Abstract
Background: Nonsystemic vasculitic neuropathy (NSVN) is an uncommon disorder. Few series with small numbers of patients have been reported. The prognosis and treatment of patients presenting with NSVN remain uninvestigated. The authors sought to address these issues by assembling a large retrospective cohort with extended follow-up.
Methods: All nerve biopsies performed over 20 years were reviewed; cases with definite, probable, or possible vasculitis were segregated for clinical correlation. Patients satisfying clinical criteria for NSVN at presentation were selected. Clinicopathologic, treatment, and outcome measures were analyzed in patients followed for ≥6 months.
Results: A total of 48 patients (30 women, 18 men) with a median of 63 months of follow-up were identified. Most patients (85%) had extensive, overlapping involvement of multiple nerves. Only one had a symmetric polyneuropathy. Most neuropathies (96%) were painful. In 96%, nerve damage was distally accentuated, but most had concurrent proximal weakness. Diagnostic sensitivity was 58% for superficial peroneal nerve/peroneus brevis muscle biopsy and 47% for sural nerve biopsy. Combination corticosteroid/cytotoxic therapy was more effective than corticosteroid monotherapy in inducing remission and improving disability, with trends toward reduced relapses and chronic pain. Treatment with cyclophosphamide for >6 months decreased the relapse rate, which was 46% for all patients. Disease/treatment-related mortality was 10%. Six percent developed cutaneous involvement. Although chronic pain persisted in 60% of survivors, 80% had good outcomes.
Conclusions: NSVN nearly always presents as an asymmetric, distally accentuated, painful, sensorimotor polyneuropathy. Risks for systemic spread and death are small, and, aside from pain, neurologic prognosis is unexpectedly good. Although this was not a randomized controlled trial, combination therapy produced the best outcome in this cohort.
In vasculitis, blood vessels become inflamed and partially destroyed, thereby damaging tissues through ischemic, inflammatory, and immune mechanisms.1 Most classifications of vasculitis include only systemic disorders that affect multiple organs.2,3⇓ However, vasculitis can also present in a “nonsystemic” fashion, confining itself to a single organ, such as skin,4 gastrointestinal5 or reproductive tract,6 lungs,7 kidneys,8 or CNS.9 Vasculitis restricted to the peripheral nervous system (PNS) was first recognized by Kernohan and Woltman in 1935.10 The concept then lay dormant until 1985, when seven such patients were described.1 In 1987, Dyck and coworkers reported 20 patients and coined the term nonsystemic vasculitic neuropathy (NSVN).11 Small numbers of patients have since appeared.12-17⇓⇓⇓⇓⇓ The largest cohort (25 patients) was reported in 1996.18 The two largest NSVN cohorts were assembled retrospectively, with patients selected for absence of extraneurologic involvement during follow-up.11,18⇓ This selection criterion preordained a relatively benign prognosis and precluded an assessment of risk for systemic spread in patients presenting with a nonsystemic-appearing vasculitic neuropathy.
An important but overlooked question concerns appropriate treatment of patients with vasculitic neuropathy in general and NSVN in particular. There are no controlled data relevant to the treatment of any type of vasculitic neuropathy, apart from one study of Churg Strauss syndrome–associated neuropathy.19 We have advocated combination therapy (corticosteroids [CS] and cyclophosphamide [CYC]) in NSVN, except for mild cases. Others favor CS monotherapy.11,20⇓ These recommendations lack evidentiary support and are extrapolated from systemic vasculitis trials or anecdotal experience. This paucity of evidence prompted us to gather data on all patients with NSVN treated at our institution over the past 20 years and analyze their long-term treatment outcomes. In contrast to other series, we included all patients meeting a predetermined definition of NSVN at the time of diagnosis, consistent with the manner in which clinicians function. Our goal was to systematically analyze treatment responses, clinical presentation, relapse rate, neurologic outcome, and mortality in patients with NSVN.
Methods.
Pathologic selection criteria.
All nerve biopsies (sural nerve, superficial peroneal nerve/peroneus brevis muscle [SPN/PBM], or superficial radial nerve) performed in the neuro-muscular laboratory of The Ohio State University from 1981 to 2001 were reviewed. Biopsy procedures and histologic techniques have been described previously.16,21⇓ Biopsies were classified as showing definite, probable, or possible vasculitis based on pre-established definitions.16 Definite vasculitis was diagnosed if at least one blood vessel was infiltrated by inflammatory cells associated with signs of vascular injury, such as fibrinoid necrosis, endothelial cell disruption, fragmentation of the internal elastic lamina, hemorrhage, or acute thrombus. Probable vasculitis required transmural or perivascular inflammation unaccompanied by vascular destruction, but combined with at least one other supportive finding, including vascular thickening, luminal obliteration, recanalized thrombus, epineurial neovascularization, hemosiderin deposits, asymmetric nerve fiber loss, ongoing Wallerian-like degeneration, focal perineurial inflammation/thickening, or muscle fiber necrosis/regeneration. Possible vasculitis was diagnosed in noninflammatory biopsies revealing predominant axonal alterations and one or more of four pathologic changes previously shown by our group to be predictive of PNS vasculitis: muscle fiber necrosis/regeneration, asymmetric nerve fiber loss, ongoing Wallerian-like degeneration, and vascular immune deposits.16
Patient selection criteria.
For all patients meeting pathologic criteria for definite, probable, or possible vasculitis, available outpatient and inpatient records were reviewed. Each patient had been evaluated by at least one neuromuscular clinician from Ohio State. In patients with pathologic diagnoses of probable or possible vasculitis, a subset with clinically probable vasculitic neuropathy was determined by application of published diagnostic criteria,16 consistent with precedent.11,18,22⇓⇓ All patients with definite or clinically probable vasculitic neuropathy were then divided into systemic versus nonsystemic groups according to standard classification schemes.2,3⇓ Diagnosis of NSVN required 1) clinicopathologic evidence of vasculitic neuropathy, 2) no clinicopathologic signs of CNS or extraneurologic involvement, and 3) no demonstrable etiology or predisposing condition (see appendix). Patients were not excluded a priori for constitutional symptoms (weight loss, fever, arthralgias, anorexia, malaise, night sweats) or monoclonal gammopathy of undetermined significance (MGUS).
All patients satisfying criteria for NSVN were next assessed for adequacy of follow-up. For patients lacking at least 2 years follow-up at our institution, attempts were made to acquire additional information by 1) telephone interviews with patients and relatives, 2) retrieval of medical records from physician offices and hospitals, and 3) re-examination of selected patients. Patients who had less than 6 months follow-up after these efforts were excluded.
Data collection.
In this manner, a cohort of 48 patients with NSVN with ≥6 months follow-up was assembled. For each patient, historical, demographic, laboratory, and pathologic information was tabulated. Electrodiagnostic data were not tracked owing to multiple examiners employing heterogeneous protocols. Charted treatment variables included agents, dosages, durations of therapy, adverse effects, and infectious complications (excluding upper respiratory syndromes, gastroenteritis, and oral/vaginal thrush). Treatment protocols were not standardized and were at the discretion of the treating neurologist.
Outcome variables included the following: 1) pain (better, unchanged, worse); 2) sensory loss (better, unchanged, worse); 3) objective weakness (better, unchanged, worse); 4) composite Medical Research Council (MRC) strength score (5− or 4+ = 4.5, 4− or 3+ = 3.5, 3− = 2.5, and 2− = 1.5), obtained by summing the most-affected-side scores for shoulder abductors, elbow flexors, elbow extensors, wrist flexors, wrist extensors, hip flexors, knee flexors, knee extensors, ankle invertors, and ankle dorsiflexors; and 5) disability score using the Prineas scale.18,23,24⇓⇓ The primary outcome measure was long-term response, defined as positive if at least one of the preceding five outcome variables improved and none worsened, with improvement sustained for ≥6 months, and negative if any of the variables worsened or all were unchanged at 6 months. Patients who improved initially but worsened before 6 months were treated as nonresponders (negative long-term response). In patients with a positive long-term response followed for ≥12 months, relapses were tracked. Relapse was defined as a new sign or symptom of weakness, sensory loss, or neuropathic pain after a sustained response to therapy. Secondary outcome measures for assessment of treatment responses were as follows: 1) change in composite MRC score, 2) change in disability score, 3) relapse rate, 4) disease or initial treatment-related mortality rate, and 5) chronic pain in patients followed for at least 24 months. Final MRC and disability scores were determined at the most recent follow-up encounter, just before relapse, or just before death. All thromboembolic events occurring within 6 months of follow-up were categorized as disease/treatment-related, in view of the recognized potential of CS and proinflammatory cytokines (e.g., interleukin-1, tumor necrosis factor-α) to promote thrombosis.25,26⇓
Statistical analyses.
Statistical analyses were performed using SAS JMP, version 4 (Cary, NC). For assessment of treatment responses, patients were divided into CS monotherapy and CS plus adjunct (combination therapy) groups according to their initial treatment. The two groups were compared for potentially confounding variables such as age, neuropathic symptom duration, initial composite MRC score, initial disability score, erythrocyte sedimentation rate (ESR), and pathologic muscle involvement, using one-way analysis of variance (ANOVA) (Student t-test with equal variances and Welch ANOVA with unequal variances) for parametric analysis of continuous variables, Wilcoxon rank-sum test for nonparametric analyses, and Fisher exact test for comparison of qualitative variables. Differences between the two groups in long-term response rate were analyzed with Fisher exact test. Differences in relapse rate and chronic pain were assessed with the Pearson χ2 test. Comparisons between the groups for changes in composite MRC and disability scores were conducted with Wilcoxon rank-sum and t-tests. The relationship between duration of CYC exposure and relapse rate was addressed with a 2 × 2 contingency table and Fisher exact test. Kaplan-Meier survival analysis was performed for the entire NSVN cohort, initial CS monotherapy subgroup, and initial CS plus adjunct subgroup. Survival data for the two subgroups were compared using the Mantel-Cox log-rank and Wilcoxon rank-sum tests. The influence of weight loss on long-term response rate and change in disability score for the entire NSVN cohort was evaluated with Fisher exact, Wilcoxon rank-sum, and t-tests.
The initial CS group was next subdivided based on the presence or absence of an inaugural IV pulse of methylprednisolone. The effects of the IV pulse on long-term response rate, relapse rate, change in composite MRC score, and change in disability score were analyzed using similar techniques to the CS monotherapy versus combination therapy comparisons, with the addition of an analysis of covariance adjusting for the initial MRC and disability scores. To determine potential predictors of a long-term response to initial CS monotherapy, five clinical variables (age at onset, sex, symptom duration, initial composite MRC score, and initial disability scores) and four laboratory variables (ESR, antinuclear antibodies [ANA], rheumatoid factor [RF], and leukocytosis) were subjected to separate logistic regressions.
For assessment of complications, the incidence of CS-related side effects in patients exposed to prednisone was compared to the incidence of CYC-related side effects in patients exposed to CYC using Fisher exact test. Infection rates for patients treated with CS alone versus CS plus immunosuppressive agents were analyzed in a similar fashion. The yield of definite pathologic evidence of vasculitis in patients undergoing sural nerve compared to SPN/PBM biopsies was analyzed with Fisher exact test.
Results.
Clinical characteristics.
Clinical characteristics of the cohort are summarized in table E-1 (available at the Neurology Web site; access www.neurology.org). Of the 48 patients with NSVN, 14 were previously reported,1,16⇓ albeit without the follow-up and treatment data obtained in this study. Thirty patients were women and 18 were men (ratio 1.7:1). Age at onset of neuropathy ranged from 21 to 88 years (mean ± SD = 61.8 ± 14.5 years). Symptom duration before diagnosis varied from 2 weeks to 8 years (mean 8.9 ± 14.9 months; median 5 months). Weight loss (mean 21 ± 10.2 pounds) occurred in 35% and unexplained fevers in 15%.
