Sleep in Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder Kanwaljit Singh, MD, MPH, and Andrew W. Zimmerman, MD Sleep problems are common in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Sleep problems in these disorders may not only worsen daytime behaviors and core symptoms of ASD and ADHD but also contribute to parental stress levels. Therefore, the presence of sleep problems in ASD and ADHD requires prompt attention and management. This article is presented in 2 sections, one each for ASD and ADHD. First, a detailed literature review about the burden and prevalence of different types of sleep disorders is presented, followed by the pathophysiology and etiology of the sleep problems and evaluation and management of sleep disorders in ASD and ADHD. Semin Pediatr Neurol 22:113-125 C 2015 Elsevier Inc. All rights reserved.

Sleep Disorders in Autism Spectrum Disorder Autism spectrum disorder (ASD) is a group of neurodevelopmental disabilities characterized by persistent deficits manifesting in early development of social communication and social interaction, restricted and repetitive patterns of behavior interests or activities, and which are not better explained by intellectual disability or global developmental delay.1 Along with the presence of behavioral issues, ASD is frequently accompanied by a variety of sleep problems that can significantly add on to the disease burden and morbidity in not only the patients themselves but also their families. Sleep problems in children with ASD not only worsen daytime behaviors and core symptoms such as stereotypical and repetitive behavior2 but also increase parental and family stress levels.3 Recent Centers for Disease Control and Prevention reports4 indicate that the prevalence of ASD has increased dramatically in the past few decades; therefore it is not unreasonable to believe that the burden of sleep disorders has increased proportionally as well. This subsection of the literature review details the burden and types of sleep disorders in patients with ASD as well as the evaluation and treatment of sleep problems in this population. From the Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA. Address reprint requests to Andrew W. Zimmerman, MD, Department of Pediatrics, University of Massachusetts Medical School, 55 Lake Ave N S5-842, Worcester, MA 01655. E-mail: Andrew.Zimmerman@ umassmemorial.org

1071-9091/15/$-see front matter & 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.spen.2015.03.006

Prevalence and Types of Sleep Disorders in ASD Although the types of sleep problems that occur in children with ASD generally span the same spectrum of disorders that occur in typically developing children, children with ASD suffer from these problems at a higher rate. The prevalence of sleep disorders in typically developing children has been estimated to be approximately 25%-40%.5,6 Studies using parent surveys report a prevalence of sleep problems in ASD as high as 50%-80%.7-10 Children with ASD also have a higher prevalence of sleep disorders than children with other neurodevelopmental disabilities. Wiggs and Stores11 reported that, as compared with parents of children with developmental disabilities such as Down syndrome and cerebral palsy, parents of children with ASD described the presence of sleep disorders at a higher rate (68% vs 55% and 43%). Schreck and Mulick,12 in a study comparing age-matched groups of children with cognitive impairment and developmental disabilities, ASD, and pervasive developmental disorder—not otherwise specified, also found that parents with children with ASD reported sleep disorders at the highest rate. It is not clear whether there is a relationship between the prevalence of sleep problems in ASD and age. Much of the research evaluating sleep disorders in ASD has been cross-sectional rather than longitudinal, which makes it difficult to accurately assess the temporal progression of sleep disorders in ASD. Although on one hand a large retrospectivelongitudinal study found no relationship of sleep disorders with developmental stages in ASD,13 another longitudinal 113

114 study14 with a short follow-up of 1 year and a few other cross-sectional studies did find that sleep difficulties tended to decrease with age.15-17 The evidence linking the increased prevalence of sleep problems with severity of cognitive and intellectual disability is also not consistent, with different studies reporting conflicting data. Richdale and Prior18 found that lower functioning children with ASD (those with intelligence quotient o55) had higher chances of increased sleep latency, shortened total sleep time, and early termination of sleep as compared with higher functioning (intelligence quotient 455) children with ASD. Gail Williams et al19 reported increased nighttime awakenings in children with ASD along with mental retardation as compared with children with ASD but without mental retardation. In contrast, several more studies have found the presence of sleep problems in patients with ASD regardless of their level of cognitive impairment.13,20-22 In addition, it has been shown that lack of adequate sleep is associated with increased severity of ASD symptoms such as stereotypical behaviors, impaired social connectivity, increased aggressiveness, and self-injurious behavior.2,7,23,24 The types of sleep disorders in ASD can be broadly classified into insomnias, parasomnias, sleep-related breathing disorders (SRBDs), and sleep-related movement disorders. Sleep-onset insomnia (SOI) or difficulty initiating sleep (increased sleep latency or time to fall asleep) and sleepmaintenance insomnia (decreased sleep duration, decreased sleep continuity, and increased and early awakenings) are among the most common sleep problems reported in ASD. Many parents’ or caregivers’ studies confirm this. Richdale and Prior18 reported that children with ASD had long sleep latencies, frequent nighttime awakenings, and shortened total sleep time. Couturier et al21 compared 23 pairs of age- and gender-matched ASD and control cases and found that patients with ASD had higher prevalence of sleep onset, sleep duration, and sleep anxiety problems. In ASD, SOI appears to be more common as compared with sleep maintenance insomnia. Gail Williams et al19 in a survey on 500 children with ASD found that although difficulty falling asleep, restlessness during sleep, inability to fall asleep in own bed, and frequent nighttime awakenings were common, problems with sleep onset were by far the most frequently reported complaint (53%). Sleepwalking, morning headaches, crying during sleep, and nightmares or night terrors were least common.19 Krakowiak et al22 in a study of 303 ASD and 163 typically developing children also reported that sleep onset problems were more prevalent (as high as 51%) as compared with sleep maintenance problems such as nighttime awakenings (10%) in the ASD group as compared with typically developing children. Several studies using noninvasive modalities such as actigraphy have confirmed the sleep questionnaire findings that insomnia, specifically sleep-onset insomnia, is the most prevalent in ASD.25,26 There are not many studies using polysomnography (PSG) that have been conducted for evaluating sleep disorders in ASD. The few that have been conducted confirm and validate the questionnaire and actigraphy findings of prolonged sleep latency and

K. Singh and A.W. Zimmerman decreased sleep efficiency,27 as well as reduced time in bed, total sleep time, sleep period time, and rapid eye movement (REM) latency.28 Although they are not as common as sleep onset or sleep maintenance insomnias, parasomnias consisting of non-REM (NREM) and REM sleep-related disorders have been described in ASD. A few studies have reported the occurrence of NREM arousal conditions such as sleepwalking and night terrors in deeper or slow-wave NREM sleep stages more often than in controls. Patzold et al20 compared 31 ASD and 36 typically developing children and found that although nighttime arousals did not differ significantly between the 2 groups, the children with ASD, when awakened, stayed awake for a longer period of time and were more likely to experience nightmares (13% vs 11%), nocturnal enuresis (10% vs 3%), and were more likely to indulge in unusual and disruptive behaviors such as muttering to self, grunting, laughing, and head banging. Schreck and Mulick12 also compared a group of 55 patients with ASD with 49 typically developing children and found that the ASD group experienced more nightmare behaviors such as screaming, sleepwalking, and acting out their dreams. Limoges et al29 performed PSGs on 16 pairs of adolescent or adult ASD and reference controls and found that patients with ASD had more frequent nocturnal awakenings combined with decreased NREM (stages 2-4) sleep and decreased slow-wave sleep. Ming et al30 performed sleep questionnaires and 2-night PSGs in a group of 23 age-matched ASD and control children pairs, and found that children with ASD had a much higher likelihood of experiencing NREM parasomnias (14 of 23) as compared with the control group children (3 of 23). These findings correlated remarkably well with questionnaire findings, which reported that 16 patients with ASD had NREM parasomnias such as sleep terrors, confusional arousals, sleepwalking, bruxism, and enuresis.30 In an earlier study, Richdale and Prior18 did not find an overall increased occurrence of nighttime arousals and nightmares in ASD; rather they reported that typically developing children were more likely to experience these episodes. A few studies evaluating sleep architecture in ASD have found an increased occurrence of REM-associated sleep disturbances in ASD. Buckley et al31 performed PSG in 60 children with autism, 15 typically developing and 13 with developmental delay, which revealed that children with ASD had a shorter total sleep time, greater slow-wave sleep percentage, and a smaller REM sleep percentage. The study by Limoges et al29 mentioned before also had fewer REMs during the REM sleep stages. The study by Ming et al30 cited earlier also reported impaired REM architecture whereby the children with ASD experienced increased spontaneous arousals, had prolonged REM latency, and a reduced REM percentage as compared with the control group. Very rarely, REM sleep behavior disorder (RBD) can also occur where the subjects may act on their dreams. Thirumalai et al32 performed nocturnal PSGs on 11 children with ASD who had symptoms of disturbed sleep and nocturnal awakenings, and reported RBD in 45% of them. This finding

Sleep in ASD and ADHD however has not been substantiated in subsequent studies, which excluded ASD subjects on psychotropic medications and did not find the occurrence of REM RBD.27,29 SRBDs such as obstructive sleep apnea (OSA) may also occur in ASD. The prevalence of SRBDs in the general pediatric population has been estimated to be approximately 1%-11%33,34 and is greatly increased in conditions such as obesity.35 There is at least 1 study that showed that the prevalence of SRBDs may be higher in ASD. Youssef et al36 described the presence of OSA in 34% of the study sample of 53 children with ASD. The risk factors for SRBD are the same in children with ASD as in typically developing children, for example, obesity, craniofacial abnormalities, abnormalities of muscle tone, the point being that ASD per se does not increase the risk of SRBD. SRBDs in children with ASD may often lead to adverse daytime behavior and possibly worsened core ASD symptoms37; however, at the same time adverse daytime behaviors are noted in typically developing children with SRBDs too.38 Indeed, treatment of sleep apnea in a case of ASD was found to improve daytime behaviors (sleep, social communication, inattention, repetitive behaviors, and hypersensitivity).39 Similar improvements in daytime behavior and inattention have been described in typically developing children after treatment of their SRBD.38 Sleep-related movement disorders such as restless legs syndrome (RLS), periodic limb movements in sleep (PLMS), periodic limb movement disorder (PLMD), and rhythmical movement disorder may occur in ASD.40 RLS is a condition characterized by an involuntary urge to move the legs. RLS may occur at any time but is more common at bedtime, is worse during rest, and relieved by movement. PLMS are repetitive stereotypic limb movements during sleep. PLMD is characterized by repetitive stereotypic movements and is accompanied by insomnia and daytime sleepiness.41 Rhythmic movement disorder is characterized by involuntary, repetitive movements of body parts such as the head, trunk, and limbs that occurs immediately before and during sleep. It most often involves the head and neck and is manifested by head banging.42 RLS causes SOI, but does not by itself disrupt sleep. PLMD disrupts sleep as the PLMs cause arousals. There are no physical symptoms while awake in PLMD, except that it may cause excessive daytime sleepiness. PLMD is diagnosed by PSG. RLS is mainly diagnosed by history. Diagnoses of these conditions such as RLS and PLMS pose special challenges in ASD because of communication and language deficits in children with ASD and because it is very difficult to perform PSG in these children owing to anxiety and sensory sensitivities.41

Pathophysiology and Causes of Sleep Disorders in ASD The causes of sleep disturbances in ASD are many, and they range from genetic mutations and disrupted neurotransmitters to medical and psychiatric comorbidities and nutritional deficiencies. Abnormal expressions of several neurotransmitters, such as serotonin, melatonin, and gamma-aminobutyric

115 acid (GABA), have been described in ASD and these neurotransmitters also play vital roles in maintenance of sleep-wake cycles. Melatonin and its metabolites are necessary for promoting sleep and some studies have described reduced melatonin levels in ASD.43 Nir et al44 found abnormal circadian patterns and reduced serum levels of melatonin in a group of young adults with severe autism. Kulman et al45 documented significantly lower serum melatonin levels in 14 children with ASD as compared with 20 age-matched controls. Tordjman et al46 compared nocturnal urinary excretion of 6-sulphatoxymelatonin (a metabolite of melatonin) in 49 ASD and 88 age-matched controls and found a significantly lower urinary excretion rate of 6-sulphatoxymelatonin in children with ASD as compared with controls. Genetic mutations in melatonin-regulating pathways have also been described. Melke et al47 discovered polymorphisms in genes regulating acetylserotonin-O-methyltransferase (ASMT) and lower levels of ASMT activity in a group of 250 children with ASD as compared with 255 reference controls. Cai et al48 also reported higher rates of partial duplication of the ASMT gene in a group of 279 subjects with ASD as compared with 248 reference controls. Jonsson et al49 identified mutations in regulatory regions of ASMT, melatonin receptor 1A, and melatonin receptor 1B in 109 patients with ASD. However, a larger study by Toma et al50 did not find any differences in ASMT gene activity in 390 ASD cases and 490 reference controls. Melatonin is produced from serotonin, and thus altered serotonin synthesis can lead to abnormal melatonin blood levels. Some studies have described abnormal platelet serotonin levels in ASD. Connors et al51 measured plasma serotonin in 17 children with ASD and their families and discovered it was lower in mothers as well as children with ASD compared with their typical siblings and fathers, in contrast to those in control families. Cook et al52 described reduced serotonin synaptic functional activity in autism. GABA is the primary inhibitory neurotransmitter in the central nervous system and activation of GABA A receptors is necessary for maintenance of sleep-wake cycles.53 Nelson et al54 have described a disruption of GABA interneurons as manifested by increased peripheral expression of brainderived neurotrophic factor in 69 children with ASD, as compared with 54 reference controls. A mutation in chromosome 15q that contains GABA genes has also been identified.55 The mutation may result in disruption of GABA-related inhibitory functions and thereby contribute to the sleep disorders in ASD. Several co-occurring medical comorbidities in ASD may also interfere with sleep. Medical conditions such as epilepsy, gastrointestinal disorders (eg, gastric reflux and constipation), and psychiatric comorbidities as well as core behavioral problems in ASD such as depression, anxiety, stereotypic or repetitive and obsessive behavior, environmental hypersensitivity, and emotional dysregulation can interfere with sleep continuity and result in a vicious feedback loop whereby these conditions can worsen insomnia and are in turn worsened by insomnia.40 Adding to that, their typical language and communication deficits can make

116 it difficult for patients with ASD to communicate some of these issues that cause pain and discomfort. Furthermore, medications commonly used to treat seizures (such as lamotrigine and barbiturates) and psychotropic medications (such as methylphenidate, risperidone, and SSRIs) can disrupt sleep.56 In addition, typical behaviors intrinsic to ASD (such as sensitivity to environmental stimuli and daytime behavioral problems) may themselves lead to sleep problems. Potential causes of insomnia in ASD also include nutritional deficiencies. These are often a manifestation of personal food preferences related to restricted diet, food phobias, and atypical mealtime rituals and behaviors.57 Some studies have reported that as many as 50%-70% of children with ASD may have problems with feeding behaviors.58-60 These behaviors may lead to nutritional deficiencies such as iron deficiency. RLS and PLMD have been shown to be associated with low serum ferritin levels.36,61 Several studies have demonstrated that correction of iron deficiency in ASD may lead to an improvement of RLS and PLMD.41,62-64

Evaluation and Management of Sleep Disorders in ASD The first step in evaluation of sleep disorders in ASD, as in any other condition, is to obtain a thorough medical, psychiatric, sleep, and family history. The sleep history in particular should include detailed information on sleeping habits, such as bedtime, waking time, any pattern of daytime sleepiness, and ability to maintain sleep during the night. It is also important to assess behaviors associated with ASD, especially as nighttime insomnia and daytime sleepiness may manifest as hyperactivity and increased core ASD behaviors. Standardized rating scales to assess behavior, such as the Aberrant Behavior Checklist,65 and questionnaires such as the Children’s Sleep Habits Questionnaire66 and Family Inventory of Sleep Habits67 may provide vital information on repetitive or stereotypical behavior, aggressiveness, selfinjurious behaviors, anxiety, and hyperactivity, as well as providing objective and easily quantified measures of sleep, bedtime routines, and sleep environment. A psychiatric consultation should be obtained if there is a suspicion of a coexisting disorder such as anxiety or depression that may also affect sleep. Family history should be obtained for insomnia or psychopathology such as maternal depression or bipolar disorder, which may help elucidate the child’s sleep problem. Two investigative modalities are available to evaluate risk factors for primary sleep disorders such as SRBD, RLS or PLMS, or epilepsy: PSG and actigraphy. PSG is a multiparametric test that involves comprehensive recording of physiological changes occurring during sleep, and monitors brain activity (electroencephalography), eye movements (electrooculography), skeletal muscle activity (electromyography), and heart rate and rhythm (electrocardiogram). Nasal and oral airflows are measured using pressure transducers along with respiratory effort using belts. Blood

K. Singh and A.W. Zimmerman oxygenation is evaluated using pulse oximetry. PSG is clinically useful to identify if there is anything that is disturbing sleep, such as SRBD or OSA and PLMD. PSG in conjunction with multiple sleep latency test (MSLT) can be used to diagnose the presence of hypersomnia and narcolepsy. PSG cannot by itself rule out parasomnias, and in fact is not usually done for establishing or ruling out a parasomnia, as with circadian disorders. It may however be done to find out if another sleep disorder such as SRBD or PLMD is driving a parasomnia. Although PSG is very reliable, its use may be problematic and challenging for children with ASD owing to tactile sensitivity and anxiety in patients with ASD. “Mock” PSG sessions may help in desensitization and improve their tolerance and chances for safe completion of the procedure. Actigraphy is performed in the home environment, evaluates sleep patterns based on limb movements, and is useful in insomnia. Because of at-home implementation, it is also helpful in cases in which the child has a high degree of anxiety or sensory sensitivities. However, it is important to recognize that PSG and actigraphy cannot be used interchangeably. That is, actigraphy is not an alternative to a PSG. Indications for each are different. Actigraphy is generally done for several days (2-4 weeks) to get a more objective idea of sleep-wake pattern (than from the history). It is used mainly for Delayed Sleep Phase Syndrome, and, in some instances for insomnia—particularly if a good history is not available or reliable.

