Seminars in Immunopathology

, Volume 31, Issue 4, pp 527–536

Central nervous system vasculitis

Authors

    • Institute of Clinical NeurosciencesFrenchay Hospital
Review

DOI: 10.1007/s00281-009-0183-2

Cite this article as:
Scolding, N.J. Semin Immunopathol (2009) 31: 527. doi:10.1007/s00281-009-0183-2

Abstract

An account of the pathology, pathogenesis, clinical features, diagnosis and management of cerebral vasculitis is presented.

Keywords

CNS vasculitisIsolated CNS angiitis

Introduction

Vasculitis affecting the central nervous system (CNS) is uncommon, but is, paradoxically, a condition both under- and over-diagnosed. It is easily missed; the diagnosis unexpectedly emerging either at post mortem or on tissue biopsy (performed for a suspected tumour, for example). Thus, in Younger et al.’s highly informative 1988 study of four New York patients with pathologically proven CNS vasculitis [1], not only was it the case that the diagnosis was made ante mortem in not one of these four reported patients, but the authors also analysed 78 definite cases (from other publications) and found that in just ten of these was a confirmed diagnosis made in life. At the same time, it is also notoriously over called. ‘CNS vasculitis’ features extremely commonly in lists of differential diagnosis (especially at clinico-pathological case conferences), and there is a long and continuing series of publications concerning patients with cerebral ‘vasculitis’ in whom the diagnosis is based on cerebral angiographic appearances, but not confirmed histopathologically. It can be a clinical label incautiously and injudiciously applied with insufficient evidence, only to be questioned and/or undone if the individual should happen to come before a new and sceptical physician.

Part of the problem undoubtedly also relates to definitions. ‘Vasculitis’ is of course not a disease but a pathological appearance, which immediately helps explain why the phrase ‘radiological diagnosis’ of vasculitis is inappropriate. The core pathological changes are seen in not one but many conditions—the vasculitides: an heterogeneous group of disorders characterised by blood vessel inflammation, occasionally with additional, specific and defining histopathological features, together producing different but frequently overlapping clinical manifestations [2]. The classical core histopathological change comprises an inflammatory infiltrate within (not just around) the vessel wall, associated with destructive mural changes (‘fibrinoid necrosis’), precipitating vascular occlusion and so infarction, microscopic or macroscopic, which in turn accounts for the clinical manifestations.

Classifying the many causes of vasculitis has proved difficult, not least because of the absence of an aetiological understanding in the vast majority of cases, and so the various sub-divisions proposed have depended on different aspects of phenotype and association (Tables 1 and 2). Histological changes allow classification according to the presence or absence of granulomata and/or the size of the vessel implicated; while clinical observation and analysis has informed the sub-division into idiopathic vasculitic disorders—for example, giant cell arteritis, polyarteritis and Wegener’s granulomatosis—and vasculitis secondary to collagen diseases, malignancy, viral infection, drugs etc. The central nervous system can be involved in virtually all of the systemic vasculitides, but ‘isolated angiitis,’ affecting either the central or the peripheral nervous system is also recognised, where there is little or no evidence of generalised inflammation. Younger’s series coined the term ‘granulomatous’ angiitis, and it is clear that at a pathological level granulomata appear to be present in the vast majority of cases studied at autopsy. (This is not the case with biopsy, the explanation for the discrepancy presumably lying in the patchy nature of the pathological process.)
Table 1

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

Medium arteries

Classical polyarteritis nodosa

Infection (e.g. Hepatitis B)

Kawasaki disease

Small vessels and medium arteries

Wegener’s granulomatosis

Vasculitis with rheumatoid disease, SLE, Sjögren’s syndrome, drugs, nfection (e.g. HIV)

Churg-Strauss syndrome

Microscopic polyangiitis

Small vessels

Henoch-Schönlein purpura

Drugs (e.g. sulphonamides, etc.)

Essential cryoglobulinaemia

Infection (e.g. hepatitis C)

Cutaneous leukocytoclastic vasculitis

Table 2

Some neurological and systemic disorders which may mimic cerebral vasculitis

Non-inflammatory vasculopathies

Infections

Susac’s syndrome

Viral or fungal vasculitis

Homocysteinuria

Lyme disease

Ehlers-Danlos syndrome

AIDS

Radiation vasculopathy

Endocarditis

Köhlmeyer-Degos disease

Whipple’s disease

Fibromuscular dysplasia

Viral encephalitis

Fabry’s disease

Legionella/mycoplasma pneumonia

Moyamoya disease

 

Amyloid angiopathy

Tumours and malignancy

CADASIL

Atrial myxoma

Marfan’s syndrome

Multifocal glioma

Pseudoxanthoma elasticum

Cerebral lymphoma

 

Paraneoplastic disease

Other immune/inflammatory diseases

 

Sarcoidosis

Miscellaneous other causes

Lupus and anti-phospholipid disease

Multiple cholesterol emboli

Behçet’s syndrome

Cerebral sinus thrombosis

Multiple sclerosis/ADEM

Mitochondrial disease

Thyroid encephalopathy

Thrombotic thrombocytopoenic purpura

The pathology of CNS vasculitis

In primary CNS vasculitis, there is neither any other clinically overt systemic vasculitis, nor any underlying causal disease: an apparently primary vasculitic process is seen and is confined to the brain and/or spinal cord. Although defined by this apparent tissue specificity, however, autopsies commonly disclose sub-clinical extracranial involvement (e.g. pulmonary arteries and abdominal viscera [3])—presumably contributing the common features of fever, rigors, weight loss, raised plasma viscosity etc.

The angiitic process typically involves both small arteries and veins. Rarely, vessels up to 1 mm in diameter are involved, but mostly the process is confined to those vessels between 200 and 300 μm. The changes are focal and segmental in distribution, and may be granulomatous, necrotising, and/or lymphocytic in character, often with mixed morphologic types in individual patients. The common term ‘granulomatous angiitis’ has fallen out of favour of late, though it has been argued that the reported very variable occurrence of granulomata is in fact only a consequence of biopsy studies, and that far more comprehensive neuropathological observation allowed by autopsy invariably reveals the presence of granulomata [4].

Additional or other pathological features may point away from isolated or granulomatous CNS angiitis and towards secondary cerebral vasculitis, where a systemic (presumably unsuspected) vasculitis has spilled over into the CNS. The presence of viral inclusions or fungal hyphae is of obvious significance. Conspicuous immune complexes may suggest cryoglobulinaemia (especially if IgA is prominent). Extravascular granulomata are present in Wegener’s granulomatosis and Churg-Strauss disease, the latter distinguished by a prominent eosinophil infiltrate.

Pathogenetic mechanisms in vasculitis

The pathophysiology of neurological vasculitis is relatively well-understood: in both primary and secondary CNS and peripheral nervous system (PNS) vasculitis, the neurological features arise principally through ischaemia and infarction. These in turn are the consequences of inflammation within the vascular wall: obstruction of the vessel lumen, increased co-agulability from the effects of pro-inflammatory cytokines on the endothelial surface, and alterations in vasomotor tone. Brain tissue becomes hypoxic or ischaemic, and neurological consequences ensue.

This much has been apparent from neuropathological studies. The sequence of pathological changes has also long been relatively well characterised [5]. Careful studies of serial sections have led to the proposal that first there is lymphocytic infiltration, particularly into the adventitia of small veins; and this is followed by fibrinoid change and the accumulation of histiocytes. Subsequently, there occurs necrosis, fragmentation of the internal elastic lamina and lymphocyte and histiocyte infiltration throughout the thickness of the vessel wall. Granulomata characteristically appear. [5]

Unfortunately, these careful and definitive neuropathological observations have not resulted in a comparably detailed understanding of the pathogenetic mechanisms underlying or leading to vascular inflammation. These appear to vary markedly with the vasculitic subtype, although both cellular and humoral factors are commonly involved. Most research interest has earlier centred on the latter, with a more recent emphasis on both lymphocyte and neutrophil involvement [6].

This said, the great majority of research effort has centred on systemic vasculitides, especially anti-neutrophil cytoplasmic autoantibodies (ANCA)-related disease, and our understanding of the cause and pathogenesis of idiopathic or isolated CNS vasculitis in particular is very sparse, where there are very rarely either immune complexes nor an ANCA or other antibody association.

Antibody-related possible mechanisms

Antibodies appear particularly relevant in the primary small vasculitides, involved either through immune complex deposition, direct attack or indirectly through interaction with neutrophils.
  1. 1.

    Direct antibody attack

     
In some systemic vasculitides, a pathogenic role for anti-endothelial cell antibodies in injuring or, paradoxically, activating endothelial cells is proposed [7], though their lack of specificity and variable frequency of detection do raise questions about any truly causal role. Rarely, antibodies against amyloid-beta deposits may precipitate cerebral vasculitis [8]
  1. 2.

    Immune complex mediated vasculitis

     
Immune complex deposition in the blood vessel wall triggers complement activation, leading to polymorph and macrophage recruitment, amplification of inflammation and the generation of lytic and injurious membrane attack complexes. Hepatitis B- and C-associated vasculitis are good examples of this process, with the latter found to underlie many cases of cryoglobulinaemic vasculitis [9]. Henoch-Schönlein purpura lesions likewise prominently feature immune complexes (characteristically containing IgA).
  1. 3.

    ANCA-related vasculitis

     

By contrast, Wegener’s granulomatosis, microscopic polyangiitis and Churg–Strauss syndrome, and the pauci-immune necrotizing vasculitides, usually lack immune complex deposits. In these disorders, ANCA are pathogenetically implicated [10]. ANCAs represent a family of antibodies directed against constituents of the neutrophil azurophil granules [11]. 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 (MPO), is less specifically found in microscopic polyangiitis and Churg-Strauss syndrome [11]. Such antibodies may play significant role in generating and maintaining vascular inflammation [12,13] (there is arguably stronger evidence implicating MPO antibodies than PR3: the latter may act more in concert with T lymphocytes [14]). However, serum titres of both often increase prior to exacerbations of disease and in various models, act to stimulate neutrophils and damage endothelial cells [10]. Recent reports suggest that chromatin fibres are released by ANCA-stimulated neutrophils; these fibres contain both PR3 and MPO antigens, and thus are bound by circulating ANCAs, so potentially playing a key role in generating vasculitic injury [15].

Cell-mediated damage

Evidence for cell-mediated involvement in tissue injury in vasculitis [16] also comes at least in part from studying microscopic polyarteritis nodosa and Wegener’s granulomatosis. In both disorders, in addition to antibodies, circulating T cells responsive to PR-3 are found, and vascular lesions contain activated T cells and antigen presenting MHC class II-positive dendritic cells. In primary CNS and peripheral nerve vasculitic lesions, the predominant infiltrate is one of CD4-positive and CD8-positive T lymphocytes and monocytes [17].

In large vessel vasculitides, specific antigen targets are more poorly defined, but cell-mediated reactions appear fundamental to the pathogenesis [18]

The clinical features of CNS vasculitis

Focal or multifocal infarction or diffuse ischaemia, affecting any part of the brain, occurring acutely, sub-acutely, recurrently or chronically, explain the protean manifestations, wide variation in disease activity, course and severity and the absence of a pathognomic or even typical clinical picture. Most accounts of both primary and secondary intracranial vasculitis describe headaches, focal or generalised 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. Systemic features such as fever, night sweats, livedo reticulares or oligoarthropathy may also be present (though very often revealed only on direct questioning). In consequence, the differential diagnosis is vast: many different types of inflammatory disorder, infections, vasculopathies and tumours can present in clinically identical fashion.

Three ‘broad-brush’ clinical phenotypes (carrying neither pathological nor therapeutic implications) have, however, been suggested, with the aim of helping to improve suspicion and recognition of CNS vasculitis [19]:
  1. 1.

    Acute or subacute encephalopathy, commonly presenting as an acute confusional state, progressing to drowsiness and coma;

     
  2. 2.

    Superficially resembling atypical multiple sclerosis (MS-plus) in phenotype, commonly, a relapsing remitting course, with features such as optic neuropathy and brain stem episodes, but also accompanied by other features less common in MS—seizures, headaches, encephalopathic episodes or hemispheric stroke-like events; and

     
  3. 3.

    Intracranial mass lesion, with headache, drowsiness, focal signs and often elevated intracranial pressure, now well described in much greater detail [20].

     

Diagnosis and management

Suspicion of the process having been entertained, possibly through recognising either of the first patterns mentioned above, further diagnosis in possible cerebral vasculitis involves three stages: exclusion of other possibilities, confirmation of intracranial vasculitis and then pursuit of the cause of this vasculitic process. Plainly, an understanding of the nature and spectrum of these causes and contexts of cerebral vasculitis is fundamental to diagnosis and will be summarised briefly before describing an approach to investigation.
  1. 1.

    Isolated granulomatous CNS vasculitis

     
Here, as mentioned already, the process is ostensibly limited to the CNS, though the clinical features are not, insofar as fever, weight loss, lassitude etc. are common. The neurological features (non-specific as they are) of vasculitis limited to the CNS are as outlined above. Two eponymous non-systemic primary disorders may involve the CNS. Cogan’s syndrome is an unusual disorder, mostly affecting young adults, characterised by recurrent episodes of interstitial keratitis and/or scleritis with vestibulo-auditary 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.
  1. 2.

    Primary systemic vasculitides with neurological involvement

     

Each of the various systemic vasculitides carries its own defining clinical and pathological characteristics. All may be complicated by neurological involvement. Constitutional disturbance—fever, night sweats, severe malaise, weight loss—is common to all, 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 causing saddle nose deformity), sinuses, larynx, trachea and lungs. Ocular involvement may occur; renal disease occurs in 80% of patients. c-ANCA testing is positive, with proteinase-3 specificity, and the biopsy is characteristic, with a necrotising, granulomatous vasculitis. Neurological involvement occurs in between 10% and 35% of patients [21], but most commonly involves the PNS rather than the CNS. Meningeal and middle ear disease may lead to significant cranial neuropathies (especially of the seventh and eighth nerves). Gadolinium-enhanced MR scanning may valuably reveal meningeal thickening and infiltration, offering a ready target for biopsy. Ocular involvement may occur with orbital pseudotumour. Cerebral small-vessel vasculitis is rare, but when it does occur is usually responsible for encephalopathies, seizures and pituitary abnormalities. More likely is the unique contiguous extension of erosive granulomata from the sinuses or from remote metastatic granulomata to the CNS.

Microscopic polyangiitis is a multisystem small vessel vasculitis which has many similarities to Wegener’s granulomatosis, including pulmonary haemorrhage, but differs in that upper respiratory tract involvement is rare and granuloma formation is not seen. Patients usually have glomerulonephritis and indeed this vasculitis is occasionally confined to the kidney. One study found mononeuritis multiplex in 55% [22]; 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, requiring aggressive therapy.

Classical polyarteritis nodosa is now recognised as an unusual disorder which may cause medium and small-sized muscular artery involvement in multiple organs, with the notable exception of the lungs and spleen. Patients often present with renal failure and hypertension (80%). Gastrointestinal involvement occurs in up to 50%, with abdominal pain due to visceral infarcts. Heart failure and myocardial infarction reflect cardiac involvement. Neurological abnormalities are prominent (50–60%), but again mostly confined to the PNS. It is thought that damage is initiated by immune complex deposition; fibrinoid necrosis is typical though not diagnostic. Although there are no specific serological tests, about 20% to 30% have hepatitis B antigen or antibody in serum. Almost uniquely, visceral angiography is diagnostically useful, showing aneurysms or occlusions of the visceral arteries.

Churg-Strauss syndrome is characterised 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% [23]. About 50% of patients are positive for p-ANCA and 25% positive for c-ANCA, but 25% have no antineutrophil cytoplasmic antibodies.

