Circadian Rhythm Abnormalities - L.S. Neurologylsneuro.org/files/c/mouvementdisorders/Circadian Rhythm... · Circadian Rhythm Abnormalities Phyllis C. Zee, MD, PhD; Hrayr Attarian,

Circadian RhythmAbnormalities

Phyllis C. Zee, MD, PhD; Hrayr Attarian, MD, FAASM, FCCP;Aleksandar Videnovic, MD, MSc

ABSTRACTPurpose: This article reviews the recent advances in understanding of the funda-mental properties of circadian rhythms and discusses the clinical features, diagnosis,and treatment of circadian rhythm sleep disorders (CRSDs).Recent Findings: Recent evidence strongly points to the ubiquitous influence ofcircadian timing in nearly all physiologic functions. Thus, in addition to the prominentsleep and wake disturbances, circadian rhythm disorders are associated with cognitiveimpairment, mood disturbances, and increased risk of cardiometabolic disorders. Therecent availability of biomarkers of circadian timing in clinical practice has improvedour ability to identify and treat these CRSDs.Summary: Circadian rhythms are endogenous rhythms with a periodicity ofapproximately 24 hours. These rhythms are synchronized to the physical environmentby social and work schedules by various photic and nonphotic stimuli. CRSDs resultfrom a misalignment between the timing of the circadian rhythm and the externalenvironment (eg, jet lag and shift work) or a dysfunction of the circadian clock or itsafferent and efferent pathways (eg, delayed sleep-phase, advanced sleep-phase,nonY24-hour, and irregular sleep-wake rhythm disorders). The most common symp-toms of these disorders are difficulties with sleep onset and/or sleep maintenance andexcessive sleepiness that are associated with impaired social and occupationalfunctioning. Effective treatment for most of the CRSDs requires amultimodal approachto accelerate circadian realignment with timed exposure to light, avoidance of brightlight at inappropriate times, and adherence to scheduled sleep and wake times. Inaddition, pharmacologic agents are recommended for some of the CRSDs. For delayedsleep-phase, nonY24-hour, and shift work disorders, timed low-dose melatonincan help advance or entrain circadian rhythms; and for shift work disorder, wake-enhancing agents such as caffeine, modafinil, and armodafinil are options for themanagement of excessive sleepiness.

Continuum (Minneap Minn) 2013;19(1):132–147.

OVERVIEW OF THE HUMANCIRCADIAN SYSTEMCircadian rhythms are physiologic andbehavioral cycles with a recurring perio-dicity of approximately 24 hours, gen-erated by the endogenous biologicalpacemaker, the suprachiasmatic nucleus(SCN), located in the anterior hypothal-amus.1 These rhythms control a varietyof biological processes, such as sleep-wake cycle, body temperature, feeding,

hormone secretion, glucose homeosta-sis, and cell-cycle regulation. The timingof these physiologic rhythms maybecome altered, leading to changes inthe phase relationship of rhythms toeach other, which can cause internaldesynchronization. This loss of coordi-nation of rhythms may have negativeconsequences on rest-activity cyclesand other physiologic and behavioralfunctions.

Address correspondence toDr Phyllis C. Zee, NorthwesternUniversity, 710 North LakeShore Dr, Chicago, IL 60611,[email protected].

Relationship Disclosure:Dr Zee has received personalcompensation for activitieswith Jazz Pharmaceuticals;Merck & Co, Inc; PerduePharma; Philips Respironics;Sanofi-Aventis; TakedaPharmaceutical CompanyLimited; UCB; and Zeo, Inc.Dr Zee receives researchsupport from PhilipsRespironics. Dr Attarianreceives personalcompensation for activitieswith American PhysiciansInstitute. Dr Videnovic reportsno disclosure.

Unlabeled Use ofProducts/InvestigationalUse Disclosure: Dr Zeediscusses the unlabeled use ofmelatonin for the treatment ofcircadian disorders. Dr Attariandiscusses the unlabeled use ofmelatonin and light boxes toadvance or delay circadianrhythms. Dr Videnovicdiscusses the unlabeled use ofmelatonin, ramelteon, andsupplemental light exposure toadvance circadian rhythms andtreat jet-lag disorder.

* 2013, American Academyof Neurology.

132 www.aan.com/continuum February 2013

Review Article

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Circadian EntrainmentCircadian rhythms are synchronizedwiththe earth’s rotation by daily adjustmentsin the timing of the SCN, following theexposure to stimuli that signal the timeof day. These stimuli are known aszeitgebers (German for ‘‘time-givers’’),of which light is the most important andpotent stimulus. The magnitude anddirection of the change in phase de-pends on when within the circadiansystem the light pulse is presented. Aplot of phase changes according to thetime of light stimulus presentationprovides a phase response curve. Expo-sure to light results in a phase responsecurve with delays in the early subjectivenight (ie, evening) and advances in thelate subjective night (ie, early morning).In addition to light, feeding schedules,activity, and the hormone melatonincan also affect the circadian timing.1

The timing of melatonin secretion bythe pineal gland is regulated by the SCN,with the onset of secretion approxi-mately 2 hours before natural sleep timeand being highest during the middle ofthe night.1 Melatonin onset measuredin a dim light environment (DLMO) is astable marker of circadian phase and isused in research as well as clinical prac-tice to determine the timing of the en-dogenous circadian rhythm.

