Elsevier

The Lancet Neurology

Volume 10, Issue 6, June 2011, Pages 561-572
The Lancet Neurology

Review
Primary angiitis of the CNS

https://doi.org/10.1016/S1474-4422(11)70081-3Get rights and content

Summary

Meaningful progress in our understanding and clinical approach to primary angiitis of the CNS (PACNS) has been made in the past three decades. Increased recognition of PACNS and general advances in diagnosis of neurological disorders have led to an aggressive diagnostic approach and a proliferation of case reports providing enriched clinical and pathological descriptions. We have witnessed major advances not only in the diagnosis of PACNS but in the recognition of its mimics. Epidemiological, clinical, neuroradiagnostic, and laboratory findings have enhanced our diagnostic accuracy and recognition of PACNS mimics, however, many challenges to our understanding and management of the disease in children and adults remain.

Introduction

Primary angiitis of the CNS (PACNS) is a rare disorder resulting in inflammation and destruction of CNS vessels without evidence of vasculitis outside the CNS. This disorder was first considered a distinct clinical entity in 1959 by Cravioto and Feigin.1 PACNS remained rare, with only 46 cases reported in peer-reviewed English-language publications by 1986.2 Since then, with increased awareness and recognition of the disease and the widespread application of diagnostic criteria proposed by Calabrese and Mallek2 in 1988, the number of reported cases has risen substantially, with over 450 cases described by 2007.3 In the same year, the largest single-centre series (101 cases from the Mayo Clinic, Rochester, MN, USA) brought the total to well over 500 cases worldwide.4 Despite these additional cases, few reports have included patient series in excess of ten cases. We do not yet have an integrated view of the clinical picture of PACNS for various reasons, including a scarcity of prospective multicentre registries with meaningful data. Additionally, in view of the many single-case and small series reports, a bias towards new or unusual features is probable.

PACNS is poorly understood, and formidable challenges to our understanding and management of the disease remain: few clinicians are highly experienced with the disease, the clinical presentations are non-specific, we lack highly efficient non-invasive modalities for diagnosis, no useful animal models exist to aid our understanding of the disease, and no randomised trials of treatments have been done. Despite such limitations, substantial progress has been made including growing recognition of a specific constellation of epidemiological, clinical, neuroradiograhic, and laboratory findings that could enhance diagnostic accuracy.5 A clear view of multiple clinical and pathological disease subtypes with prognostic implications within the spectrum of PACNS is now accepted.6 Our ability to recognise and diagnose diseases that mimic PACNS has improved, especially with the general acceptance of reversible cerebral vasoconstrictive syndrome (RCVS),7 a confounder of many early case series of PACNS and the most common diagnostic mimic. Advances in diagnostic neuroimaging, especially indirect angiography, seem promising.8 The specialty of childhood PACNS has rapidly matured.9 We review the main advancements in the clinical, diagnostic, and therapeutic approaches to adult and childhood PACNS. Moreover, we discuss the main diseases that mimic PACNS and review the substantial progress made in our clinical approach to PACNS, despite vast limitations. In view of several excellent reviews of PACNS,5, 6 we will attempt to review this topic with an emphasis on those areas that have the greatest effect on clinical management.

Section snippets

Diagnostic criteria and clinical features

Diagnostic criteria for PACNS were proposed over 20 years ago (panel 1),2 and recently adopted for childhood PACNS.10 Although unvalidated, these criteria have been used widely for clinical reporting and investigation.11 Birnbaum and Hellman5 have suggested incorporation of definite and probable diagnostic subcategories. Implicit and explicit changes in the application of these criteria have occurred with advances in diagnostic testing, the elucidation of PACNS mimics, both new and old, and the

Disease subtypes

Initial attempts at subclassification of PACNS described three broad subtypes: GACNS, benign angiopathy of the CNS (BACNS), and atypical PACNS.11 The most clinically significant advance in our understanding of BACNS is its recognition as a vasospastic disorder rather than as a subtype of PACNS, and BACNS is now subsumed by the umbrella term of RCVS. Atypical PACNS has previously been used to refer to patients who did not clearly meet criteria for either GACNS or RCVS. This terminology remains

Differential diagnosis

An accurate and timely diagnosis of PACNS remains challenging in the absence of confirmatory serological tests and the limited sensitivity and specificity of CSF examination, cerebral angiography, and brain biopsy. A common pitfall is to start immunosuppressive treatment without establishment of diagnosis or exclusion of other diseases that can mimic PACNS (panel 2). Indeed, the extremely low annual incidence of PACNS (2·4 cases per million patient-years4) makes consideration of alternative

Diagnostic assessments

Several modalities are available to assist in the diagnosis of PACNS. Critical assessment of the diagnostic sensitivity and specificity of these modalities and their role in excluding mimics of PACNS in patients with qualified pathological or angiographical findings is important.