Small vessel vasculitis usually affects post-capillary venules. The skin is most commonly involved, usually with purpura or urticaria; the frequent presence of an allergic precipitant has led historically to the term hypersensitivity vasculitis often being 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, ranging from up to 70% of classical polyarteritis nodosa and microscopic polyangiitis, to 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 as a secondary phenomenon, i.e. as a consequence of hypertensive or uraemic encephalopathy, steroid or cytotoxic drug therapy or electrolyte imbalance. Suspected cerebral vasculitis, while reported as a complication, with supportive MRI changes has never to this author’s knowledge been confirmed with tissue proof of the process. (The numerous reports in the literature of ‘cerebral vasculitis in Henoch-Schönlein purpura’ bear striking witness to the common acceptance of angiography or even conventional MRI as a means of diagnosing CNS vasculitis.)

Kawasaki disease, (mucocutaneous lymph node syndrome) usually affects children under 12 years. It has an incidence of less than five per 100,000 in the UK, but is at least 20 times as common in Japan where it was first described in 1967. Coronary artery aneurysms occur in a fifth of untreated cases, which 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. There is a possible role for anti-endothelial cell antibodies in the pathogenesis.
  1. 3.

    Secondary vasculitis: a complication of classically non-vasculitic systemic disorders

     

Autoimmune and inflammatory disease

Perhaps confusingly in an already complex area, vasculitis can occur as a direct complication of a wide variety of inflammatory and autoimmune conditions whose primary histopathological characteristic is not vasculitic.

Systemic lupus erythematosus (SLE) is a classical example. Neurological or psychiatric symptoms in SLE are common (40–50%) [24], and very well described, but by far the most frequent neuropathological finding is that of a non-inflammatory vasculopathy of small arterioles and capillaries, with resulting microinfarcts and microhaemorrhages. Histopathological studies have consistently demonstrated that vasculitis of the cerebral vessels is rare, with an incidence of 7–13%. Serology forms the mainstay of diagnosis.

Sarcoidosis affects the nervous system in only 5% of cases, commonly presenting with optic and other cranial neuropathies (especially involving the facial nerve) usually due to granulomatous meningeal and brainstem infiltration. Sarcoidosis may also be complicated by systemic vasculitis affecting small or large calibre vessels in a similar fashion to other vasculitides, with angiographic and indeed clear histological evidence of CNS vasculitis. Serum ACE and calcium levels are not always raised. CSF abnormalities are seen in 80%, usually with an elevated protein and pleocytosis, and oligoclonal bands are positive in about 45% of cases. Cranial MRI shows non-specific multiple white matter lesions or meningeal enhancement; whole body gallium scanning can be more useful, demonstrating a characteristic pattern of uptake (particularly affecting the parotid glands and lungs). More recently, PET scanning has proved useful [25]. Pathological diagnosis by Kveim test is no longer carried out in most countries (because it involves injecting human material); biopsy of cerebral or meningeal tissue provides the most reliable basis for treatment [26].

Seropositive rheumatoid disease is a well-recognised precipitant of cerebral vasculitis [24], though skin involvement and mononeuritis multiplex are far more typical manifestations of rheumatoid vasculitis. There are unusual reports of CNS angiitis in the context of systemic sclerosis, Sjögren’s syndrome and mixed connective tissue disease, even (though rarely) without a preceding history of systemic symptoms.

Cryoglobulinaemia can cause hyperviscosity and may trigger immune-complex deposition-related vasculitis (especially in association with hepatitis C infection), particularly mixed cryoglobulinaemia. Renal, joint and skin involvement with purpura progressing to necrotic ulceration is often seen. Peripheral neuropathy occurs in 22–32%, in particular as mononeuritis multiplex, with leukocytoclastic vasculitis on biopsy. The CNS is rarely affected.

Behçet’s disease is predominantly caused by vasculitis affecting small- and medium-sized vessels.

Infections

At least three mechanisms are implicated in vasculitis related to infection: direct invasion of the vessel wall, immune complex deposition, and secondary cryoglobulinaemia. The association of hepatitis C infection with cryoglobulinaemia and small vessel vasculitis is mentioned earlier; other infections, including hepatitis B, Epstein Barr virus and cytomegalovirus (CMV), Lyme disease and syphilis, malaria and coccidiomycosis all have also been linked to mixed cryoglobulinaemia.

