36 Vasculitis and collagen vascular diseases

That part of the clinical interface between neurology and general medicine occupied by inflammatory and immunological diseases is neither small nor medically trivial. Neurologists readily accept the challenges of ‘primary’ immune diseases of the nervous system (Table 36.1): these tend to be focussed on one particular target such as oligodendrocytes or the neuro-muscular junction present in predictable ways, and are amenable as a rule to rational, methodological diagnosis, and occasionally even treatment. This is proper neurology.

‘Secondary’ neurological involvement in diseases mainly considered systemic inflammatory conditions—for example, SLE, sarcoidosis, vasculitis, and Behçet’s—is a rather different matter. It may be difficult enough to secure such a diagnosis even when systemic disease has previously been diagnosed and new neurological features need to be differentiated from iatrogenic disease, particularly drug side effects or the consequences of immune suppression. But all the diseases mentioned may present with and confine themselves wholly to the nervous system; they may mimic one another, and pursue erratic and unpredictable clinical courses. In central nervous system disease, diagnosis by tissue biopsy is potentially hazardous and unattractive. Few neurologists enjoy excesses of confidence or expertise when faced with such clinical problems: the cautious diagnostician is perplexed, and the evidence-based neuroprescriber confounded. Unsurprisingly, great variations in approaches to diagnosis and management are seen (Scolding et al. 2002b).

But rheumatologically inclined general, renal or respiratory physicians, comfortable when managing inflammation affecting their system or indeed other parts of the body designed to support the nervous system, are generally also ill at ease when faced with neurological features whose differential diagnosis may be large, particularly given the near universal diagnostic non-specificity of either imaging or CSF analysis.

Here then is the subject material for this chapter: the diagnosis and management of central nervous system involvement in inflammatory and immunological systemic diseases (Scolding 1999a). In not one of these neurological conditions has a single controlled therapeutic trial been reported, and much that is published on these conditions is misleading or inaccurate. And yet the frequency with which the diagnosis is only confirmed or even first emerges at autopsy bears stark witness to both the severity and evasiveness of these disorders.

Vasculitis is not a diagnosis, still less a disease. It is best thought of as a histopathological description: intramural inflammation, often but not invariably with perivascular changes too, and necrosis of the blood vessel wall. It occurs in the context of a group of disorders, the vasculitides, whose classification is complex (Lie 1997b), with subdivisions into idiopathic primary vasculitic disorders, for example, giant cell arteritis and Wegener’s granulomatosis, and those vasculitides secondary to collagen diseases, malignancy, viral infection and according to pathological features, largely by vessel size (Table 36.2).

Nervous system involvement can occur in any of the systemic vasculitides. Additionally, isolated vasculitis of the central or peripheral nervous system is recognized, where little or no inflammation is apparent outside the nervous system: termed central or peripheral nervous system angiitis (Calabrese et al. 1988).

In primary central nervous system vasculitis, vasculitis is confined to the brain and spinal cord, and there is no discernible systemic vasculitic or other disease. Although defined by this apparently exclusive distribution, autopsies have revealed subclinical extracranial involvement for instance of pulmonary arteries and abdominal viscera (Lie 1997b) presumably helping to explain the occasional features of fever, rigors, weight loss, or raised plasma viscosity.

The angiitic process is focal and segmental in distribution, and granulomatous, necrotizing, or lymphocytic in character, often with mixed morphologic types in individual patients, therefore rendering the common title of ‘granulomatous angiitis’ difficult to sustain.

The clinical definition of cerebral vasculitis is not uniform (Scolding et al. 2002b), and this helps to explain significant differences in approach to diagnosis and therapy. Some define the disorder by its angiographic appearances, explicitly not requiring tissue confirmation. Indeed some have suggested a more favourable monophasic clinical course in the so-called ‘benign angiopathy of the central nervous system’. This is a syndrome with normal, or only mildly abnormal CSF, and evidence of a vasculitic picture on angiography alone (Calabrese et al. 1993). The concept has been questioned in view of the recognized non-specificity of angiography, the fact that those cases not proceeding to biopsy are more likely to be the less severely affected, and because children satisfying ‘benign angiopathy’ criteria often do not have a temperate, monophasic course, and have required aggressive immunotherapy (Gallagher et al. 2001). Most, however, including the current author, believe a certain diagnosis of primary central nervous system angiitis must depend on positive biopsy.

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 complicated by central or peripheral nervous involvement or systemic vasculitis (Vollertsen 1990).

Eale’s disease is an isolated retinal vasculitis causing visual loss; again, neurological complications are rarely described (Dastur and Singhal 1976; Singhal and Dastur 1976).

Virtually all of the systemic vasculitides may be complicated by neurological involvement; often they carry their own defining characteristics. Systemic disturbances—fever, night sweats, severe malaise, weight loss, rash, or arthropathy—are common.

Wegener’s granulomatosis predominantly affects the upper and lower respiratory tracts, including the nose, causing the characteristic saddle nose deformity (Fig. 36.1). Renal disease occurs in 80 per cent of patients. The anti-neurophil cytoplasmic antibody, cANCA is positive, with proteinase-3 specificity, and biopsy shows a necrotizing, granulomatous vasculitis. Neurological involvement occurs in up to 35 per cent of patients (Nishino et al. 1993) but usually of the peripheral nervous system (Section 21.15.3), cerebral small-vessel vasculitis is rare. More likely is the unique contiguous extension of erosive granulomata from the sinuses or from remote metastatic granulomata to the central nervous system. Meningeal and middle ear disease may lead to significant cranial neuropathies especially of VII and VIII. Orbital pseudotumour may occur. Gadolinium-enhanced MR scanning may valuably reveal meningeal thickening and infiltration, offering a ready target for biopsy.

Microscopic polyangiitis is a pANCA-positive multisystem small vessel vasculitis. Renal disease is again common, indeed this vasculitis is occasionally confined to the kidney, but upper respiratory tract involvement is not, and granulomata are not seen. One study found mononeuritis multiplex in 55 per cent (Guillevin et al. 1999), but central nervous system disease was uncommon, in 11 per cent, and rarely contributes to mortality.

Classical polyarteritis nodosa is an unusual disorder with medium- and small-sized muscular artery involvement in multiple organs, excepting the lungs. Patients often present with renal failure and hypertension in 80 per cent. Gastrointestinal involvement occurs in up to 50 per cent, with abdominal pain due to visceral infarcts. Heart failure and myocardial infarction reflect cardiac involvement. Neurological abnormalities are prominent occurring in 50–60 per cent, but again mostly confined to the peripheral nervous system (Section 21.15.3). About 20–30 per cent have hepatitis B antigen or antibody in serum. Visceral angiography shows aneurysms or occlusions.

Churg–Strauss syndrome is characterized by hypereosinophilia with systemic vasculitis in individuals with recently developed atopy. Asthma and mononeuritis multiplex are frequent (Section 21.15.3). Rashes, with purpura, urticaria, and subcutaneous nodules, are common. Glomerulonephritis may develop, and coronary, splanchnic and cerebral circulations are often involved. Central nervous system involvement is evident in only about 7 per cent of the cases (Sehgal et al. 1995). About 50 per cent of patients are positive for pANCA, 25 per cent positive for cANCA, and 25 per cent ANCA negative.

Henoch–Schönlein purpura is an immunologically mediated small vessel systemic vasculitis of children, affecting the skin, gastrointestinal tract, joints, and kidneys. Neurological involvement is well-described, with haemorrhage and/or encephalopathy, often apparently responsive to plasmapheresis, but although usually labelled as cerebral vasculitis, there is no reported tissue proof of the central nervous system process.

Kawasaki disease or the Mucocutaneous lymph node syndrome, usually affects children under 12 years, and is rare in the United Kingdom, <5/100 000/year, but far commoner in Japan. Coronary artery aneurysms occur in a fifth of untreated cases, and may result in myocardial infarction. Neurologically, there is commonly an aseptic meningitis, but hemiplegic strokes, encephalopathy, and facial palsy are also described. Pathologically, an acute systemic inflammatory vasculitis, with little or no fibrinoid necrosis, underlies the disease. Anti-endothelial cell antibodies may be involved.

Neuropsychiatric disease is common in systemic lupus erythematosus (Section 36.3.1), occurring in 40 to 50 per cent (Scolding 1999c), but very rarely caused by a vasculitic process and the casually used ‘lupus vasculitis’ therefore is almost invariably an incorrectly applied epithet.

This may be complicated by systemic vasculitis affecting small or large calibre vessels, with angiographic and indeed histological evidence of central nervous system vasculitis. Serum angiotensin converting enzyme and calcium levels are not always raised. CSF abnormalities are seen in 80 per cent of the cases, usually with an elevated protein and pleocytosis, and oligoclonal bands are positive in about 45 per cent of them. Cranial MRI shows non-specific white matter lesions or meningeal enhancement; whole body gallium scanning may reveal characteristic parotid gland and lung changes.

Seropositive rheumatoid disease is a well-recognized precipitant of cerebral vasculitis (Scolding 1999c), though skin involvement and mononeuritis multiplex are far more typical manifestations of rheumatoid vasculitis. There are also rare reports of central nervous system angiitis in systemic sclerosis, Sjögren’s syndrome, and mixed connective tissue disease, though rarely without a preceding history of systemic symptoms, and even more rarely with tissue confirmation.

Behçet’s disease is also considered in Section 36.5.1.

Infection-related vasculitis (Lie 1996) occurs through direct invasion of the vessel wall by Aspergillus, histoplasma or coccidioides, immune complex deposition involving hepatitis B, Epstein–Barr virus, cytomegalovirus, Lyme disease, syphilis, or malaria, and/or secondary cryoglobulinaemia. ‘Hepatitis B and C, Epstein–Barr virus, cytomegalovirus, Lyme disease, syphilis, malaria, and coccidiomycosis all have been linked to mixed cryoglobulinaemia.

In HIV infection, cytomegalovirus and toxoplasma may precipitate vasculitis, and syphilitic cerebral vasculitis has re-emerged. Bacterial causes of meningoencephalitis, mycobacteria, pneumococci, and H. influenzae, may also trigger intracranial vasculitis.

In herpes zoster ophthalmicus, secondary, localized central nervous system vasculitis affecting the ipsilateral hemisphere occurs in approximately 0.5 per cent of the cases, probably by direct viral invasion of blood vessels (Hilt et al. 1983), producing single or multiple smooth-tapered segmental narrowing on angiography. The characteristic clinical picture is an acute monophasic hemiparesis contralateral to the, usually resolving, ocular disease. The latent period is usually 3–4 weeks. A CSF mononuclear pleocytosis and raised varicella-zoster antibody titre aid the diagnosis. A generalized necrotizing, granulomatous vasculitis can also occur.

