Clinical manifestations

Presentation and course

	• Monogenetic neurodevelopment disorders have frequent sleep or circadian dysfunction.
	• Sleep disorders vary considerably in syndromes characterized by intellectual disability.
	• Behavior problems are more challenging in children with sleep problems.

Sleep disturbances, including sleep disruption, hypersomnia, sleep-related breathing impairment, and irregular sleep-wake patterns, are common in patients with intellectual disability. Mechanisms underlying sleep dysfunction in most neurodevelopment disorders are not well understood, but a review of monogenetic neurodevelopment disorders with connections to synaptic dysfunction and evidence of sleep or circadian dysfunction suggests that the concomitant maturation of sleep with synaptic physiology may explain disruption of sleep in neurodevelopment disorders (05).

Estimates of the incidence of sleep difficulties in children with intellectual disability range from 34% to 80%. Reported sleep abnormalities include difficulty settling for the night and nocturnal awakenings. The overall rate of sleep abnormalities in children with intellectual disability decreases with increasing age, although sleep problems may persist into adolescence or adult age, eg, in those with cerebral palsy. Sleep difficulties may be associated with specific behavioral abnormalities. For example, nighttime waking is strongly associated with self-injurious behavior, and decreased sleep is correlated with attachment to routines. Children with sleep problems show significantly more challenging behavior than children without sleep problems. Predictors of nocturnal sleep fragmentation and daytime sleepiness in individuals with intellectual disability include severe locomotor disability, visual impairment, and epilepsy.

Angelman syndrome. Sleep disturbances are frequent in Angelman syndrome, a genetically determined developmental disorder that features intellectual disability, epilepsy, ataxia, speech impairment, and behavioral disturbances. Sleep alterations are 1 of the diagnostic criteria of the disorder. Prader-Willi and Angelman syndromes can be due to the same deletion on chromosome 15 and the UBE3A gene, which results in dysregulation of synaptic GABAergic neurotransmission as UBE3A may play a role in regulating sleep homeostasis (18). Typical manifestations include difficulty in initiating sleep as well as maintaining sleep through the night. Sleep duration is usually less than 6 hours per night and does not affect daytime alertness and function. Other sleep abnormalities include frequent nocturnal awakenings, enuresis, hyperkinesia, bruxism, sleep terrors, sleepwalking, and snoring. Polysomnography demonstrates 2 to 3 Hz poorly defined spike-wave complexes, reduced sleep efficiency, and reduced REM sleep.

Autism spectrum disorders. This is a neurodevelopmental condition characterized by social communication impairment, restricted interests, and repetitive behaviors. It includes previously described subtypes of autistic disorder such as Asperger syndrome. Sleep disturbances affect up to 65% of children with autism spectrum disorders, which is frequently associated with intellectual disability. Common problems include initial insomnia, poor nighttime sleep, early awakenings, irregular sleep-wake pattern, poor sleep hygiene, and restless sleep. Another study found that sleep disturbances are more frequent in children with autism spectrum disorders and intellectual disability as compared with typically developing children, and this risk was increased by family history of sleep problems (26).

Genes whose products regulate endogenous melatonin modify sleep patterns and have been implicated in autism spectrum disorders. Sleep onset delay in autism spectrum disorders relates to melatonin pathway genes (48). This is the basis of melatonin therapy for this problem. In a report of a male child diagnosed with autism spectrum disorder showing cognitive and motor impairments, hyperactivity, and sleep and gastrointestinal disturbances, the analysis of whole exome sequencing data linked the manifestations to both HUWE1 (associated with X-linked intellectual disability and autism spectrum disorder) and gut as well as sleep-modulating TPH2 genes (09).

One study found that children who slept fewer hours per night had lower overall intelligence, verbal skills, overall adaptive functioning, daily living skills, socialization skills, and motor development (43). Poorly functioning autistic children have an earlier onset, higher incidence, and greater duration of sleep difficulties. Sleep disturbance of such children, highly influenced by environmental factors, has a detrimental impact on their daytime functioning. Presence of intellectual disability in these children increases the likelihood of nighttime awakenings. Young adults with autism also have decreased sleep efficiency. A study on adults with autism spectrum disorder in a residential facility who had no intellectual disability showed that sleep-wake disorders with comorbid symptoms of anxiety and depression were more common in this population than previously reported (37).

