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Neurological complications of systemic disease 

Neurological complications of systemic disease
Chapter:
Neurological complications of systemic disease
Author(s):

Neil Scolding

DOI:
10.1093/med/9780199204854.003.2420
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Essentials

Primary neuroimmune disorders such as multiple sclerosis or the Guillain–Barré syndrome are well recognized (and described elsewhere in this section), but there are numerous diverse systemic inflammatory, infective, or immunological disorders that can affect the nervous system.

Autoimmune rheumatic and vasculitic disorders

Autoimmune rheumatic disorders—(1) Systemic lupus erythematosus—neurological manifestations include headache, acute or subacute encephalopathy, fits, myelitis, strokes and movement disorders (including chorea and other extrapyramidal disorders), ataxia and brainstem abnormalities, cranial and peripheral neuropathies, and psychiatric and cognitive disturbances. Risk of stroke is particularly associated with the lupus anticoagulant and the primary antiphospholipid syndrome. (2) Other conditions—(a) rheumatoid arthritis: mononeuritis, cervical cord compression; (b) Sjögren’s syndrome: sensory neuropathy, myositis, various central nervous system complications; (c) Reiter’s disease: polyneuritis, radiculitis, various central nervous system manifestations.

Vasculitides—neurological features include (1) mixed sensory and motor neuropathy—usually rapidly progressive and often painful; (2) central nervous system disease—protean manifestations reflect focal or multifocal infarction, or diffuse ischaemia. Conditions of particular 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 specific 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 are recognized. (3) Coeliac disease—malabsorption may lead to neurological sequelae; progressive (spino)cerebellar degeneration is a recognized (but unexplained) complication.

Thyroid disease—hyperthyroidism and myxoedema both carry neurological complications (see Chapter 24.19), 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 nervous system caused by immunological, infective, or inflammatory disturbances 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. More detailed accounts of the disorders can be found in other chapters.

Systemic lupus erythematosus (SLE)

(see Chapter 19.11.2)

SLE is not rare, with a prevalence of perhaps 30 in 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 >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 enquiry and focused 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 the generation of circulating anticoagulants—also occur. Other laboratory abnormalities include the presence of a variety of autoantibodies, including antinuclear antibodies (ANA) and anti-native DNA antibodies. The diagnosis—particularly for research and therapeutic trial purposes—is now commonly based on the widely accepted revised diagnostic criteria suggested by the American College of Rheumatology (Box 24.20.1). The presence of any four (or more) of the listed features, ‘serially or simultaneously, during any interval of observation’ [my italics] are sufficient for the diagnosis, with an estimated 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—though some suggest the true figure is higher. Central nervous system (CNS) disease is much commoner than neuromuscular involvement, and is a poor prognostic sign, reducing the overall survival figures, and representing the third commonest 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 disturbances, including lupus anticoagulant activity), and more direct autoimmune events affecting the target tissue—neurons or glia—in which soluble and cellular mediators are implicated.

Headache (including that associated with dural sinus thrombosis), acute or subacute encephalopathy, fits, myelitis, strokes and movement disorders (including chorea and other extrapyramidal disorders), ataxia and brainstem abnormalities, and cranial and peripheral 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 anticoagulant (LA) 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 (ACA) and/or LA in patients without serological or clinical evidence of SLE, and introduced the term ‘antiphospholipid syndrome’ (APS).

ACAs represent an independent risk factor for stroke. CNS thrombosis in patients with primary or secondary APS takes the form of completed arterial stroke, repeated transient ischaemic attacks (TIAs), multi-infarct dementia, and cerebral venous sinus thrombosis. Vascular visual problems, including amaurosis fugax and ischaemic retinopathy, also occur. Chorea too is associated with antiphospholipid antibodies; but the putative link with migraine may be factitious.