Complications of shingles may affect children similarly, though there have been less frequent reports of chicken pox triggering cerebral or spinal vasculitis.

Coccidioides immitis spores which are endemic to the southwestern United States and Northern Mexico, can be inhaled with subsequent haematogenous spread, often to the meninges. Vasculitis involving the small penetrating branches of the major cerebral vessels, and consequent deep ischaemic infarction (de Carvalho et al. 1980), has been observed in up to 40 per cent of these cases, rarely with subarachnoid haemorrhage.

Leucocytoclastic vasculitis may occur in association with a variety of cancers as a paraneoplastic phenomenon. Central nervous system angiitis in the context of Hodgkin’s disease is also 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 derived from the T-lymphocyte. Cutaneous and pulmonary involvement are common, with nodular cavitating lung infiltrates, and neurological manifestations occur in 25–30 per cent of cases; they are the presenting feature in approximately 20 per cent of them. 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 derived from the B-cell, 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.

The most compelling evidence relates to amphetamines (Section 5.3.4), with clinical and histological evidence of multisystem necrotizing vasculitis (Citron et al. 1970). Vasculitis may follow only a single dose, but repeated amphetamine exposure is the usual history. However, many reports include no tissue confirmation, with a diagnosis of ‘vasculitis’ based on angiography despite the fact that vasospasm causes identical angiographic changes. In cocaine abuse (Section 5.3.2), the significantly increased risk of ischaemic stroke results from vasospasm, probably from increased catecholamine release, and very seldom from vasculitis (Aggarwal et al. 1996). Co-injected contagion such as hepatitis C may cause vasculitis.

Rarely, an immune reaction against spontaneous amyloid deposits within the cerebral vasculature appear to precipitate a true central nervous system vasculitis, a recently described disorder which has been termed Aβ-related angiitis, ABRA (Scolding et al. 2005).

Variably focal or multifocal infarction, or diffuse ischaemia, of any part of the central nervous system, explain the protean manifestations, wide variation in disease severity, and the absence of a pathognomic or even typical clinical picture. Consequently, most accounts of both primary and secondary intracranial vasculitis accurately but unhelpfully describe headaches, focal or generalized seizures, stroke-like episodes with hemispheric or brainstem deficits, acute or subacute encephalopathies, progressive cognitive changes, chorea, myoclonus and other movement disorders, and optic and other cranial neuropathies. The course can be acute or subacute, but chronic progressive presentations are well-described, as are spontaneous relapses and remissions. Systemic features such as fever, night sweats, livedo reticulares, or oligoarthropathy may also be present, often revealed only on direct questioning. Although included in many accounts, the clinical picture of conventional large vessel stroke, sufficiently like atheromatous thromboembolic stroke to cause diagnostic confusion, is profoundly uncommon.

Despite this clinical diversity of presentation, three broad categories, carrying neither pathological nor therapeutic implications, have been defined in the hope of improving recognition of the condition (Scolding et al. 1997):

Clinical suspicion having been raised, the diagnosis of cerebral vasculitis involves exclusion of alternative possibilities, confirmation of intracranial vasculitis, and pursuit of the cause of the vasculitic process. No single simple investigation can confirm a diagnosis of cerebral vasculitis; some can exclude it. The diagnostic process can be difficult but practical approaches have been proposed. (Joseph et al. 2002)

Blood tests and serology. Anaemia is an infrequent finding, but leucocytosis is present in about 50 per cent of patients. The ESR and C-reactive protein levels are often raised, but lack specificity. Serological testing for ANA, ANCA or rheumatoid factor is vital, but of little value in confirming isolated cerebral vasculitis. ‘False’ ANCA positivity is sometimes seen in connective tissue disorders such as lupus and rarely in individuals without vasculitis.

Spinal fluid examination. CSF analysis is non-specific but again useful in suggesting an inflammatory central nervous system process, and excluding infection and malignant diseases. An elevated cell count, usually a lymphocytosis, and/or protein occurs in 50–80 per cent of the cases (Calabrese et al. 1988; Hankey 1991; Scolding 1999b). The CSF opening pressure is raised in almost half the cases of primary angiitis of the central nervous system. Oligoclonal immunoglobulin bands are found in up to 40–50 per cent of them (Scolding et al. 1997); band patterns vary discernibly over the course of disease, occasionally even disappearing altogether, helping to exclude multiple sclerosis when part of the differential diagnosis.

Imaging. MRI is a non-specific detector of vascular disease (Harris et al. 1994), disclosing of course the results of vascular inflammation, not vasculitis itself. Ischaemic areas, periventricular white matter lesions, haemorrhagic lesions, and parenchymal- or meningeal-enhancing areas can be seen. Sensitivity is by no means perfect: in one study, of 50 territories affected by vasculitis on contrast angiography, at least one- third were normal on MRI (Cloft et al. 1999). Unsurprisingly, therefore, histopathologically proven cerebral vasculitis with normal MR imaging is well-recognized.

MR angiography is valuable in imaging of large vessel vasculitides such as Takayasu’s arteritis and classical polyorteritic nodosa, with potential to supplant contrast angiography (Atalay and Bluemke 2001), but has insufficient resolution to help in medium or small vessel cranial vasculitis.

