Overview of circadian rhythm sleep-wake disorders

INTRODUCTION — The intrinsic circadian timekeeping system influences consolidation of sleep and wake episodes and is critical for sleep health as well as optimal functioning of other organ systems.

Desynchrony between the internal circadian timing system and desired sleep-wake times, or alterations in the timing system itself, can result in one of six circadian rhythm sleep-wake disorders. Circadian dysfunction is also an important factor to consider in the approach to patients with unexplained insomnia and/or excessive sleepiness.

This topic provides an overview of the pathophysiology, clinical features, and diagnostic criteria of the circadian rhythm sleep-wake disorders. The classification and diagnosis of other types of sleep disorders are presented separately. (See "Classification of sleep disorders".)

FUNCTIONS OF THE CIRCADIAN SYSTEM — The intrinsic circadian timekeeping system modulates many physiological processes, including daily rhythms in core body temperature, melatonin secretion, cortisol, endocrine and immune function, metabolism, and many others [1-3]. The circadian system increasingly drives wakefulness across the usual wake period to offset the progressive increase in sleepiness mediated by the sleep homeostat during extended wakefulness [4-6].

The homeostatic sleep drive (or process S) accumulates during wakefulness and promotes the initiation of sleep [7]. After the first half of the sleep episode, this sleep drive rapidly diminishes. A properly aligned circadian system maintains low alertness during the night, particularly in the latter half of the night, helping to promote sleep consolidation until morning wake-up time (figure 1) [8].

In the absence of time information, the intrinsic circadian timekeeping system oscillates with a period slightly longer than 24 hours: on average, about 24.2 hours in adults [9] and potentially longer in adolescents (24.3 hours) [10,11]. To maintain alignment (entrainment) with the environmental 24-hour day, the endogenous circadian system must adjust each day; such phase shifts are achieved by time cues (zeitgebers). The most potent zeitgeber is the environmental light-dark cycle [12]. Important nonphotic zeitgebers include feeding, activity, and social interactions [13-15].

The phase shifting effect of bright light is dependent on the biological, circadian time when light exposure takes place. Typically, light exposure during the last few hours of the usual sleep period and during the hours that follow habitual wake-up time moves the circadian rhythm earlier (phase advance). Conversely, light in the evening and first two-thirds of the usual sleep period moves the circadian rhythm later (phase delay) [16].

Retinal circadian photoreceptors are maximally sensitive to blue light [17-19]. Some research suggests that avoiding the use of light-emitting devices, such as tablets and cell phones, for several hours prior to bedtime may prevent melatonin suppression and phase delay [20]. However, age, sex, genetic, and other individual traits may predispose to different responses to evening light [21]. The benefits of avoiding evening light, and especially short wavelength blue light, is a growing research area. An expert consensus recommended that during the three hours prior to bedtime, light exposure should be limited to the melanopic equivalent daylight illuminance (EDI) of 10 lux measured at the eye [22].

PATHOPHYSIOLOGY — The presumed pathophysiology of various circadian disorders relates to one of two factors:

●An intrinsic abnormality in the circadian timing system itself

●Environmental factors, such as air travel, shift work, or other circumstances or behaviors that result in inappropriate light exposure and/or imposed sleep-wake schedules that are out of sync with their intrinsic rhythms

The sleep schedule alignment relative to the 24-hour day varies according to the specific circadian disorder (figure 2).

Intrinsic circadian pathophysiology — Four of the circadian disorders are considered intrinsic disorders, with suspected pathophysiology of an individual's endogenous circadian timing system or its ability to align to the 24-hour day. However, complex interactions between endogenous circadian properties and external factors and behaviors likely underlie the conditions currently categorized as circadian rhythm sleep-wake disorders [23,24]. Ongoing work aims to delineate the heterogeneous mechanisms that underlie these abnormal sleep-wake timing presentations [23].

●Delayed sleep-wake phase disorder is multifactorial, and the underlying cause of the misalignment is not well established. Proposed factors include developmental and behavioral changes in sleep-wake timing, lengthening of the intrinsic circadian period, abnormal interaction between homeostatic and circadian processes, changes in light exposure, and altered sensitivity of the circadian system to light. Genetic variants may underlie some of these potential mechanisms. (See "Delayed sleep-wake phase disorder", section on 'Pathophysiology'.)

