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
ReviewPrimary angiitis of the CNS
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
References (74)
- et al.
Isolated angiitis of the central nervous system. Prospective diagnostic and therapeutic experience
Am J Med
(1983) - et al.
Anti-abeta therapeutics in Alzheimer's disease: the need for a paradigm shift
Neuron
(2011) Primary (granulomatous) angiitis of the central nervous system: a clinicopathologic analysis of 15 new cases and a review of the literature
Hum Pathol
(1992)- et al.
Recurrent varicella zoster virus myelopathy
J Neurol Sci
(2009) - et al.
[Central nervous system angiitis excluding systemic diseases]
Rev Med Interne
(1998) Classification and histopathologic spectrum of central nervous system vasculitis
Neurol Clin
(1997)- et al.
Treatment of small vessel primary CNS vasculitis in children: an open-label cohort study
Lancet Neurol
(2010) - et al.
Noninfectious granulomatous angiitis with a predilection for the nervous system
Neurology
(1959) - 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) - et al.
Primary angiitis of the central nervous system
Curr Treat Options Neurol
(2007)
Primary central nervous system vasculitis: analysis of 101 patients
Ann Neurol
Primary angiitis of the central nervous system
Arch Neurol
Primary Angiitis of the Central Nervous System
Clin Exp Rheumatol
Narrative review: reversible cerebral vasoconstriction syndromes
Ann Intern Med
Imaging of cerebral vasculitis
Int J Stroke
MR imaging and angiography of primary CNS vasculitis of childhood
AJNR Am J Neuroradiol
Central nervous system vasculitis in children
Curr Rheumatol Rep
Vasculitis in the central nervous system
Arthritis Rheum
Primary central nervous system vasculitis: reflections on 20 years of investigation
Clin Exp Rheumatol
Angiitis of the central nervous system
Curr Opin Rheumatol
Vasculitis of the nervous system
Curr Opin Neurol
Tumour-like mass lesion: an under-recognised presentation of primary angiitis of the central nervous system
Ann Rheum Dis
Central nervous system vasculitis
Curr Opin Rheumatol
Stereotactic biopsy of non-neoplastic lesions in adults
Clev Clin J Med
Magnetic resonance angiography in reversible cerebral vasoconstriction syndromes
Ann Neurol
Cerebral amyloid angiopathy presenting as a mass lesion
Stroke
Clinical manifestations of cerebral amyloid angiopathy-related inflammation
Ann Neurol
Familial oculoleptomeningeal amyloidosis associated with primary angiitis of the CNS
Neurology
Cerebral amyloid angiopathy with granulomatous angiitis ameliorated by steroid-cytoxan treatment
Clin Neuropharmacol
Primary central nervous system vasculitis with prominent leptomeningeal enhancement: a subset with a benign outcome
Arthritis Rheum
Angiography-negative primary central nervous system vasculitis: a syndrome involving small cerebral vessels
Medicine (Baltimore)
Mechanism of multiple infarcts in multiple cerebral circulations on diffusion-weighted imaging
J Neurol
Significance of acute multiple brain infarction on diffusion-weighted imaging
Stroke
Association of ischemic lesion patterns on early diffusion-weighted imaging with TOAST stroke subtypes
Arch Neurol
The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients
Brain
Reversible cerebral vasoconstriction syndromes: analysis of 139 cases
Arch Neurol
Postpartum angiopathy with reversible posterior leukoencephalopathy
Arch Neurol
Cited by (271)
Cerebral vasculitis as a complication of pneumococcal meningitis: A cohort study
2023, Infectious Diseases NowAssociation of remnant cholesterol with intracranial atherosclerosis in community-based population: The ARIC study
2023, Journal of Stroke and Cerebrovascular DiseasesPleocytosis in cerebrospinal fluid attributed to ischemic stroke: A review of the literature
2023, Journal of the Neurological SciencesVessel Wall Imaging in Cryptogenic Stroke
2023, Radiologic Clinics of North AmericaPrimary angiitis of central nervous system – A challenging diagnosis
2022, Journal of Neuroimmunology