Cerebral palsy. This term is used for a group of genetic and acquired childhood neurologic disorders characterized by abnormalities in tone, posture, and movement due to early injury to the developing brain. Cerebral palsy is often associated with intellectual disability, speech impairment, and epilepsy. Between 23% and 46% of children with cerebral palsy experience sleep problems. Many of the sensory motor and cognitive features of cerebral palsy (such as immobility, pain, and seizures) act as predisposing factors for sleep problems in this population (16). A systematic review of the literature identified 11 types of sleep disorders such as difficult morning awakening, insomnia, nightmares, difficulties in initiating and maintaining nighttime sleep, and sleep anxiety (28). Sleep disorders are also associated with environmental and socio-familial factors as well as therapeutic interventions.

Down syndrome. This is a genetic disorder caused by trisomy 21, ie, inheritance of 3 copies of the chromosome 21, and is associated with physical growth delays, characteristic facial features, and mild to moderate intellectual disability. Estimates of children with Down syndrome who have obstructive sleep apnea vary from 50% to 95%. Symptoms include snoring, restless sleep, and daytime sleepiness. Central sleep apnea and sleep-related hypoventilation may occur separately or in combination with obstructive apneas. Factors that predispose Down syndrome children to obstructive sleep apnea include craniofacial abnormalities, relative macroglossia due to small oral cavity, narrowing of the upper airway, hypotonia of the pharyngeal muscles, obesity, 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 (20). Obesity increases the risk of oxygen desaturation. Children with Down syndrome have significant sleep fragmentation that is only partially related to obstructive sleep apnea. Although less well-studied than in affected children, obstructive sleep apnea is also common in adults with Down syndrome (45). Trois and colleagues found an apnea-hypopnea index of greater than 15/hour in 14 of 16 adults with Down syndrome in a cohort study. The investigators also found a high rate of hypothyroidism and recommended monitoring thyroid status in persons with Down syndrome. Adenotonsillectomy often results in a significant reduction in CO2 retention and the severity of both obstructive and central apneas (44).

Kleefstra syndrome. Characteristic features of Kleefstra syndrome include developmental delay and intellectual disability, severely limited speech, and hypotonia. It is caused by the loss of the EHMT1 gene or by mutations that disable its function. The EHMT1 gene provides instructions for making the enzyme histone methyltransferase, which modifies proteins called histones that attach to DNA and give chromosomes their shape. Sleep disorders also occur in this syndrome.

MBD5 haploinsufficiency syndrome. Haploinsufficiency of MBD5 (methyl-CpG-binding domain) gene is associated with a neurodevelopmental syndrome of microcephaly, intellectual disability, severe speech impairment, and seizures. Sleep disturbances are reported in about 80% of these cases and can result in excessive daytime drowsiness (Mullegama et al 2017).

Mowat-Wilson syndrome. This is a multiple congenital anomaly syndrome caused by a heterozygous mutation or deletion of the ZEB2 gene and is associated with intellectual disability and variable other features, including agenesis of the corpus callosum. Sleep disturbances are common, particularly frequent waking at night. A study using the Sleep Disturbance Scale for Children showed that 44% scored in the clinical disorder range, and 53% scored in the borderline range, for at least 1 subscale (19). Scores were highest for the sleep-wake transition disorders subscale, with 91% of participants reaching at least the borderline disorder range. Results of this study suggest that persons with Mowat-Wilson syndrome should be screened for sleep disorders.