●Advanced sleep-wake phase disorder may be related to earlier bedtimes and rise times associated with age-related changes, as well as alteration in the circadian system's sensitivity to light. The disorder may be genetically determined in some individuals and families as well. (See "Advanced sleep-wake phase disorder", section on 'Pathophysiology' and "Sleep-wake disturbances and sleep disorders in patients with dementia", section on 'Circadian rhythms'.)

●Non-24-hour sleep-wake rhythm disorder represents a failure of the circadian system to maintain stable alignment (called "entrainment") to the 24-hour day. The most common cause is light perception blindness. Without light cues, the endogenous circadian system "free runs" on a circadian period that is usually longer than 24 hours. As a result, the endogenous system shifts to progressively later phase positions relative to the 24-hour day. Approximately one-third of blind individuals without light perception have normal entrainment, while the remaining have non-entrained circadian rhythms or have sleep patterns entrained at an advanced or delayed phase.

Notably, sighted individuals may also develop non-24-hour sleep-wake rhythm disorder, and the pathophysiology is thought to overlap with that of delayed sleep-wake phase disorder. Factors may include prolonged circadian period, exposure to light and zeitgebers timed to promote a recurrent phase delay, alterations in sensitivity of the circadian timing system to light, abnormal interaction between circadian and homeostatic regulation of sleep, and genetic alterations. Like delayed sleep-wake phase disorder, non-24-hour sleep-wake rhythm disorder in sighted individuals has been observed in association with psychiatric disorders [25]. (See "Non-24-hour sleep-wake rhythm disorder", section on 'Pathophysiology'.)

●Irregular sleep-wake rhythm disorder results from loss of the modulatory influence of the circadian system on sleep and wakefulness. It is most commonly seen in patients with dementia, probably related to both aging and additional disruption of the circadian system by the neurodegenerative process itself. (See "Sleep-wake disturbances and sleep disorders in patients with dementia", section on 'Circadian rhythms'.)

Environmentally imposed misalignment — Jet lag disorder and shift work disorder are considered of extrinsic origin.

●Jet lag disorder – In jet lag disorder, time zones are crossed more rapidly than the circadian timing system can adjust; therefore, attempted sleep, wake, and mealtimes are out of alignment with endogenous circadian phase. The severity of the misalignment depends on how many time zones have been crossed and the direction of travel. Since the natural circadian cycle is slightly longer than 24 hours, westbound travel generally causes less disruption, as it is easier to delay than advance the natural circadian cycle. (See "Jet lag", section on 'Pathophysiology'.)

●Shift work disorder – In shift work disorder, the work period overlaps with the time the circadian system typically promotes sleep, and the allotted time for sleep occurs during a period of high circadian alerting signal. The mismatch between the desired schedule and endogenous circadian rhythm results in reduced alertness during the desired waking period, which is further compounded by sleep loss due to circadian-driven insomnia. (See "Sleep-wake disturbances in shift workers", section on 'Pathophysiology'.)

CLINICAL MANIFESTATIONS — Misalignment of the circadian timekeeping system with the desired sleep schedule or impairment of the circadian modulation of sleep and wakefulness often results in clinically significant symptoms of insomnia and excessive daytime sleepiness, as well as impaired physical, neurocognitive, emotional, and social functioning [26].

Disrupted sleep-wake pattern — All circadian disorders are marked by abnormalities in the sleep-wake pattern compared with those of most healthy adults living under similar environmental conditions. The specific patterns vary according to the underlying disorder.

Delayed sleep-wake phase disorder — In delayed sleep-wake phase disorder, the circadian system promotes wakefulness until late in the night (table 1). This results in delayed sleep onset, typically occurring at midnight or later (figure 3). If sleep is attempted at an earlier desired bedtime, sleep onset insomnia will result.

In the morning, the circadian system promotes sleep later than conventional or desired wake-up times. Left undisturbed (eg, on weekends or vacation), patients sleep well into the morning, sometimes until noon or later. When conventional rise times are required by school or work, patients with delayed sleep-wake phase disorder have great difficulty waking up and feeling alert. Difficulty falling asleep at conventional times combined with a fixed wake time for school, work, social, or familial obligations results in sleep loss, adding to sleepiness. (See "Delayed sleep-wake phase disorder".)

Advanced sleep-wake phase disorder — In advanced sleep-wake phase disorder, patients become sleepy earlier in the evening than conventional or desired bedtimes, and they wake up prior to desired rise time and cannot get back to sleep (table 2). This pattern of earlier sleep-wake times may be secondary to homeostatic changes associated with aging or due to a pathologic phase advance. When patients force themselves to stay awake in the evening to meet social or professional obligations, they nonetheless wake up early and thereby accumulate sleep debt. (See "Advanced sleep-wake phase disorder".)