Neuroanatomy andNeurochemistryThe central circadian timing system hasthree distinct components: (1) a circa-dian pacemaker, the SCN, (2) inputpathways for light and other stimuli thatsynchronize the pacemaker to the envi-ronment, and (3) output rhythms thatare regulated by the pacemaker. TheSCN is the central pacemaker that linksthe 24-hour changes in the externalenvironment with the 24-hour changesin the internal environment (Figure 7-1).2

The SCN is composed from the ‘‘core’’and ‘‘shell’’ subnuclei, which have dis-

tinct neurochemical properties.1 While+-aminobutyric acid is the dominantneurotransmitter in the SCN, present innearly all SCN neurons, SCN neuropep-tides are highly localized within eitherthe core or shell nuclei. The SCN corecontains high density of vasoactive in-testinal polypeptide, gastrin-releasingpeptide, and bombesin-containing neu-rons. Somatostatin and neurophysin aredominant neurochemicals within theSCN shell.

The SCN receives photic informationfrom the retina via direct (retinohypo-thalamic) and indirect (retinogeniculate)pathways.3 The melanopsin-containingganglion cells of the retina are the pri-mary photoreceptors for the circadiansystem. The SCN also receives nonphoticinformation from the raphe nuclei. Sev-eral less-characterized afferents con-verge in the SCN from basal forebrain,pons, medulla, and posterior hypothal-amus. The major efferents from the SCNproject to the subparaventricular zoneand the paraventricular nucleus of thehypothalamus, dorsomedial hypothal-amus, thalamus, preoptic and retrochias-matic areas, stria terminalis, lateralseptum, and intergeniculate nucleus.The SCN also communicates via diffu-sion of humoral signals to the rest ofthe brain. These diffusible SCN outputslikely include transforming growth fac-tor !, cardiotrophinlike cytokine, andprokineticin 2. A major developmentin chronobiology research has beenthe discovery of circadian clocks innon-SCN brain regions and almost allperipheral tissues.4 While the signalsmediating communication between theSCN and peripheral oscillators remainunder extensive investigation, it is clearthat the central clock (ie, SCN) and pe-ripheral clocks may have distinct circa-dian synchronizers. The SCN, however,is most likely dominant in maintain-ing circadian rhythmicity of peripheralclocks.

KEY POINTS

h Circadian rhythms arephysiologic andbehavioral cycles with arecurring periodicity ofapproximately 24 hours,generated by theendogenous biologicalpacemaker, thesuprachiasmaticnucleus, located in theanterior hypothalamus.

h Circadian rhythms aresynchronized with theearth’s rotation bydaily adjustments inthe timing of thesuprachiasmaticnucleus, following theexposure to stimuli thatsignal the time of day.These stimuli areknown as ‘‘zeitgebers’’(German for‘‘time-giver’’), ofwhich light is the mostimportant and potentstimulus. The magnitudeand direction of thechange in phase dependson when within thecircadian system thelight pulse is presented.

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Genetic RegulationCircadian rhythms are determinedgenetically by a core set of clock genes,including three Per genes (the periodhomolog 1 gene,Per1; the period homo-log 2 gene, Per2; the period homolog 3gene, Per3); the circadian locomotor out-put cycles kaput gene, Clock; the cyclegene,Bmal1; and twoplant cryptochromegene homologs (the cryptochrome 1gene, Cry1, and the cryptochrome2 gene,Cry2).5 These genes and their productsinteract to form transcription-translationfeedback loops that provide the molec-ular basis of circadian rhythmicity. Dur-ing the day, Clock interacts with BMal1to activate transcription of the Per andCry genes, resulting in high levels ofthese transcripts. PER and CRY proteinstranslocate to the nucleus and inhibitCLOCKYB-MAL1-mediated transcription.

During the night, the PER-CRY repressorcomplex is degraded, and the cyclestarts again (Figure 7-2). Circadian clockgenes control a significant proportionof the genome. It is estimated that ap-proximately 10% of all expressed genesare under regulation of the clock genes.Furthermore, peripheral tissues containindependent clocks. It is likely thatperipheral clocks are synchronized byan input directly from the SCN or SCN-mediated messages. Several excellentreviews are available for more detailedoverview of the molecular regulation ofthe circadian system,3,6,7

CIRCADIAN RHYTHM SLEEPDISORDERSCircadian rhythm sleep disorders(CRSDs) are chronic patterns (for atleast 1 month) of sleep-wake rhythm

FIGURE 7-1 Schematic illustration of the pathway responsible for entrainment of melatoninsecretion by light. The circadian regulation of melatonin secretion is dependent onan 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 responsiblefor melatonin secretion via an inhibitory projection to the paraventricular nucleus of thehypothalamus. This pathway is responsible for the peak of melatonin secretion during darkness.

Reprinted with permission from Benarroch EE, Neurology.2B 2008, American Academy of Neurology. www.neurology.

org/content/71/8/594.extract.


Circadian Rhythm Abnormalities


www.neurology.org/content/71/8/594.extract

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disturbances due to alterations of thecircadian timing system or to a misalign-ment between the timing of the endog-enous circadian rhythm and the sleep-wake times required by school or workschedules. As a result, patients presentwith impairments in sleep and wakefunctioning. The diagnosis of all CRSDsis based on a careful history and sleepdiary with actigraphy. Polysomnography(PSG) is not routinely indicated toestablish the diagnosis. However, PSGis indicated to assess for other comorbidsleep disorders. In addition to comorbidsleep disorders, psychiatric disordersVparticularly depression and anxietyVarecommon in patients with nearly all typesof CRSDs and should be considered inthe differential diagnosis.

Delayed Sleep-Phase DisorderDelayed sleep-phase disorder (DSPD)is characterized by a chronic or recur-rent inability to fall asleep and wake upat socially acceptable times, resulting insymptoms of difficulty falling asleep andexcessive daytime sleepiness, particu-larly in the morning. By definition, inrelation to socially acceptable times, thereis a more than 2-hour delay in the majorsleep period. Patients have difficulty wak-ing up in the morning and are oftenlate for work or school. When patientsare allowed to sleep at their biologicallypreferred time and wake up sponta-neously after their major sleep period,sleep and daytime function normalize.

Epidemiology. The prevalence ofDSPD is 0.2% to 10.0% depending onseverity and the population groups sur-veyed. Milder cases are more prevalent,as are cases among adolescents andyoung adults. There appears to be nosex predilection, but among adolescentsthe phase delay occurs at an older age inmales than in females, with males reach-ing their peak at age 21 and femalesat age 17. A familial predisposition forDSPD also occurs, and DSPD appears

to be common (33%) in patients withhepatic cirrhosis.8

Pathophysiology. Multiple biologicaland behavioral factors contribute to thedevelopment of DSPD. The postulatedmechanisms for DSPD include (1) de-creased response to the phase-advancingeffect of light in the morning,9 (2) in-creased sensitivity to the phase-delayresponse of evening light, and (3) a longerthan normal time to complete one cir-cadian cycle (ie, long circadian period).Familial cases and the demonstration ofpolymorphisms of circadian clock genesin DSPD indicate a genetic basis for thiscondition.10 Environmental, behavio-ral, and psychological factors also playa role in the development of DSPD.For example, individuals with a delayedcircadian phase are more likely to workin the evening and be exposed toevening light, which can further delaythe timing of circadian rhythms, or theywake up late, thus perpetuating thevicious cycle of late sleep and late waketimes.11

Clinical presentation and diagnosis.Patients with DSPD usually fall asleepbetween 1:00 AM and 6:00 AM and wakeup in the latemorning to early afternoon,

KEY POINT

h Delayed sleep-phasedisorder is characterizedby chronic or recurrentinability to fall asleepand wake up at sociallyacceptable times,resulting in symptomsof difficulty fallingasleep and excessivedaytime sleepiness,particularly inthe morning.

FIGURE 7-2 Simplified representation of the transcriptioncycle.



as outlined in the International Classi-fication of Sleep Disorders, SecondEdition: Diagnostic and Coding Man-ual. Conditioned insomnia and chronicsleep deprivation may develop as a com-plication of DSPD. In addition, patientswith DSPD tend to have decreasedacademic and work performance, espe-

cially during morning hours, in additionto habitual tardiness and morning absen-ces. Diagnosis is made by careful historyand well-kept sleep diaries with or with-out actigraphy for a minimum of 7 days(preferably 14 days) (Case 7-1). Stand-ardized chronotype questionnaires areuseful tools to assess the chronotype

KEY POINT

h Diagnosis of delayedsleep-phase disorder ismade by careful historyand well-kept sleepdiaries with or withoutactigraphy for aminimum of 7 days(preferably 14 days).

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

Comment. Typical of patients with delayed sleep-phase disorder, this man hadsignificant sleep-onset insomnia andwas then sleepywhile atworkbecauseof chronic sleepdeprivationandbecausehewas forced tobeawakeduringapartofhis circadian sleep time.

FIGURE 7-3 Representative actogram of patient with delayed sleep-phase disorder. The bluearrows indicate sleep onset and the red arrows indicate the end of the majorsleep period. The black horizontal arrows indicate naps. In high-amplitude

actigraphy, dense bars are representative of wakefulness, and low, sparse bars are representativeof sleep. Note that sleep onset is 2:00 AM to 4:00 AM and the end of the major sleep period variesfrom 8:00 AM all the way to 1:00 PM (on day 7). On day 5, when total sleep duration was from2:00 AM to 7:00 AM, the patient takes two naps, resulting in less sleep homeostatic drive, andtherefore sleep onset the next night is not until 5:00 AM.




of ‘‘eveningness’’ and ‘‘morningness.’’In addition, a delay in the timing ofobjective circadian rhythms, such as theDLMO or urinary 6-sulfatoxymelatonin,is desirable to confirm the delayed cir-cadian phase. Depression, anxiety, andpersonality disorders are more com-mon among patients with DSPD.

