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Keywords:

  • advanced sleep phase disorder (ASPD);
  • circadian rhythm sleep disorders (CRSD);
  • delayed sleep phase disorder (DSPD);
  • melatonin

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CONCLUSIONS
  5. REFERENCES

The primary symptom of circadian rhythm sleep disorders (CRSDs) is the inability to sleep during the desired sleep time. CRSDs are divided into two broad classes: (i) disorders not related to forced alterations of the sleep–wake schedule or light–dark cycle (including advanced sleep phase disorder [ASPD], delayed sleep phase disorder [DSPD], non-entrained type [NET], and irregular sleep–wake rhythm [ISWR]); and (ii) disorders related to forced alterations of the sleep–wake schedule or light–dark cycle (including shift work sleep disorder [SWSD], jet lag disorder [JLD], and CRSDs related to diseases and medications). DSPD and ASPD are the common primary circadian rhythm disorders. We discuss the recent developments in the pathogenesis, diagnosis, and management of CRSDs.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CONCLUSIONS
  5. REFERENCES

The term circadian (from the Latin circa diem–“about a day”) means a period which is about 24 h long. Many physiological activities of the body have a circadian rhythm, including the sleep–wake cycle, core body temperature, and concentrations of melatonin or cortisol.

The primary symptom of circadian rhythm sleep disorders is the inability to sleep during the desired sleep time. The individual's biological clock finds it difficult to adjust to the demands of the geophysical environment. As a result, patients are awake or asleep at inappropriate times and may experience insomnia or increased daytime sleepiness.

Physiology of circadian rhythm

The generation of a circadian rhythm is essential to maintain synchrony between the metabolic pathways and the environment. The process of adapting the biological clock's intrinsic periodicity to the geosynchronous cycle of 24 h is called entrainment. Several factors which help in this process are called zeitgebers, from the German term meaning “time givers”. The most important of the zeitgebers is bright light, others being social cues and food. In mammals, circadian rhythms are generated endogenously by neurons in the suprachiasmatic nucleus (SCN) in the anterior hypothalamus.1,2 Daily exposure to bright light excites photoreceptor cells in the retina (containing melanopsin, a light-sensitive pigment required for normal circadian phase rhythm).3 The signals are transmitted through the retinohypothalamic tract to the SCN causing entrainment (Fig. 1)4 The SCN also receives input through the geniculohypothalamic tract from the intergeniculate leaflet of the thalamus and serotonergic input from midbrain raphe neurons. These may allow non-photic entrainment cues, such as feeding, exercise, and social cues, to influence the SCN.5,6 In specific experimental protocols, the intrinsic time-period of the SCN appears slightly longer (24 h, 11 ± 8 min) as compared with the environmental cycle of 24 h.7 Genetic influence on the circadian rhythm includes mutations in the hPER28 and casein kinase one-delta (CKIdelta)9 genes in the SCN which result in advanced sleep phase disorder (ASPD).

image

Figure 1. Physiology of human circadian rhythm.

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Suprachiasmatic nucleus (SCN) neurons project directly to the medial preoptic, paraventricular, and dorsomedial nuclei, and the sub-paraventricular zone of the hypothalamus and the basal forebrain and midline thalamus; secondary projections fan out to the neocortex, limbic system, hippocampus, anterior pituitary, hypothalamus, and reticular activating system (RAS) to modify wakefulness (RAS), thermoregulation and feeding (hypothalamus), memory and learning (hippocampus), mental performance (neocortex), and endocrine secretion (pituitary).10 The SCN neurons comprise distinct sub-populations that contain vasoactive intestinal peptide (VIP), gastrin-releasing peptide (GRP), arginine-vasopressin (AVP), gamma-aminobutyric acid (GABA), prokineticin2 (PK2), and, indirectly, the neuropeptides and neurohormones produced in the hypothalamus, pituitary, and pineal (melatonin, which exerts feedback regulation on SCN). PK2 is especially relevant to the sleep–wake cycle as it has been postulated as one of the output molecules that transmit behavioral circadian rhythms.11

Exposure to the 24-h cycle normally causes circadian rhythms of performance and alertness to peak during daytime hours, and sleep at night. In circadian rhythm sleep disorders (CRSD), however, the sleep–wake cycle becomes dissociated from the circadian system or the external time cues, resulting in insomnia and daytime sleepiness. CRSDs are divided into two broad classes: (i) disorders not related to forced alterations of the sleep–wake schedule or light–dark cycle (including ASPD, delayed sleep phase disorder [DSPD], non-entrained type [NET], and irregular sleep–wake rhythm [ISWR]); and (ii) disorders related to forced alterations of the sleep–wake schedule or light–dark cycle (including shift work sleep disorder [SWSD], jet lag disorder [JLD], and CRSDs related to diseases and medications). DSPD and ASPD are the common primary circadian rhythm disorders.

Disorders not related to forced alterations of the sleep–wake schedule or light–dark cycle

1. Delayed sleep phase disorder

Epidemiology.  This is the most common endogenous CRSD likely to be encountered in clinical practice. The disorder was first described in 1981 by Weitzer, et al.12 The prevalence of DSPD was 0.13% in the Japanese population in a study.13 In another study of 10 000 Scandinavians followed with sleep logs, a prevalence of 0.72% was reported.14 In this study, the mean age of onset was during adolescence at 15.4 years and the disorder had mean duration of 19.2 years. In another retrospective study, 90% of the DSPD patients reported an onset of their symptoms during childhood or adolescence.15 The disorder is uncommon among elderly population.16 It accounts for 5–10% of chronic insomnia cases seen in sleep clinics. Gender difference in the prevalence of DSPD is not known at present.

Clinical features.  In DSPD, the patient falls asleep late and rises late. The habitual bedtime (e.g. 01.00 to 06.00 hours) and arising time (e.g. 10.00 to 14.00 hours) are both delayed.17 The patient experiences insomnia if trying to sleep at a more conventional earlier sleep time and experiences daytime sleepiness. There is no difficulty initiating and maintaining sleep at the patient's preferred (and delayed) sleep time. In some patients, symptoms of DSPD are self-imposed due to social influences, schoolwork, or shift work, in which the individual chooses to stay awake late into the morning hours. In other patients, DSPD is likely due to intrinsic factors such as a longer-than-average circadian period or a reduced capacity for phase advance shifts. DSPD is often associated with psychiatric disorders, especially depression.

Pathophysiology.  There is phase delay of the circadian pacemaker with respect to the conventional sleep–wake cycles.18 A vertical pattern of inheritance consistent with either an autosomal dominant mode of inheritance with incomplete penetrance or a multifactorial mode of inheritance has been described in one family.19 Other possible risk factors for DSPD include reduced morning light exposure and excessive bright-light exposure in the evening.18

Diagnosis.  General recommendations by the American Academy of Sleep Medicine (AASM)20 regarding evaluation of CRSDs are given in Table 1. A careful sleep history looking for the clinical features, aided by a sleep log maintained by the patient can help to diagnose the disorder. Actigraphy is a relatively non-invasive method of monitoring human rest/activity cycles. A small actigraph unit, also called an actimetry sensor, is worn by the patient on the non-dominant arm to measure gross motor activity. Motor activity often under test is that of the wrist, measured by the actigraph in a wrist-watch-like package. The unit continually records the movements it undergoes. The data is later read to a computer where it can be analyzed. Sleep actigraphy for at least 7 days is a non-invasive test to establish the diagnosis of DSPD.21 Polysomnograpy is not routinely indicated for diagnosis unless another coexistent sleep disorder such as obstructive sleep apnea is suspected.20 Routine clinical use of circadian phase biomarkers like dimlight melatonin onset (DLMO) and core body temperature minimum (CBTM) is not recommended for diagnosing DSPD,20 although a recent review suggests that measuring CBT may be valuable.22

Table 1.  General recommendations for evaluation of circadian rhythm sleep disorders (CRSDs)
  1. Adapted from: Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders, American Academy of Sleep Medicine, 2007.20Supported by level 2 or consensus of level 3 evidence. Unmarked recommendations are based on inconclusive or conflicting evidence.Supported by level 1 or overwhelming level 2 evidence.

1. Use of a sleep log or diary is indicated in the assessment of patients with a suspected CRSD.
2. Actigraphy is indicated to assist in evaluation of patients suspected of CRSDs.
3. Actigraphy is useful as an outcome measure in evaluating the response to treatment for CRSDs.
4. There is insufficient evidence to recommend the routine use of the Morning-Eveningness Questionnaire for the clinical evaluation of CRSDs.
5. Circadian phase markers are useful to determine circadian phase and confirm the diagnosis of free-running disorder, but there is insufficient evidence to recommend their routine use in the diagnosis of irregular sleep–wake disorder, shift work disorder, advanced sleep phase disorder, and delayed sleep phase disorder.
6. Polysomnography is indicated to rule out another primary sleep disorder in patients with symptoms suggestive of both a CRSD and another primary sleep disorder, but is not routinely indicated for the diagnosis of CRSDs.

Differential diagnosis.  The differential diagnosis includes the “normal” delayed sleep phase seen in adolescents due to poor sleep hygiene. Psychiatric disorders, especially major depression, should be considered in the differential diagnosis. DSPD should also be differentiated from NET when patients show non-24-h, free-running like rhythm.

Treatment.  Treatment of DSPD includes advancing the sleep phase by scheduling sleep at earlier and more conventional hours. Patient motivation and modification of factors contributing to late-night activity are essential components of therapy.

In chronotherapy, an attempt is made to move bedtime and rising time later and later each day, around the clock, until these times reach the number of hours of sleep per night an individual needs to be fully functional.23 No controlled studies are available supporting the efficacy or safety of chronotherapy and lasting benefit has not been demonstrated.

Phototherapy consisting of avoidance of bright light in evening and timed early morning bright-light exposure caused phase advance of sleep onset and increased daytime alertness.24 In different studies, 2500 lux for 2–3 h prior to or at rise time was used. Natural sunlight exposure with exercise may be combined with artificial light exposure.

Melatonin administration is indicated as a therapy for DSPD. Evening administration of melatonin (dose, 0.3–5 mg) between 19.00–20.00 hours shifts circadian rhythms (indicated by DLMO and CBTM) to an earlier time. Compared to placebo, melatonin treatment reduced sleep onset latency, but there was no change in daytime alertness or total sleep time.25–27 The melatonin receptor agonist ramelteon was approved for the treatment of insomnia in 2005.28 Although this agent may be beneficial in DSPD by acting on both melatonin 1 and 2 receptors, no clinical trials have been published. Vitamin B12 is not indicated in the treatment of DSPD.29 Use of hypnotic medications to promote sleep, or the use of stimulant medications to promote alertness for DSPD is not supported by evidence.20 The response to therapy may be monitored by actigraphy.

2. Advanced sleep phase syndrome

Epidemiology.  This condition is less common compared with DSPD. The prevalence is about 1% in middle-aged adults. A survey of 10 000 Scandinavians did not find a single case of ASPD.14 The usual age of onset is middle age and the disorder is common in the elderly population (age, 60–74 years).16 In nursing homes and assisted-living facilities, it is often encouraged to go to bed in early evening and this may cause sleep phase advancement. There is insufficient data to show a gender preference.

Clinical features.  In ASPD, the sleep–wake cycle is shifted earlier compared to the conventional cycle, so the patient sleeps earlier and wakes up earlier in morning compared to the conventional sleep–wake timing. Sleep onset usually occurs from 06:00 to 09.00 hours and the wake time is usually from 02.00 to 05.00 hours. There is excessive sleepiness in the evening and inability to maintain sleep till usual morning waking up time.

Pathophysiology.  ASPD was the first human CRSD to have a well-defined mendelian pattern of inheritance in some families. An autosomal-dominant familial form of APSD has been reported in three families. Affected individuals had a mutation in the casein kinase 1 binding region of the hPER2 gene with a serine-to-glycine mutation.8 A missense mutation (T44A) in the human CKIdelta gene also resulted in familial ASPD.9 An acquired form due to early evening sleep time scheduling in nursing homes is also seen and will be discussed in more detail in the next section, “Disorders related to forced alterations of the sleep–wake schedule or light–dark cycle”.

Diagnosis.  The diagnosis is established by sleep log or actigraphy done for at least 7 days. A polysomnogram is not routinely indicated for the diagnosis of ASPD unless another coexistent sleep disorder such as obstructive sleep apnea is suspected.20 A polysomnogram shows short sleep latency and decrease in total sleep time if done during conventional sleep–wake times. The use of the Morningness-Eveningness Questionnaire (MEQ) may help to confirm the diagnosis of ASPD but should not be used routinely for diagnosis of ASPD.20 Circadian markers (urinary 6-sulfatoxy melatonin acrophase DLMO and CBTM) are useful in measuring circadian phase advancement, but their routine use for diagnosing ASPD is not recommended at present.20

Treatment.  Phototherapy of ASPD includes exposure to bright light in the evening and avoidance of light exposure in the early morning. Phototherapy was effective in improving sleep quality and reducing time in bed after awakening in the morning.30 Prescribed sleep scheduling by encouraging entrainment to a conventional sleep–awake schedule is frequently combined with phototherapy. Reverse chronotherapy by progressive earlier shifting of bedtime by 3 h every 2 days has been reported as having short-term utility in a case report.31

There is insufficient data to recommend use of melatonin for treatment of ASPD in adults.17 A recent study examined therapy of ASPD in a group of children with Smith–Magenis syndrome, a complex genetic disease caused by a deletion in chromosome 17p. Sleep, as well as melatonin phase, was delayed with the combined administration in the evening of controlled-release melatonin and in the morning a beta-adrenergic antagonist, blocking the noradrenergic neurotransmission to the pineal gland that releases melatonin.32 Actigraphy may be done to monitor response to therapy.

3. Non-entrained type (NET), also known as free-running disorder or non-24-h sleep–wake syndrome

Epidemiology.  The disorder is rarely seen in the general population. Most cases have been reported in totally blind individuals (with non-functioning retinas) who lack photic entrainment (about 50% blind individuals have NET).33 Some patients are able to entrain themselves using non-photic clues like social schedules or photic clues like the retinohypothalamic pathway. Less commonly, this disorder may be seen in individuals with intact eyesight, especially head trauma,34 dementia, and severe psychiatric disorders,35 or living prolonged hours in a submarine.36 In sighted people, the onset of NET occurs in the teenage years, and almost never after age 30. In the totally blind, the onset is probably coincident with the loss of sight. The disorder is seen more in males in sighted individuals,17 but there is no gender difference in totally blind individuals.

Clinical features.  This disorder is characterized by progressive delay of sleep onset time by, for example 1-h daily, so that the major sleep period “runs” throughout the 24-h period. The disorder is due to lack of entrainment by light, so that the circadian cycle of the individual mimics the intrinsic circadian rhythm of the SCN which is slightly longer than 24-h.7 Clinical features include marked variability in symptoms from severe daytime sleepiness to complete disappearance of symptoms for a brief period of time. The disorder is also known as hypernychthemeral disorder. For a brief period of time, the sleep–wake cycle may be synchronized with the community, but after several days, it drifts out of the phase.

In a recent study using polysomnography, actigraphy, and Braille sleep logs, sleep was studied in 26 totally blind patients and matched control subjects.37 These individuals were living in the community but were still noted to have sleep complaints, presumably as a result of a free-running cycle. Patients who were employed had a longer major sleep period than those who were retired or unemployed. Patients who had a mental handicap or multiple disabilities may cope more poorly because of increased difficulty in conforming to social routines.

Pathophysiology.  The earliest studies of human subjects in time-free environments concluded that most people have an intrinsic circadian period much longer than 24 h, averaging about 24.5 h; however, more recent studies using the forced desynchrony protocol have found the average to be significantly shorter, i.e. 24.15 h.38 In either case, the human circadian period is usually longer than 24 h. Patients with NET have circadian cycles that mimic those of subjects in time-free environments, and thus are thought to reflect a failure of entrainment.18

Diagnosis.  NET should be suspected in blind individuals who present with excessive daytime sleepiness or insomnia. It is diagnosed by sleep log and actigraphy done over at least 1 week. In sighted individuals, any central nervous system pathology or psychiatric disorder should be excluded. Routine use of MEQ or polysomnography for diagnosing NET is not recommended.17 Circadian phase markers including DLMO and CBTM are useful to determine circadian phase and confirm the diagnosis of NET in sighted and unsighted patients.

Differential diagnosis.  Physicians should differentiate DSPD from NET when patients with DSPD show a free-running-like sleep pattern, or when patients of NET present with a DSPD-like sleep pattern. DSPD patients may show free-running-like sleep-wake pattern even during vacation, especially when they stay up till late morning or experience a long flight. Even healthy persons may show free-running-like sleep–wake pattern after flight across several time zones. Another differential diagnosis is ISWR in which patients with an irregular sleep–wake cycle are capable of entrainment but disregard the cues.

Treatment.  Prescribed sleep–wake scheduling may be useful for therapy of NET in sighted individuals although there are no controlled trials. Phototherapy is done by early morning bright-light exposure in individuals with intact light perception and was successful in entraining circadian rhythms in some case reports.39

Evening or bedtime use of melatonin is useful in achieving successful phase advance in sighted individuals (most commonly used dose was 3 mg).40 Timed melatonin administration successfully entrained NET rhythms in blind individuals as well.41–44 Assessing whether bright light suppresses melatonin may be worthwhile in some blind persons, as occasionally the retinohypothalamic pathway remains intact despite the absence of sight. There are case reports in which vitamin B12 therapy successfully entrained the circadian phase.45 Its routine use in therapy of NET is not recommended.20 Actigraphy may be done to monitor response to therapy.

4. Irregular sleep–wake rhythm (ISWR)

Epidemiology.  The prevalence of this disorder increases with age.46 It is also seen in patients with severe dementia (especially Alzheimer's dementia [AD])47 and psychiatric disorders. No gender differences in prevalence of ISWR have been reported.

Clinical features.  This disorder is characterized by marked variability in daily sleep–wake times and absence of stable circadian rhythm.48 Weakened and fragmented circadian sleep and rest-activity rhythms have been shown during aging.49 However, the total sleep time over 24 h is normal or near normal for age. Patients lack capacity to entrain their internal clock to a 24-h light–dark cycle and voluntarily disregard the day–night transitions in their community, overriding their internal sleep–wake rhythm.18

Pathophysiology.  Damage to SCN due to increasing age or AD is considered an important risk factor for ISWR.50 The elderly population, especially patients with AD in nursing homes, are inadequately exposed to bright light; however, it is unclear if it predisposes to ISWR.51 It has also been shown that inadequate exposure to light aggravates sleep–wake rhythm irregularity52 and additional light improves this irregularity.53 Poor sleep hygiene may also lead to ISWR.

Diagnosis.  The diagnosis is established by sleep log, although obtaining an accurate history of the patient's sleep–wake cycle can be difficult because of poor recall, distortion, or denial. MEQ has not been used to evaluate ISWR. Actigraphy can be very useful to get more objective observations regarding the sleep–wake schedules of demented patients. The interdaily stability and median daytime activity level, and secondarily nocturnal restlessness, showed a strong relationship with the functional status and well-being of demented elderly patients.54 An acceptable reliability of the interdaily stability estimate in the elderly usually requires more than 7 days of actigraphy recording, for example, 2 weeks.55 Polysomnography is not routinely recommended for diagnosing ISWR.17 The differential diagnosis includes poor sleep hygiene and NET. Measurement of CBT rhythm and melatonin secretion rhythm may be used as circadian phase markers for confirming diagnosis of ISWR in AD patients. A set of novel functions to better describe the typical melatonin profile, which usually has a rather fixed baseline level during the day, has differences in the steepness of its rising and falling limbs, and may have a nocturnal plateau or even two peaks instead of one during the night, has been proposed recently with a sparse-sampling schedule tailored to capture the most important aspects of the melatonin curve.56

Treatment.  Prescribed sleep–wake scheduling with maintenance of regular sleep and wake time may be useful in therapy of ISWR, although there are no controlled studies. Patient counseling may be required to motivate the patient to adapt to a consistent sleep–wake schedule.

Phototherapy involving bright-light exposure during daytime may be useful. Positive results were shown in different studies evaluating the effect of daytime bright-light exposure among nursing home residents (the majority with dementia) in whom sleep disturbance was presumably consistent with an ISWR.57 Combined long-term daily treatment with whole-day bright (±1000 lux) or dim (±300 lux) light and evening melatonin (2.5 mg) for a mean of 15 months resulted in increased sleep efficiency and improved nocturnal restlessness in a double-blind, placebo-controlled, randomized trial in 189 elderly residents with dementia residing in 12 group care facilities in the Netherlands.53 Some other studies showed positive results for light treatment for a relatively brief period or only in severe dementia. In another randomized, double-blind, controlled trial, morning bright-light exposure did not induce an overall improvement in measures of sleep or the rest-activity in institutionalized patients with severe AD. Only subjects with the most impaired rest–activity rhythm responded significantly and positively to a brief (1 h) light intervention.58 In another study, 50 institutionalized AD patients were treated with 1 h of morning light exposure (≥2500 lux in gaze direction) Monday to Friday for 10 weeks and 5 mg melatonin (LM, n= 16) or placebo (LP, n= 17) in the evening. Light treatment alone did not improve night-time sleep, daytime wake, or rest–activity rhythm. Light treatment plus melatonin increased daytime wake time and activity levels and strengthened the rest–activity rhythm.59

Melatonin is not indicated for the treatment of ISWR in older people with dementia.20 Two randomized-controlled trials testing melatonin therapy in patients with Alzheimer disease with disturbed sleep patterns that were consistent with ISWR found no improvement in sleep pattern (determined by actigraphy).60,61 However, melatonin may be indicated for children with ISWR and severe psychomotor retardation58 and neurological disability.62 A recent study found that combined long-term daily treatment with whole-day bright or dim light and evening melatonin resulted in increased sleep efficiency and improved nocturnal restlessness.53 A mixed modality approach combining sleep hygiene education, daytime bright-light exposure, physical activity, and other behavioral elements was useful in improving sleep patterns in AD patients with a diagnosis of ISWR.63 Use of stimulant medications to promote alertness or use of hypnotic medications to promote sleepiness is not recommended by evidence.64 Actigraphy may be done to monitor response to therapy.

Disorders related to forced alterations of the sleep–wake schedule or light–dark cycle

1. Shift work sleep disorder (SWSD)

Epidemiology.  This disorder may be seen in an estimated 2–5% of the total population.20 The prevalence of SWSD was 32.1% in night workers and 26.1% in rotating shift workers in another study.65 The prevalence increases with advancing age.66 The prevalence is higher in female shift workers.

Clinical features.  This disorder is seen due to marked variation in working hours, rotating schedules, or permanent night-time or early morning working hours. There is marked disturbance of the sleep–wake cycle due to the requirements of work in the night-time and requirement for sleep in daytime. The patient getsdisturbed sleep in the daytime due to altered time clues of sunlight and other social activities. Clinical features range from unrefreshing sleep and daytime sleepiness to mood disturbances. It increases the risk of work-related accidents and errors. Not every night-shift worker develops SWSD and some may have another coexistent sleep disorder.

Pathophysiology.  There is inability to shift the endogenous circadian rhythm according to the altered sleep schedule, most commonly due to failure to avoid continuous sunlight exposure during the day. A quick rotating shift schedule does not give workers enough time to entrain their circadian clock to the work schedule. Though fixed night or early morning shift schedules for the long term give enough time to entrain, bright-light exposure during daytime prevents entrainment. In addition, insufficient sleep during daytime adds further to symptoms of SWSD.

Diagnosis.  The diagnosis is established by sleep log or actigraphy21 done over at least 1 week. Polysomnography is not routinely indicated.67 Individuals described as morning types using MEQ may be more predisposed to SWSD than those described as evening types; however, routine use of MEQ in diagnosing SWSD is questionable.68 Some studies have found good correlation between melatonin rhythm and circadian adaptation, but other studies using CBTM and DLMO have shown negative results. Routine use of these circadian rhythm markers is not recommended at present to diagnose SWSD.20

Treatment.  There are three aims of SWSD treatment: (i) promotion of entrainment to the work schedule for workers with a fixed night or early morning work schedule; (ii) maintenance of entrainment to the light–dark cycle for those with quick-rotating work shifts; (iii) and improvement of sleep quality during the daytime. Regular sleep–wake hours should be maintained both during work and non-work days. Other causes of sleep disturbance like poor sleep hygiene or sleep apnea should be excluded. It is important to modify the sleep environment at home to promote daytime sleep, for example, by maintaining a quiet and dark bedroom and minimum daytime noise. Planned napping, including sleeping before the night shift, and a short nap during the shift increased alertness and vigilance, improved reaction times, and decreased accidents during night-shift work, without affecting post-shift daytime sleep.69

Phototherapy of SWSD includes exposure to bright light during work hours at night and avoidance of bright light during day while sleeping. Timed bright-light exposure at regular intervals during night shift, with or without restriction of daytime light exposure using goggles, has demonstrated subjective improvements in work time performance tasks, alertness, and mood compared to ordinary light exposure.70

Administration of melatonin prior to daytime sleep improved sleep quality71 Hypnotic medications may be useful to promote daytime sleep in night-shift workers,72 but may cause sedation during night work. Psychostimulants like caffeine and methamphetamine may be useful to promote alertness during the night shift. Modafinil taken before night shift improved alertness and performance at work in two placebo-controlled trials.73 Actigraphy may be done to monitor response to therapy.

2. Jet Lag Disorder (JLD)

Epidemiology.  The symptoms of JLD were less severe in older individuals (>50 years) compared to younger individuals.74,75 No specific gender predisposition for JLD is known.

Clinical features.  JLD is characterized by sleep disturbance due to rapid travel across multiple time zones. The intrinsic circadian rhythm is temporarily aligned to the home time and has not aligned to the destination time. People traveling westward are phase-advanced relative to the destination time, while those traveling eastward are phase-delayed. There is no jet lag after north–south travel. Symptoms are more severe with eastward travel that requires the person to phase advance. After eastward flights, there is delayed sleep onset at night and difficulty waking up early in morning. The person experiences early evening sleepiness and early morning awakening after a westward flight. Bright-light exposure at improper times during the flight or at the destination may shift circadian rhythm to the opposite direction and may prolong symptoms of JLD.

