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 Table of Contents  
Year : 2020  |  Volume : 7  |  Issue : 2  |  Page : 130-134

Clinical, electrophysiological, and histopathological profile of biopsy-proven vasculitic neuropathy

1 Department of Physiology, Christian Medical College, Ludhiana, Punjab, India
2 Department of Pathology, Christian Medical College, Ludhiana, Punjab, India
3 Department of Neurology, Christian Medical College, Ludhiana, Punjab, India
4 Department of Community Medicine, Christian Medical College, Ludhiana, Punjab, India

Date of Submission20-Mar-2019
Date of Decision16-Apr-2019
Date of Acceptance25-Jun-2019
Date of Web Publication8-Oct-2020

Correspondence Address:
Mahesh P Kate
Department of Neurology, Christian Medical College, Brown Road, Ludhiana - 141 008, Punjab
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cjhr.cjhr_34_19

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Background: Vasculitic neuropathies are an uncommon heterogeneous group of nerve disorders characterized by inflammation of the vasa nervorum, which may be either systemic vasculitic neuropathy (SVN) or non-SVN (NSVN). Settings and Design: This is a retrospective, observational study. Materials and Methods: Nerve biopsy-proven cases of vasculitic neuropathy (VN) from January 2011 to December 2017 were included in the study. Results: Twenty-five percent (40/156) patients had vasculitis on biopsy, 62.5% were male and the mean age was 52.8 ± 14.9 years. The median (interquartile range) duration of symptoms before diagnosis was 75 (345) days. Thirty (75%) patients had NSVN and 10 (25%) patients had SVN. The clinical pattern of peripheral nervous system involvement was as follows: 20 (50%) had polyneuropathy, 13 (32.5%) had mononeuritis multiplex, and 7 (32.5%) had polyradiculoneuropathy. Twenty-three (57.5%) patients received immunomodulatory therapy. Conclusion: VN has a wide spectrum of clinical presentation. High index of suspicion followed by nerve biopsy is needed for diagnosis. Early treatment may improve prognosis in this group of patients.

Keywords: Nerve biopsy, polyneuropathy, vasculitic neuropathy

How to cite this article:
Deolalikar S, M. Paul PA, Jaison V, Nandi J, Arora D, Pandian JD, Kate MP. Clinical, electrophysiological, and histopathological profile of biopsy-proven vasculitic neuropathy. CHRISMED J Health Res 2020;7:130-4

How to cite this URL:
Deolalikar S, M. Paul PA, Jaison V, Nandi J, Arora D, Pandian JD, Kate MP. Clinical, electrophysiological, and histopathological profile of biopsy-proven vasculitic neuropathy. CHRISMED J Health Res [serial online] 2020 [cited 2021 Aug 5];7:130-4. Available from: https://www.cjhr.org/text.asp?2020/7/2/130/297577

  Introduction Top

Vasculitic neuropathies are uncommon heterogeneous group of peripheral nerve disorders characterized by chronic intramural inflammation of the vasa nervorum. Vasculitic neuropathy (VN) has a wide spectrum of clinical presentation. They can be broadly classified as systemic vasculitic neuropathy (SVN) and nonSVN (NSVN).[1] Systemic vasculitis with neuropathy is a disabling illness with a 5-year survival of 37%.[2] It may occur due to autoimmune diseases or infectious diseases.[3]

Neuropathy due to vasculitis without manifestations of disorders in other systems was first reported by Kernohan and Woltman in 1938.[4] Over the years, NSVN has emerged as a distinct clinical entity, thought to account for 25%–33% of cases of VN.[5] The age of onset is in the middle and elderly age group with relatively equal distribution between the sexes. Constitutional symptoms may occur, including weight loss, fever,[6] myalgia, and arthralgia. Laboratory testing is within the normal limits except elevated erythrocyte sedimentation rate (ESR).[7] NSVN can be diagnosed histopathologically with the help of a nerve biopsy[8] having diagnostic sensitivity of 50%–60%.[6]

In the workup of neuropathy, nerve biopsies are seldom performed; hence, VN remains an under-recognized condition.[8] The distinctive feature of all VN is inflammation of the epineural, perineural, and endoneurial arteries, causing thrombosis and occlusion. There are recruitment and accumulation of T-lymphocytes and macrophages in the inflammatory zone. This leads to ischemic damage and axonal neuropathy.[1] Patients with evidence of active lesions with fibrinoid necrosis, acute thrombosis, and leukocytolclasis need early and aggressive management. Patients showing improvement without new deficits may be observed without treatment. Despite recent guidelines on VN, it is difficult to diagnose and initiate early treatment in patients. There is need of more data from different parts of the world to develop clinical and laboratory predictors for rapid diagnosis and prognosis. We aim to characterize the clinical spectrum, electrophysiological, and histopathological features of VN.

