Treatment of Medical Conditions among Individuals with Autism Spectrum Disorders

自闭症谱系障碍的定义是沟通和社交障碍，以及限制性和/或重复行为的存在。最近的流行病学研究表明，在过去十年中，患有自闭症谱系障碍(ASD)的儿童数量有所增加，根据一些研究，目前的数字表明，多达1%的儿童患有自闭症谱系障碍。终生的沟通和社会功能障碍往往因医学并存而变得复杂，包括癫痫(和癫痫样放电)、胃肠功能障碍和睡眠障碍。人们对这些并存疾病的病理生理学知之甚少，对自闭症患者的治疗更是知之甚少。已经尝试了各种传统医学和替代生物医学方法，坊间报道对一个或几个人有用，但在进行随机、安慰剂对照研究时，没有一种方法被证明是有效的。因此，确定自闭症内科并发症的病因、病理生理学和治疗是一个重要的研究目标。再加上据报道受到自闭症影响的数百万儿童，潜在的公共卫生影响是巨大的。 ASD的睡眠障碍是我们研究小组特别感兴趣的，可以使用多导睡眠图(PSG)进行可靠的研究，PSG是一种对各种睡眠参数的非侵入性记录。我们的另一个项目“自闭症及相关疾病的临床和行为表型”(MH002868-03)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，并且进入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，一些假设认为记忆巩固主要发生在快速眼动睡眠期间。快速眼动睡眠对其他各种认知过程也是至关重要的，包括记忆系统中的情绪处理。尽管它与人类神经发育的关系尚不清楚，但动物研究表明，快速眼动睡眠在密集学习后会增加。这些实验室发现构成了假设的基础，即快速眼动睡眠对学习很重要，快速眼动睡眠也可能是大脑可塑性的有用指标。 盐酸多奈哌齐已被证明可以使年轻健康成年人、老年健康成年人和患有阿尔茨海默病的老年痴呆症成年人的REM睡眠正常化。此外，Mizuno等人的研究表明，在患有阿尔茨海默病的老年人中，认知能力的改善与SPT REM%的增加呈正相关。因此，多奈哌齐治疗不仅可以改善儿童的睡眠质量，而且还可以改善他们的学习和记忆能力，从而改善他们的整体行为健康和神经发育。 开展了一项盐酸多奈哌齐的小型开放标签试点研究，以评估其改善2至11岁自闭症儿童快速眼动睡眠的能力，这些儿童表现出低SPT REM%(定义为观察到的年龄标准数据的2个标准偏差以下)。这项研究的主要目的是确定使快速眼动睡眠正常化所需的多奈哌齐的最小剂量。在这项初步研究中，多奈哌齐的副作用情况也很有趣，因为以前在儿科给药方面几乎没有经验。这项研究的结果最近发表，显示每天2.5毫克的多奈哌齐足以显著增加自闭症儿童快速眼动睡眠占总睡眠的百分比。该药物还被证明可以缩短REM潜伏期。这一结果为一项更大规模的安慰剂对照研究提供了支持，以调查多奈哌齐在自闭症儿童睡眠问题治疗中的使用。该试验的另一个目标是评估多奈哌齐给药和快速眼动睡眠正常化对自闭症核心症状的影响，以及对儿童整体行为、发育和认知的影响。

Autism spectrum disorders are defined by deficits of communication and socialization 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 a 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", (MH002868-03) 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, with some hypothesizing that memory consolidation occurs primarily during REM sleep. REM sleep is also crucial to a variety of other cognitive processes, including the processing of emotion in the memory system. 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 learning and that REM sleep also may be a useful indicator of brain plasticity. Donepezil hydrochloride has been shown to normalize REM sleep in young healthy adults; in elderly healthy adults; and in elderly demented adults with Alzheimers disease. Furthermore, research by Mizuno et al showed a positive correlation between improved cognition and increased SPT REM % among elderly adults with Alzheimers disease. Thus, it is possible that donepezil treatment could produce benefits not only in the quality of the children's sleep, but also in their ability to learn and remember and consequently, in their overall behavioral health and neurodevelopment. A small open-label pilot study of donepezil hydrochloride was undertaken to evaluate its ability to enhance REM sleep in 2 to 11 year-old children with autism who exhibit a low SPT REM% (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 were recently published, showing 2.5 mg per day of donepezil was sufficient to significantly increase REM sleep as a percentage of total sleep in children with autism. The drug was also shown to decrease REM latency. The results provide support for a larger, placebo-controlled study to investigate the use of donepezil in the treatment of sleep problems in children with ASD. An additional goal of that trial will be to evaluate impact of donepezil administration and REM sleep normalization on the core symptoms of autism, and also on the children's overall behavior, development and cognition.