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Table of Contents    
Year : 2019  |  Volume : 67  |  Issue : 1  |  Page : 115-117

Primary central nervous system vasculitis in India – need for a multicenter prospective cohort study

Division of Neurology, Department of Medicine, Queen's University, Kingston, ON, Canada

Date of Web Publication7-Mar-2019

Correspondence Address:
Dr. Garima Shukla
76 Stuart Street, #02.704, Connell 7, Kingston, ON
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.253600

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How to cite this article:
Appireddy R, Shukla G. Primary central nervous system vasculitis in India – need for a multicenter prospective cohort study. Neurol India 2019;67:115-7

How to cite this URL:
Appireddy R, Shukla G. Primary central nervous system vasculitis in India – need for a multicenter prospective cohort study. Neurol India [serial online] 2019 [cited 2022 Oct 1];67:115-7. Available from: https://www.neurologyindia.com/text.asp?2019/67/1/115/253600

Primary central nervous system vasculitis (PCNSV) is a rare clinical condition with an estimated prevalence of 2.4 cases per 1 million patient years of follow-up based on data from an US Cohort.[1] PCNSV is characterized by inflammation and infiltration of blood vessels supplying the central nervous system (CNS) structures (brain, spinal cord, cranial nerves and leptomeninges) in the absence of systemic inflammation.[2],[3] Small and medium sized arteries are most commonly involved in PCNSV compared to venous structures. The etiology and pathogenesis of how the inflammation in PCNSV is triggered and sustained is not well understood.[2] The inflammation of CNS vasculature can result in a range of structural changes in the vessel well resulting in luminal narrowing, obliteration with resulting ischemia and/or infarction in the supplied territory as well as vessel wall ectasia/dehiscence/rupture resulting in hemorrhage. The resulting clinical features from ischemia and/or hemorrhage can range from very nonspecific symptoms like headache, confusion, to focal neurological deficits (hemiplegia, hemisensory disturbances, dysarthria, aphasia, ataxia, visual field deficits), seizures, rapidly progressive dementia, and encephalopathy.[3] Systemic constitutional symptoms like fever, weight loss, night sweats are usually not prominent, and presence of a significant constitutional symptom profile should raise the suspicion of secondary vasculitis. The tempo of symptom onset and progression is typically subacute but occasional cases of acute onset are known. PCNSV should be suspected in select clinical situations [Table 1]. The fairly extensive differential diagnosis of PCNSV is one of the challenges in diagnosing this condition.[4]
Table 1: Clinical scenarios that may lead to the suspicion of primary central nervous system vasculitis[4]

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In clinical practice, the most common clinical conditions that present with temporally separated ischemia/infarction in multiple vascular territories are proximal cardioembolic stroke mechanisms, prothrombotic states like antiphospholipid antibodies as well as diffuse intracranial atherosclerosis. No single laboratory or diagnostic imaging test exists that reliably diagnoses PCNSV. The diagnosis of PCNSV is made using a combination of clinical features along with compatible laboratory, diagnostic imaging and/or pathological findings AND having ruled out all secondary causes. Peripheral blood serological tests as well as cerebrospinal fluid analysis are crucial for ruling out a majority of secondary causes.[2],[5] The peripheral acute inflammatory markers like erythrocystic sedimentation rate (ESR) and C-reactive protein are often normal in PCNSV. The cerebrospinal fluid (CSF) abnormalities in the form of pleocytosis and/or elevated proteins are seen in up to 80-90% of cases and often remain abnormal during the course of the disease. A normal CSF examination has a high negative predictive value for PCNSV.[4] The CSF abnormalities are, however, non-specific, and emphasis should always be placed on ruling out secondary infectious and neoplastic pathology in cases with abnormal CSF. Reversible cerebral vasoconstriction syndrome (RCVS) is a much commoner clinical condition than PCVS and mimics it closely clinically and on diagnostic imaging. A normal CSF examination in RCVS is an important clue to its differentiation.[4] The radiological workup would involve the neuro-angiographic workup. Magnetic resonance imaging (MRI) is superior to a computed tomographic scan (CT scan) for identifying the parenchymal abnormalities (acute, subacute and chronic infarcts; microbleeds and old hemorrhages; other PCNSV mimics like lymphoma, tumors, etc.) as well as for localization of abnormalities. CT angiography (CTA) offers a better resolution in general than MR angiography (MRA), but both are inferior to a digital subtraction angiogram (DSA) for evaluation of the small and medium caliber arteries in the brain. MRA may be considered a reasonable option for non-invasive follow-up of stable patients diagnosed with PCNSV. Brain biopsy is considered the gold standard for diagnosing PCNSV. In addition to identifying the pathological subtype of inflammation (lymphocytic, granulomatous and necrotizing), it helps in ruling out other pathologies like lymphoma, infection, tumors, etc., The morbidity of brain biopsy (0.03-2%) is acceptable given the implications on diagnostic confirmation as the well side-effect profile of long term immunosuppression/cytotoxic therapy.[6]

