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Right arrow Contemporary Reviews in Sleep Medicine
(Chest. 2006;130:1915-1923.)
© 2006 American College of Chest Physicians

Circadian Rhythm Sleep Disorders*

Brandon S. Lu, MD and Phyllis C. Zee, MD, PhD

* From the Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL.

Correspondence to: Phyllis C. Zee, MD, PhD, Northwestern, University, Feinberg School of Medicine, 710 North Lake Shore Dr, Eleventh Floor, Abbott Hall, Chicago, IL 60611; e-mail: p-zee{at}northwestern.edu

Abstract

Humans exhibit endogenous circadian rhythms that are regulated by the master circadian clock of the body, the suprachiasmatic nucleus. These endogenous circadian rhythms are aligned to the outside world by social and environmental cues. Circadian rhythm sleep disorders (CRSD) occur when there is an alteration of the internal timing mechanism or a misalignment between sleep and the 24-h social and physical environment. CRSD are often underrecognized yet should be considered in the differential of patients presenting with symptoms of insomnia and/or hypersomnia. Because behavioral and environmental factors often are involved in the development and maintenance of these conditions, a multimodal treatment approach of behavioral and/or pharmacologic approaches is usually required to synchronize a patient’s circadian rhythm to the 24-h environment, consolidate sleep, and improve alertness. Rapid advances in our understanding of the physiologic, cellular, and molecular basis of circadian rhythm and sleep regulation will likely lead to improved diagnostic tools and treatments for CRSD.

Key Words: circadian rhythm • circadian rhythm sleep disorders

Circadian rhythm sleep disorders (CRSD) are characterized by misalignment between an individual’s sleep pattern with that which is desired or considered to be within the societal norm. Patients may present with complaints of difficulty falling asleep, maintaining sleep, and excessive sleepiness. The general criteria for CRSD, according to the second International Classification of Sleep Disorders,1 include the following: (1) persistent or recurrent pattern of sleep disturbance that is thought to be primarily due to either alteration in the circadian timing system or a misalignment between endogenous circadian rhythms and external factors that affect the timing of sleep; (2) sleep disturbance that leads to insomnia, excessive sleepiness, or both; and (3) sleep disturbance that is associated with impairment of function.

In this review, we will provide a brief review of the neurobiology of circadian rhythms and briefly discuss the most commonly encountered CRSD in clinical practice. CRSD can result from alterations in the endogenous circadian clock (ie, delayed sleep phase[DSP], advanced sleep phase [ASP], free-running type, and irregular sleep-wake cycle) or changes in the physical environment in relation to the endogenous clock (ie, shift work disorder and jet lag). For most of the CRSD, biological, behavioral, and environmental factors contribute to their clinical presentation. Thus, management of these conditions requires a multimodal approach.

Neurobiology of Circadian Rhythms

Circadian rhythms (near 24-h cycles) exist in all living organisms, from single cells to humans. Although the most apparent circadian rhythm in humans is the sleep/wake cycle, other physiologic and behavioral parameters, such as core body temperature, hormone secretion, cardiopulmonary function, cognitive performance, and mood, also exhibit circadian rhythmicity. There is substantial evidence that the suprachiasmatic nucleus (SCN), located in the hypothalamus, is the master circadian clock of the body.2 The basic molecular mechanism by which SCN neurons generate and maintain a self-sustaining rhythm is via an autoregulatory feedback loop in which oscillating circadian gene products regulate their own expression through a complex system of transcription, translation, and posttranslational processes.3

When isolated from external time cues, the frequency of this oscillation (free-running period) of the human circadian clock is slightly > 24 h.4 Therefore, precise alignment between internal circadian rhythms and the 24-h physical and social environments requires daily adjustments or entrainment by synchronizing agents. Light, physical activity, and melatonin from the pineal gland are the main synchronizing or entraining agents for the human circadian clock.5

Of these, the most influential entraining agent or zeitgeber (German for time-giver) is light.6 The direct neuronal pathway from the retina to the SCN, the retinohypothalamic tract, was discovered in 1972.7 The photoreceptors involved in circadian rhythm entrainment are distinct from those that mediate vision (rods and cones). Specifically, the SCN appears to receive light input from ganglion cells in the retina that contain the photopigment melanopsin, which is most sensitive to blue light.8 The effect of light on the circadian clock is dependent on the time of exposure. For example, individuals exposed to light in the early subjective morning (before usual awakening) will advance the timing of their circadian rhythms (move to an earlier clock time), while light exposure during early subjective night will cause a phase delay (move to a later clock time).6

In addition to light, melatonin produced by the pineal gland is also an important synchronizing agent for the circadian system. The nocturnal secretion of melatonin is regulated by the SCN via an indirect pathway from the superior cervical ganglion to the pineal gland.910 Similar to light, melatonin also has phase-resetting properties, so that exposure during the first half of the night will advance circadian rhythms, whereas in the morning, it will delay circadian rhythms.11 Thus, bright light and melatonin have been used in the treatment of circadian rhythm disorders. For individuals with CRSD, the timing of light and melatonin need to be adjusted based on the timing of their circadian clock.

DSP

The prevalence of DSP syndrome has been reported to be 0.17% of the general population.12 A survey13 of adolescents, however, indicates a prevalence of > 7%. The higher prevalence of DSP in adolescents is likely the result of a combination of biological (lengthening of the circadian period)14 and behavioral (social schedules) factors.15

DSP is characterized by a chronic inability to fall asleep at a desired or socially acceptable clock time. Proposed mechanisms for DSP include the following: (1) an unusually long endogenous circadian period16; (2) hypersensitivity to evening light, which delays the circadian clock, or reduced sensitivity to morning light, which decreases the phase advancing effect of morning light17; and (3) genetic mutations as exemplified by familial forms of DSP, including polymorphisms in circadian genes such as Per3, Arylalkylamine N-acetyltransferase, and Clock.18192021

Clinical Presentation and Diagnosis
The patient with DSP typically presents with complaints of difficulty falling asleep, difficulty waking up in the morning, and excessive sleepiness that interfere with daytime function. Without social and work constraints, patients usually fall asleep from 2 to 6 AM and wake up between 10 AM and 1 PM (Fig 1 ). When patients try to comply with conventional wake times, sleep duration is curtailed, leading to chronic sleep loss and impaired functioning. It is important to distinguish DSP from "evening types" without complaints or symptoms.


Figure 1
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  		Figure 1.. Schematic representation of the major CRSD. Black bars represent sleep periods of the circadian disorders; striped bar represent conventional sleep time.

 
The diagnosis of DSP is made primarily on the basis of a detailed sleep history and physical examination. In addition, sleep diary and/or actigraphy for at least 7 days is useful in establishing the delayed sleep and wake pattern on weekdays and weekends. Nocturnal polysomnography is not essential but may be indicated if other sleep disorders, such as obstructive sleep apnea or restless legs/periodic leg movements, are being considered in the differential diagnosis. With the exception of prolonged sleep latency, sleep architecture is typically normal.1

Treatment
A primary goal of therapy for DSP is to advance the timing of the sleep-wake cycle in relation to the desired social and work schedules. Several treatments have been proposed for DSP including chronotherapy, bright light, and melatonin. Chronotherapy is an approach in which the sleep and wake times are progressively delayed by approximately 3 h every 2 days until a final earlier bedtime schedule is achieved and maintained.22. Since the endogenous circadian rhythm in humans is usually > 24 h, it is generally easier to delay than to advance the sleep/wake cycle. Originally performed on an inpatient basis, chronotherapy requires strict adherence and control of light exposure and sleep/wake times. While this treatment can be effective, there are limitations to its practicality and acceptability in a clinical setting because of the strict requirements for social and professional restrictions and the prolonged duration of treatment. Despite the limitations, chronotherapy can be a useful treatment, particularly in children and adolescents.

Bright light therapy, when combined with avoidance of bright light in the evening, has been demonstrated to be an effective treatment approach to achieve earlier sleep and wake times in patients with DSP23 (Fig 2 ). A commonly recommended clinical approach is to administer bright light of 2,000 to 2,500 lux for 1 to 2 h in the morning between 6 AM and 8 AM.24 However, in patients who exhibit an extreme delay in the timing of circadian rhythms, the time of morning light exposure may need to be given later in the morning to avoid exposure at a time that would actually further delay circadian rhythms. Compliance with bright light therapy may be limited by the duration and intensity of exposure, inability of many patients to awaken in the morning, and having to restructure social and professional activities around the light regimen.2526 Various light sources are commercially available. Considerations include lamp type (output and spectrum), filter for ultraviolet, size and positioning of radiating surface, and heat emission.


Figure 2
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  		Figure 2.. Schematic representation of light therapy for CRSD. Bottom, A: Morning light therapy will phase advance DSP. Left, B: Evening light therapy will phase delay ASP. Gray pie represents conventional sleep time, and gray bars represent disordered sleep times being phase shifted.

