eMedicine Specialties > Neurology > Sleep-Related Diseases

Sleeplessness and Circadian Rhythm Disorder

Author: Mary E Cataletto, MD, Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Professor of Clinical Pediatrics, State University of New York at Stony Brook; Director of Children's Sleep Services, Winthrop University Hospital
Coauthor(s): Gila Hertz, PhD, ABSM, Director, Center for Insomnia and Sleep Disorders, Clinical Associate Professor of Psychiatry and Behavioral Sciences, State University of New York at Stony Brook
Contributor Information and Disclosures

Updated: Aug 22, 2008

Introduction

Background

Circadian rhythm describes the approximately 24-hour cycles that are generated by an organism. Most physiological systems demonstrate circadian variations. The systems with the most prominent variations are the sleep-wake cycle, thermoregulation, and the endocrine system. Circadian rhythm disturbances can be categorized into 2 main groups: transient disorders (eg, jet lag; changed sleep schedule due to work, social responsibilities, illness) and chronic disorders. 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 correlation (ie, clock polymorphisms) to circadian rhythm patterns.¹

Important terms are defined as follows:

• Circadian rhythm (from circa, meaning "about" and dies, meaning day) - Approximately 24-hour cycles endogenously generated by an organism (eg, sleep-wake cycle)
• Ultradian rhythm - Biological 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)
• Sleeplessness (insomnia) - Difficulty initiating or maintaining sleep
• Circadian rhythm disorders - Malfunction of the circadian timing system or the biological 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.

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 and 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.

Pathophysiology

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. 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.

Frequency

United States

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 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. Irregular sleep-wake schedule is common in patients with Alzheimer disease.

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

International

Dagan et al reported the characteristics of 322 Israeli patients with circadian rhythm disorder.² Most patients (85%) with circadian rhythm disorder who seek medical help have DSPS. About 90% of patients with DSPS in the study by Dagan et al reported onset of DSPS in early childhood or adolescence. A cross-sectional nationwide epidemiologic study in Norway established an overall prevalence of DSPS to be 0.17% when strict International Classification of Sleep Disorders (ICSD) criteria were used.³

Mortality/Morbidity

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, other 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. Frequency of GI symptoms, other psychosomatic symptoms, and psychiatric symptoms is also increased in shift workers.
• 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.

Race

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

The sex difference in circadian rhythm disorders seems to be age related.

• In children and adolescents, no significant prevalence based on sex is observed.
• In patients aged 20-40 years, little to no difference in prevalence based on sex is observed.
• In those older than 40 years, women are 1.3 times more likely to report insomnia than men.

Age

• 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 can be associated with 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 GI and psychosomatic symptoms, increase with age.
• Irregular sleep-wake rhythms can be seen in patients with neurological impairment, including those with dementia.

Clinical

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 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, >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. This disorder 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.
• ASPS: This syndrome 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. 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 excessive daytime sleepiness (EDS), which is associated with other sleep disorders (eg, obstructive sleep apnea [OSA]). 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.
• Shift workers: For shift workers, the need to adjust the biological 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 the biological clock adjusts to the new time.
• Total sleep time: In both 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.
• Concern about sleep pattern: Implicit in the diagnosis of circadian rhythm disorder is a desire to conform to traditionally accepted sleep-wake patterns.
• 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 flying 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.
• 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 of 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.
• Patient attempts at treatment: Perform a careful inquiry concerning the use of commonly used 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.⁴
• 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 or psychiatric problems: The 2 most commonly seen medical diseases and disorders 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.

Physical

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, OSA, and neurodegenerative disease.

• 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 evinced 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 should suggest a need for further medical evaluation.
• Neurologic examination: Alzheimer disease and other neurodegenerative diseases frequently are associated with irregular sleep-wake cycles.

Causes

Most of the time, the biological clock or the circadian rhythm is in synchronization with the 24-hour day-night environment. However, in some individuals, the biological 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 (ie, environmental cues): This 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 biological pacemakers (eg, the coupling of the sleep-wake cycle with 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 h/d after an eastward flight and 1 h/d when the flight is in a westward direction. Other factors that may affect severity of jet lag are age, ability to sleep while traveling, the time of the day at destination, and exposure to light. More recent studies even look 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 neurological 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.
• Shift work: Rapid shift changes and shift changes in the counterclockwise direction are most likely to cause symptoms.
• Other factors: Lifestyle and social pressure (to stay up late) can exacerbate circadian rhythm disorder.

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