Review of Sleep Disorders and Therapeutic Approaches in Patients With Autism Spectrum Disorder and Rett Syndrome

Katelyn Bricker; Bradley V. Vaughn

doi:10.17241/smr.2024.02509

Sleep Med Res > Volume 15(4); 2024 > Article

Bricker and Vaughn: Review of Sleep Disorders and Therapeutic Approaches in Patients With Autism Spectrum Disorder and Rett Syndrome

Review Article

Sleep Med Res 2024; 15(4): 228-236.

Published online: Dec 31, 2024

DOI: https://doi.org/10.17241/smr.2024.02509

Review of Sleep Disorders and Therapeutic Approaches in Patients With Autism Spectrum Disorder and Rett Syndrome

Katelyn Bricker, MD, MS

, Bradley V. Vaughn, MD

Department of Neurology, School of Medicine, The University of North Carolina, Chapel Hill, NC, USA

Corresponding Author Katelyn Bricker, MD, MS Department of Neurology, School of Medicine, The University of North Carolina, Chapel Hill, 101 Manning Dr, NC, USA Tel +1-4192156961 Fax +1-9849742285 E-mail katelyn_bricker@med.unc.edu

Received Oct 11, 2024 Revised Dec 3, 2024 Accepted Dec 8, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Sleep complaints are frequent in children with autism spectrum disorder and Rett Syndrome and sleep itself may influence further neurodevelopment in these disorders. This comprehensive review attempts to explore the connection between sleep disorders and brain development in children facing autism spectrum disorder and Rett Syndrome. We will evaluate the underlying neurobiological mechanisms and potential interventions.

Key words: Sleep disorders, Autism spectrum disorder, Rett syndrome, Sleep wake disorders

INTRODUCTION

Autism spectrum disorder (ASD) and Rett Syndrome (RTT) are neurodevelopmental disorders characterized by impairments in social communication, repetitive behaviors, and, in the case of RTT, loss of purposeful hand skills. These disorders affect cognitive, social, and behavioral development. Sleep disturbances are frequently reported in over two-thirds of individuals with ASD and RTT, posing additional challenges for affected individuals and their families. RTT has a known genetic component, and research suggests ASD may have genetic components as well as environmental factors early in development which play a role in the etiology of autism [1]. RTT is primarily the result of sporadic and de novo mutations in the MECP2 gene, predominantly affecting females [2]. Evidence suggests these two disorders may share genetic pathways contributing to sleep disorders in these populations. RTT was previously classified as part of a pervasive developmental disorder in DSM-IV. DSM-5 now recognizes RTT as a separate disorder. DSM-IV attempted to systematize the different clinical disorders associated with autistic features, including RTT, however, DSM-5 has taken new knowledge on the phenotype of RTT and differentiated this entity from autistic disorder. This shift occurred given the severe autistic features in RTT may be transient, as well as lack of reasoning to select RTT over other genetic disorders associated with ASD [3]. This review will explore the bidirectional relationship between sleep disorders and brain development in those with ASD and RTT.

SLEEP DISORDERS IN ASD

Prevalence and Types of Sleep Disorders in ASD

Sleep disorders, such as insomnia, circadian rhythm disturbances, and sleep-related breathing disorders, are highly prevalent in individuals with ASD. These children experience sleep disturbances at higher rates than the general population, especially insomnia [4]. The prevalence of ASD in the United States is estimated from 1 in 59 to 1 in 40 [5]. A meta-analysis found a pooled prevalence of sleep disorders in ASD being 13%, compared to 3.7% in the general population [6]. A separate systematic review found that children/adolescents with ASD presented with significantly higher sleep-onset delay, bedtime resistance, night awakenings, parasomnias, daytime sleepiness, sleep onset latency, sleep disordered breathing, general sleep problems, and lower sleep duration [7]. Recent studies suggest a bidirectional relationship between sleep and core symptoms of ASD. In ASD, disordered sleep may exacerbate autistic symptoms including deficits in social skills, ADHD, repetitive behaviors, therefore interventions to improve sleep have the potential for significant benefit [8-10]. In addition to improving a child’s daytime behavior, family functioning may also benefit from improved sleep in children. Sleep disturbances in autistic children and those with other neurodevelopmental disorders are associated with parenting stress [11-13], possibly mediated by the poor quality of parent sleep. It has been found that parents of children with ASD have poorer sleep quality than parents of typically developing children [14], and a child’s sleep quality predicts a mother’s sleep quality [15]. Therefore a child’s sleep has a direct impact on daytime behavioral measures and parental well-being.

Polysomnographic Findings in ASD

Objective findings support that children with ASD have more difficulty with sleep. Overall children with ASD take longer to fall asleep, exhibit shorter total sleep time, and have a lower sleep efficiency compared to typically developing children [16,17]. However, despite the shorter sleep times and lower sleep efficiency, a 2023 study determined that individuals with ASD exhibit a higher percentage of slow wave sleep and lower percentage of rapid eye movement (REM) sleep in comparison to typically developing children. This increased ratio of slow wave sleep in children with ASD appears to be associated with more severe core ASD symptoms, such as repetitive and stereotyped behaviors [18]. These findings also correlate with subjective reports of typical sleep symptoms in autism, such as difficulty with sleep initiation, nighttime awakening, and decreased sleep time [16].

UNDERLYING MECHANISMS OF SLEEP DISTURBANCE IN ASD

Many factors contribute to sleep disturbances in ASD, including genetic predisposition, alterations in melatonin regulation, and abnormalities in the neural circuits responsible for sleep-wake cycles. Sensory processing, neurotransmitter irregularities, synaptic dysfunction, and non-rapid eye movement (NREM)/REM disturbances are among other contributing factors. Understanding these mechanisms is crucial for developing targeted interventions.

Growing evidence suggests that sleep disturbances in children with ASD are linked to arousal dysregulation and sensory hyperresponsiveness, indicating the need for a sedation strategy to improve sleep [19]. Abnormal sensory processing or hyperalertness may interfere with sleep in ASD. Children with ASD may experience anxiety symptoms, leading to delays in sleep onset as well as insomnia. These individuals have difficulty with pre-sleep arousal and anxiety compared to typically developing children, which may be one of the challenges for them to falling asleep [20].

Insomnia in ASD is also thought to be related to abnormal melatonin levels [21]. It has been reported that children with ASD have a delayed melatonin phase contributing to the pathophysiology of their sleep disorders [22]. Melatonin is secreted by the pineal gland in the evening, starting from serotonin (5-HT), and its cyclic release aids in regulating the sleep-wake cycle as well as core body temperature rhythm [23,24]. ASD individuals show altered production of melatonin, which has been related to sleep difficulty [25]. One of the main reasons presumed to be responsible for altered circadian rhythms in ASD is attributed to low amplitude and delayed melatonin rhythm [26]. A systematic review of 35 studies assessing melatonin in ASD concluded that melatonin levels or melatonin derivatives were below average in ASD compared to controls. The melatonin pathway was also reported to be altered in multiple ASD subjects and correlated with ASD symptoms. Similarly, several studies showed administration of melatonin to ASD individuals improved overall total sleep duration, decreased number of night-time awakenings, and shortened sleep onset latency compared to placebo [27]. Prolonged treatment with melatonin for sleep issues in neurodevelopmental disorders has been found to improve both sleep and behavioral problems [28]. Pinato et al. [29] described the disrupted sleep-wake patterns, abnormal melatonin and glucocorticoid secretion, to emphasize the impaired circadian timing system in ASD. Low melatonin rhythm may have major effects. The study hypothesizes that melatonin or its analogs should be considered as pharmacologic agents to suppress inflammation and circadian dysregulation in ASD patients given the neuroendocrine dysfunction in this population [29]. Genetic variations in the melatonin receptor 1 A and B (MTNR1A, MTNR1B) and genetic mutations in acetylserotonin-O-methyltransferase may decrease melatonin levels and result in a flattening of the circadian rhythm [30]. These genetic variations have been seen in patients with ASD [31,21].

