Cited by 2,492Autoimmune Neurological Disorders and TreatmentsPeripheral Neuropathies and DisordersMyasthenia Gravis and Thymoma

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Paraneoplastic anti– N ‐methyl‐ D ‐aspartate receptor encephalitis associated with ovarian teratoma

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Dalmau, Josep, Tüzün, Erdem, Wu, Hai‐yan, Masjuan, Jaime, Rossi, Jeffrey E., Voloschin, Alfredo, Baehring, Joachim M., Shimazaki, Haruo, Koide, Reiji, King, Dale, Mason, Warren, Sansing, Lauren H., Dichter, Marc A., Rosenfeld, Myrna R., Lynch, David R.·2007·Annals of Neurology

DOI 10.1002/ana.21050PMC PMC2430743

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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.

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Authors: Dalmau, J., Tüzün, E., Wu, H., 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.
Affiliations: University of Pennsylvania (US)
Augusta University (US)
Yale University (US)
Jichi Medical University (JP)
Tokyo Metropolitan Neurological Hospital (JP)
Children's Hospital of Pittsburgh (US)
Princess Margaret Cancer Centre (CA)
Corresponding author: Dalmau, Josep
ORCID: Dalmau, Josep
Tüzün, Erdem
Rossi, Jeffrey E.
Baehring, Joachim M.
Shimazaki, Haruo
Koide, Reiji
Mason, Warren
Sansing, Lauren H.
Rosenfeld, Myrna R.
Lynch, David R.
Venue: Annals of Neurology
Publisher: Wiley
Published: 2007-01
Volume: 61
Issue: 1
Pages: 25-36
ISSN: 0364-5134 (ISSN-L)
1531-8249
DOI: 10.1002/ana.21050
PMC: PMC2430743
OpenAlex: W2114398221
Cited by: 2,492
References: 37
Citations by year: 2026: 105 · 2025: 122 · 2024: 142 · 2023: 135 · 2022: 168 · 2021: 190 · 2020: 158 · 2019: 179 · 2018: 128 · 2017: 152 · 2016: 158 · 2015: 145 · 2014: 129 · 2013: 143 · 2012: 113
FWCI: 47.94
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 28 d)
Locations: Annals of Neurology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (R01CA089054, R01CA107192)
National Institute of Neurological Disorders and Stroke (R01NS045986)
Topics: Health Sciences › Medicine › Clinical Neurology › Autoimmune Neurological Disorders and Treatments
Health Sciences › Medicine › Clinical Neurology › Peripheral Neuropathies and Disorders
Health Sciences › Medicine › Clinical Neurology › Myasthenia Gravis and Thymoma
Keywords: paraneoplastic encephalitis, anti-NMDA receptor encephalitis, ovarian teratoma, NMDA receptor subunits, NR2B, NR2A, autoantibodies, hippocampal neurons, autoimmune encephalitis, tumor resection, immunotherapy, microglial activation, neurodegeneration, psychiatric symptoms, amnesia, seizures
MeSH terms: Adolescent, Adult, Animals, Antibodies, Dissection, Encephalitis, Female, Humans, Immunohistochemistry, Immunosuppressive Agents, Magnetic Resonance Imaging, Male, Neurons, Ovarian Neoplasms, Teratoma, Transfection, Gene Expression Regulation, Neoplastic, Receptors, N-Methyl-D-Aspartate, Treatment Outcome, Rats, Wistar, Protein Subunits, Rats

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Paraneoplastic anti– N ‐methyl‐ D ‐aspartate receptor encephalitis associated with ovarian teratoma

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