Ninety-six percent of the neuropathies were painful, and most were sensorimotor in character. Only 13% of patients had predominantly or, less commonly, purely sensory findings. No patient presented with pure motor deficits. One patient had small fiber-restricted sensory loss; all others exhibited mixed sensory findings, involving both small and large fiber modalities. Most patients had extensive, overlapping involvement of multiple individual nerves, with legs more commonly affected than arms and distal nerves more commonly affected than proximal nerves (table 1). The common peroneal was the most frequently involved nerve overall, and the ulnar nerve was most commonly affected in the arm. Despite the propensity for distally accentuated damage (seen in all but two patients), proximal nerves were not routinely spared: 60% of patients had hip flexor weakness, 40% shoulder abductor and elbow flexor weakness, and 13% sensory loss in thoracic dermatomes. Only 8% of patients had cranial neuropathies, typically involving cranial nerve seven. All but one patient had asymmetric findings at presentation. Patterns of involvement were 77% asymmetric polyneuropathy (overlapping multifocal neuropathy), 13% true multiple mononeuropathy, 8% asymmetric lumbosacral plexopathy, and 2% distal symmetric polyneuropathy. Neurologic disability at presentation ranged from mild multifocal numbness and pain to severe quadriparesis and complete dependence. Median disability was 4 on the Prineas scale, consistent with partial dependence, a need for assistance with some bodily functions, and a preference for some type of walking aid. There was no significant difference in median disability or mean composite MRC score between the groups of patients with or without weight loss.
Table 1. Motor nerve involvement
Laboratory findings.
Laboratory results are detailed in table E-1 (available at www.neurology.org). Seventy-one percent of patients had an elevated ESR (≥20 mm/hour); in 25%, ESR was ≥50 mm/hour. Other laboratory markers of inflammation or autoantibody production were abnormal in a minority of patients, including positive ANA in 39%, anemia in 31%, leukocytosis in 23%, thrombocytosis in 21%, positive RF in 20%, and decreased complement (C3 or C4) in 11%. Nineteen patients underwent CSF examination; mild pleocytosis was noted in only one patient (5%). CSF protein was elevated (>50 mg/dL) in 5/19 (26%), with a mean of 47.2 ± 21.9 mg/dL and maximum of 106 mg/dL. Immunofixation electrophoresis revealed a MGUS in three patients (IgGκ, IgGλ, IgMλ), representing 8% (3/37) of patients older than 50 years.
Nerve biopsy was performed in all patients: sural nerve in 28, SPN/PBM in 18, and superficial radial nerve in 2. Two patients with nondiagnostic SPN/PBM biopsies later had sural biopsies; conversely, one patient with a nondiagnostic sural biopsy subsequently underwent SPN/PBM biopsy. Thus, a total of 30 sural nerve, 19 SPN/PBM, and 2 superficial radial nerve biopsies were performed. Pathologic diagnoses and diagnostic sensitivities for these procedures are summarized in table 2. SPN/PBM biopsy had a higher sensitivity for definite vasculitis than sural nerve biopsy, but the difference was not significant. In the 19 patients undergoing SPN/PBM biopsies, muscle revealed definite vasculitis in 3 patients (16%), inflammatory infiltrates in 8 (42%), and muscle fiber necrosis or regeneration in 13 (68%).
Table 2. Diagnostic sensitivity of nerve biopsies
Treatment.
Treatment regimens and follow-up.
Treatment and outcome measures are abstracted in table E-2 (access www.neurology.org). In survivors of the initial 6 months of therapy, follow-up ranged from 6 to 260 months (median 63 months; mean 75 ± 54 months). Twenty-eight patients were initially treated with CS alone (prednisone, IV pulse methylprednisolone, or both) and 20 with combination therapy (CS plus an adjunctive agent: oral CYC in 18, azathioprine [AZA] in 1, and IV immunoglobulin [IVIg] in 1). Starting prednisone doses ranged from 40 to 100 mg/day. The most common protocol consisted of prednisone 100 mg/day for 1 to 2 weeks, followed by 100 mg every other day. A starting dose of 100 mg every other day was employed next most frequently. Starting CYC doses were 100 or 150 mg/day. In patients successfully tapered off prednisone (no progression or relapse), duration of therapy ranged from 2 to 45 months (median 12.5, mean 14.0 ± 8.8). In the 25 patients treated with CYC as a primary or rescue agent, duration of therapy ranged from 1 to 30 months (median 5 months). CYC had to be discontinued in 40% of patients because of adverse effects (pneumonia, cellulitis, sepsis, leukopenia, anemia, thrombocytopenia, rash, or diarrhea).
Comparison between initial CS monotherapy and combination therapy groups.
For these two groups, baseline clinical and laboratory characteristics of potential relevance to therapeutic responses are charted in table 3. There were no differences between the groups in any of these attributes. For survivors of the initial 6 months of therapy, median follow-up was 54.5 months (range 12 to 172, mean 61 ± 36 months) in the CS monotherapy group and 77 months (range 6 to 260, mean 94 ± 68 months) in the combination group. Methylprednisolone (1 g/day IV for 3 to 6 days) preceded oral therapy in 57% of patients treated with CS alone and 65% of patients initially receiving combination therapy.
Table 3. Baseline characteristics of treatment cohorts
Outcome analyses are summarized in table 4. For the primary outcome measure—long-term response rate—there was a significant difference favoring the initial combination therapy group. Of the secondary response variables, the combination therapy group also exhibited a significantly greater improvement in disability and a trend toward reduced incidence of chronic pain. Eighty-five percent (17/20) of patients initially treated with CS plus a second agent had improved disability at end of follow-up compared to 57% (16/28) of those receiving CS monotherapy. Long-term responders to CS monotherapy were twice as likely to relapse as responders to combination therapy, but this difference was not quite significant. The two groups had similar disease or initial treatment-related mortality rates and changes in composite MRC score. Kaplan-Meier survival plots for the CS monotherapy and combination therapy groups are depicted in the figure. There was no significant difference between the groups. Estimated 5-year survival for the entire cohort was 87% (SE 13%).
Table 4. Outcome measures for treatment cohorts
Figure. Kaplan-Meier survival analysis for nonsystemic vasculitic neuropathy cohort, according to initial treatment (log-rank p = 0.2314). Solid line = total cohort; dotted line = group initially treated with corticosteroid monotherapy; dashed line = group initially treated with combination therapy.
Management of nonresponding and relapsing patients.
Of the 28 patients initially treated with CS alone, 11 were nonresponders (failed to achieve a long-term response). Of these 11, 2 died, 3 survived but received no further treatment, and 6 were managed by the addition of CYC (n = 4) or IVIg (n = 2) to CS. Five of these 6 (83%) exhibited a long-term response to the retreatment. The only nonresponder to initial combination therapy died without retreatment. Ten of the 17 long-term responders to initial CS monotherapy later relapsed; of these, 4 were retreated with CS alone, 3 received CS and CYC, 1 CS and IVIg, and 2 were not retreated. Seven of eight retreated patients responded. Of the 25 patients initially or secondarily treated with combined CS/CYC, 23 responded and 7 later relapsed. For the 7 relapsers, 4 of 5 responded to retreatment with CS, 1 of 1 responded to CS/CYC, and 0 of 1 responded to CS/AZA. Retreated patients who progressed on CS and CS/AZA subsequently responded to CS/CYC.
Weight loss.
There was no significant difference in long-term response rate and change in disability score for patients with and without weight loss. Seventy-six percent (13/17) of patients with weight loss exhibited a long-term treatment response versus 74% (23/31) of patients without weight loss. Likewise, 71% (12/17) of patients with weight loss had improved disability at end of follow-up compared to 68% (21/31) of patients without weight loss.
Efficacy of IV methylprednisolone pulse in initial CS monotherapy group.
Of the 28 patients initially treated with CS monotherapy, 16 received IV pulse methylprednisolone. This subgroup was significantly more affected than the non-pulsed group by composite MRC score (mean 37.8 ± 7.0 for pulsed versus 46.7 ± 5.0 for non-pulsed groups) and median disability (4 for pulsed versus 3 for non-pulsed groups). The two groups had similar long-term response rates (63% pulsed; 58% non-pulsed) and relapse rates (63% pulsed; 57% non-pulsed). Likewise, there were no differences between the groups for change in composite MRC score and change in disability score, adjusting for the baseline differences in these scores.
