Potential EEG biomarkers and antiepileptogenic strategies for epilepsy in TSC

目前癫痫的治疗方法主要是对症治疗，抑制 癫痫发作，但尚未被证明能预防癫痫或改变疾病进展。在最近 多年来，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，也是TSC患者的一个亚群 RNAs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前很小就被诊断为TSC，因为存在 非神经学发现：这些发现的存在使识别这些患者和 在癫痫发生的早期阶段开始潜在的抗癫痫治疗。第二，这些患者 在未来罹患癫痫的风险很高。因为这些因素启动了一种治疗方法 在TSC患者中，症状前阶段的潜在副作用可能是合理的。最后， 对TSC病理生理学中mTOR通路的鉴定表明mTOR抑制剂可能具有 TSC具有抗癫痫作用，但可能存在重大风险和副作用。因此，之前 在TSC患者中启动抗癫痫药物试验，将有助于获得进一步的证据 优化选择标准和治疗模式，以最大限度地提高疗效并将副作用降至最低 MTOR抑制剂，以及建立临床前和临床站点网络。在这份P20拨款申请中 我们建议进行临床前和临床研究，以确定潜在的最佳参数 抗癫痫药物试验。临床前核心将致力于确定雷帕霉素的最佳治疗方案 维持抗癫痫疗效但将副作用风险降至最低的范例。临床核心旨在 确定婴儿时期的脑电图是否是确定将发展为TSC的患者的可靠生物标志物 癫痫，因此是抗癫痫药物试验的合适候选人。我们还将建立 没有围墙的TSC癫痫中心的基础设施，这将为此类临床试验提供便利。

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 have 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 rnay 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. In 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.