Prader-Willi syndrome. This syndrome is characterized by neonatal hypotonia, hypogonadism, obesity, small hands and feet, characteristic facies, and intellectual disability. Excessive daytime sleepiness is a primary abnormality of Prader-Willi syndrome rather than purely secondary to sleep-related breathing disturbances. Patients with Prader Willi syndrome have an increased percentage of total sleep per 24-hour cycle and an increased percentage of slow-wave sleep. In addition, they have reduced nocturnal REM sleep latencies and an increased number of REM sleep periods. The excessive daytime sleepiness and REM sleep abnormalities of Prader-Willi syndrome are mostly due to hypothalamic dysfunction, although sleep-disordered breathing often contributes to sleepiness in these individuals. Approximately half of adults with Prader-Willi syndrome had obesity-hypoventilation syndrome, as defined by a body mass index of greater than 30 kg/m², and a daytime carbon dioxide tension of greater than 45 mm Hg, not explained by other known etiologies of hypoventilation. Central apnea is more common in younger patients, whereas obstructive apnea is more common in older children (10). Obesity undoubtedly plays a role in the pathogenesis of obstructive sleep apnea, but there is a poor correlation between obstructive sleep apnea and body mass index (34). Weight loss reduces the severity of sleep apnea and nocturnal hypoxemia in Prader-Willi syndrome, but it may be difficult to achieve.

The prevalence of obstructive sleep apnea in children and adolescents with Prader-Willi syndrome is almost 80% (40). Although obstructive sleep apnea is more typical, central sleep apnea has also been reported. Obstructive sleep apnea may improve with weight loss, though adenotonsillectomy, continuous positive airway pressure, or intermittent positive pressure ventilation may be required. Treatment of sleep apnea does not usually entirely resolve excessive daytime sleepiness in these individuals.

Growth hormone is approved for the treatment of Prader-Willi syndrome. It can have a dramatic effect by increasing height and muscle mass and decreasing body fat in individuals with Prader-Willi syndrome (31). In a long-term longitudinal study, children receiving growth hormone treatment had significantly higher verbal and composite IQs as well as adaptive communication and daily living skills as compared to the treatment-naïve group (17). This ancillary benefit is an additional justification for growth hormone treatment in patients with Prader-Willi syndrome. Cases of sudden death have been reported in children with Prader-Willi syndrome treated with growth hormone (12). It is unclear if this is due to a worsening of sleep apnea by growth hormone. Miller and colleagues found no overall change in sleep-disordered breathing in 20 infants initiating growth hormone treatment for Prader-Willi syndrome (30). However, 12 of the infants had an increase in the frequency of obstructive respiratory events in association with either upper respiratory infections or the diagnosis of gastroesophageal reflux. The authors recommend close monitoring of infants with Prader-Willi syndrome after growth hormone treatment is initiated, especially when they have upper respiratory infections. They also note that if gastroesophageal reflux develops during treatment, appropriate medical treatment for the gastroesophageal reflux reduces the number of desaturation events. The first few weeks after initiation of growth hormone therapy appears to represent a vulnerable time for the development of clinically significant sleep-disordered breathing (01). However, obstructive sleep apnea may develop late in growth hormone treatment, especially after an increase in dose (33). Nixon and colleagues recommend that children should be monitored for sleep apnea symptoms throughout growth hormone treatment, with polysomnography repeated if sleep apnea symptoms develop. Consensus guidelines recommend 1) polysomnography prior to growth hormone treatment, 2) that untreated severe obstructive sleep apnea is a contraindication to therapy, 3) warning patients/parents about the possibility of unexpected death during growth hormone treatment, 4) that therapy is contraindicated in children with breathing difficulties until ENT evaluation and treatment of respiratory-compromising obesity has been accomplished, and (5) that growth hormone therapy not be initiated during an acute respiratory infection (14).

Rett syndrome. This is a neurodevelopmental disorder that presents with loss of purposeful hand movements, partial or complete loss of expressive language, and seizures. It predominantly affects females, and most of the cases are due to mutations in the X-linked gene for methyl-CpG-binding protein (MECP2). Sleep disturbances affect at least 80% of patients with Rett syndrome. Frequent symptoms are delayed sleep onset, shortened nighttime sleep with increased sleep during the day, and periodic nightmares. Obstructive sleep apnea has been reported in children with Rett syndrome (24). However, obstructive respiratory events are uncommon in patients without adenotonsillar hypertrophy.

