Infantile Spasms: Tools for Therapies

描述（由申请人提供）：婴儿痉挛是儿童早期的灾难性癫痫之一。这种疾病通常会导致终身癫痫和智力迟钝。虽然ACTH可以抑制40-60%的患儿痉挛，但目前还没有治疗这种疾病的方法可以改善长期预后。由于缺乏相关的动物模型，新疗法的发展受到严重阻碍。这里提出的研究是基于复制这种临床综合征的动物模型的创建。在这个模型中，幼鼠的新皮质局部注入钠通道拮抗剂河豚毒素（TTX），导致神经元活动的区域化封锁。在2周内，许多大鼠表现出频繁的痉挛，包括短暂的轴向肌肉屈曲或伸展，这与婴儿痉挛非常相似。在儿童中，这些事件经常发生在集群中，脑电图异常实际上与儿童中看到的相同。在痉挛期间，通常有一个普遍的高电压慢波，随后是一段明显的电压衰减（电衰减），叠加有更高频率的活动。使用快速数字采样，我们最近也发现了痉挛发作时开始的高频振荡（80-200赫兹）。在间隔期间，观察到高振幅慢波与频繁的多焦点尖峰混合的高振幅慢波。在这里提出的研究中，将使用患有这种综合征的动物的长期视频/脑电图记录来充分描述这种癫痫发作障碍的自然过程。我们将确定：1)痉挛首次出现的时间；2)持续多长时间；3)不同动物和特定动物的发作频率和聚集性的变化。我们还将测试大鼠的学习和记忆损伤，并评估ACTH抑制痉挛的能力。我们的短期目标是为未来的药物试验开发可靠的药物疗效结果测量和最省时、最具成本效益的方案。我们的长期目标是利用这种动物模型来筛选新的治疗方法，基于对这种毁灭性癫痫发作疾病的生物学基础的日益了解。

DESCRIPTION (provided by applicant): Infantile Spasms is one of the catastrophic epilepsies of early childhood. The disorder commonly leads to life- long epilepsy and mental retardation. At this time, there is no treatment for this disorder that improves long- term outcome, although ACTH can suppress the spasms in 40-60% of affected children. The development of new therapies has been severely hampered by the lack of a relevant animal model. Studies proposed here are based on the creation of an animal model that reproduces this clinical syndrome. In this model, the neocortex of infant rats is locally infused with the sodium channel antagonist, tetrodotoxin (TTX), which results in a regionalized blockade of neuronal activity. Within 2 weeks, many of these rats display frequent spasms that consist of brief flexions or extensions of axial musculature, which closely resemble infantile spasms. As in children, these events often occur in clusters EEG abnormalities are virtually identical to those seen in children. During a spasm, there is typically a generalized high voltage slow wave, followed by a period of marked voltage attenuation (electrodecrement) with superimposed higher frequency activity. Using rapid digital sampling we also have recently discovered high frequency oscillations (80-200 Hz) beginning at spasm onset. During the interictal period a hypsarrhythmic pattern is observed, consisting of high amplitude slow waves intermixed with frequent multifocal spikes. In the studies proposed here long term video/EEG recordings from animals with this syndrome will be used to fully characterize the natural course of this seizure disorder. We will determine: 1) when the spasms first appear 2) how long they persist and 3) variations in seizures frequency and clustering from animal to animal and from time to time in a given animal. We will also test rats for impairments in learning and memory and assess the ability of ACTH to suppress spasms. Our short-term goal is to develop reliable outcome measures of drug efficacy and the most time efficient and cost effective protocols for future drug trials. Our long-range goal is to use this animal model to screen new therapies based on a growing understanding of the biological basis of this devastating seizure disorder. PUBLIC HEALTH RELEVANCE: Infantile Spasms is one of the most severe epilepsies of early childhood for which there is no satisfactory treatment. Using a newly developed animal model of this disorder we plan to fully characterize the spasms in these animals and test the effectiveness of ACTH in suppressing these seizures. Our goal is to develop research and analytical protocols that can be used to test new generations of rational drug therapies for this devastating neurological disorder. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.