Sleep in Autism Spectrum Disorder and At

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Sleep in Autism Spectrum Disorder and Attention

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cit 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.

Sleep Disorders in Autism

Spectrum Disorder

Autism spectrum disorder (ASD) is a group of neurodeve-lopmental 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.1Along 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 behavior2but also increase parental and family stress levels.3 Recent Centers for Disease Control and Prevention reports4indicate 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.

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 chil-dren 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 reported 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

speci-ﬁed, also reported 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 accu-rately assess the temporal progression of sleep disorders in ASD. Although on one hand a large retrospective-longitudinal study found no relationship of sleep disorders with developmental stages in ASD,13 another longitudinal

From the Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA.

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study14 with a short follow-up of 1 year and a few other cross-sectional studies didfind that sleep difficulties tended to decrease with age.15-17The 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 quotiento55) had higher chances of increased sleep latency, shortened total sleep time, and early termi-nation of sleep as compared with higher functioning (intelligence quotient 455) children with ASD. Gail Wil-liams et al19 reported increased nighttime awakenings in children with ASD along with mental retardation as com-pared with children with ASD but without mental retarda-tion. In contrast, several more studies have found the presence of sleep problems in patients with ASD regardless of their level of cognitive impairment.13,20-22In addition, it has been shown that lack of adequate sleep is associated with increased severity of ASD symptoms such as stereo-typical 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 breath-ing disorders (SRBDs), and sleep-related movement disor-ders. Sleep-onset insomnia (SOI) or difficulty initiating sleep (increased sleep latency or time to fall asleep) and sleep-maintenance insomnia (decreased sleep duration, decreased sleep continuity, and increased and early awakenings) are among the most common sleep problems reported in ASD. Many parent or caregiver reported 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 al19in a survey on 500 children with ASD reported 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, morn-ing headaches, crymorn-ing durmorn-ing sleep, and nightmares or night terrors were least common.19Krakowiak et al22in 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 questionnairefindings 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

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,parasomniasconsisting of non-REM (NREM) and REM sleep-related disorders have been described in ASD. A few studies have reported the occur-rence ofNREMarousal 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 Mulick12also 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 per-formed 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.

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however has not been substantiated in subsequent studies, which excluded ASD subjects on psychotropic medications and did notﬁnd 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.38Indeed, treatment of sleep apnea in a case of ASD was found to improve daytime behaviors (sleep, social communication, inattention, repet-itive behaviors, and hypersensitivity).39 Similar improve-ments 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.40RLS 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 Rhyth-mic 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 sleepi-ness. 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 communi-cation 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 neurotransmit-ters to medical and psychiatric comorbidities and nutritional deﬁciencies. Abnormal expressions of several neurotransmit-ters, such as serotonin, melatonin, and gamma-aminobutyric

acid (GABA), have been described in ASD and these neuro-transmitters 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 found 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 found 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 found 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 al49found mutations in regulatory regions of ASMT, melatonin recep-tor 1A, and melatonin receprecep-tor 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 levels. Some studies have described abnormal platelet serotonin levels in ASD. Connors et al51 measured plasma serotonin levels in 17 children with ASD and their families and discovered lower levels 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 al54have described a disruption of GABA interneurons as manifested by increased peripheral expression of brain-derived 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 These mutations may result in disruption of GABA-related inhibitory functions and thereby contribute to the sleep disorders in ASD.

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their typical language and communication deﬁcits can make 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 nutri-tional 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 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

Theﬁrst 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, self-injurious 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 multi-parametric test that involves comprehensive recording of physiological changes occurring during sleep, and monitors brain activity (electroencephalography), eye movements (electrooculography), skeletal muscle activity (electromyog-raphy), and heart rate and rhythm (electrocardiogram). Nasal and oral airﬂows are measured using pressure

transducers along with respiratory effort using belts. Blood 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 toﬁnd 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 inter-changeably. 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. Evaluating for 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.

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et al67conducted a study involving parent-based behavioral 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 Child-ren’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 pro-viding 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 day-time 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 tele-vision 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 night-to-night variability as possible is very important. Once established, children with ASD respond well to these bed-time routines.73 These routines 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.40A pictorial representation

of other children following the bedtime 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 reinforce-ment 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 extinc-tion” 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

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improvements in sleep latency, and these improvements 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 Besag82analyzed 27 studies on the use of melatonin and found no signiﬁcant overall increase in seizure activity in most studies, and the studies that did report an increase in seizure activity had patients with preexisting uncontrolled seizures.

In clinical practice to treat sleep-onset insomnia, melato-nin 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 approx-imately 20-50 minutes. Therefore mostly the regular release preparations have been used and are efficacious for sleep-onset 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 psychia-trists 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 neuro-logic or psychiatric conditions in ASD. For example, risper-idone may be used in patients with ASD who have coexisting aberrant behaviors such as irritability and aggressiveness.