  Materials and Methods Top

This is a retrospective, observational study. The study was approved by the Institutional Research Committee. Biopsy-proven cases of VN from January 2011 to December 2017 were included in the study. In a structured case record form clinical, electrophysiology, pathological details, and treatments details were recorded.

Clinical characteristics

On a structured case record form all demographic and clinical details were abstracted. This included age, sex, duration of illness (days), symptoms at onset, clinical diagnosis, and examination findings (motor power and sensory pattern of involvement). Laboratory results and history were also reviewed to differentiate between NSVN and SVN. SVN was defined as the presence of neuropathy and associated clinical or laboratory features satisfying the diagnostic criteria for any named vasculitis according to the Chapel Hill Consensus Conference.[6]

Electrophysiological study

Nerve conduction studies were performed (using Model no. NE -132 B Nihon Kohden corporation NCV/EMG isolation unit, model SM-930 AK SN02659. Made in Japan) in the Neurology Laboratory, Department of Neurology. The neurological protocol included motor nerve studies on ulnar, median, tibial, and peroneal nerves on both sides; as per the discretion of the clinician, additional motor studies were performed according to clinical deficits. Sensory nerve conduction studies included ulnar, median, sural nerves on both sides; as per the discretion of the clinician, additional sensory studies were performed according to clinical deficits. In addition, “F Wave” studies were done on ulnar, median, tibial and peroneal nerves. The H-reflex was also studied. All nerve conduction studies were reviewed by Neurologist (VJ and MK) and Physiologist (SD).

Nerve biopsy

Nerve biopsy was done in patients with a suspected diagnosis of VN or for atypical presentation or to decide long-term therapy in patients with demyelinating neuropathy according to the institutional protocol. Sural nerve biopsies were performed in all patients after informed consent and under all aseptic precautions. Biopsies of peripheral nerve were fixed in 10% neutral buffered formalin. Entire tissue was processed with transverse and longitudinal sections for routine histopathological processing and paraffin embedding. Serial sections were taken at 4-μ thickness and stained with hematoxylin-eosin and solochrome cyanine for myelin. In addition, Congo red stain and modified Zeihl-Neelsen stain were carried out for detecting amyloid and lepra bacilli, respectively. Immunohistochemistry by indirect immune peroxidase method was carried out using routine antibody protocols for leukocyte common antigen (LCA/CD45) for leukocytes and neurofilament for axons in select cases.

All nerve biopsies were systematically reviewed by Pathologist (PP), and findings were recorded. Histopathological diagnosis of vasculitis was confirmed based on the current established pathological criteria by Collins et al., 2010.[9] Biopsies were diagnosed with having pathologically “definite” or “probable” VN. Pathologically, definite vasculitis cases were further subclassified as having “active lesion” or “chronic lesion with the signs of healing/repair.”

Statistical analysis

All statistical analysis was performed on SPSS (Version 20, IBM, Armonk, USA). The patients were classified as systemic and nonsystemic vasculitis. Descriptive analysis was performed, and variables were presented as mean, median, the standard of deviation interquartile range (IQR), and percentages. Nominal variables including sex, patterns of neuropathy, biopsy findings, and diagnosis were analyzed using the Chi-square test, and continuous variables including age and duration of illness were assessed with Student's t-test.

  Results Top

A total number of nerve biopsies performed and analyzed during January 2011–December 2017 was 156. Forty (25.6%) patients were diagnosed to have vasculitis on nerve biopsy. The mean age in years was 52.8 ± 14.9, and 25 (62.5%) were males. The median (IQR) duration of symptoms before diagnosis was 75 (345) days. Thirty (75%) patients had NSVN, and 10 (25%) patients had SVN. SVN was associated with rheumatoid arthritis 5 (50%), Churg–Strauss syndrome 4 (40%), and cryoglobulinemia 1 (10%). In patients with NSVN, the presenting symptoms were weakness of lower limb 12 (40%), weakness of upper limb 2 (6.7%), numbness of limbs 11 (36.7%), weakness of both upper and lower limbs 2 (6.7%), generalized weakness 1 (3.3%), recurrent ulcers of the right hand 1 (3.3%), and burning sensation in feet 1 (3.3%). The clinical pattern of peripheral nervous system involvement was as follows: 20 (50%) had polyneuropathy (symmetric or asymmetric), 13 (32.5%) had mononeuritis multiplex, and 7 (32.5%) had polyradiculoneuropathy [Table 1]. Nerve conduction studies of 26 patients were available for review. Sixteen patients had axonal, 6 had demyelinating, and 4 had both axonal and demyelinating involvement.
Table 1: Baseline characteristics of vasculitic neuropathy

