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.