Establishing the diagnostic value of contrast angiography is complicated by the many reports which use this as the ‘gold standard’ for diagnostic confirmation. However, correlative radiological-pathological studies show a false negative rate of 30–40 per cent (Hankey 1991; Hellmann et al. 1992; Alrawi et al. 1999) which is explained not least by the small size of the affected vessels.

When abnormalities are present, they include segmental multifocal narrowing, with areas of localized dilatation or beading (Fig. 36.2). In PACNS, single stenotic areas in multiple vessels are more frequent than multiple stenotic areas along a single vessel. Retrospective series suggest a specificity of around 33 per cent—an enormous number of other inflammatory, metabolic, malignant, and other vasculopathies accurately mimic angiitis.

Some have reported an angiographic risk of transient, in 10 per cent, or permanent neurological deficit, in 1 per cent (Hellmann et al. 1992). Although its diagnostic importance has been overemphasized, contrast angiography remains a valuable investigational tool.

Indium-labelled white cell nuclear scanning has a limited role, particularly in disclosing areas of sometimes unsuspected systemic inflammation (Scolding et al. 1997).

Ophthalmological examination. Careful ocular examination, including slit lamp study, is vital. Subclinical conjunctival, anterior

or posterior inflammation, or retinal changes may, occasionally following conjunctival biopsy, confirm ocular, and thereby imply neurological, sarcoidosis, Behçet’s disease, or other inflammatory disorders. Dynamic examination of the episcleral vasculature, and of red cell flow therein, using video slit lamp microscopic recording and low-dose fluorescein angiography, can be a useful additional investigation (Scolding et al. 1997).

Histopathology. Histopathological confirmation, biopsying an abnormal area of brain where possible, or ‘blind’ biopsy of meninges, and non-dominant temporal white and grey matter, is important.Currently, up to 75 per cent of reported cases are ‘diagnosed’ without histopathology (Alrawi et al. 1999). A recent series of 61 patients biopsied for suspected cerebral vasculitis reported that none suffered any significant procedure-related morbidity. In this study, 36 per cent were confirmed as having cerebral vasculitis, but importantly, 39 per cent biopsies showed alternative, unsuspected diagnoses: lymphoma in 6 cases, multiple sclerosis in 2, or infection in 7 cases, including toxoplasmosis, herpes, and also two cases of cerebral abscess. Biopsy failed to yield a clear diagnosis in 25 per cent of patients, though even here, biopsy arguably might not be described as ‘non-contributory’, at least helping to exclude the alternative diagnoses mentioned above. The decision not to biopsy must be balanced against the harmful effects of immunosuppressive drugs used, potentially, unnecessarily.

A vasculitic process having been confirmed, the specific defining characteristics of the primary and secondary vasculitides must be carefully sought.

Microvascular ischaemia and infarction, including that within vasa vasora, results from three consequences of inflammation within the vascular wall: obstruction of the lumen, increased coagulation from changes on the endothelial surface, and alterations in vasomotor tone. The development of a vasculitic process depends on interplay between cellular and humoral immune factors, most research interest having centred on the latter.

Evidence for cell-mediated involvement in tissue injury in vasculitis comes in part from studying microscopic polyarteritis nodosa and Wegener’s granulomatosis. In both disorders, circulating T-cells responsive to PR-3 are found, and vascular lesions contain activated T-cells and antigen presenting major histocompatibility complex Class II positive dendritic cells (Lie 1997a). In primary central nervous system and peripheral nerve vasculitic lesions, the predominant infiltrate is one of CD4-positive and CD8-positive T-lymphocytes and monocytes (Griffith and Pusey 2001).

Most would consider cerebral vasculitis a highly treatable condition, though controlled trials are there none, not least because of the rarity of the condition and the absence of unifying diagnostic criteria. Retrospective analyses, and lessons from systemic vasculitides (Adu et al. 1997; Jayne et al. 2003), lend significant support for the use of steroids with cyclophosphamide. In biopsy-proven disease, a reasonable induction regimen might comprise high-dose steroids with intravenous methyl prednisolone, 1g daily for 3 days, then oral prednisolone 60 mg/day, decreasing by 10 mg at weekly intervals to 10 mg/day if possible, coupled from the outset with cyclophosphamide 2.5 mg/kg/day reduced to 2 mg/kg in the elderly, or in cases of renal failure). This induction combination is suggested for 9–12 weeks. Pulsed weekly intravenous cyclophosphamide appears to differ insignificantly in efficacy from daily oral treatment, and may have fewer side effects. Careful monitoring of the blood count for evidence of bone marrow suppression should force a reduction in the cyclophosphamide dose if there is leucopoenia < 4.0 × 10⁹ or neutropoenia < 2.0 ×10⁹.

Cyclophosphamide is associated with haemorrhagic cystitis which is less likely with adequate hydration and MESNA cover, a 33-fold increase in bladder cancer, other malignancies, infertility, cardiotoxicity, and pulmonary fibrosis. In a report of 145 Wegener’s disease patients treated with cyclophosphamide, and followed for 1333 patient-years, non-glomerular haematuria occurred in approximately 50 per cent of the patients, the majority of whom had macroscopic changes consistent with cyclophosphamide-induced bladder injury on cystoscopy (Talar-Williams et al. 1996). Seven of these, and none without haematuria, developed transitional cell bladder carcinoma; six had had a total cumulative dose over 100 g cyclophosphamide, and a duration of oral treatment exceeding 2.7 years.

Maintenance treatment, converting to alternate day prednisolone 10–20mg, and substituting cyclophosphamide with azathioprine 2 mg/kg/day, is commenced after induction, and continued for a further 10–12 months; it is then gradually withdrawn. Azathioprine is less toxic, but reversible bone marrow suppression can occur, hepatotoxicity is rare, and there is a small increased risk of malignancies. Deterioration, failure to respond initially, or intolerance of the above regimen may require the use of alternative agents. Methotrexate at 10–25 mg doses on a weekly basis may be used in conjunction with steroids, either during induction or maintenance. Plasmapheresis may be valuable in cryoglobulinaemia, and is also considered in severe systemic vasculitis causing pulmonary haemorrhage and severe glomerulonephritis, with 7–10 treatments over 14 days. Although there is little experience of its use in patients with intracranial disease, there is evidence of significant improvement when used in combination with steroids in cerebral disease associated with Henoch–Schönlein purpura.

A number of monoclonal antibodies directed against the CD52 (present on most lymphocytes), CD20 (B-cells), or against tumour necrosis factor are generating excitement as novel therapies in various inflammatory diseases including the vasculitides. Paradoxically the induction of vasculitis has also been reported with various of these agents (Mathieson et al. 1990; Unger et al. 2003; Booth et al. 2004; Mohan et al. 2004; Sneller 2005). Interferon-α can control not only hepatitis-C-associated hepatitis, but also associated cryoglobulinaemia and vasculitis. Unfortunately, there is regular relapse within months of treatment withdrawal.

Giant cell arteritis includes two histologically similar but clinically distinct diseases: temporal arteritis (Section 18.7.1) and Takayasu’s arteritis. Temporal arteritis is a chronic inflammatory disorder targeting large- and medium-sized arteries, which rarely affects individuals less than 55 years of age, women twice as commonly as men, with an overall prevalence of 100/105. It has an annual incidence of 17.4 per 100 000 in the over 50-year-old population, so that new onset unilateral or bilateral headache in this age group should alert the physician.

Classically it manifests as temporal headache with tender, pulseless, nodular temporal arteries, in addition, often elicited only on direct enquiry, there are symptoms of general malaise, jaw claudication, and features of polymyalgia rheumatica with stiffness and aching of the shoulder girdle, worse in the mornings, and malaise. Neuro-ophthalmological symptoms are widely feared, with blindness occurring in one-sixth of treated patients with the condition (Caselli et al. 1994). This occurs 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. The typical picture comprises locally painless loss of acuity, commonly severe, often with an altitudinal field defect. The fundal appearances may be normal, although mild swelling can be seen. Conventionally, the inflammatory process is thought to involve only the extracranial vessels and rarely to extend beyond the point of penetration of the dura. A large study of 166 patients with biopsy-proven temporal arteritis demonstrated neurological involvement in 31 per cent, describing the comprehensive range of neurological manifestation more usually associated with other forms of intracranial vasculitis: neuropsychiatric syndromes, peripheral neuropathies, mononeuropathies, spinal cord lesions, neuro-otological syndromes, various pain syndromes, transient ischaemic attacks, and stroke. However most authorities would find almost all these pictures outside their common experience of giant cell arteritis. Infarction of the vertebrobasilar territory was relatively uncommon, but there have been isolated reports of temporal arteritis presenting as lateral medullary syndrome. The expected greater incidence of cerebrovascular disease in this senior subgroup may, however, be confounding.

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-centimetre length is recommended to help avoid false-negative results, which may occur because of the multifocal nature of the disorder. Histopathological examination of the vessel reveals an inflammatory infiltrate comprising mononuclear and giant cells; the latter phagocytose 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.

The ESR may be used to monitor treatment response. However, it has been pointed out that a low ESR in active disease is not excessively rare (Salvarani and Hunder 2001), and may perhaps be explained by an inability to mount an acute phase response, or by very localized arteritis. Measuring serum interleukin-6 levels is a promising alternative to the ESR. Recent work has also emphasized that an elevated platelet count should be considered a risk factor for permanent visual loss in temporal arteritis and should accentuate the need for urgent treatment (Lincoff et al. 2000).

Steroid-resistance is extremely rare. Fear of permanent blindness encourages most to prescribe an immediate starting dose of 60–80 mg of oral prednisolone daily although prospective studies have shown lower doses of 20 mg to be as effective. After 4–7 days on a high dose, gradual reduction by perhaps 5 mg weekly should be attempted to a maintenance dose of approximately 10 mg daily, using the clinical response and ESR or plasma viscosity as a guide. Most authorities recommend continuing steroids for a period of 12–24 months; some patients still require steroids 2–5 years later. The importance of preventing long-term consequences of corticosteroids, in particular bone protection from osteoporosis, must be stressed. Azathioprine is often used as a steroid-sparing agent.

