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

大脑重置生物标志物作为治疗癫痫持续状态的辅助工具

• 批准号: 10698969
• 负责人: Timothy Noah Hutson
• 金额: $ 27.56万
• 依托单位: EPIFOCUS LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10698969
• 关键词: Abate; Accident and Emergency department; Address; Algorithms; Animals; Arizona; Biological Markers; Biomedical Engineering; Brain; Cessation of life; Clinical; Clinical Data; Clinical Management; Clinical Treatment; Clinical Trials; Collaborations; Data; Databases; Development; Disease; Effectiveness of Interventions; Electrocardiogram; Electroencephalography; Environment; Epilepsy; Exhibits; General Population; Headache; Heart; Hospitals; Human; Incidence; Individual; Intensive Care Units; Intervention; Life; Lung; Manic; Measurement; Measures; Medical center; Methodology; Migraine; Monitor; Morbidity - disease rate; Neurologic; Neurological emergencies; Neurological outcome; Neurology; Neurosciences; Organ; Panic Attack; Pathologic; Pathology; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Physicians; Probability; Quality of life; Recovery; Recurrence; Refractory; Research; Risk; Seizures; Sensitivity and Specificity; Severities; Signal Transduction; Sleep Disorders; Small Business Technology Transfer Research; Societies; Status Epilepticus; Surrogate Endpoint; Time; Treatment Effectiveness; Tremor; Validation; biomarker validation; clinical outcome measures; clinically relevant; cohort; effectiveness evaluation; effectiveness validation; experience; indexing; insight; mortality; neuroregulation; sudden unexpected death in epilepsy; tool

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.

拟议的I期STTR研究是跨学科的努力，以开发更有效的临床管理 地位癫痫持续状态（SE）与世界上领先的神经学院之一，巴罗 亚利桑那州凤凰城的神经学研究所。 SE是一种威胁生命的神经系统紧急情况 警告，其特征是复发性癫痫发作，而无需恢复癫痫发作之间正常脑功能的恢复。 公众中SE的事件率每年为每10万人10至41个，但要大得多 在癫痫患者中（癫痫患者中有20％会在生活中的某个时候经历SE）。给定水平 在SE发作期间和之后的严重程度，相对高死亡率（在难治性SE中最多40％）和 SE在癫痫患者中发生的很高可能性是在门诊环境中的重要问题 和癫痫医疗中心。时间和干预类型减轻SE会显着影响患者 结果。但是，目前尚无生物标志物可以快速，定量和客观地预测 干预措施破坏SE的有效性，指导随后的药物选择或预测神经系统 结果。这种生物标志物的开发和验证可以帮助缩短SE的持续时间，减少患者 在新的临床试验中，发病率和死亡率，并用作替代端点的替代终点。 特定目标1：在SE治疗过程中测量大脑和心脏动力学。我们以前 开发的线性多元和非线性单变量动力学将应用于长期脑电图 以及来自癫痫监测单元（EMU）治疗的大量SE患者（〜100）的ECG记录， 巴罗神经研究所的重症监护室（ICU）或急诊室（ER），产生了大量 从大脑和心脏动力学测量得出的特征值数据库。 特定目的2：生物标志物的开发和验证用于治疗的有效性 se。从特定AIM 1中的每个患者的特征值数据库，并根据我们先前的结果 SE动力学的线性和非线性测量值，我们将得出生物标志物（SE索引）来监测大脑的 实时治疗的患者的动态和将发出警告（WINEFF）的算法 治疗无效性，即，当没有统计学意义（p> 0.05）重置时 干预后的病理动力学。我们将验证生成的SE索引值和Wineff 随着时间的流逝，基于患者的临床状态的警告，由合作医师证实。 根据我们到目前为止的人类和动物SE案件相对较小的初步结果，我们 预计我们发达的生物标志物将表现出高灵敏度和特异性，以实时评估 在卧床或医院环境中管理SE治疗的有效性，因此将 构成了SE临床管理的辅助，健壮和客观的商业工具的基础， 对接受SE治疗和整个社会的患者的利益很大。