Non-24-hour sleep-wake rhythm disorder — Patients with non-24-hour sleep-wake rhythm disorder cannot align their endogenous circadian rhythm to the external 24-hour day. Because the average circadian period is longer than 24 hours, sleep and wake propensity are timed later and later each day. This results in periods when the circadian system is actively driving wake during the nighttime, resulting in insomnia, and promoting sleep during the daytime, resulting in excessive daytime sleepiness (table 3).

As the biological clock continues to "free run," periods of proper alignment eventually occur, with temporary resolution of the sleep-wake disturbances. (See "Non-24-hour sleep-wake rhythm disorder".)

Irregular sleep-wake rhythm disorder — In irregular sleep-wake rhythm disorder, sleep and wake are not timed by the circadian system. As a result, there are multiple short sleep episodes spread across the 24-hour day, interspersed with multiple periods of wakefulness (table 4). (See "Sleep-wake disturbances and sleep disorders in patients with dementia", section on 'Difficulty falling or staying asleep'.)

Jet lag disorder — Individuals with jet lag have difficulty falling asleep or maintaining sleep at night after air travel across two or more time zones. Excessive daytime sleepiness also occurs due to reduced total sleep time as well as circadian misalignment. Daytime dysfunction and somatic complaints such as gastrointestinal upset often occur because behaviors (eg, food consumption) are out of alignment with endogenous phase. These disturbances persist until the circadian system has adjusted to the new light-dark cycle at the destination. (See "Jet lag", section on 'Clinical features'.)

Shift work disorder — Shift work disorder takes place when sleep-wake schedules dictated by work shifts are misaligned with endogenous circadian phase. As a result, patients are sleepy during their work shift, have insomnia during the attempted sleep period, and accumulate sleep debt. The circadian misalignment and sleep loss related to shift work increases the risk for accidents, errors, and other adverse health outcomes. (See "Sleep-wake disturbances in shift workers", section on 'Clinical spectrum'.)

Functional impairment — As with any sleep disorder resulting in inadequate duration or quality of sleep, patients can experience impaired functioning in the workplace, at home, or in school. These impairments are thought to result from suboptimal neurobehavioral functioning in domains such as concentration, memory, and processing speed [4]. Physical fatigue may also contribute to impairment. (See "Insufficient sleep: Definition, epidemiology, and adverse outcomes", section on 'Effects of acute sleep deprivation'.)

Circadian rhythm sleep-wake disorders may also accompany psychiatric disorders. Specifically, delayed sleep-wake phase disorder and non-24-hour sleep-wake rhythm disorder are associated with mental health conditions [25]. (See "Delayed sleep-wake phase disorder", section on 'Comorbid psychiatric disorders'.)

DIFFERENTIAL DIAGNOSIS — Insomnia, excessive daytime sleepiness, or both are noted in all of the circadian disorders. However, these are nonspecific symptoms that may be caused by a myriad of sleep, medical, and psychiatric disorders (table 5 and table 6). (See "Evaluation and diagnosis of insomnia in adults" and "Approach to the patient with excessive daytime sleepiness".)

The key to suspecting an underlying circadian disorder is recognition of abnormally timed sleep-wake patterns, above and beyond the complaint of insomnia or daytime sleepiness, and, for some of the disorders, symptomatic improvement when sleep takes place during the preferred schedule.

The age of the patient and comorbidities also help raise or lower suspicion [26]. Delayed sleep-wake phase disorder commonly begins in adolescence and is rare in older adults, for example, whereas advanced and irregular sleep-wake rhythm disorders are primarily found in older adults, particularly those with dementia. Non-24-hour sleep-wake rhythm disorder predominantly affects blind individuals and some sighted patients, often with psychiatric comorbidities.

DIAGNOSTIC TOOLS — Circadian rhythm sleep-wake disorders are predominantly clinical diagnoses. However, in addition to the history, sleep diaries and wrist actigraphy to visualize sleep and activity patterns are beneficial in establishing the diagnosis and should be conducted for at least 7 days, preferably 14 days [26,27]. Objective markers of circadian phase (such as salivary or urinary profiles of melatonin secretion) are rarely used. Chronotype questionnaires allow for the assessment of diurnal preference but are not standalone diagnostic tools [28].

