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Year : 2019  |  Volume : 67  |  Issue : 4  |  Page : 1043--1047

Neurological Manifestations Do not Affect Cumulative Survival in Indian Patients with Antineutrophil Cytoplasmic Antibody Associated Vasculitis

Aman Sharma1, Roopa Rajan2, Manish Modi2, Benzeeta Pinto1, Aadhaar Dhooria1, Manish Rathi3, Tarun Mittal3, Susheel Kumar4, Kusum Sharma4, Varun Dhir1, Ritambhra Nada5, Ranjana W Minz6, Surjit Singh1,  
1 Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Neurology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Microbiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
5 Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
6 Department of Immunopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Correspondence Address:
Dr. Aman Sharma
Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012


Background: Neurological manifestations are an important cause of morbidity in antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). It is not clear whether or not they are indicative of a severe disease course with multiple organ involvement and shortened survival. Aims and Objectives: To characterize the neurological manifestations of AAV and analyze their relationship with other organ system and cumulative survival. Methods: This was a retrospective single-center cohort study of AAV patients at a tertiary care hospital in North India. Data was collected from medical records regarding clinical history, neurological examination, Birmingham Vasculitis Activity Score (BVAS), serology, electrophysiology, imaging, and histopathological examination findings of patients. Results: Ninety-two patients of systemic vasculitis were identified, 67 with granulomatosis with polyangiitis (GPA), 14 with microscopic polyangiitis, 8 with Churg–Strauss syndrome (CSS), and 3 with undifferentiated AAV. The median BVAS at presentation was 18.0 (interquartile range (IQR): 12.0). The median duration of follow-up was 31.3 months (IQR: 40.5). A total of 45.7% patients had neurological manifestations among which 23.8% presented with neurological complaints. Peripheral neuropathy was the most common manifestation noted in 23.9% of the patients. Among patients with GPA, 40.3% had neurological involvement (seen in 33.3% patients at presentation). Patients with nervous system disease were more likely to have associated musculoskeletal manifestations (P = 0.046) and less likely to have renal involvement (P = 0.017). The estimated cumulative survival of the subgroup with neurological involvement was 95.1 months from the time of diagnosis, which was not significantly different from the cohort without neurological involvement (113.8 months, P = 0.631). Conclusion: Neurological morbidity commonly accompanies systemic vasculitis. Nervous system disease does not affect the survival significantly in these patients.

How to cite this article:
Sharma A, Rajan R, Modi M, Pinto B, Dhooria A, Rathi M, Mittal T, Kumar S, Sharma K, Dhir V, Nada R, Minz RW, Singh S. Neurological Manifestations Do not Affect Cumulative Survival in Indian Patients with Antineutrophil Cytoplasmic Antibody Associated Vasculitis.Neurol India 2019;67:1043-1047

How to cite this URL:
Sharma A, Rajan R, Modi M, Pinto B, Dhooria A, Rathi M, Mittal T, Kumar S, Sharma K, Dhir V, Nada R, Minz RW, Singh S. Neurological Manifestations Do not Affect Cumulative Survival in Indian Patients with Antineutrophil Cytoplasmic Antibody Associated Vasculitis. Neurol India [serial online] 2019 [cited 2021 Jan 28 ];67:1043-1047
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Full Text

Among autoimmune disorders, systemic vasculitides are the leading causes of mortality and morbidity. The antineutrophil cytoplasmic antibody (ANCA) associated vasculitides like granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and Churg–Strauss syndrome (CSS) are known for their protean disease manifestations, and mortality is attributable predominantly to the disease activity and renal involvement.[1],[2],[3],[4]

Neurological manifestations of systemic vasculitis are diverse and involve both the peripheral and central nervous systems. Peripheral neuropathy is the most common manifestation by far, being reported in 10–48% of patients with systemic vasculitis.[5] Its pathogenesis is related to inflammation of the vasa nervosum and subsequent nerve ischemia, affecting large myelinated fibers earlier than the small unmyelinated ones.[6] In addition, mononeuritis multiplex and cranial neuropathies are also common.[7] Central nervous system manifestations include cerebrovascular events, inflammatory pseudotumors, headache, seizures, and pachymeningitis.[7]

There are geographical variations in the clinical presentations of AAV, and there is a paucity of data on the neurological manifestations from Asian countries. The present study was conducted to analyze the prevalence and associations of nervous system manifestations in Indian patients with AAV, and to see if neurological manifestation of the disease has any correlation with the survival of these patients.

