Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
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DOI：
10.1016/s1474-4422(08)70224-2
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发表时间：
2008-12
期刊：
影响因子：
48
通讯作者：
Lynch, David R.
中科院分区：
文献类型：
--
作者：
Dalmau, Josep;Gleichman, Amy J.;Hughes, Ethen G.;Rossi, Jeffrey E.;Peng, Xiaoyu;Lai, Meizan;Dessain, Scott K.;Rosenfeld, Mynna R.;Balice-Gordon, Rita;Lynch, David R.
最近发现了一种与抗NMDA受体NR1-NR2异构体抗体相关的严重脑炎。我们的目的是分析该疾病患者的临床和免疫学特征，并检查抗NMDA受体抗体在神经元培养中的作用。我们描述了100例脑炎和NR1-NR2抗体阳性患者的临床特点。使用异位表达单个或组装的NR1-NR2亚基的HEK293细胞来确定抗体的靶位。用双抗体夹心法测定抗体效价。通过对NMDA受体簇的定量分析，确定抗体对神经元培养的影响。患者的中位年龄为23岁(5-76岁)；91名女性。所有患者都有精神症状或记忆问题；76例癫痫发作，88例无反应(意识减退)，86例运动障碍，69例自主神经不稳定，66例换气不足。在有肿瘤学评估结果的98名患者中，58名(59%)患有肿瘤，最常见的是卵巢畸胎瘤。接受早期肿瘤治疗(通常使用免疫疗法)的患者比其他患者有更好的结果(p=0.004)和较少的神经复发(p=0.009)。75例患者恢复或有轻度缺陷，25例严重缺陷或死亡。改善与血清抗体滴度的降低有关。抗体靶向的主要表位位于NR1亚单位的胞外N-末端区域。患者的抗体减少了突触后树突中细胞表面NMDA受体和NMDA受体簇的数量，这一效果可以通过抗体去除而逆转。一组明确的临床特征与抗NMDA受体脑炎有关。这种疾病的发病机制似乎是由抗体介导的。
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. 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. 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 conciousness), 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. 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.