibres synapse with granule cells in layer 3, the axons which then ascend to layer 1, there forming parallel fibres that synapse with the dendrites of Purkinje cells directly, or synapse with basket cells and stellate cells in layer 1; these, in turn, form synaptic connections with dendrites of Purkinje cells. Climbing fibres ascend directly to layer 1 where they synapse with the dendrites of Purkinje cells. Axons of Purkinje cells give off collaterals as they descend both to adjacent Purkinje cells and to Golgi cells that lie in the outer part of layer 3. Functional anatomy The aforementioned brief description of cerebellar gross and cellular architecture goes some way to showing how the cerebellum is well placed to integrate a large amount of afferent information and to provide output of this integrated information to many cerebral and spinal targets. A first step to understanding the functional anatomy of the cere- bellum is to consider the main input and output pathways. The cere- bellum can roughly be divided into three functional areas, which receive particular inputs and produce output to particular areas either directly via the axons of Purkinje cells or via synapses of Purkinje cell axons on to cerebellar nuclei, which then connect to other structures. Vestibulocerebellum The main input is afferent fibres from the ipsilateral vestibular ganglion and vestibular nucleus, and the contralateral inferior oli­ vary complex. This input either goes directly to the flocculonodu­ lar lobe or reaches there via the fastigial nucleus of the cerebellum. Output is to the vestibular nuclei either directly or via the fastigial nucleus. Spinocerebellum The main inputs are ipsilateral cutaneous and proprioceptive affer- ents from the body and face via dorsal and ventral spinocerebellar, cuneocerebellar, trigeminocerebellar, and spinoreticular tracts. Further input comes from motor and sensory areas of the cerebral cortex and vestibular nuclei via pontine reticulospinal nuclei and the contralateral red nucleus, and from the contralateral inferior olivary complex. All these inputs either go directly to the anterior lobe of the cerebellum, or reach there via synapses in the globose and emboliform nuclei. Output, either direct or via these same cere- bellar nuclei, goes to the pontine reticular nuclei, the contralateral red nucleus, and a major projection to the contralateral posterior division of the ventrolateral nucleus of the thalamus. Output Cerebellar Hemispheres Flocculonodular lobe Mossy fibres Climbing fibres Intrinsic nuclei Vestibular nuclei Precerebellar nuclei Cerebral cortex Olive Pontine nuclei Spinal cord Fig. 24.7.1.1  A simplified diagram showing the principal afferents to cerebellar cortex and to intrinsic cerebellar nuclei. Both mossy (left) and climbing (right) fibre inputs project to both cortex and intrinsic nuclei. 24.7.1  Subcortical structures 5939 Pontocerebellum This receives input from the contralateral pontine nuclei, which in turn receive massive input from widespread areas of cerebral cortex, particularly the frontal and parietal lobes. Input is also received from the contralateral inferior olivary complex. Input either proceeds dir- ectly to the posterior lobes of the cerebellum or reaches there via synapses in the dentate nucleus. Output (either direct or via synapses in the dentate nucleus) goes to the contralateral red nucleus and to the cortex via the contralateral posterior division of the ventrolateral nucleus of the thalamus. Thus, in simple terms, the cerebellum has three main func- tional divisions:  the vestibulocerebellum, concerned mainly with integrating vestibular information; the spinocerebellum, concerned mainly with integrating sensory information from the body; and the pontocerebellum, concerned mainly with integrating information from the cortex regarding planned or ongoing movement. All areas of the cerebellum also receive input from the contralateral inferior olivary complex. The inputs to the cerebellum are largely excitatory, using glutamate as a neurotransmitter. In contrast, Purkinje cells, the output cells of the cerebellum, are inhibitory, using γ-​aminobutyric acid (GABA) as a neurotransmitter. Recent advances in understanding of cerebellar functional archi- tecture have revealed that the cerebellum appears to be divided into multiple ‘modules’ with similar cell structure, but receiving and giving out highly topographically organized information (Fig. 24.7.1.2). These modules are longitudinally arranged strips of the cerebellar cortex about 1–​2 mm across, each 5–​6 mm in length. This modular organization has been studied in most detail in relation to receptive fields from the forelimb of the cat. This work has demonstrated that particular sensory receptive fields in the forelimb map to particular areas of the inferior olivary complex, which in turn given off projec- tions to particular areas within cerebellar modules, called cerebellar microzones. Each area of the inferior olive may project to a variety of microzones which may be distributed widely in the cerebellar hemispheres. Crucially, however, these distributed microzones all send output to a specific area of the cerebellar output nuclei. This or- ganizational structure (called multizonal microcomplexes) permits topographically organized input to be fed into a variety of discrete areas in the cerebellum. These discrete microzones might respond to and process a particular aspect of movement control, such as timing, direction, or scaling of movement. These various aspects of movement control could then be integrated by the common output of these areas to a particular part of the cerebellar output nuclei. Parallel fibres may in addition allow integration of information be- tween microzones responsible for movements at several different muscles, but which are commonly recruited as a group or ‘synergy’. This would allow for the coordination of complex multijoint move- ments such as reaching and grasping. Function and dysfunction The main functions of the cerebellum (which are still the subject of much debate) are proposed as (1) a timing device for movement, (2) a structure that facilitates (motor) learning, and (3) a structure that allows integration of information (including information about SENSORY INPUT NUCLEUS RECEIVES CONVERGENT OUTPUT FROM ASSOCIATED CEREBELLAR MICROZONES TOPOGRAPHICALLY ORGANIZED OUTPUT FROM INFERIOR OLIVARY COMPLEX IS FED TO DIFFERENT CEREBELLAR MICROZONES CEREBELLAR OUTPUT CEREBELLAR MICROZONES CONTRALATERAL INFERIOR OLIVARY COMPLEX IPSILATERAL GLOBOSE NUCLEUS Fig. 24.7.1.2  This figure gives an example of the organization and connections of cerebellar microzones. In this example, sensory information from the limbs (which is topographically organized) is mapped onto specific topographically arranged areas of the inferior olivary complex. Output from one of these areas is shown, which is fed to several different cerebellar microzones. Output from these microzones converges onto a specific area of one of the cerebellar nuclei. section 24  Neurological disorders 5940 planning of a movement and sensory feedback information on the progress of a movement) in order to facilitate correct scaling and harmonization of muscle activity. In patients with cerebellar lesions several abnormalities can be seen in simple reaching tasks. Normal movements are usually ac- companied by precisely timed agonist–​antagonist–​agonist bursts that allow the limb to arrive exactly at the desired target. In patients with cerebellar lesions, there is first a delay in movement initiation, followed by a delay in the antagonist burst so that the patient fre- quently overshoots the target. This is the basis for dysmetria or ‘past-​ pointing’, examined at the bedside during finger–​nose or heel–​shin testing. This overshoot may be a partial cause of intention tremor (worsening tremor towards the end of movement) as well as an add- itional effect of cerebellar lesions on the timing of activity in muscle-​ stretch reflex loops (via cerebellar projections to γ-​motoneurons). Clinically, the timing and scaling role of the cerebellum can be as- sessed by looking for dysdiadochokinesia: a breakdown in force, rate, and rhythm of movement. This is often tested by asking pa- tients to tap gently, regularly, and rapidly on a table or the examiner’s hand with their fingers. This breakdown of smooth repetitive move- ments can even be detected by feel or by sound (‘listening to the cerebellum’). Midline vermal lesions usually cause truncal and gait ataxia, often in the absence of limb ataxia. The gait is wide based and particularly precarious on turning or on heel–​toe walking. Unilateral cerebellar hemispherical lesions cause deviation or falling to the ipsilateral side. Unlike a sensory ataxia, cerebellar ataxia is not made worse by shutting the eyes. Cerebellar dysarthria may often simply manifest as slurred speech, as if intoxicated. However, in addition some patients may have either scanning or explosive speech, due to an inability to modulate its rate, rhythm, and force appropriately. Dysarthria is usually present with lesions of the vermis, whole cerebellum, or its connections, but may be absent if one lateral hemisphere alone is involved. Eye movements are frequently abnormal in disease of the cerebellum or its connec- tions. This may relate in part to the extensive connections from vestibular areas to the cerebellum. The following eye-​movement abnormalities may be seen:  gaze-​evoked, rebound, downbeat, or positional nystagmus, dysmetric voluntary saccades, and jerky pursuit, square-​wave jerks (macrosaccadic oscillations), impaired vestibulo-​ocular reflex suppression, and skew deviation. Basal ganglia Gross anatomy There is no complete consensus on what structures make up the basal ganglia, but most would include the caudate nucleus, pu- tamen, globus pallidus, subthalamic nucleus, and substantia nigra (Fig. 24.7.1.3). The globus pallidus is subdivided into the globus pallidus externa and interna (GPe/​GPi), and the substantia nigra is subdivided into the pars reticulata and pars compacta (SNr/​SNc). As with the cerebellum and thalamus, the basal ganglia have additional nomenclature systems that are still in use. The most important term is the word ‘striatum’ (or sometimes neostriatum) which is used to describe the caudate nucleus and the putamen together. The globus pallidus may be called the pallidum or paleostriatum, and the globus pallidus and putamen together may be called the lentiform nucleus. The phrase ‘corpus striatum’ is used to refer to the caudate, putamen, and globus pallidus together. The basal ganglia occupy a position near the base of the cerebral hemispheres. The putamen lies lateral to the thalamus, separated from it (and from most of the caudate nucleus, except anteriorally) by the internal capsule. The caudate nucleus, with its head lying anterodorsomedial to the putamen, arcs back, following, and pro- gressively tapering with, the lateral ventricles, its tail swinging for- ward until its anteriorly pointing tip terminates in the amygdaloid nucleus. The pallidum lies medial to the putamen but still lateral to the internal capsule. The substantia nigra lies in the midbrain, transversely above the cerebral peduncles. Its pars reticulata, the termination of the striatonigral pathway, is below the internal seg- ment of the globus pallidus, and its pars compacta contains the dopaminergic neurons that form the nigrostriatal pathway. Below the thalamus, medial to the internal capsule and rostral to the mid- brain, is the subthalamic nucleus. Most of the caudate, putamen, and globus pallidus derive their arterial supply from the anterior Substantia Nigra (SN) Subthalamic Nigra (STN) Thalamus Globus Pallidus externa (GPe) Caudate nucleus Putamen Striatum Globus Pallidus interna (GPi) Fig. 24.7.1.3  Components of the basal ganglia seen in a coronal section of the brain. Reproduced from Edwards et al. Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders, Oxford University Press, 2008 with permission from Oxford University Press. 24.7.1  Subcortical structures 5941 circulation via the lateral lenticulostriate arteries and branches of the anterior choroidal and middle cerebral arteries. The thalamus, subthalamic region, and substantia nigra are supplied by the pos- terior circulation. Functional anatomy The basal ganglia receive a huge variety of input from the cerebral cortex, limbic system, and cerebellum. Although the role of the basal ganglia in motor control has been heavily emphasized, it is clear that the basal ganglia have a key role in many other aspects of behaviour, reflected in the diversity of input to and output from many ‘non-​ motor’ areas of the brain. A key concept of basal ganglia functional anatomy is their partici- pation in several parallel loops, which take information from dif- ferent (mainly cortical) areas, and then feed back, mainly to those same areas. Although the basal ganglia would seem well set up to integrate information from these various loops, in fact they seem not to do so, and information is kept remarkably separate. Five main loops are recognized: motor, oculomotor, dorsolateral prefrontal, orbitofrontal, and anterior cingulate. The motor loop has received by far the most attention, given its presumed role in move- ment disorders such as Parkinson’s disease. The main interest has fo- cused on how activity in this loop is modulated by the basal ganglia, and in particular how dopamine plays a role in this. Basic basal ganglia pathways An important first step to aid understanding of the functional or- ganization of the basal ganglia is to consider that input to the basal ganglia, whatever its source, arrives almost exclusively at the pu- tamen or caudate (i.e. the striatum). Therefore, the striatum is the main input structure of the basal ganglia. Output from the basal ganglia comes almost exclusively from either the GPi or the SNr. Therefore, the GPi/​SNr forms the main output from the basal ganglia. Crucially, these output structures send inhibitory projec- tions to the thalamus (Fig. 24.7.1.4). Ninety-​eight per cent (98%) of the neurons in the striatum are medium spiny neurons, which mainly receive excitatory input from glutamatergic neurons of the cerebral cortex. The rest of the stri- atal neuronal population is made up of large non​spiny cholinergic interneurons and GABA-​ergic interneurons. The medium spiny neurons are inhibitory and use GABA as their neurotransmitter. They form two main groups (bundled together in structures called ‘Wilson’s pencils’) which have different routes to get to the output structures (GPi/​SNr). One group projects directly to the GPi/​SNr—​ the direct pathway—​there colocalizing substance P and dynorphin as neurotransmitters. Activity in this pathway therefore inhibits basal ganglia output. The other group has an indirect route to the GPi/​SNr, projecting first to the GPe, there colocalizing enkephalin and neurotensin as neurotransmitters. The pathway continues via an inhibitory projection from GPe to subthalamic nucleus (STN), and finally via an excitatory glutamatergic projection from STN to GPi/​ SNr. The net effect of activation of this indirect pathway (combining two inhibitory and one excitatory synapse) is to excite GPi/​SNr. Activity in the indirect pathway therefore facilitates basal ganglia output (see Fig. 24.7.1.4). Output from the basal ganglia is via GABA-​ergic projections from GPi and SNr to the thalamus. The projections from GPi travel in two fibre bundles through the internal capsule; the one from the outer part of GPi is called the ansa lenticularis, and the other from the inner part of GPi is called the lenticular fasciculus. After traversing the internal capsule they meet with neurons from the SNr and join to form the thalamic fasciculus, which terminates in various nu- clei of the thalamus (for motor fibres this is mainly the ventrolat- eral medial nucleus). Additional output from GPi and SNr goes to the pedunculopontine nucleus and the superior colliculus. A crucial point is that the basal ganglia inhibits the structures to which it pro- jects; this is vital to understand the models of basal ganglia function described next. The most important neurotransmitter that regulates the activity of the basal ganglia is dopamine. Dopamine has different effects on the direct and indirect pathways. Dopaminergic neurons from the SNc ascend and synapse on striatal neurons (this is called the nigrostriatal pathway). Striatal neurons that will form the direct pathway express mainly dopamine D1-​receptors at the nigrostriatal synapses: these are stimulated by dopamine. In contrast, striatal neurons that will form the first projection of the indirect pathway express mainly dopamine D2-​receptors, which are inhibited by dopamine. Therefore, the net effect of dopamine on the striatum is to increase direct pathway activity, decrease indirect pathway activity, and therefore reduce the inhibitory output of GPi/​SNr (Fig. 24.7.1.5). How is dopamine release controlled in the basal ganglia? The an- swer may lie in recent discoveries regarding the exact make-​up of the striatum. It appears that, as well as the direct and indirect path- ways, the striatum also sends out projections direct to the SNc which stimulate activity in dopaminergic neurons projecting to the stri- atal neurons that form the direct and indirect pathways. So, the stri- atum is not formed by a homogeneous population of medium spiny neurons, but in fact is divided into two distinct subpopulations. One population forms ‘striosomes’, which are more densely packed groups of medium spiny neurons that have less cholinergic input and are rich in opiate receptors. These are the neurons that send projec- tions to the SNc (the striatonigral projection). The other population CORTEX THALAMUS SNc GPi/SNr STN GPe I D2 D1 D PUTAMEN Fig. 24.7.1.4  The direct and indirect pathways. Pink arrows indicate inhibitory connections, white arrows indicate excitatory connections. D1, dopamine receptor type 1; D2, dopamine receptor type 2; STN, subthalamic nucleus; GPi, globus pallidus interna; GPe, globus pallidus externa; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulate; I, indirect pathway; D, direct pathway. Reproduced from Edwards et al. Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders, Oxford University Press, 2008 with permission from Oxford University Press. section 24  Neurological disorders 5942 forms the ‘matrix’, which is made up of less densely packed medium spiny neurons with no output to SNc. These are the neurons that form the direct and indirect pathways. The putamen is almost all matrix, whereas the caudate has many striosomes. The striosomes receive input mainly from limbic structures, whereas the matrix re- ceives input from a variety of cortical areas, but not limbic struc- tures. The connections of these different striatal neurons has led to the idea of two striatal systems: the ventral striatum (striosome), which, via its connections with the limbic system, feeds emotional, reward and attentional information into the basal ganglia, and via its ability to modulate dopaminergic output from the SNr it can influ- ence activity in the dorsal striatum (matrix). Basic pathways and the rate model of basal ganglia function The earlier discussion about the connections of the various nuclei of the basal ganglia sets the scene for the most influential model of basal ganglia function proposed by DeLong and colleagues in 1990 (against the background of work by many others). The key to under- standing this model is to appreciate that: • output from the GPi and SNr is inhibitory to the thalamus (and therefore to the cortex), and therefore, from a motor circuit point of view, an increase in rate of GPI/​SNr firing is hypothesized to inhibit movement; • as the direct and indirect pathways have opposite effects on basal ganglia output, the rate model hypothesizes that they will have op- posite effects on movement; • dopamine has opposing effects on the direct and indirect path- ways, tending to increase direct pathway activity via D1-​receptors and decrease indirect pathway activity via D2-​receptors. The net result of dopaminergic stimulation is, therefore, to decrease GPi/​ SNr rate of firing, promoting movement. This model, sometimes described as the ‘rate model’, is successful in explaining several aspects of motor dysfunction related to the basal ganglia (e.g. the pathology of Parkinson’s disease leads to a dopamine-​depleted state which would be predicted to decrease direct pathway activity and increase indirect pathway activity). This would tend to cause an increase in GPi/​SNr (inhibitory) output to the thalamus, therefore inhibiting movement (Fig. 24.7.1.6). In con- trast, hemiballism (flinging movements of the arm and leg) is known to occur frequently with damage to, or close to, the subthalamic nu- cleus. The rate model would predict the effect of a subthalamic nu- cleus lesion to be a drop in indirect pathway activity, leading to a reduction in GPi/​SNr activity and a consequent increase in thalamic activity, promoting movement (Fig. 24.7.1.7). There is experimental support for this model (e.g. the finding from functional imaging studies that in Parkinson’s disease there is hypermetabolism of the GPi, which reverses with the administration of levodopa). However, problems occur when considering other clinical aspects of movement disorders (e.g. a lesion of the GPi in experi- mental animals tends not to cause excessive movement, as the model would predict). In fact, a lesion of the GPi can be a very successful CORTEX THALAMUS GPi/SNr I D STN PUTAMEN D2 D1 GPe SNc Fig. 24.7.1.5  The effect of dopamine and the direct and indirect pathways. Dopamine released from the substantia nigra pars compacta stimulates the direct pathway via its action on DI receptors and inhibits the indirect pathway via its action on D2 receptors. Abbreviations are the same as for Fig. 24.7.1.4. Reproduced from Edwards et al. Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders, Oxford University Press, 2008 with permission from Oxford University Press. THALAMUS CORTEX STN D I GPi/SNr SNc PUTAMEN D1 D2 GPe Fig. 24.7.1.6  How a lesion in the substantia nigra pars compacta can cause parkinsonism. Abbreviations are as in Fig. 24.7.1.4. Reproduced from Edwards et al. Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders, Oxford University Press, 2008 with permission from Oxford University Press. CORTEX THALAMUS I D GPe SNc PUTAMEN D2 D1 GPi/SNr STN Fig. 24.7.1.7  How a lesion in the subthalamic nucleus can cause hemiballismus. Abbreviations are as in Fig. 24.7.1.4. Reproduced from Edwards et al. Oxford Specialist Handbook of Parkinson’s Disease and Other Movement Disorders, Oxford University Press, 2008.with permission from Oxford University Press. 24.7.1  Subcortical structures 5943 treatment for both levodopa-​induced dyskinesia in Parkinson’s dis- ease and primary dystonia. In addition, the movement disorders characterized by excessive movement (the hyperkinetic movement disorders—​dystonia, tremor, tics, myoclonus, chorea) are variable in their clinical features, something that is difficult to explain via a model based solely on rate of GPi/​SNr firing. Beyond basic basal ganglia connections: The hyperdirect pathway and basal ganglia oscillations The connections between the basal ganglia are considerably more complex than the rate model permits (e.g. there is a ‘hyperdirect’ pathway—​a glutamatergic pathway that directly links the supple- mentary motor area and the subthalamic nucleus). In addition, there are numerous basal ganglia–​basal ganglia pathways (e.g. a direct excitatory connection from the subthalamic nucleus to GPe, and a direct inhibitory connection from GPe to GPi and SNr). These additional connections suggest the presence of two networks within the basal ganglia: an ‘extrastriatal network’ where the subthalamic nucleus is the main player, with links to GPe, GPi, and SNr, and a ‘striatal network’ that connects directly to GPi/​SNr. The development of animal models of parkinsonism, and more recent developments in human deep brain stimulation surgery for Parkinson’s disease and dystonia, have permitted direct recording from the basal ganglia. These recordings have demonstrated that alterations in pattern and synchrony of basal ganglia firing may be more important than changes in rate alone. So, for example, in patients with Parkinson’s disease, direct recordings from the basal ganglia show an increase in bursting activity in the subthalamic nu- cleus that oscillates at a low frequency (in the β band: 10–​20 Hz) and is synchronized across the basal ganglia and motor cortex. Successful treatment with levodopa is associated with a shift to higher-​frequency oscillations (into the γ band >60 Hz). One way to try to unify these disparate aspects of basal ganglia physiology into a functional whole is to first consider the basal ganglia as having a strong inhibitory bias. Therefore, although STN neurons fire quite consistently in response to cortical activity, fed to them via the hyperdirect pathway, this is not translated on the whole into changes in firing from basal ganglia output nuclei (GPi/​SNr), due to strong inhibitory control from the striatum, and therefore the tonic inhibitory discharge of the basal ganglia output continues. However, in the presence of dopamine, this situation is reversed, and the net effect of dopamine on the direct and indirect pathways causes a shift in basal ganglia output firing, allowing the information carried in the subthalamic nucleus firing patterns to be fed through to the thalamus. This occurs in a strictly segregated way, and the top- ography of input is preserved. In disease, there is a shift towards more synchronous firing within the basal ganglia with, in the case of Parkinson’s disease, a shift to- wards low-​frequency oscillations even when movement is attempted, reflecting a loss of the normal modulation of firing patterns during movement. In dystonia, a hyperkinetic disorder, the GPi shows lower firing rates compared with Parkinson’s disease (as would be predicted by the rate model), but in addition there are more frequent and irregular bursts seen with long pauses of absent activity. This might link to the clinical picture of dystonia with excessive muscle activation that stops and starts with shifting coactivation of agonists and antagonists, leading to abnormal posture, writing movements, and often a jerky tremor. Synchronization of firing across the basal ganglia undermines its ability to focus and concentrate activation in a topographically discrete manner. Function and dysfunction The earlier discussion is complex, but reflects the evolving under- standing of the functional role of the basal ganglia. The basal ganglia are hypothesized to have four main roles, all of which have most often been related to the motor function of the basal ganglia: 1 To release a desired movement from inhibitory control (e.g. before a desired eye movement the tonic discharge of the basal ganglia output nuclei drops, and this allows the movement to occur). 2 To inhibit undesired movement: in the motor system this would be reflected in the highly topographically organized nature of basal ganglia input and output. Therefore, as well as releasing the desired movement, the basal ganglia appear to play a key role in inhibiting other movements. This focusing role is also known as centre-​surround inhibition, where the desired movement (centre) is surrounded by an area of undesired movement that is actively inhibited. 3 To facilitate sequential automatic movements: in motor learning experiments, basal ganglia activity tends to increase as learning occurs. This is thought to reflect a role for the basal ganglia in coding sequences of movements that become automated. This may explain the particular difficulty showed by patients with Parkinson’s disease in performing multistage automatic move- ments, such as turning over in bed. 4 To integrate attentional, reward, and emotional information into movement and learning: via the connections of the limbic system with the ventral striatum, the basal ganglia form an important location for the integration of motivational and emotional in- formation with motor behaviour. This is particularly the case for reward-​based learning. It has been suggested that the basal ganglia can be seen as integrating two aspects of reward-​based learning: the ‘critic’, the ventral striatum system that holds infor- mation on how motivated the organism is towards a particular goal; and the ‘actor’, the dorsal striatum that holds information on the motor behaviour needed to achieve that goal. These various functions are certainly biased towards the motor system, but it is clear, from both the discussion of basal ganglia con- nections above, and the symptoms displayed by patients with dis- orders of the basal ganglia, that non​motor aspects of behaviour are strongly linked to the function of the basal ganglia. It may be par- ticularly the case for motivation and reward-​based learning, for ex- ample, lesions of the caudate nucleus have been associated with the psychiatric syndrome of abulia—​a syndrome of apathy and lack of motivation that is thought to reflect failure of normal reward-​based motivational mechanisms. The movement disorders are hypothesized to reflect dysfunc- tion within the basal ganglia, although, surprisingly, it is difficult to mimic some of these disorders simply by lesions to the basal ganglia alone. Thus, tics and myoclonus rarely occur in humans as a con- sequence solely of basal ganglia lesions. Likewise, chorea rarely occurs from lesions to the caudate nucleus alone, as one might ex- pect given the degeneration of this nucleus in Huntington’s disease. Parkinsonism, combining akinesia (slowness—​bradykinesia) and section 24  Neurological disorders 5944 progressive fatiguing of repetitive movement), rigidity (stiffness of muscles in flexion and extension), rest tremor of 5–​6 Hz, and pos- tural instability, can be seen in response to discrete lesions of the SNc. In terms of the various functions of the basal ganglia already out- lined here, both rigidity and akinesia could be seen as reflecting an inability to release the desired movement (akinesia) and a failure to inhibit undesired movement (rigidity). In Parkinson’s disease, clear deficits in reward-​related learning and performance of integrated automatic movements are seen, together with emotional and mo- tivational problems. Dystonia can also be produced by discrete basal ganglia lesions (usually to the putamen) and, in terms of the basal ganglia functions outlined here, dystonia could reflect an inability to inhibit unwanted movement, leading to the typical clinical picture of overflow of activity into adjacent muscles and cocontraction of agonists and antagonists. The huge variety of clinical presentation of movement disorders no doubt reflects the interaction of basal ganglia dysfunction with dysfunction caused by neurological dis- ease elsewhere in subcortical and cortical areas. Thalamus Gross anatomy The two thalami sit at the head of the brainstem, their medial borders largely separated by the third ventricle, but often partially fused as the massa intermedia. They constitute the largest nuclear mass in the diencephalon (the others being the hypothalamus and subthalamus). On the lateral surface of the thalamus is the external medullary lamina, containing thalamocortical and corticothalamic fibres ei- ther entering or exiting the internal capsule. The external medullary lamina and the internal capsule are separated by a thalamic nucleus called the reticular nucleus. The internal structure of the thalamus, already complex, is further confused by the existence of different nomenclatures (the one used here being that of Wessler). Inside the thalamus the internal medullary lamina (consisting of fibres leaving or entering the various thalamic nuclei) roughly divides the thalamus into three groups of nuclei—​lateral, medial, and anterior—​with each subdivided into ventral and dorsal areas. There are further nuclei that are not defined by this ventral/​dorsal system such as those that lie within the internal medullary lamina (the intralaminar nuclei), and others such as the lateral and medial geniculate and the pulvinar. The blood supply to the thalamus derives from the posterior circulation via the posterior cerebral arteries and perforators from the terminal part of the basilar artery. Cytoarchitecture Before discussing the functional anatomy of the thalamus, we briefly summarize its cellular structure. The main output cells of the thalamus are called relay cells. These form excitatory glutamatergic projections to the cortex. These cells receive multiple inputs including GABA-​ ergic inputs from interneurons within the thalamus, cholinergic input from the brainstem reticular formation, as well as glutamatergic input from particular cortical areas (usually those areas to which the relay cells then project back, forming corticothalamocortical loops). Relay cells have two modes of firing—​a burst mode and a tonic mode—​ which may have different functions (see next). Relay cells are mainly contained in the dorsal thalamic nuclei (the relay nuclei), whereas nuclei in the ventral thalamus (particularly the intralaminar nuclei) project mainly to the basal ganglia via glutamatergic projections. Functional anatomy The thalamus is in an ideal position to modulate information flow to and from the cortex. Although previously this role had been thought of as a mainly passive relay station, it is clear that the thalamus has a much greater role in moulding the information that passes through it than previously realized. Thalamic afferents arrive from five main sources. 1 Afferents from special senses (except olfaction): touch (from the body—​ventral posterolateral nucleus; face—​ventral posteromedial nucleus), taste (ventral posteromedial nucleus), vision (lateral geniculate nucleus), and hearing (medial geniculate nucleus) 2 Afferents from the output nuclei of the basal ganglia:  GPi (centromedian nucleus, ventral anterior nucleus, ventral lateral nucleus oralis and medialis) and SNr (mediodorsal nucleus and ventral anterior nucleus magnocellularis) 3 Afferents from the cerebellum: ventral lateral nucleus caudalis, to the ventral posterolateral nucleus oralis 4 Cortical afferents from many cortical areas: mainly synapse on dorsal thalamic nuclei 5 Afferents from the brainstem reticular formation Efferents from the thalamus from three main groups: 1 Efferents from thalamic nuclei to representative areas of the cortex determined by the input to the nucleus (e.g. afferents from the retina project to the lateral geniculate nucleus, which then projects to the visual cortex) 2 Efferents to cortical areas that project directly to the thalamus (corticothalamocortical loops) 3 Efferents to the striatum (mainly from the intralaminar nuclei) The functional anatomy of thalamic circuits has been most closely studied for the visual system, and this can serve as a model for other thalamic circuits (Fig. 24.7.1.8). In the visual system, the “FIRST ORDER RELAY” “SECOND ORDER RELAY” Areas 4 and 6 VISUAL CORTEX THALAMIC INTERNEURONS RELAY CELLS OF LATERAL GENICULATE NUCLEUS BRAINSTEM RETICULAR FORMATION THALAMIC RETICULAR NUCLEUS SENSORY INPUT FROM RETINA Fig. 24.7.1.8  Main connections of the lateral geniculate nucleus as an example of primary and secondary relays in the thalamus. Black arrows indicate inhibitory connections, white arrows indicate excitatory connections. 24.7.1  Subcortical structures 5945 main input to be relayed to the appropriate area of cortex comes from the retina, but, interestingly, this forms only about 5% of the input to the relevant thalamic nucleus: the lateral geniculate body. The rest of the input comes from a variety of sources including inhibitory input from thalamic interneurons and the thalamic reticular nucleus, excitatory input from the brainstem reticular formation, and layer 6 of the visual cortex. Output from the lat- eral geniculate is then primarily to layers 4 and 6 of the visual cortex. This system therefore has a primary function: transfer of visual information from the retina to the visual cortex (sometimes called the driver function or first-​order relay), but this is subject to a huge amount of modulation from other areas, both cortical and brainstem. A secondary system, often called the higher-​order relay, is dis- tinguished from this first-​order system. This system takes cortical information down to the thalamus (typically the dorsal nuclei), and then back again to the same area (corticothalamocortical loops). As for the first-​order system, this circuit is subject to mul- tiple modulatory inputs at the thalamic level. Of course, the cor- tical areas projecting as higher-​order relays may have themselves been influenced by first-​order relays, leading to a complex series of loops integrating and modulating information flow to and from the cortex. One of the most important modulating forces at work in the thal- amus arises from the brainstem reticular activating complex. This is demonstrated by the massive decease in thalamic activity seen during sleep, and the potential of certain thalamic lesions to cause coma. The influence of the reticular activating complex may occur via its ability to cause the ‘burst’ pattern of firing in thalamic relay cells. It is hypothesized that this is a ‘wake-​up’ signal to the cortex, causing diversion of attention to the particular input in question, following which relay cells switch to their normal regular tonic discharge. Function and dysfunction The previous discussion clearly demonstrates the role of the thal- amus as more than a neuronal rest stop on the way to and from the cortex. The main functions of the thalamus are thought to include: • modulation of sensory information by integration of brainstem (in particular, the reticular activating complex) and relevant cortical information • modulation of cortical activity via corticothalamocortical loops A diverse range of clinical consequences of thalamic lesions has been described, as one would expect from a region where so many different information flows coalesce (e.g. sensory abnormalities are reported with thalamic lesions), from pure hemisensory loss to deep-​seated, severe pain. Mild hemiplegia may be seen with thalamic lesions, sometimes in combination with hemisensory loss, dysaesthesia, hemiataxia, astereognosis, and hemichorea as in the thalamic syndrome of Déjèrine and Roussy. Other lesions, often spreading outside the thalamus to involve the basal ganglia, have been associated with myoclonus, dystonia, or a slow 3–​4 Hz tremor of the limbs on one side of the body. Lesions of the ventral lateral nucleus caudalis (also known as the ventral intermediate nucleus) have been used as a treatment for parkinsonian and es- sential tremor. Conclusions These three subcortical structures, the cerebellum, basal ganglia, and thalamus, provide the bridge over which information passes to and from the periphery and the cerebral cortex. Through their intri- cate structure and interconnections, they play a major role in modu- lating and integrating this information. The recent discovery of a hitherto unknown direct connection between the cerebellum and the basal ganglia again underlines the importance of considering these structures as part of a coordinated system rather than in iso- lation. The question ‘What does the cerebellum/​basal ganglia/​thal- amus do?’ therefore becomes slightly nonsensical, because in fact they do nothing in isolation, and function only as part of a system. This system can certainly be affected in particular ways by dysfunc- tion of one of its parts, but the results of discrete lesions are often hard to predict and may have wide-​ranging consequences for motor and non​motor behaviour. FURTHER READING Apps R, Garwicz M (2005). Anatomical and physiological founda- tions of cerebellar information processing. Nat Rev Neurosci, 6, 297–​311. Brown P (2003). Oscillatory nature of human basal ganglia activity: re- lationship to the pathophysiology of Parkinson’s disease. Mov Disorders, 18, 357–​63. Hammond C, Bergman H, Brown P (2007). Pathological synchroniza- tion in Parkinson’s disease: networks, models and treatments. Trends Neurosci, 30, 357–​64. Hoshi E, et al. (2005). The cerebellum communicates with the basal ganglia. Nature Neurosci, 8, 1491–​3. Lehericy S, et al. (2001). Clinical characteristics and topography of lesions in movement disorders due to thalamic lesions. Neurology, 57, 1055–​66. Lera G, et al. (2000). A combined pattern of movement disorders re- sulting from posterolateral thalamic lesions of a vascular nature: a syndrome with clinico-​radiologic correlation. Mov Disorders, 15, 120–​6. Middleton FA, Strick PL (1994). Anatomical evidence for cerebellar and basal ganglia involvement in higher cognitive function. Science, 266, 458–​61. Middleton FA, Strick PL (2000). Basal ganglia and cerebellar loops: motor and cognitive circuits. Brain Res Brain Res Rev, 31, 236–​50. Nambu A (2004). A new dynamic model of the cortico-​basal ganglia loop. Prog Brain Res, 143, 461–​6. ] Obeso JA, Rodriguez MC, DeLong MR (1997). Basal ganglia patho- physiology: a critical review. Adv Neurol, 74, 3–​18. Obeso JA, et  al. (2000). Pathophysiologic basis of surgery for Parkinson’s disease. Neurology, 55, (12 Suppl 6), S7–​12. Rothwell JC (1994). Control of human voluntary movement, 2nd edi- tion. Croom Helm, London. 24.7.2 Parkinsonism and other extrapyramidal disea 24.7.2 Parkinsonism and other extrapyramidal diseases 5946 Elisaveta Sokolov, Vinod K. Metta, and K. Ray Chaudhuri section 24  Neurological disorders 5946 24.7.2  Parkinsonism and other extrapyramidal diseases Elisaveta Sokolov, Vinod K. Metta, and K. Ray Chaudhuri ESSENTIALS Parkinson’s disease Parkinson’s disease affects about 0.2% of the population, including 2% of those over 80 years of age. The number diagnosed is expected to double from 4.1 million people diagnosed in 2005 to 8.7 million by 2030 owing to a rise in life expectancy and better diagnosis (Tanner CM, Brandabur M, Dorsey ER. Parkinson Report, Spring 2008). The main pathological feature is degeneration of neuromelanin-​ containing neurons and Lewy body inclusions in the pars compacta of the substantia nigra, which leads directly and indirectly to excessive inhibition of the thalamus and consequent bradykinesia. However, seminal studies in the early 2000s by Braak et al. suggest that the con- dition starts earlier and, from a pathological point of view, stage 1 of the disease begins with Lewy body deposition at the olfactory system and the dorsal vagal nucleus in the lower medulla, with degeneration of the olfactory bulb and the anterior olfactory nucleus. Clinically, this represents olfactory dysfunction and late-​onset hyposmia is recognized as one of the earliest symptoms of Parkinson’s disease, often preceding the development of the cardinal motor signs by up to 20 years. During stage 2 there is progression of neuropathology to the nuclei of the caudal brainstem (the locus coeruleus and other nu- clei), which are key areas mediating many non​motor symptoms such as sleep homeostasis, depression, fatigue, cognitive problems, pain, and constipation. Several of these symptoms, particularly rapid eye movement behavioural disorder are now recognized as pre-​motor features of Parkinson’s disease. Stage 3 is when patients are usually referred to the clinic as the substantia nigra is involved and patients start exhibiting classical motor features. Clinical features—​these include motor:  (1) bradykinesia; the most disabling and progressive motor symptom; (2) resting tremor (4–​7 Hz); often the presenting symptom/​sign, and often unilateral; (3) rigidity; cogwheel or lead pipe; (4) postural imbalance; fixed and stooped posture; (5) gait difficulty; shuffling and small steps, with or without festination; (6) other features; hypomimia (‘masked’ face), freezing episodes (sudden failure of movement), seborrhoea of the scalp. Non​motor symptoms are now considered integral to Parkinson’s disease and comprise of a wide range of problems. These include: (1) hyposmia, constipation, bladder disturbance; (2) sleep disorder; (3) dementia and other cognitive dysfunctions; (4) depression and anxiety; (5) chronic and regional pain; (6) fatigue; (7) sexual and auto- nomic dysfunction; (8) drug-​induced problems such as impulse con- trol disorder. Investigation and treatment—​there are as yet no specific tests for Parkinson’s disease and diagnosis remains largely clinical. However, single photon emission computed tomography imaging with DAT scan is a valuable adjunct to clinical suspicion of the diagnosis. First-​line drug treatment remains controversial and levodopa (in combination with a decarboxylase inhibitor), dopamine agonists (oral or transdermal) or monoamine oxidase-​B inhibitors are all effective and treatment needs to be individualized depending on the patient’s age, occupation, dominant side affected as well as expectations/​life style. Additionally, local funding policies might influence treatment decisions. Many authorities believe early treatment as soon as diag- nosis is made (usually motor diagnosis as the condition may have been present for many years manifesting non​motor symptoms) should be started, while some believe in a ‘wait and watch’ policy. Advanced therapeutic options consist of apomorphine injections (for rapid and reproducible ‘rescue’ from predictable off periods) and infusions, deep brain stimulation of the subthalamic nucleus or globus pallidus and intrajejunal levodopa infusion. Gastrointestinal problems such as delayed gastric emptying are highly prevalent in Parkinson’s disease and, as such, modern therapy has also focussed on non​oral therapies such as transdermal dopamine agonists as well as the advanced therapies. Stem cell, gene therapy-​based and neuro- trophic factor-​related regenerative therapies remain experimental. Other parkinsonian and extrapyramidal diseases Drug-​induced parkinsonism; dopamine-​blocking agents (neuro- leptics) such as prochlorperazine or chlorpromazine are the most common offending agents. Vestibular sedatives (used for motion sickness) are also implicated. Progressive supranuclear palsy; typically presents with gait dis- turbance and falls (backwards predominantly). Examination reveals supranuclear gaze palsy, particularly of downgaze, with extension and rigidity of the neck, a staring look due to lid retraction, and bradykinesia/​akinesia. Multiple system atrophy—​comprises a variable degree of parkin- sonism with autonomic (postural hypotension), pyramidal or cere- bellar symptoms and signs. Any response to levodopa is commonly incomplete (except the parkinsonian variant) and short-​lived. Clinical variants of progressive supranuclear palsy (a parkinsonian variant re- sponding to levodopa) as well as multiple system atrophy (parkin- sonian, cerebellar, and minimal change) has been described. Dementia with Lewy bodies—​manifestations include fluctuations in cognition and attention, recurrent and persistent visual hallucin- ations, and parkinsonian motor signs. Corticobasal ganglionic degeneration—​characterized by progres- sive gait disturbances, cortical sensory loss, and stimulus-​sensitive myoclonus which results in a jerky, useless hand. Dopa-​responsive dystonia—​characteristically shows marked diurnal variation; may start in childhood with an odd and unusual gait; diag- nosed by finding mutation in the GTP-​cyclohydrolase gene; excellent and sustained response to low-​dose levodopa. Other rare conditions mimicking parkinsonism include genetic variants of Parkinson’s disease (autosomal dominant and recessive), Wilson’s disease, neuroacanthocytosis, vascular pseudo-​parkinsonism, neuronal brain iron accumulation syndromes and neuro ferritinopathy. Other movement disorders Dystonia—​a syndrome of sustained muscle contractions, which may be focal, multifocal, or generalized, genetic, or idiopathic. Particular causes include (1) generalized idiopathic torsion dystonia; (2) tardive dyskinesia; induced by long-​term exposure to dopamine-​blocking drugs; involuntary movements usually begin with the face and mouth. See Chapter 24.7.3 for further discussion. 24.7.2  Parkinsonism and other extrapyramidal diseases 5947 Chorea and related disorders—​chorea is an irregular, rapid, uncon- trolled, involuntary, excessive movement that seems to move ran- domly from one part of the body to another; athetosis is a slower writhing and twisting movement. Causes include Huntington’s dis- ease and Sydenham’s chorea (associated with rheumatic fever). See Chapter 24.7.3 for further discussion. Tics—​these are sudden, repetitive, stereotyped, non​rhythmic, in- voluntary movement (motor tic) or sound (phonic tic); when treat- ment is required, they generally respond to drugs that decrease dopaminergic transmission. Introduction The human basal ganglia is a complex functional organiza- tion, with important interconnections with the nigrostriatal pathway, which dominates the dopaminergic innervation of the striatum (caudate nucleus and the putamen). Additionally, the globus pallidus, thalamic nuclei, the subthalamic nucleus and the pedunculopontine nucleus all play important regulatory and exci- tatory/​inhibitory roles. Neuronal loops also interconnect the basal ganglia with the cerebellum as well as the cortex, and function is mediated by dopamine as well as a complex array of neuropeptides such as serotonin, acetylcholine, catecholamines, adenosine, and γ-aminobutyric acid. The principal clinical syndromes are Parkinson’s disease (PD); other syndromes with parkinsonian features (including drug-​induced parkinsonism); progressive supranuclear palsy; multisystem atrophy; dementia with Lewy bodies; neuroacanthosis; torsion dystonia; and chorea. Apart from the use of dopaminergic agents, several drugs have beneficial effects in the management of parkinsonism and other extra- pyramidal diseases. Parkinson’s disease Parkinson’s disease was first described by the London physician James Parkinson in 1817, and later named after him by Charcot. Parkinson’s disease is one of the most important disabling illnesses of later life. It is estimated to affect 1% of those aged 70 years, but is also seen in younger people, with 10% of cases occurring before the age of 50. Epidemiology, incidence, and prevalence The exact estimation of the incidence and prevalence of PD is problematic, because there is no ‘in-​life’ marker for idiopathic PD; estimates of the annual incidence of PD are in the range of 4–​20 per 100 000 individuals. A  widely accepted figure for the prevalence of Parkinson’s disease is approximately 200 per 100 000 population. In the United Kingdom, there are approxi- mately 120 000 to 130 000 diagnosed cases, but there may be many more who remain undiagnosed. In the United States of America, it is estimated that between 750 000 and 1.5 million people have the condition. Both the incidence and prevalence of PD increase with age, and the prevalence may be as high as 1 in 50 for patients over the age of 80 years. Men are 1.5 times more likely than women to de- velop the condition. Hospital-​based studies and a limited number of epidemiological surveys in Africa have suggested that PD is less common in the black population, although this observation remains controversial. Risk factors Although PD was first described almost 200 years ago, it remains difficult to define exactly which individuals are at risk. The ageing process is related to the development of PD but is not solely re- sponsible, because some patients develop the disease early in life. Furthermore, the type of dopamine cell loss in normal ageing differs from that in PD. Certain personality traits and envir- onmental factors may increase the risk of PD (Box 24.7.2.1). People with a family history of Parkinson’s disease, particularly first-​degree relatives, are also at higher risk of developing the disease. It has been postulated that people may be affected differently by a combination of genetic and environmental factors. A possible role of an environmental toxin was triggered by the fascinating observa- tion that 1-​methyl-​4-​phenyl-​1,2,3,6-​tetrahydropyridine (MPTP), accidentally consumed as an illicit drug contaminant in the United States of America in the late 1970s and early 1980s, caused an out- break of levodopa-​responsive parkinsonism. This led to the de- velopment of MPTP as an experimental agent to cause selective nigrostriatal cell loss in animal models. Recently, similar observa- tions have been made in people in the welding trade, fuelling the hypothesis that manganese may be a causative factor. There have been conflicting reports about environmental agents that may pre- dispose to PD. These are listed in Box 24.7.2.1. Genetic factors The study of monogenetic forms of PD could lead to identification of new drug targets which may translate into new treatments for sporadic PD. Individuals with a positive family history have twice the risk of developing PD and the risk for siblings is increased significantly if there is an affected sibling with young-​onset PD. The risk increases further to 12–​24% if both a sibling and a parent are affected (see Box 24.7.2.1). α-​Synuclein was the first gene to Box 24.7.2.1  Personality trends and environmental factors Personality trends • Obsessive–​compulsive disorder Environmental factors (poor association) • Drinking well water • Insecticide/​pesticide exposure • Manganese exposure (welding) • N-​Methyl-​4-​phenyl-​1,2,3,6-​tetrahydropyridine (MPTP) (strong asso- ciation in producing parkinsonian syndrome) section 24  Neurological disorders 5948 be identified in a multigeneration Italian–​American family (the Contursi family) as causing an aggressive parkinsonism. Since then several genes have been identified, with Parkin and LRRK2 being the most prevalent ones (Table 24.7.2.1). LRRK2 stands for leucine-​rich repeat kinase 2 and is part of the family of Roco genes; it encodes for the protein dardarin. LRRK2 has been asso- ciated with familial late-​onset PD and a few cases of sporadic late-​ onset disease. It is possible that LRRK2 activity influences onset of symptoms and any treatment that lowers risk in LRRK2 associated monogenic PD could delay symptom onset in sporadic PD. The precise function of these genes is unknown, although α-​synuclein is the core protein in Lewy bodies whereas parkin may be active through the ubiquitin pathway. Mutations can cause autosomal dominant (SNCA, LRRK2, VPS35), or autosomal recessive (Parkin, DJ1, PINK1, ATP13A2) familial PD. Additionally some of these genes can incur polymorphisms, which are subsequent risk factors for PD. Other important and relatively common risk factors for parkin- sonism include mutations in the glucocerebrosidase (GBA) gene, which encodes the lysosomal enzyme that is deficient in Gaucher’s disease. There may be a gain-​of-​function that promotes α-​synuclein aggregation. Studies have shown that patients with PD and associ- ated Lewy body disorders had an increased frequency of GBA mu- tations when compared to controls. Patients with GBA-​associated parkinsonism can present with more cognitive features and an early age of onset. DNA methylation patterns vary with age, and ageing alone is a major confounding risk factor for PD. Epigenetic modification of α-​synuclein, for example, hypomethylation, is evident in sporadic PD patients’ blood. The analysis of α-​synuclein methylation can identify non​parkinsonian patients which offers a valuable instru- ment for researchers and clinicians. Overall, late-​onset PD is affiliated with autosomal dominant forms (except SNCA triplications) and early onset PD is affiliated with autosomal recessive forms and SNCA triplication. Autosomal dominant forms often present with a prominent tremor or tremor involving the legs suggesting LRRK2, and lack of tremor is associ- ated with SNCA-​related disease. These clues may give the clinician an idea of which genes to start testing first. However, routine genetic testing for PD is not available, nor is genetic counselling currently possible. Pathophysiology The main pathological feature of PD, is the degeneration of neuromelanin-​containing neurons in the pars compacta of the substantia nigra, which leads to deafferentation of the striatum. Table 24.7.2.1  Genetics of parkinsonism Symbol Inheritance Product Location Gene PARK1 AD α-​Synuclein 4q21.3–​q23 SNCA PARK2 AR, juvenile onset Parkin 6q25.2–​q27 Parkin PARK3 AD, Lewy body Unknown 2p13 SNCA PARK4 AD, Lewy body Unknown 4p15 SNCA PARK5 AD Ubiquitin C-​terminal hydrolase 1 4p14 UCHL1 PARK6 AR, early onset PTEN-​induced putative kinase 1 1p35–​p36 PARK7 AR, early onset DJ-​1 protein 1p36 PARK8 AD Leucine-​rich repeat kinase 2 (LRRK2) 12p11.2–​q13.1 PARK9 AR ATPase type 13A2. Kufor-​Rakeb syndrome 1p36 PARK10 Unknown 1p32 PARK11 GRB 10 interacting GYF protein 2 2q37.1 PARK12 X-​linked Unknown Familial PARK13 AD HtrA serine peptidase 2 2p12 PARK14 AR PLA2G6 22q13.1 PARK15 Susceptibility locus F-​box protein 7 1q32 PARK16 AR Glucocerebrosidase 1q21 Heterozygous mutations appear to confer susceptibility for classic PD, while homozygous mutations cause Gaucher’s disease DCTN1 AD Dynactin 1 Perry syndrome DYT12 AD Dystonia 12 Rapid onset dystonia parkinsonism VPS35 Vacuolar sorting protein 35 p.Asp620Asn (D620N) EIF4G1 Eukaryotic translation initiation factor 4 γ-1 Reported in monogenic and sporadic PD. Unclear as to its pathogenicity 24.7.2  Parkinsonism and other extrapyramidal diseases 5949 Normally, it has been suggested that the basal ganglia exert their motor and non​motor effects through a complex circuitry. The two main pathways are the direct (stimulatory) and indirect (inhibi- tory) pathways, a balance in favour of the direct pathway being kept by regulatory control exerted by dopamine manufactured in the substantia nigra. In PD, dopamine cell degeneration leads to overexcitation of the direct circuit, and the resultant bradykinesia, by a complex pathway that also involves paradoxical excitation of the subthalamic nucleus and internal segment of the globus pallidus. The net result of both the direct and indirect pathways in the ab- sence of dopamine is overexcitation of the medial globus pallidus, leading to excessive inhibition of the thalamus. Thalamic input to the motor cortex is excitatory and thus thalamocortical inhibition leads to akinesia and other symptoms of PD (Fig. 24.7.2.1). Lewy bodies are intracytoplasmic eosinophilic inclusion bodies, typically found in the neurons of the substantia nigra. The patho- physiological basis of PD has recently been re-​explored by Heiko Braak, who has suggested that Lewy body formation, a hallmark of dopaminergic cell degeneration in PD, actually occurs in the brainstem, in the lower medulla and the olfactory bundle (stage 1 Parkinson’s disease—​Fig. 24.7.2.2a). In stage 2 more dorsal medulla and pons are involved (Fig. 24.7.2.2b) whereas it is at stage 3 that the midbrain and the substantia nigra are involved (Fig. 24.7.2.2c). According to this hypothesis, therefore, clinical Parkinson’s disease is being detected only at stage 3. In support of this observation is the fact that several non​motor features of PD, for example, olfac- tory loss and sleep disorders such as rapid eye movement disorder (RBD), seem to occur from the brainstem and olfactory bundle in- volvement, and in fact precede the development of motor PD. A list of such non​motor features that may actually precede the develop- ment of motor signs of PD and may in future detect people ‘at risk’ of Parkinson’s disease is listed in Box 24.7.2.2. A recent twist to the pathophysiological basis of Parkinson’s disease is the observation that positron emission tomography (PET) of the brain in Parkinson’s disease identifies neuroinflammation in the brainstem, suggesting that the pathological process in Parkinson’s disease may be initiated by an inflammatory process within the glial cells. Symptoms and signs Parkinsonism is a clinical syndrome and typically, when the condition appears to be idiopathic and in particular responds to levodopa therapy, it is referred to as Parkinson’s disease. Often the presenting symptom is a slow resting tremor, worse at rest (4–​7 Hz) and often unilateral, al- though up to 30% of cases do not have a tremor at onset of the disease. The presence of an obvious tremor often leads both patients and their carers to suspect Parkinson’s disease and self-​referral. In this context, it is important to differentiate an essential tremor from a parkinsonian tremor because the former carries a more benign prognosis and is twice as common, with a prevalence of at least 400 per 100 000 (Table 24.7.2.2). Bradykinesia/​akinesia is difficulty in initiating, and slowness in exe- cuting, movement. It is the most disabling and progressive motor sign of PD and is a core feature for diagnosis of PD using the United Kingdom Parkinson’s Brain Bank criteria (Box 24.7.2.3). It first affects fine move- ments such as fastening buttons and handwriting, which becomes smaller and may progressively trail off (micrographia). Associated movements suffer, and arm swing may decrease unilaterally or bilaterally. Diagnosis of parkinsonism Gait is affected in PD, with difficulty starting walking, small steps, and shuffling. ‘Festination’ occurs when the patient appears to hurry and then stops suddenly as if rooted to the ground. The face often becomes expressionless (masked face or hypomimia) with reduced blinking. Bradykinetic laryngeal movement leads to quiet, monotonous speech that is low in volume and sometimes repetitive (palilalia). Rigidity is usually detected on examination and patients tend to complain of muscular stiffness and pain. Parkinsonian rigidity, which can be activated by performing mirror movements in the opposite limb (synkinesis), presents as one of two types: 1 ‘lead-​pipe’ rigidity—​a constant resistance to passive movement, in the absence of tremor 2 ‘cogwheel’ rigidity—​a superimposed resistance similar to a ratchet, in the presence of tremor Premotor prefrontal Suppl. motor premotor Cortex Glu DA subst P enk GABA + + + + + = excitatory − = inhibitory ++ ++ ++ −− −− −− − − − − D2 D1 Stratium STN SNr SNc Thalamus VA/VL Brainstem SC GPi Cingulate sensory motor Prefrontal insular GPe Fig. 24.7.2.1  Pathological functional anatomy of the basal ganglia in Parkinson’s disease. section 24  Neurological disorders 5950 Clinical assessment of PD is possible using several validated PD-​specific scales and questionnaires and must have regular yearly outcome measures. These include the self-​rated, 30-​item, non​motor questionnaire (NMSQuest), the simple 8-​item, Parkinson’s disease quality-​of-​life questionnaire (PDQ-​8), the motor scale (Unified Box 24.7.2.2  The non​motor symptom complex Neuropsychiatric symptoms • Depression, apathy, anxiety • Anhedonia • Attention deficit • Hallucinations, illusion, delusions • Dementia • Obsessional behaviour (usually drug-​induced), repetitive behaviour • Confusion • Delirium (could be drug-​induced) • Panic attacks Sleep disorders • Restless legs and periodic limb movements • REM (rapid eye movement) behaviour disorder and REM loss of atonia • Non-​REM sleep-​related movement disorders • Excessive daytime somnolence • Vivid dreaming • Insomnia • Sleep-​disordered breathing Autonomic symptoms • Bladder disturbances: — urgency — nocturia — frequency • Sweating • Orthostatic hypotension (OH): — Falls related to OH — ‘Coat hanger’ pain • Sexual dysfunction: — Hypersexuality (likely to be drug induced) — Erectile dysfunction • Dry eyes (xerostomia) Gastrointestinal symptoms • Dribbling of saliva • Ageusia • Dysphagia/​choking • Reflux, vomiting • Nausea • Constipation • Unsatisfactory voiding of bowel • Faecal incontinence Sensory symptoms • Pain • Paraesthesia • Olfactory disturbance Other symptoms • Fatigue • Diplopia • Blurred vision • Seborrhoea • Weight loss • Weight gain (possibly drug-​induced) (a) (b) (c) presymptomatic phase symptomatic phase locus coeruleus dorsal IXIX nucleus locus coeruleus locus coeruleus substantia nigra neocortex sec. + prim. neocortex association mesocortex dorsal IXIX nucleus dorsal IXIX nucleus mesocortex substantia nigra 1 2 3 4 5 6 presymptomatic phase symptomatic phase 1 2 3 4 presymptomatic phase symptomatic phase 1 2 Fig. 24.7.2.2  Proposed pathophysiological basis of Parkinson’s disease. (a) Stage 1 disease—​Lewy body formation in the brainstem, lower medulla, and olfactory bundle. (b) Stage 2—​more dorsal medulla and pons are involved. (c) Stage 3—​midbrain and substantia nigra involved (Fig. 24.7.2.2c). (Colour scale relates anatomical site(s) of involvement to disease progression.) 24.7.2  Parkinsonism and other extrapyramidal diseases 5951 Parkinson’s Disease Rating Scale, UPDRS), and the nonmotor scale (NMSS) (Table 24.7.2.3). The non​motor symptom complex A variety of non​motor symptom complexes (NMSs) is also seen in PD from an early stage, all of which are likely to have a major ef- fect on the health-​related quality of life of patients. These symptoms include depression, dementia, sleep disorders, bowel and bladder problems, fatigue, apathy, pain, and autonomic dysfunction (see Box 24.7.2.2). Confirmation of diagnosis There are no specific tests for the diagnosis of PD, which remains a clinical diagnosis (Table 24.7.2.4). DaTSCAN This is single photon emission computed tomography (SPECT) using the labelled cocaine derivative N-​ω-​fluoropropyl-​2β-​ carboxymethoxy-​3β-​(4-​iodophenyl)tropane (123I-​labelled β-​CIT and 123I-​labelled FP-​CIT (DaTSCANn, Fig. 24.7.2.3), and is re- commended in guidelines from the National Institute for Health and Clinical Excellence (NICE) and widely used to support diag- nosis and differentiate PD from essential tremor (Fig. 24.7.2.4). It labels the presynaptic dopamine transporter and this provides assessment of the presynaptic neurons, which degenerate in PD. Essential tremor is likely to show a normal DaTSCAN whereas in PD there is diminished uptake of the ligand, usually correl- ating with the clinically affected side, and DaTSCAN also appears to have a close correlation with the progression of PD. However, DaTSCAN does not differentiate between PD and other parkin- sonian syndromes. PET scan Using 18F-​labelled dopa the PET scan has similar properties and better resolution but is currently available as a research tool only. More recently, transcranial ultrasonography has been used to Table 24.7.2.3  Recommended good practice guide for clinical assessment of people with Parkinson’s disease A Motor assessment Hoehn and Yahr stage UPDRS (or MDS-​UPDRS) B Non​motor assessment NMS Quest (empowering patient) NMSS (measurement) PDSS HADS C Quality of life PDQ-​8 PDQ-​39 HADS, hospital anxiety and depression scale; NMS Quest, non​motor symptoms questionnaire; NMSS, non​motor symptoms scale; PDQ-​8, Parkinson’s disease questionnaire—​8 questions (short version of PDQ-​39); PDQ-​39, Parkinson’s disease questionnaire—​39 questions; PDSS, Parkinson’s disease sleep scale; UPDRS, Unified Parkinson’s Disease Rating Scale. Table 24.7.2.4  Imaging modalities for pre-​motor Parkinson’s disease Diffusion weighted imaging of olfactory tract MIBG-​SPECT Dopamine transporter SPECT Transcranial sonography 18-​F Dopa PET Table 24.7.2.2  Comparison of parkinsonian tremor and essential tremor Feature Parkinsonian tremor Essential tremor Age at onset Usually >50 years 10 years Occurrence Incidence increases with each decade of age Incidence remains the same with each decade of age Family history Rare Common Site Usually hands, also legs and jaw; head uncommon Hands, head (a no–​no or yes–​yes motion), vocal Characteristics At rest; supination/​pronation action reduces; mental concentration increases Postural; flexion/​extension action increases; mental concentration diminishes Frequency (Hz) 4–​7 8–​12 Lead-​pipe rigidity Yes No Cogwheel rigidity Yes Rare Alcohol No effect Often improves Treatment Dopaminergics β-​Blockers, primidone Box 24.7.2.3  Diagnosis of parkinsonism (Parkinson’s Brain Bank criteria) Essential features • Bradykinesia and two of the following: • Tremor (rest) and/​or • Rigidity (cogwheel/​lead pipe) • Postural imbalance, fixed, stooped posture • Gait difficulty (shuffling, short-​step gait, with or without festination) Additional features • Hypomimia (‘masked’ face) • Freezing episodes (sudden onset failure of movement) • Seborrhoea of the scalp • Mental and cognitive disturbance section 24  Neurological disorders 5952 reveal characteristic hyperechogenicity of the substantia nigra in patients with early PD, possibly suggestive of excessive iron de- position in the substantia nigra. However, this technique needs to be validated in large-​scale studies before widespread use can be advocated. CT or MRI Scans are usually not needed for diagnosis, but a brain scan should be performed if parkinsonism is purely unilateral or otherwise atypical, or if additional signs (pyramidal) are present. Computed tomography (CT) or magnetic resonance imaging (MRI) may also be used to rule out a space-​occupying lesion, vascular disease, and normal-​pressure hydrocephalus. MRI brain scan is preferable to a CT brain scan. Management of Parkinson’s disease When to initiate treatment is a critical question and it may indeed be best to start treatment at diagnosis (Table 24.7.2.5). The decision to treat may be dictated by the following clinical issues: • Involvement of the dominant hand relative to the non​dominant hand and the effect on employment/​occupation. • The particular subtype of Parkinson’s disease (bradykinesia-​ dominant disease may require earlier treatment than tremor-​ dominant disease). –​ The individual sentiments of patients and carers (offer informed choice). –​ Presence of non​motor symptoms such as pain, depression, or sleep problems. As initiating treatment, the NICE (National Institute of Health and Clinical Excellence (UK)) guidelines recommend levodopa, dopa- mine agonists, or monoamine oxidase-​B inhibitors. Levodopa is a precursor to dopamine, converted to dopamine by dopa decarb- oxylation, and restores the dopamine lost due to degeneration of striatonigral cells. The addition of a peripheral decarboxylase in- hibitor that does not cross the blood–​brain barrier, such as carbidopa or benserazide, inhibits dopa decarboxylase in the rest of the body (a) (b) Fig. 24.7.2.3  (a) A normal DaTSCAN showing the comma appearance. (b) DaTSCAN in Parkinson’s disease showing a ‘dot’ appearance on one side, indicating dopaminergic loss. Postsynaptic neuron Presynaptic neuron Postsynaptic autoreceptors Presynaptic autoreceptors Synaptic cleft Glia cell Dopamine Dopamine Storage vesicle Levodopa Tyrosine MAO monoamine oxidase COMT catechol-O-methyltransferase Cell body D D D D D D D D D D D Somatodentric autoreceptors Levodopa D D D D D Dopamine transporter Fig. 24.7.2.4  Dopaminergic neuronal transmission. 24.7.2  Parkinsonism and other extrapyramidal diseases 5953 and reduces side effects. The bioavailability of levodopa has been en- hanced further by the emergence of drugs such as tolcapone and entacapone that inhibit catechol-​O-​methyl transferase (COMT), which also breaks down dopamine. Evidence suggests that levodopa therapy should be started at the minimal effective dose (usually 50–​100 mg/​day), in combination with a decarboxylase inhibitor given three to four times daily. Doses at or above 600 mg/​day may be associated with a dyskinesia rate as high as 17% at one year. Side effects, such as light-​headedness or nausea, may be relieved by taking the medication with food or by increasing the dose of decarboxylase inhibitor or taking domperidone, which does not cross the blood–​brain barrier and hence does not cause central dopamine antagonism. Controlled-​ release preparations of levodopa, with addition of a COMT inhibitor (entacapone) to the traditional combination of levodopa and a de- carboxylase inhibitor (carbidopa), are now licensed for the treat- ment of later stage PD. In Parkinson’s disease refractory to other forms of conventional therapies, intraduodenal/​-​jejunal infusion of levodopa (Duodopa) provides an alternative route of drug adminis- tration. Duodopa is effective for motor fluctuations in advanced PD and decreases dyskinesias. Dopamine agonists Dopamine agonists stimulate dopamine receptors directly and so bypass presynaptic nigrostriatal neurons which are degenerate. Five types of dopamine receptors (D1–​D5) have been identified; these are divided into:  D1-​like and D2-​like receptors. In the 1980s and 1990s ergot dopamine agonists such as bromocriptine, pergolide, and more recently cabergoline, were typically used, however now non​ergot agonists are preferentially recommended due to the risk of cardiac valvular fibrosis with ergot dopamine agonists. Ropinirole and pramipexole are the main oral non​ergot dopamine agonists. Rotigotine, a transdermal non​ergot dopamine agonist patch, has now been released. It effectively demonstrates the concept of continuous dopaminergic stimulation and is useful when given once a day. Both ropinorole and pramipexole are available as once a day therapy which leads to improved compliance with therapy in PD (Fig. 24.7.2.4). Side effects of dopamine agonists include nausea, vomiting, postural hypo- tension, and hallucinations/​psychosis in susceptible individuals or at high doses. More specifically somnolence or sudden onset of sleep has been linked to non​ergot dopamine agonists, but it is clear now that somnolence can occur with progression of Parkinson’s disease. Patients, therefore, need to be warned about driving when starting on these drugs. Behavioural problems demonstrating disinhibition such as compulsive gambling, hypersexuality, and a complex medley of impulsive behaviour have been linked to use of dopaminergic drugs, particularly dopamine agonists. This has been termed dopamine-​ dysregulation syndrome; the exact prevalence is unknown but can be up to 7% in susceptible individuals. Apomorphine injection and infusion Apomorphine is a strong non​ergot dopamine agonist that is ad- ministered subcutaneously by an infusion pump in advanced Parkinson’s disease when oral therapy is of no further benefit. Apomorphine can be administered as a subcutaneous injection and is usually effective within 10 minutes by-​passing the stomach absorption route and is extremely effective for reversing predict- able off periods such as during early morning upon awakening. The subcutaneous infusion is delivered using a small pump and can be used from 12 to 24 hours. Subcutaneous apomorphine is particu- larly useful to control motor fluctuations and is indicated when oral or skin patch therapy is ineffective. The main side effects are skin lesions and nausea. Monoamine oxidase-​B inhibitors Selegiline 10 mg once daily or 5 mg twice daily orally (or 1.25 mg once daily by buccal administration) is a selective, irreversible blocker of intra-​ and extraneuronal monoamine oxidase B (MAOB), and re- duces metabolism of dopamine. Rasagiline is a second-​generation, irreversible, selective MAOB inhibitor that is administered orally at a dosage of 0.5–​1 mg once daily. A recent study (ADAGIO) suggests a potential disease modifying effect of rasagiline. The side effects of MAOB inhibition include hallucinations, sleep disorders, agitation, postural hypotension, and withdrawal problems. Anticholinergics not recommended Anticholinergics block the action of acetylcholine against dopamine in the basal ganglia. These drugs can occasionally be used as levo- dopa adjunct therapy, helping to control rest tremor and dystonia. However, they are not routinely recommended and should be util- ized with caution in older patients with parkinsonian syndromes be- cause of the risk of precipitating a confusional state and exacerbating dementia. Other drugs The antiviral amantadine, 100–​400 mg, daily has a moderate antiparkinsonian effect. It acts, partly, via increased dopamine syn- thesis and may also be useful to manage dyskinesias. Patients who may require surgery Surgery has gained popularity in selected patients where conven- tional pharmacological therapy has failed to control symptoms. It has a morbidity rate of approximately 2% due to the risk of stroke and infection, and a mortality rate of approximately 0.5%. The oper- ation of choice is deep brain stimulation of the subthalamic nucleus, which reverses the akinesia and controls dyskinesias. Patients with severe resistant unilateral tremor may undergo single-​side thalamic stimulation of the ventral intermediate nucleus. Additional surgical Table 24.7.2.5  New therapeutic options for motor complications (investigational or in clinical trial) COMT inhibition Opicapone A2A antagonists Istradefyline (approved in japan)/​Vipadenant (phase 2) Glutamate antagnosits Zonisamide/​Safinamide α-​2 antagonists Fipamezole 5HT agonist Pimavanserine Neurotrophic factors GDNF (IP), PDGF (IV) Incretin mimetic Exenatide Synthetic amino acid precursor Droxidopa Antimuscarinic Solifenacin Adapted from Stocchi F (2014) Neurotherapeutics 11(1): 24–​33. section 24  Neurological disorders 5954 approaches, such as delivery of viral vectors to the striatum for gene therapy or neurotransplantation, are options still in research and de- velopment. Adenosine-​associated virus, a non​pathogenic virus, is being used in human trials for gene delivery, including genes such as neurturin, glial-​cell derived nerotrophic factor, and glutamate decarboxylase. Intrajejunal levodopa infusion It is indicated for the treatment of advanced levodopa-​responsive Parkinson’s disease with severe motor fluctuations and dyskinesia. This involves giving L-​dopa in a gel formulation via a jejunostomy. It has proven to be extremely effective for motor dysfunction in ad- vanced PD as well as being beneficial for some non​motor symptoms and a subsequent health-​related improvement in quality of life. Other therapies and support A multidisciplinary approach is a requirement for optimal care of the patient with Parkinson’s. Initially, the main requirement is for information and counselling. In the later stages of the disease pro- cess, coordination of the various specialists involved in care is very important for the proper management of the patient (Fig. 24.7.2.5). Other parkinsonian/​extrapyramidal syndromes There are several degenerative diseases that have a more complex clinical picture than Parkinson’s disease and a poorer response to therapy. It may be impossible to distinguish idiopathic Parkinson’s disease from other parkinsonian syndromes. Drug-​induced parkinsonism This is one of the most common causes of secondary parkinsonism, and is often misdiagnosed as Parkinson’s disease because clinical features may be indistinguishable. It causes rigidity, bradykinesia, tremor and gait disturbance, and may be asymmetrical. Although several medications are associated with secondary parkinsonism, dopamine-​blocking agents (neuroleptics) such as prochlorperazine or chlorpromazine are the most common offending agents, and are often prescribed to older people for non​specific complaints such as dizziness, and drug-​induced parkinsonism may take up to 9 months to disappear. The incidence of drug-​induced parkinsonism is es- timated to be 15–​40% in patients receiving neuroleptics, and its prevalence increases with age. Vestibular sedatives are also impli- cated. Commonly used antiemetics and antidizziness pills need to be monitored. Treatment consists of withdrawal of the offending medication. If drug withdrawal is impractical, patients are dose reduced or changed to an atypical agent, such as clozapine or quetiapine. Occasionally emergence of parkinsonism may be permanent. Progressive supranuclear palsy Progressive supranuclear palsy (PSP or Steele–​Richardson–​ Olszewski syndrome) presents with gait disturbance and falls (pre- dominantly backwards) in over 50% of cases, and is a disease of later life. The pathological hallmark is finding of tau protein-​positive filamentous inclusions, known as neurofibrillary tangles, in the glia and neurons. The clinical picture consists of supranuclear gaze palsy, particularly downgaze with extension and rigidity of the neck, a staring look due to lid retraction, and predominant truncal extensor rigidity. Varying degrees of bradykinesia, dysphagia, personality changes, and other behavioural disturbances, such as a subcortical frontal dementia, coexist. A subtype with levodopa responsiveness have been described. It has been shown that some risk variants are shared between PSP and corticobasal degeneration. In addition, it has been shown that PSP brain volume changes on vMRI capture disease progression and cognitive changes. vMRI changes may serve as a valuable biomarker or outcome to support disease modifying therapeutic efficacy in future PSP clinical trials. Multiple system atrophy Multiple system atrophy (MSA) consists of a variable combin- ation of parkinsonism with autonomic, pyramidal, or cerebellar New patient diagnosis PDNS consultation Telling the diagnosis MDT consultation Physiotherapy Occupational therapy Speech and language therapy Neuropsychology Fig. 24.7.2.5  Multidisciplinary approach. 24.7.2  Parkinsonism and other extrapyramidal diseases 5955 symptoms and signs. In the past, patients were categorized as having the striatonigral type if there were dominant parkinsonian signs, and the olivopontocerebellar type if cerebellar signs predominated. These terms are no longer in use and, currently, striatonigral-​ and olivopontocerebellar-​type variants are called MSA-​P and MSA-​C, respectively. The pathological feature of MSA is α-​synuclein posi- tive inclusions within neurones or glial cells. These changes result in progressive and profound neuronal loss in various parts of the brain. The parkinsonian features of MSA include progressive bradykinesia, rigidity, and postural instability, typically present bilaterally. Useful clinical clues include disproportionate anterocollis, truncal dystonia (this may resemble the so-​called ‘Pisa syndrome’), characteristic sighing, and the presence of cold, blue hands. Autonomic failure, particularly postural hypotension, occurs early in MSA and is more severe than in idiopathic Parkinson’s disease. The response to levo- dopa is commonly incomplete and benefit usually declines within 1–​2 years of treatment. Dementia with Lewy bodies In dementia with Lewy bodies (DLB), widespread areas of neo- cortex as well as the brainstem and diencephalic neurons have Lewy bodies. Parkinsonian DLB can be very difficult to differentiate from Parkinson’s disease, but these patients have early onset dementia (progressive cognitive decline interfering with normal social and occupational function) and may have hallucinations, delusions, and even psychosis in the absence of dopaminergic therapy, usually within two years of disease onset. Clinical criteria for diagnosis in- clude cognitive fluctuation and attention, recurrent and persistent visual hallucinations, and parkinsonian motor signs. Repeated early falls and neuroleptic sensitivity can be seen. Occasionally the pa- tients develop a supranuclear gaze palsy leading to an incorrect diag- nosis of PSP. Corticobasal ganglionic degeneration Corticobasal ganglionic degeneration, also known as cortico­ dentatonigral degeneration with neuronal achromasia, typically presents in the sixth or seventh decade with slowly progressive, uni- lateral development of tremor, apraxia, and rigidity in an upper limb. The condition is characterized by progressive gait disturbances, cor- tical sensory loss, and stimulus-​sensitive myoclonus, which result in a jerky, useless hand. A jerky, useless lower extremity is uncommon, but may occur; it is known as the alien limb phenomenon and can occur in about 50% of patients. Gait disturbance consists of a slightly wide-​based, apraxic gait rather than the typical festinating gait of Parkinson’s disease. Patients with corticobasal ganglionic degener- ation do not benefit from levodopa, and the disease course is relent- lessly progressive. Other extrapyramidal conditions that should also be considered, including the following, are fully described in Chapter 24.7.3: • Dopa-​responsive dystonia • Wilson’s disease • Neuroacanthocytosis • Dystonia • Generalized idiopathic torsion dystonia • Tardive dyskinesia • Chorea and related disorders • Tics FURTHER READING Albanese A, et al. (2001). Consensus statement on the role of acute dopaminergic challenge in Parkinson’s disease. Mov Disorders, 16, 197–​201. Albin RL, Frey KA (2003). Initial agonist treatment of Parkinson’s dis- ease: a critique. Neurology, 60, 390–​4. Barbeau A, Sourkes TL, Murphy CF (1962). Les catecholamines de la maladie de Parkinson. In: Ajuriaguerra J (ed) Monoamines et sys­ tème nerveux central, pp. 247–​62. Symposium Bel Air, Geneva. Chaudhuri KR, Healy D, Schapira AHV (2006). The non-​motor symp- toms of Parkinson’s disease:  diagnosis and management. Lancet Neurol, 5, 235–​45. Chaudhuri KR, Pal S, Brefel-​Courbon C (2002). Do ‘sleep attacks’ or ‘unintended sleep episodes’ occur with dopamine agonists? Is this a class effect? Drug Safety, 25, 473–​83. Devos D, Defebvre L, Bordet R (2010). Dopaminergic and non-​ dopaminergic pharmacological hypotheses for gait disorders in Parkinson’s disease. Fundam Clin Pharmacol, 24, 407–​21. Dhawan V, et al. (2006). The sleep-​related problems of Parkinson’s dis- ease. Age Ageing, 35, 220–​8. Fahn S, Elton R, Members of the UPDRS Development (1987). Unified Parkinson’s disease rating scale. In: Recent developments in Parkinson’s disease, pp. 153–​63. Macmillan Healthcare Information, Florham Park, NJ. Fiszer U (2007). Adverse effects of dopamine agonists. Neurol Neurochir Pol, 41(2 Suppl 1), S34–​9. Foltyne T, et  al. (2002). The genetic basis of Parkinson’s disease. J Neurol Neurosurg Psychiatry, 73, 363–​70. Hatano T, et  al. (2009). Pathogenesis of familial Parkinson’s dis- ease: new insights based on monogenic forms of Parkinson’s disease. J Neurochem, 111, 1075–​93. Jankovic J (2005). Searching for a relationship between manganese and welding and Parkinson’s disease. Neurology, 64, 2021–​8. Kalra S, Grosset DG, Benamer HT (2010). Differentiating vascular parkinsonism from idiopathic Parkinson’s disease: a systematic re- view. Mov Disord, 25, 149–​56. Kashihara K (2007). Management of levodopa-​induced dyskinesias in Parkinson’s disease. J Neurol, 254 Suppl 5, 27–​31. Kouri N, et al. (2015). Genome-​wide association study of corticobasal degeneration identifies risk variants shared with progressive supra- nuclear palsy. Nat Commun, 6, 7247. Lindvall O, Kokaia Z (2010). Stem cells in human neurodegenerative disorders—​time for clinical translation? J Clin Invest, 120, 29–​40. Mark MH (2001). Lumping and splitting the Parkinson Plus syn- dromes:  dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and cortical-​basal ganglionic degen- eration. Neurol Clinics, 19, 607–​27, vi. Massey LA, Yousry TA (2010). Anatomy of the substantia nigra and subthalamic nucleus on MR imaging. Neuroimaging Clin N Am, 20, 7–​27. Masson, Paris. Birkmayer W, Hornykiewicz O (1962). Der l-​Dioxyphenylalanin (=DOPA) Effekt beim Parkinson-​syndrom des menschen:  zur pathogenese und behandlung der parkinson-​ akinese. Arch Psychiatr Nervenkr, 203, 560–​74. McGeer PL, McGeer EG (2008). Glial reactions in Parkinson’s disease. Mov Disorders, 23, 474–​83. National Institute for Health and Clinical Excellence (2006). Clinical guidelines for management of Parkinson’s disease in primary and sec­ ondary care. Department of Health, London. Nutt JG (2007). Continuous dopaminergic stimulation: is it the answer to motor complications of levodopa? Mov Disorders, 22, 1–​9. 24.7.3 Movement disorders other than Parkinson’s d 24.7.3 Movement disorders other than Parkinson’s disease 5956 Bettina Balint and Kailash Bhatia section 24  Neurological disorders 5956 Nyholm D, et  al. (2003). Optimising levodopa pharmacokinetics: intestinal infusion versus oral sustained-​release tablets. Clin Neuropharmacol, 26, 156–​63. Olanow CW, Watts RL, Koller WC (2001). An algorithm (decision tree) for the management of Parkinson’s disease (2001): treatment guidelines. Neurology, 56 (11 Suppl 5), S1–​88. Olanow W, Schapira AH, Rascol O (2000). Continuous dopamine-​ receptor stimulation in early Parkinson’s disease. Trends Neurosci, 23, S117–​26. Parkinson Study Group (2002). Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA, 287, 1653–​61. Rascol O, et al. (2000). A five year study of the incidence of dyskin- esias in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med, 342, 1484–​91. Rascol O, et al. (2002). Treatment interventions for Parkinson’s dis- ease: an evidence-​based assessment. Lancet, 359, 1589–​98. Stern MB, et al. (1989). Magnetic resonance imaging in Parkinson’s disease and parkinsonian syndromes. Neurology, 39, 1524. van de Vijver RAC, et al. (2001). Estimation of incidence and preva- lence of Parkinson’s disease in the elderly using pharmacy records. Pharmacoepidemiol Drug Safety, 10, 549–​54. Zhang Z, Roman G (1993). Worldwide occurrence of Parkinson’s dis- ease: an updated review. Neuroepidemiology, 12, 195–​208. 24.7.3  Movement disorders other than Parkinson’s disease Bettina Balint and Kailash Bhatia ESSENTIALS Hyperkinetic movement disorders are characterized by involuntary (and excessive) movements. The five main forms are chorea, tics, myoclonus, dystonia, and tremor, which can sometimes occur in combination. Some movement disorders are defined by their par- oxysmal occurrence (paroxysmal movement disorders) or by their presence only during sleep, and there are other conditions that lie outside the conventional list but are part of the spectrum of move- ment disorders, for example, stiff person syndrome. It is important to remember that drugs can cause a variety of movement disorders, including some very distinct presentations, and also that all organic movement disorders can be mimicked by so-​called psychogenic or functional movement disorders. It is important not to miss treatable disorders (e.g. Wilson’s dis- ease, dopa-​responsive dystonia, or some of the immune-​mediated disorders), but in most cases treatment is symptomatic, both of motor and non​motor (usually neuropsychiatric) features, which may significantly contribute to poorer quality of life. Most of the recent advances in this field are due to the discovery of new genes. The indications and application of deep brain stimu- lation has become much wider, with beneficial results not only in Parkinson’s disease but also dystonia and some tremor disorders, and even Tourette syndrome. Particular movement disorders Chorea Inherited choreiform disorders—​most are autosomal dominant, and divisible into those with onset in adulthood or childhood. Huntington’s disease is a classic form of later onset, autosomal-​dominant chorea often associated with dementia and psychiatric disturbance, whereas autosomal-​dominant ‘benign hereditary chorea’ has very early onset with a more benign prognosis. Recessive forms of chorea usually have early onset and are generally associated with a variety of other neurological or systemic signs. Acquired chorea—​possible aetiologies include drugs, immune-​ mediated, metabolic, infectious, and structural causes. The arche- typical autoimmune chorea in children is Sydenham’s chorea, but anti-​N-​methyl-​d-​aspartate receptor encephalitis is another important cause. Adult autoimmune chorea can be seen in a paraneoplastic disease and also in the context of systemic autoimmunity (e.g. anti­ phospholipid syndrome or systemic lupus erythematosus). Dystonia Dystonia as sole sign is seen in a group of disorders (previously termed primary dystonia) which can be either idiopathic or gen- etic. Presentation follows a typical pattern with regard age of onset and body distribution, such as young onset generalized dystonia or adult onset focal dystonia (writer’s cramp and craniocerivcal dys- tonia). Dystonia combined with other signs can be seen in various conditions, for example, dystonia combined with parkinsonism in dopa-​responsive dystonia (including Segawa’s disease), young onset Parkinson’s disease, and Wilson’s disease. Myoclonus Myoclonus is characterized by very brief, shock-​like, involun- tary movements that can be positive, caused by sudden muscle contraction, or negative, due to a sudden lack of muscle tone (e.g. asterixis). Causes include metabolic, toxic, infectious, and auto- immune conditions. Symptomatic treatment is with agents such as clonazepam, valproate, levetiracetam, piracetam, and primidone, often in combination. Tremor Tremor may be a sole and defining symptom (essential tremor) or be part of a syndrome (e.g. dystonic tremor or parkinsonian tremor). Treatment of tremor is purely symptomatic. Focal tremors (e.g. of head, jaw, voice) often show an excellent response to botu- linum toxin injections. Tremor of the limbs often requires medical therapy: agents used include propranolol, clonazepam, primidone, topiramate, and gabapentin. Deep brain stimulation is considered for severe and disabling tremors, and focused ultrasound may be employed in the future. Tics Tics mostly occur as primary disorders without any associated neurological disease. Presentation ranges from minor tics of self-​ limiting occurrence during childhood, which occur in up to 15% of school-​age children (boys more than girls), and persistent tic disorders like Tourette syndrome, which can result in significant 24.7.3  Movement disorders other than Parkinson’s disease 5957 physical and social disability. More rarely, tics can occur secondarily to neurodegenerative disease, in developmental disorders, as part of the spectrum of paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, or due to structural brain damage. Some drugs (e.g. amphetamines), are associated with (re-​) occurrence of tics. Other movement disorders These include restless legs syndrome and other sleep movement disorders, stiff person syndrome and related disorders, paroxysmal dyskinesias, drug-​induced movement disorders, psychogenic movement disorders, and the interphase of movement dis- orders and peripheral nerve disorders like hemifacial spasm and myokymia. Introduction Movement disorders remains a subspecialty wherein the observed clinical phenomenology is of paramount importance and guides further investigations to find the right diagnosis. Here we outline the different clinical forms of hyperkinetic movement disorders and discuss the different diseases in the context of the main movement disorder presentations. Hyperkinetic movement disorders or dyskinesias are character- ized by involuntary (and excessive) movements. The five main forms of dyskinesias include chorea, tics, myoclonus, dystonia, and tremor. In contrast to dyskinesias, hypokinetic disorders are defined by a poverty of movement such as in parkinsonian disorders. However, sometimes there can be a combination of different movement dis- orders. Some movement disorders are defined by their paroxysmal occurrence (paroxysmal movement disorders), or by their pres- ence only during sleep such as rapid eye-​movement (REM) sleep behaviour disorder (RBD), and periodic limb movements in sleep. In addition, there are still other conditions, for example, stiff person syndrome, which lie outside the conventional list of dyskinesias but are part of the spectrum of movement disorders. Also included here are miscellaneous movement disorders, such as hemifacial spasm, myokymia, and myorhythmia. It is important to remember that drugs can cause a variety of movement disorders, including some very distinct presentations, and this will be covered separately. Lastly, all organic movement disorders can be mimicked by so-​ called psychogenic or functional movement disorders, which will be discussed last. Treatment is often only symptomatic as there are mostly no cures. It is therefore important not to miss treatable disorders, such as Wilson’s disease, dopa-​responsive dystonia, or some of the immune-​mediated disorders, but also rarer entities like biotin responsive encephalopathy or glucose transporter 1 deficiency. Furthermore, apart from the movement disorder aspect, it is im- portant to recognize and treat certain non​motor (usually neuro- psychiatric) features, which may significantly contribute to poorer quality of life. Most of the recent advances in this field are due to the discovery of new genes, which start paving the way for the first genetic treat- ment trials, as in Huntington’s disease. The indications and appli- cations of deep brain stimulation have become much wider with beneficial results not only in Parkinson’s disease, but also dystonia and some tremor disorders, and even Tourette syndrome. In the following section we will discuss each of the major forms of hyperkinetic movement disorders individually. Chorea Chorea is characterized by brief, irregular, purposeless movements that unpredictably flit from one body part to another and lend the patients a fidgety, restless appearance (see Video 24.7.3.1). Key questions in the approach to a patient with chorea are tempo and age of onset, family history, drug history, and distribution. For ex- ample, involvement of just one side (hemichorea) indicates a contra- lateral structural lesion. Ballism is a more severe form of chorea and often due to vascular lesions of the contralateral subthalamic nucleus (see Video 24.7.3.2). Chorea as the sole or main feature can underlie several different aetiologies, which may be broadly divided into in- herited and acquired causes (for an overview see Table 24.7.3.1). Table 24.7.3.1  Overview of the main causes of chorea classified by aetiology Inherited Autosomal dominant Adulthood onset Huntington’s disease C9ORF72 Junctophilin-​3 Spinocerebellar ataxia 17, 1, 2, 3 DRPLA Prion disease Neuroferritinopathy Aceruloplasmenaemia Childhood onset Benign hereditary chorea (TITF-​1) ADCY5 PDE10A Autosomal recessive Ataxia teleangiectasia Ataxia with oculomotor apraxia type 1, 2 and 4 Friedreich’s ataxia Neuroacanthocytosis Wilson’s disease Aminoacidurias Niemann–​Pick C X-​linked recessive Lesch–​Nyhan syndrome Acquired Autoimmune Childhood onset Sydenham’s/​PANDAS NMDAR antibody encephalitis Adulthood onset Paraneoplastic disease (particularly related to CRMP5 and Hu-​antibodies) (continued) section 24  Neurological disorders 5958 Inherited chorea The bulk of inherited choreiform disorders are autosomal dom- inant. These can be further subdivided into those with onset in adulthood or childhood. Huntington’s disease is a classic form of later onset, autosomal-​dominant chorea often associ- ated with additional features such as dementia. On the other hand, autosomal-​dominant ‘benign hereditary chorea’ has a very early onset with chorea as the main feature and with a more benign prognosis. Recessive forms of chorea as shown in Table 24.7.3.1 usually also have early onset but, generally, a variety of other neurological or systemic signs are associated with these syndromes. Huntington’s disease Huntington’s disease (HD) is an autosomal-​dominant neurode­ generative disorder with chorea, dementia, and psychiatric dis- turbance as the main features. It was first described by George Huntington in 1872 and proved to be the most frequent inherited cause of chorea, with a prevalence of 4–​10/​100 000 in western European populations. Aetiology The underlying genetic defect is a triplet (CAG) repeat expansion, encoding polyglutamine in the huntingtin gene on chromosome 4p16.3. The mutant gene product forms aggregates in cells that lead to cell death, and neuropathologically to atrophy mainly of the cortex and caudate, more than the putamen. The CAG repeat ranges nor- mally between 10—​28 copies, but is expanded to a range of 36 and more in patients with HD. The number of CAG repeats correlates also with penetrance and phenotype. 40 or more CAG repeats are fully penetrant, whereas there is a borderline repeat range between 36 and 39 repeats with reduced penetrance. Usually, the higher the number of repeats, the earlier the presentation. There is a tendency for expansion of the triplet repeat during transmission, a phenomenon called antici- pation, particularly if the disease is inherited through the father. This is explained by meiotic instability, which increases the CAG repeat number and is greater in spermatogenesis than in oogenesis. Symptoms The disease usually manifests in the fourth decade, but age at onset can vary from adolescence (<18 years, Westphal variant with parkin- sonism rather than chorea) to milder presentations late in life (often misdiagnosed as ‘senile chorea’). Eye movement abnormalities often appear early and comprise difficulty with initiation, or slowness, of saccades and gaze distractibility. The latter can be considered part of motor impersistance, which is also reflected in the difficulty of maintaining postures, for example, tongue protrusion (‘chame- leon tongue’). Patients may also feature hyperreflexia or ‘hung up’ tendon jerks (a tonic, slow response after the classical stretch reflex). Of note, the motor symptoms may change over the disease course, being initially most frequently chorea, and changing to dystonia and akinetic-​rigid parkinsonism, with dysarthria and dysphagia in the very last stages. Other typical, non​motor accompaniments are prominent neuro- psychiatric disturbance, mainly depression and anxiety. The rate of suicides is much higher than in the general population. Cognitive problems often appear later, and encompass poor planning and judgement, lack of concentration and attention, and memory loss. Behavioural disturbance may be reflected in impulsivity or psycho- motor slowing with apathy. It appears that the weight loss in HD is a symptom in its own right due to metabolic disturbance. Diagnosis Brain imaging may give a diagnostic clue as it will often show caudate atrophy with ventricular dilatation. The diagnosis is made by gen- etic testing, which should be considered after proper genetic coun- selling. HD is a devastating disease which often has been passed on prior to development of any symptoms. Important aspects to NMDAR antibody encephalitis Antiphospholipid syndrome Vasculitis Coeliac disease Systemic Lupus erythematosus Neurobehçet Drug induced L-​dopa (L-​dopa induced dyskinesia in Parkinson’s disease) Dopamine receptor blockers (tardive dyskinesia) Anticholinergics (e.g. trihexyphenidyl) Oral contraceptives Calcium channel blockers Anticonvulsants (e.g. phenytoin) Thyroxine Benzodiazepines Monoamine oxidase inhibitors Tricyclic antidepressants (e.g. amitriptyline) Digoxin Stimulants Alcohol withdrawal Metabolic abnormality Thyroid Parathyroid Glucose Sodium Calcium Magnesium Structural lesions Stroke Abscess Tumour Demyelination Infectious HIV Prion disease Other Polycythaemia rubra vera NMDAR, N-​methyl-​d-​aspartate receptor; PANDAS, paediatric autoimmune neuropsychiatric disorder associated with streptococcal infections; HIV, human immunodeficiency virus. Table 24.7.3.1  Continued 24.7.3  Movement disorders other than Parkinson’s disease 5959 discuss beyond the nature of the disease itself are the possible test results (particularly the indeterminate range) and further ramifi- cations with respect to mortgage and health and life insurance, as well as implications for other family members. Several other dominantly inherited conditions, so-​called ‘Huntington lookalikes’ can mimic HD (Table 24.7.3.1). Among those, C9ORF72 mutations are probably the most frequent cause in Caucasian populations, whereas junctophilin-​3 mutations are often found in those of African origin and DRPLA in the Japanese population. Treatment There is no therapy that can cure or slow the progression of HD, although in 2015, the first human trial of gene silencing with admin- istration of an antisense oligonucleotide started. To date, however, treatment remains symptomatic and requires multidisciplinary management. An early, empathic discussion of the preferences regarding the long term and the living will is therefore crucial. It is often the psychiatric symptoms which cause major distress and which primarily need to be treated (e.g. depression with selective serotonergic reuptake inhibitors (SSRIs), anxiety with benzodi- azepines, psychosis with atypical neuroleptics). If treatment of chorea should be required, tetrabenazine and dopamine receptor blocking agents are acceptable options. However, tetrabenazine is to be used with caution as it can aggravate depression. Other meas- ures comprise weight maintenance with a high calorie diet, as well as speech and language therapy. Benign hereditary chorea The term ‘benign hereditary chorea’ was initially coined to describe autosomal-​dominantly inherited chorea with onset in infancy. Patients often also have disorders of the thyroid or the lungs, as the underlying gene, TITF-​1, plays an important role in the organogenesis of brain, thyroid, and lung. More recently, mutations in other genes like ADCY5 and PDE10A have emerged as another cause of autosomal-​dominant chorea with childhood onset. Acquired chorea The possible aetiologies of acquired chorea are manifold and in- clude drugs, immune-​mediated, metabolic, infectious, and struc- tural causes (Table 24.7.3.1). It is important to keep in mind treatable causes when approaching the differential diagnosis. In this context, we will focus here on autoimmune chorea. Onset age is a crucial determinant in this regard. Autoimmune chorea The archetypical autoimmune chorea in children is Sydenham’s chorea. Anti-​NMDAR encephalitis is an increasingly recognized entity affecting all age groups. Adult autoimmune chorea can be seen in a paraneoplastic disease (mostly related to lung cancer, with CRMP5-​ and Hu-​antibodies), but also in the context of systemic autoimmunity (e.g. antiphospholipid syndrome or systemic lupus erythematosus). Here, the underlying pathophysiology is however poorly understood. Sydenham’s chorea Thomas Sydenham (1624–​1689), who lent his name to the syndrome, was an English physician who described chorea affecting children and adolescents. Thereafter, its association to group A  strepto- coccal infections and rheumatic fever was recognized. Affected children usually present with acute to subacute onset of chorea or hemichorea, often accompanied by behavioural disturbance. As in many other autoimmune disorders, females are more commonly af- fected than males, and may be affected by recurrence of symptoms, particularly when taking oral contraceptives or during pregnancy. Recurrences may also occur spontaneously, but most patients ex- perience complete remission of symptoms within 5–​15 weeks. Only very few patients suffer from persistent chorea. The pathophysiology remains unclear, although a cross-​reaction (‘molecular mimicry’) between immunity directed against the streptocococcus and the basal ganglia is hypothesized. Antistreptolysin titres can support the diagnosis, whereas the previously propagated antibasal ganglia anti- bodies are nowadays considered of little value. Treatment consists of acute therapy with oral penicillin and prophylaxis with monthly benzathine penicillin injections for five years or until reaching adulthood. Anti-​NMDAR encephalitis Encephalitis with N-​methyl-​d-​aspartate receptor (NMDAR) anti- bodies can mimic Sydenham’s chorea as children often present with chorea and only mild neuropsychiatric features. In children, it can be ‘idiopathic’ or occur triggered by herpes virus encephal- itis and lead to ‘choreatic relapses’. Anti-​NMDAR encephalitis can also affect adult patients and is, in nearly half of the female patients, a paraneoplastic phenomenon associated with ovarian teratomas. Classically it presents with an acute onset of neuropyschiatric dis- turbance with subsequent development of movement disorders, epi- lepsy, cognitive impairment, loss of consciousness, dysautonomia, and central hypoventilation. Treatment consists of immunosup- pression and tumour removal where appropriate. Timely diagnosis, which can be confirmed by detection of the antibodies in serum (and more specifically, in the cerebrospinal fluid) is crucial, as the outcome is improved the earlier treatment is initiated and the condi- tion can be lethal if not recognized. Dystonia Dystonia is defined as ‘sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both’. Dystonic movements which become primarily evident on action are often patterned and twisting. Tremor can be a feature. Another char- acteristic feature is the ‘geste antagoniste’ or sensory trick, whereby dystonia movements can be alleviated by a touch of the affected body part. For example, touching the head or face in cervical dys- tonia can help reduce the torticollis. Dystonia may be a clinical feature in the presentation of several conditions in which dystonia is present as the sole symptom or as- sociated with other clinical features. Hence one must use the clin- ical characteristics such as age at onset, body distribution, temporal pattern, associated feature as markers to establish the aetiology, namely whether it is idiopathic or due to a hereditary or acquired cause. Traditionally, we used to classify dystonia as either primary dystonia or secondary dystonia. In the primary form dystonia is the sole feature (apart from tremor) and can be either idiopathic or due to a genetic cause. In contrast, where dystonia was due to secondary section 24  Neurological disorders 5960 acquired or heredodegenerative causes, additional neurological or other features were often present and dystonia was considered as part of a dystonia-​plus syndrome. A new classification now defines dystonia on a clinical and an aetiological axis. In this context, dys- tonia is considered clinically as ‘isolated’ when there are no other associated features or ‘combined’ when there are. This definition largely overlaps with the previous classification of primary gener- ally ‘isolated dystonia’ and ‘combined dystonia’ in which it is part of a syndrome due to different aetiologies which come into the differential diagnosis. The recent advances in the field of dystonia comprise the discovery of several new genes (Table 24.7.3.2 and 24.7.3.4), and the recognition of so-​called non​motor features, such as depression, which significantly contribute to the burden of the disease and impaired quality of life. Primary dystonia (isolated dystonia) Primary dystonia can be idiopathic or genetic (Table 24.7.3.2). Both forms present insidiously and follow a characteristic pattern with re- gard anatomical distribution in relation to age at onset. Discrepancy from this pattern, among other red flags (Table 24.7.3.3), cautions against primary dystonia and may suggest secondary or symptom- atic dystonia. Young onset generalized dystonia (primary torsion dystonia) Manifestation in childhood or adolescence usually involves onset in the legs with subsequent generalization (see Fig. 24.7.3.1). Thus, first symptoms typically are in-​turning of the feet and pigeon-​toed walking before, in most of the cases, over the course of months to years, dystonia spreads to other body parts. This phenotype was de- scribed by Oppenheim in 1911 as ‘dystonia musculorum deformans’ and subsequently called primary torsion dystonia. Later on, TOR1A (Torsin1A) gene mutations emerged as a frequent cause of Oppenheim’s dystonia. TOR1A mutations (also labelled as DYT1) are autosomal-​dominantly inherited, however with reduced (30–​ 40%) penetrance. They account in primary, early-​onset dystonia for c.80% of the cases in Ashkenazi Jewish populations, and up to 50% in non-​Jewish populations. Another genetic form of young onset generalized dystonia is DYT6 due to mutations in the THAP1 (thanatos-​associated protein) gene. It differs from DYT1 inasmuch the sites of onset are the upper limbs, or the craniocervical region with prominent laryngeal involvement. Adult onset focal dystonia (writer’s cramp and craniocervical dystonia) Much more (9–​12 times) frequent than young onset, generalized dystonia are, however, the focal variants with onset in middle or late adulthood, which only rarely have genetic underpinnings. Writer’s cramp and other task-​specific dystonias Writer’s cramp usually manifests in the fourth decade as abnormal posturing when attempting to write. Patients may already have diffi- culty picking up or holding a pen. When writing, they hold the pen with excessive force and dystonic posture of the hand and forearm (see Fig. 24.7.3.1), and experience increasing difficulties as writing continues. In order to cope with this, patients may try a different way to hold the pen, or pens of different sizes, or even learn to write with the other hand. However, some patients may then develop writer’s Table 24.7.3.2  Identified genes in primary (isolated) dystonia Gene (designation) Mode of inheritance Age of onset Dystonia distribution Clinical characteristics DYT1 (TOR1A) AD Childhood Generalized; rarely focal Isolated dystonia starting in legs and spreading; sparing of larynx and neck; can be jerky DYT2 (HPCA) HPCA (DYT2) AR Childhood—​early adulthood Generalized, segmental Isolated dystonia Onset with limb dystonia, slow progression to generalized or segmental dystonia with predominant craniocervical involvement DYT4 (TUBB4A) TUBB4A (DYT4) AD Adolescence—​early adulthood Focal, segmental, generalized Isolated/​combined rare cause of isolated dystonia, prominent laryngeal (‘whispering dysphonia’) and oromandibular involvement; TUBB4A mutations present more often as the complex HABC spectrum DYT6 (THAP1) THAP1 (DYT6) AD Adolescence—​early adulthood Generalized segmental Prominent laryngeal involvement; rostrocaudal gradient DYT23 (CIZ1) CIZ1 (DYT23) AD Adolescence—​ adulthood Focal (Tremulous) cervical dystonia; rare/​awaiting confirmation DYT24 (ANO3) ANO3 (DYT24) AD Childhood—​ adulthood Focal, segmental Tremulous cervical dystonia; cranial, laryngeal, UL involvement; can present with isolated arm tremor, or as a myoclonus-​dystonia DYT25 (GNAL) GNAL (DYT25) AD Childhood—​ adulthood Focal, segmental, rarely generalized Cervical dystonia; head or tremor; laryngeal dystonia; generalization in 10%; hyposmia in some cases DYT27 (COL6A3) COL6A3 (DYT27) AR Childhood—​early adulthood Segmental Mainly affecting the upper body, predominant craniocervical involvement; neck or hand being mostly the site of onset AD, autosomal dominant; AR, autosomal recessive. Table 24.7.3.3  Red flags cautioning against a diagnosis of primary dystonia • Unusual pattern with regard to age of onset and distribution • Sudden onset with rapid progression • History of perinatal birth injury • Developmental delay • Exposure to drugs (e.g. dopamine receptor blockers) • Presence of other neurological or systemic signs • Prominent bulbar involvement with tongue protrusion and dysphagia • Hemidystonia • Fixed dystonia 24.7.3  Movement disorders other than Parkinson’s disease 5961 cramp in the other hand, or develop dystonia which is not limited only to the task of writing itself, but hampers other activities such as using cutlery, brushing teeth, and so on. Other craft or occupational cramps may occur wherever repetitive, stereotyped movements are performed, and are described in piano players, typists, and hair- dressers among many others. Cervical dystonia Cervical dystonia is the most common form of dystonia with prevalence rates ranging from 89 up to 732 per 100 000. It affects mainly women in their fourth or fifth decade of life. The most fre- quent form is torticollis (head turning to one side), but variations such as laterocollis (tilt to the side), retrocollis (neck extension) and anterocollis (neck flexion), or mixed forms can occur. Cranial dystonia Dystonia affecting the face may present as blepharospasm (eye closing spasms), oromandibular dystonia, or a combination of these (‘Meige syndrome’). Laryngeal or laryngopharyngeal dystonia (‘spasmodic dysphonia’) also figures among the cranial dystonias, which are again more frequent among women and mainly occur around the sixth decade. Treatment There are several options for the symptomatic treatment of dys- tonia, but there is no cure. These include a variety of drugs such as anticholinergics, benzodiazepines, gabaergic agents, and dopa- mine receptor blockers (as well as depletors such as tetrabenazine). Intramuscular botulinum toxin injections are the preferred treat- ment for focal dystonias and functional neurosurgery with deep brain stimulation, targeting the internal segment of the globus pallidus can be very effective, particularly in primary dystonia. Other surgical procedures, such as peripheral denervation of af- fected muscles in craniocervical dystonia or lesional brain surgery targeting the globus pallidus or thalamus have been largely aban- doned due to the success and relative safety of deep brain stimu- lation. Ancillary treatments include physical and speech therapy, which are useful, whereas retraining strategies particularly for task-​ specific dystonias (e.g. musician’s dystonia) have been tried, but are of uncertain value in the long term. Dystonia plus syndromes (‘combined dystonia’) When dystonia is combined with other movement disorders, it falls into the category of ‘combined dystonia’. Besides, other neurological signs such as deafness, neuropathy, or eye movement disorders can give valuable clues to the diagnosis. In the following, we will discuss in more detail the syndromes of dystonia and parkinsonism, and dystonia and myoclonus, and provide a general overview of com- bined dystonias (Table 24.7.3.4). Dystonia and parkinsonism Dopa-​responsive dystonia Several genetic enzymatic defects affecting the dopamine synthesis pathway can cause dopa-​responsive dystonia. The archetypic form is Segawa’s disease due to autosomal-​dominantly inherited GCH1 mutations. GCH1 stands for guanidine triphosphate cyclohydrolase 1, a gene encoding the rate-​limiting enzyme in the production of tetrahydrobiopterin, itself an essential cofactor in the dopamine synthesis. Its hallmark features are dystonia commencing in child- hood or adolescence, mainly in the lower limbs, diurnal fluctuation of symptoms (increasing as the day progresses) and an exquisite re- sponse to small doses of levodopa (200–​400 mg per day). Often pa- tients also have signs of parkinsonism and, sometimes, spasticity. There are, however, other autosomal recessive forms of childhood monoamine neurotransmitter disorders, which usually give rise to a more complex phenotype (e.g. with myoclonus and epilepsy) and have less treatment response. Examples include tyrosine hydroxylase deficiency or sepiapterin deficiency. Recognition of these entities is important for the treatment implications. Thus, every child with a phenotype of cerebral palsy and every person with young onset dys- tonia (<25 years) should have a trial of levodopa. A final diagnosis can be made by genetic testing, phenylalanine loading test, and cere- brospinal fluid analysis of pterins. Young onset Parkinson’s disease Young onset Parkinson’s disease (YOPD) can sometimes present with limb dystonia (often foot dystonia). It is an important differ- ential diagnosis to dopa-​responsive dystonia. To avoid the priming effect of levodopa and subsequent dyskinesias and fluctuations, it is important to diagnose this condition, but avoid giving levodopa as a test dose when YOPD is suspected (as both dopa-​responsive dystonia and also these patients respond well to levodopa). In this regard, presynaptic dopaminergic imaging is very valuable as a dopamine transporter single-​photon emission CT (SPECT) scan (DAT scan) is generally normal in dopa-​responsive dystonia. Wilson’s disease Wilson’s disease is another important, treatable cause of dystonia and parkinsonism. It is a comparatively rare (approximately 15–​30/​ 100 000 per year), autosomal recessive copper metabolism disorder that leads to copper deposition in liver, the central nervous system Fig. 24.7.3.1  The spectrum of primary dystonia: young onset generalized dystonia, writer’s cramp, cervical dystonia with geste antagoniste, and blepharospasm. section 24  Neurological disorders 5962 Table 24.7.3.4  Combined dystonia syndromes Dystonia and parkinsonism syndromes Parkinson’s disease, particularly with young onset See text Atypical parkinsonism Corticobasal syndrome Multisystem atrophy Progressive supranuclear palsy See Chapter 24.7.2 Wilson’s disease See text Neuronal brain iron accumulation syndromes Autosomal recessive forms: PANK2 mutations (formerly Hallervorden-​Spatz disease) PLA2G6 mutations CP mutations (Aceruloplasminaemia) C9ORF12 mutations (mitochondrial membrane protein-​associated   neurodegeneration, MPAN) FA2H mutations (fatty acid hydroxylase-​associated neurodegeneration) ATP13A2-​mutations (Kufor-​Rakeb disease) CoAsy mutations (CoA synthase associated neurodegeneration, CoPAN) Autosomal dominant forms: FTL mutations (Neuroferritinopathy) X-​linked dominant WDR45 mutations (BPAN, β-propeller protein-associated   neurodegeneration; formerly SENDA, static encephalopathy of   childhood with neurodegeneration in adulthood) Group of genetic disorders characterized by brain iron accumulation with a variety of manifestations Prominent bulbar involvement and dystonic opisthotonus are red flags Rapid-​onset dystonia-​parkinsonism (ATP1A3 gene, AD, often de novo) Allelic disorder to ‘alternating hemiplegia of childhood’; prominent bulbar symptoms of abrupt onset, often associated with triggering factors (stress, alcohol, exercise, hyperthermia and hypothermia, childbirth); not responsive to L-​dopa X-​linked dystonia-​parkinsonism (DYT3; TAF1 mutations, XLR) Also called Lubag; adult onset dystonia-​parkinsonism, most prevalent in Philippino males Early-​onset dystonia-​parkinsonism (DYT16; PRKRA, ar) Early onset of generalized dystonia, prominent oromandibular involvement, retrocollis and dystonic opisthotonus Dopa-​responsive dystonias See text Dopamine transporter deficiency syndrome (SLC6A3, ar) infantile or juvenile onset dystonia-​parkinsonism not responding to levodopa Huntington’s disease See text Spinocerebellar ataxia (esp. SCA 3) See Chapter 27.7.4 on ataxia GM1 gangliosidosis Lysosomal storage disorder due to homozygous mutations of the GLB1 gene causing variable degrees of neurodegeneration Dystonia and myoclonus syndromes Myoclonus-​dystonia (DYT11; SCGE) See text ANO3 mutations (DYT24, AD) Childhood-​adulthood onset tremulous cervical dystonia that can present as a myoclonus-​dystonia KCTD17 mutations (DYT26, AD) Onset in the first or second decade of life with myoclonus of the upper limbs; dystonia develops later (mainly craniocervical, sometimes segmental with upper limb involvement, rarely generalized). TITF1 mutations (benign hereditary chorea) See text TH deficiency (DYT5b) See text Dystonia and ataxia syndromes Spinocerebellar ataxias See Chapter 27.7.4 on ataxia Ataxia telangiectasia Autosomal recessive disorder (ATM gene) causing a wide spectrum of movement disorders associated with oculomotor apraxia, telangiectasias, and immunodeficiency leading to liability to develop malignancies Ataxia with oculomotor apraxia type 1 and 2 Autosomal recessive disorders (aprataxin and senataxin mutations, respectively) which can mimic ataxia telangiectasia Friedreich’s ataxia See Chapter 27.7.4 on ataxia Neuroacanthocytosis Group of disorders characterized by acanthocytes and progressive neurological decline Wilson’s disease See text Dentatorubropallidoluysian atrophy Autosomal dominant condition (ATN1 gene) with a wide spectrum of manifestations (continued) 24.7.3  Movement disorders other than Parkinson’s disease 5963 (mainly basal ganglia, cerebellum), cornea, and kidneys, thus pre- senting with a variety of symptoms. Two main forms of manifestation are recognized; the hepatic form with earlier onset in childhood, and a neurological form with onset usually in late childhood/​early adolescence. However, late onset even at the age of 52 years has been reported and hence a high index of suspicion is warranted. Wilson’s disease has manifold neurological manifestations. Dystonia and parkinsonism, cerebellar signs, chorea, myoclonus, or psychiatric disturbance have all been described. There is also a typical tremor associated with Wilson’s disease resembling rubral tremor which is present at rest, worse on posture and most severe on action, and which has a characteristic ‘wing-​beating’ proximal component. An important pathognomonic finding is the presence of corneal ‘Kayser–​Fleischer rings’ consisting of red–​brown pigmentation around the edge of the iris due to de- position of copper in the Descemet’s membrane (see Fig. 24.7.3.2). These are best seen on slit-​lamp examination. Similarly, sunflower cataracts due to a radiating, red–​brown pattern of copper deposition in the lens can point to the diagnosis. Apart from cases with rapidly progressive liver failure, where liver transplant is the therapy of choice, the be-​all and end-​all of treat- ment in Wilson’s is copper chelation therapy. The chelating agents, penicillamine and trientene, are the mainstay of treatment initiation and can also be used for the maintenance therapy, either after suc- cessful treatment initiation or in presymptomatic subjects. Zinc can also be used in the maintenance phase, but it inhibits only the re- sorption of copper and is a less powerful drug. Both patients and treating doctors need perseverance. Firstly, there can be a worsening of neurological symptoms soon after the initiation of therapy, par- ticularly with penicillamine. This, however, reverses either with a reduced dosage or continuation of therapy in most cases. Secondly, lifelong treatment is essential and needs to be continued even when patients are asymptomatic. Thus, continuous monitoring and maintaining compliance are key. The hallmark findings in the diagnostic work-​up are low serum caeruloplasmin levels together with a raised 24-​hour urinary copper excretion. However, as those tests are not always conclusive it is sometimes necessary to resort to a liver biopsy, where a copper con- tent greater than 250 micrograms/​g dry weight of liver is considered diagnostic. Currently, genetic testing can be considered, but may be impractical as there are more than 600 mutations in the affected ATP7B gene, although there is some regional clustering of certain mutations. Brain MRI is normal in approximately 50% of the cases, but can show hyperintensities in the putamen, the pallidum, and the thalamus, or the typical ‘face of the giant panda sign’ due to midbrain atrophy and high signal in the tegmentum in T2 weighted sequences (Fig. 24.7.3.3). Myoclonus-​dystonia The typical condition combining myoclonus and dystonia is due to epsilon sarcoglycan gene mutations and termed DYT11. The term myoclonus-​dystonia is often used synonymously with DYT11, al- though there are other entities that can give rise to such a syndrome. DYT11 is an autosomal-​dominantly inherited disorder with onset in infancy or early childhood. The brief myoclonic jerks (‘lightening jerks’) which affect mainly neck and arms often dominate the clinical picture, whereas dystonia of the neck and arms tends to be a com- paratively minor feature. In fact, many cases of ‘essential myoclonus’ Multiple system atrophy See text Niemann–​Pick type C Autosomal recessive lysosomal storage disease (NPC1 mutations) with a wide spectrum of central nervous system symptoms (characteristic: vertical supranuclear gaze palsy) and hepatomegaly GM2-​gangliosidosis A group of autosomal recessive disorders caused by excessive accumulation of ganglioside GM2 and related glycolipids in the lysosomes; wide phenotypic spectrum Dystonia and neuropathy syndromes Metachromatic leukodystrophy Lysosomal storage disease with a wide spectrum of manifestations Neuroacanthocytosis See above Spinocerebellar ataxia See Chapter 27.7.4 on ataxia GM2 gangliosidosis See above Dystonia and deafness syndromes Mohr-​Tranebjaerg syndrome (TIMM8A, x-​linked recessive) Often associated with progressive blindness and dementia Mitochondrial disorders Deafness, diabetes, or myopathy are characteristic findings in mitochondrial disorders, which can manifest with a wide spectrum of phenotypes Woodhouse–​Sakati syndrome (C2ORF37, AR) Hypogonadism, partial alopecia, diabetes mellitus, mental retardation AD, autosomal dominant; AR, autosomal recessive; XLR, x-​linked recessive. Table 24.7.3.4  Continued Fig. 24.7.3.2  Kayser–​Fleischer corneal rings in Wilson’s disease. section 24  Neurological disorders 5964 have been found to be due to epsilon sarcoglycan gene mutations. The symptoms often show a dramatic response to small quantities of alcohol. Psychiatric comorbidity (e.g. obsessive-​compulsive be- haviour, anxiety, or depression), is another well-​recognized feature of the disease. However, several other genetic entities can manifest with a combination of myoclonus and dystonia, including mutations in ANO3 (DYT24), KCTD17 (DYT26), and TH (DYT5b) genes. In addition, patients with benign hereditary chorea, due to TITF-​1 gene mutations, may develop a myoclonus-​dystonia phenotype during the course of their disease. Myoclonus Myoclonus is characterized by very brief, shock-​like, involun- tary movements (see Video 24.7.3.3); it can be positive, caused by sudden muscle contraction, or negative, due to a sudden lack of muscle tone (e.g. asterixis). There are various approaches to the classification of myoclonus, for example, clinically by distribution (focal, segmental, multifocal, generalized; proximal, distal) and inducing factors (spontaneous, on action, stimulus-​sensitive or re- flex myoclonus induced e.g. by sound or touch, orthostatic). Another approach takes into account the origin of myoclonus (cortical, sub- cortical/​basal ganglia, brainstem, spinal, peripheral), which can be localized by electrophysiological investigations (see Box 24.7.3.1). Lastly, by aetiology, myoclonus can be divided into physiological, essential, epileptic, symptomatic, or psychogenic/functional. There is a multitude of disorders which can feature myoclonus, but the differential diagnosis can be narrowed down when taking into consideration age at onset, tempo of onset, precipitating factors including drugs and past medical history, and family history and associated features. Table 24.7.3.5 gives an overview of myoclonic disorders based on their phenomenology. The therapeutic approach naturally depends on the underlying aetiology and, in this regard, metabolic, toxic, infectious, and autoimmune causes deserve par- ticular consideration. Several agents such as clonazepam, valproate, levetiracetam, piracetam, and primidone are available for symp- tomatic treatment and, often, combination therapy is required. For example, in cortical myoclonus, the synergistic effects of valproate, clonazepam, and levetiracetam have proved beneficial. Isolated myoclonus Essential myoclonus See myoclonus-​dystonia/​Dyt11. Hereditary and acquired hyperekplexia and other startle syndromes Hyperekplexia is a form of brainstem myoclonus and best described as a pathological exaggeration of a normal startle response. Just as normal startle places the body in a defensive posture, it manifests with a stereotyped, generalized brisk response, mainly consisting of neck and trunk flexion, eye closure and facial grimacing, and shoulder elevation. In contrast to normal startle, however, it does neither habituate upon repeated stimulation nor attenuate with prewarning. Patients often also exhibit an uninhibited head retrac- tion reflex, which can be elicited by tactile stimulation of the mantle area (e.g. a gentle touch of forehead, nose, lips, upper chest). Other features, apart from the brisk myoclonic jerks, are longer-​lasting Fig. 24.7.3.3  Bilateral abnormal signal in the striatum and thalamus in Wilson’s disease (left) and ‘face of the giant panda’ (right) on T2 weighted MRI sequences in Wilson’s disease. Courtesy of Dr Annu Aggarwal. Box 24.7.3.1  Electrophysiological investigations in myoclonus • Polymyography (EMG): useful to establish the duration and distribu- tion of jerks and to establish the presence of negative myoclonus or stimulus-​sensitivity. Bursts of 50–​75 ms or shorter are generally seen in cortical myoclonus, while longer bursts are seen in subcortical myo- clonus such as in myoclonus-​dystonia. • Electroencephalography (EEG) and back-​averaging:  EEG per se is helpful to detect epileptic discharges. Back-​averaging is a technique of averaging out EEG activity accompanying an EMG recording of various jerks to reveal time-​locked cortical EEG discharges pre- ceding individual myoclonic jerks (as seen in cortical myoclonus). A slow rising wave prior to psychogenic/functional jerks is called the Bereitschaftspotential (premovement potential). • Somatosensory evoked potentials (SSEP): Giant SSEPs are an electro- physiological hallmark feature of cortical myoclonus. • C-​reflex: This is a long loop reflex mediated by the sensory–​motor cortex. Enhanced C-​reflexes are another characteristic of cortical myoclonus. 24.7.3  Movement disorders other than Parkinson’s disease 5965 Table 24.7.3.5  Overview of myoclonic disorders based on their phenomenology Phenomenology Disorder Aetiology Notes Isolated myoclonus Hiccup, hypnic jerks, startle response Physiological Benign neonatal sleep myoclonus Physiological Myoclonus affects limbs, occurs exclusively during sleep, and stops on awakening; self-​limiting and usually not present after 3 months of age Essential myoclonus Genetic: often epsilon sarcoglycan gene mutations/​DYT11 (AD) Very brief (‘lightening’) jerks affecting mainly neck and arms; see text Familial cortical myoclonus (also: benign adult onset familial myoclonic epilepsy) Genetic: NOL3, ADRA2B, CNTN2, other mutations (AD) Also called ‘cortical tremor’, which is a misnomer, but highlights its resemblance with tremor; fine, shivering-​like myoclonus affecting the distal limbs, mainly hands; rarely occurring without seizures; onset in 3rd or 4th decade; see text Hereditary hyperekplexia Genetic: mutations affecting the glycine receptor (GLRB, AR; GLRA1, AD, or AR) or glycine transporter (SCL6A5, AR, AD) Exaggerated startle response to touch or noise, present already at birth; usually decreasing throughout life; see text Orthostatic myoclonus Unknown Rare manifestation of autoimmune and neurodegenerative conditions with myoclonus of the legs occurring only while standing Myoclonus with dystonia Myoclonus-​dystonia Genetic: DYT11 (SGCE mutations, AD); DYT15 (18p11, AD); DYT27 (KCDT17 mutations, AD) Mostly neck and arms affected, myoclonus may be the dominant feature; see text Myoclonus with epilepsy Benign myoclonic epilepsy of infancy Unknown (probably genetic) Myoclonic jerks involving mainly neck and arms, the consciousness remains usually preserved; febrile convulsions but no other seizures associated; onset 6 months—​3 years, male preponderance Juvenile myoclonic epilepsy Genetic: GABAA1 (AD) Onset around puberty, myoclonic jerks affecting mainly the arms and occurring typically on awakening; can be associated with generalized tonic–​clonic seizures or absences Familial cortical myoclonus/​ (also: benign adult onset familial myoclonic epilepsy) Genetic: heterogeneous (ADRA2B, CNTN2, NOL3, other loci; AD) Also called ‘cortical tremor’, which is a misnomer, but highlights its resemblance with tremor; fine, shivering-​like myoclonus affecting the distal limbs, mainly hands; rarely occurring without seizures; onset in 3rd or 4th decade; see text West syndrome Various aetiologies, often symptomatic (tuberous sclerosis, perinatal hypoxia, congenital infections, malformations, craniocerebral injury) Childhood-​onset epilepsy syndrome with severe encephalopathy Dravet syndrome Genetic: De novo mutations in SCN1A, GABARG2 Childhood-​onset epilepsy syndrome with severe encephalopathy Lennox Gastaut syndrome Various aetiologies Childhood-​onset epilepsy syndrome with severe encephalopathy Doose syndrome (myoclonic astatic epilepsy) Unknown Childhood-​onset epilepsy syndrome with or without encephalopathy Epilepsia partialis continua Cortical lesion Characteristic syndrome of myoclonus affecting constantly one or adjacent body parts Myoclonus with ataxia (‘Ramsay Hunt syndrome’) • No or very mild cognitive impairment Unverricht–​Lundborg disease/​‘baltic myoclonus’ Genetic: CSTB (AR) onset between 6 to 15 yrs with stimulus-​sensitive myoclonus and generalized tonic–​clonic seizures; see text North Sea myoclonus Genetic: GOSR2 (AR) Onset around age 2 years with ataxia; myoclonus develops later, around age 6 years; other features include scoliosis and areflexia; see text Action myoclonus renal failure Genetic: SCARB2 (AR) Renal failure not an obligatory feature; onset usually in adolescence or early adulthood (continued) section 24  Neurological disorders 5966 Phenomenology Disorder Aetiology Notes Progressive myoclonus Epilepsy-​ataxia syndrome Genetic: PRICKLE1 (AR) Onset between 5 to 10 years; can feature upgaze restriction Myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK) Genetic: KCNC1 (AD) Age at onset 5–​14 years; infrequent tonic–​clonic seizures SCA14 Genetic: PRKCG (AD) Age at onset varies from early to late adulthood; other features may comprise spasticity and dystonia Coeliac disease Unknown (probably autoimmune) Gluten-​sensitive enteropathy, usually manifesting with diarrhoea • With or without cognitive impairment Dentato-​rubro-​pallido-​ luysian atrophy (DRPLA) Genetic: ATN1 (AD) Age of onset varies from 1 to 62 years; similar heterogeneity in clinical presentation, but the Ramsay Hunt presentation starts usually before 20 yrs Mitochondrial disorders, e.g. myoclonic epilepsy with ragged-​red fibres (MERRF) Genetic: MTTK, MTTL1, MTTH, MTTS1, MTTS2, MTTF (maternal) Short stature, deafness, myopathy • With cognitive impairment Lafora disease Genetic: EPM2A, NHLRC1 (AR) Onset in 2nd decade; generalized tonic–​clonic seizures, and characteristic occipital seizures; death after 2–​10 yrs; axillary skin biopsy shows pas-​positive polyglucosan inclusion bodies; see text Neuronal ceroid lipofuscinosis Genetic: CLN1-​14 (mostly AR; CLN4B AD) Visual disturbance, extrapyramidal symptoms, rapidly progressive psychomotor deterioration; see text Sialidoses Genetic: NEU1 (AR) Type 2 presents with visual disturbance, cherry red spot, skeletal dysplasia, and has a reduced life expectancy; type 1 is the more benign form where dementia is usually not a feature; see text Prion disease Genetic: PRNP (AD or sporadic) Myoclonus is diffuse, generalized, relatively rhythmic, often stimulus-​sensitive, and can persist during sleep Niemann–​Pick C Genetic: NPC1, NPC2 (AR) Hepatosplenomegaly, vertical supranuclear gaze palsy Gaucher Type III Genetic: GBA (AR) Hepatosplenomegaly, horizontal supranuclear gaze palsy GM2 gangliosidosis (Tay-​Sachs disease, Sandhoff’s disease) Genetic: HexA, HexB, GM2A (AR) group of disorders caused by excessive accumulation of ganglioside GM2 and related glycolipids in the lysosomes Late infantile and juvenile forms feature myoclonus, epilepsy, ataxia, dementia, spasticity Myoclonus with opsoclonus Opsoclonus-​myoclonus ataxia syndrome Autoimmune (+/​-​ paraneoplastic; in children often associated with neuroblastoma) Opsoclonus (spontaneous, involuntary, multidirectional, ‘chaotic’ saccades) is the key feature; see text Myoclonus with parkinsonism/​dementia Atypical parkinsonism syndromes • Multisystem atrophy (MSA) Neurodegeneration (α-​synucleinopathy) small-​amplitude myoclonus of the hands and/​or fingers on posture: ‘polyminimyoclonus’ • Dementia with Lewy bodies (DLB) Neurodegeneration (α-​synucleinopathy) cortical myoclonus • Corticobasal syndrome Neurodegeneration (usually tauopathy) Stimulus-​sensitive cortical myoclonus, usually focal affecting one arm, or less frequently one leg, and mostly associated with apraxia or rigidity • Fronto-​temporal lobar degeneration due to C9ORF72 mutations Genetic: C9ORF72 (AD) Corticobasal syndrome with dementia, anterior horn cell involvement, parkinsonism, and myoclonus Huntington’s disease HTT (AD) Myoclonus can be predominant feature particularly in younger patients with higher triplet repeat numbers; it is cortical, thus stimulus-​sensitive and action induced; see text Table 24.7.3.5  Continued (continued) 24.7.3  Movement disorders other than Parkinson’s disease 5967 Phenomenology Disorder Aetiology Notes Alzheimer’s disease Sporadic or genetic Myoclonus is usually multifocal, but can be generalized, either as single large jerks, or repetitive small ones (at rest, during action, or stimulus-​sensitive). It is present in c.50% of patients in middle and late stages of the disease; it may be present early on in those with younger age of onset, rapid progression, and in genetic forms Prion disease Sporadic or genetic Myoclonus is diffuse, generalized, relatively rhythmic, often stimulus-​sensitive, and can persist during sleep Myoclonus with encephalopathy Metabolic disturbance Liver failure, renal failure, dialysis related (acute or chronic) disturbance of electrolytes (hyponatraemia, hypocalcaemia) or glucose metabolism (hypo-​/​non​ketotic hyperglycaemia), hypomagnesaemia Often associated with asterixis (negative myoclonus, ‘liver flap’) and multifocal or generalized myoclonus (spontaneous, stimulus-​sensitive). In relation with renal dialysis, there can be both the acute dialysis syndrome, which typically occurs during rapid dialysis and is attributed to cerebral oedema, or the chronic dialysis dementia related to aluminium toxicity Drug-​related levodopa, lithium, tricyclic antidepressants, morphine, antibiotics, SSRIs, MAOIs, antipsychotic and anaesthetic agents Toxic bismuth, methyl bromide, tetraethyl lead, mercury, gasoline sniffing, lead benzene, others Acute or subacute onset of clouding of consciousness, epilepsy, and multifocal or generalized myoclonus, which is usually of cortical origin and may occur spontaneously, be stimulus sensitive and action induced encephalitis Infectious (subacute sclerosing panencephalitis, Whipple’s disease, Coxsackie, enterovirus, herpes simplex virus, HIV, others), autoimmune/​paraneoplastic (including steroid responsive encephalopathy with thyroid antibodies (SREAT), formerly known as Hashimoto’s encephalopathy; encephalitis lethargica) Subacute sclerosing panencephalitis (SSPE) is a chronic measles virus encephalitis, which is usually fatal and features characteristic ‘hung up jerks’ Biotin responsive encephalopathy Genetic: SLC19A3 mutation (AR), gene encodes a thiamine transporter Reported mainly in consanguineous families from the Middle East; Recurrent subacute encephalopathy, often triggered by febrile illness or trauma, with onset in childhood; rarely presentation as chronic disorder or with onset in adulthood; typically widespread involvement with epilepsy, ataxia, dystonia, rigidity, ophthalmoplegia, pyramidal signs. Characteristic MRI finding with T2 hyperintensities and swelling of basal ganglia in acute stages, and atrophy and necrosis on follow up. Fatal if untreated, but responds to administration of thiamine and biotin Lance-​Adams syndrome (postanoxic myoclonus) Hypoxic brain damage Non​progressive, generalized myoclonus developing days to weeks after hypoxic brain injury; negative myoclonus of legs characteristic (bouncy legs), ataxia, and cognitive involvement present to variable extent (see Video 24.7.3.3) Myoclonus with stiffness Stiff person syndrome and variants, including progressive encephalomyelitis with rigidity and myoclonus (PERM) Autoimmune (+/​-​ paraneoplastic), various antibodies (against GAD, GlyR, amphiphysin, GABAaR, gephyrin, Ri, DPPX) Spectrum of disorders characterized by stiffness and spasms; see text Acquired hyperekplexia Various aetiologies (brainstem encephalitis; strychnine intoxication; tetanus) Exaggerated startle response to acoustic or tactile stimuli with onset mainly in adulthood; other neurological signs possible Myoclonus with other focal neurological signs Various aetiologies (structural lesions, encephalitis) Myoclonus mimic Functional myoclonus Psychogenic/functional Typical presentation as propriospinal myoclonus; jerks are often distractible, variable, and/​or associated with other psychogenic/functional features, like incongruency; ‘Bereitschaftspotential’ on back-​averaging Table 24.7.3.5  Continued section 24  Neurological disorders 5968 spasms and stiffness, which can give rise to life-​threating neonatal apnoea episodes or induce ‘falls en bloque’. Hyperekplexia is a very distinct, but also very rare (incidence unknown) syndrome with genetic and acquired forms. Hereditary hyperekplexia can be caused by several mutations affecting genes mainly involved in glycinergic inhibitory neurotransmission (see Table 24.7.3.5), the classic form being due to mutations in the α-1 subunit of the glycine receptor gene. In hereditary hyperekplexia, symptoms are usually present from birth (‘stiff baby syndrome’) and may decrease over time with adult patients having only mild, residual signs. The acquired forms are due typically to an autoimmune process targeting glycinergic or gabaergic neurotransmission related to glycine receptor, glu- tamic acid decarboxylase or amphiphysin antibodies (overlap with -​> stiff person syndrome). However, brainstem encephalitis of any aetiology, just brainstem lesions, tetanus, and strychnine in- toxication, can give rise to acquired hyperekplexia. Other startle syndromes include startle epilepsy (epileptic seizures triggered by startle, mostly in patients with congenital brain damage) and cul- tural startle syndromes such as the ‘jumping Frenchmen of Maine’, ‘Latah’ (Malaysia), and ‘Myriachit’ (Siberia). Treatment depends on the underlying cause, but benzodiazepines such as clonazepam can be effective as symptomatic therapy. Myoclonus with epilepsy When myoclonus is part of an epileptic syndrome, the term epi- leptic myoclonus is often used. Several syndromes fall into this category, with a wide spectrum from benign and treatable disorders to devastating and treatment refractory epilepsies with marked en- cephalopathy. Epileptic myoclonus is typically accompanied by gen- eralized epileptiform discharges, but the myoclonus itself may be focal, segmental, or generalized. Focal myoclonus can also occur in secondary symptomatic epilepsy due to a lesion. Here we focus on two representative entities where the myoclonus is very much to the fore. For an overview of the whole spectrum, see the Table 24.7.3.5. Juvenile myoclonus epilepsy Juvenile myoclonus epilepsy accounts for 5–​10% of all epilepsies. Age at onset is typically in adolescence, but can range from 8 to 25 years. The characteristic semiology consists in myoclonic attacks affecting symmetrically and proximally both arms, and there is a cir- cadian pattern with clustering of attacks in the mornings. Thus, it is often memorized as ‘cornflakes epilepsy’ as a typical history given by patients is that of spilling the cereals at breakfast. Juvenile myo- clonus epilepsy often occurs in combination with grand mal seiz- ures (90%) upon awakening, or with absences (25%). As in other idiopathic, generalized epilepsies, seizures can be provoked by sleep deprivation, hyperventilation, or photostimulation. The treatment response overall is good, although lifelong drug therapy is required in most of the cases. However, the manifestation in adolescence ren- ders implementation of the recommended adaptation of lifestyle (regular and sufficient sleep, avoidance of alcohol and recreational drugs) sometimes more difficult. Familial cortical myoclonus This syndrome is rare and has a confusing number of descriptions, being called ‘benign autosomal-​dominant familial myoclonic epi- lepsy’, ‘familial cortical myoclonic tremor and epilepsy’, or most frequently, ‘familial cortical tremor’ (just to name a few). However, the latter is a misnomer as it only superficially resembles tremor, but is in fact a fine, shivering-​like myoclonus most prominent in the hands. It can be associated with generalized seizures. The underlying genetic heterogeneity with several genes (NOL3, ADRA2B, CNTN2) and loci identified might partly explain phenotypical variations stretching from truly benign courses to more progressive and disabling disorders. Myoclonus with ataxia With his seminal contribution ‘Dyssynergia cerebellaris myoclonica’, James Ramsay Hunt defined a clinical syndrome characterized by progressive myoclonus, ataxia, and epilepsy. Thus, there is a wide variety of underlying aetiologies, with a considerable overlap with the group of progressive myoclonus epilepsies. The myoclonus is of cortical origin and tends to be multifocal or generalized and mainly action induced, but can often also be elicited by stimuli (touch, noise, visual; ‘reflex myoclonus’). The differential diagnosis and fur- ther investigations are guided by the associated features, first of all by the presence or absence of cognitive impairment. The so-​called ‘famous five’ aetiologies of the progressive myoclonic ataxias com- prise Unverricht–​Lundborg disease with a relatively benign course and preserved cognition, mitochondrial disorders with a wide phenotypical range, and the storage disorders Lafora body disease, neuronal ceroid lipofuscinosis and sialidoses on the severe end of the spectrum, with prominent dementia and markedly reduced life expectancy (see Table 24.7.3.5). Unverricht–​Lundborg disease or Baltic myoclonus Unverricht–​Lundborg disease is the archetypical syndrome of pro- gressive myoclonus ataxia without significant cognitive impairment. Unverricht reported the first family in Estonia, and Lundborg de- scribed 10 families in Sweden. Further cases were subsequently noted in Finland, and the term ‘Baltic myoclonus’ was coined since the disease seemed to be common in Scandinavia and related coun- tries. Prevalence rates in Finland were numbered 4–​5 in 100 000. The disease is autosomal recessively inherited, and most patients are homozygous for the dodecamer expansion mutation in the cystatin B (CSTB) gene. Age at onset varies between 6 to 15 years (on average 10.6 years), with first symptoms being stimulus-​sensitive myoclonic jerks and generalized tonic–​clonic seizures, whereas cerebellar signs develop only later. Patients eventually become wheelchair bound, and there may be mild cognitive impairment at later stages of the disease. Pharmacotherapy usually consists of combination therapy with a cocktail of different antiepileptic drugs such as sodium val- proate, clonazepam, and levetiracetam. The life expectancy is re- duced with an average around 60 years. Although Unverricht–​Lundborg disease seems to remain one of the most frequent causes of progressive myoclonic ataxias without prominent cognitive involvement, there are several more recently identified disorders that resemble this phenotype. Autosomal re- cessive GOSR2 mutations were identified as the cause of ‘North Sea myoclonus’, the name again indicating a clustering of cases in the countries adjacent to the North Sea. Compared to Unverricht–​ Lundborg disease, this disorder starts earlier in life with ataxia and features scoliosis and potentially other skeletal deformities, and areflexia as distinguishing marks. The list of differential diagnosis keeps expanding by virtue of the advances in the genetics, but also comprises acquired causes like coeliac disease (see Table 24.7.3.5). 24.7.3  Movement disorders other than Parkinson’s disease 5969 Lafora body disease This rare and fatal disorder is named after the Spanish neuropath- ologist Lafora who described the characteristic inclusion bodies consisting of polyglucosan. It is autosomal recessively inherited and caused by mutations either in the laforin gene (EPM2A) or in the malin gene (NHLRC1). Either the detection of the gene mu- tations or the presence of Lafora bodies in biopsied tissue (axilla) are diagnostic. Patients usually present in adolescence with seiz- ures, followed by debilitating myoclonus and dementia. Occipital seizures and visual deterioration are characteristic. Death occurs within 2–​10 years after onset. Neuronal ceroid liposfuscinosis (Batten’s disease) Neuronal ceroid lipofuscinosis comprises a group of clinically and genetically heterogenous disorders characterized by intracellular accumulation of autofluorescent lipopigment. Different subtypes were defined by age of onset, clinical signs, and the ultrastructural pattern of the storage material. The disease runs a relentless course with dementia, epilepsy and progressive visual failure leading to blindness (not in adult onset variant). Sialidoses Both type 1 and type 2 sialidosis are rare autosomal recessive lysosomal storage diseases. Type 1 is also called ‘cherry red spot myoclonus syndrome’, because of the red spot in the retina pre- sent in nearly all the cases. It begins in the second decade, usually with a progressive loss of vision (deterioration of colour vision, night blindness, retinal degeneration, optic atrophy, corneal clouding). Further features, besides progressive myoclonic ataxia, are generalized tonic–​clonic seizures. In contrast, type 2 has an earlier age at onset, a more rapid disease progression and a re- duced life expectancy. It also differs from type 1 inasmuch there is dementia, facial dysmorphia, and skeletal dysplasia as additional features. Opsoclonus-​myoclonus This distinct syndrome is also called ‘dancing eyes-​dancing feet syndrome’, a denomination which describes the spontaneous, in- voluntary, multidirectional, ‘chaotic’ saccades seen in opsoclonus (see Video 24.7.3.4), and the myoclonus which is often gener- alized. Ataxia is often a further feature, as are sleep disturbance and behavioural changes. It seems to be immune mediated as it is often paraneoplastic, with neuroblastoma being the most fre- quent tumour in children, cancer of lung and breast prevailing in adults, but also can be post or parainfectious. In this regard, pri- mary HIV infection is one of the most frequent causes. Sometimes, however, no trigger can be identified. In most cases, no anti- body is detected. The therapeutic approach consists of treatment of any underlying malignancy where applicable, and immuno- therapy. The outcome is variable, ranging from a monophasic course with excellent recovery to treatment-​resistant chronic courses. Myoclonus with parkinsonism/​dementia Myoclonus can be a feature in various neurodegenerative dis- eases with parkinsonism or dementia as main symptom. Please see Table 24.7.3.5 and Chapter 24.7.2 for more in-​depth coverage. Tremor Tremor is a rhythmic, oscillatory movement, usually due to alternate activation of agonist and antagonist muscles. It can be described ac- cording to the body part affected, its frequency and amplitude, and when it occurs, namely at rest vs. posture vs. during movement vs. task or position specific. Kinetic tremor can be further subdivided into action tremor or intention tremor, the latter describing a tremor which increases throughout a performed movement. Tremor may be the sole and defining symptom, or be part of a syndrome with associated neurological signs. Here, we will discuss some specific tremor syndromes in more detail. Table 24.7.3.6 gives an overview of different causes arranged according to their main tremor presentation. Patients often find tremor socially embarrassing and very disabling (Fig. 24.7.3.4). Regardless of the different potentially underlying aetiologies, treatment of tremor is purely symptomatic. Focal tremors (e.g. of head, jaw, voice) often show an excellent response to botulinum toxin injections. Tremor of the limbs often requires med- ical therapy. Several options (propranolol, clonazepam, primidone, topiramate, and gabapentin) exist, but side effects and potential benefit should be weighed. The first line treatment for dystonic tremor is trihexyphenidyl, whereas parkinsonian tremors might respond to dopaminergic medication. Orthostatic tremor some- times responds to clonazepam or levodopa. For severe and disabling tremors, deep brain stimulation is worth considering. Lastly, fo- cused ultrasound may be a non​invasive technique available in the not-​so-​distant future. Essential tremor Classically, essential temor is a symmetrical postural or kinetic tremor of the arms, which gradually worsens over time and which tends to be inherited in an autosomal-​dominant manner. Patients often report that small amounts of alcohol tend to decrease the tremor. Additional neurological signs, particularly dystonia, are an exclusion criterion. Isolated voice, tongue, chin, or leg tremor as well as position-​ or task-​specific tremors are not consistent with essen- tial tremor. It is thought to be one of the most frequent neurological disorders with prevalence rates around 300 per 100 000 and a bi- modal peak of onset in the second and sixth decade. There are some cases reported with cerebellar or Lewy body pathology, but there is no consistent neuropathological finding. Despite being strongly familial, surprisingly the search for a common causative gene has not been successful so far, although there has been an association with the LINGO1 gene. Thus, it appears that essential temor is rather a syndrome than a single entity. There are no diagnostic tests for essential tremor, and the diagnosis is based on the clinical findings and exclusion of other causes for postural tremor. In this regard, en- hanced physiological tremor comes into the differential diagnosis; this is physiological tremor enhanced by drugs, metabolic, endo- crine, or other causes and may be mistaken for essential temor. Typically, it worsens with anxiety and fatigue, and usually decreases with weight loading as evident on electromyography (EMG). Dystonic tremor Dystonia itself can be tremulous and may, therefore, manifest as head tremor in patients with cervical dystonia (see Video 24.7.3.5), section 24  Neurological disorders 5970 a voice tremor (laryngeal dystonia), or hand tremor. Dystonic tremor is often rather jerky and irregular. It can be position-​ or task-​ specific (e.g. like primary writing tremor). Recent evidence shows that, rarely, tremor can precede the development of actual dystonia. Often, there is also an autosomal-​dominant family history. Again, there are no biomarkers and the diagnosis relies on clinical acumen. It appears that the most common misdiagnoses are essential tremor or benign tremulous Parkinson’s disease. However, subtle or not so subtle signs of dystonia (including geste, task and position specifi- city) and prominent asymmetry mitigate against a diagnosis of es- sential tremor (Video 24.7.3.6). Where it is difficult to differentiate dystonic tremor from Parkinson’s disease on clinical grounds only, a DAT scan is very helpful. Orthostatic tremor Orthostatic tremor is a rare, but distinct syndrome. Age at onset is typically around 50 years. The patients describe that they feel un- stable on standing only and, therefore, have difficulties queuing or during parochial ceremonies. However, they have no difficulty when walking or sitting. The cause is a high-​frequency tremor of the legs, which occurs only on standing after a small latency period. Subsequently, with progression of the condition, the tremor becomes more disabling as it occurs straightaway and with higher amplitude. The history suggests the diagnosis itself and, on examination, a high-​ frequency tremor of both legs can be felt or heard with a stetho- scope on the thighs (described as the sound of a helicopter). The tremor is often too fast to be seen, but can be confirmed with EMG, which reveals 13–​18 Hz tremor. Sometimes, a postural tremor of the arms can also be observed. In most, orthostatic tremor remains the sole symptom. The few who develop additional features such as parkinsonism or restless legs, are classified as having orthostatic tremor-​plus syndrome. The main treatment options are clonazepam and levodopa. Fragile X tremor ataxia syndrome Fragile X syndrome is one of the most frequent causes for male mental retardation. It is an x-​linked condition due to a triplet re- peat expansion (>200) in the fragile site mental retardation (FMR1) gene. A repeat expansion of 55–​200 defines Fragile X permutation carriers, who typically develop a movement disorder character- ized by tremor and ataxia called Fragile X tremor ataxia syndrome (FXTAS). FXTAS may sometimes mimic multisystem atrophy, given it can feature a combination of ataxia, parkinsonism, and autonomic dysfunction. However, cognitive impairment which may be present in FXTAS, but not multisystem atrophy, is a red flag. FXTAS can also occur in females, where it is often associated with premature ovarian failure. The brain MRI shows often shows T2 hyperintensity of the middle cerebellar peduncles (MCP sign). Tic disorders Tics are defined as rapid, brief, stereotyped movements, or vocaliza- tions. In practice, one could think of them as caricatures of normal movements, such as eye blinking, shoulder shrugging, grimacing, sniffing, or grunting. These would be examples of simple motor or vocal tics, whereas complex tics consist of a combined sequence of stereotyped movements or saying words or phrases. Typically, tics wax and wane, and are (temporarily) suppressible, but patients will describe an inner rising tension or anxiety to allow the tics to emerge. This so-​called premonitory urge resolves when allowing the tics to happen, and often there is a rebound exacerbation. Table 24.7.3.6  The main forms of tremor and their most important causes Rest tremor • Parkinson’s disease (‘pill-​rolling’ tremor) • Atypical parkinsonism (multisystem atrophy, and so on) • Drug-​induced parkinsonism • Rubral tremor • Spinocerebellar ataxias • Dystonic tremor • Severe essential tremor • Fragile X-associated tremor/ataxia syndrome (FXTAS) • Neuropathic tremor Postural tremor • Enhanced physiological tremor • Metabolic disturbance (e.g. hyperthyroidism, Cushing’s syndrome) • Drugs (β-​agonists (e.g. salbutamol), anticonvulsants (e.g. sodium valproate), thyroxine, tricyclic antidepressants, theophylline, lithium, immunosuppressive drugs (e.g. cyclosporin)) • Stimulants, drugs of abuse (e.g. coffee, alcohol, nicotine, amphetamine, cocaine, marijuana) • Toxins (e.g. mercury, toluene, solvents) • Essential tremor • Neuropathic tremor (e.g. demyelinating neuropathy, particularly with MAG-​antibodies or IgM paraproteinaemia) • Dystonic tremor • Parkinson’s disease (‘re-​emergent tremor’) • Multiple system atrophy • Spinocerebellar ataxia (esp. SCA 12) • Fragile X-​associated tremor/​ataxia syndrome (FXTAS) • Orthostatic tremor Kinetic tremor • Cerebellar disease (e.g. brainstem or cerebellar outflow pathway lesions, various aetiologies, the most common cause being multiple sclerosis) • Holmes tremor (also called rubral tremor, tripartite tremor (rest < posture < intention) due to damage of cerebello-​rubrothalamic and nigro-​striatal pathways) • Wilson’s disease (often with characteristic ‘wing-​beating tremor’) 24.7.3  Movement disorders other than Parkinson’s disease 5971 Primary tic disorders and Tourette syndrome Tics mostly occur as primary disorders without any associated neurological disease. There is a very broad spectrum of tics, span- ning from minor tics of self-​limiting occurrence during childhood, which occur in up to 15% of school-​age children (boys more than girls), and persistent tic disorders, like Tourette syndrome, which can result in significant physical and social disability. Tourette syndrome affects approximately 0.3–​0.5% of the adult population, with males being more often affected than females (4:1). Although no gene has been identified, there seems to be a genetic burden since first-​degree relatives have a higher risk (10–​100-​fold), and there are families with an autosomal-​dominant inheritance pat- tern. Our pathophysiological understanding is still limited, but ex- isting data point to a maturation defect of the corticosubcortical and corticocortical circuits regulating motor output control, and par- ticularly to altered cholinergic neurotransmission in the striatum. Tourette’s syndrome is diagnosed when multiple motor (at least two) tics and vocal utterances (at least one) have occurred (although not necessarily simultaneously) prior to the age of 18 years and persisted for more than one year. Patients with Tourette’s might also exhibit echopraxia (copying movements) or echolalia (repeating words). In contrast, copropraxia (making obscene gestures) or coprolalia (ut- tering obscenities) are much less frequent. Often however, it is the psychiatric comorbidity (obsessive-​compulsive disorder, attention deficit hyperactivity disorder (ADHD), self-​harming behaviour, de- pression) which is much more relevant for the patient’s quality of life than the actual tics, and this should be considered in the therapeutic approach. Tics can be treated with dopamine receptor antagonists, A2 receptor antagonists, or benzodiazepines. Botulinum toxin in- jections can sometimes ease the urge and are considered particularly helpful for vocal tics. Associated psychopathology can be addressed with cognitive behavioural therapy and, if needed, with drug treat- ment (e.g. SSRI for depression or obsessive-​compulsive disorder; methylphenidate for ADHD). Secondary tic disorders More rarely, tics can occur secondarily to neurodegenerative disease (e.g. neuroacanthocytosis, Huntington’s disease, Wilson’s disease, (a) (b) Fig. 24.7.3.4  Samples of handwriting and spiral drawing from patients with dystonic tremor, illustrating the difficulties patients may face in day to day life on writing or fine motor tasks. section 24  Neurological disorders 5972 neuronal brain iron accumulation), in developmental disorders (e.g. autism, fragile X syndrome, mental retardation), as part of the spec- trum of paediatric autoimmune neuropsychiatric disorders associ- ated with streptococcal infections, or due to structural brain damage (e.g. basal ganglia lesions). Lastly, there are certain drugs which are associated with (re-​)occurrence of tics (e.g. cocaine, amphetamine, methylphenidate, ecstasy; amantadine, fenfluramine; levodopa; carbamazepine). Restless legs syndrome and other sleep movement disorders Restless legs syndrome Patients with restless legs syndrome complain of the character- istic combination of unpleasant sensations in the legs and an urge to move them as this brings relief. The problem occurs only at rest and usually in the evening. It may be a primary, often familial dis- order with an autosomal-​dominant inheritance, or secondary, due to a variety of causes including pregnancy, iron deficiency anaemia, peripheral neuropathy, PD, hyperthyroidism, and multiple sclerosis. Several drugs can precipitate restless legs including interferon-α, levothyroxine, neuroleptics, or tricyclic antidepressants. Overall, it is thought to be a relatively common disorder with mild symptoms affecting up to 11% of the population, whereas clinically significant symptoms affect about 3.5%. The pathophysiology is not fully under- stood. Defective iron metabolism with low iron levels in neuronal cells, particularly in the substantia nigra has been implied, as well as dopaminergic dysfunction. Other studies suggested hyperexcitability or disinhibition of the nociceptive systems. Routine investigations in a patient presenting with restless legs syndrome should include serum ferritin levels, and clinical examination for signs of peripheral neur- opathy and parkinsonism. The first-​line treatment is dopaminergic medication (L-​dopa and dopamine agonists), whereas symptomatic forms can be alleviated by treating the underlying condition (e.g. iron substitution, treatment of uraemia). A caveat of dopaminergic treat- ment is so-​called ‘augmentation’, referring to a worsening of symp- toms (earlier occurrence in the day; increased intensity; involvement of other body parts) during treatment. Periodic limb movement of sleep Periodic limb movement of sleep consists of jerky flexion movements of the hips, knees, and ankles during non-​REM sleep. This may be idiopathic, but is often associated with restless legs syndrome, with an overlapping spectrum of symptomatic causes. Treatment with clonazepam is helpful when the disorder causes sleep disruption with consecutive daytime somnolence. REM sleep behaviour disorder It is usually the bed partner who describes the patient shouting, or being punched or kicked out of bed. In REM sleep behaviour dis- order, there is no loss of muscle tone during REM sleep, and thus, pa- tients act out their vivid dreams. This may be an idiopathic problem, but often heralds the onset of a parkinsonian disorder, usually with α-​synuclein pathology (Parkinson’s disease, dementia with Lewy bodies, multisystem atrophy). In doubt, the diagnosis can be estab- lished by polysomnography. Clonazepam or melatonin are useful when sleep quality is poor. Stiff person syndrome and related disorders Moersch and Woltman firstly described stiff person syndrome as a rare and enigmatic disorder of ‘progressive fluctuating muscular rigidity and spasm’, without other ‘firm’ neurological signs (Fig. 24.7.3.5). Classical stiff person syndrome features Fig. 24.7.3.5  Paravertebral stiffness leading to lumbar hyperlordosis with skin crease in a patient with classical stiff person syndrome; the hyperlordosis does not even out when bending down. 24.7.3  Movement disorders other than Parkinson’s disease 5973 stiffness of paravertebral and proximal muscles, leading to lumbar hyperlordosis and a stiff, wooden gait. Subsequently, a broad clinical spectrum, with stiffness and spasms as the hall- mark features, emerged. Often there is also an exaggerated startle response, and falls may occur due to sudden stiffening. We rec- ognize focal forms like stiff limb syndrome as well as progressive encephalomyelitis with rigidity and myoclonus, a variant with a more widespread involvement featuring other neurological signs and a potentially lethal disease course. Apart from the mere motor signs, patients often have a characteristic fear of walking unaided, which leads to them frequently being wrongly labelled as psychogenic. The different variants share a range of associated antibodies, which supports the notion that this is an autoimmune disease, which in some cases is triggered by an underlying neo- plasm. Among them, antibodies against glutamic acid decarb- oxylase, glycine receptor, and amphiphysin are the most frequent and account for up to 90% of the cases. According to current paradigms in neuroimmunology, it is believed that neuronal surface antibodies (see Table 24.7.3.7) are pathogenic whereas the other antibodies, targeting intracellular antigens, are rather a marker of autoimmunity driven by T cells. Apart from anti- body testing, the diagnostic work-​up includes cerebrospinal fluid analysis and electrophysiological studies (exteroceptive reflexes, continuous motor unit activity). The treatment approach com- prises immunotherapy (intravenous immunoglobulins, cortico- steroids, plasma exchange, rituximab), removal of tumour where appropriate, and symptomatic treatment with benzodiazepines (mostly clonazepam; high doses may be required and well toler- ated) and baclofen. Paroxysmal dyskinesia The paroxysmal dyskinesias are a group of rare, heterogeneous dis- orders typified by brief self-​limiting attacks of involuntary move- ments, which can be clinically classified according to the triggering factor and the duration of attacks. Between attacks, patients do not have any neurological symptoms. Onset is usually in childhood. Different genetic forms have been identified corresponding to par- ticular clinical phenotypes. Paroxysmal kinesigenic dyskinesia is the most frequent from of paroxysmal dyskinesias with brief (seconds to minutes) attacks of chorea, dystonia or mixed forms precipitated by sudden movement, or even an intention to move or acceleration of ongoing move- ment (hence kinesigenic). Up to hundred attacks may occur per day. Most cases are due to autosomal-​dominant PRRT2 mutations, which also associate with ‘Infantile convulsions with paroxysmal choreoathetosis’ (ICCA), benign familial infantile epilepsy and mi- graine. Treatment response to low doses of carbamazepine is usually excellent. Attacks of paroxysmal non​kinesiginic dyskinesias are triggered by alcohol, coffee, or fatigue. They last minutes to hours and are in- frequent compared to paroxysmal kinesigenic dyskinesia with just one to three attacks a day and several months of attack free inter- vals. In familial cases, mutations of the myofibrillogenesis regulator gene MR-​1 are the underlying cause. Treatment consists mainly in avoidance of the precipitating factors. Paroxysmal exercise-​induced dyskinesia manifests as gradual onset of dystonia in a limb after prolonged exercise of that limb. Heterozygous mutations in the SLC2A1 gene encoding for glu- cose transporter 1 (GLUT1) give rise to this phenotype in about half of the cases with paroxysmal exercise-​induced dyskinesia. Apart from genetic testing, the diagnosis can be ascertained by measuring the ratio of cerebrospinal fluid to plasma glucose levels, which is below 0.45 in affected subjects. Recognition is important as a ketogenic diet can be used successfully in these cases. There are also secondary forms of paroxysmal movement dis- orders, for example, due to basal ganglia lesions. The red flags cautioning against a diagnosis of primary paroxysmal movement disorders are a later age at onset, abnormalities on the neurological examination between attacks, and pain during the attacks. The latter is particularly frequent in the tonic spasms seen in demyelinating disorders, and in psychogenic paroxysmal attacks. Of particular interest are two conditions where the paroxysmal attack may herald avoidable damage: limb-​shaking transient ischaemic attacks (‘limb-​shaking TIA’) are typically precipitated by rising or exercise, and often accompanied by paresis of the affected limb. They are a manifestation of an internal carotid artery occlusion and indicate a critical haemodynamic state. The so-​called faciobrachial dys- tonic seizures with LGI1-​antibodies are very characteristic, brief (<10 s), frequent episodes (up to several hundred per day) of dys- tonic posturing mainly involving face, arm or leg, or combinations of these, on one side, or alternating. Again, recognition is important as immunotherapy may prevent the development of the full-​blown encephalitis. Table 24.7.3.7  Main antibodies in stiff person syndrome and related disorders Antibodies against Glutamic acid decarboxylase (GAD) Mostly non​paraneoplastic; often associated with other diabetes type 1 and other organ-​specific autoimmunity (e.g. thyroid antibodies, vitiligo) Glycine receptor (GlyR)a Mostly non​paraneoplastic (malignancies in up to 10%, mostly thymoma, lymphomas, various cancers) Amphiphysin Paraneoplastic, often associated with breast cancer Dipeptidyl-​peptidase 6 (DPPX)a Mostly in PERM variants, prominent gastrointestinal symptoms (diarrhoea or constipation) are a red flag; paraneoplastic and non​paraneoplastic (malignancies in up to 10%, mostly B-​cell lymphoma) a Neuronal surface antibodies. section 24  Neurological disorders 5974 Functional movement disorders A wide variety of drugs can cause different movement disorders, the classical scenarios being that of the tardive dyskinesia and dystonia, or akathisia, due to chronic exposure to dopamine re- ceptor blocking agents. Besides, there are acute and subacute pres- entations related to initiation of a new treatment, or alteration of plasma levels of established drugs. Drug-​induced parkinsonism, spanning from mere lack of spontaneous movements to a mimic of Parkinson’s disease, can be seen especially with dopamine receptor blocking drugs. Drug-​induced chorea, myoclonus, tics, and tremor are covered in the respective chapters. The key to diagnosis is a thorough history, taking into account that antidopaminergic drugs are also used to treat nausea or dizziness (e.g. metoclopramide, phenothiazine), and that patients may consider some medication not as drugs (e.g. oral contraceptives, herbal medicine). Moreover, intake of stimulants (coffee, alcohol, cigarettes) and illicit drugs should be enquired about. Overall, the treatment approach would be to stop the offending drug, and possibly offer symptomatic treatment. Tardive dystonia, dyskinesia, and akathisia Tardive dystonia characteristically involves axial hyperextension with retrocollis, and when severe can even cause a patch of balding on the back of the head due to the constant friction of the head on chair rests. Tardive dyskinesia typically manifests with a very char- acteristic picture of orolingual facial stereotyped movements such as chewing, lip smacking, and protrusion or writhing movements of the tongue, but also generalized chorea (see Video 24.7.3.7). The term akathisia comes from the Greek and means ‘inability to sit still’, describing a compelling need to be in motion driven by a feeling of inner restlessness. The spectrum spans from discomfort when re- quired not to move, to involuntary lower leg and trunk movements which vary from an occasional foot squirming or leg swinging when seated to constant agitated movements, getting up when seated, pacing around, or tramping on the spot. Akathisia can be severely discomforting. A combination of the different manifestations of tar- dive disorders is frequently observed. Tardive syndromes are caused mainly by chronic exposure to dopamine receptor blocking drugs and, less frequently, to the short administration or withdrawal of a dopaminergic antagonist or indirect dopaminergic inhibitors, such as SSRIs. Although the pathophysiology is not yet understood, it is assumed that particu- larly D2 receptor blockade could lead to postsynaptic dopamine receptor hypersensitivity. Other hypotheses invoke secondary mal- adaptive synaptic plasticity or neurodegeneration. The older anti- psychotics or first generation ‘typical’ neuroleptics (e.g. haloperidol, flupentixol, sulpiride, chlorpromazine, trifluoperazine, pimozide) are associated with a higher risk of inducing tardive dyskinesia (incidence of 5–​7.7% per year) than the atypical antipsychotics or newer generation neuroleptics (e.g. clozapine, quetiapine; inci- dence 2.9% per year). Tardive movement disorders rarely remit and can cause signifi- cant socially stigmatizing physical discomfort. Therefore, it is best to avoid long-​term exposure and higher doses of neuroleptics, and to give preference to the atypical neuroleptics. When tardive symptoms occur, the offending drug should be discontinued where possible. The medical treatment options are similar to those other- wise used, namely anticholinergic drugs like trihexyphenidyl for tar- dive dystonia and tetrabenazine for tardive dyskinesia. Botulinum toxin injections can bring relief in tardive dystonia and there are single reports of good responses to deep brain stimulation of the globus pallidus. Paradoxically, the (re)introduction of dopamine receptor-​blocking drugs (e.g. quetiapine, risperidone) can improve tardive dyskinesia or tardive dystonia. Treatment of akathisia is with anticholinergics such as trihexyphenidyl or procyclidine, or benzodiazepines. Acute dystonic reactions Suddenly developing jaw opening dystonia (with or without oculogyric crisis and /​or laryngospasm) should raise the sus- picion of a drug-​induced acute dystonic reaction. These occur shortly (hours to days) after administration of the offending drug. This may be a dopamine receptor blocking agent (neuro- leptics, but also antiemetics like metoclopramide), an amine depletor (tetrabenazine), an antidepressant (particularly SSRIs), or a calcium antagonist (flunarizine). Acute dystonic reactions have also been described with benzodiazepines, anticonvul- sants, general anaesthetics, and ranitidine, or with cocaine, or ec- stasy. The treatment consists of discontinuation of the offending drug, administration of anticholinergics (e.g. benzatropine or procyclidine i.v.) and prevention of recurrence by covering with trihexyphenidyl. Neuroleptic malignant syndrome and related disorders Neuroleptic malignant syndrome is a medical emergency, caused ei- ther by starting treatment, or by increasing the dose of dopamine receptor blocking drugs, and occurs in approximately 0.5–​1% of cases. The combination of rigidity, high fever, hypertension, exces- sive sweating, and a fluctuating level of consciousness should alert any physician, as this condition can be fatal. There are no diag- nostic tests, although creatine kinase and white cell blood count are usually raised. Treatment is in an ICU setting and consists of sup- portive care, administration of dantrolene as a muscle relaxant, or dopamine agonists, and discontinuation of the dopamine receptor blocker. In patients with Parkinson’s disease, sudden discontinu- ation of dopaminergic drugs can result in a similar clinical picture (parkinsonism–​hyperpyrexia syndrome, akinetic crisis). The man- agement is similar, plus reintroduction of the dopaminergic medica- tion. Related disorders are the dyskinesia–​hyperpyrexia syndrome, and serotonin syndrome. Dopamine agonist withdrawal syndrome Dopamine agonist withdrawal syndrome is a recently recognized entity, which occurs, however, in as many as 15–​19% of patients who discontinue their medication with dopamine agonists because of side effects, such as impulse control disorder. The symptoms are depression, anxiety, fatigue, insomnia, and autonomic symptoms (postural dizziness, sweating). Most of the patients recover within six months, but some patients are unable to remain off dopamine agonists. Replacement with L-​dopa is not helpful, and the fact that there seems to be an association between the risk of developing im- pulse control disorders and dopamine agonist withdrawal syndrome underlines the challenge to manage these cases. 24.7.3  Movement disorders other than Parkinson’s disease 5975 Functional movement disorders Many different terms have been used over the centuries to describe non​organic symptoms, and currently, the controversy to call them psychogenic or functional continues, fuelled by the increasing rec- ognition of this entity. Overall, it is thought that functional move- ment disorders account for 2% of all patients, but up to 20% in tertiary referral centres. They occur either in isolation (possibly with other psychogenic symptoms) or on top of an organic disease, as a ‘functional overlay’. The difficulty with functional disorders has been that there is often a reservation to make and break the diagnosis, and insecurity about the management. However, the prognosis is better the earlier the diagnosis is made and conveyed. Thus, subjecting the patient to every possible diagnostic test in order to rule out the most remote differential diagnosis is detrimental as it delays, and reinforces the patient’s notion that there may be some underlying organic condi- tion. We should keep in mind that an erroneous diagnosis of organic disease is often just as harmful as the misdiagnosis of a functional disorder in an organic disorder. The diagnosis of functional disorders rests upon the recognition of incongruity with any organic disease and positive diagnostic find- ings suggestive of a functional disorder upon clinical examination. Sometimes there is no psychological stressor identifiable, so the diag- nosis should not rely on presence or absence of it. Clues from the his- tory include an abrupt onset, often with a physical or psychological precipitant, variability of symptoms with paroxysmal exacerbations and a change in phenomenology over time. Often there are also mul- tiple additional co-​occurring neurological and systemic symptoms. The signs to look out for in clinical examination are distractibility (resolution or diminution of symptoms with distraction; see Video 24.7.3.8), variability (change of pattern; see Video 24.7.3.9), suggest- ibility (exacerbation when the attention is focused on the affected body part, and improvement with placebo manoeuvres). The ‘whack-​ a-​mole’ sign describes the shift of symptoms to other body parts, if the affected body part is restrained; for example, a tremor in one limb may appear in another when the former is kept still by the examiner. The ‘huffing and puffing sign’ describes the inappropriate effort needed for simple tasks. There is frequently ‘give-​way’ weakness of the limbs and a positive Hoover sign, or a functional pattern of sensory disturbance. The disability is often out of proportion to the objective examination findings. There are certain characteristic phenotypes of functional disorders (Box 24.7.3.2). The differential diagnosis comprises organic disorders that can give rise to unusual or even bizarre-​looking symp- toms (e.g. the gait in Huntington’s disease or stiff person syndrome, or paroxysmal movement disorders). Functional disorders must be distinguished from feigning and malingering. Miscellaneous movement disorders Hemifacial spasm This is a common condition leading to involuntary muscle twitching of the muscles innervated by the facial nerve. The twitches usually start around the eye, and later spread to involve other muscles on the same side of the face. These muscle spasms are synchronous and occur spontaneously, but can be induced by touch or cold, or facial movement. It affects approximately 7–​14/​100 000. The so-​called idiopathic forms are often caused by irritation of the facial nerve at the root exit zone by an aberrant blood vessel. Secondary forms are seen with lesions in the region of the facial nerve root exit zone, mostly tumours and demyelination. The diag- nostic work-​up should, therefore, include a MRI scan. In the primary forms, age of onset is usually in the fourth or fifth decade. There is a preponderance of females, and those with vascular risk factors such as hypertension, diabetes, and hypercholesterinaemia which makes them prone to having tortuous intracranial blood vessels. There are higher incidence rates among Asians. The treatment of choice is botulinum toxin injections. Drug treatment is usually not very effective, and the surgical approach (microvascular decompression) bears significant risks. Myokymia Myokymia is an involuntary, spontaneous, localized quivering of a few muscles, or bundles within a muscle, but which are insuffi- cient to move a joint. Myokymia has a characteristic EMG pattern of doublets and multiplets. It persists during sleep. Myokymia can be focal, multifocal, or generalized. Immune-​mediated forms are seen in Isaac’s syndrome (peripheral nerve hyperexcitability with myokymia and neuromyotonia) and Morvan’s fibrillary chorea (myokymia plus encephalitis with dysautonomia and insomnia), both due to antibodies targeting the voltage gated potassium channel complex, in particular Caspr2-​antibodies. In addition, the venom of the rattlesnake, which also blocks voltage gated potassium channels, can cause myokymia. Genetic forms are caused by KCNA1 mutations affecting potassium channels, as seen in episodic ataxia type 1. Superior oblique myokymia manifests as repeated, brief epi- sodes of rotation and (minimal) downgaze of the affected eye, super- ficially resembling monocular nystagmus and leading to diplopia. The term, however, is probably a misnomer, as there is no indication of a channelopathy as in the other forms of myokymia, but emerging evidence of neurovascular compression at the root exit zone of the trochlear nerve, a commonality shared with hemifacial spasm. Box 24.7.3.2  Some well-​recognized patterns of psychogenic (functional) movement disorders • Functional dystonia The classical case is that of a young woman, who after a minor trauma acutely develops a painful fixed posturing and in-​turning of the foot with trophic and sudomotor changes. There might be a spread of symptoms to other limbs. • Functional tremor Functional tremor is one of the most frequent psychogenic movement disorders. It is distractible (see Video 24.7.3.8) and ceases with ballistic movements of the other limb. Entrainment describes the adaptation of tremor frequency when the patient is asked to perform a rhythmic task at a certain pace dictated by the examiner. • Propriospinal myoclonus It has been recently recognized that propriospinal myoclonus, in most cases, is functional. This notion is, inter alia, based on the occurrence of a Bereitschaftspotential (premovement potential, present in the electro­ gastrogram (EGG) prior to voluntary movements). • Functional gait disturbance There are various patterns of functional gait disturbance. Patients may walk excessively slow and cautious as if ‘walking on ice’, or feel they have balance difficulties and veer from side to side, waving their arms, with a narrow base (‘tightrope walker gait’), which in fact requires excellent balance. 