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Paraneoplastic anti– N ‐methyl‐ D ‐aspartate receptor encephalitis associated with ovarian teratoma
Open accessAbstract
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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“Preliminary studies suggested the target epitopes were located in extracellular regions of NR1–NR2B NMDA receptors.5”
From Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies (2008) · cites this paper as [5]
In the citing paper
“We recently identified a disorder, designated anti-NMDA-receptor encephalitis, that associates with antibodies against NR1–NR2 heteromers and results in a characteristic neuropsychiatric syndrome.5”
From Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies (2008) · cites this paper as [5]
In the citing paper
“The first patients identified were young women with ovarian teratoma who presented with psychosis or memory problems, rapidly progressing to multiple neurological deficits requiring prolonged intensive care support.”
From Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies (2008) · cites this paper as [5]
In the citing paper
“Serum and CSF were tested for antibodies against the NMDA receptor,5 and considered positive if three immunohistochemical criteria were fulfilled (figure 1).”
From Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies (2008) · cites this paper as [5]
In the citing paper
“Despite the severity of the disorder, patients often recovered after tumour removal and immunotherapy, suggesting an immune-mediated pathogenesis.”
From Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies (2008) · cites this paper as [5]
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Metadata
- 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
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2007-01
- Volume
- 61
- Issue
- 1
- Pages
- 25-36
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- 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
- 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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