g(m1)-ganglioside and Motor-Neuron-Disease

Multifocal motor neuropathy (MMN) is characterized by asymmetric weakness of limbs and the electrophysiological finding of conduction block in motor nerves. Conduction block is the inability of nerves to propagate action potentials and is probably caused by immune-mediated dysfunction of the axon at the nodes of Ranvier or the myelin sheath. MMN immune pathogenesis has not been elucidated.. In approximately 50% of all patients, IgM antibodies that bind to the glycolipid GM1, which is abundantly expressed in peripheral motor nerves, can be detected. A recent study showed an association with HLA-DRB1*15, and virtually all patients respond to treatment with intravenous immunoglobulin (IVIG) in at least the early stages of the disease.. This review aims at providing a concise overview of what is known about MMN pathogenesis, and how the beneficial effect of IVIG might be explained.

Topics: Adult; Aged; Autoantibodies; Autoantigens; Autoimmune Diseases of the Nervous System; Female; Forecasting; G(M1) Ganglioside; Genetic Predisposition to Disease; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease; Neural Conduction; Peripheral Nerves; Young Adult

Multifocal motor neuropathy (MMN) is now a well-defined purely motor multineuropathy characterized by the presence of multifocal partial motor conduction blocks (CB), frequent association with anti-GM1 IgM antibodies, and usually a good response to high-dose intravenous immunoglobulin (IVIg) therapy. However, several issues remain to be clarified in the diagnosis, pathogenesis, and therapy of this condition including its nosological position and its relation to other chronic dysimmune neuropathies; the degree of CB necessary for the diagnosis of MMN; the existence of an axonal form of MMN; the pathophysiological basis of CB; the pathogenetic role of antiganglioside antibodies; the mechanism of action of IVIg treatments in MMN and the most effective regimen; and the treatment to be used in unresponsive patients. These issues are addressed in this review of the main clinical, electrophysiological, immunological, and therapeutic features of this neuropathy.

Topics: Animals; Autoantibodies; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Motor Neuron Disease; Motor Neurons; Neural Conduction; Neuritis; Peripheral Nerves

Topics: Alzheimer Disease; Biomarkers; G(M1) Ganglioside; Guillain-Barre Syndrome; Hematologic Tests; Humans; Motor Neuron Disease; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Specimen Handling

Multifocal motor neuropathy (MMN) is a recently identified peripheral nerve disorder characterized by progressive, predominantly distal, asymmetric limb weakness mostly affecting upper limbs, minimal or no sensory impairment, and by the presence on nerve conduction studies of multifocal persistent partial conduction blocks on motor but not sensory nerves. The etiopathogenesis of MMN is not known, but there is some evidence, based mostly on the clinical improvement after immunological therapies, that the disease has an immunological basis. Antibodies, mostly IgM, to the gangliosides GM1, and though less frequently, GM2 and GD1a, are frequently detected in patients' sera, helping in the diagnosis of this disease. Even if there is some experimental evidence that these antibodies may be pathogenic in vitro, their role in the neuropathy remains to be established. Patients with MMN do not usually respond to steroids or plasma exchange, which may occasionally worsen the symptoms, while the efficacy of cyclophosphamide is limited by its relevant side effects. More than 80% of MMN patients rapidly improve with high dose intravenous immunoglobulin therapy (IVIg). The effect of this therapy is, however, transient and improvement has to be maintained with periodic infusions. A positive response to interferon-beta has been recently reported in a minority of patients, some of whom were resistant to IVIg. Even if many progresses have been made on the diagnosis and therapy of MMN, there are still several issues on the nosological position, etiopathogenesis and long-term treatment of this neuropathy that need to be clarified.

Topics: Autoantibodies; Chronic Disease; Cyclophosphamide; Diagnosis, Differential; Electrodiagnosis; Female; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Interferon-beta; Male; Motor Neuron Disease; Neural Conduction; Peripheral Nervous System Diseases; Polyradiculoneuropathy

Topics: Amyotrophic Lateral Sclerosis; Autoantibodies; Autoimmune Diseases; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Immunoglobulin M; Motor Neuron Disease; Sensitivity and Specificity

Topics: Antibody Specificity; Autoantibodies; Autoantigens; Autoimmune Diseases; Brain; Carbohydrate Sequence; CD57 Antigens; Chronic Disease; G(M1) Ganglioside; Gangliosides; Globosides; Glycolipids; Guillain-Barre Syndrome; Humans; Immunoglobulin M; Molecular Sequence Data; Motor Neuron Disease; Myelin Sheath; Paraproteinemias; Peripheral Nervous System; Polyradiculoneuropathy; Sulfoglycosphingolipids

Topics: Autoantibodies; Cyclophosphamide; Diagnosis, Differential; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Motor Neuron Disease; Nerve Tissue; Prognosis

Topics: Autoantibodies; G(M1) Ganglioside; Humans; Motor Neuron Disease; Prognosis; Syndrome

Multifocal motor neuropathy (MMN) and some lower motor neuron syndromes are immune-mediated and treatable. These motor syndromes produce weakness that is typically distal and asymmetric, involves the arms early in the course of disease, and progresses slowly. Electrophysiologic abnormalities often include evidence of demyelination, especially focal conduction block, selectively on motor axons. High titers of serum IgM binding to GM1 ganglioside, alone or in a membrane environment, occur in 80-90% of patients with MMN. Treatments for MMN that commonly produce increased strength include IV human immune globulin (HIG) and cyclophosphamide. After an initial treatment with 2 g/kg of HIG, up to 80% of patients with MMN show short-term improvement. Long-term HIG treatment is useful in 60% of MMN patients and has few side effects but is costly. Intravenous cyclophosphamide treatment is effective in 70% of MMN patients but has significant toxicity, and is reserved for patients who have severe disease and do not respond adequately to HIG.

Topics: Antibodies; Electrodiagnosis; G(M1) Ganglioside; Humans; Motor Neuron Disease

Topics: Antibodies; Demyelinating Diseases; Diagnosis, Differential; G(M1) Ganglioside; Humans; Immunoglobulin M; Motor Neuron Disease

Autoantibodies to Gal(beta 1-3)GalNAc epitopes on glycolipids and glycoproteins are associated with motor neuron disease and motor or sensorimotor neuropathy. These epitopes are ubiquitously distributed on cell surfaces. In the nervous system they are present on axons and myelin, specifically also at the nodes of Ranvier. Binding of GM1 antibodies to the nodal area may contribute to disease development in some of these conditions.

Topics: Animals; Antigens, Tumor-Associated, Carbohydrate; Autoantibodies; Autoimmune Diseases; G(M1) Ganglioside; Humans; Motor Neuron Disease; Ranvier's Nodes

Since the first cases described in 1986, multifocal motor neuropathy with persistent conduction blocks (MMN) appears to be a well-defined nosological entity. Clinical features include male-predominant occurrence, weakness often accompanied by cramps and fasciculations; topography of the motor involvement is characterized by assymetry, upper limb predominance, relation to the distribution of individual nerves or roots. Atrophy is variable but can lack despite severe weakness. Multifocal, purely motor and persistent conduction blocks are the electrophysiological hallmark of the disease. Serum antibodies against ganglioside GM1 are frequently associated with MMN but their diagnostic sensitibity and specificity are discussed. However high level of these antibodies may be a useful immunological marker of MMN. Their pathogenic role is probable, perhaps by their interaction with ionic channels localized in node of Ranvier. Morphological findings, immunologic abnormalities and improvement with intravenous immunoglobulin therapy define MMN as a type of inflammatory demyelinating neuropathy. Their relation with CIDP are discussed.

Topics: Adult; Aged; Animals; Antibodies; Demyelinating Diseases; Female; G(M1) Ganglioside; Humans; Male; Middle Aged; Motor Neuron Disease; Neural Inhibition

We performed a meta-analysis on the diagnostic value of IgM anti-GM1 antibodies. The reported frequencies of IgM anti-GM1 antibodies ranged from 0 to 100% for patients with multifocal motor neuropathy (MMN), from 0 to 33% in the Guillain-Barré syndrome, from 0 to 65% in amyotrophic lateral sclerosis (ALS), from 0 to 77% in chronic inflammatory demyelinating neuropathy, and from 0 to 81% in lower motor neuron disease (LMND). However, using funnel graphs and a chi-square test we determined that the method of ELISA was the most important factor explaining these differences. After allowing for two factors--the use of detergent and the duration and temperature of serum incubation-studies became homogeneous in all but the LMND group of method A (no detergent, duration of serum incubation 5 hours) and the ALS group of method B (no detergent, duration of serum incubation at least 12 hours [overnight]). Since the anti-GM1 antibody assay serves to confirm clinical suspicion of MMN rather than to exclude the disease, specificity is more important than sensitivity. ELISA methods that do not use detergent and that incubate serum overnight resulted in a specificity of 90% and sensitivity of 38% in the comparison of MMN and LMND. With these values we calculated incremental ruling-in and ruling-out gain curves. Prior probabilities between 20 and 60% for having MMN changed to post-test probabilities between 50 and 85%, which is of clinical importance. In conclusion, ELISA is a useful diagnostic test to demonstrate IgM anti-GM1 antibodies provided the methods do not use detergent and do incubate serum overnight.

Topics: Antibodies; G(M1) Ganglioside; Humans; Immunoglobulin M; Motor Neuron Disease; Nervous System Diseases

Electrodiagnosis rests upon sound anatomical and physiological bases of the peripheral nervous system, which are utilized for the dynamic process of differential diagnosis. If clinical and electrophysiological findings do not conform to any of the previously known diseases, there may be a chance of identifying a new entity. As an example, we report nine Japanese patients with unilateral atrophy of the distal upper limb and the cervical cord. Symptoms typically began insideously in young adulthood, progressed for a few years and then stabilized. Distribution of the muscle weakness usually corresponded to the territories of a few peripheral nerves, although not accompanied by sensory deficits. Serum anti-GM1 IgG antibodies were elevated in 6 out of 9 patients. Electrophysiological testings disclosed absent or delayed F-waves in the nerve involved. No long tract signs of the cord were demonstrated, although the spinal cord atrophy was extensive in some patients. Three showed partial clinical improvement after cyclophosphamide therapy or intravenous immunoglobulin. These findings may suggest that this entity is immune-mediated as in multifocal motor neuropathy, with its blunt of immune attack directed not only to peripheral motor nerves but also to spinal motor neurons.

Topics: Adolescent; Adult; Diagnosis, Differential; Electrodiagnosis; Electromyography; G(M1) Ganglioside; Humans; Immunoglobulin G; Male; Median Nerve; Motor Neuron Disease; Neural Conduction; Neuromuscular Diseases

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.

Topics: Antibodies; Antigen-Antibody Reactions; Demyelinating Diseases; G(M1) Ganglioside; Humans; Motor Neuron Disease; Nervous System Diseases

Multifocal motor neuropathy has pure motor manifestation and nonremittent clinical courses. Antiganglioside antibodies, though variable in titers, are characteristically elevated in the majority of these patient. In our cases, pathological findings at the site of conduction block suggested impaired remyelination and disruption of blood-nerve barrier. These findings lead us to postulate that antibodies toward gangliosides or toward unknown antigens containing gangliosides initiate motor-specific demyelination. The lesion, once produced, may persist as a result of impaired remyelination caused by disrupted blood-nerve barrier. The antibodies bound to denuded axons may also interfere with a remyelinative process. If so, antibodies may not always be circulating, thus accounting for variable levels of titers.

Topics: Antibodies; Blood Physiological Phenomena; Demyelinating Diseases; G(M1) Ganglioside; Humans; Motor Neuron Disease; Nervous System Physiological Phenomena; Neural Conduction

Multifocal motor neuropathy (MMN) is a disorder with a highly characteristic clinical picture and one which is defined by a specific electrodiagnostic abnormality, namely, multifocal conduction block which is confined to motor axons. Sensory axons which traverse segments of severe or even complete motor conduction block conduct normally. A proportion of patients with MMN also have elevated levels of antibodies to GM1 ganglioside. However, about one half of MMN patients lack elevated levels of these antibodies and many others have only modest elevations, to a degree often seen in other neurological and even non-neurological disorders. Furthermore, clinical and electrophysiological improvement of MMN in response to treatment with high dose intravenous immunoglobulin is achieved in the absence of any change in antiglycolipid levels. Injection of serum from patients with MMN and elevated GM1 antibody levels produces demyelination in recipient rat nerves, suggesting a pathogenetic role for these antibodies in demyelination. However, sera of patients with identical antibody titers in other motor system diseases produced no demyelination, suggesting that the demyelinating factor resides in some other serum fraction. At present, there is insufficient evidence to support the contention that these antibodies play a critical pathogenetic role in MMN. Until more evidence is available it is important to define MMN on the basis of a characteristic clinical picture and a unique electrodiagnostic abnormality rather than on a pattern of serum antibodies.

Topics: Animals; Antibodies; Autoimmune Diseases; G(M1) Ganglioside; Glycolipids; Humans; Motor Neuron Disease; Nervous System Diseases; Rats

This paper describes patients with demyelinating motor neuropathies associated with conduction blocks, pure motor neuropathies and intermediate forms with resemblances to amyotrophic lateral sclerosis, in persons with raised titres of anti-GM1 antibodies. The specificity of the abnormal anti-GM1 antibody titres is discussed, and the possibilities of immunosuppressive therapy mentioned.

Topics: Antibodies; Antibody Specificity; Demyelinating Diseases; G(M1) Ganglioside; Glycolipids; Humans; Motor Neuron Disease; Neural Conduction

Topics: Autoantibodies; G(M1) Ganglioside; Humans; Motor Neuron Disease; Neuromuscular Diseases

Topics: Adult; Animals; Autoantibodies; Disease Models, Animal; G(M1) Ganglioside; Humans; Male; Middle Aged; Motor Neuron Disease; Neural Conduction; Rats

High titers of IgM anti-GM1 antibodies are commonly found in the serum of patients with some lower motor neuron disorders and peripheral neuropathies. Enzyme-linked immunosorbent assays (ELISA) are useful for the detection and quantitation of anti-GM1 antibodies. Testing for serum anti-GM1 activity is indicated in the diagnostic evaluation of lower motor neuron syndromes. The presence of high titers of anti-GM1 antibodies mandates careful electrophysiologic testing for the motor conduction block that is found in multifocal motor neuropathy, a treatable disorder. Quantitation of anti-GM1 antibodies may also be a useful guide in the treatment of multifocal motor neuropathy. Further study of antiglycolipid antibodies in motor neuron disorders and peripheral neuropathies may provide clues to the events that stimulate these antibodies and to the pathogenesis of such syndromes.