Treatment. The American Academyof Sleep Medicine (AASM) practice pa-rameters recommend appropriatelytimed morning light exposure andevening exogenous melatonin eitheralone or in combination as effectivetreatments for DSPD (Figure 7-4). Thecombination of light therapy and mel-atonin has been shown to have com-plementary benefits.12 Bright light (fullspectrum or blue enriched) in themorning for 2 hours shortly after theminimum of the core body temper-ature rhythm (typically occurring 2 to 3hours before natural wake-up time) hasbeen shown to successfully advancecircadian rhythms in patients withDSPD.13 Melatonin 0.5 mg to 5 mggiven 5.0 to 6.5 hours before DLMO (13to 14 hours after natural wake-uptime)14 advances sleep and rise times,while administration closer to DLMOis less effective. Effectiveness lasts upto 1 year with daily melatonin intake,but relapses can occur in up to 90% ofpeople after they discontinue theirmelatonin. Time to relapse rangesfrom 1 day to 6 months with the moresevere DSPD cases relapsing faster.15

Furthermore, melatonin has beenshown to improve depression inpatients with DSPD.16 Although it hasbeen reported that vitamin B12 may beeffective as an adjunctive treatment tobright light, it was not recommendedby the 2007 AASM practice parametersas a treatment for DSPD.17 There isalso limited evidence suggesting atherapeutic benefit of combining lighttherapy with cognitive-behavioral ther-apy in adolescents with DSPD.18

Advanced Sleep-Phase DisorderAdvanced sleep-phase disorder (ASPD)is characterized by an advance in thephase of the major sleep episode inrelation to the desired or required sleepand wake-up times. Patients havechronic or recurrent difficulty stayingawake until the desired or sociallyacceptable bedtime, together with anearlier than desired wake-up time. Whenpatients are allowed to choose theirpreferred schedule, sleep quality andduration are normal for age.

Epidemiology. ASPD is less com-mon than DSPD. The estimated preva-lence is 1% in the general population,which is likely an underestimate sincemany individuals successfully adapttheir social and work schedules to theadvanced sleep phase.19 Both sexes areequally affected by the disorder. Theonset of ASPD is typically during mid-dle age. Several studies suggest that agemay be a risk factor for ASPD, likely onthe basis of a phase advance of thecircadian pacemaker with aging.17

Pathophysiology. A shortened circa-dian period has been postulated to beinvolved in the pathogenesis of ASPD.Genetic factors likely play an importantrole in the development of ASPD.Several families with ASPD inherited inan autosomal dominant mode havebeen described. Two gene mutationshave been identified in some of thesefamilies, affecting the circadian clockgene hPer2 and the casein kinase 1delta gene.20 These mutations resultin a shortened circadian period. Addi-tional mechanisms include an attenu-ated ability to phase delay because of adominant phase advance region of thephase response curve to light andincreased retinal sensitivity to light inthe morning,21 resulting in a strongeradvancing signal for the circadian clock.

Clinical presentation and diagnosis.Patients with ASPD typically presentwith symptoms of daytime sleepiness,

KEY POINT

h Bright light (full spectrumor blue enriched) in themorning for 2 hoursshortly after theminimum of the corebody temperaturerhythm (typicallyoccurring 2 to 3 hoursbefore natural wake-uptime) has been shown tosuccessfully advancecircadian rhythms inpatients with delayedsleep-phase disorder.



most prominent in the late afternoon orearly evening hours; sleep maintenancedifficulty; and early morning awakening.Individuals with ASPD are usually sleepyand struggle to stay awake between6:00 PM and 9:00 PM and wake up earlierthan desired, between 2:00 AM and 5:00 AM.

The diagnosis of ASPD is based on adetailed sleep history accompanied by asleep diary and, if feasible, actigraphyover a period of least 7 days (preferably14 days) to demonstrate advancedsleep and wake times. Major depressivedisorders should be carefully differenti-ated from ASPD. Standardized chrono-type questionnaires are useful tools toassess the chronotype of eveningnessand morningness. Patients with ASPDwill score as ‘‘morning’’ types. In addi-tion, an advance in the timing of objec-

tive circadian rhythms, such as theDLMO or urinary 6-sulfatoxymelatonin,is desirable to confirm the advanced cir-cadian phase.

Treatment. The AASM practiceparameter recommends sleep-wakescheduling and timed light exposureas the primary treatments for ASPD.Practical therapeutic approaches forASPD include timed light exposure inthe evening and avoiding light in earlymorning hours (Figure 7-4). Melatoninor hypnotics may be beneficial for sleepmaintenance insomnia. Bright lightadministered before the nadir of bodycore temperature is a potent stimulusfor delaying circadian phase. The mostcommonly used treatment for ASPDis early-evening light therapy, usuallybetween 7:00 PM and 9:00 PM. This

KEY POINTS

h Patients with advancedsleep-phase disordertypically present withsymptoms of daytimesleepiness (mostprominent in the lateafternoon or earlyevening hours) sleepmaintenance difficulty,and early morningawakening.

h Practical therapeuticapproaches for advancedsleep-phase disorderinclude timed lightexposure in the eveningand avoiding light inearly morning hours.Melatonin or hypnoticsmay be beneficial forsleep-maintenanceinsomnia.

FIGURE 7-4 Summary of treatment approaches for delayed sleep-phase disorder and advancedsleep-phase disorder. Bright light administered before the nadir of bodycore temperature is a potent stimulus for delaying circadian phase. The most

commonly used treatment for advanced sleep-phase disorder is early-evening light therapy, usuallybetween 7:00 PM and 9:00 PM. This approach has been shown to improve sleep duration and sleepmaintenance, as well as daytime performance. The combination of light therapy and melatoninhas been shown to have complementary benefits. Bright light in the morning for 1 to 2 hoursshortly after the minimum of the core body temperature rhythm advances circadian rhythms and0.5 mg to 5 mg of melatonin taken 5 to 6.5 hours before dim light melatonin onset (13 to 14 hoursafter natural wake-up time) results in advanced sleep and wake times in patients with delayedsleep-phase disorder.

MLT = melatonin.




approach has been shown to improvesleep duration and sleep maintenance,as well as daytime performance. How-ever, results of evening light therapyhave not been uniformly positive.22

Compliance with timed light exposurecan be challenging, and bright light mayirritate the eyes, particularly in olderadults. A chronotherapeutic approach ofadvancing bedtime by 3 hours every 2days has been reported effective in ASPD;however, the scheduling constraint ofthis approach limits its use in clinicalpractice. Based on the phase responsecurve to melatonin, administration ofmelatonin in early morning will advancethe circadian phase, although clinicalevidence of the efficacy or safety ofmelatonin for the treatment of ASPD islacking. While hypnotic agents are pre-scribed for the management of sleepmaintenance symptoms associated withASPD, their efficacy and safety have notbeen systematically studied.

Irregular Sleep-Wake RhythmDisorderIrregular sleep-wake rhythm disorder(ISWRD) is characterized by a tempo-rally disorganized sleep and wake pat-tern, such that multiple sleep and wakeperiods occur throughout the 24-hourcycle. This disorder is more prevalentin older adults with dementia and inpatients with developmental disorders.

Epidemiology. ISWRD is commonamong institutionalized older adults,particularly those with Alzheimer dis-ease and those with late afternoon-evening agitation or sundowning. Agealone is not a risk factor for ISWRD,but age-related neurologic and psychi-atric disorders are.23 ISWRD has alsobeen described in patients with headtrauma, children with developmentaldelay, and patients with schizophre-nia, particularly those with positivesymptoms,24 independent of daytimefunctioning.25

Pathophysiology. Multiple physio-logic, behavioral, and environmentalfactors contribute to the developmentof ISWRD. The most likely mechanismsinclude central degeneration of SCNneurons and decreased exposure orinput of external synchronizing agents,such as light and activity that result in aweakened central circadian oscillationand temporal disorganization of circa-dian rhythms.26 The problem is perpe-tuated by a variety of factors inherentin the lifestyles of older adults in nurs-ing homes and other similar livingfacilities. Institutionalized elderly pa-tients get significantly less exposure tolight in both amount and intensity. Thisis a result of lower levels of light indoorsand the fact that most eye diseases,such as cataracts, reduce light input tothe SCN even further. Compoundingthe diminished light exposure is thereduction in other external synchron-izers such as structured social andphysical activities. Decreased mobility,adverse effect on sleep and alertness bymedications, and increased nappingalso play a role in the developmentof ISWRD.26 Genetic factors have beenimplicated in the development ofISWRD in Alzheimer disease.27

Clinical presentation and diagnosis.In patients with ISWRD, sleep boutsoccur in three or more short intervals ofapproximately 1 to 4 hours each, spreadover 24 hours. The longest bout gen-erally occurs between 2:00 AM and6:00 AM. The overall amount of sleepper 24-hour period, however, is relativelynormal for the patient’s age.23 Because offragmented sleep and multiple daytimenaps, patients usually present withsymptoms of sleep maintenance insom-nia and excessive daytime sleepiness. Inaddition to the typical symptomatology,diagnosis requires a history of a mini-mum of three irregular sleep-wakecycles in a 24-hour cycle recorded for14 days by sleep diary and/or actigraphy.



Treatment. Creating a cognitivelyenriched environment with structuredsocial and physical activity during theday is an important therapeutic modal-ity, especially if combined with a healthybedtime routine and a nocturnal envi-ronment conducive to sleep. Measuresinclude minimizing noise and light dur-ing the scheduled sleep period andaddressing issues such as nocturia andenuresis to reduce sleep disturbancesat night. Light, however, remains themost effective therapeutic intervention.Exposure to 3000 lux to 5000 lux brightlight for 2 hours every morning for 4weeks has been shown to improvedaytime alertness, decrease napping,consolidate nighttime sleep, and re-duce nocturnal agitation.23 Melatoninalone has not been shown to beconsistently effective in treating ISWRDin older adults or in patients withAlzheimer disease. However, effective-ness may be improved when melatoninat bedtime is combined with lightduring the day.21 Small open-label trialsusing doses of 2 mg to 20 mg of mel-atonin have shown some benefit inchildren with developmental disor-ders.28 Controlled-release formulationappeared more effective than immedi-ate release in this subpopulation. TheAASM practice parameters recommendusing a combination of environmentaland behavioral modifications and brightlight therapy for ISWRD.

