Dalmau, J. et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann. Neurol. 61, 25-36

Department of Neurology, Division of Neuro-oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Annals of Neurology (Impact Factor: 9.98). 01/2007; 61(1):25-36. DOI: 10.1002/ana.21050
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To report the autoantigens of a new category of treatment-responsive paraneoplastic encephalitis.
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).
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.
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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    • "The anti-NMDA receptor (NMDAR) encephalitis, first described in 2007, occurs especially in young woman with ovarian teratoma and represents a severe neuropsychiatric condition which can be cured by tumor removal and immunosuppressive therapy (Dalmau et al., 2007). The disease shows a characteristic time course of symptoms, with initial psychotic symptoms often indistinguishable from schizophrenia , usually followed by severe neurological impairment and respiratory insufficiency. "

    Schizophrenia Research 08/2015; 168(1). DOI:10.1016/j.schres.2015.07.029 · 3.92 Impact Factor
    • "Patients present with a typical clinical syndrome: Following a prodromal phase with low-grade fever, headache and fatigue, patients develop psychiatric symptoms including anxiety, psychosis, delusions, and hallucinations . With further progression, the disease may include abnormal movements such as orofacial dyskinesia and dystonia, autonomic instability, epileptic seizures and disorders of consciousness (Dalmau et al., 2007; Irani et al., 2010b; Titulaer et al., 2013). Immunotherapy and tumor removal lead to substantial improvement in about 80% of the patients, especially when treated at an early disease stage (Titulaer et al., 2013). "
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    ABSTRACT: The field of autoimmune encephalitides associated with antibodies targeting cell-surface antigens is rapidly expanding and new antibodies are discovered frequently. Typical clinical presentations include cognitive deficits, psychiatric symptoms, movement disorders and seizures and the majority of patients responds well to immunotherapy. Pathophysiological mechanisms and clinical features are increasingly recognized and indicate hippocampal dysfunction in most of these syndromes. Here, we review the neuroimaging characteristics of autoimmune encephalitides, including N-methyl-D-aspartate (NMDA) receptor, leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2) encephalitis as well as more recently discovered and less frequent forms such as dipeptidyl-peptidase-like protein 6 (DPPX) or glycine receptor encephalitis. We summarize findings of routine MRI investigations as well as FDG-PET and SPECT imaging and relate these observations to clinical features and disease outcome. We furthermore review results of advanced imaging analyses such as diffusion tensor imaging, volumetric analyses and resting state functional MRI. Finally, we discuss contributions of these neuroimaging observations to the understanding of the pathophysiology of autoimmune encephalitides. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 05/2015; 309. DOI:10.1016/j.neuroscience.2015.05.037 · 3.36 Impact Factor
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    • "Mature-and immature-appearing neurons in ovarian teratoma ectopically express NMDARs (Sansing et al. 2007; Seki et al. 2008; Tüzün et al. 2009); this is thought to contribute to the production of anti-NMDAR antibodies. Therefore, anti- NMDAR encephalitis has been considered to be a type of paraneoplastic encephalitis (Vitaliani et al. 2005; Dalmau et al. 2007). However, based on recent reports and the rapidly increasing number of patients with anti-NMDAR encephalitis (Prüss et al. 2010; Dalmau et al. 2011), it has become clear that this encephalitis also affects children and infants (Florance et al. 2009; Hacohen et al. 2013). "
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    ABSTRACT: Autoimmune synaptic encephalitis is characterized by the presence of autoantibodies against synaptic constituent receptors and manifests as neurological and psychiatric disorders. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is such an autoimmune disorder that predominantly affects young women. It is associated with antibodies against the extracellular region of the NR1 subunit of postsynaptic NMDAR. Each NMDAR functions as a heterotetrameric complex that is composed of four subunits, including NR1 and NR2A, NR2B, or NR2C. Importantly, ovarian teratoma is a typical complication of anti-NMDAR encephalitis in female patients and may contain antigenic neural tissue; however, antigenic sites remain unknown in female patients without ovarian teratoma. The purpose of this study was to investigate the expression of NMDARs in the ovum. We detected NR1 and NR2B immunoreactivity in protein fractions extracted from the bovine ovary and ova by SDS-polyacrylamide gel electrophoresis and immunoblotting analysis. Immunoprecipitates digested with trypsin were analyzed by reverse phase liquid chromatography coupled to tandem mass spectrometry. We obtained the following five peptides: SPFGRFK and KNLQDR, which are consistent with partial sequences of human NR1, and GVEDALVSLK, QPTVAGAPK, and NEVMSSK, which correspond to those of NR2A, NR2B and NR2C, respectively. Immunocytochemical analysis revealed that the bovine ovum was stained with the immunoglobulin G purified from the serum of a patient with anti-NMDAR encephalitis. Taken together, we propose that the normal ovum expresses NMDARs that have strong affinity for the disease-specific IgG. The presence of NMDARs in ova may help explain why young females without ovarian teratomas are also affected by anti-NMDAR encephalitis.
    The Tohoku Journal of Experimental Medicine 03/2015; 235(3):223-31. DOI:10.1620/tjem.235.223 · 1.35 Impact Factor
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