The disrupted sleep-wake cycle in children with autism have drawn many investigators to suspect an underlying dysfunction of the circadian rhythm. Tesfaye et al. [32] explored the circadian component of ASD by assessing the involvement of copy number variants surrounding circadian pathway genes and insomnia risk genes compared to ASD risk. Circadian pathway genes were found to have an impact on ASD burden, especially circadian pathway deletions. Copy number variants of genes in the circadian pathway and genes associated with insomnia had a stronger link with ASD compared to copy number variants of other genes [32]. One family of genes that function primarily as circadian rhythm maintenance are the period genes (PER) and may have an important role in ASD. PER2 mutations are associated with familial advanced sleep-phase syndrome 1 (FASPS1) and have been indicated in delayed sleep phase syndrome as well as idiopathic hypersomnia [33]. PER2 variants have been detected in individuals with ASD, suggestive of the possible role of circadian-related genes influencing the disorder. This case series alluded to loss-of-function variants in PER2 correlating with a broad variance of sleep disturbances and dysregulation of sleep overall, but it does not explain the relationship of sleep dysregulation and the pathophysiology of ASD [33]. Mutations in numerous genes (MECP2, VGAT, SLC6A1, SLC6A3, ARHGEF10, UBE3A, AHI1, PCDH10, KQNQ3, HRH1-3) can result in abnormal activity of wake-related neural circuits and subsequent sleep problems including prolonged sleep latency, waking up throughout the night, and short sleep duration [30]. Yang et al. [34] found several different mutations in patients with ASD and sleep disorders that affect gene function, suggesting circadian genes are related to the mechanism of ASD and sleep issues. PER1, PER2, and PER3 were seen more frequently in ASD than in controls and likely control gene expression in functional brain tissue. This study suggests circadian-relevant genes affecting gene function are more prevalent in ASD and may be involved in the pathogenesis of ASD [34]. Additional alerting mechanisms may involve the hypothalamic pathways for sleep and stress. Deregulation of the hypothalamic pituitary adrenal axis and cortisol production have been found in patients with ASD and linked to unchecked circadian rhythms [35].

Irregular neurotransmission may account for some of the variation of excitation and inhibition in the central nervous system (CNS) of patients with ASD. Gamma-aminobutyric acid (GABA) is a crucial inhibitory neurotransmitter in the CNS, involved in regulation of brain rhythm and spontaneous neuronal activities. Imbalances among excitation and GABAergic inhibition may contribute to CNS GABAergic system dysfunction [36]. MECP2, VGAT, and SLC6A1 gene mutations can all decrease GABA inhibition in the locus coeruleus and result in hyperactivity of the noradrenergic neurons and subsequent prolonged awakenings in ASD children. Mutations in HRH1, HRH2, and HRH3 tend to increase the expression of histamine receptors in the posterior hypothalamus, which may heighten histamine’s arousal promoting ability. KCNQ3 and PCDH10 gene mutations cause issues with regulation at the amygdala and its effect on orexinergic neurons, possibly leading to hypothalamic orexin hyperexcitability. Additionally, AHI1, ARHGEF10, UBE3A, and SLC6A3 genes have direct impacts on the processes controlling dopamine concentrations in the midbrain [30]. Although the exact pathway involving the anxiety and difficulty with reducing the arousal level prior to sleep is unknown, investigators have postulated that this may involve monoaminergic as well as hypothalamic dysregulation. Monoamine dysregulation, especially with serotonin have long been suspected. This dysregulation may in part be related to monoamine metabolism. Children with autism have been found to have reduced monoamine oxidase function in the frontal cortex, thus increasing the available synaptic alerting monoamines [37].

NREM and REM sleep disturbances can affect ASD individuals. Iron deficiency, thalamic reticular nucleus dysfunction, and butyric acid have been associated with NREM sleep disorders in children with ASD, related to PTCHD1 alterations [30]. Iron is involved as a cofactor in the production of monoamines, as well as important in presynaptic vesicle adhesion and several monoamine receptors [38]. Iron deficiency in ASD has been postulated to lead to incorrect metabolism of sleep-related transmitters and irregular formation of sleep spindles, therefore contributing to NREM sleep abnormalities. Iron deficiency is also associated with increasing movements during sleep [39]. Butyric acid is a component of GABA. Most butyric acid is produced by gut bacteria and butyric acid promotes NREM sleep by acting as a signaling molecule to the thalamus. The thalamic reticular nucleus dysfunction may be accountable for the shortened sleep duration and reduced spindle wave in NREM sleep in some individuals with ASD. Reduced abundance of butyric acid-producing bacteria in ASD children with sleep disorders may result in the decrease of butyric acid, consequently decreasing NREM sleep [30]. Mutations in genes such as SLC6A4, HTR2A, MAOA, MAOB, VMATs, TPH2, CADPS2, and SHANK3 may induce structural and functional changes in the dorsal raphe nucleus and the amygdala, disturbing REM sleep.

Synaptic dysfunction may be implicated in regulation of sleep and daytime performance and behavior. Doldur-Balli et al. [40] hypothesized that synaptic dysfunction is an underlying mechanism to explain ASD core symptoms and sleep dysfunction. Their review describes mutations affecting chromatin remodeling/transcriptional genes leading to synaptic dysfunction. Additional studies have also supported mutations in chromatin remodeling/transcriptional genes impairing synaptic function [41-43]. This synaptic dysfunction may be multifactorial. Butyric acid acts as a histone deacetylase inhibitor influencing genetic expression and synaptogenesis [44]. CDH8 also acts as a transcriptional regulator for remodeling chromatic structure and histone H1 recruitment to target genes, and has a significant role in dendritic and axon development in neuronal migration [41]. ARID1B is necessary for neuronal differentiation in brain development, and its deficiency may cause intellectual disability through inducing impaired differentiation of cortical neurons [42]. KMT5B is highly expressed in the prefrontal cortex, and its deficiency could result in autistic phenotypes by provoking synaptic dysfunction and aberrant transcription [43]. As synaptic pruning and reinforcement are thought to be an important function of sleep, synaptic function may be considered as future therapeutic targets for sleep dysfunction in ASD, and subsequently may improve other symptoms of ASD [45,40].

SLEEP DISORDERS IN RTT

Unique Sleep Patterns in RTT

RTT is characterized by distinct sleep patterns, with sleep fragmentation, increased nocturnal awakenings, and daytime hypersomnolence. Sleep disturbance is reported in over 80% of females with RTT, with impaired sleep being part of the diagnostic criteria [46]. Specific sleep problems in RTT have been found to be difficulty falling asleep, night screaming, night laughing, nocturnal seizures, bruxism, difficulty waking, daytime napping, and a high prevalence of nocturnal awakenings [47,48]. Katz et al. [49] reported altered sleep architecture in RTT subjects, including prolonged sleep latency, increased nighttime awakenings, and disrupted sleep stages. A meta-analysis of 19 studies found that most RTT subjects had taxing sleep. Excessive somnolence was found in 67% of subjects, 61% had challenges initiating and maintaining sleep, and sleep disturbance not otherwise specified was noted in 57% [50]. Young et al. [51] found sleep disorders in 80%–94% of cases of RTT (out of a total 237 case sample size), most frequently reported as daytime naps, nocturnal laughter, night screaming, seizures, and bruxism. Patients with RTT have longer sleep duration than healthy peers [52]. They also have reduced time of nighttime sleep with increased daytime sleep. These altered sleep patterns have been found to worsen over time [52]. Additionally, sleep disturbances have been interlaced with severe epilepsy, encouraging a comprehensive approach to managing both comorbidities [47]. Seizure frequency seems to be correlated with poor sleep and interferes with sleep architecture, as epilepsy may contribute to an increase in total sleep time and increased daytime sleep [47].

A meta-analysis of studies including polysomnographic results in RTT supported that these children have a shorter total sleep time and shorter sleep onset latency, longer wake after sleep onset and lower sleep efficiency. Similar to children with ASD, subjects with RTT had higher percentage of NREM stage N3, and lower percentage of REM sleep. Severe sleep disordered breathing was noted in RTT subjects, as well as severe nocturnal hypoxemia and apneic episodes [53].

Sleep disordered breathing is prevalent in RTT subjects. In a sample size of 11 subjects, a majority of patients with MECP2 mutations had obstructive sleep apnea both in REM and NREM sleep. Hypoxemia was also present throughout night sleep [54].

Sleep disturbances in RTT may exacerbate neurodevelopmental regression and cognitive decline, as evidenced by the primary caregivers of individuals with RTT. Sleep disturbance has negative impacts on children and their families, affecting development, general performance, mood, energy level, social relationships, and activities [46]. Improvement in sleep has been shown to increase mobility, eye contact, and concentration in children with RTT, but also benefits the parents [55]. The intricate relationship between sleep and cognitive function highlights the need for comprehensive therapeutic approaches.

