Current Considerations in the Diagnosis and Treatment of Circadian Rhythm Sleep-Wake Disorders in Children

Abstract

Circadian Rhythm Sleep-Wake Disorders (CRSWDs) are important sleep disorders whose unifying feature is a mismatch between the preferred or required times for sleep and wakefulness and the endogenous circadian drives for these. Their etiology, presentation, and treatment can be different in pediatric patients as compared to adults. Evaluation of these disorders must be performed while viewed through the lens of a patient’s co-morbid conditions. Newer methods of assessment promise to provide greater diagnostic clarity and critical insights into how circadian physiology affects overall health and disease states. Effective clinical management of CRSWDs is multi-modal, requiring an integrated approach across disciplines. Therapeutic success depends upon appropriately timed non-pharmacologic and pharmacologic interventions. A better understanding of the genetic predispositions for and causes of CRSWDs has led to novel clinical opportunities for diagnosis and improved therapeutics.

INTRODUCTION

Circadian rhythms are near-24-hour oscillations observed in essentially every physiological process in the human body.¹ As such, the degree of proper functioning of the circadian timing system in the synchronization of clocks across the entire body by a central pacemaker represents a measure of health; it allows for the adaptation and optimization of physiology in response to changes in our environment. Conversely, dysfunction of this system manifests as human disease. We consider sleep-wake cycling as the outward manifestation of two interacting processes, a process dependent on the circadian organizer (Process C) and a homeostatic drive to sleep that depends on the duration of wakefulness and level of physical and cognitive activity (Process S).^{2, 3} Over the span of infancy and childhood, behavioral changes in sleep are due to the dynamic interplay between these two maturing processes, which are both influenced by individual characteristics as well as familial and social environments.⁴ It is of critical importance to consider this context when assessing sleep disorders in pediatric populations as the occurrence of sleep and wakefulness at irregular times can be developmentally appropriate (e.g., irregular rest-activity rhythms in a neonate) and not a disorder at all. More work is needed to better understand factors that shape the establishment and maturation of the circadian clock.

The hallmark of Circadian Rhythm Sleep-Wake Disorders (CRSWD) is a mismatch between one’s endogenous circadian drives for sleep and wakefulness and the sleep-wake times dictated by school, work, social functions, or personal preference. CRSWD are further divided into exogenous/extrinsic and endogenous/intrinsic disorders.^{5, 6} Exogenous/extrinsic disorders, such as Shift Work Disorder and Jet Lag Disorder, are the result of sleep occurring at an adverse circadian time because of exogenously prescribed alterations in the timing of sleep and wakefulness (due to work schedules and travel, respectively) rather than a disturbance of the endogenous circadian system itself. Given that these disorders are less commonly encountered in the pediatric sleep clinic, we will not address these further in this review.

Diagnosis of Intrinsic Circadian Rhythm Sleep-Wake Disorders

The diagnostic criteria for the four intrinsic Circadian Rhythm Sleep-Wake Disorders (CRSWDs), Delayed Sleep-Wake Phase Disorder (DSWPD), Advanced Sleep-Wake Phase Disorder (ASWPD), Irregular Sleep-Wake Rhythm Disorder (ISWPD) and Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWRD), share some common features. All require that symptoms are present for at least three months. In the most recent text revision of the third edition of the International Classification of Sleep Disorders (ICSD-3-TR), sleep logs, accompanied by actigraphy monitoring whenever possible, are required for diagnosis. ⁷ For DSWPD, ASWPD, and ISWRD, monitoring should be for at least 7 days (including holidays and weekends), but preferably 14 days, while for N24SWRD, at least 14 days are required (although preferably longer for non-sighted individuals). In practice, weeks to months of monitoring may be necessary to adequately assess someone with N24SWRD. Lastly, the sleep disturbance of the aforementioned disorders requires the sleep disturbance cannot be better explained by another current sleep disorder, medical disorder, mental disorder, or by medication/substance use.