24.7.4 Ataxic disorders 5976 Nicholas Wood 24.7.4 Ataxic disorders 5976 Nicholas Wood section 24  Neurological disorders 5976 Rippling muscle disease due to autosomal-​dominant caveolin-​3 mu- tations can give rise to a clinically similar picture, but differs in elec- tromyographic silence, despite muscle movement. Myorhythmia Myorhythmia is defined as repetitive, rhythmic, slow (1–​4 Hz) movement affecting chiefly cranial and limb muscles. Oculo-​ masticatory myorhythmia is characterized by synchronous 2 Hz vergence spasms of the eyes sometimes with contraction of the mas- seter with the palate and diaphragm also being involved. It is virtu- ally pathognomonic of Whipple’s disease, a rare, systemic infectious disease caused by the bacterium Tropheryma whipplei and merits mention as a treatable disorder. FURTHER READING General Donaldson I, et  al. (2012). Marsden’s book of movement disorders. Oxford University Press, Oxford. Edwards M, et al. (2015). Parkinson’s disease and other movement disor­ ders. Oxford University Press, Oxford. Chorea Gövert F, Schneider SA (2013). Huntington’s disease and Huntington’s disease-​like syndromes: an overview. Curr Opin Neurol, 26, 420–​7. Dystonia Balint B, Bhatia KP (2014). Dystonia: an update on phenomenology, classification, pathogenesis and treatment. Curr Opin Neurol, 27, 468–​76. Myoclonus Kojovic M, Cordivari C, Bhatia K (2011). Myoclonic disorders: a prac- tical approach for diagnosis and treatment. Ther Adv Neurol Disord, 4, 47–​62. Zutt R, et al. (2015). A novel diagnostic approach to patients with myo- clonus. Nat Rev Neurol, 11, 687–​97. Tremor Gövert F, Deuschl G (2015). Tremor entities and their classifica- tion: an update. Curr Opin Neurol, 28, 393–​9. Tics and Tourette’s syndrome Ganos C, Martino D (2015). Tics and tourette syndrome. Neurol Clin, 33, 115–​36. Paroxysmal dyskinesia Erro R, Sheerin UM, Bhatia KP (2014). Paroxysmal dyskinesias re- visited: a review of 500 genetically proven cases and a new classifi- cation. Mov Disord, 29, 1108–​16. Stiff person syndrome Meinck HM, Thompson PD (2002). Stiff man syndrome and related conditions. Mov Disord, 17, 853–​66. Functional movement disorders Edwards MJ, Bhatia KP (2012). Functional (psychogenic) movement disorders: merging mind and brain. Lancet Neurol, 11, 250–​60. Morgante F, Edwards MJ, Espay AJ (2013). Psychogenic movement disorders. Continuum (Minneap Minn), 19(5 Movement Disorders), 1383–​96. Drug-​induced movement disorders Mehta SH, Morgan JC, Sethi KD (2015). Drug-​induced movement disorders. Neurol Clin, 33, 153–​74. 24.7.4  Ataxic disorders Nicholas Wood ESSENTIALS Ataxia is a feature of disorders of the cerebellum and its connections. It may be found in a large range of neurological conditions, in some of which it is the principal or main feature, but clinical assessment is complicated by the fact that few ataxic patients have disease re- stricted to the cerebellum alone. Clinical features Symptoms—​common presenting complaints are (1) gait unsteadiness—​ particularly with lesions of the vermis; (2) limb incoordination and tremor—​particularly with lesions of the cerebellar hemisphere; (3) slur- ring of speech; and (4) visual and oculomotor symptoms, although these are rare in pure cerebellar disease. Signs—​these include (1)  a broad-​based gait with a poor turn; (2) scanning dysarthria; (3)  limb ataxia—​manifest as dysmetria and dysdiadochokinesis; (4)  intention tremor; (5)  abnormal eye movements. Key points in differential diagnosis—​(1) age of onset—​early-​onset is before 20–​25 years; (2) rate of onset and the nature of the pro- gression of the illness; (3) other features of neurological involvement, which enables differentiation of the ‘pure’ ataxias from the ‘compli- cated’ ataxias. Investigation and treatment—​high-​resolution imaging, genetic testing and other investigative tools enable a diagnosis to be made in over 50% of cases. The mainstay of management is supportive: there are no drugs that help cerebellar balance problems, but active engagement in physiotherapy can help to lessen the impact of the physical disorder. Particular causes of ataxia Ataxias with early-​onset—​(1) acute and subacute ataxias with onset in childhood—​should raise the possibility of infectious, para-​infectious or vascular conditions; (2) chronic progressive ataxias of early-​onset—​ very often genetic in aetiology, typically autosomal recessive, with the commonest cause being Friedreich’s ataxia; a clear molecular genetic diagnosis can be established in most cases. Chronic progressive ataxia—​causes include (1)  genetic—​with in- heritance typically being autosomal dominant; (2) chronic alcohol abuse—​probably the most common cause of progressive cerebellar degeneration in adults; (3)  deficiency disorders (e.g. vitamin E); (4) toxic agents—​drugs (e.g. phenytoin), solvents, and heavy metals; (5) structural lesions in the posterior fossa; and (6) other (e.g. Wilson’s disease, other metabolic disorders). No cause can be found in many cases, labelled as ‘idiopathic late-​onset cerebellar ataxia’, with the commonest pattern recognized being that of multiple system at- rophy, where there is typically ataxia complicated by autonomic failure and (in some cases) Parkinsonism. Rapid, subacute onset ataxia—​should always raise the possibility of paraneoplastic or other inflammatory conditions. Acute ataxia—​the two main causes are (1) cerebellar haemorrhage—​ usually associated with headache, vertigo, vomiting, altered conscious- ness and neck stiffness; and (2) cerebellar infarction—​in which cerebellar signs are usually combined with signs of brainstem ischaemia. 24.7.4  Ataxic disorders 5977 Introduction The term ataxia derived from the Greek means ‘irregularity’ or ‘disorderliness’. Unsteadiness can result from several causes, including poor vision, impairment of postural reflexes, or due to a deficiency of sensory input (i.e. sensory ataxia). This chapter focuses on the symptoms, signs, and the pathological and clin- ical features of the disorders of the cerebellum (and its connec- tions). There are two basic clinical rules that can be applied: (1) lesions of the vermis generally cause ataxia of midline struc- ture (i.e. truncal and gait ataxia); (2) output from the cerebellar hemisphere is to the contralateral cerebral hemisphere, which provides output to the contralateral limbs, therefore cerebellar hemisphere lesions are ipsilateral. It should however be noted that, clinical assessment is complicated by the fact that many ataxic patients have additional pathology in the brain stem, spinal cord, or elsewhere. Symptoms of ataxic disorders The patient history is extremely important and the most common presenting complaints are of gait unsteadiness or slurring of speech. On direct enquiry many patients will admit to receiving ‘jokes’ or accusations of being drunk by acquaintances. The joke tends to wear thin. Some refer to ‘giddiness’ or ‘dizziness’ when they really mean unsteadiness of gait without associated vertigo or lightheadedness. A particular note in the history of the age, speed of onset, and devel- opment of other features may provide important aetiological clues. Rate of progress and any precipitating or relieving factors should also be noted. A range of genetic tests is now available, and a detailed family history is paramount. Disturbances of gait This is the most frequent presenting feature in ataxic disorders. Patients may report an inability to walk in a straight line and a tendency to bump into things. A history of it being worse in the dark may suggest a sensory ataxia and involvement of the proprio- ceptive pathways. Sudden changes of direction are particularly dif- ficult and problems turning may be reported. The duration of the gait disturbance should be established and it is worth asking about early motor milestones and athletic ability at school that may bring out a much longer history than previously appreciated. Collateral history should be sought, especially if an insidious onset is sus- pected, as this may be difficult for a patient to report. A question as to diurnal variation, particularly a history of morning unsteadi- ness that wears off later in the day, often associated with morning headache, may suggest raised intracranial pressure even if exam- ination is normal. Limb incoordination and tremor Clumsiness of the arms is often noted as the illness progresses. Generally, a tremor that is worse on action is reported and as this worsens patients notice clumsiness carrying objects and deteri- oration of their handwriting. Marked tremor is more common in multiple sclerosis than in degenerative disease. Disturbance to the midline structures may result in titubation and this, in combination with action tremor in the upper limbs, and little in the way of gait disturbance, should raise the suspicion of Wilson’s disease. Dysarthria This may be noted by friends and relatives before the patient. Classically described as having a staccato quality, it is a useful symptom or sign as it points against a purely sensory ataxia. It is also worth listening to the speech as many patients have a dysarthria with cerebellar features mixed with spastic or dysphonic elements. Visual and ocular motor symptoms Visual symptoms are relatively rare in pure cerebellar disease and, if present, are more often associated with brain stem disturbance, espe- cially episodic or persistent diplopia associated with ataxia. Vertical oscillopsia suggests downbeat nystagmus and a structural foramen magnum lesion should be suspected. Acute or subacute oscillopsia, with chaotic involuntary eye movements, may be mentioned in the history of patients with viral cerebellitis, paraneoplastic cerebellar degeneration, and the dancing eyes syndrome (opsoclonus). There are some very rare degenerative ataxias with gradual visual loss, due to either optic neuropathy or retinopathy. Other symptoms Details of any headache or vomiting should be sought. Its presence may suggest a posterior fossa mass lesion. If the history is acute then a vascular event, in particular a cerebellar haemorrhage should be considered. Whereas in cases with a more protracted course a tu- mour becomes more likely. Ancillary signs of infection should raise the possibility of an abscess. Intermittent symptoms could indicate the presence of an episodic ataxia (see later) or, if found in the pres- ence of malaise and fever, raise the possibility of posterior fossa cysticercosis. A history of vertigo is more suggestive of neoplastic, inflammatory, and vascular disease rather than the more slowly pro- gressive degenerative processes. Direct questioning should cover the urinary system, skeletal de- formities, cardiac disease, and assessment of cognitive abilities since many ataxias can be associated with disease in other systems (see Table 24.7.4.1). A detailed inquiry of drug ingestion (for both medical and recre- ational purposes, including alcohol) and occupational exposure is also required. Signs of cerebellar disease It is generally good practice in neurology to greet the patient in the waiting room; observe them rising from a chair mobilizing to the consulting room, shaking hands, and hearing their speech. In the case of the ataxic patient this sequence provides much of the information one needs to characterize the disease. Gait and posture A patient may demonstrate a broad-​based gait, with a poor turn and there is often a lurching quality to the overall sequence. More de- tailed assessment of mild gait ataxia may be obtained by asking the patient to tandem walk (heel-​toe). Asking the patient to stand still may reveal the broad base and also permits the assessment of pro- prioception via Romberg’s test. section 24  Neurological disorders 5978 Speech It is often stated that cerebellar speech is very distinctive with an ex- plosive quality, so-​called scanning dysarthria. Although when this is heard it is characteristic, frequently a combination of cerebellar and spastic features may be heard. Additional signs such as a slow-​ moving tongue and brisk jaw jerk support the latter. Muscle tone Some textbooks state firmly that cerebellar disease gives rise to hypotonia, and some even include it within the symptoms. Not only do patients never complain of hypotonia, but this is rarely detectable clinically in symmetrical slowly progressive or chronic disorders. Pendular knee jerks are also difficult to detect without the eye of faith and many patients with ‘cerebellar’ ataxic disorders have dis- ease of the spinal cord, peripheral nerves, or both, which compli- cates the clinical picture. Limb ataxia Limb ataxia is usually assessed by looking for evidence of dysmetria and dysdiadochokinesis. Dysmetria refers to errors in the range and force of movement resulting in an erratic, jerky movement which may under-​ or overshoot the target. This is most simply assessed using finger nose and heel shin tests. Dysdiadochokinesis is demon- strated by asking the patient to tap one hand on the other, alternately pronating and supinating the tapping hand, or rapidly opening and closing the fist. In addition, the tapping out of simple rhythms (with the hand or foot) is also useful for assessing both the rhythmicity and force of the tap. Traditionally testing of coordination is undertaken after the motor and sensory tests as the presence of weakness or sensory loss can confuse the picture. It should be remembered that there is a natural asymmetry in cerebellar function, with better performance, particu- larly for rapid alternating movements, in the dominant limb. About 40% of patients with vermis lesions do not have limb ataxia but have prominent gait ataxia. Tremor Intention tremor is present if a rhythmical side-​to-​side oscillation is seen on finger-​nose testing. A  combination of gross intention tremor and a postural component is often called rubral or red nu- cleus tremor, although peduncular tremor is probably a more ac- curate label. It is most commonly seen in multiple sclerosis and Table 24.7.4.1  Differential diagnosis of ataxic disorders: associated general physical signs Short stature Mitochondrial encephalomyopathy Ataxia telangiectasia Sjögren–​Larsson syndrome Cockayne syndrome Hypogonadism Recessive ataxia with hypogonadism, ataxia telangiectasia, Sjögren–​Larsson syndrome, mitochondrial encephalomyopathy, adreno-​leukomyeloneuropathy Skeletal deformity Friedreich’s ataxia, Sjögren–​Larsson syndrome, many other early-​onset inherited ataxias, hereditary motor, and sensory neuropathy Immunodeficiency Ataxia telangiectasia, multiple carboxylase deficiencies Malnutrition Vitamin E deficiency, alcoholic cerebellar degeneration Hair Argininosuccinicaciduria—​brittle Giant axonal neuropathy—​tight curls Thallium poisoning, hypothyroidism, adrenoleukomyeloneuropathy -​ Loss -​ Foramen magnum lesions -​ Low hairline Skin Telangiectases, particularly conjunctiva, nose, ears, flexures Extreme light sensitivity, tumours Pellagra-​type rash Tendinous swellings Dry skin Pigmentation Ataxia telangiectasia Xeroderma pigmentosum Hartnup’s disease Cholestanolosis Hypothyroidism, Refsum’s disease Cockayne’s syndrome Adrenoleukomyeloneuropathy Eyes Kayser-​Fleischer rings Ataxia telangiectasia Cataract Telangiectasia Aniridia Wilson’s disease Retinal angiomas in von-​Hippel-​Lindau disease Congenital rubella, cholestanolosis, Sjögren–​Larsson syndrome Gillespie syndrome Fever Abscess, viral cerebellitis, cysticercosis, dominant periodic ataxia, intermittent metabolic ataxias Haemorrhage, infarction, demyelination, posterior fossa mass lesions, intermittent metabolic ataxias Hepatosplenomegaly Niemann–​Pick disease type C, some childhood metabolic ataxias, Wilson’s disease, alcoholic cerebellar degeneration Heart disease Friedreich’s ataxia Cardiomegaly, murmurs, arrhythmias, late heart failure, abnormal ECG Mitochondrial encephalomyopathy Conduction defects 24.7.4  Ataxic disorders 5979 occasionally in late-​onset degenerative ataxias. A  nodding head tremor (titubation) with a frequency of 3–​4 Hz may be seen with midline cerebellar disease. Eye movements This assessment is really useful in patients with possible cerebellar dysfunction as it is extremely uncommon to find patients with cere- bellar disease with a completely blameless oculomotor examination. However, one may need to search quite hard for the abnormal signs. In the primary position one should spend a moment looking for the presence of square wave jerks; these are inappropriate saccades that disrupt fixation and are followed by a corrective saccade within 200 msec. In practice this appears as a quick ‘shuffle’ on and off the point of fixation. Assessment of pursuit usually reveals jerkiness as a result of saccadic intrusions. Additional isolated or multiple lesions of the third, fourth, or sixth cranial nerves suggests brain stem path- ology. Examination of the saccadic system permits an assessment of saccadic initiation, velocity, and accuracy. Also the presence of an internuclear ophthalmoplegia may be found, indicated by slow- ness of an adducting eye, and suggesting a diagnosis of multiple sclerosis, but can also rarely be associated with some degenerative ataxias. The vestibulo-​ocular reflex (dolls head manoeuvre) should then be examined to look for any supranuclear component. An in- ability to suppress the vestibulo-​ocular reflex is evidence of path- ology involving the vestibulocerebellum. Acute or subacute presentation of almost any of the aforemen- tioned eye movements especially if associated with alcohol abuse or vomiting, raises the possibility of Wernicke’s encephalopathy and re- quires urgent treatment with thiamine. Gaze-​evoked nystagmus is the most common type of nystagmus associated with cerebellar disease; eccentric gaze cannot be main- tained, and the slow phase of the nystagmus is toward the primary position, with rapid corrective movements. Apart from down beat nystagmus, which may indicate a foramen magnum lesion, gaze-​ evoked nystagmus is of limited localization value in most forms of ataxia. Positional nystagmus in a patient with vertigo and unsteadiness should be attributed to benign labyrinthine disease only if it is tran- sient, torsional, and fatigable; if it does not have these features, a pos- terior fossa lesion should be suspected. Other neurological signs and general examination As the causes of ataxia are numerous, a large variety of other neuro- logical and general physical signs may be found on examination. The range of these and their possible diagnostic significance is shown in Table 24.7.4.1. Investigations This is necessarily a brief overview of a complex area. Imaging Imaging has had a huge impact on clinical neuroscience. For the ataxias it helps identify structural lesions (e.g. tumours, vascular events, and demyelination). It may also confirm the clinical impres- sion of a degenerative process with the presence of atrophy. The use of magnetic resonance imaging (MRI) for monitoring cerebellar disease progression is still limited and generally not clinically useful as there is a poor correlation between severity of symptoms and de- gree of atrophy. However, there are occasionally distinctive imaging features (e.g. molar tooth sign in Joubert’s syndrome; thinning of corpus callosum in SPG11 and autosomal recessive spastic ataxia of Charlevoix–​ Sagueney, or ARSACS). Genetics There are some gene tests that are widely available (e.g. FRDA and some of the SCAs; see Tables 24.7.4.4 and 24.7.4.5a). Several diag- nostic labs are now offering a broader range of tests on so-​called gene panels and this will rapidly be followed by the clinical appli- cation of whole exome and whole genome sequencing approaches. This will provide much greater clarity as to potential genetic causes underlying the myriad genetic ataxias. Quantifying the anatomy Many of the conditions discussed in this chapter are complex and this author has a low threshold for requesting further investigations to help identify and quantify other deficits. This includes nerve con- duction studies (e.g. the presence of a demyelinating neuropathy ra- ther than axonal can help in dissecting the differential diagnosis); a sensory neuronopathy points to a different group of disorders compared to a generalized neuropathy and so on. A formal neuro- psychological assessment can also be very useful. Disorders of the cerebellum There are numerous pathological processes that can affect cere- bellar function. Some of them, such as multiple sclerosis and neo- plasia are discussed elsewhere (Chapter 24.10.2). In this section I have broadly attempted to classify these using age at onset and time course of the process. Developmental disorders The cerebellum has a long developmental period and is not fully ma- ture until about 18 months of age. It is therefore susceptible to many insults, including intrauterine infections, ischaemic damage, toxins, and genetically determined syndromes (see Table 24.7.4.2). Some of these developmental anomalies, such as dysgenesis or agenesis of the vermis, the cerebellar hemispheres, or parts of the brain stem, give rise to congenital ataxia. These are non​progressive disorders, and in most cases, coordination improves somewhat with age. Cerebellar dysfunction in an infant or young child may be over- looked, as it often gives rise to relatively non​specific abnormal motor development. Later there is nystagmus, obvious incoordination on reaching for objects and truncal ataxia when first attempting to sit. Associated mental retardation is common but unhelpful diagnostic- ally as there is a long differential diagnosis. Ataxia of acute or subacute onset Cerebellar ataxia with extremely acute onset has two main causes: cerebellar haemorrhage (usually associated with headache, vertigo, vomiting, altered consciousness and neck stiffness), and cerebellar infarction (in which cerebellar signs are usually com- bined with signs of brain stem ischaemia, and the presentation may section 24  Neurological disorders 5980 mimic that of haemorrhage). Imaging can help with the differential diagnosis. Subacute, reversible ataxia may occur as a result of viral infection in children 2–​10 years of age. There is usually pyrexia, limb, and gait ataxia, and dysarthria developing over hours or days. Recovery oc- curs over a period of weeks and is usually complete but can take up to 6 months. In older patients, the possibility of a postinfectious enceph- alomyelitis, particularly that related to varicella infection, should be considered. The postinfectious Miller Fisher variant of the Guillain–​ Barré syndrome may present with a triad that includes subacute ataxia, areflexia, and ophthalmoplegia. Nerve conduction studies and cerebrospinal fluid (CSF) examination may be helpful, but the former are often normal. Other infective agents are shown in Table 24.7.4.3. Viral titres and CSF examination may be helpful although serological evidence of viral infection may be difficult to establish. Other causes of subacute ataxia include paraneoplastic dis- orders (see Chapter 24.23), hydrocephalus, foramen magnum compression, posterior fossa tumour (primary or secondary), ab- scess, or parasitic infection in any age group. Several important toxins and drugs also need to be considered including thallium, lead, barbiturates, phenytoin, piperazine, alcohol, solvents, and antineoplastic drugs. Vascular disorders of the cerebellum Cerebrovascular disease is dealt with in detail in Chapter 24.10.1. Transient ischaemic attacks involving the vascular supply to the cerebellum rarely produce a pure ataxic syndrome and usually there are associated symptoms of brain stem dysfunction. Cerebellar in- farction (from embolus or, more commonly, vertebrobasilar oc- clusive disease) and haemorrhage (usually on a background of hypertension or, less commonly, secondary to a vascular malforma- tion or tumour) are relatively rare. Imaging is often necessary for early diagnosis as the later the diagnosis the worse the prognosis. Surgical intervention to relieve pressure may be required. Ataxia with an episodic course These attacks may be considered bizarre and some patients are misdiagnosed as non​organic; however, a good history can usually distinguish between the main causes (in order of approximate fre- quency): drug ingestion, multiple sclerosis, transient vertebrobasilar ischaemic attacks, foramen magnum compression, intermit- tent obstruction of the ventricular system due to a colloid cyst or cysticercosis, and a growing list of inherited episodic ataxias (n >8 at the time of writing). Autosomal dominant episodic ataxia is characterized by child- hood or adolescent onset of attacks of ataxia, dysarthria, vertigo, and nystagmus. Not all patients have affected relatives. There are at least two forms of this disorder: Episodic ataxia 1 (EA1), due to mutations in a potassium channel Kv1.1, is typified by brief attacks (minutes and occasionally hours) and clinically and electrophysio- logically myokymia may be seen. These patients may benefit from acetazolamide or phenytoin. Patients tend to be neurologically normal between the attacks. In episodic ataxia 2 (EA2) the attacks tend to be longer, lasting hours or even days. They are usually associated with vertigo and con- sequent nausea and vomiting. They tend to be more severe in child- hood with associated drowsiness, headache, and fever. Although when the disease first begins the patients are well, between attacks an interictal nystagmus can be seen. As the disease progresses a slow de- terioration in the ataxia is seen. MRI may reveal cerebellar atrophy. These patients tend to respond better to acetazolamide therapy than patients with EA1. However, increasingly other varieties of episodic ataxia are being recognized, see Table 24.7.4.5a. In children and young adults a metabolic disorder should be sus- pected, particularly defects of the urea cycle, aminoacidurias, Leigh’s syndrome, and mitochondrial encephalomyopathies. Screening in- vestigations include serum ammonia, pyruvate, lactate and amino acids, and urinary amino acids. Table 24.7.4.2  Congenital inherited ataxic disorders Syndrome Genetics Additional features Joubert’s syndrome Autosomal recessive AHI1 gene NPHP1 gene CEP290 Plus others with established and distinct loci With episodic hyperpnoea, abnormal eye movements, and mental retardation Gillespie’s syndrome Autosomal recessive PAX6 With mental retardation and partial aniridia Congenital ataxia with mental retardation and spasticity Autosomal recessive, autosomal dominant, and X-​linked NYS1-​6p NYS2—​X-​linked, and others Includes pontoneocerebellar and granule cell hypoplasia Disequilibrium syndrome Autosomal recessive Paine’s syndrome X-​linked recessive ataxia—​no gene identified With spasticity, mental retardation, and microcephaly Table 24.7.4.3  Infections causing cerebellar disease Viruses Others Echo Mycoplasma pneumoniae Coxsackie groups A and B Legionella pneumoniae Herpes simplex Lyme disease Poliovirus Toxoplasma gondii Epstein–​Barr Typhoid fever Varicella Plasmodium falciparum Congenital rubella Tick paralysis Prion disease 24.7.4  Ataxic disorders 5981 Ataxia with a chronic progressive course Chronic alcohol abuse is probably the most common cause of pro- gressive cerebellar degeneration in adults. Thiamine deficiency is the main (but not sole) explanation for the chronic progressive cere- bellar syndrome found in alcoholics. Patients with this syndrome are frequently malnourished. Ataxia may develop during periods of abstinence, and identical cerebellar degeneration has been observed in non​alcoholic patients with severe malnutrition. Cerebellar ataxia is common in the Wernicke–​Korsakoff syndrome, and the patho- logical features of both this syndrome and cerebellar degeneration are frequently found together. With administration of thiamine some improvement may occur in early cases of alcoholic cerebellar degeneration but, if the patient is already chairbound, the response to treatment is limited. There are other deficiency disorders that can give rise to a progressive ataxia. There is a rare syndrome associated with zinc deficiency that responds to oral replacement therapy. Deficiency of vitamin E, either genetic (e.g. isolated vitamin E deficiency due to mutations in α-​tocopherol transfer protein, or abetalipoproteinaemia) or acquired, may produce a progressive ataxia. Establishing the diagnosis of vitamin E deficiency is im- portant as treatment with vitamin E may prevent progression of the neurological syndrome and can, in rare circumstances, lead to some improvement. There are several toxic agents that can produce progressive cere- bellar dysfunction, including pharmaceutical products, solvents, and heavy metals. The most common cause of a cerebellar syndrome due to drug toxicity in neurological practice is that associated with anti- convulsant medication, particularly phenytoin. Transient ataxia, dys- arthria, and nystagmus usually develop when serum concentrations of phenytoin, carbamazepine, or barbiturates are above the thera- peutic range, and remit when they return to the therapeutic range. Chronic phenytoin toxicity may cause persistent cerebellar dysfunc- tion, and this is associated pathologically with loss of Purkinje cells. A  persistent cerebellar deficit, with dysarthria and limb and gait ataxia and cerebellar atrophy on imaging, has also been described as a sequel to the acute encephalopathy of lithium toxicity that is usually precipitated by fever or starvation. Recreational or accidental exposure to several solvents, including carbon tetrachloride and toluene, causes cerebellar ataxia along with other neurological problems, including psychosis, cognitive impair- ment, and pyramidal signs in the case of toluene. The neurological deficit is potentially reversible but may persist after prolonged ex- posure in solvent abusers. Exposure to heavy metals, including in- organic mercury, lead, and thallium, can also produce cerebellar damage. Structural lesions such as posterior fossa tumours, foramen magnum compression, or hydrocephalus must be excluded by imaging studies. Tumours which may involve the posterior fossa in- clude: astrocytoma, ependymoma, haemangioblastoma, and cranial nerve neuromas. Paraneoplastic cerebellar degeneration related to carcinomas of the lung or ovary usually follows a subacute course, with pa- tients losing the ability to walk within months of onset. A variety of antineuronal antibodies may be found in these patients and help to confirm the diagnosis. Approximately half of patients with paraneoplastic cerebellar degeneration have demonstrable anti- bodies directed against neurons in serum and CSF. A search for the underlying malignancy should then be undertaken involving imaging and analysis of tumour markers. Presentation with ataxia precedes diagnosis of the malignancy in 70% of cases and is usu- ally subacute, progressing to severe disability over several months or even weeks and then arresting. Onset may be acute and is sometimes accompanied by vertigo, mimicking a vascular event. There is severe truncal, gait and limb ataxia, and dysarthria. Opsoclonus may be combined with myoclonus, producing a disorder in adults similar to the dancing eyes syndrome of childhood. The latter is sometimes associated with neuroblastoma. There is currently no proof that im- munosuppressant therapy or plasma exchange improves outlook but there are anecdotal reports of some improvement or stabiliza- tion following removal of the primary tumour. The best method of screening for the underlying malignancy is debated but standard MRI imaging may be complemented by whole body positron emis- sion tomography (PET) technology. Searching for primary tumour markers may also be useful. Rarely, infectious agents can cause slowly progressive ataxia (see Table 24.7.4.3), these include the chronic panencephalitis of con- genital rubella infection in children and, in adults, Creutzfeldt–​ Jakob disease, particularly the iatrogenic form, should be considered. A specific enquiry regarding potential risk factor ex- posure should be sought, especially growth hormone replacement, although following introduction of stringent controls on source material this has become extremely rare. Multiple sclerosis only exceptionally presents as an isolated chronic progressive cerebellar syndrome. Some conditions that are not generally considered primarily as ataxic disorders may present with clumsiness, tremor, or definite cerebellar signs, particularly in childhood or adolescence. These include Wilson’s disease and several inherited neuropathies, such as Charcot-​Marie-​Tooth disease. Although intention and postural tremor are quite frequent in the demyelinating type of Charcot-​ Marie-​Tooth (type I), dysarthria and pyramidal signs do not occur. Other chronic demyelinating neuropathies, such as chronic inflam- matory and paraproteinemic neuropathies and Refsum’s disease, may give rise to prominent tremor and ataxia; the same applies to giant axonal neuropathy. Superficial siderosis is a rare disorder that causes slowly progres- sive cerebellar ataxia, mainly of gait, and sensorineural deafness, often combined with spasticity, brisk reflexes, and extensor plantar responses. The diagnosis may not be suspected clinically, but the neuroradiological abnormalities are striking, MRI showing a black rim of haemosiderin around the posterior fossa structures and spinal cord, and less often the cerebral hemispheres, on T2-​weighted im- ages. Superficial siderosis is most commonly secondary to chronic leaking of blood into the subarachnoid space. Treatment relies on identifying the source of bleeding; chelation therapy does not appear to be effective. After excluding acquired causes of ataxic disorders, there re- mains a considerable number of patients with degenerative ataxias, not all of which are overtly genetically determined. The inherited ataxias can largely be classified according to their clinical and gen- etic features (see next) and, in a small proportion of cases, a recog- nizable metabolic defect can be detected. It is important to make as accurate diagnosis as possible in these disorders for the pur- poses of prognosis, genetic counselling and, occasionally, specific therapy. section 24  Neurological disorders 5982 Progressive metabolic ataxias Ataxia may be a minor feature of storage and other metabolic neurodegenerative disorders developing in early childhood (see Chapter 24.21). Some enzyme deficiencies that usually give rise to diffuse neurodegenerative disorders, in which ataxia is a feature, developing in infancy or early childhood, include the sphingomyelin lipidoses, metachromatic leukodystrophy, galactosylceramide lipidosis (Krabbe’s disease), and the hexosaminidase deficiencies. Also within this group is adrenoleukomyeloneuropathy, a phenotypic variant of adrenoleukodystrophy. This diagnosis is supported by an increase in very long chain fatty acids or by direct genetic analysis of the AMN gene. Although X-​linked, approximately 10% of carrier females may manifest neurological abnormalities. The role of diet and dietary supplements (e.g. oleic acid and Lorenzo’s oil) remains to be established. Ataxia may be prominent in Niemann–​Pick disease type C (juvenile dystonic lipid- osis), combined with a supranuclear gaze palsy. Sphingomyelinase ac- tivity is normal but foamy storage cells are found in the bone marrow. Cholestanolosis (also called cerebrotendinous xanthomatosis or CTX) is a rare autosomal recessive disorder caused by defective bile salt metabolism, due to a deficiency of mitochondrial sterol 27 hydroxylase. It gives rise to ataxia, dementia, spasticity, peripheral neuropathy, cataract, and tendon xanthomata in the second decade of life. Treatment with chenodeoxycholic acid appears to improve neurological function. Various phenotypes that are classifiable as hereditary ataxias have been described in the mitochondrial encephalomyopathies, many of which are associated with a defect of mitochondrial DNA. These include late-​onset ataxic disorders are associated (e.g. the Kearns–​Sayre syndrome) with such features as dementia, deafness, and peripheral neuropathy. These features overlap with the syn- drome of progressive myoclonic ataxia, which may also be caused by ceroid lipofuscinosis, sialidosis, and Unverricht–​Lundborg’s disease or so-​called Baltic myoclonus. There has been substantial progress in genetic delineation of these syndromes. Acquired metabolic and endocrine disorders causing cerebellar dysfunction Acquired metabolic and endocrine disorders causing cerebellar dys- function include hepatic encephalopathy, pontine and extrapontine myelinolysis related to hyponatraemia, and hypothyroidism. The latter is only very rarely a cause of a cerebellar syndrome in both children and adults. Degenerative disorders The degenerative cerebellar and spinocerebellar disorders are a com- plex group of diseases, most of which are genetically determined. In some there is an underlying metabolic disorder, and it is important to diagnose these, as there may be important implications for treat- ment and genetic counselling. There has been a rapid growth in our knowledge of the genetic basis of many of the spinocerebellar degenerations. The current phase of research is focussed on how these genes and the abnormal proteins they produce cause cell spe- cific neuropathology. Inherited ataxic disorders can be divided ac- cording to their mode of inheritance (Tables 24.7.4.4 and 24.7.4.5). Most autosomal recessive disorders are of early-​onset (less than 20 years), and autosomal dominant disorders are usually of later onset (over 20 years). A recent review of the epidemiology points Table 24.7.4.4  Autosomal recessive ataxias Syndrome Gene defect Clinical notes Friedreich’s ataxia GAA repeat (and rarely point mutations in FRDA gene) Neuropathy, pyramidal signs, skeletal abnormalities, diabetes, and cardiomyopathy ARSACs Sacsin Demyelinating neuropathy and hypertrophied retinal nerve fibre layer (on OCT) Ataxia telangiectasia AT-​like disorder ATM hMRE11 Oculomotor apraxia, Mixed movement disorder, humoral immune difficulties, increased cancer risk Cockaynes syndrome CS type A—​ERCC8 gene CSA type B—​ERCC6 gene ‘Cachcectic dwarfism’ Mental retardation Pigmentary retinopathy Xeroderma pigmentosum ERCC2 but also probably genetically complex Skin disorder and an increased risk on skin cancer AOA1 Aprataxin Oculomotor apraxia AOA2 Senataxin Oculomotor apraxia Hypogonadism RNF216 Hypogonadotrophic hypogonadism Marinesco–​Sjögren syndrome SIL1 on chr 5q31 Cataracts and mental retardation Gillepsie syndrome PAX6 Aniridia Progressive myoclonic ataxia (Ramsay Hunt syndrome) Genetically complex Epilepsy is common Behr’s and related syndromes, e.g. 3-​methylglutaconic aciduria type III (Costeff syndrome) No gene for Behr’s yet identified OPA3 gene Optic atrophy, spasticity, and mental retardation Congenital or childhood onset deafness Genetically complex Syndromic diagnosis—​likely to have several causes Autosomal recessive late-​onset ataxia Heterogeneous Wide clinical variability Onset usually before 20 years of age. 24.7.4  Ataxic disorders 5983 out that cumulatively these disorders represent a very significant health burden. Autosomal recessive ataxias Friedreich’s ataxia This is the most common of the autosomal recessive ataxias (see Table 24.7.4.4) and accounts for at least 50% of cases of hereditary ataxia in most large series reported from Europe and the United States. The prevalence of the disease in these regions is similar, be- tween 1 and 2 per 100 000. The age of onset of symptoms, generally with gait ataxia, is usu- ally between the ages of 8 and 15 years, but onset between 20 and 30, but fulfilling all other diagnostic criteria, have been described. In addition to the progressive ataxia, one finds several vari- able features, including dysarthria and pyramidal tract involve- ment. Initially this latter feature may be mild, with just extensor Table 24.7.4.5b  Clinical impact of widely available genetic tests for the ADCAs ADCA type Genetic tests (widely available) Relative contribution to each subclass ADCA I SCA 1, 2, 3, 50% ADCA II SCA7 99% ADCA III SCA6 50% Table 24.7.4.5a  Autosomal dominant cerebellar ataxia: clinicogenetic classification. Onset usually over age of 25 years. This is a list of currently identified genes and is divided by autosomal dominant cerebellar ataxia (ADCA) subtype to facilitate clinical relevance ADCA type Clinical features Genetic loci and chromosomal location Gene ADCA I Cerebellar syndrome plus: Pyramidal signs Supranuclear ophthalmoplegia Extrapyramidal signs Peripheral neuropathy Dementia SCA1 Ataxin 1 CAG SCA2 Ataxin 2 CAG SCA3 Ataxin 3 CAG SCA8 Kelch-​like 1 CTG repeat SCA12 PPP2R2B CAG repeat SCA13 KCNC3 point mutations SCA14 PRKCG point mutations SCA15 ITPR1 SCA17 TBP CAG SCA28 AFG3L2 SCA36 Hexanucleotide repeat in NOP56 ADCA II Cerebellar syndrome plus: Pigmentary maculopathy Other signs as ADCA I SCA7 3p12-​21.1 Ataxin 7 CAG ADCA III ‘Pure’ cerebellar syndrome Mild pyramidal signs SCA5 SPTBN2 β-​III spectrin D SCA6 CACNL 1Aa CAG repeat SCA10 Ataxin 10 ATTCT repeat SCA11 TTBK2 SCA27 FGF14 point mutations Episodic ataxias EA 1 Kv1.1 EA 2 CACNL 1Aa EA3 Locus on 1q42 EA4 No gene identified aka PATX EA5 CACNB4 EA6 SLC1A3 EA8 Plus others yet to be defined Locus 1p36 a SCA6 and CACNL1A are allelic variants. section 24  Neurological disorders 5984 plantar responses, but after five or more years’ duration of the disease, invariably a pyramidal pattern of weakness in the legs is seen. Eventually this can lead to paralysis. Distal wasting, par- ticularly in the upper limbs, is seen in about 50% of patients with Friedreich’s ataxia. Skeletal abnormalities are also commonly found including scoliosis (85%) and foot deformities, typically pes cavus, in approximately 50% of patients. Additional clinical support for one’s suspicions include optic atrophy which can be seen in 25%; however, it is rare (<5%) for Friedreich’s to produce major visual impairment. Deafness is found in less than 10%, but rather more have impairment of speech discrimination. Nystagmus is seen in only about 20%, but the extraocular movements are nearly always abnormal, with broken-​up pursuit, dysmetric saccades, square wave jerks, and failure of fixation suppression of the vestibulo-​ ocular reflex. Investigation of patients reveals an axonal sensory neuropathy; an abnormal electrocardiogram (ECG) in 65% of patients with wide- spread T-​wave inversion. Diabetes mellitus occurs in 10% of patients with Friedreich’s ataxia, and a further 10­–20% have impaired glu- cose tolerance. The gene frataxin was identified in 1996. The predominant ­mutation is a trinucleotide repeat (GAA) in intron 1 of this gene. Expansion of both alleles is found in over 96% of patients. The ­remaining patients have one expansion and a point mutation in the frataxin gene. This was the first autosomal recessive condi- tion found to be due to a dynamic repeat and it has permitted the introduction of a specific and sensitive diagnostic test, as it is a relatively simple matter to measure the repeat size. On normal chromosomes the number of GAA repeats varies from 7 to 22 units, whereas on disease chromosomes, the range is anything from around 100 to 2000 repeats. The length of the repeat is a ­determinant of age of onset and therefore to some degree in- fluences the severity in that early-​onset tends to progress more rapidly. There has been substantial progress in determining the underlying molecular pathogenesis, principally implicating mitochondrial dys- function, and some hints that manipulation of genomic regulation, eg with nicotinamide may be useful. Other recessive ataxias These are individually rare but increasingly, with widespread adop- tion of whole exome and whole genome sequencing strategies, they are being genetically clarified. However, a few are worth discussing in a little more detail. Ataxic disorders associated with defective DNA repair There are several rare disorders that are characterized at a mo- lecular level by a reduced capacity to repair DNA. The most well-​ known is ataxia telangiectasia (AT). Characteristically, motor development is often delayed, and ataxia noted at the time of first walking. Growth retardation and delayed sexual development are frequent, and there is mild mental retardation in some cases. A mixed movement disorder may be seen, often with a combin- ation of ataxia, dystonia, and chorea. The cutaneous telangiectasia of AT tends to develop on the conjunctivae between the ages of 3 and 6 years, but occasionally are inconspicuous or absent in adult life. AT is associated with abnormalities of both humoral and cell-​ mediated immunity. Direct gene testing is now available. A rarer but clinically similar disease due to mutations in hMRE11 has been identified and is termed AT-​like disorder. Clinically related conditions xeroderma pigmentosum and Cockayne’s syndrome (see Table 24.7.4.4) are now broadly con- sidered disorders of excision repair (see Rapin 2013). Ataxia associated with oculomotor apraxia. There are two genetically distinct but clinically similar disorders associated with the distinctive feature of oculomotor apraxia types 1 and 2. Oculomotor apraxia represents a deficit of the voluntary saccadic system and should be suspected in the presence of head thrusts or synkinetic blinking which are used to help initiate a vol- untary saccade. AOA1, was shown to be due to mutations in a gene called aprataxin. It is characterized by the association of ataxia with chorea early in the disease course, oculomotor apraxia, peripheral neuropathy, and variable but mild learning difficulties. MRI reveals cerebellar atrophy and serum analysis may show hypercholesterol- aemia and hypoalbuminaemia. A second condition AOA2 is very similar clinically and also over- laps with the AT phenotype (see earlier). Mutations in senataxin have been shown to cause this syndrome. α-​fetoprotein is elevated in virtually all cases and is therefore a useful screen for this disorder. It also appears it may be more common than either AT of AOA1 ac- counting for approximately 8% of autosomal recessive ataxia. The other autosomal recessive ataxias are all individually rare and are listed in Table 24.7.4.4. Testing for ATM, aprataxin, and senataxin is now possible in a specialized lab. See Le Ber and colleagues (2012) for a recent review. The finding of mutations in a gene called sacsin as the cause of a complicated form of autosomal recessive ataxia (ARSACS) proved illuminating. Hitherto it had been appreciated as an extremely rare form originating in small community in Quebec. However, once the gene was identified it became clear that along with senataxin, it was second only to FRDA in terms of frequency and is found all over the world. A recent review by Pilliot et al. provides useful in- sights into the clinical features and diagnostic criteria. It is worth thinking of ARSACS in cases of young onset ataxia in which one finds a demyelinating neuropathy and optical coherence tomograph (OCT) can be useful in demonstrating retinal layer hypertrophy (Fig. 24.7.4.1). Autosomal dominant cerebellar ataxias The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically complex group of neurodegenerative disorders (see Table 24.7.4.5a, b). ADCA type I is characterized by a progressive cerebellar ataxia and is variably associated with other extracerebellar neurological features such as ophthalmoplegia, optic atrophy, per- ipheral neuropathy, pyramidal, and extrapyramidal signs. The presence and severity of these signs is, in part, dependent on the duration of the disease. Mild or moderate dementia may occur, but it is usually not a prominent early feature. ADCA type II is clinically distinguished from the ADCA type I by the presence of pigmentary macular dystrophy see Fig. 24.7.4.2, whereas ADCA type III is a relatively ‘pure’ cerebellar syndrome and generally starts at a later age. This clinical classification is still useful, despite the tremendous improvements in our understanding of the genetic basis (see next), because it provides a framework which can be used in the clinic and helps direct the genetic evaluation. 24.7.4  Ataxic disorders 5985 The genetic loci causing the dominant ataxias are given the acronym SCA (spino-​cerebellar ataxia). At the time of publica- tion there are over 30 SCA loci identified. However, with the dis- covery of the genes it becomes apparent that some of these are duplicates and there are yet still more to be found. In general clin- ical practice, five of these genes are established (SCAs 1, 2, 3, 6, and 7). Interestingly they are all caused by a similar mutational mechanism, an expansion of an exonic CAG repeat. The resultant proteins all possess an expanded polyglutamine tract and there are now at least eight conditions caused by these expansions. Other types of ADCA are rare and mutation testing is only available for a small number of these. Idiopathic degenerative late-​onset ataxias About two-​thirds of cases of degenerative ataxia developing over the age of 20 years are isolated cases, and they represent a signifi- cant clinical problem; it is difficult even to know how to label them. The literature is confusing, mixing pathological terms such as olivo-​ ponto-​cerebellar atrophy with clinical terms; the author prefers to use the term ‘idiopathic late-​onset cerebellar ataxia’ (ILOCA). A pro- portion of patients in this group, progress to develop the features of multiple system atrophy (MSA) (see Chapter 24.7.3). These patients may have or develop facial impassivity and extrapyramidal rigidity, while others present with features of autonomic failure such as pos- tural hypotension, impotence, bladder dysfunctions, and a fixed car- diac rate. A cerebellar presentation occurs in about 30% of patients with MSA. The distinction of idiopathic late-​onset cerebellar ataxia from MSA may, therefore, be difficult clinically at presentation. Most patients with idiopathic late-​onset cerebellar ataxia lose the ability to walk independently between 5 and 20 years after onset, and lifespan is slightly shortened by immobility. Those who go on to develop MSA have a particularly poor prognosis. Investigations, apart from those excluding acquired causes of cerebellar degener- ation such as malignancy and hypothyroidism, tend to be unhelpful. Electrophysiological evidence of a sensory peripheral neuropathy is found in about 50% of cases, which can be a useful pointer to the presence of a degenerative multisystem disorder. CT or MRI scan may show cerebellar and brain stem atrophy, or pure cerebellar at- rophy. The prognosis is worse in patients with clinical and radio- logical evidence of brain stem involvement, compared to those with Fig. 24.7.4.1  The retinal hypertrophy almost pathognomonic of autosomal recessive spastic ataxia of Charlevoix Sagueney (ARSACs). Courtesy of Dr Fion Bremner National Hospital London. Fig. 24.7.4.2  The distinctive maculopathy associated with SCA7 (clinically synonymous with autosomal dominant cerebellar ataxia (ADCA) II). section 24  Neurological disorders 5986 a pure cerebellar syndrome and cerebellar atrophy alone on MRI (Klockgether et al., 1990). The role of gliadin sensitivity in producing a chronic progressive ataxia (and indeed other neurological conditions), either as part of coeliac disease or as a purely neurological phenotype is still debated. A recent meta-​analysis in children did not identify a significant risk above the general population. Over the last decade a newly recognized condition has been shown to explain a small minority of cases. Usually male patients in mid to late life develop a progressive phenotype of ataxia and tremor in association with an intermediate expansion in the fragile X gene. This has been termed FXTAS (Fragile X Tremor Ataxia Syndrome). A recent review by Hagerman and Hagerman (2015) provides useful details of the core features and variable phenoptypes associated with this mutation. FURTHER READING Baloh RW (2012). Episodic ataxias 1 and 2. Handb Clin Neurol, 103, 595–​602. Campuzano V, et al. (1996). Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science, 271, 1423–​27. Cavalier L, et al. (1998). Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. Am J Hum Genet, 62, 301–​10. de Michele G, et al. (1989). Late onset recessive ataxia with Friedreich’s disease phenotype. J Neurol Neurosurg Psychiatry, 52, 1398–​403. Enevoldson PG, Sanders MD, Harding AE (1994). Autosomal dom- inant cerebellar ataxia with pigmentary macular dystrophy: a clin- ical and genetic study of eight families. Brain, 117, 445–​60. Everett CM, Wood NW (2004). Trinucleotide repeats and neuro­ degenerative disease. Brain, 127, 2385–​405. Fearnley JM, Stevens JM, Rudge P (1995). Superficial siderosis of the central nervous system. Brain, 118, 1051–​66. Gilman S, et al. (2008). Second consensus statement on the diagnosis of multiple system atrophy. Neurology, 71, 670–​6. Hadjivassiliou M, et al. (2003). Gluten ataxia in perspective: epidemi- ology, genetic susceptibility and clinical characteristics. Brain, 126, 685–​91. Hagerman PJ, Hagerman RJ (2015). Fragile X-​associated tremor/​ ataxia syndrome. Ann N Y Acad Sci, 1338, 58–​70. Harding AE (1994). The hereditary ataxias and related disorders. Churchill Livingstone, Edinburgh. Jacquemont S, et  al. (2004). Penetrance of the fragile X-​associated tremor/​ataxia syndrome in a premutation carrier population. JAMA, 291, 460–​9. Kälviäinen R (2015). Progressive myoclonus epilepsies. Semin Neurol, 35, 293–​9. Klockgether J, et  al. (1990). Idiopathic cerebellar ataxia of late onset:  natural history and MRI morphology. J Neurol Neurosurg Psychiatry, 53, 297–​305. Klockgether T, et  al. (1998). The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain, 121, 589–​600. Le Ber I, Dürr A, Brice A (2012). Autosomal recessive cerebellar ataxias with oculomotor apraxia. Handb Clin Neurol, 103, 333–​41. Libri V, et al. (2014). Epigenetic and neurological effects and safety of high-​dose nicotinamide in patients with Friedreich’s ataxia: an exploratory, open-​label, dose-​escalation study. Lancet, 384, 504–​13. Lionetti E, et al. (2010). The neurology of coeliac disease in child- hood: what is the evidence? A systematic review and meta-​analysis. Dev Med Child Neurol, 52, 700–​7. Nie S, et al. (2014). Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and man- agement. Orphanet J Rare Dis, 9, 179. Panzer J, Dalmau J (2011). Movement disorders in paraneoplastic and autoimmune disease. Curr Opin Neurol, 24, 346–​53. Pilliod J, et  al. (2015). New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-​Saguenay. Ann Neurol, 78, 871–​86. Rapin I (2013). Disorders of nucleotide excision repair. Handb Clin Neurol, 113, 1637–​50. Ruano L, et al. (2014). The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology, 42, 174–​83. Russell JF, Fu YH, Ptáček LJ (2013). Episodic neurologic disorders: syndromes, genes, and mechanisms. Annu Rev Neurosci, 36, 25–​50. Sailer A, Houlden H (2012). Recent advances in the genetics of cere- bellar ataxias. Curr Neurol Neurosci Rep, 12, 227–​36. Sandi C, et al. (2014). Epigenetic-​based therapies for Friedreich ataxia. Front Genet, 5, 165. Schneider T, et al. (2015). Magnetic resonance imaging findings in pa- tients presenting with (sub)acute cerebellar ataxia. Neuroradiology, 57, 551–​9. Teive HA, et al. (2015). Ataxia-​telangiectasia—​A historical review and a proposal for a new designation: ATM syndrome. J Neurol Sci, 15, 355, 3–​6. Tranchant C, et al. (2003). Phenotypic variability of aprataxin gene mutations. Neurology, 60, 868–​70. Vernino S (2012). Paraneoplastic cerebellar degeneration. Handb Clin Neurol, 103, 215–​23. Watanabe H, et  al. (2002). Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain, 125, 1070–​83. 24.8 Headache 5987 Peter J. Goadsby 24.8 Headache 5987 Peter J. Goadsby ESSENTIALS Headache is among the most common of human maladies. So much so that it is generally (and often incorrectly) assumed to be under- stood, especially by doctors. The classification of headache, with formal definitions of different diagnostic entities, by the International Headache Society into (1) primary—​occurring in the absence of ex- ternal causes, and (2) secondary—​some of which may have sinister cause, has greatly simplified the description, understanding, and management of this often challenging symptom. It also allows those headaches with serious or life-​threatening consequences to be dis- tinguished from other forms. Pathophysiology of primary headaches The key structures involved in producing pain appear to be the: (1) large intracranial vessels and the dura mater, (2) trigeminal nerve, (3) higher centres in the thalamus and cortex, (4) modulatory centres in the diencephalon and brainstem. Two of the most common and best studied primary headaches, migraine, and cluster headache, should be regarded as being neuro- logical or brain disorders with any vessel change being secondary, ie neurovascular. Migraine might be part of the spectrum of diseases known as channelopathies or ionopathies: the three genes currently identified as being responsible for familial hemiplegic migraine alter ion fluxes. Moreover, in studies of the more common forms of mi- graine across large patient cohorts, genome-​wide association studies have implicated excitatory, in particular glutamatergic, transmission to be key to the pathophysiology. Migraine Epidemiology and clinical features—​migraine affects 12 to 18% of the population in any one year, and about 45% of females over their lifetime; it can be highly disabling. It presents with headache, often throbbing and generally accompanied by other features such as sen- sitivity to light, sound, or movement, and often with nausea or (less often) vomiting, but none of the features is compulsory. For example, the migraine aura—​visual disturbances with flashing lights or zigzag lines moving across the fields or other neurological symptoms—​is reported in only about 25% of patients. It is noteworthy that the word migraine is used to describe the diagnosis—​a patient has mi- graine; as well as an individual attack—​a patient is having a migraine. Although a subtle distinction this concept underpins the fact that not all attacks, in all patients, every day, need to conform to standard diagnostic criteria. Treatment—​principles of management include (1)  explanation—​ migraine is an inherited tendency to have headache and cannot therefore be ‘cured’; (2) the condition can be modified and con- trolled by lifestyle adjustment and the use of medicines; (3)  it is not life-​threatening; (4) management takes time and cooperation. Most migraine sufferers will benefit from a healthy diet, regular ex- ercise, regular sleep patterns, avoiding excess caffeine and alcohol and (as far as practical) modifying or minimizing changes in stress. Preventive treatments include pizotifen, β-​blockers, some tricyc- lics, some anticonvulsants, candesartan, flunarizine, noninvasive neuromodulation, calcitonin gene-related peptide (CGRP) mono- clonal antibodies and botulinum toxin type A (the latter for chronic migraine). Acute treatments include (often in combination with an antiemetic) non​specific drugs such as aspirin, paracetamol (acet- aminophen) and non​steroidal anti-​inflammatory drugs, and specific agents such as triptans, serotonin 5-​HT1B/​1D receptor agonists and ergot derivatives and noninvasive neuromodulation. In the coming years newer agents for acute therapy will be, ditans (serotonin 5-​ HT1F receptor agonists), and gepants (calcitonin gene-​related pep- tide (CGRP) receptor antagonists) that, will offer novel and added benefits to patients with migraine and the physicians who treat them. Tension-​type headache Tension-​type headache is common, unexplained, and completely featureless, with no nausea, no vomiting, no photophobia, no phonophobia, no osmophobia, no throbbing, and no aggravation with movement. It is referred to by patients as annoying rather than disabling. When episodic, it is generally amenable to simple anal- gesics; when chronic, amitriptyline is the only proven treatment. Trigeminal–​autonomic cephalalgias Cluster headache—​characterized by bouts of excruciating retro-​ orbital boring pain associated with ipsilateral symptoms of cra- nial parasympathetic activation (a red or watering eye, the nose running or blocking) or cranial sympathetic dysfunction (eyelid droop). Prevention is with agents including verapamil, lithium, topiramate, and melatonin, while oral corticosteroids are used as bridge therapy. Treatments for acute attacks include oxygen inhal- ation, sumatriptan by subcutaneous injection, or nasal spray and zolmitriptan by nasal spray. 24.8 Headache Peter J. Goadsby section 24  Neurological disorders 5988 Other conditions—​these include (1)  paroxysmal hemicrania; (2)  short-​lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing or cranial autonomic activation (SUNCT/​SUNA); and (3) hemicrania continua. Other primary headaches Specific conditions include (1) cough headache, (2) exercise head- ache, (3) sex headache, (4) thunderclap headache, (5) cold stimulus headache, (6) external pressure headache, (7) stabbing headache, (8) nummular headache, and (9) hypnic headache. Many of these can present with daily headache and are often misdiagnosed as tension-​type headache. They can readily be identified from the his- tory, often leading to effective and specific treatments, an important element of which is reduction/​elimination of analgesic overuse. New daily persistent headache—​this presents with abrupt onset of headache that then persists. Possible causes include: (1) primary—​ migrainous type, featureless (tension-​type); (2)  secondary—​ subarachnoid haemorrhage, low cerebrospinal fluid volume headache, raised cerebrospinal fluid pressure headache, post-​ traumatic headache, chronic meningitis, giant cell arteritis. Effective and specific treatments are available for many of these conditions if a precise diagnosis can be made. Secondary headache Clinical approach—​the length of the history is crucial: if this is short, the patient requires prompt attention; if this is long, then time and patience are needed rather than alacrity. Associated fever, sudden onset of pain, or the presence of neurological signs need a positive diagnosis of a benign disorder or require brain imaging with com- puted tomography or magnetic resonance imaging. Causes and management—​medically sinister headaches requiring urgent attention include subarachnoid haemorrhage, meningitis, giant cell arteritis, and raised intracranial pressure. Other important causes of secondary headache include low volume (pressure) cerebrospinal fluid, post-​traumatic headache, and cerviocogenic headache. Many of these disorders require persistent diagnostic skills and investigation; but when combined with knowledge of general principles, including the anatomy and physiology of the key cranial structures, the management of head- ache is generally productive and beneficial for the sufferer. General principles To manage headache can be a source of extreme frustration or undiluted pleasure—​the difference simply reflects to what extent the practitioner is familiar with the subject. A formal nosology for headache disorders is to be found in the third edition of the International classification of headache disorders. Although it seems obvious, the key to successful management is establishment of a clear diagnosis. The general concept is that there are primary and secondary forms of headache, following the generic medical principle that clinical syndromes may be caused by something exogenous or secondary, or may manifest anew as the primary disease process. Such a system is outlined in Table 24.8.1. Mild secondary headache, such as that seen in association with upper respiratory tract infections, is common but only rarely worrisome. The clinical dilemma remains that, although life-​threatening headache is relatively uncommon in Western society, it occurs, and its detection requires suitable vigilance by doctors. Primary headache, in contrast, often confers considerable disability over time and although not life-​threatening certainly robs patients of quality of life. Some pointers to secondary headache are listed in Box 24.8.1. Primary headache disorders The primary headaches are a group of fascinating disorders in which headache and associated features are seen in the absence of any exogenous cause. The common syndromes (see Table 24.8.1) are tension-​type headache, migraine, and cluster headache. Some other less well-​known, indeed rarer, syndromes are mentioned because they are easily treated when diagnosed, and the most burdensome headache problems, the chronic daily headache syndromes, are explicitly covered because concepts have altered considerably in this area in recent years. Anatomy and physiology The most common disabling primary headaches, migraine, and cluster headache, have been studied extensively in re- cent times and they are now relatively well understood insofar as neurological disorders that involve the brain are concerned. In experimental animals the detailed anatomy of the connec- tions of the pain-​producing intracranial extracerebral vessels and the dura mater has built on the classic human observations of Wolff, Feindel, Penfield, McNaughton, and others. It is these structures, and not the brain itself, that are primarily involved in head pain, although it is not at all clear to what extent there is nociceptive activation as such, or simply the perception of that activation. Table 24.8.1  Common causes of headache Primary headache Secondary headache Type Prevalence (%) Type Prevalence (%) Migraine 16 Systemic infection 63 Tension-​type 69 Head injury 4 Cluster headache 0.1 Subarachnoid haemorrhage <1 Idiopathic stabbing 2 Vascular disorders 1 Exertional 1 Brain tumour 0.1 After Olesen J, et al. (2005). The headaches. Lippincott, Williams & Wilkins, Philadelphia. 24.8  Headache 5989 The key structures involved are: • the large intracranial vessels and dura mater • the peripheral terminals of the trigeminal nerve that innervate these structures • the central terminals and second-​order neurons of the caudal tri- geminal nucleus and dorsal horns of C1 and C2 (trigeminocervical complex) • higher-​centre processing in the thalamus, ventroposteromedial, and posterior thalamus and cortex • modulatory centres in the diencephalon and brainstem, such as periaqueductal grey matter, locus coeruleus, and parts of the hypothalamus The innervation of the large intracranial vessels and dura mater by the trigeminal nerve is known as the trigeminovascular system. Cranial parasympathetic autonomic outflow from the superior salivatory nucleus through the seventh cranial nerve and periph- erally through the sphenopalatine ganglion, provides the basis for symptoms such as lacrimation and nasal stuffiness, which are prom- inent are lateralized in cluster headache and paroxysmal hemicrania, although they may also be seen in migraine. It is clear from human functional imaging studies that vascular changes in migraine and cluster headache are driven by these neural vasodilator systems so that these headaches should be regarded as neurovascular. The con- cept of a primary vascular headache should be abandoned because it does not explain the pathogenesis of what are complex central nervous system (CNS) disorders, or necessarily predict treatment outcomes. The term ‘vascular’ headache has no place in modern medical practice when referring to primary headache disorders. Migraine is an episodic syndrome of headache with sensory sen- sitivity, such as to light, sound, and head movement, probably due to dysfunction of aminergic brainstem/​diencephalic sensory control systems (Fig. 24.8.1). The first of the migraine genes has been identi- fied for familial hemiplegic migraine, and includes mutations in the CACNA1A gene for the CaV2.1 (α1A) subunit of the neuronal P/​Q voltage-​gated calcium channel, the Na+/​K+ ATP pump α2-​subunit gene ATP1A2, and the voltage-​gated sodium channel SCN1A. These findings and the clinical features of migraine suggest that it might be part of the spectrum of diseases known as channelopathies, or now ionopathies—​disorders involving dysfunction of ion channel fluxes. Moreover, recent large-​scale investigations, genome-​wide association studies, have identified consistently excitatory, glutamatergic path- ways, and the transient receptor potential—​TRPM8 cold receptor, in migraine genomics even in the most common form of migraine without aura. Functional neuroimaging has suggested that brainstem regions in migraine (Fig. 24.8.2), and the region of the posterior hypothalamic grey matter, site of the human circadian pacemaker cells of the suprachiasmatic nucleus, in cluster headache (Fig. 24.8.3), are good candidates for specific involvement in primary headache. Secondary headache It is imperative to establish in the patient presenting with any form of head pain whether there is an important secondary headache declaring itself. The headaches of subarachnoid haemorrhage, men- ingitis, giant cell arteritis, and raised intracranial pressure are im- portant examples of medically sinister headaches requiring urgent attention. Perhaps the most crucial clinical feature to elicit is the length of the history. Patients with a short history require prompt attention and may require prompt investigation and management. Patients with a longer history generally require time and patience Box 24.8.1  Warning signs in head pain • Sudden onset of pain • Fever • Marked change in pain character or timing of attacks • Neck stiffness • Pain associated with higher-​centre complaints • Pain associated with neurological disturbance, such as clumsiness or weakness • Pain associated with local tenderness, such as of the temporal artery Cervical DRG TCC NRM PAG Thalamus Hypothalamus Cortex Vg Dural-vascular structures LC Fig. 24.8.1  Pathophysiology of migraine. Diagram of some structures involved in the transmission of trigeminovascular nociceptive input and the modulation of that input which form the basis of a model of the pathophysiology of migraine. Afferents from dural–​vascular structures innervated predominantly by branches of the first (ophthalmic) division of the trigeminal nerve, with cell bodies found in the trigeminal ganglion (Vg), project to second-​order neurons in the trigeminocervical complex (TCC). The TCC extends from trigeminal nucleus caudalis to the caudal portion of the dorsal horn of the C2 spinal cord. Input from cervical structures, such as joints or muscle, project through cell bodies in the upper cervical dorsal root ganglia (DRGs) to the TCC. TCC neurons project to ventrobasal thalamus (thalamus) and thence to the cortex. Sensory modulation can occur by descending influences on to the TCC that largely respect the midline (dashed line), such as those from the hypothalamus, midbrain periaqueductal grey (PAG), pontine locus coeruleus (LC), and nucleus raphe magnus (RVM). These influences are pictured as being direct but both direct and indirect projections are recognized. In addition sensory modulation can occur from at least the LC and PAG, and hypothalamic projects to thalamus nuclei as ascending systems again largely respect the midline. From Goadsby PJ (2005). Can we develop neurally-​acting drugs for the treatment of migraine? Nat Rev Drug Discovery, 4: 741–​50. section 24  Neurological disorders 5990 Fig. 24.8.2  Activations identified on positron emission tomography (PET) in migraine. In the premonitory phase hypothalamic activation is observed (a), while consistently in the headache phase there is dorsolateral pons activation in episodic migraine without aura, triggered by nitroglycerin (b), or spontaneously studied (c), and in chronic migraine (f). Moreover, there is lateralization to the right (d) and left (e) in this structure that parallels the unilateral presentation of the pain. (a) from Maniyar F, et al. (2014) Brain activations in the premonitory phase of nitroglycerin triggered migraine attacks. Brain. 2014;137:232–​42; (b) from Bahra A, et al. (2001). Brainstem activation specific to migraine headache. Lancet, 357: 1016–​17; (c) from Matharu MS, et al. (2004). Central neuromodulation in chronic migraine patients with suboccipital stimulators: a PET study. Brain, 127: 220–​30; (d, e) from Afridi S, et al. (2005). A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain, 128: 932–​9; (f) from Afridi S, et al. (2005). A PET study in spontaneous migraine. Arch Neurol, 62: 1270–​5. (b) (a) Fig. 24.8.3  Activations on PET in the posterior hypothalamic grey matter in patients with acute cluster headache (a). The activation demonstrated is lateralized to the side of the pain (May et al., 1998). When comparing the brains of patients with cluster headache with a control population, using an automatic anatomical technique known as voxel-​based morphometry which employs high-​resolution T1-​weighted MRI, a similar region is demonstrated (b) and has increased grey matter. (a) (May et al., 1998), (b) (May et al., 1999a). 24.8  Headache 5991 rather than alacrity. There are some important general features, including associated fever or sudden onset of pain (see Box 24.8.1); these demand attention. Patients with a history of recent-​onset head- ache or neurological signs need a positive diagnosis of a benign dis- order or require brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI). Patients with a history of recur- rent headache over a period of 1 year or more, fulfilling International Classification of Headache Disorders (ICHD) criteria for migraine (Box 24.8.2), and with a normal physical examination, have posi- tive brain imaging in only about 1/​1000 images. In general, it should be noted that brain tumour is a rare cause of headache, and rarely a cause of isolated long-​term histories of headache. A notable ex- ception to the general rules about secondary headache is a pituitary tumour, which can frequently trigger underlying primary headache biology, and should always be considered, especially in the differen- tial diagnosis of trigeminal autonomic cephalalgias (see next). The management of secondary headache is generally self-​ evident:  treatment of the underlying condition, such as an in- fection or mass lesion. An exception is the condition of chronic post-​traumatic headache in which pain persists for long periods after head injury. This is an interesting generic problem that may be seen after CNS infection, trauma, both blunt and surgical, intra- cranial bleeds, and other precipitants. Although the syndrome is generally self-​limiting up to 3–​5 years after the event, treatment of the headache may be required if it is disabling (see ‘Chronic daily headache’, next). Migraine Clinical features Migraine is an episodic brain disorder that affects about 12 to 18% of the population in any one year, and about 45% of females over their lifetime; it is recognized as the most common cause of neurological disability on a worldwide basis. It has been estimated to be the most costly neurological disorder in the European Union at more than €27 billion per year and its cost to the economy of the United States of America is a staggering US$19.6 billion per year. Migraine pre- sents with a headache generally accompanied by features, such as sensitivity to light, sound, or movement, and often with nausea, or less often vomiting (see Box 24.8.2). None of the features is compul- sory, and indeed, given that the migraine aura, visual disturbances with flashing lights or zigzag lines moving across the fields, or other neurological symptoms, are reported in only about 25% of patients, a high index of suspicion is required to diagnose migraine. In a controlled study of patients presenting to general practitioners with a main complaint of headache over the previous 3 months, mi- graine was the diagnosis on more than 90% of occasions, so a high index of suspicion is well rewarded. A headache diary can often be helpful in making the diagnosis, although in reality the diary usually helps more in assessing disability or recording how often patients use acute attack treatments. Phenotyping remains an essentially clinical art, mixing experience and an understanding of the prob- lems likely to present—​good headache histories are taken, not given. In differentiating the two main primary headache syndromes seen in clinical practice, migraine at its most simple level is headache with associated features, and tension-​type headache is headache that is featureless; furthermore, most disabling headache coming to the at- tention of physicians is probably migrainous in biology. By features is meant throbbing pain, or sensitivity to sensory stimuli—​visual, auditory, olfactory—​or to head movement itself. Frequent migraine If headache with associated features describes migraine attacks, then ‘headachy’ describes the person who has migraines over a lifetime. It is important to realize that the word migraine can describe both the attacks using standard criteria (see Box 24.8.2) and the disorder itself, which is more than just the attack. People who have migraines (migraineurs) inherit a tendency to have headache that is amplified at various times by their interaction with their environment, the much-​discussed ‘triggers’. The brain of the migraineur seems more sensitive to sensory stimuli and to change; and this tendency is not- ably amplified in women during their menstrual cycle. People who have a migraine may have headache when they oversleep, when tired, when they skip meals, when they overexert, or when they relax from a stressor. They are less tolerant to change, and part of successful management is to advise them to maintain regularity in their lives in the knowledge of this fluctuating biology. It is this biology that marks migraine and in clinical practice must override the phenotype of individual headaches. Migraine can certainly occur daily, indeed chronic migraine—​ defined as 15 days or more of headache a month for three months on a migrainous basis, is probably the largest part of the group of headaches known collectively as chronic daily headache that pre- sents to doctors (see next). After making a diagnosis, the second step in the clinical process is to be sure that the disease burden has been captured, how much headache patients have and, more important, what patients cannot do—​what is their degree of disability? One can ask the patient directly to get a flavour for this, keep a diary, or get a quick but accurate estimate using the Migraine Disability Assessment Scale (MIDAS), which is well validated and very easy to use in practice (Fig. 24.8.4). Principles of management of migraine After diagnosis the management of migraine begins with an explan- ation of some aspects of the disorder to the patient: • Migraine is an inherited tendency to have headache; this is caused by the patient’s genes, therefore it cannot be cured. Box 24.8.2  Simplified diagnostic criteria for migraine Repeated attacks of headache lasting 4–​72 h that have these features, normal physical examination, and no other reasonable cause for the headache: • At least two of: — Unilateral pain — Throbbing pain — Aggravation by movement — Moderate or severe intensity • At least one of: — Nausea/​vomiting — Photophobia and phonophobia Adapted from the International Headache Society Classification (Headache Classification Committee of the International Headache Society (2004). The international classification of headache disorders, 2nd edn. Cephalalgia, 24: 1–​1604). section 24  Neurological disorders 5992 • Migraine can be modified and controlled by lifestyle adjustment and the use of medicines. • Migraine is not life-​threatening or associated with serious illness, with the exception of women who smoke and use oestrogenic oral contraceptives, but migraine can make life a misery. • Migraine management takes time and cooperation (e.g. when a headache diary has to be collected, or enquiry made about the disability). Non​pharmacological management of migraine This approach aims to help migrainous patients identify things making the problem worse and encourage them to modify these. Patients need to know that the brain sensitivity that is migraine varies, so that the effect of triggers will vary. Patient associations are often very helpful in supporting migraineurs to identify triggers. The knowledge that there is variability will remove considerable frustration on the patient’s part, and will ring true to most as they have had the experience. The cru- cial lifestyle advice is to explain to the patient that migraine is a state of brain sensitivity to change. This implies that these people need to regulate their lives: healthy diet, regular exercise, regular sleep pat- terns, avoiding excess caffeine and alcohol, and, as far as practicable, modifying or minimizing changes in stress. The balanced life with fewer highs and lows will benefit most people who have migraines. Preventive treatments of migraine Patients need to understand they have an inherited, non​cur- able, but manageable problem. To start a preventive they need to have sufficient disability to wish to take a medicine to reduce the effects of the disease on their life. The basis of considering preventive treatment from a medical viewpoint is a combination of acute at- tack frequency and attack tractability that confers an unacceptable degree of disability. Patients with attacks unresponsive to abortive medications are easily considered for prevention, whereas patients with simply treated attacks may be less obvious candidates. Another important consideration is disease progress. If a patient diary shows a clear trend of an increasing frequency of attacks, it is better to ini- tiate with prevention than wait for the problem to worsen. A simple rule for frequency might be that for one to two headaches a month there is usually no need to start a preventive; for three to four it may be needed but not necessarily; and for five or more per month, prevention should definitely be considered. Options available for treatment are covered in detail in Table 24.8.2 and vary somewhat by country. One problem with preventives is that they have fallen into use for migraine from other indications and often bring unwanted or intolerable side effects. The development of calcitonin gene-​related peptide (CGRP) mechanism antagonists delivers specific therapy for migraine, which is well tolerated, and treatment with a clear mech- anism of action. It is not clear how current preventives work, although it seems likely that they modify the brain sensitivity that underlies mi- graine. Another key clinical point is that generally each drug should be started at a low dose and gradually increased to a reasonable max- imum if there is going to be a clinical effect. Relatively little has been done in terms of systematic study of patients with more intractable forms of migraine. Noninvasive neuromodulation approaches are proving helpful. Interestingly, functional imaging studies show that central processing of pain signals in migraine in the thalamus may be modified by therapy. This is an exciting and developing area. Acute attack therapies of migraine Acute attack treatments for migraine can be usefully divided into non-disease-specific treatments (analgesics and non​steroidal ­ anti-​inflammatory drugs (NSAIDs)) and disease-​specific treat- ments (ergot-​related compounds and triptans). It is important to be aware that most acute attack medications seem to have a propensity to aggravate headache frequency and can induce a state of refrac- tory daily or near-​daily headache—​medication-​overuse headache. As evidence is gathered, this seems to occur in patients with mi- graine: either a previous clear history or a family or personal his- tory of headachiness. Codeine-​containing compound analgesics are particularly troublesome when available in over-​the-​counter pre- parations. Patients with migraine should be advised to avoid taking acute attack medicines on more than 2 days a week. A proportion of patients who stop taking regular analgesics will have substantial improvement in their headache with a reduction in frequency; how- ever, for some it will not make any difference. It is crucial to empha- size to the patient that standard preventive medications often simply do not work in the presence of regular analgesic use. Treatment strategies Given the array of options to control an acute attack of migraine, how does one start? The simplest approach to treatment has been described as ‘stepped care’. In this model all patients are treated, ­assuming no contraindications, with the simplest treatment, such as aspirin 900 mg or paracetamol 1000 mg with an antiemetic. Aspirin is an effective strategy, has been proven so in double-​blind INSTRUCTIONS: Please answer the following questions about ALL your headaches you have had over the last 3 months. Write your answer in the box next to each question. Write zero if you did not do the activity in the last 3 months (Please refer to the calendar below, if necessary) On how many days in the last 3 months did you miss work or school because of your headaches? ……………………………………………………………....................................... ||| days How many days in the last 3 months was your productivity at work or school reduced by half or more because of your headaches (Do not include days you counted in question 1 where you missed work or school)? ……………………………………………… ||| days 3. On how many days in the last 3 months did you not do household work because of your headaches? ………………………………………………………...................................... ||| days 4. How many days in the last 3 months was your productivity in household work reduced by half or more because of your headaches (Do not include days you counted in question 3 where you did not do household work)? ……………………………………….….…. ||| days 5. On how many days in the last 3 months did you miss family, social, or leisure activities because of your headaches? ………………………………………........................... ||| days A. On how many days in the last 3 months did you have a headache? (If a headache lasted more than one day, count each day) ………………................... ||| days B. On a scale of 0–10, on average how painful were these headaches? (where 0 = no pain at all, and 10 = pain as bad as it can be) ……………................... ||| Version 3.0 © Innovative Medical Research 1997 Fig. 24.8.4  Migraine Disability Assessment Score (MIDAS) questionnaire. 