Potential EEG biomarkers and antiepileptogenic strategies for epilepy in TSC

描述（由申请人提供）：TSC患者癫痫的潜在EEG生物标志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，但尚未被证明可以预防癫痫或改变疾病进展。近年来，人们对开发改善疾病或“抗癫痫”疗法产生了极大的兴趣。结节性硬化症（TSC）是一种常见的癫痫遗传病因，TSC患者的一个子集可能代表一个合理的、可行的人群，以抗癫痫治疗方法为目标。首先，由于存在非神经学方面的发现，一些患者在癫痫发作前就被诊断为TSC：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启动潜在的抗癫痫治疗成为可能。其次，这些患者未来发生癫痫的风险很高。由于这些因素，在症状前阶段开始有潜在副作用的治疗可能对TSC患者是合理的。最后，在TSC病理生理中mTOR通路的发现提示mTOR抑制剂在TSC中可能具有抗癫痫特性，但可能存在显著的风险和副作用。因此，在启动TSC患者抗癫痫药物试验之前，有必要进一步收集证据，优化mTOR抑制剂的选择标准和治疗模式，以实现疗效最大化和副作用最小化，并建立临床前和临床站点网络。在此P20资助申请中，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最佳的雷帕霉素治疗模式，以保持抗癫痫疗效，但最大限度地减少副作用的风险。临床核心目的是确定婴儿期脑电图是否是一种可靠的生物标志物，以确定TSC患者是否会发展为癫痫，从而确定抗癫痫药物试验的合适候选人。我们还将为无墙的TSC癫痫中心建立基础设施，这将促进此类临床试验。

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.