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

摘要（30行） 新生儿癫痫发作每1000例活产发生一次，并与随后的发展有关。 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随后会患上癫痫（即，慢性无端 在经过几个月到几年的拖延之后，我们建议在急性胰腺炎的管理中解决三个问题 症状性新生儿癫痫我们的中心假设是，优化临床管理， 易患人群将减少癫痫的发展。一、什么是最好的二线防癫痫 急性新生儿癫痫发作的药物（ASM）？我们的初步数据表明，两种最常用的ASM， 左乙拉西坦（LEV）和苯妥英/磷苯妥英（PHT）具有大致相当的有效性。我们会进行 深入的图表提取（18个中心的780名新生儿），并应用现代统计技术进行比较 它们对短期（癫痫发作停止）和长期（2岁以下癫痫）结局的有效性。 考虑到LEV的耐受性和安全性，证明其等效性有利于使用LEV。二是如果 癫痫发作的新生儿（0-28天）在婴儿期（1-12个月）继续ASM治疗，ASM是否 选择改变婴儿痉挛综合征（ISS）的风险？我们的初步分析发现 奥卡西平（OXC）使用与ISS的关联，与最近的工作表明电压- 门控钠通道阻断可诱导小鼠癫痫痉挛（使用河豚毒素）， 人类婴儿ISS风险（病例报告和单中心数据）。这一发现需要确认， 建议避免婴儿OXC，特别是考虑到OXC和其他电压的有效性- 门控钠通道阻滞剂，用于治疗开始于出生后第一年的单基因癫痫。我们将 在587名婴儿中证实了这一发现。第三，从新生儿重症监护室出院后，哪些婴儿会 患上癫痫吗我们建议在1800名新生儿中验证我们发表的癫痫预测规则， 随后用作癫痫预防试验的入选标准。我们将使用 小儿癫痫学习健康系统（PELHS），美国学术小儿癫痫联盟 通过电子循环协作改善癫痫儿童结局的计划 健康记录（EHR）收集和分析。这组严谨的研究将产生急需的证据 支持弱势人群的治疗决策，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， 预防癫痫发作）。该提案符合临床神经科学研究的长期目标： 预测和预防高危人群的癫痫。结果将直接告知新生儿的临床护理 为急性症状性癫痫发作以及癫痫预防试验奠定基础。

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.