Topics: Amyotrophic Lateral Sclerosis; Antibody Specificity; Autoantibodies; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Motor Neuron Disease; Neuromuscular Diseases; Peripheral Nervous System Diseases

Multifocal motor neuropathy (MMN) is an immune-mediated disorder characterized by slowly progressive asymmetrical limb weakness. Treatment with immunoglobulins (IVIg) leads to improvement of muscle strength. Anecdotal evidence suggests that immunosuppressive drugs as adjunctive therapy may be beneficial. Mycophenolate mofetil (MMF) is a potent and safe immunosuppressant. Safety and efficacy of MMF as adjunctive therapy for MMN patients receiving IVIg maintenance treatment were evaluated in a randomized controlled trial. MMN patients responding to IVIg treatment were eligible for randomization. Muscle strength and functional status were assessed at monthly intervals for 1 year. Three months after the start of MMF or placebo treatment, IVIg doses were reduced stepwise, until a deterioration of functioning or decline in muscle strength could be observed. An IVIg dose reduction of 50% during adjunctive treatment was defined as a primary endpoint. Secondary outcome measures were improvement in muscle strength and functional status after 3 months and reduction of anti GM1-IgM titres after 12 months of MMF treatment. Twenty-eight patients were randomized. One patient allocated to MMF reached the primary endpoint of 50% IVIg dose reduction. After 12 months IVIg reduction did not differ significantly between the two treatment groups. Patients did not experience drug toxicity and none of the patients showed significant disease progression after 12 months. Muscle strength and functional scores after 3 months and anti GM1-IgM titres after 12 months did not change. Adjunctive treatment of MMN patients with MMF at a dose of 1 g twice daily is safe but does not alter disease course or allow significant reduction of IVIg doses.

Topics: Adult; Aged; Autoantibodies; Autoimmune Diseases; Chemotherapy, Adjuvant; Disease Progression; Double-Blind Method; Drug Administration Schedule; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Middle Aged; Motor Neuron Disease; Muscle Strength; Muscle, Skeletal; Mycophenolic Acid; Treatment Outcome

We conducted a double-blind, placebo-controlled, study of 19 patients fulfilling eligibility criteria for multifocal motor neuropathy with persistent conduction block. They were enrolled and divided into two groups: those who had never been treated previously with intravenous immunoglobulins (IVIg) (Group 1: 10 patients) and those who presented recurrent symptoms after previously successful treatment with IVIg (Group 2: nine patients). They were randomized prospectively to receive either IVIg or placebo at a dose of 500 mg/kg/day for 5 consecutive days, once a month for 3 months. At month 4, patients found to be responders remained on the same treatment for the 3 following months, while non-responders were switched to the alternative study drug for the 3 following months. Clinical assessment was conducted with the MRC score in 28 muscles and a self-evaluation scale (five daily motor activities scored from 0 to 5). In Group 1, nine patients completed the study, of whom initially four received IVIg and five placebo; four patients responded to IVIg (two at months 4 and 7, and a further two at month 7 after switching treatment at month 4), two patients responded to placebo at months 4 and 7, and three patients did not respond to either treatment. In Group 2, nine patients completed the study. Five patients first received IVIg and all responded at months 4 and 7. Four patients first received placebo and none responded at month 4; all were then switched to IVIg and three responded at month 7. When the 18 patients were considered together, seven out of the nine patients who received IVIg first were responders at month 4, compared with two of the nine patients who received placebo first, a difference that was statistically significant (P = 0.03). On the other hand, there was no significant difference in MRC score but a significant difference in the self-evaluation score, at month 4, between IVIg patients and placebo patients. Electrophysiological studies did not show significant differences at month 4 in motor parameters between IVIg patients and placebo patients. IgM anti-GM1 titres did not change significantly in patients treated with IVIg compared with those who received placebo, between baseline, month 4 and month 7. However, of five patients who had significantly high anti-GM1 titres (>3200) at baseline, four responded to IVIg. This trial confirms that IVIg is a promising therapeutic option for multifocal motor neuropathy.

Topics: Adult; Aged; Autoantibodies; Double-Blind Method; Electromyography; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease; Motor Skills; Neural Conduction; Polyradiculoneuropathy; Prospective Studies; Treatment Outcome

We studied the effects of intravenous immunoglobulin (IVIg) in 12 patients with motor neuron syndromes associated with high titers of anti-GM1 antibodies. Five of the patients had conduction blocks. The study design was a double-blind, placebo-controlled, crossover trial with IVIg (0.4 g/kg body weight per day injected for 5 consecutive days). We evaluated the patients before and 5, 28, and 56 days after drug administration using a computerized analyzer for muscle strength, the Norris scale for disability, motor nerve conduction velocities for patients with conduction blocks, and measurements of immunologic markers. Compared with placebo, IVIg induced a significant increase in muscle strength only in the patients with conduction blocks.

Topics: Adult; Autoantibodies; Double-Blind Method; Female; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Isometric Contraction; Male; Middle Aged; Motor Neuron Disease

To determine if response to immunosuppressive treatment in motor neuron syndromes could be predicted on the basis of clinical features, anti-GM1 antibodies, or conduction block.. Prospective, uncontrolled, treatment trial using prednisone for 4 months followed by intravenous cyclophosphamide (3 g/m2) continued orally for 6 months.. All patients were referred to university hospital medical centers.. Sixty-five patients with motor neuron syndromes were treated with prednisone; 11 patients had elevated GM1 antibody titers, and 11 patients had conduction block. Forty-five patients received cyclophosphamide, eight of whom had elevated GM1 antibodies and 10 had conduction block.. One patient responded to prednisone, and five patients responded to cyclophosphamide treatment. Only patients with a lower motor neuron syndrome and conduction block improved with either treatment. Response to treatment did not correlate with GM1 antibodies.. GM1 antibodies did not serve as a marker for improvement in patients with motor neuron syndrome treated with immunosuppressive drugs. Patients with amyotrophic lateral sclerosis failed to improve irrespective of laboratory findings.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Cyclophosphamide; Female; G(M1) Ganglioside; Humans; Immunosuppressive Agents; Male; Middle Aged; Motor Neuron Disease; Neural Conduction; Prednisone; Prospective Studies

Multifocal motor neuropathy is a rare, immune-mediated motor neuropathy with asymmetric, often debilitating progressive weakness. The efficacy of intravenous immunoglobulin in this disease is well established; however, the response typically wanes over time. No other agent has shown similar therapeutic efficacy. We describe a case of anti-ganglioside GM1 IgM-positive multifocal motor neuropathy with typical incomplete and diminishing response to intravenous immunoglobulin over time. Sixteen years after symptom onset, rituximab was administered at 2 g/m2 over 2 weeks. No significant progression of disease has occurred over the following 10 years despite no additional treatments, including intravenous immunoglobulin, being given. Only case reports and small, mostly uncontrolled studies have reported the use of rituximab in multifocal motor neuropathy with mixed results. However, given its potential benefits and lack of an established second-line agent, treatment with rituximab may be considered in select patients with refractory multifocal motor neuropathy.

Topics: G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Motor Neuron Disease; Polyneuropathies; Rituximab

Multifocal motor neuropathy (MMN) is a rare neuropathy and detailed descriptions of larger patient cohorts are scarce. The objective of this study was to evaluate epidemiological, clinical, and laboratory features of MMN patients and their response to treatment in Austria and to compare these data with those from the literature.. Anonymized demographic and clinical data about MMN patients until 31.12.2017 were collected from registered Austrian neurologists. Exploratory statistics on clinical and laboratory features as well as treatment regimens and responses were performed.. 57 Patients with MMN were identified, resulting in a prevalence of 0.65/100.000. Mean age of onset was 44.1 ± 13.1 years, the diagnostic delay 5.5 ± 8.4 years. In 77% of patients, symptom onset was in the upper limbs, and in 92%, it occurred in distal muscles. Proximal onset was never observed in the lower limbs. At the final follow-up, the majority of patients had atrophy (88%) in affected regions. Definite motor conduction blocks (CB) were found in 54 patients. Anti-GM1-IgM antibodies were present in 43%. Treatment with intravenous immunoglobulins improved muscle strength and INCAT score initially, but at last follow-up, both scores deteriorated to values before treatment.. The findings of the present study corroborate the previous findings in MMN. Onset typically occurs in the upper limbs and mostly distal, CBs are found in the majority of cases, while anti-GM1-IgM antibodies are detected in only approximately 40%. Our study underlines that the initial good response to treatment fades over time.

Topics: Adolescent; Adult; Age of Onset; Aged; Austria; Autoantibodies; Female; Follow-Up Studies; G(M1) Ganglioside; Humans; Immunoglobulin M; Male; Middle Aged; Motor Neuron Disease; Neurologists; Prevalence; Surveys and Questionnaires; Young Adult

We tested autoantibodies to neurofascin-186 (NF186) and gliomedin in sera from patients with multifocal motor neuropathy (MMN, n=53) and chronic inflammatory demyelinating polyneuropathy (CIDP, n=95) by ELISA. IgG antibodies to NF186 or gliomedin were found in 62% of MMN and 1% of CIDP sera, and IgM antibodies to the same antigens in 12% of MMN and 1% of CIDP sera. These autoantibodies activated complement. Ten percent of the MMN sera without IgM anti-GM1 reactivity had anti-NF186 antibodies. Because NF186 and gliomedin play a crucial role for salutatory conduction, the autoantibodies may contribute to produce motor nerve conduction block and muscle weakness in MMN.

Topics: Animals; Autoantibodies; Cell Adhesion Molecules; Computational Biology; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Male; Membrane Proteins; Motor Neuron Disease; Nerve Growth Factors; Nerve Tissue Proteins; Polyneuropathies; Protein Isoforms; Rats; Transfection

Multifocal motor neuropathy (MMN) usually progresses insidiously with lower motor neuron-type weakness, minimal or no sensory symptoms. Diagnostic criteria include motor conduction block (CB) at sites not exposed to compression or entrapment. CBs may persist or reverse irrespective of clinical outcome. Acute onset with generalized weakness is uncommon. We report four patients who presented acutely areflexia, pure motor deficits without sensory disturbances, multifocal CBs persisting at the same motor nerves on serial electrophysiological studies. Three patients had preceding infections; two showed IgM reactivity against the ganglioside GM1. Intravenous immuneglobulin (IVIg) improved or stabilized symptoms. Patients 2,3,4 receive maintenance therapy with IVIg for years. Acute-onset MMN (AMMN) should be differentiated from other immune-mediated neuropathies such as acute inflammatory polyneuropathy either demyelinating (AIDP) or axonal (AMAN), acute motor conduction block neuropathy (AMCBN), acute-onset chronic inflammatory demyelinating polyneuropathy (CIDP). The correct diagnosis deserves implications for patient long-term treatment and prognosis. Moreover, the authors address the problem of defining the spectrum of MMN particularly in the acute setting.

Topics: Action Potentials; Aged; Electromyography; Female; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease; Neural Conduction; Polyneuropathies; Young Adult

The pathogenesis of multifocal motor neuropathy (MMN) has yet to be established. MMN patients often carry anti-GM1 IgM antibodies, suggesting an autoimmune process involving complement. Intravenous immunoglobulin (IVIG) is the first line treatment, but its action mechanism is unknown.. To test whether anti-GM1 IgM antibodies in MMN sera activate complement, inducing and propagating the disease and whether IVIG inhibits complement activation, resulting in clinical improvement.. Sera with anti-GM1 IgM but not IgG or IgA reactivity were obtained from 13 patients with MMN. We tested whether their anti-GM1 IgM antibodies produced complement component deposits on GM1-coated microtiter plates and whether IVIG blocks such deposition.. C1q, C4b, C3b and C5b-9 were deposited on GM1-coated wells. Their depositions were highly correlated with anti-GM1 IgM antibody titre. IVIG reduced the deposition of these complement components dose-dependently.. Anti-GM1 IgM antibodies bound to GM1 and activated complement in vitro. The results together with earlier data from our group suggest that IgM-induced, complement-mediated injury occurs at the nodes of Ranvier in peripheral motor nerves and generates conduction block and muscle weakness. In vitro IVIG inhibited this type of complement activation, suggesting that in vivo, the resulting reduction in membrane attack complex-mediated damage leads to improved muscle strength.

Topics: Antibodies; Antibodies, Anti-Idiotypic; Autoantibodies; Blood Proteins; Complement C3b; Complement Pathway, Classical; Complement System Proteins; Dose-Response Relationship, Immunologic; G(M1) Ganglioside; Immunoglobulin M; Immunoglobulins, Intravenous; Immunotherapy; Motor Neuron Disease; Neural Conduction; Ranvier's Nodes

The identification of a distinct subgroup of patients within the spectrum of lower motor neuron syndromes (LMNS) is crucial as some are potentially treatable. We describe the clinical and neuropathological characteristics of a patient presenting with a rapidly progressive LMNS associated with high titers of anti-GM1 antibodies, leading to respiratory failure within 10 months. Histopathological study of a biopsy of a obturator nerve motor branch demonstrated a predominantly axonal motor neuropathy, while electron microscopy analysis localized macrophages located within the periaxonal space. Immunohistochemistry demonstrated deposits of complement activation products (C3i) and immunoglobulins (IgM) on nerve fibers. The patient's clinical, immunological and pathological findings are consistent with a diagnosis of a chronic motor axonal neuropathy (CMAN), likely of immune-mediated origin.

Topics: Autoantibodies; Autoantigens; Fatal Outcome; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Middle Aged; Motor Neuron Disease

Serum IgM binding to GM1 ganglioside (GM1) is often associated with chronic acquired motor neuropathies. This study compared the frequency and clinical associations of serum IgM binding to a different antigen, a disulphated heparin disaccharide (NS6S), with results of IgM binding to GM1.. Serums and clinical features were retrospectively compared from 75 patients with motor neuropathies and 134 controls with amyotrophic lateral sclerosis (ALS), chronic immune demyelinating polyneuropathy (CIDP) and sensory neuropathies. Clinical correlations of positive IgM anti-GM1 testing found in 27 of 2113 unselected serums were also reviewed. Serum testing for IgM binding to NS6S and GM1 used covalent antigen linkage to ELISA plates.. High titre IgM binding to NS6S and GM1 each occurred in 43%, and to one of the two in 64%, of motor neuropathy patients. Motor neuropathy syndromes were present in 25 of 27 patients with high titre serum IgM binding to GM1 in the unselected serums. IgM anti-GM1 or NS6S antibody related motor neuropathy syndromes usually have asymmetric, predominantly distal, upper extremity weakness.. IgM binding to NS6S disaccharide is associated with motor neuropathy syndromes and occurs with similar frequency to IgM binding to GM1. Testing for IgM binding to NS6S in addition to GM1 increases the frequency of finding IgM autoantibodies in motor neuropathies from 43% to 64%. High titres of serum IgM binding to GM1, tested with covalent ELISA methodology, have 93% specificity for motor neuropathy syndromes. High titres of serum IgM binding to NS6S have specificity for immune motor neuropathies compared with ALS and CIDP.