A severe acute ischaemic encephalopathy is also described, with confusion, obtundation, an hyperreflexic quadriparesis (usually asymmetrical), with or without systemic disturbances (dermatological and renal). Examination of the cerebrospinal fluid may show only a raised protein; a fatal outcome is common. The disorder may represent a focal variant of the recently described ‘catastrophic antiphospholipid 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 pupuric rash and other haemorrhagic complications. 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 to 85% of cases, and the ESR is commonly elevated (contrasting with the CRP which usually is not)—but neither a normal ESR nor negative serology at the time of neurological episode allows a confident exclusion of neurological lupus as the underlying cause. MRI changes are common, though neither invariable nor specific. Abnormal scans are commoner in individuals with focal events, and normal scans in patients with more diffuse problems, such as headaches, meningism, memory impairment, confusion, and seizures. Examination of the cerebrospinal fluid reveals some form of abnormality (raised protein or a neutrophil or lymphocyte pleocytosis) in 40 to 50% of cases; Oligoclonal band analysis of the cerebrospinal fluid is positive in perhaps 20%—all changes which can resolve with successful immunotherapy. A skin biopsy can be extremely helpful in suspected lupus.

Management of neuropsychiatric lupus

Symptomatic therapies are important in patients with encephalopathies, epilepsy, and/or psychiatric ailments. Disease-modifying therapeutic efforts fall into two categories depending on the presumed underlying mechanisms—stroke prevention in cerebral ischaemia, particularly that associated with ACA, probably best achieved with moderate to high dose warfarin, and immunotherapy of ‘other’ CNS complications. Here, intravenous methylprednisolone, followed by oral steroid treatment is the mainstay of treatment. Cyclophosphamide may be exhibited for severe or steroid-resistant disease, with azathioprine to maintain remission and spare steroids. Plasmapheresis synchronized with cyclophosphamide, and intravenous immunoglobulin, may prove useful. More recent attention has focused on the promising role of the anti-B cell monoclonal antibody rituximab. Anti-tumour necrosis factor α‎ (TNFα‎) therapy may actually increase disease activity.

Rheumatoid arthritis

An inflammatory peripheral neuropathy occurs in approximately 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 distribution, precipitated by synovial swelling. Pannus formation and cervical spine subluxation with resulting cord compression represent the commonest cause of CNS involvement. More rarely, rheumatoid vasculitis, or deposition of rheumatoid nodules, may involve the CNS; the former warrants treatment with cyclophosphamide and steroids. Recent excitement has emerged concerning the potential therapeutic role of anti-TNF and anti-B-cell therapies.

Sjögren’s syndrome

Sjögren’s syndrome characteristically comprises a triad of (1) keratoconjunctivitis sicca, and (2) xerostomia, occurring in approximately 50% of cases (3) in the context of another connective tissue disease, usually rheumatoid arthritis. Speckled antinuclear antibodies anti-Ro (SS-A) or anti-La (SS-B) are present in up to 75 to 80% of patients. Conventionally, the principal neurological manifestations have been held to be peripheral, with descriptions both of a mainly sensory neuropathy and of myositis. Trigeminal sensory neuropathy is also classically described.

More recently, attention has been drawn to various CNS complications of the disorder, with seizures, focal stroke-like or brainstem neurological deficits, and encephalopathy with or without an aseptic meningitis, often with raised cerebrospinal fluid 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 (optic neuropathy is particularly associated), though most such patients have additional 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.

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. PNS disease predominates, particularly painful trigeminal neuropathy; myopathy, with an elevated CPK 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 systemic lupus erythematosus coincide, and high levels of antibodies directed against extractable nuclear antigens—ribonucleoproteins or RNP—are found (Table 7.1). 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.

Reiter’s disease

The clinical triad of seronegative arthropathy, nonspecific urethritis, and conjunctivitis, usually following venereal or dysenteric infection, constitute Reiter’s syndrome. As many as 25% of patients are reported to have neurological 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. A recent report suggests that ciclosporin may be of value in severe Reiter’s disease.

Psoriasis

Psoriasis is included as the third seronegative arthropathy, but its neurology 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. (1) Primary or idiopathic isolated CNS vasculitis can occur, wherein symptoms are confined to the nervous system. (2) There are a number of primary systemic vasculitides, usually involving the lungs and/or kidneys—e.g. polyarteritis and Wegener’s granulomatosis—which can also secondarily affect the nervous system. (3) 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 secondary vasculitis of the nervous system, neurological features arise from inflammation and necrosis of the vasculature—principally through infarction.

Clinical features

The picture of peripheral nerve vasculitis is relatively straightforward: 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 asymmetrical polyneuropathy or a distal symmetric neuropathy.

CNS disease is infinitely more varied—focal or multifocal infarction or diffuse ischaemia affecting any part of the brain, explaining the protean manifestations, the wide variation in disease activity, course, and severity, and the absence of a pathognomic or even typical clinical picture. Thus, in primary and secondary intracranial vasculitis, headache (perhaps 50% of cases), focal and generalized seizures (10–20%), acute and subacute encephalopathies, progressive cognitive changes, behavioural disturbances, chorea, myoclonus and other movement disorders, optic and other cranial neuropathies are all seen. (Although it is included in many accounts, the conventional clinical picture of isolated large vessel stroke, so resembling atheromatous thromboembolic stroke as to cause diagnostic confusion, is profoundly 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) resembling atypical multiple sclerosis (‘MS-plus’)—with a relapsing–remitting course, and features such as optic neuropathy and brainstem 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 drowsiness and coma; (3) intracranial mass lesion—with headache, drowsiness, focal signs and (often) raised intracranial pressure. This grouping carries neither pathological nor therapeutic implications, 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 alternative possibilities (Table 24.20.1), the confirmation of intracranial vasculitis, and pursuit of the causes of the vasculitic process.

Table 24.20.1 Some disorders that may mimic cerebral vasculitis

Other vasculopathies

Infections

Susac’s syndrome

Lyme disease

Homocysteinuria

AIDS

Ehlers–Danlos syndrome

Endocarditis

Radiation vasculopathy

Whipple’s disease

Köhlmeyer–Degos disease

Viral encephalitis

Fibromuscular dysplasia

Legionella/mycoplasma pneumonia

Fabry’s disease

Tumours and malignancy

Moyamoya disease

Atrial myxoma

Amyloid angiopathy

Multifocal glioma

CADASIL

Cerebral lymphoma

Marfan’s syndrome

Paraneoplastic disease

Pseudoxanthoma elasticum

Other disorders

Viral or fungal vasculitis

Multiple cholesterol emboli

Other immune/inflammatory diseases

Thrombotic thrombocytopoenic purpura

Sarcoidosis

Cerebral sinus thrombosis

Lupus and anti-phospholipid disease

Mitochondrial disease

Behçet’s syndrome

Multiple sclerosis/ADEM

Thyroid encephalopathy

ADEM, acute disseminated encephalomyelitis; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Confirming cerebral vasculitis

No single simple investigation is universally useful in confirming cerebral vasculitis. Serological markers, including ANCA, are important. Spinal fluid examination is, like ESR testing, often abnormal, but lacks specificity, with changes in cell count and/or protein in 65 to 80% of cases; oligoclonal immunoglobulin bands may be present. Cerebrospinal fluid pressure is frequently raised, as may be the glucose level. MRI may disclose ischaemic areas, periventricular white matter lesions, haemorrhagic lesions, and parenchymal or meningeal enhancing areas, but lacks both specificity and sensitivity. Contrast angiography 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 disorders such as Takayasu’s arteritis and classical polyarteritis nodosa (PAN). Nuclear imaging of labelled leucocytes 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 nondominant temporal white and grey matter, is important. Biopsy may reveal an underlying process not otherwise suspected with profound therapeutic implications, such as infective or neoplastic (principally lymphomatous) vasculopathies, but is not a trivial procedure, carrying a risk of serious morbidity estimated at 0.5 to 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

Wegener’s granulomatosis 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 characteristic, 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 PAN is now recognized as an unusual disorder which may have some overlap and coexist with microscopic polyangiitis, 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 pathologically by a granulomatous necrotizing vasculitis, and clinically by prominent asthma with an eosinophilia. Small vessel vasculitis commonly affects postcapillary venules. The skin is most commonly involved, 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 term.

In all these disorders, PNS involvement, 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 Wegener’s disease. 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 Wegener’s disease. Middle ear disease may lead to cranial nerve VII and VIII neuropathies.

Neurological vasculitis complicating nonvasculitic systemic disorders

Although the clinical picture of cerebral vasculitis may closely be mimicked by SLE, a noninflammatory vasculopathy is far more commonly responsible—though occasional instances of vasculitis are described. In 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 involvement are common. The diagnosis, however, will only be made if blood is collected into a plain tube, immediately placed in water and kept at a temperature 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 disease, 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 clinical and histological evidence of multisystem necrotizing vasculitis. The majority of strokes occurring with cocaine abuse are associated with arterial 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 vascular damage—direct invasion, immune complex formation and deposition, and (in part related to the second), secondary cryoglobulinaemia. Although the association of hepatitis C infection with cryoglobulinaemia and small-vessel vasculitis has been stressed above, other infections, including hepatitis B, Epstein–Barr virus (EBV), cytomegalovirus (CMV), Lyme disease, syphilis, malaria, and coccidiomycosis have all also been linked to mixed cryoglobulinaemia.

Primary invasion of the vascular wall by the infectious agent is, however, the commonest precipitant of infection-associated vasculitis. 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 infection, CMV and toxoplasma may precipitate 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 Haemophilus influenzae—may also trigger intracranial vasculitis.

Herpes zoster can precipitate cerebral vasculitis in approximately 0.5% of cases, usually causing a monophasic illness, with hemiparesis contralateral to the eye disease. However, more generalized necrotizing and granulomatous vasculitis can also occur.

Malignancy, lymphomatoid granulomatosis, and malignant angioendothelioma

Leukocytoclastic vasculitis (often dermatological) may occur in association 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 derivation. 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 approximately 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; characteristic skin manifestations occur.

Treatment of cerebral vasculitis

Retrospective analyses support the use of cyclophosphamide with steroids in vasculitis. In proven cerebral vasculitis a 3 to 4 month induction regime might comprise high-dose intravenous, then oral steroids, with oral or pulsed intravenous cyclophosphamide; 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 immunoglobulin may be useful. Cyclophosphamide is associated with haemorrhagic cystitis (less likely with adequate hydration and mesna cover), bladder cancer, other malignancies, infertility, cardiotoxicity, and pulmonary fibrosis. Biological agents—monoclonal antibodies and TNF receptor antagonists—have shown promise.

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-auditory symptoms, which may be complicated 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 commonest large-vessel vasculitis, rarely affects individuals less than 55 years of age. It affects women twice as commonly as men, with an overall prevalence of 1 in 1000. 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 occasionally general malaise. The affected temporal artery (-ies) may be thickened and cord-like, often nonpulsatile, 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 results, which may occur because of the focal or multifocal nature of the disorder.

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. Vasculitic changes may still be apparent in biopsies taken 14 days or more after the commencement 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 posterior 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 defect. 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/day) in view of the risk of permanent blindness. The dose is generally reduced slowly (5 mg decrements weekly) after 4 to 7 days to a maintenance dose of perhaps 10 mg daily; thereafter, some would suggest continuing for 12 to 24 months before closely monitored phased withdrawal. 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 osteoporosis, diabetes, cataract, and peptic ulceration.

Behçet’s disease

Behçet’s disease is a chronic relapsing multisystem inflammatory disorder whose clinical manifestations vary. The classical triad of recurrent 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 h) are also required to confirm the diagnosis.

Approximately one-third of patients develop neurological involvement, 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 meningoencephalitis, encephalopathy, brainstem syndromes, cranial neuropathies, movement disorders, and cortical sensory and motor deficits. Psychiatric and progressive cognitive manifestations are reported. 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 nonspecific.

Treatment

Recent retrospective studies indicate an improved survival in patients with CNS Behçet’s treated with steroids and immunosuppressants. 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 CRP 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. Optic and other cranial neuropathies (especially involving the facial nerve), often due to meningeal infiltration, and brain stem and spinal cord disease are the commoner manifestations. Cognitive and neuropsychiatric abnormalities are reported. Peripheral nerve and muscle involvement is also well described.

The diagnosis can be difficult: presentation with isolated neurological deficits may be commoner in sarcoidosis than in other systemic inflammatory or immunological conditions. Serum and CSF angiotensin converting enzyme (ACE) 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 remains a useful indicator of systemic disease. Cranial MRI may show multiple white-matter lesions or meningeal enhancement. The diagnosis is confirmed where possible by biopsy, either of cerebral or meningeal tissue, or of lung or conjunctiva where appropriate.

The mainstay of medical treatment in neurosarcoidosis is corticosteroids, though response rates as low as 29% have been reported. Methotrexate, azathioprine, hydroxychloroquine, and cyclophosphamide have been used in steroid-resistant cases. TNF inhibition appears very promising.

Organ-specific autoimmune disease

Ulcerative colitis and Crohn’s Disease

The neurological complications of ulcerative colitis (see Chapter 15.12) and Crohn’s disease (see Chapter 15.11), seen in around 5% of patients, are similar. Three types of CNS disease have been associated: (1) 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; (2) epileptic seizures, focal and generalized, and not always in connection with dehydration or sepsis; and, in some reports, (3) a slowly progressive myelopathy.

Peripheral neuropathy is seen in 0.5 to 1.0% of cases; an acute Guillain–Barré syndrome is the commonest phenotype. Lastly, myopathy, sometimes of metabolic origin but mostly inflammatory, is also reported.

Whipple’s disease

Whipple’s disease (see Chapter 15.10.6) is an uncommon multisystem disorder characterized by arthropathy, respiratory symptoms, anaemia, fever, erythema 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 24.20.2).

Diagnosis and management

Up to 20% of cases of cerebral Whipple’s disease occur in the absence of gastrointestinal or indeed other systemic symptoms. CT and MRI scanning may be normal, although the latter can also reveal non-specific abnormalities—multiple high signal intensity areas on T2-weighted images, or more striking enhancing mass lesions warranting biopsy. Similarly, the cerebrospinal fluid 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 cerebrospinal fluid samples may reveal pathognomic periodic acid–Schiff-positive bacilli; repeat spinal fluid examination increases this yield. Approximately 30% of cases have a noninformative small-bowel biopsy, though electron microscopy increases the sensitivity. Lymph node biopsy can also be useful. Polymerase chain reaction (PCR) 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 nowadays, co-trimoxazole. Prompt treatment is vital in patients with neurological disease, which may (if untreated) run a profoundly aggressive and not unusually rapidly fatal course. Successful reversal of neurological deficits, including cognitive impairment, may follow antibiotic treatment.

Coeliac disease

Coeliac disease (nontropical sprue) is an immunologically-mediated disorder resulting from intolerance to dietary gluten; it causes weight loss with steatorrhoea and/or diarrhoea, and malabsorption (see Chapter 15.10.3). In common with other enteropathies, neurological sequelae of a predictable nature may complicate coeliac disease as a direct consequence of malabsorption. CNS complications apparently unrelated 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.

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 complications generally considered direct consequences of abnormal thyroxine levels—anxiety, tremor, occasionally chorea, etc., in thyrotoxicosis, and lethargy, myopathy, and dementia in hypothyroidism (see Chapter 13.4). By contrast, Grave’s ophthalmoplegia and Hashimoto’s encephalopathy are both thought to be immunologically driven.

In dysthyroid eye disease, the orbit and extraocular muscles are oedematous and infiltrated with inflammatory cells and glycosaminoglycans, resulting in proptosis and a restrictive ophthalmopathy. Upgaze limitation is the commonest presenting sign. Vision is occasionally threatened by a complicating infiltrative or compressive optic neuropathy. Circulating TSH receptor-stimulating antibodies cross-reactive with orbital fibroblasts are found. Steroid treatment and radiotherapy are equally effective.

Hashimoto’s encephalopathy exhibits 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 CT or even MR 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 received further immunosuppressive therapy, such as cyclophosphamide or azathioprine.

Further reading

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