Anti-myelin Associated Glycoprotein Antibodies Research Articles

Long-standing Multifocal Motor Neuropathy Presenting With Delayed Clinical Features of Anti–Myelin-Associated Glycoprotein Neuropathy and Elevated Anti–Myelin-Associated Glycoprotein Antibody Titers

Multifocal motor neuropathy with conduction block (MMN) and anti-myelin-associated glycoprotein (MAG) neuropathy are rare chronic acquired demyelinating neuropathies with distinct clinical and electrophysiological characteristics. These neuropathies are generally not known to coexist. This report describes a patient with long-standing MMN who subsequently developed clinical features of anti-MAG neuropathy. This suggests that subtypes of chronic inflammatory neuropathies may not be sharply defined. In addition, a presentation of MMN with anti-MAG titers may be a prognostic indicator of poor response to standard MMN treatment.

Demyelinating polyneuropathy with anti-myelin associated glycoprotein antibodies responsive to lenalidomide in combination with rituximab (P1.449)

Demyelinating polyneuropathy with anti-myelin associated glycoprotein antibodies responsive to lenalidomide in combination with rituximab (P1.449)

Prevalence, correlates and impact of pain and cramps in anti-MAG neuropathy: a multicentre European study.

The frequency of pain and cramps is uncertain in anti-myelin associated glycoprotein antibody (anti-MAG) neuropathy. Whether these symptoms may affect function/quality of life is unknown. A cross-sectional study of the prevalence, correlates and impact of pain, pain subtypes and cramps, their severity, frequency and anatomical distribution was performed for 55 clinically stable patients with anti-MAG neuropathy. Pain of any type was reported by 80% of subjects. The most common subtype was paraesthesiae and dysaesthesiae (70%). Cramps were reported by >60% of patients, with lower limb cramps in all and upper limb cramps in about 20%. Cramps affected daily activities in >30% of these subjects, sleep in 60%, ability to exercise in >30%. Total pain score correlated with several Short Form 36 health-related quality of life (SF-36 HR-QoL) measures (P<0.05), with Inflammatory Rasch-built Overall Disability Scale (I-RODS) (P=0.006) and 10-m timed walk (P=0.019). An independent association was ascertained with I-RODS (P=0.002). Different pain subtypes showed multiple associations with SF-36 HR-QoL measures and/or functional scales. Upper limb cramps had multiple SF-36 HR-QoL functional correlates, with an independent association with the Overall Neuropathy Limitation Score (ONLS) (P=0.004). Cramp severity correlated with ONLS (P=0.04) and I-RODS (P=0.028) and inversely with level of physiotherapy input (P=0.009). Cramp frequency was associated with tremor score (P=0.004) and multiple SF-36 HR-QoL subsections. Neuropathic pain and cramps may affect function and quality of life in anti-MAG neuropathy. Optimizing treatments of these symptoms, including by adequate levels of physiotherapy, may be beneficial in affected patients and requires further research.

Determinants of health-related quality of life in anti-MAG neuropathy: a cross-sectional multicentre European study.

Our objective was to assess determinants of quality of life (QoL) in anti-myelin associated glycoprotein antibody (MAG) neuropathy. The SF-36 questionnaire was assessed in 55 patients, from Marseille, Angers (France) and Birmingham (UK). Routine clinical evaluations included Medical Research Council (MRC) sum score, inflammatory neuropathy cause and treatment (INCAT) sensory score, inflammatory Rasch-built overall disability score (I-RODS), ataxia score, Jamar grip dynamometry, timed 10-m walk, neuropathic pain symptom inventory (NPSI) score, and fatigue severity score (FSS). Physical component summary (PCS) and mental component summary (MCS) of the SF36 questionnaire were significantly lower than in reported normal subjects of both countries (p < 0.001). All SF-36 domains correlated with I-RODS, except MCS for which significance was, however, approached (p = 0.056). PCS correlated with MRC sum score, ataxia score, timed 10-m walk, tremor, Jamar grip dynamometry, NPSI pain score, FSS and level of social support. MCS correlated exclusively with FSS and level of social support. In multivariate regression, PCS was associated independently with I-RODS (p < 0.001) and NPSI pain score (p = 0.011), whereas MCS was associated independently with FSS (p = 0.022). QoL is accurately predicted in anti-MAG neuropathy by the I-RODS and FSS, lending support to their use in clinical and research settings. Effective measures to improve QoL should include tremor and neuropathic pain treatment, fatigue management, and improved social support.

Clinical and Neurophysiological Evaluation of Peripheral Nervous System Abnormalities in Patients with Lymphoproliferative Disorders (P06.018)

Objective: To evaluate clinical and neurophysiological manifestation in association with onconeural antibodies among patients with lymphoproliferative disorders. Background Lymphoproliferative disorders are recognized among important causes of paraneoplastic neurological syndromes (PNS). Subacute sensory neuropathy is the most frequents typical PNS, however other types of neuropathy are also observed. Systemic studies in homogenous group of patients with malignancies have not been conducted. Design/Methods: The study included in 25 patients with lymphoproliferative disorders: 8 lymphoma cases (32%), 13 myeloma (52%) and 4 leukemia ones 16%). According to the examination protocol, routine electromyographic examinations were carried out, and onconeuronal antibodies were evaluated by means of indirect immunofluorescence as a screening test and Western blotting for confirmation. Results: Symptoms of sensory-motor polyneuropathy were found in 36%, sensory polyneuropathy in 28%, and mononeuropathy in 8% of patients. Autoimmune reaction limited to anti-Myelin Associated Glycoprotein antibodies were detected in 16% of cases. In patients with abnormalities in neurological examination following neurophysiological findings were observed: reduction of amplitude of responses from motor fibres in the ulnar nerve (P=0.005), increased polyphasy in the right interossalis muscle (P=0.023) and right dorsiflexor (P=0.022) in comparison with subjects without clinical deficit. In lymphoma patients nerve conduction was decreased (P=0.041) when compared with myeloma patients, and the Motor Unit Action Potential (MUAP) in right tibial anterior was prolonged in myeloma cases (P = 0.029). Moreover, a proportion of MUAP polyphasy (r=-0.4624; P=0.0200) and amplitude of response from sensory fibers of median (r=-0.4149; P=0.0490) and ulnar nerve (r=- 0.5403; P=0.0139) correlated with the duration of chemotherapy. Conclusions: Sensory disorders are dominant among patients with lymphoproliferative disorders, clinically manifest as sensory or sensory-motor polyneuropathy, and neurophysiological examination reveals axonal changes. In subjects with lymphoma the neurophysiological disorders in peripheral nerves of lower limbs are significantly more advanced than in myeloma cases. Disclosure: Dr. Rogoziewicz has nothing to disclose. Dr. Wiszniewska has nothing to disclose. Dr. Wiszniewski has nothing to disclose. Dr. Michalak has nothing to disclose. Dr. Kozubski has nothing to disclose.

Anti-myelin associated glycoprotein antibodies recognize HNK-1 epitope on CNS

Antibodies to myelin-associated glycoprotein (MAG) are associated with demyelinating polyneuropathy and are specific for the HNK-1 epitope. To test if anti-MAG IgM recognize HNK-1 on CNS, sera from 20 patients and 238 controls were tested on rat slices by indirect immunofluorescence (IIF). IgM from anti-MAG positive patients, but not from control sera, stained rat brain with perineuronal or neuropil pattern, depending on the CNS region. IIF titers significantly correlated with ELISA anti-MAG titers. The staining of patients’ sera were inhibited by mouse anti-HNK-1 monoclonal antibody. Our results demonstrate that anti-MAG IgM recognizes HNK-1 outside the peripheral nerve myelin carriers.

Serum Anti-Myelin—Associated Glycoprotein Antibodies in Egyptian Autistic Children

Autoimmunity to brain could play an etiopathogenic role in a subgroup of autistic patients. The frequency of serum anti-myelin-associated glycoprotein antibodies, as an index for autoimmunity to brain, and their relation to family history of autoimmunity were investigated in 32 autistic and 32 healthy matched children. Autistic children had significantly higher serum anti-myelin-associated glycoprotein antibodies than healthy children (2100 [1995] and 1138 [87.5] Buhlmann titre unit, P < .001). Anti-myelin-associated glycoprotein positivity was elicited in 62.5% of autistic children. Family history of autoimmunity in autistic children (50%) was significantly higher than controls (9.4%). Anti-myelin-associated glycoprotein serum levels were significantly higher in autistic children with than those without such history (P < .05). In conclusion, autism could be, in part, one of the pediatric autoimmune neuropsychiatric disorders. Further studies are warranted to shed light on the etiopathogenic role of anti-myelin-associated glycoprotein antibodies and the role of immunotherapy in autism.

European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of paraproteinaemic demyelinating neuropathies: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society*

Paraprotein-associated neuropathies have heterogeneous clinical, neurophysiological, neuropathological and haematological features. Objectives. To prepare evidence-based and consensus guidelines on the clinical management of patients with both a demyelinating neuropathy and a paraprotein (paraproteinaemic demyelinating neuropathy, PDN). Search of MEDLINE and the Cochrane library, review of evidence and consensus agreement of an expert panel. In the absence of adequate data, evidence based recommendations were not possible but the panel agreed the following good practice points: (1) Patients with PDN should be investigated for a malignant plasma cell dyscrasia. (2) The paraprotein is more likely to be causing the neuropathy if the paraprotein is immunoglobulin (Ig)M, antibodies are present in serum or on biopsy, or the clinical phenotype is chronic distal sensory neuropathy. (3) Patients with IgM PDN usually have predominantly distal and sensory impairment, with prolonged distal motor latencies, and often anti-myelin associated glycoprotein antibodies. (4) IgM PDN sometimes responds to immune therapies. Their potential benefit should be balanced against their possible side-effects and the usually slow disease progression. (5) IgG and IgA PDN may be indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy, clinically, electrophysiologically, and in response to treatment. (6) For POEMS syndrome, local irradiation or resection of an isolated plasmacytoma, or melphalan with or without corticosteroids, should be considered, with haemato-oncology advice.

Antibodies in Neurosarcoidosis

A 33-year-old African American woman was admitted to our hospital with bilateral facial nerve palsy. One week prior to presentation, the patient experienced numbness and paresthesia of her face. Paresthesia was located over her upper lip, and around the eyes and frontal area. Three days before presentation, the patient developed facial droop, difficulty closing eyes, inability to smile, loss of taste, and ocular dryness. The patient's past medical history was unremarkable. She was a life long nonsmoker. Physical examination at admission revealed normal vital signs. Neurological examination showed bilateral facial nerve palsy and decreased sensation to touch and pain in the ophthalmic and maxillary distributions of the trigeminal nerve. Mental status and the remaining neurological examination were normal. Skin, chest, cardiac, and abdominal examinations were unremarkable. Cerebral magnetic resonance imaging (MRI) showed no meningeal signal enhancement, intracranial mass, cerebral or brain stem signal abnormality, or vascular disease. Lumbar puncture with cerebrospinal fluid (CSF) sampling was done. The CSF opening pressure was normal. CSF analysis showed a white cell count of 66 /uL, lymphocytes 92%, glucose of 46 mg/dl (normal range 40-70mg/dl), protein of 70 mg/dl (normal rage 15-55 mg/dl), negative CSF Venereal Disease Research Laboratory value (VDRL), negative CSF Lyme antibody, and negative Herpes virus polymerase chain reaction. Other laboratory findings included a negative human immunodeficiency virus antibody, erythrocyte sedimentation rate of 30 mm/min, negative anti-nuclear antibody, angiotensin-converting enzyme of 32 U/L, and mildly elevated hepatic aminotransferases. Computed tomographies scan of the chest showed right hilar and right paratracheal lymphadenopathies. Bronchoscopy with transbronchial lung biopsy as well as fine needle aspiration of the lymphadenopathy was performed. Fine needle aspiration cytology and flow cytometery were negative for malignancy. The transbronchial biopsy showed granulomatous pneumonitis consistent with a diagnosis of sarcoidosis. Tissue cultures and special stains for mycobacterial and fungal infections were negative. The patient was started on oral prednisone 80 mg daily. The facial palsy improved on oral prednisone. Pulmonary function testing was not possible due to her bilateral facial paralysis (the patient was unable to make a seal around the mouthpiece). The finding of noncaseating pulmonary granulomas of unknown cause, facial never palsy, and mediastinal lymphadenopathy is characteristic of sarcoidosis. Interestingly, the CSF antimyelin-associated glycoprotein antibody titer by enzymelinked immunosorbent assay (ELISA) was 1:1600 (Titers >1500 are considered positive). Sarcoidosis is systemic disorder of unknown cause that is characterized by noncaseating granuloma formation in affected organs. Nervous system involvement is also commonly seen in sarcoidosis. Abnormal antibody production may contribute to the disease process and nervous system injury in sarcoidosis. Autoantibodies to brain endothelial cells have been described in patients with neurosarcoidosis1. Local synthesis of Kveim-specific IgG antibody in the cerebrospinal fluid of patients with neurosarcoidosis has also been detected2. Myelin oligodendrocyte glycoprotein (MOG) is a specific central nervous system myelin glycoprotein that is exclusively seen on the external surface of the myelin sheath and oligodendrocyte membrane. Antibodies to MOG have been implicated in the immunopathogenesis of multiple sclerosis. AntiMOG antibodies in neurosarcoidosis have been reported in the literature. As MOG antigen can activate both encephalogenic T-cells and demyelinating antibodies in experimental animals, it may be important in the pathogenesis of neurosarcoidosis3. Anti-myelin-associated glycoprotein (MAG) antibody is another antibody associated with neurological disorders. Elevated anti-MAG antibody titers can be detected in autoimmune demyelinating sensorimotor neuropathies4. Elevated anti-MAG antibody in neurosarcoidosis has not been reported before. Further Antibodies in Neurosarcoidosis 2 of 3 studies are necessary to define the role of anti-MAG antibody and other antibodies in the pathogenesis of neurosarcoidosis.

Immunotherapy for IgM anti-Myelin-Associated Glycoprotein paraprotein-associated peripheral neuropathies.

Serum monoclonal anti-Myelin Associated Glycoprotein antibodies may be pathogenic in some patients with IgM paraprotein and demyelinating neuropathy. Immunotherapies aimed at reducing the level of these antibodies might be expected to be of benefit in the treatment of the neuropathy. Many potential therapies have been described in small trials, uncontrolled studies and case reports. To examine the efficacy of any form of immunotherapy in reducing disability and impairment resulting from IgM anti-Myelin Associated Glycoprotein paraprotein-associated demyelinating peripheral neuropathy. We searched the Cochrane Neuromuscular Disease Group register (August 2002) and MEDLINE (January 1966 - August 2002) and EMBASE (January 1980 - August 2002) for controlled trials, checked the bibliographies to identify other controlled trials and contacted authors and other experts in the field. Types of studies: randomised or quasi-randomised controlled trials. patients of any age with anti-Myelin Associated Glycoprotein antibody associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance of any severity. Types of interventions: any type of immunotherapy. Types of outcome measures: Primary: improvement in the Neuropathy Disability Score or Modified Rankin Scale six months after randomisation Secondary: Neuropathy Disability Score and/or the Modified Rankin Score 12 months after randomisation. Ten metre walk time, subjective clinical scores and electrophysiological parameters at six and 12 months after randomisation. IgM paraprotein levels and anti-Myelin Associated Glycoprotein antibody titres six months after randomisation. Adverse effects of treatments. We identified six randomised controlled trials of which five were included after discussion between the authors. One author extracted the data and the other checked them. No missing data could be obtained from authors. The five eligible trials used four of the many available immunotherapy treatments. Only two had comparable interventions and outcomes but these were only short-term studies. There were no significant benefits of the treatments used in the predefined outcomes. However intravenous immunoglobulin showed benefits in terms of improved Modified Rankin Scale at two weeks and 10 metre walk time at four weeks. Serious adverse effects of intravenous immunoglobulin are known to occur from observational studies but none were encountered in these trials. There is inadequate reliable evidence from trials of immunotherapies in anti-Myelin Associated Glycoprotein paraproteinaemic neuropathy to recommend any particular immunotherapy treatment. Intravenous immunoglobulin is relatively safe and may produce some short-term benefit. Large well designed randomised trials are required to assess the efficacy of promising new therapies.