Smith-Magenis syndrome. This syndrome with multiple congenital anomalies and intellectual impairment is due to haploinsufficiency of the RAI1 (retinoic acid induced) gene mapping to chromosome 17p11.2, which results in the disrupted circadian rhythmicity via abnormal regulation of the transcription of the circadian locomotor output cycles kaput (CLOCK) gene (52). Persons with this syndrome have diurnal instead of nocturnal secretion of melatonin, resulting in early sleep onset, fragmented nocturnal sleep, and daytime sleepiness. In a reported case of Smith-Magenis syndrome, sleep issues are likely due to a combination of disturbed melatonin cycle, facial anatomy, and obesity-related ventilatory problems. Noninvasive ventilation has been successful in treating underlying obesity hypoventilation syndrome and obstructive sleep apnea (11). Growth hormone deficiency has also been implicated in sleep irregularities, such as nocturnal awakening and abnormality of REM.

Prognosis and complications

Poor nocturnal sleep patterns may lead to exhaustion of caregivers and increase the likelihood of institutionalization. Cor pulmonale, probably due at least in part to chronic nocturnal hypoventilation and hypoxemia, is a common cause of death in Prader-Willi syndrome patients. Untreated obstructive sleep apnea may lead to worse cognitive outcomes in those with intellectual disability, especially Down syndrome (06).

Clinical vignette

Mr. BB was referred for a sleep evaluation several years ago, at the age of 30, for falling asleep during the day and spending significant time awake at night. He was referred by the neurologist at the state institution for the intellectually disabled at which he resides. Reported symptoms included snoring and excessive daytime sleepiness. He denied symptoms suggestive of cataplexy, sleep paralysis, or hypnagogic hallucinations.

His past medical history was remarkable for Prader-Willi syndrome, tonsillectomy, status post-orchiectomy for testicular cancer, hypertension, and pituitary tumor that was treated with bromocriptine. Examination revealed obesity (weight 221 pounds, height 64.25 inches, body mass index 37 kg/m2), a high-arched hard palate, a large uvula, and narrow pharyngeal arches. Although polysomnography revealed only a modest apnea-hypopnea index of 8.5/hr (normal, < 5/hr), severe hypoxemia followed obstructive apnea episodes during REM sleep. REM sleep latency was 50 minutes (normal, > 60 minutes). Mr. BB was diagnosed with obstructive sleep apnea. After a continuous positive airway pressure (CPAP) titration, nasal CPAP was initiated at 6 cm H2O. Initial poor compliance with CPAP was somewhat improved by asking the staff at the state home to help him put on the CPAP mask every night and to encourage its use. Steroid nasal spray was later added for CPAP-induced nasal congestion. After a change in staff at the institution, CPAP use markedly declined; Mr. BB became unwilling to wear the CPAP mask. Approximately 6 months later, during a routine bed-check in the middle of the night, he was found cyanotic and unresponsive but quickly recovered. Evaluation at the university hospital found no clear etiology, and this episode was attributed to obstructive sleep apnea by the inpatient neurology service. His nasal mask was refitted and Mr. BB was scheduled for a repeat CPAP titration, which confirmed that nasal CPAP at 6 cm H2O prevented obstructive respiratory events. In anticipation that CPAP use would continue to be sporadic, Mr. BB was also referred to the otolaryngology service for evaluation for an uvulopalatopharyngoplasty.

Biological basis

Etiology and pathogenesis

	• Etiology of sleep disorders is multifactorial and varies from one disorder to another.
	• Electrophysiological disturbances, irregularities of sleep-wake cycle, genetic variations, and comorbid medical conditions are frequent findings.

Etiology of sleep disturbances varies from 1 disorder to another, and more than 1 factor may play a role as already outlined in the description of each disorder. However, some general statements can be made.

Sleep apnea. Although obstructive sleep apnea is frequent in patients with Prader-Willi syndrome, the sleepiness in these individuals usually does not entirely remit with treatment of the obstructive sleep apnea. Brain dysfunction at the brainstem level is implicated in increased central apneas in Down syndrome. It has also been hypothesized that the sleepiness and REM sleep abnormalities seen in this disorder are due to primary central hypothalamic dysfunction (08). Hypothalamic dysfunction, specifically dysfunction of the hypocretin system, appears to play some role in the sleep abnormalities seen in Prader-Willi patients, but this dysfunction may not be identical to that seen in narcolepsy.

Electrophysiological disturbances. The temporal organization of electrophysiological aspects of sleep in intellectually impaired patients appears to be abnormal. Although REM periods in both normal subjects and intellectually impaired patients demonstrate a clear ultradian pattern, only normal subjects demonstrate a periodicity in the distribution of eye movements within REM sleep periods. REM sleep disturbances usually correlate with severity of intellectual disability and disturbed sleep patterns in these patients, which are largely due to brain dysfunction.

Disturbances of sleep-wake cycle. This topic is dealt with in more detail in the Medlink article Irregular sleep-wake rhythm disorder. The irregular sleep-wake schedule often seen in children with severe intellectual impairment may be due to a decreased response to environmental time cues (known as zeitgebers). Although the pathophysiology of this decreased response to time cues is not known, there are several possible explanations. Children with severe intellectual impairment may be unable to perceive time cues or entrain their sleep-wake cycle to a 24-hour day due to the nature of their underlying central nervous system pathology. For example, blindness may prevent response to light. Furthermore, they may lack social relationships, which is a putative zeitgeber.

Longer total sleep time and more frequent awakenings and body movements in Down syndrome are consistent with a general disturbance of areas of the central nervous system involved in sleep maintenance and wake maintenance.

The quality of sleep in intellectual disability is generally poor. A meta-analysis of 21 publications showed that sleep time of persons with an intellectual disability due to genetic syndrome or developmental disorder was an average of 18 min less than those without an intellectual disability (42).

Genetic variants. A sequencing study reported mutations of GRIA3 gene, which encodes GluA3, in 2 male children with developmental delay and extreme disturbance of sleep-wake cycle (13). The authors reproduced the sleep-wake cycle by gene editing and introduction of this mutation in a mouse model.

Somatic abnormalities and comorbid conditions. In addition to brain pathology, somatic abnormalities can contribute to disordered sleep. Some of these may be associated with congenital malformations. In Down syndrome, several coexisting conditions predispose to the development of obstructive sleep apnea, including midfacial and mandibular hypoplasia, obesity, generalized hypotonia, increased secretions, and small upper airway. Medical comorbidity has also been proposed as a contributor to sleep disturbance. Children with intellectual impairment and medical conditions have a higher rate of sleep disturbance than those with intellectual impairment without medical comorbidity (21).

Epidemiology

• Sleep disturbances are very common in intellectually disabled individuals and prevalence varies according to the cause of disability.

The prevalence of sleep disorders varies with the underlying cause of intellectual disability. Up to 80% of patients with intellectual disability have sleep disturbances of sufficient severity to affect their psychosocial functioning or their family's functioning. However, the high prevalence of sleep disturbances reported in the literature must be interpreted with caution. Most of the epidemiological studies examining the rates of sleep disorders in individuals with intellectual disability have focused on children or institutionalized adults. Relatively normal sleep-wake patterns have also been reported in community-dwelling adults with intellectual disability.

Prevention

• Good sleep hygiene and correction of risk factors are preventive measures for sleep disorders in intellectual disability.

Good sleep hygiene with appropriate limit-setting may prevent or reduce the severity of disrupted sleep in some children with intellectual disability. Prevention of obesity may reduce the severity of sleep disordered breathing. Correction of anatomical abnormalities in upper airways that predispose to obstructive sleep apnea may be helpful.

Differential diagnosis

Confusing conditions

The differential diagnosis of disturbed sleep in these patients includes dysfunction of brain and brainstem systems involved in sleep-wake regulation, circadian rhythm disorder, central or obstructive sleep apnea, nocturnal seizures, poor sleep hygiene, psychosocial factors, and medications. Brain dysfunction as the cause is more likely in patients with severe intellectual disability. Snoring, witnessed episodes of apnea, and craniofacial malformations favor a diagnosis of obstructive sleep apnea. Circadian rhythm disorders should be suspected in patients with blindness. Psychosocial factors are a major consideration in patients with daytime behavioral problems or when stress, irritability, or marital difficulties are apparent in the parents or caretakers.

Associated or underlying disorders

Obstructive sleep apnea in children with Down syndrome often remains undiagnosed, perhaps because failure to thrive and pulmonary hypertension, common sequelae of the obstructive sleep apnea syndrome, are also common features of Down syndrome. Obstructive sleep apnea should be suspected in Down syndrome patients when pulmonary hypertension occurs in the absence of cardiac abnormalities or when it is out of proportion to the severity of cardiac anomalies.

In Prader-Willi syndrome, the occurrence of REM sleep at the onset of sleep is common and may suggest a diagnosis of narcolepsy. However, patients with Prader-Willi syndrome rarely have other symptoms of narcolepsy such as cataplexy, sleep paralysis, and hypnagogic hallucinations.

Epileptic encephalopathies associated with intellectual impairment can be ruled out by characteristic sleep EEG patterns and history of seizures.

Diagnostic workup

	• Sleep-wake log
	• Actigraphy
	• Polysomnography
	• Thyroid function

For patients with disrupted sleep patterns, a sleep-wake log combined with assessment of medications, daily schedule of activities, and the psychosocial situation may help to identify circadian rhythm abnormalities and extrinsic influences on sleep-wake patterns. Actigraphy is useful for evaluating sleep disturbances in individual patients and is even more useful for epidemiological research (47). Polysomnography should be obtained when sleep apnea is a consideration, although there are technical difficulties in performing such studies in individuals with profound intellectual impairment. Because of the high rate of sleep-disordered breathing in patients with Prader-Willi syndrome and Down syndrome, there should be a low threshold for the decision to perform polysomnography on persons with these disorders (51). Video-EEG polysomnography may be required if nocturnal seizures are a consideration.

Sleep EEG becomes progressively more abnormal with age, and older Rett syndrome patients have virtually continuous spike-and-wave epileptiform activity during sleep. Although the abnormal EEG activity affects all stages of sleep, it is greatest during stages 1 and 2 of NREM sleep and is concentrated in the early hours of the morning. A polysomnographic study on girls with Rett syndrome showed poor sleep quality, with alterations in slow wave and REM sleep stages (02).

Hypothyroidism, a potential contributor to sleep-disordered breathing, is common in children with Down syndrome and has also been associated with other syndromes with intellectual impairment; thyroid functioning should be assessed in children with intellectual disability who have new-onset obstructive sleep apnea.

Management

	• For most of sleep disorders in developmental disorders with intellectual impairment, there are no specific guidelines.
	• Routine management includes behavioral programs and sleep medications unless a correctable cause such as obstructive sleep apnea is identified.
	• Nutritional interventions improve sleep in persons with intellectual disabilities.
	• Hypnotics are of limited value, but melatonin may be useful for regulating circadian rhythm.

Behavioral techniques. For patients with insomnia, behavioral approaches that emphasize good sleep hygiene with regular sleeping hours and attempts to minimize daytime sleep are important elements. Although instruction in sleep hygiene is often useful, the communicative impairment may make it difficult to teach children with intellectual impairment. Parents of children with intellectual impairment can be given instruction in behavioral treatment of sleep problems either conventionally (face-to-face) or by means of written instructions. Findings of a meta-analysis of single case and group studies indicate that behavioral interventions are a promising evidence-based approach to improving sleep problems in persons with intellectual disability (35).

Behavioral techniques can be used for the treatment of insomnia in children with autism. Weighted blankets, when compared to usual weight blankets, do not improve objective or subjective measures of insomnia in children with autism spectrum disorder, but are preferred by children and parents and are well tolerated (23).

In children with Rett syndrome, a behavioral program of systematic delay of bedtime hours and interruption of daytime sleep may lead to a more regular sleep-wake pattern. Behavioral techniques used for the treatment of insomnia in children with normal intellectual functioning can be tried in children with intellectual impairment. This approach is supported by a systematic review of studies on behavioral interventions for neurodevelopmental disorders, with most of the studies on children with autism spectrum disorders and attention-deficit/hyperactivity disorder (36). Common sleep problems across the neurodevelopmental disorder populations were similar to sleep problems in developing children. Behavioral interventions were also similar, and their effectiveness in some cases suggests the feasibility of developing behavioral sleep therapies suitable for children with a range of neurodevelopmental disorders.