Targeted biopsy (biopsy of abnormal areas on MRI) and adequate surgical sampling (open wedge of 1cm 3 involving white and grey matter, sampling of leptomeninges and cortical vessels) increases the yield of the biopsy.

The strength of epidemiological evidence to guide in the management of PCNSV is weak due to the paucity of rigorous and robust clinical trials. The current practice is mostly guided by evidence from retrospective cases series and expert consensus. This is not unusual given the rarity of the condition. The cornerstone of the treatment involves immunosuppression to induce remission and sustain it using glucocorticoids (oral prednisone or intravenous pulse steroids). Addition of cyclophosphamide (oral or intravenous) is recommended in cases with a sub-optimal response, disease relapse, or steroid intolerance. Switching to a less toxic steroid sparing regimen using azathioprine, methotrexate, and mycophenolate mofetil is also suggested by the European League Against Rheumatism (EULAR). In the French PCNSV registry, the addition of another immunosuppressant (cyclophosphamide mainly) in the induction phase has shown to achieve remission in 95% of cases. The combination immunosuppression (glucocorticoids with another agent, azathioprine most commonly) has also shown better functional results during the follow-up period.[7] Interested readers are referred to the recently published literature on PCNSV for additional reading.[2],[3],[4],[5],[7],[8],[9],[10]

The study by Sundaram et al., is a significant contribution to the existing literature on PCNSV from an Indian perspective.[11] The study highlights some very crucial aspects of PCNSV. The study highlights the rarity of this condition with only a limited number of cases diagnosed over a span of 15 years in a high-volume tertiary neuroscience referral center in India along with some of the challenges in the diagnostic workup and therapeutic management. Certain features of the cohort, like the delayed presentation from symptom-onset (median: 48 days), and a higher prevalence of headache (24%) and seizures (18%) highlight the well described subacute nature of the condition as well as presence of non-focal neurological symptoms. The study cohort also had isolated involvement of small vessels (27%) and medium vessels (10%) on digital subtraction angiography (DSA), highlighting the utility of using DSA over CTA/MRA for diagnosing small and medium sized vasculitis. The authors reinforce the known variability in angiographic appearance of the PCNSV spectrum with 29% of cases having a normal DSA and the need for further invasive workup like brain biopsy in suspected cases. The authors also noted the higher diagnostic utility of targeted biopsy, highlighting the role of comprehensive diagnostic workup before invasive testing. The definition of relapse used by the French PCNSV registry is “new neurological event associated with new significant radiological abnormality.”[7] The definition used by the authors in the current study seems different from the French PCNSV definition and as such could have resulted in misclassification of the relapses. The 15.6% mortality noted in the study cohort is higher than that noted in the French PCSNV cohort (8%). Another notable difference is the cause of mortality in between these cohorts. The neurological deterioration was the predominant cause of death in the French cohort compared to the complications of immunosuppressive therapy in the Indian cohort.[7] This highlights the need for careful follow-up of patients on immunosuppression. The delay in onset-to-diagnosis and onset-to-treatment noted in the Indian cohort possibly highlights issues around lack of awareness and the diagnostic challenges in PCNSV and perhaps a higher threshold among physicians for more invasive work-up (DSA and/or brain biopsy) and initiating immunosuppressive therapy in this context.

A point of importance is the omission of information available from histopathologically proven cases and series of PCSNV, previously published from India.[12],[13] For a rare condition like this, collating all data available through a systematic review, could also possibly provide greater understanding of similarities and dissimilarities among different ethnic populations presenting with this disorder. This could aid in the designing of registries or other multicenter studies.

The authors duly acknowledge some of the limitations of the study. The predominantly retrospective chart review study design spanning 15 years, lends itself to significant biases with resulting measurement error and misclassification of exposure and outcome. Some considerations for future research include the selection of the outcome measures for PCNSV. Modified Rankin Scale is a standard stroke outcome measure used in clinical trials assessing various interventions and has been used for assessing functional outcome in PCNSV during the follow up period.[7] Perhaps, the use of additional outcome measures that assess the disease activity like high resolution 3-Tesla MRI with vessel wall imaging, in addition to measuring functional disability, offers more insights into the disease course as well as response to treatment.[14] The randomized controlled trial (RCT) design offers the highest quality of evidence about the efficacy of an intervention. However, designing and conducting an RCT for PCNSV offers logistic challenges due to the very low incidence and prevalence of PCNSV, diagnostic challenges and issues around the presence or lack of clinical equipoise about the efficacy of the various intervention arms amongst the clinicians. Alternatively, a well-designed multi-center prospective clinical trial of parallel arm interventions (glucocorticoids vs combination) stratified by disease severity and/or diagnostic imaging surrogate markers offers a better chance at identifying the optimal treatment strategy for this condition. The spectrum and variety of infectious and non-infectious neurological conditions seen in the Indian subcontinent is very different from those seen in the west. Going ahead, the prospect of setting up a well-designed multicenter prospective epidemiological study in India similar to the French cohort should be entertained by the authors and other researchers in this field. Carefully designed prospective observational epidemiological studies is the first step towards understanding the clinical profile and natural course of this uncommon clinical condition which can in turn result in design of effective therapeutic trials.

  References Top

Salvarani C, Brown RD Jr, Calamia KT, Christianson TJ, Weigand SD, Miller DV, et al. Primary central nervous system vasculitis: Analysis of 101 patients. Ann Neurol 2007;62:442-51.  Back to cited text no. 1
Limaye K, Samaniego EA, Adams HP Jr. Diagnosis and treatment of primary central nervous system angiitis. Curr Treat Options Neurol 2018;20:38.  Back to cited text no. 2
Beuker C, Schmidt A, Strunk D, Sporns PB, Wiendl H, Meuth SG, et al. Primary angiitis of the central nervous system: Diagnosis and treatment. Ther Adv Neurol Disord 2018;11:1756286418785071. doi: 10.1177/1756286418785071.  Back to cited text no. 3
Byram K, Hajj-Ali RA, Calabrese L. CNS vasculitis: An approach to differential diagnosis and management. Curr Rheumatol Rep 2018;20:37.  Back to cited text no. 4
Spence S, Ng D, Casault C. Atypical presentation of fulminant primary central nervous system angiitis. J Neuroimmunol 2019;330:1-4.  Back to cited text no. 5
Elbers J, Halliday W, Hawkins C, Hutchinson C, Benseler SM. Brain biopsy in children with primary small-vessel central nervous system vasculitis. Ann Neurol 2010;68:602-10.  Back to cited text no. 6
de Boysson H, Arquizan C, Touze E, Zuber M, Boulouis G, Naggara O, et al. Treatment and long-term outcomes of primary central nervous system vasculitis. Stroke 2018;49:1946-52.  Back to cited text no. 7
Tamaki H, Hajj-Ali RA. Therapeutic management of CNS vasculitis. Curr Treatt Options in Rheum 2017;3:220-9.  Back to cited text no. 8
Schuster S, Bachmann H, Thom V, Kaufmann-Buehler AK, Matschke J, Siemonsen S, et al. Subtypes of primary angiitis of the CNS identified by MRI patterns reflect the size of affected vessels. J Neurol, Neurosurg Psychiatry 2017;88:749-55.  Back to cited text no. 9
Mandal J, Chung SA. Primary angiitis of the central nervous system. Rheum Dis Clin North Am 2017;43:503-18.  Back to cited text no. 10
Sundaram S, Menon D, Khatri P, Sreedharan SE, Jayadevan ER, Sarma P, et al. Primary angiitis of the central nervous system: Clinical profiles and outcomes of 45 patients. Neurol India 2019;67:105-12.  Back to cited text no. 11
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Suri V, Kakkar A, Sharma MC, Padma MV, Garg A, Sarkar C. Primary angiitis of the central nervous system: A study of histopathological patterns and review of the literature. Folia Neuropathol 2014;52:187-96.  Back to cited text no. 12
Panda KM, Santosh V, Yasha TC, Das S, Shankar SK. Primary angiitis of CNS: neuropathological study of three autopsied cases with brief review of literature. Neurol India. 2000;48:149-54.  Back to cited text no. 13
Obusez EC, Hui F, Hajj-Ali RA, Cerejo R, Calabrese LH, Hammad T, et al. High-resolution MRI vessel wall imaging: Spatial and temporal patterns of reversible cerebral vasoconstriction syndrome and central nervous system vasculitis. AJNR American J Neuroradiol 2014;35:1527-32.  Back to cited text no. 14


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