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.
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 common type
Distinct disease subtypes have been identified in children and adults with PACNS and found to be associated with typical demographic characteristics
Newly acquired neurological or psychiatric deficits in children and adults mandate an evaluation for an underlying inflammatory brain disease
Diagnosis of inflammatory brain diseases should include a thorough clinical evaluation, targeted laboratory investigations and specific parenchymal and vascular neuroimaging techniques, including vessel wall imaging and, if required, an elective brain biopsy
The comparison of PACNS in children and adults has revealed major differences in classification strategies, clinical phenotypes, inflammatory markers, neuroimaging characteristics and inflammatory pathways
Evaluated treatment regimens are available for childhood PACNS and treatment recommendations are now available for adult PACNS
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Benseler, S. M. et al. Primary central nervous system vasculitis in children. Arthritis Rheum. 54, 1291–1297 (2006).
Kraemer, M. & Berlit, P. Primary central nervous system vasculitis: clinical experiences with 21 new European cases. Rheumatol. Int. 31, 463–472 (2011).
Salvarani, C. et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann. Neurol. 62, 442–451 (2007).
Cravioto, H. & Feigin, I. Noninfectious granulomatous angiitis with a predilection for the nervous system. Neurology 9, 599–609 (1959).
Mc, C. H. & Neubuerger, K. T. Giant-cell arteritis involving small meningeal and intracerebral vessels. J. Neuropathol. Exp. Neurol. 17, 471–478 (1958).
Newman, W. & Wolf, A. Non-infectious granulomatous angiitis involving the central nervous system. Trans. Am. Neurol. Assoc. 56, 114–117 (1952).
Calabrese, L. H. & Mallek, J. A. Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore) 67, 20–39 (1988).
Benseler, S. M. Central nervous system vasculitis in children. Curr. Rheumatol. Rep. 8, 442–449 (2006).
Lanthier, S. et al. Isolated angiitis of the CNS in children. Neurology 56, 837–842 (2001).
Jennette, J. C. et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 37, 187–192 (1994).
MacLaren, K., Gillespie, J., Shrestha, S., Neary, D. & Ballardie, F. W. Primary angiitis of the central nervous system: emerging variants. QJM 98, 643–654 (2005).
Salvarani, C. et al. Primary CNS vasculitis with spinal cord involvement. Neurology 70, 2394–2400 (2008).
Molloy, E. S., Singhal, A. B. & Calabrese, L. H. Tumour-like mass lesion: an under-recognised presentation of primary angiitis of the central nervous system. Ann. Rheum. Dis. 67, 1732–1735 (2008).
Neel, A. & Pagnoux, C. Primary angiitis of the central nervous system. Clin. Exp. Rheumatol. 27 (Suppl. 52), S95–S107 (2009).
Salvarani, C. et al. Primary central nervous system vasculitis: comparison of patients with and without cerebral amyloid angiopathy. Rheumatology (Oxford) 47, 1671–1677 (2008).
Schwab, P., Lidov, H. G., Schwartz, R. B. & Anderson, R. J. Cerebral amyloid angiopathy associated with primary angiitis of the central nervous system: report of 2 cases and review of the literature. Arthritis Rheum. 49, 421–427 (2003).
Scolding, N. J. et al. Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain 128, 500–515 (2005).
Hajj-Ali, R. A., Furlan, A., Abou-Chebel, A. & Calabrese, L. H. Benign angiopathy of the central nervous system: cohort of 16 patients with clinical course and long-term followup. Arthritis Rheum. 47, 662–669 (2002).
Singhal, A. B. et al. Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch. Neurol. 68, 1005–1012 (2011).
Golomb, M. R., Fullerton, H. J., Nowak-Gottl, U. & Deveber, G. Male predominance in childhood ischemic stroke: findings from the international pediatric stroke study. Stroke 40, 52–57 (2009).
Benseler, S. M. et al. Angiography-negative primary central nervous system vasculitis in children: a newly recognized inflammatory central nervous system disease. Arthritis Rheum. 52, 2159–2167 (2005).
Hutchinson, C. et al. Treatment of small vessel primary CNS vasculitis in children: an open-label cohort study. Lancet Neurol. 9, 1078–1084 (2010).
Sen, E. S. et al. Treatment of primary angiitis of the central nervous system in childhood with mycophenolate mofetil. Rheumatology (Oxford) 49, 806–811 (2010).
Gallagher, K. T. et al. Primary angiitis of the central nervous system in children: 5 cases. J. Rheumatol. 28, 616–623 (2001).
Yaari, R. et al. Childhood primary angiitis of the central nervous system: two biopsy-proven cases. J. Pediatr. 145, 693–697 (2004).
De Tiege, X. et al. Primary angiitis of the central nervous system: neurologic deterioration despite treatment. Pediatrics 127, e1086–e1090 (2011).
Bitter, K. J., Epstein, L. G., Melin-Aldana, H., Curran, J. G. & Miller, M. L. Cyclophosphamide treatment of primary angiitis of the central nervous system in children: report of 2 cases. J. Rheumatol. 33, 2078–2080 (2006).
Volcy, M., Toro, M. E., Uribe, C. S. & Toro, G. Primary angiitis of the central nervous system: report of five biopsy-confirmed cases from Colombia. J. Neurol. Sci. 227, 85–89 (2004).
Salvarani, C. et al. Angiography-negative primary central nervous system vasculitis: a syndrome involving small cerebral vessels. Medicine (Baltimore) 87, 264–271 (2008).
Salvarani, C. et al. Rapidly progressive primary central nervous system vasculitis. Rheumatology (Oxford) 50, 349–358 (2011).
Salvarani, C. et al. Primary central nervous system vasculitis with prominent leptomeningeal enhancement: a subset with a benign outcome. Arthritis Rheum. 58, 595–603 (2008).
Chenevier, F. et al. Primary angiitis of the central nervous system: response to mycophenolate mofetil. J. Neurol. Neurosurg. Psychiatry 80, 1159–1161 (2009).
Myung, J. et al. B-cell dominant lymphocytic primary angiitis of the central nervous system: four biopsy-proven cases. Neuropathology 30, 123–130 (2010).
Cellucci, T., Pullenayegum, E., Tyrell, P. N. & Benseler, S. M. von Willebrand factor antigen—a novel biomarker of disease activity in childhood CNS vasculitis [abstract 1537]. Arthritis Rheum. 60 (Suppl. 10), S573–S574 (2009).
Calabrese, L. H., Duna, G. F. & Lie, J. T. Vasculitis in the central nervous system. Arthritis Rheum. 40, 1189–1201 (1997).
Ford-Jones, E. L. et al. Acute childhood encephalitis and meningoencephalitis: diagnosis and management. Paediatr. Child. Health 3, 33–40 (1998).
Graus, F. et al. The expanding clinical profile of anti-AMPA receptor encephalitis. Neurology 74, 857–859 (2010).
Graus, F., Saiz, A. & Dalmau, J. Antibodies and neuronal autoimmune disorders of the CNS. J. Neurol. 257, 509–517 (2010).
Dalmau, J. et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 7, 1091–1098 (2008).
Luca, N. et al. Anti-N-methyl-D-aspartate receptor encephalitis: A newly recognized inflammatory brain disease in children. Arthritis Rheum. 63, 2516–2522 (2011).
Aviv, R. I. et al. MR imaging and angiography of primary CNS vasculitis of childhood. AJNR Am. J. Neuroradiol. 27, 192–199 (2006).
Gomes, L. J. The role of imaging in the diagnosis of central nervous system vasculitis. Curr. Allergy Asthma Rep. 10, 163–170 (2010).
White, M. L. & Zhang, Y. Primary angiitis of the central nervous system: apparent diffusion coefficient lesion analysis. Clin. Imaging 34, 1–6 (2010).
Kuker, W. et al. Vessel wall contrast enhancement: a diagnostic sign of cerebral vasculitis. Cerebrovasc. Dis. 26, 23–29 (2008).
Scolding, N. Can diffusion-weighted imaging improve the diagnosis of CNS vasculitis? Nat. Clin. Pract. Neurol. 3, 608–609 (2007).
Willinsky, R. A. et al. Neurologic complications of cerebral angiography: prospective analysis of 2,899 procedures and review of the literature. Radiology 227, 522–528 (2003).
Cloft, H. J. et al. Correlation of angiography and MR imaging in cerebral vasculitis. Acta Radiol. 40, 83–87 (1999).
Eleftheriou, D. et al. Investigation of childhood central nervous system vasculitis: magnetic resonance angiography versus catheter cerebral angiography. Dev. Med. Child. Neurol. 52, 863–867 (2010).
