Modeling West Syndrome to Prevent Neurobehavioral Disabilities

韦斯特综合征是儿童早期最常见的灾难性癫痫。发病最常见的是 在生命的第一年内，患有这种疾病的婴儿有非常短暂的癫痫发作（在婴儿期只有几秒钟）。 持续时间）-因此创造的替代名称婴儿痉挛。癫痫痉挛通常发生在 在几分钟内聚集到100个痉挛，沿着高度混乱的脑电图模式， 高心律失常被认为是导致大多数儿童严重智力残疾的原因。确实 在痉挛发作时经常观察到神经发育停止或退化。其他神经行为 合并症也包括多动症。在治疗方面，促肾上腺皮质激素和氨己烯酸是FDA 被批准停止痉挛，对约50%的儿童有效。然而，这两种药物都可以产生严重的 副作用.更重要的是，虽然这些药物可以消除一些儿童的痉挛，但大多数情况下， 神经行为共病持续存在并且是终生的。因此，需要的治疗不仅要阻止 痉挛，但也防止智力残疾和其他神经行为缺陷。近期大型 多中心临床试验报告了更乐观的结果。他们建议及时诊断和 痉挛的快速消除可导致改善的神经行为结果。例如，结果是 如果在诊断后1周内开始治疗，而不是2个月内开始治疗，效果更好。这些结果和其他结果， 他们已经导致了一份立场声明，得到了儿童神经学会和美国癫痫学会的认可。 及时治疗癫痫痉挛是必不可少的，以防止更坏的发展和智力 成果。在本申请中，我们建议建立婴儿痉挛症的TTX动物模型， 发现预防神经行为共病的新疗法。该模型已经具有良好的外部 效度此外，这里报告的初步结果表明，痉挛动物有学习和 记忆缺陷和伴随的多动表型。我们提出了四个具体目标。第一，我们 将充分表征这些动物中的学习和记忆缺陷和多动表型。在 第二，我们将确定氨己烯酸和神经活性药物的新型联合治疗的最佳剂量。 肽（1-3）IGF-1，其与氨己烯酸协同作用以增强GABA能突触传递并快速 消除了大多数动物的痉挛。在第三和第四个目标中，我们将建立预测性的 通过用联合疗法治疗大鼠证实了模型的有效性， 高心律失常可改善神经行为合并症，但延迟治疗不能。如果成功， 这些研究将建立TTX模型，作为发现毒性更小、更有效的一种急需的工具 新的治疗方法，这将显着改善这种毁灭性癫痫发作的儿童的长期结果 disorder.

West syndrome is the most common of the catastrophic epilepsies of early childhood. Onset is most often within the first year of life and babies with this disorder have very brief seizures (only a few seconds in duration) – thus the coining of the alternate name infantile spasms. The epileptic spasms commonly occur in clusters of up to 100 in a few minutes. The spasms, along with the highly chaotic EEG patterns called hypsarrhythmia, are thought to contribute to the severe intellectual disabilities seen in most children. Indeed neurodevelopmental arrest or regression is frequently observed upon spasm onset. Other neurobehavioral comorbidities evolve as well including hyperactivity. In terms of treatments, ACTH and vigabatrin are FDA approved to stop the spasms and are effective in ~ 50% of children. However, both drugs can produce serious side effects. More importantly, while these drugs can eliminate spasms in some children, most often the neurobehavioral comorbidities persist and are life-long. Thus treatments are needed that will not only stop the spasms but also prevent the intellectual disabilities and other neurobehavioral deficits. Recent large multicenter clinical trials have reported more optimistic outcomes. They suggest that prompt diagnosis and rapid elimination of spasms can result in improved neurobehavioral outcomes. For instance, outcomes are better if treatment is initiated within 1 week of diagnosis rather than 2 months. These results and others like them have led to a position statement endorsed by the Child Neurology Society and American Epilepsy Society that prompt treatment of epileptic spasms is essential in order to prevent worse developmental and intellectual outcomes. In this application, we propose to establish the TTX animal model of infantile spasms for the discovery of new treatments to prevent neurobehavioral comorbidities. The model already has good external validity. In addition, preliminary results reported here indicate that animals with spasms have learning and memory deficits and an accompanying hyperactivity phenotype. We propose 4 specific aims. In the first, we will fully characterize the learning and memory deficits and hyperactivity phenotype in these animals. In the second, we will establish the best dosing for a novel combination therapy of vigabatrin and the neuroactive peptide (1-3)IGF-1 that synergies with vigabatrin to enhance GABAergic synaptic transmission and rapidly eliminates spasms in a large majority of animals. In the third and fourth aims, we will establish the predictive validity of the model by treating rats with the combination therapy and showing that early elimination of spasms and hypsarrhythmia will ameliorate neurobehavioral comorbidities but delayed treatment will not. If successful, these studies will establish the TTX model as a much-needed tool for discovering less toxic and more effective new therapies, which will significantly improve long-term outcomes for children with this devastating seizure disorder.