Treatment of Medical Conditions among Individuals with Autism Spectrum Disorders

自闭症谱系障碍的定义是社会沟通的缺陷和限制性和/或重复行为的存在。最近的流行病学研究记录了在过去十年中被确定患有自闭症谱系障碍（ASD）的儿童数量的增加，根据一些人的说法，目前的数字表明多达1%的儿童患有ASD。沟通和社会功能的终身障碍往往因存在医学共病而复杂化，包括癫痫（和癫痫样放电）、胃肠道紊乱和睡眠障碍。 对这些共病的病理生理学知之甚少，对自闭症患者的这些疾病的治疗更是知之甚少。 各种传统的医学和替代的生物医学方法已经被尝试过，并有传闻说对一个或几个人有用，但没有一个被证明是有效的，当受到严格的随机，安慰剂对照研究。 因此，确定自闭症的病因学，病理生理学和医学共病的治疗是一个重要的研究目标。 当乘以数百万报告受ASD影响的儿童时，潜在的公共卫生影响是巨大的。 ASD中的睡眠障碍是我们研究小组特别感兴趣的，并且可以使用多导睡眠图（PSG）进行可靠的研究，PSG是一种非侵入性记录各种睡眠参数的方法。 我们的另一个项目“自闭症和相关疾病的临床和行为表型分析”（NCT 00298246）的初步观察显示，与总睡眠时间相比，自闭症儿童在快速眼动（REM）睡眠阶段的时间异常短，并且REM睡眠的潜伏期延长。 快速眼动睡眠被认为在学习和记忆中起着关键作用，并且可能对学习和行为中的情感记忆的整合特别重要。虽然它与人类神经发育的关系尚不清楚，但动物研究表明，快速眼动睡眠在强化学习课程后会增加。 这些实验室发现为REM睡眠对中枢神经系统的健康发育很重要的假设奠定了基础，也可能是大脑可塑性的有用指标。 多奈哌齐是一种可逆的乙酰胆碱酯酶抑制剂，进行了一项小型开放标签的试点研究，以评估其增强2至11岁自闭症儿童和相对REM缺乏症（定义为低于2个标准偏差的观察到的年龄正常数据）的REM睡眠的能力。 该研究的主要目的是确定使REM睡眠量正常化所需的多奈哌齐的最小剂量。 多奈哌齐的副作用也是这项初步研究的兴趣，因为以前很少有儿科用药的经验。 这项研究的结果表明，每天2.5毫克的多奈哌齐足以显着增加REM睡眠到正常范围，作为自闭症儿童总睡眠的百分比。 该药物还显示出减少REM潜伏期。 这些初步数据为一项更大规模的安慰剂对照研究提供了支持，该研究刚刚启动，旨在通过使REM正常化来研究多奈哌齐在ASD治疗中的应用，目的是增加学习和可塑性的潜力（NCT 01887132）。该试验的招募正在进行中，基线PSG决定受试者是否随机接受多奈哌齐或安慰剂（如果存在REM睡眠缺陷）或接受开放标签的多奈哌齐（以检查多奈哌齐对没有REM睡眠缺陷的儿童的行为影响）。 此外，我们最近发表了一项关于用于评估临床人群睡眠结构异常的方法的研究。 虽然PSG是昂贵且耗时的检查，但它们可以产生关于特殊人群睡眠生理学的有价值的信息。我们比较了第一次和第二次夜间多导睡眠图（PSG）的结果，以测试自闭症儿童中所谓的第一夜效应。 这是第一个研究自闭症或其他发育障碍儿童睡眠参数夜间变化的研究之一。分析的目的是检查第一和第二个晚上的睡眠质量，从16名特征良好的ASD儿童中获得PSG。重要的是，我们的研究结果表明，在实验室中只需要一个晚上就可以检测到这一人群的睡眠结构异常。 这不仅可能节省大量成本，而且还提高了自闭症儿童睡眠研究的耐受性和可行性。

Autism spectrum disorders are defined by deficits of social-communication and the presence of restrictive and/or repetitive behaviors. Recent epidemiologic studies have documented an increase in the number of children identified with autism spectrum disorder (ASD) over the past decade and according to some, the current numbers indicate that as many as 1% of children have an ASD. The life-long impairments in communication and social function are often complicated by the presence of medical comorbidities, including epilepsy, (and epileptiform discharges), gastrointestinal disturbances and sleep disorders. Little is known about the pathophysiology of these comorbid conditions and even less about treatment of these disorders in autistic individuals. A variety of traditional medical and alternative biomedical approaches have been tried and anecdotally reported to be useful for one or a few individuals, but none has proven efficacious when subjected to rigorous randomized, placebo-controlled investigation. Thus, identifying the etiology, pathophysiology and treatment of the medical comorbidities of autism is an important goal for research. When multiplied by the millions of children reported to be affected by ASD, the potential public health impact is tremendous. Sleep disorders in ASD are of particular interest to our research group and can be reliably investigated using polysomnography (PSG), a non-invasive recording of a variety of sleep parameters. Preliminary observations from another of our projects, "Clinical and Behavioral Phenotyping of Autism and Related Disorders", (NCT00298246) revealed that children with autism spent an abnormally short time in the Rapid Eye Movement (REM) stage of sleep compared to total sleep time and had a prolonged latency to REM sleep. Rapid Eye Movement sleep is thought to play a key role in learning and memory and may be particularly important for the integration of emotional memories in learning and behavior. Although its relationship to human neurodevelopment is unknown, animal studies have shown that REM sleep increases after intensive learning sessions. These laboratory findings formed the basis for the hypothesis that REM sleep is important for the healthy development of the central nervous system and may also be a useful indicator of brain plasticity. A small open-label pilot study of donepezil, a reversible inhibitor of acetylcholinesterase, was undertaken to evaluate its ability to enhance REM sleep in 2 to 11 year-old children with autism and a relative REM deficiency(defined as below 2 standard deviations of observed normative data for age). The primary purpose of the study was to determine the minimum dosage of donepezil required to normalize the amount of REM sleep. The side-effects profile of donepezil was also of interest in this pilot study, as there has been little previous experience with pediatric administration of the drug. Results of this study showed that 2.5 mg per day of donepezil was sufficient to significantly increase REM sleep into the normal range, as a percentage of total sleep in children with autism. The drug was also shown to decrease REM latency. The pilot data provided support for a larger, placebo-controlled study which has just been launched to investigate the use of donepezil in the treatment of ASD, via normalizing REM with the goal of increasing the potential for learning and plasticity(NCT01887132). Enrollment in the trial is underway, with baseline PSG's determining whether subjects are randomized to receive either donepezil or placebo (if REM sleep deficits are present) or receive open-label donepezil (to examine behavioral effects of donepezil among children without REM sleep deficits). In addition, we recently published a study regarding the methodology used for evaluating sleep architecture abnormalities in clinical populations. Although PSGs are expensive and time consuming exams, they can yield valuable information regarding sleep physiology in special populations. We compared first and second night polysomnography (PSG) results in order to test the so-called first night effect among children with autism. This was one of the first studies to examine night-to-night variation of sleep parameters among children with autism or other developmental disorders. The goal of the analysis was to examine sleep quality on the first and second nights that PSGs were obtained from 16 well-characterized children with ASD. Importantly, our results suggest that only a single night in laboratory is needed to detect abnormalities of sleep architecture in this population. Not only is this a potentially large cost savings, but it also improves the tolerability and feasibility of the sleep studies for children with autism.