Topics: Adult; Age of Onset; Aged; Disaccharides; Electrodiagnosis; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Heparin; Humans; Immunoglobulin M; Male; Middle Aged; Motor Neuron Disease; Muscle Weakness; Neural Conduction; Neuromuscular Diseases; Predictive Value of Tests; Young Adult

The effects of intravenous immunoglobulins (IVIg) on anti-GM1 IgM titer and function, classical complement pathway activity, and antibody-complement interaction were investigated in 62 patients with multifocal motor neuropathy (MMN). In vitro, IVIg decreased complement deposition by anti-GM1 IgM antibodies. First IVIg treatment (2 g/kg) decreased C1q and C4 concentrations and classical pathway activity in serum. In sera from patients receiving IVIg maintenance therapy (0.4 g/kg) C4 concentrations and classical pathway activity were generally lower at higher IgG concentrations. The beneficial effects of IVIg in MMN may be explained by reduced antibody-mediated complement deposition in nerves amplified by a systemically attenuated classical pathway.

Topics: Adult; Analysis of Variance; Case-Control Studies; Complement Pathway, Classical; Complement System Proteins; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease

Multifocal motor neuropathy is a well described condition characterized by slowly progressive, predominantly distal, asymmetric limb weakness and wasting, predominantly in the arms within an anatomical distribution of individual motor nerves, with minimal or no sensory involvement.. The aim of this retrospective study was to look for a significant reduction of the amplitude of sensory potentials in a cohort of 21 patients with defined multifocal motor neuropathy according to the Workshop Report criteria [Workshop Report, 2001. 79th ENMC International Workshop. Multifocal motor neuropathy 14-15 April 2000, Hilversum. The Netherlands. Muscle Nerve 11, 309-314], within a follow-up of at least 3 years.. Thirteen patients (62%) (Group 1) had a reduction of the amplitude of at least one sensory potential, of whom four patients had abnormalities of two or more sensory potentials, while eight patients (Group 2) had no abnormality. No significant differences were found for gender, age at onset, number of involved motor nerves, CSF protein count, presence/absence of anti-GM1 serum antibodies and response to IgIV between the two groups.. This study underlines the difficulty in defining criteria for multifocal motor neuropathies capable of distinguishing them from other chronic acquired demyelinating polyneuropathies, and mainly from multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, also called Lewis-Sumner's syndrome.

Topics: Adult; Age of Onset; Aged; Cerebrospinal Fluid Proteins; Electromyography; Evoked Potentials, Somatosensory; Female; Follow-Up Studies; G(M1) Ganglioside; Humans; Male; Middle Aged; Motor Neuron Disease; Motor Neurons; Neural Conduction; Prognosis; Retrospective Studies

A 38-year-old man presented with distal-dominant limb weakness two weeks after an upper respiratory infection. He had no sensory and autonomic signs and no cranial nerve involvement during the course of the disease. Tendon reflexes were preserved except for an absent Achilles' tendon reflex. His disability at nadir was grade 2 on the Hughes functional scale. Cerebrospinal fluid analysis showed albuminocytologic dissociation and he was diagnosed with pure motor Guillain-Barré syndrome (GBS). Thin-layer chromatography immunostaining and an enzyme-linked immunosorbent assay revealed an immunoglobulin G antibody to the ganglioside complex GM1/GalNAc-GD1a in his acute phase serum. A serial nerve conduction study revealed conduction block in the median and ulnar nerve trunks and temporal dispersion in the tibial nerve, without an evident remyelination pattern during the course of the disease. A sensory nerve conduction study was normal. According to Hadden's criteria, the electrodiagnostic findings were judged as a primary demyelinating pattern. Weakness and abnormal motor nerve conduction recovered rapidly after intravenous immunoglobulin therapy. In view of the localization of GM1 and GalNAc-GD1a on the axolemma of the motor nerves, the clinical course and electrophysiological features may have resulted from functional conduction failure at the nodes of Ranvier of the motor nerves, rather than primary demyelination or axonal degeneration. The illness resembled acute motor conduction block neuropathy characterized by preserved sensory function, an early conduction block at intermediate nerve segments, and good recovery. GM1 and GalNAc-GD1a may form a complex in the axolemma at the nodes of Ranvier or paranodes of the motor nerves, and may be a target antigen in pure motor GBS; especially in the form with acute motor conduction block neuropathy. The present case is the first description of a GBS patient with an IgG anti-GM1/GalNAc-GD1a antibody.

Topics: Autoantibodies; G(M1) Ganglioside; Gangliosides; Guillain-Barre Syndrome; Humans; Immunoglobulin G; Male; Motor Neuron Disease; Neural Conduction

Acute motor axonal neuropathy (AMAN) in humans is associated with the presence of GM1-specific antibodies. Immunization of rabbits with GM1-containing ganglioside mixtures, purified GM1, or Campylobacter jejuni lipo-oligosaccharide exhibiting a GM1-like structure elicits GM1-specific antibodies, but axonal polyneuropathy only occurs in a subset of animals. This study aimed to dissect the molecular basis for the variable induction of AMAN in rabbits. Therefore, we analyzed the pro-inflammatory characteristics of GM1-specific antibodies in plasma samples from ganglioside-immunized rabbits with and without neurological deficits. GM1-specific plasma samples from all rabbits with AMAN were capable of activating both complement and leukocytes, in contrast to none of the plasma samples from rabbits without paralysis. Furthermore, GM1-specific IgG-mediated activation of leukocytes was detected before the onset of clinical signs. These data suggest that AMAN only occurs in rabbits that develop GM1-specific antibodies with pro-inflammatory properties.

Topics: Acute Disease; Animals; Autoantibodies; Axons; Cell Degranulation; Complement Activation; G(M1) Ganglioside; Immunoglobulin Fab Fragments; Immunoglobulin G; Leukocytes; Motor Neuron Disease; Muscle Hypotonia; Paralysis; Rabbits; Receptors, IgG

To define the clinical spectrum in a large cohort of patients with multifocal motor neuropathy (MMN) and the effectiveness of IVIg treatment. We also test two neurophysiologic criteria for conduction block (CB) for relevance to treatment responsiveness.. Retrospective case cohort analysis of 47 patients with MMN followed for up to 12 years.. A total of 32 (70%) had an upper-limb onset with most showing clinical features of conduction block: weakened but non-wasted muscles (67%) and differential weakness across muscles supplied by a common terminal motor nerve (54%). Differential weakness of finger extension was a characteristic early sign. Application of consensus criteria for definite CB would have denied a trial of treatment to 6 patients with a typical phenotype compared with new criteria. No association was found between CB and presence of anti-GM1 ganglioside antibody. A total of 24 (51%) patients were treated with IVIg, which was associated with a marked initial improvement in self-reported disability in most patients. The magnitude of initial disability improvement was not sustained in all patients over time. However, the majority of treated patients reported significantly less disability at last follow-up than prior to treatment. Patients converted to a domiciliary IVIg program maintained function at least as well as hospital treated patients.. The importance of the clinical phenotype of multifocal motor neuropathy (MMN) is emphasized. Neither conduction block (CB) nor antibody status is a reliable predictor of treatment responsiveness. Over-reliance upon consensus CB criteria can deny IVIg to patients with MMN who are treatment responsive.

Topics: Adult; Aged; Electrophysiology; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease; Neural Conduction; Retrospective Studies; Treatment Outcome

Multifocal motor neuropathy (MMN) was first distinguished from other motor neuropathies in 1986. It is characterised by slowly progressive predominantly distal and asymmetric limb weakness and wasting that predominates in the arms, with muscle cramps and fasciculations, within an anatomical distribution of individual motor nerves. Sensory involvement is minimal or absent. The electrodiagnostic hallmark is focal motor conduction block (CB), persisting for years at atypical sites. The most typical laboratory finding is increased serum IgM autoantibody titers to the ganglioside GM1. High-dose intravenous immunoglobulin (IVIg) is currently the gold-standard treatment for MMN. To document short-term and long-term responses to IVIg, we conducted a retrospective study of 40 patients with MMN defined using ENMC Workshop criteria and treated with periodic IVIg infusions (Tégéline) between 1995 and 2003. For the short-term analysis we compared the 22 patients who had never previously received IVIg with the 18 IVIg-experienced patients. For the long-term evaluation (> 6 months), the patients were classified into four groups according to their dependence on periodic IVIg. The MRC score improved significantly in 14 (70% ; 95% CI 0.46 to 0.88) of the 20 assessable treatment-naive patients (data were missing for two patients). This rate was significantly higher than at six months in a historical group of placebo-treated patients (20%; p < 0.0001). No criteria predictive of the response were identified. At the end of follow-up (mean 2.2 +/- 2.0 years) only 8 patients (22%) in the cohort remained in remission after a good initial response to IVIg, while 25 patients (68%) were dependent on periodic IVIg infusions. This study confirms the good short-term response of MMN to IVIg but indicates that the longer-term results are variable. New therapeutic strategies are required to increase the short-term and long-term efficacy of IVIg, and to reduce reliance on this treatment.

Topics: Adult; Aged; Autoantibodies; Autoimmune Diseases of the Nervous System; Drug Evaluation; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease; Motor Neurons; Neural Conduction; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Lower motor neuron syndromes (LMNS) are heterogenous conditions, which include patients with progressive lower motor neuron disease (LMND) and cases with the clinical phenotype of motor neuropathy (MN). The aim of this study was to estimate the IgM anti-GM1 ganglioside antibodies titer and the ratio of the light chains in order to define the presence of autoimmunity process in particular cases with LMNS. Twenty-eight patients were diagnosed with LMND and 15 patients were diagnosed with MN (10 patients with multifocal motor neuropathy with conduction block, five patients with MN without conduction block). Total of 103 patients with classical amyotrophic lateral sclerosis (ALS) and 50 healthy, age-matched persons were also tested. The IgM anti-GM1 ganglioside titer and the ratio of lambda/kappa light chains in serum were determined using the ELISA technique. High titer of IgM anti-GM1 antibodies were detected in serum of 46% LMND patients, 80% of MN patients, and 18% of the classical ALS cases. An elevated ratio of lambda/kappa light chains appeared in 18% of LMND patients, and in 67% of the MN cases. The lambda/kappa light chains ratio was normal in all ALS patients. The presence of elevated titer of IgM anti-GM1 ganglioside antibodies and the changed ratio of the light chains supports the presence of autoimmune process in LMNS and may provide clues for their management.

Topics: Adult; Amyotrophic Lateral Sclerosis; Autoantibodies; Autoimmunity; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Immunoglobulin M; Male; Middle Aged; Motor Neuron Disease; Neuromuscular Diseases

Pathological studies, including novel teased peripheral nerve fiber studies, were performed in a patient who presented with a rapidly progressive, lower motor neuron syndrome and high titer of immunoglobulin M anti-GM1 ganglioside antibody. In the central nervous system, there was a severe loss of motor neurons and central chromatolysis with ubiquitin immunopositive cytoplasmic inclusions in residual motor neurons. In the peripheral nervous system, axonal degeneration of myelinated fibers in the anterior nerve roots was evident. Pathologic evidence of sensory nerve involvement was also found despite the absence of clinical or electrophysiological sensory abnormalities. Sectional studies of single myelinated nerve fibers from an antemortem sural nerve biopsy showed remyelination and globular paranodal swellings due to focal complex myelin folding and degeneration in 13% of fibers. Postmortem studies of the sural nerves 4 weeks later showed paranodal demyelination (90% of fibers), but no paranodal swellings and similar findings were present in samples of the ulnar, radial, median, tibial, and common peroneal nerves. Paranodal abnormalities of enlargement of the adaxonal space, myelin degeneration, and axonal compaction were found on cross-sectional studies of individual teased fibers, which on conventional light microscopic assessment appeared normal. These changes suggest a disturbance of paranodal axonal-myelin adhesion due to binding of the anti-GM1 ganglioside antibody to the common epitope known to be present on the myelin sheath and nodal axolemma in the paranodal region of both motor and sensory nerves.

Topics: Adult; Central Nervous System; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Microscopy, Electron; Motor Neuron Disease; Myelin Sheath; Nerve Degeneration; Peripheral Nervous System

The authors report a newborn with motor neuropathy associated with anti-GM1 antibodies from an affected mother. This finding suggests that the disorder was due to transplacental transfer of pathogenic antibodies.

Topics: Adult; Antibody Specificity; Female; G(M1) Ganglioside; Humans; Immunity, Maternally-Acquired; Immunoglobulin G; Infant, Newborn; Isoantibodies; Maternal-Fetal Exchange; Motor Neuron Disease; Neural Conduction; Paraproteinemias; Pregnancy; Pregnancy Complications

Multifocal motor neuropathy (MMN) with conduction block is an acquired, autoimmune-mediated neuropathy that is responsive to treatment. The clinical history is one of slowly, progressive distal weakness, which more commonly involves the upper extremities, and it affects mainly young adults. Physical examination reveals weakness without sensory loss in the distribution of individual nerves. Atrophy may be present, but hyperreflexia and spasticity are not seen. Electrophysiological studies reveal motor conduction blocks at sites not prone to compression with normal sensory responses. Immunoglobulin M anti-GM1 titers may be elevated. Treatment with human immunoglobulin or cyclophosphamide has been shown to improve strength in the majority of patients with MMN in the short term. However, motor strength and function may gradually decline over years in spite of long-term therapy.

Topics: Adult; Atrophy; Autoimmune Diseases; Cyclophosphamide; Diagnosis, Differential; Electrophysiology; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Motor Neuron Disease; Neural Conduction; Peripheral Nervous System Diseases; Prognosis

Motor neuropathy with multifocal conduction blocks represents a recently identified autoimmune disorder of the peripheral nerve myelin. Association of motor neuropathies or neuronopathies with thyroid disorders, such as hyperthyroidism, hypothyroidism or thyroid neoplasms has been rarely described. We studied a 61-year-old man with a 2-year-history of slowly progressive weakness of the left limbs with atrophy and fasciculations. Nerve conduction velocity studies revealed multifocal motor conduction blocks. Serum IgM titer of antibodies against GM1 was elevated (1:1280; n.v. up to 1:640). Thyroid studies were compatible with Hashimoto's thyroiditis. Therapy with high dose intravenous immunoglobulins was followed by a prompt clinical recovery. Then the disease assumed an intravenous immunoglobulins dependent course with a full clinical, but transient, recovery. This is the first observation of an association of multifocal motor neuropathy with high titers of GM1 and Hashimoto's thyroiditis and reinforces the multifocal motor neuropathy autoimmune origin as well as the repeated clinical recoveries after intravenous immunoglobulins. This case also suggests to deeply investigate the thyroid function in patients with multifocal motor neuropathy.