Polysomnography in a sleep laboratory or home sleep apnea testing is not routinely indicated except when suspicion exists for a comorbid sleep disorder such as obstructive sleep apnea [27]. If obtained at conventional laboratory times, abnormalities related to the circadian rhythm sleep-wake disorder, such as prolonged sleep onset latency in delayed sleep-wake phase disorder or increased wake after sleep onset in advanced sleep-wake phase disorder, may be observed by virtue of study timing. Therefore, modified laboratory protocols should be considered to appropriately time polysomnography (if indicated) in individuals with suspected circadian rhythm sleep-wake disorders. (See "Overview of polysomnography in adults", section on 'Indications'.)

Sleep diary — A sleep diary is a key component of the evaluation of patients with suspected circadian rhythm sleep-wake disorders. Patients are asked to keep daily record of each sleep episode, noting parameters such as the bedtime and wake-up time, estimates of the time to fall asleep, the number and duration of awakenings, and the total sleep time. Symptoms such as daytime sleepiness and fatigue may also be recorded in the diary.

A 24-hour diary (form 1) or one of several sleep diaries derived from a consensus conference (table 7 and table 8) can be used [29].

Sleep diaries are required to make the diagnosis of all circadian rhythm sleep-wake disorders except for jet lag [26], and they are helpful in demonstrating the changes in timing and/or quality of sleep and wakefulness. For circadian disorders in particular, review of sleep-wake patterns on both work/school days and non-work/non-school days is important, as the intrinsic circadian rhythm is often most apparent when bedtimes and wake times are not imposed by professional or school obligations. Sleep diary monitoring for at least 7 days and preferably 14 days is recommended [26].

Actigraphy — Whenever possible, actigraphy monitoring should accompany sleep log recording [26]. Actigraphy is acquired using a movement sensor worn continuously on the wrist (typically nondominant), usually for a week or more. Some sensors also detect light. Computer-based algorithms estimate sleep episodes by looking for continuous minutes of reduced movement compared with movement during presumed ambulatory wakefulness.

Wrist actigraphy has reasonably good correlation with polysomnography for the parameters of total sleep time and sleep efficiency [30]. It is also a useful method for assessing the timing of sleep episodes as well as the consolidation or fragmentation of sleep episodes over multiple nights (figure 3). Actigraphy allows for the manual visualization of the sleep episode timing. In addition, motion data can be modeled mathematically to identify abnormalities in the circadian rest activity pattern [31,32] and predict the phase of the central clock [33-36]. (See "Actigraphy in the evaluation of sleep disorders", section on 'Interpreting results'.)

In the evaluation of circadian disorders, actigraphy augments subjective data from sleep diaries, or it may be the sole source of data on patients who cannot complete a sleep diary (eg, patients with severe neurodevelopmental disorders, or patients with advanced neurodegenerative diseases) [30,37]. With the widespread use of fitness activity trackers purporting to measure sleep, concern has been raised that not all of these off-the-shelf devices provide accurate estimation of sleep, and that unsupervised use might even increase distress in some individuals with insomnia symptoms [38,39]. Work is ongoing to understand the capacity of fitness trackers and smart watches to estimate sleep. (See "Actigraphy in the evaluation of sleep disorders", section on 'Consumer wearable devices'.)

Melatonin sampling — Objective determination of an individual's circadian phase is most easily accomplished by assessment of the 24-hour rhythm of the hormone melatonin. The dim light melatonin onset (DLMO) protocol [40] involves periodic sampling of blood or (more commonly) saliva melatonin levels every 30 to 60 minutes, from approximately six hours prior to and one hour following habitual bedtime. The time at which melatonin levels rise above threshold provides a valid and reliable indicator of circadian phase position.

Measurement of DLMO may aid in confirming diagnoses in challenging cases and to help identify optimal timing for interventions that aim to shift circadian phase (eg, exposure to bright light, exogenous melatonin administration).

The DLMO protocol is used commonly in research studies but is rarely adopted in clinical practice due to lack of availability and reimbursement. Methods have been tested to allow patients to perform the DLMO procedure at home, while attempting to preserve accuracy in the timing of saliva sample collections and adherence to other procedural elements [41,42].

Core body temperature measurements — Prior to the advent of melatonin profiling, core body temperature was the most commonly used method to assess circadian phase.

Core temperature is assessed by a rectal temperature sensor, or less commonly by an ingestible temperature sensing pill. In order for results to be valid, patients or research participants must be kept in conditions that minimize biasing effects on the daily temperature rhythm; this involves staying awake on bed rest (typically for 30 to 36 hours) and ingesting food and fluids in small hourly doses [43].