Summary

Sleep disorders are common in ASD and if untreated can significantly add to morbidity. There is no single approach that is helpful in treating these disorders in this population. Management of sleep disorders in ASD is often multifactorial and in most patients may require a degree of individualiza-tion, depending upon their specific needs and symptomatol-ogy. Ultimately, a combination of behavioral interventions and sleep hygiene routines along with pharmacologic agents such as melatonin may be effective. Research into the effective use of drugs is lacking, and more studies, especially placebo-controlled studies, are needed with long-term follow-up to conclusively demonstrate the safety and efficacy of drugs such as melatonin in ASD.

Sleep Disorders in Attention

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cit 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 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

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had increased rates of SOI, nighttime awakenings, para-somnias, decreased total sleep time, and increased daytime sleepiness.

Stein et al95administered a sleep questionnaire inquiring about the presence of insomnia, restless sleep, hypersomnia, morning and daytime fatigue, headaches following awaken-ing, snorawaken-ing, 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 con-trols did not differ in the presence or severity of sleep disturbances, the medicated participants with ADHD had worse scores on majority of the questionnaire domains, indicating a higher prevalence and increased severity of sleep disturbances. LeBourgeois et al96 compared the 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. Shur-Fen Gau97 investigated the 6-month prevalence rates of sleep-related problems and their association with daytime napping, inattention, hyperactivity, impulsivity, and opposi-tional symptoms in a school-based sample of 2463 children. They reported that parasomnias, dyssomnias, sleep-disordered breathing problems, daytime inadvertent nap-ping, and abnormal sleep schedules were related to ADHD-related 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,101in a large study of 853 participants with ADHD and 19,299 control participants, reported that after control-ling 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 meth-ods such as PSG or actigraphy have reported more variable

ﬁndings.

Some studies have reported increased sleep-onset latency. Hvolby et al85 performed actigraphy in 45 children with ADHD, 64 psychiatric controls, and 97 healthy controls, and reported that children with ADHD had signiﬁcantly longer sleep latencies (26.3 minutes vso19 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 reported 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.

Increased REM sleep latency has been described in a few studies. The study by Palm et al103cited earlier reported 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 reported 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, reported similar ﬁndings of increased sleep latency in children with ADHD. Silvestri et al108performed 1-night PSGs on 55 children with ADHD and 20 controls and reported 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 reported a decreased REM sleep percent-age in ADHD as compared with controls. Gruber et al109 performed 1-night PSG on 15 ADHD and 23 controls and also reported a decrease in REM percentage in the ADHD group. The study by Silvestri et al108mentioned earlier also reported 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 percent-age. Kirov et al110 performed 2-night PSGs on 17 ADHD and 20 controls and also reported an increased total REM percentage.

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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 reported that the actigraphy itself showed no differences between ADHD and controls, although parents reported 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 al115performed 1-night PSGs on 97 ADHD participants and found that only a small percentage 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 reported no sleep abnormalities. Interestingly though, as both of these studies (Crabtree et al and Sangal et al) did not have a control group, theirfindings 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 al87performed 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 Sadeh117, in yet another 5-night actigraphy study on 24 ADHD and 25 control participants, again reported a similar night-to-night varia-bility 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 differ-ent 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 substan-tiated by objective measures.106The 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.118Therefore, the charac-teristics 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, mem-ory, and learning processes.118 Osterloo et al119 compared 74 adults with hypersomnia and 61 adults with ADHD to assess possible diagnostic confusion between excessive day-time 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 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 symp-toms 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, found a relatively high correlation between positive hyperactivity index (HI) scores and restless legs as measured by a validated PLMS ques-tionnaire. 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 al123evaluated the occurrence of ADHD symptoms in 62 adults with RLS, 32 adults with insomnia, and 77 adult controls, and found that as compared with patients with insomnia and adult controls, a signiﬁcantly greater percentage of RLS patients with RLS (26% vs 6%) had ADHD symptoms using the age-adjusted DSM-IV ADHD criteria.

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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 mainte-nance 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 I), primarily hyperactive impulsive type (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 I subtype were sleepier than ADHD-HI 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 awaken-ings, 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 reported 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.132In adults, it has been found 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-amphet-amine—are known to disrupt sleep. Sangal et al116 described the results of a randomized, double-blind, cross-over 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,134in 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 reported that although insomnia was reported at all doses used in the study (18, 36, and 54 mg), the proportion of patients reporting 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 dimesy-late to treat ADHD, Coghill et al136reported 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. These comorbidities, such as oppositional disorder, mood disorders, anxiety disorders, learning dis-orders, tics, and 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 manifes-tation 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 com-mon 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 close-ended 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 sleep-related 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

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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 affect attention and motivation, and may further exacerbate sleep problems, thus affecting 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 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 manage-ment 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, andL-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

50-800mg) 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 disturban-ces of ADHD in a study. Blumer et al142performed 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 distur-bances. 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 sions-improvement Scale (CGI-I) and clinical global impres-sions-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 mela-tonin 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 follow-up of the participants of the Van der Heijden144study, 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, day-time 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, thus indicating that although melatonin was generally effective and well tolerated, discontinuation of melatonin led to a relapse of insomnia even after several years of treatment.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 pharma-cologic treatment of ADHD-related sleep problems. There-fore, 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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