THE NEUROLOGICAL VASCULITIDES

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CHAPTER 97 THE NEUROLOGICAL VASCULITIDES

Disorders caused by immunological or inflammatory disturbances affecting the nervous system account for a wide range of neurological diseases. They include primary or idiopathic neuroimmune disorders, which may affect any part of the neuraxis (e.g., multiple sclerosis, Guillain-Barré syndrome, myasthenia gravis) and which are common and familiar territories for the working neurologist. However, secondary disorders, in which the neurological disturbance reflects involvement of the nervous system in a (conventionally) systemic inflammatory process, although often no less common, infrequently manifest or behave in the ordered and predictable clinical manner of proper neurological diseases. Neurosarcoidosis, central nervous system (CNS) lupus, vasculitis, and neuro-Behçet’s disease all occasionally mimic one another, pursue erratic and unpredictable clinical courses, and confine themselves wholly to the nervous system, which renders diagnosis by tissue biopsy hazardous and unattractive; they evade the cautious diagnostician, and they confound the evidence-based therapist. This chapter provides a brief overview only of vasculitic diseases or vasculitides, which are more than capable of harboring most of these unsociable habits and so strike particular anxiety in the heart of the neurologist. (Table 97-1)

TABLE 97-1 Immunological and Inflammatory Diseases of the Nervous System

Site Primary Disease
Brain (and spinal cord) Multiple sclerosis
Spinal cord Inflammatory myelitides
Stiff-person syndrome
Peripheral nerve Guillain-Barré syndrome and variants
Chronic inflammatory demyelinating polyneuropathy
Multifocal motor neuropathy
Myasthenia gravis
Polymyositis
Dermatomyositis
Secondary Disease
Vasculitides
Lupus, rheumatoid disease; other connective tissue diseases, anticardiolipin syndromes
Behçet’s disease
Sarcoidosis
Paraneoplasia
Organ-specific autoimmune disease (e.g., celiac disease, Hashimoto’s disease)

The vasculitides are a heterogeneous group of disorders characterized by blood vessel inflammation, occasionally with additional, specific, and defining pathological features, together producing different but frequently overlapping clinical manifestations.1 The classic core histopathological change consists essentially of an inflammatory infiltrate within (not just around) the vessel wall, in association with destructive mural changes (fibrinoid necrosis), precipitating vascular occlusion and then infarction—microscopic or macroscopic—which in turn accounts for the clinical manifestations.

Classification of the vasculitides is complex, with subdivisions into idiopathic vasculitic disorders—for example, giant cell arteritis, polyarteritis, and Wegener’s granulomatosis—and vasculitis secondary to collagen diseases, malignancy, viral infection, drugs, and so forth. The histological characteristics allow further classification, including the presence or absence of granulomas and/or the size of the vessel implicated (Table 97-2; Fig. 97-1).

TABLE 97-2 Classification of the Vasculitides According to Size

Dominant Vessel Involved Primary Secondary
Large arteries Giant cell arteritis Aortitis with rheumatoid disease; infection (e.g., syphilis)
Takayasu’s arteritis Infection (e.g., hepatitis B)
Medium arteries Classic polyarteritis nodosa
Kawasaki syndrome
Small vessels and medium arteries Wegener’s granulomatosis Vasculitis with rheumatoid disease, SLE, Sjögren’s syndrome, drugs, infection (e.g., HIV)
Churg-Strauss syndrome
Microscopic polyangiitis
Small vessels Henoch-Schönlein purpura Drugs (e.g., sulfonamides)
Essential cryoglobulinemia Infection (e.g., hepatitis C)
Cutaneous leukocytoclastic vasculitis

HIV, human immunodeficiency virus; SLE, systemic lupus erythematosus.

image

Figure 97-1 Left, The typical angiographic appearances of multifocal areas of narrowing/stenosis and vascular occlusion are shown: these may, however, be seen in many nonvasculitic disorders.

(Courtesy of Dr. Shelley Renowden, Bristol, United Kingdom.) Right, The histopathological characteristics of classic cerebral vasculitis include leukocytic infiltration and destruction of the vascular wall, with vascular occlusion and areas of microhemorrhage.

The CNS or peripheral nervous system (PNS) can be involved in virtually all of the systemic vasculitides, but “isolated angiitis,” affecting either the CNS or the PNS, is also recognized when there is little or no evidence of generalized inflammation.

MECHANISMS OF TISSUE DAMAGE

In both primary and secondary CNS and PNS vasculitis, the neurological features arise principally through ischemia and infarction. These in turn result from three consequences of inflammation within the vascular wall: obstruction of the vessel lumen, increased coagulation from the effects of proinflammatory cytokines on the endothelial surface, and alterations in vasomotor tone. The development of a vasculitic process depends on interplay between cellular and humoral factors; most research interest has centered on the latter.2

Antibody-Dependent Mechanisms

Direct Antibody Attack

In some systemic vasculitides, a pathogenic role for anti–endothelial cell antibodies in injuring or, paradoxically, activating endothelial cells is proposed,3 although their lack of specificity and variable frequency of detection do raise questions about any truly causal role. In rare cases, antibodies against amyloid-β deposits may precipitate cerebral vasculitis.4

Antineutrophil Cytoplasmic Antibody–Related Vasculitis

Antineutrophil cytoplasmic antibodies (ANCAs) represent a family of antibodies directed against constituents of the neutrophil azurophil granules.6 Cytoplasmic ANCA (c-ANCA) targets proteinase-3 and is associated with nearly 95% specificity for Wegener’s granulomatosis. Perinuclear ANCA (p-ANCA), directed at myeloperoxidase, is less specifically found in patients with microscopic polyangiitis and Churg-Strauss syndrome.6 Such antibodies may play a significant role in generating and maintaining vascular inflammation.7,8

Cell-Mediated Damage

Evidence for cell-mediated involvement in tissue injury in vasculitis9 comes in part from studies of microscopic polyarteritis nodosa and of Wegener’s granulomatosis. In both disorders, circulating T cells responsive to proteinase-3 are found, and vascular lesions contain activated T cells and antigen-presenting major histocompatibility complex class II–positive dendritic cells. In primary CNS and PNS vasculitic lesions, the predominant infiltrate is one of CD4+ and CD8+ T lymphocytes and monocytes.10

CAUSES OF NEUROLOGICAL VASCULITIS

Primary (Isolated) Angiitis of the Nervous System

In primary CNS vasculitis, there is no discernible recognized systemic vasculitic or, indeed, other disease, and vasculitis is confined to the brain and spinal cord. Although it is defined by this apparent exclusive distribution, autopsy studies have revealed subclinical extracranial involvement (e.g., of the pulmonary arteries and abdominal viscera11), which presumably helps explain the occasional features of fever, rigors, weight loss, raised plasma viscosity, and so forth.

The angiitic process is focal and segmental in distribution and granulomatous, necrotizing, or lymphocytic in character, often with mixed morphological types in individual patients (therefore, the common term “granulomatous angiitis” is difficult to sustain).

The clinical definition of cerebral vasculitis is not uniform, and this helps explain significant differences in the approach to diagnosis and therapy. Some authorities have defined the disorder by its angiographic appearances,11a which implies that tissue confirmation is not needed. (Indeed, some authors have suggested a more favorable monophasic clinical course in the so-called benign angiopathy of the CNS. This is a syndrome with normal or only mildly abnormal CSF and evidence of vasculitis on angiography alone.12 The concept has been questioned, in view of the recognized nonspecificity of angiography, the fact that cases not proceeding to biopsy are more likely to be less severe, and because pediatric cases satisfying “benign angiopathy” criteria often do not have a temperate, monophasic course and have required aggressive immunotherapy.13) Most authorities, however, including this author, believe that a certain diagnosis of primary CNS angiitis must depend on a positive biopsy.

Two eponymous nonsystemic primary disorders may involve the CNS. Cogan’s syndrome is an unusual disorder, affecting mostly young adults and characterized by recurrent episodes of interstitial keratitis and/or scleritis with vestibulo-auditory symptoms, which may be complicated by CNS, PNS, or systemic vasculitis. In Eale’s disease, an isolated retinal vasculitis occurs, causing visual loss; again, neurological complications are well described.

Primary PNS vasculitis closely parallels CNS disease. Otherwise termed nonsystemic vasculitic neuropathy, there is likewise no overt evidence of any recognizable vasculitic disorder elsewhere; however, authorities have varied in their definitions and in whether cases that include mild constitutional symptoms or serological abnormalities should be excluded.14 As with primary CNS disease, the arguments are finely balanced as to whether nonsystemic vasculitic neuropathy is truly an exclusively neurological disease or a systemic vasculitis in which the overwhelming burden of disease falls on the PNS.1518 This is not merely an academic question, because upon it hinges (at least partly) the justification for extrapolating therapeutic data from the systemic vasculitides.

Primary Systemic Vasculitides with Neurological Involvement

Virtually all of the systemic vasculitides may be complicated by neurological involvement; many have their own defining characteristics. Constitutional disturbances—fever, night sweats, severe malaise, weight loss—are common and may be accompanied by a rash or arthropathy.

Wegener’s granulomatosis predominantly affects the upper and lower respiratory tracts: the nose (often with destructive cartilaginous change that causes saddle nose deformity), sinuses, larynx, trachea, and lungs. Ocular involvement may occur, and renal disease occurs in 80% of affected patients. c-ANCA measurements are positive, with proteinase-3 specificity, and the biopsy findings are characteristic, with a necrotizing, granulomatous vasculitis. Neurological involvement occurs in up to 35% of affected patients19 but most commonly involves the PNS. Meningeal and middle ear disease may lead to significant cranial neuropathies (especially of nerves VII and VIII). Gadolinium-enhanced magnetic resonance imaging (MRI) is valuable in that it may reveal meningeal thickening and infiltration, which are ready targets for biopsy. Ocular involvement may occur with orbital pseudotumor. Cerebral small-vessel vasculitis is rare but, when it does occur, is usually responsible for encephalopathies, seizures, and pituitary abnormalities; however, this manifestation may be indistinguishable from that of any other form of intracranial vasculitis. More likely is the unique contiguous extension of erosive granulomas from the sinuses or from remote metastatic granulomas to the CNS.

Microscopic polyangiitis is a multisystem small-vessel vasculitis that has many similarities to Wegener’s granulomatosis, including pulmonary hemorrhage, but differs in that upper respiratory tract involvement is rare and granuloma formation is not seen. Affected patients usually have glomerulonephritis, and, indeed, this vasculitis is occasionally confined to the kidneys. In one study, mononeuritis multiplex was found in 55% of patients20; in this study, the brain was seldom affected (11%), and CNS disease did not contribute to mortality. There are, however, infrequent reports of p-ANCA–positive, rapidly progressive glomerulonephritis associated with cerebral vasculitis, necessitating aggressive therapy.

Classic polyarteritis nodosa is now recognized as an unusual disorder that may cause medium- and small-sized muscular artery involvement in multiple organs, with the notable exception of the lungs and spleen. Eighty percent of affected patients present with renal failure and hypertension. Gastrointestinal involvement occurs in up to 50%, with abdominal pain caused by visceral infarcts. Heart failure and myocardial infarction reflect cardiac involvement. Neurological abnormalities are prominent (in 50% to 60%) but, again, are confined mostly to the PNS. It is believed that damage is initiated by immune complex deposition; fibrinoid necrosis is typical, although not diagnostic. Although there are no specific serological tests, about 20% to 30% of patients have hepatitis B antigen or antibody in serum. Visceral angiography displays aneurysms or occlusions of the visceral arteries.