Topics: Demyelinating Diseases; Electromyography; Enzyme-Linked Immunosorbent Assay; Fasciculation; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease; Muscle Weakness; Muscular Atrophy; Neural Conduction; Thyroiditis, Autoimmune

High-affinity anti-GM1 antibodies are frequently described in several nervous system diseases, mainly in multifocal motor neuropathy (MMN) and some acute neuropathies. These antibodies are currently detected using enzyme-linked immunosorbent assay (ELISA) and immuno-thin-layer-chromatography (immuno-TLC) methods. We report in this article a new method based on the incorporation of exogenous GM1 in a selected cell line to detect anti-GM1 antibodies using flow cytometry (FC). This method is evaluated on 80 sera from normal blood donors (NBD) and patients suffering various nervous system diseases. It appears to be as sensitive as our method ELISA for the diagnosis of some motor neuron syndromes.

Topics: Autoantibodies; Flow Cytometry; G(M1) Ganglioside; Glioblastoma; Humans; Motor Neuron Disease; Neuroblastoma; Sensitivity and Specificity; Tumor Cells, Cultured

Increased titers of IgM anti-GM1 antibodies are present in some patients with Lower Motor Neuron Disease (LMND) or Motor Neuropathy (MN), but their pathogenic role and the mechanism of action are unclear. Previous studies have shown that the B subunit of Cholera Toxin (CT), which binds and crosslinks ganglioside GM1, modulate intracellular calcium in murine neuroblastoma cells via the activation of L-type voltage-dependent calcium channels (VGCC). Therefore, using a fluorimetric approach, we have examined the hypothesis that the pentameric IgM anti-GM1 antibodies, could similarly alter calcium concentration in N18 neuroblastoma cells. Sera with human IgM anti-GM1 antibodies were obtained from 5 patients with LMND and 2 patients with MN. Human IgG anti-GM1, IgM anti-Myelin Associated Glycoprotein (MAG), IgM anti-sulfatide antibodies and lectin peanut agglutinin (PNA), that recognizes specifically the Gal(betal-3)GalNAc epitope, were used as control sera. Direct application of either human IgM anti-GM1 antibodies or the B subunit of CT to N18 neuroblastoma cells induced a sustained influx of manganese ions, as indicated by a quench of the intracellular fura-2 fluorescence. Furthermore, the dihydropyridine L-type channel antagonists completely inhibited the manganese influx, suggesting that it is due to activation of an L-type VGCC. The magnitude of the influx was correlated with antibody titers. None of human IgG anti-GM1, IgM anti-MAG, IgM anti-sulfatide antibodies or PNA induce an ion influx, pointing to the selective participation of the pentameric IgM isotype of anti-GM1 in the modulation of L-type calcium channels opening. Given that L-type calcium channels are present on motor neurons, the modulation of L-type calcium channels by IgM GM1 antisera may have important implications in diseases such as LMND and MN.

Topics: Adult; Autoantibodies; Calcium; Calcium Channels; Cholera Toxin; G(M1) Ganglioside; Homeostasis; Humans; Immunoglobulin G; Immunoglobulin M; Middle Aged; Motor Neuron Disease; Neuroblastoma; Neurons; Tumor Cells, Cultured

Paraneoplastic neurological disorders may result from autoimmunity directed against antigens shared by the affected neurons and the associated cancer cells. We have recently reported the case of a woman with breast cancer and paraneoplastic lower motor neuron syndrome whose serum contained autoantibodies directed against axon initial segments and nodes of Ranvier of myelinated axons, including the axons of motoneurons. Here, we show that major targets of the autoantibodies of this patient are betaIVSigma1 spectrin and betaIV spectrin 140, two isoforms of the novel betaIV spectrin gene, as well as a neuronal surface epitope yet to be identified. Partial improvement of the neurological symptoms following cancer removal was associated with a drastic reduction in the titer of the autoantibodies against betaIV spectrin and nodal antigens in general, consistent with the autoimmune pathogenesis of the paraneoplastic lower motor neuron syndrome. The identification of betaIV spectrin isoforms and surface nodal antigens as novel autoimmune targets in lower motor neuron syndrome provide new insights into the pathogenesis of this severe neurological disease.

Topics: Autoantibodies; Autoimmunity; Breast Neoplasms; Female; G(M1) Ganglioside; Humans; Molecular Weight; Motor Neuron Disease; Nerve Tissue Proteins; Paraneoplastic Syndromes; Spectrin

Multifocal motor neuropathy (MMN) is a disorder of peripheral nerve often associated with a high monosialoganglioside (GM1) antibody and multifocal conduction block. It has a chronic, indolent course with involvement of predominantly peripheral motor nerves, usually in an asymmetric fashion. There have been few reported cases of progression to frank quadriplegia. Secondary amyloidosis refers to the deposition of amyloid in various tissues due to an underlying chronic inflammatory state. We report the first case, to our knowledge, of a patient with MMN associated with high titer of GM1 antibody who developed acute paraplegia with both cranial nerve and worsening sensory involvement associated with multiorgan compromise due to a secondary amyloidosis involving the myocardium.

Topics: Amyloidosis; Autoantibodies; Fatal Outcome; Femoral Nerve; G(M1) Ganglioside; Humans; Male; Median Nerve; Middle Aged; Motor Neuron Disease; Neural Conduction; Tibial Nerve; Ulnar Nerve

Intravenous immunoglobulin (IVIg) is used in the treatment of a variety of autoimmune diseases. The blocking of disease-associated antibodies by anti-idiotype antibodies present in IVIg has been proposed as an action mechanism. Anti-GM1 antibodies have been implicated in motor neuropathies. Although IVIg is frequently applied for these diseases, the presence in IVIg or in human plasma of anti-idiotype antibodies that recognize anti-GM1 antibodies has not been clearly demonstrated. Here we present evidence that normal human plasma contains antibodies that inhibit the binding of anti-GM1 IgG-antibodies from neuropathy patients but do not inhibit anti-GM1 IgG-antibodies of rabbit origin with the same fine specificity. The significance of these findings in the course of acute and chronic neuropathies is discussed.

Topics: Adult; Animals; Antibodies, Anti-Idiotypic; G(M1) Ganglioside; Humans; Immunoglobulin G; Motor Neuron Disease; Rabbits

Twenty-two patients (12 men, 10 women, age range 16 to 60) affected with an adult-onset, sporadic, lower motor neuron disease were studied. Motor weakness was associated with a severe muscular atrophy but never in a peripheral nerve distribution. Weakness predominated in the proximal parts of the limbs in 3 cases, in distal parts in 10 cases involving predominantly the upper limbs in 10. It was diffuse in all four limbs in six cases and was monomelic in the last 2 two others. Reflexes were generally lost in weak muscles. Electrodiagnostic findings consisted of pure motor axonal features, subtle sensory involvement was present in 3 cases with an IgM monoclonal gammopathy, in only one case the neurological syndrome was associated with a lymphoproliferative disorder despite complete investigations. All patients had dysimmune biological features (MGUS or anti-GM1 antibodies). We studied SMN gene in 12 patients and found no deletion. 16 patients were treated with IVIg and five improved but in 2 cases the improvement was transcient and lasted less than six months. Intravenous cyclophosphamide (1g/m(2) repeated monthly during 6 to 9 months) was used in six patients and three improved. Among these three patients two received also plasma exchanges on two days before the infusion. In all three patients, muscle weakness gradually deteriorated in the months following the end of the treatment. Nor the weakness pattern nor the type of biological marker was predictive of a good response to treatment. Lower motor neuron diseases appear to be much less sensitive to treatment than multifocal motor neuropathy with conduction block. However, treatment with IVIg or cyclophosphamide must be considered in the most severe forms or in case of a young onset.

Topics: Adolescent; Adult; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antineoplastic Agents, Alkylating; Cyclophosphamide; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease; Muscle, Skeletal; Peripheral Nerves; Severity of Illness Index

We used an ELISA technique to measure IgG and IgM antibodies to the ganglioside GM1, with the results expressed in arbitrary units. We tested 1007 sera from patients with peripheral neuropathy or muscle weakness. For IgG and IgM antibodies, the distribution of results differed significantly from a normal distribution. In the patient group, 81 of 1007 sera had elevated levels of IgG antibodies (> 10 units). Of these, 11 patients had very high levels (> 50 units). These 11 patients had diagnoses of GBS (4), motor neurone disease (3) or non-specific idiopathic neuropathy (4). For IgM antibodies, 115 of 1007 sera were positive (> 20 units). Of these, 18 patients had very high levels (> 50 units). These 18 patients had diagnoses of Guillain-Barré syndrome or Miller Fisher syndrome (4), multifocal motor neuropathy (4), motor neurone disease (2), non-specific neuropathy (2). We conclude that anti-GM1 antibodies in high titre are uncommon. Patients with multifocal motor neuropathy have high levels of antibody. However, patients with other disorders may also have high levels, so that anti-GM1 antibody levels alone are not a specific test for multifocal motor neuropathy. We found that antibodies to GM1 were present in the sera of patients with chronic idiopathic neuropathy, leading us to suggest that these antibodies may sometimes arise as a secondary response to disease.

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; Biomarkers; Female; G(M1) Ganglioside; Guillain-Barre Syndrome; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Motor Neuron Disease; Peripheral Nervous System Diseases

Topics: Autoantibodies; Enzyme-Linked Immunosorbent Assay; Evaluation Studies as Topic; G(M1) Ganglioside; Immunoglobulin M; Immunologic Tests; Motor Neuron Disease; Reproducibility of Results; Sensitivity and Specificity

An association between motor neuron disease and Waldenström disease is rarely reported in the literature. The association with peripheral neuropathy and IgM monoclonal gammapathy is well known.. In our patient, the malignant monoclonal gammapathy had an unusual antigen pattern. This patient was MAG (myelin-associated glycoprotein) negative but showed a very positive serology for GM1 ganglioside and SGPG (3-sulfated glycuronly paragloboside).. This is the fifth such case to be reported associated a malignant dyglobulinemia with an MAG-negative IgM gammapathy. It is the first case with positive serology for both the GM1 ganglioside and SGPG.

Topics: Aged; G(M1) Ganglioside; Humans; Middle Aged; Motor Neuron Disease; Myelin-Associated Glycoprotein; Serologic Tests; Waldenstrom Macroglobulinemia

Electrodiagnostic testings including electromyography have become increasingly important tools in clinical practice of neurology. These tests should not merely be referred to a technician, but be viewed as a clinical tool used by a neurologist. Recent advances in clinical electromyography, nerve conduction tests, and tests for axonal function including the newly developed threshold electrotonus are reviewed. These not only serve as a diagnostic tool, but also are useful in clinical trials by providing an objective parameter of nerve function. Computerized threshold tracking techniques such as threshold electrotonus enable us to monitor molecular events in various ion channels in axons of patients. Further development is expected toward clinical molecular neurophysiology.

Topics: Amyotrophic Lateral Sclerosis; Autoantibodies; Axons; Diagnosis, Differential; Electrodiagnosis; Electromyography; Electrophysiology; Excitatory Postsynaptic Potentials; G(M1) Ganglioside; Humans; Motor Neuron Disease; Neural Conduction

Topics: Acute Disease; Adult; Female; G(M1) Ganglioside; Humans; Immunoglobulin G; Motor Neuron Disease; Pneumonia, Mycoplasma; Polyradiculoneuropathy

Topics: G(M1) Ganglioside; Humans; Immunoglobulins; Motor Neuron Disease; Polyradiculoneuropathy

Topics: Animals; Autoantibodies; G(M1) Ganglioside; Humans; Motor Neuron Disease; Motor Neurons; Neural Conduction; Rats; Sodium Channels

We made a retrospective long-term follow-up study of 25 patients with multifocal motor neuropathy (Lewis-Sumner). The diagnosis was based upon criteria modified from those of AAEM (Sumner 1997). The electrophysiological findings indicating conduction block or focal demyelinative lesions were more diagnostic than anti-GM 1 antibody titers, which were elevated in only 40% of these patients. Demonstration of definite conduction block was not always possible in those patients who responded favorably to intravenous immunoglobulins (IVIg), whereas indirect pieces of evidence such as F-wave abnormalities or focal conduction delay or dispersion were equally helpful. IVIg had superior outcome to cyclophosphamide, which sometimes caused serious adverse effects. Three patients with severe axonal involvement showed elevated monospecific antibodies to GalNAc-GD1a.

Topics: Adolescent; Adult; Aged; Autoantibodies; Biomarkers; Demyelinating Diseases; Electrophysiology; Female; Follow-Up Studies; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease; Synaptic Transmission; Syndrome

We report a 63-year-old man who died of respiratory failure. He was well until 1992 (57 years of his age), when he had an onset of progressive weakness of the bilateral upper limbs. He showed no improvement with TRH administration in other hospital. On January 12, 1994, he admitted to our department because of the progressive muscle weakness. Neurologic examination revealed a muscular atrophy associated with severe weakness and hyporeflexia in both upper limbs, and fasciculation were seen in his tongue. Electrophysiological studies revealed mild conduction block in the left medial nerve, and F-waves were not evoked in the left ulnar nerve and bilateral median nerves. After an administration of 25 g/day of human gamma-immunoglobulin for 5 days, conduction block as well as F-wave abnormalities in the left median and left ulnar nerve were improved, yet no improvement of muscle weakness was seen. The anti-GM1 IgG titer was transiently elevated in the patient's serum after gamma-immunoglobulin therapy. On September 8, 1994, subtotal gastrectomy was performed because of the early stage gastric cancer. Histological examination showed poorly differentiated adenocarcinoma (signet-ring cell carcinoma). His muscle weakness had been gradually extended to the lower limbs and he couldn't walk himself on January, 1998. On March, 1998, he developed tetraplegia, mild dysphagia, dysuria and the respiratory disturbance. On April 12, 1998, he admitted to our department for the second time. Neurologic examination revealed a muscular atrophy and fasciculation associated with severe weakness in all of his limbs, tongue and musclus masseter. Neither deep tendon reflex nor pathologic reflex was evoked in his upper and lower extremities. His ocular movements and sensations were well preserved. He died of respiratory failure on May 1, 1998. The patient was presented in a neurological CPC. Neurological and laboratory findings suggested a spinal progressive muscular atrophy (SPMA). However, there were several unusual points as a typical SPMA in this case, that is, an improvement of the electrophysiological abnormalities by gamma-globulin treatment, as well as transient elevation of anti-GM1 antibody. The clinical neurologists have arrived at the conclusion that the patient had lower motor neuron syndrome associated with anti-ganglioside antibody and cause of death was ascribed to the respiratory failure. We discussed whether this case was SPMA or multifocal motor neuropathy. Postmort

Topics: Autoantibodies; Carcinoma, Signet Ring Cell; Diagnosis, Differential; Diverticulum, Colon; G(M1) Ganglioside; gamma-Globulins; Humans; Male; Middle Aged; Motor Neuron Disease; Muscular Atrophy, Spinal; Stomach Neoplasms; Thyroiditis

IgG antibodies to the minor gangliosides GM1b and GalNAc-GD1a frequently are present in sera of Japanese patients with Guillain-Barré syndrome. The relationship between these autoantibodies and Campylobacter jejuni infection, the type of disease (acute motor axonal neuropathy [AMAN], or acute inflammatory demyelinating polyneuropathy [AIDP]) has yet to be established. Sera samples were obtained from 55 Chinese patients with clinically defined Guillain-Barré syndrome. An electrophysiology study showed nine AIDP, 28 had AMAN, and 18 unclassified. C. jejuni serology was positively correlated with anti-GM1b and anti-GalNAc-GD1a IgG antibodies (respective P values, 0.007 and 0.02). The frequencies of positive anti-GM1b and anti-GalNAc-GD1a serology were greater in AMAN (32 and 21%) than in AIDP (11 and 0%), but the differences were not significant. Infection by C. jejuni may induce IgG anti-GM1b antibody in some patients and IgG anti-GalNAc-GD1a antibody in others. A larger population of patients must be studied to show whether there is a definite correlation.

Topics: Acute Disease; Adolescent; Adult; Autoantibodies; Axons; Campylobacter Infections; Campylobacter jejuni; Child; Child, Preschool; China; Female; G(M1) Ganglioside; Gangliosides; Humans; Male; Middle Aged; Motor Neuron Disease; Polyradiculoneuropathy

To investigate the incidence of hyperreflexia in patients with Guillain-Barré syndrome (GBS), and its relation with electrodiagnosis of acute motor axonal neuropathy (AMAN), antiganglioside GM1 antibody, and Campylobacter jejuni infection. It was reported that patients with AMAN in northern China often had hyperreflexia in the recovery phase.. In 54 consecutive Japanese patients with GBS, sequential findings of tendon reflexes were reviewed. By electrodiagnostic criteria, patients were classified as having AMAN or acute inflammatory demyelinating polyneuropathy (AIDP). Anti-GM1 and anti-C jejuni antibodies were measured by enzyme linked immunosorbent assays.. Seven (13%) patients developed hyperreflexia with the spread of the myotatic reflex to other segments in the early recovery phase, one of whom already had hyperreflexia in the acute progressive phase. Of the seven patients, six had AMAN and all seven had anti-GM1 antibodies, whereas only two had anti-C jejuni antibodies. Hyperreflexia was more often found in patients with AMAN than AIDP (6/23 v 1/18, p=0. 002), and in patients with anti-GM1 antibodies than without them (7/26 v 0/28, p=0.01). Hyperreflexic patients had milder peak disabilities than patients without hyperreflexia (p=0.03). Increased motor neuron excitability in the hyperreflexic patients was supported by increased soleus H-reflex amplitudes and the appearance of H-reflexes in the small hand or foot muscles.. Hyperreflexia often occurs in patients with GBS especially with AMAN, anti-GM1 antibodies, and milder disease. Increased motor neuron excitability further characterises the subgroup of patients with GBS with AMAN and anti-GM1 antibodies.

Topics: Acute Disease; Adult; Antibodies; Antibodies, Bacterial; Campylobacter jejuni; Electrodiagnosis; Female; G(M1) Ganglioside; H-Reflex; Humans; Male; Middle Aged; Motor Neuron Disease; Polyradiculoneuropathy; Reflex, Abnormal; Reflex, Stretch; Syndrome

To our knowledge, this is the first reported application of immunoadsorption in a patient with multifocal motor neuropathy (MMN). The diagnosis relied on the typical clinical features, markedly increased IgM-GM1 antibodies, multiple motor conduction blocks, and motor nerve biopsy. Immunoadsorption was carried out in seven cycles of two sessions each within 97 days. From the first therapy, muscle force as well as nerve conduction velocity and conduction blocks deteriorated continuously. As a consequence, immunoadsorption cannot be recommended as a treatment for MMN.

Topics: Antibodies, Anti-Idiotypic; Blood Component Removal; Demyelinating Diseases; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Immunosorbent Techniques; Middle Aged; Motor Neuron Disease; Peripheral Nervous System Diseases

Topics: Demyelinating Diseases; Diagnosis, Differential; G(M1) Ganglioside; Humans; Motor Neuron Disease; Syndrome

Topics: Autoantibodies; Autoimmune Diseases of the Nervous System; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Motor Neuron Disease; Predictive Value of Tests

Topics: Autoantibodies; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Immunoglobulin M; Motor Neuron Disease; Reference Values; Sensitivity and Specificity

A series of monoclonal IgM anti-GM1 ganglioside antibodies has been cloned from peripheral blood lymphocytes of patients with multifocal motor neuropathy and Guillain-Barré syndrome. In solid-phase immunoassay, the antibodies react with GMI, and also in differing degrees to the structurally related glycolipids asialo-GM1 (GA1) and GD1b. Here we describe the binding patterns of six human anti-GM I antibodies to epitopes within the human nervous system. Antibodies were observed to bind to motor neurons and spinal grey matter, dorsal and ventral spinal roots, dorsal root ganglion neurons, nodes of Ranvier, neuromuscular junctions and skeletal muscle. The distribution of immunoreactive epitopes, which included sensory structures, extended beyond those sites conventionally regarded as pathologically affected in anti-GM1 antibody-associated motor nerve syndromes. This undermines a model of disease pathogenesis based solely on antigen distribution. Factors other than the presence or absence of antigen, such as the local ganglioside topography, antibody penetration into, and pathophysiological vulnerability of a particular site may also influence the clinicopathological outcome of anti-GM1 antibody-mediated autoimmune attack.

Topics: Antibodies, Monoclonal; Autoimmune Diseases; Diaphragm; Epitopes; Femoral Nerve; G(M1) Ganglioside; Ganglia, Spinal; Gangliosides; Humans; Immunoglobulin M; Motor Neuron Disease; Nerve Tissue Proteins; Organ Specificity; Peripheral Nerves; Polyradiculoneuropathy; Spinal Cord; Spinal Nerve Roots

We performed detailed electrophysiologic studies on 16 patients with clinically defined multifocal motor neuropathy and found a wide spectrum of demyelinating features. Only five patients (31%) had conduction block in one or more nerves. However, in 15 patients (94%) at least one nerve showed other features of demyelination. We also noted a significant degree of superimposed axonal degeneration in 15 patients. Eight patients (50%) had individual nerves with pure axonal injury, despite the presence of demyelinating features in other nerves. Antiganglioside antibodies were elevated in four of five patients with conduction block and five of 11 patients without conduction block. We conclude that multifocal motor neuropathy is characterized electrophysiologically by a wide spectrum of axonal and demyelinating features. Diagnostic criteria requiring conduction block may lead to underdiagnosis of this potentially treatable neuropathy.

Topics: Adult; Antibodies; Cyclophosphamide; Female; G(M1) Ganglioside; Humans; Immunoglobulin G; Immunoglobulins, Intravenous; Male; Median Nerve; Middle Aged; Motor Neuron Disease; Neural Conduction; Peripheral Nervous System Diseases; Radial Nerve; Retrospective Studies; Ulnar Nerve

We describe the first two European cases of acute axonal motor neuropathy with both IgG and IgA anti-GD1a antibodies following Campylobacter enteritis. Both patients acutely developed severe weakness without sensory involvement, had antibodies to Campylobacter jejuni and polyclonal IgG and IgA titers > or = 12,800 to GD1a at onset, which decreased during follow-up. Serial electrophysiologic studies showed: 1, normal or only slightly slowed motor conductions; 2, evidence of a progressive loss of excitability and conduction failure in nerve fibers undergoing axonal degeneration in intermediate nerve segments and evidence of distal axonal involvement in one nerve; 3, normal sensory conductions, sensory potential amplitudes and somatosensory evoked potentials. Although we cannot exclude that axonal degeneration followed demyelination, we think that anti-GD1a antibodies account for the axonal involvement because GD1a is present in the axolemma and exposed at the node of Ranvier and in nerve terminals. The exclusive motor involvement could be explained by the fact that GD1a has a different internal structure in motor and sensory fibers.

Topics: Adult; Aged; Antibodies, Bacterial; Autoantibodies; Axons; Campylobacter Infections; Campylobacter jejuni; Europe; Evoked Potentials, Motor; Evoked Potentials, Somatosensory; Female; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosides; Humans; Immunoglobulin A; Immunoglobulin G; Male; Median Nerve; Motor Neuron Disease; Neural Conduction; Polyradiculoneuropathy; Ulnar Nerve

IgM anti-GM1 antibodies are associated with motor neuropathy syndromes, including multifocal motor neuropathy (MMN). We compared the ability of serum IgM from patients with multifocal motor neuropathy to bind to GM1 ganglioside alone and to GM1 as a component of a lipid mixture that also contained galactocerebroside and cholesterol (GGC). Our results showed that high-titer selective serum IgM binding to GGC has strong specificity for MMN. Further, over 40% more serums from patients with MMN have high-titer serum IgM binding to GGC than to GM1 alone. The specific composition and structure of the lipid mixture altered the ability of serum IgM to bind to GM1 ganglioside. Substitutions of other lipids for galactocerebroside or cholesterol could completely inhibit the antibody binding. We conclude that serum IgM anti-GGC autoantibodies have specificity for MMN and their binding is strongly influenced by the lipid environment of GM1 ganglioside.

Topics: Cholesterol Esters; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Galactosylceramides; Humans; Immunoglobulin M; Lipids; Motor Neuron Disease; Sensitivity and Specificity

Eighteen patients (15 men, three women; age range 30 to 71 years, mean 45.8 years) with multifocal motor neuropathy treated with high dose intravenous immunoglobulin (IVIg) were evaluated for nine to 48 months (mean follow up 25.3 months). The median time between onset of multifocal motor neuropathy and treatment was 5.8 years. The dose of IVIg was 0.4 g/day for three to five days. The interval between each treatment was determined for each patient by the evaluation of the effect of the first course. Muscle strength was evaluated by a computerised analyser. Clinical improvement was seen in 12 patients treated with IVIg (67%). Isometric strength increased from 32% to 97% (mean 54.5%) of the initial value. Functional scales corroborated these findings. No clear predictive factors of response to IVIg was found except the presence of high titres of IgM anti-GM1 antibodies. Often, patients needed repeated courses of IVIg to maintain the improvement. In two patients, IVIg infusions were stopped without signs of relapse after one year. Four patients were initially treated with prednisone (1 mg/kg/day), without any clear improvement. Five patients with no response to IVIg or who were IVIg dependent were treated with cyclophosphamide, but only one showed improvement. These results show the long term benefits and safety of IVIg in multifocal motor neuropathy but also the transient effect of this expensive treatment in most patients.

Topics: Adult; Aged; Antibodies; Female; Follow-Up Studies; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Isometric Contraction; Male; Middle Aged; Motor Neuron Disease; Neural Conduction; Peripheral Nervous System Diseases; Tensile Strength; Treatment Outcome

IgM anti-GM1 antibodies occur with increased frequency in the serum of patients with multifocal motor neuropathy (MMN). We tested the ability of serum IgM from patients with MMN to bind to GM1 ganglioside covalently bound to secondary amino groups on ELISA plates (Co-GM1). The Co-GM1 technique detected high titer (> 1,800), selective, serum IgM binding to GM1 ganglioside in 85% of our MMN patients (23/27), a significantly greater frequency compared with figures of 37% and 52% found using our previous testing methods. Selective IgM anti-GM1 antibodies showed disease specificity. The only other patients with selective, high-titer IgM anti-GM1 antibodies had either chronic motor neuropathy without conduction block or acute immune neuropathy in China. No patient from the amyotrophic lateral sclerosis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré, or systemic immune disorder control groups had selective IgM anti-GM1 antibodies at titers greater than 1,800 detected using Co-GM1 ganglioside as ELISA antigen. Titers of IgM anti-GM1 antibodies in MMN (averaging 31,000 +/- 15,000) were more than fourfold higher with Co-GM1 than with previous anti-GM1 assay methods, using conventional ELISA plates with GM-1 antigen alone (7,200 +/- 4,400) or in a lipid environment (3,600 +/- 1,300). We conclude that using ELISA testing with Co-GM1 antigen, serum anti-GM1 autoantibodies are a useful marker for MMN, because they are present in 85% of MMN patients and, at titers greater than 1,800, have strong specificity for immune-mediated motor neuropathies.

Topics: Amyotrophic Lateral Sclerosis; Antigen-Antibody Reactions; Autoantibodies; Demyelinating Diseases; Diagnostic Techniques, Neurological; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Immunoglobulin M; Motor Neuron Disease; Sensitivity and Specificity

Topics: Autoantigens; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; G(M1) Ganglioside; Humans; Male; Middle Aged; Motor Neuron Disease

Anti-ganglioside (anti-GM1) antibodies have been implicated in the pathogenesis of Guillain-Barré syndrome, multifocal motor neuropathy and motor neuron diseases. It has been held that they may interfere with saltatory conduction by blocking sodium channels. We tested this hypothesis by analysing action potentials from 140 single nerve fibres in 22 rat ventral roots using external longitudinal current measurement. High-titre anti-GM1 sera from Guillain-Barré syndrome or multifocal motor neuropathy patients, or anti-GM1 rabbit sera were applied to the rat ventral root, where saltatory conduction in single motor fibres was serially observed for 4-12 h (mean 8.2 h). For control experiments, we also tested anti-galactocerebroside (anti-GalC) sera, which causes acute demyelinative conduction block, and tetrodotoxin (TTX), a sodium channel blocker. Conduction block was found in 82% of the fibres treated with anti-GalC sera and 100% treated with TTX, but only in 2% (one out of 44) treated with the patients' sera and 5% (two out of 38) treated with rabbit anti-GM1 sera. All the nodes blocked by anti-GM1 sera revealed intense passive outward membrane current, in the internode just beyond the last active node. This pattern of current flow was similar to that in fibres blocked by demyelination with anti-GalC sera, and quite different from that seen in fibres blocked by reducing sodium currents with TTX. Our findings suggest that anti-GM1 sera neither mediate conduction block nor block sodium channels on their own. We conclude that physiological action of the antibody alone is insufficient to explain clinically observed conduction block in human diseases.

