Central nervous system vasculitis

Journal of Neurological Sciences 153 (1998) 159–171

Central nervous system vasculitis C. Fieschi*, M. Rasura, A. Anzini, M. Beccia Department of Neurosciences, University of Rome ‘ La Sapienza’, Rome, Italy

Abstract Vasculitis is inflammation of blood vessel walls, which produces dysfunction in both the peripheral and central nervous system (CNS). Cerebral ischemia is the major cause for neurological manifestations of CNS vasculitis. Unfortunately, a universally accepted classification of vasculitis has not emerged. Vasculitis affecting the CNS alone is referred to as primary angiitis of the CNS; secondary vasculitis occurs in association with a variety of conditions, including infections, drug abuse, lymphoproliferative disease and connective tissue diseases. The pathogenesis of vasculitis includes different immunological mechanisms. Recently, anti-neutrophil cytoplasmatic antibody (ANCA) has been demonstrated to play an active role in the immunopathogenesis of the vasculitis. Diagnosis of vasculitis depends on a combination of clinical, radiographic and pathologic features. A wide spectrum of clinical features may occur. The most typical clinical picture of CNS vasculitis is troke, encephalopathy or seizures. Assays for ANCA, serum cytokines, antibodies to endothelial cell antigens have been reported to be useful in diagnosing or monitoring the disease activity. The gold standard in diagnosis is confirmation of vasculitis in a biopsy specimen. Angiography may suggest the diagnosis but no abnormalities are pathognomonic. Ideally, the therapy of each vasculitis would focus on the specific immunologic mechanism causing the disease. Such specific interventions are not yet available. In general the most important approaches induce global immunosuppression. The goal of therapy, however, is to prevent recurrence of disease.  1998 Elsevier Science B.V. Keywords: Vasculitis; Vascular inflammatory diseases; Central nervous system

1. Introduction Vasculitides are a heterogeneous group of disorders characterized by inflammation and necrosis of blood vessel walls and, ultimately, occlusion of the inflamed vessels. Within the spectrum of vascular inflammatory diseases, vasculitis affecting the central nervous system (CNS) is traditionally viewed as one of the most challenging clinical problems. The reasons for this include: lack of specificity of associated signs and symptoms, inaccessibility of the end organ tissues for pathologic examination, lack of efficient non-invasive diagnostic tests and the relative rarity of the disorders. The classification of vasculitis has received much attention during the past 40 years. Unfortunately, a universally accepted classification has not emerged, as the knowledge of the etiology and pathogenesis of vasculitis is still incomplete.

*Corresponding author. Fax: 139 64958344. 0022-510X / 98 / $19.00  1998 Elsevier Science B.V. All rights reserved. PII S0022-510X( 97 )00288-8

Quite recently, two classification systems have been proposed. The American College of Rheumatology has published in 1990 diagnostic criteria for the diagnosis of seven common forms of vasculitis, including polyarteritis nodosa (PAN), Churg–Strauss syndrome, Wegener’s granulomatosis (WG), hypersensitivity vasculitis, Henoch– Schonlein purpura, temporal arteritis and Takayasu’s arteritis. These criteria, based on a five-year analysis of over 800 patients from 48 different medical centres, employ both a traditional approach (based on clinical diagnostic criteria) and a computer-generated classification tree approach (Bloch et al., 1990; Fries et al., 1990). However this approach, useful for epidemiologists, does not help the clinician make an early diagnosis in individual patients. The second classification is the product of an international consensus conference that tried to reach agreement upon the nomenclature of the major vasculitic syndromes as well as to establish definitions for the syndromes so named (Jennette et al., 1994). The pathogenesis of vasculitis includes different immunological mechanisms that induce a final pathway of vascular inflammation that favours leucocytes to adhere to

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endothelial cells, penetrate into vessel walls, and release injurious products (Moore, 1995). Systemic and local immuno-complex damage may occur when an antigen that initially circulated is subsequently trapped in the vessel wall where antibodies react with it. The prototype clinical entity with this pathogenetic mechanism is hypersensitivity vasculitis. In these patients, circulating immune complexes occur. Immunoglobulin and complement can be demonstrated in biopsied cutaneous lesions. Immune complex mechanisms may also play a role in polyarteritis nodosa, since half of the patients have circulating immune complexes and one-third have a hepatitis B antigenemia (Duffy et al., 1976). Immune complexinduced vasculitis may also occur in various viral infections such as human Epstein–Barr virus infection and serum hepatitis, as well as in nonviral infections (Neisseria gonococcus, N. meningococcus). Some medications and toxins (such as sulphonamide) may be associated with immune complex-mediated vasculitis. Furthermore vasculitis in patients with rheumatoid arthritis, systemic lupus erythematosus (SLE), and cryoglobulinemia may follow these pathogenetic principles. In CNS–SLE the presence of neuronal / lymphocyte autoantibodies has been documented, even if their sensitivity and specificity is highly variable (Bluestein and Zvaifler, 1976). However, it is not clear whether neuronal autoantibodies access the nervous system through a damaged blood–brain barrier, or alternatively, are produced locally. A substantial number of antigenic targets, from cell surface to intracellular determinants, are involved in the pathogenesis of SLE. They are antigens against neurofilaments, phospholipids, glycolipids, glycoproteins (especially B2 glycoprotein 1), endothelial cell surface antigens, ribosomal P proteins and neuronal cell surface antigens, some of which cross-react with lymphocytes (Minota and Winfield, 1987; Hanley and Hong, 1993). B2 glycoprotein has been used to induce an antiphospholipid antibody (APLA) syndrome, with its attendant ischemic and related cerebrovascular events in an animal model; however, whether any of the nervous system involvement in APLA syndrome is directly antibody-mediated, or a consequence of thromboembolic events related to the presence of APLA is not yet certain. Whether the presence of autoantibodies direct against lymphocyte / neuronal antigens, or ribosomal P proteins are directly related to development of ‘diffuse’ CNS– SLE and whether conversely APLA cause ‘focal’ events should be investigated (Denburg and Behmann, 1994). The evidence for T cells involvement in systemic vasculitis is increasing (Mathieson et al., 1992). The level of soluble IL-2 receptor, which is a marker of T cell activation, has been found to rise at times of active vasculitis granulomatosis and has been reported an association between HLA class II genes and primary systemic vasculitis (Stegeman et al., 1993; Zhang et al., 1995). Griffith et al. (1996) demonstrated in patients with perinu-

clear anti-neutrophil-cytoplasmatic antibody (p-ANCA) or cytoplasmatic ANCA (c-ANCA) the presence of T cells responding to MPO or PR3, respectively. y-Interferon from the T-cell often induces the occurrence of adhesion molecules on the endothelial cell as well as release of cytokines by the endothelial cells, which recruit nonantigen-specific T-cells to the site. This mutually stimulatory interaction of lymphocytes and endothelial cells is normally highly regulated. In the vasculitides, regulation may be defective either because of persistent antigen stimulation or an abnormality in the regulatory process. During the last few years, there is increasing evidence to suggest that anti-neutrophil cytoplasmatic antibody (ANCA) play an active role in the immunopathogenesis of the vasculitis. At a cellular level, ANCA can stimulate both a respiratory burst with production of reactive oxygen species and degranulation of neutrophils by means of both the antigen-specific portion of the antibody and the Fc tail, which engages the Fc receptor. Furthermore, the process occurs more easily if neutrophils are primed by inflammatory cytokines such as tumour necrosis factor. A possible consequence of neutrophil activation by ANCA might be endothelial injury when cytokine-primed neutrophils adhere to cytokine-activated endothelium as a prelude to transmigration into tissues. Such endothelial injury is thought to precede and promote the vasculitic lesions (Cohen-Tervaert and Kallenberg, 1993) Other processes may also contribute to vascular injury; antibodies bound to vascular endothelial cells may activate endothelial cells or injure them (Carvalho and Savage, 1996), recruit T cells to vasculitic lesions (Griffith et al., 1996) or impair proteinase 3 inactivation by alpha1-antitrypsin. In 50% of all vasculitis cases ANCA are present, ie, Wegener’s granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome, whereas in classic polyarteritis nodosa only 14–20% of patients are ANCA positive. ANCA negativity is more common in individuals with Wegener’s granulomatosis limited to the upper respiratory tract. Two major types of ANCA have been recognized. The first type is called c-ANCA (cytoplasmic ANCA) and is strongly associated with Wegener’s granulomatosis. These anti bodies produce a characteristic granular cytoplasmic staining pattern on ethanol-fixed granulocytes when detected by a standard indirect immunofluorescence technique. The antigen recognized by c-ANCA is proteinase 3, a 29-kd glycoprotein from azurophilic granules with serine protease, antibiotic and myeloblastic activity. The second type of ANCA is called p-ANCA (perinuclear ANCA) and is found in many different inflammatory disorders. These antibodies produce a perinuclear pattern on ethanol-fixed granulocytes. The antigens recognized by p-ANCA are different myeloid proteins, that is, myeloperoxidase (MPO), elastase, cathepsin G, lactoferrin, lysozyme, Bglucuronidase and other not yet characterized proteins.

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Antibodies to MPO and / or elastase are specifically associated with idiopathic vasculitis. Antibodies to other myeloid proteins are found in a wide variety of different inflammatory disorders, not specific for a particular disease (Cohen-Tervaert and Kallenberg, 1993). Proteinase 3 (pr3) antibodies are highly sensitive for active Wegener’s granulomatosis. In cases of extended disease characterized by the triad of granulomatous inflammation, systemic vasculitis and necrotizing and / or crescentic glomerulonephritis (NCGN) (‘renal vasculitis’), Pr3 antibodies are present in more than 90% of the cases (Kallenberg et al., 1992). In 67–86% of the patients with more localized disease, for example, without renal involvement, Pr3 antibodies are detected. Pr3 antibodies have also been found in about 50% of patients with microscopic polyangiitis, in 40–50% of patients with pauciimmune NCGN without histologic proof of extrarenal granulomatous inflammation or vasculitis and in 50–60% of patients with biopsy-proven necrotizing arteritis involving small and / or medium-sized vessels that do not fulfil the classic histologic criteria for WG or CSS. Myeloperoxidase (MPO) antibodies are found in about 70–80% of patients with Churg–Strauss syndrome and in nearly all patients with pauciimmune NCGN who are negative for Pr3 antibodies. Elastase antibodies are rarely found in patients with vasculitis or other systemic autoimmune disease (drug induced). Searching for the presence of these antibodies

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seems to be useful only in those cases suspected of having active WG or other forms of vasculitis without Pr3 and MPO antibodies. A substantial number of serum samples, which are positive by indirect immunofluorescence, recognize neither PR3 nor MPO (double-negative samples). Zhao et al. (1995) found that certain of these double-negative samples recognized a 55-kD doublet of which the first eight residues shared N-terminal aminoacid sequence homology with bactericidal / permeability-increasing protein (BPI), a potent antibiotic towards gram-negative bacteria. The BPI has been used to establish that autoantibodies to this antigen may be important serological markers for vasculitis. Despite the strong evidence of autoimmune features in systemic vasculitis, there is no agreement about correlations with the major histocompatibility complex (MHC) locus, whereas the association with alpha1-antitrypsin gene polymorphisms and with polymorphic variations of the type IIa receptor for IgG (FcyRIIa) have been suggested (Esnault et al., 1993; Porges et al., 1994).

2. Clinical aspects of systemic vasculitis In the European Union the annual incidence of systemic vasculitis is approximately 40 per million with direct health costs of 500 million ECU per year (Scott and Watts,

Table 1 Classification of cerebral vasculitis Infectious Vasculitis – Spirochetal (syphilis) – Mycobacterial – Fungal – Rickettsial – Bacterial (purulent) meningitis – Viral – Other organisms Necrotizing Vasculitides – Classic polyarteritis nodosa – Wegener’s granulomatosis – Allergic angiitis and granulomatosis (Churg–Strauss) – Necrotizing systemic vasculitis-overlap syndrome – Lymphomatoid granulomatosis Vasculitis Associated with Collagen Vascular Diseases – Systemic lupus erythematosus – Rheumatoid arthritis – Scleroderma – Sjogren’s syndrome Vasculitis Associated with Other Systemic Diseases – Behcet’s disease – Ulcerative colitis – Sarcoidosis – Relapsing polychondritis – Kohlmeier–Degos disease

Giant Cell Arteritides – Takayasu’s arteritis – Temporal (cranial) arteritis Hypersensitivity Vasculitides – Henoch–Schonlein purpura – Drug-induced vasculitides – Chemical vasculitides – Essential mixed cryoglobulinemia Miscellaneous – Vasculitis associated with neoplasia – Vasculitis associated with radiation – Cogan’s syndrome – Dermatomyositis-polymyositis – X-linked lymphoproliferative syndrome – Thromboangiitis obliterans – Kawasaki syndrome Primary Central Nervous System Vasculitis

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1994). Patients of any age may be affected, although young and middle-aged are more at risk (Fieschi et al., 1996; Carolei et al., 1993; Bogousslavsky and Regli, 1987). Vasculitis affecting the CNS alone is referred to as primary angiitis of the CNS; secondary vasculitis occurs in association with a variety of conditions, including infections, lymphoproliferative diseases, drug abuse, connective tissue diseases and other forms of systemic vasculitis (Table 1). Cases of CNS vasculitis from secondary causes far exceed in number those of primary CNS vasculitis. Clinicians must consider the various secondary causes of cerebral vasculitis for two reasons: many secondary causes of vasculitis have specific treatments other than immunosuppression, and thus, prompt definitive diagnosis may improve clinical outcome. Conversely, secondary causes must be excluded before treating patients with immunosuppressants.

3. Secondary vasculitis Vasculitis of the CNS has been reported in association with numerous infective agents. The pathophysiologic mechanisms involved in infectious arteritis can include: a direct cytopathic effect on the vasculature, immune-mediate damage via the induction of neoantigen expression on endothelial cells or an immune complex-mediated process. A number of agents have been incriminated including bacteria, fungi, spirochetes, mycobacteria and viruses, particularly in immunosuppressed patients (Cupps, 1992). Among viruses-induced vasculitis Herpes zoster can be associated with CNS vasculitis in two syndromes: a limited form following eruption of zoster in the dermatome of the ophthalmic division of the trigeminal nerve and a more diffuse form involving the CNS that may follow more remote outbreaks of zoster. Reactivation, occurring in 20% of individuals, correlates with advancing age and with impaired cell-mediated immunity (Gilbert, 1974; Hilt et al., 1983). Cerebral infarctions and haemorrhages are noted on postmortem examination in a size able minority of patients with human immunodeficiency virus type I (HIV). Cerebral vasculitis accounts for a small proportion of these opportunistic infections (such as syphilis, herpes zoster, and aspergillus) and lymphoma commonly complicate HIV infection and predispose to cerebral vasculitis (Kieburtz et al., 1993; Mizusawa et al., 1988; Gray et al., 1992). This form of cerebral vasculitis may be the precursor of the AIDS-dementia complex (Sharer et al., 1986). Cerebral vasculitis also occurs in children with HIV infection without strokes (Joshi et al., 1987). Later in the course of HIV infection, a variety of vasculitic syndromes have been reported: fulminant, necrotizing vasculitis of mixed cell type affecting small

vessels produced multiple haemorrhages; eosinophil invasion of a temporal artery. In patients with HIV infection, meningovascular neurosyphilis can occur. Neurosyphilis is the classic infectious cause of cerebral vasculitis. Large and medium sized artery vasculitis (Heubner’s endarteritis) produces more focal neurologic deficits, whereas small artery vasculitis (Nissl’s endarteritis) tends to produce a more encephalopathic presentation (Peters et al., 1993).

4. ANCA-associated vasculitis The vasculitis of ANCA-associated Wegener’s granulomatosis and microscopic polyangiitis may be a microvasculitis, an arteritis or, in Wegener’s granulomatosis, a granulomatous arteritis. Microvasculitis is often the dominant feature of systemic disease and often affects the lungs, kidneys and skin. In the lungs, there is infiltration of the capillaries, arterioles and venules by neutrophils, which leads to widespread alveolar haemorrhage. In the kidney, the process primarily occurs in the glomeruli. Early capillary thromboses result in segmental necrosis of glomerular tufts, capillary rupture and bleeding into Bowman’s space, that triggers the accumulation and proliferation of monocytes and epithelial cells and the formation of crescents. The amount of immunoglobulin deposited in the glomeruli is small, which has led to the widespread use of the descriptive term ‘pauci immune glomerulonephritis’. In the skin, a leucocytoclastic vasculitis with neutrophil infiltration in and around the vessel wall is seen, accompanied by fragmentation of leucocytecell nuclei. Medium-sized and small arteries may also be affected in ANCA-positive diseases. Fibrinoid necrosis, inflammation, and destruction of the arterial wall, are similar processes to those that occur in classic polyarteritis nodosa. Granulomatosus vasculitis is occasionally seen in Wegener’s granulomatosis and Churg–Strauss syndrome, and affects medium-sized vessels- usually with thrombosis (Savage et al., 1997). Wegener’s granulomatosis (WG) is a necrotizing granulomatous vasculitis involving the upper and lower respiratory tracts in association with glomerulonephritis. In the series studied by Hoffman et al. (1992) 77% of patients developed frank glomerulonephritis. Renal disease is a strong predictor of a negative outcome, particularly oliguric renal failure. Other commonly affected organs include skin, eyes, ears and nervous system. The peak incidence is in the fourth or fifth decade, with a slight male predominance. Neurologic abnormalities develop from contiguous extension of granulomas from primary sites in the nasopharynx and from vasculitis. Thus, the prominent cranial neuropathies reflect erosion of the bony structures at the base of the brain from contiguous extension of sinus

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granulomas. Hearing loss, proptosis, ophtalmoplegias, and trigeminal and facial paresis are prominent features. There are scattered reports of hypothalamic or pituitary abnormalities, which also appear to develop by this mechanism. Small-vessel vasculitis in the parenchyma of the CNS accounts for the encephalopathies, seizures, pituitary abnormalities, and focal motor and sensory changes. Clinically, peripheral neuropathies include both mononeuropathy multiplex and sensorymotor polyneuropathy, although the other patterns that are seen in polyarteritis nodosa are also seen in WG. At times, neurodiagnostic studies such as magnetic resonance imaging (MRI) are crucial for identifying visual loss secondary to a compressing granuloma or to ischemia of the ophthalmic artery. Recent studies revealed that the incidence of neurological abnormalities may be declining with earlier, more aggressive therapy (Moore, 1995). The association of Wegener’s granulomatosis and cANCA autoantibodies helps the diagnosis (Cohen-Tervaert et al., 1991). Whether or not the titre of cANCA reflects disease is, however, still debated. Microscopic polyangiitis (MPA) is characterized by necrotizing and / or crescentic glomerulonephritis (NCGN) (‘renal vasculitis’) and a multisystem vasculitis involving small vessels. MPA shares many features with WG. Clinically, the most important difference is the lack of respiratory tract manifestations, apart from alveolar haemorrhage, in MPA. Patients present with malaise, fever, arthralgias and purpura in association with impaired renal function, proteinuria and microscopic haematuria. As in WG, the renal disease may rapidly deteriorate, pulmonary haemorrhage may be fatal, rashes can occur and mononeuritis multiplex is seen infrequently. By contrast, ocular and nasopharyngeal symptoms are less common (CohenTervaert and Kallenberg, 1993). The diagnosis of MPA is based on clinical findings, the presence of either proteinase 3 or myeloperoxidase antibodies, and histopathologic findings (pauciimmune necrotizing glomerulonephritis with crescent formation and vasculitis involving arterioles and / or small interlobular arteries). Churg–Strauss syndrome (CSS) is an uncommon condition in that multiple organs can be involved with a necrotizing vasculitis. Clinical and haematological features distinguish it from PAN. The hallmarks of Churg–Strauss syndrome are the presence of asthma and pulmonary infiltrates (resulting from vasculitis affecting pulmonary vessels) and the presence of eosinophilia. Neurologic abnormalities are similar to those in PAN, but encephalopathies occurring early in the course of the disease are more frequent, reflecting the small size of vessels involved. Allergic granulomas can sometimes be demonstrated in the vasculitic lesions, but it may occur in no more than 20% of patients. However, in any single biopsy specimen, the pattern may appear very similar to PAN (Masi et al.,

