Sleeplessness and Circadian Rhythm Disorder 

Updated: Jan 07, 2015
Author: Mary E Cataletto, MD; Chief Editor: Selim R Benbadis, MD 

Overview

Practice Essentials

Disturbances in circadian rhythm—the approximately 24-hour cycles that are endogenously generated by an organism—can be categorized into 2 main groups: transient disorders (eg, jet lag or a changed sleep schedule due to work, social responsibilities, or illness) and chronic disorders (eg, delayed sleep-phase syndrome [DSPS], advanced sleep-phase syndrome [ASPS], and irregular sleep-wake cycle). Sleeplessness (insomnia) is defined as difficulty initiating or maintaining sleep.

Essential update: FDA approves first treatment for non-24 hour sleep-wake disorder in totally blind individuals

In January 2014, the FDA approved the melatonin receptor agonist tasimelteon (Hetlioz) as the first treatment for non-24- hour sleep-wake disorder (“non-24”), a chronic circadian disorder that affects the timing of sleep, in individuals who are completely blind.[1] Tasimelteon should be taken at the same time every night before bedtime, with limited activities after taking the drug.[1]

Approval was based on 2 studies of 104 totally blind patients with non-24 disorder in which tasimelteon treatment significantly increased nighttime sleep and decreased daytime sleep duration compared with placebo.[1] The most common side effects with tasimelteon use were headache, elevated alanine aminotransferase levels in the blood, drowsiness, upper respiratory or urinary tract infection, nightmares/unusual dreams, and disturbed nighttime sleep.[1]

Signs and symptoms

Consider the following to determine the nature of the patient’s circadian rhythm disorder:

  • Duration of symptoms (transient vs chronic)

  • Pattern of the sleep-wake cycle: Allows diagnosis within chronic subtypes

  • Shift work (rotating morning/evening/night shifts vs a consistent shift)

  • Total sleep time (normal vs shortened)

  • Peak alertness (late evening/night vs early morning vs no pattern)

  • Recent travel: Symptoms from high-altitude flight in general (< 24 h) versus those from jet lag (persist for days; more likely to occur if ≥3 time zones are crossed)

  • Daytime sleepiness: Seen in all circadian rhythm disorders, with varying severity/timing

  • Psychological assessment: Psychophysiological insomnia, depressive disorders, other psychiatric disorders (symptoms may be similar to those of circadian rhythm disorders)

  • Cognition (ie, impact of circadian rhythm disorder on complex cognitive tasks such as selective attention and executive function)

  • Patient attempts at treatment (sleep aids) (eg, alcohol, herbal preparations, nonprescription/over-the-counter drugs)

  • Medication history and timing of administration

  • Snoring, with/without witnessed apnea

  • Other medical conditions (eg, congestive heart failure [CHF], chronic obstructive pulmonary disease, chronic pain syndromes, thyroid disease)

  • Environmental cues (light intensity, noise level, environmental temperature) and sleep hygiene (exercise and/or stimulant intake before bedtime)

  • Any history of motor vehicle accidents or other accidents due to decreased alertness and/or excessive sleepiness

DSPS is characterized by the following:

  • Persistent inability (>6 mo) to fall asleep and awaken at socially accepted times

  • Ability to maintain sleep once sleep is achieved

  • Normal total sleep times

  • Peak alertness in late evening and night

  • Typically seen in adolescents, young adults, and night workers

ASPS occurs much less frequently than DSPS and has the following features:

  • Persistent, early evening sleep onset (between 6:00 pm and 9:00 pm)

  • Early morning wake-up time (generally between 3:00 am and 5:00 am)

  • Peak alertness in early morning

  • Usually stable sleep schedule

  • Normal total sleep time

  • Most frequently occurs in elderly patients and in depressed individuals

Irregular sleep-wake cycles include the following characteristics:

  • Excessive daytime sleepiness and/or insomnia

  • Multiple sleep episodes without evidence of recognizable ultradian (biologic rhythms with < 24-h cycle) or circadian features of sleep and wakefulness

  • Normal total sleep time

  • Irregularity of sleep and of daytime activities, including eating

  • Random fluctuation of body temperature

  • No consistent pattern of peak alertness

  • Frequently associated with Alzheimer disease and other neurodegenerative diseases

Patients with sleeplessness/insomnia have a lower than normal total sleep time due to difficulties in initiating or maintaining sleep.

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of circadian rhythm disorders is primarily based on a thorough history. In cases of sleeplessness, it is important to distinguish individuals with difficulty initiating sleep from those with difficulty maintaining sleep, those with significant daytime impairment, and those with nonrestorative sleep.

The physical examination is focused on identifying risk factors for other conditions that may precipitate, exacerbate, or mimic sleeplessness/insomnia (eg, depression, obstructive sleep apnea [OSA], neurodegenerative disease). Examination includes the following assessments:

  • General affect or sense of well-being in those with sleeplessness/insomnia as a primary sleep complaint

  • Body mass index (BMI): Increased risk for OSA with higher BMI measurements

  • Craniofacial morphology: Large tonsils, narrow oropharyngeal spaces, and large necks (increased risk for OSA)

  • Chest: Barrel chest (associated with chronic lung disease); crackles, murmurs, and cardiac enlargement (as evidenced by displaced point of maximum impulse) may be CHF

  • Digital clubbing: Associated with chronic lung disease or congenital heart disease, or it may be familial; further medical evaluation may be needed

  • Neurologic examination

Sleep tests

  • Sleep logs: For assessing sleeplessness; identifies sleep-wake cycles in the patient's normal environment; permits a subjective assessment of alertness over a 2-week period

  • Multiple Sleep Latency Test (MSLT): For objective measurement of sleepiness

  • Epworth Sleepiness Scale: For an indication of sleepiness; correlated with sleep apnea

Imaging studies

  • Brain imaging: For evaluation of suspected neurodegenerative disease

  • Actigraphy: For gross measurement of sleep-wake cycles over time

  • Overnight polysomnography: For identification of OSA, periodic limb movements of sleep, or sleep-state misperception; for evaluation of narcolepsy when used in conjunction with the MSLT

See Workup for more detail.

Management

Therapy for circadian rhythm disturbances is largely behavioral. However, the direction of evaluation and treatment plans is influenced by differentiating between transient and chronic circadian rhythm disorders as well as between primary and secondary disorders.

DSPS often resolves in adulthood. ASPS often responds well to a combination of behavioral and pharmacologic intervention.

Treatment for circadian rhythm disturbances includes the following:

  • Behavioral therapy

  • Bright light therapy

  • Chronotherapy

  • Enhancing environmental cues

  • Lifestyle changes

  • Mixed modalities

Pharmacotherapy

  • Benzodiazepines (eg, triazolam, temazepam, estazolam, quazepam, flurazepam)

  • Nonbenzodiazepine hypnotics (eg, zolpidem, eszopiclone, zaleplon)

  • Melatonin receptor agonists (eg, tasimelteon, ramelteon, melatonin)

  • Orexin receptor antagonists (eg, suvorexant)

Surgery

Sleep disturbances associated with OSA syndrome may be treatable with surgical intervention.

See Treatment and Medication for more detail.

Background

Disturbances in circadian rhythm—the approximately 24-hour cycles that are endogenously generated by an organism—can be categorized into 2 main groups: transient disorders and chronic disorders. Transient disorders include jet lag or a changed sleep schedule due to work, social responsibilities, or illness. (See Etiology, Prognosis, and Presentation.)

The most common chronic disorders are delayed sleep-phase syndrome (DSPS), advanced sleep-phase syndrome (ASPS), and irregular sleep-wake cycle. Katzenberg et al suggested genetic correlations (ie, clock polymorphisms) to circadian rhythm patterns.[2] The International Classification of Sleep Disorders (ICSD-2) recognizes 9 distinct circadian rhythm seep disorders.

Most physiologic systems demonstrate circadian variations. The systems with the most prominent variations are the sleep-wake cycle, thermoregulation, and the endocrine system. (See Etiology.)

Terminology

Important terms associated with circadian rhythm are defined as follows:

  • Circadian rhythm (from circa, meaning "about," and diem, meaning “day”) - Approximately 24-hour cycles endogenously generated by an organism (eg, sleep-wake cycle)

  • Ultradian rhythm - Biologic rhythms shorter than a 24-hour cycle (eg, sleep stages)

  • Entrainment - Synchronization of the circadian rhythms with environmental cues

  • Free-running clock - Persistence of circadian rhythms in the absence of environmental cues (eg, in patients with impaired ability to entrain or in those without time cues)

  • Zeitgeber (time giver) - Specific environmental variables that provide time cues (eg, light, food-availability cycles); light is the strongest zeitgeber

  • Sleeplessness (insomnia) - Difficulty initiating or maintaining sleep

  • Circadian rhythm disorders - Malfunctions of the circadian timing system or the biologic clock

DSPS is characterized by a persistent inability (>6 mo) to fall asleep and awaken at socially accepted times. Once asleep, these patients are able to maintain their sleep and have normal total sleep times. In contrast, patients with insomnia have a lower than normal total sleep time due to difficulties in initiating or maintaining sleep. (See Etiology, Prognosis, Presentation, Workup, Treatment, and Medication.)

ASPS is characterized by persistent, early evening sleep onset (between 6:00 pm and 9:00 pm), with an early morning wake-up time, generally between 3:00 am and 5:00 am. ASPS is less common than DSPS; it most frequently occurs in elderly patients and in individuals who are depressed.

An irregular sleep-wake schedule features multiple sleep episodes without evidence of recognizable ultradian or circadian features of sleep and wakefulness. As with ASPS and DSPS, total sleep time is normal. Daily sleep logs demonstrate irregularity not only of sleep but also of daytime activities, including eating.

Physiology

The neural basis of the circadian rhythm, the suprachiasmatic nuclei (SCN), is located in the anterior ventral hypothalamus and has been identified as the substrate that generates circadian activity. SCN lesions produce loss of circadian rhythmicity of the sleep-wake cycle, the activity-rest cycle, skin temperature, and corticosteroid secretion. (See Etiology.)

Other pacemakers that are not located in the SCN are observed. For instance, core body temperature rhythm persists despite bilateral ablation of SCN. Furthermore, free-running studies have provided evidence for multiple circadian oscillators. Under free-running conditions, circadian rhythm may split into independent components.

Complications

The consequences of poor sleep are well established. They include irritability, impaired social interactions and psychomotor coordination, poor daytime performance, and daytime sleepiness. The literature supports the relationship of poor sleep to automobile accidents, heavy machinery accidents, and other catastrophes. (See Prognosis.)

Etiology

Most of the time, the biologic clock or the circadian rhythm is in synchronization with the 24-hour day-night environment. However, in some individuals, the biologic circadian rhythm of sleep and wakefulness is out of phase with the conventional or desired sleep-wake schedule. Postulated reasons for that breakdown are as follows.

Sensitivity to zeitgebers

Sensitivity to zeitgebers (ie, environmental cues) may be altered or disrupted, which can be demonstrated under free-running conditions. Altered or disrupted sensitivity to zeitgebers is probably the most common cause of circadian rhythm disorder.

Disrupted pacemaker function

A dysfunction may be present in the internal coupling mechanisms of biologic pacemakers (eg, the coupling of the sleep-wake cycle with the temperature cycle).

Environment

Light, higher levels of noise, and elevated room temperature are not conducive to good sleep and are important variables to consider in shift and night workers

Travel

The severity of jet lag is related to the direction of travel (ie, more frequently seen when traveling in an eastward direction) and the number of time zones crossed. Most patients experience jet lag if they cross 3 or more time zones. The rate of adjustment is 1.5 hours per day after an eastward flight and 1 hour per day when the flight is in a westward direction.

Other factors that may affect the severity of jet lag are age, the ability to sleep while traveling, the time of the day at the destination, and exposure to light. Studies have even looked at cabin pressure and the slight oxygen deprivation experienced during flights as contributing factors to symptoms of jet lag.

Neurologic disease

Alzheimer disease is one of the more common examples of neurologic disease associated with circadian rhythm disturbance; however, irregular sleep-wake cycles also can be seen in other neurodegenerative diseases. The phenomenon of sundowning is best described in Alzheimer disease and is characterized by sleep disruptions with awakenings and confusion.

Circadian rhythm disturbances have been reported in children with cancer and may be seen following injury to the hypothalamus or brainstem in those with endocrine dysfunction or following cranial irradiation.[3]

In children with autism spectrum disorder, sleep onset and sleep maintenance insomnia have been described.[4] They have also been associated with abnormal sleep-wake rhythms.

Shift work

Rapid shift changes and shift changes in the counterclockwise direction are most likely to cause symptoms.

Lifestyle

Lifestyle and social pressure (to stay up late) can exacerbate a circadian rhythm disorder.

Epidemiology

Occurrence in the United States

Delayed sleep-phase syndrome (DSPS) is common. Approximately 7-10% of patients who complain of insomnia are diagnosed with a circadian rhythm disorder, most often DSPS. The prevalence of DSPS is probably higher than that, because the total sleep time is typically normal in patients with DSPS and because patients with DSPS adjust their lifestyle to accommodate their sleep schedule and do not seek medical treatment. In adolescence, the prevalence is approximately 7%.

True advanced sleep-phase syndrome (ASPS) is probably quite rare. However, an age-related phase advance is common in elderly patients because they tend to go to sleep early and get up early.

The prevalence of irregular sleep-wake schedules has not been established but is said to be quite high. An irregular sleep-wake schedule is common in patients with Alzheimer disease.

Approximately 20% of US workers perform shift work, but not all of these workers develop shift-work syndrome, and individual phase tolerance is observed.

International occurrence

Dagan et al reported the characteristics of 322 Israeli patients with circadian rhythm sleep disorder and found that most of these patients (83.5%) had DSPS. About 90% of the patients with DSPS reported onset of the syndrome in early childhood or adolescence.[5]

A cross-sectional, nationwide epidemiologic study in Norway established an overall prevalence of DSPS of 0.17% when strict International Classification of Sleep Disorders (ICSD) criteria were used.[6]

Race-related demographics

Race has been associated with variations in incidence of obstructive sleep apnea (OSA); however, many variables may be associated with these differences, and further research is necessary to evaluate this.

Sex-related demographics

The sex difference in circadian rhythm disorders seems to be age related. In children and adolescents, no significant prevalence based on sex is observed. Moreover, little to no difference in prevalence based on sex is observed in patients aged 20-40 years. In persons older than 40 years, however, women are 1.3 times more likely than men to report insomnia.

Age-related demographics

Circadian rhythm cycles undergo changes during puberty, as do other physiologic systems. At this time, increased daytime sleepiness is seen along with the development of sleep-phase delay. Early school start times at this critically important developmental phase, coupled with afterschool activities and homework, are associated with sleep deprivation and phase shifting in children and adolescents. This can lead to symptoms of daytime sleepiness, poor concentration, and impaired performance.

DSPS is the most common circadian rhythm disorder in children and adolescents. ASPS is more likely to appear in elderly individuals. Health risks associated with shift work, such as gastrointestinal (GI) and psychosomatic symptoms, increase with age.

Irregular sleep-wake rhythms can be seen in patients with neurologic impairment, including those with dementia.

Prognosis

Prognoses in circadian rhythm disorders include the following:

  • Jet lag - This is a transient condition that has a good prognosis

  • Shift work - Abrupt changes in schedule and counterclockwise shifts are associated with daytime sleepiness and impaired performance; older patients may not adjust well to shift work

  • Delayed sleep-phase syndrome (DSPS) - This is typically seen in adolescents and young adults; this sleep pattern often resolves in adulthood

  • Advanced sleep-phase syndrome (ASPS) - This is prominent in the elderly and often responds well to a combination of behavioral and pharmacologic intervention

  • Other conditions - Children with special needs, including attention deficit hyperactivity disorder and developmental disabilities, generally respond well to behavioral intervention

Morbidity and mortality

The mortality rates associated with circadian rhythms are difficult to assess. Many deaths related to circadian rhythm disorders are the result of impaired performance secondary to sleep deprivation; therefore, many times, the deaths are categorized into different headings (eg, motor vehicle accidents, heavy machinery accidents). Sometimes, deaths are sequelae of the use of hypnotics, alcohol, or both to treat insomnia.

Shift workers have been found to have a 40% greater cardiovascular disease risk than nonshift workers. The frequency of GI, psychosomatic, and psychiatric symptoms is also increased in shift workers. In addition, increased alcohol and drug use, as well as emotional problems, have been described.

Daytime sleepiness in students with DSPS has been correlated with negative mood and increased smoking and alcohol consumption.

Some of the features of depressive disorders, such as early morning awakening and decreased rapid eye movement (REM) latency, are suggestive of ASPS. Whether these changes are secondary to depression or actually cause it has not been established.

Patient Education

Education can play a critical role in therapeutic response; however, education in sleep hygiene without other interventions is often insufficient.

Patients should be advised of risks secondary to sleepiness and have follow-ups after treatment to determine if risk factors have been satisfactorily addressed.

For patient education information, see the Mental Health Center and the Sleep Disorders Center, as well as Insomnia, Primary Insomnia, Insomnia Medications, Sleep Disorders in Women, Sleep Disorders and Aging, and Sleeplessness and Circadian Rhythm Disorder.

 

Presentation

History

The diagnosis of circadian rhythm disorders is primarily based on a thorough history. Differentiation of transient disorders from chronic disorders and primary disorders from secondary disorders influences the direction of evaluation and treatment plans.

As with all medical and psychiatric histories, the nature of the complaint is the first order of business. In cases of sleeplessness, distinguishing individuals with difficulty initiating sleep from those with difficulty maintaining sleep, those with significant daytime impairment, and those with nonrestorative sleep is important.

Duration of symptoms

Transient changes can be seen with air flights of long duration, jet lag, transient stresses (eg, illnesses), and short-term sleep schedule disruptions (eg, shift work). Chronic circadian changes can be seen with advanced sleep-phase syndrome (ASPS), delayed sleep-phase syndrome (DSPS), and irregular sleep-wake cycles.

Pattern of the sleep-wake cycle

This is an important part of the history in patients with circadian rhythm disturbances. The pattern of the sleep-wake cycle allows diagnosis within the chronic subtypes. DSPS is characterized by a persistent inability (ie, >6mo) to fall asleep and awaken at socially accepted times. Once asleep, these patients are able to maintain their sleep and have normal total sleep times.

DSPS is most frequently identified in adolescents, college students, and night workers. Differential diagnosis includes lifestyle preference, inadequate sleep hygiene, primary insomnia, jet lag, and psychophysiologic insomnia. Teenagers with DSPS are at increased risk for behavioral problems and depression.

Advanced sleep-phase syndrome

ASPS is characterized by persistent, early evening sleep onset (between 6:00 pm and 9:00 pm), with an early morning wake-up time, generally between 3:00 and 5:00 am. The sleep schedule is usually stable. ASPS occurs much less frequently than DSPS and is seen most commonly in the elderly and in persons who are depressed. It needs to be differentiated from exogenous depression and from excessive daytime sleepiness (EDS), which is associated with other sleep disorders (eg, obstructive sleep apnea [OSA]).

Irregular sleep-wake cycle

An irregular sleep-wake schedule features multiple sleep episodes without evidence of recognizable ultradian or circadian features of sleep and wakefulness. As with APSD and DPSD, total sleep time is normal. Daily sleep logs demonstrate irregularity not only of sleep but also of daytime activities, including eating. Body temperature also randomly fluctuates. The principal complaints are excessive daytime sleepiness and/or insomnia.

Shift workers

For shift workers, the need to adjust the biologic clock is coupled with the social pressure of more noise and disturbance during the day, leading to difficulties in sleeping. This is most difficult for workers who must switch their schedule and rotate between morning, evening, and night shifts. For those who consistently work the same shift, only environmental issues affect sleep quality once their biologic clock adjusts to the new time.

Total sleep time

In ASPS and DSPS delays, total sleep time is normal. Shift workers, even those who work a consistent night shift, tend to have shorter sleep times.

