Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal.
OBJECTIVE
To report the definitive diagnosis of anti-NMDA receptor (NMDAR) encephalitis in four Japanese women previously diagnosed with "juvenile acute nonherpetic encephalitis" of unclear etiology, and to describe their long-term follow-up in the absence of tumor resection.


METHODS
We extensively reviewed the case histories with current clinical and laboratory evaluations that include testing for antibodies to NR1/NR2 heteromers of the NMDAR in serum/CSF available from the time of symptom onset (4 to 7 years ago) and the present.


RESULTS
All patients sequentially developed prodromal symptoms, psychosis, hypoventilation, severe orofacial dyskinesias, and bizarre immunotherapy-resistant involuntary movements that lasted 1 to 12 months. Two patients required mechanical ventilation for 6 and 9 months. Initial tests were normal or unrevealing, including the presence of nonspecific CSF pleocytosis, and normal or mild changes in brain MRI. Eventually, all patients had dramatic recovery of cognitive functions, although one had bilateral leg amputation due to systemic complications. Antibodies to NR1/NR2 heteromers were found in archived serum or CSF but not in long-term follow-up samples. An ovarian teratoma was subsequently demonstrated in three patients (all confirmed pathologically).


CONCLUSIONS
1) These findings indicate that "juvenile acute nonherpetic encephalitis" or a subset of this disorder is mediated by an antibody-associated immune response against NR1/NR2 heteromers of the NMDA receptor (NMDAR). 2) Our patients' clinical features emphasize that anti-NMDAR encephalitis is severe but potentially reversible and may precede by years the detection of an ovarian teratoma. 3) Although recovery may occur without tumor removal, the severity and extended duration of symptoms support tumor removal.
Iizuka
T
T
Department of Neurology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa, 228-8555, Japan. takahiro@med.kitasato-u.ac.jp
Sakai
F
F
Ide
T
T
Monzen
T
T
Yoshii
S
S
Iigaya
M
M
Suzuki
K
K
Lynch
D R
DR
Suzuki
N
N
Hata
T
T
Dalmau
J
J
D000293:Adolescent; D000328:Adult; D000342:Affective Symptoms / Q000276:immunology / Q000503:physiopathology; D001284:Atrophy / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology*; D015415:Biomarkers / Q000032:analysis; D002460:Cell Line; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000276:immunology / Q000503:physiopathology; D020820:Dyskinesias / Q000276:immunology / Q000503:physiopathology; D005260:Female; D006801:Humans; D020363:Limbic Encephalitis / Q000175:diagnosis* / Q000276:immunology* / Q000503:physiopathology; D008032:Limbic System / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D010051:Ovarian Neoplasms / Q000150:complications / Q000276:immunology*; D011379:Prognosis; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*; D020127:Recovery of Function / Q000276:immunology; D013724:Teratoma / Q000150:complications / Q000276:immunology*; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon
D001323:Autoantibodies; D015415:Biomarkers; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate