Clinical manifestations

Presentation and course

	• Sleep disorders are commonly seen in monogenetic and polygenetic neurodevelopmental disorders.
	• Sleep disorders manifest in a spectrum of daytime and nighttime symptoms in individuals with intellectual disability.
	• The appearance or exacerbation of daytime and nighttime behavioral issues may hallmark the presence of underlying sleep disturbances.

Patients with intellectual ability commonly exhibit sleep disturbances, such as sleep disruption, hypersomnia, sleep-related breathing impairment, excessive nocturnal movement, parasomnias, circadian rhythm disorders, and irregular sleep-wake patterns. In addition to the traditional sleep-related symptoms, children, especially those with intellectual challenges, may manifest their sleep issues with changes in behavior. Typically, these include features of defiance or aggression, but they may also be more subtle, such as withdrawal or a decrease in new learning. For these patients, exacerbation of underlying dysfunctional behaviors may also be a clue to underlying sleep disruption. Although the direct impact of sleep disorders on neurodevelopmental issues is not well understood, untreated sleep disorders can worsen underlying neurologic problems. In a review, Barone and colleagues point out that sleep influences neuronal and synaptic regulation and, thus, sleep issues impact the brain in different ways across a child’s development (13). This may also account for more subtle influences of sleep in children (61).

Sleep disorders are included in the diagnostic criteria for many neurodevelopmental disorders (94). Studies have shown that up to 86% of patients who have neurodevelopmental disorders will experience sleep dysfunction (32). Challenges with sleep in this population include, but are not limited to, difficulty with sleep onset, nocturnal awakenings, and sleep fragmentation. Sleep disorders in children with neurodevelopmental dysfunction commonly last into adolescence and adulthood, unlike typically developing individuals (08). Several neurodevelopmental disorders have prominent concomitant sleep disturbances (94). Commonly seen across these disorders are greater restlessness in sleep, difficulty initiating or maintaining sleep, bedtime resistance, daytime sleepiness, difficulty awakening in the morning, or the emergence of sleep-related events, such as sleepwalking or sleep terrors. Some of these sleep issues may be associated with specific behavioral characteristics. These behavioral issues may be subtle, as the child becomes withdrawn or decreases in learning new tasks, or they may be more obvious symptoms, such as aggressive or defiant behaviors. Underlying behavioral issues can be more challenging in children with sleep problems and less responsive to standard interventions (107). Children may also show other physical changes, such as weight change, development of elevated blood pressure, decreased growth, or exacerbation of underlying epilepsy. As a result of the sleep disturbances, both children and their families suffer severe adverse effects on quality of life (17). Following is a more specific description of the sleep issues in each disorder.

Angelman syndrome. Angelman syndrome is characterized by intellectual disability, psychomotor delay, epilepsy, ataxia, speech impairment, and behavioral disturbance. Sleep dysfunction is common in Angelman syndrome, with sleep alterations being part of the diagnostic criteria for the disorder. Angelman syndrome is caused by a pathologic deletion of the UBE3A sleep-regulation gene on maternal chromosome 15 (72), which is thought to be involved in regulating sleep by regulating the accumulation of sleep-inducing chemicals during wakefulness (35). Sleep difficulties in this disorder manifest as arousals and awakenings during sleep, daytime somnolence, bruxism, hyperkinesia, enuresis, sleep terrors, snoring, and sleepwalking (97). An increased power in the delta frequencies on EEG during periods of wakefulness and overnight NREM sleep is nearly universally seen throughout the early development of these children (70). Polysomnography demonstrates 2 to 3 Hz poorly defined spike-wave complexes (77), reduced sleep efficiency, increased time in N3 sleep, reduced REM sleep, and decreased overall total sleep time as well as time spent in stage N2 sleep (70).

Attention deficit and hyperactivity disorder (ADHD). ADHD is diagnosed in approximately 5% of children (83). Sleep issues are frequently noted in over half of the individuals. In previous diagnostic criteria (DSM-III-R), sleep issues were part of the diagnosis (05). For these patients, the severity of daytime issues appears to correlate with the severity of the sleep problems. This relationship has been the basis of several hypotheses involving a reciprocal relationship between ADHD and sleep. Patients with ADHD tend to have prolonged sleep latency, lower sleep efficiency, more nighttime awakenings, nighttime movement, and daytime sleepiness (88). The prolonged sleep latency and frequent awakenings may be related to underlying sleep issues. Delayed sleep phase syndrome is noted in some children with ADHD. Nighttime movement appears as periodic limb movement and as nonperiodic movement. The increase in movement may have several different explanations. Restless legs syndrome is also more frequently noted in children who carry the diagnosis of ADHD and is associated with periodic limb movements in sleep (31). Insomnia is a common finding in children with ADHD (117). The insomnia may be more frequent with a variety of issues, spanning from more stimulating sleep environments, associated psychiatric issues, and medication effect. Children have more disturbances in sleep with stimulant use. Insomnia is frequently noted when the patient is taking doses late in the day. This is supported by the notation that randomized controlled trials for stimulant medication in ADHD have higher rates of insomnia in the treatment arm than in placebo arms. Obstructive sleep apnea appears to have a bidirectional relationship with ADHD and is possibly present in over half of pediatric cases of ADHD (104). Although tonsillectomy has been shown to result in short-term improvement in patients with obstructive sleep apnea and ADHD, the longer-term lack of success suggests that the relationship goes beyond simple structural issues of the airway (104). Sleep disorders also appear to increase with ADHD combined with autism spectrum features (88).

Autism spectrum disorders. This lifelong neurodevelopmental disorder is characterized by persistent deficits in social communication, restricted interests, and repetitive patterns of behavior with abnormal sensory responses (American Psychiatry Association 2022). Children and adolescents with autism spectrum disorder present with higher rates of sleep disturbances than the general population (59). Autism spectrum manifests as a variety of symptoms leading to multiple possible clinical presentations. The prevalence of sleep disorders in autism spectrum disorder ranges from 2% to 72%, and sleep disorders are observed more frequently in children than in adolescents (19). Problems with sleep include resisting bedtime, sleep initiation insomnia, nighttime and early morning awakenings, short sleep period, irregular sleep-wake pattern, poor sleep hygiene, bruxism, and restless sleep (115). Patients with autism spectrum disorder often have short sleep times, bedtime resistance, and reduced sleep pressure compared to those without autism spectrum disorder (30). The same study also highlighted a link between sleep difficulties and irritability, with deficits in social skills and behavioral problems.

Developmental delay and emotional/behavioral difficulties have been associated with insomnia (40). Tesfaye hypothesized that sleep is essential for the optimization of cognitive development, memory, and learning (103). Children with insomnia are more likely to show internalizing (anxiety/depressed symptoms), externalizing (aggressive/social problems), and global behavioral difficulties compared to those without sleep deprivation (40). The predilection for aggression in autism spectrum disorder may be heightened by insomnia (40). Children with autism spectrum disorder and sleep deprivation were negatively impacted in regard to intellectual ability and verbal skills and displayed more deficits in skills needed to complete typical daily living tasks, socialization skills, and motor development (102). These children also experienced more nighttime awakenings and sensitivity to sleep environment disturbances, such as noise (102). Individuals with autism tend to have longer sleep-onset latency, lower sleep efficiency, and decreased total sleep time as well as more sedentary lifestyle and lower daytime exposure to light (76). This same pattern was found in adults with autism spectrum disorder and associated with sedentary daily behavior and increased nocturnal activity (11).

Cerebral palsy. This diagnosis is a collection of genetic and acquired childhood disorders that affects motor function, tone, and posture as a result of injury to the developing brain (112). Children with cerebral palsy, especially those who are nonambulatory, are more likely to have sleep problems than their typically developing peers (56). Cerebral palsy has also been associated with epilepsy, intellectual disability, communication issues, and sensory disturbances (82). Children with cerebral palsy may have risk factors (brain injury, physical disabilities) that make them more likely to have sleep problems when compared to typically developing children (54). The prevalence of sleep problems in children with cerebral palsy is high and has been reported in more than 40% of children with this disorder (71). A population-based study found the most common sleep issues to be difficulty initiating and maintaining sleep, reduced total sleep duration, daytime sleepiness, behavioral issues, nocturnal seizures, and pain. Pain is reported in this patient population, particularly in the most severely affected children, and may be a strong predictor for issues with initiation and maintenance of sleep.

Down syndrome. Also known as trisomy 21, Down syndrome is the most frequent genetic disorder and is associated with cognitive and physical impairments, including sleep disorders, obesity, hypotonia, and motor and neurologic developmental delays (64). Individuals across all ages with Down syndrome experience sleep problems. Sleep issues in Down syndrome can lead to significant behavioral and cognitive morbidities in this population (92). Sleep-disordered breathing is frequent in patients with Down syndrome, with a prevalence ranging from 60% to 95% (92). Children with Down syndrome have anatomical narrowing of the upper airway at different levels and are more prone to airway collapse leading to obstructive sleep apnea (75). They also have relative macroglossia due to small oral cavity, obesity, hypotonia of the pharyngeal muscles, and enlarged tonsils or adenoids. Compared with controls, children with Down syndrome evaluated by sleep nasopharyngoscopy have more pharyngeal and lingual collapse but less adenoidal hypertrophy (39). Respiratory instability appears early in life. These patients also have high prevalence for central apnea early in life and hypoventilation at various stages of development (38). More commonly seen in childhood and adolescents, obstructive apnea is a common feature. In one retrospective review, up to 82% of young adults with Down syndrome who underwent polysomnography were found to have obstructive sleep apnea, and one third were severe (26). In addition to sleep-related breathing issues, this population suffers from restless sleep, snoring, bruxism, frequent night awakenings, nocturnal enuresis, and daytime behavioral problems (hyperactivity) more than daytime sleepiness (75).

Kleefstra syndrome. Kleefstra syndrome is characterized by intellectual disability, childhood hypotonia, autistic-like features, and distinctive facial features (65). It is a rare genetic disorder caused by the loss of the EHMT1 gene or by mutations that disable this gene’s function. Sleep disturbance is described as frequent nocturnal and early morning awakenings and excessive daytime wakefulness. In adolescents and young adults, sleep disturbance may be a precursor for severe regression and possibly even the development of psychoses.

MBD5 haploinsufficiency syndrome. Characteristics of this neurodevelopmental disorder include developmental delay, intellectual disability, seizures, severe speech impairment, sleep disturbances, and abnormal behaviors (78). Sleep disturbances affect about 90% of children, consisting of frequent nighttime waking, short sleep duration, night terrors, and early morning awakenings.

Mowat-Wilson syndrome. Children with Mowat-Wilson syndrome, a genetic syndrome, are recognized by their square-shaped face, widely spaced deep-set eyes, a prominent pointed chin, and a broad nasal bridge with a rounded tip of the nose. In addition to the distinctive facial features, affected patients may have congenital heart defects, Hirschsprung disease, agenesis of the corpus callosum, limited or absent speech, microcephaly, seizures, and moderate to severe intellectual disability (03). This genetic disorder is caused by a heterozygous mutation or deletion of the ZEB2 gene (03). Sleep disturbances are common in Mowat-Wilson syndrome. Using the Sleep Disturbance Scale for Children, Evans found approximately 44% scored in the clinical disorder range and over half scored in the borderline range for at least one subscale (37). Over 29% of this cohort noted frequent movement issues near sleep-wake transitions and parasomnias at sleep-wake transitions. Therefore, this study suggests this population should be screened for sleep disorders.

In a study utilizing video polysomnography to analyze sleep structure, children with Mowat-Wilson demonstrated a reduction of total sleep time, an increase in wake after sleep onset, and increased arousal index when compared to controls (33). These findings could all be signs of disturbed sleep. The same study also noted a significant increase in the percentage of stage N3 sleep in children with Mowat-Wilson syndrome older than 7 years old, which may be attributable to the slowing of EEG background activity typical of this syndrome.

Prader-Willi syndrome. This genetic syndrome is a result of the absence of expression of the paternally active genes on the long arm of chromosome 15. From infancy, this syndrome is characterized by hypotonia, feeding difficulties, hypogonadism, characteristic facial features, and small hands and feet (53). Children then go on to develop intellectual disability, global developmental delay, behavioral concerns, sleep disturbance, hyperphagia, and obesity. Sleep disorders commonly affect patients with Prader-Willi syndrome, especially central sleep apnea, obstructive sleep apnea, features of narcolepsy with or without cataplexy, insomnia, and restless sleep (34).

Patients may suffer from both central and obstructive sleep apnea, and the prevalence of each may change with age. Central apnea is more prevalent in infants with Prader-Willi syndrome compared to older children (24). Up to 43% of infants with Prader-Willi syndrome have central sleep apnea, compared to approximately 5% of kids between the ages of 2 and 18 years (24). Sleep-disordered breathing, including obstructive sleep apnea, is present in more than 80% of children with Prader-Willi syndrome (22). Unfortunately, untreated obstructive sleep apnea in Prader-Willi syndrome is associated with more severe delays in developmental milestones in adolescents and young adults (80), among other behavioral concerns. Increasing BMI has been associated with more severe hypoxemia during sleep and more sleep disruptions (34).

Approximately half of those with Prader-Willi syndrome have REM sleep disorders that are considered phenotypic variations of narcolepsy, including sleep-onset REM periods, frequent arousals during REM sleep, and a significant increase in total REM sleep (51). This can be confounded by a high prevalence of excessive daytime sleepiness. Approximately 67% of adults with Prader-Willi syndrome have excessive daytime sleepiness (43), which is demonstrated by decreased wakefulness combined with increased time in stage N3 sleep during the day and night (111). Additionally, the prevalence of insomnia in Prader-Willi syndrome is approximately 29% (04). To complicate this further, disrupted sleep and awakenings may contribute to nighttime foraging for food in this population as well as inappropriately amplify the circadian drive for food at night (34).

Rett syndrome. This is a severe X-linked dominant neurodevelopmental disorder that predominantly affects females (101). It is caused by a mutation in the methyl-CpG-binding protein 2 (MeCP2) gene (113) and is characterized by poor growth, feeding difficulties, hyperventilation and breath holding, seizures, scoliosis, and disrupted sleep (46). The prevalence of sleep problems in Rett syndrome is estimated to be more than 80% (119). Patients with Rett syndrome have a high percentage of slow-wave sleep (93). In a large sample study of 237 cases from the Australian Rett syndrome database, Young and colleagues investigated sleep characteristics and found that these patients experienced laughter during the night, daytime naps, night screaming, bruxism, seizures, obstructive sleep apnea, delayed sleep onset, and reduced sleep efficiency (119). Epilepsy has been reported in 50% to 80% of cases (45). Frequent seizures are associated with poor sleep and fragmented sleep architecture (18).

