van Baalen Andreas, Häusler Martin, Plecko-Startinig Barbara, Strautmanis Jurgis, Vlaho Stefan, Gebhardt Boris, Rohr Axel, Abicht Angela, Kluger Gerhard, Stephani Ulrich, Probst Christian, Vincent Angela, Bien Christian G
Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
Neuropediatrics. 2012 Aug;43(4):209-16. doi: 10.1055/s-0032-1323848. Epub 2012 Aug 21.
Febrile infection-related epilepsy syndrome (FIRES) is a severe postinfectious epileptic encephalopathy in previously healthy children and has three phases: the initial phase with a simple febrile infection, a few days later the acute phase characterized by a peracute onset of highly recurrent seizures or refractory status epilepticus often with no more fever and generally without additional neurological features (the classical pure seizure phenotype), and last, the chronic phase with a drug-resistant epilepsy and neuropsychological impairments. FIRES seems to be sporadic and very rare: we estimated the annual incidence in children and adolescents by a prospective hospital-based German-wide surveillance as 1 in 1,000,000. Because of the preceding infection and lacking evidence of infectious encephalitis, an immune-mediated pathomechanism and, therefore, a response to immunotherapies may be involved. To test the hypothesis that antibodies against neuronal structures cause FIRES, we analyzed sera of 12 patients aged 2 to 12 years (median 6 years) and cerebral spinal fluids (CSFs) of 3 of these 12 patients with acute or chronic FIRES. We studied six patients (two including CSF) 1 to 14 weeks (median 3 weeks) and six patients 1 to 6 years (median 3.5 years) after seizure onset. All samples were analyzed for antibodies against glutamate receptors of type N-methyl-D-aspartate (NMDA) and type α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), gamma-aminobutyric acid (GABA)B-receptors, voltage-gated potassium channel (VGKC)-associated proteins leucin-rich glioma inactivated 1 (LGI1) and contactin-associated protein like 2 (CASPR2), and glutamic acid decarboxylase (GAD) by a multiparametric recombinant immunofluorescence assay employing human embryonic kidney (HEK) cells transfected with cDNAs for the antigens. In addition, indirect immunohistochemistry using rat whole-brain sections was done in three patients. Finally, sera of 10 patients were tested for VGKC complex antibodies by radioimmunoprecipitation assay (RIA). None of the antibody tests were positive in any of the patients. Moreover, steroids, immunoglobulins, and plasmapheresis had no clear effect in the seven patients receiving immunotherapy. The failure of antibody-detection against the known neuronal antigens as well as the ineffectiveness of immunotherapy questions a role for autoantibodies in the epileptogenesis of classical FIRES. As we discuss, other underlying causes need to be considered including the possibility of a mitochondrial encephalopathy.
发热感染相关癫痫综合征（FIRES）是一种发生在既往健康儿童中的严重感染后癫痫性脑病，有三个阶段：初始阶段为简单的发热感染，几天后进入急性期，其特征是癫痫频繁发作或难治性癫痫持续状态急性起病，通常不再发热且一般无其他神经功能特征（典型的单纯发作表型），最后是慢性期，表现为药物难治性癫痫和神经心理障碍。FIRES似乎是散发性的，非常罕见：我们通过一项基于德国全国范围的前瞻性医院监测估计儿童和青少年的年发病率为百万分之一。由于有前驱感染且缺乏感染性脑炎的证据，可能涉及免疫介导的发病机制，因此可能对免疫治疗有反应。为了验证针对神经元结构的抗体导致FIRES这一假说，我们分析了12例年龄在2至12岁（中位年龄6岁）患者的血清以及这12例急性或慢性FIRES患者中3例的脑脊液（CSF）。我们研究了癫痫发作后1至14周（中位时间3周）的6例患者（2例包括脑脊液样本）以及1至6年（中位时间3.5年）的6例患者。所有样本均通过多参数重组免疫荧光测定法检测针对N-甲基-D-天冬氨酸（NMDA）型和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型谷氨酸受体、γ-氨基丁酸（GABA）B受体、电压门控钾通道（VGKC）相关蛋白富含亮氨酸的胶质瘤失活蛋白1（LGI1）和接触蛋白相关蛋白样2（CASPR2）以及谷氨酸脱羧酶（GAD）的抗体，该测定法使用转染了抗原cDNA的人胚肾（HEK）细胞。此外，对3例患者进行了使用大鼠全脑切片的间接免疫组织化学检测。最后，通过放射免疫沉淀测定法（RIA）检测了10例患者血清中的VGKC复合抗体。所有患者的抗体检测均为阴性。此外，在接受免疫治疗的7例患者中，类固醇、免疫球蛋白和血浆置换均无明显效果。针对已知神经元抗原的抗体检测失败以及免疫治疗无效，对自身抗体在经典FIRES癫痫发生中的作用提出了质疑。正如我们所讨论的，需要考虑其他潜在原因，包括线粒体脑病的可能性。