Aviv, R. I. et al. Angiography of primary central nervous system angiitis of childhood: conventional angiography versus magnetic resonance angiography at presentation. AJNR Am. J. Neuroradiol. 28, 9–15 (2007).
Lie, J. T. Primary (granulomatous) angiitis of the central nervous system: a clinicopathologic analysis of 15 new cases and a review of the literature. Hum. Pathol. 23, 164–171 (1992).
Coffey, R. J., Lunsford, L. D. & Taylor, F. H. Survival after stereotactic biopsy of malignant gliomas. Neurosurgery 22, 465–473 (1988).
Javedan, S. P. & Tamargo, R. J. Diagnostic yield of brain biopsy in neurodegenerative disorders. Neurosurgery 41, 823–828 (1997).
Alrawi, A., Trobe, J. D., Blaivas, M. & Musch, D. C. Brain biopsy in primary angiitis of the central nervous system. Neurology 53, 858–860 (1999).
Venkateswaran, S., Hawkins, C. & Wassmer, E. Diagnostic yield of brain biopsies in children presenting to neurology. J. Child. Neurol. 23, 253–258 (2008).
Miller, D. V. et al. Biopsy findings in primary angiitis of the central nervous system. Am. J. Surg. Pathol. 33, 35–43 (2009).
Elbers, J., Halliday, W., Hawkins, C., Hutchinson, C. & Benseler, S. M. Brain biopsy in children with primary small-vessel central nervous system vasculitis. Ann. Neurol. 68, 602–610 (2010).
Tamargo, R. J. et al. Clinicopathological review: primary angiitis of the central nervous system in association with cerebral amyloid angiopathy. Neurosurgery 53, 136–143 (2003).
Nogueras, C. et al. Recurrent stroke as a manifestation of primary angiitis of the central nervous system in a patient infected with human immunodeficiency virus. Arch. Neurol. 59, 468–473 (2002).
Alreshaid, A. A. & Powers, W. J. Prognosis of patients with suspected primary CNS angiitis and negative brain biopsy. Neurology 61, 831–833 (2003).
Panda, K. M., Santosh, V., Yasha, T. C., Das, S. & Shankar, S. K. Primary angiitis of CNS: neuropathological study of three autopsied cases with brief review of literature. Neurol. India 48, 149–154 (2000).
Wong, S. H., Robbins, P. D., Knuckey, N. W. & Kermode, A. G. Cerebral amyloid angiopathy presenting with vasculitic pathology. J. Clin. Neurosci. 13, 291–294 (2006).
Hajj-Ali, R. A. Primary angiitis of the central nervous system: differential diagnosis and treatment. Best Pract. Res. Clin. Rheumatol. 24, 413–426 (2010).
Gilden, D. H., Kleinschmidt-DeMasters, B. K., LaGuardia, J. J., Mahalingam, R. & Cohrs, R. J. Neurologic complications of the reactivation of Varicella-Zoster virus. N. Engl. J. Med. 342, 635–645 (2000).
Kleinschmidt-DeMasters, B. K. & Gilden, D. H. Varicella-Zoster virus infections of the nervous system: clinical and pathologic correlates. Arch. Pathol. Lab. Med. 125, 770–780 (2001).
Rossi, C. M. & Di Comite, G. The clinical spectrum of the neurological involvement in vasculitides. J. Neurol. Sci. 285, 13–21 (2009).
Seror, R. et al. Central nervous system involvement in Wegener granulomatosis. Medicine (Baltimore) 85, 54–65 (2006).
Pomper, M. G., Miller, T. J., Stone, J. H., Tidmore, W. C. & Hellmann, D. B. CNS vasculitis in autoimmune disease: MR imaging findings and correlation with angiography. AJNR Am. J. Neuroradiol. 20, 75–85 (1999).
von Scheven, E., Lee, C. & Berg, B. O. Pediatric Wegener's granulomatosis complicated by central nervous system vasculitis. Pediatr. Neurol. 19, 317–319 (1998).
Nishino, H., Rubino, F. A., DeRemee, R. A., Swanson, J. W. & Parisi, J. E. Neurological involvement in Wegener's granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann. Neurol. 33, 4–9 (1993).
Moshous, D. et al. Primary necrotizing lymphocytic central nervous system vasculitis due to perforin deficiency in a four-year-old girl. Arthritis Rheum. 56, 995–999 (2007).
Nadeau, S. E. Neurologic manifestations of systemic vasculitis. Neurol. Clin. 20, 123–150 (2002).
Dale, R. C., Brilot, F. & Banwell, B. Pediatric central nervous system inflammatory demyelination: acute disseminated encephalomyelitis, clinically isolated syndromes, neuromyelitis optica, and multiple sclerosis. Curr. Opin. Neurol. 22, 233–240 (2009).
Pardo, C. A. et al. The pathology of Rasmussen syndrome: stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia 45, 516–526 (2004).
Florance, N. R. et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann. Neurol. 66, 11–18 (2009).
Tsiodras, S., Kelesidis, I., Kelesidis, T., Stamboulis, E. & Giamarellou, H. Central nervous system manifestations of Mycoplasma pneumoniae infections. J. Infect. 51, 343–354 (2005).
Cross, A. H. & Golumbek, P. T. Neurologic manifestations of celiac disease: proven, or just a gut feeling? Neurology 60, 1566–1568 (2003).
Kirton, A., Diggle, J., Hu, W. & Wirrell, E. A pediatric case of reversible segmental cerebral vasoconstriction. Can. J. Neurol. Sci. 33, 250–253 (2006).
Kasapcopur, O. et al. Cogan's syndrome: a rare vasculitis in childhood. J. Rheumatol. 27, 1824–1825 (2000).
Kundell, S. P. & Ochs, H. D. Cogan syndrome in childhood. J. Pediatr. 97, 96–98 (1980).
Sneddon, I. B. Cerebro-Vascular Lesions and Livedo Reticularis. Br. J. Dermatol. 77, 180–185 (1965).
Kraemer, M. & Berlit, P. Primary central nervous system vasculitis and moyamoya disease: similarities and differences. J. Neurol. 257, 816–819 (2010).
Begelman, S. M. & Olin, J. W. Fibromuscular dysplasia. Curr. Opin. Rheumatol. 12, 41–47 (2000).
Aoki, S. et al. Radiation-induced arteritis: thickened wall with prominent enhancement on cranial MR images report of five cases and comparison with 18 cases of Moyamoya disease. Radiology 223, 683–688 (2002).
Testai, F. D. & Gorelick, P. B. Inherited metabolic disorders and stroke part 2: homocystinuria, organic acidurias, and urea cycle disorders. Arch. Neurol. 67, 148–153 (2010).
Testai, F. D. & Gorelick, P. B. Inherited metabolic disorders and stroke part 1: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Arch. Neurol. 67, 19–24 (2010).
Cellucci, T. & Benseler, S. M. Central nervous system vasculitis in children. Curr. Opin. Rheumatol. 22, 590–597 (2010).
Siva, A. Vasculitis of the nervous system. J. Neurol. 248, 451–468 (2001).
Kraemer, M. & Berlit, P. Systemic, secondary and infectious causes for cerebral vasculitis: clinical experience with 16 new European cases. Rheumatol. Int. 30, 1471–1476 (2010).
Berlit, P. Diagnosis and treatment of cerebral vasculitis. Ther. Adv. Neurol. Disord. 3, 29–42 (2010).
Amlie-Lefond, C. et al. Predictors of cerebral arteriopathy in children with arterial ischemic stroke: results of the International Pediatric Stroke Study. Circulation 119, 1417–1423 (2009).
Berlit, P. Isolated angiitis of the CNS and bacterial endocarditis:similarities and differences. J. Neurol. 256, 792–795 (2009).
Shahane, A., Khasnis, A. & Hajj Ali, R. Three unusual mimics of primary angiitis of the central nervous system. Rheumatol. Int. http://dx.doi.org/10.1007/s00296-010-1679-1678.
Kalyoncu, U. et al. Familial Mediterranean fever and central nervous system involvement: a case series. Medicine (Baltimore) 89, 75–84 (2010).
The histopathology images were kindly provided and reviewed by Dr C. Hawkins from The Hospital for Sick Children, Toronto, Canada.
The authors declare no competing financial interests.
About this article
Cite this article
Twilt, M., Benseler, S. The spectrum of CNS vasculitis in children and adults. Nat Rev Rheumatol 8, 97–107 (2012). https://doi.org/10.1038/nrrheum.2011.197
“When should primary angiitis of the central nervous system (PACNS) be suspected?”: literature review and proposal of a preliminary screening algorithm
Neurological Sciences (2020)
Journal of Neurology (2019)
Pediatric Rheumatology (2018)
InFo Neurologie & Psychiatrie (2015)
Current Treatment Options in Rheumatology (2015)