Isolated vasculitis of the peripheral nervous system.

Vasculitis restricted to the peripheral nervous system (PNS), referred to as nonsystemic vasculitic neuropathy (NSVN), has been described in many reports since 1985 but remains a poorly understood and perhaps under-recognized condition. There are no uniform diagnostic criteria. Classification is complicated by the occurrence of vasculitic neuropathies in many systemic vasculitides affecting small-to-medium-sized vessels and such clinical variants as nonsystemic skin/nerve vasculitis and diabetic/non-diabetic lumbosacral radiculoplexus neuropathy. Most patients present with painful, stepwise progressive, distal-predominant, asymmetric or multifocal, sensory-motor deficits evolving over months-to-years. NSVN is identical to but less severe than systemic vasculitis-associated neuropathies (SVNs). All vasculitic neuropathies are axonal by electrodiagnostic/pathologic criteria. Laboratory testing is unremarkable except for mildly elevated erythrocyte sedimentation rate (ESR) in 50%. Highly elevated ESRs, leukocytosis, rheumatoid factors, and anti-neutrophil cytoplasmic antibodies (ANCAs) raise concern for underlying systemic vasculitis. Without a specific clinical/laboratory marker, the condition depends on nerve biopsy for diagnosis. Biopsies showing necrotizing vasculitis are about 50% sensitive, mandating reliance on "suspicious" changes in many patients. Vasculitic lesions predominate in smaller epineurial vessels and are milder than those in SVNs. The disorder is often accompanied by subclinical involvement of adjacent muscles and skin. NSVN has the potential to spontaneously relapse and remit but neurologic deficits accumulate. No randomized controlled trials have been performed, but one retrospective cohort survey showed combination therapy to be more effective than prednisone alone. Although most patients have a good outcome, more than 30% relapse and 60% have residual pain. Many nosologic, pathogenic, diagnostic, and therapeutic questions remain unanswered.

Influence of the surface EMG electrode on the compound muscle action potential.

The recording characteristics of surface EMG electrodes were investigated. Compound muscle action potential (CMAP) and surface recorded motor unit action potentials were recorded from different muscles, using different surface electrode shapes and sizes. The CMAP was smaller for larger surface electrodes. This was more pronounced in smaller muscles. The CMAP was minimally affected by the geometry of the recording surface. With larger surface electrodes, shunting contributes to the reduction in MUAP amplitude. This is offset by a larger uptake area which gives a much smaller reduction in the CMAP amplitude for the larger muscles.

Non-systemic vasculitic neuropathy.

PURPOSE OF REVIEW: This article reviews the literature on non-systemic vasculitic neuropathy, with emphasis on recent advances, summarizing the clinical presentation, diagnosis, pathology, treatment, and outcome of this condition, and speculating on its nosological status vis-à-vis the systemic vasculitides. RECENT FINDINGS: A new cohort of non-systemic vasculitic neuropathy patients was recently reported. Analysis of the clinical characteristics of this cohort demonstrated a higher incidence of painful, asymmetric, overlapping deficits than in previous studies. Extended follow-up revealed a high relapse rate, low risk of systemic spread, high incidence of chronic pain, relatively good neurological outcome, and low mortality rate. Analysis of therapeutic responses showed better outcomes with combination therapy than corticosteroid monotherapy. Another recent report proposed a role for magnetic resonance angiography in the diagnosis and follow-up of non-systemic vasculitic neuropathy. Recent pathological studies implicated proinflammatory cytokines and matrix metalloproteinase-9 in the mediation of vascular and axonal damage in non-systemic vasculitic neuropathy. SUMMARY: Non-systemic vasculitic neuropathy is one of many localized vasculitides, with involvement restricted to nerves and (possibly) muscles. Inclusion and exclusion criteria differ between reported cohorts. All require a nerve biopsy diagnostic of or suspicious for vasculitis and no extra-neuromuscular involvement. Patients typically present subacutely with a painful, multifocal/asymmetric, distal-predominant neuropathy. In the absence of clinical or laboratory evidence of systemic vasculitis or a condition predisposing to such, prognosis with treatment is good. Pathological data are supportive of a primary T-cell-mediated immunopathogenesis. Some patients classified as having non-systemic vasculitic neuropathy have a systemic vasculitis presenting with neuropathy; in others, the disease is organ-specific.

Nonsystemic vasculitic neuropathy: insights from a clinical cohort.

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 > or = 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.

New parkin mutations and atypical phenotypes in families with autosomal recessive parkinsonism.

The frequency of parkin mutations was evaluated in 30 families of highly diverse geographic origin with early-onset autosomal recessive parkinsonism. Twelve different mutations, six of which were new, were found in 10 families from Europe and Brazil. Patients with parkin mutations had significantly longer disease duration than patients without the mutation but with similar severity of disease, suggesting a slower disease course. Two patients with parkin mutations had atypical clinical presentation at onset, with predominant tremor when standing.

Pseudo-dominant inheritance and exon 2 triplication in a family with parkin gene mutations.

The authors report an Italian family with pseudo-dominant inheritance of parkinsonism attributable to parkin gene mutations. The father (disease onset at age 57 years) was homozygous for a triplication of exon 2 that is so far unique. The unaffected mother was heterozygous for deletions of exons 3 and 4, and the son (onset at age 31 years) was a compound heterozygote carrying both mutations. Thus, pseudo-dominant inheritance of parkin gene mutations has to be considered in early-onset parkinsonism, and sensitive screening techniques, such as semiquantitative multiplex PCR, should be applied.

Three parkin gene mutations in a sibship with autosomal recessive early onset parkinsonism.

The objective was to describe a family with autosomal recessive, early onset parkinsonism, with affected siblings carrying three different exon rearrangements in the parkin gene. The living affected siblings were personally examined. Molecular genetic analyses included exon dosage of the parkin gene using a semiquantitative multiplex polymerase chain reaction (PCR) protocol and haplotype analysis. The index case was a compound heterozygote with a deletion of exon 5 and a duplication of exon 3. His affected sister was a compound heterozygote for a deletion of exon 5 and a deletion of exons 3-9. Haplotype analysis confirmed the presence of three mutant alleles at the parkin locus. The phenotype was early onset parkinsonism with marked response to levodopa, and a very slow, prolonged course. In conclusion, the frequency of mutations in the parkin gene in certain populations might be high enough to cause allelic heterogeneity in the same sibship.

The wild-type conformation of the Mos-1 inverted terminal repeats is suboptimal for transposition in bacteria.

The two inverted terminal repeats (ITRs) flanking the Mos-1 mariner element differ in sequence at four positions. Gel retardation experiments indicated that each of these differences has a significant impact on the quality of the interaction between the ITR and the Mos-1 transposase. We showed that the transposase binds to the 3' ITR better than to the 5' ITR. The results of transposition assays performed in Escherichia coli indicated that these differences have an influence on the rate of transposition and the stability of the transposition products. Finally, we find that the wild-type configuration of the Mos-1 element, with one 5' ITR and one 3' ITR, is less efficient for transposition in bacteria than that of an element having two 3' ITRs.

Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from Founder effects.

A wide variety of mutations in the parkin gene, including exon deletions and duplications, as well as point mutations, result in autosomal recessive early-onset parkinsonism. Interestingly, several of these anomalies were found repeatedly in unrelated patients and may therefore result from recurrent, de novo mutational events or from founder effects. In the present study, haplotype analysis, using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, was performed in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations in the parkin gene, and each mutation was detected in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder.

Superficial peroneal nerve/peroneus brevis muscle biopsy in vasculitic neuropathy.

