title: Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma.
abstract: OBJECTIVE
  To report the autoantigens of a new category of treatment-responsive paraneoplastic encephalitis.
  
  
  METHODS
  Analysis of clinical features, neuropathological findings, tumors, and serum/cerebrospinal fluid antibodies using rat tissue, neuronal cultures, and HEK293 cells expressing subunits of the N-methyl-D-aspartate receptor (NMDAR).
  
  
  RESULTS
  Twelve women (14-44 years) developed prominent psychiatric symptoms, amnesia, seizures, frequent dyskinesias, autonomic dysfunction, and decreased level of consciousness often requiring ventilatory support. All had serum/cerebrospinal fluid antibodies that predominantly immunolabeled the neuropil of hippocampus/forebrain, in particular the cell surface of hippocampal neurons, and reacted with NR2B (and to a lesser extent NR2A) subunits of the NMDAR. NR2B binds glutamate and forms heteromers (NR1/NR2B or NR1/NR2A/NR2B) that are preferentially expressed in the adult hippocampus/forebrain. Expression of functional heteromers (not single subunits) was required for antibody binding. Eleven patients had teratoma of the ovary (six mature) and one a mature teratoma in the mediastinum; five of five tumors examined contained nervous tissue that strongly expressed NR2 subunits and reacted with patients' antibodies. Tumor resection and immunotherapy resulted in improvement or full recovery of eight of nine patients (paralleled by decreased antibody titers); two of three patients without tumor resection died of neurological deterioration. Autopsies showed extensive microgliosis, rare T-cell infiltrates, and neuronal degeneration predominantly involving, but not restricted to, the hippocampus.
  
  
  CONCLUSIONS
  Antibodies to NR2B- and NR2A-containing heteromers of the NMDAR associate with a severe but treatment-responsive encephalitis. Our findings provide a diagnostic test and suggest a model of autoimmune NMDAR-related encephalitis with broad implications for other immune-mediated disorders of memory, behavior, and cognition.
authors.affiliation: Department of Neurology, Division of Neuro-oncology, University of Pennsylvania, Philadelphia, PA 19104, USA. josep.dalmau@uphs.upenn.edu
authors.forename: Josep
authors.initials: J
authors.lastname: Dalmau
authors.forename: Erdem
authors.initials: E
authors.lastname: Tüzün
authors.forename: Hai-yan
authors.initials: HY
authors.lastname: Wu
authors.forename: Jaime
authors.initials: J
authors.lastname: Masjuan
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Rossi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Voloschin
authors.forename: Joachim M
authors.initials: JM
authors.lastname: Baehring
authors.forename: Haruo
authors.initials: H
authors.lastname: Shimazaki
authors.forename: Reiji
authors.initials: R
authors.lastname: Koide
authors.forename: Dale
authors.initials: D
authors.lastname: King
authors.forename: Warren
authors.initials: W
authors.lastname: Mason
authors.forename: Lauren H
authors.initials: LH
authors.lastname: Sansing
authors.forename: Marc A
authors.initials: MA
authors.lastname: Dichter
authors.forename: Myrna R
authors.initials: MR
authors.lastname: Rosenfeld
authors.forename: David R
authors.initials: DR
authors.lastname: Lynch
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000906:Antibodies / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D004210:Dissection / Q000379:methods; D004660:Encephalitis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009474:Neurons / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D021122:Protein Subunits / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology* / Q000378:metabolism*; D013724:Teratoma / Q000150:complications* / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D007166:Immunosuppressive Agents; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate