CHILDHOOD ABSENCE EPILEPSY RX, PK-PD-PHARMACOGENETICS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。儿童期失神性癫痫（CAE）的特征是异常频繁的失神性癫痫发作，其脑电图通常表现为每秒3次的双侧、同步、对称的尖波模式，背景活动正常。在所有癫痫患儿中，CAE发生率为5%至10%，在15岁以下儿童中，年发病率为每10万人6.3至8人。癫痫发作通常在4至8岁之间，6至7岁为发病高峰。缺乏性癫痫的长期缓解率从21%到89%不等。如此广泛的报道范围可能是由于研究纳入标准、方法、随访时间和结果定义不一致和多变所致。20%患有CAE的年轻人在失神发作期间受伤。因失神发作而造成意外伤害的风险估计为每人每年3%。三种抗癫痫药物（AED），乙氧亚胺（ETX），拉莫trogine （LTG）和丙戊酸（VPA），通常被用作CAE的初始单药治疗。这三种aed各有优缺点。埃索昔胺、拉莫曲津和丙戊酸是仅有的有对照临床试验证据证明对失神癫痫有效的抗癫痫药。然而，迄今为止还没有研究在前瞻性随机对照临床试验中检验这些aed的长期疗效和耐受性。这三种抗癫痫药的疗效在50% ~ 70%之间。没有一种AED是CAE普遍接受的首选药物。目前CAE的药物治疗仍然主要是经验性的：(1)根据临床医生的偏好选择三种常用AED中的一种作为一线治疗，(2)AED的剂量根据经验以可变增量递增到主要主观的临床终点，(3)当癫痫发作未能得到充分控制或初始治疗出现毒性时，选择一线AED替代治疗。本研究拟：(1)确定用于CAE患儿初始治疗的最佳抗惊厥药物；(2)确定抗惊厥药物疗效和毒性个体间差异的药理学和其他非遗传因素；(3)确定并对比乙氧亚胺、拉莫trogine和丙戊酸单药治疗对CAE患儿认知（注意力）、行为和生活质量的影响。

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) is characterized by very frequent absence seizures in an otherwise normal child with an EEG usually demonstrating 3 per second bilateral, synchronous, symmetrical spike-wave pattern with normal background activity. CAE occurs in 5% to 10% of all children with epilepsy with an annual incidence of 6.3 to 8 per 100,000 in children less than 15 years of age. Epilepsy onset is typically between the ages of 4 to 8 years with a peak incidence of 6 to 7 years of age. The long-term remission rates for absence epilepsy range from 21% to 89%. This wide reported range likely resulted from inconsistent and variable study inclusion criteria, methods, follow-up length, and outcome definitions. Twenty percent of young adults with CAE had an injury during an absence seizure. The risk of accidental injury resulting from an absence seizure has been estimated to be 3% per person year. Three anti-epileptic drugs (AED), ethosuximide (ETX), lamotrogine (LTG), and valproic acid (VPA), are commonly used as initial monotherapy for CAE. These three AEDs have advantages and disadvantages. Ethosuximide, lamotrogine, and valproic acid are the only AEDs with controlled clinical trial evidence of efficacy in absence seizures. No study to date, however, has examined the long-term efficacy and tolerability of these AEDs in a prospective randomized controlled clinical trial. The efficacy for these three AEDs are in the 50% to 70% range. No one AED is the universally accepted drug of first choice for CAE. Current medication treatment for CAE remains largely empiric: (1) one of three commonly used AEDs is selected as first line therapy based on clinician preference, (2) the AED dosage is empirically escalated in variable increments to a primarily subjective clinical endpoint, and (3) an alternative first line AED is selected when seizures fail to be adequately controlled or toxicity supervenes for the initial therapy. This study proposes to: (1) identify the optimal anticonvulsant used for the initial treatment of children with CAE, (2) determine the pharmacogenetic and other non-heritable factors underlying the inter-individual variation in anticonvulsants response efficacy and toxicity, and (3) define and contrast the effects of ethosuximide, lamotrogine, and valproic acid monotherapy on cognition (attention), behavior and quality of life in children with CAE.