Anti-NMDA receptor encephalitis in Japan: Long-term outcome without tumor removal

Department of Neurology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa, 228-8555, Japan.
Neurology (Impact Factor: 8.29). 03/2008; 70(7):504-11. DOI: 10.1212/01.wnl.0000278388.90370.c3
Source: PubMed


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.
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.
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).
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.

Download full-text


Available from: Takahiro Iizuka, May 26, 2015
    • "For example, sequential PET imaging in a 25-year-old woman with marked limb rigidity showed an increased striatal metabolism in parallel to the diffuse cortical metabolic hypoactivity that normalized upon clinical recovery (Maeder-Ingvar et al., 2011). Single photon emission tomography (SPECT) revealed either increased (Vitaliani et al., 2005; Iizuka et al., 2008) or decreased perfusion in the medial frontal and temporal cortex in single patients (Vitaliani et al., 2005; Iizuka et al., 2010; Tsuyusaki et al., 2014). Diffusion tensor imaging analyses detected widespread white matter changes, i.e. reduction of fractional anisotropy and increase of mean diffusivity, that correlated with individual disease severity (Finke Fig. 2 "
    [Show abstract] [Hide abstract]
    ABSTRACT: The field of autoimmune encephalitides associated with antibodies targeting cell-surface antigens is rapidly expanding and new antibodies are discovered frequently. Typical clinical presentations include cognitive deficits, psychiatric symptoms, movement disorders and seizures and the majority of patients responds well to immunotherapy. Pathophysiological mechanisms and clinical features are increasingly recognized and indicate hippocampal dysfunction in most of these syndromes. Here, we review the neuroimaging characteristics of autoimmune encephalitides, including N-methyl-D-aspartate (NMDA) receptor, leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2) encephalitis as well as more recently discovered and less frequent forms such as dipeptidyl-peptidase-like protein 6 (DPPX) or glycine receptor encephalitis. We summarize findings of routine MRI investigations as well as FDG-PET and SPECT imaging and relate these observations to clinical features and disease outcome. We furthermore review results of advanced imaging analyses such as diffusion tensor imaging, volumetric analyses and resting state functional MRI. Finally, we discuss contributions of these neuroimaging observations to the understanding of the pathophysiology of autoimmune encephalitides. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 05/2015; 309. DOI:10.1016/j.neuroscience.2015.05.037 · 3.36 Impact Factor
  • Source
    • "Although NR3 subunit can complex with NR1 subunit to form a glycine-responsive excitatory receptor, it does not bind glutamate (Chatterton et al. 2002). Initially, anti-NMDAR encephalitis, which is potentially lethal, manifests clinically as a range of psychiatric symptoms, and subsequently as intractable seizure disorders, dyskinesia, autonomic instability or hypoventilation (Dalmau et al. 2007, 2008; Iizuka et al. 2008). An anti-neural antibody for the NR1/NR2 heteromer of NMDARs has been identified as a disease-specific hallmark (Vitaliani et al. 2005; Dalmau et al. 2008). "
    [Show abstract] [Hide abstract]
    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.
    The Tohoku Journal of Experimental Medicine 03/2015; 235(3):223-31. DOI:10.1620/tjem.235.223 · 1.35 Impact Factor
  • Source
    • "De manière moins spécifique, le LCR révèle une pléïocytose lymphocytaire, une hyperprotéinorachie, associées à des bandes oligoclonales [4] [5] [6] [7]. Les examens complémentaires doivent systématiquement rechercher une étiologie tumorale à l'encéphalite [1] [3] [4]. Il est donc recommandé de réaliser, à visée systématique, une IRM pelvienne, un TEP-Scan corps entier, une imagerie thoracoabdomino-pelvienne , une échographie pelvienne plus ou moins endo-vaginale chez la fille, une échographie testiculaire chez le garçon. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Anti-NMDAR encephalitis is a serious central nervous system disorder, not well known, that may lead to non specific psychiatric symptoms, ranging from psychosis to catatonia. We report the case of a 15-year-old girl, without significant medical history, hospitalized in a context of first-episode psychosis, quickly followed by agitated and stuporous catatonia, with only poor response to benzodiazepine treatment. Titration of autoantibodies in the cerebrospinal fluid confirmed the diagnosis of anti-NMDAR encephalitis. Recovery was obtained thanks to corticotherapy and immunosuppressive agents. In complement to this clinical report, we propose a literature update on anti-NMDA-R encephalitis and the excitatory/inhibitory imbalance as the potential mechanism at the root of catatonia.
    Neuropsychiatrie de l Enfance et de l Adolescence 02/2015; 63(3). DOI:10.1016/j.neurenf.2014.12.003
Show more