Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features

Akita University, Department of Neuropsychiatry, Akita, Japan. .
BMC Psychiatry (Impact Factor: 2.21). 05/2012; 12(1):37. DOI: 10.1186/1471-244X-12-37
Source: PubMed


Causative role of encephalitis in major psychotic features, dyskinesias (particularly orofacial), seizures, and autonomic and respiratory changes has been recently emphasized. These symptoms often occur in young females with ovarian teratomas and are frequently associated with serum and CSF autoantibodies to the NMDA receptor (NMDAR).
The study included a total of 61 patients from age 15 to 61 and was carried out between January 1, 2005, and Dec 31, 2010. The patients were divided into the following three clinical groups for comparison. Group A; Patients with typical clinical characteristics of anti-NMDAR encephalitis. Group B; Patients with narcolepsy with severe psychosis. Group C; Patients with schizophrenia or schizo-affective disorders.
Ten out of 61 cases were anti-NMDAR antibody positive in typical encephalitis cases (group A: 3 of 5 cases) and cases in a broader range of psychiatric disorders including narcolepsy (group B: 3 of 5 cases) and schizophrenia (group C: 4 of 51 cases).
In addition to 3 typical cases, we found 7 cases with anti-NMDAR antibody associated with various psychotic and sleep symptoms, which lack any noticeable clinical signs of encephalitis (seizures and autonomic symptoms) throughout the course of the disease episodes; this result suggest that further discussion on the nosology and pathophysiology of autoimmune-mediated atypical psychosis and sleep disorders is required.

Download full-text


Available from: Keiko Tanaka, Dec 13, 2013

Click to see the full-text of:

