Elsevier

The Lancet Neurology

Volume 7, Issue 12, December 2008, Pages 1091-1098
The Lancet Neurology

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Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies

https://doi.org/10.1016/S1474-4422(08)70224-2Get rights and content

Summary

Background

A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures.

Methods

We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters.

Findings

Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0·004) and fewer neurological relapses (p=0·009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal.

Interpretation

A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies.

Funding

National Institutes for Health, University of Pennsylvania Institute for Translational Medicine, Lankenau Institute for Medical Research, Foederer Foundation of the Children's Hospital of Philadelphia.

Introduction

NMDA receptors are ligand-gated cation channels with crucial roles in synaptic transmission and plasticity. The receptors are heteromers of NR1 subunits that bind glycine and NR2 (A, B, C, or D) subunits that bind glutamate.1 NR1 and NR2 combine to form receptor subtypes with distinct pharmacological properties, localisation, and ability to interact with intracellular messengers. Overactivity of NMDA receptors causing excitotoxicity is a proposed underlying mechanism for epilepsy, dementia, and stroke, whereas low activity produces symptoms of schizophrenia.2, 3, 4

We recently identified a disorder, designated anti-NMDA-receptor encephalitis, that associates with antibodies against NR1–NR2 heteromers and results in a characteristic neuropsychiatric syndrome.5 The first patients identified were young women with ovarian teratoma who presented with psychosis or memory problems, rapidly progressing to multiple neurological deficits requiring prolonged intensive care support. Despite the severity of the disorder, patients often recovered after tumour removal and immunotherapy, suggesting an immune-mediated pathogenesis. Preliminary studies suggested the target epitopes were located in extracellular regions of NR1–NR2B NMDA receptors.5 However, selective disruption of receptors containing NR2B, which are predominantly expressed in the forebrain and hippocampus, would not explain the extensive deficits of patients. We postulated that the crucial epitopes were present in the more widely expressed NR1 subunit. If the antibodies were pathogenic we reasoned that their effects on NMDA receptors would be reversible because most patients recover.

We report the clinical features of 100 patients, analysing the frequency and type of tumour association, antibody titres, and response to treatment. We also investigate the epitopic region of the NMDA receptor and how antibodies affect NMDA receptors in primary cultures of hippocampal neurons.

Section snippets

Patients and procedures

Clinical information was obtained by the authors or provided by referring physicians, and has been partly reported for 21 patients.5, 6, 7, 8, 9 The webappendix contains additional information and details of control individuals. Control samples were obtained from 20 healthy individuals and 230 patients with suspected autoimmune or paraneoplastic encephalitis, or patients with tumours without encephalitis examined during the period of this study. Samples were from patients seen at University of

Results

Table 1 summarises the clinical information. 86 patients who could be assessed had headache, low-grade fever, or a non-specific viral-like illness within 2 weeks before hospital admission. 77 patients presented with prominent psychiatric symptoms, including anxiety, agitation, bizarre behaviour, delusional or paranoid thoughts, and visual or auditory hallucinations. 23 presented with short-term memory loss or seizures alone or associated with psychiatric manifestations.

During the first 3 weeks

Discussion

Of 100 patients with anti-NMDA-receptor encephalitis, a disorder that associates with antibodies against the NR1 subunit of the receptor, many were initially seen by psychiatrists or admitted to psychiatric centres but subsequently developed seizures, decline of consciousness, and complex symptoms requiring multidisciplinary care. While poorly responsive or in a catatonic-like state, 93 patients developed hypoventilation, autonomic imbalance, or abnormal movements, all overlapping in 52

References (30)

  • JT Coyle

    Glutamate and schizophrenia: beyond the dopamine hypothesis

    Cell Mol Neurobiol

    (2006)
  • EA Waxman et al.

    N-methyl-D-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease

    Neuroscientist

    (2005)
  • CG Lau et al.

    NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders

    Nat Rev Neurosci

    (2007)
  • J Dalmau et al.

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

    Ann Neurol

    (2007)
  • LH Sansing et al.

    A patient with encephalitis associated with NMDA receptor antibodies

    Nat Clin Pract Neurol

    (2007)
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    These authors contributed equally to this paper

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