Biomarkers for Brain Resetting as an Assistive Tool in the Treatment of Status Epilepticus

拟议的第一阶段STTR研究是一项跨学科的努力，旨在开发更有效的临床管理。 与世界领先的神经学研究所之一Barrow合作研究癫痫持续状态(SE) 亚利桑那州凤凰城的神经学研究所。SE是一种危及生命的神经紧急情况，如果没有 警告，以反复发作为特征，发作之间没有恢复正常的大脑功能。 在普通公众中，SE的发病率每年为每10万人中有10至41人，但它的发病率要大得多 在癫痫患者中(20%的癫痫患者会在他们一生中的某个时候经历SE)。给定的级别 其严重性，在SE发作期间和之后的死亡率相对较高(难治性SE高达40%)，以及 癫痫患者发生SE的可能性很高，在门诊环境中，SE是一个值得关注的问题 和癫痫医疗中心。减少SE的干预时机和类型对患者有显著影响 结果。然而，目前还没有生物标志物可以快速、定量和客观地预测 干扰SE、指导后续用药选择或预测神经学的干预措施的有效性 结果。此类生物标志物的开发和验证有助于缩短SE的持续时间，减少患者的 在治疗SE的新临床试验中，可以作为发病率和死亡率的替代终点。 具体目标1：在SE治疗过程中测量脑和心脏动力学。我们以前的 发展的线性多变量和非线性单变量动力学测量将应用于长期脑电 以及在癫痫监测单元(EMU)接受治疗的大量SE患者(~100人)的心电记录， 巴罗神经科研究所的重症监护病房(ICU)或急诊室(ER)，产生了大量的 根据大脑和心脏动力学测量得出的特征值的数据库。 具体目标2：开发和验证治疗红斑狼疮疗效的生物标志物 请注意。从特定目标1中每个患者的特征值的数据库中，并基于我们之前来自 对于SE动态的线性和非线性测量，我们将得出用于监测大脑的生物标志物(SE指数 正在接受治疗的患者的实时动态，以及一种算法，该算法将在 治疗无效，即没有统计意义(p&gt；0.05)的观察到的重置 干预后的病理动力学。我们将验证生成的SE索引值和窗口 警告基于患者随着时间的推移的临床状态，并得到合作医生的证实。 根据到目前为止我们从相对较小的人类和动物SE病例队列中获得的初步结果，我们 预计我们开发的生物标记物将显示出高灵敏度和特异度，用于实时评估 在门诊或医院环境中给予SE治疗的有效性，因此 构成SE临床管理的辅助性、健壮和客观的商业工具的基础； 对正在接受SE治疗的患者和整个社会都有很大的好处。

The proposed phase-I STTR research is an interdisciplinary effort to develop more effective clinical management of Status Epilepticus (SE) in collaboration with one of the leading neurological institutes in the world, the Barrow Neurological Institute in Phoenix, Arizona. SE is a life-threatening neurological emergency that can occur without warning and is characterized by recurrent seizures without recovery of normal brain function between seizures. The incidence rate of SE in the general public is 10 to 41 per 100,000 individuals per year, but it is much bigger in patients with epilepsy (20% of epilepsy patients will experience SE at some point in their lives). Given the level of its severity, relatively high mortality rate during and after an episode of SE (up to 40% in refractory SE), and the high probability of its occurrence in epilepsy patients, SE is of a significant concern in ambulatory settings and epilepsy medical centers. Timing and type of intervention to abate SE significantly influence patient outcomes. However, there are currently no biomarkers to rapidly, quantitatively and objectively predict the effectiveness of an intervention to disrupt SE, guide subsequent medication choices, or predict neurologic outcome. Development and validation of such biomarkers could help shorten the duration of SE, reduce patients’ morbidity and mortality, as well as serve as surrogate endpoints in new clinical trials for treatment of SE. Specific Aim 1: Measurement of brain and heart dynamics during SE treatment. Our previously developed linear multivariate and nonlinear univariate measures of dynamics will be applied to long-term EEG and ECG recordings from a large number of SE patients (~100) treated at the Epilepsy Monitoring Unit (EMU), Intensive Care Unit (ICU) or Emergency Room (ER) of the Barrow Neurological Institute, generating a substantial database of feature values derived from measures of brain and heart dynamics. Specific Aim 2: Development and validation of biomarkers for the effectiveness of treatment of SE. From the database of feature values per patient in Specific Aim 1, and based on our previous results from linear and non-linear measures of SE dynamics, we will derive biomarkers (SE indices) for monitoring the brain’s dynamics of the patient under treatment in real time, and an algorithm which will issue warnings (Wineff) on ineffectiveness of treatment, i.e. when there is no statistically significant (p>0.05) resetting of the observed pathological dynamics following intervention. We will validate the generated SE index values and Wineff warnings based on the clinical state of the patient over time, corroborated by collaborating physicians. Based on our preliminary results from a relatively small cohort of human and animal SE cases so far, we expect that our developed biomarkers would exhibit high sensitivity and specificity for real time assessment of the effectiveness of the administered treatment of SE in an ambulatory or hospital environment, and will thus constitute the basis for an assistive, robust and objective commercial tool for the clinical management of SE, much to the benefit of patients undergoing SE treatment and the society at large.