24.8  Headache 5993 Table 24.8.2  Some preventive treatments in migrainea Drug Dose Selected side effects Pizotifen 0.5–​2 mg daily Weight gain Drowsiness β-​Blocker Propranolol 40–​120 mg twice daily Reduced energy Tiredness Postural symptoms Contraindicated in asthma Metoprolol 25–​100 mg twice daily Tricyclics Amitriptyline Dosulepin (dothiepin) Nortriptyline 25–​75 mg at night Drowsiness Note: some patients are very sensitive and may only need a total dose of 10 mg, although generally 1–​1.5 mg/​kg body weight is required Venlafaxine 75–​150 mg Drowsiness, urinary retention, arrhythmias Anticonvulsants Valproate 400–​600 mg twice daily Drowsiness Weight gain Tremor Hair loss Fetal abnormalities Haematological or liver abnormalities Other mechanism Topiramate 50–​200 mg/​day Paraesthesiae Cognitive dysfunction Weight loss Care with a family history of glaucoma Nephrolithiasis Candesartan 4–​16 mg daily Dizziness Flunarizine 5–​15 mg daily Drowsiness Weight gain Depression Parkinsonism Calcitonin gene-related peptide (CGRP) mechanism blockers erenumab 70 to 140 mg monthly s/c Mild injection site reactions fremanezumab 225 mg monthly or 675 mg quarterly s/c Mild injection site reactions Neuromodulation Single pulse transcranial magnetic stimulation 2 to 8 pulses two to three times daily Transcutaneous supraorbital nerve stimulation Twenty minutes daily galcanezumab 120 to 240 mg monthly s/c Mild injection site reactions Botulinum toxin type Ad 155 units in 31 sites Neck pain Muscle weakness Single studiesb Lisinopril Neutriceuticalsc Riboflavin Coenzyme Q10 Feverfew 20 mg daily 400 mg daily 100 mg three times daily 6.25 mg three times daily Cough Gastrointestinal upset No convincing controlled evidence Verapamil Gabapentin studies shown to have been falsely reported Controlled trials to demonstrate no effect Nimodipine Clonidine SSRIs: fluoxetine a Commonly used preventives are listed with reasonable doses and common side effects. The local national formulary should be consulted for detailed information. b Compounds not widely considered mainstream but with a positive randomized control trial against placebo. c Non​pharmaceuticals with at least one positive randomized controlled trial against placebo. d Using the PREEMPT strategy (Dodick et al., 2010—​see Further reading) and only proven in chronic migraine. SSRI, selective serotonin reuptake inhibitor. section 24  Neurological disorders 5994 controlled clinical trials, and is best used in its most soluble formula- tions. The alternative is a strategy known as ‘stratified care’, by which the physician determines, or stratifies, treatment at the start, based on the likelihood of response to levels of care. An intermediate op- tion may be described as stratified care by attack. This is what many headache authorities suggest, and what patients often do when they have the option: they use simpler options for their less severe attacks, relying on more potent options when their attacks or circumstances demand them (Table 24.8.3). Non​specific acute migraine attack treatments As simple drugs, such as aspirin and paracetamol, are cheap and can be effective, dosages should be adequate and the addition of domperidone (10 mg orally), metoclopramide (10 mg orally) or ondansetron 4 mg can be very helpful. NSAIDs can very useful when tolerated. Their success is often limited by inappropriate dosing, and adequate doses of naproxen 500–​1000 mg orally or rectally, with an antiemetic, ibuprofen 400 to 800 mg orally, or tolfenamic acid 200 mg orally can be extremely effective. Specific acute migraine attack treatments When simple analgesic measures fail or more aggressive treatment is required, the specific antimigraine treatments are required (Table 24.8.4). Although ergotamine remains a useful treatment, it can no longer be considered the treatment of choice in acute migraine. There are particular situations in which ergotamine is very helpful, but its use must be carefully controlled as ergotamine overuse produces dreadful headache in addition to a host of vascular problems. The triptans, serotonin 5HT1B/​1D-​receptor agonists, have revolutionized the life of many patients with migraine and are clearly the most powerful option available to stop a migraine attack. They can be rationally applied by considering their pharmacological, physicochemical, and pharmaco- kinetic features, as well as the formulations that are available. Recent data suggest that combining a triptan with an NSAID can improve efficacy and reduce headache recurrence. Neuromodulation approaches to migraine Neuromodulation approaches to migraine have now emerged, with single pulse transcranial magnetic stimulation (TMS) being proven with a randomized placebo-​controlled trial. It is a safe, effective strategy that works for acute treatment and may have a preventive role. Its proper place in management is yet to be de- termined, but its simplicity suggests a potentially major shift in treatment approach because neuromodulation such occipital nerve stimulation has hitherto been aimed at medically refrac- tory patients using invasive techniques. Other techniques such as supraorbital nerve and non​invasive vagal nerve stimulation are being studied. Table 24.8.3  Oral acute migraine treatments Non​specific treatmentsa Specific treatments Aspirin 900 mg Ergot derivatives Paracetamol [acetaminopheno] 1000 mg Ergotamine 1–​2 mg NSAIDs Triptans Naproxen 500–​1000 mg Sumatriptan 50 or 100 mg Ibuprofen 400–​800 mg Naratriptan 2.5 mg Tolfenamic acid 200 mg Rizatriptan 10 mg Diclofenac K 50 mg Zolmitriptan 2.5 or 5 mg Eletriptan 40 or 80 mg Almotriptan 12.5 mg Frovatriptan 2.5 mg a Often used with antiemetic/​prokinetics, such as domperidone 10 mg (care in patients using medicines altering the QT interval), metoclopramide 10 mg or ondansetron 4 mg. Table 24.8.4  Stratification of acute migraine treatments Clinical situation Treatment options Failed analgesics/​ NSAIDS First tier Sumatriptan 50 mg or 100 mg orally Almotriptan 12.5 mg orally Rizatriptan 10 mg orally Eletriptan 40 mg orally Zolmitriptan 2.5 mg orally Slower effect/​better tolerability Naratriptan 2.5 mg orally Frovatriptan 2.5 mg orally Single pulse transcranial magnetic stimulation Infrequent headache Ergotamine 1–​2 mg orally Dihydroergotamine nasal spray 2 mg Dihydroergotamine 0.5 mg by inhalation Early nausea or difficulties taking tablets Zolmitriptan 2.5 mg by dissolving wafer or nasal spray Sumatriptan 20 mg nasal spray Rizatriptan 10 mg MLT wafer Sumatriptan transdermal patch Headache recurrence Ergotamine 2 mg (most effective rectally/​usually with caffeine) Naratriptan 2.5 mg orally Almotriptan 12.5 mg orally Eletriptan 40 mg Dihydroergotamine 0.5 mg by inhalation Tolerating acute treatments poorly Naratriptan 2.5 mg Almotriptan 12.5 mg Single pulse transcranial magnetic stimulation Early vomiting Zolmitriptan 5 mg nasal spray Sumatriptan 25 mg rectally Sumatriptan 6 mg subcutaneously Menstrually related headache Prevention Ergotamine orally at night Oestrogen patch Treatment Triptans Dihydroergotamine nasal spray Very rapidly developing symptoms Zolmitriptan 5 mg nasal spray Sumatriptan 6 mg subcutaneously, needle or needle-​free Dihydroergotamine 1 mg intramuscularly 24.8  Headache 5995 Tension-​type headache Clinical features As its name suggests, tension-​type headache (TTH) is the least understood primary headache form. TTH is diagnosed often and, although the phenotype is common, much of the disabling headache that goes under the name TTH is likely to be migrainous in terms of its biology. TTH has two forms—​episodic TTH, where attacks occur on fewer than 15 days a month, and chronic TTH, where attacks, on average over time, are seen on 15 days or more a month. The latter is part of the broader clinical syndrome of chronic daily headache, but these terms are not equal. TTH has been defined by the International Headache Society for both its episodic and chronic forms, although the admixture of symptoms allowed has consistency problems. A useful clinical ap- proach is to diagnose TTH when the headache is completely fea- tureless: no nausea, no vomiting, no photophobia, no phonophobia, no osmophobia, no throbbing, and no aggravation with movement. Such an approach neatly divides migraine, which has one or more of these features and is the main differential diagnosis from TTH. Pathophysiology The pathophysiology of TTH is very poorly understood. This results from the fact that the name implies to most that it is a product of nervous tension, for which there is no clear evidence, and the defin- itions employed have undoubtedly admitted patients with migraine to the studies. Moreover, the concept that TTH in some way involves muscle contraction is incorrect because the evidence is that muscle contraction is no more likely than it is in migraine. It seems likely that TTH is due to a primary disorder of CNS pain modulation alone in contrast with migraine, which is a more generalized dis- turbance of sensory modulation. Management Adopting the clinical approach to TTH outlined here earlier results in diagnosing a headache form that is usually less disabling, more often described by patients as irritating. Its episodic form is generally amen- able to simple analgesics, paracetamol, aspirin, or NSAIDs, which can be purchased over the counter. There are clear clinical studies to dem- onstrate that triptans in TTH alone are not helpful, although, germane to the previous discussion, triptans are effective in TTH where the pa- tient also has migraine. For chronic TTH, amitriptyline is the only treatment with a clear evidence base; the other tricylic antidepressants, selective serotonin reuptake inhibitors, or benzodiazepines have not been shown in controlled trials to be effective. Similarly, there is no controlled evidence for the use of electromyography (EMG) biofeed- back, relaxation therapy, or acupuncture. Botulinum toxin has been shown reasonably clearly to be ineffective. Stress management has been shown to be an effective approach in a controlled trial. Trigeminal–​autonomic cephalalgias Cluster headache Cluster headache is a rare form of primary headache with a population frequency of 0.1%. It is covered in specialist books. As a clinical anchor, it is about as common as multiple sclerosis in the United Kingdom, and must be regarded as a disorder best managed by neurologists or headache specialists. It is perhaps the most painful condition of humans; in the cohort of more than 1000 patients seen by the author not a single one has had a more painful experience, including childbirth, multiple fractures of the limbs and renal stones. It is one of a group of conditions known now as trigeminal–​autonomic cephalalgias (TACs), whose clinical Table 24.8.5  Cluster headache, other trigeminal–​autonomic cephalalgias (TACs), and short-​lasting headaches TACsa Other short-​lasting headaches Cluster headache Primary stabbing headache Paroxysmal hemicranias Trigeminal neuralgia SUNCT/​SUNAb syndrome Primary cough headache Primary exercise headache Cold stimulus headache External pressure headache Nummular headache Hemicrania continua Primary sex headache Hypnic headache a Beware of pituitary tumour-​related headache in the differential diagnosis of these TACs. b Short-​lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/​cranial autonomic features. Box 24.8.3  Diagnostic criteria for cluster headache Diagnostic criteria A At least five attacks fulfilling B–​D B Severe or very severe unilateral orbital, supraorbital and/​or temporal pain lasting 15–​180 min if untreated C Headache is accompanied by at least one of the following: (1) ipsilateral conjunctival injection and/​or lacrimation (2) ipsilateral nasal congestion and/​or rhinorrhoea (3) ipsilateral eyelid oedema (4) forehead and facial sweating (5) ipsilateral forehead and facial sweating (6) ipsilateral miosis and/​or ptosis or (7) a sense of restlessness or agitation D Attacks have a frequency from one every other day to eight per day E Not attributed to another disorder Episodic cluster headache Description: occurs in periods lasting 7 days to 1 year separated by pain-​ free periods lasting 1 month or more Diagnostic criteria A All fulfilling criteria A–​E of 3.1 B At least two cluster periods lasting from 7 to 365 days and separated by pain-​free remissions of ≥3 month Chronic cluster headache Description: attacks occur for more than 1 year without remission or with remissions lasting less than 3 month Diagnostic criteria A All alphabetical headings of 3.1 B Attacks recur over more than 1 year without remission periods or with remission periods less than 1 month Adapted from the International Headache Society Classification (Headache Classification Committee of the International Headache Society (2018). The international classification of headache disorders, 3rd edn. Cephalalgia, 38:1–211). section 24  Neurological disorders 5996 signature is lateralization of symptoms, and thus needs to be differ- entiated from other TACs and the short-​lasting headaches without cranial autonomic symptoms, such as lacrimation or conjunctival injection (Table 24.8.5). The core features of cluster headache are lateralized symptoms and signs, and periodicity, be it circadian or in terms of active and inactive bouts over weeks and months (Box 24.8.3). The typical cluster headache patient is male, with a 3:1 predominance, who has bouts of one to two attacks of relatively short duration unilateral pain every day for 8–​10 weeks a year. They are generally perfectly well in between. Patients with cluster headache tend to move about during attacks, pacing, rocking, or even rubbing their head for relief. The pain is usually retro-​orbital, boring, and very severe. It is asso- ciated with ipsilateral symptoms of cranial (parasympathetic) auto- nomic activation: a red or watering eye, running or blocked nose, or cranial sympathetic dysfunction—​eyelid droop. Cluster headache is likely to be a disorder involving neurons in or around the central pacemaker regions of the posterior hypothalamic grey matter (see Fig. 24.8.2). Although cluster headache patients may also experi- ence nausea, photophobia, and phonophobia, the last two, particu- larly photophobia, tend to be ipsilateral to the pain only in TACs. The TACs—​cluster headache, paroxysmal hemicrania, SUNCT syndrome, and hemicrania continua—​present a distinct group to be differentiated particularly from short-​lasting headaches that do not have prominent cranial autonomic syndromes, notably trigem- inal neuralgia, idiopathic (primary) stabbing headache, and hypnic headache. By determining the cycling pattern, length of attack, fre- quency of attack, and timing of the attacks, most patients can be usefully classified. The importance of clinical classification of this group is threefold: first, the clinical phenotype determines the likely secondary causes that must be considered and appropriate investi- gations ordered; second, the appropriate classification gives clarity to the patient with a clear diagnosis and allows the physician to draw on available literature to comment on natural history; and third, the correct diagnosis determines therapy that can be very different in these conditions, being very good if the diagnosis is correct but largely ineffective if it is not (Table 24.8.6). Managing cluster headache Cluster headache is managed using acute attack treatments and pre- ventive agents. Acute attack treatments are usually required by all cluster headache patients at some time, whereas preventives can seem almost life-​saving for the patients with chronic cluster head- ache, and are often needed to shorten the active periods in patients with the episodic form of the disorder. Preventive treatments The options for preventive treatment in cluster headache depend on the bout length (Table 24.8.7). Patients with short bouts require medicines that act quickly but will not necessarily be taken for long periods, whereas those with long bouts or indeed those with chronic cluster headache require safe, effective medicines that can be taken for long periods. Verapamil is now widely considered as the first-​ line preventive treatment when the bout is prolonged, or in chronic cluster headache. By contrast, limited courses of oral corticosteroids or a greater occipital nerve injection can be very useful strategies when the bout is relatively short. Verapamil has been suggested as a useful option for the last decade and compares favourably with lithium or topiramate. What has clearly emerged from clinical practice is the need to use higher doses than had initially been considered and certainly higher than those used routinely in cardiological indications. Although most patients will start on doses as low as 40 to 80 mg twice daily, doses up to 960 mg daily are often re- quired. Side effects, such as gingival hyperplasia, constipation, and leg swelling, are recognized, as are cardiac dysrhythmias. Verapamil can cause heart block by slowing conduction in the atrioventricular (AV) node, monitored clinically by the PR interval on the electrocardiogram (ECG). Given that the effects on the AV node take up to 10 days to manifest, 2-​week intervals are recommended between dose changes on the first exposure, with ECGs before the next escalation, and routine six-​monthly ECGs after the dose has been established. Acute attack treatment Cluster headache attacks often peak rapidly and thus require a treat- ment with quick onset. Many patients with acute cluster headache Table 24.8.6  Differential diagnosis of short-​lasting headaches Feature Cluster headache Paroxysmal hemicrania SUNCT/​SUNAa Primary stabbing headache Trigeminal neuralgiaa Hypnic headache Gender M > F 3: 1 F = M 1.5 M to 1 F F > M F > M M = F Pain Type Boring/​ throbbing Boring/​throbbing Stabbing/​throbbing Stabbing Stabbing Throbbing Severity Very severe Very severe Very severe Severe Very severe Moderate Cranial location Any Any Any Any V2/​V3 >V1 Generalized Duration 15–​180 min 2–​30 min 15–​600 s <10 s <5 s 15–​30 min Frequency 1–​8/​day 1–​40/​day 1/​day–​30/​h Any Any 1–​3/​night Autonomic + + + –​ –​ –​ Alcohol + One-​third –​ –​ –​ –​ Cutaneous trigger to attacks –​ –​ + –​ + –​ Indometacin –​ + –​ + –​ –​ SUNCT, short-​lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing; SUNA, short-​lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms. a SUNCT/​SUNA generally has no refractory period to trigger additional attacks, although this is a very common feature of trigeminal neuralgia. 24.8  Headache 5997 respond very well to treatment with oxygen inhalation. This should be given as 100% oxygen at 10 to 12 litres/​min for 15–​20 min. It is important to have a high flow and high oxygen content. Injectable sumatriptan 6 mg is effective, rapid in onset, and has no evidence of tachyphylaxis. Sumatriptan 20 mg and zolmitriptan 5 mg nasal sprays are effective in acute cluster headache in controlled trials, and offer a useful option. Sumatriptan is not effective when given pre-​emptively as 100 mg orally three times daily, and there is no evidence that it is useful when used orally in the acute treatment of cluster headache; indeed it can be associated with medication-​overuse headache prob- lems. Most recently, two sham-controlled randomised studies dem- onstrated that noninvasive vagal nerve stimulation (nVNS) is effective for the acute treatment of attacks in episodic cluster headache. Surgical treatment The surgical treatment of cluster headache has been completely revolutionized with the introduction of neurostimulation therapies. Surgical treatment of cluster headache is reserved for the most refrac- tory patients, typically with chronic cluster headache. Destructive procedures, such as sphenopalatinectomy (pterygopalatinectomy) or radiofrequency lesions of the trigeminal ganglion, have been used: the former with no clear effects, and the latter being helpful, but often at significant cost, includ­ing ocular complications or an- aesthesia dolorosa. Trigeminal rhizotomy has also been employed, with all the complications of radiofrequency lesions and the occa- sional death. Destructive procedures have no place in the modern treatment of chronic cluster headache. Driven by functional imaging work describing activations in the posterior hypothalamic region, deep brain stimulation approaches in the same region seem to be highly effective in about two-​thirds of medically refractory patients, although they are hazardous, with risk of death. Occipital nerve stimulation has proved a frustrating approach to management of in- tractable chronic cluster headache with technical issues and a lack of any controlled trial evidence. Sphenopalatine (pterygopalatine) ganglion stimulation now has one randomized sham-​stimulation controlled trial and represents a logical and very promising ap- proach. Non​invasive vagal nerve stimulation is being studied and its early results are also very promising. Paroxysmal hemicrania Sjaastad and Dale (1976) first reported eight cases of a frequent uni- lateral severe but short-​lasting headache without remission coining the term chronic paroxysmal hemicrania. In a large series Cittadini and colleagues (2008) reported a daily frequency of attacks varying from 2 to 50 with a median of 9, and with pain persisting for a me- dian of 19 minutes. The site and associated autonomic phenomena were similar to cluster headache, and the attacks of chronic parox- ysmal hemicrania were suppressed completely by indomethacin. The essential features of paroxysmal hemicrania that we have seen from a substantial cohort of patients are: • unilateral, very severe pain • short-​lasting attacks, typically 20 min in length • very frequent attacks (usually >5/​day with a mean of 10) • marked autonomic features ipsilateral to the pain • robust, quick (<72 h), excellent response to indomethacin The pathophysiology of paroxysmal hemicrania is marked by acti- vations on PET (positron emission tomography) in the contralateral posterior hypothalamic region and contralateral ventral midbrain. The posterior hypothalamic region activity is shared with cluster headache, SUNCT, and hemicrania continua, whereas the ventral midbrain activity is only seen in hemicrania continua, which re- markably is also an indometacin-​sensitive primary headache. The therapy of paroxysmal hemicrania may be complicated by gastrointestinal side effects seen with indometacin, in which topiramate and noninvasive vagal nerve stimulation (nVNS) may be helpful. Secondary paroxysmal hemicrania is more likely if the pa- tient requires high doses (>200 mg/​day) of indometacin and raised cerebrospinal fluid pressure should be suspected in apparent bilat- eral paroxysmal hemicrania. It is worth noting that indometacin reduces cerebrospinal fluid pressure by an unknown mechanism. Recent evidence suggests the mechanism of action of indometacin is via nitric oxide synthase. It is appropriate to image patients, with MRI if practical, when a diagnosis of paroxysmal hemicrania is being considered. SUNCT/​SUNA Sjaastad and colleagues (1989) reported three male patients whose brief attacks of pain in and around one eye were associated with sudden conjunctival injection and other autonomic features of cluster headache. In a large series attacks Cohen and colleagues (2006) reported three attack phenotypes: stabs, groups of stabs, or a saw-​tooth pattern. They were not abolished by indomethacin. Brain imaging has suggested that they share with cluster headache and par- oxysmal hemicrania the feature on activation studies of involvement of the posterior hypothalamic region. Of the patients recognized with this problem, males dominate slightly and the paroxysms of pain may last between 5 and 300 s, although longer, duller interictal pains are recognized. In SUNCT conjunctival injection and tearing are often obvious. If one of either conjunctival injection or tearing is absent, or nei- ther is present but another cranial autonomic symptom is seen, the term SUNA is used. The key clinical features of SUNCT/​SUNA are that the attacks can be triggered with no refractory period to triggering. The latter serves as a very useful distinction between SUNCT/​SUNA and trigeminal neuralgia. SUNCT/​SUNA can be treated very frequently with lamotrigine, and if that is unhelpful topiramate or gabapentin. Carbamazepine often has a useful but incomplete effect. Given what has been reported, cranial MRI with pituitary and posterior fossa views is highly recommended when SUNCT/​SUNA is considered as a diagnosis. Table 24.8.7  Preventive management of cluster headache Short-​term prevention (episodic cluster headache) Long-​term prevention (episodic cluster headache and prolonged chronic cluster headache) Prednisolone Verapamil Daily nocturnal frovatriptan Lithium Topiramate Greater occipital nerve injection Melatonin ? Gabapentin ? Non​invasive vagal nerve stimulation Sphenopalatine ganglion stimulation ? = unproven but promising. section 24  Neurological disorders 5998 Hemicrania continua Two patients were initially reported with this syndrome, a woman aged 63 years and a man of 53, who developed unilateral headache without obvious cause. Both patients were relieved completely by indometacin whereas other NSAIDs were of little or no benefit. Cittadini and colleagues (2010) reported 39 patients with strictly lat- eralized headache and cranial autonomic symptoms. When present photophobia and phonophobia were ipsilateral to pain in nearly one-​ half. The following are the essential features of hemicrania continua: • Unilateral pain • Pain is continuous but with exacerbations that may be severe • Complete resolution of pain with indometacin • Exacerbations may be associated with cranial autonomic features Apart from analgesic overuse as an aggravating factor, and a re- port in an HIV-​infected patient, the status of secondary hemicrania continua is unclear. Cittadini and colleagues (2010) proposed a placebo-​controlled Indotest with 100 or 200 mg of intramuscular indomethacin. Used in conjunction with PET, it has been shown that there is activation of the contralateral posterior hypothalamic region and ipsilateral dorsal rostral pons in association with the headache of hemicrania continua, as well as activation of the ipsi- lateral ventrolateral midbrain. The alternative is a trial of oral indo- methacin, initially 25 mg three times daily, then 50 mg three times daily, and 75 mg three times daily. One should allow up to 2 weeks for any dose to have a useful effect. After the headache is controlled the dose can usually be reduced yet control maintained. Acute treat- ment with sumatriptan has been employed and reported to be of no benefit. Cyclooxygenase II (COX-​II) antagonists seem effective, al- though undesirable now, and topiramate is helpful in some patients, as is and noninvasive vagal nerve stimulation (nVNS) and greater occipital nerve injection. Other primary headaches Primary cough headache Sharp pain in the head on coughing, sneezing, straining, laughing, or stooping has long been regarded as a symptom of organic intra- cranial disease, commonly associated with obstruction of the cerebrospinal fluid pathways. The presence of an Arnold–​Chiari malformation or any lesion causing obstruction of cerebrospinal fluid pathways or displacing cerebral structures must be excluded before cough headache is assumed to be benign. Cerebral aneurysm, carotid stenosis, and vertebrabasilar disease may also present with cough or exercise headache as the initial symptom. The term ‘be- nign Valsalva’s manoeuvre-​related headache’ covers the headaches provoked by coughing, straining, or stooping but ‘cough headache’ is more succinct and so widely used that it is unlikely to be displaced. The following are the essential clinical features of primary cough headache: • Bilateral headache of sudden onset, lasting seconds to 2 h • Brought on by cough, strain, or other Valsalva manoeuvre • May be prevented by avoiding coughing • Diagnosed only after structural lesions, such as posterior fossa tumour, have been excluded by neuroimaging Indomethacin is the medical treatment of choice in cough head- ache. Raskin followed up an observation of Sir Charles Symonds reporting that some patients with cough headache are relieved by lumbar puncture. This is a simple option when compared with pro- longed use of indomethacin. The mechanism of this response re- mains unclear. Primary exercise headache The relationship of this form of headache to cough headache is un- clear and certainly much is shared. Indeed the relationship to mi- graine also requires delineation. The following are the clinical features: • Pain specifically brought on by strenuous physical exercise • Lasting less than 48 hours • Prevented by avoiding excessive exertion, particularly in hot weather or at high altitude. The acute onset of headache with straining and breath-​holding, as in weightlifter’s headache, may be explained by acute venous dis- tension. The development of headache after sustained exertion, particularly on a hot day, is more difficult to understand. Anginal pain may be referred to the head, probably by central connections of vagal afferents, and may present as exercise headache, so-​called cardiac cephalgia. The link to exercise is the important clinical clue. Phaeochromocytoma may occasionally be responsible for exercise headache. Intracranial lesions or stenosis of the carotid arteries may have to be excluded as discussed for benign cough headache. Headache may be precipitated by any form of exercise. The most obvious form of treatment is to take exercise gradually and pro- gressively whenever possible. Indomethacin at daily doses varying from 25 to 150 mg is generally very effective in exercise head- ache. Indomethacin 50 mg, ergotamine tartrate 1–​2 mg orally, or dihydroergotamine by nasal spray, 30 to 45 min before exercise are useful preventive measures. Primary sex headache Sex headache may be precipitated by masturbation or coitus and usually starts as a dull bilateral ache while sexual excitement in- creases, suddenly becoming intense at orgasm. The term ‘orgasmic cephalgia’ is not accurate because not all sex headache requires orgasm. Two types of primary sex headache are recognized in practice: a dull ache in the head and neck that intensifies as sexual excitement increases, and a sudden severe (‘explosive’) headache occurring at orgasm, although this distinction has no known physiological basis. Low cerebrospinal fluid volume headache may also be precipitated by sexual activity and is considered as a form of new daily persistent headache (see next). The following are the essential clinical features of a sex headache: • Precipitation by sexual excitement • Bilateral at onset • Severe headache may be present from one minute to 24 h • Prevented or eased by ceasing sexual activity before orgasm Headaches developing at the time of orgasm are not always benign, and consideration of a diagnosis of subarachnoid headache is es- sential. Sex headache affects men more often than women and may occur at any time during the years of sexual activity. It may develop 24.8  Headache 5999 on several occasions in succession, and then not trouble the patient again, despite no obvious change in sexual technique. In patients who stop sexual activity when the headache is first noticed it may subside within a period of 5 min to 2 h, and it is recognized that more frequent orgasm can aggravate established sex headache. About one-​half of the patients with sex headache have a history of exercise headache, but there is no excess of cough headache in patients with sex headache. In about 50% of patients, sex headache will settle in 6 months. Migraine is reported in about 25% of patients with sex headache. Primary sex headaches are usually irregular and infrequent in oc- currence, so management can often be limited to reassurance and advice about ceasing sexual activity if a milder, warning headache develops. When the condition recurs regularly or frequently, it can be prevented by the administration of propranolol; the dosage required varies from 40 mg to 200 mg daily. An alternative is the calcium channel blocking agent diltiazem 60 mg three times daily, which this author finds particularly useful in such patients. Frovatriptan 2.5 mg or indomethacin (25–​50 mg) taken about 30–​60 min before sexual activity can also be helpful. Primary thunderclap headache Sudden-​onset severe headache may occur in the absence of sexual activity; the differential diagnosis includes the sentinel bleed of an intracranial aneurysm, cervicocephalic arterial dissection, re- versible cerebral vasoconstriction syndrome, and cerebral venous thrombosis. Headaches of explosive onset may also be caused by the ingestion of sympathomimetic drugs or tyramine-​containing foods in a patient who is taking monoamine oxidase inhibitors, and can also be a symptom of a phaeochromocytoma. Whether thun- derclap headache can be the presentation of an unruptured cere- bral aneurysm is debated. Day and Raskin (1986) reported on a woman with three episodes of sudden-​onset, very severe headache who was found to have an unruptured aneurysm of the internal ca- rotid artery, with adjacent areas of segmental vasospasm. In the ab- sence of a CT scan or cerebrospinal fluid evidence of subarachnoid haemorrhage, studies indicate that such patients do very well, and there indeed seems to be a form of benign or primary thunderclap headache. Wijdicks et al. (1988) followed up 71 patients whose CT scans and cerebrospinal fluid findings were negative for an average of 3.3 years: 12 patients had further such headaches and 31 (44%) later had regular episodes of migraine or tension-​type headache. Factors identified as precipitating the headache were sexual intercourse in 3 cases, coughing in 4, and exertion in 12, while the remainder had no obvious cause. A history of hypertension was found in 11 and of previous headache in 22. Markus (1991) compared the presenta- tion of 37 patients with subarachnoid haemorrhage and 189 with a similar thunderclap headache and normal cerebrospinal fluid exam- ination, and could not discern any characteristic to distinguish the two conditions. Investigation of any sudden-​onset severe headache, be it in the context of sexual excitement or isolated thunderclap headache, should be driven by the clinical context. The first presentation should be vigorously investigated with CT and cerebrospinal fluid examination, and where possible MRI/​MR venography/​MR angiog- raphy. Bearing in mind the entity of reversible cerebral vasoconstric- tion syndrome, which may be seen in apparent primary thunderclap headache without there being an intracranial aneurysm, caution in interpretation of the findings is crucial. Cold stimulus headache It has become recognized that cold stimuli applied either externally or by ingestion can provoke headache. For external cold stimulus headache the pain is generalized, de- velops during exposure to lowered temperature, and resolves with the removal of the stimulus. For headache associated with ingestion or inhalation of a cold stimulus there is typically a short-​lasting frontal or temporal pain as the cooling substance passes over the palate or posterior pharyn- geal wall, sometimes called ice cream headache. Typically, the pain resolves in 10 min after cessation of the stimulus. The phenomenon has previously been termed ‘ice cream headache’ and is often seen in migraineurs. External pressure headache Headache can arise from compression or traction on pericranial structures as may be seen, for example, with swimmer’s goggles or long hair in a ponytail. It is bought on by the pressure, distributes around the pressure or traction, and is relieved within an hour of relief of the compression or traction. Primary stabbing headache Short-​lived jabs of pain, defined by the International classification of headache disorders as primary stabbing headache, are well docu- mented in association with most types of primary headache. The following are the essential clinical features: • Pain confined to the head, although rarely is it facial • Stabbing pain lasting from 1 to 10 seconds and occurring as a single stab or a series of stabs • Recurring at irregular intervals (hours to days). These pains have been called ice-​pick pains or jabs and jolts. They generally respond to indometacin 25–​50 mg two to three times daily. The symptoms tend to wax and wane and after a period of control on indometacin it is appropriate to withdraw treatment and observe the outcome. Most patients will not want treatment when the nature of the problem is explained and they are reassured that the attacks are not sinister in any way. Nummular headache The pain occurs in a small circumscribed area of the head without any underlying lesion. The area of pain is generally round or ellip- tical and of fixed size and shape, typically 1–​6 cm in diameter. The pain can be continuous or may come and go. There is no clear patho- physiology, and sensory change including tenderness, dysaesthesia, or allodynia are often reported. The treatments are typically tricylics or anticonvulsants as are used in migraine. Hypnic headache This syndrome was first described by Raskin in patients aged from 67 to 84 who had headache of a moderately severe nature which typically came on a few hours after going to sleep. A large series in imaging has suggested structural changes in the posterior hypo- thalamic region with loss of grey matter volume. These headaches last from 15 to 30 min, are typically generalized, although may be section 24  Neurological disorders 6000 unilateral, and can be throbbing. Patients may report falling back to sleep only to be awoken by a further attack a few hours later, with up to three repetitions of this pattern over the night. In Dodick’s series of 19 patients, 16 (84%) were female and the mean age at onset was 61 ± 9 years. Headaches were bilateral in two-​thirds and unilateral in one-​third, and in 80% of cases mild or moderate. Three patients reported similar headaches when falling asleep during the day. None had photophobia or phonophobia and nausea is unusual. Patients with this form of headache generally respond to a bed- time dose of lithium carbonate (200–​600 mg); in those who do not tolerate this, verapamil at bedtime may be alternative strategies. Remarkably one to two cups of coffee or caffeine 60 mg orally at bed- time can be very helpful. This is a simple approach that is effective in about one-​third of patients, and should be tried in each patient first. An important secondary cause of hypnic headache is hypertension, which should be carefully pursued and appropriately investigated as treatment of the blood pressure will arrest the headache problem. Chronic daily headache Each of the aforementioned primary headache forms can occur very frequently. When a patient experiences headache on 15 days or more a month one can apply the broad diagnosis of chronic daily headache. Chronic daily headache is not one thing but a collection of very different problems with different management strategies. Crucially not all daily headache is simply TTH (Table 24.8.8). This is a very common clinical misconception in headache, confusing the clinical phenotype with the headache biotype. Population-​based estimates of daily headache are remarkable, demonstrating that about 5% of Western populations have daily or almost daily head- ache. Daily headache may again be primary or secondary, and it seems clinically useful to consider the possibilities in this way when making management decisions (Table 24.8.8). It should be said that population-​based studies bear out clinical practice in that a large group of refractory daily headache patients overuse various over-​ the-​counter preparations. Chronic migraine Although it is widely accepted that some of the primary head- aches, tension-​type headache, cluster headache, and paroxysmal hemicrania, have chronic varieties, this question seems to have be- come unnecessarily troublesome for migraine. The concept behind chronic migraine is that some patients who inherit a migrainous biology end up with daily headache. The typical patient will have daily dull, non​specific head pain, punctuated by more severe attacks that would often, in isolation, fulfil standard criteria for migraine. In headache specialty clinics this group is dominant, with about 90% of patients in referral headache clinics having chronic migraine, usu- ally with medication overuse. It could be suggested that they have a biologically more difficult problem and this is the basis for their overrepresentation in referral centres, although it is equally possible that they are simply more disabled. If one applies the concepts outlined for TTH (see earlier) then the diagnosis of chronic TTH (CTTH) is made when the patient has 15 days or more a month of entirely featureless generalized dull or pressure-​like pain. When any of the attacks on some days have migrainous features—​nausea, photophobia, phonophobia, throbbing, or aggravation with movement—​then chronic migraine is more likely to be the diagnosis. Formally the current International Classification of Headache Disorders seeks eight such days a month. Clearly both chronic migraine and CTTH exist. Moreover, some pa- tients must simply have coexisting CTTH and episodic migraine; however, it is simply impossible on clinical or other grounds to de- termine whom they are in biological terms. The approach outlined here may overdiagnose chronic migraine, taking that to be a bio- logical entity, and underdiagnose the coexistence of CTTH and epi- sodic migraine. The converse would be true—​if one diagnoses them all as CTTH and episodic migraine then chronic migraine is missed. In clinical practice the concept of chronic migraine is particularly helpful. Given that the lifestyle advice is identical for both TTH and migraine, and that the range of therapeutic options for preventive treatment in migraine is so much greater, the clinician loses abso- lutely nothing diagnosing chronic migraine, and the patient has much to gain. For research there are other imperatives. Management The management of daily headache can be very rewarding. Most pa- tients overusing analgesics respond very sensibly when the problem is explained. The keys to managing daily headache are: • Exclude treatable causes (see Table 24.8.8) • Obtain a clear analgesic history • Make a diagnosis of the primary headache type involved Medication overuse Medication overuse is defined as consuming an acute attack therapy on 10 days or more per month, except for paracetamol [acetamino- phen] where 15 days is allowed under current guidance. It is es- sential that analgesic overuse be reduced and eliminated if one is to see the underlying headache phenotype and start to manage the Table 24.8.8  Classification of chronic daily headache Primary Secondary 4 h daily <4 h daily Chronic migrainea Chronic cluster headacheb Post-​traumatic Head injury Iatrogenic Postinfectious Chronic tension-​type headachea Chronic paroxysmal hemicrania Inflammatory, such as giant cell arteritis Sarcoidosis Behçet’s syndrome Hemicrania continuaa SUNCT Chronic CNS infection New daily persistent headachea Hypnic headache Substance abuse headache CNS, central nervous system; SUNCT, short-​lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. a May be complicated by analgesic overuse. In the case of substance abuse headache, the headache is completely resolved after the substance abuse is controlled (Headache Classification Committee of the International Headache Society, 202013—​see ‘Further reading’). Clinical experience suggests that many patients continue to have headache even after cessation of analgesic use. The residual headache probably represents the underlying headache biology. b Chronic cluster headache patients may have more than 4 h/​day of headache. The inclusion of the syndrome here is to emphasize that, by and large, the attacks themselves are less than 4 h duration. 24.8  Headache 6001 problem. Patients can reduce their use by, as an example, 10% every week or two, depending on their circumstances, or if they wish, and there is no contraindication, by immediate cessation of use. Either approach can be facilitated by first keeping a careful diary over a month or two to be sure of the size of the problem. A small dose of an NSAID, such as naproxen 500 mg twice daily if toler- ated, will take the edge off the pain as analgesic use is reduced, as does a greater occipital nerve injection with local anaesthetic and depo-​corticosteroid. It is a useful aside that NSAID overuse does not seem to be a common issue in daily headache when patients are dosed once or twice daily, whereas with more frequent dosing problems may develop. When the patient has reduced analgesic use substantially a preventive should be introduced. It must be empha- sized that preventive therapies often do not work in the presence of analgesic overuse. Thus, some patients must reduce the anal- gesics or the entire attempt to use the preventive is largely wasted, although this helpful rule must have some limitations that require study. The most common cause of intractability to treatment is the use of a preventive when analgesics continue to be used regularly. For some patients this is very difficult, and often one must be blunt that some degree of pain is inevitable in the first instance if the problem is to be controlled. Some patients with medication overuse will require admission for detoxification. Broadly this consists of two groups—​those who fail outpatient withdrawal or those who have a significant complicating medical indication, such as brittle diabetes mellitus, or complicating medicines, such as opioids or barbiturates, where withdrawal may be problematic as an outpatient. When such patients are admitted acute medications are withdrawn completely on the first day, unless there is some contraindication. Antiemetics, such as domperidone orally or as a suppository, ondansetron, or aprepitant; and fluids are administered as required, as well as clonidine for opioid withdrawal symptoms. For acute intolerable pain during the waking hours as- pirin (1 g intravenously) is useful and at night chlorpromazine by injection, after ensuring adequate hydration. To settle the headache optimally a course of intravenous dihydroergotamine can be used over 5 days. As time goes by, one feels that dihydroergotamine is indispensable in this setting. Often 5HT3 receptor antagonists, such as ondansetron and granisetron, or even sometimes the substance P/​neurokin 1 receptor antagonist aprepitant will be required with dihydroergotamine because it is essential to ensure that the patient does not have significant nausea. Preventive treatments The tricylic antidepressants (TCAs), amitriptyline, dosulepin (dothiepin), and nortriptyline, at doses up to 1 mg/​kg are very useful in patients with chronic migraine. TCAs are started in low dose (10–​25 mg) daily and best given 12 h before the patient wishes to wake up to avoid excess morning sleepiness. The other very useful medications for these patients are the anticonvulsants, such as val- proate, topiramate, and gabapentin, and AII receptor antagonist candesartan. For valproate, doses up to 1500 mg daily are used, starting at 200 mg twice daily and increasing to 400 or 600 mg twice daily as tolerated over 2-​ to 4-​week intervals. The blood count and liver enzymes should be checked at baseline and the various side effects explained to patients, especially the fetal abnormalities to women. For topiramate one can start at 25 mg nightly and in- crease by 25 mg every 10–​14 days to aim for 50 mg twice daily. For gabapentin the dose is 1800–​3600 mg daily; it is very well tolerated, although probably less effective from a population viewpoint. For candesartan one can start at 4 mg nightly after checking electro- lytes and renal function and increase to 16 mg nightly as tolerated. For some patients flunarizine can be very effective, as can phenel- zine, although the latter is little used currently. Botulinum toxin type A  (onabotulinum toxin) has been shown in a randomized controlled trial to be useful in chronic migraine. One might con- sider its use, for example, in chronic migraine perhaps after three preventive classes have failed. There is now open label experience with single pulse transcranial magnetic stimulation, which is ex- tremely well tolerated. New daily persistent headache New daily persistent headache (NDPH) is a clinically useful con- cept with a range of important possible causes because some are very treatable (Table 24.8.9). The new International Classification of Headache Disorders sees a widening of the primary NDPH category to include what is listed in Table 24.8.9 as primary (i.e. it may have migrainous features). It seems clinically useful to re- member the secondary headaches that may commence in this fashion lest such patients go undiagnosed and thus untreated. The patient with NDPH presents with a history of headache on most if not all days, starting from one day to the next. The onset of headache is abrupt, often from one moment to the next, but at least in less than a few days with three suggested as an upper limit. The typical history is for the patient to recall the exact day and circum- stances, so from one moment to the next a headache develops that never leaves them. This presentation triggers certain key questions about the onset and behaviour of the pain. The pressing issues arise from considering the secondary headache possibilities. Although subarachnoid haemorrhage is listed for some logical consistency, as the headache may certainly come on from one moment to the next, it is not likely to produce diagnostic confusion in this group of patients. Suffice it to say that subarachnoid haemorrhage is so im- portant that it must always be considered if only to be excluded, ei- ther by history or by appropriate investigation. Primary NDPH Initial descriptions of primary NDPH recognized that it occurs in both males and females. Migrainous features were common, with unilateral headache in about one-​third and throbbing pain in about one-​third. Nausea was reported in about one-​half of the patients, as were photophobia and phonophobia. Many of these patients have a previous history of migraine, but not more than one might Table 24.8.9  Differential diagnosis of new daily persistent headache (NDPH) Primary Secondary Migrainous type Subarachnoid haemorrhage Featureless (tension-​type) Low CSF volume headache Raised CSF pressure headache Post-​traumatic headachea Chronic meningitis CSF, cerebrospinal fluid. a Includes postinfective forms. section 24  Neurological disorders 6002 expect given the population prevalence of migraine. It is remark- able that the initial report noted that 86% of patients were headache free at 24 months. It is general experience among those interested in headache management that primary featureless NDPH is per- haps the most intractable and least therapeutically rewarding form of headache. In general one can classify the dominant phenotype—​ migraine or TTH—​and treat with preventives according to that subclassification. Secondary NDPH The secondary causes of the syndrome of NDPH are worthy of con- sideration, because they have distinctive clinical pictures that can guide investigation (Box 24.8.4). Low cerebrospinal fluid volume headache The syndrome of headache as a result of persistent low cerebro- spinal fluid volume is an important diagnosis not to miss. The more immediately obvious version of this problem is encountered com- monly after lumbar puncture. In that situation the headache usually settles rapidly with bed rest. In the chronic situation the patient typ- ically presents with a history of headache from one day to the next. The pain is generally not present on waking, worsens during the day, and is relieved by lying down. Recumbency usually improves the headache in minutes, and it takes only minutes to an hour for the pain to return when the patient is again upright. The patient may give a history of an index event: lumbar puncture or epidural injection, or a vigorous Valsalva manoeuvre, such as with lifting, straining, coughing, clearing the Eustachian tubes in an aeroplane, or multiple orgasms. Patients may volunteer, or a history may be obtained, that soft drinks with caffeine provide temporary respite. Spontaneous leaks are recognized, and the clinician should not be put off the diagnosis if the headache history is typical when there is no obvious index event. As time passes from the index event the postural nature may be less obvious; certainly cases with an index event several years before the eventual diagnosis are recognized. The term ‘low volume’ rather than ‘low pressure’ is used, because there is no clear evidence at which point the pressure can be called low. Although low pressures, such as 0 to 5 are often identified, a pressure of 16 cmCSF has been recorded with a documented leak. One should be aware of the possibility of the development of sub- dural collections in patients with low cerebrospinal fluid volume headaches, which makes imaging before any invasive studies all the more important. The investigation of choice is MRI with gadolinium (Fig. 24.8.5), which produces a striking pattern of diffuse pachymeningeal en- hancement, although in about 10% of cases a leak can be docu- mented without enhancement. The finding of diffuse meningeal enhancement is so typical that in the clinical context immediate treatment is appropriate. It is also common to see Chiari malforma- tions on MRI with some degree of descent of the cerebellar tonsils. This is important because surgery in such settings simply worsens the headache problem. It seems appropriate that any patient being considered for such surgery for a headache indication should first be reviewed by a neurologist. If the diagnosis is clear clinically treatment is bed rest in the first instance. False-​positive transient improvement in persistent low cerebrospinal fluid volume headache with chiropractic and other similar therapies is recognized where the treatment necessi- tates the patient lying down for a prolonged period for the therapy. Intravenous caffeine (500 mg in 500 ml saline administered over 2 h) is a standard and often very efficacious treatment. The ECG should be checked for any arrhythmia before administration. A  reason- able practice is to carry out at least two infusions separated by four Box 24.8.4  Other secondary headaches • Giant cell arteritis • Cervicogenic headache • Reader’s paratrigeminal neuralgia • Tolosa–​Hunt syndrome • Headache as a presentation of cervical dystonia • Headache in temporomandibular dysfunction • Cardiac cephalalgia • Headache with endocrine disturbance, particularly pituitary tumour • Neck–​tongue syndrome • Red-​ear syndrome Fig. 24.8.5  MRI scan showing diffuse meningeal enhancement after gadolinium administration in a patient with low cerebrospinal fluid volume (pressure) headache. 24.8  Headache 6003 weeks after obtaining the suggestive clinical history and MRI with enhancement. As intravenous caffeine is safe, and can be curative, by an unknown mechanism, it spares many patients the need for further tests. If that is unsuccessful, an abdominal binder may be helpful. Investigation for leaks is evolving. Lumbar puncture alone seems counterintuitive, while indium-​111-​labelled DPTA (diethyl aminetriaminepentaacetic acid) cerebrospinal fluid studies have a high false negative rate in practice, although they can demon- strate the site, early emptying of tracer into the bladder, or lack of progression of tracer over the cerebral convexities. Most centres would now do spinal T2-​weighted MRI, and then consider either CT myelogram, or more recently some radiologists are using intra- thecal gadolinium with MRI. If a leak is identified, an autologous blood patch is usually curative. In more intractable situations where as leak is not identified theophylline is a useful alternative that offers outpatient management, although its onset of action is rather slow. Raised cerebrospinal fluid pressure headache As is the case for low cerebrospinal fluid pressure states, raised cere- brospinal fluid pressure as a cause of headache is well recognized by neurologists. Brain imaging can often reveal the cause, such as raised pressure due to a space-​occupying lesion. The particular setting in which patients enter the spectrum of NDPH are those with idio- pathic intracranial hypertension who present with headache without visual problems, particularly with normal fundi. It is recognized that intractable chronic migraine can be triggered by persistently raised intracranial pressure. These patients typically give a history of gener- alized headache that is present on waking, and gets better as the day goes on. It is generally worse with recumbency. Visual obscurations are frequently reported. Fundal changes on raised intracranial pres- sure would make the diagnosis relatively straightforward, but it is in those without such changes that the history must drive the investi- gation. Patients often report a curious whooshing sensation in the occipital region. Brain imaging is mandatory if raised pressure is suspected, and it is most simple in the long run to obtain an MRI scan, and include MR venography (MRV). The cerebrospinal fluid pressure should be measured by lumbar puncture, taking care to do so when the pa- tient is symptomatic, so that both the pressure and response to re- moval of cerebrospinal fluid can be determined. A raised pressure and improvement in headache with removal of cerebrospinal fluid are diagnostic of the problem. The fields should be formally docu- mented even in the absence of overt ophthalmic involvement. Initial treatment can be with acetazolamide (250–​500 mg twice daily). The patient may respond in weeks with improvement in headache. If this is not effective topiramate has many actions that may be useful in this setting: carbonic anhydrase inhibition, weight loss, and neur- onal membrane stabilization probably through actions on phos- phorylation pathways. A small number of severely disabled patients who do not respond to medical treatment will come to intracranial pressure monitoring and even shunting. In patients who are over- weight, some would advocate bariatric surgery at this point. This is an evolving area. Post-​traumatic headache The issue of post-​traumatic headache is vexed. The Headache Classification Committee accepts the existence of such a syn- drome. Much of the scientific discussion becomes marred by the often-​quoted medicolegal morass concerning delayed effects of head injury. Recent military experience suggests that even mild trauma can produce headache and through this sad path the condition is be- coming more widely investigated. The term is used here to indicate trauma in a very broad way. NDPH may be seen after a blow to the head but more commonly after an infective episode, typically viral, or even malarial meningitis. A recent series identified that one-​third of all patients with NDPH reported the headache starting after an influenza-​like illness. The patient may note a period in which they had a significant infection: fever, neck stiffness, photophobia, and marked malaise. The headache starts during that period and never stops. Investigation reveals no current cause for the headache. It has been suggested that some patients with this syndrome have a per- sistent Epstein–​Barr virus infection, but this syndrome is anything but clearly delineated. A complicating factor will often be that the patient had a lumbar puncture during that illness, so a persistent low cerebrospinal fluid volume headache needs to be considered first. Post-​traumatic headache may be seen after carotid artery dissection, subarachnoid haemorrhage, and following intracranial surgery for a benign mass. The underlying theme seems to be that a traumatic event involving the dura mater can trigger a headache process that lasts for many years after that event. The treatment of this form of NDPH is substantially empir- ical. TCAs, notably amitriptyline, and anticonvulsants, valproate, topiramate, and gabapentin, have been used with good effects. The monoamine oxidase A inhibitor phenelzine may also be useful in carefully selected patients. On the positive side, the headache seems to run a limited course of 3–​5 years in most patients, so will eventu- ally settle. It can certainly be very disabling in that period. Other important forms of secondary headache See Box 24.8.4. Giant cell arteritis This is an important cause of headache because delay in steroid treatment may result in blindness due to retinal artery ischaemia. It is also known as temporal arteritis or cranial arteritis. Patients are usually older with focal tenderness of the scalp, which may be pro- voked markedly by resting the head on the pillow. Jaw claudication provoked by chewing is a characteristic, but relatively uncommon, feature. Constitutional symptoms are common, particularly weight loss, malaise, or polymyalgia rheumatica. An elevated erythrocyte sedimentation rate (ESR) is a strong pointer to the diagnosis. The temporal artery may be tenderly inflamed, swollen, or pulseless. On suspicion of this diagnosis, corticosteroid treatment should be started pending the result of temporal artery biopsy. Treatment is very often long term and requires careful monitoring for reactiva- tion and the side effects of corticosteroids. Cervicogenic headache It is a time-​honoured concept that the neck is responsible for many headaches. Unfortunately, as with much of history, the good story is often ruined by the facts. Although there is little doubt that there is a rich overlap between the innervation of intracranial pain-​producing structures by the ophthalmic division of the trigeminal nerve, and the posterior fossa and high cervical innervation by branches section 24  Neurological disorders 6004 especially of the C2 dorsal root, causality is another issue. The Headache Classification Committee recognizes that head pain can arise from the neck and labels this ‘cervicogenic headache’. The term has been used by others to define a syndrome that is so poorly de- scribed as to be useless in practice. Most patients with neck discom- fort and headache referred to specialty practice have migraine. They will have neck stiffness or discomfort as a premonitory symptom that can clearly persist in all stages of the attack. They may respond to local therapies, such as greater occipital nerve injection; how- ever, this implies no more than triggering, and is to be expected. The pursuit of neck pathology and the treatment of patients with migraine by manipulative or physical means have no support in the controlled literature, and are rarely of long-​lasting value. FURTHER READING Afridi S, et al. (2005). A PET study in spontaneous migraine. Arch Neurol, 62, 1270–​5. Afridi S, et al. (2005). A PET study exploring the laterality of brain- stem activation in migraine using glyceryl trinitrate. Brain, 128, 932–​9. Afridi SK, et al. (2006). Greater occipital nerve injection in primary headache syndromes—​prolonged effects from a single injection. Pain, 122, 126–​9. Akerman S, et al. (2011). Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci, 12, 570–​84. Andlin-​Sobocki P, et  al. (2005). Cost of disorders of the brain in Europe. Eur J Neurol, 12, 1–​27. Andreou AP, Shields KG, Goadsby PJ (2010). GABA and valproate modulate trigeminovascular nociceptive transmission in the thal- amus. Neurobiology of Disease, 37, 314–​23. 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Long-​term follow up of 71 patients with thunderclap headache mimicking subarachnoid haemorrhage. Lancet, ii, 68–​70. 24.9 Brainstem syndromes 6006 David Bates 24.9 Brainstem syndromes 6006 David Bates ESSENTIALS Brainstem syndromes typically cause ipsilateral cranial nerve lesions and contralateral long tract signs. They are commonly due to brain- stem ischaemia, but can also be caused by neoplasia, demyelination, infective, and hamartomatous lesions. Imaging, ideally with mag- netic resonance imaging rather than computed tomography, is ob- ligatory and only then—​and possibly following other investigations to identify systemic abnormality or cerebrospinal fluid changes—​can appropriate therapy be introduced. Particular brainstem syndromes These include:  (1) Thalamic syndrome—​typically presents with unpleasant dysaesthetic burning pain, often following a hemi- plegic and hemianaesthetic stroke. First-​line treatment is with centrally acting analgesic agents (e.g. amitriptyline). (2) Midbrain syndromes—​characterized by contralateral long tract signs and ip- silateral defects of the third and fourth cranial nerves. (3) Pontine syndromes—​present with ipsilateral cerebellar signs, abnormal- ities of ocular movements, and contralateral paralysis and impair- ment of sensation, with details of the deficits depending on the location of the lesion within the pons. (4) Medullary syndromes— ​(a) medial—​causes paralysis of the tongue on the side of the lesion, with contralateral paralysis of the arm and leg, and impaired pro- prioception over the contralateral half of the body; (b) lateral—​ causes ipsilateral Horner’s syndrome, vocal cord paralysis, limb ataxia and sensory loss, oscillopsia and nystagmus, and contralat- eral impairment of pain and thermal sensation. Introduction The classic presentation of brainstem syndromes, including the long tracts and deficits of cranial nerve nuclei, commonly causes crossed cranial nerve and motor or sensory long tract deficits; the cranial nerve lesions are ipsilateral to the lesion and the long tract signs are contralateral. It is important to assess the extracra- nial vascular supply to the posterior circulation, especially to listen for bruits over the subclavian vessels and to record the pulse and blood pressure in both upper limbs, remembering that the vertebral arteries arise from the subclavian vessels. Apart from the cranial nerve and long tract deficits, there may be ataxia, vertigo, the pres- ence of an internuclear ophthalmoplegia and unreactive pupils, the symptoms of diplopia and oscillopsia, and the finding of nystagmus or ocular paresis. The circulation to the brainstem is supplied by the vertebral ar- teries, which are the main arteries to the medulla, and then the basilar artery, which supplies the pons and midbrain. The vertebral arteries are frequently asymmetrical and commonly give rise to the large posteroinferior cerebellar arteries shortly before they join to form the basilar artery. The vertebral arteries are susceptible to trauma within the cervical spine, but the most common lesion affecting the vertebral arteries is dissection, which is probably underrecognized, and thrombosis. The basilar artery branches are paramedian, supplying the area of the pons close to the midline, the short circumferential branches that supply the lateral two-​thirds of the pons, the long circumfer- ential branches that are the supero and anteroinferior cerebellar arteries, and several interpeduncular branches that arise at the bi- furcation of the basilar artery and supply the subthalamic and high midbrain regions. Strokes in the posterior circulation account for 20% of all is- chaemic cerebrovascular disease. Although most brainstem syn- dromes are due to vascular or inflammatory demyelinating lesions, an increasing proportion are shown on magnetic resonance imaging (MRI) to be due to cavernomas, which may or may not calcify and which were impossible to diagnose before modern imaging. The management of such cavernomas is difficult and may involve sur- gery or stereotactic radiotherapy. A small proportion of lesions in the brainstem are infective and inflammatory; occasionally a causa- tive organism, commonly an adenovirus, can be identified, and may be seen as a complication of AIDS; when no identifiable infective agent is identified, the condition is termed ‘Bickerstaff’s encephalitis’. The brainstem syndromes Diencephalic syndrome Commonly seen in children under the age of 3 years, Russell’s syn- drome consists of emaciation with increased appetite, euphoria, 24.9 Brainstem syndromes David Bates 24.9  Brainstem syndromes 6007 vomiting, and excessive sweating. There may also be motor hyper- activity. The differential diagnosis includes hyperthyroidism, dia- betes mellitus, a tumour in the region of the fourth ventricle, such as a malformation of the great vein of Galen, and a hypothalamic tumour. There can often be optic atrophy and rarely nystagmus. Investi­ gation may show an elevated serum growth hormone and an MRI will show a hypothalamic mass lesion. Although contraindicated if there is a significant structural pathology, the cerebrospinal fluid may contain malignant cells or an excess of human chorionic gonadotropin in the case of germinoma. Thalamic syndrome Originally described by Dejerine and Roussy in 1906, thalamic pain has a particularly distressing quality. Sometimes spontaneously, but commonly after a recognized hemiplegic and hemianaesthetic stroke, the patient develops altered sensation in a hemisensory distribution together with unpleasant dysaesthetic burning pain (thalamic pain). The pain may be worsened by stimulation and is as- sociated with hemianaesthesia, sometimes proprioceptive loss, and some evidence of hemiparesis. Anatomically the lesion is usually in the ventroposterolateral nucleus of the thalamus and is commonly caused by either a vascular event or a tumour. The investigation required is imaging and therapy is with centrally acting analgesic agents, such as amitriptyline, carbamazepine, gabapentin, and pregabalin. When pain is intractable, deep brain stimulation to the ventroposteromedial nuclei may be considered. Tectal deafness There is a rare syndrome associated with damage at the level of the inferior colliculi, due to either neoplasia or vascular lesions, which results in bilateral deafness with associated difficulty in coordin- ation, weakness, and vertigo. The condition must be differentiated from bilateral conductive hearing loss, cochlear disorders, bilateral cranial nerve VIII lesions, and pure word deafness. Brain imaging will identify the lesion. Thalamic stroke syndrome Lesions affecting the thalamus are commonly vascular and arise from infarction within the distribution of the posterior commu- nicating artery, the basilar, and the anterior and posterior chor- oidal arteries. There is usually hemiparesis with hemianopia, hemianaesthesia, and sometimes hemiataxia. There is often con- fusion and disorientation, and there may be language disturbance. On occasion there may be vertical gaze ophthalmoplegia, loss of pupillary reflexes, and an inability to converge the eyes. There may also be memory impairment and, on occasions, visual perceptual disturbances are recorded. Midbrain syndromes Damage to areas of the midbrain is characterized by long tract signs contralateral to the lesion with defects of cranial nerves III and IV ipsilaterally. They may occur with lesions in the brainstem or as the evolution of symptoms of rostrocaudal deterioration associated with supratentorial brain swelling (Figs. 24.9.1 and 24.9.2). They are characterized by ipsilateral cranial nerve III and IV palsies together with contralateral hemiparesis, loss of vibration, proprioception, and stereognosis, contralateral loss of pain and temperature, and an ipsilateral Horner’s syndrome. Ataxia may occur and there can be eyelid ptosis, diplopia, supranuclear horizontal-​gaze paresis, and an internuclear ophthalmoplegia. The association of an ipsilateral oculomotor palsy with a crossed hemiplegia due to a lesion at the base of the midbrain is called Weber’s syndrome. Claude’s syndrome causes an ipsilateral oculomotor palsy with contralateral cerebellar ataxia and tremor, and is due to a lesion in the tegmentum of the midbrain involving the red nucleus and nerve III nucleus. Benedikt’s syndrome also involves the tegmentum of the midbrain, resulting in an oculomotor palsy with contralateral cerebellar ataxia, tremor, and corticospinal signs; it can be regarded as a combination of Claude’s and Weber’s syndromes. Nothnagel’s syndrome occurs with unilat- eral or bilateral involvement of nerve III nucleus together with the superior cerebellar peduncle and causes bilateral ptosis, paralysis of gaze, and cerebellar ataxia. Damage in the region of the dorsal midbrain results in Parinaud’s syndrome in which there is paralysis of upward gaze due to damage to the supranuclear mechanisms for upward gaze, loss of accommo- dation, and fixed pupils. Although this may be seen with ischaemic lesions, it is more common with pineal tumours. Third nerve Cerebral aqueduct Middle lateral midbrain syndrome Substantia nigra Spinothalamic tract Medial lemniscus Periaqueductal gray Middle medial midbrain syndrome Medial longitudinal fasciculus Brachium of superior colliculus Midbrain reticular formation Third nucleus Edinger-Westphal nucleus Superior colliculus Pineal Medial geniculate Red nucleus Cerebral peduncle Fig. 24.9.1  Midbrain at the superior colliculus level, showing the medial and lateral territories involved with occlusive stroke in this region. Corticospinal tract Fourth nucleus Inferior lateral midbrain syndrome Medial lemniscus Spinothalamic tract Midbrain reticular formation Medial longitudinal fasciculus Inferior medial midbrain syndrome Substantia nigra Lateral lemniscus Nucleus of inferior colliculus Middle cerebellar peduncle Fig. 24.9.2  Midbrain at the inferior colliculus level showing the medial and lateral territories involved with ischaemic stroke syndromes in this area. Reprinted with permission from DeArmond SI, Fusco MM, Dewey MM, 1976, Structure of the human brain, 2nd edn. Oxford University Press, New York. section 24  Neurological disorders 6008 Pontine syndromes Lesions in the pons and medulla are commonly identified as involving either the medial or the lateral aspect of the brainstem, depending upon whether the paramedian or short circumferential vessels from the basilar have been involved. In the pons the fol- lowing three levels of damage can be identified and the basal syn- drome can occur at any level. Superior pontine syndrome The medial superior pontine syndrome results in ipsilateral cere- bellar ataxia, internuclear ophthalmoplegia, and palatal and pha- ryngeal myoclonus with contralateral paralysis of face, arm, and leg, and sometimes loss of sensation contralaterally. The lateral superior syndrome causes ataxia of the limbs and gait with dizziness, nausea, and vomiting; there is horizontal nystagmus, paresis of conjugate gaze towards the side of the lesion, loss of optokinetic nystagmus, and sometimes skew deviation of the eyes. There may also be an ip- silateral Horner’s syndrome, and there is contralateral loss of pain and thermal sensation on the face and limbs with impaired touch, vibration, and position sense (Fig. 24.9.3). Midpontine syndrome The medial, midpontine syndrome causes ipsilateral ataxia of the limbs and gait with contralateral paralysis of the face, arm, and leg, deviation of the eyes away from the lesion, and variably impaired sen- sation contralaterally. The lateral syndrome at this level causes ataxia of the limbs on the side of the lesion together with paralysis of the muscles of mastication and impaired sensation over the face on the same side due to damage to cranial nerve V (Figs. 24.9.4 and 24.9.5). Inferior pontine syndrome The medial syndrome causes paralysis of conjugate gaze to the side of the lesion, nystagmus, ataxia of limbs on the same side, and double vision on gaze to that side. Contralaterally there is paralysis of the face, arm, and leg, with impaired touch and proprioception over the opposite side of the body. The lateral syndrome involves ip- silateral, horizontal, and vertical nystagmus with vertigo and nausea, ipsilateral facial paralysis, paralysis of conjugate gaze to the side of the lesion, deafness, tinnitus, and ataxia on the side of the lesion, with impaired sensation of the face on that side. On the opposite side there is impaired sensation over half the body (Fig. 24.9.6). Basal pontine syndrome (locked-​in syndrome) Bilateral lesions of the paramedian vessels from the basilar, com- monly seen in patients with hypertension, result in infarction of the basal pontine and cause quadriplegia with loss of the ability to speak. The ascending reticular activating system is intact and Lateral superior pontine syndrome Medial lemniscus Spinothalamic tract Medial longitudinal fasciculus Corticospinal tract Medial superior pontine syndrome Lateral lemniscus Superior cerebellar peduncle Fig. 24.9.3  Superior pontine level, showing the medial and lateral territories involved with occlusive stroke in this region. Reprinted with permission from Adams RD, Victor M, 1993, Principles of neurology, 5th edn. McGraw-​Hill, New York. Fifth motor nucleus Medial lemniscus Spinothalamic tract Medial longitudinal fasciculus Corticospinal tract Middle lateral pontine syndrome Lateral lemniscus Fifth nerve Middle medial pontine syndrome Middle cerebellar peduncle Fifth sensory nucleus Superior cerebellar peduncle Fig. 24.9.4  Midpontine level, showing the medial and lateral territories involved with ischaemic stroke syndromes in this locality. Reprinted with permission from Adams RD, Victor M, 1993, Principles of neurology, 5th edn. McGraw-​Hill, New York. (b) (a) Fig. 24.9.5  MRI of a midpontine infarction. 24.9  Brainstem syndromes 6009 consciousness is therefore preserved. Vertical eye movements and eye closure are all that are possible and under voluntary control in the ‘locked-​in syndrome’. Pseudobulbar palsy Bilateral lesions of the long descending tracts in the brainstem can result in pseudobulbar palsy, although this condition is more com- monly seen with lesions higher in the cerebrum. The symptoms are those of spastic dysarthria, dysphagia, bilateral facial weakness with quadriparesis, and emotional lability. Medullary syndromes The medial medullary syndrome may occur with occlusion of the ver- tebral artery or a branch of the lower basilar artery; it causes paralysis and atrophy of the tongue on the side of the lesion with contralateral paralysis of the arm and leg but sparing the face, and impaired tactile proprioceptive sensation over the contralateral half of the body. The lateral medullary syndrome, eponymously called Wallenberg’s syndrome, occurs most commonly with dissection or occlusion of the vertebral artery, resulting in ischaemia into the posteroinferior cerebellar artery; this causes pain, numbness, and impaired sensa- tion of the ipsilateral half of the face with ataxia of limbs on that side, the symptoms of vertigo and nausea, double vision, and oscillopsia, and the signs of nystagmus. There is an ipsilateral Horner’s syn- drome, often dysphagia with paralysis of the vocal fold ipsilaterally, and loss of sensation on the arm, trunk, and leg. There is contralat- eral impaired pain and thermal sensation over half the body and possibly the face (Fig. 24.9.7). A syndrome involving ipsilateral cranial nerve VII and VI pal- sies with a contralateral hemiplegia is called the Millard–​Gubler syndrome; the involvement of cranial nerve X, causing paralysis of the soft palate and vocal fold with contralateral hemianaesthesia, is termed Avellis’s syndrome and is due to a lesion in the tegmentum of the medulla. Investigations and treatment Brainstem syndromes occurring on a vascular basis are increas- ingly easy to diagnose because of MRI and MR angiography. Once a brainstem lesion is suspected, its detection and identification will require neuroimaging, preferably by MR techniques including diffusion weighted imaging and perfusion studies. The use of newer techniques in computed tomography (CT) imaging with dual energy and iterative reconstruction makes CT perfusion more usable and both MRI and CT complement interventional radiology. Interventional angiography may be used to direct the delivery of fibrinolytic agents, attempt the rescue of an embolus, or stent a narrowed portion of the vertebral or basilar artery but such techniques remain the subject of controlled trials and benefit is not yet established. Other investigations (e.g. to search for systemic disease including vasculitis), immunodeficiency, or sources of emboli, may also be re- quired. Vascular lesions within the brainstem often carry a remark- ably good prognosis, but, if the syndrome appears to be evolving, the possibility of anticoagulation must be considered. In those lesions in which damage affects the medulla, it may be important to protect the airway and avoid aspiration during the early phases of the illness. FURTHER READING Adams RD, Victor M (1989). Principles of neurology, 4th edition. McGraw-​Hill, New York, NY. Caplan LR (1988). Vertebrobasilar system syndromes. In: Vinken PJ, Bruyn GW, Klawans HL (eds) Handbook of clinical neurology, pp. 390–​3. Elsevier, Amsterdam. Chimowitz MI (2013) Endovascular treatment for acute ischaemic stroke: still unproven. N Engl J Med, 368, 952–​5. Hurley MC, et  al. (2012). Neuroimaging in acute stroke:  choosing the right patient for neurointervention. Tech Vasc Interv Radiol, 15, 19–​32. Renard D, et  al. (2008). MRI-​based score for acute basilar artery thrombosis. Cerebrovasc Dis, 25, 511–​6. Medial lemniscus Cerebellum Medial longitudinal fasciculus Spinothalamic tract Corticospinal and corticobulbar tracts Sixth nerve Inferior lateral pontine syndrome Inferior medial pontine syndrome Seventh nerve Eighth nerve Descending tract and nucleus of five Dorsal cochlear nucleus Seventh nucleus Eighth nuclei Paramedian pontine reticular formation Sixth nucleus Fourth ventricle Fig. 24.9.6  Inferior pons at the level of nerve VI nucleus, showing the medial and lateral territories involved with occlusive stroke in this area. Reprinted with permission from Adams RD, Victor M, 1993, Principles of neurology, 5th edn. McGraw-​Hill, New York. Medial lemniscus Medial longitudinal fasciculus Inferior olive Twelfth nerve Descending nucleus and tract of five Spinothalamic tract Lateral medullary syndrome Nucelus ambiguus Vestibular nucleus Tractus solitarius with nucleus Pyramid Twelth nucleus Medial medullary syndrome Sympathetic tract Tenth nerve Fig. 24.9.7  Cross-​section of medulla at the level of the inferior olivary complex, showing the medial and the more common lateral territory involved with ischaemic stroke in this brainstem site. Reprinted with permission from Adams RD, Victor M, 1993, Principles of neurology, 5th edn. McGraw-​Hill, New York. CONTENTS CONTENTS David Hilton- Jones 24.19.4 Metabolic and endocrin David Hilton- Jones 24.19.4 Metabolic and endocrine disorders 6334 David Hilton- Jones and Richard Edwards section 24  Neurological disorders 6334 Myotonic dystrophy type 2 (DM2) Despite the similarity in name, and overlapping clinical features, there should generally be little difficulty distinguishing this condi- tion from DM1. There appears to be remarkable variability in the in- cidence of this disorder between countries, only partly explained by missed or failed diagnosis of the condition. Thus, in Germany DM2 appears to be about as prevalent as DM1; it is common in North America, but only a handful of families have been identified in the United Kingdom. Similar to DM1, the underlying molecular basis is an unstable nucleotide repeat expansion in an untranslated part of a gene, the consequences of which seem to be mediated through disruption of RNA metabolism. Despite the superficial similarities to myotonic dystrophy, there are also differences. Onset, or at least presentation, is usually in mid-​adult life. Muscle pain and stiffness, particularly affecting the thighs, are common, and are sometimes the presenting symptoms. The pattern and distribution of myotonia are similar to DM1, but, in contrast to DM1, early proximal weakness is usually evident, but hand weakness may also be prominent. Cataracts may be indistin- guishable from those seen in myotonic dystrophy. Cardiac conduc- tion problems appear to be less common. Male hypogonadism and deafness occur. A congenital form of DM2 has not been described. Cognitive involvement appears to be rare and excessive daytime sleepiness does not appear to be a major feature. FURTHER READING Myotonic dystrophy type 1 Brook JD, et  al. (1992). Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat in the 3′ end of a transcript encoding a protein kinase family member. Cell, 68, 799–​808. Gagnon C, et al. (2010). Health supervision and anticipatory guidance in adult myotonic dystrophy type 1. Neuromuscular Disorders, 20, 847–​51. Harper P (2001). Myotonic dystrophy, 3rd edition. W.B. Saunders, London. Harper P, et al. (2004). Myotonic dystrophy: present management, future therapy. Oxford University Press, Oxford. Reardon W, et al. (1993). The natural history of congenital myotonic dystrophy: mortality and long term clinical aspects. Arch Dis Childh, 68, 177–​81. Turner C, Hilton-​Jones D (2014). Myotonic dystrophy:  diagnosis, management and new therapies. Curr Opin Neurol, 27, 599–​606. Myotonic dystrophy type 2 Day JW, et al. (2003). Myotonic dystrophy type 2: molecular, diag- nostic and clinical spectrum. Neurology, 60, 657–​64. Meola G, Cardini R (2015). Myotonic dystrophies: an update on clin- ical aspects, genetics, pathology and molecular pathomechanisms. Biochimica et Biophysica Acta, 1852, 594–​606. Ranum LPW, et al. (1998). Genetic mapping of a second myotonic dystrophy locus. Nat Genet, 19, 196–​8. Molecular basis of myotonic dystrophy Machuca-​Tzili L et al. (2005). Clinical and molecular aspects of the myotonic dystrophies: a review. Muscle Nerve, 32, 1–​18. Treatment Logigian E, et  al. (2010). Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1. Neurology, 74, 1441–​8. 24.19.4  Metabolic and endocrine disorders David Hilton-​Jones and Richard Edwards† ESSENTIALS Disturbances of the biochemical or ionic balance of muscle re- sulting in impaired muscle function can be caused by a disparate group of conditions, including primary inherited disorders af- fecting enzymes or ion channels, and secondary disorders in which metabolic or endocrine disequilibrium disturbs normal function. Primary metabolic myopathies The primary metabolic myopathies are mostly autosomal recessive disorders in which lack of activity of a specific enzyme impairs ad- enosine triphosphate generation. Clinical presentation is with exer- cised-​induced symptoms, but there are fundamental differences in manifestations depending upon whether the enzyme defect affects glycogen/​glucose metabolism or fatty acid metabolism, reflecting the very different contributions that these pathways make to energy production depending on the nature of the exercise. Disorders of glycogen and glucose metabolism—​these include: (1) Myophosphorylase deficiency (McArdle’s disease)—​the most common (but still very rare) glycogenosis; symptoms usually start in childhood, but are often not recognized at that time; cardinal features are pain, weakness, and stiffness of muscles early in exercise, relieved by rest; strenuous exercise may precipitate rhabdomyolysis and acute kidney injury. Diagnosis is established by histochemical demonstra- tion of the absence of phosphorylase staining (or by enzyme assay) on muscle biopsy, or by genetic studies. There is no specific treatment. (2) Acid maltase deficiency—​typically presents with a slowly progres- sive, painless, proximal myopathy; diaphragmatic involvement is common and can lead to presentation with respiratory failure; there are no exercise-​induced symptoms. Enzyme replacement therapy may benefit some patients. (3)  Other conditions—​these include debrancher enzyme deficiency and phosphofructokinase deficiency. Disorders of fatty acid metabolism—​these include: (1) Carnitine palmitoyltransferase deficiency—​symptoms are precipitated by sustained exercise (e.g. long-​distance running) or prolonged fasting, and severe episodes may precipitate rhabdomyolysis and acute kidney injury; diagnosis requires enzyme assay; treatment with a high-​carbohydrate, low-​fat diet may reduce the number of attacks. (2) Other conditions—​numerous defects of β-​oxidation. †  Sadly, Professor Edwards died after completion of the original script. 24.19.4  Metabolic and endocrine disorders 6335 Secondary metabolic and endocrine myopathies Endocrine myopathies—​nearly all forms of endocrine disturbance can be associated with weakness, typically relatively mild and involving the proximal muscles. The most common are Cushing’s syndrome (including iatrogenic steroid excess), and hypo-​ and hyperthyroidism. Weakness resolves when the hormone imbalance is corrected. Disorders of calcium, vitamin D, and parathyroid hormone metabolism—​myopathy is a feature of osteomalacia, primary hyper- parathyroidism, renal osteodystrophy, dialysis osteodystrophy, and ischaemic myopathy. Other conditions—​(1) Alcohol excess—​alcoholics frequently have muscle weakness, but it is often unclear whether the primary cause is myopathic or neuropathic. Alcoholic rhabdomyolysis typically follows a binge. (2) Drug-​induced myopathies—​the most common cause seen in clinical practice is statins. Skeletal muscle channelopathies These rare inherited disorders affect muscle membrane ion chan- nels, resulting in altered electrical characteristics:  (1) periodic paralysis—​underlying mutations affect either the sodium or cal- cium channels; manifest with episodic weakness; (2)  myotonic dystrophies—​see Chapter  24.19.3; (3)  malignant hyperthermia—​ caused by mutations in the calcium channel associated ryanodine receptor; muscle relaxants and anaesthetic agents may trigger gen- eralized muscle contraction with rapid rise in body temperature that can be fatal if untreated. Introduction This section deals with disorders of voluntary muscle that arise as the result of either a disturbance of muscle metabolism or dis- ordered ion flux. In many cases precise mechanisms have yet to be defined. The term ‘metabolic myopathy’ is applied to those disorders in which there is a primary defect, usually an enzyme deficiency, in the biochemical pathways associated with energy generation (adeno- sine triphosphate or ATP synthesis). This group includes the mito- chondrial disorders, which are some of the most common causes of primary metabolic myopathy seen in clinical practice. Endocrine myopathies and nutritional and toxic myopathies, including those that are drug induced, can be considered as sec- ondary (acquired) metabolic myopathies. Defects in genes coding for subunits of the skeletal muscle so- dium and calcium channels underlie primary hyperkalaemic and hypokalaemic periodic paralysis, respectively. Both autosomal dominant and autosomal recessive myotonia congenita are caused by mutation in the skeletal muscle chloride channel. Mutations affecting two skeletal muscle calcium channels, the dihydropyridine (DHPR) and ryanodine (RYR1) receptors, are associated with malignant hyperthermia (MH). The congenital myopathy cen- tral core disease is allelic to MH and is associated with RYR1 mutations. The cardinal symptoms of myopathy are weakness, fatigue and/​ or pain; altered excitability may also occur. It is important that the physician appreciates several points. There are non​specific effects, such as loss of muscle, which may be far more important as a cause of weakness than the energetic consequences of the biochemical defect. Visual inspection and circumference measurements tend to underestimate the extent of wasting, which may be better docu- mented by quantitative scanning methods (MRI or CT). Not all the biochemical abnormalities cause symptoms. Clinical expression of the underlying defect depends on the habitual de- mands on the muscle for movement and weight lifting. A patient with a metabolic myopathy may have common, non-​ myopathic, musculoskeletal complaints that have no relation to the inherited or acquired defect. Muscle symptoms may have no physiological connection with the underlying defect and may be consequences of somatization or other psychological processes. The practical assessment of metabolic myopathy should in- clude consideration of the World Health Organization’s (WHO’s) International classification of impairments, disabilities, and handi- caps (ICIDH-​2) (2000)—​a classification of the functioning and dis- ability criteria of impairment, activities, and participation (revised from the ICIDH of the WHO from 1980). In this generic consid- eration, the relationship between antigravity muscle strength and the body weight to be carried is crucial: performance may be im- proved as much or more by weight reduction as by therapeutic at- tempts to reverse the myopathy, provided that calorie restriction does not aggravate the metabolic defect (e.g. in the case of carnitine palmitoyltransferase deficiency, where carbohydrate starvation may exacerbate the energy supply problem of the underlying enzyme defect). An objective assessment of a response to treatment requires the measurement of individual muscle strength and/​or timing of the performance of tasks relevant to the patient’s symptoms, and the everyday life demands placed on the diseased muscles. Metabolic myopathies are unusual or rare conditions that are very variable in presentation. They are not easy to discuss in the light of current, evidence-​based healthcare philosophies, which are largely based on the results of randomized controlled trials (RCTs) of therapeutic interventions. The treatments of the metabolic my- opathies tend to fall under the general rubric of ‘orphan drugs’ and ‘orphan diseases’, because, as with other rare diseases, a commercial return on the investment in research and development to deliver effective treatments is unlikely. Furthermore, in view of their rarity, there is little or no chance of formal treatment evaluation by RCTs. These conditions are, therefore, still to be evaluated by thoughtful clinical research employing the most relevant modern biochemical and physiological approaches. The patient with a metabolic myopathy is a person and, there- fore, far more important and complex to understand and help than the underlying metabolic diagnosis, difficult though that may be. It is essential to the humane and effective management of such a patient to see the individual as coping in a personal and social sense despite the metabolic impairment. The aim is to determine what is likely to best improve the patient’s overall quality of life. Here, as with other disabilities, the constructive analysis and re- commendations of the WHO are useful as a basis for working with the patient to determine an individual management plan (Table 24.19.4.1). section 24  Neurological disorders 6336 Primary metabolic myopathies The principal energy currency of living cells is ATP. Whereas in most organs the rate of ATP utilization is fairly constant, in volun- tary muscle the change from rest to strenuous activity may increase the demand on ATP generation several thousandfold. If that de- mand is not met, contractile failure (i.e. fatigue or weakness) will develop and may be accompanied by the destruction of muscle fibres. In many of the primary metabolic myopathies it is often as- sumed that exercise-​induced symptoms relate to a failure of ATP generation and, although this is probably not always correct, it is a useful generalization. Although exercise-​induced symptoms are often a striking feature of this type of metabolic myopathy, they are not always present. Some patients develop a chronic progressive myopathy. The main fuels providing energy for ATP generation in skeletal muscle are glycogen, fatty acids, and glucose (Fig. 24.19.4.1). Their relative contributions depend upon the state of nutrition and, more importantly, the level and duration of exercise. A gross oversimplifi- cation of these pathways aids understanding of the clinical features of the different forms of metabolic myopathy. At rest, the main fuel source is circulating free fatty acids, with a lesser contribution from circulating glucose. Small amounts of ATP may be generated directly from glycolysis, but the production of the energy-​rich electron carriers (reduced nicotinamide adenine dinucleotide or NADH and reduced flavin adenine dinucleotide (FADH2) from fatty acid β-​oxidation, and the citric acid cycle) is more important. Transfer of electrons to molecular oxygen through the electron transport chain of the mitochondria releases energy for the generation of ATP (oxidative phosphorylation). The increased demand on ATP generation during early strenuous exercise cannot be met by oxidative pathways. The resting blood flow provides an inadequate delivery of oxygen and substrate, and compression of blood vessels by the contracting muscle exacerbates the problem. ATP is therefore generated by the breakdown of muscle fibre stores of glycogen (anaerobic glycolysis). The relative lack of oxygen leads to increasing levels of NADH and pyruvate. NADH accumulation would inhibit glycolysis, and thus ATP generation, and is avoided by the reduction of pyruvate to lactate, explaining the lactic acidosis seen in disorders of oxidative metabolism. Adaptive processes occur as exercise continues; muscle blood flow increases, the respiratory rate rises, and free fatty acids are mobilized from adipose stores. Glycogen stores in muscle become depleted and circulating free fatty acids become the main energy source, with a very small contribution from circulating glucose. Certain deductions can be made from the aforementioned that are largely borne out in clinical practice. Disorders of glycogen and glucose metabolism are typically asymptomatic at rest, but produce symptoms early in exercise when anaerobic glycolysis is important for energy supply. If low levels of exercise can be sustained, symptoms can improve as fatty acid oxidation increases (‘second wind’ phe- nomenon in McArdle’s disease). Disorders of fatty acid metabolism, Table 24.19.4.1  Key features of disability evaluation and management in metabolic myopathy Body Person Society Impairment Activities (limitations) Participation (restriction) Metabolism/​function/​structure Severity, localization, duration Difficulties, duration, assistance needed Extent, facilitators, environmental demands of barriers Harmful consequences, e.g. myoglobinuria, falls Physical and mental adaptive responses Positive or negative psychosocial factors Treatment options: modification of chemistry by diet or drugs? Counselling for exercise behaviour modification; avoidance of excessive weight gain; mechanical solutions, e.g. wheelchair/​bicycle Better popular understanding of side effects of prescription drugs and alcohol; positive attitudes to assisting those with locomotor disability, improved access Developed from World Health Organization (2000). International classification of functioning and disability ICIDH-​2. Geneva, WHO. Available at: http://​www3.who.int/​icf/​icftemplate. Glucose Blood Free fatty acids Glycogen Cytosol ATP NADH NAD NADH ATP CoA Fatty acyl-CoA Carnitine CoA CPT I CPT II PDH β-oxidation Acetyl-CoA Fatty acyl-CoA FADH2 NADH TG droplets Mitochondrial matrix NAD FAD ATP H2O NADH FADH2 ADP O2 Pyruvate Lactate Intermembrane space Plasma membrane Outer mm ACAS PT Inner mm C R CoA FAC FADH2 NADH Krebs’ cycle Fig. 24.19.4.1  Major pathways associated with energy production in skeletal muscle. ACAS, acyl-​CoA synthetase; ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; CPT, carnitine palmitoyl transferase; FAC, fatty acylcarnitine; FAD, flavin adenine dinucleotide; FADH2, reduced FAD; mm, mitochondrial membrane; NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; PDH, pyruvate dehydrogenase complex; PT, pyruvate translocase; RC, respiratory chain; TG, triglyceride. 