Peak alertness

Patients with DSPS have their peak alertness in late evening and night, whereas patients with ASPS have their peak alertness in the early morning. Patients with irregular sleep-wake cycles demonstrate no consistent pattern of alertness.

Recent travel

Jet lag is a form of transient circadian rhythm disturbance. It results from an inability to synchronize one's normal rhythm to rapidly changing time shifts of environmental cues.

Although many of the symptoms have been associated with high-altitude flight in general, the distinguishing factor seems to be the length of symptoms. Symptoms related to flight generally last less than 24 hours, whereas those of jet lag may persist for days. The duration of the flight is the primary determinant of the intensity and duration of the jet lag. In general, jet lag is most likely to be experienced if 3 or more time zones are crossed. The likelihood of sleep disturbance during travel across time zones increases with aging.[7]

Daytime sleepiness

Daytime sleepiness is seen in all circadian rhythm disorders, although the severity may vary from individual to individual and from day to day. Assess for the presence of consequences of daytime sleepiness, which include poor concentration, impaired performance (including a decrease in cognitive skills), and poor psychomotor coordination. Headaches may also be present. The presence of early morning headaches should suggest further investigation for obstructive sleep apnea (OSA).

For children and adolescents, early school hours are associated with shorter total sleep time and increased daytime sleepiness. This is more prominent in teenagers.

Psychological assessment

Psychophysiological insomnia, depressive disorders, and other psychiatric disorders may present with symptom profiles similar to those of circadian rhythm disorders. Assess patients for these disorders.

Cognition

Assess impact on complex cognitive tasks such as selective attention and executive function as these will impact on risks for both work and school performance.

Patient attempts at treatment

Perform a careful inquiry concerning the patient’s use of commonly employed sleep aids, including alcohol, herbal preparations, and over-the-counter (OTC) sleep aids. Residual sleepiness can be seen with some of these preparations, as well as with prescription hypnotics and some of the allergy preparations. Johnson et al reported that 13% of the general population had used alcohol as a short-term sleep aid during the previous year.[8]

Medication history

Obtain a careful medication history regarding the timing of administration of drugs. For example, beta-adrenergic drugs, typically used in the treatment of asthma, can delay sleep because of their stimulant effect. Amphetamines, caffeine, selective serotonin reuptake inhibitor (SSRI) antidepressants, steroids, nicotine, theophylline, and clonidine can also affect sleep.

Snoring

Chronic loud snoring with or without witnessed apnea should direct the physician to evaluate the patient for risk factors for upper airway resistance syndrome and OSA.

Other medical problems

The 2 most commonly seen medical diseases that affect sleep and daytime function are congestive heart failure and chronic obstructive pulmonary disease. Chronic pain syndromes and thyroid disease also affect sleep and daytime function. Hyperthyroidism is associated with sleep disruption, whereas hypothyroidism is associated with daytime sleepiness and fatigue.

Environmental cues and sleep hygiene

This is particularly important to assess in shift workers. The intensity of light, level of noise, and environmental temperature can influence sleep. Exercise and stimulant intake prior to bedtime are frequent lapses in good sleep hygiene and can be easily addressed.

Finally, inquire about any history of motor vehicle accidents or other accidents occurring as a result of decreased alertness/excessive sleepiness.

Physical Examination

The physical examination complements the history in patients with insomnia. Focus the physical examination on identifying risk factors for other conditions that may precipitate, exacerbate, or mimic insomnia. These may include depression, obstructive sleep apnea (OSA), and neurodegenerative disease. The exam can include the following evaluations:

  • Affect - Assess general affect and sense of well-being in patients presenting with insomnia as a primary sleep complaint

  • Body mass index - Patients with obesity who have increased body mass indices are at increased risk for OSA

  • Craniofacial morphology - The head and neck examination is important in assessing risk for OSA; patients with large tonsils, narrow oropharyngeal spaces, and large necks are at risk for OSA

  • Chest - Barrel chest (ie, increased anteroposterior diameter) is associated with chronic lung disease; crackles, murmurs, and cardiac enlargement evidenced by displaced point of maximum impulse (PMI) suggest congestive heart failure

  • Digital clubbing - Clubbing may be associated with chronic lung disease or congenital heart disease, or it may be familial; this finding suggests a need for further medical evaluation

  • Neurologic examination - Alzheimer disease and other neurodegenerative diseases frequently are associated with irregular sleep-wake cycles

 

DDx

Diagnostic Considerations

Jet lag should be differentiated from delayed sleep-phase syndrome (DSPS). DSPS should be differentiated from lifestyle preference, inadequate sleep hygiene, primary insomnia, and psychiatric conditions. (Psychopathology has been found in 50% of patients with DSPS.)

Transient circadian rhythm disturbances define themselves by their timing. Many psychiatric conditions distinguish themselves by short sleep times and disrupted sleep. Regardless of their bedtime, patients with psychiatric disorders have sleep-onset insomnia. Coping styles distinguish the night owl.

Advanced sleep-phase disorders should be differentiated from atypical depression, seasonal affective disorder, and excessive daytime sleepiness (EDS) associated with other sleep disorders.

