CHILDHOOD ABSENCE EPILEPSY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 儿童失神癫痫（CAE）是一种常见的儿科癫痫综合征，影响10-15%的癫痫儿童，治疗反应的个体间差异的基础尚未确定。通常被误认为是良性癫痫综合征，CAE患者表现出对治疗的可变反应，表现出认知缺陷，并表现出长期的心理社会困难。本提案的目的是：1）确定可产生并维持最高癫痫控制率以及最低治疗限制性毒性发生率的抗癫痫药物（AED），以及2）确定AED疗效和毒性个体间差异的药物遗传学和非遗传因素。将在CAE儿童中进行一项以无失败率为主要终点的乙琥胺（ETX）、拉莫三嗪（LTG）和丙戊酸盐（VPA）作为初始单药治疗的随机、双盲比较试验。美国的20家研究中心将在3年内入组473名2- 13岁儿童。治疗成功将被定义为癫痫控制和短期和长期耐受性的复合指标。将研究每种AED对认知（特别是注意力）、行为和生活质量的影响。每个病人的癫痫综合征将广泛的表型与视频脑电图。使用群体药代动力学（PK）方法确定的个体全身药物暴露量将定义药物处置中患者间变异性对AED疗效和毒性的影响，并将用于选定药物代谢酶的药物遗传学（pG）相关研究。 将研究T型钙通道α 1G、α 1H、α 1 I亚基编码基因多态性变异对治疗应答的作用。将研究每种AED最常见治疗限制的潜在预测因素，包括发生LTG相关皮疹、VPA诱导的体重增加或神经认知技能受损证据（所有AED的潜在限制）的患者的pG、pK和临床特征。这项研究将确定AED，提供最大的癫痫控制可能性，以及最佳的短期和长期耐受性。通过全面定义失神发作沿着的表型谱以及pG和非遗传因素，这些因素是AED反应的患者间变异性的基础，该提议将形成基于综合征的AED治疗的合理方法的基础。本研究所获得的知识将为CAE儿童提供个性化治疗，并可推广到其他儿科和成人癫痫发作疾病。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Childhood Absence Epilepsy (CAE), a common pediatric epilepsy syndrome affecting 10-15% of all children with epilepsy, and the basis for the inter-individual variation in response to therapy, has not been defined. Commonly misperceived as a benign epilepsy syndrome, patients with CAE demonstrate variable response to therapy, exhibit cognitive deficits, and demonstrate long-term psychosocial difficulties. The objectives of this proposal are 1) to identify the anti-epileptic drug (AED) that produces and sustains the highest rate of seizure control coupled with the lowest incidence of treatment limiting toxicity for children with CAE, and 2) to determine the pharmacogenetic and non-heritable factors underlying the inter-individual variation in AED efficacy and toxicity. A randomized, double blind comparative trial of ethosuximide (ETX), lamotrigine (LTG) and valproate (VPA) as initial monotherapy will be performed in children with CAE utilizing freedom from failure rate as the primary endpoint. Twenty sites in the U.S. will enroll 473 children, 2- 13 years of age, over a 3-year period. Treatment success will be defined as a composite of seizure control and short and long-term tolerability. Each AED's impact on cognition (especially attention), behavior, and quality of life will be studied. Each patient's epilepsy syndrome will be extensively phenotyped with video EEGs. Individual systemic drug exposures, determined using a population pharmacokinetic (pK) approach, will define the impact of interpatient variability in drug disposition on AED efficacy and toxicity, and will be utilized in pharmacogenetic (pG) correlative studies of select drug metabolizing enzymes. The role of polymorphic variation in the genes coding for the a1G, a1H, a1I subunits of the T type calcium channels in response to therapy will be investigated. Factors potentially predictive for the most common treatment limitations of each AED will be studied, including the pG, pK and clinical profiles of patients developing LTG associated rash, VPA induced weight gain or evidence of impaired neurocognitive skills (potential limitation of all AEDs). This study will determine the AED that provides for the greatest likelihood of seizure control coupled with the best short and long term tolerability. By comprehensively defining the phenotypic spectrum of absence seizures along with pG and non-heritable factors that underlie interpatient variability in AED response, this proposal will form the foundation of a pharmacologically rational approach to syndrome based AED therapy. Knowledge gained by this study will lead to individualized treatment for children with CAE that can be generalized to other pediatric and adult seizure disorders.