24.19.4  Metabolic and endocrine disorders 6337 insufficient to cause symptoms at rest, are likely to be exposed by sustained exercise and fasting. The central role of oxidative phos- phorylation explains why disorders of the respiratory chain may be symptomatic at rest. The clinical presentation will also depend upon whether the enzyme defect is restricted to skeletal muscle or is more generalized, thereby causing dysfunction of other tissues and organs. Systemic features may dominate in disorders of β oxidation and in mitochondrial disorders, but are absent in McArdle’s disease because the defective enzyme is muscle specific. Disorders of glycogen and glucose metabolism (See also Chapter 12.3.1.) Several of the glycogenoses show significant skeletal muscle in- volvement. The major pathways of metabolism, and the enzymes associated with these disorders, are shown in Fig. 24.19.4.2. They are autosomal recessive disorders, except for the X-​linked reces- sive, phosphoglycerate kinase deficiency. In most of these disorders serum creatine kinase (CK) is elevated at rest, and massively so after exercise-​induced muscle damage. Acid maltase deficiency (type II glycogenosis) Acid maltase is a lysosomal enzyme not directly involved in ener- getic pathways, and exercise-​induced symptoms are absent. In the infantile form (Pompe’s disease) there is widespread organomegaly as well as skeletal muscle involvement, and death occurs by the age of 2 years due to cardiac or respiratory failure. The adult form is of considerable importance and has probably been underdiagnosed. The most obvious feature is a slowly progressive, painless, proximal myopathy. Diaphragmatic involvement is an important character- istic, and some of these patients first present with respiratory failure. Nocturnal non​invasive ventilation alleviates sleep-​disordered breathing and may prolong survival for many years. Serum CK ac- tivity is usually moderately elevated, but can be normal. Muscle bi- opsy typically shows acid phosphatase positive, glycogen-​containing vacuoles, but is often normal, or shows only non​specific changes. If the diagnosis is suspected, it can readily be proven or excluded by a recently developed, cheap, enzyme assay that uses a dried blood spot. DNA analysis is available but is not undertaken routinely in most centres. Enzyme replacement therapy has been shown to be effective in the severe infantile form, substantially prolonging survival. In the late-​onset form, the evidence of benefit remains limited, and has to be considered against the enormous cost of treatment. Myophosphorylase deficiency (type V glycogenosis—​McArdle’s disease) The onset of symptoms is usually during childhood, although they are often not recognized at that time, and the cardinal features are pain, weakness, and stiffness of muscles early in exercise, relieved by rest. The prevalence is estimated to be around 1 in 100 000 population but many cases are undiagnosed. Strenuous exercise, such as helping to push a car or lift heavy furniture, may induce painful, muscle con- tractures (if electrophysiological studies could be performed, the contractures would be noted to be electrically silent, unlike the con- tractures associated with cramps which are due to high-​frequency nerve discharge). Muscle fibre breakdown is reflected in myalgia and myoglobinuria (dark red/​black urine), which, if severe, may cause renal failure. Muscle breakdown is accompanied by a large release of CK into the blood, and a failure to see such a rise in serum CK levels should cast doubt on a diagnosis of myoglobinuria. Conversely, if renal failure is present, then no myoglobinuria may be seen and the only evidence of rhabdomyolysis is the raised CK level. Exercise-​in- duced symptoms may ease (‘second wind’ phenomenon) if low levels of activity are maintained, as circulating free fatty acids and glucose become available as alternative fuels. Even when at rest, and asymp- tomatic, the serum CK activity level is usually moderately elevated. GLYCOGEN UDPG Phosphorylase Limit dextrin Debrancher enzyme Glucose 1-phosphate Fructose 6-phosphate Fructose 1,6-diphosphate Phosphofructokinase Glyceraldehyde 3-phosphate 1,3-Diphosphoglycerate Phosphoglycerate kinase 3-Phosphoglycerate Phosphoglycerate mutase 2-Phosphoglycerate Pyruvate Lactate Lactate dehydrogenase Lysosomal acid maltase GLUCOSE Glucose 6-phosphate Fig. 24.19.4.2  Pathways of glycogenolysis and glycolysis. Enzymes known to be associated with particular clinical syndromes are shown. section 24  Neurological disorders 6338 Progressive proximal weakness frequently develops in middle age and is sometimes the mode of presentation in late-​onset cases. Failure of lactate generation (accompanied by increased blood ammonia and hypoxanthine concentrations) during forearm exer- cise is consistent with the diagnosis. However, this is not specific because it also occurs in other glycogenolysis disorders, and may be seen to some extent in acquired conditions such as alcoholic myop- athy or hypothyroidism. Also, the test may give a misleading (‘false-​ negative’) result if the myophosphorylase deficiency is only partial. The definitive diagnosis is established by histochemical demonstra- tion of the absence of phosphorylase staining (or by enzyme assay) on muscle biopsy, or by genetic studies of the coding and expression of muscle phosphorylase. Debrancher enzyme deficiency (type III glycogenosis—​Cori–​ Forbes disease) In infancy and childhood, the main features of this disorder are hepatomegaly, hypoglycaemia, and failure to thrive. During ado- lescence muscle symptoms become more prominent. A small group of patients first present during adult life with muscle symptoms, but may give a history of a protuberant abdomen in childhood. Both exercise intolerance (although less striking than in McArdle’s disease) and a slowly progressive proximal myopathy are present. Some patients develop a potentially fatal cardiomyopathy. The forearm exercise test shows impaired, but not absent, lac- tate generation, muscle biopsy shows glycogen accumulation, and the administration of glucagon fails to produce a hyperglycaemic response. The definitive diagnosis is established by enzyme assay in samples of muscle, liver, erythrocytes, and leucocytes. Phosphofructokinase deficiency (type VII glycogenosis—​Tarui’s disease) The clinical picture is very similar to that of myophosphorylase defi- ciency, but a phosphofructokinase (PFK) deficiency in erythrocytes leads to the additional features of haemolytic anaemia and gout. It is very much rarer than myophosphorylase deficiency. Unlike patients with myophosphorylase deficiency, ingested glucose does not im- prove exercise tolerance in those with PFK deficiency because of the position of PFK in the sequence of enzymes in the glycolytic pathway (see Fig. 24.19.4.2), and indeed may worsen symptoms (sometime called the ‘out-​of-​wind’ phenomenon). Diagnosis is established by enzyme assay in muscle. Defects of distal glycolysis Deficiencies of phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase have been found but are all ex- tremely rare. All three are associated with exercise intolerance and myoglobinuria. It is possible that other defects of glycolysis, causing similar symptoms, remain to be discovered. Treatment With the exception of the recent introduction of enzyme replace- ment therapy for acid maltase deficiency there is, as yet, no specific treatment for any of the disorders described here. Attempts at dietary manipulation have generally proved unsuccessful. Patients must be aware of the risk to renal function from myoglobinuria, and try to avoid intense exercise. There is evidence, in patients with muscle pain due to McArdle’s disease and other metabolic myopathies, that maintaining a reasonable level of aerobic fitness is beneficial, by sus- taining sufficient activity of muscle mitochondria to provide energy from oxidative phosphorylation to adapt to the deficiencies in en- ergy availability from glycogenolysis. Disorders of lipid metabolism Unlike glycolysis, lipid metabolism is entirely dependent on oxida- tive processes. Moreover, there is a close relationship between the disorders described next and defects of the mitochondrial respira- tory chain (e.g. lipid accumulation in muscle is a common histo- logical feature in respiratory chain disorders). Free fatty acids, mainly from the blood but also from trigly- ceride droplets stored within muscle fibres, are a major fuel at rest and during sustained exercise (see Fig. 24.19.4.1). They are con- verted to fatty acyl-​CoA at the outer mitochondrial membrane which, within the mitochondrial matrix, can undergo β oxi- dation. A transport system involving carnitine and the enzyme system carnitine palmitoyltransferase is required to enable fatty acyl-​CoA to cross the inner mitochondrial membrane. Defects involving carnitine, carnitine palmitoyltransferase, and β oxida- tion are recognized. Carnitine deficiency Secondary carnitine deficiency is common and seen in association with many primary metabolic disorders, including defects of fatty acid oxidation and respiratory chain disorders. Primary carnitine deficiency is very rare and is caused by a defective carnitine trans- porter, OCTN2. It may cause varying combinations of myopathy, hypoketotic hypoglycaemia, and hepatic encephalopathy. Defects of β oxidation Many enzyme deficiencies have been described, but clinical fea- tures are limited. They may present during the neonatal period with hypotonia, hypoglycaemia, cardiomyopathy, failure to thrive, and early death. Such defects may be a cause of some cases of sudden infant death syndrome. Later-​onset cases develop Reye’s syndrome-​ like crises, muscle weakness, and cardiomyopathy. Secondary carnitine deficiency is common. A high-​carbohydrate and low-​fat diet may help. Carnitine palmitoyltransferase deficiency This rare autosomal recessive disorder shows a male predomin- ance. It is the most common of the lipid disorders to present with myopathic features. Symptoms are precipitated by sustained exer- cise (e.g. a route march) or prolonged fasting, and consist of muscle pain followed by myoglobinuria, which may cause renal failure. The diagnosis may be strongly suggested by tandem mass spec- trometry, looking at the acylcarnitine profile, in a blood sample taken after an overnight fast, but confirmation requires enzyme assay, usually on cultured fibroblasts. A high-​carbohydrate, low-​fat diet may reduce the number of attacks. Myoadenylate deaminase deficiency Deficiency of myoadenylate deaminase has been suggested as a cause of exercise-​induced myalgia, weakness, and cramps but its exact status remains controversial. It has been described as an incidental finding in muscle needle biopsies taken from normal volunteers to study muscle chemistry in sports science research. The enzyme 24.19.4  Metabolic and endocrine disorders 6339 catalyses the reaction adenosine monophosphate (AMP) → inosine monophosphate (IMP) + ammonia (NH3). Theoretically, this re- action may aid ATP production by removing AMP and increasing flux through the adenylate kinase reaction 2ADP → ATP + AMP. The diagnosis is established from the absence of a rise in the plasma ammonia level during forearm exercise testing and from the histo- chemical demonstration of absent enzyme activity. Endocrine myopathies Although weakness is a common symptom in many endocrine dis- orders, the mechanisms are generally poorly understood. However, the myopathy responds to treatment of the underlying hormonal disorder, and extensive investigation of the myopathic component is rarely required. The most common pattern is limb-​girdle weakness. Thyroid disorders (See also Chapter 13.3.1.) Thyrotoxicosis Typically, weakness develops shortly after the onset of other thyrotoxic symptoms, and 80% of patients have demonstrable weak- ness at presentation. The shoulder girdle muscles tend to be involved before the pelvic musculature. Muscle atrophy is usually slight. Asymmetrical and distal weakness, myalgia, cramps, and fascicula- tions are rare findings. The serum CK level is usually normal, but electromyography shows features consistent with muscle disease. The myopathy re- sponds to treatment of the thyrotoxicosis. Thyrotoxic periodic paralysis Most cases have been reported in individuals from the Orient, with a strong male predominance. Clinical features closely mimic those of familial hypokalaemic periodic paralysis. The weakness is dis- proportionate to any muscle wasting. The onset of paralytic attacks usually follows the development of hyperthyroid symptoms and the attacks cease when the patient is rendered euthyroid. A genetic basis has not been established. Thyroid ophthalmopathy (Graves’ ophthalmoplegia) The classic features of this condition include eyelid lag, retraction and swelling, as well as progressive swelling of the extraocular muscles and orbital soft tissues, leading to proptosis and diplopia and, in severe cases, corneal ulceration, papilloedema, and optic at- rophy. An extremely important, but often missed, variant is the pa- tient who presents with minimal diplopia only. In mild cases, MRI or CT is useful for detecting extraocular muscle swelling. Simple tests of thyroid function may be normal. Estimation of antithyroglobulin and antimicrosomal antibodies, and the performance of a thyrotropin-​releasing hormone stimula- tion test may be required. Thyroid-​stimulating immunoglobulins are present in most patients. If thyrotoxic, the patient should be rendered euthyroid. Lid retrac- tion may respond to topical 10% guanethidine. Persisting major eye problems may require high-​dose prednisolone, plasma exchange, or orbital decompression. Tarsorrhaphy protects the cornea. Thyroid disease and myasthenia Patients with myasthenia gravis have an increased incidence of thyroid disease, including hyperthyroidism, hypothyroidism, Hashimoto’s thyroiditis, and increased antibodies to thyroglobulin or microsomal fractions. Thyroid disease may predate or follow the onset of myasthenia and must be considered as a cause of deteri- oration in an otherwise stable patient with myasthenia. Some 5% of patients with myasthenia will develop thyroid disease, but only about 0.1% of thyrotoxic patients develop myasthenia. Hypothyroidism Although hypothyroid myopathy may be asymptomatic, mild weak- ness is probably present in most patients. Muscle biopsy charac- teristically shows evidence of type II (fast twitch, glycolytic, high intrinsic force) muscle fibre atrophy with type I fibre dominance. Even in the absence of weakness the serum CK level is often mark- edly raised. Slow relaxation of the tendon jerks may be present in isolation. Muscle pain and cramps are common. In children, the combination of hypothyroidism, weakness, and muscle hypertrophy is referred to as the Kocher–​Debré–​Semelaigne syndrome. In adults, Hoffman’s syndrome describes the combination of hypothyroidism, weakness, muscle hypertrophy, cramps and myoedema (the forma- tion of a localized ridge of muscle following direct percussion). They probably represent variants of the same disorder. All hypothyroid myopathic symptoms respond to thyroxine replacement. Pituitary–​adrenal axis disorders Clinically, the most important of these is iatrogenic steroid myop- athy, discussed next under ‘Glucocorticoid excess’. Acromegaly Proximal weakness, pelvic more than shoulder girdle, is present in about half of patients. Common complaints include tiredness, weakness, and myalgia; muscle wasting is slight. Serum CK levels are normal or slightly raised. Normalizing growth hormone levels improves the myopathy, but recovery may be incomplete. Hypopituitarism Growth hormone deficiency in childhood impairs muscle and skel- etal development proportionately; weakness is not usually a fea- ture. In adults, panhypopituitarism causes generalized weakness and fatigue, which usually responds to thyroxine and cortisone replacement therapy. Replacement of growth hormone in growth hormone-​deficient adults has been associated with varying degrees of improvement in the strength of wasted muscles. Glucocorticoid excess Adrenocorticotropic hormone excess, from either a functioning pi- tuitary adenoma or ectopic production, is usually associated with high glucocorticoid levels, producing pituitary or ectopic Cushing’s syndrome. Weakness is common and thought to relate to gluco- corticoid excess. Weakness may occur in Nelson’s syndrome, in which there is a high level of adrenocorticotropic hormone, but no glucocorticoid excess. The myopathy associated with Cushing’s syndrome is prob- ably related to glucocorticoid excess, and the clinical features are section 24  Neurological disorders 6340 essentially the same as those of iatrogenic steroid myopathy. The 9α-​ fluorinated steroids, including dexamethasone, triamcinolone, and betamethasone, appear to have the greatest myopathic potential. Topical steroids can cause myopathy. The most common picture is of a slowly progressive limb-​girdle wasting and weakness, pelvic more than shoulder girdle, often ac- companied by myalgia. The drug-​induced form may have a more acute onset. Myopathy without other features of glucocorticoid ex- cess is unusual. The serum CK level is usually normal and muscle biopsy shows non​specific type II fibre atrophy. Steroid withdrawal is followed by recovery over several months. If steroid therapy for the primary disorder has to be continued, then a non​fluorinated compound such as prednisolone should be used, preferably on an alternate-​day basis. Successful treatment of Cushing’s syndrome leads to recovery. Conn’s syndrome Weakness is present in about 75% of patients and is due to the as- sociated hypokalaemia. Secondary hypokalaemic periodic paralysis may occur. Addison’s disease Weakness, fatigue, and myalgia occur in up to half of patients. Rare myopathic presentations include progressive flexion contractures and secondary hyperkalaemic periodic paralysis. The serum CK level is normal or slightly increased. Glucocorticoid replacement therapy is curative. Disorders of calcium, vitamin D, and parathyroid hormone metabolism (See also Chapter 13.4.) There are complex interactions of vitamin D metabolism, calcium and phosphate homeostasis, and parathyroid hormone activity. Myopathy occurs in several clinical situations, but the precise patho- physiological mechanisms are unclear. Osteomalacia Weakness is the presenting symptom in a third of patients, affecting predominantly the pelvic girdle musculature. Bone pain is prom- inent. The serum CK level is usually normal. Muscle biopsy may show type II fibre atrophy, sometimes severe. The pain responds fairly rapidly to vitamin D treatment, but the weakness recovers more slowly and may be incomplete. Primary hyperparathyroidism Myalgia, stiffness, and complaints of fatigue are common, but overt weakness is rare. Symptoms resolve when the underlying parathy- roid adenoma is removed and serum calcium levels fall. Renal osteodystrophy End-​stage renal failure is frequently accompanied by a predomin- antly pelvic girdle myopathy, sometimes with buttock and thigh pain. Symptoms respond to dialysis, transplantation, or vitamin D treatment. Dialysis osteodystrophy Some patients undergoing dialysis develop a severe myopathy with bone pain, fractures, and vitamin D resistance. It probably relates to aluminium toxicity. Fatigue and muscle weakness are common. Objective muscle testing is needed to distinguish true changes in muscle function from the non​specific causes of fatigue and ill-​health seen in patients on dialysis. Ischaemic myopathy Rarely, a painful ischaemic myopathy with arterial narrowing due to calcium deposition complicates renal failure. Skin ulceration and bowel infarction may also occur. Nutritional and toxic myopathies Although malnutrition causes muscle wasting, specific myopathic effects of nutritional deficiencies are uncommon, a notable excep- tion being vitamin D deficiency, discussed next. Myopathies due to ingested toxins are relatively more common than the inherited metabolic myopathies and include those due to alcohol, and thera- peutic drug excess or idiosyncrasy. Alcoholic myopathies People with chronic alcohol problems may develop subacute or slowly progressive, proximal muscle weakness with mild-​to-​ moderate wasting and muscle biopsy evidence of type II fibre at- rophy, mainly affecting the lower limbs. Occasionally the wasting is more generalized, as alcoholism may be associated with neurogenic muscle atrophy secondary to concomitant thiamine deficiency and more generalized malnutrition. It is thus still debated whether the so-​called chronic alcoholic myopathy is purely myopathic, neuro- pathic, or both, and whether the cause is a direct toxic effect of alcohol or a secondary phenomenon, perhaps relating to malnutri- tion. Abstinence may lead to some degree of recovery. Much more dramatic is acute alcoholic myopathy (‘alcoholic rhabdomyolysis’), which usually occurs during or shortly after a binge. There may be widespread cramps, pain, and weakness. However, the most striking feature is the development of ex- tremely painful muscle swelling, which may be localized or gen- eralized. Myoglobinuria presents a threat to renal function, and hyperkalaemia may be present in severe cases. The serum CK is ele- vated and muscle biopsy shows acute necrosis. Recovery, which may be incomplete, occurs over several weeks. Vitamin E deficiency Vitamin E deficiency probably causes a myopathy, but interpretation is confused by the presence of additional neurological problems including neuropathy and ataxia. Drug-​induced myopathies Drug-​induced neuromuscular disorders are common, under­ recognized and underreported. Numerous drugs have been impli- cated, several mechanisms are responsible (Table 24.19.4.2), and some drugs can affect both muscle and peripheral nerves (e.g. vincristine, d-​penicillamine, and perhexiline). Arguably the most important is statin-​induced myopathy, because myopathic symptoms are relatively common and the prescription of statins is becoming ever more wide- spread, with over-​the-​counter preparations being available in some countries. A small percentage of patients develop myalgia, usually with elevation of the serum CK, but without demonstrable weakness. 24.19.4  Metabolic and endocrine disorders 6341 The symptoms resolve on drug withdrawal. Much more rarely, statins may induce rhabdomyolysis/​myoglobinuria, and deaths have been re- ported. Risk factors include high doses of statins (e.g. >40 mg daily of simvastatin) and, probably in more than 60% of cases, concomitant use of drugs that interfere with statin metabolism (e.g. ciclosporin). Very recently evidence has emerged that statins may trigger an immune-​ mediated myopathy, with antibodies against HMGCoA reductase (the enzyme inhibited by statins), that persists on statin withdrawal but responds to immunosuppressant therapy. There remains debate as to whether a pre-​existing myopathy, symptomatic or not, or carrying a muscle disease related gene, increases the risk of stain-​induced my- opathy. Current expert advice is that statins are not contraindicated in such circumstances, but that the patient should be aware of the debate, serum CK should be measured before starting treatment and again if symptoms develop, and that the drug should be discontinued imme- diately if muscle symptoms develop. Skeletal muscle channelopathies There has been an explosion in the identification of central and per- ipheral nervous system and cardiac disorders caused by ion channel dysfunction. Ion channels may be ligand gated or voltage gated. In the field of muscle diseases, the most important ligand-​gated channel is the skeletal muscle nicotinic acetylcholine receptor, at the neuromus- cular junction. Antibody-​mediated destruction underlies acquired myasthenia gravis, whereas inherited mutations of genes coding for the subunits of the receptor are the basis of several forms of congenital myasthenic syndrome. Acquired neuromyotonia and Lambert–​Eaton myasthenic syndrome are caused by antibody-​mediated damage to the voltage-​gated potassium and calcium channels, respectively, of the terminal axon, and are discussed, together with myasthenia gravis and the myasthenic syndromes, in Chapter 24.18. The following section is concerned with inherited disorders of skel- etal muscle voltage-​gated sodium, calcium, and chloride channels. In passing, it should be noted that channelopathies are not confined to muscle, and note was made earlier of two neuronal channelopathies. Other disorders caused by an inherited channel defect include certain forms of epilepsy (nocturnal frontal lobe epilepsy, benign neonatal convulsions), episodic ataxia, hemiplegic migraine, deafness, night blindness, cardiac long QT syndromes, and nephrolithiasis. Periodic paralyses Marked hypokalaemia and hyperkalaemia from whatever cause may produce weakness or paralysis (secondary periodic paralysis). The primary periodic paralyses are familial, dominantly inherited dis- orders characterized by recurrent attacks of paralysis. These have previously been subdivided into hyperkalaemic, hypokalaemic, and normokalaemic forms on the basis of changes in the serum potas- sium level during attacks. Recent evidence has shown that the pri- mary abnormality in the hyperkalaemic and normokalaemic forms is a mutation affecting the adult skeletal muscle sodium channel, whereas the hypokalaemic form is caused by a mutation affecting the skeletal muscle calcium channel. Hypokalaemic periodic paralysis Attacks usually start during the second decade of life and then vary in frequency from daily to years between episodes. Weakness may be present on waking or develop during the day, typically in response to a heavy carbohydrate meal or during rest after strenuous exer- cise. The weakness involves the legs more than the arms, proximal muscles more than distal, and may be asymmetrical. Bulbar and re- spiratory muscle weakness is rare. Attacks last from hours to sev- eral days. The tendon reflexes may be depressed or lost during an attack. Permanent and progressive proximal weakness often develop by middle age. The serum potassium level typically falls during an attack, but not necessarily outside the normal range. The disorder is caused by a mutation in the CACNA1S gene (on chromosome 1)  encoding the DHPR component of the skeletal muscle calcium channel. The DHPR is located within the transverse tubular system, and acts as a voltage sensor for the RYR1 component of the calcium channel, which is located in the sarcoplasmic reticulum and is responsible for triggering calcium release and thus muscle con- traction. Different mutations in the same gene, and mutations in the RYR1 gene, are associated with malignant hyperthermia (see next). Table 24.19.4.2  Drug-​induced myopathies Focal damage/​fibrosis Intramuscular   Opiates   Antibiotics   Paraldehyde Necrosis Heroin Clofibrate ε-​Aminocaproic acid Myoglobinuria/​rhabdomyolysis Heroin Methadone Amphetamines Barbiturates Diazepam Isoniazid Carbenoxolone Phenformin Amphotericin B Statins Inflammatory myopathy Procainamide d​-Penicillamine Hypokalaemic weakness Diuretics Carbenoxolone Liquorice Purgatives Subacute or painless proximal myopathy Corticosteroids Chloroquine β-​Blockers Myasthenia d-​Penicillamine Aminoglycosides Malignant hyperthermia Suxamethonium Cyclopropane Halothane Enflurane Ketamine section 24  Neurological disorders 6342 Acetazolamide is the treatment of choice to prevent attacks. Acute attacks respond to oral potassium, given as an unsweetened aqueous solution. Apparently identical attacks may occur in association with thyro- toxicosis and resolve when the patient is rendered euthyroid. Hyperkalaemic periodic paralysis Attacks tend to start at an earlier age than in the hypokalaemic form, and do not last as long. Precipitants include cold, fasting, rest after exercise, pregnancy, alcohol intake, and potassium loading. Readily utilized carbohydrate sources, such as a sweet drink, may abort an at- tack. A progressive proximal myopathy may also develop. Myotonia is present in some patients (see next). The serum potassium level may rise during an attack, but the change is often slight. The underlying abnormality is a mutation within the SCNA4 gene (on chromosome 17) encoding the α-​subunit of the skeletal muscle sodium channel. Mild attacks respond to carbohydrate ingestion. Kaliuretic diur- etics usually prevent attacks. Paramyotonia congenita Paramyotonia congenita describes a dominantly inherited condition characterized by cold-​induced weakness and muscle stiffness (para­ myotonia), which is sometimes accompanied by periodic paralysis. The relationship between this disorder and primary hyperkalaemic periodic paralysis had been much debated, but recent evidence has shown that hyperkalaemic periodic paralysis, hyperkalaemic periodic paralysis with myotonia, paramyotonia congenita and paramyotonia congenita with periodic paralysis are allelic disorders involving the SCNA4 gene (on chromosome 17) encoding the α-​subunit of the skeletal muscle sodium channel. Myotonia congenita Autosomal dominant (Thomsen’s disease) and recessive (Becker-​ type) forms of this condition are recognized, with the recessive type being much more common. Onset tends to be earlier in the dom- inant form, but both usually become apparent in childhood. There is muscle stiffness, worse after rest and exacerbated by cold, minimal, or no weakness, readily demonstrable percussion myotonia, and muscle hypertrophy, which tends to be more marked in the recessive form. Both the recessive and dominant forms are caused by mutations in the CLCN1 gene (on chromosome 7) encoding the skeletal muscle chloride channel. Malignant hyperthermia The main features of this autosomal dominant disorder are a rapidly rising body temperature and generalized muscular rigidity during anaesthesia. Additional features include skin mottling, cyanosis, tachypnoea, tachycardia, cardiac dysrhythmias, and autonomic instability. Attacks in susceptible individuals may be triggered by suxamethonium and anaesthetic agents (halothane, cyclopropane, enflurane, ketamine). A  similar disorder may be associated with heavy exercise in very hot conditions (e.g. recruits undergoing route marches on mountains during a hot summer). Attacks are life-​threatening. Treatment consists of withdrawing the offending agent and providing general supportive measures and intravenous dantrolene 2 mg/​kg body weight. Disturbed calcium homeostasis underlies the attacks, with ex- cessive Ca2+ influx into the sarcoplasmic reticulum. The disorder is genetically heterogeneous. In many families the underlying abnor- mality affects the skeletal muscle calcium channel with a mutation in either the RYR1 gene (on chromosome 19) or the CACNA1S gene (on chromosome 1). RYR1 mutations may also cause central core disease (CCD)—​CCD and MH are allelic disorders and may occur together in the same individual or independently. Other CACNA1S gene mutations cause hypokalaemic periodic paralysis. Screening for MH susceptibility involves muscle biopsy and in vitro testing for a reduced contractile threshold to halothane and caffeine. It is hoped that specific molecular biological tests will be- come available. A significant practical problem is the management of family members who fear that they may be at risk. As with those patients who have suffered hyperpyrexia under anaesthesia (even in those in whom repeated exposure has not led to a consistent re- occurrence), it is advisable for those individuals of proven or sus- pected risk to wear, at all times, some form of bracelet or locket giving details of the risk, in case they are casualties in an emergency such as a road accident. Myoglobinuria This important symptom and sign must be differentiated from haematuria and haemoglobinuria. Red cells are visible on micros- copy in the former but not in the latter. In all three conditions, the haemoperoxidase stick test is positive. Myoglobin is a protein that acts as an oxygen store within skel- etal muscle fibres. Myoglobinuria causes a dark-​brown/​red dis- coloration of the urine, the main concern being that the protein can cause renal tubular necrosis and thus renal failure. Numerous disorders are known to be associated with myoglobinuria (Table 24.19.4.3). In the metabolic disorders, the presumed mechanism Table 24.19.4.3  Causes of myoglobinuria Metabolic Glycogenoses Carnitine palmitoyl transferase defi ciency Severe electrolyte disturbance Excessive activity/​ temperature Marathon running Military training Status epilepticus Malignant hyperthermia Neuroleptic malignant syndrome Drugs and toxins Several drugs (see Table 24.24.4.2) Venoms and animal toxins Infection Viral Toxic shock Clostridial infection/​gangrene Ischaemia and trauma Crush Coma Any cause of severe ischaemia Compartment syndrome Electric shock Inflammatory myopathies Dermatomyositis Polymyositis ESSENTIALS ESSENTIALS SECTION 24  Neurological disorders 5802 Neuromuscular transmission disorders Myasthenia gravis and Lambert–​Eaton myasthenic syndrome are diagnosed by single-​fibre EMG (see previously) or repeti- tive stimulation of motor nerve. The studies are carried out pref- erentially in proximal nerves such as the accessory nerve or the musculocutaneous nerve. Care is mandatory to reduce the effect of movement artefacts. At single stimulation the compound muscle ac- tion potential amplitudes are usually normal in myasthenia gravis but reduced in Lambert–​Eaton myasthenic syndrome. At slow rates of stimulation of 2–​5 Hz, decrements of the compound muscle ac- tion potential occur in both disorders. At high rates of stimulation of 20–​50 Hz or after a maximal voluntary contraction, the com- pound muscle action potential is greatly increased (facilitation) in Lambert–​Eaton myasthenic syndrome. FURTHER READING Albers JW, Kelly JJ (1989). Acquired inflammatory demyelinating polyneuropathies:  clinical and electrodiagnostic features. Muscle Nerve, 12, 435–​51. Binnie CD, et al. (1995). EMG, nerve conduction and evoked poten- tials. In:  Osselton JW (ed) Clinical neurophysiology, pp. 43–​321. Butterworth-​Heinemann Ltd, Oxford. Bouche P et al. (1999). Electrophysiological diagnosis of motor neuron disease and pure motor neuropathy. J Neurol, 246, 520–​25. Brown WF, Bolton CF (eds) (1993). Clinical electromyography I, 2nd edition. Butterworth-​Heinemann, Boston, MA. Buchthal F (1957). An introduction to electromyography. Scandinavian University Books, Copenhagen. Buchthal F (1985). Electromyography in the evaluation of muscle disease: symposium in electrodiagnosis. Neurol Clinics, 3, 573–​98. Buchthal F, Kamieniecka Z (1982). The diagnostic yield of quantified electromyography and quantified muscle biopsy in neuromuscular disorders. Muscle Nerve, 5, 265–​80. Chiappa KH (ed) (1997). Evoked potentials in clinical medicine, 2nd edition. Lippincott-​Raven, Philadelphia, PA. Crone C, Krarup C (2013). Neurophysiological approach to periph- eral nerve disorders. In: Said G, Krarup C (Vol. 115, eds 3rd series); Aminoff M, Boller F, Swaab D (series eds) Peripheral nerve disorders, handbook of clinical neurology, pp. 81–​114. Elsevier, Waltham. Fuglsang-​Frederiksen A (1981). Electrical activity and force during voluntary contraction of normal and diseased muscle. Munksgaard, Copenhagen. Fuglsang-​Frederiksen A (2000). The utility of interference pattern ana- lysis. Muscle Nerve, 23, 18–​36. Ho TW et al. (1997). Patterns of recovery in the Guillain–​Barré syn- dromes. Neurology, 48, 695–​700. Kimura J (1989). Electrodiagnosis in diseases of nerve and muscle: principles and practice, 2nd edition. FA Davis Co., Philadelphia, PA. Krarup C (1999). Pitfalls in electrodiagnosis. J Neurol, 246, 1115–​26. Magistris MR, et al. (1998). Transcranial stimulation excites virtually all motor neurons supplying the target muscle: a demonstration and a method improving the study of motor evoked potentials. Brain, 121, 437–​50. Mauguière F (1995). Evoked potentials. In: Osselton JW (ed) Clinical Neurophysiology, pp. 325–​572. Butterworth-​Heinemann, Oxford. Niedermeyer E, Lopes da Silva F (eds) (1993). Electroencephalography: basic principles, clinical applications, and related fields, 3rd edition. Williams & Wilkins, Baltimore, MA. Nuwer MR (1999). Spinal cord monitoring. Muscle Nerve, 22, 1620–​30. Sandberg A, Hansson B, Stålberg E (1999). Comparison between con- centric needle EMG and macro EMG in patients with a history of polio. Clin Neurophysiol, 110, 1900–​8. Simonetti S, Nikolic M, Krarup C (1999). Electrophysiology of the motor unit. In:  Younger DS (ed) Textbook of motor disorders, pp. 45–​60. Lippincott Williams & Wilkins, Philadelphia, PA. Stålberg E, Trontelj JV. (1979). Single fibre electromyography. Mirvalle Press, Old Woking, Surrey. 24.3.3  Imaging in neurological diseases Andrew J. Molyneux, Shelley Renowden, and Marcus Bradley ESSENTIALS Computed tomography and magnetic resonance imaging are the most important imaging techniques in the diagnosis of neurological disease. Computed tomography During exposure to a series of narrow X-​ray beams, a detector array spins around the patient and measures the absorption coefficients of tissues within the beam, the different coefficients providing image contrast. Modern helical multidetector computed tomography acquires data from large volumes of tissue simultaneously with the patient moving continuously through the machine. This enables very rapid scanning and the ability to acquire angiographic (computed tomography angi- ography and venography) and functional information (computed tom- ography perfusion). The volume data set is acquired and multiplanar reconstructions can be obtained in the sagittal, coronal, and oblique planes, as required. Iodinated contrast agents, as employed in general vascular imaging, are commonly used for image enhancement. Magnetic resonance imaging When the body is placed in a magnetic field, a small number of the tissue protons align themselves with the main magnetic field. They are subsequently displaced from their alignment by application of a radiofrequency gradient, and when this radiofrequency pulse termin- ates, the protons realign themselves with the main magnetic field, re- leasing a small pulse of energy as a radio signal that can be detected, localized, and processed by a computer to produce a cross-​sectional anatomic image. Many different and complex radiopulse sequences are used in magnetic resonance imaging, each of which is designed and used to answer particular clinical questions. They detect different aspects of tissue properties known as the ‘relaxation times’ of the pro- tons; times that will vary according to the proton-​containing tissue and the relative mobility of the protons. These are called T1 and T2 relaxation times. Gadolinium-​labelled compounds, which shorten the T1 relaxation time, are commonly used for image enhancement. 24.3.3  Imaging in neurological diseases 5803 Choice of imaging modality The choice between computed tomography or magnetic reson- ance imaging depends on several factors. Computed tomography is usually more readily available, is quicker to do, and is used in most acute situations, particularly in stroke and subarachnoid haemor- rhage, intracranial infection, trauma, and suspected intracranial masses. Magnetic resonance imaging is the imaging modality of choice in suspected spinal pathology and also in the detailed in- vestigation of cranial neurological diseases, particularly those af- fecting the white matter, epilepsy, stroke, tumours, and congenital anomalies. Introduction The modern imaging techniques of computed tomography (CT) and magnetic resonance imaging (MRI) for the demonstration of structural neurological disease have developed rapidly since their first introduction in the 1970s and 1980s, respectively. They have undergone further technological evolution, particularly in the last 10 years, and continue to do so. A variety of both CT-​ and MRI-​based techniques can provide anatomical, angiographic, and functional information. In addition, biochemical data may be obtained using magnetic resonance (MR) spectroscopy (MRS) and microstructural information can be obtained using diffusion tensor imaging. Historical perspective CT CT was developed by the British scientist and engineer Godfrey Hounsfield during the early 1970s and was the first technique to provide non​invasive and cross-​sectional images of the brain. It was introduced into clinical practice at the Atkinson Morley Hospital in Wimbledon, London in 1972, and the first results were published in 1973. Before this, invasive techniques such as angiography and air encephalography were required to diagnose neurological disease. CT was the beginning of a complete revolution in radiological imaging, for which Hounsfield received the Nobel Prize for medicine in 1979. CT rapidly became the imaging modality of choice in the diagnosis of structural brain disease until the advent of MRI, developed by British scientists in Nottingham and Aberdeen, and at a similar time in California during the early 1980s. It was introduced into wide- spread clinical use during the late 1980s and early 1990s. However, CT still remains an essential tool, particularly in the acute situation, when MRI is contraindicated, and in countries and regions where the availability cost of MRI systems is prohibitively expensive. CT produces a series of cross-​sectional images, usually in the axial plane. During exposure to an X-​ray beam, a detector array spins around the patient and measures the absorption coefficients of tissues within the beam. It is the different coefficients that pro- vide image contrast. Early machines measured a single slice at a time but the development of helical and multidetector CT now rou- tinely produce 256 slices and more, with the patient moving con- tinuously through the machine. The most modern scanners now acquire a volume data set rather than slices. This has enabled very rapid scanning with subsecond scan times and time-​resolved data, and the ability to acquire angiographic (CT angiography and venog- raphy data) and functional information (CT perfusion). MRI MRI is fundamentally very different from CT. No ionizing radiation is involved. It is based on the ability of a small number of protons within the body to absorb and emit radiowave energy when the body is placed within a strong magnetic field. Different tissues absorb and release radiowave energy at different rates. When the body is placed in a magnetic field, a small number of the tissue protons (hydrogen ions) align themselves with the main magnetic field. They are subsequently displaced from their alignment by application of a radiofrequency gradient. When this radiofrequency pulse terminates, the protons realign themselves with the main magnetic field, releasing a small pulse of energy as a radio signal that is detected, localized, and processed by a com- puter to produce a cross-​sectional anatomical image. Many different and complex radiopulse sequences are used in MRI and are determined by the way the radiofrequency pulses are timed. They are designed and used to answer certain clinical ques- tions in a variety of neurological circumstances. They detect dif- ferent aspects of tissue properties known as ‘the relaxation times of the protons’—​times that will vary according to the proton-​ containing tissue and the relative mobility of the protons. The most basic and most commonly used sequences are termed ‘T1-​weighted’ and ‘T2-​weighted’ sequences. The appearance of these scans is quite different, for example, fluid structures such as cerebrospinal fluid are white (high signal) on T2-​weighted and dark (low signal) on T1-​weighted images (Fig. 24.3.3.1b, c). Some tissues such as fat (unless suppressed by a specific sequence) and some blood breakdown products (e.g. methaemoglobin) will appear bright on T1-​ and T2-​weighted images. Flowing blood is usually markedly hypointense (black) on both sequences (‘a signal void’), as are cortical bone and air. Specific MR sequences have also been designed to produce non-​ invasive angiographic information and usually do not require an in- jection of a contrast agent (MR angiography and MR venography). Perfusion-​weighted MRI (PWI) can assess cerebral perfusion and diffusion-​weighted MRI (DWI), by assessing Brownian motion of mobile protons, is useful in diagnosis of hyperacute and acute is- chaemic stroke and may be also used to differentiate malignant tu- mour from an abscess (see later). A more sophisticated variant of DWI called diffusion tensor imaging gives a more detailed direc- tional analysis of the changes in diffusion and provides microstruc- tural information about the orientation of white matter tracts, useful in surgical planning. This is called tractography. MRS may provide useful biochemical information and may be used to grade brain tu- mours, differentiate malignant tumour from radiation necrosis, and malignant tumour from abscess. Functional MRI (fMRI) may lo- calize specific brain functions (e.g. motor function, sensory func- tion, and language, and can be useful for surgical planning where mass lesions are close to or involve eloquent cortex). The resolution of modern MR scanners is submillimetre, most are 1.5 T (15 000 G) and increasingly 3-​T scanners are being introduced. This higher field strength (measured in tesla (T): 1 tesla = 104 gauss (G)) allows faster scanning and higher resolution. SECTION 24  Neurological disorders 5804 The sensitivity of MR for the detection of intracranial anatomy and pathology is extremely high and its multiplanar capacity is an additional advantage. MRI might be contraindicated in patients with certain metallic implants, especially cardiac pacemakers (although MRI-​compatible cardiac pacemakers are now available), some heart valves, older an- eurysm clips, and metallic foreign bodies in the orbit. It is also opti- mally avoided if possible in the first trimester of pregnancy. Contrast enhancement in brain imaging Intravenous contrast in brain imaging is frequently used to enhance conspicuity of pathology, to determine the vascularity of structures, leakiness of the blood-​brain barrier, and to improve the demonstra- tion of the blood vessels. In practice, it usually adds little to the spe- cific diagnosis. It will show the extent and pattern of enhancement in tumours, abscesses, and inflammatory lesions. For CT, the same iodinated contrast agents employed in general vascular imaging are used. In MRI, gadolinium-​labelled compounds, which shorten the T1 relaxation time, are used and show the same patterns of enhance- ment as iodinated contrast media used in CT. The sensitivity of MRI contrast agents is significantly greater in the detection of metastatic lesions and the extent of tumour spread. Gadolinium enhancement is particularly useful in the assessment of meningeal disease. An add- itional advantage of MRI is that blood vessels can be labelled using (a) (b) (d) (c) Fig. 24.3.3.1  Normal computed tomography (CT) and magnetic resonance (MR) scans of the brain at the level of the ventricles. (a) Normal axial CT image at the level of the lateral ventricles. (b) Normal axial T2-​weighted image of a brain at the level of the ventricular system. Note that the cerebrospinal fluid (CSF) is white, the white matter is dark, and the grey matter is lighter than the white matter. This is the most commonly used MRI sequence and it is usually the most sensitive in the detection of pathological processes. (c) Axial, T1-​weighted, unenhanced MR image, showing the cerebrospinal fluid to be dark (low signal) and the white matter lighter than the grey matter. (d) Coronal FLAIR (fluid-​attenuated inversion recovery) MRI: these are T2-​weighted images but normal cerebrospinal fluid is dark on this sequence. This improves the visibility of lesions in the brain, especially adjacent to the ventricles. The mild asymmetry of the bodies of the lateral ventricles seen on this scan is within the normal range. 24.3.3  Imaging in neurological diseases 5805 specific imaging sequences without actually administering contrast. Examples of these techniques include time-​of-​flight imaging, phase contrast imaging, and arterial spin labelling. Cerebral angiography In the last five years, CT angiography (CTA) and MR angiog- raphy (MRA) have largely replaced diagnostic, transfemoral, intra-​ arterial, digital subtraction angiography (DSA) for demonstration of the intra-​ and extracerebral vessels. Transfemoral angiography involves the selective catheterization of the carotid and/​or vertebral arteries via the femoral artery and direct injection of iodinated con- trast media into these arteries. It is used primarily for investigation of intracranial haemorrhage (ICH), where CTA has not demon- strated the cause, and in the investigation and assessment of com- plex neurovascular disorders (e.g. arteriovenous malformations). The basic techniques of DSA are used for endovascular therapy in the treatment of cerebral aneurysms, arteriovenous malformations, fistulae, and thrombectomy for acute ischaemic stroke. In the investigation of a transient ischaemic attack (TIA) and minor stroke caused by suspected extracranial carotid or vertebral stenosis, Doppler ultrasonography of the neck vessels is usually the main screening test. CTA or MRA is an alternative technique and useful where carotid intervention to relieve stenosis (usually carotid endarterectomy) is planned. This has been shown to be of substan- tial benefit in patients with critical stenoses to prevent recurrent stroke. In contrast, patients with intracranial stenosis do not benefit from endovascular intervention to open up stenotic vessels. Myelography This has largely been superseded by spinal MRI. It involves a lumbar puncture and injection of water-​soluble contrast into the lumbar subarachnoid space, followed by radiography to demonstrate the lumbar and cervical nerve roots and the spinal cord in patients with radiculopathy, suspected cauda equina compression, and myelop- athy, when MRI cannot be performed. Imaging of common neurological diseases Cerebrovascular disease and stroke The most frequent neurological presentation is acute stroke. Patients presenting with sudden onset of neurological deficit should be deemed to have suffered a vascular event until proved otherwise. In practice the clinical diagnosis of stroke is very accurate, provided that an adequate history is available. However, clinical differenti- ation of haemorrhage from infarction is not possible. The primary role of imaging is to identify whether the acute stroke is ischaemic or haemorrhagic and, when there is diagnostic doubt, whether a stroke has occurred. CT is the most reliable way of excluding primary intracerebral haemorrhage as a cause of acute stroke, provided that it is performed within about a week of onset. In ischaemic stroke, depending on the extent and location of infarct and timing of the examination relative to the onset of neurological deficit, it will only variably detect acute infarction. Within hours of the ictus, CT may show a vague area of low density, loss of grey/​white differentiation, or slight swelling and ef- facement of the sulci in the area of infarction, or it may be normal (Fig.  24.3.3.2a). In the latter especially, in hyperacute ischaemic stroke, when thrombolysis or clot extraction is contemplated, CT perfusion (CTP) (Fig.  24.3.3.2b) and CTA (Fig.  24.3.3.2c) are useful additional techniques and can be performed very quickly in a multislice CT scanner to provide information about the site and (a) (c) (b) Fig. 24.3.3.2  (a) CT scan showing an acute right middle cerebral territory infarction within a few hours of onset of the neurological deficit with a left hemiplegia. Note the subtle loss of differentiation between the grey and white matter on the right side, the slight but definite reduction in attenuation, and the effacement of the Sylvian fissure and cortical sulci. (b) CT perfusion image obtained with a 64-​slice multidetector CT scanner showing widespread reduced perfusion and area of penumbra (blue) on the right side. (c) CT angiogram showing acute thrombus at right middle cerebral artery bifurcation. SECTION 24  Neurological disorders 5806 extent of arterial occlusion, and extent and location of the infarcted brain but, most important, the extent of ischaemic but potentially viable brain. Standard MRI may also be normal within the first 3 h on fluid-​ attenuated inversion recovery (FLAIR) images and up to 8 h on T2W (except that the occluded vessel may show absence of flow void) but DWI can demonstrate decreased diffusion in the ischaemic/​ infarcted brain within minutes of the ictus. PWI will also provide in- formation to discriminate between ischaemic and viable brain from infarcted brain. MRA will demonstrate the site of vascular occlu- sion. CT techniques are of more practical value in the evaluation of hyperacute ischaemic stroke, in the United Kingdom at least. Over the next 24 h or so, there is progressive development of a low-​density area on CT involving the cortex and white matter, in a vascular distribution and with mild mass effect. Swelling increases from day 3 to day 7, and the area of infarction is progressively better defined. Loss of volume in the damaged area occurs over time from about 4 weeks (Fig. 24.3.3.3). On MRI, an area of high T2 signal is demonstrated, in the area of infarction, involving cortex and white matter (Fig. 24.3.3.4). In the acute phase, there may also be some swelling around the area, representing oedema with effacement of sulci and ventricles but, with time, volume loss occurs. There was a change in the evidence base for treatment of hyperacute ischaemic stroke in 2015 when several major randomized control trials published in quick succession showed that endovascular neurointervention (mechanical thrombectomy) leads to improved clinical outcomes for selected patients with anterior circulation large vessel (internal carotid artery and proximal middle cerebral artery) occlusion compared to intravenous thrombolysis. Additional ran- domized control trials confirmed that the time window for suc- cessful thrombectomy in large vessel occlusion could be substantially increased dependent upon perfusion imaging with CT, defining sal- vageable ischaemic but potentially viable brain. Transient ischaemic attacks and minor stroke During the 1990s it was shown in the in two large randomized trials, the North American Carotid Surgery Trial and the European Carotid Surgery Trial, that carotid endarterectomy significantly reduced the risk of disabling stroke or death in patients with severe Fig. 24.3.3.3  CT showing mature left middle cerebral infarction. Note the large area of very low attenuation, with loss of volume on that side. (a) (c) (b) Fig. 24.3.3.4  (a) T2-​weighted axial MRI showing an acute middle cerebral territory infarct affecting the right perisylvian region. (b) MRI showing acute infarct (bright) on diffusion-​weighted MR image. (c) Diffusion-​weighted MRI showing the apparent diffusion coefficient (ADC map) and restricted diffusion (dark). 24.3.3  Imaging in neurological diseases 5807 carotid stenosis who had suffered a minor stroke or TIA. Recent work has shown that the risk of recurrent major stroke after a TIA or minor stroke is very high in the early period (two weeks, par- ticularly in the first few days after the ictus). Recent guidance from the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom recommends that patients with these symp- toms need urgent specialist assessment (within 24 hours for those with a high ABCD2 score), including brain and carotid imaging to detect those with significant carotid stenosis. The goal is to iden- tify patients with treatable stenosis and urgently treat other risk factors. Non​invasive imaging using Doppler ultrasonography, MRI and MRA, and CT and CTA are all used to identify these pa- tients. MRI with DWI has the advantage of identifying with much greater sensitivity areas of acute ischaemia or small infarcts that will not be detected on CT and or on standard MRI sequences (Fig. 24.3.3.5a, b). Intracranial haemorrhage Acute primary intracranial bleeding (ICH) into the brain paren- chyma is easily detected on CT. Fresh blood appears as an area of high density (Fig. 24.3.3.6a). Blood generally remains hyperdense for 2 weeks but, as the clot gets broken down, it becomes the same density as brain tissue at 2 to 4 weeks, and then is of lower density than brain after 4 weeks. The speed of resolution depends on the size of the clot. After an ICH, a decision must be made whether to investigate patients in more detail for the presence of an underlying lesion re- sponsible for the haemorrhage, such as an intracranial aneurysm, (b) (a) (d) (c) Fig. 24.3.3.5  (a) CT scan of a patient with a primary intracerebral haemorrhage in the right parietal lobe. High-​attenuation area represents the acute clot. (b) CT scan of a patient with an acute subarachnoid haemorrhage from a ruptured basilar termination aneurysm, with clot in the prepontine cistern and around the brainstem, showing a white (as opposed to dark) cerebrospinal fluid. (c) Lateral internal carotid angiogram showing large internal carotid aneurysm at the origin of the posterior communicating artery. (d) Angiogram after placement of detachable platinum coils to occlude the aneurysm. SECTION 24  Neurological disorders 5808 vascular malformation, or occasionally a tumour. If the distribution of ICH suggests that the cause may be aneurysmal, then prompt angiographic evaluation is necessary. Otherwise, selection of which patients should undergo cerebral angiography is sometimes difficult and largely depends on the intention to treat if an underlying le- sion is found. This will depend on patient’s age, clinical state, loca- tion of haematoma, and patient’s comorbidities. Cerebral amyloid angiopathy may account for a significant fraction of ICH in older patients. Where there is a decision to investigate and treat, cranial MRI may also be useful. It will diagnose haemorrhage related to tu- mour, anatomically localize an arteriovenous malformation and is necessary to exclude cavernous angiomas, a rarer cause of haemor- rhage that is angiographically occult. Blood in the subarachnoid space after a haemorrhage (SAH) may be visible around the base of the brain as a white layer, in contrast to the normal dark outline of cerebrospinal fluid in the basal cisterns. Cranial CT performed within 24 h of a SAH is about 90–​95% sensitive (see Fig. 24.3.3.5b) with some reports suggesting that sensitivity approaches 100% at less than six hours. Its sensi- tivity diminishes with time, depending on the extent of haemor- rhage. With a large SAH, the scan will remain positive for three to four days (see Fig. 24.3.3.5b). Lack of visible blood on CT does not exclude the diagnosis of SAH, and lumbar puncture to look for red blood cells is essential if this diagnosis is suspected clinically and CT scan is negative or equivocal. Lumbar puncture should be per- formed by an experienced operator to lessen the risk of a traumatic tap which may make exclusion of SAH impossible and ultimately lead to unnecessary cerebral angiography with its inherent risk of stroke. It is, however, very important not to miss a very small SAH, un- detectable on CT, which may have resulted from rupture of an intra- cranial aneurysm. Aneurysmal SAH is potentially life threatening because re-​rupture of the aneurysm is common. All patients who survive an SAH and are in good clinical con- dition should undergo urgent imaging of the cerebral vessels by either CTA or DSA to detect the presence of a berry aneurysm that may be responsible for the haemorrhage. If CTA is negative, formal intra-​arterial DSA is usually performed. Around 15% of patients with proven subarachnoid haemorrhage will not have an aneurysm. Recently ruptured aneurysms have a high likelihood of rebleeding, as high as 30% in the first four weeks after the haemor- rhage. Without treatment there is a 50% mortality rate at six months. Aneurysms should be detected and treated as soon as possible, either by endovascular techniques using detachable platinum coils (see Fig. 24.3.3.5c, d) or by neurosurgical clipping. A large multicentre randomized trial, the International Subarachnoid Aneurysm Trial, has reported improved clinical outcomes at one year after coil em- bolization compared with surgical clipping, an advantage main- tained over many years of follow-​up. Other cerebrovascular diseases Cerebral venous sinus thrombosis This uncommon, potentially fatal, condition presents non-​ specifically with headache, confusion, variable neurological deficits including coma, and sometimes seizures. Cranial CT may be normal or may demonstrate generalized or local cerebral swelling and/​or haemorrhagic venous infarction. Dense thrombus may be seen in the occluded sinuses and veins. The diagnosis is usually made by MRI when it is suspected, where lack of flow void is seen on some sequences (T2 weighted) and high-​signal methaemoglobin on T1-​weighted sequences are seen in thrombosed dural sinuses. Flow-​sensitive MRI sequences (MR venography) demonstrate the obstructed sinus well and are some- times useful because the signal returned by clot varies according to age of clot, and the particular sequence and field strength of the scanner (Fig. 24.3.3.7). CT venography on multislice scanners is an excellent alternative technique, readily demonstrating the extent of thrombosis. (a) (b) Fig. 24.3.3.6  (a) Diffusion-​weighted MRI showing restricted diffusion, in a patient with a recent transient ischaemic attack (TIA), as a bright area in the left basal ganglia. (b) CT angiogram obtained on 64-​slice multidetector CT (MDCT), with workstation reconstructions showing tight stenosis at the origin of the internal carotid artery. 24.3.3  Imaging in neurological diseases 5809 Anticoagulation is urgently required because progression of the thrombosis can lead to ICH and fatal venous infarction. Local pharmacomechanical thrombolysis/thrombectomy may be indicated where there is clinical deterioration despite adequate anticoagulation. Inflammatory diseases of the nervous system Multiple sclerosis One of the most common neurological diseases after stroke in western countries is multiple sclerosis (MS). Imaging plays a cru- cial role in the diagnosis, but it is important to understand the MR appearances are not pathognomonic. Clinical presentation, history, and neurological examination are crucial. The typical MS plaque is a well-​defined, ovoid, periventricular, white matter lesion with a long axis perpendicular to the ventricle and long axis of the brain, reflecting the perivenular inflammatory process (Fig.  24.3.3.8a). Sometimes, they enhance, may cavitate, and may be associated with oedema, and can be confused with tumours. When patients present with symptoms of spinal cord disease (myelopathy), MRI of both the spine and brain is indicated. The entire spinal cord is imaged to exclude spinal cord compression. (a) (c) (b) Fig. 24.3.3.7  (a) Sagittal T1W MRI showing extensive sagittal sinus thrombus; there is intermediate signal in the sagittal sinus, but normally there would be a black flow void in this T1-​weighted sequence. (b) Sagittal T2-​weighted sequence showing clot in the superior sagittal sinus. (c) Coronal MR venogram showing lack of filling in the sagittal sinus and the left transverse sinus. (a) (b) Fig. 24.3.3.8  (a) T2W axial MR image demonstrates a typical ovoid-​shaped white matter plaque in the deep white matter of the right hemisphere. (b) Cervical spine T2 sagittal MR image showing a demyelinating (multiple sclerosis) plaque in the cord with swollen cervical cord and diffuse high signal. The differential is between an inflammatory process and a spinal cord tumour. History will help to clarify. SECTION 24  Neurological disorders 5810 An inflammatory plaque may be seen in the spinal cord, often in the cervical cord (Fig. 24.3.3.8b), although failure to identify such a lesion does not mean that one is not present. If MS-​type le- sions are also demonstrated in the brain the chance of that patient developing clinical MS within the next 10 years is high, around 80%. The difficulty comes in older patients aged over 45  years, where, increasingly, incidental small white matter lesions may be seen normally in the brain presumably due to age-​related vascular pathology. Neoplasms Primary intracranial tumours The neuroimaging appearances of individual brain tumours are rarely specific. The imaging tumour differential diagnosis takes not only tumour location into account but also patient age. Primary intracranial tumours can be broadly divided into those arising outside the brain (extrinsic, extra-​axial, parasellar, pineal region, cerebellopontine angle, and so on.) and those arising in the cerebral substance (intrinsic, intra-​axial). The range of path- ology of the locations is fundamentally different, as often is the prognosis. Differentiation between intrinsic and extrinsic lesions is usually easier on MRI than on CT because of the multiplanar capability of MRI (Fig. 24.3.3.9). Extrinsic intracranial tumours The most common tumours arising from structures outside the brain are meningiomas and vestibular schwannomas (often called ‘acoustics’) arising from cranial nerve VIII. Both are usually benign and present with symptoms of local pressure: cranial nerve VIII tu- mours can produce sensorineural deafness and/​or sometimes diz- ziness, whereas meningiomas may be incidental, and may cause seizures and/​or a wide variety of deficits according to location. The imaging characteristics of meningiomas and vestibular schwannomas are similar. CT scans usually show a slightly hyperdense mass causing local displacement of cerebral tissue. They generally enhance uniformly after the administration of intravenous contrast, although they may occasionally con- tain areas of low density representing necrosis or occasionally cyst formation within the tumour (Fig. 24.3.3.10a). On MRI, these lesions return a uniform intermediate signal on T1-​ and T2-​weighted sequences and both show intense gadolinium enhancement (Fig. 24.3.3.10b). Intrinsic cerebral tumours Most intrinsic tumours arise from glial cells and are classi- fied as gliomas. There are various types (e.g. astrocytoma, Fig. 24.3.3.9  Axial MRI T2-​weighted image showing typical lesions adjacent to the ventricles and in the white matter. (a) (b) Fig. 24.3.3.10  (a) Enhanced CT scan showing left frontal convexity meningioma. (b) Coronal T1W MR image after intravenous contrast: convexity meningioma showing broad dural origin (different patient). 24.3.3  Imaging in neurological diseases 5811 oligodendroglioma, oligoastrocytoma, ependymoma). The ma- jority are malignant, but low-​grade lesions may appear stable over many years and grow very slowly. They are all mass lesions and most are seen as areas of low density on CT, low signal on T1-​weighted MRI, and high signal on T2-​weighted MRI, with dis- tortion of normal structures. They may show abnormal enhance- ment following intravenous contrast. The presence or absence of haemorrhagic changes, necrosis, calcification, and extent of contrast enhancement will vary among tumours of different but also similar histological type. However, in general, high-​grade tu- mours are more likely to be heterogeneous with foci of necrosis, areas of haemorrhage, heterogeneous contrast enhancement, and oedema (Fig. 24.3.3.11a). Low-​grade tumours are more likely to be homogeneous and without haemorrhage or oedema. MRS (spectroscopy) may enable demonstration of character- istic biochemical patterns in some cerebral tumours, enabling the distinction of more aggressive tumours and differentiating nec- rotic tumours from abscesses, and distinguishing radiation ne- crosis from tumour recurrence. DWI may also help differentiate malignant glioma from abscess and primary cerebral lymphoma. Perfusion MRI may demonstrate foci of neovascularity more typ- ical of malignant tumours. The current role of imaging is primarily not to provide a precise histological diagnosis (that is the role of the neuropathologist) but rather to make the correct diagnosis of a ‘brain tumour’ and differentiate it from other mass lesions: acute or subacute infarcts, focal cortical dysplasias (congenital), abscesses, and inflammatory lesions such as acute MS plaques. This is not al- ways straightforward. Imaging is also important for precise tumour (a) (c) (b) (d) Fig. 24.3.3.11  (a) Contrast-​enhanced CT scan showing a large, deeply situated necrotic mass in the left hemisphere, with considerable enhancement, and appearances typical of a glioblastoma multiforme. (b) T2-​weighted axial MRI showing diffuse infiltrating necrotic glioblastoma deeply situated in the left hemisphere and extending into the splenium of the corpus callosum; this a typical pattern of spread in this type of tumour. (c) Contrast-​enhanced, axial T1-​weighted MR image of glioblastoma, showing marked irregular contrast enhancement of the margins of the tumour, with lack of central enhancement, reflecting the extensive necrosis that is often a feature of these tumours. (d) Sagittal T1-​weighted image without contrast, showing the marked enlargement of the splenium of the corpus callosum depicted in the same patient. SECTION 24  Neurological disorders 5812 localization and determination of the relationship to eloquent cortex and, therefore, is necessary for surgical planning and follow-​ up for assessment of surgical resection, radiotherapy, and chemo- therapy treatment. Imaging may also suggest the most appropriate site for biopsy. After brain tumours have been treated with surgery and chemoradiotherapy, it can be difficult to distinguish radiation necrosis from tumour recurrence. Both MRS and perfusion MR may be helpful in these circumstances. Oligodendroglioma These tumours are the most benign of the intrinsic cerebral tu- mours. They often present with seizures rather than neurological deficit. Their radiological hallmark is calcification, best detected on CT. Calcification may be invisible on MRI, but they are also more likely to appear heterogenous. The time course of these tumours may be very long, often evolving over 10–​20 years. Oligodendrogliomas may remain static for long periods (Fig. 24.3.3.12). Posterior fossa tumours Intrinsic posterior fossa tumours are the most common intracranial tumours in children. The most common lesion is a medulloblastoma, which usually arises in the roof of the fourth ventricle and accounts for about 30% of posterior fossa tumours in children. Other tu- mours commonly encountered are ependymomas, and fibrillary and pilocytic astrocytomas, both of which have a better prognosis than medulloblastomas. Medulloblastomas and ependymomas commonly metastasize down the spinal canal, producing what are known as ‘drop metastases’ to the lumbar or sacral region. Other intracranial tumours Colloid cyst This is a very characteristic benign lesion that arises at the foramen of Munro, between the lateral and third ventricles, and presents with obstructive hydrocephalus. Colloid cysts are usually readily detectable on CT and MRI, and although density and signal charac- teristics can vary quite widely, the location is absolutely character- istic (Fig. 24.3.3.13). They never enhance. Pituitary region tumours MRI is the investigation of choice for suspected pituitary/​parasellar lesions. Parasellar tumours, which arise outside the brain itself, are asso- ciated with a characteristic range of pathology. The most common Fig. 24.3.3.12  Axial T2-​weighted MRI showing a diffuse homogenous high-​signal lesion in the frontal lobe with a diffuse mass effect and sulcal effacement. These appearances are typical for a lower-​grade glioma. (a) (b) Fig. 24.3.3.13  (a) CT scan showing typical appearance of a colloid cyst (bright), but can be of any density. The location of this lesion at the foramen of Munro is absolutely characteristic and there is not really a differential diagnosis. (b) Coronal T2W MRI showing colloid cyst in characteristic location at the foramen of Munro at the junction of the lateral and third ventricles. 24.3.3  Imaging in neurological diseases 5813 lesion is a non​functioning pituitary adenoma, followed by hor­ monally active tumours (diagnosed initially not by MRI but by biochemical assay techniques), namely ACTH-​producing tumours (Cushing’s disease), prolactinomas, and growth-​hormone-​secreting tumours (acromegaly). All these have similar imaging character- istics, but their size varies widely: ACTH-​secreting adenomas are usually very small and may not be detectable even on high-​quality MRI. Non​functioning macroadenomas tend to present late, often with visual loss and/​or pituitary failure due to the large size and optic chiasmal compression (Fig. 24.3.3.14). Lesions invading the ­cavernous sinus may result in ophthalmoplegia. Meningiomas may also occur in the parasellar region and appear very similar. Craniopharyngioma This benign tumour arises in the hypothalamic region from rem- nants of Rathke’s cleft, usually in young patients, and presents with visual loss and/​or pituitary failure. The characteristic finding on CT is calcification. There is almost invariably a cystic as well as a solid component to the lesion. Brainstem gliomas These relatively uncommon tumours occur at a relatively young age. However, because of their location there is no prospect of any surgical approach and, if any treatment is appropriate, it is usually radiotherapy. Brainstem gliomas may vary widely in their aggres- siveness, from rapidly progressive lesions to indolent lesions that may remain static for many years. Secondary cerebral tumours These are among the most common intracranial tumours in adults and may be the presenting feature in some patients. Lung, breast, renal, and gastrointestinal tumours, as well as melanomas, metasta- size especially to the brain. Secondary tumours may be solitary or multiple and are fairly characteristic on the imaging, with intracranial masses (solid or cystic) surrounded by oedema and frequently with enhancement after intravenous contrast (Figs. 24.3.3.15 and 24.3.3.16). The dif- ferential diagnosis of multiple ring-​enhancing lesions in the brain is between cerebral metastases, abscesses, and inflammatory lesions. DWI may help to differentiate abscesses, which show decreased diffusion. Malignant meningeal deposits of the central nervous system (CNS) or systemic tumours are relatively uncommon, but they do occur and may be difficult to detect on non-​contrast-​enhanced imaging. MRI with gadolinium enhancement is the most sensitive detection method and is more sensitive than cerebrospinal fluid cytology. Intracranial infections Although intracranial infections are less common in Western coun- tries than tumours, it is vital that they are detected as urgent and (a) (b) Fig. 24.3.3.14  (a) Sagittal T1W MRI of pituitary adenoma with considerable suprasellar extension. (b) Coronal T1W MRI of pituitary adenoma invading the left cavernous sinus. Fig. 24.3.3.15  T1-​weighted enhanced MRI showing two secondary deposits (ring-​enhancing lesions with oedema) in the superior of the right frontal and parietal lobes. SECTION 24  Neurological disorders 5814 definitive diagnosis and treatment are essential to their effective management. Bacterial infections Bacterial meningitis is the most common bacterial intracranial in- fection. Cranial CT is usually normal in uncomplicated cases but may show meningeal enhancement and/​or mild hydrocephalus. A  patient who is neurologically intact and has a Glasgow Coma Scale score of 15 does not require cranial CT before lumbar punc- ture. Note that mild communicating hydrocephalus is not a contra- indication to lumbar puncture (see next). In a patient with suspected meningitis, cranial CT is important, but antibiotics must not be de- layed by imaging. Cranial CT is often useful in diagnosing some of the compli- cations associated with bacterial meningitis (e.g. hydrocephalus, ventriculitis, cerebral oedema, cerebral abscess, subdural empyema, cerebral infarction, and venous sinus thrombosis). Cerebral abscess Pyogenic brain abscesses are usually single but may be multiple. In the early stage they may not be particularly well defined and begin as an area of cerebritis, which then evolves into an abscess—​a character- istic ring-​enhancing mass surrounded by oedema (Fig. 24.3.3.17). MRI is particularly useful in the specific diagnosis of an abscess and its differentiation from a malignant tumour. Abscesses show de- creased diffusion on DWI and have characteristic MR spectra. If a pyogenic abscess is suspected, then burr-​hole aspiration is mandatory to establish the diagnosis and drain the abscess. Abscesses may be seen at various stages of evolution if associated with a septicaemic illness. The source is either blood spread or direct spread from the infection in the paranasal sinuses or the mastoid. Subdural empyema This is a rare, but important, intracranial infection often caused by spread from a paranasal sinus infection. Pus accumulates in the subdural space, causing a spreading cortical thrombophlebitis. Empyema is usually due to the anaerobic bacterium Streptococcus milleri. Such abscesses are rapidly fatal if they are not treated aggressively with antibiotics and neurosurgical drainage. CT findings are subtle. The most obvious sign may be that of sulcal effacement due to cortical swelling and contrast enhancement may emphasize the thin subdural collection of fluid, which spreads over the brain surface, often alongside the falx. MRI is more sensitive in the detection of the small subdural collec- tions, but it is unnecessary if the diagnosis is clear on CT scans (Fig. 24.3.3.18). The underlying brain appears swollen and tight with the sulci obliterated; it will show moderate meningeal enhancement after intravenous contrast. Tuberculosis This most often manifests as tuberculous meningitis, a basal men- ingitis, and less often as either abscesses or granulomas in the brain. Fig. 24.3.3.16  T1-​weighted axial enhanced MRI showing metastases in the ventricular wall reflecting spread of disease in the subarachnoid space. (a) (b) Fig. 24.3.3.17  (a) T2-​weighted axial MRI showing large brain abscess near the left lateral ventricle—​a cystic lesion with oedema. (b) T1-​weighted axial MRI with contrast showing typical regular enhancement of the capsule of the abscess with surrounding oedema. 24.3.3  Imaging in neurological diseases 5815 If the meninges are involved there is almost invariably a degree of hydrocephalus. The basal meningitis may take a while to evolve on imaging. Viral encephalitis and HIV The most common cerebral viral infection is herpes simplex en- cephalitis (HSE). The imaging findings are often fairly typical, al- though CT scan changes may be very subtle during the early phase. Cranial CT shows a mild swelling with diffuse low density in the anterior and medial temporal lobes and insular cortex, often bi- lateral. MRI is much more sensitive and can be fairly specific (Fig. 24.3.3.19). Later, similar changes are seen in the cingulate gyri. Classically, there is sparing of the basal ganglia. A detailed description of HIV-​related cerebral imaging find- ings is beyond the scope of this textbook. The incidence of HIV encephalitis and the other more commonly associated oppor- tunistic infections has decreased since HAART (highly active retroviral therapy) became available in 1996, with the exception of progressive multifocal leucencephalopathy (PML). HAART has increased the survival of those infected with the JC virus that causes PML. In HIV encephalitis, the white matter is damaged and MR dem- onstrates high signal in the deep white matter bilaterally. There is also volume loss. The white matter changes are optimally demon- strated on MRI and are not well appreciated on CT. Toxoplasmosis produces multiple enhancing solid or cavitating nodules with oedema not distinguishable from other bacterial or fungal infections. Cryptococcal infection causes meningitis and imaging may be normal or enlargement of the perivascular spaces may be seen be- cause this fungus produces a mucoid material. Choroid plexitis sometimes occurs. PML invades oligodendrocytes and causes demyelination, classically in the parieto-​occipital white matter. MRI detects the disease more accurately and earlier, and is the investigation of choice. Dementia imaging This is an area of increasing interest due to the ageing population. The purpose of imaging is twofold; firstly, to identify any intracra- nial pathology that may mimic a dementing illness, and secondly, to assist with distinguishing different neurodegenerative processes that lead to dementia. Some patients present with cognitive impairment without a focal neurological deficit, but have pathology readily identified with imaging. Some examples include a large frontal meningioma, or an infiltrating primary brain tumour, or chronic subdural haematoma, or obstructive hydrocephalus. There are many forms of dementia and, in specialist clinics, imaging is used to help make a diagnosis when clinical features Fig. 24.3.3.18  Left frontal subdural empyema: a contrast-​enhanced axial CT scan showing a collection of fluid in the left frontal subdural or extradural space in a patient with a large subdural empyema. Note that there is considerable soft-​tissue swelling over the frontal region. The paranasal sinuses are often the source and show opacification (not visible on this image). (a) (b) Fig. 24.3.3.19  (a) Axial T2-​weighted MRI of patient with herpes simplex encephalitis (HSE) shows bilateral hippocampal involvement with high T2 signal, much worse on the left, and extending into the anterior part of the temporal lobe. (b) Axial T2-​weighted MRI of patient with HSE showing high T2 signal in the left insular cortex of the temporal lobe. SECTION 24  Neurological disorders 5816 are uncertain or when treatment options may be radically dif- ferent. Cross-​sectional imaging with CT and MR can be used to identify patterns of volume loss. Alzheimer’s disease may show preferential volume loss in the temporal lobes. Other forms of dementia may show less specific structural change. Radionuclide investigations such as brain perfusion SPECT (single-​photon emission computed tomography), DAT (dopamine active trans- porter), and brain PET (positron emission tomography) can show patterns of alteration in blood flow (in the case of SPECT), glu- cose metabolism (in the case of PET), or dopamine transporters (for DAT). These may be used to distinguish Alzheimer’s disease, frontotemporal dementias, and diffuse cortical Lewy body dis- ease, among others. Hydrocephalus An understanding of hydrocephalus and its two main types is im- portant, knowing whether it is ‘safe to carry out a lumbar puncture’ in a patient or not. ‘Obstructive or non​communicating hydrocephalus’ is the term given to enlargement of the ventricles caused by an obstruction, usually a mass lesion in the cerebrospinal fluid pathways within the brain (i.e. between where the cerebrospinal fluid is produced from the choroid plexus in the lateral ventricles and the out- flow from the fourth ventricle). It is usually caused by a tumour pressing on the ventricles or aqueduct. (Fig. 24.3.3.13a shows a colloid cyst causing obstructive hydrocephalus.) Communicating hydrocephalus If cerebrospinal fluid escapes from the fourth ventricle, but there is disturbance of flow around the basal cisterns or over the cortex, or there is a failure of absorption of cerebrospinal fluid, this is termed ‘communicating hydrocephalus’ or ‘cerebrospinal fluid absorption failure hydrocephalus’. Communicating hydrocephalus occurs most commonly after an SAH or meningitis. It may require temporary ventricular or lumbar drainage. However, because cerebrospinal fluid escapes from the fourth ventricle and circulates round the spinal cerebrospinal fluid spaces, it means that it is safe to perform a lumbar puncture to measure and, if appropriate, lower cerebrospinal fluid pressure. Seizures MRI is the imaging modality of choice in patients presenting with a seizure, and especially so in those with seizures refrac- tory to medication. An MRI scan should optimally be performed within four weeks in a patient presenting with an unprovoked seizure to exclude mass lesions, vascular malformations, strokes, and so on, although the diagnostic pick-​up rate here is low. By contrast, in refractory seizures—​often focal and most often temporal—​the pick-​up rate is much higher, and MRI (particu- larly 3T, providing enhanced signal-​to-​noise ratio and better resolution) is important to diagnose those lesions responsible because surgical excision may either cure the epilepsy or signifi- cantly reduce the frequency of seizures. Hippocampal sclerosis and dysplastic lesions are optimally demonstrated using MR (see Fig. 24.3.3.20). Congenital anomalies and paediatric imaging Any detailed discussion of this subject is beyond the scope of this chapter, and the reader is directed to specialist texts (see also Chapter 24.17). Where available, MRI is the investigation of choice in infants and children presenting with suspected congenital anomalies of the brain. It provides the most information and avoids exposure of young patients to ionizing radiation. The main drawback in this age group is the need for sedation or general anaesthesia. The most common indication for imaging in such patients is developmental delay or seizure disorders. It also plays a vital role in the imaging of a suspected, neonatal, hypoxic ischaemic insult, and in elucidating the cause of cerebral palsy. CT is a reasonable alternative, but cannot be relied on to detect all relevant pathology, particularly in hypoxic ischaemic injury. A wide variety of congenital anomalies is possible, ranging from minor abnormalities of neuronal migration, or localized areas of dysplastic cortex, to major anomalies of the whole brain and encephaloceles, in which there is an associated defect of the skull or spine such as a spina bifida. The most frequent is the Chiari 1 mal- formation of the posterior fossa associated with cerebellar ectopia. The cerebellar tonsils, classically peg-​shaped, extend below the for- amen magnum a distance of at least 5 mm. There may be associated syringomyelia. Summary and possible future developments Modern imaging techniques have revolutionized the diagnosis of neurological disease in the last 30 years. The techniques are likely to become even more sophisticated and accurate with further ex- tension into functional imaging and spectroscopic techniques, both with MR and nuclear medicine’s single-​photon emission CT (SPECT) and PET. The contribution of these techniques to the efficient and effective diagnosis of intracranial and spinal pathology, together with the ability to effectively exclude structural disease, has had a huge im- pact on neurological and neurosurgical clinical practice. In addition, the development of endovascular interventional neuroradiological techniques for the treatment of vascular diseases of the brain Fig. 24.3.3.20  Coronal T2W MR image in a patient with refractory right temporal lobe seizures, demonstrates a small high T2 signal scarred right hippocampus. Indications Indications CONTENTS 24.3.1 Lumbar puncture  5781 R. Rhys Davies and Andrew J. Larner 24.3.2 Electrophysiology of the central and peripheral nervous systems  5785 Christian Krarup 24.3.3 Imaging in neurological diseases  5802 Andrew J. Molyneux, Shelley Renowden, and Marcus Bradley 24.3.4 Investigation of central motor pathways: Magnetic brain stimulation  5817 K.R. Mills 24.3.1  Lumbar puncture R. Rhys Davies and Andrew J. Larner ESSENTIALS Lumbar puncture for cerebrospinal fluid analysis is most often undertaken in cases of suspected central nervous system infection, bleeding, and inflammatory disease. Attention to technical aspects of the procedure is key to successful lumbar puncture, along with prompt analysis of cerebrospinal fluid samples and informed inter- pretation of laboratory findings. Introduction Lumbar puncture for examination of the cerebrospinal fluid (CSF) has been an integral part of neurological practice since the pioneering work of Quincke at the end of the 19th century. The proximity of nervous tissue and CSF may afford insights into patho- logical processes within the nervous system through examination of the CSF, which may not easily be accessed by other investiga- tional modalities. Because of this importance, guidelines on routine CSF analysis have been published. The related procedure of cervical or cisternal puncture may also be used to obtain CSF, but is far less frequently performed. Cerebrospinal fluid samples should always be regarded as precious, and hence every effort made to ensure correct analysis and interpretation; suboptimal performance is not infrequently encountered in day-​to-​day clinical practice. Indications Since lumbar puncture may be associated with morbidity and mor- tality, it should be undertaken only after careful clinical evaluation of the patient by history, examination and, when necessary, non-​ invasive investigations, to ascertain the precise potential values and hazards of the procedure. Indications for lumbar puncture may be diagnostic and/​or therapeutic. The most common indications for diagnostic lumbar puncture are suspected central nervous system (CNS) infection or intracranial bleeding. CNS infections include meningitis and encephalitis. A variety of organisms, bacterial, viral, fungal, and protozoal can be responsible, and the pattern of findings in the CSF constituents might point to specific diagnoses, as might actual identification of the infecting organism(s) by means of special staining procedures, polymerase chain reaction, or microbial culture. CNS infection may also be sus- pected in some patients with acute confusional states or status epi- lepticus and hence these clinical scenarios may be an indication for lumbar puncture. Suspected intracranial bleeding, particularly subarachnoid haem- orrhage, for example presenting with thunderclap headache, is an indication for lumbar puncture to look for evidence of bleeding and pigments produced by the breakdown of haemoglobin. Suspected CNS inflammatory disease is an indication for lumbar puncture to look for indices of inflammation (increased cell count, oligoclonal bands). Therapeutic roles for lumbar puncture include the temporary re- duction of CSF pressure, for example, to relieve postural headache with visual obscurations in idiopathic intracranial hypertension. Drainage of 20–​30 ml of CSF (the ‘tap test’) may improve gait and 24.3 Clinical investigation of neurological disease SECTION 24  Neurological disorders 5782 possibly cognition in cases of suspected normal pressure hydroceph- alus (NPH), although this is not always a reliable predictor of success with more permanent CSF shunting procedures, perhaps in part be- cause of underlying neurodegenerative brain disorders (Alzheimer’s disease, progressive supranuclear palsy) in patients initially thought to have idiopathic NPH. Lumbar puncture may also permit intrathecal administration of medications. Fatalities related to inadvertent administration of anticancer drugs intrathecally, rather than systemically, have oc- curred, sometimes leading to high profile legal cases and disciplining of the clinicians at fault. Contraindications It is important to exclude cerebral mass lesions prior to lumbar puncture, since raised intracranial pressure, perhaps evident as papilloedema, may risk brain herniation (coning) through the ten- torium or foramen magnum, with potentially fatal consequences. In the presence of papilloedema, brain imaging (CT or MRI) is re- quired before lumbar puncture. Papilloedema without cerebral mass lesion may be due to idiopathic intracranial hypertension, menin- geal inflammation, or malignancy, conditions which require lumbar puncture and CSF examination for diagnosis. Therapeutic anticoagulation and other bleeding diatheses such as thrombocytopenia predispose to needle-​induced haemorrhage (epidural, subdural, subarachnoid), and hence should be reversed prior to lumbar puncture if the procedure is elective. Patients re- ceiving warfarin should have the medication discontinued at least 4–​5 days before lumbar puncture, with international normalized ratio (INR) checked and less than 1.2 before the procedure. If lumbar puncture goes ahead with INR greater than 1.2, close moni- toring of sensorimotor function for at least 24 hours is recom- mended. Urgent lumbar puncture in warfarinized patients requires reversal with fresh frozen plasma and vitamin K. For patients on low molecular weight heparin, lumbar puncture should be delayed for 12–​24 hours depending on whether the dose is low or high, and restarted 18–​24 hours post lumbar puncture. Antiplatelet medica- tions such as aspirin or other non​steroidal anti-​inflammatory medi- cations present no contraindication, but thienopyridine derivatives such as clopidogrel and ticlopidine should ideally be discontinued 7 and 14 days, respectively, before lumbar puncture. GP IIb/​IIIa in- hibitors should be discontinued to allow recovery of platelet func- tion before lumbar puncture (8 hours for tirofiban and eptifibatide, 24–​48 hours for abciximab). Data are scant for patients requiring lumbar puncture who are receiving thrombolytics or fibrinolytics, but impaired hameostasis persists for beyond 24 hours. For patients with thrombocytopenia less than 20 000/​μl, platelet transfusion immediately prior to lumbar puncture is required. Local skin sepsis overlying the spine is a contraindication to lumbar puncture. Procedure Patients are often, and not unreasonably, anxious at the prospect of having a needle stuck in their back (perhaps by analogy with being ‘knifed in the back’?); tales of agonizing procedures suffered by others are not uncommon. Careful explanation before and during the procedure may allay many of these anxieties. For elective pro- cedures, signposting to online information may be helpful (e.g. http://​www.clinicspeak.com/​lumbar-​puncture/​). Key to success is correct patient posture: left lateral decubitus (for a right-​handed operator) with the knees drawn up to the chest, sup- ported with a pillow between the legs, to keep the spinal column horizontal and avoid the rolled-​over (‘Rokeby Venus’) position. The procedure should be performed under strict asepsis, with all requisite equipment (manometer, sample bottles, fixative) immediately to hand. Anatomical landmarks may be used to guide the operator: a vertical line down from the anterior superior iliac spine should inter- sect the vertebral column around the desired L3/​4 space. Under local anaesthesia (ensure adequate time is allowed for this to work), the needle is directed slightly craniad, as though aiming for the navel. With luck, the patient may even be unaware when the needle is passed. However, even the most experienced operator may some- times require more than one pass to succeed, or may fail altogether. Further passes at a lower (L4/​5) or higher (L2/​3) intervertebral space, safe because the conus normally ends at L1 vertebra, or in the sit- ting position or under X-​ray guidance, may be attempted. Cervical or cisternal puncture may be tried if the clinical indication for CSF ana- lysis is sufficiently compelling, although few clinicians have adequate experience in performing this. Lumbar puncture under ultrasound guidance is becoming an increasingly popular option. All procedures undertaken should be fully documented in the patient record. Cerebrospinal fluid analysis should ideally occur immediately after sample collection, which may necessitate liaison to forewarn specialist laboratories prior to lumbar puncture being performed, and the clinician personally taking the sample to the laboratory if on site. There is always potential for mix-​up if acute samples must travel to other sites for analysis. Complications Serious complications of lumbar puncture are thankfully un- common. The most alarming is coning in the presence of raised intracranial pressure associated with a mass lesion, but this is ex- tremely rare. Some bleeding may be associated with the procedure (‘bloody tap’) which may affect the interpretation of CSF findings, but infection is rare. Headache is the most common complication of lumbar puncture, as a consequence of CSF leakage and consequent low pressure, so it is sensible to warn patients of this possibility. Use of atraumatic needles may reduce the risk of post lumbar puncture headache. Remaining recumbent post-​procedure (advice varies from 30 min- utes to 2 hours), adequate hydration, and simple analgesia as re- quired are often recommended. If these measures fail, caffeine may help. Use of a blood patch (epidural injection of autologous blood to produce thrombotic tamponade of the dural breach) is sometimes required, usually undertaken by an anaesthetist. Cerebrospinal fluid Normal ranges for standard CSF parameters are shown in Table 24.3.1.1. 24.3.1  Lumbar puncture 5783 Opening pressure The Monro–​Kellie doctrine or hypothesis describes the pressure-​ volume relationship of the cranial compartment: since this is incom- pressible (in adults), cranial volume is fixed, such that the summed volumes of brain, CSF, and intracranial blood must remain constant, an increase in any one constituent being compensated by a decrease in the others, otherwise intracranial pressure will rise. Raised intra- cranial pressure may compromise cerebral perfusion pressure, for example, to the retina, resulting in papilloedema and sometimes the symptom of visual obscurations, an alarming clinical finding. In addition to analysis of CSF constituents, the fluid opening pres- sure should be measured routinely with a manometer. The pressure level in the right atrium is the reference level, with the patient in the lateral decubitus position; opening pressure cannot be measured in the sitting position. Normal CSF pressure reflects the balance between CSF production and resorption, and is generally around 50–​200 mmH2O, sometimes higher in obese individuals (ca. 250 mmH2O). Disruption of produc- tion and/​or resorption may lead to abnormal CSF opening pressure. High opening pressure may be seen in CNS infections (meningitis, encephalitis), acute stroke, cerebral venous occlusion, or stenosis, and in idiopathic intracranial hypertension (pseudotumor cerebri). Increased pressure also occurs with intracranial mass lesions but lumbar puncture is usually contraindicated in this situation. Low opening pressure may be technical (incorrect needle place- ment) or pathological, in conditions such as dehydration, spinal subarachnoid block, CSF leak, spontaneous intracranial hypoten- sion (Schaltenbrand’s syndrome) and the related ‘frontotemporal brain sagging syndrome’. Blood and pigments A ‘bloody tap’ due to needle trauma is a common hazard of lumbar puncture, resulting in the CSF appearing turbid (500–​6000 red blood cells (RBC)/​μl) or frankly bloody (>6000 RBC/​μl). In the case of turbid CSF, laboratory RBC counts in successively taken CSF sam- ples may help to differentiate between a bloody tap (reducing RBC count) and intrathecal bleeding (consistent admixed RBC count). Bloody CSF may also contain protein and increased numbers of white cells contributed by the blood, for which correction needs to be made (see next). Normal CSF appears ‘crystal clear’ to naked eye observation (cell count <400–​500/​ μl). Xanthochromia describes CSF with a pinkish or yellow pigmentation due to the presence of RBC haemoglobin breakdown compounds such as bilirubin and oxyhaemoglobin. This pigmentation may be evident on visual inspection of CSF at the bedside (e.g. held in front of a white piece of paper, or compared to water), but detection is facilitated by spectrophotometry (which can also detect methaemoglobin), hence this is the preferred assessment method in patients with suspected subarachnoid haemorrhage. Oxyhaemoglobin, released by RBC lysis, may be detected in the supernatant fluid within 2 hours of subarachnoid haemorrhage, reaching a maximum in about the first 36 hours and gradually disappearing over 7–​10 days. Bilirubin is produced in vivo by lepto- meningeal cells after haemolysis, and is first detected about 10 hours after subarachnoid haemorrhage, reaching a maximum at 48 hours and persisting for between 2 to 4 weeks. Since lumbar puncture may be negative if undertaken in the first 12 hours after the subarachnoid haemorrhage ictus, published recommendations are to delay lumbar puncture until over 12 hours, to send the least blood-​stained sample (usually the last) for bilirubin analysis, and to protect the sample from light and avoid vacuum tube transport systems. Cell count and cytology The consensus is that normal CSF should have ≤5 white blood cells (WBC)/​μl. An elevated CSF WBC count suggests disease of the CNS and/​or meninges. Since blood in the CSF as a consequence of a bloody tap may in- crease the WBC count, correction may need to be made. If the pa- tient has a normal peripheral blood count, then the ratio of white cells to red cells is approximately 1:1000. Hence, if the CSF red cell count is 10 000 ​μl, the expected CSF white cell count would be 10/​μl. An approximation to the true CSF WBC count can be obtained by subtracting this from the actual count. If the peripheral blood count shows significant anaemia or leuco- cytosis, CSF WBC count before the blood was added may be deter- mined using the following formula: True CSF WBC = blood WBC x CSF RBC / blood RBC x 100 ( ) ( )   An elevated CSF WBC count, or pleocytosis, may be encountered in various infective, inflammatory, and neoplastic disorders (see Table 24.3.1.2), as well as stroke, subarachnoid haemorrhage, cerebral vas- culitis, and acute demyelination. Cerebrospinal fluid eosinophilia is typical of parasitic infections such as neurocysticercosis. Raised WBC count is not typically found in multiple sclerosis or acute in- flammatory neuropathies (Guillain–​Barré syndrome); if elevated, this should prompt the clinician to question these diagnoses. Cytological staining for cellular morphology is most often under- taken if there is clinical suspicion of leptomeningeal infiltration by neoplastic disease. Sensitivity of CSF cytology is influenced by sample volume and time to fixation. It has been recommended that at least 10 ml of CSF should be taken and that formalin fixative be added to the sample at the bedside or on the ward before it is sent to the laboratory. Repeated CSF studies may sometimes be required to confirm a suspected diagnosis of leptomeningeal metastasis. Protein CSF is an ultrafiltrate of plasma, the integrity of the blood:CSF barrier determining the CSF protein content. This is related to patient age (higher in neonates, and after 60 years of age), site of CSF collection (higher caudally), and possibly posture (higher in the bed-​ridden). The CSF:serum albumin concentration quotient, Qalb (normal <0.01), is preferred to total protein by some authorities, since this par- ameter evaluates blood:CSF barrier integrity, is method-​independent, Table 24.3.1.1  Normal cerebrospinal fluid constituents (liaise with local laboratory for their ranges) Parameter Normal range Opening pressure Lymphocytes or mononuclear cells Red blood cells Total protein CSF:serum glucose ratio Xanthochromia ca. 50–​200 mmH2O (CSF) No more than 5/​μl None ca. 0.15–​0.5 g/​litre 60–​80% of blood glucose concentration None SECTION 24  Neurological disorders 5784 corrects for plasma concentration of albumin, and is not influenced by intrathecal protein synthesis. Marginal elevation of CSF total protein may be a non​specific finding; clinical context is all important. Protein is elevated in meningitides, more so in bacterial and tuberculous than viral, and encephalitides (although may be normal in herpes simplex enceph- alitis early in the course), invariably in association with cellular re- action (see Table 24.3.1.2). Non​infectious causes of elevated protein include subarachnoid haemorrhage, CNS vasculitis, leptomeningeal metastases, and sometimes with neoplasms and in Creutzfeldt–​ Jakob disease. Classically there is elevated protein in the absence of cellular reaction in Guillain–​Barré syndrome, the dissociation albumin-​cytologique, although this elevation may not be apparent early in the disease course. Very high CSF protein content may cause increased CSF vis- cosity, with yellowish discolouration, a finding sometimes known as Nonne–​Froin sign after the first descriptions in association with spinal tumour (e.g. ependymoma) and meningitis, respectively. Immunoglobulins Intrathecal immunoglobulin (Ig) synthesis occurs in certain inflam- matory CNS disorders. The CSF:serum IgG concentration quotient, QIgG, is closely correlated with Qalb, their ratio constituting the CSF IgG index (QIgG/​Qalb; normal <0.65). However, the detection of CSF oligoclonal bands using, for example, isoelectric focusing is a su- perior method of detecting intrathecal IgG synthesis than IgG index. Since some immunoglobulins are passively transferred from plasma to CSF, the production pattern in serum mirrors that in CSF. Hence it is mandatory that paired blood and CSF samples are examined to determine whether immunoglobulin synthesis confined to the CSF compartment is occurring. Although the finding of CSF oligoclonal bands is non​specific, in the particular clinical situation it may help to support a clinical diagnosis of multiple sclerosis. They may also be found in infective, neoplastic, paraneoplastic, and granulomatous disorders, and even on occasion in neurodegenerative disorders such as Alzheimer’s disease. Glucose Serum and CSF glucose should be measured concurrently, since the latter is dependent on the former, to provide a CSF:serum glucose ratio which is normally 0.6–​0.8. This ratio may be lower (down to 35%) in the presence of hyperglycaemia in the four hours before lumbar puncture in the absence of neurological disease. Low CSF glucose (hypoglycorrhachia) may be a feature of bac- terial, fungal, or tuberculous (but generally not viral) meningitides, Table 24.3.1.2  Cerebrospinal fluid findings in neurological conditions in which lumbar puncture is frequently performed Opening pressure (mmH2O) WBC/​μl Protein (g/​l) Glucose (mmol/​l)* Acute bacterial meningitis Usually elevated Several hundred to more than 60 000; usually a few thousand, but occasionally <100 (especially meningococcal, or early in disease). Polymorphonuclear cells predominate Usually 1–​5, occasionally >10 0.2–​2.2 in most cases (in the absence of hyperglycaemia) Viral meningitis Normal to moderately elevated 5 to a few hundred; but may be >1000, particularly with lymphocytic choriomeningitis. Lymphocytes predominate, but there may be >80% polymorphonuclear cells in the first few days Frequently normal or slightly elevated; <1; may show greater elevation in severe cases Normal (may be reduced in some cases of mumps) Tuberculous meningitis Usually elevated; may be low with dynamic block in advanced stages Usually 25–​100; rarely more than 500. Lymphocytes predominate except in early stages when polymorphonuclear cells may account for 80% Nearly always elevated, usually 1–​2; may be much higher if dynamic block Usually reduced; <2.5 in three-​quarters of cases Cryptococcal meningitis Usually elevated 0–​800; average 50. Lymphocytes predominate Usually 0.2–​5; average 1 Reduced in most cases; average 1.7 (in absence of hyperglycaemia) Herpes simplex encephalitis Usually elevated 10–​200; lymphocytes predominate Usually 0.6–​6 Normal (rarely reduced) Acute neurosyphilis Usually elevated Average 500. Usually lymphocytes; rarely polymorphonuclear cells Average 1 Normal (rarely reduced) Neurocysticercosis Often increased; low with dynamic block Increased mononuclear and polymorphonuclear cells with 2–​7% eosinophilia in about half of cases Usually 0.5–​2 Reduced in a fifth of cases Neurosarcoidosis Normal to considerably elevated 0 to fewer than 100 mononuclear cells Slight to moderate elevation Reduced in half of cases CNS tumour† Normal or elevated 0 to several hundred mononuclear cells plus malignant cells on cytology Elevated often to high levels Normal or greatly reduced (low in three-​quarters of carcinomatous meningitis cases) Idiopathic intracranial hypertension† Elevated, by definition Normal cell count Usually normal Normal Compare with plasma glucose to calculate CSF:serum glucose ratio. † Brain imaging (CT, MRI) mandatory before undertaking lumbar puncture if these diagnoses are suspected on clinical grounds. Introduction Introduction Jonathan M. Schott 24.5 Epilepsy and disorders of Jonathan M. Schott 24.5 Epilepsy and disorders of consciousness 5860 24.5.1 Epilepsy in later childhood and adulthood 5860 24.5 Epilepsy and disorders of consciousness CONTENTS 24.5.1 Epilepsy in later childhood and adulthood  5860 Arjune Sen and M.R. Johnson 24.5.2 Narcolepsy  5882 Matthew C. Walker 24.5.3 Sleep disorders  5886 Paul J. Reading 24.5.4 Syncope  5896 Andrew J. Larner 24.5.5 The unconscious patient  5901 David Bates 24.5.6 Brainstem death and prolonged disorders of consciousness  5908 Ari Ercole, Peter J. Hutchinson, and John D. Pickard 24.5.1  Epilepsy in later childhood and adulthood Arjune Sen and M.R. Johnson ESSENTIALS Epilepsy is a common, serious neurological disease, with a preva- lence 1% and a cumulative lifetime risk of 5%. An epileptic seizure is a transient occurrence of signs and/​or symptoms due to abnormal excessive or synchronous neuronal ac- tivity in the brain. Epilepsy is defined as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition. Traditionally epilepsy was diagnosed after a patient had two or more unprovoked seizures. However, a more modern definition of epilepsy would also include patients who have had an isolated seizure and have evidence for an enduring alteration in the brain that increases the likelihood of future seizures such as an ‘epileptiform’ electroencephalogram abnormality or an appropriate lesion on structural brain imaging (computed tomography or mag- netic resonance imaging). Epilepsy cannot, though, be diagnosed unless there has been at least one clinical event compatible with an unprovoked seizure. Pathophysiology Epileptic seizures are thought to arise at cortical sites. Focal (previ- ously referred to as partial) seizures begin in one part of the brain; generalized seizures infer widespread, bilateral cortical involve- ment from onset. Underlying mechanisms have been best defined for generalized absence seizures, where a thalamocortical circuit is responsible for generating synchronous burst firing of neur- ones. In different types of epilepsy, roles for specific ion channels (e.g. voltage-​dependent calcium channel, (T-​channel)), recep- tors (e.g. GABAA-​receptors), and neurotransmitters (e.g. serotonin) have been suggested, but modern genetic research is increasingly implicating other aspects of synaptogenesis in the aetiology of epi- lepsy. Epilepsy may occur solely as the result of an inherited predis- position (formally referred to as ‘idiopathic epilepsy’ but increasingly referred to as ‘genetic epilepsy’), or as a consequence of a congenital or environmentally acquired brain injury. Genetic inheritance is complex for most genetic epilepsies, although important mendelian disorders are recognized. Clinical features—focal seizures Epileptic seizures can be variously classified in terms of their ana- tomical substrate (focal, multifocal, or generalized) or according to the extent of functional impairment, focal impaired awareness aware. Focal impaired aware seizures are not synonymous with temporal lobe seizures and may occur with focal seizures arising from elsewhere in the brain. Examples of focal aware seizures in- clude focal sensory or motor seizures, occipital lobe seizures with visual hallucinations, mesial temporal seizures including transient disturbances of memory such as déjà vu or other psychic phe- nomena, or lateral temporal seizures involving simple auditory hal- lucinations. Focal seizures with impaired awareness are those with altered or loss of conscious awareness. In the case of temporal lobe seizures various automatic activities or movement (automatisms) may occur (of which the patient is unaware). Temporal lobe focal impaired awareness seizures usually evolve slowly over seconds to minutes, whereas other focal seizures, such as those arising from frontal lobes, may have abrupt onset. 24.5.1  Epilepsy in later childhood and adulthood 5861 Clinical features—​generalized seizures These include (1) bilateral tonic–​clonic seizures—​the tonic phase is associ­ated with contraction of axial and then limb muscles; clonic movements appear and slowly increase in amplitude; finally, all movements cease, and the patient is flaccid. Injury is common; urinary and/​or faecal incontinence may occur. Confusion and disorientation are usual when the patient wakes. (2)  Absence seizures—​activity suddenly ceases (behavioral and speech arrest) for 10–​20 s, but without loss of posture. (3) Myoclonic seizures—​ brief, shock-​like contractions of muscle, occurring either in a gen- eralized or focal distribution. (4) Atonic seizures—​result in sudden loss of muscle tone and patients may crumple to the floor like a rag doll. (5) Tonic seizures—​associate with patients having sudden posturing of the arms or falling stiffly like a tree being felled. The terms ‘grand mal’ for tonic–​clonic seizures and ‘petit mal’ for ab- sence seizures should no longer be used. Status epilepticus—​defined as a single prolonged seizure or suc- cessional seizures without recovery of consciousness between attacks. The duration of continuous seizure activity that should be treated as status epilepticus has been recently redefined and is ex- plored more formally in this chapter. Investigation First seizures should be assessed from a general medical perspec- tive, with urgent and careful consideration given to the possibility of an underlying life-​threatening condition such as encephalitis. Acute underlying medical emergencies (stroke, encephalitis, meta- bolic precipitants, most particularly hypoglycaemia, arrhythmia, and forth) should be carefully excluded. All patients with a suspected first seizure must have an electrocardiogram (ECG). Subsequent key investigations are often electroencephalography and structural imaging (usually magnetic resonance imaging). The diagnosis of epilepsy confers important implications and should be made by an epilepsy-​competent service. Treatment Whether the patient requires anti-epileptic drugs or not is judged on the likelihood of having further seizures, For a patient with a single generalized tonic–​clonic seizure, no risk factors for seizures, normal electroencephalogram, and normal MRI brain imaging, their chance of further seizures is approximately 50% over the next two years, with the bulk of the risk falling within the first 6 months after the first seizure. If all such patients with a first seizure were treated, then approximately 50% of patients will have been treated unneces- sarily as they were not destined to have a further seizure. However, if a first seizure is associated with a clear epileptiform abnormality on the electroencephalogram, or occurred in the presence of an appropriate structural brain lesion (such as a tumour), treatment with antiepileptic drug therapy may be indicated. Epidemiological studies have shown that the presence of two or more seizures in- dicates a high risk of further seizures, and it is this epidemiological principle that informs the usual practice to treat following a second epileptic seizure. Treatment decisions should be made by an epilepsy-​ competent service, and carefully considered and discussed with the patient. Patients with first seizures or epilepsy must be informed of driving regulations. The choice of anticonvulsant is informed by individual patient circumstances, as well as national and local guidelines such as those from the UK National Institute of Health and Clinical Excellence. Broadly, for generalized epilepsy (tonic–​clonic, absence, or myoclonic) sodium valproate is an appropriate first choice in men. In women of childbearing potential and generalized epilepsy, lamotrigine or levetiracetam are often considered as first-​line agents. For focal seiz- ures, with or without generalization, carbamazepine, lamotrigine, and levetiracetam are probably the drugs of choice. Many new antiepileptic drugs have been introduced over the last 20 years: each has an individual role and profile of unwanted effects. Antiepileptic drug therapy can pose specific problems in relation to pregnancy, drug withdrawal, driving and long-​term adverse effects (such as increased fracture risk) requiring expert management. Status epilepticus is a medical emergency and special consider- ations apply. Definitions An epileptic seizure is a transient occurrence of signs and/​or symp- toms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is therefore a disorder of neuronal networks and is defined as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobio- logical, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure and evidence for an enduring alteration in the brain that increases the likelihood of future seizures such as an ‘epileptiform’ electroencephalogram (EEG) abnormality, an appro- priate lesion on structural brain imaging (CT or MRI), or the pres- ence of recurrent (two or more) unprovoked seizures. Excluded are febrile seizures and neonatal seizures (the latter are defined as those occurring in the first 4 weeks of life), and acute symptomatic seizures such as those arising from acute brain injury or hypoglycaemia. Epidemiology Incidence Most reported incidence rates for epilepsy lie between 40 and 70/​ 100 000. Age-​specific rates show a bimodal distribution, with the first peak in the first two decades, and a second peak in later life. In the developed world the incidence is highest in the older popu- lation and as populations age across the world, the prevalence of epilepsy will rise. Prevalence Prevalence figures for epilepsy lie between 4 and 10/​1000, with higher rates in low to middle income countries. Cumulative inci- dence (or lifetime prevalence) rates, excluding febrile seizures, are higher, producing a figure up to 5% in old age. Sex Males have slightly higher prevalence rates than females. Socioeconomic status Higher prevalence rates have been reported in the lower socio­ economic groups, in both developed and developing countries. section 24  Neurological disorders 5862 Pathophysiology Inherent in any discussion of epilepsy mechanisms is the need to de- fine a homogeneous population of patients in whom epilepsy occurs. Generalized tonic–​clonic seizures, for example, can occur with many different epileptic syndromes. Epileptic seizures are thought to arise at cortical sites: focal seizures begin at one point in the cortex and generalized seizures infer widespread, bilateral, cortical involvement from the start. An interictal discharge occurs when a group of pyr- amidal neurons is synchronously activated. During the discharge, the cells develop a large and prolonged depolarization, which is termin- ated by a hyperpolarizing potential. It is conceived that the generation of synchronized neuronal activity results from an imbalance between inhibitory (γ-​aminobutyric acid (GABA)-​mediated) and excitatory (glutamate-​mediated) neurotransmission, the latter prevailing. The underlying mechanisms behind epileptic discharges have been best defined for absence seizures where a thalamocortical circuit is re- sponsible for generating synchronous burst firing of neurons. The cir- cuit involves neocortical pyramidal neurons, thalamic relay neurons, and neurons of the nucleus reticularis thalami. The last are exclusively GABA in type. A  voltage-​dependent calcium channel (T-​channel) appears critical in allowing burst firing of neurons. After activation, the T channels acquire repolarization via GABAB-​receptors present on thalamic relay neurons. GABAA-​receptors also play an important regulatory role in synchronized thalamocortical burst firing. Less information is available on the pathophysiological mechan- isms of generalized convulsive seizures. Roles for GABAA-​receptors and altered serotoninergic neurotransmission have been suggested. Recently, inflammatory mechanisms have been implicated in both the occurrence of focal epilepsy following brain injury and in main- tenance of focal epilepsy, which may provide future opportunities for disease modification in epilepsy and potentially even prevention of epilepsy in high-​risk groups. Classification In 2010 the ILAE (International League against Epilepsy) revised the previously widely accepted 1981 classification of epilepsy. The new classification has been much more controversial than its predecessor and has struggled to gain universal acceptance. A further modification to try and ensure more clarity was made in 2017. Given these changes, the ILAE have therefore created an online guide to help with classifica- tion and terminology (https://​www.epilepsydiagnosis.org/​index.html) In essence, epilepsy can be divided into generalized epilepsy where there are discharges in both hemispheres, although these can be asym- metric, or focal epilepsy where discharges begin in one hemisphere and may spread or secondarily generalize to involve both hemispheres (Table 24.5.1.1). Traditionally focal seizures where consciousness was not impaired were termed ‘simple partial seizures’ and those where consciousness was impaired (or there was any loss of contact with environs) were termed ‘complex partial seizures’. In the 2010 classi- fication, the latter were termed focal dyscognitive seizures and such seizures are now termed focal impaired awareness seizures. However, although it has wide ranging implications (e.g. for driving) it can be very difficult to determine whether consciousness is affected during a focal seizure. While remaining a source of active discussion, many now term seizures which have a focal onset ‘focal seizures’ and then comment on whether, as best as can be determined, there is or is not loss of awareness. The 2017 classification tried to operationalise this while acknowledging that further delineation beyond a seizure having focal onset might be difficult. Previous simple partial seizures should now be referred to as focal aware seizures while complex partial/focal dyscognitive seizures should be termed focal impaired awareness seiz- ures. Secondary generalized seizures are now called 'focal to bilateral tonic clonic' and if it is not possible to determine the type of seizure this should be referred to as an unclassified seizure. The 2010 classification had proposed that generalized epilepsy be named ‘genetic generalized epilepsy’ rather than ‘idiopathic gener- alized epilepsy’. Clinicians have found this difficult as the underlying genetic basis for generalized epilepsy is still being disentangled and defining a condition as common as generalized epilepsy as ‘genetic’ might engender concern and stigmatization in patients. In the current chapter, ‘focal epilepsy’ will be used for seizures arising from a focus and ‘generalized epilepsy’ for seizures with bi-​ hemispheric origin. The terms ‘cryptogenic’, ‘symptomatic’, ‘petit mal’ and ‘grand mal’ should all now be avoided. Despite disagreements over terminology, every effort should be made to define each seizure type a patient experiences, even if in descriptive rather than technical language, to determine the underlying aetiology of the epilepsy and to classify a patient’s epilepsy as far as practicable. Clinical features Focal seizures Focal motor seizures Any part of the body can be affected by a focal motor seizure, ac- cording to the cortical site of origin of the discharge. Sometimes the seizure remains localized to the same area (e.g. the hand) and some- times it ‘marches’ along the motor cortex, producing successional Table 24.5.1.1  Summary of classification of epilepsy, 2017 I. Focal seizures A. Without impairment of consciousness or awareness (previously termed simple partial seizures) With motor onset (automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, tonic) With nonmotor onset (autonomic, behaviour arrest, cognitive, emotional, sensory) B. With impairment of awareness (previously termed complex partial seizures) C. Focal seizures evolving to bilateral tonic-clonic seizure (previously termed secondarily generalized seizure) II. Generalized seizures Motor (tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, epileptic spasms) Nonmotor/absence (typical, atypical, myoclonic, eyelid myoclonia) III. Unknown onset Motor (tonic-clonic, epileptic spasms) Nonmotor (behaviour arrest) IV Unclassified (seizures where it is not possible to be more specific owing to inadequate information or inability to place in other categories) Motor (tonic-clonic, epileptic spasms) Nonmotor (behaviour arrest) 24.5.1  Epilepsy in later childhood and adulthood 5863 jerking of contiguous body parts (Jacksonian seizures). During the focal stage, consciousness is preserved. With secondary generaliza- tion (i.e. diffuse secondary bilateral spread) consciousness is lost. The parts of the body most commonly affected by this type of seizure correlate with their area of representation in the motor cortex, so isolated focal seizures of the foot, for example, are relatively un- common (the foot motor homunculus being relative small). Other focal motor disturbances reflecting epileptic discharges include ro- tation of the head and eyes contralaterally (from the dorsolateral prefrontal cortex), and head turning with arm extension on the same side (supplementary motor cortex). After such seizures there may be paralysis of the affected part lasting for minutes or hours (Todd’s paresis), but prolonged focal weakness following a seizure should not be automatically attributed to Todd’s paresis. Focal sensory seizures Seizures emanating from the sensory cortex produce paraesthesiae or numbness. The seizure can march in an analogous fashion to a motor seizure and, similarly, can then become generalized. When the tongue or face is involved, the symptoms are sometimes felt bilat- erally. More complex sensory phenomena may be experienced and, with discharges in the second sensory area, the limb sensations can be ipsilateral, contralateral, or bilateral. Occipital lobe seizures Visual symptoms predominate, usually as simple, rather than com- plex, phenomena. The latter phenomena, producing alteration of size, shape, or depth of objects, are associated with seizures arising at the occipitoparietotemporal interface. In addition, there may be ocular deviation, jerking, or forced closure of the eyelids. Visual hal- lucinations may occur. Frontal lobe seizures Frontal lobe seizures are commonly nocturnal and frequently as- sociated with turning to a prone position. Vocalization is common and tends to consist of a continuous monotone with moaning or grunting. An aura before the attack is unusual. Other recognized features include pelvic thrusting, rocking of the body, bicycling leg movements, and head movements. Rapid postictal recovery is common. Temporal lobe seizures The distinction between different types of focal seizures is blurred, based as it is on evidence of altered consciousness (Fig. 24.5.1.1). Olfactory, gustatory, and vertiginous sensations occur. The taste and smell sensations are sometimes pleasurable but often disagree- able. A metallic taste is common. Abdominal sensations also occur, which are typically ill-​defined, and may ascend to the chest and throat from the epigastrium. Psychic symptoms are more often as- sociated with focal seizures with loss of awareness. There may be intense pleasure or fear ushering in the attack. The patient can ex- perience a sense of loss of personal or environmental reality (de- personalization and derealization, respectively). There may be a sense of intense familiarity (déjà vu) or unfamiliarity (jamais vu). Pg1 Pg2 F3 Fz F4 F8 T3 O2 C3 C2 C4 C T4 T6 P4 Pz P3 T5 F7 O P 4 Fp1 Fp2 Fp2–F8 100 µV F8–T4 T4–T6 T6–O2 Fp1–F7 F7–T3 T3–T5 T5–O1 T4–C4 C4–Cz Cz–C3 C3–T3 T4–RSp RSp–LSp LSp–T3 1 s ECG1–ECG2 03/03/1992 LF = 0.5 Hz HF = 40 HZ File D: \LASER\pp001.P01 23:21:57 23:21:58 23:21:59 23:22:00 23:22:01 23:22:02 23:22:03 23:22:04 23:22:05 23:21:56 Fig. 24.5.1.1  Ictal spike and slow-​wave complex in a patient with focal impaired awareness seizures. The discharges are particularly apparent over the left temporal lobe (T3 to T5), but there are some independent discharges over the right temporal lobe (T4 to T6). Record kindly provided by Professor David Fish. section 24  Neurological disorders 5864 Epileptic déjà vu is typically unpleasant. Epileptic anger is un- provoked and rapidly subsides and tends to associate with other features of temporal lobe epilepsy such as olfractory or gustatory halluncinations. Illusions are encountered, in the form of dis- ordered visual perceptions, and visual or auditory hallucinations, sometimes of considerable complexity. Where consciousness is disturbed, various automatic activities or movements that the patient is unaware of (automatisms) may occur. These may take the form of eating (chewing or swallowing), speaking, gesture, or more elaborate skilled activities. Manual au- tomatisms, if unilateral, tend to be ipsilateral to the seizure focus. When elaborate, the patient may partly undress, or move about from one room to another. The symptomatology of mesial and lateral temporal lobe discharges has been distinguished, the latter having somatosensory, visual, or auditory manifestations in addition to the other features mentioned earlier. Sometimes automatic movements are also seen with absence seizures. Other, rarer focal seizure types are confined to childhood. In be- nign childhood epilepsy with centrotemporal spikes, consciousness is preserved. The sensory phenomena are usually confined to the mouth where motor activity may also occur. Speech arrest occurs if the dominant hemisphere is affected. In Panayiotopoulous syn- drome, which occurs in otherwise unaffected children, seizures are characterized by predominantly autonomic symptoms and seizures may be prolonged. The EEG shows variable and moving foci, often with occipital predominance. Any of the focal epilepsies can lead to secondary generalization. Consciousness is lost, and a bilateral convulsive seizure is the usual outcome. Prolonged focal seizures (epilepsia partialis continua) lead to a repetitive or continuous focal motor activity that may last for weeks or months and is most often the consequence of a focal cortical insult. Generalized seizures Bilateral tonic-clonic seizures Some patients report a premonition for hours or even days before the attack. These symptoms are usually a vague sense of loss of well-​being and do not necessarily imply a focal origin for the attack. Similarly, a brief aura lasting a few seconds before the onset does not necessarily imply focal origin for the attack (although it should raise this possi- bility). The tonic phase of a convulsion is associated with contraction of axial and then limb muscles. If upright, the patient can fall heavily. Injury is common. Contraction of the jaw can lead to tongue injury and in this context the tongue is frequently lacerated laterally or the inside of the cheek may be bitten. Forcible contraction of the dia- phragm results in a sudden gasp or epileptic cry. Cyanosis results from a loss of respiratory activity. Subsequently clonic movements appear and slowly increase in amplitude. Gradually, periods of relaxation intervene between the clonic contractions until finally all movements cease. The patient is then flaccid. Urinary or faecal incontinence, or both, may occur at this stage. Subsequently the patient is liable to sleep, often heavily. If the patient wakes, initial confusion and disorientation are usual. Headache and muscle pains are common. Incomplete forms occur in which the clonic or tonic phase predominates. In addition to injuries incurred in falling, and those resulting from biting of the cheeks or tongue the seizures may be of such violence that vertebral compression fractures occur. Sudden death occurring soon after a tonic–​clonic seizure is a recognized, although rare, complication. Absence seizures Patients are unaware of their absence seizures. Activity suddenly ceases but without loss of posture. Adventitious movements occur (e.g. slight contractions of the eyes or some lip movement). The head may drop slightly. More typically, the patient simply stares blankly and is unresponsive. Attacks last around 10 to 20 s and are accompanied by a 3 Hz spike-​and-​wave discharge on EEG recording (Fig. 24.5.1.2). In some cases, more overt limb movement occurs. Atypical absences are defined as attacks that begin less abruptly, last longer, and frequently lead to loss of postural tone. They usually coincide with other seizure types. Absence seizures begin in child- hood and usually cease in adult life, although 50% of patients will later develop tonic–​clonic seizures. In some absence seizures there may be additional features such as eyelid myoclonia, a particular feature of Jeavon’s syndrome. Myoclonic seizures Myoclonus consists of brief, shock-​like contractions of muscle, occurring in either a generalized or a focal distribution. Cortical myoclonus is usually less than 50 msec in duration. Many forms of myoclonus are not epileptic. Those associated with epilepsy are ac- companied by an ictal EEG discharge. In primary generalized epi- leptic myoclonus, the myoclonus is accompanied by diffuse cortical epileptic discharges and has an early morning preponderance, usu- ally occurring within the first hour of two after waking, and more likely to occur if the patient is tired or has taken alcohol to excess. Atonic/​tonic seizures Atonic seizures result in sudden loss of muscle tone. If the hypotonia is generalized, falls occur, often with substantial injury. The attacks begin in infancy or childhood. The episodes are brief and recovery rapid unless injury has occurred. Tonic seizures, which may be seen in conditions such as tuberous sclerosis, consist of sudden stiffening and posturing of arms or of abrupt falls to the floor. A  possible clinical distinction is that in atonic seizures patients crumple like a rag doll while in tonic seiz- ures, they fall like a tree being felled. Status epilepticus Status epilepticus has recently been redefined. Traditionally status epilepticus was defined as a single seizure lasting more than 30 min or successional seizures without recovery of consciousness between. However, there is now an appreciation that if a seizure is longer than 5 minutes in duration, then it should be treated aggressively. In status epilepticus, the seizures are usually convulsive, but both focal impaired awareness seizures and absence seizures can occur in the form of status epilepticus. In such cases, alteration of the conscious level is likely to be the major clinical feature with little motor activity, particularly with absence seizures. Epilepsy syndromes The need to define epileptic syndromes arises from the fact that in- dividual seizure types may be a manifestation of several differing 24.5.1  Epilepsy in later childhood and adulthood 5865 conditions, all with individual characteristics and prognosis. The epileptic syndrome is based on a combination of seizure type, presumed localization (according to clinical features and EEG characteristics) and age of onset. Causes of epilepsy In most surveys, approximately 60% of epilepsy will have no cause other than a genetic predisposition with other causes distributed mainly among cerebral vascular disease, trauma, brain tumour, central nervous system infection, and developmental disorders. Genetically determined What constitutes an epilepsy gene is a matter of considerable debate. For some genetically determined disorders, epilepsy is only one feature of the condition (for example Tuberous Sclerosis). Many such disorders have features other than epi- lepsy and typically produce significant neurological disability. Examples include forms of progressive myoclonic epilepsy such as those associated with Lafora body disease, mitochondrial disorders, and Unverricht–​Lundborg disease. More relevant, in clinical terms, are those genetically determined conditions in which epilepsy is the sole or major manifestation. Generalized epilepsies The generalized epilepsies (now sometimes termed genetic gen- eralized epilepsies) account for about 30% of all epilepsy. For the vast majority of patients with generalized epilepsy, inheritance is complex and, to date, no common genetic variant has been unequivocally associated with generalized epilepsy, although a few de novo rare mutations associated with the condition have been described. However, our knowledge of genetic risk factors for generalized epilepsy is likely to be transformed in the next few years through the widespread utilization of whole genome sequencing. Focal epilepsies Similarly, genetic focal epilepsies may arise as a result of both men- delian inheritance and (more commonly) complex inheritance. Several forms of familial (mendelian) focal epilepsy have now been identified. Benign familial neonatal seizures are caused by mutations in the potassium channel genes, KCNQ2 and KCNQ3. Benign familial infantile convulsions, which present between four Fp2–F4 100 µV F4–C4 C4–P4 P4–O2 Fp1–F3 F3–C3 C3–P3 P3–O1 Fp2–F8 F8–T4 T4–T6 T6–O2 Fp1–F7 F7–T3 T3–T5 T5–O1 1 s 22:41:23 22:41:24 22:41:25 22:41:26 22:41:27 22:41:28 22:41:29 22:41:30 22:41:31 22:41:32 Pg1 Pg2 F3 Fz F4 F8 T3 O2 C3C2 C4 C T4 T6 P4 Pz P3 T5 F7 O P 4 26/11/1992 LF = 0.5 Hz HF = 40 Hz File D: \ LASER \ hs004.P01 Fp2 Fp1 Fig. 24.5.1.2  Electroencephalogram (EEG) of a typical absence seizure. The first 2.5 s of the record are entirely normal. The event begins with a large downward deflection which records eye closure, immediately followed in all channels by a spike-​and-​wave discharge at a frequency of three cycles/​s. The seizure terminates as abruptly as it began. Record kindly provided by Professor David Fish. section 24  Neurological disorders 5866 and eight months of life, are associated with three loci mapped to chromosomes 19, 16, and 2. Benign familial neonatal infantile seizures, an intermediate clinical variant of the previous two, are associated with mutations of the sodium channel, α2 subunit. Autosomal dominant, nocturnal, frontal lobe epilepsy is a childhood-​onset epilepsy characterized by the clustering of noc- turnal frontal lobe seizures. The syndrome has been associated with mutations in genes coding for the α4 subunit and β2 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4 and CHRNB2). Autosomal dominant, lateral temporal lobe epilepsy is charac- terized by focal seizures with auditory, visual, psychic, or dysphasic symptoms. In some families the condition is linked to mutations in the leucine-​rich glioma-​inactivated 1 (LGI1) gene—​epitempin. Febrile seizures are the most common seizure type in children, with an incidence of 2 to 5%. The inheritance is complex and the clinical pattern heterogeneous. Loci have been reported on chromo- somes 6q22, 8q13–​q21, 19p, 2q23–​q24, and 5q14–​q15. Typically, febrile seizures occur between the ages of 6 months and 3 years. Simple febrile seizures are generalized and last less than 15 min. Complex febrile seizures have focal features, are longer lasting, or recur within a 24-​h period. About two-​thirds of children with fe- brile seizures do not have a recurrence. A proportion of children with febrile seizures develop epilepsy at a later age. Malformations of cortical development Malformations of cortical development are structural brain de- fects that are acquired during cortical development. They are a common cause of drug-​refractory epilepsy in adults. The defect may be global (agyria), hemispheric (hemimegalencephaly), or focal—​ periventricular and subcortical nodular heterotopia and focal cortical dysplasia. The associated epilepsy tends to arise during childhood and adolescence. The seizures may be generalized or focal, and the type of seizure does not necessarily follow the distribution of the malformation. EEG frequently reveals continuous epileptiform discharges in patients with focal cortical dysplasia. MRI can detect particular signal changes in focal cortical dysplasia, although specialized sequences are often required. Trauma Approximately 70% of those individuals who eventually develop post-​traumatic epilepsy will have their first seizure within 2 years of the original injury. Risk factors that predict post-​traumatic epi- lepsy include early seizures (those occurring in the first week), a depressed skull fracture, or evidence of intracranial haemorrhage. There is no justification for the use of prophylactic anticonvul- sants in the hope of preventing the development of post-​traumatic seizures. Tumour Although adult-​onset epilepsy is often equated with the presence of tumour, the cause of developing epilepsy in adulthood, particu- larly in later life is more likely to be cerebrovascular or Alzheimer’s disease. The likelihood of a tumour producing seizures increases as the tumour is sited more anteriorly in the hemisphere, so that over 50% of patients with frontal lobe tumours have epilepsy. Adult-​onset status, in someone without a history of epilepsy, is po- tentially suggestive of frontal lobe tumour. Cerebrovascular disease The prevalence of epilepsy after stroke has been reported to lie be- tween 6 and 15%, and appears as likely with cerebral infarction as with cerebral haemorrhage. Infection In large-​scale surveys, infection has been considered the cause of epilepsy in 3–​5% of cases. Differences in rate between countries are often attributed to the variable prevalence of certain aetiologies (e.g. neurocysticercosis). Other tropical infections that have been con- sidered potential contributors to epilepsy prevalence include mal- aria, schistosomiasis, and trypanosomiasis. Epilepsy is a recognized feature of bacterial, tuberculous, and fungal meningitis and of viral encephalitis. Epilepsy may be the first symptom of a tuberculoma. Dementia Patients with Alzheimer’s disease of mild-​to-​moderate severity have a cumulative incidence of unprovoked seizures of around 8% over a 7-​year period. Seizures are more common in patients with familial Alzheimer’s disease and, while epilepsy was previously considered secondary to neuronal loss in hippocampal structures, there is now evidence that seizures contribute to the aetiopathogeneisis of that neuronal loss. Multiple sclerosis The prevalence of epilepsy in multiple sclerosis (MS) is probably of the order of 2%. Both generalized and focal seizures have been at- tributed to MS. Rarely, status epilepticus, and epilepsia partialis con- tinua have been recorded. Antibody-​mediated epilepsy It is increasingly recognized that certain antibodies associate with epilepsy. In particular, limbic encephalitis associated with anti- bodies to components of the voltage-​gated potassium channel com- plex or to the N-​methyl-​d-​aspartate (NMDA) receptor can associate with seizures. Antibodies to the leucine-​rich glioma-​inactivated 1 protein (LGI1; the same protein implicated in auditory epilepsy) can result in very specific seizure type consisting of brief jerks of the arm and face with dystonic posturing and preservation of aware- ness (see Video 24.5.1.1). So termed facio-​brachio dystonic seizures are considered almost pathognomonic of LGI1 associated disease and treatment with steroids can prevent the patient progressing to a limbic encephalitis. Treatment of antibody-​mediated epilepsy is primarily directed at immunomodulation with steroids, immuno- globulin, plasma exchange and possibly other agents including rituximab and cyclophosphamide. Treatment with antiepileptic medication alone is unlikely to be effective and patients with anti- body-​mediated epilepsy are more prone to developing rashes with antiepileptic medication than other people with epilepsy. Alcohol Alcohol lowers seizure threshold. Seizures may occur during binge drinking or during a period of withdrawal after alcohol excess. Long-​term alcoholism may predispose to chronic epilepsy, although the extent to which this is due directly to the alcohol itself or to 24.5.1  Epilepsy in later childhood and adulthood 5867 the consequences of alcoholism, such as brain injury, are unclear. Patients with epilepsy should be counselled not to drink to excess, in particular to not binge consume alcohol and to remain within government recommended limits on alcohol consumption. Metabolic disorders Seizures may occur in association with hypocalcaemia, hyper­ calcaemia, hypomagnesaemia, hypoglycaemia, hyponatraemia, and hypernatraemia. Severe renal and hepatic failure can both precipitate seizures. Certain drugs are considered to lower seizure threshold and are relatively contraindicated in patients with epilepsy. Examples include the tricyclic antidepressants, the phenothiazines, and isoniazid. Rapid withdrawal of barbiturates or benzodiazepines (perhaps particularly clonazepam) can trigger seizures in those without a history of epilepsy. Precipitants of epilepsy Recognized precipitants of epilepsy include inadequate sleep, al- cohol abuse and ingestion of certain drugs. In catamenial epilepsy the attacks are confined to around the menstrual period. Seizures confined to sleep are well recognized and sleep EEG recordings are characteristically more likely to register abnormal discharges than recordings made in the alert individual. In reflex epilepsy, attacks are triggered by a particular stimulus. Precipitants include photic stimulation, startle, noise, and movement. Rarer forms of reflex epilepsy have been linked to musical passages, reading, eating, showering in hot water and performance of certain mental tasks (e.g. Mah Jhong epilepsy). Differential diagnosis Syncope Misdiagnosis of syncope as epilepsy is common, and many refer- rals to ‘first seizure’ clinics are for people who have had a syncopal blackout rather than an epileptic seizure. Syncope is thus an im- portant differential diagnosis of seizures, and familiarity with the clinical features of syncope is mandatory if diagnostic errors are to be minimized. Syncope tends to occur from the standing pos- ture and after exposure to provoking factors such as seeing blood or pain. Most individuals who faint experience a characteristic set of symptoms before loss of consciousness. These include feelings of light-​headedness, mental slowing, fading of vision, altered hearing (particularly sound diminution), malaise, and sweating. The process is the result, in varying combination, of bradycardia and profound arterial vasodilatation in skeletal muscle. Unless the individual lies down, loss of consciousness occurs, and the patient falls to the ground. Characteristically the fall is gentle, and self-​injury relatively uncommon. In falls associated with convulsive or tonic seizures, the fall is precipitate and injury much more likely. Not uncommonly, in faints, there may be brief clonic jerks of the limbs or multifocal myo- clonus, lasting a few seconds, and following the loss of posture. The eyes tend to remain open. Lateral head turns, repetitive movements (such as lip licking), and hallucinations are all recognized features. After the episode there may be brief confusion and feelings of weak- ness, but these rapidly resolve. If, on the other hand, the upright posture is maintained (e.g. a soldier on parade) then stiffness of the limbs or repetitive generalized shaking may occur which are virtu- ally indistinguishable from the movements occurring with epilepsy. Usually, however, a true tonic–​clonic sequence does not occur in these circumstances. Incontinence of urine is common in syncope, and on its own does not differentiate between syncope and seizures. Micturition syncope Micturition syncope occurs predominantly in older males, but can affect any age group. The attacks are almost always nocturnal, often after an evening of alcohol consumption. Onset is usually during, or shortly after micturition. The warning symptoms are often brief. The attacks seldom occur frequently; if they do, then the individual, if male, is advised to micturate in the sitting position. Cough syncope Patients with cough syncope effectively perform Valsalva’s man- oeuvre during a bout of prolonged coughing. Treatment is directed at the underlying chest condition. Driving restrictions beyond those for simple vasovagal attacks apply. Cardiac syncope Various cardiac abnormalities, all having in common the end re- sult of failing cardiac output and reduced cerebral perfusion, are associated with syncopal attacks. Mechanisms include complete heart block, paroxysmal ventricular tachycardia or fibrillation, and supraventricular tachycardia or bradyarrhythmia. In add- ition to disorders of rhythm, abnormalities of ventricular con- tractility or obstruction of outflow can have a similar outcome, usually when increased output is required during a period of ex- ertion. Rarely, pedunculated masses within the heart (e.g. an atrial myxoma), cause outflow obstruction when the patient assumes certain postures. Features suggesting that a cardiac lesion may be responsible for a syncopal attack include a history of cardiac dis- ease, palpitations, dyspnoea, or chest pain in association with the attack and the finding of cardiac abnormalities on clinical exam- ination. This exemplifies the need for all patients with a presumed first seizure to have a thorough cardiological examination and an electrocardiogram (ECG). Separate from these mechanisms are cases of syncope associated with postural hypotension. Autonomic failure resulting in pos- tural hypotension is a feature of multiple system atrophy, certain neuropathies with autonomic fibre involvement, such as diabetes, and drug therapy (e.g. with phenothiazines and tricyclic antidepres- sants). The correct diagnosis is usually readily established from the history. Carotid sinus syncope Patients with this condition usually present with either vertigo or syncopal attacks. The syncopal attacks are sometimes followed by flushing and may be triggered by pressure over the neck (e.g. during neck rotation). In most patients, the syncope is related to atrioven- tricular block or asystole. Occasionally, a pure vasodilator reaction occurs, with peripheral pooling of blood. Notably, while tachycardia is common with seizures, some pa- tients become bradycardic or even asystolic following seizures and section 24  Neurological disorders 5868 in patients with frequent seizures and concerning symptoms (pro- longed cyanosis after an event) there should be a low threshold for cardiac monitoring. Detection of significant ictal arrhythmia war- rants discussion with the cardiologists about consideration of pace- maker insertion. Transient ischaemic attacks These attacks should seldom be confused with epilepsy. In some patients with carotid occlusion (or severe stenosis), attacks of limb shaking occur in which involuntary limb movements described as shaking, trembling, or twitching occur, usually for seconds. The movements, which are coarse and irregular, predominate distally. Sometimes the attacks coincide with limb weakness or speech dif- ficulty. It is rare for patients with transient ischaemic attacks to lose consciousness. The attacks are not influenced by anticonvulsants but can be relieved by endarterectomy where there is an underlying sig- nificant carotid stenosis. Migraine Loss of consciousness is a recognized feature of basilar migraine. The condition presents in children or adolescents. The headache is occipital. Visual disturbances are common, along with altered sen- sations (typically bilateral), ataxia, and dysarthria. Typically the pa- tient, if unconscious, can be roused. Rarely, tonic–​clonic seizures are seen with the attacks. Hyperventilation Most patients with the hyperventilation syndrome do not develop carpopedal spasm or tetany. Rather, they have a constellation of symptoms that are liable to be confused with other conditions such as epilepsy. Those symptoms include dizziness or vertigo, weakness, paraesthesiae, chest pain, and altered consciousness. Probably some 5 to 15% of patients lose consciousness during hyperventilation, but never with a tonic–​clonic progression that would cause real diag- nostic difficulty. Narcolepsy and cataplexy Narcolepsy is defined as excessive daytime sleepiness, often occurring under unusual circumstances. The onset of sleep is usu- ally preceded by a feeling of tension, tiredness, or a noise in the head. In some patients, onset occurs without warning. At times, patients have periods of semiautomatic behaviour for which they may sub- sequently be amnesic. Cataplexy is typically triggered by sudden arousal. Attacks are brief and may lead to such loss of muscle control that the patient falls. During the attack, the patient is flaccid, the eyes may roll or di- verge, and the facial muscles flicker. Despite this, the patient usually remains fully alert. The parasomnias Parasomnias are largely confined to children. They consist of either abnormal motor activity or excessive autonomic activity. Motor ac- tivity includes sleep myoclonus, bruxism and head banging. Sleep myoclonus produces repetitive leg contraction, typically dorsi- flexion of the feet. It increases with age and is usually idiopathic. Head banging, which may coincide with body rocking, is usually only seen in children or infants. The movements, which typic- ally occur in clusters, are often accompanied by various forms of vocalization. In most cases, the child is otherwise unaffected. Sleep terrors usually happen within the first hour or two of sleep, occur in children, and result in a sudden cry followed by anxiety, tachycardia, sweating, and hyperkinesis. The child is not completely aware of the episodes, which sometimes necessitate short-​term treatment with benzodiazepines. Dissociative seizures Dissociative seizures, also termed non​epileptic attacks or psycho- genic non​epileptic seizures, sometimes occur in isolation, or less frequently in those with epilepsy. They account for up to 20% of the patients referred to specialist epilepsy units, usually with a diagnosis of refractory epilepsy. The condition is more common in women than in men, although both sexes are affected. People with dissocia- tive seizures may have a past personal history of psychiatric disorder, a history of suicide attempt(s), evidence of sexual maladjustment, and current depressive symptoms. Certain features from the history should alert the physician to the diagnosis. The attacks more commonly take place with witnesses present. They develop gradually rather than suddenly, and the move- ments displayed are often unpredictable and bizarre. The eyes are usually closed during the attacks. Attempts to constrain the patient may be resisted, or there is other evidence for consciousness during the attack such as being able to squeeze the hand of a bystander if asked to or being able to recollect things during a period of reported loss of consciousness. Vocalization; incontinence, and tongue biting are commonly reported, and self-​injury is a recognized feature. Typically dissociative seizures are difficult to control. Obtaining a hand held video of an attack, which should only be done within the limits of safety, can be helpful, but in some cases videotelemetry is necessary to differentiate epileptic from non​epileptic seizures. Non​epileptic seizures are not voluntary and require treatment in their own right. That treatment should be psychologically rather than pharmacologically-​mediated. Early confirmation of the diag- nosis and referral to a skilled psychologist or psychiatrist is likely to improve outcome. Investigations Investigation of a patient with suspected epilepsy (or a single seizure) is performed for three main reasons: the investigation may provide valuable support for the diagnosis, it may give an indication as to which part of the brain initiated the seizure and imaging may help determine the underlying structural process, where such exists. Cardiac examination and routine ECG should be undertaken in all patients with suspected epilepsy to avoid treatable structural or electrical abnormalities of the heart being missed. Electroencephalography (EEG) Certain caveats about the EEG must be understood before interpret- ation is attempted. Epileptiform discharges are encountered in be- tween 0.5 and 4% of individuals who have never had a seizure and who do not do so during a period of follow-​up. Furthermore, a rou- tine EEG in adults with established epilepsy shows epileptiform ab- normalities in only 40 to 50% of cases. With repeat recording, with or without sleep records, the figure rises to 70–​80%. Therefore, some patients with unequivocal epilepsy will have persistently normal 24.5.1  Epilepsy in later childhood and adulthood 5869 or, at least, non​epileptic EEGs. Serial EEG recording is sometimes helpful in an attempt to define the origin of the seizure and to better delineate the seizure type. If photosensitivity is suspected (10% of in- dividuals with seizures occurring between 1 and 7 years are photo- sensitive), serial recordings are appropriate, as they also are in any individual with atypical status or in whom cognitive impairment might be due to subclinical epileptic activity. Where surgical inter- vention is being planned for epilepsy, routine and sleep recordings are followed by videotelemetry in order to record individual attacks. Magnetoencephalography (MEG) localizes focal epileptic discharges by measuring the changes in the extracranial magnetic fields that these discharges generate. The system costs around 25 times as much as a conventional EEG system and has limited availability. Although in most patients spikes can be detected on both MEG and EEG, in certain patients spikes are seen with only one or other technique. For some patients, depth electrodes will be needed to establish the seizure source and define the epileptogenic zone. Depth electrodes are positioned stereotactically at sites determined by clinical and sur- face EEG criteria. Depth recordings are more accurate and sensitive in detecting focal discharges than scalp recording, but associate with a defined risk and careful consideration by a multidisciplinary team should be made before intracranial recording is performed. The EEG has also been used to attempt prediction of seizure recur- rence in individuals after a single seizure of unknown cause. Epileptic discharges, in one series, predicted a seizure recurrence over 2 years of 83%, compared with a 12% rate in individuals with a normal re- cording. The EEG has also been used to predict seizure recurrence during or after drug withdrawal in someone whose epilepsy has gone into remission on medication. The predictive value of EEG abnor- malities in such cases has varied widely from series to series. CT Neuroimaging is carried out in order to define whether a structural abnormality underlies the patient’s epilepsy and, if so, whether some additional treatment, other than anticonvulsants, might be required. CT scanning was originally the most frequently used imaging pro- cess, before the more widespread availability of MRI. MRI is advo- cated in all patients with epilepsy, other than for those epilepsies that are clearly generalised in onset (e.g. absence seizures, juvenile myoclonic epilepsy, and benign rolandic epilepsy) or when it is not practical to do so (e.g. severe learning disability, severe dementia). MRI MRI is both more sensitive and more specific than CT in detecting and defining brain lesions and abnormalities of the cerebral cortex thought to be relevant in the genesis of epilepsy, perhaps par- ticularly malformations of cortical development (Fig. 24.5.1.3). Protocols setting out to achieve high sensitivity and specificity re- quire T1-​weighted, thin-​slice volumetric sequences, T2 FLAIR (fluid-​attenuated inversion recovery), and high-​resolution T2 spin echo. All coronal sequences need to be oriented orthogonal to the long axis of the hippocampus. The most common abnormalities detected are hippocampal sclerosis, malformations of cortical de- velopment, vascular malformations, tumours, and acquired cortical damage. MRI is particularly indicated in focal seizures, onset of generalized or unclassified seizures in adult life, patients with fixed focal clinical or neuropsychological deficit, and for those patients with poor seizure control. Quantitative measures of the hippocampi improve the diagnostic sensitivity of MRI for hippocampal sclerosis. MR spectroscopy (MRS), examining nuclei 31P and 1H, has been used for assessment of patients with focal seizures for possible sur- gery. Functional MRI is commonly used to localize the motor cortex before resection of adjacent neocortex, to lateralize language func- tion, and to help predict the consequences of temporal lobe resec- tion on memory. Single-​photon emission computed tomography As a result of its poor time resolution, ictal perfusion SPECT usually displays both the ictal onset zone and the seizure propagation path- ways. Although it has been assumed that the region with the most (b) (a) Fig. 24.5.1.3  (a) CT and (b) MRI: the readily visible cavernome on MRI is only just visible on CT. section 24  Neurological disorders 5870 intense hyperperfusion is the ictal onset zone, this is not necessarily the case. The earlier the injection is given after seizure onset, the more likely it is that the most intense focus represents the ictal onset zone. Analysis of ictal SPECT is usually done in comparison with an interictal SPECT image using a variety of techniques. Positron emission tomography Interictal fluorodeoxyglucose positron emission tomography (FDG-​ PET) has proved a valuable tool in the presurgical evaluation of pa- tients with refractory focal epilepsy. FDG-​PET appears to be superior to standard MRI in the detec- tion of neuronal migration disorders. Sequential scans indicate a correlation between the extent of cortical glucose hypometabolism on PET and the quality of epilepsy control. Besides measurement of cerebral blood flow and regional cerebral glucose metabolism, PET can be used to assess the distribution of specific receptors—​ such as the benzodiazepine–​GABAA-​receptor complex, using [11C] fluamzenil (FMZVD) (Fig. 24.5.1.4). It appears that abnormalities in FMZVD are also linked to the pattern of recent seizure activity. 15O-​labelled water PET is likely as reliable as the intracarotid amytal (Wada) test for language lateralization, but this role is being rapidly supplanted by functional MRI. It has been suggested that high uptake of α-​[11C]methyl-​l-​ tryptophan (AMT) on PET occurs in a subset of epileptogenic tubers in patients with tuberous sclerosis, consistent with the loca- tion of the seizure focus. Treatment: Drug therapy Choice of drug therapy Several principles can be stated in relation to drug therapy. Does the patient require anticonvulsants? The issue of whether isolated seizures should be treated remains un- resolved. Seizure recurrence rate after a single seizure reaches 80% in untreated individuals, the vast majority recurring within 2 years of onset. Many patients prefer to defer treatment after a single seizure until at least investigations are complete. Were the EEG to show frank epileptiform discharge or the MRI show a salient lesion, further dis- cussions should be held about starting an antiepileptic drug. Similar discussions should take place after a second seizure even if investiga- tions are normal. It is important to engage the patient fully in these ini- tial discussions as antiepileptic medications are a long-​term treatment with potential side effects and good concordance with the medication is essential. For a patient who has very infrequent seizures, say five or more years apart, it may seem logical to withhold medication. Choice of anticonvulsant An algorithm can provide some guidelines regarding drug treat- ment (Fig. 24.5.1.5). For generalized seizures (tonic–​clonic, absence, or myoclonic) sodium valproate is the drug of choice in males with lamotrigine or levetiracetam being favoured in women of childbearing potential owing to the potential teratogenicity associated with sodium val- proate. Topiramate, zonisamide, and perampanel are also used in generalized epilepsy. Ethosuximdie can be very effective for absence seizures and clonazepam can help with myoclonic jerks. Myoclonus can be exacerbated by carbamazepine, gabapentin, pregabalin and, in some cases, lamotrigine. Absence seizures can be worsened by carbamazepine and gabapentin. For focal seizures, with or without generalization, carbamazepine, lamotrigine, and levetiracetam are first-​line agents. If one of these does not suit, then an alternative first-​line agent can be explored. Fig. 24.5.1.4  Positron emission tomography (PET) scan showing a region of probable cortical dysplasia in the right temporal lobe. The [11C]fluamzenil volume of distribution (FMZVD) is an index of γ-​aminobutyric acid A (GABAA)-​receptor density. Epilepsy diagnosis confirmed Generalised epilepsy (GGE/IGE) Focal epilepsy +/- secondary generalisation 1st line treatments: Valproate in men Lamotrigine/ Levetiracetam in women 1st line treatments: Carbamazepine Lamotrigine Levetiracetam If not seizure free: Alternative first line agent or Topiramate Perampanel Zonisamide If not seizure free: Alternative first line agent or Clobazam, Lacosamide, Oxcarbazepine, Perampanel, Topiramate, Zonisamide; Brivaracetam, Eslicarbazepine, Pregabalin, Gabapentin, Acetazolamide Clonazepam for myoclonus Ethosuximide for absence seizures Refer all pharmacoresistant focal epilepsy to an epilepsy surgery programme Vagal nerve stimulation can be considered in pharmacoresistant focal epilepsy (if not candidate for resection) or refractory generalised epilepsy Specific treatments, e.g. ketogenic diet should be considered in selected cases Fig. 24.5.1.5  Basic schema of treatment options in epilepsy. 24.5.1  Epilepsy in later childhood and adulthood 5871 There are a myriad of second-​/​third-​line agents, including clobazam, eslicarbazepine, gabapentin, lacosamide, oxcarbazepine, perampanel, pregabalin, topiramate, and valproate. Phenytoin and phenobar- bitone are not drugs of choice for long-​term prescribing in modern epileptology. Choice, especially of adjunctive therapy, is often influenced by comorbidity and side effect profile. In addition, determining which drug to try will be influenced by the patient’s age, sex (regarding the use of oral contraceptives and likelihood of pregnancy), reliability of adherence to a particular drug regimen and the patient’s own wishes. Dosage Although standard dose regimens tend to be quoted, many anticon- vulsants are sometimes effective in relatively low doses. Accordingly the drug is introduced in low dosage, which is then gradually in- creased according to need and tolerance. Sometimes only dosages that lead to toxic serum levels appear effective. Some patients tol- erate such toxic levels without difficulty. Failure of first drug Initially, a single appropriate medication should be commenced. Should that not be effective or associated with side effects, a second agent should be added and uptitrated. Once the second medication is at therapeutic dose, the first can be weaned away. One change at a time should be made wherever possible and all medications should begin at a low dose and titrate up slowly (start low, go slow principle). An exception to this is if a patient develops a rash with an anti-epileptic drug which generally mandates prompt withdrawal of the offending agent. Clobazam can be helpful to cover such drug withdrawal. Drug combinations If drugs given individually have failed then drug combinations should be considered, remembering that they may interact with each other. However, nowadays all patients who have pharmacoresistant epilepsy (incomplete seizure control despite adequate trial of two appropriate medications) should be referred to a specialist epilepsy centre for evaluation. This applies to generalized epilepsy and focal epilepsy. In all cases this is to help with diagnostic clarity and in patients with focal epilepsy to consider whether epilepsy surgery may be indicated. Generic prescribing In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA) have given guidance on generic pre- scribing. If possible, a patient should be initiated on a generic version of an antiepileptic drug and it is perhaps preferable to keep to that generic version when feasible. Some patients can only tolerate one formulation of a medication, be that generic or branded, and those patients should be enabled to continue on their preferred formulation. Controlled re- lease medications should remain as the same formulation. The problem of adherence Lack of adherence is a significant problem with anticonvulsants and is a potent cause of poor control. A full explanation of each drug’s side effect profile and its potential interactions is essential and ap- pears conducive to improved compliance. Drugs that are given once or twice a day are preferred to ones needing more frequent prescrip- tions. Slow-​release preparations allow drug regimens to be simplified. Mechanisms of action At a mechanistic level, epilepsy is often viewed as an imbalance be- tween excitatory and inhibitory neurotransmission with an excess of the former and a lack of the latter (Fig. 24.5.1.6). Antiepileptic drugs suppress seizures but are not antiepileptogenic, namely they do not alter the underlying process that causes the seizures. There are three main targets for antiepileptic medications, modu- lation of voltage-​gated ion channels, potentiation of GABA-​medi- ated inhibition, and reduction of glutamateric excitation. Several commonly utilized antiepileptic drugs act on voltage-​ gated sodium channels. Phenytoin, carbamazepine, oxcarbazepine, eslicarbazepine, lamotrigine, and can all reduce the rate of recovery from inactivation of depolarized voltage-​dependent sodium chan- nels, thereby blocking sustained repetitive firing of action potentials in depolarized neurons. Lacoscamide also acts on sodium chan- nels although on slow inactivating channels, rather than the fast inactivating sodium channels that the others target. Topiramate, zonisamide, and valproate also act on sodium channels although these three medications have multiple sites of action, potentially ex- plaining their role in treating multiple seizure types. Voltage-​dependent calcium ion currents are thought to be of im- portance in the genesis of epileptic events. Ethosuximide acts by in- hibition of one class of voltage-​dependent calcium ion currents (T currents) and is a drug of choice for the treatment of absence seiz- ures. Similarly, valproate and zonismaide may also have an effect on T calcium channels and be effective in absence epilepsy. The now withdrawn retigabine targeted voltage-​gated potassium channels. The prime role of GABA-​mediated inhibition in the epileptic process implies that drugs that enhance GABAA-​receptor-​medi- ated inhibition will have anticonvulsant activity. Both barbiturates and benzodiazepines act by potentiating GABAA-​mediated in- hibition. The barbiturates bind to the β subunit to potentiate ac- tion of endogenous agonist GABA and prolong the opening time of the chloride ion channel. Benzodiazepines bind to the α sub- unit to potentiate the action of GABA and increase the frequency of opening of the chloride ion channel. GABA is metabolized by GABA transaminase. Vigabatrin irreversibly binds to GABA transaminase to inhibit degradation of GABA while tiagabine pre- vents removal of GABA from the synaptic cleft by blocking GABA transport. Gabapentin acts presynaptically to promote GABA synthesis or release. Many other drugs including valproate and topiramate have also been implicated in influencing GABAergic function. The second major neurotransmitter system involved in the genesis of epileptic activity is excitatory utilizing glutamate and, perhaps, aspartate as neurotransmitters. They act on several different recep- tors including α-​amino-​3-​hydroxy-​5-​methylisoxazole-​proprionic acid (AMPA) and NMDA. The NMDA receptor is activated by glu- tamate or aspartate together with glycine. Blockade of the NMDA receptor results in antiepileptic effects. Felbamate probably acts, at least in part, through its effects on the NMDA receptor. However, the only currently available antiepileptic drug to specifically target glutamaterigc signalling is peramapnel which is a non​competitive AMPA anatagonist. Other modes of action include levetiracetam binding to synaptic vesicle protein 2A and medications, such as topiramate, zonisamide, and acetazolamide, being carbonic anhydrase inhibitors, and thereby section 24  Neurological disorders 5872 attenuating excitatory neurotransmission through increased local bicarbonate concentration. Selected drugs See Table 24.5.1.2. Carbamazepine Carbamazepine is a first-​line drug for focal seizures. It can also be used in the treatment of convulsive seizures in generalized epilepsy, but may make absence seizures and myoclonus worse. It should be prescribed in controlled release formulation whenever possible. Dosage typically ranges from 400 mg/​day to 1600 mg/​day. A drug rash occurs in perhaps 3% of patients and demands drug withdrawal. The rash is particularly seen in the Han Chinese population, espe- cially those with the HLA-​B1502 allele. Other side effects include dizziness, blurring of vision, double vision, balance difficulties, and gastrointestinal disturbance. Leucopenia occurs and can lead to a frank aplastic anaemia. Hyponatraemia and oedema are recognized features, associated with a mild degree of inappropriate antidiuretic hormone production. The drug influences atrioventricular conduc- tion and should not be given to patients with atrioventricular con- duction abnormalities unless they are already paced. The relationship between dosage and plasma concentrations is linear meaning that, unlike other antiepileptic medications, carbamazepine levels gener- ally correlate with efficacy and tolerability. Carbamazepine is a liver enzyme inducer and is potentially teratogenic. Lamotrigine Lamotrigine is licensed for both generalized and focal seizures. Lamotrigine too is a first-​line drug for focal epilepsy and for women with generalized epilepsy who are of child bearing poten- tial. Occasionally it exacerbates myoclonus. Doses seldom exceed 400 mg/​day, although up to 600 mg daily may be used. A drug rash occurs in about 3% of patients. Lamotrigine interacts with enzyme-​ inducing anticonvulsants, which lower its plasma level. Valproate enhances lamotrigine levels and therefore lamotrigine should only be introduced slowly in patients already taking valproate. The drug can be given once daily. Originally said to be non​teratogenic, recent studies suggest that this is not the case. Levetiracetam Levetiracetam is an increasingly used antiepileptic drug for both focal and generalized epilepsy. Levetiracetam is a first-​line agent for focal epilepsy and for generalized epilepsy in women of childbearing Propagated action potential Gabapentin Pregabalin Benzodiazepines Barbiturates Postsynaptic neuron Retigabine has now been withdrawn GABAA receptor AMPA receptor Retigabine Levetiracetam Brivaracetam Voltage-gated Na+ channel Na+ Depolarization Vesicular release SV2A GABA GAT-1 α2δ-subunit of Ca2+ channel Ca2+ K+ Also inhibits glial GAT-1 KCNQ K+ channel K+ Ethosuximide T-type Ca2+ channel Glutamate Cl– Na+ Ca2+ KCNQ K+ channel Inhibitory synapse Not illustrated: Vigabatrin → ↓ GABA degradation and drugs with multiple mechanisms: Topiramate → ↓ Na+ channels, ↓ AMPA/kainate receptors, ↑ GABAA receptors Felbamate → ↓ Na+ channels, ↑ GABAA receptors, ↓ NMDA receptors Valproate → ↑ GABA turnover, ↓ Na+ channels, ↓ NMDA receptors Excitatory synapse Retigabine Tiagabine Phenytoin Carbamazepine Oxcarbazepine Eslicarbazepine acetate Lamotrigine Lacosamide Zonisamide Perampanel Fig. 24.5.1.6  Mechanism of action of antiepileptic medications. Antiepileptic medications operate through a variety of molecular mechanisms with effects on both inhibitory (left hand side) and excitatory (right hand side) nerve terminals. AMPA, α-​amino-​3-​hydroxy-​5-​methyl-​4-​isoxazole propionic acid; GABA, γ-​aminobutyric acid; GAT-​1, sodium-​ and chloride-​dependent GABA transporter 1; SV2A, synaptic vesicle glycoprotein 2A. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Neurology. Löscher, W. & Schmidt, D. (2012) Perampanel—​new promise for refractory epilepsy? Nat. Rev. Neurol. 8, 661–​2, copyright © 2012; modified with permission from Macmillan Publishers Ltd © Bialer, M. & White, H. S. Nat. Rev. Drug Discov. 9, 68–​82 (2010). 