Patients with irregular sleep-wake schedules are distinguished by the irregularity not only of their sleep cycle, but also of their cycles of eating and other daily activities. The rhythm of body temperature also is affected. Irregular sleep-wake schedules should be differentiated from psychiatric disorders and from insomnia associated with shift work.

Daytime sleepiness in DSPS should be distinguished from sleep-disordered breathing, narcolepsy, and atypical depression. All of these conditions often present with early bedtime.

Nocturnal eating disorder may also have a substantial impact on circadian cycles, with frequent awakenings for feeding. Sleep distribution may resemble that of infants, with sleep and feeding distributed over a 24-hour period.

Insomnia is a core feature of posttraumatic stress disorder and has been reported in 70% of patients.

 

Workup

Approach Considerations

When assessing sleeplessness, a sleep log is often used. Although not technically a laboratory test, this diary allows identification of sleep-wake cycles in the patient's normal environment and permits subjective assessment of alertness over a 2-week time period. The Practice Parameters (2007) from the American Academy of Sleep Medicine recommend the use of sleep logs in the evaluation of the following sleep disorders[9] :

  • Shift-work syndrome

  • Jet lag

  • Advanced sleep-phase syndrome (ASPS)

  • Delayed sleep-phase syndrome (DSPS)

  • Free-running disorder

  • Irregular sleep-wake rhythm

Failure to diagnose other medical conditions associated with increased daytime sleepiness, such as obstructive sleep apnea (OSA), may carry significant consequences in terms of added morbidity and mortality. Another potential treatment pitfall is failure to assess a patient’s risk for motor vehicle accidents.

Implicit in the diagnosis of circadian rhythm disorder is a desire to conform to traditionally accepted sleep-wake patterns.

Imaging studies

Consider imaging studies if the patient is to be evaluated for neurodegenerative disease. Also consider imaging studies in patients with OSA to determine the etiology of obstruction.

Actigraphy

An actigraph is a small motion-sensing device worn on the nondominant wrist, generally for 1 week. It is based on the premise that wrist motion is decreased during sleep. This allows a very gross measurement of sleep-wake cycles over time.

Overnight polysomnography

This study is of value in identifying the patient with OSA, periodic limb movements of sleep (PLMS), or sleep-state misperception. It also is used in conjunction with the Multiple Sleep Latency Test (MSLT) to evaluate patients with narcolepsy. It is not routinely used in the diagnostic evaluation of patients with insomnia or in the diagnostic evaluation of patients with circadian rhythm disturbances.

Sleep Tests

Multiple Sleep Latency Test

The MSLT allows for objective measurement of sleepiness. Normal adult values range from 10-20 minutes, whereas sleep latencies of less than 5 minutes indicate abnormal sleepiness. MSLT is indicated when suspicion of narcolepsy is raised by the clinical history. Following a normal night's sleep documented by overnight polysomnography, specific abnormalities in MSLT (ie, 2 or more sleep-onset rapid eye movements [SOREMs]) support a diagnosis of narcolepsy.

Epworth Sleepiness Scale

The Epworth Sleepiness Scale (ESS) is based on a questionnaire that asks patients to rate their responses to 8 situations on a scale of 0-3, based on whether the situation was likely to be associated with dozing behavior. It was designed to give an indication of sleepiness and has been correlated with sleep apnea.

Morningness Eveningness Questionnaire

The evidence is insufficient to recommend the routine use of the Morningness Eveningness Questionnaire (MEQ) for the evaluation of circadian rhythm disturbances.

 

Treatment

Approach Considerations

Therapy for circadian rhythm disturbances is largely behavioral. Light therapy has been shown to be an effective modifier of circadian cycles. Mixed modalities may be effective in elderly patients with dementia who have irregular sleep-wake rhythms. A combination of planned sleep scheduling, timed light exposure, and timed melatonin administration can be helpful.

Bright light therapy

Circadian rhythm disturbances respond very well to light therapy, especially bright light (>600 lux). For entrainment purposes, bright room light over time may be sufficient; however, a higher intensity of light (>6000 lux over 30-60 min) is often necessary to accomplish acute phase shifts.

The timing of light therapy is also important because it affects the degree and direction of the rhythm shift. For example, light therapy applied in the early evening and nighttime hours delays the cycle (in patients with advanced sleep-phase syndrome [ASPS]), whereas therapy given in the early morning stimulates morning alertness and an earlier bedtime (in patients with delayed sleep-phase syndrome [DSPS]).

Chronotherapy

This behavioral treatment consists of a gradual shift in sleep time in accordance with the patient's tendency. Thus, in DSPS, a progressive delay of 3 hours per day is prescribed, followed by strict maintenance of a regular bedtime hour once the desired schedule is achieved. In ASPS, chronotherapy focuses on advancing bedtime by 2-3 hours per night over 1 week until a desired schedule is achieved.

Enhancing environmental cues

This is an important part of the treatment of circadian rhythm disorders. Patients are encouraged to keep a dark, quiet room during sleep and a well-lit room upon awakening. Bright light exposure in the evening should be avoided, and regular hours of eating and other activities should be enforced.