Management of Sleep Problems in ASD Treatment of sleep disorders in ASD is multifactorial. Medical conditions should be evaluated and treated along with sleep disorders. Confirming the presence of primary sleep disorders will ensure that the conditions that are treatable (such as OSA) are identified and treated. As described earlier, if a diagnosis of PLMS or RLS is found and subsequent laboratory tests show low ferritin levels, correction of iron deficiency in ASD may lead to an improvement of RLS and PLMS symptoms.41,63,64 If no primary treatable causes are found, the treatment of insomnia is based on a combination of ensuring good sleep hygiene and environment and behavioral interventions. Pharmacologic therapy using melatonin or other drugs such as clonidine should be considered, either in conjunction with behavioral interventions or if the behavioral measures have limited effects.

Sleep Hygiene and Behavioral Interventions Sleep education and good sleep hygiene along with behavioral interventions are the cornerstones of successful management of sleep problems in ASD. Behavioral interventions that involve parents in treating sleep problems in children with ASD are not only helpful in alleviating sleep problems themselves but also improve parental stress levels and their ability to cope with their child’s sleep problems.68 Reed et al67 conducted a study involving parent-based behavioral

Sleep in ASD and ADHD interventions and sleep educational workshops on insomnia in parents of 20 children with ASD who had chronic sleep problems. These workshops involved teaching parents about how to establish effective daytime and bedtime routines and habits, and optimize parental interactions during bedtime and nighttime awakenings. At the end of 2 weeks, significant improvements in both subjective (parent-reported Children’s Sleep Habit Questionnaire scores) as well as objective (improved sleep latency) measures of sleep health were reported.67 Moon et al69 assessed the effectiveness of a distance-based approach using telephone contact and providing a treatment handbook for parents of children with ASD and demonstrated a long-lasting improvement in their children’s sleep onset latency. Good sleep hygiene involves not only bedtime routines but also habits during the daytime and evening routines, and ensuring optimal sleeping environment. Limiting daytime naps and caffeine intake, exercise during the day, and decreasing visual stimulation (especially electronics such as television) during the evening hours all help promote good nighttime sleep habits. Limiting exposure to television and video screens during the evening hours is especially important. Salti et al70 found that daily exposure to television screens for 1 week in children 6-13 years of age leads to a decrease in urinary excretion of melatonin metabolites. Gooley et al (2011) found that exposure to room light before bedtime suppressed melatonin secretion duration by approximately 90 minutes and a reduction of presleep melatonin levels by 71.4%.43 Ensuring that the sleeping location is without any unnecessary extraneous lights and distracting noises will help promote good sleep hygiene. Some children may benefit from using a machine that generates “white-noise” which will help buffer distracting noises that interrupt sleep.40 Many children with ASD, on the contrary, may be hypersensitive to background noises; thus ensuring an optimal sleep environment may require some degree of individualization. In addition to light and sound sensitivity, some children with ASD have tactile sensitivity. It has been suggested that weighted blankets may provide a consistent sensory input, help calm the child, and ensure uninterrupted sleep.71 However, a recent phase 3, randomized, placebo-controlled, crossover trial of weighted blankets in 73 children with ASD failed to demonstrate any significant benefits as measured by actigraphy (such as increased total sleep time or improved behavioral outcomes).72 Ensuring a consistent bedtime routine with as little nightto-night variability as possible is very important. Once established, children with ASD respond well to these bedtime routines.73 They should consist of simple bedtime tasks and activities that are performed daily and help with supporting circadian rhythms by serving as time cues. A visual reminder of the bedtime routines is helpful in reinforcing the routines. A “photo-story” consisting of the steps involved in the routines can help and children follow the story as told by the pictures.40 A pictorial representation of other children following the bedtime

117 routines may help provide an “example” to follow and help caretakers to communicate the expectation for sleep to the children. For those children with ASD who are higher functioning and have bedtime resistance (as manifested by crying, calling out, or leaving their rooms at bedtime), positive reinforcement behavioral modifications such as the Bedtime Pass Program can be helpful.74,75 This program has been shown to be helpful in greatly reducing bedtime resistance—at least in typically developing children, and consists of requiring children to go to bed, providing them with a card exchangeable for 1 trip out of the room or a parental visit. The Autism Treatment Network recommends that this Pass Program may help children with ASD too (ATN/AIR-P Sleep Quick Tips).76 For those children who have trouble falling asleep (SOI), an approach involving initially moving the bedtime hour to later in the night (the bedtime fading approach) as well as restricting the sleep hours may be helpful. Once the child is trained to fall asleep quickly the time-to-bed may be gradually moved up and sleep hours gradually increased.40 Another approach that has been considered very helpful —at least in typically developing children, is a “systematic ignoring” approach which, in its most extreme form (unmodified extinction, or “crying it out” approach) involves putting the child to bed at a designated bedtime and then ignoring the child until a set point the next morning. However, this approach can be understandably distressing to the parents. An alternative “graduated extinction” approach involves gradually weaning the child from the parent being present in the room with the child on a chair until the child falls asleep, and then very gradually moving the chair further out toward the door on successive nights until the child is able to gradually learn to fall asleep alone.77 The effectiveness of these approaches in children with ASD requires further study.

Pharmacologic Interventions As described earlier, behavioral intervention and promotion of sleep hygiene are generally the first steps toward treating sleep disorders in ASD. Even though there are no medications approved by the United States Food and Drug Administration specifically for treating insomnia in children, melatonin is frequently used in conjunction with behavioral intervention with variable degrees of success. Synthetic melatonin is available over the counter in both regular (short-acting) and long-acting forms. Several short-term studies have suggested that melatonin is generally efficacious and reasonably well tolerated. Rossignol and Frye78 conducted a metaanalysis combining the data (comprising 57 patients) on 5 randomized, double-blind placebo-controlled trials of melatonin in ASD and found that as compared with placebo, treatment with melatonin (treatment duration of 14 days to 6 months) resulted in an increased sleep duration by 73 minutes and decreased sleep latency by 66 minutes. Andersen et al79 treated 108 children with ASD using melatonin (dose: 0.75-6 mg) and reported significant

118 improvements in sleep latency, which were mostly maintained until the 12-month follow-up visits. The most common side effects, although rare, were parental reports of morning sleepiness and increased enuresis.79 A few studies have reported a possible increase in seizure activity by melatonin.80,81 However, in another review, Jain and Besag82 analyzed 27 studies on the use of melatonin and found no significant overall increase in seizure activity in most studies, and those that did report an increase in seizure activity had patients with preexisting uncontrolled seizures. In clinical practice to treat sleep-onset insomnia, melatonin is generally prescribed with doses starting at 1 mg approximately 30 minutes before the intended bedtime. Doses may be raised up to as high as 3 mg depending upon clinical efficacy. Very rarely high doses of 6 mg or more may be prescribed. Lower doses of melatonin may be used to advance the timing of sleep onset. In this situation the dose is administered 3-4 hours before bedtime. Long-term administration is needed to maintain the sleep pattern even after the clinical effective dosage has been reached and sleep pattern stabilized. Melatonin has a short half-life of approximately 20-50 minutes. Therefore mostly the regular release preparations have been used and are efficacious for sleeponset insomnia. Its efficacy for sleep maintenance insomnia is less clear. Extended release preparations can be used in these cases but are not available in liquid form. There is very limited evidence with respect to other medications to treat sleep disorders in ASD. Although Owens et al83 performed a survey of child and adolescent psychiatrists on the use of drugs such as clonidine, antidepressants, and atypical antipsychotics for treatment of insomnia in their practices, the data on these drugs in ASD are very limited. Ming et al84 performed an open-label study on the use of clonidine in children with ASD and reported its efficacy in reducing sleep latency and nighttime awakenings in the majority of 19 children in the study. The use of other medications such as antidepressants or atypical antipsychotics is usually based on the presence of other coexisting neurologic or psychiatric conditions in ASD. For example, risperidone may be used in patients with ASD who have coexisting aberrant behaviors such as irritability and aggressiveness.

Sleep Disorders in Attention Deficit Hyperactivity Disorder Attention deficit hyperactivity disorder (ADHD) is a chronic condition marked by persistent inattention, varying degrees of hyperactivity, and sometimes impulsivity. Like autism, many studies have shown a high prevalence of sleep disorders in ADHD. As many as 25%-50% of children and more than 50% of adults with ADHD have been reported to experience sleep problems.85-87 Similar to ASD, sleep disturbances in ADHD may affect cognitive and physical function that can worsen ADHD symptoms.88,89 However, unlike autism, the evidence in ADHD is rather inconsistent, with a significant discrepancy between the studies using

K. Singh and A.W. Zimmerman subjective parent questionnaires and studies using objective measures (such as PSG and actigraphy), the latter reporting different types of sleep disorders in ADHD. In addition, there is also a question of whether sleep disorders in ADHD are intrinsic to the disorder or whether they are because of comorbid sleep disorders, or even if in some cases, sleep disorders lead to ADHD-type symptoms. This subsection of the literature review details the burden and types of sleep disorders in patients with ADHD as well as the evaluation and treatment of the sleep problems in this population.

Types of Sleep Disorders in ADHD Studies Using Parent Questionnaires Several studies using parent questionnaires have consistently reported sleep problems in ADHD, with the most frequent problems reported being SOI, increased nighttime awakenings, snoring, parasomnias and nightmares, short total sleep time, and subsequent daytime sleepiness. Ball et al90 in a comparison of 102 children with ADHD and 78 control children found that parents of children with ADHD more frequently reported the presence of sleep problems (difficulty initiating sleep, waking up at night, insisting on keeping a light on during sleep, frequent nightmares, and subsequent daytime fatigue and sleepiness) than the parents of control children. Chervin et al91 compared 27 children with ADHD and 43 non-ADHD psychiatric controls and found that patients with ADHD reported more habitual snoring than the control group participants. Marcotte et al examined 43 children with ADHD and compared them to 86 reference controls for the presence of sleep and breathing problems, sleepiness, and behavioral problems, using a custom-developed research questionnaire. They found that the ADHD group had worse scores on the sleep and breathing problems scale and sleepiness scale—indicating that children with ADHD were more likely to have severe sleep and breathing problems.92 Ring et al compared 13 children with ADHD with their 16 healthy siblings and found that children with ADHD had higher rates of SOI and frequent nighttime awakenings, as well as presence of nocturnal enuresis and sleepwalking. Notably, the mean total sleep time did not differ between children with ADHD and controls.93 Owens et al94 compared 46 ADHD and reference control pairs and found that children with ADHD had increased rates of SOI, nighttime awakenings, parasomnias, decreased total sleep time, and increased daytime sleepiness. Stein et al95 administered a sleep questionnaire inquiring about the presence of insomnia, restless sleep, hypersomnia, morning and daytime fatigue, headaches following awakening, snoring, and the use of hypnotics in 17 adolescents with ADHD on medication, 18 adolescents with ADHD not on medication, and 46 reference controls, and found that although nonmedicated participants with ADHD and controls did not differ in the presence or severity of sleep disturbances, the medicated participants with ADHD had worse scores on the majority of the questionnaire domains, indicating a higher prevalence and increased severity

Sleep in ASD and ADHD of sleep disturbances. LeBourgeois et al96 compared 45 children with ADHD and 29 reference controls for the presence of sleep disturbances, and found that children with ADHD had a higher rate of daytime sleepiness, poor sleep quality, SOI, and trouble waking up in the morning. ShurFen Gau97 investigated the 6-month prevalence rates of sleep-related problems and their association with daytime napping, inattention, hyperactivity, impulsivity, and oppositional symptoms in a school-based sample of 2463 children. They reported that parasomnias, dyssomnias, sleepdisordered breathing problems, daytime inadvertent napping, and abnormal sleep schedules were related to ADHDrelated symptoms as assessed by mothers’ and teachers’ ratings.97 Lim et al98 compared 101 children with ADHD and 60 controls and found a reduced total sleep time in the ADHD group compared with reference controls. Sung et al99 reported that in a group of 239 children with ADHD, 30% had mild sleep problems and 45% of them had moderate to severe sleep problems such as SOI, nighttime awakenings, restlessness during sleep, and daytime fatigue. Hvolby et al100 in a comparison of 45 participants with ADHD and 276 controls found that children with ADHD had increased bedtime resistance, increased sleep-onset latency, sleep-talking, bruxism, nightmares, and difficulty waking up in the morning as compared with healthy controls. Finally, Li et al,101 in a large study of 853 participants with ADHD and 19,299 control participants, reported that after controlling for age, gender, and medication status, a history of ADHD was associated with SOI, sleep anxiety, nighttime awakenings, parasomnias, sleep-disordered breathing, and daytime sleepiness.

