Infantile Spasms: Tools for Therapies

描述(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生癫痫和智力低下。尽管ACTH可以抑制40%-60%受影响儿童的痉挛，但目前还没有治疗这种疾病的方法来改善长期结果。由于缺乏相关的动物模型，新疗法的开发受到了严重阻碍。这里提出的研究是基于建立一个复制这种临床综合征的动物模型。在这个模型中，新生大鼠的大脑皮层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性阻断。在2周内，这些大鼠中的许多会表现出频繁的痉挛，包括短暂的轴向肌肉屈曲或伸展，这与婴儿痉挛非常相似。就像在儿童中一样，这些事件经常成群性地发生，脑电异常实际上与儿童中所见的相同。在痉挛期间，通常会有一个普遍的高压慢波，然后是一段明显的电压衰减(电减)，并叠加更高的频率活动。使用快速数字采样，我们最近也发现了开始于痉挛开始的高频振荡(80-200赫兹)。在发作间期观察到一种节律模式，由高幅度慢波和频繁的多灶性棘波混合组成。在这里提出的研究中，来自患有这种综合征的动物的长期视频/脑电记录将被用来充分描述这种癫痫障碍的自然过程。我们将确定：1)痉挛第一次出现的时间，2)持续多久，3)癫痫发作频率和聚集的变化，从动物到动物，以及在给定的动物中不时发生的变化。我们还将测试大鼠的学习和记忆障碍，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制定可靠的药物疗效结果衡量标准和最具时间效率和成本效益的方案。我们的长期目标是利用这种动物模型，在对这种毁灭性癫痫障碍的生物学基础日益了解的基础上，筛选新的治疗方法。 与公共卫生相关：婴儿痉挛是儿童早期最严重的癫痫之一，目前还没有令人满意的治疗方法。使用一种新开发的这种疾病的动物模型，我们计划完全描述这些动物的痉挛特征，并测试ACTH在抑制这些癫痫发作方面的有效性。我们的目标是开发研究和分析方案，可以用来测试这种破坏性神经疾病的新一代合理药物疗法。 免责声明：请注意，以下批评是由评审员在研究小组会议之前准备的，基本上是以未经编辑的形式提供的。虽然审查员有机会根据小组的讨论更新或修订其书面评价，但不能保证在会议讨论之后更新了个别批评意见。因此，这些评论可能不能完全反映个别评审员在小组讨论结束时的最终意见或小组的最终多数意见。因此，讨论纪要和总结是审查员在会议上实际上认为至关重要的最后结论。

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.