24.5.1  Epilepsy in later childhood and adulthood 5873 Table 24.5.1.2  Characteristics of commonly used antiepileptic drugs in adults Name Indication Initial dose Titration schedule Usual daily therapeutic dose Common side effects* Particular features Brivaracetam Adjunctive therapy in focal epilepsy 50 mg bd Initial dose is therapeutic. Maximum dose 100 mg bd 100–​200 mg daily Dizziness, fatigue, gastrointestinal disturbance, somnolence Derivative of Levetiracetam Cannot be used in combination with Levetiracetam. Can start at lower than therapeutic dose also and up-titrate Carbamazepine (slow release generally preferred) Focal epilepsy Can help with convulsions in generalized epilepsy 200 mg (100 mg in older patients) 200 mg every 2 weeks 400–​1200 mg Rash, dizziness, ataxia, blurring of vision, gastrointestinal difficulties, hyponatraemia Rash more common in Han Chinese(HLA-​B1502 allele) Enzyme inducer Monitor vitamin D Can exacerbate absences and myoclonus Clobazam Adjunctive therapy all types, but especially focal epilepsy 10 mg 10 mg every two weeks 20–​40 mg Drowsiness Behavioural change especially in patients with learning difficulties Can be used at times of vulnerability e.g. with intercurrent infection Clonazepam Myoclonus 1 mg 1 mg every 2 weeks 2–​8 mg Drowsiness Avoid abrupt withdrawal as risk of seizures Eslicarbazepine Adjunctive therapy in Focal epilepsy 400 mg nocte 400 mg every two weeks 800–​1200 mg Rash. Similar side effect to Carbamazepine but more prone to cause hyponatraemia Rash more common in Han Chinese (HLA-​B1502 allele) Enzyme inducer Monitor Vitamin D Ethosuximide Absence seizures 250 mg 250 mg every 2 weeks 1000–​1500 mg Ataxia, rash, blood dyscrasias, GI disturbance Only for absences Predominantly used in paediatric practice Gabapentin Adjunctive therapy in Focal epilepsy 300 mg 300 mg every 2 to 3 days 600–​1200 mg tds Dizziness, drowsiness Well tolerated, but efficacy perhaps less than mainstay AEDs Lamotrigine Focal epilepsy Generalized epilepsy 25 mg 25 mg every 2 weeks 100–​500 mg Rash is common (1 in 30 risk), GI disturbance, tremor, effect on sleep Interaction with valproate. Start 25 mg alternate days if patient taking valproate. Monitor levels in pregnancy May sometimes worsen myoclonus Levetiracetam Focal epilepsy Generalized epilepsy All seizure types 250 mg 250 mg every 2 weeks 1000–​3000 mg Irritability Effect on sleep No pharmacokinetic interactions Lacosamide Adjunctive therapy in Focal epilepsy 50 mg 50 mg every 2 weeks 100–​400 mg Nausea, dizziness, palpitations, effect on mood Check PR interval on ECG before starting Oxcarbazepine Adjunctive therapy in Focal epilepsy 300 mg daily 300 mg every two weeks 600–​2400 mg Rash. Similar side effect to Carbamazepine but more prone to cause hyponatraemia Enzyme inducer Monitor vitamin D Perampanel Adjunctive therapy in Focal epilepsy Generalized epilepsy 2 mg nocte 2 mg every 4 weeks 6–​12 mg Dizziness, balance difficulties, effect on mood Long half-​life Targets glutamatergic signalling Phenytoin All forms of epilepsy Now only started in emergency setting 300 mg nocte N/​A 300 mg day Higher doses are used Rash, gingival hypertrophy, hirsutism, diplopia, ataxia, GI disturbance, coarsening of facial features. In longer-​term neuropathy and adverse impact on bone health Not a drug of choice for long-​term prescribing Non​linear pharmacokinetics Enzyme inducer Monitor vitamin D (continued) section 24  Neurological disorders 5874 Name Indication Initial dose Titration schedule Usual daily therapeutic dose Common side effects* Particular features Phenobarbital All forms of epilepsy Now only started in emergency setting 60 mg 15 mg every 2 weeks 60–​180 mg Rash, effect on cognition, effect on mood, ataxia Gradual introduction and slow withdrawal. Cognitive slowing can be significant hence now rarely initiated Monitor vitamin D Pregabalin Adjunctive therapy in Focal epilepsy 25 mg bd 25 mg every week 200–​600 mg Drowsiness, ankle oedema, weight gain, dry mouth Also anxiolytic and often prescribed for neuropathic pain Sodium Valproate Generalized epilepsy Also effective in focal epilepsy 200 mg to 300 mg bd 200 mg steps every 3 to 7 days 1000–​2500 mg Weight gain, hair changes, thrombocytopaenia, tremor, encephalopathy (check ammonia), liver dysfunction Particularly teratogenic Aim to avoid in women of childbearing potential May cause acute pancreatitis Monitor vitamin D Topiramate Adjunctive therapy in Focal epilepsy Generalized epilepsy 25 mg nocte 25 mg every 2 weeks 100–​500 mg Effect on cognition, effect on mood, paraesthesiae, weight loss, renal stones, Rarely rash Advise to hydrate well If patient presents with acute red eye, consider acute closed angle glaucoma Thought to be particularly teratogenic, although not as high risk as valproate Zonisamide Adjunctive therapy in Focal epilepsy Generalized epilepsy 25 mg nocte 25 mg every 2 weeks 100–​500 mg Rash, GI disturbance, effect on mood, effect on cognition, weight loss, paraesthesiae, weight loss, renal stones Advise to hydrate well Notes: All drugs can cause idiosyncratic reactions and patients should be directed to the product inserts for the full side effect profile Rash is seen with many antiepileptic drugs (AEDs). If a patient develops a rash with an AED, particularly within 12 weeks of starting the medication then medical attention should be sought promptly and consideration given to discontinuation of the drug Many newer antiepileptic medications can associate with an adverse impact on mood and, potentially, unusual or even suicidal thoughts. Patients and carers must be counselled about this possible risk In older people, typically starting and ceiling doses are halved as is the rate of titration. For all patients, medications are started at low dose and gradually escalate to try and minimize side effects In patients taking enzyme-​inducing drugs or valproate, vitamin D levels should be checked and supplemented if the patient is deficient. It has been suggested that all people with epilepsy should take vitamin D supplementation. All AEDs are potentially teratogenic. There is particular teratogenic risk with valproate and topiramate Table 24.5.1.2  Continued 24.5.1  Epilepsy in later childhood and adulthood 5875 potential. It is effective against all generalized epilepsy seizure types. Typical dosing is from 1000 to 3000 mg and sometimes up to 4000 mg daily. The drug has no known pharmacokinetic interactions, has high oral bioavailability, and is given in twice-​daily dosing. Rash is uncommon but does occur. The main disadvantages relate to mood and behavioural changes, with some patients reporting irritability. Other common side effects also include somnolence, asthenia, diz- ziness, and headache. Sodium valproate Sodium valproate is the first-​line treatment in males with generalized epilepsy and seems effective against all generalized epilepsy types as well as being effective in focal epilepsy. The dose ranges from 600 mg/​ day to 2500 mg/​day and it is given twice per day. A slow-​release prep- aration can be given once daily and chronospheres can be mixed with, for example, yoghurt to aid compliance in patients who are resistant to taking medications. Valproate is not enzyme inducing and, therefore, does not influence the metabolism of the oral contra- ceptive. Liver toxicity, ankle oedema and acute pancreatitis are recognized, although rare, hazards. Elevated serum liver enzyme activities are more common, but usually return to normal without the need for drug withdrawal. Thrombocytopenia can be observed. Gastrointestinal effects are fairly common. Nausea and weight loss are seen, but appetite stimulation with weight gain is more common. Tremor occurs as a dose-​related effect and hair loss, of a mild de- gree, is not uncommon; after a few months, hair regrowth occurs, often more curly than before. Sedation is less troublesome than with other anticonvulsants. Disturbances of menstruation are recognized. Plasma levels are not a useful guide to efficacy. Valproate, particularly at doses above 800 mg daily is potently teratogenic, meaning that should not be given to women of child bearing potential unless alter- native antiepileptic drugs have been explored. Second-​ and third-​line agents Acetazolamide Use of this drug is largely confined to childhood epilepsies. Brivaracetam Brivaracetam is the most recently licensed antiepileptic medication. A derivative of levetiracetam, it does not require up-​titration and initial dose of 50 mg bd is therapeutic. Maximum dose is 100 mg bd. Potential side effects include dizziness, gastrointestinal difficulties, fatigue, and somnolence. It must not be administered concomitantly with levetiracetam. Clonazepam Clonazepam is effective for tonic–​clonic seizures but is particularly valuable in the treatment of myoclonic epilepsy. Sedation is a major problem, and the drug must be introduced cautiously. Similarly abrupt withdrawal can result in seizures. The maximum tolerated dose is about 8 mg/​day. Clobazam Although it was thought that tolerance to clobazam can develop fairly readily, many patients continue to derive benefit from the medication on a long-​term basis. Typical dosing is from 10 to 40 mg daily with principal side effects being dizziness and drowsiness. It is often used intermittently at times of seizure vulnerability, for example, at times of intercurrent infection or when travelling on holiday or around the time of menses. Eslicarbazepine Eslicarbazepine is a derivative of carbamazepine and shares common features to carbamazepine and oxcarbazepine. It is licensed as ad- junctive therapy in focal epilepsy with total daily dose typically being between 400 and 1200 mg daily taken as a single bedtime dose. Side effect profile is similar to carbamazepine. Both eslicarbazepine and oxcarbazepine are more likely to associate with hyponatraemia than carbamazepine. Ethosuximide Ethosuximide is only used in the treatment of absence seizures. Gastrointestinal disturbances are common along with drowsiness, dizziness, and ataxia. Agranulocytosis or aplastic anaemia has rarely been encountered. The dose range is usually 1–​1.5 g daily. Gabapentin Gabapentin is used as add-​on therapy for focal seizures with or without secondary generalization. Up to 4.8 g is given in three div- ided doses. The drug is generally well tolerated and has limited drug-​ drug interaction. Its anticonvulsant effect appears to be relatively weak, but it can be effective for some patients. Lacosamide Lacosamide causes slow inactivation of sodium channels and is an adjunctive therapy in focal epilepsy. Typical daily dosing is 100–​400 mg daily with main side effects being dizziness, headaches, gastro- intestinal disturbance, and double vision. Lacosamide can prolong the PR interval and a baseline ECG to evaluate any conduction dif- ficulties is mandatory before initiation of lacosamide. Although drug-​drug interactions are not reported, there does appear to be a pharmacodynamic interaction with sodium channel blockers such as carbamazepine and oxcarbazepine. Oxcarbazepine This drug is closely related to carbamazepine but is a less potent hepatic enzyme inducer. It is licensed as monotherapy or ad- junctive therapy in focal seizures with or without secondary gener- alization. Its side effect profile is similar to that of carbamazepine although it is more prone to cause hyponatraemia than carbamaze- pine. Patients who are hypersensitive to carbamazepine should not receive oxcarbazepine. The dosage range lies between 600 and 2400 mg daily, in adults. Perampanel Perampanel is the only currently licensed antiepileptic drug to target the AMPA receptors, thereby modulating glutamatergic transmis- sion. It was initially licensed as adjunctive therapy for focal epilepsy, but in 2015 was also granted a licence for generalized epilepsy. It is taken once daily with effective doses being between 4 to 12 mg nocte. Potential side effects include dizziness, lethargy, and an effect on mood. Pregabalin Similar to gabapentin, pregabalin binds to the α2δ subunit of the voltage-​dependent calcium channel in the central nervous system. It is used as adjunctive therapy in focal seizures with or without section 24  Neurological disorders 5876 secondary generalization. It is thought to have anxiolytic effects and this may make it more suitable for some patients with psychological comorbidity. Typical doses in epilepsy prescribing range from 100 to 600 mg in two doses. Adverse effects include dizziness, drowsiness, weight gain, blurred vision, and ataxia. There are no interactions with other anticonvulsants. Topiramate This drug is licensed both for primary generalized tonic–​clonic seizures and as adjunct therapy for focal seizures. The total daily dose (given as a twice-​daily regimen) typically ranges from 100 mg to 500 mg daily. Nausea, anorexia, and weight loss are encoun- tered. Behavioural disturbances are reported, including emotional lability, mood change, and aggression. Topiramate can affect cog- nition, associating particularly with word finding difficulty. There is an increased incidence of renal stones in those taking the drug. Importantly, topiramate is thought particularly teratogenic, al- though risk is not as high as with high-​dose valproate. Zonisamide Zonisamide has multiple modes of action. Its effect appears to come through action at sodium and calcium channels. It is licensed as adjunctive therapy in patients with focal seizures with or without secondary generalization and can be effective in generalized epi- lepsy. Daily dosing is usually between 100 to 500 mg daily. The side effect profile is not dissimilar to topiramate with common side ef- fects including dizziness drowsiness, an effect on mood, an effect on thinking, weight loss, paraesthesiae, and renal stones. The drug is a sulphonamide and various toxic effects have been described including Stevens–​Johnson syndrome. It is teratogenic. Antiepileptic medications, now rarely used in long-​term prescribing Felbamate Felbamate is licensed for use in focal seizures. The drug has serious side effects, including liver failure and aplastic anaemia, and should only be used by specialized centres and for patients in whom it is clear that the benefits outweigh the risks. Phenobarbital Phenobarbital is a very effective anticonvulsant but often badly tol- erated and again should not be a long-​term agent in modern epi- lepsy prescribing. Phenobarbitione affects cognition, mood, and behaviour adversely. Children may become hyperactive on the drug and adults (particularly older people) heavily sedated. Doses of up to 180 mg/​day are used. It has a long half-​life and can be given once daily. Rapid withdrawal of phenobarbital in patients who do not have epilepsy can trigger seizures. Over-​rapid withdrawal in someone with epilepsy can trigger status epilepticus. Methyl pheno- barbital is largely converted to phenobarbital by the liver and pheno- barbital is the main metabolite of primidone, although primidone’s other metabolite, phenylethylmalonamide, probably possesses anti- convulsant activity. Phenytoin Experience with phenytoin is vast and, despite its side effect pro- file and complex pharmacokinetics, large quantities of the drug continue to be prescribed. The drug is effective in both generalized tonic–​clonic seizures and focal seizures. However, owing to its mul- tiple long-​term side effects, phenytoin is not a drug of choice for chronic prescribing in modern epilepsy practice. Phenytoin has a long half-​life, and can be given once daily. Sedation is common. Toxic effects, generally dose related, include drowsiness, ataxia, con- fusion, blurred vision, and dizziness. Most patients who are intoxi- cated with the drug have nystagmus. Permanent cerebellar ataxia and peripheral neuropathy are recorded. Other side effects or toxic effects include rashes, gum hypertrophy, thickening of the facial fea- tures, chorea, and sleep disturbance. The drug is a potent enzyme inducer and is teratogenic. The relationship between dosage and plasma concentrations is nonlinear. Once the dose exceeds 300 mg/​ day, increments should be limited to 50 mg or even 25 mg at a time. Retigabine Retigabine was licensed as an adjunctive therapy in focal epilepsy. It modulates potassium channels. However, postmarketing surveil- lance revealed a blue discolouration to skin and retina. Consequently, retigabine has been withdrawn. Tiagabine Tiagabine is a GABA uptake inhibitor, resulting in increased syn- aptic GABA levels. The initial dose in adults is 4–​5 mg twice-​daily. Most studies have used 32 to 56 mg/​day, in three divided doses. The drug is licensed as add-​on therapy in refractory epilepsy. Side effects include dizziness, tiredness, tremor, and altered mood. Exacerbations of seizures and cases of non​convulsive status epilep- ticus have been recorded. Vigabatrin Vigabatrin is an effective antiepileptic medication. Dosage should not exceed 3 g/​day. However, owing to its association with idiosynchratic retinal damage it is now not conventionally initiated in adults. Up to a third of patients develop concentric constriction of the visual fields, more marked nasally than temporally. The defect is often asymptom- atic initially and is irreversible. In patients who are still maintained on vigabatrin, regular visual field analysis is mandatory. Antiepileptic drugs continue to be developed and specific drugs for very targeted indications also exist, including stripentol in Dravet’s Syndrome and rufinamide in Lennox Gastaut syndrome. Cannabidiol is also being developed as a potential treatment, par- ticularly for epileptic encephalopathies in the first instance. Particular issues Enzyme induction Drugs that induce liver enzymes (e.g. phenytoin, phenobarbital, carbamazepine) will alter the pharmacokinetics of other agents or drugs that undergo hepatic metabolism. Women taking an oral contraceptive pill need to take a preparation containing at least 50 µg ethinylestradiol. If breakthrough bleeding still occurs, the dose of oestrogen can be increased to a maximum of 100 µg daily. Alternatively, an injectable long-​term contraceptive can be used, or an intrauterine device. The interactions between anticonvulsants are complex—​another reason for avoiding drug combinations where possible and ensuring patients on antiepilepsy drugs are managed and advised by experts. All the enzyme-​inducing anticonvulsants have the potential for accelerating vitamin D metabolism. Those individuals at risk for 24.5.1  Epilepsy in later childhood and adulthood 5877 developing vitamin D deficiency (e.g. due to poor nutrition) are at risk of developing osteomalacia or rickets when taking certain anti- convulsants. It is prudent to check vitamin D levels in patients taking enzyme-​inducing medication, or valproate, and prescribe supple- ments of vitamin D if the patient is found to be deficient. Drug monitoring Anticonvulsant levels are measured far too frequently and most drug levels do not correlate with efficacy or tolerability. There are specific circumstances where the measurement of drug levels is of value: • to ascertain compliance • to monitor dosage adjustment with phenytoin • to ascertain the unpredictable effect of combining anticonvulsant preparations. • in pregnancy for certain medications, particularly lamotrigine and levetiracetam Phenytoin undergoes saturatable hepatic metabolism. Regular moni- toring of the serum level is advisable, particularly after dose adjust- ment. Occasionally, measurement of the levels of carbamazepine and phenobarbital aids management, particularly where epilepsy control has been poor. Carbamazepine epoxide, a metabolite of carbamaze- pine, can sometimes be the cause of carbamazepine toxicity even when carbamazepine levels are in the therapeutic range: this can be a particular concern when carbamazepine is coprescribed with so- dium valproate, since valproate can increase the epoxide metabolite, and here measurement of carbamazepine epoxide levels can be im- portant. The ‘therapeutic ranges’ of the anticonvulsants should be interpreted with caution. Some patients respond to a drug despite ‘subtherapeutic’ levels. Others need toxic levels to achieve seizure control and can often tolerate such levels without overt difficulty. Pregnancy Pregnancy and preconception counselling present special chal- lenges in the management of epilepsy and require expert guidance. In women who develop seizures in pregnancy, eclampsia must be actively excluded. Seizure frequency increases in pregnancy in about a 10% of pa- tients with epilepsy, but most patients who are seizure free at the start of pregnancy will remain seizure free during their pregnancy. It is no longer recommended that vitamin K be given in the last month of pregnancy in women on enzyme-​inducing drugs. Babies should receive i.m. vitamin K as per standard practice. Women who are taking antiepileptic drugs should plan in ad- vance of any future pregnancy when possible and take folic acid 5 mg daily for three months prior to conception and likely through the pregnancy itself. Women are vulnerable to seizures during labour owing to multiple potential provoking factors. They are advised to deliver in hospital, receive adequate analgesia, and be under the care of a specialist obstetric team. There is an increased risk of congenital malformations in women who have taken anticonvulsants during pregnancy (approxi- mately 4–​8% overall risk, compared to a background risk in the general population of 1–​3%). The critical period for development of the major malformations is in the first trimester. The potential teratogencity of antiepileptic drugs for a given woman will depend on the number of drugs taken, the doses of these drugs and the type of drugs being taken. It is generally recommended that women with epilepsy take folic acid 5mg daily for three months prior to conception and through at least the first trimester—particularly if they are taking valproate. Most evidence of teratogenicity has accumulated for phenytoin, phenobarbital, valproate, and carbamazepine. Data on the newer anticonvulsants is emerging. Lamotrigine and levetiracetam do ap- pear to have a favourable teratogenic profile while topriamte appears to have a higher risk than other modern antiepileptic drugs. Data are scarce for many of the more recent antiepileptic drugs. Valproate is the most teratogenic of all the antiepileptic medica- tions. That risk is dose dependent with a significant increase in risk with valproate doses above 800 mg daily. Valproate associates with an increased incidence of neural tube defects along with other mid- line abnormalities such as hypospadias, partial agenesis of the corpus callosum, and ventricular septal defects. The risk approaches 10%. There is evidence that exposure in utero to valproate increases the risk of neurodevelopmental delay and this may affect as many as 30 to 40% of pregnancies exposed to valproate. Use of valproate in women of childbearing potential is a special situation and requires expert opinion and close discussion with the patient. The European Medicines Agency and MHRA have recently strengthened their ad- vice in this regard. They now recommend that all women taking val- proate for epilepsy who are capable of becoming pregnant have at least annual specialist review to consider alternatives to valproate. Should valproate continue then the woman and her treating specialist are required to adhere to the stipulations of the 'prevent' programme which, for example, recommends long term user independent contraception for women who take valproate and could conceive. Monitoring of lamotrigine levels can be helpful as lamotrigne levels can fall precipitously on conception or through the pregnancy. Having a baseline lamotrigine level in women who are seizure free prior to conception allows the clinician to treat to the level and in- crease dosing if required. If the dose of lamotrigine has been ad- justed owing to low levels, then generally women should return to their preconception dosing within 24–​48 hours after delivery. The epilepsy risk in the offspring of an affected patient is around 5% for generalized epilepsy, but may vary according to the precise underlying genetic aetiology. Breastfeeding Breastfeeding is recommended. The concentration of antiepileptic medication in breast milk is very low. If the mother is on a barbit- urate or a benzodiazepine, sedation of the baby is possible. If breast- feeding then ceases abruptly, a withdrawal reaction can occur in the infant with tremor and agitation. Importantly, breastfeeding should be done in a safe environment, such that were the mother to have a seizure while breastfeeding the chance of injury to her or the baby is minimized. Drug withdrawal Generally medication is continued until a minimum of 3–​5-​year period free of seizures has been established. Factors known to pre- dispose to recurrence of epilepsy after drug withdrawal include neurological abnormalities on examination, an underlying struc- tural basis for the epilepsy, the need for multiple drug therapy and a history of difficulty in establishing initial control. The EEG is of limited value in predicting outcome although rather better in chil- dren than in adults. Any drug withdrawal should be gradual, for example over three to six months. Absence seizures in patients with childhood absence epilepsy, but not in juvenile absence epilepsy, section 24  Neurological disorders 5878 usually remit spontaneously in late adolescence. Juvenile myoclonic epilepsy has a greater tendency to recur after drug withdrawal. Driving In the United Kingdom, driving must cease for six months after any type of seizure, providing that the patient has been assessed by an appropriate specialist and no relevant abnormalities found on inves- tigation. If a nocturnal pattern of sleep seizures has been established for one year and there have never been any seizures from wakeful- ness, driving can then continue even if nocturnal seizures are still occurring. If there has been a seizure from wakefulness, the pattern of nocturnal seizures alone must be established for three years be- fore a return to driving. Patients with simple focal seizures alone for more than a year who have no impairment in their ability to act during a seizure and who have never had any other type of seizure may also be eligible to continue to drive. The Driver and Vehicle Licensing Agency (DVLA) prefers patients not to drive during a period of drug withdrawal, and for six months after the withdrawal has been completed. For drivers of large goods vehicles, a five-​year period of seizure freedom must be established, and the criteria de- fined earlier again met. Furthermore, a continuing liability to epi- lepsy must be excluded. All patients with a suspected first seizure should be asked to stop driving until formal evaluation has occurred. In cases where there is uncertainty, discussions should be held with the DVLA about a patient’s possible eligibility to continue to drive. Advice regarding driving alters periodically although the DVLA or other licensing body always remain the final arbiters with regards to driving. Status epilepticus Status epilepticus has very recently been redefined to try and better capture that time is critical and that aetiology is important. The proposed new formal definition is ‘Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-​term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures’. In generalized tonic–​clonic status epilepticus, t1 is typically 5 min- utes and t2 typically 30 minutes. The new definition also includes four axes (seimiology, aetiology, EEG correlates, and age) to help in determining possible aetiologies and thereby hopefully help clinical management. Precipitants of status epilepticus include sudden anticonvul- sant withdrawal and alcohol abuse. Although noncompliance and subtherapeutic drug levels may cause status epilepticus, several studies have established that most individuals with epilepsy who present in status have therapeutic drug levels at or around the time of presentation. At least half of the cases occur in the absence of pre- vious epilepsy and, if refractory, is termed New Onset Refractory Status Epilepticus (NORSE). Status in the absence of previous epi- lepsy is followed by unprovoked seizures in about half the cases. Status epilepticus is a condition with high morbidity and mor- tality. The mortality figures for status epilepticus have varied substantially from series to series. In one prospective, population-​ based study, the overall incidence was estimated at 41 to 61/​100 000 person-​years with a mortality rate of 22%. Incidence rises in older people, as does mortality. From other series, overall mortality rates lie between 8 and 37%. The diagnosis is by no means straightforward. In one study, half the patients transferred to a specialist centre for management of their status were either in ‘pseudostatus’ or in drug-​induced coma. The diagnosis of pseudostatus should be considered if the attacks are atypical or if the status does not respond to initial therapy. Subtle forms of status can also be difficult to recognize, often presenting as coma. Immediate management of the patient must be directed at safety and resuscitation. The patient should be moved away from possible hazards, such as broken glass, an airway established, and oxygen administered. Lorazepam is probably the drug of choice. It is given in a dose of up to 0.1 mg/​kg intravenously (usually a 4 mg bolus, repeated once after five minutes) at the rate of 2 mg/​min. Alternatives include di- azepam (Diazemuls) given intravenously in a dose of 10–​20 mg at a rate of 5 mg/​min. Buccal midazolam may also prove of value where immediate intravenous access is difficult (e.g. in young children and in appropriately supervised non​hospital settings). Simultaneous with the administration of benzodiazepines, blood glucose should be checked and, if necessary, 50 ml of 50% glucose should be administered intravenously. Thiamine (Pabrinex I/​V High Potency) in a dose of 250 mg should be given by slow intravenous injection over 10 min if there is suspicion of alcohol withdrawal. Thiamine can produce an anaphylactic response. In addition to plasma glucose measurement, blood should be taken for urea, elec- trolytes (including calcium and magnesium), acid–​base balance, liver function tests, and full blood count. A serum sample should be stored in case anticonvulsant, alcohol, or toxin levels are required subse- quently. Blood cultures should be performed if the patient is febrile. If immediate therapy is successful and the patient is receiving phenytoin or valproate, those drugs can be given intravenously before reverting to oral therapy. If the patient is not on anticonvulsants, a phenytoin infusion to a dose of 15–​20 mg/​kg in 0.9% sodium chloride should be given at a maximum rate of 50 mg/​min into a large vein can- nulated for single use. An alternative is fosphenytoin, a water-​soluble drug, which is metabolized to phenytoin with a half-​life of 8–​15 min. It is given intravenously in the same dose at 150 mg/​min in order to achieve a comparable effect. The drug is more expensive than pheny- toin but causes less phlebitis and less hypotension, and is better toler- ated. Nowadays levetiracetam is often loaded in the acute setting with data suggesting that the loading dose should likely be between 20 to 60mg/kg. Valproate may also be considered (20 to 30mg/kg). If phenytoin/levetiracetam infusion is unsuccessful, and seizures continue, the patient should be transferred to the intensive care unit and phenobarbital can be considered, given at a loading dose of up to 10 mg/​kg intravenously at a rate not faster than 100 mg/​min. Should seizures persist then anaesthesia will be required with one or more of midazolam, propofol, or thiopentone initially. In super-​ refractory status epilepticus, multiple agents are utilized including levetiracetam, lacosamide, and topiramate as antiepileptic agents and ketamine as an anaesthetic agent. Every effort should be made to identify a cause including full metabolic testing, MRI brain imaging, cerebrospinal fluid analysis, analysis for toxins, and evaluation for mitochondrial disease. All patients with super-​refractory status epilepticus should be evalu- ated for a possible neuroinflammatory/​autoimmune cause to their 24.5.1  Epilepsy in later childhood and adulthood 5879 status epilepticus and treated with immunomodulation (steroids, IVIg, plasma exchange). Patients should ideally be on a neurointensive care unit and must be on an intensive care unit (ITU) with access to regular EEG moni- toring. Intially the aim is for the patient to enter EEG burst suppres- sion and EEG is critical to determining when it may be possible to begin to wean anaesthetic agents. Perhaps most critical to optimal management of patients with re- fractory status epilepticus is good systemic care and full engagement with the intensive care team. Meticulous attention to haemodynamic control, ventilation, feeding, skin care, metabolic parameters, and infection will all help improve outcome. Mortality and epilepsy Patients with epilepsy have an increased risk of death compared with age-​ and sex-​matched controls. Seizures may be fatal owing to injury or drowning. Comorbidity, including psychological comorbidity, is higher in patients with epilepsy and this too can contribute to mortality. Sudden unexpected death in epilepsy (SUDEP) predominates in younger age groups and in those with more severe epilepsy. It is more common in those with poor adherence to medication and if there is concomitant alcohol excess. The median incidence in patients with refractory epilepsy has been estimated at 3.6/​1000. The precise physiological mechanism of SUDEP is not known, but it is recommended that the concepts of SUDEP are discussed with patients with epilepsy at or soon after diagnosis. Surgery Despite optimal treatment, some 30% of patients with epi- lepsy continue to have attacks. For a proportion of patients with pharmacoresistant focal epilepsy resective surgery of the epilepto- genic zone can be considered. A prerequisite in patient selection for surgery is accurate localization of the epileptic discharges and understanding of circumstances where a resection might prove det- rimental in terms of functional deficit. Patients with pharmacoresistant focal epilepsy (pharmacoresis­ tance being defined as ongoing seizures despite adequate trials of two appropriate antiepileptic agents) should be referred promptly to a specialist epilepsy centre for assessment. Localization techniques incorporate seizure semiology, imaging, electrophysiological re- cording, neuropsychometry, and neuropsychiatric evaluation. Mesial temporal lobe epilepsy, secondary to hippocampal scler- osis, is the most common cause of medically refractory focal seiz- ures in adults. Improvements in imaging have revolutionized the care of these patients as the structural abnormality can be better visualized. MRI characteristics of mesial temporal sclerosis include atrophy or increased signal on T2-​weighted images. The presence of atrophy is the best predictor for a good surgical outcome. Besides visual inspection, measurement of hippocampal volume and tech- niques for measuring the T2 signal change are used to improve sen- sitivity. SPECT and PET measure the changes in cerebral blood flow and cerebral glucose metabolism, respectively, that accompany the epileptic process. Both have relatively high sensitivity and moderate specificity for the diagnosis of temporal lobe seizures, but lower sen- sitivity for epilepsy arising at other sites. Interictal PET and ictal SPECT produce very similar results in predicting outcome after temporal lobectomy. Proton MRS can contribute to recognition of the lateralization of the epileptic focus and to the identification of those patients with bilateral changes who are less likely to respond to surgery. Similarly, improvements in MRI criteria have allowed better recognition of areas of focal cortical dysplasia and assist in planning the extent of cortical resection. Continuous surface EEG monitoring is usually undertaken as part of the work-​up for patients being considered for surgical inter- vention. The technique, however, has limitations. It often fails to de- tect seizure activity arising in areas distant from surface electrodes, such as the orbitofrontal cortex and may falsely lateralize foci, par- ticularly in the presence of large lesions. For improving EEG local- ization intracranial recording may be necessary. Depth electrodes are used to sample deeper structures such as the hippocampus. Electrocorticography is performed at the time of surgery. Subdural electrodes, sometimes with depth electrodes, measure directly from the surface of the exposed brain (Fig. 24.5.1.7). In optimal cases, resection of hippocampal sclerosis can offer up to a 70% chance of seizure remission, although longer-​term studies suggest that remission persists in about 50% of cases. Disabling neurological complications after surgery, such as hemianopia, hemi- paresis, or dysphasia, occur in about 1–​2% of patients. Depression and psychosis are recognized complications of temporal lobectomy. Other less commonly performed surgical procedures include neo- cortical resections (e.g. for focal cortical dysplasia), lesionectomies, hemispherectomies, multilobar resections, and corpus callostomy. Hemispherectomy is performed when a diffuse epileptogenic region has been localized within one hemisphere, the other hemisphere being normal. It is rarely performed in adults. As an alternative hemispherotomy has been devised, attempting a complete deaffer- entation of hemispheric neural connections with maximal preser- vation of cerebral tissue. Division of the corpus callosum (typically Fig. 24.5.1.7  Intracranial recording (electrocorticography) can be performed by placing a grid of electrodes over the surface of the brain (as shown here) or by placing depth electrodes into the substance of the brain. Intracranial recording is much more accurate than scalp recording in defining the seizure onset zone. Stimulation through an intracranial grid can also help to delineate eloquent cortex. © Oxford Medical Illustrations, Oxford University Hospitals NHS Trust. section 24  Neurological disorders 5880 anterior corpus callosum) is sometimes performed in patients with severe secondary generalized epilepsy who have disabling drop attacks. Multiple subpial transection disconnects horizontally coursing cortical fibres over 5 mm apart while preserving vertically oriented projection fibres. Although the procedure was designed to reduce postoperative neurological deficit, it is probably less effective in seizure control compared with cortical resection and again is only very occasionally suggested in adult practice. Stimulation therapies Vagal nerve stimulation (VNS) is achieved through the implant- ation of a small stimulator on the left vagus. The exact mechanism of action remains uncertain. The nucleus of the tractus solitarius, the main terminus for vagal afferents, has projections to the locus ceruleus, raphe nuclei, reticular formation, and other brainstem nu- clei, which have been shown to influence cerebral seizure suscep- tibility. In patients with chronic refractory focal seizures who are not amenable to surgical resection, VNS implantation may be con- sidered. VNS is also now indicated for pharmacoresistant general- ized epilepsy. VNS associates with a reduction in the frequency and intensity of seizures, rather than their elimination. Effectiveness also appears to increase with the passage of time. VNS devices also have a magnet that can be swiped across the pulse generator to give an extra stimulation if the start of a seizure is recognized. The ASPIRE SR device has been developed which can automatically detect a rise in heart rate that can be seen associated with a seizure and deliver an extra stimulation without needing ac- tivation by the magnet while more recently the SenTiva VNS device has become available which offers many more programming op- tions. Another modification of the VNS is the transcutaneous VNS device which does not require implantation and electrode placement around the vagus nerve, but rather stimulates the auricular branch of the vagus non​invasively. Deep brain stimulation (DBS) for epilepsy is also being actively developed. The SANTE trial has provided evidence that DBS may be effective in some patients and will likely enter the panoply of surgical treatment options for epilepsy in the near future. Careful patient se- lection for the appropriate surgical intervention and a holistic multi- disciplinary approach to potential surgical candidates is essential. Comorbidity in epilepsy Patients with epilepsy are prone to multiple comorbidities, particu- larly cognitive difficulties, psychological difficulties, and psycho- social difficulties. Systemic illness is also more common in patients with epilepsy. Cognitive difficulties and epilepsy The principal cognitive problem that patients with epilepsy report is memory difficulties. This may relate to the underlying cause of the epilepsy, the seizures or, sometimes, the medication. Standard neuropsychometric assessment may not reveal much deficit as many patients with active epilepsy exhibit accelerated long-​term forgetting. Consequently, patients may perform quite well over testing periods for a few hours, but memory declines more quickly than the general population over the next week or so. Clinically this may manifest by patients watching the same movie two weeks after first seeing the film and not recollecting that they have seen the film before. Many novel antiepileptic medications are ‘cognitively-​neutral’ demonstrating minimal adverse impact on cognition. Older drugs such as phenobarbitone can significantly affect cognition. Valproate can associate with hyperammonemic encephalopathy, which can be improved by lactulose to clear the gut. Topiramate and zonisamide can also affect cognition, the former associating with word finding difficulties. Patients with cognitive difficulties and epilepsy may require re- ferral to a clinical psychologist to help identify specific areas of cog- nitive impairment that might require attention. Psychiatric aspects of epilepsy A substantial proportion of patients with poorly controlled epilepsy are likely to have psychiatric symptoms. One-​third of patients will develop depression and the rate of suicide is increased in patients with epilepsy. Those symptoms may partly reflect the underlying structural process in the brain, the effects of repeated seizures, the effects of any social stigma attached to the diagnosis and as a reaction to the patient’s anticonvulsants. Psychiatric symptoms occurring around the time of the seizures tend to be affective or cognitive if be- fore or with the seizure, but psychotic afterwards. Typically, postictal psychosis occurs following a latent period of one to two days after the seizure. Additional psychiatric morbidity is encountered as an interictal phenomenon. In addition, an adverse psychiatric outcome may follow epilepsy surgery. Antiepileptic medications, particularly modern antiepileptic medications (levetiracetam, lacosamide, perampanel, topiramate, zonisamide) may have an adverse impact on mood. However, cer- tain antiepileptic medications may be mood stabilizing (carbamaze- pine, lamotrigine, valproate) or anxiolytic (pregabalin). Mood difficulties in patients with epilepsy are often inadequately addressed. Modern antidepressants (escitalopram, citalopram, sertraline) tend not to reduce seizure threshold and patients may also benefit from talking therapies. Psychosis or severe psycho- logical difficulties should be managed by psychiatrists experienced in the management of patients with epilepsy. Psychosocial impact of epilepsy Even in the 21st century epilepsy, which was described in Babylonian texts, remains a deeply stigmatized condition. Given its prevalence, this is perhaps surprising. However, epilepsy is generally an episodic condition and therefore can remain a ‘hidden’ disease. The unpredictability of seizures, need for regular treat- ment, driving and potentially employment restrictions all con- tribute to the psychosocial impact upon the person with epilepsy and also their family and friends. It is beholden on those helping in the management of patients with epilepsy to strive to enable pa- tients to achieve their full potential in all spheres. The role of specialist nurses and the general practitioner Optimal management of people with epilepsy requires close liaison across all sectors of care. Studies suggest that an epilepsy specialist nurse, working either in general practice or in association with a hospital clinic, can make a tangible difference to patient care. Where joint care is to be achieved between general practice and hospital, it is vital that there is good quality communication and record 24.5.1  Epilepsy in later childhood and adulthood 5881 keeping. Giving files that document vital information, including their drug regimen, to the patient is valuable. As in other conditions, Patients prefer the continuity of care achievable through seeing the same doctor at each consultation and are more likely to engage with medical advice under those circumstances. Prognosis The prognosis for people with epilepsy who are sufficiently stable to be followed in the community is considerably better than for a hospital-​based population. Fig. 24.5.1.8 records the percentage of patients in remission (defined as being seizure free for five years). Factors that influence outcome adversely include a combination of focal impaired awareness and bilateral tonic-clonic seizures, clustering of seizures, abnormal physical signs, and the presence of learning difficulties. The influence of antiepileptic drugs on the natural history remains unknown and it has been suggested that a proportion of patients with epilepsy enter permanent remission regardless of treatment. Overall care For many patients, shared care among a hospital, a specialist nurse, and a general practice is ideal. Such an arrangement necessitates a reasonable level of epilepsy experience from the GP, allowing many issues to be resolved without recourse to hospital consultation. The complexities of epilepsy care in terms of new drug develop- ments, issues relating to pregnancy, the question of non​epileptic seizures, diagnostic uncertainties, and the potential for surgery for many patients with poorly controlled epilepsy make the case for epilepsy clinics staffed by neurologists expert in the management of epilepsy. FURTHER READING Arruda F, et  al. (1996). Mesial atrophy and outcome after amygdalohippocampectomy or temporal lobe removal. Ann Neurol, 40, 446–​50. Berg AT, Shinnar S (1994). Relapse following discontinuation of anti-​ epileptic drugs: a meta-​analysis. Neurology, 44, 601–​8. Berg AT, et al. (2010). Revised terminology and concepts for organ- ization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–​2009. Epilepsia, 51, 676–​85. Betjemann JP, Lowenstein DH (2015). Status epilepticus in adults. Lancet Neurol, 14, 615–​24. Binnie CD, Stefan H (1999). Modern electroencephalography: its role in epilepsy management. Clin Neurophysiol, 110, 1671–​97. Blümcke I, et al. (2011). The clinicopathologic spectrum of focal cor- tical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia, 52, 158–​74. Crawford P, et al. (1999). Best practice guidelines for the management of women with epilepsy. Seizure, 8, 201–​17. Dedeurwaerdere S, et al. (2012). Finding a better drug for epilepsy: antiinflammatory targets. Epilepsia, 53, 1113–​8. Dichter MA (1994). Emerging insights into mechanisms of epilepsy: implications for new antiepileptic drug development. Epilepsia, 35 Suppl 4, S51–​7. Duncan JS (1997). Imaging and epilepsy. Brain, 120, 339–​77. Fisher RS, et  al. (2005). Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and International Bureau for Epilepsy (IBE). Epilepsia, 46, 470–​2. Fisher R, et al. (2014). ILAE official report: a practical clinical defin- ition of epilepsy. Epilepsia 55, 475–​82. Fisher R, et al. (2017). Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia, 58, 522–30. Goldstein LH (1990). Behavioural and cognitive–​behavioural treat- ment for epilepsy: a progress review. Br J Clin Psychol, 29, 257–​69. Irani S, et al. (2011). Faciobrachial dystonic seizures precede Lgi1 anti- body limbic encephalitis. Ann Neurol, 69, 892–​900. Johnson MR (2011). The genetic contribution to epilepsy: the known and missing heritability. In: Shorvon SD, Andermann F, Guerrini R (eds) The causes of epilepsy, pp. 63–​7. Cambridge University Press, Cambridge. Keezer MR, et al. (2015). Comorbidities of epilepsy: current concepts and future perspectives. Lancet Neurol, S1474–​42. Kotsopoulos IA, et al. (2002). Systematic review and meta-​analysis of incidence studies of epilepsy and unprovoked seizures. Epilepsia, 43, 1402–​9. Krishnamoorthy ES, Brown RJ, Trimble M (2001). Personality and psychopathology in non-​epileptic attack disorder:  a prospective study. Epilepsy Behav, 2, 418–​22. Lempert T, Bauer M, Schmidt D (1994). Syncope:  a videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol, 36, 233–​7. Manford M, et al. (1992). The national general practice study of epi- lepsy applied to epilepsy in a general population. Arch Neurol, 49, 801–​8. Mattson RH, et al. (1985). Comparison of carbamazepine, phenobar- bital, phenytoin, and primidone in partial and secondarily general- ized tonic–​clonic seizures. NJEM, 313, 145–​51. Percentage in remission 80 60 40 20 0 Years after diagnosis 5 6 10 15 20 Fig. 24.5.1.8  Probability of seizure recurrence after a first epileptic seizure. The top curve indicates the percentage of patients achieving a 5-​year period of remission at any time during the 20-​year period of follow-​up. The middle curve refers to those patients in remission for at least the last 5 years at the time of sampling. The difference between the top and middle curves represents those patients who have relapsed after achieving a 5-​year remission. The bottom curve indicates the probability of being in remission while not taking anticonvulsants. The curves flatten off, indicating that remission becomes less likely the longer the seizures persist. Data from the National General Practice Study of Epilepsy, reproduced by kind permission. Neurological complications of systemic disease 637 Neurological complications of systemic disease 6376 Neil Scolding ESSENTIALS Primary neuroimmunological disorders such as multiple sclerosis or the Guillain–​Barré syndrome are well recognized (and described elsewhere in this section), but many diverse systemic inflammatory or immunological disorders also can affect the nervous system. Autoimmune rheumatological disorders (1) Systemic lupus erythematosus—​neurological manifestations include headache, acute or subacute encephalopathy, fits, mye- litis, strokes, and movement disorders (including chorea and other extrapyramidal disorders), ataxia and brainstem abnormalities, cra- nial and peripheral neuropathies, and psychiatric and cognitive disturbances. The risk of stroke is particularly associated with the lupus anticoagulant and the primary antiphospholipid syndrome. (2) Rheumatoid arthritis: mononeuritis, cervical cord compression. (3) Sjögren’s syndrome: sensory neuropathy, myositis, various cen- tral nervous system complications. (4) Reiter’s disease: polyneuritis, radiculitis, various central nervous system manifestations. Vasculitic disorders Neurological features include (1) mixed sensory and motor neuropathy—​usually rapidly progressive and often painful; (2) cen- tral nervous system disease—​protean manifestations reflect focal or multifocal infarction, or diffuse ischaemia. Conditions of par- ticular note include (1) giant cell arteritis—​anterior ischaemic optic neuropathy is a feared and common complication; (2) Behçet’s disease—​cerebral venous sinus thrombosis is one of the more spe- cific serious complications; (3) sarcoidosis—​often manifests with optic and other cranial neuropathies. Other autoimmune disorders (1) Ulcerative colitis and Crohn’s disease—​may be associated with cerebrovascular accidents, epileptic seizures and (rarely) slowly progressive myelopathy. (2) Whipple’s disease—​a wide variety of neurological manifestations is recognized. (3) Coeliac disease—​ malabsorption may lead to neurological sequelae; progressive (spino)cerebellar degeneration is a recognized (but unexplained) complication. (4) Thyroid disease—​hyperthyroidism and myxoe- dema both carry neurological complications (see Chapter 24.21), but thyroid disease may be associated with immunologically driven neurological complications including (1) dysthyroid eye disease—​ Graves’ ophthalmoplegia; (2) Hashimoto’s thyroiditis-​associated encephalopathy. Introduction The range and breadth of diseases of the central nervous system (CNS) caused by immunological, infective, or inflammatory dis- turbances is very large. Involvement of the nervous system in a systemic inflammatory disease is no less common than idiopathic immune disorders. In this account a brief overview is provided; and the aim is not to be comprehensive. One general and rather important point, emerging in recent years, applies to all these diseases. The ever-​increasing exploration and use of monoclonal antibodies directed against key targets in the im- mune system to control inflammatory diseases has brought about a new phenomenon, namely the precipitation of one inflammatory condition in the context of treating another. CNS inflammatory demyelination arising from treatment with tumour necrosis factor (TNF)-α blockade is one example; autoimmune thyroid disease from treating inflammatory demyelination with anti-​CD52 mono- clonal antibodies (alemtuzumab) is another. Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is not rare, with a prevalence of perhaps 30/​100 000. Its incidence has more than tripled over the past 40 years. Like many autoimmune diseases, it occurs far more in women than men (probably over 10 times more, and especially in the childbearing years), and those of African-​Caribbean and Asian racial origin. The neurologist should not (but usually does) omit direct en- quiry and focussed systemic examination to exclude fever and general malaise, skin changes—​classically, the malar butterfly rash and/​or photosensitivity, and large and small joint arthritis. Glomerulonephritis, pleurisy, and pneumonitis, pericarditis and (so-​called) Libmann–​Sachs endocarditis, and haematological disorders—​anaemia, thrombocytopoenia, leukocytopoenia, and 24.22 Neurological complications of systemic disease Neil Scolding 24.22  Neurological complications of systemic disease 6377 the generation of circulating anticoagulants—​also occur. Other la- boratory abnormalities include the presence of a variety of auto- antibodies, including antinuclear antibodies and antinative DNA antibodies. The diagnosis—​particularly for research and therapeutic trial purposes—​is now commonly based on the widely accepted re- vised diagnostic criteria (Table 24.22.1) suggested by the American College of Rheumatology. The presence of any four (or more) of the listed features, ‘serially or simultaneously, during any interval of ob- servation’ (my italics) are sufficient for the diagnosis, with an esti- mated specificity and sensitivity of 96%. Neurological complications Neurological involvement in SLE is seen in perhaps 50% of cases; neurological presentation in perhaps 3% of cases—​although some suggest the true figure is higher. CNS disease is much more common than neuromuscular involvement and is a poor prognostic sign, re- ducing the overall survival figures and representing the third most common cause of death (after renal involvement and iatrogenic causes). An enormous variety of CNS complications can occur, reflecting two broad pathogenetic mechanisms—​thromboembolic (triggered either by changes in endothelial surfaces, or by coagulation dis- turbances, including lupus anticoagulant activity), and more direct autoimmune events affecting the target tissue—​neurones or glia—​in which soluble and cellular mediators are implicated. Headache (including that associated with dural sinus throm- bosis), acute or subacute encephalopathy, fits, myelitis, strokes, and movement disorders (including chorea and other extrapyramidal disorders), ataxia and brain stem abnormalities, and cranial and per- ipheral neuropathies are all seen in the context of SLE. Psychiatric and cognitive disturbances have also long been associated. Stroke, the lupus anticoagulant, and the primary phospholipid syndrome The thrombotic tendency in patients with SLE and lupus anti- coagulant manifests itself principally in the form of stroke and recurrent spontaneous abortion. Intra-​abdominal and deep venous thrombosis, and peripheral arterial thrombosis are also seen. Thrombocytopoenia is a key additional feature. Importantly, Hughes also showed that a similar clinical picture was associated with the presence of anticardiolipin antibody and/​or lupus anticoagulant in patients without serological or clinical evidence of SLE, and introduced the term ‘antiphospholipid syndrome’. ACAs represent an independent risk factor for stroke. CNS thrombosis in patients with primary or secondary antiphospholipid syndrome takes the form of completed arterial stroke, repeated transient ischemic attacks, multi-​infarct dementia, and cerebral venous sinus thrombosis. Vascular visual problems, including am- aurosis fugax and ischaemic retinopathy, also occur. Chorea too is associated with antiphospholipid antibodies; but the putative link with migraine may be a false association. A severe acute ischaemic encephalopathy is also described, with confusion, obtundation, a hyperreflexic quadriparesis (usually asymmetrical), with, or without, systemic disturbances (dermato- logical and renal). Cerebrospinal fluid (CSF) examination may show only a raised protein; a fatal outcome is common. The disorder may represent a focal variant of the recently described catastrophic anti- phospholipid syndrome, in which there is severe multiorgan failure and a mortality of the order of 60%. There are both clinical and pathological similarities between microangiopathic complications of lupus and the syndrome of thrombotic thrombocytopoenic purpura. In this latter uncommon disorder, multiorgan involvement is also seen, with hepatic and renal disease, and fever, together with thrombocytopoenia and an associated purpuric rash and other haemorrhagic complica- tions. Neurologically, an encephalopathy occurs, often with fits, with or without focal deficits. Pathologically, there are widespread microangiopathic changes in the brain and systemically. Plasma exchange is commonly recommended. Diagnosis of CNS lupus It is clearly vital in such cases to exclude infectious complications of immune suppressants or steroids, now a major cause of death in patients with SLE. Serological tests are positive in 75–​85% of cases, and the erythrocyte sedimentation rate (ESR) is commonly elevated (contrasting with the C-​reactive protein, which usually is not)—​but neither a normal ESR nor negative serology at the time of neurological episode allow a confident exclusion of neurological lupus as the underlying cause. MRI changes are common, though neither invariable nor specific. Abnormal scans are more common in individuals with focal events, and normal scans in patients with more diffuse problems, such as headaches, meningism, memory im- pairment, confusion, and seizures. CSF examination reveals some form of abnormality (raised protein or a neutrophil or lymphocyte pleocytosis) in 40–​50% of cases; CSF oligoclonal band analysis is positive in perhaps 20%—​all changes which can resolve with suc- cessful immunotherapy. A skin biopsy can be extremely helpful in suspected lupus The management of neuropsychiatric lupus Symptomatic therapies are important in patients with encephal- opathies, epilepsy and/​or psychiatric ailments. Disease-​modifying therapeutic efforts fall into two categories depending on the pre- sumed underlying mechanisms—​stroke prevention in cerebral Table 24.22.1  American College of Rheumatology diagnostic criteria for SLE ‘A person shall be said to have SLE if four or more of the 11 criteria are present, serially or simultaneously, during any interval of observation’ • malar flush • discoid rash • photosensitivity • oral ulcers • arthritis • serositis (-​ pleurisy or pericarditis) • renal disorder (proteinuria >0.5 g/​24 h or cellular casts) • neurological disorder (seizures, psychosis; other causes excluded) • haematological disorder (haemolytic anaemia, leukopoenia or lymphopoenia on two or more occasions, or thrombocytopoenia) • immunological disorder—​LE cells, or anti-​dsDNA or anti-​Sm or persistent false positive syphilis serology • antinuclear autoantibodies section 24  Neurological disorders 6378 ischaemia, particularly that associated with acute bacterial endo- carditis, probably best achieved with moderate to high-​dose war- farin; and immunotherapy of ‘other’ CNS complications. Here, intravenous methyl prednisolone, followed by oral steroids is the mainstay of treatment. Cyclophosphamide may be used for se- vere or steroid-​resistant disease, with azathioprine to maintain remission and spare steroids. Hydroxychloroquine can be useful (likely through toll-​like receptor inhibition) and is less toxic. Plasmapheresis synchronized with cyclophosphamide, and intra- venous immunoglobulin, may prove useful. More recent attention has focussed on the promising role of the anti-​B-​cell monoclonal antibody rituximab, while antitumour necrosis factor-​α therapy may increase disease activity. Rheumatoid arthritis An inflammatory peripheral neuropathy occurs in approxi- mately 30% of seropositive rheumatoid cases. A relatively benign mononeuritis is typical, but a more severe and aggressive axonal polyneuropathy or mononeuritis multiplex may be seen when rheumatoid arthritis is accompanied by a vasculitis. More common than either are entrapment neuropathies of conventional distribu- tion, precipitated by synovial swelling. Pannus formation and cer- vical spine subluxation with resulting cord compression represent the most common cause of CNS involvement. More rarely, rheuma- toid vasculitis, or deposition of rheumatoid nodules, may involve the CNS; the former warrants treatment with cyclophosphamide and steroids. Anti-​TNF agents are highly effective in systemic disease, though their value in neurological complications of rheumatoid disease is less clear. Anti-​B-​cell therapies may also be considered. Sjögren’s syndrome Sjögren’s syndrome characteristically comprises a triad of (1)  keratoconjunctivitis sicca and (2)  xerostomia, these two occurring in approximately 50% of cases in the context of (3) another connective tissue disorder, usually rheumatoid arthritis. Speckled antinuclear antibodies of the anti-​Ro (SS-​A) or anti-​La (SS-​B) are present in up to 75–​80% of patients. Conventionally, the principal neurological manifestations have been held to be peripheral, with descriptions of both a mainly sensory neuropathy and of myositis. Trigeminal sensory neuropathy is also classically described. More recently, attention has been drawn to various CNS com- plications of the disorder, with seizures, focal stroke-​like or brain- stem neurological deficits, and encephalopathy with or without aseptic meningitis, often with raised CSF pressure, protein level, and white cell count, together with oligoclonal immunoglobulin bands. Psychiatric abnormalities may occur; spinal cord involvement may take the form of an acute transverse myelitis, a chronic myelopathy, or intraspinal haemorrhage. Occasionally, the features resemble those of multiple sclerosis—​and a particular relationship with neuromyelitis optica is emerging. Often, such patients have add- itional neurological features of peripheral neuropathy or myositis. Steroids may be insufficient for patients with CNS complications of Sjögren’s syndrome; more powerful immunosuppressants are probably more useful though, as is so often the case, their value is yet to be proven objectively—​and this includes the use of so-​called biologics. Systemic sclerosis Systemic sclerosis results from the excessive deposition of collagen in the skin, and other affected tissues. The cutaneous manifestation, scleroderma, may exist in isolation, but in multisystem disease, it is accompanied by Raynaud’s phenomenon, calcinosis, and atrophy of subcutaneous tissues, telangiectasia, and oesophageal strictures. Neurological complications are not common. An association with an acute cerebral vasculopathy is recently reported, but other- wise peripheral nervous system disease predominates, particularly painful trigeminal neuropathy; myopathy, with an elevated creatine phosphokinase also occurs. A myelopathy may be associated. No treatment is of proven benefit. Mixed connective tissue disease In this disorder, features of scleroderma, polymyositis and sys- temic lupus erythematosus coincide, and high levels of antibodies directed against extractable nuclear antigens—​ribonucleoproteins or RNP—​are found. Rheumatoid factor is also often present. In common with both systemic sclerosis and Sjögren’s syndrome, trigeminal neuralgia and/​or sensory neuropathy are described. Seronegative arthritides Ankylosing spondylitis Neurological disease in the setting of ankylosing spondylitis usually reflects advanced bony disease; a cauda equina syndrome is well-​ reported, unexplained, and difficult to treat. Reactive arthritis The clinical triad of seronegative arthropathy, non​specific ureth- ritis, and conjunctivitis, usually following venereal or dysenteric infection, constitute reactive arthritis, formerly known as Reiter’s syndrome. As many as 25% of patients are reported to have neuro- logical features. Peripherally, radiculitis and polyneuritis occur; CNS disorders include aseptic meningoencephalitis, seizures, and psychiatric disturbances, particularly paranoid psychosis. Cranial neuropathies, pyramidal signs, and myelopathy are also reported. Cyclosporine may be of value in severe reactive arthritis. Psoriasis Included as the third sero-​negative arthropathy, the neurology of psoriasis is not extensive. Cord compression from cervical psoriatic spondylosis is described, but reports of a complicating polyneuritis have not been substantiated. Vasculitis The clinical and histopathological picture of CNS vasculitis is seen in three contexts. First, primary or idiopathic isolated CNS vas- culitis can occur, wherein symptoms are confined to the nervous system. Second, there are several primary systemic vasculitides, usu- ally involving the lungs and/​or kidneys—​for example, polyarteritis and granulomatous polyangiitis—​which can also secondarily affect the nervous system. Third, various systemic conditions can include vasculitis—​occasionally with neurological involvement—​among their complications. These range from rheumatological or connective tissue diseases, to drugs, toxins, and infections. In both primary and 24.22  Neurological complications of systemic disease 6379 secondary vasculitis of the nervous system, neurological features arise from inflammation and necrosis of the vasculature—​principally, through infarction. The clinical features of vasculitis of the nervous system The picture of peripheral nerve vasculitis is relatively straight- forward: a mixed sensory and motor neuropathy, usually rapidly progressive, and often painful. About 50% of patients present with mononeuritis multiplex, the remainder with a more diffuse asym- metrical polyneuropathy or a distal symmetric neuropathy. CNS disease is infinitely more varied; focal or multifocal infarc- tion, or diffuse ischaemia, affecting any part of the brain, explaining the protean manifestations, wide variation in disease activity, course and severity, and the absence of a pathognomic or even typical clin- ical picture. Thus, in primary and secondary intracranial vasculitis, headache (perhaps 50% of cases), focal and generalized seizures (10–​20%), acute and subacute encephalopathies, progressive cog- nitive changes, behavioural disturbances, chorea, myoclonus, and other movement disorders, optic and other cranial neuropathies are all seen. (Although included in many accounts, the conventional clinical picture of isolated large vessel stroke, so resembling ather- omatous thromboembolic stroke as to cause diagnostic confusion, is extremely uncommon.) The course is commonly acute or subacute, but monophasic, chronic progressive, and spontaneously relapsing-​ remitting presentations all occur. Despite this range, three broad phenotypes of presentation may be delineated: (1) a picture resembling, but not quite typical of, (‘MS-​plus’)—​with a relapsing-​remitting course, and features such as optic neuropathy and brain stem episodes accompanied by other features less common in multiple sclerosis—​seizures, severe, and persisting headaches, encephalopathic episodes, or hemispheric stroke-​like episodes; (2)  acute or subacute encephalopathy, with headache with an acute confusional state, progressing to drowsi- ness and coma; and (3) intracranial mass lesion—​with headache, drowsiness, focal signs, and (often) raised intracranial pressure. This grouping carries neither pathological nor therapeutic im- plications, but may help improve recognition of this condition. Systemic features—​fever and night sweats, livedo reticulares, or oligoarthropathy—​may be present (though often only revealed on direct enquiry) even in so-​called isolated CNS vasculitis. Diagnosis and management The diagnosis of cerebral vasculitis involves the exclusion of alter- native possibilities (Table 24.22.2), the confirmation of intracranial vasculitis and pursuit of the causes of the vasculitic process. Confirming cerebral vasculitis No single simple investigation is universally useful in confirming cerebral vasculitis. Serological markers, including antineutrophil cytoplasmic antibodies (ANCA), are important. Spinal fluid exam- ination is, like ESR testing, often abnormal, but lacks specificity, with changes in cell count and/​or protein in 65–​80% of cases; oligoclonal immunoglobulin bands may be present. CSF pressure is frequently raised, as may be the glucose level. Magnetic resonance imaging may disclose ischaemic areas, periventricular white matter lesions, haemorrhagic lesions, and parenchymal or meningeal enhancing areas, but lacks both specificity and sensitivity. Contrast angiog- raphy may show segmental (often multifocal) narrowing and areas of localized dilatation or beading, often with areas of occlusion, rarely also with aneurysms. Again, though these changes are not specific, and angiography carries a false-​negative rate of up to 50%, and a risk of 10% for transient neurological deficit, and of 1% for permanent deficit. MR angiography is not sufficiently sensitive for most CNS vasculitides but is valuable in imaging of large vessel dis- orders such as Takayasu’s arteritis and classical polyarteritis nodosa (PAN). Nuclear imaging of labelled leukocytes, and examination of the ocular vasculature may be useful. Histopathological confirmation, biopsying an abnormal area of brain where possible, or by ‘blind’ biopsy, incorporating meninges, and non​dominant temporal white and grey matter, is important. Biopsy may reveal an underlying process not otherwise suspected with profound therapeutic implications, such as infective or neo- plastic (principally lymphomatous) vasculopathies, but is not a trivial procedure, carrying a risk of serious morbidity estimated at 0.5–​2%—​though immune suppressant treatment may have a higher morbidity than biopsy, emphasizing the rationale behind this procedure. A vasculitic process having been confirmed, the specific defining characteristics of the primary and secondary vasculitides must be painstakingly sought. Neurological vasculitis complicating systemic vasculitides Granulomatous polyangiitis predominantly affects the upper and lower respiratory tracts—​nose (often with destructive cartilaginous change causing saddle nose deformity), sinuses, larynx, trachea, and lungs. Ocular involvement may occur; renal disease is usual. cANCA is positive, with proteinase-​3 specificity, and the biopsy is charac- teristic, with granulomatous vasculitis. Microscopic polyangiitis is a multisystem small vessel vasculitis which can involve almost any organ, or may rarely be confined to a single organ. Renal involvement is almost invariable. The diagnosis usually rests upon a combination of renal biopsy and ANCA serology (commonly pANCA). Classical polyarteritis nodosa is now recognized as an unusual disorder which may have some overlap and coexist with microscopic polyangiitis, Table 24.22.2  Some disorders which may mimic cerebral vasculitis Other vasculopathies Susac’s syndrome Homocysteinuria Ehlers–​Danlos syndrome Radiation vasculopathy Köhlmeyer–​Degos disease Fibromuscular dysplasia Fabry’s disease Moyamoya disease Amyloid angiopathy CADASIL Marfan’s syndrome Pseudoxanthoma elasticum Viral or fungal vasculitis Other immune/​inflammatory diseases Sarcoidosis Lupus and antiphospholipid disease Behçet’s syndrome Multiple sclerosis/​ADEM Thyroid encephalopathy Ion channel antibody syndromes Infections Lyme disease AIDS Endocarditis Whipple’s disease Viral encephalitis Legionella/​mycoplasma pneumonia Tumours and malignancy Atrial myxoma Multifocal glioma Cerebral lymphoma Paraneoplastic disease Muscellaneous Multiple cholesterol emboli Thrombotic thrombocytopoenic purpura Cerebral sinus thrombosis Mitochondrial disease section 24  Neurological disorders 6380 but often occurs alone. Medium sized vessels are affected in PAN, and the kidneys are again commonly involved; renal angiography may reveal microaneurysms. pANCA testing is also often positive in Churg-​Strauss syndrome, a multisystem disease characterized patho- logically by a granulomatous necrotizing vasculitis, and clinically by prominent asthma with an eosinophilia. Small vessel vasculitis com- monly affects postcapillary venules. The skin is most commonly in- volved, usually with purpura or urticaria; the common presence of an allergic precipitant has led historically to the term hypersensitivity vasculitis often being used synonymously in this context; cutaneous leukocytoclastic vasculitis is the currently preferred epithet. In all these disorders, peripheral nervous system involve- ment, often with mononeuritis multiplex, is considerably more common than CNS disease, ranging from up to 70% of classical polyarteritis nodosa and microscopic polyangiitis cases, to around 30% of patients with granulomatous polyangiitis. CNS disease can, however, also occur. Direct effects of the granulomatous process—​ either by contiguous invasive spread, or from remote metastatic granulomata—​represent a mode of neurological involvement unique to granulomatous polyangiitis. Middle ear disease may lead to VIIth and VIIIth cranial neuropathies. Neurological vasculitis complicating non​vasculitic systemic disorders Although the clinical picture of cerebral vasculitis may closely be mimicked by systemic lupus erythematosus, a non​inflammatory vasculopathy is far more commonly responsible for SLE (though instances of vasculitis are described). By contrast, seropositive rheumatoid disease is a well-​recognized precipitant of vasculitic mononeuritis multiplex and (far more rarely) of CNS vasculitis. There are rare reports of CNS vasculitis in the context of systemic sclerosis, Sjögren’s syndrome, and mixed connective tissue disease. The clinical features of cryoglobulinaemia represent the combined consequences of hyperviscosity and of immune complex deposition-​ triggered vasculitis, particularly in mixed cryoglobulinaemia, when associated with hepatitis C infection. Skin disease, with purpura progressing to necrotic ulceration, and renal and joint involve- ment are common. The diagnosis, however, will only be made if blood is collected into a plain tube, immediately placed in water in a thermos at 37°C, taken to the laboratory and tested forthwith. Peripheral neuropathy occurs in a quarter of patients with essential cryoglobulinaemia; CNS involvement is rare. Peripheral nerve dis- ease, and/​or histologically and angiographically evident vasculitis of the CNS, usually in the context of granulomatous meningitis, may occur in sarcoidosis. Drug-​induced vasculitis The issue of vasculitis and drugs is complex. The most compelling evidence of a direct association relates to amphetamines, with clin- ical and histological evidence of multisystem necrotizing vasculitis. Most strokes occurring with cocaine abuse are associated with ar- terial spasm, platelet aggregation, severe abrupt hypertension, or migrainous phenomena, not vasculitis, although histologically proven cerebral vasculitis does occur. Infections At least three mechanisms may underlie microbe-​related vas- cular damage—​direct invasion, immune complex formation and deposition, and (in part related to the second), secondary cryoglobulinaemia. Although the association of hepatitis C infec- tion with cryoglobulinaemia and small vessel vasculitis has been stressed earlier, other infections, including hepatitis B, Epstein–​ Barr virus, and cytomegalovirus, Lyme disease, and syphilis, malaria, and coccidiomycosis all have also been linked to mixed cryoglobulinaemia. Primary invasion of the vascular wall by the infectious agent is, however, the most common precipitant of infection-​associated vas- culitis. Histoplasma, coccidioides, and aspergillus are among the fungal causes of this picture, usually confined to immune suppressed patients (including individuals with diabetes mellitus). In HIV in- fection, cytomegalovirus and toxoplasma may cause vasculitis, and syphilitic cerebral vasculitis has re-​emerged in the context of HIV. More general bacterial causes of meningeal or cerebral infection—​ mycobacteria, pneumococci, and H. influenzae—​may also trigger intracranial vasculitis. Herpes zoster can precipitate cerebral vasculitis in approximately 0.5% cases, usually causing a monophasic illness, with hemiparesis contralateral to the eye disease. However, more generalized necro- tizing and granulomatous vasculitis, can also occur. Malignancy, lymphomatoid granulomatosis, and malignant angioendothelioma Leukocytoclastic vasculitis (often dermatological) may occur in as- sociation with a variety of cancers as a paraneoplastic phenomenon. CNS disease in the context of Hodgkin’s disease with a pathological picture indistinguishable from conventional isolated CNS angiitis is reported. Lymphomatoid granulomatosis is a lymphomatous disorder centred on the vascular wall, with destructive change and secondary inflammatory infiltration lending the appearance of true vasculitis; the infiltrating neoplastic cell is of T-​lymphocyte deriv- ation. Cutaneous and pulmonary involvement are common, with nodular cavitating lung infiltrates, and neurological manifestations occur in 25–​30% of cases; they are the presenting feature in approxi- mately 20%. Neoplastic or malignant angioendotheliosis is also a rare, nosologically separate disorder, wherein the neoplastic process is intravascular (i.e. within the lumen), and the lymphomatous cells are B-​cell derived, and characteristically do not invade the vascular wall. The neurological features of each disorder are similar, largely representing those of cerebral vasculitic disease; in malignant angioendotheliomatosis, lung involvement is not the rule; charac- teristic skin manifestations occur. Treatment of cerebral vasculitis Retrospective analyses support the use of cyclophosphamide with steroids in vasculitis. In proven cerebral vasculitis, a 3–​4 month induction regime might comprise high-​dose intravenous, then oral steroids, with oral or pulsed intravenous cyclophospha- mide; this is followed by a maintenance regime of alternate day steroids with azathioprine. In resistant disease, methotrexate (10–​25 mg once weekly; again, with steroids), or intravenous im- munoglobulin may be useful. Cyclophosphamide is associated with haemorrhagic cystitis (less likely with adequate hydration and MESNA cover), bladder cancer, other malignancies, infer- tility, cardiotoxicity, and pulmonary fibrosis. Biological agents—​ monoclonal antibodies and TNF-​receptor antagonists, have shown promise. 24.22  Neurological complications of systemic disease 6381 Two eponymous primary disorders may involve the CNS. Cogan’s syndrome is an unusual disorder, mostly affecting young adults, characterized by recurrent episodes of interstitial keratitis and/​or scleritis with vestibulo-​auditary symptoms, which may be compli- cated by CNS, peripheral nervous system, or systemic vasculitis. In Eale’s disease, an isolated retinal vasculitis occurs, causing visual loss; again, neurological complications are well described. Giant cell arteritis Giant cell arteritis, the most common large vessel vasculitis, rarely affects individuals less than 55 years of age. It affects women twice as commonly as men, with an overall annual incidence of some 20 per 100 000 people. Generally, it presents with uni-​ or bilateral scalp pain, often severe, with exquisite tenderness. Additional symptoms include jaw claudication and polymyalgia rheumatica, with stiffness and aching of the shoulder girdle, worse in the mornings, and oc- casionally general malaise. The affected temporal artery (-​ies) may be thickened and cord-​like, often non​pulsatile, and tender. A raised ESR, often accompanied by a normochromic normocytic anaemia, must be followed by temporal artery biopsy—​a specimen of several centimetres length is recommended to help avoid false-​negative re- sults, which may occur because of the focal or multifocal nature of the disorder. Both ultrasound examination and positron emission tomography scanning are acquiring roles in the diagnosis and moni- toring of giant cell arteritis. Histopathological examination of the vessel reveals changes of vasculitis, with an inflammatory infiltrate comprising mononuclear and giant cells; the latter phagocytose the elastic laminae, causing characteristic fragmentation. Immunoglobulin and complement deposits are apparent in lesions, but activated T cells predominate in the inflammatory infiltrate, suggesting cell-​mediated immune damage. Recently, evidence of the involvement of varicella-​zoster virus in giant cell arteritis has emerged. Vasculitic changes may still be apparent in biopsies taken 14 days or more after the commence- ment of steroids. Neurological complications Blindness occurs in approximately one-​sixth of treated patients with temporal arteritis, as a consequence of anterior ischaemic optic neuropathy following vasculitic involvement of the pos- terior ciliary arteries and/​or the ophthalmic artery, from which they are derived. A  typical picture comprises (locally) painless loss of acuity, commonly severe, often with an altitudinal field de- fect. The fundal appearances may be normal, although swelling (usually mild) may be seen. Intracranial involvement is much less common; vertebral artery involvement is typical. An elevated platelet count should be considered a risk factor for permanent visual loss Treatment Oral steroids should be used immediately there is serious suspicion of the disease, and in high doses—​60–​80 mg a day—​in view of the risk of permanent blindness. The dose is generally reduced slowly—​ in perhaps 5  mg decrements weekly—​after 4–​7  days to a main- tenance dose of some 10 mg daily; thereafter, some would suggest continuing for 12–​24 months before closely monitored phased with- drawal. Such a duration of steroid therapy, particularly in this elderly population, should direct attention to the treatable or preventable long-​term consequences of corticosteroids, particularly osteopor- osis, diabetes, cataract, hypertension, and peptic ulceration. Behçet’s disease Behçet’s disease is a chronic relapsing multisystem inflammatory dis- order whose clinical manifestations vary. The classical triad of recur- rent uveitis with oral and genital aphthous ulceration remains clinically useful, though formal diagnostic criteria have now been proposed and generally adopted. Recurrent oral ulceration (at least three times in one 12-​month period) is an absolute criterion; any two of (1) recurrent genital ulceration, (2) uveitis (anterior or posterior) or retinal vasculitis, (3) skin lesions, including erythema nodosum, or acneiform nodules, pseudofolliculitis or papulopustular lesions, or (4) a positive pathergy test (read at 24–​48 hours) are also required to confirm the diagnosis. Approximately one-​third of patients develop neurological in- volvement, although this includes the very common occurrence of benign headache. Neurological presentation may occur in up to one-​fifth of cases. Cerebral venous sinus thrombosis is one of the more specific serious complications; others include sterile men- ingoencephalitis, encephalopathy, brainstem syndromes, cranial neuropathies, movement disorders, and cortical sensory and motor deficits. Psychiatric and progressive cognitive manifestations are re- ported. Investigation may reveal an active CSF, and oligoclonal IgA and IgM bands—​but apparently not IgG—​may be present. Evoked potentials may be diagnostically useful. MRI abnormalities are non​specific. Treatment of Behçet’s disease Recent retrospective studies indicate an improved survival in pa- tients with CNS Behçet’s treated with steroids and immunosuppres- sants. The place of thalidomide in steroid-​unresponsive Behçet’s is currently under review; chlorambucil is often advocated. Anti-​TNF based therapy may be valuable. Monitoring treatment is difficult—​ neither the ESR nor C-​reactive protein levels are useful; MRI might have such a role. Sarcoidosis Sarcoidosis is a multisystem granulomatous disease of unknown aetiology commonly affecting the lungs and, in approximately 5% of patients, the nervous system. (Cardiac involvement is increas- ingly recognized.) Optic and other cranial neuropathies (especially involving the facial nerve), often due to meningeal infiltration, and brain stem and spinal cord disease (longitudinally extensive trans- verse myelitis is well recognized) are the commoner manifest- ations. Cognitive and neuropsychiatric abnormalities are reported. Peripheral nerve and muscle involvement is also well described. The diagnosis can be difficult: presentation with isolated neuro- logical deficits may be more common in sarcoidosis than in other systemic inflammatory or immunological conditions. Serum and CSF angiotensin converting enzyme levels may be elevated; the CSF may reveal more general abnormalities of protein or cell count and oligoclonal bands may be present. Whole body gallium scanning re- mains a useful indicator of systemic disease. Cranial MRI may show multiple white matter lesions or meningeal enhancement. The diag- nosis is confirmed where possible by biopsy, either of cerebral or meningeal tissue, or of lung or conjunctiva where appropriate. section 24  Neurological disorders 6382 The mainstay of medical treatment in neurosarcoidosis is cortico- steroids, though response rates as low as 29% have been reported. Methotrexate, azathioprine, hydroxychloroquine, and cyclophos- phamide have been used in steroid-​resistant cases. Tumour necrosis factor inhibition appears very promising. Organ-​specific autoimmune disease Ulcerative colitis and Crohn’s disease The neurological complications of ulcerative colitis and Crohn’s dis- ease, seen in around 5% of patients, are similar. Three types of CNS disease have been associated:  cerebrovascular accidents, mostly precipitated by the hypercoagulable state, and including venous or arterial thromboembolism, cerebral sinus venous thrombosis and (more rarely and less explicably) vasculitis; epileptic seizures, focal and generalized, and not always in connection with dehydration or sepsis; and, in some reports, a slowly progressive myelopathy. Peripheral neuropathy is seen in 0.5–​1.0% cases; an acute Guillain–​Barré syndrome is the most common phenotype. Lastly, myopathy, sometimes of metabolic origin but mostly inflammatory, is also reported. Whipple’s disease Whipple’s disease is an uncommon multisystem disorder charac- terized by arthropathy, respiratory symptoms, anaemia, fever, ery- thema nodosum, and severe wasting in addition to steatorrhoea and abdominal distension, caused by Tropheryma whippelii. Approximately 10% of patients have neurological involvement; 5% present in this way. A wide variety of features is seen (Box 24.22.1). Diagnosis and management Up to 20% of cases of cerebral Whipple’s disease occur in the ab- sence of gastrointestinal or indeed other systemic symptoms. CT and MRI scanning may be normal, although the latter can also re- veal non​specific abnormalities—​multiple high signal intensity areas on T2-​weighted images, or more striking enhancing mass lesions warranting biopsy. Similarly, the CSF may be normal, or show an elevated protein and/​or raised cell count; widely varying ratios of monocytes and polymorphonucleocytes are reported. One-​third of CSF samples may reveal pathognomic PAS-​positive bacilli; repeat spinal fluid examination increases this yield. Approximately 30% of cases have a non​informative small bowel biopsy, though electron microscopy increases the sensitivity. Lymph node biopsy can also be useful. Polymerase chain reaction analysis of blood, lymph node, spinal fluid, small bowel tissue, or brain is increasingly used. Whipple’s disease usually responds to tetracyclines, penicillin or, more commonly, co-​trimoxazole. Prompt treatment is vital in pa- tients with neurological disease, which may (if untreated) run a pro- foundly aggressive and not unusually rapidly fatal course. Successful reversal of neurological deficits, including cognitive impairment, may follow antibiotic treatment. Coeliac disease Coeliac disease (non​tropical sprue) is an immunologically medi- ated disorder resulting from intolerance to dietary gluten; it causes weight loss with steatorrhoea and/​or diarrhoea, and malabsorption. In common with other enteropathies, neurological sequelae of a predictable nature may complicate coeliac disease as a direct con- sequence of malabsorption. CNS complications apparently unre- lated to deficiency states may also occur in perhaps 10% of patients. Rarely, vasculitis is responsible, but the cause of the most commonly described and distinctive CNS association, a progressive cerebellar or spinocerebellar degeneration, with eye movement disorders, myoclonus, and occasionally epilepsy, remains unresolved—​the proposal of antigliadin antibody-​associated neurological disease re- mains controversial. Major psychiatric complications and dementia are well described as a significant cause of morbidity and have been studied in detail. Thyroid disease Hyperthyroidism and myxoedema both carry neurological com- plications generally considered direct consequences of abnormal thyroxine levels—​anxiety, tremor, occasionally chorea, and so on, in thyrotoxicosis, and lethargy, myopathy, and dementia in hypothyroidism (see Chapter 13.3.1). By contrast, Grave’s ophthal- moplegia (dysthyroid eye disease) and Hashimoto’s encephalopathy are both thought to be immunologically driven. In dysthyroid eye disease, the orbit and extraocular muscles are oe- dematous and infiltrated with inflammatory cells and glycosamino- glycans, resulting in proptosis and a restrictive ophthalmopathy. Upgaze limitation is the most frequent presenting sign. Vision is oc- casionally threatened by a complicating infiltrative or compressive optic neuropathy. Circulating thyroid stimulating hormone receptor-​ stimulating antibodies cross-​reactive with orbital fibroblasts are found. Steroid treatment and radiotherapy are equally effective. Hashimoto’s encephalopathy exhibits a female:male ratio of up to 9:1. Most cases are clinically and biochemically euthyroid at presentation, and two modes of presentation occur. The relapsing-​ remitting variety causes stroke-​like episodes, with or without mild cognitive impairment, focal or generalized seizures, and episodes of encephalopathy. The second group present with a more diffuse progressive disease, with dementia, psychotic features, seizures, and occasionally myoclonus, tremor and/​or ataxia; focal neurological deficits are uncommon. Imaging by computed tomography or even magnetic resonance is often normal, as is angiography, though isotope brain scanning may show patchy uptake. Spinal fluid examination may reveal a raised protein level but typically a normal cell count. Very high titres of antithyroid antibodies are found, usually antimicrosomal. Most patients respond well to steroid treatment; some have Box 24.22.1  Neurological features of Whipple’s disease (in approximate order of frequency) Cognitive changes, dementia, and/​or psychiatric disease Supranuclear gaze palsy Pyramidal signs Hypothalamic features —​  somnolence, polydipsia, increased appetite, hypogonadism Myoclonus Oculo-​masticatory myorythmia Cranial neuropathies. Fits Eye disease —  keratitis, uveitis, papilloedema, ptosis Ataxia 24.22  Neurological complications of systemic disease 6383 received further immunosuppressive therapy, such as cyclophos- phamide or azathioprine. FURTHER READING Margaretten M (2017). Neurologic Manifestations of Primary Sjögren Syndrome. Rheum Dis Clin North Am, 43(4), 519–29. Cervera R, Rodríguez-Pintó I, Espinosa G (2018). The diagnosis and clinical management of the catastrophic antiphospholipid syn- drome: A comprehensive review. J Autoimmun, 92, 1–11. Bathon JM, Moreland LW, DiBartolomeo AG (1989). Inflammatory central nervous system involvement in rheumatoid arthritis. Semin Arthritis Rheum, 18, 258–​66. Brey RL, et al. (2002). Neuropsychiatric syndromes in lupus: preva- lence using standardized definitions. Neurology, 58, 1214–​20. Cooke WT, Smith WT (1966). Neurological disorders associated with adult coeliac disease. Brain, 89, 683–​722. Dyck PJ, et al. (1987). Nonsystemic vasculitic neuropathy. Brain, 110, 843–​54. Amaral TN, Peres FA, Lapa AT, Marques-Neto JF, Appenzeller S (2013). Neurologic involvement in scleroderma: a systematic review. Semin Arthritis Rheum, 43(3), 335–47. Ferro JM, Oliveira SN, Correia L (2014). Neurologic manifestations of inflammatory bowel diseases. Handb Clin Neurol, 120, 595–​605. Hanly JG (2014). Diagnosis and management of neuropsychiatric SLE. Nat Rev Rheumatol, 10, 338–​47. Higashida J, et  al. (2005). Safety and efficacy of rituximab in pa- tients with rheumatoid arthritis refractory to disease modifying antirheumatic drugs and anti-​tumor necrosis factor-​alpha treat- ment. J Rheumatol, 32, 2109–​15. Hochberg MC (1997). Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum, 40, 1725. Jeltsch-​David H, Muller S (2014). Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers. Nat Rev Neurol, 10, 579–​96. Joaquim AF, Appenzeller S (2015). Neuropsychiatric manifestations in rheumatoid arthritis. Autoimmun Rev, 14, 1116–​22. Joseph FG, Scolding NJ (2002). Cerebral vasculitis—​a practical ap- proach. Pract Neurol, 2, 80–​93. Joseph FG, Scolding NJ (2007). Neuro-​Behçet’s disease in Caucasians: a study of 22 patients. Eur J Neurol, 14, 174–​80. Joseph FG, Lammie GA, Scolding NJ (2007). CNS lupus: a study of 41 patients. Neurology, 69, 644–​54. Kampylafka EI, et al. (2016). Immunotherapies for neurological mani- festations in the context of systemic autoimmunity. Neurotherapeutics, 13, 163–​78. Matthews WB (1968). The neurological complications of ankylosing spondylitis. J Neurol Sci, 6, 561–​73. McInnes IB, Schett G (2011). The pathogenesis of rheumatoid arth- ritis. N Engl J Med, 365, 2205–​19. McKeon A, et al. (2014). The neurologic significance of celiac disease biomarkers. Neurology, 83, 1789–​96. Nishino H, et  al. (1993). Neurological involvement in Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol, 33, 4–​9. Saip S, Akman-​Demir G, Siva A (2014). Neuro-​Behçet syndrome. Handb Clin Neurol, 121, 1703–​23 Scolding NJ (1999). Immunological and inflammatory diseases of the central nervous system. Butterworth-​Heinemann, Oxford, pp. 210–​58. Scolding NJ, Joseph FG (2002). The neuropathology and pathogenesis of systemic lupus erythematosus. Neuropathol Appl Neurobiol, 28, 173–​89. Scolding NJ, et al. (2005). A{beta}-​related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain, 128, 500–​15. Streifler JY, Molad Y (2014). Connective tissue disorders:  systemic lupus erythematosus, Sjögren’s syndrome, and scleroderma. Handb Clin Neurol, 119, 463–​73. Weyand CM, Goronzy JJ (2014). Clinical practice. Giant-​cell arteritis and polymyalgia rheumatica. N Engl J Med, 371, 50–​7. Zajicek JP (1999). Sarcoidosis and the nervous system. In: Scolding NJ (ed) Immunological and inflammatory diseases of the central nervous system, pp. 193–​209. Butterworth-​Heinemann, Oxford. Patrick F. Chinnery and D.M. Turnbull Developmenta Patrick F. Chinnery and D.M. Turnbull Developmental abnormalities of the central nervous system 6350 Chris M. Verity, Jane A. Hurst, and Helen V. Firth ESSENTIALS The brain and spinal cord arise from a sheet of cells that develop through a series of distinct transformations into the final complex structure. Congenital abnormalities of the central nervous system are considered in the context of this process, which may fail at distinct stages of development. General clinical approach A rigorous approach to the diagnosis of and counselling for devel- opmental abnormalities of the central nervous system is required. Referral for specialist advice is recommended because of the far-​ reaching consequences of misdiagnosis. Many abnormalities can be identified by detailed ultrasonography, and magnetic resonance imaging in utero is proving to be particularly useful for accurate in- vestigation of the fetal brain. Prenatal diagnosis is available for some conditions, with non​invasive prenatal diagnosis (and preimplantation diagnosis) becoming available for some conditions where a precise genetic diagnosis is possible. In the absence of a specific diagnosis genetic advice is usually limited and empirical, but where a specific gene is implicated parental questions can often be accurately ad- dressed. Where there are strong environmental factors, it is imperative to reduce the risk to future pregnancies by taking appropriate meas- ures (e.g. folic acid or iodide supplementation before conception). A. Malformations resulting from abnormalities in the major steps of central nervous system formation Neural tube defects Clinical features and epidemiology—​neural tube defects such as spina bifida and anencephaly reflect a failure of closure of the ectoderm folds that normally fuse 18–​26 days after ovulation. Prevalence rates vary greatly by geographical area but worldwide they remain among the most frequent and the most devastating congenital anomalies. Most cases are caused by interactions between genes and environ- mental factors such as nutritional folic acid, but in the presence of additional features, they may be part of a genetic disorder. Screening—​many serious (open) neural tube defects lead to an in- creased concentration of α-​fetoprotein in maternal serum, and at-​ risk women with this elevated biomarker on screening—​or those with a history of an affected pregnancy—​are recommended to have fetal ultrasonography from 12 weeks onwards. Prevention—​the incidence of neural tube defects can be markedly reduced at a population level by preconceptual supplementation of folic acid (400 μg daily), which has been effectively introduced in some countries by fortification of foods with folic acid. Where possible, avoidance of drugs periconceptually and in pregnancy that impair folate metabolism (eg. folate antagonists, anticonvulsants such as sodium valproate). Treatment and prognosis—​the major focus is on prevention, but neurosurgical procedures are employed for closure and for relief of hydrocephalus by diversion of cerebrospinal fluid through shunt procedures. The outcomes and prognosis of affected children vary greatly and surgical management remains controversial, except for those with mild abnormalities. Other developmental abnormalities of the spinal cord—​these include syringomyelia, which usually presents in later life and is associated with the Chiari malformation and hydrocephalus. Agenesis of the sa- crum with abnormalities of the distal cord is associated with maternal diabetes mellitus. Disorders of regionalization of the fully formed neural tube Numerous genes, including those encoding signalling molecules that induce the expression of homeotic genes involved throughout evo- lution in regional and segmental development, are implicated in the complex process of regionalization of the neural tube. Disorders af- fecting these pathways often involve gene–​environment interactions and give rise to abnormalities of the specification of cells in the fore- brain, midbrain, hindbrain, and spinal cord (e.g. holoprosencephaly). Disorders of cortical development Numerous genetic determinants have been identified for disorders of cortical development such as microcephaly and lissencephaly, which reflect abnormalities of proliferation and cellular migration (respectively). Microcephaly may also be caused by environmental influences in pregnancy, including radiation, drugs, infections and maternal hyperphenylalaninemia (a preventable factor of import- ance in the management of women with phenylketonuria). Malformations of posterior fossa structures Hindbrain development is disturbed in the Chiari II malformations and the Dandy–​Walker syndrome (agenesis of the vermis, with dila- tation of the fourth ventricle and enlargement of the posterior fossa). 