Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor

Neurology. 2018 Apr 17;90(16):e1386-e1394. doi: 10.1212/WNL.0000000000005329. Epub 2018 Mar 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-N-Methyl-D-Aspartate Receptor Encephalitis / blood*
  • Anti-N-Methyl-D-Aspartate Receptor Encephalitis / cerebrospinal fluid*
  • Anti-N-Methyl-D-Aspartate Receptor Encephalitis / diagnostic imaging
  • Autoantibodies / blood*
  • Autoantibodies / cerebrospinal fluid*
  • Brain / metabolism
  • Brain / pathology
  • Cells, Cultured
  • Cohort Studies
  • Dementia / blood
  • Female
  • HEK293 Cells
  • Humans
  • Immunoglobulin A / blood
  • Immunoglobulin G / blood
  • Immunoglobulin M / blood
  • Male
  • Mice
  • Mutation / genetics
  • Neurons / metabolism
  • Positron-Emission Tomography
  • Rats
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / immunology*
  • Schizophrenia / blood
  • Stroke / blood
  • Transfection


  • Autoantibodies
  • Immunoglobulin A
  • Immunoglobulin G
  • Immunoglobulin M
  • Receptors, N-Methyl-D-Aspartate