Chronic motor neuropathies.
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Autoantibodies↗
Biomedical subjects
A Pestronk
Publications and source records attributed to A Pestronk.
Increased incidence of paraproteinemia and autoantibodies in patients with normal-pressure glaucoma.
We assessed the incidence of paraproteins and autoantibodies in 44 patients (mean age, 65.3 +/- 1.9 years) with normal-pressure glaucoma and 41 patients (mean age, 68.8 +/- 1.8 years) monoclonal proteins occurred more often (P = .0047) in patients with normal-pressure glaucoma (eight of 44, 18%) than in control subjects with primary open-angle glaucoma (zero of 41, 0%). Autoantibodies to extractable nuclear antigens, most often Sjögren's syndrome A antigen (SSA[Ro]), were also found more frequently (P = .0022) in patients with normal-pressure glaucoma (13 of 44, 30%) than in control subjects (one of 41, 2%). Paraproteins and autoantibodies to extractable nuclear antigens generally occurred in different patients with an overall incidence of 20 of 44 (45%) patients with normal-pressure glaucoma. In contrast, no significant difference in the incidence of antinuclear antibodies existed between the groups. These findings suggest that humoral immune mechanisms may have a role in the pathogenesis of optic neuropathy in patients with normal-pressure glaucoma.
Adult↗
Trial of immunosuppression in amyotrophic lateral sclerosis using total lymphoid irradiation.
Although the cause of amyotrophic lateral sclerosis (ALS) remains unknown, recent studies have suggested an autoimmune mechanism of pathogenesis. Previous trials of immunosuppressive treatment have yielded inconclusive results. Our study was designed to determine whether more powerful and prolonged immunosuppression, produced by total lymphoid irradiation (TLI), would alter the course of ALS. In a double-blind, randomized, placebo-controlled study, 30 patients with classic ALS were treated with TLI, and 31 were given sham radiation. Quantitative measurements of muscle strength, functional motor activity, and humoral and cellular immune status were followed for 2 years, or until death or respirator dependence. Motor function in the TLI-treated and control groups showed no significant differences throughout the study. Overall survival was not significantly different in the TLI-treated and control groups. TLI effectively suppressed cellular and humoral immune function throughout the 2-year study period. Analysis of the relationship between immunosuppression and motor functions showed no consistent effect of treatment. We conclude that powerful and prolonged immunosuppression produced by TLI did not benefit patients with ALS. This fails to support the concept of an autoimmune mechanism of pathogenesis of ALS.
Amyotrophic Lateral Sclerosis↗
The clinical correlates of high-titer IgG anti-GM1 antibodies.
Serum IgG anti-GM1 antibodies have been reported to occur in a variety of disorders, including Guillain-Barré syndrome and chronic polyneuropathies. Of over 5,000 serums tested in our laboratory, high titers of selective IgG anti-GM1 antibodies (> 1:1,000) and without binding to sulfatide were found in 35 patients. Clinical correlation revealed that almost all patients had axonal, motor neuropathies. One subgroup was comprised of individuals with an acute motor neuropathy, described either as an acute axonal Guillain-Barré-like syndrome that was occasionally associated with a prodrome of Campylobacter jejuni enteritis or as Chinese paralysis syndrome. A second group of patients had chronic asymmetric lower motor neuron (LMN) syndromes with no conduction block or other evidence of demyelination. The presence of selective high-titer IgG anti-GM1 antibody reactivity in serum is uncommon but when present is strongly associated with acute axonal motor neuropathies or chronic asymmetric LMN syndromes.
Antibodies↗
Rapidly evolving myopathy with myosin-deficient muscle fibers.
Five patients with rapidly evolving, severe weakness had an unusual myopathy with virtually complete loss of myosin in 5 to 40% of muscle fibers. Three of the 5 patients began to develop weakness 1 to 2 weeks after lung transplantation. The fourth became weak after a febrile illness. The fifth presented with diabetic ketoacidosis and weakness. All patients had received corticosteroid therapy. In all cases the weakness was progressive and led to severe disability, with respiratory failure in 4 patients. Initial diagnostic testing did not localize an underlying cause for the weakness. Creatine kinase was normal or minimally elevated. Electromyography generally showed mildly myopathic or nondiagnostic changes. However, muscle biopsy revealed numerous small angular fibers with no myosin ATPase staining at any pH. Immunocytochemical staining and ultrastructural studies confirmed a severe loss of myosin in many fibers. This rapidly evolving myopathy with myosin-deficient muscle fibers appears to be different clinically and pathologically from previously described syndromes involving rapidly progressive weakness. Slow recovery over a period of months is the most common outcome.
Adult↗
The clinical and diagnostic role of anti-GM1 antibody testing.