Anti-myelin associated glycoprotein antibodies: variability in patterns of IgM binding to peripheral nerve

We previously found that serums with anti-sulfatide antibodies have several different patterns of binding to neural tissue. In this study, we asked whether serums with anti-myelin associated glycoprotein (MAG) antibodies also have similar variations in patterns of tissue binding. We examined binding to peripheral nerve in 49 serums with IgM anti-MAG antibodies and 13 serums with IgM anti-sulfoglucuronyl paragloboside (SGPG) antibodies but no MAG binding. We correlated patterns of binding with titers of IgM binding to MAG and SGPG measured by ELISA methods. Our results show that IgM in most anti-MAG serums stained areas of non-compact myelin, including the periaxonal and outer myelin membranes and Schmidt–Lanterman incisures. However, other patterns included IgM binding to areas of compact myelin and to non-myelin structures including axons and endoneurial macrophages. IgM in anti-SGPG serums bound to axons or macrophages, but rarely to myelin-related structures. A total of 11/62 (18%) of serums had IgM binding to axons, six with anti-MAG antibodies and five with anti-SGPG antibodies. The majority of these serums (73%) had SGPG titers greater than MAG titers when measured by ELISA. We conclude that anti-MAG serums have several different binding patterns to neural tissue, including axonal binding, especially when anti-MAG antibodies cross-react with SGPG. These different binding patterns may relate to the ability of anti-MAG serum IgM to bind both MAG and SGPG or to other molecules with a sulfated glucuronic acid epitope that are present in peripheral nerve.

DNA sequence analysis and comparison of the variable heavy and light chain regions of two IgM, monoclonal, anti-myelin associated glycoprotein antibodies

The complete variable heavy and light chain gene sequences of two monoclonal, IgM, anti-myelin associated glycoprotein (MAG) antibodies associated with peripheral neuropathy, are presented. Comparative analysis of the two V H regions has revealed that they are 88% homologous to one another and are both members of the V H3 gene family. They are also highly homologous to a gene which is frequently utilized in the fetal B-cell repertoire. The V κ light chain gene of one of the antibodies is 99% homologous to a V κII gene and the V λ light chain gene of the other antibody is only 72% homologous to other known V λ genes. Further analysis of V genes utilized by anti-MAG antibodies should reveal the structural basis for their binding activity.

Effect of Passive Transfer of Human Anti-Myelin-Associated Glycoprotein IgM in Marmoset

Adult and one week old marmosets were injected intravenously within a one month period or intraperitoneally within a 6 week period respectively, with monoclonal IgM having an anti-myelin associated glycoprotein antibody activity. No clinical or electrophysiological abnormalities could be detected in experimental animals. However, indirect immunofluorescence studies showed IgM deposition in close contact to myelin sheaths. Minor but distinct alterations of nerves were found in the adult: the enlargement of Schmidt-Lanterman incisures seen in electron microscopy could explain the decrease of the proportion of fibers of small diameter found by morphometry of semi-thin section, and the reduction of the mean internodal length in fibers of a given diameter seen in teased nerve fibers studies.

Intracranial suppuration.

<h3>Background</h3> Treatment with anti-B cell antibody rituximab may ameliorate the disease course in a subgroup of patients with polyneuropathy associated with IgM monoclonal gammopathy. Polymorphisms of leukocyte IgG receptors (FcγR) that influence efficiency of antibody-dependent cell-mediated cytotoxicity determine rituximab efficacy in patients with lymphoma and autoimmune disease. <h3>Objective</h3> To investigate the association of FcγRIIA and FcγRIIIA polymorphisms with the response to rituximab treatment in a cohort of patients with polyneuropathy associated with IgM monoclonal gammopathy (PNP-IgM) with and without antimyelin-associated glycoprotein antibodies. <h3>Methods</h3> We determined FcγRIIA-R/H131 and FcγRIIIA-V/F158 genotypes in 27 patients with PNP-IgM using allele-specific PCR and Sanger sequencing. <h3>Results</h3> The FcγRIIIA-V/V158 genotype was associated with functional improvement (p=0.02) after 1 year. <h3>Conclusions</h3> FcγRIIIA polymorphisms are potential biomarkers for response to rituximab treatment in polyneuropathy associated with IgM monoclonal gammopathy.