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1990). P-ANCA autoantibodies may be associated with the disease although the sensitivity is quite low, less than 50%. Polyarteritis nodosa (PAN) is a necrotizing angiitis of the medium and small muscular arteries throughout the body with the exceptions of the lungs and spleen. The triad that alerts a physicians to the diagnosis is systemic inflammation, peripheral neuropathy and abnormal visceral angiogram with evidence of enteric vascular disease. PAN is a diagnosis of exclusion, and therefore the diagnosis of PAN can only be made when the disease cannot fit into another presently recognized vasculitic syndrome. A substantial proportion of patients with PAN are hepatitis B virus (HBV) antigen positive. The prognosis and therapy for HBV associated PAN is different from idiopathic PAN (Duffy et al., 1976). At present, two different forms of idiopathic PAN are being recognized: systemic PAN, with vasculitic involvement of visceral organs (kidneys, heart, or gastrointestinal tract), and limited PAN, vasculitis restricted to the skin, nerves, and / or musculoskeletal system, also known as cutaneous PAN and nonsystemic vasculitic neuropathy. The disease is seen at any age; its mean age of onset is 45 to 55 years. Most patients initially present with nonspecific symptoms such as weight loss, fever, arthralgias, and (often severe) muscle weakness. Neurologic involvement also is frequently found and dominates the clinical picture in many instances. In large series PNS involvement was found in 50% to 75% of the cases (Said et al., 1988). Clinical manifestations suggestive of CNS involvement are much less common and are usually a late manifestation of the disease. CNS involvement varies from 4% to 41%. Cranial nerve palsies and inflammatory myopathy are only occasionally found. Diffuse or multifocal cerebral symptoms and signs, such as headache, confusion or psychiatric syndromes, and generalized or focal seizures are more common than stroke. There are no serological markers of disease and only 14–20% of patients are ANCA positive. The diagnosis of PAN relies on clinical, histopathologic, and / or angiographic findings. Diagnostic biopsies that show necrotizing arteritis are most frequently obtained from skeletal muscle, nerve, kidney, skin and / or subcutaneous tissue.

5. Other systemic necrotizing vasculitis Cutaneous leucocytoclastic angiitis (LCA) or cutaneous necrotizing vasculitis is a form of vasculitis that predominantly involves the skin. Idiopathic cutaneous LCA is a diagnosis of exclusions. At least three clinically distinctive types of idiopathic cutaneous LCA exist: idiopathic palpable purpura (lesions on the lower extremities), urticarial (or hypocomplementemic) vasculitis, and erythema elevatum diutinum (persistent red to purple papules usually

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localized to the extensor surfaces of the extremities especially over the joints). Symptoms such as low-grade fever, malaise, and / or arthralgias are present in only a small proportion of cases. Even during long-term follow-up there is no progression to systemic disease. Neurologic manifestation, include pseudotumour cerebri, meningitis of unknown origin, convulsions, and / or mononeuropathy (Swelick and Lawley, 1991). The diagnosis of idiopathic cutaneous LCA is based on clinical and histopathologic findings. Histologic examination of the skin shows leucocytoclastic angiitis involving capillaries, arterioles, and venules. No IgA deposits are detected by immunofluorescence microscopy. Polyangiitis overlap syndrome is characterized by a necrotizing vasculitis of medium and small sized muscular arteries occurring in combination with either cutaneous leucocytoclastic angiitis, granulomatous inflammation, or lung involvement and not fulfilling the criteria for one of the other recognized vasculitic syndromes (Leavit and Fauci, 1986). By using combined clinical, serologic, and histopathologic criterias for classification, most patients with polyangiitis overlap syndrome can be classified as having (incomplete forms of) WG or CSS. Patients with polyangiitis overlap syndrome tend to be younger than other patients with systemic vasculitis. Nearly all patients present with constitutional symptoms and rapidly progressive systemic disease. The diagnosis relies on clinical, histopathologic, and / or angiographic findings and can only be made after exclusion of other presently recognized syndromes. Kawasaki disease is a disease characterized by high fever, conjunctivitis, strawberry tongue, diffuse reddening of oral and pharyngeal mucosa, swelling of cervical lymph nodes, polymorphous exanthema and erythema with desquamation of the skin of the finger tips. Mucocutaneous lymph node syndrome is the defining feature that sets Kawasaki disease apart from polyarteritis nodosa. The absence of involvement of vessels smaller than arteries distinguishes Kawasaki disease from microscopic polyangiitis. Most cases occur in young children usually under four years of age. The disease is complicated by a systemic necrotizing vasculitis predominantly symptomatic in the coronary arteries.

6. Vasculitis associated with connective tissue disease Systemic lupus erythematosus (SLE) is a disorder characterized by the generation of pathogenic autoantibodies and immune complexes which cause immunologically mediated damage to multiple organs, most notably the kidneys, skin, and joints. Reports on the neurologic and neuropathologic manifestations of systemic lupus erythematosus have long emphasized the frequency of central

