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.

拟议的第一阶段STTR研究是一项跨学科的努力，以开发更有效的临床管理 癫痫持续状态（SE）与世界领先的神经学研究所之一，巴罗 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系统紧急情况， 警告，其特征是反复癫痫发作，两次癫痫发作之间没有恢复正常的脑功能。 一般公众中SE的发病率为每年每10万人10至41人，但要高得多 癫痫患者（20%的癫痫患者会在一生中的某个时候经历SE）。考虑到 严重程度，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的概率很高，因此在门诊环境中值得关注 癫痫病医疗中心减轻SE的干预时间和类型显著影响患者 结果。然而，目前还没有生物标志物来快速、定量和客观地预测 干扰SE、指导后续药物选择或预测神经功能的干预措施的有效性 结果。这些生物标志物的开发和验证可以帮助缩短SE的持续时间，减少患者的并发症， 发病率和死亡率，以及作为替代终点在新的临床试验治疗SE。 具体目标1：SE治疗期间脑和心脏动力学的测量。我们先前 开发的线性多变量和非线性单变量动态措施将适用于长期脑电图 以及在癫痫监测中心（EMU）接受治疗的大量SE患者（约100例）的ECG记录， 巴罗神经病学研究所的重症监护室（ICU）或急诊室（ER），产生大量 从大脑和心脏动力学的测量导出的特征值的数据库。 具体目标2：开发和验证生物标志物，以有效治疗 SE.根据特定目标1中每个患者的特征值数据库，并基于我们之前的结果， 通过SE动态的线性和非线性测量，我们将推导出用于监测大脑的生物标志物（SE指数）。 在真实的时间中治疗中的患者的动态，以及将发出警告（Wineff）的算法。 治疗无效，即当观察到的 干预后的病理动力学。我们将验证生成的SE索引值和Wineff 基于患者随时间推移的临床状态的警告，由合作医生证实。 根据我们迄今为止从相对较小的人类和动物SE病例队列中获得的初步结果， 预期我们开发的生物标志物将表现出高灵敏度和特异性，用于真实的时间评估， 在门诊或医院环境中对SE进行治疗的有效性，因此 构成了SE临床管理的辅助性、稳健性和客观性商业工具的基础， 这对接受SE治疗的患者和整个社会都有好处。