Advanced sleep-wake phase disorder

INTRODUCTION — Advanced sleep-wake phase disorder (ASWPD) is a circadian rhythm sleep-wake disorder in which sleep quality and duration are normal but sleep onset and wake times are earlier than desired or earlier than socially acceptable times. Patients often force themselves to stay awake in the evenings but continue to wake up early, thereby accumulating sleep debt and excessive daytime sleepiness.

The clinical features, evaluation, and treatment of ASWPD will be reviewed here. An overview of circadian rhythm sleep-wake disorders and a more general approach to the patient with excessive daytime sleepiness are presented separately. (See "Overview of circadian rhythm sleep-wake disorders" and "Approach to the patient with excessive daytime sleepiness".)

EPIDEMIOLOGY — The incidence and prevalence of advanced sleep-wake phase disorder (ASWPD) are not well established. Based on a few large survey studies examining sleep timing and symptoms of ASWPD, the disorder may be more prevalent among older adults and men [1-5]. Young-onset and familial forms also exist, and in these cases, the onset of early sleep-wake timing is usually established before age 30 [6].

One population-based study estimated a prevalence of 0.25 to 7 percent among more than 4000 adults aged 20 to 59 years using various definitions of ASWPD derived from a self-administered questionnaire [7]. A second study using a sleep disorders center population found an extreme morning chronotype (time of day preference) in 0.33 percent of patients and an estimated ASWPD prevalence of 1 in 2500 patients presenting for sleep medicine evaluation [6]. Prevalence is thought to be highest in older adults.

PATHOPHYSIOLOGY

Clock genes and familial ASWPD — In some individuals, a genetic basis for advanced sleep-wake phase disorder (ASWPD) is supported by an autosomal-dominant, highly penetrant inheritance pattern within the family [6,8-10].

Familial ASWPD was first described in 29 individuals ranging from 8 to 69 years of age from three European families [8]. Compared with unrelated, healthy age- and sex-matched controls, probands had earlier average sleep onset (7:25 PM versus 11:10 PM), sleep offset (4:18 AM versus 7:44 AM), dim light melatonin onset (5:31 PM versus 9:21 PM), and core temperature nadir (11:22 PM versus 3:35 AM).

The earlier sleep-wake times observed in these patients may be related to differences in their internal biological clocks, referred to as the circadian timekeeping system. In humans, the time it takes for the internal clock to complete one cycle ("period length" or "tau") is close to, but not usually exactly, 24 hours. The clock is reset or "entrained" daily to stay on the external 24-hour schedule. If the internal clock fails to reset, sleep times and circadian rhythms can drift. Those with a tau shorter than 24 hours tend to have sleep schedules that advance or become earlier, whereas those with a tau longer than 24 hours experience delays in sleep timing. One patient with familial ASWPD who was studied in time isolation showed an internal period length of 23.3 hours, compared with 24.2 hours in an age-matched control [8], supporting the notion that a shorter internal circadian period length may be responsible for some cases of ASWPD.

Genetic analyses of familial ASWPD have identified multiple unique genetic variations that result in ASWPD phenotypes. The source of familial advanced sleep phase syndrome type 1 (FASPS1) is a serine-to-glycine substitution located at 2q37 that alters the casein kinase 1 epsilon (CK1-epsilon)-binding region of the period circadian regulator 2 (PER2) clock gene, the human homolog of the period gene in Drosophila [11]. The variant leads to hypophosphorylation of PER2 by CK1-epsilon, which shortens the circadian period.

Additional genetic variants have been identified in other kindreds with ASWPD. In familial advanced sleep phase syndrome type 2 (FASPS2), a point mutation (A to G) in the CK1-delta (CSNK1D) gene produces a threonine-to-alanine alteration at amino acid 44 of the CK1-delta protein, which reduces enzymatic activity, resulting in hypophosphorylation of PER1, PER2, and PER3 [12]. Study of a family with cosegregation of ASWPD and migraine headaches implicated the same variant in CSNK1D [13].

The genetic basis of familial advanced sleep phase syndrome type 3 (FASPS3), in which affected individuals have ASWPD, depressive symptoms, and sensitivity to seasonal changes in solar day length, is attributed to two missense variants in the period circadian regulator 3 (PER3) gene. Transgenic mice with this variant exhibit depressive behaviors, particularly when housed in a short “winter-like” photoperiod [14].

The genetic heterogeneity of familial ASWPD indicates that clock function is likely influenced by other mechanisms as well, such as transcriptional regulation and post-transcriptional control of clock gene proteins. Animal and in vitro studies have identified additional variability and complexity in how clock gene variants affect circadian rhythms at the species level [15,16].

Season of birth and prematurity — Environmental exposures during neurodevelopment affect circadian rhythms, and certain patterns of light exposure may increase propensity for ASWPD. Studies of the association between circadian phase preference and season of birth show a stronger tendency for "morningness" among individuals born in autumn and winter versus spring and summer, with a stronger association in males than females [17,18].

Some have hypothesized that preterm infants exposed to artificial light-dark cycles in the neonatal intensive care unit may have altered circadian preference and circadian rhythmicity as adults. Studies of sleep-wake patterns among adults born prematurely with very low birth weight (<1500 grams) have found that these adults have earlier bed times [19,20] and wake times [20,21] than controls born at term.

Other contributing factors — The internal biological clock has the capacity to phase delay (ie, shift later with respect to external clock time) and phase advance (ie, shift earlier with respect to external clock time). Attributes that change the input to or responsiveness of the internal biological clock to alterations in the light-dark cycle may thereby contribute to the development of ASWPD. These include:

●Decreased exposure to phase-delaying zeitgebers (ie, "time givers," such as light, activity, meals, and social time cues), which act to synchronize or entrain the internal circadian clock with the environmental light-dark cycle (see "Overview of circadian rhythm sleep-wake disorders", section on 'Functions of the circadian system')

●Decreased responsiveness to evening light, which ordinarily would delay the internal circadian phase

●Increased responsiveness to morning bright light, resulting in an undesirable advance in the internal circadian phase compared with the environmental cycle

Among older patients, changes in responsiveness to light due to cataracts [22,23] and decreases in circadian amplitude [24] might also contribute to ASWPD.

CLINICAL FEATURES — The defining clinical features of advanced sleep-wake phase disorder (ASWPD) are excessive evening sleepiness and chronic early morning awakening.

Patients typically report that they cannot stay awake in the early evening beyond about 7:00 PM to do expected or desired activities. When they force themselves to stay awake later than times dictated by their internal circadian rhythm, they do so with great difficulty and/or distress. Patients also report that no matter what time they go to bed, they wake in the early morning hours (eg, 3:00 to 4:00 AM) and cannot fall back to sleep.

As a result of this condition, if patients force themselves to stay awake in the evening but continue to wake up too early to obtain a full night's sleep, they may accumulate chronic sleep debt and experience excessive daytime sleepiness. On the other hand, if patients with ASWPD forgo evening activities and retire to bed at the time when they feel sleepy and ready for bed (ie, 7:00 to 8:00 PM), sleep quality and duration as well as daytime functioning are normal.

DIAGNOSIS — Advanced sleep-wake phase disorder (ASWPD) should be suspected in patients who complain of early sleep onset and early wake times with resultant distress and excessive daytime sleepiness. A family history of early sleep-wake times also may be reported. The diagnosis is confirmed by demonstration of an advanced circadian rhythm on sleep log or actigraphy and exclusion of alternative diagnoses such as depression or insomnia.

Evaluation

●Sleep history – A sleep history should elicit a detailed description of the patient's sleep problem and sleep habits. Patients should be asked about their typical weekday and weekend bedtimes and wake times, the length of time it takes to fall asleep at night, and the number, duration, and cause of nighttime awakenings. When circadian disturbances are being considered, it can be helpful to ask patients to describe the quality and duration of their sleep when they are allowed to sleep at preferred times (eg, on vacation or when they have no scheduled engagements).