There is increasing evidence that multifocal motor neuropathy (MMN) and some lower motor neuron (LMN) syndromes are immune-mediated and treatable. The frequent occurrence of high titers of anti-GM1 antibodies in these motor neuropathies raised hopes that serum testing would provide useful diagnostic information. Unfortunately, in routine practice, simple quantification of IgM binding to GM1 ganglioside has proved to be a test with poor sensitivity and specificity. We have found that much greater sensitivity and specificity for MMN and LMN syndromes can be obtained by determining serum antibody binding to panels of antigens, such as GM1, histone H3, and NP-9. These results suggest that combined measurement of serum antibody binding to GM1 and other antigens can provide tests that are useful in the diagnosis and management of motor neuropathy syndromes.
Antibodies↗
Treatable gait disorder and polyneuropathy associated with high titer serum IgM binding to antigens that copurify with myelin-associated glycoprotein.
We studied clinical and electrodiagnostic features of 9 patients with very high titers (> 1:10,000) of serum IgM binding to a CNS myelin antigen (CMA) preparation that copurified with myelin-associated glycoprotein (MAG). We found that 8 of the 9 patients had a combined syndrome of gait ataxia and polyneuropathy (GAPN) with late-age onset (mean = 70 years of age). In the 8 GAPN patients progressive difficulty with ambulation led to significant functional disability and frequent falling. Examination showed a wide-based unsteady gait, especially when standing still or turning. There was mild-to-moderate distal sensory loss with involvement of joint position sense only in the toes. Motor changes, when present, were mild and mainly involved distal leg musculature. Treatment of 5 GAPN patients resulted in clear improvement of 2 after intravenous human immunoglobulin and of 3 others after other immunodulating agents. Immune-mediated GAPN syndromes with high titers of serum IgM binding to CMA appear to be treatable causes of gait disorders in older patients.
Aged↗
Chronic immune demyelinating neuropathies.
The classification of immune-mediated demyelinating polyneuropathies has become more complex in recent years. Initial definitions of chronic inflammatory demyelinating polyneuropathy (CIDP) were often broad enough to include almost any acquired polyneuropathy with demyelinating features. However, subdivision of acquired demyelinating polyneuropathies into different categories seems justified because 1) several distinct clinical syndromes have been identified, 2) characteristic and distinctive patterns of serum antibody binding are associated with each specific clinical syndrome and, 3) the syndromes respond differently to immune modulating treatments (Table 1). Larger series and controlled trials will be necessary to determine the therapeutic regimens that optimize the benefit:risk considerations for patients with these syndromes.
Autoantibodies↗
Distal lower motor neuron syndrome with high-titer serum IgM anti-GM1 antibodies: improvement following immunotherapy with monthly plasma exchange and intravenous cyclophosphamide.
Motor neuropathies associated with electrodiagnostic evidence of motor conduction block often improve after treatment with immunotherapy, but there is less evidence about the responsiveness of lower motor neuron (LMN) syndromes without conduction block. In this study we treated four patients with an asymmetric, predominantly distal LMN syndrome associated with high serum titers of IgM anti-GM1 ganglioside antibodies but without conduction block on electrodiagnostic testing. Treatment courses consisted of five to seven repeated monthly regimens of plasma exchange on 2 consecutive days followed, on day 3, by intravenous cyclophosphamide (1 g/m2). The results of treatment were quantitatively measured using hand-held dynamometry. We found that all four patients showed progressive improvement in strength over the 6 to 24 months following treatment. Improvement was documented by both objective muscle testing and patient reports of increased strength and less fatigability. We conclude that immunotherapy may be followed by useful functional benefit in selected patients with an asymmetric, predominantly distal LMN syndrome associated with high serum titers of IgM anti-GM1 antibodies. Gradual improvement often begins as late as 6 to 9 months after the onset of treatment and may persist for 1 to 2 years, or longer, after immunosuppressive treatment is stopped.
Adult↗
Progression of multifocal motor neuropathy during apparently successful treatment with human immunoglobulin.
We report a patient with multifocal motor neuropathy (MMN) who experienced a paradoxical decline in baseline strength to below pretreatment levels during a period of improvement associated with human immunoglobulin (HIG) administration. This outcome suggests that HIG may not limit progression of MMN and may reduce the utility of HIG as chronic therapy.
Humans↗
Anti-MAG antibodies: major effects of antigen purity and antibody cross-reactivity on ELISA results and clinical correlation.
There is controversy regarding the relationship of polyneuropathy syndromes to the presence of serum antibody binding to myelin-associated glycoprotein (MAG). Using standard ELISA methodology, we identified 74 sera that appeared to have high titers of IgM binding to MAG and found that only 34% of these sera stained MAG using Western blot methodology. Follow-up studies showed that two factors greatly influence concordance between ELISA and Western blot testing for anti-MAG antibodies. Sera with high titers of binding to both MAG and histone H3 identified by ELISA rarely stain MAG on Western blot. In addition, sera analyzed by ELISA often bind to impurities in the semipure MAG that is frequently used in ELISA assays. Further purifications to separate MAG from other contaminants improved concordance between ELISA and Western blot results to 85% to 90% in a retrospective analysis, as well as in a prospective study of 49 additional sera. Patients with a polyneuropathy and serum IgM binding to MAG preparations by ELISA but not by Western blot methodology had several different clinical syndromes, including gait disorders and asymmetric motor neuropathies. Patients with IgM binding to MAG by both assay methods usually had a distal, sensory-motor, symmetric polyneuropathy with some features of demyelination on electrodiagnostic testing.
Adult↗
A novel therapy for myasthenia gravis by reducing the endocytosis of acetylcholine receptors.
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Animals↗
Autoimmune myasthenia gravis.
The evident defect in this disease is postsynaptic dysfunction due to anti-acetylcholine receptor antibodies. The postsynaptic membrane is simplified, the number of acetylcholine receptors is reduced, and neuromuscular transmission is impaired. Antiacetylcholinesterase drugs still play a role in management. Newer options include prednisone, azathioprine, and cyclosporine.
Adult↗
Immune-mediated neuropathies.
Identification of immune-mediated neuropathies is important as these disorders often respond to treatment. Patterns of binding of serum M (monoclonal) proteins and autoantibodies correlate with, and may be diagnostic markers for, specific polyneuropathy syndromes. There is evidence that some of these antibodies may play a pathogenic role in polyneuropathy syndromes. Identification of specific immune polyneuropathy syndromes provides guidance regarding immunosuppressive regimens that may be effective treatments.
Autoantibodies↗
Duchenne dystrophy: randomized, controlled trial of prednisone (18 months) and azathioprine (12 months)
Prednisone has been shown to improve strength in Duchenne dystrophy. Azathioprine often benefits corticosteroid-responsive diseases and can reduce the dose of prednisone needed. The present study reports a randomized, controlled trial of prednisone and azathioprine designed to assess the longer-term effects of prednisone and to determine whether azathioprine alone, or in combination with prednisone, improves strength. Ninety-nine boys (aged five to 15 years) with Duchenne dystrophy were randomized to one of three groups: (I) placebo; (II) prednisone 0.3 mg/kg/d; or (III) prednisone 0.75 mg/kg/d. After 6 months, azathioprine 2 to 2.5 mg/kg/d was added in groups I and II and placebo added in group III. The study showed that the beneficial effect of prednisone (0.75 mg/kg/d) is maintained for at least 18 months and is associated with a 36% increase in muscle mass. There was weight gain, growth retardation, and other side effects. Azathioprine did not have a beneficial effect. This study suggests that prednisone's beneficial effect is not due to immunosuppression.
Adolescent↗
High-titer selective serum anti-beta-tubulin antibodies in chronic inflammatory demyelinating polyneuropathy.
Although chronic inflammatory demyelinating polyneuropathy (CIDP) is presumed to be an autoimmune disorder, no neural antigen has been recognized as an immune target. We found that serum IgM from a patient with CIDP and an IgM paraprotein reacted with a 53-kd protein by Western blot analysis. Amino acid sequence analysis identified this protein as beta-tubulin. We then studied sera from 70 CIDP patients, 35 Guillain-Barré syndrome (GBS) patients, and 483 disease (amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis, diabetes, and other polyneuropathies) and normal controls for selective high-titer anti-beta-tubulin using ELISA methodology. Forty-two percent (30/70) of patients with CIDP had selective high titer IgM reactivity against beta-tubulin; 23% (16/70) had selective high-titer IgG reactivity against beta-tubulin. Overall, 57% of CIDP patients, 20% of GBS patients, and 2% of control patients had selective, high serum IgM or IgG anti-beta-tubulin reactivity. Selective high-titer serum anti-beta-tubulin antibodies occur in a majority of patients with CIDP but are rare in other chronic neuropathies or CNS disorders.
Adult↗
Monoclonal gammopathy and neuropathy.
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Antibodies, Monoclonal↗
Nerve conduction studies in amyotrophic lateral sclerosis.
Nerve conduction studies (NCS) are an integral part of the evaluation of amyotrophic lateral sclerosis (ALS) patients and are useful in distinguishing ALS from disorders that mimic it. The question often arises whether in the presence of severe atrophy and reduction of the compound muscle action potential amplitude, abnormal conduction velocity (CV), distal latency (DL), or F-wave latency (F) exceeds what can be expected from ALS alone. To determine the limits of abnormality in classic ALS, we prospectively evaluated NCS data from 61 patients who met a strict clinical definition of ALS. We related CV, DL, and F to distal evoked amplitude (AMP) in peroneal (n = 63 observations), median (n = 50), and ulnar (n = 52) nerves. In nerves with reduced AMP, CV rarely fell to less than 80% of the lower limit of normal, and DL and F rarely exceeded 1.25 times the upper limit of normal. Utilizing the entire data set and regression analyses, 95% confidence limits for expected values for CV, F, and DL as a function of AMP were calculated. These limits thus derived suggest criteria for NCS abnormalities in ALS and may be useful in differentiating ALS from other illnesses.
Action Potentials↗