Childhood PACNS

Primary CNS vasculitis in children is an important consideration in the workup of childhood vascular strokes.60 Childhood PACNS is confined to the CNS by contrast with secondary CNS vasculitis occurring in the setting of systemic vasculitis, systemic lupus erythematosus, infections, metabolic diseases such as mitochondrial diseases, malignancies, radiotherapy, and drug exposure.61, 62 This disease was thought to be rare; however, evidence suggests that childhood PACNS could be an important

Treatment of adult PACNS

The optimum modes of assessing disease activity and monitoring treatment remain gaps in our understanding. Unlike in RCVS, appearance of changes on serial angiography might not substantially improve but could merely stabilise.51 CSF abnormalities (ie, increased concentrations of cells and proteins), when present, do improve,72 but this effect has not been studied on a large-scale in terms of timing and concordance with global disease activity.

Clinical signs and symptoms are problematic when

Conclusions

Meaningful progress in our understanding and clinical approach to PACNS has been made in the past three decades. From the early 1980s, when the total number of cases described was less than 30, increased recognition of PACNS and general advances in diagnosis of neurological disorders have led to an aggressive diagnostic approach and a proliferation of case reports providing more enriched clinical and pathological descriptions.

The criteria proposed by Calabrese and Mallek2 have promoted the

Search strategy and selection criteria

We searched PubMed from October, 1950, to April, 2011, using the terms “cerebral angiopathy”, “central nervous system vasculitis”, “reversible cerebral vasoconstrictive syndrome”, and “primary angiitis of the central nervous system”. Articles were also identified through searches of the authors' own files and abstracts presented at the American College of Rheumatology. We also searched Medline and Embase, using the OVID system, for articles about childhood primary angiitis of the CNS with

References (74)

  • C Salvarani et al.

    Primary central nervous system vasculitis: analysis of 101 patients

    Ann Neurol

    (2007)
  • J Birnbaum et al.

    Primary angiitis of the central nervous system

    Arch Neurol

    (2009)
  • A Neel et al.

    Primary Angiitis of the Central Nervous System

    Clin Exp Rheumatol

    (2009)
  • LH Calabrese et al.

    Narrative review: reversible cerebral vasoconstriction syndromes

    Ann Intern Med

    (2007)
  • W Kuker

    Imaging of cerebral vasculitis

    Int J Stroke

    (2007)
  • RI Aviv et al.

    MR imaging and angiography of primary CNS vasculitis of childhood

    AJNR Am J Neuroradiol

    (2006)
  • SM Benseler

    Central nervous system vasculitis in children

    Curr Rheumatol Rep

    (2006)
  • LH Calabrese et al.

    Vasculitis in the central nervous system

    Arthritis Rheum

    (1997)
  • L Calabrese

    Primary central nervous system vasculitis: reflections on 20 years of investigation

    Clin Exp Rheumatol

    (2009)
  • JT Lie

    Angiitis of the central nervous system

    Curr Opin Rheumatol

    (1991)
  • DS Younger

    Vasculitis of the nervous system

    Curr Opin Neurol

    (2004)
  • ES Molloy et al.

    Tumour-like mass lesion: an under-recognised presentation of primary angiitis of the central nervous system

    Ann Rheum Dis

    (2008)
  • RA Hajj-Ali et al.

    Central nervous system vasculitis

    Curr Opin Rheumatol

    (2009)
  • DM Whiting et al.

    Stereotactic biopsy of non-neoplastic lesions in adults

    Clev Clin J Med

    (1992)
  • SP Chen et al.

    Magnetic resonance angiography in reversible cerebral vasoconstriction syndromes

    Ann Neurol

    (2010)
  • CE Briceno et al.

    Cerebral amyloid angiopathy presenting as a mass lesion

    Stroke

    (1987)
  • JA Eng et al.

    Clinical manifestations of cerebral amyloid angiopathy-related inflammation

    Ann Neurol

    (2004)
  • JD Dowell et al.

    Familial oculoleptomeningeal amyloidosis associated with primary angiitis of the CNS

    Neurology

    (2007)
  • TI Mandybur et al.

    Cerebral amyloid angiopathy with granulomatous angiitis ameliorated by steroid-cytoxan treatment

    Clin Neuropharmacol

    (1992)
  • C Salvarani et al.

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

    Arthritis Rheum

    (2008)
  • C Salvarani et al.

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

    Medicine (Baltimore)

    (2008)
  • AH Cho et al.

    Mechanism of multiple infarcts in multiple cerebral circulations on diffusion-weighted imaging

    J Neurol

    (2007)
  • JK Roh et al.

    Significance of acute multiple brain infarction on diffusion-weighted imaging

    Stroke

    (2000)
  • DW Kang et al.

    Association of ischemic lesion patterns on early diffusion-weighted imaging with TOAST stroke subtypes

    Arch Neurol

    (2003)
  • A Ducros et al.

    The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients

    Brain

    (2007)
  • AB Singhal et al.

    Reversible cerebral vasoconstriction syndromes: analysis of 139 cases

    Arch Neurol

    (2011)
  • AB Singhal

    Postpartum angiopathy with reversible posterior leukoencephalopathy

    Arch Neurol

    (2004)
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