Clinicians should also inquire about frequency and duration of intentional naps and unintentional daytime sleep episodes, as well as daytime symptoms such as grogginess, difficulty with cognitive tasks, and mood problems. It is important to ask about sleepiness while driving, as patients with ASWPD may be driving in the early evening hours, at times when their circadian clock is maximally promoting sleep.

The sleep history also includes an assessment of any symptoms of disturbed sleep (eg, loud snoring, leg kicking, or other nighttime behaviors) that may indicate the presence of another sleep disorder, as well as the duration of the symptoms and their relation to the patient's early sleep-wake patterns. A physical exam should be completed to assess physical characteristics that may increase risk of a sleep disorder, such as a crowded posterior oropharynx as a sign of possible obstructive sleep apnea.

●Sleep log – Patients with suspected ASWPD should complete a sleep log for at least 7 days, preferably 14 days, including both work or school days and free days. Either the 24-hour log (form 1) or the Consensus Sleep Diary (table 1 and table 2) can be used; the 24-hour log has the advantage of charting sleep timing visually, which can help detect an advanced sleep-wake pattern.

●Actigraphy – Actigraphy, which records sleep-wake patterns via a wrist-worn monitoring device, is a useful adjunct to the sleep log if available. Some actigraphs also record light levels, which can be helpful in determining whether the patient has a light exposure pattern that may be contributing to advanced sleep phase (ie, extremely low light levels in the evening or very high light levels in the morning). Objective measurement of sleep patterns is especially important in patients who are unable to complete a sleep log reliably. (See "Actigraphy in the evaluation of sleep disorders".)

Sleep patterns recorded by sleep log or actigraphy must demonstrate a stable advance in the timing of the habitual sleep period, and both work or school days and free days must be included within this monitoring (form 2) [25].

●Melatonin sampling – Demonstration of a relatively early melatonin onset with salivary or plasma melatonin sampling or earlier phase of melatonin metabolite excretion via urinary 6-sulfatoxymelatonin may also assist in making the diagnosis [26], although these tests are not yet available in most centers for clinical purposes. (See "Overview of circadian rhythm sleep-wake disorders", section on 'Melatonin sampling'.)

●Role of polysomnography – Polysomnography is not indicated in the evaluation of circadian rhythm disturbances unless an alternative or comorbid sleep disorder such as sleep apnea is suspected that might explain excessive daytime sleepiness. (See 'Differential diagnosis' below.)

Diagnostic criteria — Diagnostic criteria for ASWPD (table 3) as defined by the International Classification of Sleep Disorders, Third Edition (ICSD-3), require all of the following [25]:

●The phase of the major sleep episode is advanced (early) in relation to the desired or required sleep time and wake-up time, as evidenced by a chronic or recurrent complaint of difficulty staying awake until the required or desired conventional bedtime, together with difficulty remaining asleep until the required or desired time for awakening.

●Symptoms are present for at least three months.

●When patients are allowed to choose their ad libitum schedule, they will exhibit improved sleep quality and duration and maintain advanced timing of their 24-hour sleep-wake pattern.

●The sleep disturbance is not better explained by another current sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder.

Differential diagnosis — The diagnosis of ASWPD requires exclusion of alternative causes of earlier-than-desired sleep onset or wake times.

●Chronic insomnia – Chronic insomnia with sleep maintenance difficulties is the most common sleep disorder that must be considered in patients with suspected ASWPD. Although patients with insomnia may experience daytime sleepiness as a result of disturbed sleep at night, they are less likely than patients with ASWPD to report that they feel ready for their nighttime sleep episode in the late afternoon or early evening. Patients with insomnia are also more likely than those with ASWPD to report multiple night awakenings, rather than a specific early morning awakening, and more likely to experience hyperarousal and dysfunctional or compensatory attitudes and behaviors. (See "Evaluation and diagnosis of insomnia in adults", section on 'Clinical features'.)

It is important to note, however, that ASWPD can be comorbid with insomnia. Patients whose sleep difficulties begin with ASWPD may develop a component of insomnia due to the recurrent experience of waking earlier than expected. Similarly, repetitive exposure to light in the morning hours may advance circadian rhythms among patients whose sleep difficulties are rooted in chronic insomnia.

●Other sleep disorders – Other common sleep disorders that result in sleepiness in the early evening or night awakenings should also be considered, including sleep-disordered breathing. If the sleep history and physical exam raise suspicion for sleep-disordered breathing, overnight polysomnography or a home sleep apnea test, if appropriate, should be performed. (See "Overview of polysomnography in adults".)

●Mood disorders – Early wake times are a relatively common symptom of major depression [27]. Although the root cause of early morning awakenings in depression may be circadian dysfunction, this should not be confused with ASWPD, as different first-line treatments are recommended. In most cases, depression can be distinguished from ASWPD by the presence and chronology of depressive symptoms. As an example, a patient with ASWPD might report not participating in evening social activities because of sleepiness, whereas a patient with depression may avoid socializing at all times of day due to lack of interest or poor motivation. (See "Unipolar depression in adults: Assessment and diagnosis", section on 'Assessment'.)

MANAGEMENT — Bright light therapy in the evening is the primary treatment for advanced sleep-wake phase disorder (ASWPD). The goal of evening light therapy is to delay the circadian phase so that it is better aligned with the environmental light-dark cycle and social conventions.

Timed melatonin might theoretically help to delay the circadian phase, but this has not been studied systematically. The use of melatonin or other hypnotics for the symptom of early morning awakening is discouraged due to the potential for daytime sedation.

Bright light therapy — The rationale for bright light therapy is grounded in human phase-response curves to light (figure 1) [28,29], which indicate that bright light in the evening and early part of the biological night produces a phase delay that will correct the early sleep onset and wake times in ASWPD.

A reasonable approach for patients with ASWPD is to use bright light therapy for one to three hours per night with an intensity of 2500 to 10,000 lux, beginning at the time that they usually experience evening sleepiness. We instruct patients to use a commercially available bright light source that filters ultraviolet light. Patients should sit about two feet from the bright light source [30]. They can read or perform other activities and are not expected to stare directly at the light.

Side effects and adverse reactions to light therapy are uncommon and usually self-limiting. Patients should be informed that eyestrain, nausea, agitation, headache, and hypomania can occur with light treatment [31]. Reducing light intensity or the duration of light treatment can help mitigate these side effects. Patients with eye disease and those taking photosensitizing medications should have periodic ophthalmologic and dermatologic monitoring.

There are no data available to guide duration of treatment, and patients should be monitored closely for clinical response. In our experience, some patients may respond to intermittent treatment or may need longer or shorter treatment durations (ie, both length of time in front of the light box each evening and number of days of treatment), depending on season.

Use of bright light as a therapeutic modality for ASWPD is supported by a randomized trial in which 12 older adults with earlier-than-desired awakenings (mean age 70 years) were exposed to two hours of 4000 lux bright light or a red light control condition between the hours of 8:00 and 11:00 PM for 12 consecutive days [32]. Bright light produced a 2.4-hour circadian phase delay (as measured by core body temperature minimum) and an average increase in total sleep time of 50 minutes per night. Another study failed to find measurable changes in circadian phase or total sleep time with use of low-intensity evening light (approximately 250 lux for two to three hours per night), although patients reported subjective improvement in symptoms, possibly due to direct-alerting effect of light [33]. These results suggest that brighter light is likely necessary to produce circadian delays.

Appropriate timing of bright light is a critical factor for producing circadian phase shifts. To produce a phase delay, light exposure should begin approximately four hours prior to natural, ad libitum sleep onset and end about three hours prior to natural, ad libitum sleep offset [30].  

Patients who do not respond initially — Bright light therapy is the mainstay treatment for ASWPD, and patients who do not respond to initial treatment with bright light may need a higher "dose," operationalized as a longer duration and/or a brighter intensity of light. Avoidance of bright light exposure in the hours following natural, ad libitum rise time, which could perpetuate circadian phase advance and possibly counteract the phase-delaying effects of increased evening light, may also help [34]. Alternative or comorbid sleep disorders should also be considered. (See 'Evaluation' above and 'Differential diagnosis' above.)