The MECP2 gene encodes a DNA methylation reader protein that functions in transcriptional repression, transcriptional activation, and RNA binding [56]. Mutations can occur de novo or be inherited and lead to a loss of MECP2 function, having an effect on neuronal development and synaptic plasticity [57]. MECP2 mutations may alter the proper functioning of specific brain regions and have effects on the neurotransmitters involved in the sleep-wake cycle [58]. Mouse studies with different MECP2 mutations have pinpointed various impairments likely contributing to sleep disorders [59,60]. Approximately 90% of RTT patients have MECP2 mutations, a small portion carry mutations in other genes, such as CDKL5 and FOXG1, and can also result in phenotypes resembling RTT [61]. Failure of MECP2 and other genes mentioned in critical brain areas involving sleep-wake control may explain some of the sleep wakeproblems in disorders such as RTT [62]. Interestingly, synaptic dysfunction seen in RTT is also seen in ASD, and both disorders have associated sleep disturbance.

Mechanism of Sleep Disturbance in RTT

The mechanism of sleep disturbance in RTT can be explained through the use of animal models, showing highly fragmented sleep and circadian rhythm alterations [62]. Circadian rhythm abnormalities manifest as reduced night sleep, altered sleep/ wake patterns that worsen over time, delayed sleep onset, night waking, and naps [52,48]. The MECP2 gene is highly expressed in the suprachiasmatic nucleus (central circadian clock) and is phosphorylated with photic stimulation [63]. Li et al. [64] found that MECP2 mutant mice overall had quite deficient circadian rhythm activity, described as low in power, highly fragmented, and low precision rhythms, suggesting a weak circadian output. MECP2 mutant mice had increased fragmentation of sleep distinguished by an increase in the number of sleep bouts and a decrease in duration of each sleep bout. The mutant mice were noted to have difficulty initiating sleep (increased sleep latency) and have extremely fragmented sleep [64]. These findings suggest an important role of MECP2 in circadian timing and may explain a mechanism for sleep/wake disruption.

Loss of glutamate homeostasis appears to play a role in RTT sleep dysfunction. Glutamate is an important molecule involved in CNS signaling and involvement in regulation of wakefulness. Glutamate can induce neuronal and glial cell death via oxidative stress or excitotoxicity. MECP2-deficient microglia cells release excessive glutamate [65]. MECP2 regulates glutamate activity through transcriptional repression and epigenetic modification of various receptors [66]. Mouse studies have shown that MECP2-null mice have a significant increase in “in vivo” cortical glutamate levels in comparison to wild-type mice [67], and similar cerebrospinal fluid glutamate concentrations have been found to be significantly higher in RTT patients than controls [68]. This enhanced neuronal excitation may indicate the role of increased excitation underlying sleep dysfunction, as chaotic sleep in mice with MECP2 deficiency correlated with elevated baseline glutamate levels in the brain, and very high glutamate elevations associated with prolonged wakefulness [69]. Evidence from Jin et al. [65] supports the notion that both glutamate clearance and production are irregular in MECP2-deficient astrocytes, and may assist in the pathology of RTT.

Findings from Zhang et al. [54] support prevalent sleep disordered breathing in RTT. In a clinical sample of 11 female RTT subjects, more than half with MECP2 mutations had obstructive sleep apnea. Hypoxemia was also present throughout nocturnal sleep. Notably, sleep macrostructure did not differ upon the presence of sleep disordered breathing in RTT patients [54]. However, it is known that increased apnea hypopnea index causes sleep fragmentation through the presence of airway obstruction during sleep, terminated by brief microarousals [70]. Zhang et al. [62] reviewed 13 studies of animal models in RTT, finding that sleep fragmentation was common in animal models of RTT, characterized by disturbed sleep efficacy and continuity, with increased numbers of sleep bouts. A possible contributor to this sleep fragmentation and insomnia may be related to the degree of sleep disordered breathing, though further research is needed in this area.

Epileptic seizures are prevalent in RTT, even in sleep. Glaze et al. [71] report epilepsy occurring in up to 60% of RTT females, though other studies endorse up to 80%–94% prevalence [72,73]. Electroencephalography patterns show high-frequency oscillations, or sharp waves, which could be markers of seizure onset zones in epileptic brains [62]. Frequent seizures and severe epilepsy have been associated with poor sleep in RTT and interfere with sleep architecture [47]. Sleep fragmentation secondary to seizures may be another mechanism for insomnia in this population.

