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COMMENTARY |
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| Year : 2022 | Volume
: 25
| Issue : 6 | Page : 999-1000 |
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Primary angiitis of the central nervous system: A terra incognita
Rajesh Verma, Rajarshi Chakraborty
Department of Neurology, King George's Medical University, Lucknow, Uttar Pradesh, India
| Date of Submission | 14-Jul-2022 |
| Date of Acceptance | 14-Jul-2022 |
| Date of Web Publication | 08-Aug-2022 |
Correspondence Address:
Rajesh Verma
Professor, Department of Neurology, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/aian.aian_611_22
How to cite this article:
Verma R, Chakraborty R. Primary angiitis of the central nervous system: A terra incognita. Ann Indian Acad Neurol 2022;25:999-1000 |
Primary angiitis of the central nervous system (PACNS) represents a rare but important severe inflammatory vasculitis of brain, meninges, and/or spinal cord in the absence of any systemic vasculitis elsewhere.[1] Historical records dates back to early 20th century when Harbitz described an unknown form of angiitis affecting the central nervous system (CNS).[2] It was first proposed to be a distinct clinicopathological entity in 1959 by Cravioto and Feign who named it 'non-infectious granulomatous angiitis of CNS'.[3]
The estimated incidence rate of PACNS is 2.4 cases per million/year with equal sex distribution and median age of diagnosis at around 50 years.[4] In 1988, Calabrese and Mallek proposed the diagnostic criteria for PACNS, which comprised development of an acquired neurologic deficit not explained by any other process, presence of either an angiography with typical vasculitis features or CNS biopsy indicating vasculitis in the absence of systemic vasculitis or other mimcs.[5] A modification of these criteria was proposed by Birnbaum and colleagues in 2009 in order to prevent misdiagnosis, particularly in view of reversible cerebral vasoconstriction syndrome (RCVS).[6] The level of certainty in diagnosis was further divided into 'definite' in presence of biopsy-proven vasculitis, and 'probable' in high suspicious cases with evidence on angiogram without tissue confirmation.
The exact etiopathogenesis of PACNS is not yet elucidated. Infections like varicella zoster, mycoplasma, rickettsia, treponemas, human immunodeficiency virus are potentially postulated as triggering agents. However, these are also the mimics of the same condition.[7] Langford listed three possible mechanisms that could be involved in the pathogenesis of primary vasculitis syndromes: immune complex formation, anti-neutrophil cytoplasmic antibody production, and pathogenic T-lymphocyte responses with granuloma formation.[8] Significant CD45R0+ T cell infiltration from biopsied tissues reveal the role of T lymphocytes and antigen-specific immune response in its etiology. The medium and small vessels supplying brain, meninges, and spinal cord are largely affected transmurally by inflammatory cells with relative sparing of veins and venules. The affected blood vessel shows infiltration by T and B lymphocytes and plasma cells leading to vessel wall destruction and resultant stenosis with intimal proliferation. It leads to vaso-occlusive manifestations of brain and spinal cord. Histopathologically, granulomatous (most common), lymphocytic, and necrotizing inflammatory lesion are the three principal subtypes of PACNS.[9]
PACNS is divided into adult PACNS (age >18 years) and childhood PACNS (age <18 years). Adult PACNS is further classified into granulomatous ACNS (GACNS), benign ACNS (BACNS) [now excluded] and atypical PACNS (lymphocytic PACNS, angiographically defined PACNS, mass-lesion presentation and amyloid-b-related cerebral angitis).[10] Childhood PACNS is subdivided into large-medium vessel cPACNS (progressive and non-progressive) and small vessel cPACNS.[11] Clinical features are highly variable and nonspecific. Headache, cognitive impairment, focal neurological deficits, seizure, ataxia, diplopia, myelopathy are common initial presentations. Ischemic strokes and recurrent transient ischemic attacks are frequently encountered; however, hemorrhagic patterns are also noted to lesser incidence. Of note, PACNS should always be considered as a possible cause of rapidly progressive cognitive decline and personality changes of unknown etiology. There have been a few landmark studies till date at Mayo, France, and India which describes the clinico-laboratorical profile en toto.[4],[12],[13]
A plethora of diseases can mimic this condition, which needs to be explored out before labeling as PACNS. It includes infections, systemic vasculitis, demyelinating disorder, malignancies, drug and toxins, vasculopathies, hypercoagulable states, intracranial atherosclerotic disease, cryoglobulinemia, etc. Imaging of brain and spinal cord can detect the parenchymal and meningeal lesions extensively while the crux lies within the vascular imaging. Angiogram can detect arterial stenosis, fusiform dilatations, 'string of beads pattern', luminal irregularity, delayed contrast enhancement, early venous filling, attenuation of distal branches, and collateral formation in multiple vessels (predominant involving anterior circulation).[14] Newer advances in imaging techniques like TOF-MRA (time of flight), high-resolution MR vessel wall imaging (HRVWI) have better yield in visualizing the vessel characteristics of PACNS esp concentric wall thickening and enhancement.[15]
Biopsy is still regarded as the gold standard for the diagnosis of PACN, not only because it can confirm the presence of CNS vasculitis but also for excluding other causes.[16] Radiologically targeted biopsy from meninges and parenchymal tissues can yield better results. Cerebrospinal fluid analysis shows inflammatory pattern with pleiocytosis, elevated protein concentration and normal glucose in around 80-90% cases.[4]
Treatment guidelines are basically based on previous cohort studies, case series, and case reports as a randomized control trial is yet to be performed in PACNS. The initial induction phase is treated with combination therapy of glucocorticoid (intravenous pulse dose of 1g/day in adults or 30 mg/kg child body-weight/day for 3-5 days, followed by full dose of oral steroids for 4-6 weeks and a taper over total 6 months) with cyclophosphamide (monthly intravenous dose of 750 mg/m2 or daily oral dose of 2 mg/kg/day).[17] Rituximab therapy can be added in rapidly progressive PACNS for better outcome.[18] Azathioprine, mycophenolate mofetil, or methotrexate are the principal steroid-sparing immunomodulators to be given for maintenance therapy for a prolonged period and de-escalation of therapy can be planned based upon the clinical response and subsequent neuroimaging.[18]
The relapse rate is approximately 25-30% with mortality of 6-16%.[12] Patients can have a prolonged clinical course lasting years, additional flares can result in worsening of neurological deficits.[19] Predictors of poor outcome in PACNS are categorized under initial Modified Rankin Score >2, National Institutes of Health Stroke Scale >4, small-vessel vasculitis, and gadolinium enhancing lesions.[13]
In this article, the authors have tried to elucidate the evidence-based review of literature of PACNS. It is a relatively unexplored, yet important entity of nervous system.[20] The etiology and pathogenesis of this unusual vasculitis needs extensive research. The role of genetics in PACNS is yet to be focused. Newer diagnostic advancement for small vessel imaging and better biopsy targeting techniques will favor better detection. Meanwhile, a high degree of clinical suspicion, angiogram features, and/or CNS biopsy of vasculitis can lead to higher yield in diagnosing this rare entity. The relatively non-specific clinical features and a protean versatility of mimickers pose a challenge in diagnosis of this condition. Further, a randomized control study is mandatory and very much anticipated in coming future for predicting treatment, relapse, and mortality.
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