nervous system complications. However, if the numerous studies on the central nervous system complications of SLE published over the years have one feature in common, it is the strikingly low frequency of documented vasculitic changes in the vessels on postmortem examination (Bluestein, 1992). Some patients have had tapering occlusions of the middle cerebral artery or internal carotid artery, a finding that was felt to be indicative of arteritis but no histologic confirmation was available (Trevor et al., 1972). Only recently has attention been called to the possibility that cardiogenic brain embolism (with or without associated Libman–Sacks endocarditis) may be an important mechanism of stroke in patients with SLE (Kitagawa et al., 1990). Thrombotic thrombocytopenic purpura, (thrombocytopenia, microangiopathic haemolytic anaemia, fever, renal failure, central nervous system signs) may be an important but underdiagnosed mechanism of stroke in the terminal stages of SLE. The association of thrombotic events with the presence of the ‘circulating anticoagulant’ in patients with lupus was noted nearly 30 years ago, but it has only been in the last decade that attention has been called to the possible association of antiphospholipid antibodies with cerebrovascular disease, systemic thrombotic events, spontaneous abortion, and thrombocytopenia. The exact cause of thrombosis in patients with antiphospholipid antibodies is unknown, but possible mechanisms include the binding of antiphospholipid antibody to platelet membranes or vascular endothelium, or the inhibition of various coagulation factors (Ferro et al., 1992). Patients with IgM anticardiolipin antibody isotype may not be as prone to develop thrombotic events as those with IgG isotype (Levine et al., 1995). Rheumatoid arthritis Central nervous system complications are rare and tend to occur in the setting of longestablished disease with either clinical (fever, weight loss, active arthritis) or laboratory (elevated rheumatoid factor, elevated erythrocyte sedimentation rate) evidence of disease activity. Central nervous system vasculitis, either isolated or in association with systemic rheumatoid vasculitis has been documented on rare occasions. Some of these cases had associated pachymeningitis (Scott et al., 1981). Usually the small vessels of the leptomeninges are affected by fibrinoid necrosis, perivascular nodule formation (similar to polyarteritis nodosa) and ‘onion skin’ proliferation. One of the most feared neurologic complications of rheumatoid arthritis is compressive myelopathy secondary to c 1 –c 2 vertebral subluxation, or massive vertebrobasilar territory infarction as a result of vertebral artery thrombosis probably resulted from pinching of the vertebral artery between the odontoid and rim of the foramen magnum or stretching of the vertebral arteries between the transverse foramina of the c 1 and c 2 vertebrae (Jones and Kaufmann, 1976).

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Scleroderma (progressive systemic sclerosis) rarely directly causes central nervous system manifestations. Convulsions, stroke, and pathologic findings of arterial changes in the brains of patients with scleroderma are the result of hypertension (Cohen-Tervaert and Kallenberg, 1993). Sjogren’s syndrome is a chronic inflammatory autoimmune disorder characterized by decreased lacrimal and salivary gland secretion resulting in dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia). The condition may be either primary or secondary to some other connective tissue disease. There is some uncertainty over the frequency and severity with which central nervous system complications occur in patients with primary Sjogren’s syndrome (Talal, 1992). Neuropathy occurs in 10 to 20% of patients. Approximately two thirds of patients have a chronic, distal sensory motor neuropathy and one third have pure sensory involvement. In 40% of patients, the neuropathy precedes the sicca symptoms, sometimes by several years. A sensory neuronopathy with severe ataxia has also been reported with Sjogren’s syndrome on the basis not of vasculitis, but rather dorsal root ganglionitis (diagnosed by dorsal root ganglion biopsy). These patients, most commonly women, develop a prominent sensory ataxia over months to years, with less severe involvement of pain and temperature sensation. Most patients also have evidence of autonomic insufficiency. The cranial nerves can also be involved in Sjogren’s syndrome; up to 15% of patients develop unilateral or bilateral trigeminal sensory loss. The optic nerves, facial nerves and other cranial nerves are less commonly affected. Finally, the course of Sjogren’s syndrome may be complicated by CNS dysfunction secondary to an inflammatory vasculopathy of the small vessels of the cortex and meninges. Angiographic findings compatible with vasculitis are seen in only about 20% of patients, and few patients have been studied histologically. Many issues remain unresolved regarding CNS vasculitis in Sjogren’s syndrome, including its prevalence, pathophysiology and treatment (Calabrese, 1995). Relapsing polychondritis is a rare relapsing and remitting disease of cartilages, with rare CNS involvement. Peripheral neuropathy is still rarer. There is widespread necrotizing vasculitis. Confusional states, seizures, strokes, cranial neuropathies, ischemic optic neuropathy, and sensorineural deafness have been reported. Malignant atrophic papulosis (Kohlmeier Degos disease) is a progressive vasculopathy that affects the skin, cerebral circulation, and other organ systems and occurs most often in teenage boys (Horner et al., 1976). The appearance of cutaneous lesions (umbilicated raised papules with a white centre) usually precedes neurologic manifestations, sometimes for years. Bowel perforations, ulcerative colitis and celiac disease may occur. Neurologic complications are varied: transient ischemic

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attack or stroke, progressive focal deficits, spinal cord involvement. Computerized tomograms have demonstrated multifocal areas of infarction, haemorrhage,and even subdural haemorrhage. Pathologic examination of brain vessels has documented a peculiar ‘fibrous intimal proliferation’ or ‘deposition of fibrous material’ between endothelium and internal elastic lamina, similar to vascular lesions in the skin. The exact etiology of this proliferative and occlusive vasculopathy has not been established. Lymphomatoid granulomatosis is characterized by necrotizing granulomas that involve primarily the lungs. Some can progress to lymphomas. Skin lesions are frequent. A minority of patients have clinical CNS vasculitic involvement, with confusion, seizures, or hemiplegia. Mononeuritis multiplex and cranial neuropathies are also possible. Behcet’s disease is an inflammatory multisystem condition of unknown etiology that is clinically typified by the triad of recurrent oral aphthous ulcers, genital ulcers, and uveitis. Other manifestations include arthritis, cutaneous vasculitis, thrombophlebitis, colitis, and central nervous system disease (Chajek and Fainaru, 1975). Central nervous system complications usually occur in 10 to 30% and in patients who have established cutaneous or ocular disease, but there are well-documented instances of neurologic presentation (O’Duffy and Goldstein, 1976). Neurologic manifestations are varied, and few clinical features point to the underlying diagnosis in the absence of the cutaneous or ocular manifestations. Many reports have emphasized a fluctuating course with exacerbations and remissions that are atypical for cerebrovascular disease. Histologically, it is a small-vessel vasculitis affecting venules primarily.

