Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies.
Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies.
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DOI：
10.1016/s1474-4422(13)70299-0
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Dalmau J
中科院分区：
文献类型：
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作者：
Petit-Pedrol M;Armangue T;Peng X;Bataller L;Cellucci T;Davis R;McCracken L;Martinez-Hernandez E;Mason WP;Kruer MC;Ritacco DG;Grisold W;Meaney BF;Alcalá C;Sillevis-Smitt P;Titulaer MJ;Balice-Gordon R;Graus F;Dalmau J
越来越多的证据表明，癫痫发作和癫痫持续状态可以是免疫介导的。我们的目的是描述一种新的癫痫疾病的临床特征，并建立靶抗原和患者的抗体对神经元培养的影响。在这项观察性研究中，我们选择了140例脑炎、癫痫发作或癫痫持续状态患者的血清和CSF样本进行抗原表征，以及未知神经元抗原的抗体。这些样本来自2006年4月28日至2013年4月25日期间全球转诊的疑似自身免疫性疾病患者。我们使用了来自75名健康个体和416名患有一系列神经系统疾病的患者的样本作为对照。我们使用免疫沉淀、质谱、基于细胞的测定和共聚焦显微镜分析培养的大鼠海马神经元中的抗体效应来评估样品。神经细胞膜免疫沉淀与血清的两个指数患者发现GABAA受体序列。用表达GABAA受体α1/β3亚基的HEK 293进行的基于细胞的测定显示6名患者的血清抗体（>1：160）和CSF抗体的高滴度。所有6例患者（年龄3-63岁，中位年龄22岁; 5例男性患者）均发生难治性癫痫持续状态或部分持续性癫痫沿着广泛皮质-皮质下MRI异常; 4例患者需要癫痫诱导昏迷。416例其他疾病的对照患者中有12例仅在血清样品中检测到低滴度的GABAA受体抗体，其中5例还具有GAD-65抗体，而健康对照组中没有。这12名患者（年龄2-74岁，中位年龄26.5岁; 7名男性患者）出现了可能提示共存自身免疫性疾病的更广泛的症状：6名脑炎伴癫痫发作（1名癫痫持续状态需要癫痫诱导昏迷; 1名部分性癫痫持续），4名僵硬人综合征（1名癫痫发作伴边缘系统受累），2名眼阵挛-肌阵挛。总体而言，15例治疗和结局可评估的患者中有12例对免疫治疗或对症治疗有完全（3例）或部分（9例）反应，3例死亡。患者的抗体导致突触处GABAA受体簇的选择性减少，但不影响沿着树突，而不改变NMDA受体和桥蛋白（一种锚定GABAA受体的蛋白质）。高滴度的血清和CSF GABAA受体抗体与严重形式的脑炎伴癫痫发作、难治性癫痫持续状态或两者兼而有之相关。抗体导致突触GABAA受体的选择性减少。这种疾病通常与GABA能和其他共存的自身免疫性疾病一起发生，并且是潜在的可治疗的。美国国立卫生研究院、麦克奈特脑疾病神经科学、Fondo de Investigaciones Sanitarias、Fundació la Marató de TV 3、荷兰科学研究组织（Veni-incentive）、荷兰癫痫基金会。
Increasing evidence suggests that seizures and status epilepticus can be immune-mediated. We aimed to describe the clinical features of a new epileptic disorder, and to establish the target antigen and the effects of patients’ antibodies on neuronal cultures. In this observational study, we selected serum and CSF samples for antigen characterisation from 140 patients with encephalitis, seizures or status epilepticus, and antibodies to unknown neuropil antigens. The samples were obtained from worldwide referrals of patients with disorders suspected to be autoimmune between April 28, 2006, and April 25, 2013. We used samples from 75 healthy individuals and 416 patients with a range of neurological diseases as controls. We assessed the samples using immunoprecipitation, mass spectrometry, cell-based assay, and analysis of antibody effects in cultured rat hippocampal neurons with confocal microscopy. Neuronal cell-membrane immunoprecipitation with serum of two index patients revealed GABAA receptor sequences. Cell-based assay with HEK293 expressing α1/β3 subunits of the GABAA receptor showed high titre serum antibodies (>1:160) and CSF antibodies in six patients. All six patients (age 3–63 years, median 22 years; five male patients) developed refractory status epilepticus or epilepsia partialis continua along with extensive cortical-subcortical MRI abnormalities; four patients needed pharmacologically induced coma. 12 of 416 control patients with other diseases, but none of the healthy controls, had low-titre GABAA receptor antibodies detectable in only serum samples, five of them also had GAD-65 antibodies. These 12 patients (age 2–74 years, median 26·5 years; seven male patients) developed a broader spectrum of symptoms probably indicative of coexisting autoimmune disorders: six had encephalitis with seizures (one with status epilepticus needing pharmacologically induced coma; one with epilepsia partialis continua), four had stiff-person syndrome (one with seizures and limbic involvement), and two had opsoclonus-myoclonus. Overall, 12 of 15 patients for whom treatment and outcome were assessable had full (three patients) or partial (nine patients) response to immunotherapy or symptomatic treatment, and three died. Patients’ antibodies caused a selective reduction of GABAA receptor clusters at synapses, but not along dendrites, without altering NMDA receptors and gephyrin (a protein that anchors the GABAA receptor). High titres of serum and CSF GABAA receptor antibodies are associated with a severe form of encephalitis with seizures, refractory status epilepticus, or both. The antibodies cause a selective reduction of synaptic GABAA receptors. The disorder often occurs with GABAergic and other coexisting autoimmune disorders and is potentially treatable. The National Institutes of Health, the McKnight Neuroscience of Brain Disorders, the Fondo de Investigaciones Sanitarias, Fundació la Marató de TV3, the Netherlands Organisation for Scientific Research (Veni-incentive), the Dutch Epilepsy Foundation.