Topics: Action Potentials; Animals; Antibodies; Autoantibodies; Axons; G(M1) Ganglioside; Humans; Inflammation; Membrane Potentials; Motor Neuron Disease; Motor Neurons; Nerve Fibers; Neural Conduction; Polyradiculoneuropathy; Rabbits; Rats; Rats, Wistar; Sodium Channel Blockers; Spinal Nerve Roots; Tetrodotoxin

It has been recently recognized that increased titers of serum anti-GM1 antibodies may be associated with motoneurone diseases or with multiple motor neuropathy with or without conduction block and also with chronic sensorimotor neuropathy and Guillain-Barré syndrome. Santoro et al. were the first to note that anti-GM1 antibodies were able to bind to the nodes of Ranvier of the sural nerve of a patient with clinical signs and symptoms mostly resembling amyotrophic lateral sclerosis who also showed, in nerve conduction studies, multifocal motor nerve fibers conduction block and serum IGM anti-GM1 antibodies. The two patients presented in this report had asymetrical motor neurone disease with signs and symptoms of lower motoneurone involvement, and other signs, in the first patient, which suggested the existence of upper motoneurone damage. Besides, the second patient also had clinical sensory impairment in the lower limbs. Electrophysiologically, none of them had nerve conduction block but both showed inexcitable median and sural nerve sensory fibers. Both had high titers of anti-GM1. A sural biopsy of both patients showed immunoglobulins into the sensory fibers. However, we do not know whether the anti-GM1 antibodies bind to a cross-reactive glycolipid other than the GM1 itself. In any case, it seems that the presence of anti-GM1 antibodies might be a marker signalling a potentially treatable immune disorder which may have signs of lower and upper motor neurone disease and, also, clinical and electrophysiological evidences of peripheral sensory involvement.

Topics: Aged; Antibodies; G(M1) Ganglioside; Humans; Male; Middle Aged; Motor Neuron Disease

In this study, we preincubated the sera of 3 patients with neuropathies associated with elevated titers of IgM anti-GM1 antibodies, with increasing concentrations of intravenous Ig (IVIg) and assayed the inhibitory effect of this mixture on antibody binding to immobilized GM1 by an enzyme-linked immunosorbent assay. Pharmacologic concentrations of IVIg, ranging from 0.1 microgram/ml to 100 mg/ml, inhibited anti-GM1 binding to its target antigen from 26 +/- 3 to 71 +/- 7%, respectively, in a dose-dependent manner. A similar inhibition of binding was also observed with IVIg F(ab')2 fragments. These findings provide a possible mechanism for the clinical efficacy of IVIg in motor neuropathies.

Topics: Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; gamma-Globulins; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Motor Neuron Disease; Protein Binding

Observations are presented on nine selected patients with chronic upper limb demyelinating neuropathy to illustrate the range of manifestations that may be observed. In three, the involvement was purely motor, in five, mixed motor and sensory and, in one, virtually purely sensory; in seven the symptoms were unilateral and in two bilateral. The presence of reduced nerve conduction velocity and conduction block and the response to treatment in seven of the cases indicate that they represented examples of chronic inflammatory demyelinating polyneuropathy (CIDP) with focal involvement. This was confirmed by nerve biopsy in two cases. The presentation in one patient was accompanied by forearm swelling initially suspected of being a tumour but shown to be due to muscle hypertrophy. This was probably the consequence of recurrent muscle cramps and fasciculation and possibly neuromyotonia. The patient with predominant sensory involvement restricted to the upper limbs demonstrates that sensory CIDP can present focally. In one patient with monomelic motor and sensory involvement, nerve biopsy showed multifocal areas of hypertrophic demyelinating neuropathy distally in the ulnar nerve without inflammatory infiltration. This patient failed to respond to therapy. Response in the others was satisfactory, although one patient with a monomelic motor neuropathy showed a severe deterioration after being given corticosteroids; he subsequently improved with intravenous human immunoglobulin therapy.

Topics: Adolescent; Adult; Aged; Arm; Biopsy; Demyelinating Diseases; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Male; Microscopy, Electron; Middle Aged; Motor Neuron Disease; Muscle Contraction; Neural Conduction; Ulnar Nerve

We have recently cloned a panel os monoclonal IgM anti-GM1 ganglioside antibodies from peripheral blood lymphocytes of patients with multifocal motor neuropathy and Guillain Barré syndrome. In solid-phase immunoassay, the antibodies all reacted with GM1 and also reacted to different degrees with the structurally related glycolipids asialo-GM1 and GD1b. These antibodies are being used to study the pathogenesis of the anti-GM1 antibody-medicated neuropathy in different experimental systems. In the present immunofluorescence study we report the binding patterns of 5 of these antibodies in the rodent nervous system. The antibodies demonstrated highly diverse binding patterns on tissue sections and teased fibers when compared to one another and between species. The antibodies bound many central and peripheral nervous system structures, including neurons and myelin, motor end plate regions, and muscle spindles. The diversity of binding shown by these antibodies provide evidence that may account for the differing clinical phenotypes, including normality, associated with elevated titers of anti-GM1 antibodies.

Topics: Animals; Competitive Bidding; G(M1) Ganglioside; Humans; Immunohistochemistry; Mice; Microscopy, Confocal; Motor Neuron Disease; Nervous System; Rats; Rats, Sprague-Dawley

Elevated titers of antibodies directed at ganglioside epitopes have been associated with multifocal motor neuropathy (MMN), motor variant of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), amyolrophic lateral sclerosis (ALS), and other motor neuropathies. Anti-GM1 antibodies were measured in 675 patients: 180 age- and sex-stratified healthy blood bank controls, 132 normal controls who had full neurologic assessment including electromyography, 121 patients with definite ALS, 19 patients with pure sensory neuropathy, and 173 consecutive patient serum samples submitted for GM1 antibody testing. Antibodies to three ganglioside epitopes were determined by ELISA: IgM and IgG anti-monosialo GM1, asialo GM1, and disialo GD1b. Antibody titers for normal subjects and patients with ALS were used to determine normal values and borderline levels below which 99% of normal and 99% of ALS patient titers were found. Clinical evaluation of the next 173 consecutive patients referred for anti-GM1 antibody testing revealed 36 patients with motor neuropathies. Sera from 18 of these patients had titers above the 99% normal threshold and 14 had titers above the ALS and normal borderline threshold. All 14 with elevated sera titers were from patients with motor neuropathy or neuronopathy. Sixteen patients met the clinical and electrophysiologic criteria for MMN; 10 had elevated titers. Ten patients had the motor variant of CIDP without conduction block and three had elevated titers. Anti-IgM asialo GM1 antibodies had the highest sensitivity and specificity. High-titer IgM antibodies against monosialo GM1 occurred only in patients with various forms of pure motor neuropathy (100% specificity). The sensitivity was 50% for this referral-based population.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Antibodies; Epitopes; Female; G(M1) Ganglioside; Humans; Male; Middle Aged; Motor Neuron Disease; Sensitivity and Specificity

The acute motor axonal neuropathy (AMAN) form of the Guillain-Barre syndrome is a paralytic disorder of abrupt onset characterized pathologically by motor nerve fiber degeneration of variable severity and by sparing of sensory fibers. There is little demyelination or lymphocytic inflammation. Most cases have antecedent infection with Campylobacter jejuni and many have antibodies directed toward GM1 ganglioside-like epitopes, but the mechanism of nerve-fiber injury has not been defined. In 7 fatal cases of AMAN, immunocytochemistry demonstrated the presence of IgG and the complement activation product C3d bound to the axolemma of motor fibers. The most frequently involved site was the nodal axolemma, but in more severe cases IgG and C3d were found within the periaxonal space of the myelinated internodes, bound to the outer surface of the motor axon. These results suggest that AMAN is a novel disorder caused by an antibody- and complement-mediated attack on the axolemma of motor fibers.

Topics: Acute Disease; Adolescent; Adult; Axons; Campylobacter jejuni; Child, Preschool; Complement Activation; Complement C3d; Demyelinating Diseases; Female; G(M1) Ganglioside; Humans; Immunoglobulin G; Immunohistochemistry; Male; Middle Aged; Motor Neuron Disease; Nerve Degeneration; Severity of Illness Index

In a study on 67 chronic neuropathies, we have shown that anti-GM1 antibodies are particularly frequent in multifocal motor neuropathies (MMN) with conduction blocks (17/24 cases). The detection of these antibodies by ELISA necessitates a confirmation by immunodetection on thin-layer chromatography, so as to distinguish the anti-GM1 antibodies present in MMN from natural antibodies which are polyreactive and of low affinity. There is no direct correlation between the anti-GM1 antibody titer, the immunosuppressive treatment and the clinical evolution. Nevertheless, the detection of high titer of anti-GM1 antibodies is an additional argument in favor of treatment by IVIg.

Topics: Autoantibodies; Chromatography, Thin Layer; Chronic Disease; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Motor Neuron Disease; Peripheral Nervous System Diseases; Time Factors

The following report is a case of multifocal demyelinating motor neuropathy (MMN) presenting as a gradual development of asymmetric motor weakness without sensory involvement. Electrophysiological studies showed mainly a conduction block with normal or slightly slow nerve conduction velocity. Cerebrospinal fluid (CSF) protein and serum protein electrophoresis were normal, but serum IgM anti-GM1 ganglioside antibody was elevated. The patient had a poor response to steroid, plasmapheresis and chemotherapy with cyclophosphamide, but significant improvement was noted after intravenous immunoglobulin (IVIG) infusion. MMN is a potentially treatable condition which clinically mimics a motor neuron disease; if treatment with steroid, plasmapheresis and cyclophosphamide have failed, IVIG may be effective.

Topics: Demyelinating Diseases; G(M1) Ganglioside; Humans; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease

Twenty four patients with pure motor neuropathy are reported. The chronic motor involvement associated with fasciculations and cramps, mainly in the arms, led, in most patients, to an initial diagnosis of motor neuron disease. In some patients (nine of 24), there was no appreciable muscle atrophy. Tendon reflexes were often absent or weak. The finding of persistent multifocal conduction block confined to motor nerve fibres raises questions about the nature and the importance of this syndrome. Segmental reduction of motor conduction velocity occurred at the site of the block, but significant slowing of motor nerve conduction was not found outside this site. The response to intravenous IVIg treatment seems to be correlated with the absence of amyotrophy. Patients with little or no amyotrophy had an initial and sustained response to IVIg, and did not develop amyotrophy during the follow up study. They could be considered to have a variant of chronic inflammatory demyelinating polyneuropathy. Patients with pronounced amyotrophy independent of the disease duration did not respond as well to IVIg treatment, suggesting the existence of a distinct entity. Among the patients treated about two thirds who had an initial good response to IVIg had high or significant antiganglioside GM1 (anti-GM1) antibody titres, but there was no correlation between the high titres before treatment and long lasting response to IVIg treatment.

Topics: Adult; Aged; Antibodies, Anti-Idiotypic; Case-Control Studies; Female; Follow-Up Studies; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease; Neural Conduction; Treatment Outcome

Multifocal motor neuropathy (MMN) is associated with serum autoantibodies to gangliosides, but their pathogenic role is uncertain. We have used a novel approach to study the effects of serum and plasma from 8 patients with this syndrome, 6 of whom were anti-GM1 positive. The nerve stimulus required to evoke muscle contraction and endplate potentials (EPPs) was measured in the mouse phrenic nerve-diaphragm preparation during 4 to 6 hours of direct application (plasma at 1:1 or serum 1:2 dilution) and following intraperitoneal injection of plasma (1 ml/day) for 1 to 5 days ("passive transfer"). Direct application of MMN serum or plasma produced a progressive increase in stimulus threshold, followed by complete block of nerve-evoked muscle contraction in 3 cases, and an associated decline to about 50% of the EPP amplitude followed by sudden loss of EPPs. These effects were complement independent. Even with complete block of nerve-evoked EPPs, miniature EPP (MEPP) frequency could be increased by raising external K+ to depolarize the nerve terminal directly. Passive transfer of 1 ml of MMN plasma (n = 5) for 3 days caused similar but less marked changes. These results demonstrate that serum factors in MMN can block nerve conduction at distal motor nerves.

Topics: Adult; Aged; Animals; Evoked Potentials; G(M1) Ganglioside; Humans; Immunization, Passive; Immunoglobulin M; Male; Mice; Middle Aged; Motor Endplate; Motor Neuron Disease; Motor Neurons; Muscle Contraction; Nerve Block; Neural Conduction

Topics: Antibodies; G(M1) Ganglioside; Humans; Immunosuppressive Agents; Motor Neuron Disease

Increased titers of IgG anti-GM1 and anti-asialo GM1 (GA1) ganglioside antibodies are present in some patients with the Guillain-Barré syndrome, particularly with the motor axonal variant, and following infection with Campylobacter jejuni or parenteral administration of gangliosides. The subclass distribution of IgG anti-GM1 or GA1 antibodies from 19 patients with acute motor neuropathy and elevated antibody titers were measured by ELISA using mouse monoclonal antibodies specific for human IgG subclasses. The anti-GM1 or GA1 antibodies were predominantly of the IgG1 and IgG3 subclasses, which are capable of complement fixation, and are characteristic of a T cell-dependent antibody response.

Topics: Campylobacter Infections; Campylobacter jejuni; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Immunoglobulin G; Motor Neuron Disease; Polyradiculoneuropathy

Topics: Adult; Arm; Demyelinating Diseases; Diagnosis, Differential; Electromyography; France; G(M1) Ganglioside; Humans; Immunoglobulin M; Male; Median Nerve; Motor Neuron Disease; Muscular Atrophy; Neural Conduction; Peripheral Nervous System Diseases; Recurrence

IgM class antibodies against the ganglioside GM1 have been found in a subgroup of patients with lower motor neuron syndromes and multifocal motor neuropathies (MMN). The pathogenic relevance of these antibodies is still unclear, but some MMN patients with IgM antibodies against GM1 seem to profit from immunosuppressive therapy. A reliable test for IgM antibodies against GM1 may be useful for identifying these patients. We have assessed the comparability of the ELISA tests used for the determination of IgM against GM1 by sending coded serum samples to nine laboratories. In three samples high-titre IgM antibodies against GM1 were detected by all laboratories. This result was confirmed by dot blot immunodetection and thin-layer chromatography immuno-overlay. Seven samples were read as negative by nearly all laboratories. Major discrepancies between laboratories were noted in the analysis of one sample with results ranging from negative to "high titre".

