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

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