Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma
Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma
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DOI：
10.1002/ana.21050
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发表时间：
2007-01-01
影响因子：
11.2
通讯作者：
Lynch, David R.
中科院分区：
文献类型：
--
作者：
Dalmau, Josep;Tuzun, Erdem;Lynch, David R.
目的：报告一类新的治疗反应性副肿瘤性脑炎的自身抗原。方法：使用大鼠组织、神经元培养物和表达N-甲基-D-天冬氨酸受体（NMDAR）亚单位的HEK 293细胞分析临床特征、神经病理学发现、肿瘤和血清/脑脊液抗体。12名女性（14-44岁）出现了明显的精神症状、健忘症、癫痫发作、频繁的运动障碍、自主神经功能障碍和意识水平下降，通常需要辅助支持。所有患者的血清/脑脊液抗体主要免疫标记海马/前脑的神经元，特别是海马神经元的细胞表面，并与NMDAR的NR 2B（以及较小程度的NR 2A）亚基反应。NR 2B结合谷氨酸并形成在成年海马/前脑中优先表达的异构体（NR 1/NR 2B或NR 1/NR 2A/NR 2B）。抗体结合需要功能性异源聚体（而不是单个亚基）的表达。11名患者患有卵巢畸胎瘤（6名成熟），1名患者患有纵隔成熟畸胎瘤;检查的5个肿瘤中有5个含有强烈表达NR 2亚基并与患者抗体反应的神经组织。肿瘤切除术和免疫治疗导致9例患者中有8例改善或完全恢复（由于抗体滴度降低）; 3例未切除肿瘤的患者中有2例死于神经功能恶化。尸检显示广泛的小胶质细胞增生，罕见的T细胞浸润，神经元变性为主，涉及，但不限于，hippocamps.Interpretation：抗体NR 2B-和NR 2A-含有异聚体的NMDAR与一个严重的，但治疗反应性脑炎。我们的研究结果提供了一个诊断测试，并提出了一个模型的自身免疫性NMDAR相关的脑炎与其他免疫介导的记忆，行为和认知障碍的广泛影响。
Objective: To report the autoantigens of a new category of treatment-responsive paraneoplastic encephalitis.Methods: Analysis of clinical features, neuropathological findings, tumors, and serum/cerebrospinal fluid antibodies using rat tissue, neuronal cultures, and HEK293 cells expressing subunits of the N-methyl-D-aspartate receptor (NMDAR).Results: Twelve women (14-44 years) developed prominent psychiatric symptoms, amnesia, seizures, frequent dyskinesias, autonomic dysfunction, and decreased level of consciousness often requiring ventilatory support. All had serum/cerebrospinal fluid antibodies that predominantly immunolabeled the neuropil of hippocampus/forebrain, in particular the cell surface of hippocampal neurons, and reacted with NR2B (and to a lesser extent NR2A) subunits of the NMDAR. NR2B binds glutamate and forms hereromers (NR1/NR2B or NR1 /NR2A/NR2B) that are preferentially expressed in the adult hippocampus/forebrain. Expression of functional heteromers (not single subunits) was required for antibody binding. Eleven patients had teratoma of the ovary (six mature) and one a mature teratoma in the mediastinum; five of five tumors examined contained nervous tissue that strongly expressed NR2 subunits and reacted with patients' antibodies. Tumor resection and immunorherapy resulted in improvement or full recovery of eight of nine patients (paralleled by decreased antibody titers); two of three patients without tumor resection died of neurological deterioration. Autopsies showed extensive microgliosis, rare T-cell infiltrates, and neuronal degeneration predominantly, involving, but not restricted to, the hippocampus.Interpretation: Antibodies to NR2B- and NR2A-containing heteromers of the NMDAR associate with a severe but treatment-responsive encephalitis. Our findings provide a diagnostic test and suggest a model of autoimmune NMDAR-related encephalitis with broad implications for other immune-mediated disorders of memory, behavior, and cognition.