 
Several studies272829303132 have also demonstrated the potential benefit of melatonin administered in the evening. However, the variability in dose, time of administration in many studies, together with the lack of large randomized placebo-controlled studies, have made it difficult to establish clinical practice guidelines for melatonin in the treatment of DSP. A recent study33 showed that treatment with melatonin, 0.3 to 3 mg, in the early evening (approximately 5 to 7 h before sleep time) for 4 weeks was effective for the treatment of patients with DSP. Clearly more studies on the long-term efficacy and safety of melatonin are needed.

Despite its potential usefulness for the treatment of some of the CRSD, the clinical effectiveness and guideline for the use of melatonin have not been established. In addition, length of treatment, dosing parameters, and timing of administration of melatonin have also not been established. Melatonin is not approved by the Food and Drug Administration (FDA) for the treatment of CRSD, and its production is largely unregulated. As an example, four of six melatonin products purchased from health stores around the United States were found to contain unidentified impurities.34 The side effects of melatonin include headaches, nausea, and exacerbation of cardiovascular disease35 (Table 1 ).


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  		Table 1.. Overview of Clinical Characteristics and Treatment of CRSD

 
Education on proper sleep hygiene should be included for all patients (Table 2 ). In addition to alignment of circadian rhythms, treatment of DSP needs to address other factors, such as the severity of the disorder, comorbid psychopathology, ability and willingness of the patient to comply with the treatment, school schedule, work obligations, and social pressures.252636 Therefore, a multimodal treatment approach is recommended. Alternatively, no medical treatment may be necessary if lifestyle modifications, such as later work schedules, can be made to accommodate the sleep schedule.


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  		Table 2.. Essential Elements of Good Sleep Hygiene

 
ASP

ASP is a sleep disorder in which there is a stable advance of the major sleep period, characterized by habitual and involuntary sleep onset and wake-up times that are several hours earlier relative to conventional and desired times. The actual prevalence of ASP is estimated to be much lower than DSP.12373839 ASP is more common among middle age and older adults, with an estimated prevalence of 1% of middle-age adults.37 Possible etiologies of ASP include the following: (1) shortened endogenous circadian period,40 (2) increased retinal sensitivity to light in the morning,41 and (3) genetic mutation (hypophosphorylation of Per2 protein or mutation of CK1{delta} gene).4243

Clinical Presentation and Diagnosis
Patients with ASP will have complaints of late afternoon or early evening sleepiness, and difficulty maintaining sleep during the early morning hours. Individuals with ASP usually report sleep onset between 6 PM and 9 PM and wake time between 2 AM and 5 AM.4445 When required to conform to later sleep times, patients continue to wake up earlier than desired, thus leading to chronic partial sleep deprivation.

Diagnostic criteria for ASP include a history of chronic early evening sleepiness and early morning awakening/insomnia, normal sleep quality and duration for age when allowed to sleep at an advanced schedule, and 7-day actigraphy or sleep diary that demonstrates a stable advance in the timing of the habitual sleep and wake times. Polysomnography may be useful to exclude other sleep disorders that can cause hypersomnia.1

Treatment
Various modalities of therapy have been utilized for the management of ASP. Bright light exposure in the early evening is the most widely used approach and has been shown to delay wake time, reduce wake time during sleep, and improve sleep efficiency.46 Although much less studied in ASP than DSP, chronotherapy, with phase advancement of bedtime by 3 h every 2 days, has also been shown to be effective in the treatment of ASP.44 While melatonin administered in the morning can theoretically be used to delay the timing of the sleep/wake cycle, the potential for residual morning drowsiness and inconvenience of early morning administration may limit its usefulness in the clinical setting.

Free-Running Type (Nonentrained Type, Non–24-h Sleep-Wake Syndrome, Hypernychthemeral Syndrome)

The sleep and wake times of patients with free-running type vary because their circadian rhythm is not stably entrained to the 24-h day. The endogenous circadian period is typically slightly > 24 h.4 When the circadian rhythm is not entrained to the 24-h day but allowed to run freely, the sleep period will drift later each day. As light is the strongest synchronizing agent of the circadian clock, most patients with nonentrained sleep/wake cycles are blind. It has been estimated that approximately 50% of blind people have disturbed sleep.47 This condition is relatively rare in sighted individuals48; a recent report49 identified 57 cases of free-running type in sighted individuals over a 10-year period.

While the etiology of nonentrained type sleep disorder in blind people is likely due to lack of light perception,47 the precise etiology in sighted individuals is unknown. Decreased exposure or responsiveness of the circadian clock to light or nonphotic entraining agents, and/or an unusually long free-running circadian period that is outside the range of entrainment have been postulated as contributing factors in sighted individuals.5051

Clinical Presentation and Diagnosis
Patients with free-running type will typically present with periods of insomnia, excessive sleepiness, or both, alternating with short asymptomatic periods. Because the timing of the circadian sleep/wake cycle is progressively drifting, symptoms will depend on when an individual tries to sleep in relation to the phase of the endogenous circadian rhythm.

Diagnosis is made on the basis of the clinical history and evidence of a pattern of sleep and wake times that typically delay each day with a period > 24 h.1 A sleep diary or actigraphy monitoring for a period of ≥ 2 weeks are useful to confirm the nonentrained 24-h sleep/wake cycle rhythm. Inadequate sleep hygiene, other causes of hypersomnia and mood disorders should be considered in the differential diagnosis.

Treatment
Sleep hygiene education and structured social and physical activities should be encouraged in all individuals with free-running type.52 In addition, melatonin has been shown to be an effective treatment for nonentrained rhythms in blind persons.53 Earlier studies used melatonin of 10 mg 1 h before bedtime, but a more recent study54 demonstrated that entrainment can be maintained with a lower dose (0.5 mg) of melatonin taken at 9 PM. In sighted patients or in blind patients with light perception, bright light therapy may be tried.55 A combined approach of sleep hygiene education, structured social and physical activities and, when required, pharmacotherapy with melatonin is recommended for the management of this condition.

Irregular Sleep-Wake Rhythm

Irregular sleep-wake disorder is characterized by a lack of a clearly discernable sleep-wake circadian rhythm. Sleep and wake periods are distributed in three or more short bouts (lasting 1 to 4 h) throughout the 24 h. The etiology of this disorder is thought to be due to either disruption of the circadian clock (SCN), entrainment pathways, and/or as a result of decreased exposure to environmental synchronizing agents. Although the exact prevalence of the disorder is unknown, it is most often seen in individuals with neurologic disorders such as dementia, mental retardation, and brain injury.565758

Clinical Presentation and Diagnosis
Depending on the time of the day, patients with irregular sleep-wake rhythm may complain of insomnia or excessive sleepiness. While sleep and wake periods are fragmented, the longest sleep period tends to occur from 2 to 6 AM.58 Diagnosis is made by the clinical history of fragmented sleep and wake periods along with chronic complaints of insomnia, excessive sleepiness, or both. Sleep diary and/or actigraphy for at least 7 days shows irregular intervals of sleep and wake periods within a 24-h period. Other sleep, medical, or neuropsychiatric disorders with similar sleep complaints must also be excluded.1

Treatment
Treatment for irregular sleep-wake rhythm is aimed at consolidating sleep during the night and maintaining wakefulness during the day. Proposed treatments include increasing social interactions, physical activity, and light exposure during the day, along with minimizing nighttime light and noise.596061 The studied bright light regimens are 2,500 to 3,000 lux exposure for 2 h in the morning.5962 Studies using melatonin have yielded mixed results. For example, treatment with 3 mg of melatonin daily improved nighttime sleep and reduced daytime sleep in psychomotor retarded children with irregular sleep-wake type.63 However, in a large randomized controlled trial64 in Alzheimer disease, melatonin failed to consolidate sleep. A combined approach with bright light, structured activities was reported to have a 45% success rate in one study.65

Shift Work Disorder

Shift work disorder (SWD) is characterized by complaints of insomnia, excessive sleepiness, and impaired performance that occur when work hours are scheduled during the usual sleep period. The condition usually persists for the duration of the work shift period. Sleep problems and sleepiness are most commonly seen in relation to the night and early morning shifts.

While it is estimated that 20% of the workforce in industrialized countries are shift workers, and 40 to 80% of night workers complain of sleep difficulties, the actual prevalence of clinically significant cases is unknown.5866 A 2004 study67 indicated that 5 to 10% of the shift work population meets criteria for SWD.

Clinical Presentation and Diagnosis
Patients with SWD can present with difficulty falling asleep or maintaining sleep, unrefreshing sleep, and sleepiness at work. Sleep in night-shift workers is usually shortened by 1 to 4 h compared to daytime workers, with sleep loss involving mostly stage 2 and rapid eye movement sleep.686970 Chronic partial sleep deprivation associated with shift work can impair social and cognitive function, and pathologic sleepiness can result in safety and health hazards.

