N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis

Ann Neurol. 2012 Dec;72(6):902-11. doi: 10.1002/ana.23689.


Objective: To determine the presence and kinetics of antibodies against synaptic proteins in patients with herpes simplex virus encephalitis (HSE).

Methods: Retrospective analysis of 44 patients with polymerase chain reaction-proven HSE for the presence of a large panel of onconeuronal and synaptic receptor antibodies. The effect of patients' serum was studied in cultures of primary mouse hippocampal neurons.

Results: N-Methyl-D-aspartate receptor (NMDAR) antibodies of the immunoglobulin (Ig) subtypes IgA, IgG, or IgM were detected in 13 of 44 patients (30%) in the course of HSE, suggesting secondary autoimmune mechanisms. NMDAR antibodies were often present at hospital admission, but in some patients developed after the first week of HSE. Antibody-positive sera resulted in downregulation of synaptic marker proteins in hippocampal neurons.

Interpretation: Some patients with HSE develop IgA, IgG, or IgM autoantibodies against NMDAR. Sera from these patients alter the density of neuronal synaptic markers, suggesting a potential pathogenic disease-modifying effect. These findings have implications for the understanding of autoimmunity in infectious diseases, and prospective studies should reveal whether the subgroup of patients with HSE and NMDAR antibodies may benefit from immunotherapy. .

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antibodies / blood*
  • Antibodies / cerebrospinal fluid*
  • Antibodies / classification
  • Cells, Cultured
  • Child
  • Embryo, Mammalian
  • Encephalitis, Herpes Simplex / blood*
  • Encephalitis, Herpes Simplex / cerebrospinal fluid*
  • Female
  • Hippocampus / cytology
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Middle Aged
  • Neurons / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / immunology*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapsins / metabolism
  • Transfection
  • Young Adult


  • Antibodies
  • NR1 NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Synapsins