Studies Using Objective Modalities In contrast to studies using questionnaires, which more or less consistently reported the presence of similar types of sleep disturbances in ADHD, studies using objective methods such as PSG or actigraphy have found more variable findings. Some studies have identified increased sleep-onset latency. Hvolby et al85 performed actigraphy in 45 children with ADHD, 64 psychiatric controls, and 97 healthy controls, and concluded that children with ADHD had significantly longer sleep latencies (26.3 minutes vs o19 minutes in the control group). Van der Heijden et al102 performed actigraphy on 87 children with ADHD with SOI and 33 children with ADHD without SOI, and found that the ADHD with SOI group had, not surprisingly, significantly longer sleep onset latency. Some studies have also demonstrated daytime sleepiness. Palm et al103 in a small 2-night PSG study of 10 children with deficits in attention, motor control, and perception (DAMP) and 18 reference controls reported that some children with DAMP had decreased sleep onset latency in the MSLT, indicating daytime sleepiness. Golan et al104 performed 1-night PSG on 34 ADHD and 32 control participants and found that the ADHD group had symptoms suggestive of daytime sleepiness.

119 Increased REM sleep latency has been described in a few studies. The study by Palm et al103 cited earlier described an increase in REM sleep latency on the second night of the PSG in patients with DAMP. Busby et al105 performed a 5-night PSG in 11 hyperkinetic children and 11 controls and identified an increased REM latency in the hyperkinetic group. O’Brien et al106 performed 1-night PSGs in 71 children with ADHD and 39 controls and reported that children with ADHD had an increased REM sleep latency as compared with reference controls. O’Brien et al,107 in another 1-night PSG study on 100 children with ADHD and 49 reference controls, obtained similar findings of increased sleep latency in children with ADHD. Silvestri et al108 performed 1-night PSGs on 55 children with ADHD and 20 controls and concluded that as compared with controls, children with ADHD had an increased REM sleep latency. There are significant discrepancies among studies as to whether ADHD has an increased or decreased REM sleep percentage. For instance, both of the O’Brien106,107 studies mentioned earlier found a decreased REM sleep percentage in ADHD as compared with controls. Gruber et al109 performed 1-night PSG on 15 ADHD and 23 controls and also described a decrease in REM percentage in the ADHD group. The study by Silvestri et al108 mentioned earlier also demonstrated that the ADHD group had a decreased REM sleep percentage. The study by Golan et al104 mentioned earlier on the contrary reported an increased REM sleep percentage. Kirov et al110 performed 2-night PSGs on 17 ADHD and 20 controls and also found an increased total REM percentage. Confusion also exists regarding the total sleep time in ADHD as reported in studies using PSG. For example, the study by Kirov et al110 mentioned earlier identified an increase in total sleep time in ADHD. On the contrary, Miano et al111 compared 20 pairs of ADHD and control participants in a 2-night PSG study and found a decrease in total sleep time. The study by Gruber et al109 mentioned earlier also described a decrease in total sleep time in ADHD. Owens et al112 performed a 5-night actigraphy study on 107 children with ADHD and 46 controls and found that the ADHD group had a decreased real sleep time, which was attributed to more interruptions during sleep. The study by Silvestri et al108 mentioned earlier also demonstrated a decrease in total sleep time in the ADHD group. There are at least a few studies using actigraphy and PSG that reported no sleep abnormalities in ADHD. Corkum et al113 performed a 7-night actigraphy on 25 pairs of ADHD and control participants and concluded that the actigraphy itself showed no differences between ADHD and controls, although parents described increased sleep duration, latency, restless sleep, and difficulty getting up in the morning. Wiggs et al114 had similar findings; they performed a 5-night actigraphy study on 42 ADHD and 21 control participants, and found that, although parents reported some sleep disturbances (earlier sleep onset time and increased latency), there were no significant differences in actigraphies. Crabtree et al115 studied 1-night PSGs on 97 ADHD participants and found that only a small percentage

120 had abnormalities on PSG (6%-7% had sleep-disordered breathing and sleep fragmentation). Sangal et al116 performed 1-night PSG on 40 ADHD participants and identified no sleep abnormalities. Interestingly though, as both of these studies (Crabtree et al and Sangal et al) did not have a control group, their findings are likely not readily comparable. A few more studies using PSG or actigraphy in ADHD have described night-to-night variability in the sleep architecture. Gruber et al87 performed 5-night actigraphy on 38 children with ADHD and 64 controls, and although they found no significant differences in sleep onset latency or total sleep time between ADHD and controls, the standard deviations of these variables were significantly different between the 2 groups. Gruber and Sadeh,117 in yet another 5-night actigraphy study on 24 ADHD and 25 control participants, again reported a similar night-to-night variability in sleep onset time, total sleep time, and true sleep time in the ADHD group. The fact that there is such a wide discrepancy in the types of sleep disturbances reported in the studies using objective methodologies and the way they differed from subjective parent-reported symptoms may be partly due to differences in research methodology. Different investigators used different methods, for example, actigraphy vs PSG. There also are differences in the duration of follow-up: some studies employed 1-night PSG, others used 2-night PSGs; there are similar differences in the nights that were employed for actigraphy. Some researchers have suggested that the discrepancy between studies using parent reports and those using objective methodologies might be due to parents of children with ADHD being more likely to report a pattern of disturbed sleep in their child, which may not be substantiated by objective measures.106 The diversity of reports may also reveal the complexity of ADHD, where a patient who presents with, for example, ADHD and increased REM sleep, has a type of ADHD that is different from a patient who has ADHD and decreased REM sleep.118 Therefore, the characteristics of ADHD and sleep used to define study subjects may account for variable outcomes among the studies. Primary Sleep Disorders Causing ADHD-like Symptoms There are at least a few studies which have described ADHD-like symptoms occurring in primary sleep disorders. Although it is not known for sure if primary sleep disorders are causative of ADHD or not, sleep fragmentation and sleep deprivation in these disorders may lead to excessive daytime sleepiness, which interferes with attentiveness, mood, memory, and learning processes.118 Osterloo et al119 compared 74 adults with hypersomnia and 61 adults with ADHD to assess possible diagnostic confusion between excessive daytime sleepiness and ADHD in adults. All patients completed the Epworth Sleepiness Scale. The investigators found that as many as 19% of patients with hypersomnia fulfilled the Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorder (DSM-IV) criteria of ADHD.119 Some studies have reported the occurrence of ADHD symptoms in RLS and PLMS. Picchietti and Walters120

K. Singh and A.W. Zimmerman conducted a retrospective review of 129 children and adolescents with PLMS, and they found that 93% of children with moderate to severe PLMS had ADHD symptoms and met the DSM-IV ADHD criteria. Chervin et al,121 in a large study of 866 children enrolled from community based general pediatrics clinics, demonstrated a relatively high correlation between positive hyperactivity index (HI) scores and restless legs as measured by a validated PLMS questionnaire. Gaultney et al122 administered a Pediatric Sleep Questionnaire to the parents of 283 children and also found a strong correlation between symptoms of PLMS and ADHD. Wagner et al123 evaluated the occurrence of ADHD symptoms in 62 adults with RLS, 32 adults with insomnia, and 77 adult controls, and concluded that as compared with patients with insomnia and adult controls, a significantly greater percentage of patients with RLS (26% vs 6%) had ADHD symptoms using the age-adjusted DSM-IV ADHD criteria. Studies have also described an association of ADHD-like symptoms with SRBDs. Chervin and Archbold124 in an observational study of 113 children with suspected SRBD administered a PSG and Conners Parental Rating Scale and found that children with SRBD on PSG had high hyperactivity scores on the Conners scale. The study by Chervin et al125 mentioned earlier, also identified an association between high HI scores and habitual snoring. Urschitz et al126 explored an association between SRBDs and impaired attention and neurocognitive deficits as assessed by poor school academic performance in 1144 children. They described an association between snoring frequency and intermittent hypoxia (measured by nocturnal home pulse oximetry) and poor school performance.126 Melendres et al127 administered the Connors Abbreviated Symptom Questionnaire on 108 children with suspected SRBD and demonstrated a correlation between symptoms of ADHD and SRBD. The study by Gaultney et al122 described earlier also reported the occurrence of ADHD symptoms in patients with SRBD. In an earlier study, Ali et al128 described a significant improvement in aggression, inattention, and hyperactivity on the Conners Parental Rating Scale after adeno-tonsillectomy in children with moderate SRBD. A few studies have also described the occurrence of ADHD symptoms in patients with OSA. Lewin et al129 compared 28 otherwise healthy children with OSA and 10 reference controls and concluded that all children with OSA had significantly more behavioral problems than controls, and children with moderate to severe OSA had lower scores on a time cancellation task that was designed to test sustained attention. Mazza et al130 performed a battery of attention tests measuring maintenance of wakefulness, sustained attention, and divided attention in 20 adult patients with OSA and 40 reference controls, and found that patients with OSA performed significantly worse on all 3 tests.

ADHD Subtypes and Sleep Problems There are 3 subtypes of ADHD: primarily inattentive type (ADHD-I), primarily hyperactive impulsive type (ADHD-

Sleep in ASD and ADHD HI), and combined type (ADHD-C). There is evidence that different ADHD subtypes are likely to experience different difficulties with sleep. LeBourgeois et al96 showed that children with ADHD-I subtype were sleepier than ADHDHI and ADHD-C subtypes and chronic nocturnal snoring was greater in the ADHD-HI subtype. Mayes et al131 reported that children with ADHD-I subtype had increased daytime sleepiness and sleep duration as compared with those with the ADHD-C subtype, and the ADHD-C subtype had more initial insomnia, restlessness, nighttime awakenings, and nightmares. In the study by Silvestri et al108 mentioned earlier, a subgroup analysis revealed that the ADHD-HI and ADHD-C subtype had more periodic limb movements per hour than the ADHD-I subtype. Chervin et al121 also described an association between ADHD-C subtype and sleep-related involuntary movements. Similar findings (association of RLS or PLMS with the ADHD-C subtype) were reported earlier by Corkum et al.132 In adults, it has been suggested that patients with ADHD-I subtypes have a later circadian preference than the other 2 subtypes.133

Pathophysiology and Causes of Sleep Problems in ADHD Sleep disturbances in ADHD are likely multifactorial, and may result from adverse effects of medications used to treat ADHD, psychiatric comorbidities, elements intrinsic to ADHD, or a combination of multiple factors. The most commonly used drugs to treat ADHD— stimulants such as methylphenidate and dextro-amphetamine—are known to disrupt sleep. Sangal et al116 described the results of a randomized, double-blind, crossover clinical trial of atomoxetine vs methylphenidate in 85 children diagnosed with ADHD, in which treatment with methylphenidate resulted in longer sleep onset latency, reduced total sleep time, and reduced sleep efficiency. In an earlier study, Wilens et al,134 in a long-term (24 months) open-label follow-up study of methylphenidate, reported a 15% prevalence of insomnia. The sleep disruption effect of methylphenidate is probably dose related134. Stein et al135 conducted a dose titration study of methylphenidate in 47 children with ADHD and found that although insomnia was present at all doses used in the study (18, 36, and 54 mg), the proportion of patients with sleep disruption increased from 9% at 18 mg to 25% at the 54 mg dose. Lisdexamfetamine dimesylate, the first long-acting stimulant for treatment of ADHD, is also known to disrupt sleep. In a metaanalysis of 6 randomized double-blind placebo-controlled trials of lisdexamfetamine dimesylate to treat ADHD, Coghill et al136 reported the occurrence of insomnia in 12%20% of patients. The sleep disrupting effect of these stimulant drugs is due to disruption of dopaminergic and noradrenergic release and reuptake in the central nervous system.137,138 Co-occurring psychiatric comorbidities in ADHD can also disrupt sleep. For example, oppositional disorder, mood disorders, anxiety disorders, learning disorders, tics, and

