Elsevier

The Lancet

Volume 380, Issue 9843, 25–31 August 2012, Pages 767-777
The Lancet

Seminar
Adult primary central nervous system vasculitis

https://doi.org/10.1016/S0140-6736(12)60069-5Get rights and content

Summary

Primary CNS vasculitis is an uncommon disorder of unknown cause that is restricted to brain and spinal cord. The median age of onset is 50 years. The neurological manifestations are diverse, but generally consist of headache, altered cognition, focal weakness, or stroke. Serological markers of inflammation are usually normal. Cerebrospinal fluid is abnormal in about 80–90% of patients. Diagnosis is unlikely in the presence of a normal MRI of the brain. Biopsy of CNS tissue showing vasculitis is the only definitive test; however, angiography has often been used for diagnosis even though it has only moderate sensitivity and specificity. The size of the affected vessels varies and determines outcome and response to treatment. Early recognition is important because treatment with corticosteroids with or without cytotoxic drugs can often prevent serious outcomes. The differential diagnosis includes reversible cerebral vasoconstriction syndromes and secondary cerebral vasculitis.

Introduction

Primary CNS vasculitis is an uncommon and poorly understood vasculitis restricted to brain and spinal cord. Recognition of this disorder as a distinct nosological entity dates back to the mid-1950s when Cravioto and Feigin1 described several cases of non-infectious granulomatous angiitis associated with the nervous system.2 Since then, primary CNS vasculitis has been referred to as granulomatous angiitis of the CNS,3, 4 or more specifically, non-infectious5 or idiopathic6 granulomatous angiitis of the CNS, and giant-cell arteritis of the CNS,7 isolated angiitis of the CNS,8 primary angiitis of the CNS,9 and benign angiopathy of the CNS.10 Outcome in early reports was frequently fatal, and diagnosis was often made at autopsy.1, 2, 3, 5, 7, 11 By contrast, in later studies outcomes were more favourable, and biopsy and angiography were used for diagnosis.8, 9, 12 Primary CNS vasculitis needs to be differentiated from disorders that closely resemble it so that appropriate treatment can be provided.10, 13

Section snippets

Diagnostic criteria

Calabrese and Mallek9 proposed criteria for diagnosis of primary CNS vasculitis on the basis of clinical experience and evidence from published work. Diagnosis is made if all three of the following criteria are met: history or clinical findings of an acquired neurological deficit of unknown origin after a thorough initial basic assessment; cerebral angiogram with classic features of vasculitis, or a CNS biopsy sample showing vasculitis; and no evidence of systemic vasculitis or any other

Epidemiology

In the Mayo Clinic series,15 the incidence of primary CNS vasculitis in Olmsted County, MI, USA, was estimated to be 2·4 cases per 1 000 000 person-years, which is the only incidence information available. Primary CNS vasculitis occurs at the same frequency in men as in women.15, 25 The median age at diagnosis is about 50 years, and 50% of patients were between 37 and 59 years of age at diagnosis. Long-term survival is reduced in primary CNS vasculitis.15 Increased mortality has been linked to

Pathophysiology

The cause and pathogenesis of primary CNS vasculitis are unknown. Infectious agents have been proposed as triggers because of the well known association of cerebral vasculitis with infections—in particular varicella zoster virus (VZV).26 In fact, a wide array of infectious agents have been linked to vasculitis of CNS (panel).

Inoculation of turkeys intravenously with Mycoplasma gallisepticum induced cerebral vasculitis similar to primary CNS vasculitis,27 and in two cases of primary CNS

Histopathology

Primary CNS vasculitis is a vasculitis histologically affecting small and medium-sized leptomeningeal and parenchymal arterial vessels. Three main histopathological patterns are seen:23, 34 granulomatous, lymphocytic, and necrotising vasculitis. Granulomatous vasculitis is the most common (58%), showing vasculocentric mononuclear inflammation and well formed granulomas with multinucleated cells (figure 1A). β4 amyloid deposition is seen in almost 50% of biopsy specimens with this pattern (

Clinical manifestations

Clinical manifestations at diagnosis are non-specific, and many symptoms are usually present (table 1).12, 15, 25 The onset of disease can be acute, but it is more frequently insidious and slowly progressive. Diagnosis is made in 75% of patients within 6 months of the onset of symptoms. Headache, the most common symptom, can be generalised or localised, it often slowly worsens, can spontaneously remit for periods, and varies in severity. Cognitive impairment is also often insidious in onset,

Special subsets

Several subsets of primary CNS vasculitis have been identified that can differ in terms of prognosis and optimum management. Spinal cord abnormalities are implicated in about 5% of patients but are rarely the only manifestation.35 The thoracic cord is predominantly affected. Careful medical assessment should be undertaken to verify diagnosis of primary CNS vasculitis and to exclude other disorders associated with acute or subacute transverse myelitis.

