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Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma.
Ann Neurol. 2007 Jan; 61(1):25-36.AN

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.

INTERPRETATION

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+Show Affiliations

Department of Neurology, Division of Neuro-oncology, University of Pennsylvania, Philadelphia, PA 19104, USA. josep.dalmau@uphs.upenn.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17262855

Citation

Dalmau, Josep, et al. "Paraneoplastic anti-N-methyl-D-aspartate Receptor Encephalitis Associated With Ovarian Teratoma." Annals of Neurology, vol. 61, no. 1, 2007, pp. 25-36.
Dalmau J, Tüzün E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61(1):25-36.
Dalmau, J., Tüzün, E., Wu, H. Y., Masjuan, J., Rossi, J. E., Voloschin, A., Baehring, J. M., Shimazaki, H., Koide, R., King, D., Mason, W., Sansing, L. H., Dichter, M. A., Rosenfeld, M. R., & Lynch, D. R. (2007). Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Annals of Neurology, 61(1), 25-36.
Dalmau J, et al. Paraneoplastic anti-N-methyl-D-aspartate Receptor Encephalitis Associated With Ovarian Teratoma. Ann Neurol. 2007;61(1):25-36. PubMed PMID: 17262855.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. AU - Dalmau,Josep, AU - Tüzün,Erdem, AU - Wu,Hai-yan, AU - Masjuan,Jaime, AU - Rossi,Jeffrey E, AU - Voloschin,Alfredo, AU - Baehring,Joachim M, AU - Shimazaki,Haruo, AU - Koide,Reiji, AU - King,Dale, AU - Mason,Warren, AU - Sansing,Lauren H, AU - Dichter,Marc A, AU - Rosenfeld,Myrna R, AU - Lynch,David R, PY - 2007/1/31/pubmed PY - 2007/3/28/medline PY - 2007/1/31/entrez SP - 25 EP - 36 JF - Annals of neurology JO - Ann. Neurol. VL - 61 IS - 1 N2 - 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. INTERPRETATION: 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. SN - 0364-5134 UR - https://www.unboundmedicine.com/medline/citation/17262855/Paraneoplastic_anti_N_methyl_D_aspartate_receptor_encephalitis_associated_with_ovarian_teratoma_ L2 - https://doi.org/10.1002/ana.21050 DB - PRIME DP - Unbound Medicine ER -