Delayed Sleep-Wake Phase Disorder (DSWPD)

In addition to the previously mentioned criteria, a diagnosis of DSWPD requires a significant delay in the phase of the primary sleep bout in relation to the preferred or required sleep onset and offset time that results in functional consequence (Figure 1A). When the child is allowed to sleep ad libitum, however, those with DSWPD will see an improvement in their sleep quality and duration. This response to ad libitum scheduling distinguishes disorders of phase from other differential diagnoses, such as chronic insomnia or hypersomnolence disorders which do not see improvements in sleep quality or wakefulness when allowed to sleep as much or as often as desired. Sleep logs and actigraphy over 7+ days typically demonstrate a delayed sleep onset and sleep offset usually greater than 2 hours relative to times that are socially acceptable. Polysomnography performed during the delayed phase of the primary sleep bout is typically normal for age.

Figure 1.

Double-plotted actograms demonstrating representative rest-activity cycles of individuals with (A) DSWPD, (B) ASWPD, (C) ISWRD, and (D) N24SWRD. Each row of these actograms shows two successive days next to each other, in different columns on a single row. Successive days are beneath each other, on different rows in the same column.

Several pediatric populations may be at higher risk to develop DSWPD of a likely multifactorial etiology. DSWPD is frequently comorbid in adolescents with ADHD⁸ and having an evening chronotype was more prevalent for individuals with ADHD compared with healthy controls.^{9, 10} Children with autism spectrum disorder can also have ISWRD and DSWPD with some positing that such circadian desynchrony creates a vulnerability to develop symptoms of autism spectrum disorder.¹¹ Typically developing teens are also at particular risk of developing DSWPD, as they experience maturational changes in their sleep biology which include the delaying of circadian phase, a slowing of the accumulation of sleep homeostatic pressure across the waking day, and a slowing of the dissipation of sleep homeostatic pressure (late adolescence).^12–14 DSWPD prevalence estimates in teenagers vary widely (0.4 to 16%).^15–19

In addition to the aforementioned possible etiological explanations for DSWPD, there is additional evidence in the literature for a circadian phase delay. ^{20, 21} Other supported causes include a prolonged circadian period,²² a differential sensitivity to light at different times of day,²³ and patterns of daily light exposure supportive of a delayed sleep phase.^{24, 25}

Advanced Sleep-Wake Phase Disorder (ASWPD)

To diagnose ASWPD, there must be an appreciable advance in the phase of the primary sleep bout in relation to the preferred or required sleep onset time and wake-up time (Figure 1B). Similar to DSWPD, an ad libitum schedule results in improved sleep quality and duration. Also similar to DSWPD, monitoring by sleep logs and actigraphy typically demonstrate a 2+ hour advancement of the phase of the major sleep bout. Those with ASWPD typically have normal polysomnographic findings when the study timing is aligned with the ad libitum primary sleep bout.

ASWPD in pediatric populations is infrequently encountered, such that a diagnosis in a pediatric sleep clinic should prompt further consideration of a genetic (de novo or inherited) cause.^{26, 27} Given this, prior to diagnosis in children of a young developmental age, it is important to consider what constitutes developmentally appropriate sleep time and wake time for a child. A caregiver’s complaint of “early morning waking” may in fact be appropriate for age (though not at the parent’s preferred timing) or the result of excessive time in bed.

An expanding literature continues to document familial forms of ASWPD with heritable mutations in clock genes. In addition, neurogenetic syndromes, such as Smith-Magenis syndrome have altered circadian dynamics, which can include an advancement in their sleep phase.^{28, 29} Interestingly, while not ASWPD, an advanced sleep phase has been seen in adolescents who were born prematurely.^{30, 31} Proposed etiologies for ASWPD include a shortened circadian period,^{32, 33} an impaired ability to phase delay, and an altered ability of zeitgebers (entraining agents) to modulate circadian dynamics.³⁴

Irregular Sleep-Wake Rhythm Disorder (ISWPD)

A diagnosis of ISWRD requires a chronic or recurrent pattern of sleep and wake episodes that are irregularly timed and often of variable duration (typically between 2–4 hours) throughout a 24-hour period (Figure 1C). Insomnia during the scheduled sleep time, napping during the day, or both, can be seen. Sometimes, a major sleep period cannot be established, although many patients will have a slightly longer sleep episode at night.³⁵ Rarely seen in typically developing children, ISWPD is more commonly seen in those children with neurodevelopmental disorders, including some with Angelman syndrome,³⁶ autism spectrum disorder,^{37, 38} Smith-Magenis syndrome,²⁸ and Rett syndrome,³⁹ or neurodegenerative disorders, such as neuronal ceroid lipofuscinosis.⁴⁰ ISWPD also affects patients with congenital blindness,⁴¹ traumatic brain injury,⁴² or survivors of pediatric brain tumors.^{43, 44}

Putative etiological explanations for ISWRD relate to the dysfunction of inputs to the suprachiasmatic nucleus (SCN), the central organizer of the circadian timing system, of the SCN itself, or of its outputs.^{34, 45} Processes that can affect the signals that entrain the circadian timing system, that involve retinal and/or retinohypothalamic tract pathology,^{40, 41} or that can affect SCN integrity are suspect in ISWRDs. Furthermore, perturbations of the rhythmicity of SCN outputs, such as reduced melatonin secretion,^{36, 39} impaired core body temperature regulation,⁴⁶ and decreased synchronization of brain rhythms,⁴⁷ can lead to aberrant physiologic rhythms and inappropriate feedback to the SCN, resulting in ISWRDs.

Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWRD)

In N24SWRD, the patient is not able to entrain their sleep - wake cycle to a 24-hour schedule. In addition to the above diagnostic criteria, there must be a history of insomnia, excessive daytime sleepiness, or both, with alternating periods without symptoms, when the patient’s sleep-wake propensity is aligned with the external 24-hour light-dark cycle. Typically, patients exhibit a progressive phase delay in circadian rhythms⁴⁸(Figure 1D), although progressive phase advances may occur depending on the patient’s endogenous circadian period length (tau). Clues to this diagnosis in pediatric populations are 1) caregiver complaints about a predictable misalignment between a child’s patterns of sleep and the 24-hour light-dark cycle and 2) periods of “spontaneous” symptom remission when the child’s patterns of sleep and the 24-hour light-dark cycle are aligned.

Non-sighted individuals are at high risk for N24SWRD, as are those with certain neurodevelopmental abnormalities (such as children with optic nerve hypoplasia, especially if there is a hypoplastic corpus callosum and other midline abnormalities), given the high likelihood of dysfunction of SCN inputs. Prevalence estimates near 40% in those non-sighted individuals without light perception.⁴⁹ It is posited those non-sighted individuals without N24SWRD are able to remain entrained to a 24-hour schedule because of non-photic stimuli (eg. variably timed rest-activity schedules, social and exercise stimuli, and exogenous agents) whose rhythms of influence synchronize to a 24-hour light-dark cycle⁵⁰ and/or retained ocular photoreception in the absence of image-forming vision.^50–52 Sighted individuals may also develop N24SWRD, although prevalence estimates are not known. Individuals may first present with DSWPD (often with later, longer sleep times when considering the average of those with DSWPD),^{22, 53, 54} and subsequently develop N24SWRD, suggesting that N24SWRD may be an extreme expression of DSWPD.⁵⁵ Empirical evidence in such populations posits in certain individuals, DSWPD and N24SWRD may result from reduced melanopic phototransduction leading to non-entrainment.⁵⁶ Endogenous circadian periods whose lengths are outside the range of entrainment to the 24-hour light-dark cycle are also proposed to cause N24SWRD in some,²² as are altered rates of accumulation of homeostatic pressure. There are case reports of sighted individuals who acquired N24SWRD after traumatic brain injury;⁵⁷ in at least one, microscopic brain damage in the vicinity of the SCN or its output pathways was hypothesized. N24SWRD has also developed after chronotherapy for DSWPD.^{54, 58} In pediatric patients with neurodevelopmental disorders, such as autism spectrum disorder, Rett syndrome, and Angelman syndrome, it is proposed an inability to properly perceive or attend to photic and non-photic cues can manifest as N24SWRD.⁷ Older children with limited exposure to photic and non-photic entraining cues have also developed this disorder.