 Materials and Methods

We conducted a retrospective analysis of clinical records of patients with a diagnosis of AAV seen under the Rheumatology services at PGIMER, Chandigarh, India. Patients attending the clinic from January 2007 to April 2014 were included. Data regarding history, examinations, and available investigations such as baseline hemogram, renal function parameters, autoantibodies screen (antinuclear antibody [ANA] and ANCA by indirect immunofluorescence [IIF]; proteinase 3 [PR3]-ANCA by enzyme-linked immunosorbent assay [ELISA]) were captured on a pre-specified proforma.

Symptomatic patients and those with evidence of neurological dysfunction on clinical examination underwent further evaluation including neurophysiological studies (Medtronic Keypoint 4 CH machine) and magnetic resonance imaging (MRI) of the brain and orbit. Neuropathy was defined as mononeuritis multiplex, if the clinical presentation was consistent with involvement along the distribution of individual nerves, and nerve conduction revealing asymmetrical neuropathy. Patients with clinically symmetrical involvement in a glove-and-stocking distribution with comparable abnormalities on bilateral nerve conduction studies were considered to have symmetrical peripheral neuropathy. Confirmatory biopsies (cutaneous, peripheral nerve, lung, and renal) were performed in patients in whom the diagnosis was not established by other means. Nerve biopsy specimens were subjected to histopathological examination as per the standard protocol. The American College of Rheumatology criteria/Chapel Hill Consensus Conference System was followed for nomenclature of vasculitides.[8],[9] Birmingham Vasculitis Activity Score (BVAS) was calculated for all patients.[10] The study was approved by the ethics committee of the Institute.

Statistical analysis

Statistical analysis was done using student t-test to compare means, Chi-square test for nonparametric data, and Kaplan–Meier curves with log rank test for survival analysis. All tests were performed using the Statistical Package for the Social Sciences (SPSS) software (version 16.0; IBM, Armonk, NY, USA).


Data was collected from the medical records of 92 patients with systemic vasculitis and analyzed. The median age was 42.0 years [Interquartile range (IQR): 24], and 63.0% of the subjects were females. The median Birmingham Vasculitis Activity Score (BVAS) at presentation was 18.0 (IQR: 11). The median duration of follow-up was 31.3 months (IQR: 40.5). Neurological involvement was noted in 45.7% of the patients and was the initial clinical presentation in 23.8% of these patients (these formed 10.9% of entire cohort). The rest of the patients developed neurological signs and symptoms during the follow-up. Non-GPA patients had a significantly higher incidence of neurological involvement. No other differences were noted in baseline variables among the groups [Table 1].{Table 1}

The majority of patients were classified as GPA (72.8%), followed by MPA (15.2%), CSS (8.6%) and undifferentiated AAV (3.3%). Patients with MPA were significantly older (P = 0.031). The most common neurological manifestation was peripheral neuropathy (21.7%), which was consistent with mononeuritis multiplex in 65% of the patients. Nerve conduction studies revealed axonal involvement in 95% of the patients. Sural nerve biopsies showed inflammatory infiltrates or evidence of vasculitis in 90.9% of the biopsied patients. Neurological complications, especially peripheral neuropathy, were more common in CSS and undifferentiated AAV (P = 0.003). Other manifestations are summarized in [Table 2]. Sensorineural hearing loss (17.9%) and facial palsy (10.5%) were seen only in GPA patients. Other central nervous manifestations encountered are shown in [Table 3]. Patients with neurological involvement were more likely to have associated musculoskeletal manifestations (P = 0.046) and less likely to present with renal involvement (P = 0.017). None of the other organ system manifestations (cardiac, gastrointestinal, upper respiratory) were significantly associated with neurological involvement.{Table 2}{Table 3}

A total of 97.6% of the patients with nervous system involvement, including all patients of peripheral neuropathy, received oral or intravenous steroids as part of the remission induction therapy. Intravenous cyclophosphamide was used in 87.5% of these patients for induction as well as maintenance of remission. One patient each received intravenous immunoglobulin and therapeutic plasma exchange for non-neurological indications. One patient each with hypertrophic pachymeningitis and demyelinating neuropathy refractory to standard therapy achieved remission with rituximab. The estimated cumulative survival of the subgroup with neurological involvement was 95.1 months from the time of diagnosis, which was not significantly different from the cohort without neurological involvement (113.8 months, P = 0.631) [Figure 1].{Figure 1}


Our data confirms that a significant number of patients with AAV have nervous system involvement, as seen in other series [Table 4].[11],[12],[13],[14],[15] A large number of patients had neurological involvement at presentation, probably owing to the delay in presentation to the hospital. This was similar to various other series which have reported neurological involvement to be more commonly encountered after a few years of disease activity.[14] However, ongoing neurological involvement at the presymptomatic and early stages of the disease can be seen in a subset of patients. This is consistent with the recent data, which shows that peripheral nervous system involvement predominates.[16] CNS involvement likely points towards more severe disease activity, which is encountered less frequently nowadays due to a widespread earlier initation of treatment. The increased use of diagnostic procedures might also contribute to the higher diagnosis rate in the recent reports.{Table 4}

The cumulative prevalence of peripheral neuropathy (23.9%) in our study was similar to that observed in other large series.[14] In other cohorts, symmetrical neuropathy was encountered more often with GPA, especially in earlier stages of the disease.[12] The etiopathogenic correlate of vasculitic neuropathy is peripheral nerve ischemia. Depending on the size of the nerves involved, different clinical patterns emerge; mononeuritis multiplex with large nerve infarction, patchy neurological deficits with fascicular involvement, and distal symmetrical neuropathy with chronic peripheral nerve ischemia.[17],[18] The electrophysiological correlate of peripheral nerve ischemia is axonal damage, which was reflected in the nerve conduction studies in our patients.[19] Secondary loss of myelin may lead to changes of demyelination, as was seen in a small number of cases in this study. Accordingly, a higher disease activity and later presentation probably account for a larger number of patients with mononeuritis multiplex. The nerve biopsy (n = 11) was consistent with vasculitis in all our biopsied patients except one. The yield of sural nerve biopsy is reported to be between 50–75% depending on the expected diagnosis, duration of illness and pattern of involvement.[20],[21] Isolated nerve biopsy has a lesser yield for systemic vasculitis compared to non-systemic vasculitic neuropathy, and a combined nerve-muscle biopsy can increase the diagnostic yield.[22]

Central nervous system involvement was slightly more common compared to that observed in the previous reports.[12],[13] Although traditionally associated with a longer disease duration, we encountered central nervous system involvement as the first and isolated manifestation of systemic vasculitis in 10.9% of the entire cohort. All patients with CNS involvement had underlying granulomatous pathology. Treatment options were guided predominantly by the severity of renal and pulmonary involvement. The majority of the patients received steroids and cyclophosphamide and demonstrated a good response. Hypertrophic pachymeningitis refractory to standard therapy was successfully treated with rituximab, as we have reported previously.[23] These neurological manifestations are similar to that observed in other reported cohorts, unlike giant cell arteritis, which is very rare in the Indian population.[24],[25]

Nervous system involvement, central or peripheral, does not contribute to mortality in these patients. Unadjusted survival times were similar for those with or without neurological manifestations. To the best of our knowledge, survival times in patients of AAV and neurological involvement have not been reported previously in literature. Nervous system involvement was not predictive of life-threatening involvement of other organ systems. These findings are important while considering therapeutic options, as neurological symptoms often tend to persist after standard therapy. The use of enhanced immunosuppression in this setting must be judiciously weighed against the risks of cytopenia and infection.[26]


Our study confirms that neurological manifestations occur in a significant number of Indian patients suffering from systemic ANCA-associated vasculitis. Traditionally thought to occur during the course of a well-established vasculitic illness, our data shows that a significant proportion of patients may present with either central or peripheral nervous system involvement early in the course of their disease. Survival is unaffected by nervous system involvement. It would be prudent to consider these findings while weighing the treatment risks and benefits for patients with neurological disease activity refractory to standard treatment.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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