7. Hypersensitivity vasculitides (HSV) Hypersensitivity vasculitides, the most frequently encountered of all the vasculitides, is a heterogeneous group of clinical syndromes characterized by inflammation of small vessels typically venules. The unifying feature of these diseases is that the skin is the predominantly affected organ. Clinically, these lesions appear as purpura or urticaria. In many instances, the vessels inflammation can be identified as a response to a precipitating antigen such as a drug, foreign protein, or microbe (Zax et al., 1990). Among the hypersensitivity group of disorders, several diseases deserve special mention. Henoch–Schonlein purpura (HSP) is a hypersensitivity vasculitis most frequently seen in children characterized by palpable purpura, gastrointestinal involvement and, in about 50% glomerulonephritis. Neurological involvement is rare. Cases of cerebral infarction and intracranial haemorrhage have been described. The pathogenesis of HSP appears to involve IgA

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containing immune complexes which can be found in both the cutaneous microvasculature and the glomeruli. Central nervous system complications may develop in patients with mixed cryoglobulinemia and include diffuse encephalopathic syndromes with focal sign, seizures, myelopathy, and occasionally stroke. Classification of cryoglobulinemia has traditionally been based upon the immunologic nature and content of the cryoprecipitates (monoclonal, polyclonal, mixed) and whether there is any recognized associated disease present. In the past few years the majority of patients, with what previously has been referred to as cryoglobulinemia of essential origin, are now recognized to have underlying infection with hepatitis C (Zhang and Agnello, 1993).

8. Giant cell arteritides Giant cell arteritis (GCA) refers to two histologically similar but clinically distinct diseases: temporal arteritis and Takayasu’s arteritis. Temporal arteritis, an acute inflammatory disease, is a systemic panarteritis, clinically affecting the extracranial vasculature. Classic histologic features, present on biopsy in half the patients, include giant cells in a granulomatous inflammation in the intima media junction (Hunder et al., 1993). Fragmentation of the internal elastic lamellae is typical but not pathognomonic and it may occur in normal, elderly patients. Inflammation of the arteries of the head and neck are responsible for the major neurologic symptoms of headache and visual loss. Stroke, although uncommon, is a well documented and potentially fatal complication. Headache, the most common symptom, may be associated with scalp tenderness and a palpable, pulseless, thickened superficial temporal artery and jaw claudication. Systemic symptoms including malaise, anorexia, and weight loss are also frequent and almost invariably associated with elevation of the sedimentation rate. Giant cell arteritis is closely associated with polymyalgia rheumatica, a symptom complex characterized by pain and stiffness involving the muscles of the shoulder and pelvic girdles (Willkens, 1987). Visual loss is the most feared complication of giant cell arteritis. Anterior ischemic optic neuropathy is the most common cause of visual loss in giant cell arteritis, as result of thrombosis of the posterior ciliary arteries. Temporal artery biopsy is the most helpful diagnostic procedure. Yet the segmental nature of the disease means that a normal temporal artery biopsy does not exclude the diagnosis of giant cell arteritis. Takayasu’s arteritis (pulseless disease, idiopathic aortitis) is a chronic, recurrent large vessel granulomatous arteritis that affects the aorta, its main branches, and occasionally the pulmonary artery. The process is initially

inflammatory and later occlusive. The disease affects females from 15 to 45 years of age and is of greatest prevalence in Asia, Latin America, and eastern Europe. Takayasu’s differs in distribution from giant cell arteritis, in fact it tends to involve the origins of aortic branches rather than the more distal portions of the vessels. The vessels most often affected include the aortic arch and subclavian and carotid arteries. Four types of Takayasu’s disease are delineated on the basis of the distribution of the arterial changes (Hall and Buchbinder, 1990). Takayasu’s arteritis begins with a panarteritis consisting of mononuclear cell infiltrates and often, giant cells. Disruption of the elastic lamina and destruction of smooth muscle cells are characteristic. These inflammatory changes may be accompanied by intraluminal thrombosis distal to the site of involvement. Proliferation of the intima and fibrosis throughout the arterial wall follow and result in stenosis or complete occlusion of the arterial lumen. Like giant cell arteritis, constitutional symptoms (malaise, weight loss, fever and elevated erythrocyte sedimentation rate are common). Takayasu’s arteritis is recognized by signs of decreased blood flow to the limbs and viscera. Symptoms of arm claudication and syncope occur more frequently than retinal or cerebral ischemia. Brachial pressures and pulses are frequently asymmetric, and there may be asymmetry between pressures in the arms and legs.

9. Miscellaneous Ischemic and haemorrhagic stroke is a complication of illicit drug use (Kaku and Lowenstein, 1990; Citron et al., 1990). Most commonly, the implicated substances are amphetamines, cocaine, heroin, phenylpropanolamine, hydrochloride, and pentazocine lactate injection in combination with triphelenamine. Complications of stroke caused by illicit drug use have been attributed to drug-induced sympathomimetic pressor effects, hypersensitivity mediated arterial hypotension, enhanced platelet aggregation, decreased fibrinolytic activity, infective endocarditis, cardiac arrhythmias, foreign particle embolization, vasospasm, direct arterial injection, acquired immunodeficiency syndrome, and / or drug-induced vasculitis. A necrotizing vasculitis, pathologically similar to periarteritis nodosa, was demonstrated. Vasculitis, usually cutaneous, is associated with a variety of malignancies. Lymphoproliferative disorders predominate, but solid tumours also occur with this association (Greer et al., 1988). Immuno suppression caused by malignancy or its treatment may allow an infectious agent to cause vasculitis. Conversely, cytotoxic agents used to treat vasculitis may

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produce a ‘second malignancy’. Both Hodgkin’s disease and non-Hodgkin’s lymphomas are associated with cerebral vasculitis. The relationships among herpes zoster reactivation, lymphoproliferative disease, and cerebral vasculitis are complex. Occurrence of cerebral vasculitis following herpes zoster infection, suggests that some cases of malignancy associated cerebral vasculitis may be due to opportunistic infections. Patients with malignancies may demonstrate cerebral infarction or haemorrhage from a number of diverse mechanisms including emboli, venous thrombosis, and alteration of coagulation mechanisms. Acceleration of atheromatous disease in the neck vessels has been described as a sequel to radiation therapy. Although the appearance of extracranial large vessel atherosclerotic disease is not usually confused with vasculitic processes, radiation induced occlusive vasculopathy may also occur intracranially (Chuang, 1994). The intracranial changes are accompanied by areas of cystic encephalomalacia on CT or MRI. The angiographic features are not easily separable from vasculitis, but the clinical setting and absence of abnormalities outside of the radiation field favour the differential diagnosis. Cogan’s syndrome is a disease characterized by interstitial keratitis and audiovestibulatory abnormalities consisting of episodic vertigo, tinnitus and profound deafness. Other symptoms include nausea, vomiting, nystagmus, fever, and weight loss. A systemic vasculitis and / or aortitis is present in a minority of the patients. Neurologic manifestations are frequently observed. Retinocochleocerebral vasculopathy (Susac’s syndrome) is an unusual syndrome of small-vessel occlusion in the retina, cochlea, and brain affecting predominantly young women (Susac et al., 1979; Monteiro et al., 1985). Extracerebral clinical manifestations have included multiple episodes of visual loss, related to retinal arteriolar occlusions, sensorineural hearing loss, and tinnitus. Ophthalmoscopy reveals bilateral retinal arteriolar occlusions with focal areas of retinal infarction. Segments of retinal arterioles are occluded by columns of white material oscillating with the pulse but there is no clinical or angiographic evidence of concurrent vasculitis. Neurologic manifestations include encephalopathy with prominent disturbances in cognition memory and behaviour dysarthria, pseudobulbar affect, ataxia, vertigo, hemiparesis, and hemisensory loss. Extensive laboratory testing has failed to reveal a specific etiology; cerebrospinal fluid examination typically shows pleocytosis and increased protein. Cerebral angiography is usually normal. Computerized tomograms are usually normal, but MRI may either be normal or demonstrate increased signal abnormalities on T 2 -weighted images in the white matter and deep gray matter. Brain biopsy has demonstrated gliosis microinfarcts, small vessel ‘sclerosis’, or ‘healed arteritis’. The etiology remains obscure. Some patients have