INTERVENTIONS AND THERAPEUTIC APPROACHES

Accurate diagnosis and monitoring of sleep disorders in ASD and RTT require a multidimensional approach, including sleep diaries, actigraphy, and polysomnography. Integrating these assessments into routine clinical practice is essential for timely intervention.

Clinical approach to these perplexing disorders can take two avenues. Strategies to improve the downstream behaviors and sleep pattern can involve augmenting the environmental clues for sleep and invoking strategies to promote the circadian rhythm.

Impaired sleep predisposes children to behavior, mood, and cognitive impairments that can also impact physical health [74]. Evidence shows that insufficient sleep has negative effects on learning, cognitive function, memory, attention, and other executive functions [75]. Sleep loss results in increased irritability, impulsivity, depression, hyperactivity, and aggressiveness [76]. Similarly, improved sleep can help daytime behavior and functioning. Optimization of sleep hygiene is the first line therapy for treatment of sleep dysfunction in both typically developing children and those with neurodevelopmental disorders [77], with the ultimate goal of improving daytime functioning.

Tailored interventions, such as behavioral therapies, pharmacological approaches, and melatonin supplementation, have shown promise in ameliorating sleep disturbances in ASD and RTT. Behavioral interventions, including sleep hygiene practices, structured routines, and cognitive-behavioral therapy, may mitigate sleep disturbances in children with neurodevelopmental disorders [78]. In a large study on behavioral interventions for sleep in children with ASD, mean sleep latency improved from a statistically significant 58.2 minutes to 39.6 minutes [78]. A personalized and multidisciplinary approach is crucial for optimizing treatment outcomes. The first line therapy for children with typical and atypical neurodevelopment is sleep hygiene, such as increasing daytime activities and bright light supplementation to limit daytime sleep, improve bedtime routines, and improve sleeping environment. Although medications are employed as second line agents for management, these medications are often chosen to manage the insomnia in children with neurodevelopmental disorders, as most of these medications promote sleep [79]. Notably, many hypnotics do not substantially reduce sleep issues in RTT.

The use of melatonin in managing sleep disturbance in children with neurodevelopmental disorders is attributed to the mechanism of altered melatonin production in this population. Wasdell et al. [80] studied the effects of controlled-release melatonin 5–15 mg given 20–30 minutes before bedtime in 50 children aged 2–18 years with multiple heterogeneous neurodevelopmental disorders and delayed sleep syndrome. They found that melatonin improved total nighttime sleep duration by 31 minutes and significantly decreased sleep onset latency compared to placebo [80]. A 2014 study assessed the pharmacokinetics of exogenous melatonin administration in ASD children, and found that melatonin’s benefits in this population may not only just correct the deficiency but may have additional beneficiary functions such as additive hypnotic effect, circadian rhythm shifting, and improvement in anxiety [81].

Clonidine acts centrally as an α2-adrenergic agonist to presynaptically inhibit norepinephrine activity and decrease sympathetic outflow [82]. It has sedative effects which may be beneficial in management of sleep in neurodevelopmental disorders. Clonidine is commonly used for poor sleep in children with neurodevelopmental disorders, especially associated with behavioral symptoms, yet has limited results [83].

Gabapentin crosses the blood brain barrier and binds to presynaptic α2δ-1 subunit of voltage gated calcium channels [84]. Gabapentin is one of a few medications that increases Stage N3 sleep and decreases arousals and fragmentation in adults. In a study of 23 children (87% had neurodevelopmental disorders) with refractory insomnia, gabapentin given at an average dose range of 5 mg/kg up to a maximum of 15 mg/kg, 30–45 minutes before bedtime, resulted in sleep improvement in 78% of patients [85]. This medication may have sleep benefit in neurodevelopmental disorders with sleep, but is not often used first line.

Benzodiazepines demonstrate hypnotic effects through the action of GABA_A receptors. Medications such as clonazepam may decrease sleep latency, increase total sleep time, and improve sleep maintenance but can be tied to increased daytime sleepiness, habituation, and risk of withdrawal when discontinued. Therefore use should typically be limited to short-term and as needed [82].

Trazodone is frequently used for its sedating effects in pediatric insomnia, though evidence is lacking in both typically developing children and those with neurodevelopmental disorders [83]. A small study including 17 children with opsoclonus-myoclonus syndrome, trazodone at 25 mg up to a maximum dose of 100 mg significantly increased the number of sleeping hours and decreased night awakenings [86].