Non–24-Hour Sleep-WakeDisorderNonY24-hour sleep-wake disorder(N24SWD) (nonentrained rhythm disor-der formerly known as free-runningrhythm disorder) is characterized by achronic or recurrent pattern of sleep andwake cycles that are not synchronized tothe 24-hour environment. Typically aconsistent daily drift (usually to laterand later times) of sleep-onset andwake-up times occurs.

Epidemiology. Sleep disturbances inpeople who are blind are common, andapproximately 50% may have N24HSWD.Much less commonly, N24HSWD canoccur in sighted people. Onset of symp-toms typically occurs during the secondor third decade of life.29 In blind andsighted individuals, there is a malepredilection with a ratio of 2.6/1.30

Pathophysiology. The etiology ofN24HSWD in blind people is clearly amarked decrease or absence of lightperception. However, not all patientswho are blind exhibit this lack ofentrainment, because in some, lightinformation from the retinal ganglioncells can still reach the SCN, or othersynchronizing agents (such as struc-tured social and physical activity) cansufficiently entrain circadian rhythms.30

Although the exact mechanism insighted individuals remains to be eluci-dated, evidence suggests that a longcircadian period that is beyond thenormal range of entrainment is likely arisk factor.30 Other postulated mecha-nisms that can lead to an abnormalinteraction between sleep homeostasisand endogenous circadian rhythmsinclude (1) decreased photosensitivity,30

(2) alteration and reduction of socialcues because of psychiatric illnessYinduced social withdrawal,21 (3) muta-tion in the creatinine kinase 1 ( (CK1()gene,21 and (4) desynchrony betweenthe melatonin and sleep rhythms.30

Clinical presentation and diagnosis.The presenting symptoms depend onwhen the person is required to sleep inrelation to his or her nonentrainedendogenous circadian rhythm of sleep-wake propensity. Patients typicallypresent with symptoms of insomnia,excessive daytime sleepiness, or bothfor several weeks. These symptomaticepisodes alternate with days to weeksin which the patient is asymptomatic.The prevailing complaint is the interfer-ence of the sleep-wake schedule with

KEY POINTS

h Creating a cognitivelyenriched environmentwith structured social andphysical activity duringthe day is an importanttherapeutic modality forpatients with irregularsleep-wake rhythmdisorder, especially ifcombined with a healthybedtime routine and anocturnal environmentconducive to sleep.

h NonY24-hour sleep-wakedisorder is characterizedby a chronic or recurrentpattern of sleep andwake cycles that are notsynchronized to the24-hour environment.Typically a consistent dailydrift (usually to later andlater times) of sleep-onsetand wake-up timesoccurs.




work, school, and other social obliga-tions.29 Patients with this disorder canhave, at various times, excessive day-time sleepiness and sleep-onset insom-nia or early morning awakenings.Napping is quite common, and carefulanalysis of sleep-wake rhythms mayreveal two distinct sleep-wake cycleperiods separated by phase jumps (ie,when sleep onset is delayed for morethan 4 hours).21

Diagnosis is made by a careful historyand documenting that the sleep com-plaints are present for at least 2 months.A minimum of 14 days of sleep diaryand/or actigraphy can be very helpful.Actigraphy of a patient with N24HSWD isshown in Figure 7-5. Continuous corebody temperature measurements, iffeasible, or serial measurements of thetiming of the melatonin rhythm fromserum, saliva, or urine can be confirma-tory as they exhibit the same nonY24-hour rhythm as the disorder itself.21

Frequent comorbid psychiatric condi-tions, primarily mood disorders, needto be addressed as well. Care has to betaken to differentiate N24HSWD from

DSPD. Most sighted patients withN24HSWD also have an evening chro-notype. A misdiagnosis can be problem-atic, as chronotherapy for DSPD mayinduce a nonY24-hour rhythm. In thelargest cohort of sighted N24HSWD pa-tients, one-fourth had received a pre-vious misdiagnosis of DSPD.21

Treatment. In blind patients withN24SWD, melatonin is the therapeuticmainstay together with strong struc-tured behavioral and social cues, suchas timing of meals, planned activities,and regular physical exercise.29 Thissame approach is recommended forsighted persons, with the additionaloption of bright light exposure in themorning shortly after awakening. Al-though the dose of melatonin for thetreatment of N24HSWD varies amongstudies, a practical recommendation isto start with a higher dose (3 mg to10 mg) 1 hour before bedtime or a fewhours before predicted DLMO for thefirst month. Entrainment usually occurswithin 3 to 9 weeks but must be main-tained by regular low-dose (0.5 mg)melatonin to prevent a relapse. If the

KEY POINT

h In blind patients withnonY24-hoursleep-wake disorder,melatonin is thetherapeutic mainstaytogether with strongstructured behavioraland social cues such astiming of meals, plannedactivities, and regularphysical exercise. Thissame approach isrecommended forsighted persons, with theadditional option ofbright light exposure inthe morning shortly afterawakening.

FIGURE 7-5 Actigraphy record of a sighted patient with nonY24-hour sleep-wake disorder.Note the daily delay drift of the onset and offset of the sleep-wake rhythm with acircadian period that is longer than 24 hours.



initiation dose fails, an alternate methodis a 0.5-mg dose over a period of severalmonths. Most blind patients whose cir-cadian period is close to 24 hours canmaintain entrainment with very lownightly doses of 20 2g to 300 2g.Vitamin B12 trials have been unsuccess-ful in sighted patients, but evidencefrom case reports suggests that a com-bination of timed melatonin doses of0.5mg to 5.0mg taken nightly at 9:00 PM,exposure to bright light, and a regularsleep-wake schedule is successful in en-training these patients.17

Jet-Lag DisorderJet-lag disorder results from travel acrossseveral time zones and subsequent mis-alignment of the internal circadian clockand the destination’s local time. Symp-toms of jet lag usually emerge within 1 to2 days after travel. Main manifestationsof jet lag are generalized malaise, sleepdisturbances, impaired daytime alert-ness, poor appetite, diminished cogni-tive performance, depressed mood,irritability, and anxiety.

Pathophysiology. Internal desynch-ronization of physiologic rhythmsresulting from time-zone changes isresponsible for most of the symptomsof jet-lag disorder. The severity and typeof jet-lag symptoms depend on severalvariables, including the number of timezones crossed and the direction oftravel.31 Eastward travel may be moredifficult to adapt to than westwardtravel, because the former requiresadvancing circadian rhythms and thelatter a phase delay. Humans generallyhave an endogenous circadian periodthat is slightly longer than 24 hours, sothat a delay shift is more easilyachieved. Older adults may have moredifficulty with circadian realignmentthan younger people.32 Typically, symp-toms of jet lag subside within a few daysbut may persist for a few weeks in sometravelers. The speed of this resynchro-

nization is somewhat faster with west-bound travel (1.0 hour per day)compared with eastbound travel (1.5hours per day). Not all travelers crossingmultiple time zones develop jet-lag dis-order, but most will experience somelevel of sleep and wake disturbance.

Clinical presentation and diagnosis.Patients with jet-lag disorder typicallypresent with symptoms of recurrentinsomnia and daytime somnolence asa result of rapid travel across two ormore time zones. The sleep disturb-ance leads to clinically significant im-pairment in daytime functioning. Themost common sleep disturbances asso-ciated with jet lag are sleep fragmenta-tion, early morning awakenings, andsleep-initiation insomnia. People travel-ing eastward develop difficulty fallingasleep and awakening the next day.Westbound travelers experience exces-sive somnolence in the early evening,and early morning awakening. In addi-tion to impairments of sleep and wakefunction, travelers affected by jet lagreport gastrointestinal disturbances,menstrual irregularities, and the exacer-bation of affective disorders. Cognitiveimpairment emerging from jet lag mayhave serious consequences, such asimpaired decision-making for businesstravelers or impaired performance inathletes.33 Effects of jet lag not onlyaffect travelers but can also have rathersignificant consequences for airlinepilots and need to be considered whenplanning work schedules, stopoverdurations, and rest periods betweenflights.

Treatment. The main objective intreating jet lag is to improve sleepquality and daytime alertness by realign-ing the endogenous circadian rhythmwith the required or desired sleep andwake times of the destination’s timezone. However, when the time in thedestination is expected to be brief(2 days or less), circadian adaptation

KEY POINT

h Internal desynchronizationof physiologic rhythmsresulting from time-zonechanges is responsible formost of the symptomsof jet-lag disorder. Theseverity of jet lag dependson several variables,including the number oftime zones crossed andthe direction of travel.




may be counterproductive and treat-ment should be aimed at improving oralleviating jet-lag symptoms.34

Nonpharmacologic treatment ap-proaches are important in the man-agement of jet-lag disorder. Strategicexposure and avoidance of exposure tolight have been utilized as an effectivetreatment approach. Inappropriatetiming of light exposure may result infurther desynchronization of the circa-dian system at the destination. Theoptimal timing or avoidance of lightexposure depends on the direction oftravel and the number of time zonescrossed.9 For example, after an east-bound flight from Chicago to Paris,passengers should avoid bright lightin early morning and expose them-selves to bright light in late morningand afternoon (to advance circadianrhythms). If flying westbound, effortsshould be made to stay awake duringthe daylight hours, maximize lightexposure in the afternoon and earlyevening, and not sleep until nighttimeat the destination. Shifting the circa-dian clock by using timed exposure tolight several days before travel may beuseful in minimizing jet-lag symptomsbut has practical limitations for a fre-quent business traveler.

Currently, no US Food and DrugAdministration (FDA)Yapproved phar-macologic agents are available for thetreatment of jet-lag disorder. Based onits ability to phase shift circadian rhythmsand its potential soporific effect, melato-nin has been studied. Administration ofmelatonin at doses of 0.5 mg to 10mg inthe early evening hours several daysbefore eastbound travel followed by ad-ministration at bedtime at the destina-tion effectively reduces symptoms ofjet lag.22 Significant improvements withmelatonin were demonstrated by self-reported sleep and mood measures aswell as objective circadian measures(ie, melatonin and cortisol rhythms).

Immediate-release melatonin appearsto be more effective than extended-release formulations.34 A CochraneReview of 10 randomized placebo-controlled trials of melatonin and airtravel concluded that melatonin at dosesof 2 mg to 5 mg taken before bedtimeover 2 to 4 days is effective in reducingjet-lag symptoms.35 A combination ap-proach incorporating melatonin withtimed physical activity and light exposureusually results in additional improve-ments of symptoms.

