NS-PEACE Neonatal Seizures -Predicting Epilepsy and Assessing Comparative Effectiveness.

NS-PEACE 新生儿癫痫发作 - 预测癫痫并评估比较有效性。

• 批准号: 10568397
• 负责人: Zachary Michael Grinspan
• 金额: $ 72.25万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568397
• 关键词: Accounting; Acute; Acute Brain Injuries; Address; Age; Anticonvulsants; Benchmarking; Biological Markers; Brain Stem; Caring; Case Study; Cerebral Palsy; Child; Chronic; Clinical; Clinical Management; Collaborations; Collection; Data; Development; Effectiveness; Electroencephalography; Electronic Health Record; Enrollment; Epilepsy; Epileptogenesis; Evolution; Foundations; Goals; Health system; Hour; Human; Infant; Infantile spasms; Injury; Intellectual functioning disability; Intervention; Learning; Levetiracetam; Life; Live Birth; Magnetic Resonance Imaging; Methods; Modeling; Modernization; Mus; Neonatal Intensive Care Units; Neurosciences Research; Observational Study; Outcome; Phenobarbital; Phenytoin; Predictive Value; Prevention trial; Publishing; Recommendation; Recording of previous events; Research; Research Design; Research Personnel; Risk; Risk Reduction; Safety; Sample Size; Seizures; Selection Bias; Selection for Treatments; Site; Sodium Channel; Sodium Channel Blockers; Spasm; Statistical Data Interpretation; Survivors; Syndrome; Techniques; Tetrodotoxin; Tuberous Sclerosis; Validity and Reliability; Variant; Vigabatrin; Vulnerable Populations; Work; acquired epilepsy; childhood epilepsy; clinical care; comparative effectiveness; comparative effectiveness study; compare effectiveness; electronic structure; fosphenytoin; hazard; high risk; high risk population; improved outcome; infancy; neonatal care; neonatal seizure; neonate; oxcarbazepine; peace; prevent; preventable epilepsy; programs; voltage

ABSTRACT (30 lines) Neonatal seizures occur once per 1000 live births and are associated with subsequent development of epilepsy, cerebral palsy, and intellectual disability. Most (85%) are acute symptomatic seizures (i.e., due to an acute injury). Roughly one-quarter of survivors will subsequently develop epilepsy (i.e., chronic unprovoked seizures) after a months-to-years delay. We propose to address three questions in the management of acute symptomatic neonatal seizures. Our central hypothesis is that optimizing the clinical management of this vulnerable population will reduce the development of epilepsy. First, what is the best second-line anti-seizure medication (ASM) for acute neonatal seizures? Our preliminary data suggest the two most used ASMs, levetiracetam (LEV) and phenytoin/fosphenytoin (PHT), have roughly equivalent effectiveness. We will conduct in-depth chart abstraction (780 neonates at 18 centers) and apply modern statistical techniques to compare their effectiveness for short-term (seizure cessation) and long-term (epilepsy by age 2) outcomes. Demonstration of equivalence would favor the use of LEV, given its tolerability and safety profile. Second, if neonates with seizures (age 0-28 days) continue ASM therapy in infancy (age 1-12 months), does ASM selection alter the risk to develop infantile spasms syndrome (ISS)? Our preliminary analyses found an association of oxcarbazepine (OXC) use with ISS, in alignment with recent work demonstrating that voltage- gated sodium channel blockade can induce epileptic spasms in mice (using tetrodotoxin) and may increase the risk for ISS in human infants (case reports and single-center data). This finding needs confirmation before recommending avoidance of OXC in infants, particularly given the effectiveness of OXC and other voltage- gated sodium channel blockers for some monogenetic epilepsies that begin in the first year of life. We will confirm this finding in 587 infants. Third, after discharge from the neonatal intensive care unit, which infants will develop epilepsy? We propose to validate our published epilepsy prediction rule in 1800 neonates for subsequent use as enrollment criteria for epilepsy prevention trials. We will conduct this work using the Pediatric Epilepsy Learning Health System (PELHS), a consortium of US academic pediatric epilepsy programs that work collaboratively to improve outcomes for children with epilepsy through cycles of electronic health record (EHR) collection and analysis. This rigorous set of studies will generate much-needed evidence to support treatment decisions in a vulnerable population, in alignment with the 2020 Epilepsy Research Benchmarks, including II-3 (biomarkers), II-5 (interventions to prevent epileptogenesis), and III-4 (predict, prevent seizures). The proposal is aligned with a long-standing goal of clinical neuroscience research: to predict and prevent epilepsy in high-risk individuals. The results will directly inform clinical care for neonates with acute symptomatic seizures as well as lay the foundation for epilepsy prevention trials.

摘要（30行） 新生儿癫痫发作一次每1000例活产一次，与随后的发展有关 癫痫，脑瘫和智力残疾。大多数（85％）是急性症状性癫痫发作（即，由于 急性损伤）。大约四分之一的幸存者将随后发展癫痫（即慢性无端 癫痫发作）延迟了一个月后。我们建议在急性管理方面解决三个问题 有症状的新生儿癫痫发作。我们的中心假设是优化对此的临床管理 脆弱的人口将减少癫痫的发展。首先，什么是最好的二线反塞兹 急性新生儿癫痫发作的药物（ASM）？我们的初步数据表明，两个最常用的ASM， Levetiracetam（LEV）和苯妥英钠/磷烯滋养（PHT）具有大致相等的有效性。我们将进行 深入图表抽象（18个中心的780名新生儿），并应用现代统计技术来比较 它们对短期（癫痫发作）和长期（按2岁）结局的有效性。 鉴于其耐受性和安全性，对等效性的证明将有利于使用LEV。第二，如果 癫痫发作（0-28天）的新生儿继续在婴儿期（1-12个月）继续进行ASM 选择会改变发展婴儿痉挛综合征（ISS）的风险？我们的初步分析发现 奥卡西平（OXC）与ISS的使用，与最近的工作相一致，表明电压 封闭的钠通道阻滞可以在小鼠中诱导癫痫痉挛（使用四毒素），并可能增加 人类婴儿中ISS的风险（病例报告和单中心数据）。这一发现需要确认 建议避免在婴儿中避免OXC，特别是考虑到OXC和其他电压的有效性 封闭式钠通道阻滞剂，用于一些从生命的第一年开始的单基因癫痫。我们将 在587名婴儿中确认这一发现。第三，从新生儿重症监护病房出院后，婴儿将 发展癫痫？我们建议在1800名新生儿中验证我们已发表的癫痫预测规则 随后用作预防癫痫预防试验的入学标准。我们将使用 小儿癫痫学习卫生系统（PELHS），美国学术小儿癫痫的财团 通过电子周期进行癫痫病儿童的结合程序，以改善癫痫病的结局 健康记录（EHR）收集和分析。这组严格的研究将产生急需的证据 在脆弱人群中支持治疗决策，与2020年癫痫研究保持一致 基准，包括II-3（生物标志物），II-5（预防癫痫发生的干预措施）和III-4（预测，预测，预测， 防止癫痫发作）。该提案与临床神经科学研究的长期目标保持一致： 预测和预防高危个体癫痫。结果将直接为新生儿提供临床护理 具有急性症状性癫痫发作，并为预防癫痫预防试验的基础奠定了基础。