Churg-Strauss syndrome is characterized by hypereosinophilia with systemic vasculitis, occurring in individuals with recently developed atopic features. Asthma and mononeuritis multiplex are frequent manifestations of this disease. Rashes, with purpura, urticaria, and subcutaneous nodules, are common. Glomerulonephritis may develop; it may also affect coronary, splanchnic, and cerebral circulations. CNS involvement is evident in only about 7% of affected patients.21 About 50% of patients are seropositive for p-ANCA, 25% are seropositive for c-ANCA, and 25% have no antineutrophil cytoplasmic antibodies.

Small-vessel vasculitis commonly affects postcapillary venules. The skin is most commonly involved, usually with purpura or urticaria; because of the common presence of an allergic precipitant, the term hypersensitivity vasculitis is often used synonymously; cutaneous leukocytoclastic vasculitis is the currently preferred epithet.

In all these disorders, PNS involvement, usually with mononeuritis multiplex, is considerably more common than CNS disease, affecting from up to 70% of patients with classic polyarteritis nodosa and microscopic polyangiitis and 30% of patients with Wegener’s disease.

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; hypertensive or uremic encephalopathy, steroid or cytotoxic drug therapy, or electrolyte imbalance can also cause severe CNS symptoms. Suspected cerebral vasculitis is reported as a complication, with supportive MRI changes but without tissue proof of the process.

Kawasaki’s disease (mucocutaneous lymph node syndrome) usually affects children younger than 12 years. It has an incidence of fewer than 5 per 100,000 in the United Kingdom, but it is at least 20 times more common in Japan, where in 1967 it was first described. Coronary artery aneurysms occur in one fifth of untreated cases, which may result in myocardial infarction. Neurologically, aseptic meningitis is common, 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. There is a possible role for anti–endothelial cell antibodies in the pathogenesis.

Secondary Vasculitis: A Complication of “Nonvasculitic” Systemic Disorders

Autoimmune and Inflammatory Disease

Neurological or psychiatric symptoms in systemic lupus erythematosus (see Chapter 119) are common (40% to 50%),22 but the most frequent neuropathological finding is that of a noninflammatory vasculopathy of small arterioles and capillaries, with resulting microinfarcts and microhemorrhages. Histopathological studies have consistently demonstrated that vasculitis of the cerebral vessels is rare, with an incidence of 7% to 13%. Serological study naturally forms the mainstay of diagnosis.

Sarcoidosis (see Chapter 96) affects the nervous system in only 5% of cases, commonly manifesting with optic and other cranial neuropathies (especially involving the facial nerve) and usually caused by granulomatous meningeal and brainstem infiltration. Sarcoidosis may be complicated by systemic vasculitis affecting small- or large-caliber vessels in a manner similar to that of other vasculitides, with angiographic and, indeed, histological evidence of CNS vasculitis. Serum angiotensin-converting enzyme and calcium levels are not always raised. CSF abnormalities are seen in 80% of affected patients, usually with an elevated protein level and pleocytosis, and oligoclonal bands are present in about 45%. Cranial MRI exhibits nonspecific multiple white matter lesions or meningeal enhancement; whole-body gallium scanning can be more useful, demonstrating a characteristic pattern of uptake (affecting the parotid glands and lungs in particular). Pathological diagnosis by the Kveim test or, better still, by biopsy of cerebral or meningeal tissue provides the most reliable basis for treatment.23

Seropositive rheumatoid disease is a well-recognized precipitant of cerebral vasculitis, although skin involvement and mononeuritis multiplex are far more typical manifestations of rheumatoid vasculitis.22 There are unusual reports of CNS angiitis in the context of systemic sclerosis, Sjögren’s syndrome, and mixed connective tissue disease, even (although rarely) without a preceding history of systemic symptoms.

Cryoglobulinemia can cause hyperviscosity and may trigger immune-complex deposition-triggered vasculitis (especially in association with hepatitis C infection), which is particularly common in mixed cryoglobulinemia. Renal, joint, and skin involvement with purpura progressing to necrotic ulceration is often present. Peripheral neuropathy occurs in 22% to 32% of affected patients, particularly as mononeuritis multiplex, and leukocytoclastic vasculitis is evident in biopsy specimens. The CNS is rarely affected.

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