121 Tourette syndrome, are common in ADHD and contribute to and magnify sleep disorders in ADHD.139 Sleep problems in ADHD may also stem from a manifestation of their intrinsic, core ADHD symptoms. This is especially true in patients who have SOI, whereby children complain of their inability to turn off their thoughts, lie in bed in a hyper-alert state of mind, and try to seek other stimuli to pass the time until they are finally able to fall asleep. Parents may perceive this phenomenon to be an adverse behavior and try to put the child to bed even earlier, which further increases the time between going to bed and finally feeling tired enough to fall asleep. This can create a vicious cycle with the end result of an increasing sleep latency.140

Evaluation and Management of Sleep Problems in ADHD As it is clear that sleep problems and ADHD may have a bidirectional relationship with sleep problems being common in ADHD and which further worsen daytime behaviors, the correction of sleep disorders should be considered by health care providers as a general pragmatic approach to treating ADHD. As in the case of evaluating sleep disorders in ASD, a detailed medical, psychiatric, sleep, and family history should be obtained. The sleep history in particular should include detailed information on sleeping habits, such as bedtime, waking time, any pattern of daytime sleepiness, and ability to maintain sleep during the night. Specific closeended questions regarding the presence of sleep disorders, such as reduced alertness, sleep-onset delay, and increased nighttime activity, should be asked, which may help elucidate the etiology of the sleep disorder. A psychiatric consultation should be obtained if there is a concern for a coexisting psychiatric disorder such as anxiety or depression that may also affect sleep. If the clinical history suggests the presence of sleeprelated movement disorder (such as PLMS or RLS) an assessment of serum ferritin levels should be considered as they have been reported to be associated with PLMS or RLS.62 Objective modalities for the evaluation of sleep in children with ADHD are PSG, actigraphy, and MSLT.108 ADHD is associated with lifestyle management problems. A majority of symptoms of ADHD, such as procrastination, and mood, motivation, and energy problems, may be traced back to sleep difficulties. There is a risk of a vicious cycle becoming established, in which inadequate and inefficient sleep affects daytime mood, which may in turn decrease attention and motivation, and may further exacerbate sleep problems, thus impairing school or workplace performance. Therefore, the management of sleep problems in ADHD is multifactorial and eventually may require a combination of behavioral interventions and if necessary, pharmacologic treatment. Good sleep hygiene practices such as avoiding stimuli like television or computer screen before bedtime, daytime exercise, and the adoption of bedtime routine that allows the patient to “wind down” should be encouraged. Sleep diaries and logs to keep track of bedtimes and rising

K. Singh and A.W. Zimmerman

122 times should be maintained. The behavioral interventions that are described in the previous section on ASD have been shown to be helpful in typically developing children also. For a detailed description of behavioral interventions that might be useful, see the section on “Evaluation and management of sleep disorders in ASD.” Pharmacologic management of sleep problems in ADHD should be considered in conjunction with behavioral interventions, particularly if behavioral modalities have a limited effectiveness. Some of the agents that may be considered to treat sleep problems in ADHD include drugs such as clonidine, zolpidem, melatonin, and L-theanine. Prince et al141 performed a systematic medical record review of 62 children and adolescents with ADHD who were treated with clonidine (at nightly doses ranging from 50800 mg) for ADHD-associated sleep disturbances. After controlling for age, gender, comorbidity, and concurrent pharmacotherapy, more than 85% of patients were much or very much improved as measured by the National Institute of Mental Health global assessment of improvement (sleep). Adverse effects were seen in 31% of cases and were generally mild, such as morning sedation and fatigue. Rare side effects were worsening of nightmares and depression in 1 case.141 Zolpidem has also been investigated to treat sleep disturbances of ADHD in a study. Blumer et al142 performed a placebo-controlled trial of oral zolpidem (at a dose of 0.25 mg/kg/d) in 201 children and adolescents, with ADHD and sleep disturbances. The investigators found that although there was no effect of zolpidem on sleep latency, sleep efficiency, or total sleep time as measured by a PSG, the clinical global impressions-improvement Scale (CGI-I) and clinical global impressions-severity scale (CGI-S) scores were significantly improved. However, adverse effects were noted in up to 63% cases, including dizziness, headaches, and hallucinations.142 A few studies have investigated the use of melatonin to treat sleep disturbances in ADHD. Van der Heijden et al143 performed a double-blind placebo-controlled trial of melatonin in 105 children with ADHD-related sleep disorders. Overall, 53 participants were treated with melatonin for a duration of 4 weeks at a dose of 3-6 mg/kg body weight. Melatonin was observed to significantly decrease sleep latency, increase total sleep time and sleep efficiency, reduce nocturnal awakenings, and significantly ameliorated core ADHD symptoms as reported by parents. The most common adverse effects were headaches, hyperactivity, dizziness, and abdominal pains in 3%-6% of participants.143 Subsequently, Hoebert et al performed a long-term followup of the participants of the Van der Heijden144 study, who were now all taking melatonin. At the end of 3.7 years, the majority of participants (65%) were still using melatonin with effective amelioration of their sleep disturbances. Most common adverse effects were dizziness, bedwetting, sleep maintenance insomnia, headaches, nausea, nightmares, daytime sedation, and constipation in up to 5% of participants. Totally 22 children discontinued melatonin during the follow-up and that resulted in return of sleep-onset delays in 92% of them.144

One study has also investigated the use of a non-protein amino acid, L-theanine (γ glutamylethylamide) to treat ADHD-related sleep disturbances. Lyon et al145 performed a double-blind placebo-controlled trial of L-theanine in 93 ADHD male children and adolescents. Although this study failed to demonstrate significant improvements in sleep latency or total sleep time; there was a significant increase in sleep efficiency and a reduction in nocturnal activity.145 Thus in conclusion, there is insufficient evidence that meets high levels of scientific merit regarding the pharmacologic treatment of ADHD-related sleep problems. Therefore, as in ASD, a combination of behavioral interventions and sleep hygiene routines along with pharmacologic agents such as melatonin or clonidine may be effective in treating sleep problems in ADHD.

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Sleep in Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder.

Sleep problems are common in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Sleep problems in these disorders may...
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