Smith-Magenis syndrome. This syndrome is characterized by distinctive facial features, developmental delay, cognitive impairment, behavioral abnormalities, sleep disturbance, and obesity (95). It is the result of haploinsufficiency of the RAI1 (retinoic acid induced) gene mapping to chromosome 17p11.2, which regulates transcription of the circadian locomotor output cycles kaput (CLOCK) gene, resulting in disrupted circadian rhythmicity (116). Patients with Smith-Magenis syndrome have altered circadian rhythms (98) with an inverted (diurnal) pattern of melatonin characterized by elevated daytime and low nighttime melatonin levels (96). This results in less total night sleep, lower sleep efficiency, earlier sleep onset, earlier final wake times, increased waking after sleep onset, and increased daytime naps. Growth hormone deficiency has been implicated in the sleep disturbance in Smith-Magenis (57). Individuals with Smith-Magenis syndrome also have more sleep-disordered breathing than typically developing children, which may be attributable to their facial anatomy or to obesity-related ventilatory problems (25).

Prognosis and complications

A meta-analysis has shown that people with intellectual disabilities experience poorer quality and shorter sleep duration than their typically developing peers (100). Sleep problems tend to be chronic and can cause cognitive and behavioral difficulties that affect the entire family’s well-being (14). As the patient ages, the sleep issues may change and, thus, adjustment to these changes is necessary in hopes of improving sleep. Certain sleep behaviors are related to important developmental skills, including attention and listening (14). Poor sleep may lead to impairment of these skills, caregiver exhaustion, and increased likelihood of institutionalization.

Clinical vignette

A 6-year-old male with trisomy 21 presented with disruptive daytime behavior at school, more irritability at home, and snoring. The child also reverted to taking an afternoon nap. The pediatrician evaluated the child and noted tonsillar hypertrophy and a crowded oropharynx. The child also had a history of tonsillitis. The child was referred to the sleep clinic and was sent for overnight polysomnogram. Polysomnogram revealed an AHI of 9 (moderate obstructive sleep apnea) and multiple apnea-related arousals. The child was referred to ENT for adenotonsillectomy.

At 6 months following adenotonsillectomy, the child had a repeat polysomnogram showing an AHI of 2.1 and improvement of snoring. Daytime behavior improved, and the child stopped taking an afternoon nap. Due to the residual apnea and snoring, the child was placed on a nasal decongestant, which resolved the snoring.

Biological basis

Etiology and pathogenesis

	• Sleep disorder etiologies are multifactorial and often vary from one disorder to another.
	• Electrophysiological disturbances, irregularities of sleep-wake cycle, genetic variations, and comorbid medical conditions are frequent findings.

The etiology of sleep disturbances varies, and more than a single factor typically plays a role. However, some general statements can be made. Various factors that may contribute to sleep dysfunction in neurodevelopmental disorders include developmental delay, learning disabilities, psychiatric disturbances, seizure disorders, upper airway obstruction, gastroesophageal reflux, sensory issues, and physical deformities (16).

Sleep apnea. In Prader Willi syndrome, hypothalamic dysfunction, developmental brain abnormalities, craniofacial dysmorphia, hypotonia, obesity, and chest wall deformities can all contribute to the presence and severity of sleep-disordered breathing (09). In Down syndrome, factors that specifically contribute to obstructive sleep apnea include craniofacial abnormalities, such as midfacial and mandibular hypoplasia, narrow nasopharynx, and relative macroglossia, in addition to adenotonsillar hypertrophy, alteration in upper airway muscle tone, and obesity (75). Very young patients with Down syndrome tend to have an increased propensity for central apnea, which may be resultant of hypotonia and immature respiratory control (38). Other central nervous system factors may also influence the control of the upper and lower respiratory muscles in sleep, thus, increasing the likelihood of sleep apnea.

Hypercapnia. Adults with Prader-Willi syndrome often have abnormal hypercapnic ventilatory response (10), and children with the disorder have also been found to be hypercapnic (02). The severity of this hypoxic ventilatory response appears to be independent of the degree of obesity (118). These individuals tend to have lower nocturnal basal blood oxygen saturation levels (SpO2), with clusters of desaturations, compared to controls (60). Increased nocturnal hypoventilation may be a result of this poor ventilatory control as well as a loss of functional reserve capacity (02). Children have disproportionately longer periods of hypoventilation in comparison to typically developing children with the same AHI (02).

Sleep features and sleep state maintenance issues. Children with neurodevelopmental disorders and intellectual impairment may have select electrophysiological features of sleep—specifically, a vulnerability to abnormal spindle generation (48). Sleep spindles are generated from the thalamus and require specific neuronal relay to the cortex to function. Similarly, slow-wave generation is typically thought to involve cortical to cortical synchronization. Levin and colleagues found that low-frequency (2 to 4 Hz) delta rhythms were increased in Angelman syndrome during wake and during all stages of NREM sleep in overnight EEGs (70). Lower sleep efficiency REM ratios have been characterized as neurophysiological effects of Down syndrome, autism, and Angelman syndrome (36).

Although the mechanisms for the control of REM sleep are not completely understood, a relationship between the control of REM sleep and wake is thought to involve the neurotransmitter, hypocretin, also known as orexin. This neurotransmitter is primarily in the hypothalamus and appears to play a role in the maintenance of wakefulness and eating behavior. In Prader-Willi syndrome, some children are noted to have narcolepsy-like features and eating control issues. Failure to develop the hypocretin system has been hypothesized as a potential etiology for these patients (79).

Disturbances of the sleep-wake cycle. This topic is discussed in more detail in the MedLink article Irregular sleep-wake rhythm disorder. Irregular sleep-wake schedules often seen in children with severe intellectual impairment might be linked to the specific syndrome genotype or phenotype, an endogenous endocrine dysfunction or neurotransmitter release, or to an altered perception of environmental time cues (also known as zeitgebers) (08). These cues include the light-dark cycle, food schedule, maternal inputs, etc. Those with severe intellectual impairment often have underlying central nervous system pathology. This may result in difficulty perceiving time cues to entrain a sleep-wake cycle to a 24-hour day, such as regular mealtimes, activity, and social interactions.

Several hypotheses exist as to the underlying mechanism of sleep issues in autism spectrum disorders. Some researchers suggest that the melatonin pathway is impaired, causing insomnia in autism spectrum disorder. Genes whose products regulate endogenous melatonin modify sleep patterns and have been implicated in autism spectrum disorders (108). Genes involved in melatonin and receptor function, lower melatonin concentrations, and altered melatonin circadian rhythm have all been assessed as contributing to autism spectrum disorder in a systematic review (91). Therefore, melatonin therapy has been a basis of treatment, with some success.

The overall sleep quality in intellectual disability is poor. A meta-analysis of sleep time revealed that people with intellectual disability slept for an average of 18 minutes less than people without (100).

Genetic variants. The TCF20 (transcription factor 20) gene encodes a transcriptional co-regulator structurally similar to RAI1, the gene responsible for Smith-Magenis syndrome. Pathogenic variants are associated with a novel syndrome with clinical characteristics similar to those in Smith-Magenis syndrome. Two pathogenic loss-of-function variants were recurrent in unrelated families, and patients presented with phenotypes illustrated as intellectual disability, hypotonia, dysmorphic features, and sleep disturbance (110).

The SNORD116 gene has been implicated in Prader-Willi syndrome (15). The gene is also implicated in sleep, as two individuals with small deletions in this gene exhibited increased REM/non-REM ratios, increased REM fragmentation, and increased amplitude of theta waves during REM sleep (69). Mice lacking the SNORD116 gene were found to have reduced gray matter volume in the ventral hippocampal areas and septum regions important for maintaining theta rhythms in the brain (69).

A study notes alterations in genes related to circadian rhythms, such as CLOCK genes, and melatonin levels (30). These patients also showed altered hypothalamic pituitary adrenal axis and autonomic functions, which may result in a propensity towards hyperarousal and hypersympathetic state.

Somatic abnormalities and comorbid conditions. Some of the disorders of intellectual impairment are associated with congenital malformations, such as craniofacial abnormalities. Predisposing factors to obstructive sleep apnea in Down syndrome include mandibular or maxillary hypoplasia, airway abnormalities (narrow nasopharynx, laryngomalacia, tracheomalacia), small upper airway, hypotonia, relative macroglossia, and obesity (58). Sleep disturbance may also be a result of medical comorbidity. Children with intellectual impairment and medical conditions tend to have more sleep disturbance than those with intellectual impairment without medical comorbidity (42).

Table 1. Sleep Disorder Etiology by Disorder

Disorder	Cause	Symptoms	Prevalence of sleep disorders
Angelman syndrome	Deletion of the UBE3A gene on maternal chromosome 15	Arousals/awakenings during sleep, irregular sleep-wake cycles, daytime somnolence, bruxism, hyperkinesia, enuresis, sleep terrors, snoring, sleepwalking	72% (97)
Attention deficit hyperactivity disorder		Prolonged sleep latency, low sleep efficiency, increase in wake after sleep onset, frequent awakenings and arousals, increased nocturnal movements	> 50% (88)
Autism spectrum disorder		Insomnia, nighttime and early morning awakenings, short sleep period, irregular sleep-wake pattern, poor sleep hygiene, bruxism, and restless sleep	2% to 72% (19)
Cerebral palsy		Difficulty initiating and maintaining sleep, nightly seizures disrupting sleep, reduced total sleep duration, daytime sleepiness, pain	23% to 50% (71)
Down syndrome	Gain of one additional copy of chromosome 21	Obstructive sleep apnea, central sleep apnea, restless sleep, snoring, bruxism, frequent night wakings, nocturnal enuresis, daytime behavioral problems	Obstructive sleep apnea: 60% to 95% (92)
Kleefstra syndrome	Loss of the EHMT1 gene	Frequent nocturnal and early morning awakenings, excessive daytime wakefulness
MBD5 haploinsufficiency	Heterozygous deletion of 2q23.1 encompassing the MBD5 gene	Frequent nighttime waking, short sleep duration, night terrors, early morning awakenings	90% (78)
Mowat-Wilson syndrome	Mutation or deletion of the ZEB2 gene	Sleep-wake transition disorders, reduction of total sleep time, increase in wake after sleep onset, increased arousal index	44% to 53% (37)
Prader-Willi syndrome	Absence of expression of the paternally active genes on the long arm of chromosome 15	Ventilatory control during sleep, central sleep apnea, obstructive sleep apnea, features of narcolepsy with or without cataplexy, insomnia, restless sleep	Insomnia: 29% (34) Sleep-disordered breathing: > 80% (22)
Rett syndrome	Mutation in the MeCP2 gene	Laughter during the night, daytime naps, night screaming, bruxism, seizures, obstructive sleep apnea, delayed sleep onset, reduced sleep efficiency	> 80% (119)
Smith-Magenis syndrome	Haploinsufficiency of the RAI1 gene on chromosome 17p11.2	Altered circadian rhythms with an inverted (diurnal) pattern of melatonin characterized by elevated daytime and low nighttime melatonin levels, less total night sleep, lower sleep efficiency, earlier sleep onset, earlier final wake times, increased waking after sleep onset, increased daytime naps	95% (95)

Epidemiology

• Sleep disturbances commonly present in the intellectually impaired population, and prevalence may vary depending on the cause of disability.

The prevalence of sleep disturbances in children with intellectual disability is estimated to be between 25.5% to 36.2% (89), and these sleep disturbances are more prevalent and severe than in typically developing children if left untreated (99). For some specific syndromes, the rate of sleep issues may be over 80%, and in others, such as Angelman syndrome, the sleep issues may help define the disorder (Table 1). These problems tend to be chronic and affect the entire family’s functioning, in addition to worsening learning and behavioral difficulties (08).

Prevention

	• Good sleep hygiene and risk factor reduction may help prevent some sleep issues, but clinicians must maintain vigilance for possible underlying sleep disorders.
	• A regular sleep schedule that accentuates bedtime routines may help improve signaling of the approach of sleep time.
	• Establishment of daytime activity, timed sunlight exposure, and regular mealtimes may help with daytime alertness.
	• Screening for sleep-disordered breathing and sleep dysfunction may help identify the problem in the early stages and prevent poor outcomes.

Sleep education and the implementation of healthy sleep practices is always the first-line intervention for children with sleep problems (55). Good sleep hygiene and appropriate limit-setting may prevent or reduce the severity of sleep disruption in intellectually disabled children. Children benefit from consistent bedtimes and wake times, even on weekends. If age appropriate, naps should be at a consistent time each day. Electronic devices, such as tablets, television, computer, or video games, should be avoided before bed and kept outside of the bedroom. Attention should be given to the sleep environment such that the bedroom is conducive for sleep. This environment should be dark, cool, quiet, comfortable, and absent of any stimulating devices or objects. Exercise during the day can help sleep and is best done earlier in the day rather than in the evening. Exercise and stimulating activities in the evening can delay the sleep phase. Diet can also play an important role; consistent mealtimes, a healthy diet, and avoidance of high sugar–containing foods may help with sleep. Avoid consumption of caffeinated beverages and products (sodas, chocolate, tea, coffee). Additionally, the child should be placed in bed drowsy but awake so that the association of sleep is made with the bedroom.

Obesity prevention may reduce the severity of sleep-disordered breathing in the intellectually impaired. Anatomical (such as craniofacial) abnormalities of the upper airways predispose to obstructive sleep apnea. It may be helpful to correct anatomical abnormalities of the upper airways that predispose to obstructive sleep apnea. Negative outcomes may be avoided if this population is frequently screened for sleep disturbance.

Differential diagnosis

Confusing conditions

The differential diagnosis of sleep disturbance in the intellectually impaired includes brain and brainstem dysfunction involved in sleep-wake regulation, circadian rhythm disorder, central or obstructive sleep apnea, nocturnal seizures, poor sleep hygiene, psychosocial factors, and medications. Patients with severe intellectual disability are more likely to have brain dysfunction as the cause. Snoring, witnessed apneas, and craniofacial abnormalities tend to favor a diagnosis of obstructive sleep apnea. Patients with blindness are more likely to have circadian rhythm disorders. When patients have daytime behavioral problems or major life stressors, including social issues at home or with caregivers, psychosocial issues should be suspected as a culprit for sleep disturbance.

Associated or underlying disorders

Children with Down syndrome often have undiagnosed obstructive sleep apnea. The prevalence of obstructive sleep apnea in Down syndrome has been reported to be as high as 66% in a large cohort study (74; 38). Even in those without a history of snoring or witnessed apnea, the prevalence was 53.8%. The potential negative consequences of obstructive sleep apnea include failure to thrive, pulmonary hypertension, fragmented sleep, and poor daytime cognitive functioning. The American Academy of Pediatrics recommends a polysomnogram in all children with Down syndrome at the age of 4 years or earlier when there is a history for upper airway obstruction during sleep (21).

Patients with Prader Willi syndrome frequently have underlying sleep-related breathing disorders, such as obstructive and central apnea. Excessive daytime sleepiness and REM sleep disorders (sleep-onset REM, REM sleep in naps, many arousals during REM, and significant decrease in total REM sleep) can also occur in Prader-Willi syndrome, similar to patients with narcolepsy (51). However, symptoms of cataplexy and sleep paralysis are rarely seen in these patients (34).

Diagnostic workup

	• Thorough sleep history, including the daytime and nighttime activities
	• Sleep-wake log
	• Actigraphy
	• Polysomnography
	• Thyroid function

The cornerstone of delineating any sleep issue is a thorough history and physical exam. The history should review the symptoms, time course, things that aggravate and relieve the symptoms, medications and supplements, features of the sleep, sleep environment and sleep routine, and daily habits. Also, typical diagnostic workup for a patient with disrupted sleep includes a sleep-wake diary. Actigraphy is beneficial in measuring circadian rhythms and is applicable in adults with intellectual disability (49). A polysomnogram will aid in identifying physiological changes during sleep, but this will not measure total sleep as the sleep laboratory is not the home environment. These tests should be obtained when sleep-disordered breathing, movement issues, or other nighttime issues are suspected. Typically, these studies are technically challenging and, thus, should be performed in a laboratory with technologists and sleep physicians who are experienced in handling these patients. Due to the high likelihood of sleep-disordered breathing in this population, these studies should include measurement of carbon dioxide, and there should be a low threshold to perform these studies.

Hypothyroidism may be a contributor to obstructive sleep apnea, though the mechanisms are not completely clear (68). Because hypothyroidism is also prevalent in Down syndrome and other syndromes with intellectual impairment, thyroid function should be assessed in intellectually impaired children with sleep-disordered breathing (07).

Management

	• There are no specific guidelines for most sleep disorders with intellectual impairment.
	• Behavioral programs are typically first-line, followed by sleep medications if no correctible cause, such as obstructive sleep apnea, is identified.
	• Nutritional interventions may improve sleep in patients with intellectual impairment.
	• Melatonin by be useful in regulating the circadian rhythm. Hypnotics and benzodiazepines have minimal use.

Behavioral techniques. The recognition and treatment of sleep disorders is crucial for the management of children with neurodevelopmental disorders and may have a positive impact on their daytime behavior (14). Behavioral approaches focusing on good sleep hygiene and regularly scheduled sleeping hours with minimization of daytime sleep are important in the treatment of insomnia. In situations in which an underlying sleep pathology is ruled out, initiation of behavioral therapy may be beneficial in the treatment of disturbed sleep and chronic insomnia (34). A meta-analysis found that behavioral interventions can be helpful to improving sleep problems in those with intellectual disability (85).

No single intervention has been proven to be effective across all sleep problems in children with autism. Behavioral techniques, melatonin, and parent education/education program interventions were the most effective in treating autistic patients with multiple domains of sleep problems compared to other interventions. Some of these interventions included a combination of the following: extinction (standard and graduated), sleep hygiene, positive reinforcement, chronotherapy, sleep restriction, cueing, stimulus fading, scheduled awakening, and faded bedtime with response cost (27). Some alternative therapies included massage therapy and aromatherapy as well as iron supplementation (27). Children with autism also tend to prefer a weighted blanket but do not improve objective or subjective measures of insomnia (47).

Nutritional interventions. Harper and colleagues found that dietary patterns can be an important factor in improving the quantity and quality of sleep in the intellectually impaired (50). Individuals with intellectual disabilities are commonly lower in essential vitamins, minerals and whole grains, and fruits and vegetables. A healthy, balanced diet may help with sleep. As with the general population, a reduction in caffeine can help with sleep. However, there is not enough current evidence to recommend specific foods nor nutraceuticals to help with sleep in this population. In Prader-Willi syndrome, improving food security in the home may improve anxiety and sleep disruptions (34).

Pharmacotherapy. Sleep issues in those with intellectual impairment are typically chronic, rendering hypnotics and other sedating medications of limited use. Patients may develop tolerance to the sleep-inducing medications and suffer daytime sleepiness or increased cognitive impairment as a result. Discontinuation of these medications may result in rebound insomnia.

Kleefstra syndrome is an exception to the typical approach of starting treatment with behavioral interventions. In three case studies of Kleefstra syndrome, severe regression presented after sleep disturbances. Treatment with the usual behavioral programs and sleep medication resulted in intellectual deterioration. However, rapid treatment with high-dose antipsychotics restored sleep, prevented further regression, and improved functioning of daily life (109).

Melatonin is a key regulator of the circadian rhythm. Melatonin promotes sleep onset and the timing of other circadian functions, and it is involved in immune regulation (106), but it does not have a role in decreasing nighttime awakenings. Evidence suggests impaired regulation of melatonin production in children with autism spectrum disorder (66). In Smith-Magenis syndrome, melatonin production is shifted to the daytime hours. Melatonin replacement therapy has been an approach in disorders such as Smith-Magenis syndrome and autism (73). Melatonin has been shown to significantly decrease sleep latency, with little impact on duration of sleep or behavior (63). A combination of nocturnal melatonin and daytime administration of acebutolol, an adrenergic melatonin antagonist, may be beneficial in increasing nocturnal melatonin concentrations and improving nocturnal sleep (29). A randomized, double-blind, placebo-controlled study found that nightly prolonged-release melatonin at a dose of 2, 5, or 10 mg is safe and effective for long-term treatment in children and adolescents with autism and insomnia (73). No detrimental effects on growth or pubertal development were observed, and there were no withdrawal or safety issues on discontinuation of melatonin. In a double-blind, placebo-controlled crossover study, patients treated with tasimelteon for 4 weeks demonstrated a significant improvement in sleep (84). In a randomized, placebo-controlled study of eight children with Angelman syndrome and idiopathic chronic insomnia, melatonin advanced sleep onset by 28 minutes, decreased sleep latency by 32 minutes, increased total sleep time by 56 minutes, and reduced the number of nights with wakes from 3.1 to 1.6 nights per week (20).

In a case series of three children with Prader-Willi syndrome, excessive daytime sleepiness was treated with the histamine 3 receptor agonist pitolisant. The study observed that pitolisant decreased daytime sleepiness and improved cognition as shown by increased processing speed and improved mental clarity (87). It has been suggested that pitolisant may relieve some of the cognitive disability, excessive daytime sleepiness, and poor-quality nighttime sleep associated with Prader-Willi syndrome (87). Modafinil has also been effective in treating excessive daytime sleepiness in some children with Prader-Willi syndrome (28).

Sleep-related breathing disorders

Adenotonsillectomy for obstructive sleep apnea. Adenotonsillectomy is the standard of treatment for obstructive sleep apnea in children without intellectual impairment and has a typical success rate of 71% to 87% (01). Children with Prader-Willi syndrome undergoing adenotonsillectomy for obstructive sleep apnea show improvements in polysomnography and quality of life. Despite improvements, these children tend to have a substantial risk of postoperative complications requiring additional interventions, especially velopharyngeal insufficiency, and many have residual obstructive sleep apnea (23). In Down syndrome, the success rate of adenotonsillectomy is poor, and persistent obstructive sleep apnea is observed in 30% to 50% of children (62). A prospective study found that drug-induced sleep endoscopy (DISE)-directed treatment may be a useful method for the detection and treatment of the cause of upper airway obstruction in children with Down syndrome after adenotonsillectomy (01). Lingual tonsillectomy is another surgical treatment option for patients with Down syndrome and persistent airway obstruction following adenotonsillectomy (86).

Sleep apnea and hypoventilation

Continuous positive airway pressure (CPAP). Given the high rate of residual obstructive sleep apnea following adenotonsillectomy in children with disorders such as Prader-Willi and Down syndrome, CPAP is often the next step. CPAP is also a primary therapy for obesity-related hypoventilation. Although consistent CPAP usage has been found to reduce the severity of obstructive sleep apnea, compliance to treatment is an issue (67). Children with Down syndrome may be good candidates for bilevel positive airway pressure (BIPAP) when CPAP is not adequate as they tend to have hypoventilation that is out of proportion to the severity of their obstructive sleep apnea (41). Autism spectrum disorder is a common comorbidity in children with Down syndrome, and sensory issues may require mask desensitization and acclimation of the mask before adherence is possible (81). Even adults with Down syndrome struggle with adherence to CPAP therapy. A prospective trial of CPAP in community-dwelling adults with Down syndrome and obstructive sleep apnea showed that CPAP use led to improvements in subjective sleepiness, behavioral and emotional outcomes, and cognitive function in those with moderate to severe intellectual disability (52). Partial neural recovery can occur during short periods of treatment with CPAP. Adaptive alterations in the neurocognitive architecture that underlies the reduced sleepiness and improved verbal episodic memory in patients with obstructive sleep apnea can occur with 1 month of CPAP treatment (90). Similarly, noninvasive ventilation appears to be beneficial in treating obesity hypoventilation and obstructive sleep apnea in Smith-Magenis syndrome (25).

When a patient with intellectual disability develops obstructive sleep apnea, the need for CPAP management, or difficulty with sleep that is outside of the scope of the primary care physician, consider referral to a sleep center.

In some patients, central apneas are not responsive to PAP therapy. A retrospective cohort study found that oxygen therapy improved central sleep-disordered breathing and oxygenation in infants with Prader-Willi syndrome and central sleep apnea (105).

A multidisciplinary approach, including a sleep specialist, can be helpful in the management of many of these complex patients.

Special considerations

Anesthesia

Anesthesia for these patients may require extra attention as their response to anesthetic agents may vary. Anesthesiologists should be updated about a patient’s obstructive sleep apnea severity prior to an operation. Patients who use nasal continuous positive airway pressure should use it immediately following extubation until the effects of sedatives or anesthesia have worn off.