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The Spectrum of CNS Vasculitis in Children and Adults Marinka Twilt and Susanne M

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The Spectrum of CNS Vasculitis in Children and Adults Marinka Twilt and Susanne M REVIEWS The spectrum of CNS vasculitis in children and adults Marinka Twilt and Susanne M. Benseler Abstract | Children and adults who present with severe, newly acquired neurological or psychiatric deficits should be evaluated for an underlying inflammatory brain disease—the inflammation could be reversible, if diagnosed and treated rapidly. In our experience, primary angiitis of the central nervous system (PACNS) is the most common inflammatory brain disease and is increasingly recognized across patients of all ages. Distinct disease subtypes have been reported with characteristic disease courses, neuroimaging features and histopathological findings. In this Review, we provide a comprehensive comparison of childhood and adult PACNS, revealing distinct gender distributions, characteristic presenting clinical phenotypes and tailored differential diagnosis evaluations in the different subtypes of PACNS. Novel and traditional laboratory markers can help to define disease subtype and activity, whilst MRI and angiography can aid diagnosis in both children and adults. Characteristic patterns of parenchymal lesions and vessel involvement have been identified in PACNS and differ markedly between subtypes. Brain histopathology has also revealed distinct inflammatory pathways at different ages. Immunosuppressive treatment protocols have been shown to be effective and safe across the age spectrum; overall, in the past few years, the mortality of PACNS has decreased dramatically. Twilt, M. & Benseler, S. M. Nat. Rev. Rheumatol. 8, 97–107 (2012); published online 20 December 2011; doi:10.1038/nrrheum.2011.197 Introduction Diagnosis Primary angiitis of the central nervous system (PACNS) Primary CNS vasculitis subtypes is an increasingly recognized condition in the expand- The diagnosis of PACNS is based on the diagnostic cri- ing spectrum of inflammatory brain diseases in both teria proposed by Calabrese and Mallek:7 these include children and adults.1–3 PACNS was first described in a newly acquired neurological deficit; specific angio- adults in 1959.4 Most historical cases are characterized graphic and/or histopathological features of angiitis by granulomatous inflammation of the cerebral arter- within the CNS; and no evidence of an underlying sys- ies with fatal outcomes.4–6 Calabrese and Mallek7 first temic disorder that explains the features.7 These criteria reviewed the adult literature and proposed diagnostic were adopted for childhood PACNS with the addition of criteria for PACNS in 1988. Since then, numerous pedi- a newly developed psychiatric deficit and the age limit atric and adult case series and cohorts have been reported. of ≤18 years of age at diagnosis.8 However, these cases can represent the most severe end of the spectrum with regard to PACNS, suffer from poten- Childhood PACNS tial publication bias and, thus, can underestimate the true In children, three distinct disease entities in the spec- incidence of pediatric and adult PACNS as only the worst trum of childhood PACNS are currently recognized. cases are often published. These include the two large-vessel diseases—namely In clinical practice, the cut-off point of 18 years of age is ­angiography-positive nonprogressive childhood PACNS arbitrary; this age definition is used to differentiate adult and progressive childhood PACNS, and the small-vessel from childhood PACNS and can influence both diagnostic entity, angiography-negative small-vessel childhood evaluation and treatment choices. In fact, no studies have PACNS.1 In general in CNS vasculitis, the description ever compared the two age groups to explore if differences ‘large vessel’ or ‘medium-to-large’ refers to all vascular occur in the clinical presentation, histopathology, treat- seg­ments visible on angio­graphy, whereas ‘small vessel’ Division of ment response and disease course in adults and children. refers to those vessel diameters solely detectable on brain Rheumatology, Department of Disease phenotypes can occur independent of age group- histo­logy. All children with PACNS have so far been Pediatrics, The Hospital ing. This Review compares presenting features of adult assigned to one category (large-vessel [angiography-­ for Sick Children, University of Toronto, and pediatric patients with PACNS, provides a diagnostic positive] or small-vessel [angiography-negative] vasculi- 555 University Avenue, approach and summarizes the evidence-based treatment tis) exclusively; a girl, described in 2001 by Lanthier and Toronto, ON M5G 1X8, 9 Canada (M. Twilt, recommendations. The wide differential diagnosis of colleagues, with angiographic evidence of a single steno- S. M. Benseler). PACNS