Takayasu’s arteritis was originally described in young Oriental women; it is now globally recognized. It is alternatively named ‘pulseless disease’, since 98 per cent of affected individuals have at least one major arterial pulse absent, as a result of the characteristic involvement of the aorta and its large branches. The disease process is initially inflammatory, and later occlusive, during which phase most of the neurological abnormalities occur. Syncope is reported in at least 50 per cent of patients, but also seen are strokes, transient ischaemic attacks, and visual abnormalities, all exacerbated by hypertension. One should suspect this illness in a patient under the age of 40 years with symptoms of limb claudication, one or more absent pulses, systolic blood pressure difference between the arms of >10 mmHg, and the presence of arterial bruits. Early histological features of the disease include granulomatous changes in the media and adventitia of the aorta and its branches, later followed by intimal hyperplasia, medial degeneration, and sclerotic adventitial fibrosis.

Systemic lupus erythematosus, or SLE, is one of a family of rheumatic disorders, which include rheumatoid arthritis, scleroderma, polymyositis, dermatomyositis, and Sjögren’s syndrome. It is a chronic relapsing-remitting autoimmune disease of uncertain aetiology (Croker and Kimberly 2005). It may cause widespread organ involvement with consequences ranging from mild and transient to life-threatening. glomerulonephritis, pleurisy, and pneumonitis; pericarditis and so-called Libmann–Sachs endocarditis. Haematological disorders also occur: anaemia, thrombocytopoenia, leucocytopoenia, and the generation of circulating anticoagulants. Other laboratory abnormalities include the presence of a variety of auto-antibodies, including anti-nuclear antibodies and anti-native DNA antibodies.

The diagnosis, particularly for research and therapeutic trial purposes, is based on the widely accepted American College of Rheumatology revised diagnostic criteria (Table 36.4).

Neurological complications. Neurological involvement in systemic lupus erythematosus is seen in perhaps 50 per cent of cases; neurological presentation, in perhaps 3 per cent. Central nervous system 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 and iatrogenic death.

An enormous variety of central nervous system complications can occur, reflecting two broad pathogenetic mechanisms:

The classic histopathological studies of the nervous system in systemic lupus erythematosus are those of Johnson and Richardson (1968) and Ellis and Verity (1979). Studying between them almost a hundred cases, they reported strikingly concordant changes: small vessel infarction, particularly in the cerebral cortex and brainstem, correlating well with the clinical signs in most cases. These authors gave a clear and in essence unchallenged description (Scolding et al. 2002a) of small blood vessel changes, with evidence of necrosis of the vessel wall, extravasations of fibrin and red blood cells together with endothelial cell proliferation, hypertrophy, and the appearance of fibrin thrombi. These destructive and proliferative changes were responsible for the numerous areas of microinfarction and, less commonly, macroscopic haemorrhage. Importantly, vasculitis was found only rarely in approximately 5 per cent of cases.

Headache, including that associated with dural sinus thrombosis, acute or subacute encephalopathy, fits, myelitis which is often severe and dramatic, strokes and movement disorders, ataxia and brainstem abnormalities, and cranial and peripheral neuropathies are all seen in the context of systemic lupus erythematosus chorea, though often quoted as the classical neurological feature in systemic lupus erythematosus, occurs in no more than 4 per cent of patients. Aseptic meningitis and optic neuropathy are also both well-documented. Psychiatric and cognitive disturbances have also long been associated with systemic lupus erythematosus.

Stroke, the lupus anticoagulant, and the primary phospholipid syndrome. The thrombotic tendency in systemic lupus erythematosus with lupus anticoagulant manifests principally as stroke and recurrent spontaneous abortion. Intra-abdominal, deep venous, and peripheral arterial thrombosis are less common. Thrombocytopoenia is a key additional feature. Importantly, Hughes also showed that a similar clinical picture was associated with the presence of anticardiolipin antibodies and/or lupus anticoagulant in patients without serological or clinical evidence of systemic lupus erythematosus, and introduced the term ‘antiphospholipid syndrome’ or lupus anticoagulant.

Anticardialipin antibodies are an independent risk factor for stroke. Central nervous system thrombosis in patients with primary or secondary antiphospholipid syndrome takes the form of completed arterial stroke, repeated transient ischaemic attactes, multi-infarct dementia, and cerebral venous sinus thrombosis. Vascular visual problems, including amaurosis fugax, and ischaemic retinopathy, also occur. Chorea too is associated with anti-phospholipid antibodies; but the putative link with migraine may be factitious.

A very severe, indeed commonly fatal acute ischaemic encephalopathy is also described, with confusion, obtundation, spastic quadriparesis which is usually asymmetrical, with or without systemic disturbances usually dermatological and renal. CSF examination may show only a raised protein. The disorder may represent a focal variant of the recently described catastrophic anti-phospholipid syndrome, in which there is severe multi-organ failure and a mortality of the order of 60 per cent (Asherson 2005).

Diagnosis of central nervous system lupus. Serological tests lie at the heart of diagnosis. A number of studies have suggested a link between anti-ribosomal P antibodies and neurological or psychiatric systemic lupus erythematosus (Trysberg et al. 2004). CSF may contain a raised protein level and a neutrophil or lymphocyte pleocytosis. 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 systemic lupus erythematosus. Oligoclonal band analysis is positive in up to 50 per cent patients but, interestingly, can vanish with successful immunotherapy. MRI changes are common, though neither invariable nor specific. A skin biopsy can be extremely helpful in suspected lupus.

Management of neuropsychiatric lupus. Symptomatic therapies are vital 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 anticardiolipin antibody, considered best achieved with moderate- to high-dose warfarin, and immunotherapy of ‘other’ central nervous system complications. Here, intravenous methyl prednisolone, 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. Mycophenolate appears a more than reasonable substitute for both induction and maintenance therapy (Chan et al. 2000; Ong et al. 2005) Plasmapheresis synchronized with cyclophosphamide, and intravenous immunoglobulin, may prove useful, especially in more ‘malignant’ forms of the disease (Uthman et al. 2005). More recent attention has focussed on the promising role of the anti-B-cell monoclonal antibody Rituximab (Ginzler and Dvorkina 2005; Sfikakis et al. 2005; Thatayatikom et al. 2006)—perhaps not surprising in view of the pathognomic production of autoantibodies in systemic lupus erythematosus. The apparent increase in disease activity following anti-tumour necrosis factor-α therapy (De Bandt M. et al. 2005), whilst disappointing in the short term, may hold valuable clues as the cause of tissue damage.

There are both clinical and pathological similarities between microangiopathic complications of lupus and the syndrome of thrombotic thrombocytopoenic purpura. In this uncommon disorder, multi-organ involvement is also seen, with hepatic and renal disease, and fever, together with thrombocytopoenia and an associated purpuric 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.

An inflammatory peripheral neuropathy occurs in approximately 30 per cent seropositive rheumatoid cases, but central nervous system disease, either rheumatoid vasculitis, or deposition of rheumatoid nodules, is much less common. Pannus formation and cervical spine subluxation can result in cord compression. Recent excitement has emerged concerning the potential therapeutic role of anti-TNF and anti-B-cell therapies (Furst et al. 2005; Higashida et al. 2005).

Sjögren’s syndrome comprises a triad of (i) keratoconjunctivitis sicca, and (ii) xerostomia, occurring in (iii) the context of another connective tissue in approximately 50 per cent of cases, usually rheumatoid arthritis. Speckled antinuclear antibodies, anti-Ro, SS-A, or anti-La, SS-B, are present in most patients. Conventionally, the principal neurological manifestations are considered peripheral, with descriptions of both a mainly sensory neuropathy (Sections 21.13.1 and 21.18.10) including the classical trigeminal sensory neuropathy, and of myositis.

However, attention has also been drawn to apparent central nervous system complications, with seizures, focal stroke-like or brainstem neurological deficits, and an encephalopathy with or without an 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 be seen, with acute transverse myelitis, 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 and the usual more powerful immunosuppressants are recommended, again with no sound evidence base.

Systemic sclerosis results from the excessive deposition of collagen in the skin and other affected tissues, of unknown cause (Sakkas 2005). 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. Peripheral nervous system disease predominates, particularly painful trigeminal neuropathy; myopathy, with an elevated creatine kinase also occurs. A myelopathy may be associated. No treatment is of proven benefit, but evidence implicating B-cells in the pathogenesis has stimulated interest in the potential of monoclonal antibodies such as infliximab in therapy (Sakkas 2005).

In this disorder, features of scleroderma, polymyositis, and systemic lupus erythematosus coincide with high levels of antibodies directed against extractable nuclear antigens, ribonucleoproteins. Rheumatoid factor is also often present. Again, trigeminal neuralgia and/or sensory neuropathy are described.

Ankylosing spondylitis. Neurological involvement usually reflects advanced bony disease; a cauda equina syndrome is well-reported, unexplained, and difficult to treat.

Reiter’s disease. Central nervous system disorders associated with this syndromic triad of seronegative arthropathy, non-specific urethritis, and conjunctivitis, usually following venereal infection or dysentery, include aseptic meningoencephalitis, seizures, and psychiatric disturbances, particularly paranoid psychosis, neurological features occurring in up to 25 per cent of patients. Cranial neuropathies, pyramidal signs, and myelopathy are also reported. Peripherally, radiculitis and polyneuritis occur. Cyclosporine may be of value in severe disease.

Sarcoidosis is a multisystem granulomatous disease whose aetiology continues to defy explanation. Rational collaborative approaches to study have failed to elucidate causal factors (Semenzato 2005). Paradoxically, the wholly accidental finding of an exacerbation of sarcoid disease activity in patients treated with interferon-α (Leclerc et al. 2003) may ultimately prove informative, not least since the mononuclear phagocyte, the predominant cell type in the non-caseating epithelioid cell granuloma, is both highly responsive to, and produces interferon-α.

Pulmonary and/or systemic features in sarcoidosis are accompanied in approximately 5 per cent of patients, by nervous system involvement (Zajicek et al. 1999). Optic and other cranial neuropathies, especially the facial nerve, often due to meningeal infiltration, are the commoner manifestations. Aseptic meningitis may feature, and brainstem and spinal cord disease can occur. Cognitive and neuropsychiatric abnormalities are reported. The region of the pituitary gland appears peculiarly sensitive, and consequent endocrine, hypothalamic, or optic chiasmatic symptomatology are seen. Peripheral nerve and muscle involvement is also well-described (Section 21.18.6).