Angiography-negative, biopsy-positive

Laboratory findings, electroencephalography, and imaging

Results of blood tests in patients with primary CNS vasculitis are usually normal, and consist of tests for acute-phase reactants, antinuclear antibodies, antineutrophil cytoplasm antibodies, and antiphospholipid antibodies.15, 25

CSF analysis is abnormal in 80–90% of patients.15 Changes consist of a mildly increased leucocyte count and total protein concentration. Patients with angiography-negative primary CNS vasculitis often have greatly raised protein concentrations.20 CSF analysis should be

Differential diagnosis

Primary CNS vasculitis should be differentiated from other similar disorders to avoid therapeutic and prognostic errors. The most common mimicker of primary CNS vasculitis is reversible cerebral vasoconstriction syndrome.

In 2007, reversible cerebral vasoconstriction syndrome was proposed as a collective name for various disorders that are characterised by brain vasoconstriction rather than by vasculitis13 (ie, Call-Fleming syndrome, post-partum angiopathy, migrainous vasospasm, drug-induced

Treatment and course

No randomised clinical trials of medical management in primary CNS vasculitis exist; therefore, treatment for primary CNS vasculitis has been derived from therapeutic strategies used in other vasculitides, from anecdotal reports, and from cohort studies. Earliest reports suggested a poor outlook with fatal outcome in most patients, and transient or doubtful effectiveness of glucocorticoids.4, 12, 100 Studies, including those by Cupps and colleagues,8 reported the effectiveness of

Future directions

Our understanding of primary CNS vasculitis and the delineation of its range and subsets has advanced, but we still need to clarify methods of diagnosis and optimum management. Biomarker and outcome investigations might identify risk factors for an aggressive course leading to treatment tailored to disease severity. Effectiveness and safety profiles of intravenous pulse and oral cyclophosphamide treatment, and clarification of which patients need cyclophosphamide at disease onset, need to be

Search strategy and selection criteria

We searched the Cochrane Library, Medline, and Embase with the search terms “vasculitis”, “angiitis”, or “angiopathy” in combination with the terms “central nervous system”, “cerebral”, or “intracranial”. We selected articles mostly in English from the past 5 years, without excluding older articles that we thought were highly relevant to this Seminar. We searched the reference lists of articles identified by this search and selected those that we judged relevant. We included some reviews

References (105)

  • B Tabarki et al.

    Kawasaki disease with predominant central nervous system involvement

    Pediatr Neurol

    (2001)
  • S Hirohata

    Histopathology of central nervous system lesions in Behçet's disease

    J Neurol Sci

    (2008)
  • SG Ellis et al.

    Central nervous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, 1955–1977

    Semin Arthritis Rheum

    (1979)
  • N Caballol Pons et al.

    Isolated cerebral vasculitis associated with rheumatoid arthritis

    Joint Bone Spine

    (2010)
  • RK Niemelä et al.

    Primary Sjögren's syndrome with severe central nervous system disease

    Semin Arthritis Rheum

    (1999)
  • WP Lawrence et al.

    Radiological manifestations of neurosarcoidosis. Report of three cases and review of the literature

    Clin Radiol

    (1974)
  • H Cravioto et al.

    Noninfectious granulomatous angiitis with a predilection for the nervous system

    Neurology

    (1959)
  • F Harbitz

    Unknown forms of arteritis, with special reference to their relation to syphilitic arteritis and periarteritis nodosa

    Am J Med Sci

    (1922)
  • R Sandhu et al.

    Granulomatous angiitis of the CNS

    Arch Neurol

    (1979)
  • W Newman et al.

    Non-infectious granulomatous angiitis involving the central nervous system

    Trans Am Neurol Assoc

    (1952)
  • TL Vollmer et al.