24.20 Developmental abnormalities of the central nervous system Chris M. Verity, Jane A. Hurst, and Helen V. Firth 24.20  Developmental abnormalities of the central nervous system 6351 Complex malformations of the brain and cord Many types are recognized, including agenesis of the corpus callosum and porencephaly. These disorders are rare, but are increased in children with other developmental abnormalities. Agenesis or hypogenesis of the corpus callosum may be caused by mutations in a single highly penetrant gene (e.g. ARID1B; Coffin-​Siris syndrome), chromosomal imbalance, and some rare metabolic syndromes (e.g. non​ketotic hyperglycinaemia). Porencephaly may be a prenatal manifestation of mutations in COL4A1/​2. Vascular developmental abnormalities These include Sturge–​Weber syndrome (where a vascular birthmark on the face is associated with an angioma involving the meninges overlying the cerebral cortex) cerebral cavernomas, capillary and venous malformations resulting from somatic mosaicism. B. Clinical problems associated with abnormalities of central nervous system development Enlargement of the cerebral ventricles (ventriculomegaly) Ventriculomegaly may be discovered on antenatal scanning and may be isolated or associated with other cerebral developmental abnor- malities. Sometimes it is an early sign of hydrocephalus—​this results from expansion of the ventricles secondary to a block in the normal flow pathway of cerebrospinal fluid. Intellectual disability can result from both the damage associated with ventricular expansion and other abnormalities associated with the underlying cause of the problem. Disorders of the developing brain caused by external factors Alcohol—​fetal alcohol syndrome may cause microcephaly, structural anomalies of the brain such as partial or complete agenesis of the corpus callosum, cerebellar hypoplasia, and a dysmorphic appear- ance. Fetal alcohol spectrum disorders are much more common than fetal alcohol syndrome. Drugs of abuse—​there is emerging evidence that prenatal exposure to stimulants such as cocaine and methylamphetamine can affect brain development and function Congenital infections—​for example, toxoplasmosis, herpes simplex, cytomegalovirus, rubella, and syphilis. Primary maternal infection is implicated in most instances; hence measures to prevent these infec- tions are important. The cerebral palsies These are an important but heterogeneous group of non​progressive disorders of the immature brain that cause defects of movement and posture that may have associated manifestations such as deafness, seiz- ures, and learning difficulties. Several clear genetic factors have been identified, and environmental exposure to toxins such as carbon mon- oxide, alcohol, and methyl mercury may also be responsible. Although cerebral palsy has in the past been attributed to ‘asphyxia’ at birth, this view is now changing; premature infants are at a greatly increased risk. Normal development of the human central nervous system The human central nervous system (CNS), like that of all vertebrates, develops from a two-​dimensional sheet of cells into a complex three-​dimensional structure. A range of abnormalities results from failures at distinct stages of development. This chapter uses the normal development of the human CNS as a framework to discuss these disorders. Only structural abnormalities of the CNS that are present at birth have been included, not the numerous metabolic and degenerative disorders that can affect the infant brain. During intrauterine life the brain develops from a plate of ecto- dermal cells into the complex structure seen in the full-​term infant as is shown in Fig. 24.20.1. A. Malformations resulting from abnormalities in the major steps of CNS formation Disorders of neural tube formation The nervous system develops from a tube formed when part of the em- bryonic ectoderm folds and separates from the remaining ectoderm (Fig. 24.20.2). Closure of this tube starts at a level corresponding to the future hindbrain/​spinal cord junction and then proceeds towards both the head (rostrally) and the tail (caudally). This process gener- ates the entire neural tube except for the most caudal part, which is formed by thickening of the neural plate and the subsequent forma- tion of a cavity. A population of cells (the neural crest) then migrates out of the dorsal part of this tube to form the peripheral nervous system, while those that remain in the tube form the CNS. The neural tube usually fuses completely between 18 and 26 days after ovulation (32 and 40 days, respectively, after the first day of the last menstrual period). Failure of closure leads to malformations that include anen- cephaly, encephalocele, spina bifida, and spina bifida occulta. They are malformations of the neuroectoderm, which are associated to a variable extent with abnormalities of the surrounding mesodermal structures. The term ‘dysraphism’ is used when there is continuity between the posterior neuroectoderm and cutaneous ectoderm. Craniorachischisis is the most severe type of neural tube defect, in which almost the entire brain and spinal cord are open. Epidemiology The prevalence of neural tube defects varies according to geography and race. High rates (more than 8 per 1000 births) have been reported in Northern Ireland, Egypt, India, and China. There are worldwide reports of decreasing prevalence. In England and Wales there was a substantial decline in the birth prevalence which started in the early 1970s—​in 1964 the rate was 3.6/​1000 births and this fell 93% to 0.3/​1000 in 2004. It was estimated that 59% of the fall was due to an underlying decrease in the prevalence of neural tube defects and 34% to antenatal screening and termination of pregnancy. During this period there was an increase in dietary folate and there is evi- dence of a protective effect of adequate folate consumption, however some of the decreased prevalence remains unexplained. In England and Wales anencephaly and spina bifida have been of approximately equal prevalence, together making up 95% of all neural tube defects. Aetiology Genetic factors Most neural tube defects result from a complex interaction between several genes and environmental factors, but a minority occur as part of a Mendelian disorder (e.g. Meckel’s syndrome). If one section 24  Neurological disorders 6352 member of a family is affected by an isolated (i.e. non​syndromic defect), there is a small increased risk in their first-​degree rela- tives of c.3% for all types of neural tube defect. Major genes have been identified that cause neural tube defects in the mouse, but their relevance to human defects is still not clear. Some genes have been shown to alter risk modestly (e.g. mutations in the methylene tetrahydrofolate reductase gene are associated with elevated blood homocysteine levels in pregnant women and a twofold increased risk of neural tube defects). At this time, however, genetic investi- gations offer little in the management of families with one member having an isolated neural tube defect. Environmental factors Periconceptual multiple vitamin supplements containing folic acid have been shown to reduce substantially the incidence of neural tube defects. In England it is currently recommended that women who are planning pregnancy should take 400 µg folic acid daily before conception and during the first 12 weeks of preg- nancy. To prevent recurrence of neural tube defects a higher dose of 4–​5 mg/​day is recommended. In the United Kingdom, the Food Standards Agency has recommended the mandatory addition of folic acid to bread or flour. In North America fortification of cer- tain foodstuffs with folic acid has been mandatory since 1998. Since many pregnancies are unplanned, countries that have insti- tuted folic acid fortification policies have seen reductions in neural tube defects of 27–​50%. Some drugs taken during pregnancy may increase the risk of neural tube defects in the fetus, including sodium valproate and folic acid antagonists such as trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbitone, and primidone. Prenatal diagnosis Ultrasonography This is recommended for all at-​risk women—​those who have had one or more affected child and those taking drugs associated with neural tube defects in the fetus. Anencephaly can be detected by ultrasonography from week 12 of gestation and spina bifida from 16 to 20 weeks (Fig. 24.20.3a, b), although even the best ultrason- ographers may occasionally miss spina bifida, particularly in the L5-​S2 region. The recent marked improvement in the resolution of fetal ultrasonography has meant that direct sampling of the amni- otic fluid (mniocentesis) is no longer performed. However, when ad- equate ultrasound images cannot be obtained, amniocentesis with measurement of α-​fetoprotein and assay of neuronal acetylcholin- esterase does provide an alternative method of prenatal diagnosis. α-​fetoprotein levels in maternal serum The fetal liver is the main source of α-​fetoprotein, which leaks through open neural tube defects into the amniotic fluid and then into maternal blood. The consequent abnormal increase in maternal serum α-​fetoprotein is best detected at 16–​18 weeks of pregnancy. Maternal serum screening does not detect closed defects (those covered by skin). The widespread use of prenatal ultrasound for fetal anomaly screening has superseded maternal serum α-​fetoprotein as a screening measure in pregnancy in many countries. Cranial abnormalities of neural tube closure Anencephaly This is a lethal defect that results from failure of fusion of the rostral folds of the neural tube. The cranial vault is absent and an 5 WEEKS 11 WEEKS MIDBRAIN (MESENCEPHALON) CEREBELLUM CEREBRUM PONS DIENCEPHALON TELENCEPHALON PONS HINDBRAIN (RHOMBENCEPHALON) SPINAL CORD DIENCEPHALON TELENCEPHALON FOREBRAIN (PROSENCEPHALON) 9 MONTHS CEREBELLUM MEDULLA OBLONGATA MEDULLA OBLONGATA Fig. 24.20.1  Diagram showing some of the key stages in normal brain development. 24.20  Developmental abnormalities of the central nervous system 6353 angiomatous membranous mass lies on the floor of the cranium. The eyes are protuberant as a result of shallow orbits and there is variable involvement of the spinal cord. Before the advent of pre- natal diagnosis by ultrasonography most anencephalic babies were liveborn; now an increasing number of such pregnancies are ter- minated. In liveborn anencephalic babies, the initial neurological examination may be surprisingly normal if brainstem structures are reasonably intact. However, the infants usually die in hours or days. Cephaloceles A cephalocele is a herniation of the cranial contents through a skull defect. There are several subtypes: a cranial meningocele con- tains only meninges, an encephalocele contains brain tissue, and a ventriculocele contains part of the ventricle within the herniated portion of the brain. Cephaloceles are less common than anen- cephaly or spina bifida, occurring in 1 to 3 per 10 000 live births. Posterior cephaloceles are the most common group in Western countries and most are occipital encephaloceles, whereas anterior cephaloceles are more common in some parts of Asia. Anterior cephaloceles are associated with other brain abnormalities such as agenesis of the corpus callosum, abnormal gyration, or, in the case of posterior defects below the tentorium, cerebellar defects. They may be part of a recognized syndrome such as frontonasal dys- plasia. Posterior encephaloceles may be a feature of an underlying ciliopathy such as Meckel syndrome. Spinal abnormalities of neural tube closure Spina bifida This can be divided into spina bifida occulta, which consists of failure of closure of the vertebral arches without an external lesion, and spina bifida cystica in which there is a cystic lesion on the back. The lesion may be either a meningocele without neural tissue or a myelomeningocele in which the spinal cord is a component of the cyst wall. The term ‘rachischisis’ is used for the most severe defect, which is a widely patent dorsal opening of the spine, often associated with anencephaly. Myelomeningocele This spinal defect represents the abnormality found in 80–​90% of children with spina bifida cystica. It is lumbosacral in about 80% of cases and consists of a sac covered with a thin membrane that may leak cerebrospinal fluid (Fig. 24.20.3c). Neurological abnormalities depend on the level of the lesion. There is usually a mixture of upper Neural plate Neural groove Notochord Neural crest cells Epidermis Neural tube Caudal/ posterior neuropore Open spina bifida Cranio- rachischisis Closure 1 Closure 3 Anencephaly Rostral neuropore 0 Fig. 24.20.2  The upper part of the diagram shows neural tube defects arising from errors in the multisite closure of the neural tube. The coloured section shows how the embryonic ectoderm separates, folds, and closes to form the neural tube. (b) (a) (c) (d) (e) Fig. 24.20.3  (a) Prenatal ultrasonography of a child with a neural tube defect, showing the ‘lemon sign’ resulting from the change in shape of the back of the skull (on the left-​hand side in the image) which is associated with the Chiari II malformation described in the text. (b) Prenatal ultrasonography of a child with a neural tube defect, showing a cystic lumbar meningomyelocele in the caudal neural tube. (c) Lumbar meningomyelocele: photograph of a newborn infant. (d) Chiari I malformation and syringomyelia in an asymptomatic girl aged 11 years. Photograph of tuft of hair seen over the lumbar region at birth. The associated central nervous system malformations are shown in (e). (e) Chiari I malformation and syringomyelia. T1-​weighted sagittal MRI shows that there is herniation of the cerebellar tonsils through the foramen magnum (arrow) and a syrinx of the lower cervical spinal cord (C5–​7) (arrow head). The associated tuft of lumbar hair is shown in (d). section 24  Neurological disorders 6354 and lower motor neuron signs, disturbance of bladder and bowel sphincters, and bladder detrusor dysfunction. The sensory level cor- relates with the severity of abnormalities in the urinary tract and has prognostic significance regarding long-​term disability. Higher lesions of the cord are associated with bladder outlet obstruction, dilatation of the upper urinary tract, and chronic pyelonephritis. Hydrocephalus complicates about 90% of cases of lumbosacral meningomyelocele. Usually it is associated with the Chiari II mal- formation, where there is downward displacement of the cerebellar vermis or tonsils through the foramen magnum to overlap the spinal cord. The fourth ventricle is elongated and the midbrain distorted, causing palsies from involvement of the lower cranial nerves and central apnoea (which may be misdiagnosed as epilepsy in older children). Hydrocephalus may also be due to aqueduct stenosis or have no clear structural cause. If there is evidence of progressive ven- tricular dilatation (often detected by ultrasonography) or signs of increasing intracranial pressure, insertion of a ventriculoperitoneal shunt is usually necessary. Meningocele Here there is protrusion of the meninges outside the spinal canal: the sac does not contain any neural tissue. Meningoceles account for about 5% of cases of spina bifida cystica. There is no associated hydrocephalus and the neurological examination is usually normal. They must be distinguished from meningomyeloceles because the prognosis is so different. Spina bifida occulta This term is often applied to a defect of the posterior arch of one or more lumbar or sacral vertebrae (usually L5 and S1). It is found incidentally by radiography in 25% of children admitted to hos- pital and may be a normal variant. However, if examination of the skin over the spine reveals a naevus, hairy patch (Fig. 24.20.3d), dimple, sinus, or subcutaneous mass, further evaluation including magnetic resonance imaging (MRI) of the spinal cord is indicated. Several clinical abnormalities may be found on examination. Spinal cord malformation may cause an asymmetrical lower motor neuron weakness with wasting, deformity, and diminished reflexes in the lower limb, or progressive gait disturbance with spasticity. Either presentation may be associated with disturbed bladder con- trol. Dorsal dermal sinuses may connect the skin surface to the dura or an intradural dermoid cyst. An open sinus tract can cause recurrent meningitis so ideally it should be explored and excised before infections occur. Lipomyelomeningoceles present as a bulge in the lumbosacral region, usually lateral to the midline. They con- sist of a lipoma or lipofibroma attached to a low-​lying abnormal spinal cord. Diastematomyelia is the presence of a sagittal cleft that divides the spinal cord into two halves, each surrounded by its own pia mater. A bony or cartilaginous spur may transfix the cord, fixing it in a low position as the child grows. The cleft is usu- ally in the low thoracic or lumbar region, but cervical clefts have been reported. If any abnormality involving the cord or nerve roots is found there may be a good case for neurosurgical intervention. The aim is to free the spinal cord from its abnormal attachments to allow for growth and prevent further damage. Early intervention may prevent worsening motor deficits and urological complications, but the indi- cations for intervention are controversial. Management of neural tube defects The major emphasis is on primary prevention. It is recommended that women planning to conceive supplement their diet with folic acid, which reduces the risk of neural tube defects. Screening of ma- ternal serum for α-​fetoprotein is possible and prenatal diagnosis by ultrasonography is available. This is discussed above. Treatment of infants with meningomyeloceles became possible with the development of ventriculoatrial and ventriculoperitoneal shunts. In the early 1960s, it was argued that closure of the defect within 24 h of birth reduced mortality and morbidity by avoiding infection and reducing trauma to the exposed neural tissue. A se- lective approach to the surgical management of affected infants was proposed but this has been controversial. Lorber reported four ad- verse criteria that he thought were contraindications to treatment: a high level of paraplegia, clinically evident hydrocephalus at birth, lumbar kyphosis, and the presence of other major malformations. However, even using these criteria, the outcome was uncertain; many infants survived even though they did not have closure of the defect within 24 h, and some children with a supposedly good prog- nosis were left with major disabilities after surgery. Other developmental abnormalities of  the spinal cord Syringomyelia This is a tubular cavitation of the spinal cord that is often associated with the Chiari I malformation and hydrocephalus (Fig. 24.20.3e). It tends to be in the cervical region but may involve the whole cord. It rarely becomes symptomatic in children. Treatment is controver- sial. Shunting of the abnormal cavity is sometimes performed and posterior fossa exploration may be undertaken if there is a Chiari I malformation. Sacral agenesis This is strongly associated with maternal diabetes mellitus. Absence of the sacrum and coccyx is usually associated with abnormalities of the lumbosacral cord. There may be arthrogryposis at birth (de- fined as a fixed deformity of one or more joints). A flaccid neuro- genic bladder causes incontinence and there are sensory and motor deficits in the legs. Sacral agenesis may also occur as part of the single gene disorder Currarino syndrome due to heterozygous mu- tation of the homeobox gene HLXB9. Disorders of regionalization Once the neural tube has developed, specification of different regions and individual cells within these regions occurs. This patterning oc- curs in both the rostrocaudal and dorsoventral axes. The three basic regions of the CNS (forebrain, midbrain, and hindbrain) develop at the rostral end of the tube, with the spinal cord more caudally. Within the developing cord the specification of the different popu- lations of neural precursors (neural crest, sensory neurons, inter- neurons, glial cells, and motor neurons) is observed in progressively more ventral locations. This process reflects the interaction between 24.20  Developmental abnormalities of the central nervous system 6355 genes whose expression defines individual territories or cell types and diffusible signalling molecules secreted by adjacent areas of the embryo. Of particular importance are the extracellular signalling molecules such as sonic hedgehog required for ventral induction, and a family of genes called homoeotic genes. Most of these encode proteins containing a conserved homeodomain motif that binds DNA sequences involved in the regulation of expression of other genes, so controlling cell differentiation. Failure of normal development of the most rostral portion of the neural tube (the mediobasal prosencephalon) and associated struc- tures caused by disturbances in the process of ventral induction may result in various abnormalities of the brain and face. The most severe CNS abnormality is holoprosencephaly in which there is failure of the prosencephalon to separate into two cerebral hemispheres. The mildest is olfactory aplasia with no other cerebral malformations. The severity of the associated facial abnormalities tends to parallel those in the brain. In the most severe facial abnormality there is an- ophthalmia and absence of the nose. However, there may be just mild hypotelorism (closely set eyes) or a single central incisor tooth, or the face appear normal. Holoprosencephaly (prosencephaly) This occurs with a frequency of approximately 1 in 250 conceptuses and c.1 in 10 000 births. There is failure of formation of the two cere- bral hemispheres, resulting in abnormalities of varying severity. There are many possible causes that act within a short vulnerable period, because ventral induction probably occurs before 23 days. Environmental factors are important and it is at least 20 times more common in the infants of mothers with diabetes than in the general population. In addition, there are several genetic causes, with at least 12 genetic loci and 9 holoprosencephaly (HPE) genes identified in humans. One (HPE3 on chromosome 7q36) is the sonic hedgehog gene, and mutations in PTCH, the receptor for sonic hedgehog, have also been found in some individuals with holoprosencephaly. Many other genes are implicated in the pathogenesis of holoprosencephaly and it is associated with chromosomal abnormalities that include trisomy and other abnormalities of chromosome 13, partial deletion of the short arm of chromosome 18, ring chromosome 18, and par- tial trisomy of chromosome 7. In alobar holoprosencephaly, the completely undivided fore- brain is in the shape of a horseshoe surrounding a single cavity. The thalami are fused but the brain stem and cerebellum are well developed. The associated facial abnormalities are severe—​ there may be anophthalmia or cyclopia in which there is a single orbit. In holoprosencephaly with median cleft lip there is marked hypotelorism. In semilobar holoprosencephaly the brain is div- ided into two hemispheres posteriorly but anteriorly the two hemi- spheres are fused (Fig. 24.20.4). In lobar holoprosencephaly there is almost complete separation of the hemispheres and the face may be normal. The head is usually microcephalic unless there is associated hydrocephalus. In some families in which the condition is inherited in autosomal dominant pattern, the severity can be variable, with some family members having only minor features such as a single central incisor, and others with severe holoprosencephaly. When providing genetic counselling it is therefore important to look for minor signs in both parents of an affected child. The signs include orbital hypotelorism, median cleft lip, flat nose with or without a single nostril, anosmia, and a single central incisor. Prenatal diagnosis can be made by ultra- sonography from week 16 of pregnancy, with orbital hypotelorism an important feature for antenatal diagnosis. The most severely affected infants die in the neonatal period. Less severely affected patients may live for months or years. The survivors often develop infantile spasms or other seizures. Some patients with significant structural abnormalities may survive to adulthood but usually there are severe learning difficulties. Associated anomalies suggest a syndromic cause (e.g. Trisomy 13) and include congenital heart disease, scalp defects, and polydactyly. Disorders of cortical development Modern brain imaging, in particular MRI, has resulted in the identi- fication of many previously unrecognized developmental abnormal- ities of the cerebral cortex. The best characterized of these arise from defects in one of two basic processes in cortical development. The first is the proliferation of the stem cell population which generates all the neurons required for the cortex. This occurs throughout fetal development in the region next to the ventricle (germinal layer). The second is the migration of the newly formed neurons away from this ventricular region into the overlying cortex to form appropriate con- nections with other neurons. Abnormalities in migration are shown schematically in Fig. 24.20.5. Disorders of proliferation Microcephaly A failure of proliferation results in a reduced number of cells, causing a head that is disproportionately small (less than the 0.4th centile) in relation to the rest of the body. This microcephaly is often associated with significant additional abnormalities of the nervous system such as pyramidal tract signs and learning difficulties. Microcephaly is a feature of many genetically determined developmental disorders/​syn- dromes. Autosomal recessive primary microcephaly is the term used to describe a genetically determined form of microcephaly previously known as ‘microcephaly vera’, with a severe and non​progressive re- duction in head circumference (more that four standard deviations (b) (a) Fig. 24.20.4  (a) Semilobar holoprosencephaly in a girl aged 2 years imaged with T1-​weighted sagittal MRI. This midline view shows absence of the corpus callosum and fusion of the frontal lobes. (b) Semilobar holoprosencephaly in the same patient using T2-​weighted axial MRI. There is fusion of the frontal lobes of both cerebral hemispheres and a common central ventricle. section 24  Neurological disorders 6356 below the mean for age) associated with mild-​to-​moderate learning disability but normal height, weight, and appearance. Many of the genes identified encode centrosomal proteins that are crucial for cell division. In many types of genetic microcephaly the head size may not become abnormal until as late as 32–​34 weeks of gestation or even after birth. Severe microcephaly may also be a feature of a more gen- eralized disorder of growth (e.g. microcephalic primordial dwarfism where birth weight is typically <2 kg); this is a genetically heteroge- neous group due to genes encoding proteins involved in fundamental cellular processes including genome replication, DNA damage, re- sponse mRNA splicing, and centrosome function Non​genetic causes of microcephaly include ionizing radiation in the first two trimesters of the pregnancy, intrauterine infections, alcohol, drugs, and other chemicals, circulatory disturbance, and perinatal hypoxic–​ischaemic events. In 2016 there was an epidemic of microcephaly in Central and South America associated with Zika virus infection in pregnancy. Poor dietary control in mothers with phenylketonuria is also an important and preventable cause of microcephaly, because the fetal brain is very sensitive to the toxic effects of phenylalanine. When there is a significant perinatal insult to the brain, the head circumference may be normal at birth, with subsequent failure of growth in the first few months of life. Macrocephaly The term ‘macrocephaly’ is used when the head circumference is above the normal range for the age, sex, and race of the child. This may result from abnormalities outside the brain parenchyma such as hydrocephalus, arachnoid cysts, congenital abnormal- ities of the cerebral veins, fluid collections over the surface of the brain, or abnormalities of the skull. Cranial imaging is necessary to make the diagnosis. The subsequent discussion deals only with megalencephaly, which is increased size of the brain itself. Although many normal individuals have large heads, megalencephaly can be associated with significant learning difficul- ties, autism, neurological abnormalities, and seizures, and this com- bination of features can have a genetic basis. The brains may have bulky gyri and usually all parts of the cerebrum are diffusely enlarged, with normal-​sized or mildly enlarged ventricles. Occasionally, par- ticular parts of the brain such as the cerebellum are disproportion- ately large. No consistent microscopic alterations are reported in the cortex, but minor anomalies such as small heterotopias may be found. The abnormality may be part of a specific disorder, for ex- ample, one of the neurocutaneous syndromes, an overgrowth dis- order such as Sotos’ syndrome (OMIM 117550), or Greig syndrome due to GLI3 mutation. Large heads can run in families (‘familial megalencephaly’), in some of which there may be no abnormalities, and it is important to check the head circumference of the parents. Hemimegalencephaly or unilateral megalencephaly may involve all parts of the brain on the same side or there may be enlargement of one hemisphere only. This can be associated with other neurological problems such as intractable seizures. It may also be associated with marked developmental delay, hemiparesis, and overgrowth of one side of the face. Some children with hemimegalencephaly have the disorder due to a somatic mutation (a postzygotic mutation arising several divisions after fertilization) that affects a percentage of cells in the developing baby, e.g. megalencephaly-​capillary malformation-​polymicrogyria syndrome due to somatic mutation in the PIK3CA gene. Disorders of migration Migration defects occur when neurons generated by the division of stem cells in the ventricular region fail to reach their intended destination in the cerebral cortex. The different classes of defect are illustrated schematically in Fig. 24.20.5. If neurons fail to leave stem cell neuronal precursor Normal cortical development Type II – Lissencephaly Type I – Lissencephaly Periventricular Heterotopias Fig. 24.20.5  Diagrammatic representation of the cerebral cortex showing normal development and neuronal migration defects. In type I lissencephaly neurons fail to reach their intended destination. In type II lissencephaly there is overmigration of neuroglial precursors through a disrupted pial-glial limiting membrane, resulting in nodules of ectopic neurons. If neurons fail to leave the ventricular zone entirely, periventricular heterotopias result. 24.20  Developmental abnormalities of the central nervous system 6357 the ventricular zone entirely, periventricular heterotopias result. If neurons leave the ventricular zone but then fail to complete their migration in the cortex, this causes a group of disorders of varying severity. There may be complete absence of gyri, in which case the term ‘agyria’ is used. Pachygyria describes a reduced number of broadened and flat gyri with less folding of the cortex than normal. There may be varying degrees of agyria–​pachygyria in the same brain. The term ‘lissencephaly’ (Greek: smooth brain) is commonly used to describe the spectrum of malformations from complete agyria to regional pachygyria. If, however, only a subpopulation of neurons is affected and the others complete their migration normally, this results in nodular or subcortical band heterotopias. Migration disorders are found as part of recognized genetic syndromes and there are also acquired types as a result of intrauterine infections, circulatory disturbances, and toxins (al- cohol or phenytoin, for example). The classification of these dis- orders is evolving as a result of rapid advances in brain imaging and molecular biology. Type I or classic lissencephaly This is the most common type and is characterized by a smooth or almost smooth cerebral surface. The cortex is thickened (10–​20 mm) usually with no other major brain malformations, although agenesis of the corpus callosum or severe cerebellar hypoplasia can be seen due, in the latter, to mutations in the reelin (RELN) gene. Infants with type I or classic lissencephaly may be divided into those who have the isolated lissencephaly sequence with no dysmorphic features (the majority) and those with the dysmorphic features of the Miller–​Dieker syndrome (OMIM 247200). Genes causing type I lissencephaly in humans include:  PAFAH1B1 (LIS1), TUBA1A, and DCX. DCX (double cortin) is on the X chromosome, explaining why inheritance of lissencephaly is in some cases X-​linked. While affected males in these families show the full isolated lissencephaly sequence pheno- type, carrier females can show band heterotopia, in which a subset of neurons fails to complete migration and forms bilateral sym- metrical ribbons of grey matter in the centrum semiovale. This is thought to reflect X inactivation of the normal DCX gene in these neurons, while those that inactivate the mutation-​containing X chromosome migrate normally. In Miller–​Dieker syndrome, there is a severe seizure disorder with severe/​profound hypotonia and developmental delay ac- companied by postnatal growth deficiency and microcephaly. The dysmorphic features include a tall narrow forehead, a depressed nasal bridge, anteverted nares, midfacial hypoplasia, a prom- inent upper lip with a thin vermilion border, retrognathism, and hypervascularization of the retina. About 50–​70% of cases have a deletion of chromosome 17p13.3 visible by light microscopy and almost all the remainder have a submicroscopic deletion demon- strable by genomic array. Heterozygous deletion of the PAFAH1B1 (LIS1) gene causes the lissencephaly seen in the Miller–​Dieker syndrome and the facial dysmorphism may be caused by loss of adjacent genes. The diagnosis of type I lissencephaly is made by CT or MRI, which shows a thick cortical plate with no or few sulci separated from the white matter by an undulating border (Fig. 24.20.6a). Prenatal diag- nosis is not possible by ultrasonography before 24 weeks because tertiary sulci do not appear before then. Type II or ‘cobblestone’ lissencephaly This is a completely different malformation from type I lissencephaly. The smooth cortex has a granular surface and the meninges are thickened due to mesenchymal proliferation. The cerebellum is small with an absent vermis and the pyramidal tracts are usually absent. Hydrocephalus is present in 75% of cases. Microscopically there is complete disorganization of the cortex which consists of neurons separated by bundles of gliomesenchymal tissue continuous with the meninges. More deeply, there is a thin layer of white matter lying above islands of heterotopic grey matter. These abnormalities are thought to result from overmigration of neuroglial precursors through a dis- rupted pial-glial limiting membrane, resulting in the nodules of ec- topic neurons that generate the granular texture of the brain. This is caused in some cases by abnormalities of adhesion molecules, such as dystroglycan—​responsible for anchoring the endfeet of the glial cells that define the migratory pathway of the neurons to the over- lying pial membrane. As these same adhesion molecules are required for attachment of muscle fibres and retinal cells to their overlying basement membranes, many type II lissencephaly syndromes are associated with muscle and eye abnormalities. These disorders con- stitute a group of autosomal recessive congenital muscular dystro- phies associated with defects in O-​glycosylation of α-​dystroglycan, which includes Walker–​Warburg syndrome, Fukuyama cerebral and muscular dystrophy, and muscle–​eye–​brain disease. The most severe forms of these diseases often have a fetal presentation. Elevation of creatinine kinase suggests this condition and targets genetic analysis. Heterotopias Periventricular heterotopias are abnormally placed groups of neurons that have failed to start or complete their migration. These often cause seizures and may be associated with intellectual im- pairment. Failure of migration results in the neurons remaining in the ventricular region, under the ependymal cells that line the ventricle, generating periventricular or subependymal heterotopias (see Fig. 24.20.6b). These may be the result of single gene disorders such as a mutation in the filamin A (FLNA) gene on the X chromo- some. Filamin protein reorganizes the cytoskeleton, consistent with (b) (a) Fig. 24.20.6  (a) Lissencephaly type I in a boy with a de novo deletion in the LIS1 gene on chromosome 17. T1-​weighted axial MRI shows agyria of the parietal and occipital lobes of the brain, with pachygyria of the frontal lobes. This anterior-​to-​posterior severity gradient is characteristic of LIS1 deletions or mutations. (b) Nodular heterotopias in a boy aged 13 years. The T2-​weighted axial image shows that the nodular heterotopias are subependymal (arrow) and subcortical (arrow head). section 24  Neurological disorders 6358 a role in cell migration. Families with periventricular heterotopia have been described in which females are affected whereas affected males appear to die before or soon after birth. Just as in DCX mu- tations, discussed earlier, it is likely that the heterotopias present in affected females result from X inactivation of the normal FLNA gene in those cells, whereas those cells inactivating the abnormal FLNA gene migrate normally. Males have only one X chromosome and so all cells will fail to migrate—​a lethal phenotype. A failure to complete migration generates subcortical heterotopias, which can be divided into two groups: nodular heterotopias of grey matter are found in association with other migration disorders (see Fig. 24.20.6b) and subcortical laminar heterotopias, also known as band heterotopias, as discussed above. Non​lissencephalic cortical dysgenesis Polymicrogyria is the most important type of abnormality in this section. The surface of the cortex can be relatively smooth, resem- bling pachygyria, because the small gyri pile up on each other to form a thickened cortex. The histology of polymicrogyria varies, sug- gesting that different migration defects are responsible for the failure to form the normal six-​layered cortex. It is suggested that the devel- opmental disturbance occurs near the fifth month of pregnancy. Case reports of polymicrogyria in the infant brain after maternal trauma or asphyxiation during the pregnancy suggest that the abnormality may sometimes be due to failure of cerebral perfusion with resulting hypoxia. The clinical manifestations of polymicrogyria depend on the location and extent of the abnormalities. Small patches may be found incidentally in the absence of symptoms, but there may be involvement of the whole cortex, resulting in developmental delay. A substantial proportion of cases have a genetic basis (e.g. GPR56 causing bilateral perisylvian polymicrogyria) or an inherited meta- bolic disorder such as Zellweger syndrome, so referral for a clinical genetics opinion is recommended. Other disorders of cortical development Cortical microdysgenesis or dyplasia Macroscopic and microscopic abnormalities of cortical structure have been described in the brains of patients with epilepsy or learning difficulties, and have also been reported in autism, schizophrenia, and fetal alcohol syndrome. These abnormalities include persistence of the subpial layer, aggregates of large neurons in the plexiform zone, a frag- mented appearance of the superficial neuronal layers, excess ectopic cells in the cortex, and excess numbers of cells in the molecular layer. Their causes and the extent to which these cause global abnormalities in brain function remain unknown, as such abnormalities can be found in normal individuals. However, they do cause cortical excitability in generalized epilepsy. Focal cortical dysplasias are an important cause of early onset seizures that may be focal or generalized (Fig. 24.20.7) and patients with refractory epilepsy should therefore have the best possible neuroimaging even if they have generalized seizures. Disorders of cortical organization Once migration is complete, the neurons begin the complex tasks of elaborating dendrites and axons, and forming synapses to establish the connectivity required for correct functioning of the human brain. These tasks remain poorly understood, but there is increasing interest in their abnormalities because they may represent important causes of epilepsy and developmental delay. Although subtle compared with the gross anatomical defects created by the migration disorders, it is likely that this group of disorders will become increasingly well rec- ognized as imaging and other investigative techniques improve. Malformations of posterior fossa structures Once regionalization has been completed, the developmental pro- cesses that generate the cerebellum and brain stem are distinct from those responsible for cortical development. Consequently, although some genetic mutations result in abnormalities in both anterior and posterior fossae (e.g. RELN and the type II lissencephalies), there are several specific posterior fossa malformations. These are now identified using prenatal ultrasonography and MRI, which is superior to CT for showing posterior fossa structures. Recently, cilia-​related genes have been implicated in several congenital dis- orders (ciliopathies) characterized by cerebellar abnormalities such as Joubert syndrome, Meckel–​Gruber syndrome, Bardet–​Biedl (c) (b) (a) Fig. 24.20.7  (a) Cortical dysplasia in a boy aged 4 years. Focal seizures started at 1 year of age and consisted of a giggle, flexion of the left arm, and a vacant stare. T1-​weighted coronal MRI shows cortical dysplasia in the right parietal region (arrow). (b) The same patient. On T2-​weighted axial MRI, the cortical dysplasia is marked with an arrow. (c) Cortical dysplasia in a boy aged 3 years. Seizures commenced at 9 months of age and consisted of daytime absences and nocturnal generalized tonic–​clonic seizures. A T2-​weighted coronal MRI shows an abnormal fissure in the cortex on the right (arrow). The right lateral ventricle is abnormal in size and shape. 24.20  Developmental abnormalities of the central nervous system 6359 syndrome, and orofaciodigital syndrome, suggesting that cilia play an important role in cerebellar development. Aplasia and hypoplasia of the cerebellum This is a heterogeneous group of conditions that affect cerebellar de- velopment in various ways; total cerebellar aplasia is exceptional and unilateral hypoplasia occurs very infrequently. Neocerebellar aplasia (Fig. 24.20.8a) is characterized by a small vermis and extreme small- ness or absence of the cerebellar hemispheres, except for persistent floccules. There may be associated anomalies in the brain stem such as dysplasia of the inferior olivary nucleus and other brainstem nuclei. Many cases are associated with genetic syndromes, some of which (including most of the ciliopathies) are autosomal reces- sive and have a high recurrence risk. Recent attention has been drawn to a group of disorders classified under the broad headings of pontocerebellar hypoplasia or olivopontocerebellar atrophy. Pontocerebellar hypoplasia is found in carbohydrate-​deficient glycoprotein syndromes, dystroglycanopathies (Walker–​Warburg syndrome, Fukuyama syndrome, and muscle–​eye–​brain diseases—​ see earlier), disorders of the glycosylphosphatidylinositol (GPI) complex that anchors extracellular proteins to the plasma membrane, and various rare mitochondrial disorders. MRI dem- onstrates cerebellar hypoplasia often with a hypoplastic ventral pons. Pontocerebellar hypoplasia type 1 (caused by biallelic muta­ tion of the VRK1 gene) is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration resembling infantile spinal muscular atrophy (SMA type 1). The Chiari malformations There are four types: the most common, Chiari II malformation, is usually associated with a meningomyelocele and is dealt with earlier under neural tube defects. In Chiari I malformation there is down- ward displacement of the lower cerebellum, including the tonsils. It rarely causes symptoms in childhood but may be associated with hydrocephalus and syringomyelia. Chiari III malformation con- sists of downward displacement of the cerebellum into a posterior encephalocele and Chiari IV malformation is a form of cerebellar hypoplasia. Chiari malformation may also occur as a component of various rare genetic disorders including Apert syndrome and Pfeiffer syndrome. Abnormalities of the vermis Dandy–​Walker malformation and Dandy–​Walker variant The Dandy–​Walker malformation (Fig.  24.20.8b) consists of the following triad: • complete or partial agenesis of the vermis • cystic dilatation of the fourth ventricle • enlarged posterior fossa with upward displacement of lateral sinuses, tentorium, and torcula, while a variant form lacks pos- terior fossa enlargement There is an association between Dandy–​Walker malformation and chromosomal abnormalities including trisomies 13 and 18, and the malformation is a feature of many rare genetic disorders. Prenatal ultrasound studies may reveal the abnormality at 18 weeks’ ges- tation, 3 weeks after the development of the inferior vermis, and show that most fetuses with the Dandy–​Walker malformation have other anomalies including ventriculomegaly, holoprosencephaly, agenesis of the corpus callosum, occipital encephaloceles, and struc- tural heart defects. Fetal MRI may be helpful in clarifying the nature of the brain anomaly. The clinical outcome of babies presenting with Dandy–​Walker malformation ranges from severe learning disabilities and physical impairments to normal development. The abnormality is often rec- ognized only when the infant is investigated for signs of hydroceph- alus, which may not become apparent until late in the first year of life, or later in life with learning difficulties. Cerebellar signs tend not to be prominent, but cranial nerve palsies, nystagmus, and truncal ataxia have been described. Radiological diagnosis is relatively straightforward for the com- plete Dandy–​Walker malformation, although without sagittal MRI the variant may be difficult to distinguish from a prominent cisterna magna or a retrocerebellar arachnoid cyst. Joubert syndrome This rare autosomal recessive ciliopathy is characterized by brain- stem and cerebellar malformations resulting in a ‘molar tooth’ ap- pearance on cranial MRI together with variable involvement of (a) (b) (c) (d) Fig. 24.20.8  (a) Cerebellar hypoplasia in a boy aged 5 years, who was born preterm at 26 weeks of gestation, with no neurological problems apart from absence seizures of unknown cause. T1-​weighted coronal MRI shows almost complete absence of the cerebellar hemispheres and hypoplasia of the cerebellar vermis. (b) Dandy–​Walker malformation in a 1-​year-​old girl. Axial CT shows absence of the roof of the fourth ventricle. A large cyst is continuous with the fourth ventricle and fills the posterior fossa. (c) Joubert syndrome in a girl aged 10 years. T1-​weighted sagittal MRI shows that the superior cerebellar peduncles run horizontally (arrow) and the cerebellar vermis is absent. (d) Joubert syndrome in a girl aged 9 months who was hypotonic and visually unresponsive, with ‘wandering’ nystagmus. Axial CT shows the superior cerebellar peduncles (arrows) run horizontally and stand out because of the absence of the vermis (‘molar tooth sign’). The prominent fourth ventricle has a typical shape (sometimes looking like a ‘bat’s wing’). section 24  Neurological disorders 6360 other body systems (e.g. renal cystic disease, retinal dystrophy). It is genetically heterogeneous and many genes encoding cilial and basal-​ body proteins have now been implicated. Features include absence or hypoplasia of the posteroinferior part of the cerebellar vermis. In some cases, enlargement of the fourth ventricle and the cisterna magna has been reported. Microscopically, heterotopias have been seen in the cerebellar hemispheres with fragmentation of the den- tate nuclei. Brainstem abnormalities include absence of pyramidal decussation, abnormal inferior olivary nuclei, and subtle dysplasias in the nuclei of the solitary and descending trigeminal tracts and of the dorsal columns. The common clinical abnormalities are marked hypotonia (particularly in the neonatal period and infancy), poor balance (walking occurs in 50% of cases and is late—​at approximately 4 years), and variable cognitive problems (some affected children are unable to talk but others develop language, read, and write). The associated abnormalities are dysmorphic facial features, episodic hyperpnoea and/​or apnoea in up to 75% of patients (most marked in the neonatal period), eye abnormalities, and microcystic renal disease. Typically, CT or MRI shows the ‘molar tooth’ sign in the axial plane, which consists of: (1) a deeper than normal posterior interpeduncular fossa, (2) prominent or thick- ened superior cerebellar peduncles, and (3) vermian hypoplasia or dysplasia. MRI in the coronal and axial plane shows clefting of the vermis; in the sagittal plane it shows an abnormally shaped and rostrally placed fourth ventricle (Fig. 24.20.8c, d). Renal sur- veillance is indicated as some children have cystic renal disease which may lead to renal failure. Complex malformations of the CNS Thus far we have presented disorders of the cerebral cortex resulting from defects in a single part of brain development. However, this is oversimplistic because many of these developmental processes occur simultaneously (and will therefore all be affected by terato- gens or other extrinsic perturbations) or rely on the timely comple- tion of a prior step for their initiation. As a result, there are several well-​recognized malformations that cannot be ascribed precisely to abnormalities in one step or the major steps in development and result in more complex defects. Agenesis of the corpus callosum The true prevalence of this abnormality is not accurately known because it can be present without any symptoms. Estimated preva- lence has varied from 0.05 per 10 000 to 70 per 10 000 in the general population, increasing to 230 per 10 000 in children with develop- mental disabilities. In the normal developing brain, the first fibres cross the midline at 11–​12 weeks to form the corpus callosum, which extends back in the occipital direction to assume the adult form by 18–​20 weeks. There are two types of ‘true’ callosal agenesis: defects in which axons are unable to cross the midline and defects in which the commissural axons or their parent cell bodies fail to form in the cerebral cortex. The former is probably the most common type, al- though the latter is seen in the Walker–​Warburg syndrome and other types of lissencephaly. There are also two secondary types: absence associated with major malformations of the embryonic forebrain, such as holoprosencephaly, and degeneration or atrophy, as is seen in some syndromes in which the corpus callosum is thinned but not shortened. When agenesis of the corpus callosum is the only lesion there may be no symptoms, although tests of perception and lan- guage may demonstrate disturbances of integration of hemispher- ical function. However, even if there is no clearly defined syndrome, some patients have learning disabilities, seizures, or cerebral palsy. Agenesis or hypoplasia of the corpus callosum may occur as a component of many single gene disorders (e.g. ARID1B syndrome (Coffin-​Siris syndrome), ARX syndrome) and FOXG1. It has also been associated with several chromosomal imbalances. Callosal agenesis may occur in several metabolic disorders including non-​ ketotic hyperglycinaemia. Diagnosis is based on brain imaging (Fig. 24.20.9). The abnormal- ities that can be found are widely spaced parallel lateral ventricles, colpocephaly (enlarged posterior horns of the lateral ventricles), upward displacement of the third ventricle, absent callosal tissue, or midline dorsal cyst. Prenatal ultrasonography allows diagnosis from week 20 of gestation. After birth MRI is best because it gives sagittal views of the corpus callosum. The scan should be care- fully reviewed for other midline anomalies (such as agenesis of the (c) (b) (a) Fig. 24.20.9  (a) Normal brain in a girl aged 2 years. A T1-​weighted sagittal MRI shows normal corpus callosum and cingulate gyrus (arrow). (b) Agenesis of the corpus callosum in a girl aged 6 years who has microcephaly and moderate learning difficulties. A T1-​weighted sagittal MRI shows absence of the corpus callosum and of the cingulate gyrus, which normally runs parallel to the corpus callosum. (c) Agenesis of the corpus callosum in the same girl as in (b). Axial CT shows typical appearance of parallel lateral cerebral ventricles, with divergence of the anterior horns of the ventricles and colpocephaly (dilated posterior part of the lateral ventricles). 24.20  Developmental abnormalities of the central nervous system 6361 septum pellucidum) or generalized defects (such as lissencephaly). The eyes may show optic nerve hypoplasia (as seen in septo-​optic dysplasia) or choroidal lacunae (as seen in Aicardi syndrome). Neonates with seizures or other significant neurological problems may have an underlying metabolic disorder, for example, non​ketotic hyperglycinaemia (raised cerebrospinal fluid glycine) or a mitochon- drial disease sometimes withraised cerebrospinal fluid lactate). Porencephaly The term ‘porencephaly’ is often used indiscriminately for all large cavities in the brains of infants, but should be reserved for circum- scribed hemispherical necrosis that occurs in utero before the adult features of the hemisphere are fully developed (Fig. 24.20.10b). The developmental origin of such lesions is shown by their smooth walls and disturbances in the development of the adjoining cortex. These disturbances may take the form of polymicrogyria or local distor- tion of the gyral pattern. In contrast, areas of damage resulting from insults in the terminal phase of the pregnancy or in postnatal life have irregular shaggy walls, and do not alter the gyral environment except by atrophy or scarring. Porencephaly may be an important prenatal presentation of a genetic disorder caused by heterozygous mutation in the COL4A1/​2 genes. Schizencephaly This term is used to describe clefts that traverse the full thickness of the hemisphere, connecting the ventricle to the subarachnoid space. They are described as type I or ‘fused lip’ when the walls of the cleft are opposed, and type II or ‘open lip’ when cerebrospinal fluid sep- arates the walls (Fig. 24.20.10d). Some authors think that the clefts are usually the result of destruction of brain tissue and the term ‘porencephaly’ should be used for them all. However, there is now evidence that some of them are genetic, because familial and spor- adic cases have been recognized in association with mutations in the homeobox gene EMX2. This is one of the vertebrate homeobox genes thought to play a role in patterning the forebrain. The clefts are frequently bilateral and symmetrical, the most severe form being large bilateral defects. Even when unilateral, they are often combined with cortical dysplasia of the opposite hemisphere. Clinical features are variable, depending on the site and size of the lesion. Epilepsy is common and there may be hemiplegia, quadriplegia, and learning difficulties of variable degree. The diagnosis is made by MRI. Hydranencephaly In this condition, the cerebral hemispheres are almost completely replaced by fluid-​filled sacs. The defect typically corresponds to the territory of the anterior and middle cerebral arteries, although the major cranial arteries do not usually show evidence of obstruction. Preservation of the temporal lobes and the tentorial parts of the oc- cipital lobes is common, but the extent of preservation of the basal ganglia varies. The cause of hydranencephaly is not clear in many cases. It has been described after intoxication of pregnant women with gas at about week 25 of gestation. It can result from intrauterine infections and has been described in association with a proliferative vasculopathy due to biallelic mutation of the FLVCR2 gene. Affected infants may be born after a normal pregnancy and be surprisingly normal on neurological examination for the first few weeks of life. Gradually they become hypertonic and irritable and develop infantile spasms, which is surprising because of the almost complete lack of cerebral hemispheres. The head may en- large because of associated hydrocephalus. The diagnosis can be made by transillumination of the skull, which lights up like a lan- tern in a darkened room. Similar appearances can be caused by (a) (b) (c) (d) Fig. 24.20.10  (a) Cerebral palsy: spastic diplegia. Probable periventricular leucomalacia in a girl aged 6 years. There was threatened premature labour at 29 and 32 weeks, but she was born at term with no perinatal problems. She walked late with a diplegic gait. T2-​weighted axial MRI shows abnormal signal change lateral to the body of the left lateral ventricle and posterolateral to the posterior horn of the left lateral ventricle (arrow). This is a characteristic distribution of periventricular leucomalacia, but such appearances should be interpreted with caution because there are other causes of white matter abnormalities in children (e.g. the leukodystrophies). (b) Cerebral palsy: left hemiplegia. Porencephalic cyst in a boy aged 18 months. He was delivered by forceps at 38 weeks with no resuscitation, but nasogastric feeding for several days after birth. At 10 months of age he was not moving the left arm normally. T2-​weighted axial MRI shows that there is dilatation of the anterior horn of the right lateral ventricle with loss of overlying cerebral cortex and a small periventricular cyst adjacent to the anterior horn of the right lateral ventricle. These abnormalities may result from periventricular leucomalacia. Such loss of tissue due to in utero damage of the developing brain is called a porencephalic cyst. (c) Cerebral palsy: left hemiplegia. Tissue loss in middle cerebral artery territory in a young woman aged 17 years. There were no perinatal problems, reduced movement of the left arm from 6 months of age, nocturnal generalized tonic–​clonic seizures from 4 years of age, normal intelligence, abnormal posture of the left hand, and shortening of the left leg. T1-​weighted axial MRI shows that there is a loculated cystic lesion in the distribution of the supply of the right middle cerebral artery. Also ex vacuo enlargement of the right lateral ventricle and small ipsilateral right hemicranium. (d) Open-​lip schizencephaly in a 49-​year-​old woman. An axial CT scan shows that there is a wide cleft joining the right lateral ventricle to the subarachnoid space. section 24  Neurological disorders 6362 hydrocephalus with a very thin cortical mantle, so MRI is indicated to confirm the diagnosis. Infants with hydranencephaly often die in a few months, but they may survive for several years and may need a ventriculoperitoneal cerebrospinal fluid shunt if there is progres- sive hydrocephalus. Septo-​optic dysplasia This is the association of optic nerve hypoplasia with absence of the septum pellucidum. Disturbances of the hypothalamopituitary axis may occur. The most severely affected patients are blind and have severe learning difficulties. The optic discs have a character- istic double contour: the true disc at the centre is small and there is a peripheral ring about the size of a normal optic nerve head. It is im- portant to search for evidence of endocrine disturbance when these abnormal discs are identified—​deficiencies of growth hormone, corticotrophin, luteinizing hormone, and follicle-​stimulating hor- mone have been described, together with hypoglycaemia and dia- betes insipidus. Most cases are sporadic. Also some sporadic cases of the more common mild forms of pituitary hypoplasia are associated with heterozygous mutations of the HESX1 gene. Vascular developmental anomalies Sturge–​Weber syndrome occurs due to a somatic gain of function R183Q mutation in the GNAQ gene and is characterized by an ex- tensive port-​wine stain vascular birthmark affecting the face. If this occurs in the distribution of the trigeminal nerve, there may be in- volvement of underlying cortex and associated epilepsy. Cerebral cavernomas are developmental anomalies of the cerebral vasculature. When multiple, they are termed congenital cavernous malformations and may be caused by germline mutation in the KRIT1, CCM2, or PCD10 gene Arteriovenous malformations (AVMs) may be sporadic and can be caused by a somatic mutation as in Parkes–​Weber syndrome where a cutaneous flush is accompanied by underlying multiple micro arteriovenous fistulas often associated with soft tissue and skeletal hypertrophy. Capillary malformation-​arteriovenous malformation (CM-​AVM) is an autosomal dominant disorder characterized by multifocal ca- pillary malformations and a high risk for fast-​flow lesions that may occur anywhere in the body including vein of Galen malformation. CM-​AVM is caused by a germline mutation in the RASA1 gene. B. Clinical problems associated with abnormalities of CNS development In the previous sections, we classified the malformations of the developing brain by their anatomical location, taking advantage of the advances in imaging that have greatly increased our ability to diagnose these conditions. However, clinical problems can be asso- ciated with factors that have a more generalized impact on the CNS, and some of the most important of these are considered next. Fetal cerebral ventriculomegaly Dilatation of the lateral cerebral ventricles is the most common CNS abnormality identified by prenatal imaging. It may be difficult to counsel the parents because of uncertainty about the cause and the prognosis. When ventriculomegaly is detected on ultrasound screening there may be an underlying genetic disorder. Fetal MRI may demonstrate additional structural abnormalities that allow for more accurate counselling. Various CNS abnormalities may be found, such as dysgenesis of the corpus callosum, cerebellar hypoplasia, spinal cord defects, Chiari malformations, lissencephaly, and Dandy–​Walker malformations. Those fetuses with additional CNS malformations and those with marked ventricular dilatation are less likely to progress to live delivery and to survive the neonatal period. In contrast fetuses with mild cerebral ventriculomegaly and no associated abnormality may show normal early postnatal development. Hydrocephalus This is ventriculomegaly caused by a disturbance of the normal flow pathway of cerebrospinal fluid. Cerebrospinal fluid is pro- duced by the choroid plexus in the lateral ventricles, from where it flows through the foramen of Munro into the third ventricle and then the fourth ventricle via the aqueduct of Sylvius. It leaves the ventricular system via small openings in the roof of the fourth ventricle, the foramina of Magendie and Luschka. From here the fluid flows in the subarachnoid space before being reabsorbed into the blood supply via arachnoid villi. Hydrocephalus is a rela- tively common problem, recently estimated to affect 11 in 10 000 infants. Two major forms of hydrocephalus are recognized: in commu- nicating hydrocephalus the ventricular pathways are clear and a failure of reabsorption by the arachnoid villi (after, for example, a bleed into the subarachnoid space) results in increased cerebro- spinal fluid volume. In obstructive or non​communicating hydro- cephalus the blockage occurs at one of the ventricular levels, with expansion of the ventricular system above the block (Fig. 24.20.11). The major clinical sign that results is increasing head circumference following the ventricular enlargement, and this allows the distinc- tion from cases in which increased ventricular size resulting from cerebral atrophy is associated with a decreased head circumference. Fig. 24.20.11  Aqueduct stenosis in a boy aged one month with a bulging anterior fontanelle and increasing head circumference. Axial CT shows a gross dilatation of the third and lateral ventricles (the fourth ventricle is not shown, but was normal in size). Note the periventricular low density due to transependymal exudation of cerebrospinal fluid under pressure (arrow). 24.20  Developmental abnormalities of the central nervous system 6363 Learning difficulties can result from both the damage associated with ventricular expansion and other abnormalities related to the underlying cause of the problem. Hydrocephalus may be acquired as the result of an extrinsic event acting on a structurally normal brain. The most common cause of acquired hydrocephalus in infants is haemorrhage (e.g. intraventricular haemorrhage), most often as a result of pre- maturity. Other important causes include neoplasm and in- fection. Intrauterine infections with enterovirus, lymphocytic choriomeningitis, cytomegalovirus, and toxoplasmosis have all been associated with hydrocephalus. Hydrocephalus may be genetically determined, indeed there are many rare genetic disorders that can present with hydroceph- alus, or in which this may be a clinical feature. Stenosis of the aqueduct between the third and fourth ventricles can result from mutations in the cell adhesion molecule L1CAM. Hydrocephalus then occurs in association with hypoplasia of the corpus callosum, learning difficulties, spastic paraplegia, and adducted thumbs. Mutations in the X-​linked gene L1CAM are found in as many as 75% of cases with a family history and 15% of apparently isolated cases. The abnormal genes that underlie congenital muscular dys- trophies may also cause hydrocephalus early in the clinical presen- tation of these disorders Most patients with neural tube defects have hydrocephalus, which may be multifactorial in origin. Hydrocephalus may be part of syndromes associated with intracranial cysts and also with megalencephaly (overgrowth of cerebral tissue). The devel- opmental abnormalities of the cerebellum in both the Dandy–​ Walker syndrome and the Arnold–​Chiari malformation (see earlier) may also be associated with obstructive hydrocephalus. Although treatment via a ventriculoperitoneal shunt can relieve the obstruction, the other problems associated with these abnor- malities remain. Disorders of the developing brain caused by external factors Alcohol Worldwide, alcohol is one of the most common preventable causes of learning difficulty and neurobehavioural disturbance in young children. Fetal alcohol syndrome may cause microcephaly, struc- tural anomalies of the brain such as partial or complete agenesis of the corpus callosum, cerebellar hypoplasia, and a dysmorphic appearance. These children may have impaired fine motor skills, sensorineural deafness, poor hand–​eye coordination, and a poor tandem gait. Its prevalence depends on geographical location. An international survey in 1997 found that in the United States of America the prevalence per 1000 live births in Seattle was 2.8 and in Cleveland it was 4.6. The diagnosis of fetal alcohol syndrome can be made on the basis of the characteristic clinical features with or without confirmed maternal alcohol exposure. The term partial fetal alcohol syndrome can be used when there is a confirmed history of prenatal alcohol exposure without all the components of the full fetal alcohol syndrome. An alcohol-​related neurodevelopmental disorder (fetal alcohol spectrum disorder) is also recognized that includes learning difficul- ties, poor impulse control, problems with social perception, deficits in higher level receptive and expressive language, poor capacity for abstraction, and difficulties with memory, attention, and judgement. The causes of these clinical features remain undefined, but animal studies show that alcohol is likely to affect multiple steps in CNS development including migration and neuronal survival. It is esti- mated that fetal alcohol spectrum disorder is one of the main causes of intellectual disability worldwide with a suggested prevalence as high as 2–​5% of younger school children in the United States and Western Europe. Both regular and binge drinking can cause fetal alcohol syndrome and fetal alcohol spectrum disorder. Unlike many other teratogens, alcohol has harmful effects throughout pregnancy and it remains un- clear whether any amount of alcohol can be considered safe. Drugs of abuse Evidence is beginning to emerge that prenatal exposure to the stimulant drugs cocaine and methamphetamine may be particu- larly toxic to dopamine-​rich basal ganglia regions of the brain, al- though the interpretation of such findings is limited by the problem of polysubstance abuse and the difficulty of obtaining precise ex- posure histories. Congenital infections Cytomegalovirus, herpes simplex virus, parvovirus, rubella, syphilis, toxoplasmosis, and varicella virus are all recognized as teratogens, with primary infection rather than reinfection of the mother during pregnancy being more likely to result in congenital infection. Congenital infection should always be considered in the differential diagnosis of microcephaly. Intracranial calcifica- tion identified on cranial ultrasonography or CT (calcification is not picked up well by MRI) during the investigation of develop- mental delay or seizures suggests congenital infection, especially cytomegalovirus or toxoplasmosis. Ophthalmological assess- ment may show chorioretinitis (pigmentary retinopathy) or cata- ract, the former being characteristic of intrauterine infection by cytomegalovirus or toxoplasmosis. Sensorineural deafness is a common sequel to congenital infection with cytomegalovirus, ru- bella, and toxoplasmosis. There are several genetic disorders that mimic congenital infection with intracranial calcification evident on cranial imaging and sometimes with chorioretinal involvement. These include pseudo-​TORCH syndrome due to biallelic mutation in OCLN or JAM3 and the pseudo-​toxoplasmosis syndrome due to Aicardi–​Goutières syndrome. Cytomegalovirus Although the risk of maternal–​fetal transmission with primary cyto- megalovirus infection is as high as 40%, fewer than 10% of infants with intrauterine infection are symptomatic at birth. Of those, ap- proximately 90% have one or more of microcephaly, periventricular calcification, chorioretinitis, optic atrophy, and sensorineural deaf- ness. Of the 90% of infants who are asymptomatic at birth, approxi- mately 15% have sequelae including sensorineural deafness and/​or developmental delay. Herpes simplex virus Intrauterine infection with herpes simplex virus is rare and neonatal infection acquired at the time of delivery is a more common cause of neurodisability than congenital infection. Congenitally affected in- fants may have microcephaly, chorioretinitis, and microphthalmos. section 24  Neurological disorders 6364 Neonatal infection may cause meningitis and encephalitis with re- sulting neurological damage. The risks of perinatally acquired infec- tion may be reduced by appropriate obstetric intervention (such as delivery by caesarean section for women with active genital lesions resulting from herpes simplex virus) and by treatment of affected neonates with aciclovir. Rubella The classic triad of defects associated with congenital rubella syn- drome is sensorineural deafness, congenital heart disease, and eye abnormalities (retinopathy, cataracts, microphthalmos, and con- genital glaucoma). Microcephaly and developmental delay may also occur. The spectrum of defects in an individual child is determined by the stage of pregnancy at which intrauterine infection occurs. The risk of congenital infection is more than 90% if the mother has an infection in the first 10 weeks of the pregnancy and falls to zero be- yond 18 weeks. Toxoplasmosis The risk of intrauterine infection with toxoplasmosis increases with the stage of pregnancy at which the mother acquires her primary infection; however, the sequelae of intrauterine infection diminish with advancing gestation. Congenital toxoplasmosis syndrome in- cludes hydrocephalus, intracranial calcification, microcephaly, seiz- ures, and developmental delay. There may also be sensorineural deafness and chorioretinitis with visual impairment. Aicardi–​ Goutières syndrome is an important condition that can mimic con- genital toxoplasmosis and is caused by biallelic mutation in several genes resulting in a constitutive upregulation of type I interferon activity. Varicella Congenital varicella syndrome follows primary maternal varicella occurring at 1–​20 weeks of gestation, but the risk of sequelae is small at around 2%. Cataracts and chorioretinitis may occur together with hypoplasia of the optic disc. Microcephaly and porencephaly have been described. Zika virus Zika virus disease is spread to people primarily through the bite of an infected Aedes species mosquito. This is the same mosquito that transmits dengue, chikungunya, and yellow fever. The most common symptoms of Zika infection are fever, rash, joint pain, and conjunctivitis (red eyes). The illness is usually mild with symptoms lasting for several days to a week. In 2016 there were numerous cases of microcephaly and other syndromes in babies of mothers who were infected with Zika virus while pregnant. The virus can persist in the semen for some weeks and is transmissible through sexual contact. The cerebral palsies Although the aforementioned conditions are classified by aetiology or by anatomy, one important group of disorders is conventionally classified by their clinical presentation. These are the cerebral pal- sies, defined as a heterogeneous collection of non​progressive dis- orders of movement and posture resulting from defects or lesions of the immature brain. Although the underlying causes of the cerebral palsy syndromes are by definition not progressive, the symptoms and signs of cerebral palsy do change with age (e.g. some children who are destined to have major problems with spasticity are ini- tially very hypotonic). In some cases, it can therefore be difficult to be sure whether or not a child with suspected cerebral palsy has a progressive underlying disorder. It may be necessary to allow the passage of time and children may be 3 or 4 years old before the diag- nosis of cerebral palsy can be made with confidence. Whatever the age at diagnosis, with the recent advances in imaging and genetics it is not satisfactory to label a child with neurological problems as having ‘cerebral palsy’ and go no further. It is important to deter- mine the type and distribution of the abnormality of motor control and evaluate other potential neurological problems, such as learning difficulties, epilepsy, and hearing or visual loss. Classification Patients may be classified according to the type of motor abnor- mality as follows: spastic, dyskinetic (dystonic or athetoid), ataxic, or hypotonic. The clinical picture is rarely clear cut and individuals may exhibit complex mixtures of motor disability. Patients are then subclassified according to the distribution of motor abnormality—​ in diplegia the legs are involved more than the arms, in quadriplegia all four limbs are involved, and in hemiplegia just one side of the body is involved. Epidemiology Overall, cerebral palsy rates since the mid-​1950s have remained re- markably constant at about 2 to 2.5 per 1000 live births, although there have been some fluctuations with time. In 1970 the rate fell to 1.5 in Sweden, Western Australia, and Mersey (United Kingdom), rising again in the 1980s. In contrast, cerebral palsy rates stratified by birth weight do show marked changes with time. Most population-​ based registers have shown increases in rates in infants of very low birth weight (<1500 g) since the 1970s. For instance, in Mersey in the early 1970s the rate in infants of very low birth weight fluctuated around 10 per 1000 live births. In the late 1970s the rate increased sharply to about 50 per 1000 live births, presumably because more children of very low birth weight were surviving with neurological deficits. This increase was seen for all cerebral palsy types. However, to put the increasing cerebral palsy rates in survivors of very low birth weight in perspective, during this time an increasing propor- tion of patients were also surviving unimpaired. Although the risk of cerebral palsy is higher for preterm infants, the key observation is that most children with cerebral palsy are born at term. Overall rates have been determined mainly by the numbers of term infants born with cerebral palsy (and have remained fairly constant)However the contribution of prematurity and its complications to the prevalence of cerebral palsy has increased with time. Aetiology Genetic causes Genetic causes are clearly important because families have been reported in which spastic diplegia and quadriplegia (often with as- sociated learning difficulties) appear to be inherited in autosomal recessive, autosomal dominant, or X-​linked recessive patterns. There can be a significant recurrence risk to future children, par- ticularly in populations where consanguineous marriage is rela- tively common. The highest risk of recurrence is in the category of 24.20  Developmental abnormalities of the central nervous system 6365 children with ataxic cerebral palsy. However, there are many con- ditions that cause ataxia in children, making it important to search for an underlying cause before giving genetic advice, rather than to ‘lump’ this group together and give an overall recurrence risk. Recent genetic studies of sporadic cerebral palsy cases using exome sequencing show that 14% of cases have likely causative single-​gene mutations. Furthermore, babies with a pre-​existing genetically de- termined neurodevelopmental disorder may be less resilient to ad- verse perinatal factors. Factors shown to increase the risk of cerebral palsy The rate of cerebral palsy among neonatal survivors born very pre- maturely is up to 30 times higher than among those born at term. Cerebral scans performed in newborn babies have shown that the strongest predictor of cerebral palsy in these infants is periventricular leucomalacia. This term is used for abnormal echolucency, often as- sociated with cystic change, which is found particularly in the white matter dorsolateral to the lateral ventricles (see Fig.  24.20.10a). Babies born small for their gestational age are also at increased risk of cerebral palsy and the risk increases with the degree of birth weight deficit. The underlying mechanism is not clear and it should be noted that most small-​for-​date infants do not have cerebral palsy. The prevalence of cerebral palsy is much higher in twins than in sin- gletons, particularly in those who survive after the other twin has died in utero and in monochorionic twins. The risk rises with the number of fetuses carried. When considering children born at term in developed countries, 10 risk factors for cerebral palsy have been identified in a systematic review: placental abnormalities, major and minor birth defects, low birthweight, meconium aspiration, instru- mental/​emergency caesarean delivery, birth asphyxia (see next), neonatal seizures, respiratory distress syndrome, hypoglycaemia, and neonatal infections. Other possible causes include maternal iodine deficiency in early pregnancy which may cause endemic cretinism (spastic diplegia and deafness). Abnormal thyroid function in pregnancy may play a role in developed countries. Exposure to viral infections and to toxins during pregnancy may cause cerebral palsy—​recognized examples are methylmercury, alcohol, and carbon monoxide poisoning. Finally, postnatal causes include CNS infections, accidental and non​accidental head injuries, cerebrovascular accidents, and hypoxia (suffocation, near drowning). The role of birth asphyxia An important and controversial question that has significant medicolegal implications is the role of birth asphyxia in cerebral palsy. Although there may be some cases caused by intrapartum events that are preventable, these are likely to be rare. The best evidence for this comes from studies examining the impact of in- tensive electronic monitoring of the fetal heart rate during labour. These studies have found an increase in caesarean section rates and a reduced rate of neonatal seizures. There was, however, no impact on the rates of cerebral palsy. Epidemiological studies have shown that the origins of most cases of cerebral palsy are prior to labour. Currently, then, it is likely that many cases of cerebral palsy are wrongly attributed to an acute event during labour. In 1999, a con- sensus statement for the International Cerebral Palsy Task Force outlined a template for defining a causal relationship between acute intrapartum events and cerebral palsy. The statement emphasized the difficulty of retrospectively identifying the antenatal causes of cerebral palsy in the individual case and the non​specific nature of the clinical signs that lead to the suspicion of fetal hypoxia in labour. Brain imaging in children with cerebral palsy Neuroimaging, especially MRI, plays an increasing role in the assess- ment of children with cerebral palsy, with abnormalities reported in almost 90% of affected children in published case series. The MRI findings vary according to the child’s gestational age at birth (term versus preterm) and according to the type of cerebral palsy. MRI abnormalities are most often seen in children with spastic and dyskinetic cerebral palsy and least often in those with the (relatively rare) ataxic type. The most common lesion in preterm infants is periventricular leucomalacia, which is necrosis of periventricular white matter in the watershed regions dorsal and lateral to the lateral ventricle (see Fig. 24.20.10a). This is said to be characteristic of damage in the early third trimester. Despite the fact that preterm children with cerebral palsy often have a pattern of injury corresponding to the time of birth the scan findings do not provide exact information about the timing of the injury. In term infants, brain maldevelopment and grey matter lesions are more often seen than in preterm infants. Other findings are seen in infants born at or near term. These are infarcts in the arterial border zones in the parasagittal regions, leading to cortical and subcortical injury, bilateral lesions of the basal ganglia and the thalamus, areas of subcortical leucomalacia, and multicystic leucomalacia (replace- ment of the brain tissue by fluid-​filled cysts). Basal ganglia/​thalamus or bilateral cortico-​subcortical lesions are highly associated with problems in the perinatal period. However, this conclusion cannot be drawn on the basis of the scan alone without other supporting clinical evidence. Children with hemiplegias are sometimes found to have periven- tricular leucomalacia, porencephalic cysts (see Fig. 24.20.10b), or cortical/​subcortical lesions in the middle cerebral artery territory distribution (see Fig. 24.20.10c). The lesions tend to be unilateral, but bilateral lesions are also seen. Rarely they may have schizencephaly (see Fig. 24.20.10d), focal pachygyria, or focal heterotopia. Clinical approach to diagnosis and genetic counselling Assessing the nervous system in children History General The importance of the history cannot be overemphasized. Children may give a history themselves, but usually the parents or carers are an essential source of information, amplified by teachers, therapists, and other health professionals. Past history The pregnancy details are important. Significant events in the first trimester may include a threatened miscarriage, hyperemesis, or a viral infection, or the mother may have been taking medication. Later there may have been unsatisfactory fetal growth or reduced fetal movements. The perinatal history is relevant, including weeks section 24  Neurological disorders 6366 of gestation at delivery, and details of labour, birth weight, and head circumference. In the neonatal period the infant may have required treatment for early hypoglycaemia, seizures, breathing, or feeding difficulties. A developmental history is essential—​particular areas of concern in infants are lack of social response, absence of a social smile, poor fixing and following of the eyes, and lack of symmetrical organized limb movements. Later a characteristic pattern of delayed development may emerge (e.g. global delay is found in the most se- vere brain abnormalities or there may be mainly motor delay in the milder forms of cerebral palsy). Family and social history A three-​generation family tree is required, with details of con- sanguinity, epilepsy, motor disorders, and learning disabilities. Considerable effort may be needed to obtain relevant facts—​some families may not know about relatives with severe disability, per- haps because they are in institutions. Social factors are important in determining the environment in which the child grows up and they also determine the quality of care available for a child with sig- nificant disability. Examination Observation of spontaneous activity is essential. It may be helpful to use toys, bricks, beads for threading, paper, and crayons. The quality and symmetry of spontaneous movements should be noted and also any abnormal movements. If possible, it is best to assess muscle power by watching the child run, jump, and climb stairs. Fine motor function can be assessed while the child is drawing or threading beads. The conventional examination of the nervous system may be difficult in infants or young children (e.g. examination of the cranial nerves should be made a game by using a toy to observe eye move- ments and by encouraging the child to smile, whistle, close the jaw tight, stick out the tongue, and so on). The examiner may need to adapt the order of events or even come back later—​a useful assess- ment cannot be made if an infant is deeply asleep or upset and crying. Developmental assessment may be undertaken using one of the standardized schedules, such as the Bailey Scales of Infant Development or the Denver Developmental Screening Test. Later the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) and the Wechsler Intelligence Scale for Children (Revised) (WISC-​ R) may be used, usually by a psychologist. Dysmorphic features are particularly relevant in the context of a suspected abnormality of the nervous system. There may be birth- marks (port-​wine stain in Sturge–​Weber syndrome or midline skin abnormalities such as hairy patches or dimples over the spine in neural tube defects). Other important skin abnormalities may ap- pear in infancy or early childhood. Examples are the pale ash-​leaf patches, shagreen patches, and angiofibromas of the face (‘adenoma sebaceum’), which are found in tuberous sclerosis, or the café-​au-​ lait patches and axillary freckling found in neurofibromatosis type I. A full eye examination is essential. In babies it may be necessary to dilate the eyes and come back to perform fundoscopy while the child is feeding (and therefore preoccupied). Indirect ophthalmos- copy by an experienced ophthalmologist is probably best. There may be abnormalities of the iris (such as colobomas in trisomy 13 and CHARGE syndrome, Lisch nodules in older children with neuro- fibromatosis type I, or Kayser–​Fleischer rings in Wilson’s disease). Pale hypoplastic optic nerve heads are seen in septo-​optic dysplasia and other congenital and acquired conditions. Significant retinal abnormalities include the chorioretinitis seen in congenital toxo- plasmosis, cytomegalovirus infections or KIF11 syndrome and the retinal ‘lacunae’ seen in Aicardi syndrome. Growth should be assessed by measuring weight, length (height), and head circumference, and plotting them on up-​to-​date growth charts. The head circumference should be related to the age of the child and to the other measurements. Changes with time may be significant, for example, after a severe perinatal insult the head cir- cumference may initially be in the normal range and then fall pro- gressively further below the expected centile line in the first few months of life. Investigations Cranial MRI is the cornerstone of investigations in children or adults with suspected disorders of CNS development. It is important to discuss the investigation with a neuroradiologist because spe- cial imaging sequences not normally performed may be required to visualize relevant abnormalities (e.g. subependymal nodules in tuberous sclerosis). Infants and young children may require sed- ation or anaesthesia for the procedure. CT does not provide the resolution of CNS structure obtained with MRI, but may be valuable if intracerebral calcification is suspected (as in tuberous sclerosis or cytomegalovirus infection). When routine antenatal ultrasound has shown abnormalities, there is increasing use of MRI scanning during pregnancy yielding images of the fetal brain before birth. Further investigations will depend on the specific diagnosis in question. Metabolic disorders can cause structural abnormalities in the developing CNS and routine investigations that may be appro- priate include plasma and urine amino acids, together with urine organic acids. In addition, further specific investigations may be in- dicated (e.g. in suspected Zellweger’s syndrome which is associated with pachygyria and is caused by abnormalities of very-​long-​chain fatty acid metabolism). Developmental anomalies of the CNS are seen in many chromo- somal disorders and so a genomic array is an important investiga- tion. These investigations may point to a diagnosis for which one or more genes have been shown to be responsible. A detailed clinical work-​up is important to delineate the phenotype and facilitate inter- pretation of genetic investigations. Sequencing of individual genes is often an expensive and laborious investigation and is being rap- idly replaced by whole exome or whole genome sequencing studies. Establishing a genetic diagnosis enables confirmation of the clinical diagnosis and accurate assessment of risks for other family members following extended family testing. It may also enable more tailored clinical management and in future may be important for stratifica- tion of patients for therapy as response to different treatments may in some instances be dependent on the underlying molecular mech- anism of disease. Knowledge about the genetic basis of diseases is growing rap- idly but remains very incomplete. It is therefore valuable to take blood in order to extract and store DNA if no precise diagnosis can be reached, especially if life expectancy is short. Immediately after death it may be appropriate to obtain a muscle or liver biopsy to help establish a diagnosis. Skin may be also obtained at this time to establish a fibroblast culture enabling further genetic and biochem- ical testing. Later other tissues can be frozen if a full post-​mortem examination is performed. The ability to perform new tests many years after the death of the index case may be extremely valuable to other family members concerned about risks to their own offspring. 24.20  Developmental abnormalities of the central nervous system 6367 Risk assessment, genetic counselling, and prenatal diagnosis Many families request genetic advice regarding a developmental disorder of the nervous system and they usually have four ques- tions in mind: • What is it? • Why did it happen? • Will it happen again? • What can be done to reduce the chance of it happening again, or to detect it if it does? If it is possible to make a specific genetic diagnosis (e.g. by identifying a pathogenic mutation), these questions can often be answered very accurately. In contrast, in the absence of a specific diagnosis, gen- etic advice is usually limited to empirical estimates. It is important to note that providing accurate genetic advice about developmental anomalies of the nervous system is a challenging task and that errors have far-​reaching consequences for the families concerned. Referral for specialist advice by geneticists is strongly recommended. Prenatal diagnosis and termination of affected pregnancies is only one of a range of reproductive options open to parents at in- creased risk of having children with neurodevelopmental abnor- malities, but for many couples it is the option of choice. When a specific diagnosis has been made and a chromosomal anomaly, genetic mutation, or biochemical defect has been identified, it is usually possible to offer prenatal diagnosis by chorionic villus sam- pling at 11–​12 weeks’ gestation in a future pregnancy. Non​invasive prenatal testing for trisomy using free fetal DNA in the maternal serum is now widely available. Bespoke non​invasive single gene diagnosis is offered in some centres. Detailed ultrasonography may be helpful in other instances such as suspected neural tube de- fects. Ultrasonography has the potential to detect some structural anomalies but it does not provide information about key aspects of neurodevelopment, such as cognition, behaviour, vision, or hearing, and these limitations need to be discussed with parents. Although ultrasonography remains the initial investigation of choice for evaluating the fetus in utero, fast MRI is increasingly being used to image the fetal brain if there is concern about the ultrasound im- ages. MRI provides better images of CNS abnormalities and is not limited by interference from bony structures, so that posterior fossa abnormalities can be seen. In utero MRI is becoming increasingly valuable in antenatal counselling. For developmental disorders of the nervous system with proven disease-​causing mutations and a high recurrence risk, preimplantation genetic diagnosis is available in some centres; up-​to-​date advice should be sought. For a condition following Mendelian inheritance, the option of donor gametes could be discussed. For conditions with a strong envir- onmental component, it is imperative that measures are taken to min- imize the risk of exposure in a future pregnancy, such as periconceptual supplementation with high-​dose folate, which has been shown to re- duce the risk of recurrence of neural tube defects (see earlier). Acknowledgements We are very grateful to Dr Nagui Antoun (Addenbrooke’s Hospital, Cambridge), Dr Fred Pickworth (Norfolk and Norwich Hospital), and Mr Paul Chamberlain (John Radcliffe Hospital, Oxford) for the scans shown in this chapter and for advice on their interpretation. Many thanks to Mr Michael Cafferkey (Senior Illustrator, Medical Photography and Illustration, Addenbrooke’s Hospital, Cambridge) for producing Figs. 24.20.2 and 24.20.5. FURTHER READING Beeghly M, et al. (2010). Neurodevelopmental outcome of fetuses re- ferred for ventriculomegaly. Ultrasound Obstet Gynecol, 35, 405–​16. Cooper GM, et al. (2011). 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