Article

Paraneoplastic N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma

Department of Neurology, Division of Neuro-oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Annals of Neurology (Impact Factor: 11.91). 01/2007; 61(1):25-36. DOI: 10.1002/ana.21050
Source: PubMed

ABSTRACT 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, Jul 20, 2015
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    • "Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an increasingly recognized etiology of previously unexplained encephalopathy and encephalitis, since its original description in 2007 [1] [2]. The disease has initially been described in women with an ovarian teratoma but can also be seen in seen in women without an ovarian teratoma, men [3]. "
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    ABSTRACT: Since its original description in 2007, anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis associated with an ovarian teratoma is an increasingly recognized etiology of previously unexplained encephalopathy and encephalitis. Extreme delta brush (EDB) is a novel electroencephalogram (EEG) finding seen in many patients with anti-NMDAR encephalitis. The presence of this pattern is associated with a more prolonged illness, although the specificity of this pattern is unclear. Additionally, the frequency and sensitivity of EDB in anti-NMDAR encephalitis and its implications for outcome have yet to be determined. We report a patient with early evidence of extreme delta brush and persistence of this pattern 17.5 weeks later with little clinical improvement.
    12/2014; 2. DOI:10.1016/j.ebcr.2014.01.002
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    • "encephalitis has been reported to be associated with ovarian teratomas [19]. Clinical improvement in these patients has been observed along with a simultaneous decrease in antibody titers [20]. It has been demonstrated, however, that in paraneoplastic limbic encephalitis that is associated with neuronal surface antibodies, the intraneuronal antibodies often coexist, and the response to immunotherapy is poor [21]. "
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    ABSTRACT: Paraneoplastic neurological syndromes (PNS) are disorders of the nervous system that are associated with remote effects of malignancy. PNS are considered to have an autoimmune pathology. It has been suggested that immune antitumor responses are the origin of improved outcome in PNS. We describe cell-mediated immune responses in PNS and their potential contributions to antitumor reactions. Experimental and neuropathological studies have revealed infiltrates in nervous tissue and disturbances in lymphocyte populations in both cerebrospinal fluid and peripheral blood. A predominance of cytotoxic T lymphocytes (CTLs) over T helper cells has been observed. CTLs can be specifically aggressive against antigens shared by tumors and nervous tissue. Based on genetic studies, a common clonal origin of lymphocytes from blood, tumor, and nervous tissue is suggested. Suppressive regulatory T (Treg) lymphocytes are dysfunctional. Simultaneously, in tumor tissue, more intense cell-mediated immune responses are observed, which often coincide with a less aggressive course of neoplastic disease. An increased titer of onconeural antibodies is also related to better prognoses in patients without PNS. The evaluation of onconeural and neuronal surface antibodies was recommended in current guidelines. The link between PNS emergence and antitumor responses may result from more active CTLs and less functional Treg lymphocytes.
    Clinical and Developmental Immunology 12/2013; 2013:630602. DOI:10.1155/2013/630602 · 2.93 Impact Factor
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    • "This is in line with data from studies looking primarily at anti-NMDA encephalitis patients that have also tested healthy controls (e.g. Dalmau et al. 2007; Irani et al. 2010; Wandinger et al. 2011), and that failed to find evidence of antibody positivity in healthy controls. The reasons for the strikingly different results of this study remain unclear: the authors of the discrepant paper suggest that the relatively greater age of their control population may have been relevant insofar as autoantibody prevalence correlates with age across both health and disease. "
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    ABSTRACT: Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is an autoimmune condition caused by immunoglobulin (Ig)G antibodies directed against the NR1 subunit of the NMDA glutamate receptor. Approximately 65% of cases present with psychiatric symptoms, particularly psychosis. It remains to be established whether anti-NMDA receptor antibodies can cause a 'purely' psychotic illness without overt neurological symptoms. We conducted a systematic literature search to establish what proportion of patients with schizophrenia and related psychoses have antibodies directed against the NMDA receptor. Studies were included if (a) subjects had a diagnosis of schizophrenia, schizophrenia spectrum disorder or first-episode psychosis (FEP) using standard criteria, (b) serum was analysed for the presence of anti-NMDA receptor antibodies; and (c) the purpose of the study was to look for the presence of anti-NMDA receptor antibodies in patients with a primary psychiatric diagnosis without clinical signs of encephalitis. Seven studies were included, comprising 1441 patients, of whom 115 [7.98%, 95% confidence interval (CI) 6.69-9.50] were anti-NMDA receptor antibody positive. Of these, 21 (1.46%, 95% CI 0.94-2.23) patients were positive for antibodies of the IgG subclass. Prevalence rates were greater in cases than controls only for IgG antibodies; other subclasses are of less certain aetiological relevance. There was significant heterogeneity in terms of patient characteristics and the antibody assay used. A minority of patients with psychosis are anti-NMDA receptor antibody positive. It remains to be established whether this subset of patients differs from antibody-negative patients in terms of underlying pathology and response to antipsychotic treatment, and whether immunomodulatory treatments are effective in alleviating psychotic symptoms in this group.
    Psychological Medicine 12/2013; DOI:10.1017/S003329171300295X · 5.43 Impact Factor
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