The diagnosis can be difficult in isolated central nervous system disease, or patients with previously confirmed systemic sarcoidosis who have received chronic immune-modulating therapy and whose neurological presentation could therefore alternatively represent opportunistic infection or even lymphoma. Serum and CSF angiotensin converting enzyme levels may be elevated, but not reliably. The CSF may reveal wholly non-specific elevations of protein or cell count, and oligoclonal bands may be present. Whole body gallium scanning remains a useful indicator of systemic disease, and may disclose clinically cryptic areas of activity suitable and safe for biopsy. Cranial MRI may show multiple white matter lesions or meningeal enhancement and the latter also may be amenable to biopsy. Tissue diagnosis is invaluable where feasible.

The mainstay of medical treatment in neurosarcoidosis is corticosteroids, though response rates as low as 29 per cent have been reported. Methotrexate (Baughman et al. 2000), azathioprine, hydroxychloroquine, and cyclophosphamide (Doty et al. 2003) have been used in steroid-resistant cases though meta-analysis has confirmed the lack of an evidence base for even systemic disease (Paramothayan et al. 2003). Tumour necrosis factor inhibition appears promising (Pritchard et al. 2004; Baughman et al. 2005; Doty et al. 2005).

Behçet’s disease is a chronic relapsing multisystem inflammatory disorder classically causing a triad of recurrent uveitis with oral and genital aphthous ulceration. Formal diagnostic criteria include recurrent oral ulceration occurring at least three times in one

12-month period as an absolute criterion, plus any two of (i) recurrent genital ulceration, (ii) anterior or posterior uveitis or retinal vasculitis, (iii) skin lesions, including erythema nodosum, or acneiform nodules, pseudofolliculitis or papulopustular lesions, or (iv) a positive pathergy test read at 24–48 h.

Neurological involvement is not uncommon and is well- documented (Akman-Demir et al. 1999). Cerebral venous sinus thrombosis is one of the more specific serious complications; others include sterile meningoencephalitis, encephalopathy, brainstem syndromes, cranial neuropathies, 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 non-specific (Fig. 36.3).

Recent retrospective studies indicate an improved survival in patients with central nervous system Behçet’s treated with steroids and immunosuppressants. The place of thalidomide in steroid-unresponsive Behçet’s is currently under review; chlorambucil is often advocated. Monitoring treatment is difficult as neither the ESR nor C-reactive protein levels are useful; MRI might have such a role. Anti-tumour necrosis factor therapy is recently reported of value (Sarwar et al. 2005).

This is a rare inflammatory disorder, not truly vasculitic, whose principal features are ocular, with uveitis and retinal haemorrhages, and dermatological, with patches of depigmentation in the eyebrows, eyelashes, and scalp hair “poliosis”, as well as vitiligo (Moorthy et al. 1995). The disorder is relatively benign, but senorineural deafness is common, and other cranial neuropathies can occur, particularly involving ocular motor nerves. However, aseptic meningitis is the main neurological manifestation. Neuropsychiatric changes may occur, as may signs of parenchymal involvement, including hemiplegia and transverse myelitis.

Spinal fluid analysis usually reveals a lymphocytic pleocytosis with a variably raised protein. CT and MRI may reveal characteristic choroidal changes, and in some patients MRI shows high signal density periventricular lesions (Ibanez and Pettigrew 1994). Both MR angiography and contrast angiography have shown vasculopathic changes suggestive of vasculitis (Ryan and Pettigrew 1995), but the neuropathological changes, whilst rarely reported, include inflammation, with perivascular cuffing, a brisk microglial reaction, and no true vasculitis (Alema et al. 1981).

A close Class II major histocompatibility complex antigen association has been reported to DR4 and DQ4 (Islam et al. 1994). The ocular aqueous fluid contains a predominance of activated T-lymphocytes, and peripheral cellular and humoral immune responses to uveal and retinal antigens have been described. Melanocytes represent the most obvious target and melanin-laden macrophages are found in the cerebrospinal fluid (Nakamura and Yano 1996). Considerable evidence of cytotoxic T-cell activity against these cells has been presented (Norose and Yano 1996; Sugita et al. 1996).

Conventional treatment comprises high-dose intravenous steroids (Ikeda et al. 1997); cyclosporine has been advocated in refractory cases. Intravenous immunoglobulin has also been suggested (Helveston and Gilmore 1996). It has been observed that 60 per cent of patients retain moderate to good vision (Rubsamen and Gass 1991).

Susac’s syndrome is an unusual, histologically non-inflammatory microvasculopathy, predominantly affecting females, and recognizable by a triad of deafness, retinal microinfarction, and encephalopathy (Susac et al. 1979; Susac 1994). Peripheral indices of systemic inflammation are not elevated, and spinal fluid examination shows no cellular reaction; oligoclonal immunoglobulin bands are not present. Most case reports initially described a monophasic, self- limiting course, but as clinical recognition of the syndrome increased, it became clear that recurrent attacks variably including one or more of the ocular, cerebral, or cochlear manifestations represented the more typical course. Chronic stable deficits in vision, hearing, and/or cognition commonly persist. High-dose steroids, and various immune suppressant or immune modulatory therapies have been exhibited and are empirically recommended. It is of unknown cause; one case is reported in which the Factor V Leiden mutation was present (Barker et al. 1999).

Degos disease is a rare non-inflammatory occlusive vasculopathy particularly involving the skin, gastrointestinal tract, and the central nervous system, causing a combination of papular skin lesions, perforation of the gut and peritonitis, and haemorrhagic strokes (Dastur et al. 1981; McFarland et al. 1978; Subbiah et al. 1996).