Pharmacotherapy

Tasimelteon (Hetlioz) was approved by the US Food and Drug Administration (FDA) in January 2014 for treatment of non–24-hour sleep-wake disorder in the totally blind. Approval was based on results of 2 trials: the Safety and Efficacy of Tasimelteon (SET) trial, a 26-week study that included 84 patients, and the Randomized Withdrawal study of the Safety and Efficacy of Tasimelteon (RESET), a 19-week trial that included 20 patients, all of whom had been previously screened during the SET trial and entrained during open-label tasimelteon treatment.

Entrainment of the circadian rhythm, as measured by urinary 6-hydroxymelatonin sulfate (aMT6s), a main metabolite of melatonin, was the primary efficacy endpoint for SET. Scores on the 24-hour clinical response scale were another defined endpoint for SET. Outcomes for RESET included maintenance of entrainment (aMT6s) and maintenance of clinical response. Study results demonstrated that tasimelteon entrains the master clock (both melatonin and cortisol) and has clinically meaningful effects on the sleep-wake cycle in terms of the timing and amount of sleep, and improved measure of global functioning.[10, 11]

Lifestyle

Patients may respond to shifts in their active phases by exhibiting signs of sleep deprivation. For example, teenagers may have difficulty keeping late hours and getting up for an early morning class. Shift workers may have difficulty if shifts are changed too rapidly before they have had a chance to adjust.

Surgical care

Sleep disturbances associated with obstructive sleep apnea (OSA) syndrome may be treatable with surgical intervention.

Consultations

Consultation with the following specialists can be useful in managing circadian rhythm disorders:

  • Sleep medicine specialist

  • Neurologist

  • Psychiatrist

  • Pulmonologist

Diet

Nocturnal eating disorder is an entity distinct from circadian rhythm disorders and is characterized by an inability to maintain sleep over the night. Sleep is interrupted and patients are unable to return to sleep without eating or drinking.

Dietary advice includes the following:

  • Limit large meals

  • Avoid intake of excessive fluids before bedtime; this is an element that is generally emphasized when attempting to improve sleep hygiene

  • Discourage obesity

Additional concerns and follow-up

Address associated psychological issues. Patients with DSPS who initially respond to chronotherapy may gradually shift back to their old sleep pattern. Often, chronotherapy must be repeated every few months to maintain long-lasting results.

Emphasize the importance of good sleep hygiene and avoidance of the use of alcohol, stimulants (eg, nicotine, caffeine), and strenuous exercise before bedtime.

Transfer

The overwhelming majority of patients with insomnia (except elderly patients) are treated as outpatients.

In the elderly, in whom numerous other physical, psychiatric, and pharmacologic concerns can be present, institutional care is often necessary. The presence of significant sleep disruption is often a predictor of which patients require institutionalization.

Deterrence and prevention

Strategies to prevent circadian rhythm disorders include the following:

  • Encourage good sleep hygiene

  • Control of the sleep environment with regulation of light/dark exposure has been helpful to shift workers in maintaining sleep

  • For patients anticipating jet lag, advise that they change their schedule to the time of the new location prior to departure; this can modify the effects of jet lag

  • For shift workers, advise shifting the schedule in a clockwise direction; this is often better tolerated

Activity

In patients with irregular sleep-wake cycles, behavioral modification has been shown to be helpful. This includes encouraging structured daytime activity, even in the presence of fatigue. Attendants in nursing homes can help elderly patients to remain awake by involving them in activities and restricting sleep to conventional time periods. Encourage afternoon naps scheduled daily at a regular time. This helps to avoid multiple brief daytime naps and to consolidate sleep to the desired time.

Emphasizing a program of regular morning exercise is a component of promoting sleep hygiene. Advise patients to avoid strenuous exercise before bedtime.

 

Medication

Medication Summary

Short-acting benzodiazepines are often prescribed in the early treatment of sleep-onset insomnia, while long-acting agents are often used to treat long-standing insomnia with sleep maintenance, as well as sleep-onset, insomnia.

Nonbenzodiazepine hypnotics have come into increased use because they do not significantly affect sleep architecture and, unlike benzodiazepines, are not associated with a rebound phenomenon.

Melatonin reportedly is effective against jet lag, as well as in the treatment of sleep-onset insomnia in elderly patients who are melatonin deficient. Melatonin agonists can be prescribed for insomnia characterized by difficulty with sleep onset.

Benzodiazepines

Class Summary

These agents are recommended in preference to barbiturates because of their low toxicity and clinical efficacy. They have a rapid onset of action. Concerns remain with regard to rebound insomnia, residual daytime effects, and addictive potential.

Short-acting benzodiazepines are often chosen in the early treatment of sleep-onset insomnia and are used in conjunction with behavioral therapy. Long-standing insomnia with sleep maintenance, as well as sleep-onset, insomnia often requires long-acting agents.

Triazolam (Halcion)

Triazolam is frequently chosen as a short-term adjunct to behavioral therapy. This short-acting agent is effective in helping patients fall asleep. It is not effective in persons with sleep maintenance problems.

For patients with sleep maintenance insomnia, a benzodiazepine with an intermediate half-life (eg, estazolam [ProSom]) or a long half-life (eg, quazepam) may be considered.

