Iizuka Takahiro, Sakai Fumihiko, Mochizuki Hideki
Department of Neurology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan.
Brain Nerve. 2010 Apr;62(4):331-8.
A new category of treatment-responsive encephalitis has been proposed in association with antibodies to neuronal cell membrane antigens, including voltage-gated potassium channel (VGKC), N-methyl-D-aspartic acid receptor (NMDAR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma-aminobutyric acid (GABA) B receptor and other antigens that have not yet been characterized. Among the forms of encephalitis under this category, anti-NMDAR encephalitis is a distinct disorder characterized by the predictable sequential development of symptoms; prodromal symptoms are initially noted, followed by prominent psychiatric symptoms, seizures, an unresponsive/catatonic state, hypoventilation, and involuntary orofacial-limb movements. This disorder usually affects young women with ovarian teratoma but may also affect women of any age or even men. A recent study revealed that the main epitope targeted by anti-NMDAR antibodies lies in the extracellular N-terminal domain of the NR1 subunit (25-380 amino-acid residues); the NR2B subunit is not necessarily involved. The antibodies are shown to produce selectively and reversibly reduce postsynaptic NMDARs clusters without complement activation. Considering the symptomatology of anti-NMDAR encephalitis and the results of cell culture analysis, we speculate that the overall antibody-mediated inhibition of NMDARs expressed on GABAergic interneurons, glutamatergic neurons and dopaminergic neurons may cause neuropsychiatric symptoms and dyskinesias via dopamine and glutamate dysregulation. We also hypothesize that these antibodies affect not only trafficking/localization/clustering of postsynaptic NMDARs, but also the expression of other receptors including AMPAR and dopamine receptors, by including a chronic state of exposure to excessive or decreased neurotransmitters release. The establishment of an animal model is awaited to resolve these issues. Anecdotal reports have revealed that recovery may be spontaneous without tumor resection but early tumor resection along with aggressive immunotherapy facilitates early functional recovery. In a recent case, a microscopic teratoma was detected on autopsy; therefore exploratory laparotomy may be considered in severe refractory cases.
一种与神经元细胞膜抗原抗体相关的新型治疗反应性脑炎已被提出，这些抗原包括电压门控钾通道（VGKC）、N-甲基-D-天冬氨酸受体（NMDAR）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）、γ-氨基丁酸（GABA）B受体以及其他尚未明确特征的抗原。在这一类别下的脑炎形式中，抗NMDAR脑炎是一种独特的疾病，其症状具有可预测的顺序发展；最初会出现前驱症状，随后是明显的精神症状、癫痫发作、无反应/紧张性木僵状态、通气不足以及不自主的口面部-肢体运动。这种疾病通常影响患有卵巢畸胎瘤的年轻女性，但也可能影响任何年龄的女性甚至男性。最近的一项研究表明，抗NMDAR抗体靶向的主要表位位于NR1亚基的细胞外N端结构域（25 - 380个氨基酸残基）；NR2B亚基不一定参与其中。这些抗体显示出在无补体激活的情况下选择性且可逆地减少突触后NMDAR簇。考虑到抗NMDAR脑炎的症状学以及细胞培养分析结果，我们推测抗体介导的对GABA能中间神经元、谷氨酸能神经元和多巴胺能神经元上表达的NMDAR的整体抑制可能通过多巴胺和谷氨酸失调导致神经精神症状和运动障碍。我们还假设这些抗体不仅影响突触后NMDAR的运输/定位/聚集，还通过包括长期暴露于神经递质释放过多或减少的状态来影响其他受体的表达，包括AMPAR和多巴胺受体。有待建立动物模型来解决这些问题。轶事报道显示，即使不进行肿瘤切除，恢复也可能是自发的，但早期肿瘤切除以及积极的免疫治疗有助于早期功能恢复。在最近的一个病例中，尸检时发现了微小畸胎瘤；因此，对于严重难治性病例，可考虑进行剖腹探查。