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appeared to respond to steroids and immunosuppressants, while others have progressed despite these treatments. Eales’ disease describes patients with unexplained peripheral retinal vascular occlusion and secondary preretinal neovascularization or peripheral proliferative retinopathy (Renie et al., 1983). This develops in a large number of vascular or inflammatory diseases associated with retinal ischemia, but, in Eales’ disease, the cause of the peripheral retinal vascular occlusion is unknown and the diagnosis can only be made after excluding other possible causes. Visual prognosis is usually good, because the peripheral preretinal neovascularization can usually be readily controlled by laser therapy. The long-term followup of patients showed that a high percentage of patients have associated vestibulo-auditory dysfunction. Central nervous system vasculitis also occurs as the central feature of an idiopathic disease: isolated CNS angiitis, a recurrent inflammatory vascular disease whose involvement is restricted to vessel of the CNS. The clinical manifestations are different. Most patients are young or middle-aged, although patients of a wide age range are affected (8 to 72). Typical clinical features would include a headache and encephalopathy with multifocal motor, sensory, or cerebellar abnormalities. The range of clinical features includes headaches, strokes, abnormal behaviour, psychoses, diminished cognition, field cuts, scotomas, cranial neuropathies, myelopathies, and radiculopathies. Evidence of recurrent or progressive disease is typical and useful in diagnosis. Clinical symptoms result from diminished blood flow within the dural reflections. Ischemia may result from the vascular inflammation early in the course of the disease or scarring later in the course of the disease. A central feature of disease is the absence of evidence of systemic inflammation. Leucocytes, erythrocytes, and platelets are normal, as is the sedimentation rate. Immune complexes and autoantibodies are not associated with the disease. The criteria used for diagnosis are:

1. Recent onset of headache, confusion, and multifocal neurologic deficits with evidence of recurrent disease unless the disease onset is severe or progressive. 2. Cerebral angiographic changes suggestive of vasculitis. 3. Exclusion of systemic disease or infection. 4. Leptomeningeal parenchymal biopsy to confirm the presence of vascular inflammation and exclude infection, neoplasia, and noninflammatory vascular disease (Moore, 1989). The etiology of isolated angiitis of the CNS is unknown. Possibly an earlier, self limited viral infection may have resulted in an inappropriate, persistent expression of adhesion molecules that continue to recruit lymphocytes in the absence of an antigenic target.

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Table 2 Operating characteristics of diagnostic studies for CNS vasculitis Test

Sensitivity

Estimated specificity

CT

33–50% (Even in biopsy-proven cases) 50–100% (It approaches 100% in histologically confirmed cases and is lowest in those diagnosed only by angiography) 30–100% (It is less than 40% in histologically confirmed cases, and 100% in reports not supported by histology)

Data not available (No pathognomonic findings) Data not available (No pathognomonic findings)

MRI

Angiography

Biopsy

75% (The negativity can be due to the patchy nature of the disease and small tissue sample)

10. Diagnosis In recent years, assays for antineutrophil cytoplasmatic antibodies (ANCA), serum cytokines, antibodies to endothelial cell antigens, and factor VIII-related antigen have been reported to be useful in either diagnosing or monitoring the disease activity in different vasculitic syndromes. With the possible exception of the ANCA in Wegener’s granulomatosis, these tests lack the sensitivity and specificity to be of significant utility in diagnosing or following individual patients. There are no invasive tests or blood studies of sufficient positive predictive value to secure the diagnosis of vasculitis. Fortunately, a number of recent investigations have helped clarify the utility of neurologically oriented diagnostic tools. Cerebrospinal fluid analysis (CSF) is an essential part of the diagnostic process for CNS vasculitis. In over 90% of patients with histologically confirmed CNS vasculitis, the CSF is abnormal. The CSF findings usually are characteristic of aseptic meningitis, with a modest pleocytosis, normal glucose and elevated protein. Increased Ig←G synthesis and the presence of oligoclonal bands have been reported rarely and generally are unhelpful because of the lack of specificity. Most importantly, the CSF should be cultured rigorously to search for CNS infection (Calabrese, 1995). Magnetic resonance imaging (MRI) findings suggestive of vasculitis are multiple, bilateral lesions in the cortex, white matter, and / or leptomeninges. Lesions in the white matter may be mistaken for demyelinating disease, but the presence of grey matter involvement should exclude the possibility of multiple sclerosis. The grey matter lesions can appear as large or small vessel infarctions and can be haemorrhagic (Greenan et al., 1992). The utility of MR angiography (MRA) in the diagnosis of CNS vasculitis has not yet been systematically evaluated. Duna and Calabrese (1995) recently concluded that findings compatible with vasculitis (segmental narrowing

22% (Assessed in only one study* but may be higher if vasculitis secondary to other causes are excluded) 80% (The same pattern of inflammation can be due to other causes

and occlusion, microaneurysms and vascular beading) are commonly found in nonvasculitis disorders, including atherosclerosis, vasospasm and infection. Therefore, angiographic results of any type must be interpreted considering the clinical setting and other laboratory findings. However, if present, angiographic abnormalities may be useful to suggest the diagnosis of vasculitis and depict sites of major involvement for possible biopsy. At present, MRA is only useful in detecting abnormalities in large calibre vessels, such as carotids, vertebral and basilar arteries, and the circle of Willis. Its lower spatial resolution compared with conventional angiography is a disadvantage for defining small-vessel disease. In the future, MR spectroscopy and positron emission tomography (PET) may provide useful adjuncts in diagnosis and for the evaluation of response to treatment. In those patients in whom a systemic evaluation is unrevealing and in whom the angiography is negative, a brain biopsy should be considered. The role of stereotactic biopsy in the diagnosis of CNS vasculitis is undefined, but it has been reported to be successful and is probably the preferred technique for a mass lesion. Parisi and Moore considered the temporal tip of the nondominant hemisphere (sampling an area with a longitudinally-oriented surface vessel) the preferred biopsy site in patients without focal lesions (Parisi and Moore, 1994) biopsy specimens should also include the leptomeningeal sample, as the leptomeninges are often involved. As the involvement is frequently diffuse, the presence of a negative biopsy result does not entirely exclude the diagnosis of vasculitis (Berlit et al., 1993). A summary of the diagnostic sensitivity and specificity of these techniques is shown in Table 2.

11. Treatment Ideal treatment of systemic vasculitis should consider the specific immunologic mechanisms causing the disease.

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Table 3

Corticosteroids Cyclophosphamide Azathioprine Cyclosporine Methotrexate Plasma exchange IVIG NSAIDS Antiplatelet Antiprostaglandin Dapsone Immunotherapy

Polyarteritis nodosa

Churg–Strauss syndrome

Wegener’s granulomatosis

Isolated CNS angiitis

Temporal arteritis

Takayasu’s arteritis

Hypersensitivity angiitis

Behc¸et’s disease

11 11 1 a ? ? 1 b ? 1

11 11 1 a ? ? ? ? 1

1 111 1 a ? ? ? ? ?

1 111 1 a ? ? ? ? 1

111 ? ? ? ? ? ? ?

? ? – ? 1 ? ? ?

1 ? – ? ? 1 ? 1

1 ? 1 ? ? ? ? 1

? ?

? ?

? ?

? ?

? ?

? ?

1 ?

? ?

c

b

(111 / 11 / 1) Treatment approaches that have shown efficacy; (1) may be given under certain circumstances; (?) efficacy unknown. a May be tried in patients that cannot tolerate cyclophosphamide. b May be tried in patients in whom standard therapy failed. c May be tried in patients in whom glucocorticoids cannot be tapered (Hoffman et al., 1992).

Unfortunately, the lack of a complete knowledge of the etiology avoids the utilisation of more specific therapies. Table 3 summarises the medical management of vasculitis based on pathogenic mechanisms and their efficacy. An updated analysis in 1992 of the National Institutes of Health, Bethesda, who had been treated with a ‘standard protocol’ (Table 4) focus much attention on the treatment complications and progression of disease (Hoffman et al., 1992). Daily oral cyclophosphamide and prednisolone were used for disease remission induction with conversion to azathioprine for maintenance of remission. Low-dose weekly methotrexate in combination with corticosteroids was useful in patients intolerant of cyclophosphamide or those who did not have life-threatening disease. A prospective, randomized, placebo-controlled study demonstrated the efficacy of cotrimoxazole (800 mg of sulphamethoxazole and 160 mg of trimethoprim) given twice daily for 24 months in preventing relapses in patients with Wegener’s granulomatosis in remission during or after treatment with cyclosphamide and prednisolone (Stegeman et al., 1996).

Intravenous immunoglobulin has been proposed in patients unresponsive to standard therapies. Jayne et al. (1993) reported successful treatment of patients with microscopic polyangiitis, Wegener’s granulomatosis and rheumatoid vasculitis, whereas in an uncontrolled study, IVIG treatment was found to confer limited benefit on a significant minority of patients with ANCA-associated systemic vasculitis, suggesting that the inhibition of ANCA activity by anti-idiotypes present in the IVIG preparation is not the crucial mechanism behind the clinical effect of IVIG in these patients (Richter et al., 1995). In case of severe renal or pulmonary involvement, plasma exchange or methylprednisolone in doses up to 15 mg / kg daily for three days was proposed (Savage et al., 1997). Antiviral therapy may have a primary role in the treatment of virus-induced vasculitis, such as interferon alpha-2a in mixed cryoglobulinemia secondary to hepatitis C virus (Misiani et al., 1994) and vidarabine in hepatitis B-associated polyarteritis nodosa (Guillevin et al., 1993). Current treatment regimens showed important differences between European centres in the doses of steroids

Table 4

Induction therapy 4–6 months

Maintenance therapy 6–24 months Escalation therapy

Cytotoxic agent

Corticosteroids

Cyclophosphamide 2mg / kg daily by mouth (max 150 mg); lower dose by 25 mg if .60 years WBC must be .4.0x10 9 / l Azathioprine 2 mg / kg daily

Prednisolone 1 mg / kg daily (max 80 mg); Reduce weekly to 10 mg / day by 6 months

Prednisolone 5–10 mg / day

Acute severe disease with creatinine .500 mmol / l or pulmonary haemorrhage; Consider 7–10 plasma exchange treatment over 14 days such that 60 ml / kg of plasma is exchanged for 4.5% or 5% human albumin solution or Consider three pulses of methylprednisolone, 15 mg / kg daily for 3 days These patients (if under 60 years) may also require 2.5 mg / kg daily of cyclophosphamide.

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used, in the choice and duration of cytotoxic therapy, in relapse rates and in second line or salvage therapies. In response to these problem, the ECSYSVASTRIAL group has been constituted by European Community funds. The aims of the group are the design and standardisation of disease scoring by Birmingham Vasculitis Activity Score (BVAS) and Vasculitis Damage Index (VDI), data collection tools and database, the design of clinical trials and the creation of national and European networks to favour clinical trials in ANCA-associated systemic vasculitis (Wegener’s granulomatosis, microscopic polyangiitis and renal-limited vasculitis). Steroids and cyclophosphamide were accepted as the standard induction and remission treatment for ‘early systemic’ disease and as essential induction treatment if renal vasculitis or imminent failure of another vital organ was present, i.e. ‘generalised or a severe renal disease’. Several studies have addressed the use of intravenous cyclophosphamide for induction treatment in renal vasculitis and in some patients with Wegener’s granulomatosis with a lower cumulative dosage and reduced adverse-effect rates (Rasmussen et al., 1995). For patients unresponsive to the standard therapies, recent interest has focus on anti-lymphocyte antibodies therapies, as a result of the elucidation of the role of T and B cell autoimmunity in the pathogenesis of the systemic vasculitis (Lockwood et al., 1993). Monoclonal anti-T cell therapy and anti-thymocyte globulin have been demonstrated to induce disease remission in the majority of these patients without important side-effects (Jayne and Lockwood, 1993).

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