    Idiopathic granulomatous angiitis of the central nervous system: diagnostic challenges

    Arch Neurol

    (1993)
  • HM McCormick et al.

    Giant-cell arteritis involving small meningeal and intracerebral vessels

    J Neuropathol Exp Neurol

    (1958)
  • LH Calabrese et al.

    Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria

    Medicine (Baltimore)

    (1988)
  • LH Calabrese et al.

    Benign angiopathy: a distinct subset of angiographically defined primary angiitis of the central nervous system

    J Rheumatol

    (1993)
  • PM Moore

    Diagnosis and management of isolated angiitis of the central nervous system

    Neurology

    (1989)
  • LH Calabrese et al.

    Narrative review: reversible cerebral vasoconstriction syndromes

    Ann Intern Med

    (2007)
  • SM Benseler et al.

    Primary central nervous system vasculitis in children

    Arthritis Rheum

    (2006)
  • C Salvarani et al.

    Primary central nervous system vasculitis: analysis of 101 patients

    Ann Neurol

    (2007)
  • GF Duna et al.

    Limitations of invasive modalities in the diagnosis of primary angiitis of the central nervous system

    J Rheumatol

    (1995)
  • KG Harris et al.

    Diagnosing intracranial vasculitis: the roles of MR and angiography

    AJNR Am J Neuroradiol

    (1994)
  • J Birnbaum et al.

    Primary angiitis of the central nervous system

    Arch Neurol

    (2009)
  • RH Swartz et al.

    Intracranial arterial wall imaging using high-resolution 3-tesla contrast-enhanced MRI

    Neurology

    (2009)
  • Y Kadkhodayan et al.

    Primary angiitis of the central nervous system at conventional angiography

    Radiology

    (2004)
  • C Salvarani et al.

    Angiography-negative primary central nervous system vasculitis: a syndrome involving small cerebral vessels

    Medicine (Baltimore)

    (2008)
  • JE Parisi et al.

    The role of biopsy in vasculitis of the central nervous system

    Semin Neurol

    (1994)
  • DV Miller et al.

    Biopsy findings in primary angiitis of the central nervous system

    Am J Surg Pathol

    (2009)
  • A Alrawi et al.

    Brain biopsy in primary angiitis of the central nervous system

    Neurology

    (1999)
  • LH Calabrese et al.

    Vasculitis in the central nervous system

    Arthritis Rheum

    (1997)
  • MA Nagel et al.

    The varicella zoster virus vasculopathies: clinical, CSF, imaging, and virologic features

    Neurology

    (2008)
  • L Thomas et al.

    Studies of PPLO infection. I. The production of cerebral polyarteritis by Mycoplasma gallisepticum in turkeys; the neurotoxic property of the mycoplasma

    J Exp Med

    (1966)
  • G Arthur et al.

    Mycoplasma-like structures in granulomatous angiitis of the central nervous system. Case reports with light and electron microscopic studies

    Arch Pathol Lab Med

    (1977)
  • T Iwase et al.

    Involvement of CD45RO+ T lymphocyte infiltration in a patient with primary angiitis of the central nervous system restricted to small vessels

    Eur Neurol

    (2001)
  • PL Williams et al.

    Levels of matrix metalloproteinase-9 within cerebrospinal fluid in a rabbit model of coccidioidal meningitis and vasculitis

    J Infect Dis

    (2002)
  • C Salvarani et al.

    Primary central nervous system vasculitis: comparison of patients with and without cerebral amyloid angiopathy

    Rheumatology (Oxford)

    (2008)
  • DT Winkler et al.

    Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy

    J Neurosci

    (2001)
  • JA Eng et al.

    Clinical manifestations of cerebral amyloid angiopathy-related inflammation

    Ann Neurol

    (2004)
  • C Salvarani et al.

    Primary CNS vasculitis with spinal cord involvement

    Neurology

    (2008)
  • RA Hajj-Ali et al.

    Benign angiopathy of the central nervous system: cohort of 16 patients with clinical course and long-term followup

    Arthritis Rheum

    (2002)
  • AR Woolfenden et al.

    Angiographically defined primary angiitis of the CNS: is it really benign?

    Neurology

    (1998)
  • C Salvarani et al.

    Primary central nervous system vasculitis with prominent leptomeningeal enhancement: a subset with a benign outcome

    Arthritis Rheum

    (2008)
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