Numerous infectious agents have been implicated in primary invasion of the vascular wall, a more direct infection-associated vasculitis [27]. Aspergillus, histoplasma and coccidioides are among the fungal causes usually confined to immune suppressed patients—though this includes diabetes mellitus. In HIV infection, CMV and toxoplasma may precipitate vasculitis, and syphilitic cerebral vasculitis (in the context of HIV) has also re-emerged. Bacterial causes of meningoencephalitis, mycobacteria pneumococci and H influenzae, may also trigger intracranial vasculitis.

One infection that deserves particular attention in this context is herpes zoster ophthalmicus. This can cause secondary, localised CNS vasculitis affecting the ipsilateral hemisphere, probably by direct viral invasion of blood vessels [28], producing single or multiple smooth-tapered segmental narrowing on angiography. The characteristic clinical picture, seen in approximately 0.5% cases, is that of an acute monophasic hemiparesis contralateral to the (usually by now resolving) ocular disease. The latent period may last from days to months, but is usually of the order of 3–4 weeks. A CSF mononuclear pleocytosis and raised varicella-zoster antibody titre aid the diagnosis. A more generalised necrotising and granulomatous vasculitis can also occur.

Complications of shingles may affect children similarly, though there have been less frequent reports of chickenpox triggering cerebral vasculitis. Occasionally only the spinal cord is involved in herpetic disease; rarely more generalised vasculitis may occur with ophthalmic or remote zoster infection.

Chronic viral infection with parvovirus B19 has been implicated in polyarteritis nodosa, Kawasaki disease, and Wegener’s granulomatosis, though causality is far from proven [27]. Tuberculosis-associated vasculitis may be driven by tuberculoprotein immune complexes. Hepatitis B, Epstein-Barr virus, CMV, Lyme disease, syphilis and malaria cause vasculitis by a similar mechanism, while in coccidiomycosis, vascular inflammation may be directly related to infection, or occur via cryoglobulinaemia.

Spores of the dimorphic fungus Coccidioides immitis, endemic to Southwestern USA 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, has been observed in up to 40% of these cases, and rarely subarachnoid haemorrhage.

Malignancy, lymphomatoid granulomatosis and malignant angioendothelioma

Leukocytoclastic vasculitis may occur in association with various cancers as a paraneoplastic phenomenon. CNS disease in the context of Hodgkin’s disease with a pathological picture indistinguishable from conventional isolated CNS angiitis is reported. Lymphomatoid granulomatosis is a lymphomatous disorder centred on the vascular wall, with destructive change and secondary inflammatory infiltration lending the appearance of true vasculitis; the infiltrating neoplastic cell is of T lymphocyte derivation. Cutaneous and pulmonary involvement is common, with nodular cavitating lung infiltrates, and neurological manifestations in 25–30% of cases; they are the presenting feature in approximately 20%. Neoplastic or malignant angioendotheliosis is also a rare, nosologically separate disorder, wherein the neoplastic process is intravascular, i.e. within the lumen, and the lymphomatous cells B cell derived, characteristically not invading the vascular wall. The neurological features of both disorders are similar and largely those of cerebral vasculitic disease; in malignant angioendotheliomatosis lung involvement is unusual, but characteristic skin manifestations occur.

Drug and toxin-induced cerebral vasculitis

The most compelling evidence of a direct association relates to amphetamines, with clinical and histological evidence of multisystem necrotising vasculitis [29]. This usually but not invariably requires repeated amphetamine exposure. However, in many other reports of drug-associated vasculitis there is no tissue confirmation, and the diagnosis of ‘vasculitis’ is based on angiography, despite the fact that vasospasm can cause identical angiographic changes. Certainly, in cocaine abuse, the significantly increased risk of ischaemic stroke results from vasospasm (probably from increased catecholamine release), and very seldom from any form of vasculitis [30]. In intravenous abuse, co-injected contaminants such as hepatitis C may cause vasculitis.

Rarely, an immune reaction against (spontaneous) amyloid deposits within the cerebral vasculature appears to precipitate a true CNS vasculitis, a recently described disorder which has been termed A-beta-related angiitis [8].