in both children and adults will also be discussed. sis of the middle cerebral artery plus evidence of vasculitis on brain biopsy is the only published exception to this Correspondence to: S. M. Benseler Competing interests categoriza­tion. Of importance to note is that the use of susanne.benseler@ The authors declare no competing interests. the terminology of ‘large vessel’ for all cerebral vessels is sickkids.ca NATURE REVIEWS | RHEUMATOLOGY VOLUME 8 | FEBRUARY 2012 | 97 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Key points patients who had evidence of vasculitis on both modali- ties and therefore overlapped diagnostic categories. All ■■ Inflammatory brain diseases can affect males and females of all ages; in our experience, primary angiitis of the central nervous system (PACNS) is the most adult series include substantial numbers of patients who common type did not have a confirmatory test (angiography or brain ■■ Distinct disease subtypes have been identified in children and adults with biopsy) ac­cording to the Calabrese criteria.5 PACNS and found to be associated with typical demographic characteristics Some clinicians distinguish spinal cord involvement, ■■ Newly acquired neurological or psychiatric deficits in children and adults tumor-like lesions, or amyloid protein deposit angiitis mandate an evaluation for an underlying inflammatory brain disease as subgroups of PACNS.12–17 In the past, ‘benign angio­ ■ Diagnosis of inflammatory brain diseases should include a thorough clinical ■ pathy of the central nervous system’ described by Hajj- evaluation, targeted laboratory investigations and specific parenchymal and 18 vascular neuroimaging techniques, including vessel wall imaging and, Ali et al. was considered a separate PACNS subgroup. if required, an elective brain biopsy In 2011, this entity was re-classified as ‘reversible cere- ■■ The comparison of PACNS in children and adults has revealed major differences bral vasoconstriction syndrome’ (RCVS) and is now con­ in classification strategies, clinical phenotypes, inflammatory markers, sidered a noninflammatory vasospastic disease.19 Singhal neuroimaging characteristics and inflammatory pathways et al.19 described 139 RCVS cases, reporting a female pre- ■■ Evaluated treatment regimens are available for childhood PACNS and treatment dominance and presentation with thunderclap headache recommendations are now available for adult PACNS in 85% of patients. Cerebral angiographic abnormalities normalized within 2 months of diagnosis. A good clini- cal outcome was reported in 90% of patients.19 As symp- dis­cordant from the Chapel Hill classifications for vascu- toms are overlapping and RCVS can mimic PACNS on litis, in which only the aorta and its major branches are angiography, distinguishing these disease entities early considered large vessels.10 in the disease course is important as the outcome and treatment differ markedly. Early repeat of neuroimaging Adult PACNS with a possible role for vessel wall enhancement should In the literature pertaining to adult patients, PACNS be considered in a patient with high suspicion of RCVS. classifications differ between studies. The US Cleveland Clinic cohort and initial literature review by Calabrese Demographic characteristics and Mallek7 defined PACNS categories by evidence of PACNS can develop at any age and can affect both men characteristic findings of vasculitis on angiography and/or and women. In adults, PACNS predominantly occurs brain biopsy. The authors of this study recognized the between the fourth and sixth decades of life.14 In chil- limited specificity of angiographic findings in adults, dren, no specific age distribution has been reported given potential confounding by arteriosclerosis or other for PACNS—disease onset can be at any age until, by vascular processes. Calabrese and Mallek7 reported definition, 18 years of age.1 Interestingly, a male pre- angio­graphy descriptors and proposed associated test dominance exists in angiography-positive childhood prob­abilities. Patients with a high clinical suspicion and PACNS, which corresponds to the male predominance negative or ‘low probability’ angiographic findings fre- in childhood stroke.20 By contrast, angiography-negative, quently had additional brain biopsies performed. This biopsy-positive­ small-vessel childhood PACNS has an process led to identification of a group of patients who had overwhelming female predominance.21,22 In adults, more both findings from angio­graphy and brain biopsy samples females are reported to develop angiography-positive supporting the diagnosis of PACNS. Overall, Calabrese PACNS, although, in angiography-negative disease, the and Mallek7 reported patients with PACNS in categories genders are affected equally.3,11 No ethnic predominance of classic, abnormal, or normal on angiography, in addi- has yet been
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