Modeling West Syndrome to Prevent Neurobehavioral Disabilities

West综合征是儿童早期灾难性癫痫中最常见的一种。发病最常见的是 在生命的第一年内，患有这种疾病的婴儿会有非常短暂的癫痫发作(只有几秒钟 (持续时间)--因此产生了婴儿痉挛的别名。癫痫痉挛通常发生在 在几分钟内聚集到100个。痉挛与高度混乱的脑电模式一起被称为 重度心律失常被认为是导致大多数儿童严重智力残疾的原因之一。确实如此 痉挛发作时，常可观察到神经发育停滞或退化。其他神经行为 包括多动症在内的合并症也会进化。在治疗方面，ACTH和Vigabatrin是FDA 经批准可停止痉挛，对约50%的儿童有效。然而，这两种药物都会产生严重的 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 神经行为合并症持续存在，而且是终生的。因此，需要进行治疗，不仅要阻止 痉挛还可以预防智力残疾和其他神经行为缺陷。最近的大型 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 迅速消除痉挛可以改善神经行为结果。例如，结果是 如果在确诊后一周内开始治疗而不是两个月内开始治疗，效果会更好。这些结果和其他类似的结果 他们已经发表了一份立场声明，得到了儿童神经病学协会和美国癫痫学会的支持 迅速治疗癫痫痉挛是预防发育和智力恶化的关键。 结果。在这项应用中，我们建议建立TTX婴儿痉挛动物模型，用于 发现预防神经行为合并症的新疗法。这款车型已经有了很好的外在 有效性。此外，这里报告的初步结果表明，痉挛的动物有学习和 记忆缺陷和伴随的多动表型。我们提出了四个具体目标。首先，我们 将充分描述这些动物的学习和记忆缺陷以及多动表型。在 其次，我们将建立一种新的Vigabatrin和神经活性药物联合治疗的最佳剂量 与Vigabatrin协同增强GABA能突触传递的肽(1-3)IGF-1 消除大多数动物的痉挛。在第三和第四个目标中，我们将建立预测 联合疗法治疗大鼠模型的有效性及早期消除痉挛的效果 心律失常将改善神经行为并发症，但延迟治疗不会。如果成功， 这些研究将建立TTX模型，作为发现毒性较低和更有效的亟需工具 新的治疗方法，将显著改善患有这种毁灭性癫痫的儿童的长期结果 无序。

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.