The diagnosis should be made when these complaints occur in relation to the work schedule and other causes of insomnia and excessive sleepiness have been excluded. Polysomnography may be indicated to exclude sleep disorders, such as sleep apnea. Sleep diary or actigraphy monitoring is useful in demonstrating the disrupted sleep-wake cycle associated with shift work periods.1

Treatment
Treatment for SWD requires a multimodal approach that should optimize circadian alignment, sleep quality, and performance and safety at work. Circadian adaptation can be enhanced by bright light exposure (continuous or intermittent) beginning early during the night shift and terminating 2 h before the end of the shift to improve adaptation of circadian rhythm.7172 In addition, avoiding bright light by wearing dark glasses during the morning commute can facilitate circadian phase adjustment.71 Improved circadian alignment can lead to better sleep, less fatigue, and better mood, underscoring the importance of circadian manipulation for the treatment of SWD.73 Bright light exposure has the additional benefit of its short-term alerting effects.74

Sleep hygiene education and cognitive behavioral therapy should be prescribed for all SWD patients with insomnia. If needed, hypnotic medications or melatonin can help improve sleep quality.75 Melatonin (non-FDA approved) when taken before bedtime in the early morning can improve daytime sleep duration but has limited effects on alertness.75 Hypnotics, preferably shorter-acting ones, have been used to treat the insomnia associated with SWD.76

In addition to improving sleep, management of excessive sleepiness is an important component of the overall treatment plan. There is evidence that a nap 1 or 2 h prior to the shift can improve wakefulness.777879 When required, wake-promoting agents such as caffeine and modafinil can also be used.8081 In a recent study,80 modafinil was shown to reduce sleepiness and also improve performance on vigilance tests in patients with SWD. Although both sleepiness and performance parameters improved with modafinil, the level of sleepiness remained within the pathologic range.82

Jet Lag

Jet lag is characterized by a temporary misalignment between the endogenous circadian sleep/wake rhythm and the external physical environment due to a change in time zones. Jet lag can affect all individuals who travel, but symptoms may be more severe in the elderly. Symptoms are usually temporary and include sleep initiation and maintenance insomnia, daytime sleepiness, and decreased performance. Symptoms are often more severe with increasing time zones crossed and with eastward flights than westward flights. Because the endogenous circadian clock is slightly > 24 h, phase advancement after eastward flights is much more difficult than phase delay after westward flights.83

Treatment
Treatment of jet lag is based on resynchronization of the endogenous circadian rhythms to the physical environment. Strategically timed light exposure can aid the traveler in the resynchronization process. On eastward flights, one should stay awake and avoid bright light in the morning and be exposed to as much light as possible in the afternoon. On westward flights every attempt should be made to stay awake while light is out and not sleep until nighttime at the destination.84 Melatonin has also been used to expedite the re-entrainment of the endogenous circadian rhythms. The Cochrane review recommends a dose of 2 to 5 mg at bedtime on arrival, which may be repeated for up to 4 nights.85 It should be noted that melatonin is non-FDA approved, and its potential problems are discussed above.

In addition to using light therapy, other behavioral techniques such as good sleep hygiene should always be practiced (Table 2). Preventive strategies including adequate hydration, avoidance of caffeine and alcohol, and static exercises on the plane have also been advocated.86 A trial of hypnotics is reasonable if the above strategies are unsuccessful at treating jet lag. The use of 10 mg of zolpidem for the initial 3 nights after arrival has been shown to improve sleep quality and duration.87

Summary

Although there is strong evidence that a common etiology of CRSD is an alteration in the circadian timing system, or as a result of misalignment between endogenous rhythms and the external environment, the exact mechanisms responsible for most of these disorders are unknown. However, rapid advances in our knowledge of the physiologic, cellular, and molecular basis of circadian rhythm and sleep regulation should lead to improved diagnostic tools and treatments. Because behavioral and environmental factors play such an important role in the presentation and maintenance of these disorders, treatment interventions need to address circadian physiology, as well as behavioral and environmental influences.

Footnotes

Abbreviations: ASP = advanced sleep phase; CRSD = circadian rhythm sleep disorders; DSP = delayed sleep phase; FDA = Food and Drug Administration; SCN = suprachiasmatic nucleus; SWD = shift work disorder

The authors have no conflicts of interest with the subject in discussion.

Received for publication February 7, 2006. Accepted for publication June 15, 2006.

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