The investigation of suspected CNS vasculitis

First line investigations

No single simple investigation can confirm a diagnosis of cerebral vasculitis; some can exclude it. Anaemia, a non-specific leukocytosis, and elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein levels are often present. Some authorities have stipulated a normal ESR to be a defining feature of primary angiitis of the central nervous system (PACNS); others report moderately elevated values in two thirds of patients [31]. Serological testing (ANA, ANCA etc.) is vital to exclude lupus or help define any systemic origin of an established intracranial vasculitis, but is of little value in confirming or refuting isolated cerebral vasculitis. ‘False’ ANCA positivity is sometimes seen in connective tissue disorders such as lupus, and rarely in individuals with no apparent vasculitic disorder at all.

Cerebrospinal fluid analysis is non-specific but again useful in providing support or otherwise for an inflammatory process within the CNS, and importantly for helping to exclude infection and malignancy. Pooled case reviews suggest an elevation in cell count (mainly a lymphocytosis) and protein in 50–80% [3133], while the opening pressure is raised in almost 50%. CSF oligoclonal immunoglobulin bands have been studied infrequently, but are also found in up to 50% [19]). Oligoclonal band patterns which vary substantially on repeat testing, perhaps disappearing altogether, point away from multiple sclerosis, should this be part of the differential diagnosis.

Radiography

Magnetic resonance imaging (MRI) is a sensitive but not specific detector of vascular disease [34], 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. Correlation between MR changes and blood vessel involvement may be poor: in one study, of 50 territories affected by vasculitis on contrast angiography, at least one third were normal on MRI [35]. Other reports describe cases of definite cerebral vasculitis with normal MR imaging. Neither the disclosure of cerebral microbleeds nor diffusion weighting offer specificity for vasculitis, though both may be of value in monitoring established disease [36,37].

SPECT appears to be a useful but non-specific imaging tool, again mirroring but not defining a vasculitic process [19]. FDG-PET scanning may be of great value in disclosing large vessel vasculitis [38], but a role in CNS disease is yet to be clarified.

Magnetic resonance angiography is also finding a niche in imaging large vessel vasculitides such as Takayasu’s arteritis and classical PAN, with potential to supplant contrast angiography [39], but does not enjoy sufficient resolution to offer great value in medium or small vessel cranial vasculitis.

Establishing the diagnostic value of contrast angiography is complicated by the many studies which have used this as the ‘gold standard’ for confirmation. Publications based on pathological proof of the disease, however, show a false negative rate of 30–40% [32,33], and there are published examples of patients with histologically proven PACNS with normal angiograms, probably explained by the affected vessels being beyond the resolution of conventional imaging.

When abnormalities are present, they include segmental (often multifocal) narrowing with areas of localised dilatation or beading. Single stenotic areas in multiple vessels are more frequent than multiple stenotic areas along a single vessel segment in PACNS. Retrospective series suggest a sensitivity of only 24–33% [33,40], with a specificity of a similar order; an enormous number of inflammatory, metabolic, malignant or other vasculopathies can accurately mimic angiitis. Some authors have reported a risk of transient (10%) or permanent neurological deficit (1%) [41]. As long as its non-specific nature is recognised, contrast angiography remains a valuable investigational tool, helpful in building (or otherwise) a case for biopsy, and also in more definitively diagnosing certain non-vasculitic disorders, including moyamoya and fibromuscular dysplasia.

Indium-labelled white cell nuclear scanning has a limited role, particularly in disclosing areas of (sometimes unsuspected) systemic inflammation [19].

Opthalmological examination

Careful ocular examination, including slit lamp study, forms a vital part of the assessment of patients with suspected cerebral vasculitis. Sub-clinical 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.

Histopathology

Histopathological confirmation, biopsying an abnormal area of brain where relevant and safe, or alternatively by ‘blind’ biopsy of meninges and (usually non-dominant temporal) white and grey matter, is crucially important. Biopsy may reveal an underlying process not otherwise suspected with profound therapeutic implications, such as infective or neoplastic (principally lymphomatous) vasculopathies, but is not a trivial procedure, carrying a risk of serious morbidity estimated at 0.5–2%. Sensitivity is limited to (at best) approximately 70% [32,33,40]. Nevertheless, the significant risk means that up to 75% of reported cases are ‘diagnosed’ without histopathology [3].