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Based on Peripheral Nerve Society guidelines criteria 34 (85%) were classified as definite vasculitis, and 6 (15%) were classified as probable vasculitis [Figure 1]. In patients with NSVN, 83.3% (25/30) had definite vasculitis; six patients had active lesions and 19 patients had chronic lesions. In patients with NSVN 50% (15/30) had both perineural and endoneurial vessels involved, and 50% (15/30) had only perineural vessels involved. The cellular infiltrates in biopsy was isolated lymphocytic or neutrophilic in 56.7% (17/30); in 30% (9/30), it was a combination of lymphocytes, neutrophils, histiocytes, or eosinophils. Other findings included fibrinoid necrosis 6.7% (2/30), leukocytoclasis 13.3% (4/30), thrombotic occlusion 20% (6/30), vessel wall thickening 63.3% (19/30), endothelial swelling 66.7% (20/30), luminal narrowing 63.3% (19/30), and demyelination 66.7% (20/30).
Figure 1: (a) Active vasculitis - leukocytoclasis (black arrows), dense mixed transmural inflammatory infiltrate of neutrophils, lymphocytes and histiocytes, with marked luminal narrowing and endothelial swelling. (b) Active vasculitis - fibrinoid necrosis (asterix). (c) Chronic lesion - transmural vasculitis with predominant lymphocytic infiltrate. (d) Probable vasculitis - thickening of perineurial vessel wall with luminal narrowing (red arrow), mild perivascular lymphocytic infiltrate, H and E, ×400. (e) Myelin stain - moderate demyelination, ×400. (f) Neurofilament immunohistochemistry for axons - marked axonal loss, ×400

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In patients with SVN, 90% (9/10) had definite vasculitis, 6 had active lesions and 3 had chronic lesions. Eighty percent (8/10) had isolated perineural vessel involved and remaining two patients had both perineural and endoneurial involvement. The cellular infiltrate in biopsy was isolated lymphocytic in 10% (1/10), it was a combination of lymphocytes, histiocytes, neutrophils, and eosinophils in 72.7% (9/10). Other findings included fibrinoid necrosis 40% (4/10), leukocytoclasis 60% (6/10), thrombotic occlusion 20% (2/10), vessel wall thickening 100% (10/10), endothelial swelling 90% (9/10), luminal narrowing 70% (7/10), and demyelination 70% (7/10). Perineural infiltrates (P = 0.09), fibrinoid necrosis (P = 0.01), leukocytoclasis (P = 0.003), and vessel wall thickening (0.02), was more commonly seen in SVN compared to NSVN. There was no difference in the other histopathological parameters.

A total of 23 out of 40 patients received immunomodulatory therapy. The therapy included prednisolone 12 (52.2%), prednisolone plus azathioprine 8 (34.8%), prednisolone plus intravenous cyclophosphamide 2 (8.7%), and azathioprine plus cyclophosphamide 1 (4.3%). Follow-up data were available only in 15 patients. Four patients expired, of which 3 patients in NSVN and 1 patient in the SVN group.

  Discussion Top

In our study, a higher proportion of patients (25.6%) had vasculitis on nerve biopsies. The spectrum of presentation was wide and diagnosis was delayed. On histopathology, fibrinoid necrosis, leukocytoclasis, perineural infiltrates, and vessel wall thickening was more common in SVN compared to NSVN.

Asymmetric limb weakness is the most common presentation followed by polyneuropathy pattern in patients with VN [Table 2]. These presentations are seen in Hansen's disease and diabetic neuropathy as well. It is difficult to confirm a diagnosis of VN clinically, however stepwise progression, presence of serum antimyeloperoxidase antibody, ESR >100 mm/h, antineutrophilic cytoplasmic antibody, and rheumatoid factor seropositivity may suggest VN.[6],[14] High-resolution ultrasonography may show an enlargement in the longitudinal diameter of superficial peroneal nerve.[11] A normal or primarily demyelinating nerve conduction study points against VN.[14] In our study, 6 patients had primarily demyelinating nerve conduction studies. One patient had Churg–Strauss disease and presented with mononeuritis, but the remaining five patients had NSVN. The diagnosis did indeed come as unexpected. Hence, nerve biopsy should be considered in patients with suspected VN; however, the yield may be low (20%), and in unsuspected patients, it is only 3%.[6] The yield of diagnosis increases by 15%–23% with a combined nerve and muscle biopsy.[15],[16] Recent Brighton Collaboration Case definition allows a level 3 diagnosis (minimum acceptable evidence) in resource poor settings where nerve biopsy cannot be done.[17] Electrodiagnostic evidence of peripheral neuropathy and a clinical presentation that is typical for VN (multifocal or asymmetric, involving sensory or sensory-motor nerves, lower limb-predominant, painful and with one or more acute attacks) may suggest a clinically probable VN.
Table 2: Review of literature

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In our study, 58% of patients received immunomodulatory therapy. Patients with persistent or progressive disability, recurrence, and active vasculitis on nerve biopsy should be considered for treatment. The response of VN to steroids and other immunomodulatory therapies is variable.[18] Treatment with combined steroids and cyclophosphamide, azathioprine, or methotrexate is recommended if there is no response.[18] Good outcomes have been reported in VN with adequate therapy in previous studies[5],[19] with 5-year survival rates up to 87%.[6]

  Conclusion Top

VN is an under-recognized cause of neuropathy. Nerve biopsy is needed for diagnosis. Early treatment in patients with recurrence and active vasculitis on biopsy may be associated with good prognosis.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Blaes F. Diagnosis and therapeutic options for peripheral vasculitic neuropathy. Ther Adv Musculoskelet Dis 2015;7:45-55.  Back to cited text no. 1
Hawke SH, Davies L, Pamphlett R, Guo YP, Pollard JD, McLeod JG. Vasculitic neuropathy. A clinical and pathological study. Brain 1991;114 (Pt 5):2175-90.  Back to cited text no. 2
Collins MP. The vasculitic neuropathies: An update. Curr Opin Neurol 2012;25:573-85.  Back to cited text no. 3
Kernohan JW, Woltman HW. Periarteritis nodosa: A clinicopathologic study with special reference to the nervous system. Arch Neurol Psychiatry 1938;39:655-86.  Back to cited text no. 4
Mathew L, Talbot K, Love S, Puvanarajah S, Donaghy M. Treatment of vasculitic peripheral neuropathy: A retrospective analysis of outcome. QJM 2007;100:41-51.  Back to cited text no. 5
Collins MP, Hadden RD. The nonsystemic vasculitic neuropathies. Nat Rev Neurol 2017;13:302-16.  Back to cited text no. 6
Collins MP, Periquet MI. Isolated vasculitis of the peripheral nervous system. Clin Exp Rheumatol 2008;26:S118-30.  Back to cited text no. 7
Lawrence A, Nagappa M, Mahadevan A, Taly AB. Vasculitic neuropathy in elderly: A study from a tertiary care university hospital in South India. Ann Indian Acad Neurol 2016;19:323-6.  Back to cited text no. 8
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Collins MP, Dyck PJ, Gronseth GS, Guillevin L, Hadden RD, Heuss D, et al. Peripheral nerve society guideline on the classification, diagnosis, investigation, and immunosuppressive therapy of non-systemic vasculitic neuropathy: Executive summary. J Peripher Nerv Syst 2010;15:176-84.  Back to cited text no. 9
Zhang Y, Sun A, Zhang B, Zhong Y, Dong R, Fan D. The clinical electrophysiology and pathological characteristics of 15 cases of vasculitic neuropathy. Zhonghua Nei Ke Za Zhi 2014;53:384-9.  Back to cited text no. 10
Üçeyler N, Schäfer KA, Mackenrodt D, Sommer C, Müllges W. High-resolution ultrasonography of the superficial peroneal motor and sural sensory nerves may be a non-invasive approach to the diagnosis of vasculitic neuropathy. Front Neurol 2016;7:48.  Back to cited text no. 11
Ramineni KK, Chandra SR, Mahadevan A, Kulkarni GB, Ramanujam CN. Clinical, electrophysiological and laboratory parameters, and outcome in patients with biopsy proven systemic and nonsystemic vasculitic neuropathy. Neurol India 2019;67:S62-S70.  Back to cited text no. 12
Hui M, Meena AK, Rajasekhar L, Sireesha Y, Afshan J, Mridula R, et al. Vasculitic neuropathy: A retrospective analysis of nerve biopsies and clinical features from a single tertiary care center. Ann Indian Acad Neurol 2019;22:180-6.  Back to cited text no. 13
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Nathani D, Barnett MH, Spies J, Pollard J, Wang MX, Kiernan MC. Vasculitic neuropathy: Comparison of clinical predictors with histopathological outcome. Muscle Nerve 2019;59:643-9.  Back to cited text no. 14
Agadi JB, Raghav G, Mahadevan A, Shankar SK. Usefulness of superficial peroneal nerve/peroneus brevis muscle biopsy in the diagnosis of vasculitic neuropathy. J Clin Neurosci 2012;19:1392-6.  Back to cited text no. 15
Vital C, Vital A, Canron MH, Jaffré A, Viallard JF, Ragnaud JM, et al. Combined nerve and muscle biopsy in the diagnosis of vasculitic neuropathy. A 16-year retrospective study of 202 cases. J Peripher Nerv Syst 2006;11:20-9.  Back to cited text no. 16
Hadden RD, Collins MP, Živković SA, Hsieh ST, Bonetto C, Felicetti P, et al. Vasculitic peripheral neuropathy: Case definition and guidelines for collection, analysis, and presentation of immunisation safety data. Vaccine 2017;35:1567-78.  Back to cited text no. 17
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  [Figure 1]

  [Table 1], [Table 2]


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