Diagnosis.  The diagnosis is based on clinical symptoms. The Columbian Jet Lag Scale is a questionnaire designed to diagnose and assess severity of JLD,76 but is not commonly used in clinical practice. Actigraphy was used in one study to validate the diagnosis of JLD,77 but is not used routinely. Routine use of polysomnography to diagnose JLD is not recommended.20 Circadian phase markers, including urinary melatonin and cortisol, CBTM, and salivary DLMO have been used to monitor circadian phase response to treatment of JLD; however, their routine measurement in diagnosis of JLD is not recommended.20

Treatment.  The sleep–wake cycle should be changed to that at the destination time on the day of arrival if a prolonged stay of more than a few days is expected at the destination, although there is no evidence to support its benefit. However, if the destination stay is of short duration (2 days or less), keeping home-based sleep hours is recommended. A study compared keeping home-based sleep hours versus adopting destination sleep hours when time at destination was 2 days or less after a 9-h westward flight, and found that keeping home-based hours resulted in less jet lag symptoms.78

Phototherapy using evening exposure for westward travel and morning exposure for eastward travel is useful. The combination of early morning bright-light exposure in combination with adjustment of sleep schedule 1 h earlier per day for 3 days prior to eastward travel resulted in fewer symptoms of jet lag in a simulation study.79 In another study, exposure to 3 h of evening bright light (3000 lux) after a westward flight resulted in circadian phase entrainment.80

Melatonin used in doses ranging from 0.5 to 5 mg administered at bedtime for up to 3 days prior to departure and up to 5 days upon arrival at the destination, resulted in reduced symptoms of jet lag and better sleep in different randomized, double-blind, placebo-controlled trials.81,82 Melatonin improved the duration and quality of sleep as measured both subjectively and objectively.83–85 Aside from this hypnotic effect, melatonin treatment may well accelerate circadian phase resetting to the new time zone. The strongest data supporting the impact of melatonin on entrainment comes from a study that examined the effect of melatonin on cortisol rhythms in subjects crossing 7 time zones in an eastward direction.86 Most studies have tested melatonin for eastward flight, for which taking melatonin at bedtime could involve benefits from both hypnotic and phase-resetting mechanisms. With westward flight, melatonin taken at bedtime could, in theory, inhibit phase resetting. However, in two randomized, controlled trials exploring the use of melatonin following westward travel, improvements in jet lag scores and sleep were seen.87,88

Short-term use of a benzodiazepine receptor antagonist hypnotic at bedtime improved subjective sleep quality after arriving at the destination. Use of newer non-benzodiazepine hypnotics like zolpidem and zopiclone at bedtime also improved sleep duration and quality following travel. However, these hypnotics may increase daytime sleepiness. Caffeine may help if there is excessive daytime sleepiness.

A summary of treatment recommendations for CRSDs is given in Table 2.

Table 2.  Summary of treatment recommendations for circadian rhythm sleep disorders
TherapyDSPDASPDNETISWRSWSDJLD
  1. Adapted from: Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders, American Academy of Sleep Medicine, 2007.20Supported by level 2 or consensus of level 3 evidence.Supported by level 1 or overwhelming level 2 evidence. Unmarked recommendations are based on inconclusive or conflicting evidence. ASPD, advanced sleep phase disorder; DSPD, delayed sleep phase disorder; ISWR, irregular sleep–wake rhythm; JLD, jet lag disorder; NET, non-entrained type; SWSD, shift work sleep disorder.

Planned sleep schedulesYesYesYesMixed modalityYesYes
Timed phototherapyYesYesYesYesYesYes
Timed melatonin administrationYesYesYes (in blind)Yes for selected childrenYesYes
HypnoticsNoYesYes
StimulantsYesYes
Alerting agents (modafinil)Yes

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CONCLUSIONS
  5. REFERENCES

There is rapid progress in basic sciences studies and clinical trials studying pathophysiology and treatment of CRSDs. These incapacitating disorders (especially endogenous disorders) are largely underdiagnosed, but there is growing awareness for early diagnosis and appropriate treatment of CRSDs. Future studies on circadian biomarkers and molecular genetics will help in accurate diagnosis as well as understanding genetic influences in circadian sleep disorders. Large multicenter, controlled trials are needed to study unproven and inconclusive therapies in these disorders.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CONCLUSIONS
  5. REFERENCES