A retrospective study of some 61 patients biopsied for suspected cerebral vasculitis valuably illuminated this topic [40]. No patients suffered any significant morbidity as a result of the procedure. Thirty-six per cent of patients were confirmed as having cerebral vasculitis, but equally importantly, 39% biopsies showed an alternative, unsuspected diagnosis—lymphoma (six cases), multiple sclerosis (two cases) or infection (seven cases, including toxoplasmosis, herpes and also two cases of cerebral abscess). Many of these non-vasculitic disorders are treatable, often indeed curable, while inappropriate treatment with steroids alone, or with more potent immunosuppressive agents, would at best have no useful effect, and very often, serious adverse consequences. Biopsy failed to yield a clear diagnosis in 25% of patients in this study, though even here, the result has at least helped partially to exclude some of the alternative diagnoses mentioned earlier. The decision not to biopsy must be balanced against the harmful effects of immunosuppressive drugs.

A vasculitic process having been confirmed, the specific defining characteristics of the primary and secondary vasculitides must be painstakingly sought (see earlier discussion).

The treatment of cerebral vasculitis

Notwithstanding the problems in recognition and diagnosis, cerebral vasculitis is considered a highly treatable condition. Prospective controlled randomised trials could not be conducted because of the rarity of the condition and the absence of unifying diagnostic criteria [42]. Retrospective analyses have been our main tool, and from this, together with lessons from systemic vasculitides [43] has emerged significant support for the use of steroids with cyclophosphamide in confirmed cases [42].

In biopsy-proven cerebral vasculitis, we believe a reasonable induction regime should commence with high-dose steroids—e.g. intravenous methyl prednisolone, 1 g daily for 3 days, followed by oral prednisolone 60 mg/day, decreasing by 10 mg at weekly intervals to 10 mg/day if possible. This should be coupled from the outset with cyclophosphamide 2.5 mg/kg (lower dose of 2 mg/kg in the elderly or in renal failure) per day. This induction combination continues for 9–12 weeks. Pulsed weekly intravenous cyclophosphamide appears not to differ 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 of the cyclophosphamide dose if there is leucopoenia (total wbc count falling to below 4.0 × 109) or neutropoenia (below 2.0 × 109).

Cyclophosphamide is associated with haemorrhagic cystitis (a complication reduced by adequate hydration and MESNA cover), a 33-fold increase in bladder cancer, other malignancies, infertility, cardiotoxicity and pulmonary fibrosis and hair loss. In a study of 145 patients treated with this agent for systemic Wegener’s disease, and followed for a total of 1,333 patient-years, non-glomerular haematuria occurred in approximately 50%, the majority of whom had macroscopic changes consistent with cyclophosphamide-induced bladder injury on cystoscopy. Seven of these (and none without haematuria) developed transitional cell bladder carcinoma; six had had a total cumulative dose in excess of 100 g cyclophosphamide, and a duration of oral treatment exceeding 2.7 years [44].

The maintenance phase of treatment, converting to a regime of alternate day steroids (10–20 mg prednisolone), and substituting azathioprine (2 mg/kg/day) for cyclophosphamide, is commenced after induction, and continued for a further 10 months; it is then gradually withdrawn. Azathioprine is thought to be 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 regime mentioned earlier 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. Intravenous immunoglobulin (0.4 mg/kg/day for 5 days), with its good safety record, has been found useful in cases of systemic vasculitis, though may induce only partial remission [45].

Plasmapheresis may be valuable in cryoglobulinaemia. It is also considered in severe life-threatening disease (e.g. pulmonary haemorrhage and severe glomerulonephritis) with 7–10 treatments over 14 days [46]. 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-α, are generating much excitement as novel therapies in various inflammatory diseases including the vasculitides, though paradoxically, the induction of vasculitis has also been reported with various of these agents [4751]. Interferon-α can control not only hepatitis C-associated hepatitis, but also cryoglobulinaemia and vasculitis. Unfortunately, there is regular relapse within months of treatment withdrawal (Fig 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs00281-009-0183-2/MediaObjects/281_2009_183_Fig1_HTML.jpg
Fig. 1

The histological appearance of isolated CNS angiitis

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