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
Source: PubMed


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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Available from: Haruo Shimazaki
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    • "Further studies focusing particularly on the cognitive deficits have shown that there is a long-term morbidity in this disorder, with a good outcome for the patient dependent on early and aggressive treatment (Finke et al. 2012). The brains of these patients show few inflammatory cells (mostly T cells) (Tuzun et al. 2009;Camdessanche et al. 2011;Martinez-Hernandez et al. 2011;Bien et al. 2012) and magnetic resonance imaging (MRI), and pathological studies show that the neuronal loss in most cases is remarkably mild (Dalmau et al. 2007;Iizuka et al. 2010;Bien et al. 2012). The antibodies have been shown to be pathogenic, at least in vitro. "
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    ABSTRACT: This review reports the available evidence on the activation of the innate and adaptive branches of the immune system and the related inflammatory processes in epileptic disorders and the putative pathogenic role of inflammatory processes developing in the brain, as indicated by evidence from experimental and clinical research. Indeed, there is increasing knowledge supporting a role of specific inflammatory mediators and immune cells in the generation and recurrence of epileptic seizures, as well as in the associated neuropathology and comorbidities. Major challenges in this field remain: a better understanding of the key inflammatory pathogenic pathways activated in chronic epilepsy and during epileptogenesis, and how to counteract them efficiently without altering the homeostatic tissue repair function of inflammation. The relevance of this information for developing novel therapies will be highlighted.
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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. "

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    • "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.
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