Other behavioral interventions — Chronotherapy, a technique whereby patients go through repetitive advances in their bedtimes and wake times until desired bed and wake times are achieved, has been tested in a single case study [2]. The reported patient was a 62-year-old man with an eight-year history of a usual bedtime of 6:30 PM. Chronotherapy was employed by advancing his sleep three hours earlier every two days until bedtime was reset to 11:00 PM; this advancing schedule approach resulted in at least five months of stable sleep times from 11:00 PM to 7:00 AM. Thus, chronotherapy is a potential treatment for ASWPD that warrants clinical consideration and further study [31].

Role of pharmacotherapy — There are no pharmacologic treatments for ASWPD. Theoretically, according to the phase-response curve for melatonin (figure 1) [35], exogenous melatonin administration at the end of the biological night or the hours following natural, habitual rise time could produce a phase delay of the circadian clock and thereby mitigate symptoms of ASWPD. However, there are no systematic studies or even case reports showing that this is a safe or effective treatment [36], and no information about appropriate dosing is available. The biggest concern related to ingestion of melatonin at this time is daytime sedation.

Similarly, short-acting hypnotics administered at the undesired early wake time would be expected to facilitate falling back to sleep in patients with ASWPD, but, due to concerns about daytime sleepiness, hangover effects, and risks of falls in older patients, hypnotics are not recommended [31].

Driving safety — Patients with ASWPD may be driving at times when their circadian clock is promoting sleep, and all patients should be asked about drowsy driving and educated about prevention and countermeasures (table 4). (See "Drowsy driving: Risks, evaluation, and management", section on 'Prevention and countermeasures'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Parasomnias, hypersomnias, and circadian rhythm disorders".)

SUMMARY AND RECOMMENDATIONS

●Definition – Advanced sleep-wake phase disorder (ASWPD) is a circadian rhythm sleep-wake disorder in which sleep quality and duration are normal but sleep onset and wake times are earlier than desired or earlier than socially acceptable times. The disorder may be more common in older adults and males. (See 'Epidemiology' above.)

●Genetics – Families with ASWPD inherited in an autosomal-dominant pattern have been identified. Some families carry variants in the period circadian regulator 2 (PER2) or casein kinase 1 delta (CSNK1D) genes leading to hypophosphorylation of clock genes and shortened circadian periods. (See 'Clock genes and familial ASWPD' above.)

●Clinical features – The cardinal features of ASWPD are excessive evening sleepiness and chronic early morning awakening (form 2). When patients force themselves to stay awake in the evenings, they continue to wake up early, resulting in accumulated sleep debt and daytime sleepiness. (See 'Clinical features' above.)

●Diagnosis – ASWPD should be suspected in patients who report early sleep onset and early wake times with resultant distress and excessive daytime sleepiness (table 3). The diagnosis is confirmed by demonstration of an advanced rest-activity pattern on sleep log (form 1) or actigraphy and exclusion of alternative diagnoses such as depression and insomnia. (See 'Diagnosis' above.)

●Management – The goal of therapy is to delay the circadian phase so that it is better aligned with the environmental light-dark cycle and social conventions.

•Light therapy – For patients with ASWPD, we suggest light therapy in the evenings, beginning when the patient usually experiences the onset of sleepiness (Grade 2C). (See 'Bright light therapy' above.)

•Avoidance of hypnotics – Pharmacotherapy has no role in this disorder, and patients should be discouraged from use of hypnotics for the symptom of early awakening, due to potential for daytime sedation and other risks. (See 'Role of pharmacotherapy' above.)

•Driving safety – Driving safety with regard to drowsy driving should be reviewed, as patients may be driving at times when their circadian clock is promoting sleep. (See "Drowsy driving: Risks, evaluation, and management", section on 'Prevention and countermeasures'.)

ACKNOWLEDGMENT — The views, thoughts, and opinions expressed in the text belong solely to the author, and not necessarily to the author's employer, organization, committee or other group or individual.