CHILDHOOD ABSENCE EPILEPSY RX, PK-PD-PHARMACOGENETICS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（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。所列机构为中心，不一定是研究者所在机构。儿童失神癫痫（Childhood Absence Epilepsy，CAE）是一种以异常频繁的失神发作为特征的疾病，其EEG表现为每秒3次的双侧同步对称棘波，背景活动正常。CAE发生在所有癫痫儿童的5%至10%中，在15岁以下的儿童中，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，发病高峰在6至7岁。失神癫痫的长期缓解率为21%至89%。这种广泛的报告范围可能是由于不一致和可变的研究纳入标准，方法，随访时间和结局定义。20%的CAE年轻人在失神发作期间受伤。据估计，失神发作造成意外伤害的风险为每人每年3%。 三种抗癫痫药物（AED），乙琥胺（ETX），拉莫三嗪（LTG）和丙戊酸（VPA），通常用作CAE的初始单药治疗。这三种AED各有利弊。乙琥胺、拉莫三嗪和丙戊酸是仅有的在失神发作中有疗效的对照临床试验证据的AED。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查这些AED的长期疗效和耐受性。这三种AED的疗效在50%至70%的范围内。没有一种AED是普遍接受的CAE首选药物。目前对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之一作为一线治疗，（2）AED剂量根据经验以可变增量递增至主要主观的临床终点，以及（3）当癫痫发作未能得到充分控制或初始治疗出现毒性时，选择替代的一线AED。 这项研究建议：（1）确定用于CAE儿童初始治疗的最佳抗惊厥药，（2）确定抗惊厥药疗效和毒性个体间差异的药物遗传学和其他非遗传因素，（3）确定和对比乙琥胺、拉莫三嗪和丙戊酸单药治疗对CAE儿童认知（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.