Topics: Adolescent; Adult; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Male; Middle Aged; Motor Neuron Disease; Reproducibility of Results

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.

Topics: Adult; Antibodies; Cyclophosphamide; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunotherapy; Infusions, Intravenous; Middle Aged; Motor Neuron Disease; Neural Conduction; Peripheral Nerves; Plasma Exchange

We report an ELISA-type titertray assay for autoantibodies against the ganglioside GM1. Trays were coated with ganglioside GM1 and reacted with patients' sera; bound IgM was detected with rabbit antibody to human IgM. High-titer serum from a patient was used as calibrator, another patient's serum as the positive control, and the GM1-specific cholera toxin as the control for GM1 coating. Regression curves of serum titers obtained from different patients were linear and parallel. Intra- and interassay CVs were 4.0-7.8% and 5.5-16%, respectively. We detected antibodies at a titer of 1:250 in normal subjects. Analytical specificity of the calibrator serum against GM1 was demonstrated by immune thin-layer chromatography. Anti-GM1 antibodies were increased in patients with chronic inflammatory demyelinating polyradiculoneuropathy (P < 0.002) or multiple sclerosis (P < 0.01). In Guillain-Barré syndrome, preliminary longitudinal studies showed a decrease in anti-GM1 titer that was related to clinical recovery.

Topics: Autoantibodies; Carcinoma, Small Cell; Drug Stability; Enzyme-Linked Immunosorbent Assay; Ethanol; G(M1) Ganglioside; HIV Seropositivity; Humans; Immunoglobulin M; Lung Neoplasms; Motor Neuron Disease; Multiple Sclerosis; Polyradiculoneuropathy; Sensitivity and Specificity; Solvents

To compare the titre of anti-ganglioside antibodies (AGA) to GM1 ganglioside in patients with central and peripheral neurological disease and pure motor and sensorimotor neuropathy, in patients with classic autoimmune diseases, and controls.. AGA to GM1 were measured using an enzyme linked immunosorbent assay (ELISA) technique, highly purified bovine GM1 ganglioside, and sequential dilution of control and test sera. Antibody titre was calculated using the optical density readings of three consecutive serum dilutions multiplied by the dilution factor.. A considerable overlap was evident in the titre of AGA to GM1 in control and test sera. High antibody titres were most frequent in patients with multifocal motor neuropathy with conduction block (MMNCB). Low AGA titre were observed in several patient groups. Compared with the controls, the median titre of AGA to GM1 was significantly higher in patients with multiple sclerosis, rheumatoid arthritis, primary Sjögren's syndrome and systemic lupus erythematosus. In contrast, the median titre in patients with diabetic peripheral neuropathy, motor neurone disease, sensorimotor neuropathy and chronic inflammatory demyelinating polyneuropathy was no different from that in normal control subjects.. Estimation of AGA to GM1 may be helpful in the diagnosis of MMNCB in patients with a pure motor neuropathy but in few other conditions. Low titre AGA to GM1 are evident in several autoimmune conditions. The pathogenetic importance of AGA to GM1 in patients with neuropathy is not clear.

Topics: Arthritis, Rheumatoid; Autoimmune Diseases; G(M1) Ganglioside; Humans; Immunoglobulin M; Motor Neuron Disease; Multiple Sclerosis; Peripheral Nervous System Diseases; Sjogren's Syndrome

We reviewed the clinical and electrophysiologic features of 36 patients with increased titers of IgM anti-GM1 antibodies. Mildly elevated titers of up to 3,200 were not associated with any particular clinical syndrome or disease. Clinically, 14 of 16 patients with highly elevated titers of 6,400 or higher had progressive weakness with lower motor neuron signs; six had active tendon reflexes and eight had absent reflexes, but none had definite upper motor neuron signs. Electrophysiologic studies showed spontaneous activity in all 14 patients, one or more motor conduction blocks in nine, slowed motor conductions in one, and normal conductions in four patients. None had abnormal sensory conductions. These patients presented with a syndrome that has features of, but is distinct from, both motor neuron disease and demyelinating neuropathy.

Topics: Adult; Aged; Antibodies; Electrophysiology; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Male; Middle Aged; Motor Activity; Motor Neuron Disease; Nervous System Diseases; Neural Conduction; Paraproteinemias; Reflex, Stretch

During a study evaluating GM1 ganglioside as a possible treatment for Alzheimer's disease, two patients suffered immune responses that appeared to be limited to localized inflammation at the sites of the intramuscular GM1 injections. We determined that one patient's anti-GM1 IgM antibody titer rose from 1:400 to 1:3200 and her anti-GM1 IgG titer from < 1:50 to 1:400,000 during the immune response. The second patient's titer rose from < 1:50 to 1:3200 IgM and from 1:3200 to 1:400,000 IgG. These findings document that patients may experience acute rises in their anti-GM1 antibody levels in response to GM1 and that such rises may not necessarily cause significant acute clinical neuronal injury.

Topics: Aged; Alzheimer Disease; Antibodies; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Motor Neuron Disease; Peripheral Nervous System Diseases

A subset of human anti-GM1 ganglioside antibodies cross-reacts with Gal(beta 1-3)GalNAc bearing glycoproteins in peripheral nerve and spinal cord. The same oligosaccharide determinant is recognized by the lectin peanut agglutinin (PNA) which binds at the nodes of Ranvier in intact peripheral nerve. The Gal(beta 1-3)GalNAc bearing glycoproteins were isolated using PNA lectin affinity chromatography followed by separation on Western blot, and the proteins were subjected to partial amino acid sequence analysis. Two major PNA binding glycoproteins were identified in peripheral nerve and spinal cord; one had an approximate molecular weight of 120 kD and had sequence homology to the oligodendrocyte-myelin glycoprotein (OMgp). The other migrated between 70 and 80 kD and had sequence homology to the hyaluronate binding domain of versican, which has been reported to share sequence homology with the 70 kD proteins hyaluronectin and the glial hyaluronic acid binding protein (GHAP). By immunocytochemistry, OMgp was localized to the paranodal region of myelin, and the protein homologous to the hyaluronate binding domain of versican was localized to the nodal gap in peripheral nerve. These PNA binding glycoproteins might be target antigens for autoantibodies in peripheral nerve.

Topics: Amino Acid Sequence; Blotting, Western; G(M1) Ganglioside; Glycoproteins; Humans; Immunohistochemistry; Lectins; Molecular Sequence Data; Motor Neuron Disease; Peanut Agglutinin; Peripheral Nerves; Ranvier's Nodes; Sequence Analysis; Spinal Cord

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.

Topics: Antibodies; Axons; Campylobacter Infections; Demyelinating Diseases; Enteritis; G(M1) Ganglioside; Humans; Immunoglobulin G; Motor Neuron Disease; Paralysis; Polyradiculoneuropathy; Syndrome

Patients with multifocal motor neuropathy frequently have elevated titers of serum antibodies reactive with GM1 ganglioside. Although these antibodies may cause the syndrome, this has yet to be proven directly. As part of our studies on the nature and pathogenic potential of anti-GM1 antibodies, we have cloned B cells from the peripheral blood of 3 patients with multifocal motor neuropathy and generated four stable heterohybridoma cell lines secreting human monoclonal IgM anti-GM1 antibodies. In this report we describe the basic properties of these monoclonal antibodies in comparison with the patient's sera from which they were derived. The antibodies all differ in their pattern of reactivity with GM1 and other Gal(beta 1-3)GalNAc-containing glycoconjugates. They have widely varying thermal ranges and their reactivities are strongly influenced by the presence of accessory lipids. Affinity purification of the patient's sera with GM1 led to the identification of previously unrecognized paraproteins that were resolvable above the background of polyclonal anti-GM1 IgM. Our data demonstrate considerable heterogeneity in the immune response to GM1 both within individual sera and between different patients, which is likely to be of importance to their role in disease pathogenesis.

Topics: Adult; Antibodies, Monoclonal; Autoantibodies; Chromatography, Affinity; Chromatography, Thin Layer; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Isoelectric Focusing; Middle Aged; Motor Neuron Disease

We tested monoclonal IgM anti-GM1 and asialo-GM1 antibodies from 6 patients with chronic motor neuropathies for binding to lipopolysaccharides (LPS) from three stains of Campylobacter jejuni. Four of the 6 patients showed strong reactivity with LPS from at least one of the three C. jejuni strains tested as shown by enzyme-linked immunosorbent assay or western blot. Preabsorption with GM1 or asialo-GM1, or blocking with cholera toxin, prevented antibody binding to LPS. These studies indicate that human anti-GM1 or anti-asialo-GM1 antibodies cross-react with LPS from certain strains of C. jejuni, and that bacterial LPS might provide antigenic stimuli for the activation of B cells expressing anti-GM1 antibodies.

Topics: Antibodies, Monoclonal; Arachis; Campylobacter jejuni; Cholera Toxin; Cross Reactions; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Glycolipids; Humans; Immunoglobulin M; Lectins; Lipopolysaccharides; Motor Neuron Disease; Paraproteinemias; Peanut Agglutinin; Plant Lectins; Species Specificity

We review clinical, neurophysiological, immunological, and experimental data concerning multifocal motor neuropathy (MMN), a newly recognized disorder that mimics MND. It is separated from MND by the presence of multifocal conduction block (CB) demonstrated electrophysiologically, and in some instances by the association of high titers of GM1 antibodies. The possible immunopathogenetic effect of GM1 antibodies is discussed. However, 70% of patients with MMNCB do not have elevated titers of GM1 antibodies, but may respond nevertheless to immunosuppressive treatment. Thus, so far unrecognized antibodies may react against some other epitopes in the paranodal region than those attacked by GM1 antibodies to cause CB.

Topics: Animals; Antibodies; Antibodies, Anti-Idiotypic; Demyelinating Diseases; G(M1) Ganglioside; Humans; Immunoglobulin M; Mice; Motor Neuron Disease; Nervous System Diseases; Neural Conduction; Rabbits; Rats

Synthesis of anti-ganglioside GM1 antibodies of the IgM class by peripheral blood mononuclear cells (PBMNC) from patients with immune-mediated neuropathies and motor neuron diseases and from normal controls was stimulated by Pokeweed mitogen (PWM) in vitro. In patients with acute Guillain-Barré syndrome or multifocal motor neuropathy and high serum titers of IgM anti-ganglioside GM1 antibodies this culture response was greatly enhanced as compared to controls and already detectable in unstimulated cultures. Limiting dilution analysis demonstrated high frequencies of GM1-specific B cells in these patients. Anti-ganglioside GM1 antibodies of the IgG and IgA class were only produced by PBMNC from patients with Guillain-Barré syndrome corresponding to serum titers. In cultures taken at intervals over 6 months in vitro B cell activity for IgM, IgG and IgA anti-ganglioside GM1 antibodies in two Guillain-Barré syndrome patients declined accompanied by clinical improvement and falling serum titers. We conclude that GM1-specific PWM-responsive B cells pre-exist in peripheral blood and respond to T cell-dependent stimulation in Guillain-Barré syndrome and multifocal motor neuropathy.

Topics: Adult; Aged; B-Lymphocytes; Cells, Cultured; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Male; Middle Aged; Motor Neuron Disease; Polyradiculoneuropathy; T-Lymphocytes

A 31-year-old man had noticed slowly progressive weakness in his right upper limb girdle. On admission at age 32, fasciculation and muscle atrophy were observed in the right pectoralis major muscle. There was mild muscle weakness in the right triceps brachii muscle. The deep tendon reflexes were normal and the pathologic reflexes were absent. Sensory and autonomic nerve functions were intact. Needle EMG showed fibrillation potentials and positive sharp waves in the right pectoralis major, infraspinatus, extensor carpi radialis, extensor digitorum muscles, the bilateral sternocleidomastoideus and triceps brachii muscles. Motor nerve conduction studies revealed normal conduction velocities and distal latencies as well as no evidence of conduction block or abnormal temporal dispersion. Serum immunoelectrophoresis failed to detect an M protein. Thin-layer chromatography with immunostaining revealed that the serum contained auto antibodies which reacted with asialo-GM1, GM1 and LM1. This case must belong to "proximal lower motor neuron syndrome" proposed by Pestronk et al.

Topics: Adult; Autoantibodies; G(M1) Ganglioside; Gangliosides; Humans; Male; Motor Neuron Disease

IgM M-proteins in some motor neuron disease (MND) patients bind immunologically to shared determinants on gangliosides GM1 and GD1b. Since patients with these M-proteins have improved with immunotherapy the antibodies may be important in the pathogenesis of MND. To study how the M-proteins might damage motor neurons, we established co-cultures of human neurons from spinal cord explants and human myotubes. Antibodies from patient but not control serum bound to the cultured neurons. Neurons in co-cultures degenerated after incubation with patient but not control serum. These results demonstrate that anti-GM1 antibodies can bind to and destroy spinal cord neurons that are cultured with muscle. Nerve-muscle co-cultures can serve as a system to examine effects of anti-GM1/GD1b M-proteins on motor neurons.

Topics: Binding Sites; Carbohydrate Sequence; Cell Communication; Cells, Cultured; Fetus; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin M; Middle Aged; Molecular Sequence Data; Motor Neuron Disease; Muscles; Neurons; Paraproteins; Spinal Cord

We report the results of immunosuppressive treatment with intravenous cyclophosphamide in 12 patients with lower motor neuron syndrome and elevated titers of serum autoantibodies to GM1 ganglioside. All patients had lower motor neuron dysfunction including proximal or distal weakness, fasciculation and muscle atrophy, but no upper motor neuron dysfunction such as hyperreflexia, spasticity or Babinski's sign. Electrophysiological studies revealed no evidence of conduction block, but EMG findings of acute or chronic denervation in the limbs were present. Serum biochemistry and immunological studies were negative for M protein. After a 6-month follow-up, despite a fall in antibody titer, there was no significant clinical improvement in any of the patients.

Topics: Aged; Autoantibodies; Cyclophosphamide; Electromyography; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunosuppressive Agents; Male; Middle Aged; Motor Neuron Disease; Motor Neurons; Muscular Atrophy; Syndrome

A patient with a progressive lower motor neuron syndrome and neurophysiological evidence of motor axon loss, multifocal proximal motor nerve conduction block, and high titres of anti-ganglioside GM1 antibodies. Neuropathological findings included a predominantly proximal motor radiculoneuropathy with multifocal IgG and IgM deposits on nerve fibres associated with a loss of spinal motor neurons. These findings support an autoimmune origin of this lower motor neuron syndrome with retrograde degeneration of spinal motor neurons and severe neurogenic muscular atrophy.