DIAGNOSTIC CRITERIA — For all of the circadian rhythm sleep-wake disorders, the following three general criteria must be met according to the International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR) [26]:

●A chronic or recurrent pattern of sleep-wake rhythm disruption, primarily due to alteration of the endogenous circadian timing system or its entrainment mechanisms, or to misalignment between the endogenous circadian rhythm system and the sleep-wake schedule desired or required by an individual's physical environment or social/work schedules

●A complaint of insomnia, excessive sleepiness, or both

●Clinically significant distress or impairment in mental, physical, social, occupational, educational, or other important areas of functioning

In addition to these general criteria, each disorder has specific criteria based on the pattern and timing of sleep-wake propensity established by history, sleep diary, or actigraphy (table 1 and table 2 and table 3 and table 4). (See "Delayed sleep-wake phase disorder", section on 'Diagnostic criteria' and "Advanced sleep-wake phase disorder", section on 'Diagnosis' and "Sleep-wake disturbances in shift workers", section on 'Diagnostic criteria' and "Jet lag" and "Non-24-hour sleep-wake rhythm disorder".)

MANAGEMENT — Treatment strategies for circadian rhythm sleep-wake disorders are specific to each disorder. The primary goal of treatment is to realign the circadian timing of sleep and wake with the desired or required sleep-wake period [27,44].

Depending on the disorder, useful approaches may include careful manipulations of bedtimes and rise times, appropriately timed melatonin, melatonin receptor agonists, and light therapy [23,27,44,45]. Additionally, symptoms of insomnia or excessive daytime sleepiness may be targeted directly [27,44].

Behavioral and pharmacologic therapies are discussed in more detail in the following topics:

●(See "Delayed sleep-wake phase disorder", section on 'Management' and "Advanced sleep-wake phase disorder", section on 'Management'.)

●(See "Non-24-hour sleep-wake rhythm disorder", section on 'Management'.)

●(See "Sleep-wake disturbances and sleep disorders in patients with dementia", section on 'Management'.)

●(See "Jet lag", section on 'Management'.)

●(See "Sleep-wake disturbances in shift workers", section on 'Management'.)

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

●Functions of the circadian system – The intrinsic circadian timekeeping system modulates sleep, wakefulness, and many other physiological systems, including daily rhythms in core body temperature, melatonin secretion, cortisol, and appetite. (See 'Functions of the circadian system' above.)

●Pathophysiology – Circadian rhythm sleep-wake disorders arise either from presumed intrinsic abnormalities in the circadian system itself or from extrinsic factors (eg, shift work, air travel) that cause misalignment between the environmental light-dark cycle and an individual's internal circadian rhythm. Interactions of external light-dark schedules and self-selected behaviors with the endogenous timekeeping system play a role in pathogenesis. (See 'Pathophysiology' above.)

●Clinical disorders – Six circadian rhythm sleep-wake disorders are recognized and defined by specific patterns of sleep-wake disruption resulting in insomnia or excessive daytime sleepiness. These conditions can also have a negative impact on neurobehavioral performance, mental and physical health, and social and occupational functioning (see 'Clinical manifestations' above):

•Delayed sleep-wake phase disorder (table 1) (see 'Delayed sleep-wake phase disorder' above)

•Advanced sleep-wake phase disorder (table 2) (see 'Advanced sleep-wake phase disorder' above)

•Non-24-hour sleep-wake phase disorder (table 3) (see 'Non-24-hour sleep-wake rhythm disorder' above)

•Irregular sleep-wake rhythm disorder (table 4) (see 'Irregular sleep-wake rhythm disorder' above)

•Jet lag disorder (see 'Jet lag disorder' above)

•Shift work disorder (see 'Shift work disorder' above)

●Diagnostic evaluation – Circadian rhythm sleep-wake disorders are clinical diagnoses, made by history and review of sleep diaries, ideally in conjunction with actigraphy. Melatonin sampling is rarely used in clinical settings but may be useful in challenging cases. Polysomnography is only indicated when a comorbid sleep disorder such as obstructive sleep apnea is suspected. (See 'Diagnostic tools' above.)

●Differential diagnosis – Insomnia and excessive daytime sleepiness are common symptoms with a myriad of potential etiologies (table 5 and table 6). The key to suspecting an underlying circadian disorder is recognition of abnormally timed sleep-wake patterns, above and beyond the complaint of insomnia or daytime sleepiness. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges James K Wyatt, PhD, who contributed to an earlier version of this topic review.