While our knowledge of normal circadian physiology continues to expand rapidly, the utilization of these insights to inform clinical practice has been hindered, in part, by limitations of current phenotyping and diagnosis. First, the diagnosis of a phase disorder which relies on a misalignment of the circadian timing system with a preferred or required sleep time (rather than a fixed “clock” time) is an issue. Second, while the etiologies of certain diagnostic entities are thought to be secondary to abnormalities of the underlying circadian timing system, querying that system is not required for diagnosis. This has significant implications for the treatment of these disorders, which is often designed to alter circadian phase. Without objective circadian measurements, such treatments may be applied inappropriately. It has been noted some individuals with extreme sleep timing actually have normal circadian timing.²⁰ Objective measurements of circadian timing could lead to the identification of subpopulations more likely to benefit from a particular therapy. The development of practical measures of central and peripheral circadian oscillations promises to lead to significant field advances.⁵⁹

Considerations for Clinical Evaluation

Detecting the Clock - Assessments Related to the Evaluation of CRSWDs Non-physiologic Measurements

As stated, the current diagnosis of CRSWDs requires the demonstration of a functionally impactful inability to fall asleep and awaken at preferred times. Non-physiologic methods of assessment to determine an individual’s sleep-wake behavior include sleep logs (required for most CRSWD diagnoses⁷), actigraphy, and questionnaires. Sleep logs, also called sleep diaries, are used to record the daily metrics of the sleep wake cycle such as bedtime, time of sleep onset, wake time, time of medication dose, etc. The primary function is to note the time of each metric, though subjective information such as sleep quality may also be included. They are available in both paper and electronic forms and are completed by patients or caregivers, typically for at least two weeks. Sleep logs have many advantages; they are easily accessible, very low cost, non-invasive, relatively simple to use, and provide reliable data.⁶⁰ Sleep log data collected at least five weekday nights from adolescents spread over four continents demonstrated good inter-cohort reliability and sleep log data collected from a population subgroup showed stable sleep patterns over a 12-week period.⁶¹ Drawbacks of sleep logs include a lower compliance as compared to other evaluation methods, such as actigraphy, and the presence of inherent confounders, such as recall, observer, and recency bias.⁶²

Actigraphy is a method determining a patient’s rest-activity pattern. This is done with the use of an actigraph unit, a small, non-invasive, battery powered device which is typically worn on the non-dominant wrist and measures movement with accelerometry. Over the past 20 years, actigraphy’s use has grown in the clinical evaluation of individuals with suspected or confirmed sleep disorders for whom understanding rest-activity patterns (as a proxy for sleep-wake habits) across multiple nights is needed.⁶³ The proliferation of research and consumer-grade wearables and personal home monitoring devices that can collect non-directional acceleration data (in addition to other physiologic measurements) also has made this method of assessment more accessible recently. It is now understood that such information can inform clinical decision-making. As such, the AASM has issued a conditional recommendation for its use in the assessment of pediatric patients with CRSWDs.⁶³

The metrics provided by actigraphy can be used in conjunction with sleep logs, though may not have complete concordance. Sleep log data and actigraphy data obtained during the evaluation of CRSWDs in children showed good correspondence for certain sleep parameters, such as sleep latency and time of sleep onset. However estimates of total sleep time were shorter, and time of sleep offset earlier, with actigraphy compared to sleep logs.⁶⁰ Using rest-activity data to predict the state of the endogenous circadian timing system is an area of active research. Although rest-activity rhythms need not reflect timing of the central clock (eg. in shift workers, in the non-sighted), promising recent research utilizing actigraphy (and sometimes light) data and mathematical modeling has allowed researchers to estimate DLMO within hours for children, healthy adults and those with displaced sleep.^64–67

Standardized questionnaires to assess a person’s chronotype can also be used in the clinic. A chronotype relates to a preference for or to actual behavioral activity timing within the 24-hour day. It is thought to reflect the entrained phase of the individual’s circadian clock.⁶⁸ Chronotype assessments query (1) an individual’s self-reported preference to perform certain activities at specific times (as performed in the Horne-Östberg questionnaire, also called the Morningness-Eveningness Questionnaire [MEQ]),⁶⁹ (2) sleep-wake timing on free days (assumed to reflect circadian timing) and work/school days (assumed to reflect social constraints) as performed in the Munich Chronotype Questionnaire (MCTQ)⁷⁰ and the mini-Munich Chronotype Questionnaire (μMCTQ),⁷¹ and (3) a child’s circadian preference (as in the Children’s ChronoType Questionnaire (CCTQ)),⁷², using caregiver report of that child’s mid-sleep time on “free” days and a multi-item morningness/eveningness score. Both mid-sleep time on “free” days and the morningness/eveningness score correlate with dim light melatonin onset (DLMO), the current gold standard circadian phase measure in humans.⁷² Measures that consider more general aspects of sleep timing for adults include the Pittsburgh Sleep Quality Index⁷³ and others in the NIH PhenX Toolkit,⁷⁴ while additional children’s measures include the Children’s Sleep-Wake Scale⁷⁵ and the Children’s Sleep Habits Questionnaire.⁷⁶

The widespread utilization of smartphone technology⁷⁷ and social media^{78, 79} has inspired innovative uses of these to evaluate circadian rhythmicity and how behaviors may influence these rhythms,⁸⁰ although such methods are not utilized clinically yet.

Physiologic Measurements

Physiologic assessment measures hold promise they may actually report on the state of the endogenous circadian timing system. This not only will offer diagnostic/therapeutic clarity regarding CRSWDs, but will also offer important mechanistic insights regarding the circadian timing system itself in health and disease.

The current gold standard for determination of phase of the central circadian pacemaker relies on the detection of the hormone melatonin, which can be measured in the saliva, blood, or urine (as 6-sulfatoxy melatonin, a metabolite of melatonin). Normally, melatonin conveys important information about light-dark cycling to the brain and the rest of the body. Light information sensed by the photosensitive retinal ganglion cells (pRGCs; also known as melanopsin retinal ganglion cells or intrinsically photosensitive retinal ganglion cells (ipRGCs)) is modulated by rod and cone inputs within the retina,⁸¹ is transmitted via the retinohypothalamic tract to the SCN (which contains the central circadian pacemaker), and serves to entrain the SCN to the external environment. The SCN then predominantly controls the secretion of melatonin by the pineal gland,^{82, 83} a fact which is key to the relevance of melatonin as a circadian rhythm biomarker.⁶⁸ Other physiologic changes in core body temperature, in somnolence, and in the EEG that reflect the start of the SCN-regulated biological night⁸⁴ are tightly correlated with melatonin rhythm dynamics. Very low daytime melatonin levels begin to rise 1–3 hours before a person’s habitual sleep time and are high during the biological night, returning to low daytime levels within 1 hour of habitual wake time.⁸⁵ The evening onset of melatonin secretion under dim light conditions is termed dim light melatonin onset (DLMO). Although masked by light, the masking effects of the sleep-wake cycle on melatonin are small. DLMO determination is extremely useful for circadian researchers, but also for clinicians, with some arguing for its necessity in the appropriate, timely treatment of those with CRSWDs with therapies that include light therapy, chronotherapy, and melatonin.⁸⁶ DLMO determination can be done relatively non-invasively (salivary), is sensitive and specific, and is robust (valid in many situations and in different populations)⁶⁷. However, its clinical use is still limited. Currently, the circadian clinics employing the detection of DLMO require patients to self-pay, as there is questionable reimbursement by insurance. In addition, the collection conditions (sampling occuring every 30–60 minutes in dim light (<5–10 lux) beginning at least 6–7 h before habitual bedtime and continuing until habitual bedtime or later) necessary for interpretable results can be prohibitive for some patients. However, measuring melatonin in clinical settings such as hospitals or nursing homes is sometimes easier than in other environments.⁶⁸ Protocols for in-home sampling for DLMO detection have been developed and validated in patient populations,^{87, 88} including children.^89–91 The clinician should also be aware that melatonin profiles can be modulated by activity,⁹² posture,⁹³ medications such as NSAIDs and beta-blockers,^94–96 and substances/foods including caffeine, alcohol, pitted fruits, and bananas.^97–100 In fact, suppression of endogenous melatonin rhythms in those with a CRSWD along with timed administration of exogenous melatonin, has been used for clinical benefit.¹⁰¹

Physiologic variables, such as blood pressure, heart rate, blood glucose or skin temperature, that may be assessed through ambulatory monitoring, may also be useful in the determination of circadian phase. However, their varied reliability, consistency, and their ability to be affected by sleep-wake state, feeding status, and body position limit their current use in isolation to determine circadian timing.⁶⁸ Recently, innovative methods utilizing multiple regression or neural network approaches have used data from the simultaneous recording of several of these variables (often along with behavioral data) to determine melatonin phase.⁶⁷ Pupillometry also holds promise as a way to query the status of the circadian timing system, if not to determine circadian phase. While the pupillary light reflex (PLR) is routinely used clinically to assess retinal and optic nerve function, easy-to-use protocols are able to assess the rod, cone, and melanopsin contributions to pupillary dynamics.^{102, 103} These dynamics relate to assessments of circadian system robustness¹⁰⁴ and are impaired in those with DSWPD and N24SWRD,⁵⁶ as well as in those with idiopathic hypersomnia with long sleep time, which may be driven by a circadian process.¹⁰⁵

Recent scientific advances have generated great excitement for the evaluation of central and peripheral circadian processes by -omics approaches, in part, because such assessments may only require one or two samples to determine circadian phase. Analysis of rhythmic gene expression patterns in skin,^106–108 blood,^109–113 hair follicles,^114–116 and of the metabolome^{117, 118} promise not only to estimate central and peripheral clock time, but also to yield fundamental insights regarding circadian physiology. It is understood, however, that prior to translation of any of these to the clinical setting, these putative biomarkers will not only require rigorous assessments of reliability, sensitivity, and specificity, but must also be validated against current gold standards using realistic protocols in healthy and clinical populations.

Behavioral Sleep Medicine

As noted, CRSWD are more prevalent in children with neurodevelopmental disorders including ADHD and ASD; further, youth with mood disorders are at elevated risk for a delayed sleep phase.¹¹⁹ Sleep duration and instability in the sleep-wake rhythm are associated with greater depression and mania symptoms and there is greater functional impairment in those with sleep disturbances; thus, changes in sleep and energy levels together with mood lability and other symptoms are therefore essential for early intervention and prognosis.¹²⁰ Clinical assessment of CRSWD should include identification of current and historical psychiatric diagnoses and treatment with a focus on current management practices, symptomatology, and functional impairment that could serve as barriers to effective treatment. Whereas sleep onset and sleep maintenance difficulties are core symptoms of CRSWD when the affected person is attempting to sleep out of phase with their circadian rhythm, some individuals may develop chronic insomnia and thus experience sleep difficulties even when sleeping in phase with their circadian rhythm. Evidence suggests that over half of adolescents with DSWPD also meet criteria for insomnia.¹²¹ Thus, ongoing assessment of the severity of insomnia symptoms pre-, during, and post-CRSWD is critical.

Considerations for Treatment

Basic Concepts for Timing

Correctly timed exposure to light, darkness, exogenous melatonin, hypnotics (to aid in sleep onset), and sleep consolidating medications (to aid in sleep continuity), among other forms of treatment, can be used therapeutically to stabilize sleep onset. The incorporation of appropriately timed therapy is critical for establishing consistent sleep onset times, and eventually to phase shift circadian rhythms, as a means to move sleep onset time earlier or later.^{122, 123} However, the timing of any therapy relative to an individual’s internal circadian clock is integral to the success of the selected or preferred treatment. The direction and extent of movement of a patient’s circadian rhythm is dependent on the sleep phase response curve.^124–127

Timing of Sleep (i.e., Delaying sleep phase)

Since most humans have an endogenous clock that runs slightly longer than 24 hours,¹²⁸ it is generally easier to phase delay (shift sleep onset later).¹²² In turn, it is often more difficult to phase advance (shift sleep time earlier) in a patient that presents with a delayed sleep phase (later sleep onset time).¹²² It is critical to stabilize sleep onset (establish consistent sleep onset times) prior to phase shifting a patient’s circadian rhythm, regardless of whether the effort is focused on phase delaying or phase advancing.

Light / Blue light exposure or avoidance

The circadian system has evolved around the 24-hour solar day.¹²⁹ The central clock in the brain is located in the SCN of the hypothalamus and acts as the master pacemaker for the other peripheral clocks located throughout the body.¹³⁰ The circadian system is designed to support nocturnal sleep, coinciding with increasing levels of circulating melatonin.¹³¹ Since daylight can synchronize the central clock located in the SCN through retinal ganglion cells,¹³² it is important to understand how different wavelengths of light impact the central clock, thus modifying circadian rhythms. In fact, targeted light therapy is now used as a method of advancing or delaying the sleep cycle.¹³³ Blue light (wavelengths between 446–477 nm), for example, is particularly effective at shifting these circadian rhythms.^{133, 134} However, the effects on the sleep wake cycle are dependent on the timing of exposure relative to a specific individual’s internal clock and nadir in core body temperature.^{135, 136} Exposure to ambient light or from light-emitting diode (LED) sources (ie. computer, television, phone, tablet, screens) in the evening can delay secretion of melatonin from the pineal gland,^{137, 138} thus decreasing sleepiness^{137, 139} and prolonging time to sleep onset.¹³⁹ Coincidentally, the photoreceptors within the circadian system are maximally sensitive to blue light.^{140, 141} In a study of ~1,500 Americans that were interviewed on the association between use of technology and sleep disturbance, 9 out of 10 respondents used a technological device in the hour leading up to bedtime.¹⁴² It is no surprise, then, that sleep physicians recommend against using blue-light emitting devices in the hours before bedtime, and specifically, close to the expected sleep onset time.

Behavioral Sleep Medicine

Effective clinical management of CRSWD is multi-modal and warrants a multidisciplinary approach. Behavior change is fundamental to the successful implementation of evidence-based treatment for CRSWD.¹⁴³ For example, taking medication, turning off electronics and/or going to bed/waking up at a prescribed time requires behavioral change. A fundamental first step in CRSWD therapy is to establish stable sleep by aligning patients’ sleep-wake schedules with their intrinsic circadian phase for sleep. Such behavior change requires individual and family motivation, consistent implementation, and use of reinforcement or behavioral contingencies to ensure compliance and maintenance of improvements.¹⁴⁴ CRSWD treatment may also require adjunctive evidence-based treatment for insomnia and/or anxiety/depression/disruptive behaviors if sleep onset and sleep maintenance persist despite aligning the patients’ circadian phase for sleep with their sleep-wake schedule. Guiding and supporting families with the implementation of behavioral contingencies to optimize CRSWD treatment and the delivery of clinically indicated cognitive behavioral therapy for insomnia and co-ocuring concerns that may compromise CRSWD treatment falls within the scope of behavioral sleep medicine practice. Accordingly, integration of a behavioral sleep medicine provider on the sleep treatment team will facilitate optimal treatment for CRSWD.

Medical Therapy

The American Academy of Sleep Medicine clinical practice guidelines recommend consideration of treatment using appropriately timed melatonin in children and adolescents with DSWPD.⁶ There are currently no medications approved by the Food and Drug Administration for use specifically in pediatric insomnia.¹⁴⁵ In general, medications are commonly prescribed for sleep disorders in the pediatric population,¹⁴⁶ despite the fact that prescription medications are used exclusively off-label. Pharmacologic therapies in pediatric sleep disorders have been predominantly acquired from use in the adult population, with very limited randomized clinical trials performed specifically in children and adolescents. Treatment teams should carefully consider extrapolation of such data for use in children, including weight-based adjustments in children, metabolic and enzymatic differences between pediatric and adult populations, the possibility of paradoxical reactions in younger patients, and differences the effects of polytherapy in this population, among other considerations.¹⁴⁷ While medications can certainly be an effective part of the treatment recommendations specifically for circadian disorders in children, the medication should be carefully chosen for individualized treatment.¹⁴⁶ For example, the presence of other sleep disorders, such as periodic limb movement disorder, may require specific classes of medications for treatment of both the underlying etiology and the resulting insomnia and circadian rhythm disorder. As is always the case for any targeted therapy, appropriately timed administration of pharmacologic therapy based on the phase-response curve and intrinsic circadian time is absolutely critical for safe and effective treatment of any circadian disorder. In fact, use of inappropriate classes of medication or incorrect timing of medication relative to the intrinsic clock can exacerbate underlying sleep and circadian rhythm disorders. Use of sleep-promoting or sleep-consolidating agents can be very useful in improving sleep latency and sleep quality with these points in mind.

Historically, medications used as sleep aids include those originally used or designed for other disorders, such as neurologic or psychiatric disorders.¹⁴⁸ For the general purposes of this review, we will herein give an example of a class of medications specifically designed for sleep. Orexin (hypocretin) receptor antagonists have been recently developed to help with falling asleep (sleep onset) and staying asleep (sleep consolidator). This class of medications specifically binds receptors in the lateral hypothalamus that are part of the arousal system,^{149, 150} thus inducing sleep. In fact, melatonin aids sleep onset by blocking orexin receptors.¹⁵¹ Unlike other medications that bind receptors more broadly present throughout the central nervous system, orexin receptor antagonists are thought to have fewer side effects and abuse potential.¹⁵² Originally approved for chronic insomnia in adults, suvorexant (specifically) was shown to be safe and effective in adolescents with insomnia.¹⁵³ More recently, suvorexant was demonstrated to be safe, well-tolerated, and effective in treating circadian rhythm disorders in children, specifically those with neurodevelopmental disorders.^{154, 155}

Genetics of Circadian Disorders and Genetic Evaluation

Given the role of the molecular circadian clock in sleep phenotypes, it is understandable that changes to the transcription factors that make up the feedback loop could impact sleep. For example, genetic modification has occurred spontaneously and through site-directed mutation of these players in animals.^{156, 157} In humans, genetic variations among components of the circadian clock have been identified that lead to changes in sleep patterns, such as ASWPD^{158, 159} and DSWPD.¹⁶⁰ This knowledge potentially offers new avenues for diagnosis and treatment. For example, improved understanding of the genes involved in epilepsy and those involved in disease pharmacogenetics have led to epilepsy gene panels.^{161, 162} This genetic approach to better understand those genes that directly contribute to sleep phenotypes has already been used to apply machine learning to identify candidate sleep genes.¹⁶³ In fact, this information was previously used to develop a sleep gene panel for the identification of mutations specifically in targets that would contribute to altered sleep phenotypes.¹⁶⁴

CONCLUSIONS

Current research efforts have made great strides in circadian research and clinical developments. Using recent technologies such as actigraphy, DLMO, genetic analyses, and multidisciplinary, multi-faceted care approaches to help diagnose and treat many patients, research has led to a more formalized standard-of-care for patients seeking guidance for circadian disorders and complex sleep needs. Research efforts have also helped us to characterize and phenotype each circadian diagnosis, which has facilitated new clinical practices and diagnostic tools. We can look forward to future advancements in melatonin analyses, expanded medication therapies for new treatment opportunities, and optimizing protocols.