Topics: Aged; Autoantibodies; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Immunohistochemistry; Male; Motor Neuron Disease; Neural Conduction; Neuromuscular Junction; Peripheral Nerves; Spinal Cord

Six of 110 patients (5.5%) with forms of motor neuron disease had abnormal titers of GM1 antibodies of 1:1,600 or higher. Four others came with previously known high titers. Three patients with upper motor neuron (UMN) signs had titers of 1,600; those with probable or no UMN signs had higher titers. Nine patients had conduction block; six of them had abnormal antibody titers, four with 6,400 or higher. Therefore, patients with motor neuron disease and abnormal anti-GM1 titers may have UMN signs or conduction block.

Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Autoantibodies; Female; G(M1) Ganglioside; Humans; Male; Middle Aged; Motor Neuron Disease; Paraproteinemias

We treated five consecutive patients with multifocal motor neuropathy (MMN) with high-dose intravenous immunoglobulin (IVIg). Four patients had increased levels of anti-asialo-GM1 IgM and two of anti-GM1 IgM as well; one patient had no reactivity. We treated them twice with 0.4 g/kg IVIg for 5 consecutive days at a 2-month interval, followed by maintenance infusions up to 6 to 12 months. All patients with high anti-asialo-GM1 had a consistent clinical improvement starting 3 to 10 days after the first IVIg course; in one patient, recovery was complete and persistent for 12 months without additional treatment, while in three patients, improvement only lasted 20 to 30 days. There was a similar improvement in these patients after the second course of IVIg which was maintained by periodic 2-day IVIg infusions. Clinical improvement in these patients was associated with a reduction of conduction block in most, but not all, motor nerves, while antibody titers were not consistently modified by treatment. There was no clinical or electrophysiologic improvement in the patient without antiglycolipid activity after 6 months of IVIg. IVIg may be a safe and effective therapy for MMN.

Topics: Adult; Autoantibodies; Female; G(M1) Ganglioside; Humans; Immunoglobulin M; Immunoglobulins, Intravenous; Male; Middle Aged; Motor Neuron Disease; Neural Conduction

Increased titers of anti-GM1 antibodies have been associated with motor neuron disease and motor neuropathy with or without conduction block. To investigate the pathogenetic role of anti-GM1 antibodies we injected into rat tibial nerves sera from patients with multifocal motor neuropathy and conduction block (MMN) or progressive spinal muscular atrophy (PMA), both presenting anti-GM1 antibodies. Sera of patients with MMN produced reduction of amplitude and dispersion of compound muscle action potential from proximal stimulation. Morphometry revealed demyelination in 6.2% of fibers. Sera of patients with PMA did not produce clear-cut electrophysiological or morphological changes. Differential effects of sera from patients presenting high-titer anti-GM1 antibodies, but with distinct clinical syndromes, might depend on differences in anti-GM1 antibody affinity, valency, or ability to fix complement. Alternatively, circulating factors other than, or in addition to, anti-GM1 antibodies present in sera of patients with MMN, but not of PMA patients, might be responsible for conduction abnormalities and reproduce them after passive transfer.

Topics: Animals; Antibodies; Demyelinating Diseases; G(M1) Ganglioside; Humans; Male; Motor Neuron Disease; Muscular Atrophy, Spinal; Neural Conduction; Rats; Rats, Sprague-Dawley; Tibial Nerve

We studied serum antibodies to GM1 ganglioside by enzyme linked immunosorbent assay (ELISA) in 55 patients with motor neuron disease (MND) composed of 36 ALS and 19 lower motor neuron disease (LMND), 44 patients with demyelinating neuropathy (DN) composed of 29 Guillain-Barré syndrome (GBS) and 15 chronic inflammatory demyelinating polyneuropathy (CIDP), and 21 healthy controls. High levels of serum antibodies against GM1 were confirmed by thin-layer chromatography overlay procedure. In MND group, the mean level of anti-GM1 IgM antibodies was not significantly elevated in comparison with controls. There was no significant difference in anti-GM1 antibodies between ALS group and LMND group, while anti-GM1 IgM antibodies in DN group, especially in GBS group, were significantly elevated (p < 0.001). High levels of anti-GM1 IgM antibodies (greater than the mean level plus 3 standard deviations of controls) were detected in 9 patients (6 with ALS and 3 with LMND) with MND (16.4%) and 16 patients (11 with GBS and 5 with CIDP) with DN (36.4%). Serum antibodies to GM1 reacted with GD1b ganglioside in only one patient with MND and 10 patients (8 with GBS and 2 with CIDP) with DN. Anti-GM1 IgG antibodies were elevated significantly in DN group. There was no correlation among anti-GM1 IgM antibodies and both duration and severity of illness in MND. In some patients with MND, levels of anti-GM1 IgM antibodies became high in the advanced stage. It is unclear whether these antibodies are primary manifestation or consequence of motor neuron disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Autoantibodies; Demyelinating Diseases; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Motor Neuron Disease

Topics: Adult; Aged; Autoantibodies; Autoimmune Diseases; Chlorambucil; Female; G(M1) Ganglioside; Humans; Male; Middle Aged; Motor Neuron Disease; Neurologic Examination; Synaptic Transmission

We report here our studies on IgM reactivity towards peripheral nervous system gangliosides, in motor-neuron diseases (MND) without IgM gammopathies, and in peripheral neuropathies with IgM gammopathies. We showed by enzyme linked immunosorbent assay technique, that anti-GM1 IgM antibodies were often present at a low level in normal controls in contrast to anti-GD1b antibodies, which were never detected in control sera. We evidenced that several steps of the ELISA technique were critical such as the nonaddition of detergent in buffer solutions used for dilutions and for washing and the choice of the ELISA plates. We studied 50 cases of motor-neuron diseases, among which 40 typical cases of Amyotrophic Lateral Sclerosis, only a few had high anti-GM1 antibodies levels, which were always confirmed by immunodetection on thin-layer chromatography. These antibodies were generally directed against the oligosaccharide epitope present also in asialoGM1. No correlation has been as yet established in relation to the clinical state of the patients. In a few cases of polyneuropathies associated with IgM gammopathies, antiganglioside antibodies have been reported. We have found anti-GD1b antibodies to be present in a sensory-motor axonal neuropathy; axonal involvement was evidenced by electrophysiological study.

Topics: Autoantibodies; Chromatography, Thin Layer; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Gangliosides; Humans; Immunoassay; Immunoglobulin M; Motor Neuron Disease; Peripheral Nervous System Diseases; Reference Values

The gangliosides GM1 and GD1b have recently been reported to be potential target antigens in human motor neuron disease (MND) or motor neuropathy. The mechanism for selective motoneuron and motor nerve impairment by the antibodies directed against these gangliosides, however, is not fully understood. We recently investigated the ganglioside composition of isolated bovine spinal motoneurons and found that the ganglioside pattern of the isolated motoneurons was extremely complex. GM1, GD1a, GD1b, and GT1b, which are major ganglioside components of CNS tissues, were only minor species in motoneurons. Among the various ganglioside species in motoneurons, several were immunoreactive to sera from patients with MND and motor neuropathy. One of these gangliosides was purified from bovine spinal cord and characterized as N-glycolylneuraminic acid-containing GM1 [GM1(NeuGc)] by compositional analysis, fast atom bombardment mass spectra, and the use of specific antibodies. Among seven sera with anti-GM1 antibody activities, five sera reacted with GM1(NeuGc) and two did not. Two other gangliosides, which were recognized by another patient's serum, appeared to be specific for motoneurons. We conclude that motoneurons contained, in addition to the known ganglioside antigens GM1 and GD1b, other specific ganglioside antigens that could be recognized by sera from patients with MND and motor neuropathy.

Topics: Animals; Antigen-Antibody Reactions; Cattle; Cell Separation; Epitopes; G(M1) Ganglioside; Gangliosides; Humans; Immune Sera; Motor Neuron Disease; Motor Neurons; Spinal Cord

Using an enzyme-linked immunosorbent assay (ELISA) sera from 100 individuals, 20 with motor neuron disease (MND), 25 with peripheral neuropathy (PN), 15 with degenerative dementia and 40 controls, were examined in order to detect serum IgM and IgG anti-GM1 and anti-GD1a antibodies. Patients with MND showed statistically significant higher levels of IgM anti-GM1 antibody compared to the control group. Three patients with peripheral neuropathy had very high levels of anti-GM1 and anti-GD1a antibodies. Antibody levels in patients with degenerative dementia showed no difference compared to the controls. These results suggest that a further inquiry into the role of serum anti-GM1 and anti-GD1a activity in motor neuron disease and peripheral neuropathy is necessary.

Topics: Aged; Autoantibodies; Female; G(M1) Ganglioside; Gangliosides; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Motor Neuron Disease; Neurologic Examination

High titers of serum antibodies against GM1 ganglioside occur frequently in patients with lower motor neuron (LMN) syndromes. We compared the specificities of the antiganglioside antibody reactivities in LMN patients with those arising after immunization of Lewis rats with several ganglioside containing preparations including purified GM1, human central nervous system (CNS) grey matter and white matter. Serums with high titers of anti-GM1 antibodies from patients with LMN syndrome usually showed limited cross-reactivity to other glycolipids but often bound to a Gal(beta 1-3)GalNAc-containing neoglycoprotein. In contrast, serums with anti-GM1 antibody arising after immunization showed broad cross-reactivity with other glycolipids but did not bind to the neoglycoprotein. We conclude that the serum patterns of antiganglioside antibody reactivity secondary to immunization with gangliosides and CNS components are different from the natural autoantibodies found in LMN patients. The antiganglioside antibodies seen in LMN patients are unlikely to be a result of autoreactivity to gangliosides after nervous tissue damage.

Topics: Animals; Brain; Female; G(M1) Ganglioside; Galactosylceramides; Glycoproteins; Immunization; Immunoglobulin G; Motor Neuron Disease; Peripheral Nerves; Rats; Rats, Inbred Lew

Anti-GM1 IgM antibodies were found in 23% of 56 patients with motor neuron disease (MND), in 19% of 69 patients with neuropathy and in 7% of 107 controls with other neurological and non-neurological diseases. Most patients had anti-GM1 IgM titers of 1:80 or less, while slightly higher titers (up to 1:640) were found in 1 patient with MND and 2 with neuropathy, and very high titers (1:20,480) were restricted to a patient with MND and an IgMk M-protein reacting with GM1, GD1b and asialo-GM1. Anti-GM1 IgM antibodies may be a normal constituent of the human antibody repertoire but their frequency and, at times, their levels are higher in patients with MND or neuropathy. The possible pathogenetic role of these antibodies remain to be established.

Topics: Autoantibodies; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Immunoglobulin M; Male; Middle Aged; Motor Neuron Disease; Neurologic Examination

A 34-year-old man had noted progressive weakness in his right hand. On admission at age 39, cranial nerves were not involved. Fasciculations were observed in his upper limb girdles. Neurological examination revealed severe wasting and weakness of arms and the right hand, whereas mild in the left hand. The deep tendon reflexes were absent in the upper extremities, but normal in the lower extremities. No sensory disturbances were observed. Motor and sensory nerve conduction velocities were normal, and multifocal conduction block was not observed. EMG showed neuropathic changes in all 4 limbs and sternocleidomastoideus muscles. Serum immunoelectrophoresis failed to detect an M protein. High-performance thin-layer chromatography with immunostaining revealed that his serum IgM reacted with GM1, but not reacted with GM2, GD1a, GD1b, and asialo-GM1.

Topics: Adult; Autoantibodies; G(M1) Ganglioside; Humans; Immunoglobulin M; Male; Motor Neuron Disease

We studied the ability of anti-GM1 ganglioside antibodies to bind to GM1 in a lipid, "membrane-like" environment. Liposomes containing GM1 were synthesized to simulate this environment. We then compared the binding of anti-GM1 a autoantibodies to GM-1-liposomes and to purified GM1. Antibody binding was quantitated using enzyme-linked immunosorbent assay methodology. Our results showed a 250-fold variation in the ability of anti-GM1 antibodies to bind to GM1-liposomes. There was no correlation between GM-1-liposome binding and the carbohydrate specificities of the anti-GM1 antibodies. However, anti-GM1 antibodies from patients with amyotrophic lateral sclerosis (ALS) showed a 4 fold greater binding to GM1-liposomes than antibodies from patients with lower motor neuron (LMN) syndromes. We conclude that a lipid, presumably "membrane-like", environment may greatly influence the degree of anti-GM1 antibody binding to GM1. The low levels of anti-GM1 antibody binding to GM1-liposomes in patients with LMN syndromes may provide a diagnostic means for distinguishing these patients from those with ALS. Anti-GM1 antibodies from patients with ALS may bind especially well to neuronal membranes containing GM1 in vivo.

Topics: Amyotrophic Lateral Sclerosis; Autoantibodies; Chromatography, High Pressure Liquid; Enzyme-Linked Immunosorbent Assay; G(M1) Ganglioside; Humans; Immunoglobulin M; Liposomes; Motor Neuron Disease

Clinical correlations of antiganglioside GM1 antibodies are important because high titers of these antibodies may have therapeutic significance. To further evaluate this significance, we reviewed our experience with 78 patients who had the following diagnoses: amyotrophic lateral sclerosis (ALS), ALS syndromes in patients with gammopathy or thyroid abnormalities, cervical spondylosis simulating ALS, motor neuropathies, and chronic inflammatory demyelinating polyneuropathies (CIDP). Antiganglioside antibody titers were measured "blind" by ELISA assay at the neuromuscular clinical laboratory, Johns Hopkins School of Medicine. We conclude that anti-GM1 antibodies are found in a wide variety of neuromuscular conditions. Patients with classical ALS had a mean anti-GM1 antibody titer significantly lower than patients with CIDP or motor neuropathy. Patients with ALS associated with gammopathy or thyroid disorders had higher anti-GM1 titers than seen in classical ALS. The highest mean titer occurred in patients with CIDP, a treatable neuropathy.

Topics: Amyotrophic Lateral Sclerosis; Autoantibodies; Cervical Vertebrae; Demyelinating Diseases; Enzyme-Linked Immunosorbent Assay; Female; G(M1) Ganglioside; Humans; Male; Middle Aged; Motor Neuron Disease; Spinal Osteophytosis