Temazepam (Restoril)

Temazepam's intermediate rate of absorption and duration of action make it useful for treating initial and middle insomnia. Because temazepam has no active metabolite, cognitive impairment and grogginess the following day are reduced. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.

Estazolam

Estazolam is an intermediate-acting agent with a slow onset of action and a long duration. It is a good agent for sleep-maintenance insomnia. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.

Quazepam (Doral)

Quazepam is used for sleep-maintenance insomnia. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.

Flurazepam

Flurazepam is frequently chosen as a short-term treatment of insomnia. It enhances the inhibitory effects of the GABA neurotransmitter on neuronal excitability that results by increased neuronal permeability to chloride ions. The shift in chloride ions results in hyperpolarization and stabilization of the neuronal membrane.

Nonbenzodiazepine hypnotics

Class Summary

These agents are gaining popularity because they do not have a significant effect on sleep architecture and are not associated with the rebound phenomenon seen with benzodiazepines.

Zolpidem (Ambien, Ambien CR, Edluar)

Zolpidem is a nonbenzodiazepine hypnotic of the imidazopyridine class. It is rapidly absorbed, has an elimination half-life of 2.5 hours, and is a good short-term option for patients with sleep-onset insomnia who require pharmacologic support. The extended-release product (Ambien CR) consists of a coated, 2-layer tablet and is useful for insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The first layer releases drug content immediately to induce sleep; the second layer gradually releases additional drug to provide continuous sleep.

Eszopiclone (Lunesta)

Eszopiclone is a nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. Its precise mechanism of action is unknown, but the drug is believed to interact with the gamma-aminobutyric acid (GABA) receptor at binding domains close to or allosterically coupled to benzodiazepine receptors. It is indicated for insomnia, to decrease sleep latency and improve sleep maintenance. It has a short half-life of 6 hours.

The starting dose is 1 mg immediately before bedtime, with at least 7-8 h remaining before the planned time of awakening. The dose may be increased if clinically warranted to 2-3 mg HS in nonelderly adults, and 2 mg in elderly or debilitated patients.

Zaleplon (Sonata)

Zaleplon is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. It has a chemical structure unrelated to benzodiazepines, barbiturates, or other hypnotic drugs but interacts with the GABA-benzodiazepine receptor complex. It binds selectively to the omega-1 receptor situated on the alpha subunit of the GABAA receptor complex in the brain. Zaleplon potentiates t-butyl-bicyclophosphorothionate (TBPS) binding and has preferential binding to the omega-1 receptor of the GABA receptor family.

Melatonin Receptor Agonists

Class Summary

Melatonin receptor agonists (tasimelteon, ramelteon) have been approved by the FDA. Tasimelteon is indicated for non–24-hour sleep-wake disorder. Ramelteon is indicated for insomnia characterized by difficulty with sleep onset.

Melatonin (herbal/alternative) has been reported to be useful in the treatment of jet lag and in the treatment of sleep-onset insomnia in elderly patients who are melatonin deficient. Recommendations regarding melatonin are based on the extensive literature review from the Cochrane Library.[12]

However, because of the phenomenon of publication bias, studies showing efficacy are more likely to be available for review than those that do not show efficacy. Furthermore, potential users of melatonin should be cautioned that variations in quality, purity, and quantity of active ingredient in natural pharmaceuticals make interpretation of studies difficult and raises concerns about interactions and contaminants.

Tasimelteon (Hetlioz)

Tasimelteon is a melatonin receptor agonist with high affinity for MT1 and MT2 receptors in the suprachiasmatic nucleus of the brain. MT1 and MT2 are thought to synchronize the body's melatonin and cortisol circadian rhythms with the day-night cycle in patients with non–24-hour disorder. It is indicated for non–24-hour sleep-wake disorder in the totally blind.

Ramelteon (Rozerem)

Ramelteon is a melatonin receptor agonist with high selectivity for human melatonin MT1 and MT2 receptors. MT1 and MT2 are thought to promote sleep and to be involved in the maintenance of circadian rhythm and the normal sleep-wake cycle.

Melatonin

Melatonin is available as an over-the-counter (OTC) preparation. It is used to enhance the natural sleep process and for resetting the body's internal time clock when an individual is traveling through different time zones. It has also been used for the treatment of circadian rhythm sleep disorders in blind people with no light perception.

No recommended daily allowance (RDA) of melatonin has been approved by the US Food and Drug Administration (FDA), nor is FDA-approved prescribing information available for any of the doses discussed here. Individual patients may or may not experience the reported benefits of melatonin.

Physicians and patients should consider the risks and benefits of each therapeutic option. Slow-release products are reported to be less effective. Melatonin is believed to be effective in persons crossing 5 or more time zones and is less effective in individuals traveling in a westward direction.

Orexin Receptor Antagonists

Class Summary

Orexin promotes wakefulness. Antagonism of the orexin receptor suppresses this action by orexin.

Suvorexant (Belsomra)

Suvorexant is an orexin receptor antagonist. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R by suvorexant is thought to suppress wake drive. It is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.