N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes

Department of Clinical Neurology, L6 West Wing, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
Brain (Impact Factor: 9.2). 06/2010; 133(Pt 6):1655-67. DOI: 10.1093/brain/awq113
Source: PubMed


Antibodies to the N-methyl-d-aspartate subtype of glutamate receptor have been associated with a newly-described encephalopathy that has been mainly identified in young females with ovarian tumours. However, the full clinical spectrum and treatment responses are not yet clear. We established a sensitive cell-based assay for detection of N-methyl-d-aspartate receptor antibodies in serum or cerebrospinal fluid, and a quantitative fluorescent immunoprecipitation assay for serial studies. Although there was marked intrathecal synthesis of N-methyl-d-aspartate receptor antibodies, the absolute levels of N-methyl-d-aspartate receptor antibodies were higher in serum than in cerebrospinal fluid. N-methyl-d-aspartate receptor antibodies were of the immunoglobulin G1 subclass and were able to activate complement on N-methyl d-aspartate receptor-expressing human embryonic kidney cells. From questionnaires returned on 44 N-methyl-d-aspartate receptor antibody-positive patients, we identified a high proportion without a detected tumour (35/44, 80%: follow-up 3.6-121 months, median 16 months). Among the latter were 15 adult females (43%), 10 adult males (29%) and 10 children (29%), with four in the first decade of life. Overall, there was a high proportion (29%) of non-Caucasians. Good clinical outcomes, as defined by reductions in modified Rankin scores, correlated with decreased N-methyl-d-aspartate receptor antibody levels and were associated with early (<40 days) administration of immunotherapies in non-paraneoplastic patients (P < 0.0001) and earlier tumour removal in paraneoplastic patients (P = 0.02). Ten patients (23%) who were first diagnosed during relapses had no evidence of tumours but had received minimal or no immunotherapy during earlier episodes. Temporal analysis of the onset of the neurological features suggested progression through two main stages. The time of onset of the early features, characterized by neuropsychiatric symptoms and seizures preceded by a median of 10-20 days, the onset of movement disorders, reduction in consciousness and dysautonomia. This temporal dichotomy was also seen in the timing of cerebrospinal fluid, electroencephalographic and in the rather infrequent cerebral imaging changes. Overall, our data support a model in which the early features are associated with cerebrospinal fluid lymphocytosis, and the later features with appearance of oligoclonal bands. The immunological events and neuronal mechanisms underlying these observations need to be explored further, but one possibility is that the early stage represents diffusion of serum antibodies into the cortical grey matter, whereas the later stage results from secondary expansion of the immunological repertoire within the intrathecal compartment acting on subcortical neurons. Four patients, who only had temporal lobe epilepsy without oligoclonal bands, may represent restriction to the first stage.

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    • "This increased frontotemporal-occipital gradient was associated with disease severity and normalized following recovery in two patients. Similar PET imaging findings were reported in other studies (Vitaliani et al., 2005; Mohr and Minoshima, 2010; Fisher et al., 2012; Wegner et al., 2014), although distinct patterns with occipital hypermetabolism (Irani et al., 2010b), widespread cortical hypometabolism (Pillai et al., 2010; Maqbool et al., 2011) or more lateralized effects (Caballero, 2011; Baumgartner et al., 2013) have been described as well. In accordance with frequent abnormal movements in NMDAR encephalitis , altered basal ganglia metabolism was described in several patients (Maeder-Ingvar et al., 2011; Abers et al., 2013; Baumgartner et al., 2013). "
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    • "Dans les encéphalites avec anticorps anti-NMDAR, l'aspect le plus évocateur est l'existence d'un gradient métabolique cortical antéro-postérieur avec hypermétabolisme frontotemporal et hypométabolisme pariéto-occipital. Un hypermétabolisme des ganglions de la base est possible [11] [12] [13] [14] [15]. Dans les encéphalites avec anticorps anti-LGI1, on retrouve plus souvent un tableau d'hypermétabolisme touchant les régions temporales et les ganglions de la base. "
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    • "Ovarian teratoma was frequently detected in early series of patients with anti-NMDAR encephalitis; therefore, it was initially reported as paraneoplastic autoimmune encephalitis (Vitaliani et al. 2005; Dalmau et al. 2007). However, based on recent studies comprising large numbers of patients with anti-NMDAR encephalitis, we discovered that ovarian teratomas were detectable in only about half of the affected females (Irani et al. 2010; Dalmau et al. 2011; Titulaer et al. 2013). Another feature of anti-NMDAR encephalitis is that the vast majority of the patients are of reproductive age (Kamei et al. 2009; Dalmau et al. 2011; Titulaer et al. 2013). "
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