Other sedating medications including atypical antipsychotics, antihistamines, and antidepressants, are sometimes used off-label for treatment of refractory insomnia in children with neurodevelopmental disorders [79]. The sedating properties of these medications may provide some additional benefit for insomnia when dosed at bedtime [83]. There is little evidence to support the use of these medications in this population for insomnia and can be associated with serious toxicity risks. Typically these medications are considered when comorbid conditions exist.

Trofinetide is an analog of a naturally occurring neuroprotective tripeptide, glycine-proline-glutamate, which is a product of the cleavage of insulin-like growth factor 1 (IGF-1) found in the brain [87]. It is US FDA approved for the treatment of RTT. Many studies (primarily in rat brains) indicate that Trofenitide improves synaptic functions, restores synaptic structure, reduces effects of neuroinflammatory substances in the brain, enhances antioxidant responses, attenuates injury-induced apoptosis, normalizes synthesis of essential proteins, restores normal brain homeostasis, and augments the concentration of IGF-1 in the CNS [88-91]. Trofinetide’s mechanism is not fully established, though it is reported to improve neuronal morphology and synaptic functioning [92]. Therefore Trofinetide may have promise in improving the symptoms of RTT including sleep. In a case study of RTT treated with Trofinetide, one child showed overall improvement in sleep while on the medication [93]. Additionally, in a double-blind placebo-controlled trial of trofinetide using the Rett Syndrome Behavioral Questionnaire, significant improvement was noted in nighttime behaviors, mood, and anxiety suggesting improved sleep with the medication [88].

Similar to RTT, melatonin supplementation is often considered in the treatment of ASD sleep disorders if behavioral interventions fail. Melatonin is a hormone essential for regulating the sleep-wake cycle. A systematic review published in 2020 reported sleep recommendations in ASD based on their findings. Children with ASD are at an increased risk of coexisting medical conditions that may contribute to sleep disturbance, such as epilepsy, intellectual disability, reflux, depression, anxiety, ADHD, and behavior issues. These children are more likely to use stimulating medications that disrupt normal sleep or psychotropic medications. Coexisting medical conditions should be screened for and treated. If behavioral strategies such as environmental and bedtime routines, good sleep hygiene, and positive routines are ineffective, then melatonin can be tried. Immediate-release forms of melatonin are more helpful for sleep onset, and controlled release may help with sleep maintenance [94]. A recent meta-analysis found melatonin to be effective in treating insomnia in children with ASD by shortening sleep onset latency, reducing frequency of night awakenings, and prolonging total sleep time [95].

Several mechanisms cited above contribute to sleep issues in RTT and ASD. RTT and ASD have overlap of some of these proposed mechanisms such as circadian rhythm dysfunction and changes to neurotransmitter levels. Children with ASD have circadian rhythm dysfunction, abnormal melatonin production and glucocorticoid secretion, imbalances among excitation and GABAergic inhibition, in addition to synaptic dysfunction. While in RTT, MECP2 mutation and its role in circadian timing as well as loss of glutamate homeostasis contribute to poor sleep. Future treatment approaches could focus on targeting these mechanisms. Understanding the commonality of some mechanisms allows for similar management strategies such as improvement of the circadian rhythm through enhancement of entrainment factors. Yet others offer the promise for more individualized therapies.

CONCLUSION

This mini-review highlights the complex relationship between sleep disorders and brain development in individuals with ASD and RTT. Sleep disorders profoundly influence brain development in pediatric neurodevelopmental disorders, particularly in suboptimal conditions.

By understanding the relationship between sleep and brain development, we can develop more effective interventions and improve the quality of life for affected children and their families. Early identification and intervention for sleep disorders in children with neurodevelopmental disorders are crucial for optimizing developmental outcomes. Multidisciplinary collaboration between pediatricians, neurologists, psychologists, and sleep specialists is essential. Further research is needed to enhance our knowledge and treatment options in these areas.

NOTES

Availability of Data and Material

Data sharing not applicable to this article as no datasets were generated or analyzed during the study.

Author Contributions

Conceptulatization: all authors. Data curation: all authors. Writing—original draft: Katelyn Bricker. Writing—review & editing: all authors.

Conflicts of Interest

The authors have no potential conflicts of interest to disclose.

Funding Statement

None

ACKNOWLEDGEMENTS

None

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