Circadian Rhythm Abnormalities

Review Article

Address correspondence to Dr Phyllis C. Zee, Northwestern University, 710 North Lake Circadian Rhythm Shore Dr, Chicago, IL 60611, [email protected]. Relationship Disclosure: Abnormalities Dr Zee has received personal compensation for activities Phyllis C. Zee, MD, PhD; Hrayr Attarian, MD, FAASM, FCCP; with Jazz Pharmaceuticals; Merck & Co, Inc; Perdue Aleksandar Videnovic, MD, MSc Pharma; Philips Respironics; Sanofi-Aventis; Takeda Pharmaceutical Company Limited; UCB; and Zeo, Inc. ABSTRACT Dr Zee receives research Purpose: This article reviews the recent advances in understanding of the funda- support from Philips mental properties of circadian rhythms and discusses the clinical features, diagnosis, Respironics. Dr Attarian receives personal and treatment of circadian rhythm sleep disorders (CRSDs). compensation for activities Recent Findings: Recent evidence strongly points to the ubiquitous influence of with American Physicians circadian timing in nearly all physiologic functions. Thus, in addition to the prominent Institute. Dr Videnovic reports no disclosure. sleep and wake disturbances, circadian rhythm disorders are associated with cognitive Unlabeled Use of impairment, mood disturbances, and increased risk of cardiometabolic disorders. The Products/Investigational recent availability of biomarkers of circadian timing in clinical practice has improved Use Disclosure: Dr Zee discusses the unlabeled use of our ability to identify and treat these CRSDs. melatonin for the treatment of Summary: Circadian rhythms are endogenous rhythms with a periodicity of circadian disorders. Dr Attarian approximately 24 hours. These rhythms are synchronized to the physical environment discusses the unlabeled use of melatonin and light boxes to by social and work schedules by various photic and nonphotic stimuli. CRSDs result advance or delay circadian from a misalignment between the timing of the circadian rhythm and the external rhythms. Dr Videnovic environment (eg, jet lag and shift work) or a dysfunction of the circadian clock or its discusses the unlabeled use of melatonin, ramelteon, and afferent and efferent pathways (eg, delayed sleep-phase, advanced sleep-phase, supplemental light exposure to nonY24-hour, and irregular sleep-wake rhythm disorders). The most common symp- advance circadian rhythms and toms of these disorders are difficulties with sleep onset and/or sleep maintenance and treat jet-lag disorder. excessive sleepiness that are associated with impaired social and occupational * 2013, American Academy of Neurology. functioning. Effective treatment for most of the CRSDs requires a multimodal approach to accelerate circadian realignment with timed exposure to light, avoidance of bright light at inappropriate times, and adherence to scheduled sleep and wake times. In addition, pharmacologic agents are recommended for some of the CRSDs. For delayed sleep-phase, nonY24-hour, and shift work disorders, timed low-dose melatonin can help advance or entrain circadian rhythms; and for shift work disorder, wake- enhancing agents such as caffeine, modafinil, and armodafinil are options for the management of excessive sleepiness.

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OVERVIEW OF THE HUMAN hormone secretion, glucose homeosta- CIRCADIAN SYSTEM sis, and cell-cycle regulation. The timing Circadian rhythms are physiologic and of these physiologic rhythms may behavioral cycles with a recurring perio- become altered, leading to changes in dicity of approximately 24 hours, gen- the phase relationship of rhythms to erated by the endogenous biological each other, which can cause internal pacemaker, the suprachiasmatic nucleus desynchronization. This loss of coordi- (SCN), located in the anterior hypothal- nation of rhythms may have negative amus.1 These rhythms control a variety consequences on rest-activity cycles of biological processes, such as sleep- and other physiologic and behavioral wake cycle, body temperature, feeding, functions.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 1 KEY POINTS Circadian Entrainment tinct neurochemical properties. While h + Circadian rhythms are Circadian rhythms are synchronized with -aminobutyric acid is the dominant physiologic and the earth’s rotation by daily adjustments neurotransmitter in the SCN, present in behavioral cycles with a in the timing of the SCN, following the nearly all SCN neurons, SCN neuropep- recurring periodicity of exposure to stimuli that signal the time tides are highly localized within either approximately 24 hours, of day. These stimuli are known as the core or shell nuclei. The SCN core generated by the zeitgebers (German for ‘‘time-givers’’), contains high density of vasoactive in- endogenous biological of which light is the most important and testinal polypeptide, gastrin-releasing pacemaker, the potent stimulus. The magnitude and peptide, and bombesin-containing neu- suprachiasmatic nucleus, located in the direction of the change in phase de- rons. Somatostatin and neurophysin are anterior hypothalamus. pends on when within the circadian dominant neurochemicals within the h system the light pulse is presented. A SCN shell. Circadian rhythms are plot of phase changes according to the The SCN receives photic information synchronized with the earth’s rotation by time of light stimulus presentation from the retina via direct (retinohypothalamic) and indirect (retinogeniculate) daily adjustments in provides a phase response curve. Expo- the timing of the pathways.3 The melanopsin-containing sure to light results in a phase response suprachiasmatic curvewithdelaysintheearlysubjective ganglion cells of the retina are the pri- nucleus, following the night (ie, evening) and advances in the mary photoreceptors for the circadian exposure to stimuli that late subjective night (ie, early morning). system. The SCN also receives nonphotic signal the time of day. In addition to light, feeding schedules, information from the raphe nuclei. Sev- These stimuli are activity, and the hormone melatonin eral less-characterized afferents con- known as ‘‘zeitgebers’’ canalsoaffectthecircadiantiming.1 verge in the SCN from basal forebrain, (German for The timing of melatonin secretion by pons, medulla, and posterior hypothal- ‘‘time-giver’’), of the pineal gland is regulated by the SCN, amus. The major efferents from the SCN which light is the most with the onset of secretion approxi- project to the subparaventricular zone important and potent stimulus. The magnitude mately 2 hours before natural sleep time and the paraventricular nucleus of the hypothalamus, dorsomedial hypothal- and direction of the and being highest during the middle of change in phase depends 1 amus, thalamus, preoptic and retrochias- the night. Melatonin onset measured on when within the in a dim light environment (DLMO) is a matic areas, stria terminalis, lateral circadian system the stable marker of circadian phase and is septum, and intergeniculate nucleus. light pulse is presented. used in research as well as clinical prac- The SCN also communicates via diffu- tice to determine the timing of the en- sion of humoral signals to the rest of dogenous circadian rhythm. the brain. These diffusible SCN outputs likely include transforming growth fac- Neuroanatomy and tor !, cardiotrophinlike cytokine, and Neurochemistry prokineticin 2. A major development The central circadian timing system has in chronobiology research has been three distinct components: (1) a circa- the discovery of circadian clocks in dian pacemaker, the SCN, (2) input non-SCN brain regions and almost all pathways for light and other stimuli that peripheral tissues.4 While the signals synchronize the pacemaker to the envi- mediating communication between the ronment, and (3) output rhythms that SCN and peripheral oscillators remain are regulated by the pacemaker. The under extensive investigation, it is clear SCN is the central pacemaker that links that the central clock (ie, SCN) and pe- the 24-hour changes in the external ripheral clocks may have distinct circa- environment with the 24-hour changes dian synchronizers. The SCN, however, in the internal environment (Figure 7-1).2 is most likely dominant in maintain- The SCN is composed from the ‘‘core’’ ing circadian rhythmicity of peripheral and ‘‘shell’’ subnuclei, which have dis- clocks.

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FIGURE 7-1 Schematic illustration of the pathway responsible for entrainment of melatonin secretion by light. The circadian regulation of melatonin secretion is dependent on an indirect pathway that originates in photosensitive ganglion cells in the retina and reaches the suprachiasmatic nucleus, the circadian pacemaker, via the retinohypothalamic tract. The suprachiasmatic nucleus controls the sympathetic output to the pineal gland, which is responsible for melatonin secretion via an inhibitory projection to the paraventricular nucleus of the hypothalamus. This pathway is responsible for the peak of melatonin secretion during darkness.

Reprinted with permission from Benarroch EE, Neurology.2 B 2008, American Academy of Neurology. www.neurology. org/content/71/8/594.extract.

Genetic Regulation During the night, the PER-CRY repressor Circadian rhythms are determined complex is degraded, and the cycle genetically by a core set of clock genes, starts again (Figure 7-2). Circadian clock including three Per genes (the period genes control a significant proportion homolog 1 gene, Per1; the period homo- of the genome. It is estimated that ap- log 2 gene, Per2; the period homolog 3 proximately 10% of all expressed genes gene, Per3); the circadian locomotor out- are under regulation of the clock genes. put cycles kaput gene, Clock; the cycle Furthermore, peripheral tissues contain gene, Bmal1; and two plant cryptochrome independent clocks. It is likely that gene homologs (the cryptochrome 1 peripheral clocks are synchronized by gene, Cry1, and the cryptochrome 2 gene, an input directly from the SCN or SCN- Cry2).5 These genes and their products mediated messages. Several excellent interact to form transcription-translation reviews are available for more detailed feedback loops that provide the molec- overview of the molecular regulation of ular basis of circadian rhythmicity. Dur- the circadian system,3,6,7 ing the day, Clock interacts with BMal1 to activate transcription of the Per and CIRCADIAN RHYTHM SLEEP Cry genes, resulting in high levels of DISORDERS these transcripts. PER and CRY proteins Circadian rhythm sleep disorders translocate to the nucleus and inhibit (CRSDs) are chronic patterns (for at CLOCKYB-MAL1-mediated transcription. least 1 month) of sleep-wake rhythm

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. disturbances due to alterations of the circadian timing system or to a misalignment between the timing of the endogenous circadian rhythm and the sleep- wake times required by school or work schedules. As a result, patients present with impairments in sleep and wake functioning. The diagnosis of all CRSDs is based on a careful history and sleep diary with actigraphy. Polysomnography (PSG) is not routinely indicated to establish the diagnosis. However, PSG is indicated to assess for other comorbid sleep disorders. In addition to comorbid V FIGURE 7-2 Simplified representation of the transcription sleep disorders, psychiatric disorders cycle. particularly depression and anxietyVare common in patients with nearly all types of CRSDs and should be considered in the differential diagnosis. to be common (33%) in patients with KEY POINT Delayed Sleep-Phase Disorder hepatic cirrhosis.8 h Delayed sleep-phase Delayed sleep-phase disorder (DSPD) Pathophysiology. Multiple biological disorder is characterized is characterized by a chronic or recur- and behavioral factors contribute to the by chronic or recurrent inability to fall asleep rent inability to fall asleep and wake up development of DSPD. The postulated and wake up at socially at socially acceptable times, resulting in mechanisms for DSPD include (1) de- acceptable times, symptoms of difficulty falling asleep and creased response to the phase-advancing resulting in symptoms 9 excessive daytime sleepiness, particu- effect of light in the morning, (2) in- of difficulty falling larly in the morning. By definition, in creased sensitivity to the phase-delay asleep and excessive relation to socially acceptable times, there response of evening light, and (3) a longer daytime sleepiness, is a more than 2-hour delay in the major than normal time to complete one cir- particularly in sleep period. Patients have difficulty wak- cadian cycle (ie, long circadian period). the morning. ing up in the morning and are often Familial cases and the demonstration of late for work or school. When patients polymorphisms of circadian clock genes are allowed to sleep at their biologically in DSPD indicate a genetic basis for this preferred time and wake up sponta- condition.10 Environmental, behavio- neously after their major sleep period, ral, and psychological factors also play sleep and daytime function normalize. a role in the development of DSPD. Epidemiology. The prevalence of For example, individuals with a delayed DSPD is 0.2% to 10.0% depending on circadian phase are more likely to work severity and the population groups sur- in the evening and be exposed to veyed. Milder cases are more prevalent, evening light, which can further delay as are cases among adolescents and the timing of circadian rhythms, or they young adults. There appears to be no wake up late, thus perpetuating the sex predilection, but among adolescents vicious cycle of late sleep and late wake the phase delay occurs at an older age in times.11 males than in females, with males reach- Clinical presentation and diagnosis. ing their peak at age 21 and females Patients with DSPD usually fall asleep at age 17. A familial predisposition for between 1:00 AM and 6:00 AM and wake DSPD also occurs, and DSPD appears up in the late morning to early afternoon,

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KEY POINT h Diagnosis of delayed as outlined in the International Classi- cially during morning hours, in addition sleep-phase disorder is fication of Sleep Disorders, Second to habitual tardiness and morning absen- made by careful history Edition: Diagnostic and Coding Man- ces. Diagnosis is made by careful history and well-kept sleep ual. Conditioned insomnia and chronic and well-kept sleep diaries with or with- diarieswithorwithout sleep deprivation may develop as a com- outactigraphyforaminimumof7days actigraphy for a plication of DSPD. In addition, patients (preferably 14 days) (Case 7-1). Stand- minimum of 7 days with DSPD tend to have decreased ardized chronotype questionnaires are (preferably 14 days). academic and work performance, espe- useful tools to assess the chronotype

Case 7-1 A 21-year-old man presented with nightly complaints of difficulty falling asleep that started 4 to 5 years earlier. He had no problem staying asleep, but it took several hours to fall asleep, and he had difficulty staying alert during the workday. He was concerned because his work performance was suffering and he had been seen dozing at his desk. Actigraphy recording of his sleep and wake cycle is shown in Figure 7-3.

FIGURE 7-3 Representative actogram of patient with delayed sleep-phase disorder. The blue arrows indicate sleep onset and the red arrows indicate the end of the major sleep period. The black horizontal arrows indicate naps. In high-amplitude actigraphy, dense bars are representative of wakefulness, and low, sparse bars are representative of sleep. Note that sleep onset is 2:00 AM to 4:00 AM and the end of the major sleep period varies from 8:00 AM all the way to 1:00 PM (on day 7). On day 5, when total sleep duration was from 2:00 AM to 7:00 AM, the patient takes two naps, resulting in less sleep homeostatic drive, and therefore sleep onset the next night is not until 5:00 AM.

Comment. Typical of patients with delayed sleep-phase disorder, this man had significant sleep-onset insomnia and was then sleepy while at work because of chronic sleep deprivation and because he was forced to be awake during a part of his circadian sleep time.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT of ‘‘eveningness’’ and ‘‘morningness.’’ Advanced Sleep-Phase Disorder h Bright light (full spectrum In addition, a delay in the timing of Advanced sleep-phase disorder (ASPD) or blue enriched) in the objective circadian rhythms, such as the is characterized by an advance in the morning for 2 hours DLMO or urinary 6-sulfatoxymelatonin, phase of the major sleep episode in shortly after the is desirable to confirm the delayed cir- relation to the desired or required sleep minimum of the core cadian phase. Depression, anxiety, and and wake-up times. Patients have body temperature personality disorders are more com- chronic or recurrent difficulty staying rhythm (typically mon among patients with DSPD. awake until the desired or socially occurring2to3hours Treatment. The American Academy acceptable bedtime, together with an before natural wake-up of Sleep Medicine (AASM) practice pa- earlier than desired wake-up time. When time) has been shown to successfully advance rameters recommend appropriately patients are allowed to choose their circadian rhythms in timed morning light exposure and preferred schedule, sleep quality and patients with delayed evening exogenous melatonin either duration are normal for age. sleep-phase disorder. alone or in combination as effective Epidemiology. ASPD is less com- treatments for DSPD (Figure 7-4). The monthanDSPD.Theestimatedpreva- combination of light therapy and mel- lence is 1% in the general population, atonin has been shown to have com- which is likely an underestimate since plementary benefits.12 Bright light (full many individuals successfully adapt spectrum or blue enriched) in the their social and work schedules to the morning for 2 hours shortly after the advanced sleep phase.19 Both sexes are minimum of the core body temper- equally affected by the disorder. The ature rhythm (typically occurring 2 to 3 onset of ASPD is typically during mid- hours before natural wake-up time) has dle age. Several studies suggest that age been shown to successfully advance may be a risk factor for ASPD, likely on circadian rhythms in patients with the basis of a phase advance of the DSPD.13 Melatonin 0.5 mg to 5 mg circadian pacemaker with aging.17 given 5.0 to 6.5 hours before DLMO (13 Pathophysiology. A shortened circa- to 14 hours after natural wake-up dian period has been postulated to be time)14 advances sleep and rise times, involved in the pathogenesis of ASPD. while administration closer to DLMO Genetic factors likely play an important is less effective. Effectiveness lasts up role in the development of ASPD. to 1 year with daily melatonin intake, Several families with ASPD inherited in but relapses can occur in up to 90% of an autosomal dominant mode have people after they discontinue their been described. Two gene mutations melatonin. Time to relapse ranges have been identified in some of these from 1 day to 6 months with the more families, affecting the circadian clock severe DSPD cases relapsing faster.15 gene hPer2 and the casein kinase 1 Furthermore, melatonin has been delta gene.20 These mutations result shown to improve depression in in a shortened circadian period. Addi- patients with DSPD.16 Although it has tional mechanisms include an attenu- been reported that vitamin B12 may be ated ability to phase delay because of a effective as an adjunctive treatment to dominant phase advance region of the bright light, it was not recommended phase response curve to light and by the 2007 AASM practice parameters increased retinal sensitivity to light in as a treatment for DSPD.17 There is the morning,21 resulting in a stronger also limited evidence suggesting a advancing signal for the circadian clock. therapeutic benefit of combining light Clinical presentation and diagnosis. therapy with cognitive-behavioral ther- Patients with ASPD typically present apy in adolescents with DSPD.18 with symptoms of daytime sleepiness,

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KEY POINTS h Patients with advanced most prominent in the late afternoon or tive circadian rhythms, such as the sleep-phase disorder early evening hours; sleep maintenance DLMO or urinary 6-sulfatoxymelatonin, typically present with difficulty; and early morning awakening. is desirable to confirm the advanced cir- symptoms of daytime Individuals with ASPD are usually sleepy cadian phase. sleepiness (most and struggle to stay awake between Treatment. The AASM practice prominent in the late 6:00 PM and 9:00 PM and wake up earlier parameter recommends sleep-wake afternoon or early than desired, between 2:00 AM and 5:00 AM. scheduling and timed light exposure evening hours) sleep The diagnosis of ASPD is based on a as the primary treatments for ASPD. maintenance difficulty, detailed sleep history accompanied by a Practical therapeutic approaches for and early morning sleep diary and, if feasible, actigraphy ASPD include timed light exposure in awakening. over a period of least 7 days (preferably the evening and avoiding light in early h Practical therapeutic 14 days) to demonstrate advanced morning hours (Figure 7-4). Melatonin approaches for advanced sleep and wake times. Major depressive or hypnotics may be beneficial for sleep sleep-phase disorder disorders should be carefully differenti- maintenance insomnia. Bright light include timed light ated from ASPD. Standardized chrono- administered before the nadir of body exposure in the evening type questionnaires are useful tools to core temperature is a potent stimulus and avoiding light in early morning hours. assess the chronotype of eveningness for delaying circadian phase. The most Melatonin or hypnotics and morningness. Patients with ASPD commonly used treatment for ASPD may be beneficial for will score as ‘‘morning’’ types. In addi- is early-evening light therapy, usually sleep-maintenance tion, an advance in the timing of objec- between 7:00 PM and 9:00 PM.This insomnia.

FIGURE 7-4 Summary of treatment approaches for delayed sleep-phase disorder and advanced sleep-phase disorder. Bright light administered before the nadir of body core temperature is a potent stimulus for delaying circadian phase. The most commonly used treatment for advanced sleep-phase disorder is early-evening light therapy, usually between 7:00 PM and 9:00 PM. This approach has been shown to improve sleep duration and sleep maintenance, as well as daytime performance. The combination of light therapy and melatonin has been shown to have complementary benefits. Bright light in the morning for 1 to 2 hours shortly after the minimum of the core body temperature rhythm advances circadian rhythms and 0.5 mg to 5 mg of melatonin taken 5 to 6.5 hours before dim light melatonin onset (13 to 14 hours after natural wake-up time) results in advanced sleep and wake times in patients with delayed sleep-phase disorder. MLT = melatonin.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. approach has been shown to improve Pathophysiology. Multiple physio- sleep duration and sleep maintenance, logic, behavioral, and environmental as well as daytime performance. How- factors contribute to the development ever, results of evening light therapy of ISWRD. The most likely mechanisms have not been uniformly positive.22 include central degeneration of SCN Compliance with timed light exposure neurons and decreased exposure or can be challenging, and bright light may input of external synchronizing agents, irritate the eyes, particularly in older such as light and activity that result in a adults. A chronotherapeutic approach of weakened central circadian oscillation advancingbedtimeby3hoursevery2 and temporal disorganization of circa- days has been reported effective in ASPD; dian rhythms.26 The problem is perpe- however, the scheduling constraint of tuated by a variety of factors inherent this approach limits its use in clinical in the lifestyles of older adults in nurs- practice. Based on the phase response ing homes and other similar living curve to melatonin, administration of facilities. Institutionalized elderly pa- melatonin in early morning will advance tients get significantly less exposure to the circadian phase, although clinical light in both amount and intensity. This evidence of the efficacy or safety of is a result of lower levels of light indoors melatonin for the treatment of ASPD is and the fact that most eye diseases, lacking. While hypnotic agents are pre- such as cataracts, reduce light input to scribed for the management of sleep the SCN even further. Compounding maintenance symptoms associated with the diminished light exposure is the ASPD, their efficacy and safety have not reduction in other external synchron- been systematically studied. izers such as structured social and physical activities. Decreased mobility, Irregular Sleep-Wake Rhythm adverse effect on sleep and alertness by Disorder medications, and increased napping Irregular sleep-wake rhythm disorder also play a role in the development (ISWRD) is characterized by a tempo- of ISWRD.26 Genetic factors have been rally disorganized sleep and wake pat- implicated in the development of tern, such that multiple sleep and wake ISWRD in Alzheimer disease.27 periods occur throughout the 24-hour Clinical presentation and diagnosis. cycle. This disorder is more prevalent In patients with ISWRD, sleep bouts in older adults with dementia and in occur in three or more short intervals of patients with developmental disorders. approximately 1 to 4 hours each, spread Epidemiology. ISWRD is common over 24 hours. The longest bout gen- among institutionalized older adults, erally occurs between 2:00 AM and particularly those with Alzheimer dis- 6:00 AM. The overall amount of sleep ease and those with late afternoon- per 24-hour period, however, is relatively evening agitation or sundowning. Age normal for the patient’s age.23 Because of alone is not a risk factor for ISWRD, fragmented sleep and multiple daytime but age-related neurologic and psychi- naps, patients usually present with atric disorders are.23 ISWRD has also symptoms of sleep maintenance insom- been described in patients with head nia and excessive daytime sleepiness. In trauma, children with developmental addition to the typical symptomatology, delay, and patients with schizophre- diagnosis requires a history of a mini- nia, particularly those with positive mum of three irregular sleep-wake symptoms,24 independent of daytime cycles in a 24-hour cycle recorded for functioning.25 14 days by sleep diary and/or actigraphy.

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KEY POINTS h Creating a cognitively Treatment. Creating a cognitively Epidemiology. Sleep disturbances in enriched environment enriched environment with structured peoplewhoareblindarecommon,and with structured social and social and physical activity during the approximately 50% may have N24HSWD. physical activity during day is an important therapeutic modal- Much less commonly, N24HSWD can the day is an important ity, especially if combined with a healthy occur in sighted people. Onset of symp- therapeutic modality for bedtime routine and a nocturnal envi- toms typically occurs during the second patients with irregular ronment conducive to sleep. Measures or third decade of life.29 In blind and sleep-wake rhythm include minimizing noise and light dur- sighted individuals, there is a male disorder, especially if ing the scheduled sleep period and predilection with a ratio of 2.6/1.30 combined with a healthy addressing issues such as nocturia and Pathophysiology. The etiology of bedtime routine and a enuresis to reduce sleep disturbances N24HSWD in blind people is clearly a nocturnal environment at night. Light, however, remains the marked decrease or absence of light conducive to sleep. most effective therapeutic intervention. perception. However, not all patients h Y Non 24-hour sleep-wake Exposure to 3000 lux to 5000 lux bright who are blind exhibit this lack of disorder is characterized light for 2 hours every morning for 4 entrainment, because in some, light by a chronic or recurrent weeks has been shown to improve information from the retinal ganglion pattern of sleep and wake cycles that are not daytime alertness, decrease napping, cells can still reach the SCN, or other synchronized to the consolidate nighttime sleep, and re- synchronizing agents (such as struc- 23 24-hour environment. duce nocturnal agitation. Melatonin tured social and physical activity) can 30 Typically a consistent daily alone has not been shown to be sufficiently entrain circadian rhythms. drift (usually to later and consistently effective in treating ISWRD Although the exact mechanism in later times) of sleep-onset in older adults or in patients with sighted individuals remains to be eluci- and wake-up times Alzheimer disease. However, effective- dated, evidence suggests that a long occurs. ness may be improved when melatonin circadian period that is beyond the at bedtime is combined with light normal range of entrainment is likely a during the day.21 Smallopen-labeltrials risk factor.30 Other postulated mecha- usingdosesof2mgto20mgofmel- nisms that can lead to an abnormal atonin have shown some benefit in interaction between sleep homeostasis children with developmental disor- and endogenous circadian rhythms ders.28 Controlled-release formulation include (1) decreased photosensitivity,30 appeared more effective than immedi- (2) alteration and reduction of social ate release in this subpopulation. The cues because of psychiatric illnessY AASM practice parameters recommend induced social withdrawal,21 (3) muta- using a combination of environmental tioninthecreatininekinase1( (CK1() and behavioral modifications and bright gene,21 and (4) desynchrony between light therapy for ISWRD. the melatonin and sleep rhythms.30 Clinical presentation and diagnosis. Non–24-Hour Sleep-Wake Thepresentingsymptomsdependon Disorder when the person is required to sleep in NonY24-hour sleep-wake disorder relation to his or her nonentrained (N24SWD) (nonentrained rhythm disor- endogenous circadian rhythm of sleep- der formerly known as free-running wake propensity. Patients typically rhythm disorder) is characterized by a present with symptoms of insomnia, chronic or recurrent pattern of sleep and excessive daytime sleepiness, or both wake cycles that are not synchronized to for several weeks. These symptomatic the 24-hour environment. Typically a episodes alternate with days to weeks consistent daily drift (usually to later in which the patient is asymptomatic. and later times) of sleep-onset and The prevailing complaint is the interfer- wake-up times occurs. ence of the sleep-wake schedule with

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT work, school, and other social obliga- DSPD. Most sighted patients with h 29 In blind patients with tions. Patients with this disorder can N24HSWD also have an evening chro- nonY24-hour have, at various times, excessive day- notype. A misdiagnosis can be problem- sleep-wake disorder, time sleepiness and sleep-onset insom- atic, as chronotherapy for DSPD may melatonin is the nia or early morning awakenings. induce a nonY24-hour rhythm. In the therapeutic mainstay Napping is quite common, and careful largest cohort of sighted N24HSWD pa- together with strong analysis of sleep-wake rhythms may tients, one-fourth had received a pre- structured behavioral reveal two distinct sleep-wake cycle vious misdiagnosis of DSPD.21 and social cues such as periods separated by phase jumps (ie, Treatment. In blind patients with timing of meals, planned when sleep onset is delayed for more N24SWD, melatonin is the therapeutic activities, and regular than 4 hours).21 mainstay together with strong struc- physical exercise. This same approach is Diagnosis is made by a careful history tured behavioral and social cues, such recommended for and documenting that the sleep com- as timing of meals, planned activities, 29 sighted persons, with the plaints are present for at least 2 months. and regular physical exercise. This additional option of A minimum of 14 days of sleep diary same approach is recommended for bright light exposure in and/or actigraphy can be very helpful. sighted persons, with the additional the morning shortly after Actigraphy of a patient with N24HSWD is option of bright light exposure in the awakening. shown in Figure 7-5. Continuous core morning shortly after awakening. Al- body temperature measurements, if though the dose of melatonin for the feasible, or serial measurements of the treatment of N24HSWD varies among timing of the melatonin rhythm from studies, a practical recommendation is serum, saliva, or urine can be confirma- to start with a higher dose (3 mg to tory as they exhibit the same nonY24- 10 mg) 1 hour before bedtime or a few hour rhythm as the disorder itself.21 hours before predicted DLMO for the Frequent comorbid psychiatric condi- first month. Entrainment usually occurs tions, primarily mood disorders, need within 3 to 9 weeks but must be main- tobeaddressedaswell.Carehastobe tained by regular low-dose (0.5 mg) taken to differentiate N24HSWD from melatonintopreventarelapse.Ifthe

Y FIGURE 7-5 Actigraphy record of a sighted patient with non 24-hour sleep-wake disorder. Note the daily delay drift of the onset and offset of the sleep-wake rhythm with a circadian period that is longer than 24 hours.

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KEY POINT h Internal desynchronization initiation dose fails, an alternate method nization is somewhat faster with west- of physiologic rhythms is a 0.5-mg dose over a period of several bound travel (1.0 hour per day) resulting from time-zone months. Most blind patients whose cir- compared with eastbound travel (1.5 changes is responsible for cadian period is close to 24 hours can hours per day). Not all travelers crossing most of the symptoms maintain entrainment with very low multiple time zones develop jet-lag dis- of jet-lag disorder. The nightly doses of 20 2gto3002g. order, but most will experience some severity of jet lag depends Vitamin B12 trials have been unsuccess- level of sleep and wake disturbance. on several variables, ful in sighted patients, but evidence Clinical presentation and diagnosis. including the number of from case reports suggests that a com- Patients with jet-lag disorder typically time zones crossed and bination of timed melatonin doses of present with symptoms of recurrent the direction of travel. 0.5 mg to 5.0 mg taken nightly at 9:00 PM, insomnia and daytime somnolence as exposure to bright light, and a regular a result of rapid travel across two or sleep-wake schedule is successful in en- more time zones. The sleep disturb- training these patients.17 ance leads to clinically significant impairment in daytime functioning. The Jet-Lag Disorder most common sleep disturbances asso- Jet-lag disorder results from travel across ciated with jet lag are sleep fragmenta- several time zones and subsequent mis- tion, early morning awakenings, and alignment of the internal circadian clock sleep-initiation insomnia. People travel- and the destination’s local time. Symp- ing eastward develop difficulty falling toms of jet lag usually emerge within 1 to asleep and awakening the next day. 2 days after travel. Main manifestations Westbound travelers experience exces- of jet lag are generalized malaise, sleep sive somnolence in the early evening, disturbances, impaired daytime alert- and early morning awakening. In addi- ness, poor appetite, diminished cogni- tion to impairments of sleep and wake tive performance, depressed mood, function, travelers affected by jet lag irritability, and anxiety. report gastrointestinal disturbances, Pathophysiology. Internal desynch- menstrual irregularities, and the exacer- ronization of physiologic rhythms bation of affective disorders. Cognitive resulting from time-zone changes is impairment emerging from jet lag may responsible for most of the symptoms have serious consequences, such as of jet-lag disorder. The severity and type impaired decision-making for business of jet-lag symptoms depend on several travelers or impaired performance in variables, including the number of time athletes.33 Effects of jet lag not only zones crossed and the direction of affect travelers but can also have rather travel.31 Eastward travel may be more significant consequences for airline difficult to adapt to than westward pilots and need to be considered when travel, because the former requires planning work schedules, stopover advancing circadian rhythms and the durations, and rest periods between latter a phase delay. Humans generally flights. have an endogenous circadian period Treatment. The main objective in that is slightly longer than 24 hours, so treating jet lag is to improve sleep that a delay shift is more easily quality and daytime alertness by realign- achieved. Older adults may have more ing the endogenous circadian rhythm difficulty with circadian realignment with the required or desired sleep and than younger people.32 Typically, symp- waketimesofthedestination’stime toms of jet lag subside within a few days zone. However, when the time in the but may persist for a few weeks in some destination is expected to be brief travelers. The speed of this resynchro- (2 days or less), circadian adaptation

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT may be counterproductive and treat- Immediate-release melatonin appears h Nonpharmacologic ment should be aimed at improving or to be more effective than extended- treatment approaches are 34 34 alleviating jet-lag symptoms. release formulations. ACochrane important in the Nonpharmacologic treatment ap- Review of 10 randomized placebo- management of jet-lag proaches are important in the man- controlled trials of melatonin and air disorder. Strategic agement of jet-lag disorder. Strategic travel concluded that melatonin at doses exposure and avoidance exposure and avoidance of exposure to of2mgto5mgtakenbeforebedtime of exposure to light have light have been utilized as an effective over 2 to 4 days is effective in reducing been utilized as an treatment approach. Inappropriate jet-lag symptoms.35 A combination ap- effective treatment timing of light exposure may result in proach incorporating melatonin with approach. further desynchronization of the circa- timed physical activity and light exposure dian system at the destination. The usually results in additional improve- optimal timing or avoidance of light ments of symptoms. exposure depends on the direction of Ramelteon, an MT1/MT2 melatonin travel and the number of time zones receptor agonist with greater affinity for crossed.9 For example, after an east- melatonin receptors and longer half-life bound flight from Chicago to Paris, compared to melatonin, may be effec- passengers should avoid bright light tive in treating symptoms of jet lag. In a in early morning and expose them- recent placebo-controlled study, a sig- selves to bright light in late morning nificant decrease in sleep latency was and afternoon (to advance circadian achieved with administration of ramel- rhythms). If flying westbound, efforts teon (1 mg), administered at bedtime should be made to stay awake during for 4 nights at the new destination.36 In the daylight hours, maximize light this study, beneficial effects of ramel- exposure in the afternoon and early teon were strongly influenced by light evening, and not sleep until nighttime exposure since only participants main- at the destination. Shifting the circa- tained in constant dim light had signifi- dian clock by using timed exposure to cant differences in latency to persistent light several days before travel may be sleep. Further studies are needed to useful in minimizing jet-lag symptoms prove the efficacy of ramelteon for jet lag. but has practical limitations for a fre- Several other pharmacologic agents, quent business traveler. including caffeine and hypnotic medica- Currently, no US Food and Drug tions, have been explored as options to Administration (FDA)Yapproved phar- alleviate jet-lag symptoms. Short-acting macologic agents are available for the hypnotic medications can be used to treatment of jet-lag disorder. Based on treat insomnia associated with jet lag.9 its ability to phase shift circadian rhythms Several studies demonstrated beneficial and its potential soporific effect, melato- effects of caffeine on fatigue and the nin has been studied. Administration of reduced alertness associated with jet lag. melatonin at doses of 0.5 mg to 10 mg in In a randomized placebo-controlled the early evening hours several days study of modafinil, improved alertness before eastbound travel followed by ad- and other jet-lag symptoms were ministration at bedtime at the destina- achieved after administration of 150 mg tion effectively reduces symptoms of of modafinil.37 Based on the AASM jet lag.22 Significant improvements with practice parameters, timed melatonin melatonin were demonstrated by self- administration is recommended as treat- reported sleep and mood measures as ment for jet-lag disorder. Additional well as objective circadian measures treatment options include maintain- (ie, melatonin and cortisol rhythms). ing home-based sleep hours for brief

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KEY POINTS h Based on the American travel, short-term hypnotic use for help not only by showing total sleep Academy of Sleep insomnia, and caffeine to alleviate day- duration but also by demonstrating 21 Medicine practice time sleepiness. circadian-sleep misalignment. On parameters, timed nonworking days, individuals with melatonin Shift Work Disorder SWD tend to revert back to more administration is Shift work disorder (SWD) is character- traditional daytime activities and night recommended as ized by a history of chronic (at least 1 sleep schedules, contributing further treatment for jet-lag month) excessive sleepiness during the to the circadian misalignment. Night disorder. required wake (work) time and/or shift workers and rotating shift work- h Night shift workers and insomnia symptoms during the associ- ers get less sleep than day workers or rotating shift workers ated required or desired sleep period evening shift workers. Night shift get less sleep than day that occurs in relation to unconventional workers generally have no difficulty workers or evening shift work schedules. falling asleep but complain primarily workers. Epidemiology. Almost 20% of the of difficulty maintaining sleep during h Shift work disorder is workforce in the developed world is the late morning or afternoon. Exces- accompanied by engaged in shift work. The prevalence sive sleepiness is most marked during significant social and of SWD is approximately 1% in the gen- the last half of the work hours and economic burdens in the eral population and up to 10% among while commuting to home at the end form of accidents, lost night and rotating shift workers. In the of the shift. Other symptoms of SWD days of work, poorer general population, men are slightly at include chronic fatigue, malaise, mood performance, and 38 increased health care use. higher risk than women for SWD. In disorder, and nonspecific complaints, certain populations, such as nurses, the such as dyspepsia and decreased prevalence of SWD can reach about libido.29 Risk of alcohol and substance 40%.38 abuseisincreased,asistheriskof Pathophysiology. The primary etiol- weight gain, hypertension, and cardio- ogy of SWD is the opposition of vascular disease, and some studies sug- required sleep and wake times to their gest an association with breast and endogenous circadian rhythm of sleep endometrial cancer.39 In addition to and wake propensity. This often results the medical comorbidities, SWD is ac- in shortened sleep duration by 1 to 4 companied by significant social and eco- hours. In addition, trying to stay awake nomic burdens in the form of accidents, during the night, when the circadian lost days of work, poorer performance, alertness signal is low, leads to excessive and increased health care use.39 sleepiness during the work hours.21 Treatment. The primary aim of treat- The overnight shift is usually associated ment is to improve alertness during the with the most severe symptoms, but required wake time and sleep quality patients may report symptoms of SWD during the scheduled sleep time. All with any shift that requires one to be patients with SWD should be counseled awake at an adverse circadian time. regarding conservative nonpharmaco- Tolerance to the effects of shift work logic measures. These include opti- may vary with age, chronotype, comor- mizing the sleep environment (eg, bid sleep disorders, social situation, and darkened room, comfortable temper- distance of commute between home ature, noise reduction), adherence to and work.21 good sleep habits (eg, maintain a regular Clinical presentation and diagno- sleep and wake schedule, avoid exces- sis. The diagnosis is made by careful sive caffeine), patient and family educa- history of symptoms and work sched- tion, and scheduled naps when possible. ule. A minimum of 2 weeks of sleep Appropriately timed light therapy has logs with or without actigraphy can been shown to accelerate circadian

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Case 7-2 A 26-year-old female security guard reported chronic fatigue and difficulty keeping up with her duties. She had started her job 4 months ago and worked 8- to 9-hour night shifts for 4 to 5 consecutive days (from 11:00 PM or midnight to 7:00 AM). On days off she usually went to bed when her husband did at midnight and slept until late morning. She reported difficulty staying asleep during the day when off duty, and sleepiness and decreased concentration during her shift at night. She described malaise, anxiety, and decreased libido. When working, she consumed large amounts of caffeine and sugar to help her stay awake. Her sleep-wake diary before and after treatment is shown in Figure 7-6. Comment. As shown in Figure 7-6, after appropriate treatment the patient is sleeping in the ‘‘compromised circadian position’’ with sleep and wake times that allow time for some social activities during her days off, yet the change in sleep-wake times between days off and days on duty is FIGURE 7-6 Sleep-wake diary of a patient with shift work disorder. A, Patient’s sleep not dramatically different. diary for 1 week before treatment. B, Patient’s sleep diary for 1 week This sleep-wake schedule after 1 month of treatment with a combination of intermittent naps when possible before the shift, bright light exposure (yellow) during the shift, and allows for more sleep avoidance of light on the morning commute (sunglasses) together with maintaining a consolidation and longer dark and quiet bedroom. In addition, 3 mg of melatonin (purple pill) was started to sleep duration throughout improve sleep as needed. Bright light exposure for 30 minutes to 1 hour (light bulb) was also initiated shortly after awakening during work days. During days off, she was the week. instructed to maintain a compromised sleep and wake schedule so that she would have time with her husband and friends, but not completely revert to a daytime schedule.

adaptation to night shift work. For night 3- or 6-hour blocks or in 20-minute or shift workers, bright light exposure rang- 1-hour blocks (ending 2 hours before ingfrom1000luxto10,000luxeitherin the end of the shift) has been shown to

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KEY POINT accelerate circadian adaptation to night clinical correlations. Neurology 2008;71(8): h For night shift workers, 594Y598. bright light exposure work and improve both alertness and performance (Case 7-2).40 Complemen- 3. Dardente H, Cermakian N. Molecular ranging from 1000 lux circadian rhythms in central and peripheral to 10,000 lux either in tary to light exposure during work, it is clocks in mammals. Chronobiol Int 2007; 3- to 6-hour blocks or in important to avoid bright light expo- 24(2):195Y213. 20-minute to 1-hour sure during the morning commute by 4. Cermakian N, Boivin DB. The regulation of blocks (ending 2 hours usingappropriateeyewear.17 central and peripheral circadian clocks in before the end of the Data on the use of melatonin, at humans. Obes Rev 2009;10(10 suppl 2):25Y36. shift) has been shown to various doses, have produced conflict- 5. Takahashi JS, Hong HK, Ko CH, McDearmon accelerate circadian ing results. However, melatonin when EL. The genetics of mammalian circadian adaptation to night order and disorder: implications for taken at bedtime does appear to physiology and disease. Nat Rev Genet 2008; work and improve modestly improve daytime sleep, but 9(10):764Y775. both alertness and performance. without any significant impact on 6. Ko CH, Takahashi JS. Molecular components nighttime alertness or performance. of the mammalian circadian clock. Hum Y All other pharmacologic modalities fail Mol Genet 2006;15:R271 R277. to address the circadian misalignment 7. Lowrey PL, Takahashi JS. Mammalian circadian biology: elucidating genome-wide but can be used for improving alert- levels of temporal organization. Annu Rev ness during work hours or sleep Genomics Hum Genet 2004;5:407Y441. during the scheduled sleep time. 8. Montagnese S, Middleton B, Mani AR, et al. Therefore, pharmacologic agents Sleep and circadian abnormalities in patients should be used in combination with with cirrhosis: features of delayed sleep phase syndrome? Metab Brain Dis 2009; light and behavioral modalities. Hyp- 24(3):427Y439. notics are not specifically indicated for 9. Kolla BP, Auger RR. Jet lag and shift work SWD but may be prescribed for the sleep disorders: how to help reset the treatment of insomnia that is often internal clock. Cleve Clin J Med 2011;78(10): seen in these patients. Caffeine com- 675Y684. bined with timed naps improves per- 10. Archer SN, Carpen JD, Gibson M, et al. Polymorphism in the PER3 promoter formance and alertness during the associates with diurnal preference and 41 night shift. The wake-promoting delayed sleep phase disorder. Sleep 2010; agents modafinil (200 mg) and armo- 33(5):695Y701. dafinil (150 mg) have been shown to 11. Crowley SJ, Carskadon MA. Modifications to improve performance and alertness weekend recovery sleep delay circadian phase in older adolescents. Chronobiol Int when taken at the beginning of the 2010;27(7):1469Y1492. night shift.17 Both modafinil and armo- 12. Paul MA, Gray GW, Lieberman HR, et al. dafinil are approved by the FDA for the Phase advance with separate and treatment of excessive sleepiness as- combined melatonin and light treatment. sociated with SWD. The AASM practice Psychopharmacology (Berl) 2011;214(2): Y parameters recommend planned nap- 515 523. ping before and/or during the work shift, 13. Smith MR, Revell VL, Eastman CI. Phase advancing the human circadian clock with timed light exposure, and stimulants blue-enriched polychromatic light. Sleep such as caffeine or modafinil during the Med 2009;10(3):287Y294. 17 night shift to improve alertness. 14. Crowley SJ, Acebo C, Fallone G, Carskadon MA. Estimating dim light melatonin onset (DLMO) phase in adolescents using summer REFERENCES or school-year sleep/wake schedules. 1. Golombek DA, Rosenstein RE. Physiology Sleep 2006;29(12):1632Y1641. of circadian entrainment. Physiol Rev 2010; 15. van Geijlswijk IM, Korzilius HP, Smits MG. 90(3):1063Y1102. The use of exogenous melatonin in delayed 2. Benarroch EE. Suprachiasmatic nucleus and sleep phase disorder: a meta-analysis. melatonin: reciprocal interactions and Sleep 2010;33(12):1605Y1614.

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