Nutritional interventions. Diet is an important factor for improving the quality and quantity of sleep, but the current literature regarding the benefit of improved nutrition on sleep in people with an intellectual disability needs to be reassessed (25).

Pharmacotherapy. Because sleep difficulties are typically chronic, hypnotics and other sedating medications are of limited value in the treatment of sleep disorders in intellectually impaired individuals. Tolerance to the sleep-inducing effects of medications often develops, and daytime sleepiness or increased cognitive impairment may occur. Rebound insomnia is common on discontinuation of many commonly used products.

Behavioral programs and sleep medications for sleep disorders may not always be the best approach in Kleefstra syndrome, as illustrated by case reports of 3 patients where sleep disturbances led to intellectual deterioration despite routine management, but rapid treatment with high doses of antipsychotics contributed to restoration of sleep, halted further regression, and improved functions of daily life (49).

Melatonin plays a key role in regulating circadian rhythm and has antioxidant and neuroprotective effects. Melatonin decreases sleep-onset latency and increases total sleep time but does not decrease night awakenings. Melatonin at a dose of 3 mg given 60 minutes prior to bedtime usually increases the duration of the total sleep period in patients with Angelman syndrome. Decreased CYP 1A2 activity, genetically determined or resulting from concomitant medication, can slow metabolism, with loss of variation in melatonin level and loss of effect. This can be managed by adjustment of dose. No serious adverse effects of melatonin have been identified, and studies in animals and limited human data suggest that it does not exacerbate seizures (07). Melatonin can be useful for the performance of sleep EEGs and as sedation for brainstem auditory evoked potential studies. A phase 3, randomized, double-blind, placebo-controlled study showed that nightly pediatric prolonged-release melatonin at optimal dose (2, 5, or 10 mg) is safe and effective for long-term treatment in children and adolescents with autism spectrum disorder and insomnia (29). There were no observed detrimental effects on children's growth and pubertal development and no withdrawal or safety issues related to the use or discontinuation of the drug.

A preliminary study found that oxygen therapy improved central sleep-disordered breathing in infants with Prader-Willi syndrome and central sleep apnea (46).

The safe and effective use of modafinil to treat excessive daytime sleepiness in a small number of children with Prader-Willi syndrome has been described (15). A case report noted a decrease in cataplectic episodes in addition to improvement in sleepiness (50).

Adenotonsillectomy. For nonintellectually impaired children with obstructive sleep apnea, adenotonsillectomy (palatine tonsillectomy and adenoidectomy) is the standard treatment and is usually effective. A meta-analysis has shown that adenotonsillectomy improves obstructive sleep apnea in children with Prader-Willi syndrome but residual obstructive sleep apnea was frequently observed postoperatively in these patients (27). Obstructive sleep apnea persists in more than half of Down syndrome children treated with adenotonsillectomy (41). Endoscopic-assisted lingual tonsillectomy has been used in children with persistent obstructive sleep apnea after adenotonsillectomy, including some with Down syndrome. Rapid maxillary expansion improves obstructive respiratory symptoms in children with Down syndrome.

Continuous positive airway pressure (CPAP). Due to the higher incidence of postoperative complications following adenotonsillectomy in children under the age of 3, other treatments such as nasal CPAP or even tracheostomy are often initially used in this age group. Sleep apnea is a transient phenomenon in some infants with Down syndrome; they may outgrow the need for CPAP (38). Nasal CPAP treatment can produce dramatic results in patients able to cooperate with its use. For children both with and without intellectual impairment, adherence to CPAP therapy during the first week of treatment is a predictor of long-term use over 2 to 3 months. Taking steps to improve adherence during the first week of CPAP treatment may increase long-term CPAP use. One month of CPAP treatment has been shown to lead to adaptive alterations in the neurocognitive architecture that underlies the reduced sleepiness and improved verbal episodic memory in patients with obstructive sleep apnea (39). The authors hypothesize that partial neural recovery occurs during short periods of treatment with CPAP.

Special considerations

Anesthesia

The anesthesiologist should be forewarned about a patients obstructive sleep apnea prior to an operation. For patients using nasal continuous positive airway pressure, this should be applied at their customary pressure immediately after extubation until the effects of sedatives or anesthesia have worn off.