Predictors of long-term response to initial CS monotherapy.
None of the clinical (age at onset, sex, symptom duration, composite MRC score, disability score) or laboratory (ESR, leukocytosis, ANA, RF) variables predicted a long-term response to initial treatment with CS alone.
Duration of CYC and relapse rate.
Eighteen patients were initially treated with CS and CYC; 17 exhibited a long-term response and 1 died at 2 months. Seven more patients were treated with CS/CYC after an initial failure or relapse on CS monotherapy; six responded and one died. Of the 23 long-term responders to CS/CYC, 22 were followed for ≥12 months, permitting an assessment of relapse risk. Relapses occurred in 7 (32%) of these 22 patients. In patients treated with CYC for ≤6 months, the relapse rate was 7/13 (54%). In patients treated with CYC for >6 months, no relapses occurred (0/9), a significant reduction (p = 0.017).
Adverse effects.
Complications of treatment are summarized in tables 5 and 6⇓.
Table 5. Infectious complications of treatment
Table 6. Noninfectious complications of treatment
Prognosis and outcome.
Table 7 itemizes outcome measures for the entire NSVN cohort. Of the five patients whose deaths were believed to be related to the disease or its treatment, three died within 2 to 4 months of diagnosis: two from pulmonary emboli and one from myocardial infarction. The two patients with pulmonary emboli had limited mobility secondary to vasculitic involvement of the lower limbs. The fourth patient died from Pseudomonas sepsis at 12 months and the fifth from metastatic bladder cancer 5 years after her last exposure to CYC. In three patients, vasculitis spread to the skin (livedoid rashes in two cases and ulcers in the third) 2, 12, and 60 months after initiation of therapy (two patients on prednisone; one untreated). The 18 patients (46%) who relapsed did so from 6 to 47 months after onset of treatment (median 15, mean 19 ± 12 months). The number of relapses per patient ranged from one to four (median 1.5). At the time of first relapse, 10 patients had been tapered off treatment altogether and eight were on prednisone doses ranging from 10 to 70 mg every other day (mean 40 mg every other day). No patient relapsed on CYC.
Table 7. Final outcome in NSVN cohort
Discussion.
The NSVN cohort assembled for this study was larger than previous cohorts and had more extensive follow-up, permitting more representative characterization of the clinical features and evolution of NSVN. The most important aspect of the study was its attention to therapeutic outcomes, as no controlled treatment data on NSVN have been reported. The key finding was that combination therapy (generally CS and CYC) was more effective than CS monotherapy in inducing remission (long-term response) and improving disability in NSVN, with trends toward reduced relapse rate and chronic pain. The increased efficacy of combination therapy in NSVN parallels observational studies in systemic vasculitides27-29⇓⇓ and corroborates the only other NSVN study permitting comparative assessment of treatments.18 In that report, disability scores improved in 91% (10/11) administered combination therapy and only 55% (6/11) of those receiving CS alone, figures similar to ours.
The evidence favoring combination therapy in NSVN runs contrary to expert advice and, to some extent, our own practice over the past 20 years. There appears to be a hesitancy to use CYC in this ostensibly non-life-threatening disease because of side effects. In this study, patients treated with both CS and CYC had more adverse effects than patients exposed to CS alone, but this difference was not significant. Pneumonia and sepsis, in particular, occurred primarily in patients treated with standard therapy, and there were two combination therapy-related deaths (one sepsis and one bladder cancer). Nevertheless, CYC did not increase overall disease or treatment-related mortality, combination therapy produced greater improvement in disability than CS monotherapy, and prednisone-related side effects were more common than those associated with CYC. From a side effect standpoint, it thus may be more important to accelerate prednisone tapering than to reduce or eliminate CYC.
