Potential EEG biomarkers and antiepileptogenic strategies for epilepy in TSC

描述(申请人提供)：TSC中癫痫的潜在脑电生物标记物和抗癫痫策略目前的癫痫治疗方法主要是抑制癫痫发作的对症治疗，但尚未被证明能预防癫痫或改变疾病进展。近年来，人们对开发疾病修饰或“抗癫痫”疗法产生了极大的兴趣。结节性硬化症(TSC)是癫痫的常见遗传原因，TSC患者的一部分可能代表了针对抗癫痫治疗方法的合理、可行的人群。首先，一些患者在癫痫发作之前的年轻年龄就被诊断为TSC，这是由于存在非神经系统的发现：这些发现的存在使得在癫痫发生的早期阶段识别这些患者并开始潜在的抗癫痫治疗是可行的。其次，这些患者未来患癫痫的风险很高。由于这些因素，在症状前阶段启动具有潜在副作用的治疗在TSC患者中很可能是合理的。最后，mTOR通路在TSC病理生理学中的鉴定表明，mTOR抑制剂在TSC中可能具有抗癫痫作用，但可能存在显著的风险和副作用。因此，在TSC患者开始抗癫痫药物试验之前，获得更多的证据来优化选择标准和治疗方案，以最大限度地提高mTOR抑制剂的疗效并将副作用降至最低，以及建立临床前和临床站点网络将是有益的。在这项P20拨款申请中，我们建议进行临床前和临床研究，为潜在的抗癫痫药物试验建立最佳参数。临床前核心将旨在确定维持抗癫痫疗效并将副作用风险降至最低的最佳雷帕霉素治疗范例。临床核心旨在确定婴儿时期的脑电是否是识别将发展为癫痫的TSC患者的可靠生物标记物，从而适合进行抗癫痫药物试验。我们还将建立一个无墙的TSC癫痫中心的基础设施，这将为此类临床试验提供便利。

DESCRIPTION (provided by applicant): Potential EEG biomarkers and antiepileptogenic strategies for epilepsy in TSC Current therapeutic approaches for epilepsy primarily represent symptomatic treatments that suppress seizures, but have not been demonstrated to prevent epilepsy or modify disease progression. In recent years, there has been tremendous interest in developing disease-modifying or "antiepileptogenic" therapies. Tuberous Sclerosis Complex (TSC) is a common genetic cause of epilepsy and a subset of TSC patients may represent a rational, feasible population to target an antiepileptogenic treatment approach. First of all, some patients are diagnosed with TSC at a young age before the onset of epilepsy due to the presence of non-neurological findings: The presence of these findings makes it feasible to identify these patients and initiate a potential antiepileptogenic treatment at an early stage of epileptogenesis. Second, these patients are at high risk for developing epilepsy in the future. Because of these factors initiating a therapy with potential side effects in a presymptomatic stage can likely be justified in TSC patients. Finally, the identification of the mTOR pathway in the pathophysiology of TSC suggests that mTOR inhibitors could have antiepileptogenic properties in TSC but there may be significant risks and side effects. Therefore, before initiating an antiepileptogenic drug trial in TSC patients, it would be beneficial to obtain further evidence to optimize the selection criteria and treatment paradigms to maximize efficacy and minimize side effects of mTOR inhibitors, as well as establish a network of preclinical and clinical sites. n this P20 grant application we propose to conduct pre-clinical and clinical studies that establish optimal parameters for a potential antiepileptogenic drug trial. The preclinical core will aim to determine the optimal rapamycin treatment paradigms that maintain antiepileptogenic efficacy but minimize risks of side effects. The clinical core aims to determine whether EEGs during infancy are a reliable biomarker to identify TSC patients that will develop epilepsy and thus appropriate candidates for an antiepileptogenic drug trial. We will also establish the infrastructure for a TSC Epilepsy Center Without Walls, which will facilitate such clinical trials.