OBJECTIVE: To determine the sensitivity and specificity of superficial peroneal nerve (SPN)/peroneus brevis muscle (PBM) biopsy in a cohort of patients with suspected peripheral nerve vasculitis. BACKGROUND: In patients with suspected vasculitic neuropathy, combined nerve and muscle biopsies have been advocated as a way to increase the diagnostic yield, but the sensitivity and specificity of this approach have not been evaluated. Pathologic predictors of biopsy-proven peripheral nerve vasculitis have also not been analyzed in a systematic fashion. METHODS: The clinical, laboratory, and pathologic data for all patients undergoing SPN/PBM biopsy for possible vasculitis from 1986 through 1996 were analyzed. Biopsies were classified as positive, negative, or suspicious for vasculitis. Patients were then divided into vasculitis and nonvasculitis cohorts by final clinical diagnosis. RESULTS: Of 70 SPN/PBM biopsies, 22 (30%) showed definite vasculitis; nerve was diagnostic in 90% (n = 20) and muscle in 50% (n = 11). Nerve biopsy had a higher yield than muscle in patients with nonsystemic vasculitic neuropathy (p = 0. 0047) but not in those with systemic vasculitis. The estimated sensitivity of a positive SPN/PBM biopsy for vasculitis was 60%. Considering biopsies either positive or suspicious for vasculitis increased the sensitivity to 86% with a corresponding specificity of 85%. Pathologic features associated with necrotizing vasculitis were muscle fiber necrosis/regeneration (relative risk 18.1; 95% CI 3.4 to 96.1), predominant axonal nerve pathology (>8.8; >1.0 to 77.4), Wallerian-like degeneration (5.6; 1.4 to 21.9), and asymmetric nerve fiber loss (4.6; 1.4 to 15.9). CONCLUSIONS: These findings establish the yield, sensitivity, and specificity of SPN/PBM biopsy for diagnosing vasculitic neuropathy and validate the use of suggestive pathologic features for diagnosing cases lacking definite necrotizing vascular changes.

Painful sensory neuropathy: prospective evaluation using skin biopsy.

OBJECTIVE: In patients presenting with painful, burning feet with minimal signs of neuropathy, the following questions were addressed: 1) How many of these patients have a peripheral neuropathy? 2) What is the role of skin biopsy in establishing a diagnosis of neuropathy? 3) What conditions are associated with the neuropathy? and 4) What laboratory studies are useful in this patient population? METHODS: A total of 117 consecutive patients referred for evaluation were prospectively studied. All underwent nerve conduction studies (NCS) and a battery of blood tests, including antinerve antibodies. If NCS were normal, a punch biopsy of the skin of the distal leg was performed to ascertain the intraepidermal nerve fiber (IENF) density. In a subset of 32 patients, the sensitivity of skin biopsy was compared to quantitative sudomotor axon test (QSART) and quantitative sensory tests (QST). RESULTS: Three groups emerged. Group 1, with abnormal NCS (n = 60, 34 F/26 M, mean age 60 +/- 14 years), represented 51% of the cohort. The majority had neuropathies of undetermined cause, but 18 (30%) had associated conditions. Group 2, with normal NCS and reduced IENF density (n = 44, 29 F/15 M, mean age 57 +/- 14 years), represented 38% of the cohort. Three in this group had associated conditions. Group 3, with normal NCS and IENF density (n = 13, 6 F/7 M, mean age 53 +/- 13 years), represented 11% of the cohort; most had no diagnoses but two had MS. In a comparative subset analysis, skin biopsy was more sensitive than QSART or QST in diagnosing a neuropathy. CONCLUSIONS: Patients presenting with painful feet are heterogeneous, consisting of both large and small fiber sensory neuropathies. In rare cases, a central cause for pain can be found. Over one-third of patients required a skin biopsy to diagnose a small fiber sensory neuropathy. A limited battery of blood tests facilitated diagnosis, but serum antinerve antibodies were not helpful.

Quantitative electrophysiologic studies in sporadic inclusion body myositis.

Sporadic inclusion body myositis (S-IBM) is a progressive, acquired disease of unknown etiology. Prior studies have suggested neurogenic involvement based on electrophysiologic data, although the biopsy is compatible with a myopathic process. Quantitative electrophysiologic studies were performed in the biceps brachii of 17 subjects with biopsy-proven S-IBM. Quantitative motor unit action potential (MUAP) analysis was compatible with myopathy in 16 subjects, with the remaining subject being within normal limits. Quantitative interference pattern was myopathic in all 13 subjects studied. Macro-EMG MUAP amplitude was reduced in 3 of 17 studies; the remainder were within normal range, and none was increased as would be expected in neurogenic disease. Fiber density was normal to borderline increased in all subjects. Possible reasons for encountering neurogenic-appearing MUAPs may include choice of muscle studies, because some patients have co-existing polyneuropathy and large-amplitude MUAPs from hypertrophied muscle fibers. The data from this study indicate that S-IBM is a myopathic process.