Our study also showed that longer (>6 month) courses of CYC were more effective in preventing relapses than shorter courses. This finding is concordant with standard therapy for Wegener granulomatosis, where oral CYC is continued for 12 months after remission is achieved.27 However, there has been a push in recent years to reduce patient exposure to CYC in systemic vasculitides and thereby minimize CYC-related toxicity.30-34⇓⇓⇓⇓ One approach is to replace continuous oral CYC with periodic IV pulses. Many controlled trials in patients with systemic vasculitis have shown that pulse CYC is as effective as oral CYC in inducing remission, with decreased infections and CYC-specific side effects, but at the expense of a higher relapse rate.34 A second approach involves replacing oral CYC with an alternate agent once remission is induced, typically in 3 to 6 months.30-33⇓⇓⇓ The most commonly employed maintenance drug is AZA (1 to 2 mg/kg/day) for 12 to 24 months.30,32⇓ An 18-month, randomized, controlled trial in antineutrophil cytoplasmic autoantibody-associated vasculitis showed AZA to be as effective as continued oral CYC in maintaining remission.32 There are also uncontrolled data supporting the use of methotrexate,31,35⇓ cyclosporine,36 and mycophenolate mofetil37 for maintenance of remission.
Sixty percent of our patients with NSVN treated with CS alone achieved remission. No clinical or laboratory variable predicted CS responsiveness. In particular, mild neuropathies were no more likely to respond than severe ones, and the use of IV methylprednisolone did not influence outcome. Thus, if NSVN is treated with CS alone, close follow-up is mandatory, with CYC added for any signs of neuropathy progression.
Important conclusions on the clinical presentation of NSVN can also be drawn from this study. First, 96% of neuropathies in this series were painful. Second, 98% of our patients had asymmetric findings, consistent with other recent reports,22,38⇓ but contrasting with a 25% prevalence of distal symmetric distributions in the overall vasculitic neuropathy literature and in series dedicated to NSVN alone.11-13,15,18⇓⇓⇓⇓ The basis for this discrepancy is unclear, but may relate to the fact that even minor asymmetries in sensory, motor, or reflex function were recorded for this study’s data set. Third, only 13% of our patients with NSVN exhibited a discrete multifocal pattern; in the rest, individual mononeuropathies overlapped. This contrasts with an ∼50% prevalence of multiple mononeuropathies in the general vasculitic neuropathy literature and in NSVN-restricted series.11,15,18⇓⇓ We suspect that this inconsistency is due to differing definitions of discrete versus overlapping multifocal neuropathy. Fourth, although findings were distally accentuated in all but two of our patients, proximal weakness was common. Fifth, our data showed a much higher prevalence of individual motor nerve involvement than that described in the literature, especially for tibial and proximal leg nerves (see table 1). Sixth, although sensorimotor presentations were the norm, 13% of patients had pure or primarily sensory findings, a proportion compatible with other series.11,16,19,22,24,39,40⇓⇓⇓⇓⇓⇓ Pure motor presentations are almost unheard of. Translating these conclusions into practice, vasculitic neuropathy is unlikely in patients with 1) no asymmetries, 2) pure motor involvement, 3) no pain, or 4) entirely proximal findings.
Weight loss occurred in 35% of our patients and fever in 15%. Although potentially indicative of a systemic process, weight loss might also result from the pain and anorexia associated with vasculitic neuropathy. We opted not to exclude patients with such constitutional symptoms based on precedent in other localized vasculitides4,7-9⇓⇓⇓ and one previous NSVN series.11 Analysis of weight loss as a predictor of initial disease severity and treatment responsiveness revealed no differences between patients with and without weight loss in initial composite MRC and disability scores, long-term response rate, and post-treatment change in disability. Thus, our decision to include such patients appears reasonable. The number of patients with fever was too small (n = 7) to permit similar analyses. However, review of these patients suggested that fever was not a predictor of disease severity or treatment response.
The estimated 5-year survival of 87% for our cohort was less than that for another large cohort, in which only 1 of 25 patients died over a median 2.8 years follow-up.18 In the Mayo Clinic series, 3 of 20 patients died, but survival analysis was not reported.11 Both of these cohorts probably included a greater proportion of benign cases than ours, as absence of systemic involvement over long-term follow-up was a selection criterion. Ten percent of our patients died from the vasculitis or its treatment, contrasting with 12 to 17% of patients in modern systemic vasculitis series.27,29,33,41⇓⇓⇓ Thus, NSVN is less likely to be lethal than the systemic vasculitides.
In our cohort, only 3 patients (6%) developed vasculitis in non-neural, nonmuscular tissues over long-term follow-up, and in these 3, the only organ affected was the skin. In the only other study to address this issue, 37% of 29 patients with isolated vasculitic neuropathy followed for a mean of 6 years developed systemic manifestations.20 However, this cohort was incompletely described and included patients with systemic disease at outset, as 22% had chronic hepatitis B.12 Our observation of several patients with restricted nerve and skin vasculitis complements similar reports in the dermatologic literature, suggesting a relationship between some NSVN and cutaneous periarteritis nodosa.4,42-44⇓⇓⇓
More common than systemic spread in our patients was emergence of new neuropathy symptoms following a sustained treatment response. Relapses of this nature occurred in 46% of responders, typically 1 to 2 years after initiation of treatment. All relapsers were off therapy or receiving low doses of CS, an argument for longer courses of CYC or an alternate agent. In two other NSVN studies with fewer patients and shorter follow-up, relapses occurred in 24% and 32%.18,20⇓ The relapse rate for NSVN overlaps with those for most systemic vasculitides (20 to 60%).27-30,32,33,41⇓⇓⇓⇓⇓⇓
Final neurologic disability in our long-term survivors (see table 7) was similar to that in another NSVN cohort—17% no signs or symptoms, 65% mild to moderate disability, 13% moderately severe disability (assisted ambulation), and 4% severe disability (nonambulatory).18 These outcomes are surprisingly good and suggest that NSVN-related deficits are not exclusively the result of ischemia-induced axonal degeneration.18 Structural or functional conduction blocks likely also contribute, supported by our observation that many patients show improved motor function (especially in proximal muscle groups) during the first 1 to 2 months of follow-up, prior to expected effects from axonal regeneration. Possible mechanisms for conduction block in this disease include acute ischemia-induced axonal swelling and attenuation with secondary segmental demyelination,45 chronic ischemia-induced structural alterations at nodes of Ranvier,46 reperfusion-precipitated and macrophage-mediated segmental demyelination,47 and inactivation of nodal voltage-gated sodium channels by regional anoxia.48 Most clinical recovery in vasculitic neuropathy, however, evolves after months have passed and continues for 1 to 2 years, consistent with axonal regeneration. Although most of our patients had relatively mild neurologic deficits at last follow-up, chronic pain was a persistent concern in 60%.
Many features of NSVN overlap with the systemic vasculitides. For example, a substantial minority of patients develop constitutional symptoms. Most patients have elevated ESR, and 20 to 40% have anemia, leukocytosis, thrombocytosis, and autoantibodies. Muscle biopsies often reveal coexisting muscle involvement. Vasculitis extends to the skin in some patients. Nerve pathology is similar to that observed in systemic vasculitic neuropathy.16,49⇓ The disease is better controlled with combination therapy than CS alone, analogous to most systemic vasculitides. Relapse rates are similar. Taken together, these observations support the premise that “nonsystemic” vasculitic neuropathy is actually a systemic process, but unique in its predilection for peripheral nerve involvement, perhaps predicated on a PNS-enriched antigen or inflammatory nidus.
Appendix: Diagnostic criteria for nonsystemic vasculitic neuropathy
Inclusions
Clinical evidence of neuropathy by history and examination
Electrodiagnostic findings consistent with neuropathy
Nerve or nerve/muscle biopsy diagnostic of or suspicious for necrotizing vasculitis
Exclusions
Clinical, laboratory, radiologic, or pathologic evidence of organ involvement outside peripheral nervous system (except muscle)
Identified etiologic agent (drug exposure or infection, especially hepatitis B, hepatitis C, HIV, cytomegalovirus, or varicella zoster virus)
Underlying systemic condition predisposing to vasculitis (connective tissue diseases, malignancies, diabetes mellitus, mixed cryoglobulinemia)
Acknowledgments
Acknowledgment
The authors thank Lucia F. Dunn, PhD, and Stephen Cosslett, PhD, for their assistance with several of the statistical analyses.
Footnotes
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the September 9 issue to find the title link for this article.
- Received November 26, 2002.
- Accepted in final form June 5, 2003.
References
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