Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis in Children and Adolescents

Division of Neurology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Annals of Neurology (Impact Factor: 9.98). 07/2009; 66(1):11-8. DOI: 10.1002/ana.21756
Source: PubMed


To report the clinical features of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in patients < or = 18 years old.
Information was obtained by the authors or referring physicians. Antibodies were determined by immunocytochemistry and enzyme-linked immunosorbent assay (ELISA) using HEK293 cells ectopically expressing NR1.
Over an 8-month period, 81 patients (12 male) with anti-NMDAR encephalitis were identified. Thirty-two (40%) were < or =18 years old (youngest 23 months, median 14 years); 6 were male. The frequency of ovarian teratomas was 56% in women >18 years old, 31% in girls < or =18 years old (p = 0.05), and 9% in girls < or =14 years old (p = 0.008). None of the male patients had tumors. Of 32 patients < or =18 years old, 87.5% presented with behavioral or personality change, sometimes associated with seizures and frequent sleep dysfunction; 9.5% with dyskinesias or dystonia; and 3% with speech reduction. On admission, 53% had severe speech deficits. Eventually, 77% developed seizures, 84% stereotyped movements, 86% autonomic instability, and 23% hypoventilation. Responses to immunotherapy were slow and variable. Overall, 74% had full or substantial recovery after immunotherapy or tumor removal. Neurological relapses occurred in 25%. At the last follow-up, full recovery occurred more frequently in patients who had a teratoma that was removed (5/8) than in those without a teratoma (4/23; p = 0.03).
Anti-NMDAR encephalitis is increasingly recognized in children, comprising 40% of all cases. Younger patients are less likely to have tumors. Behavioral and speech problems, seizures, and abnormal movements are common early symptoms. The phenotype resembles that of the adults, although dysautonomia and hypoventilation are less frequent or severe in children. Ann Neurol 2009;66:11-18.

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Available from: Heather Elspeth Moss, Mar 17, 2014
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    • "Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis exhibits a characteristic set of neurological and psychiatric symptoms including acute behavioral changes, seizures , memory deficits, involuntary movement, autonomic and breathing dysfunctions, and consciousness disturbance that necessitates intensive-care treatment. This predominantly occurs in young women with ovarian teratoma, and these patients express autoantibodies against the NMDA subtype of ionotropic glutamate (Dalmau et al. 2008; Florance et al. 2009; Titulaer et al. 2013). It is now recognized that anti-NMDAR antibody-mediated syndromes can present as partial and sometimes monosymptomatic neurological disease and rank among the most frequent forms of autoimmune encephalitis (Dalmau et al. 2011). "
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    ABSTRACT: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is now widely recognized and the patients with this disease show prominent psychiatric symptoms followed by seizures, respiratory failure, involuntary movement, autonomic instability, and amnesia. The anti-NMDAR antibody titer coincides with disease activity, and antibody-deprivation treatment ameliorates neurological symptoms. Previous studies have shown that clusters of NMDARs on the neuronal surface decrease in density upon incubation with the cerebrospinal fluid from patients (NMDAR-CSF), and that the induction of long-term potentiation, a cellular mechanism underlie learning and memory processes, was suppressed with NMDAR-CSF. In this study, we exposed mice to NMDAR-CSF in an attempt to reproduce the human symptoms in mice. CSF was continuously administered via a cannula placed in the lateral ventricle of the mouse that connected to an osmotic pump transplanted in the back of the mouse. From day 8-18, we evaluated the behavior of the mice using standardized tests that were performed serially. Mice exposed to NMDAR-CSF showed impaired spatial memory, as detected with the Morris water maze test. Brain tissue from mice with memory disturbances had decreased content of NMDAR protein in the hippocampal area shown by immunohistochemistry, which is consistent with the anti-NMDAR antibodies affect the expression and function of NMDARs, resulting in anti-NMDAR encephalitis-like symptoms. Also, the mice treated with the NMDAR-CSF did not show inflammatory cell infiltration or neuron loss in their brain tissue and this lack of nervous tissue destruction is encouraging as it is consistent with the idea that this disease can be treated through immunotherapy.
    Preview · Article · Nov 2015 · The Tohoku Journal of Experimental Medicine
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    • "L'évolution peut être sévère et conduire à une prise en charge en réanimation. Elles peuvent être associées à un tératome ovarien, mais avant l'âge de 12 ans les formes paranéoplasiques sont rares [3] [4] [5] [6]. "
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    ABSTRACT: Dysimmune encephalitis are frequent and disabling pathologies with efficacious treatments (immunotherapy). Evocative clinical signs are: rapid progressive evolution, seizure, movement disorder, psychiatric troubles, memory defect, dysautonomia and hyponatremia. Classical ancillary test: magnetic resonance imaging (MRI) and standard cerebro-spinal fluid (CSF) analysis can be normal. In this context, the cerebral positron emission tomography (PET) is helpful for the diagnosis. More often reported patterns are: association of hyper- and hypo-metabolism; fronto-temporal hyper-metabolism/parieto-occipital hypo-metabolism gradient (anti-N-methyl-D-aspartate receptor [NMDAR] encephalitis); temporal and basal ganglia hyper-metabolism (anti-leucine-rich glioma inactivated protein 1 [LGI1] encephalitis); temporal hyper-metabolism (other limbic encephalitis); parieto-occipital ± basal ganglia hypo-metabolism (neurolupus); unihemispheric diffuse hypo-metabolism (Rasmussen encephalitis). The diagnosis could require research of specific antibodies. Finally, the cerebral PET is also useful during the follow-up: treatment's efficacy (improvement of metabolism), relapse (aggravation of metabolism's alteration), and evaluation of possible sequelae.
    Full-text · Article · Apr 2015 · Medecine Nucleaire
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    • "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). Furthermore, among the female patients with anti-NMDAR encephalitis, only about half were associated with ovarian teratoma (Irani et al. 2010; Titulaer 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.
    Preview · Article · Mar 2015 · The Tohoku Journal of Experimental Medicine
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