Article: Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features

191.57 KB

See full-text
  • Source
    • "A Japanese group found anti-NMDAr antibodies in 4 of 51 schizophrenic patients. They reported also three of five hypocretin deficient narcolepsy patients with severe psychosis (13). Immunomodulatory treatment in narcolepsy has provided rather poor results (14). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aim: Hypnagogic and hypnopompic hallucinations are characteristic symptoms of narcolepsy, as are excessive daytime sleepiness, cataplexy, and sleep paralysis. Narcolepsy patients may also experience daytime hallucinations unrelated to sleep–wake transitions. The effect of medication on hallucinations is of interest since treatment of narcolepsy may provoke psychotic symptoms. We aim to analyze the relation between sodium oxybate (SXB) treatment and psychotic symptoms in narcolepsy patients. Furthermore, we analyze the characteristics of hallucinations to determine their nature as mainly psychotic or hypnagogic and raise a discussion about whether SXB causes psychosis or if psychosis occurs as an endogenous complication in narcolepsy. Method: We present altogether four patients with narcolepsy who experienced psychotic symptoms during treatment with SXB. In addition, we searched the literature for descriptions of hallucinations in narcolepsy and similarities and differences with psychotic symptoms in schizophrenia. Results: Three out of four patients had hallucinations typical for psychosis and one had symptoms that resembled aggravated hypnagogic hallucinations. Two patients also had delusional symptoms primarily associated with mental disorders. Tapering down SXB was tried and helped in two out of four cases. Adding antipsychotic treatment (risperidone) alleviated psychotic symptoms in two cases. Conclusion: Psychotic symptoms in narcolepsy may appear during SXB treatment. Hallucinations resemble those seen in schizophrenia; however, the insight that symptoms are delusional is usually preserved. In case of SXB-induced psychotic symptoms or hallucinations, reducing SXB dose or adding antipsychotic medication can be tried.
    Frontiers in Neurology 08/2014; 5:136. DOI:10.3389/fneur.2014.00136
  • Source
    • "Healthy controls 230 36 (12) 159 (69) .. .. Dickerson et al. (2013) Acute mania b 57 35 (13) 16 (28) .. .. Schizophrenia or schizoaffective disorder (multi-episode, chronic) 234 42 (12) 137 (59) .. .. Bipolar disorder (acute depressive state) 28 38 (14) 6 (21) .. .. Healthy controls 207 33 (11) 80 (39) .. .. Haussleiter et al. (2012) Schizophrenia (NR) 44 43 (13) 15 (34) 21 (7) Schizoaffective disorder (NR) 4 45 (7) 1 (25) 13 (3) Tsutsui et al. (2012) "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: N-methyl-d-aspartate receptor (NMDAR) antibodies have been documented in the serum of individuals with primary psychiatric disorders from several independent cohorts, but these findings have not been systematically assessed in aggregate or in relation to methodological covariates. METHODS: We searched MEDLINE, EMBASE, and PsycINFO for studies in any language that provided data on NMDAR antibody seropositivity or absolute serum titers in schizophrenia or schizoaffective, bipolar, or major depressive disorders. We used a random effects model to pool estimates across studies. RESULTS: Nine studies met the eligibility criteria. Five studies (3387 participants) provided data on NMDAR antibody seropositivity in psychiatric versus control groups based on high-specificity seropositivity thresholds (cell-based assays [CBAs]: 1:320 dilution, 1:200 dilution, visual score>1; enzyme-linked immunosorbent assay [ELISA]: 90(th) percentile of control titers). Meta-analysis showed significantly higher odds of NMDAR antibody seropositivity among those with schizophrenia or schizoaffective, bipolar, or major depressive disorders compared with healthy controls (odds ratio [OR], 3.10; 95% confidence interval [CI], 1.04-9.27; P=.043; I(2)=68%). Four studies (3194 participants) provided outcome data for these groups based on low-specificity seropositivity thresholds (CBAs 1:10 dilution; ELISA: 75(th) percentile of control titers). Meta-analysis showed greater heterogeneity and no significant between-group difference (OR, 2.31; 95% CI, 0.55-9.73; P=.25; I(2)=90%). Seropositive participants in psychiatric groups had various combinations of IgG, IgM, and IgA class antibodies against NR1, NR1/NR2B, and NR2A/NR2B subunits. Subgroup analysis revealed significantly higher odds of seropositivity among all participants based on 1:10 versus 1:320 dilution seropositivity thresholds (OR, 4.56; 95% CI, 2.41-8.62; P<.001; I(2)=0%; studies=2, n=2920), but no apparent difference between first-episode and chronic schizophrenia or schizoaffective disorder (OR, 1.15; 95% CI, 0.19-7.24; P=.88, I(2)=43%, studies=2, n=1108). Average NR2A/NR2B antibody titers determined by ELISA were significantly higher among participants with first-episode schizophrenia (P<.0001) and acute mania (P<.01) compared with healthy controls. Levels decreased by 58% at 8weeks in first-episode schizophrenia, and by about 13% at 4days in acute mania. CONCLUSIONS: Individuals with schizophrenia or schizoaffective, bipolar, or major depressive disorders are collectively about three times more likely to have elevated NMDAR antibody titers compared with healthy controls based on high-specificity, but not low-specificity, seropositivity thresholds, though considerable methodological and statistical heterogeneity exists. Evidence concerning the effect of disease state and time of serum acquisition is varied and consistent, respectively. Adequately powered longitudinal studies employing standardized assay methods and seropositivity threshold definitions, and quantifying NMDAR antibodies in both sera and cerebrospinal fluid are needed to further elucidate the clinical and pathophysiological implications of this association. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved. KEYWORDS: Antibodies; Bipolar disorder; Immunoglobulin; Major depressive disorder; Meta-analysis; N-methyl-d-aspartate receptor; Psychoimmunology; Schizoaffective disorder; Schizophrenia; Systematic review
    Schizophrenia Research 05/2014; 157(1-3). DOI:10.1016/j.schres.2014.05.001 · 3.92 Impact Factor
  • Source
    • "Several mechanisms may explain the epidemiologic data [Strous and Shoenfeld, 2006]. Individuals with auto-immune diseases have elevated prevalence of antibodies directed against brain proteins or may produce antibodies that cross-react with brain proteins [Irani and Lang, 2008]; individuals with SZ can also produce antibodies against proteins in the frontal cortex [Henneberg et al., 1994], cingulate gyrus [Ganguli et al., 1987; Kelly et al., 1987; Henneberg et al., 1994], hippocampus [Ganguli et al., 1987] and against glutamate receptors [Tsutsui et al., 2012]. Individuals with autoimmune disorders also develop further CNS dysfunction in conjunction with microbial infections [Benros et al., 2011]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Associations between human leukocyte antigen (HLA) polymorphisms on chromosome 6p and schizophrenia (SZ) risk have been evaluated for over five decades. Numerous case-control studies from the candidate gene era analyzed moderately sized samples and reported nominally significant associations with several loci in the HLA region (sample sizes, n = 100-400). The risk conferred by individual alleles was modest (odds ratios < 2.0). The basis for the associations could not be determined, though connections with known immune and auto-immune abnormalities in SZ were postulated. Interest in the HLA associations has re-emerged following several recent genome-wide association studies (GWAS); which utilized 10- to 100-fold larger samples and also identified associations on the short arm of chromosome 6. Unlike the earlier candidate gene studies, the associations are statistically significant following correction for multiple comparisons. Like the earlier studies; they have modest effect sizes, raising questions about their utility in risk prediction or pathogenesis research. In this review, we summarize the GWAS and reflect on possible bases for the associations. Suggestions for future research are discussed. We favor, in particular; efforts to evaluate local population sub-structure as well as further evaluation of immune-related variables in future studies. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2014; 165(1). DOI:10.1002/ajmg.b.32195 · 3.42 Impact Factor
Show more