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


RESULTS
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 consciousness), 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.


CONCLUSIONS
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.
Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA. josep.dalmau@uphs.upenn.edu
Josep
J
Dalmau
Amy J
AJ
Gleichman
Ethan G
EG
Hughes
Jeffrey E
JE
Rossi
Xiaoyu
X
Peng
Meizan
M
Lai
Scott K
SK
Dessain
Myrna R
MR
Rosenfeld
Rita
R
Balice-Gordon
David R
DR
Lynch
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D020274:Autoimmune Diseases of the Nervous System / Q000175:diagnosis / Q000276:immunology* / Q000503:physiopathology; D001921:Brain / Q000276:immunology* / Q000503:physiopathology; D002460:Cell Line; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004660:Encephalitis / Q000175:diagnosis / Q000276:immunology* / Q000503:physiopathology; D004827:Epilepsy / Q000276:immunology / Q000503:physiopathology; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019965:Neurocognitive Disorders / Q000276:immunology / Q000503:physiopathology; D010051:Ovarian Neoplasms / Q000276:immunology / Q000503:physiopathology; D020361:Paraneoplastic Syndromes, Nervous System / Q000276:immunology / Q000503:physiopathology; D021122:Protein Subunits / Q000276:immunology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*; D013724:Teratoma / Q000276:immunology / Q000503:physiopathology; D055815:Young Adult
D001323:Autoantibodies; D001324:Autoantigens; D000939:Epitopes; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate