Makoto Hara1, Eugenia Martinez-Hernandez1, Helena Ariño1, Thais Armangué1, Marianna Spatola1, Mar Petit-Pedrol1, Albert Saiz1, Myrna R Rosenfeld1, Francesc Graus1, Josep Dalmau2. 1. From the Clinical and Experimental Neuroimmunology Program, August Pi i Sunyer Biomedical Research Institute, Hospital Clínic (M.H., E.M.-H., H.A., T.A., M.S., M.P.-P., A.S., M.R.R., F.G., J.D.), and Department of Neurology, Sant Joan de Deu Childrens Hospital (T.A., J.D.), University of Barcelona, Spain; Division of Neurology (M.H.), Department of Medicine, Nihon University School of Medicine, Japan; University of Lausanne (M.S.), Switzerland; Department of Neurology (M.R.R., J.D.), University of Pennsylvania, Philadelphia; and Catalan Institution for Research and Advanced Studies (J.D.), Barcelona, Spain. 2. From the Clinical and Experimental Neuroimmunology Program, August Pi i Sunyer Biomedical Research Institute, Hospital Clínic (M.H., E.M.-H., H.A., T.A., M.S., M.P.-P., A.S., M.R.R., F.G., J.D.), and Department of Neurology, Sant Joan de Deu Childrens Hospital (T.A., J.D.), University of Barcelona, Spain; Division of Neurology (M.H.), Department of Medicine, Nihon University School of Medicine, Japan; University of Lausanne (M.S.), Switzerland; Department of Neurology (M.R.R., J.D.), University of Pennsylvania, Philadelphia; and Catalan Institution for Research and Advanced Studies (J.D.), Barcelona, Spain. Jdalmau@clinic.cat.
Abstract
OBJECTIVE: To determine the frequency and clinical relevance of immunoglobulin (Ig)G, IgA, and IgM N-methyl-d-aspartate receptor (NMDAR) antibodies in several diseases, and whether the IgG antibodies occur in disorders other than anti-NMDAR encephalitis. METHODS: Evaluation of IgG, IgA, and IgM NMDAR antibodies in serum of 300 patients with anti-NMDAR encephalitis, stroke, dementia, schizophrenia, or seronegative autoimmune encephalitis. Antibodies and their effect on cultured neurons were examined with cell-based assays and brain and live neuronal immunostaining. Retrospective analysis of the clinical diagnoses of a cohort of 1,147 patients with IgG NMDAR antibodies identified since 2005. RESULTS: Among the 300 patients studied, IgG NMDAR antibodies were only identified in those with anti-NMDAR encephalitis and all reacted with brain and live neurons. By cell-based assay, IgA or IgM antibodies were detected in 22 of 300 patients (7%) with different diseases, but only 10 (3%) reacted with brain and 7 (2%) with live neurons. In cultured neurons, IgG but not IgA or IgM antibodies caused a decrease of synaptic and extrasynaptic NMDAR. Among the cohort of 1,147 patients with IgG NMDAR antibodies, 1,015 (88.5%) had anti-NMDAR encephalitis, 45 (3.9%) a limited form of the disease, 41 (3.6%) autoimmune post-herpes simplex encephalitis, 37 (3.2%) overlapping syndromes (anti-NMDAR encephalitis and demyelinating disease), and 9 (0.8%) atypical encephalitic syndromes; none had schizophrenia. CONCLUSIONS: IgG NMDAR antibodies are highly specific for anti-NMDAR encephalitis and cause a decrease of the levels of NMDAR. In contrast, IgA or IgM antibodies occur infrequently and nonspecifically in other diseases and do not alter the receptor levels.
OBJECTIVE: To determine the frequency and clinical relevance of immunoglobulin (Ig)G, IgA, and IgM N-methyl-d-aspartate receptor (NMDAR) antibodies in several diseases, and whether the IgG antibodies occur in disorders other than anti-NMDAR encephalitis. METHODS: Evaluation of IgG, IgA, and IgM NMDAR antibodies in serum of 300 patients with anti-NMDAR encephalitis, stroke, dementia, schizophrenia, or seronegative autoimmune encephalitis. Antibodies and their effect on cultured neurons were examined with cell-based assays and brain and live neuronal immunostaining. Retrospective analysis of the clinical diagnoses of a cohort of 1,147 patients with IgG NMDAR antibodies identified since 2005. RESULTS: Among the 300 patients studied, IgG NMDAR antibodies were only identified in those with anti-NMDAR encephalitis and all reacted with brain and live neurons. By cell-based assay, IgA or IgM antibodies were detected in 22 of 300 patients (7%) with different diseases, but only 10 (3%) reacted with brain and 7 (2%) with live neurons. In cultured neurons, IgG but not IgA or IgM antibodies caused a decrease of synaptic and extrasynaptic NMDAR. Among the cohort of 1,147 patients with IgG NMDAR antibodies, 1,015 (88.5%) had anti-NMDAR encephalitis, 45 (3.9%) a limited form of the disease, 41 (3.6%) autoimmune post-herpes simplex encephalitis, 37 (3.2%) overlapping syndromes (anti-NMDAR encephalitis and demyelinating disease), and 9 (0.8%) atypical encephalitic syndromes; none had schizophrenia. CONCLUSIONS: IgG NMDAR antibodies are highly specific for anti-NMDAR encephalitis and cause a decrease of the levels of NMDAR. In contrast, IgA or IgM antibodies occur infrequently and nonspecifically in other diseases and do not alter the receptor levels.
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