Ramelteon, an MT1/MT2 melatoninreceptor agonist with greater affinity formelatonin receptors and longer half-lifecompared to melatonin, may be effec-tive in treating symptoms of jet lag. In arecent placebo-controlled study, a sig-nificant decrease in sleep latency wasachieved with administration of ramel-teon (1 mg), administered at bedtimefor 4 nights at the new destination.36 Inthis study, beneficial effects of ramel-teon were strongly influenced by lightexposure since only participants main-tained in constant dim light had signifi-cant differences in latency to persistentsleep. Further studies are needed toprove the efficacy of ramelteon for jet lag.

Several other pharmacologic agents,including caffeine and hypnotic medica-tions, have been explored as options toalleviate jet-lag symptoms. Short-actinghypnotic medications can be used totreat insomnia associated with jet lag.9

Several studies demonstrated beneficialeffects of caffeine on fatigue and thereduced alertness associated with jet lag.In a randomized placebo-controlledstudy of modafinil, improved alertnessand other jet-lag symptoms wereachieved after administration of 150 mgof modafinil.37 Based on the AASMpractice parameters, timed melatoninadministration is recommended as treat-ment for jet-lag disorder. Additionaltreatment options include maintain-ing home-based sleep hours for brief

KEY POINT

h Nonpharmacologictreatment approaches areimportant in themanagement of jet-lagdisorder. Strategicexposure and avoidanceof exposure to light havebeen utilized as aneffective treatmentapproach.



travel, short-term hypnotic use forinsomnia, and caffeine to alleviate day-time sleepiness.

Shift Work DisorderShift work disorder (SWD) is character-ized by a history of chronic (at least 1month) excessive sleepiness during therequired wake (work) time and/orinsomnia symptoms during the associ-ated required or desired sleep periodthat occurs in relation to unconventionalwork schedules.

Epidemiology. Almost 20% of theworkforce in the developed world isengaged in shift work. The prevalenceof SWD is approximately 1% in the gen-eral population and up to 10% amongnight and rotating shift workers. In thegeneral population, men are slightly athigher risk than women for SWD.38 Incertain populations, such as nurses, theprevalence of SWD can reach about40%.38

Pathophysiology. The primary etiol-ogy of SWD is the opposition ofrequired sleep and wake times to theirendogenous circadian rhythm of sleepand wake propensity. This often resultsin shortened sleep duration by 1 to 4hours. In addition, trying to stay awakeduring the night, when the circadianalertness signal is low, leads to excessivesleepiness during the work hours.21

The overnight shift is usually associatedwith the most severe symptoms, butpatients may report symptoms of SWDwith any shift that requires one to beawake at an adverse circadian time.Tolerance to the effects of shift workmay vary with age, chronotype, comor-bid sleep disorders, social situation, anddistance of commute between homeand work.21

Clinical presentation and diagno-sis. The diagnosis is made by carefulhistory of symptoms and work sched-ule. A minimum of 2 weeks of sleeplogs with or without actigraphy can

help not only by showing total sleepduration but also by demonstratingcircadian-sleep misalignment.21 Onnonworking days, individuals withSWD tend to revert back to moretraditional daytime activities and nightsleep schedules, contributing furtherto the circadian misalignment. Nightshift workers and rotating shift work-ers get less sleep than day workers orevening shift workers. Night shiftworkers generally have no difficultyfalling asleep but complain primarilyof difficulty maintaining sleep duringthe late morning or afternoon. Exces-sive sleepiness is most marked duringthe last half of the work hours andwhile commuting to home at the endof the shift. Other symptoms of SWDinclude chronic fatigue, malaise, mooddisorder, and nonspecific complaints,such as dyspepsia and decreasedlibido.29 Risk of alcohol and substanceabuse is increased, as is the risk ofweight gain, hypertension, and cardio-vascular disease, and some studies sug-gest an association with breast andendometrial cancer.39 In addition tothe medical comorbidities, SWD is ac-companied by significant social and eco-nomic burdens in the form of accidents,lost days of work, poorer performance,and increased health care use.39

Treatment. The primary aim of treat-ment is to improve alertness during therequired wake time and sleep qualityduring the scheduled sleep time. Allpatients with SWD should be counseledregarding conservative nonpharmaco-logic measures. These include opti-mizing the sleep environment (eg,darkened room, comfortable temper-ature, noise reduction), adherence togood sleep habits (eg, maintain a regularsleep and wake schedule, avoid exces-sive caffeine), patient and family educa-tion, and scheduled naps when possible.

Appropriately timed light therapy hasbeen shown to accelerate circadian

KEY POINTS

h Based on the AmericanAcademy of SleepMedicine practiceparameters, timedmelatoninadministration isrecommended astreatment for jet-lagdisorder.

h Night shift workers androtating shift workersget less sleep than dayworkers or evening shiftworkers.

h Shift work disorder isaccompanied bysignificant social andeconomic burdens in theform of accidents, lostdays of work, poorerperformance, andincreased health care use.




adaptation to night shift work. For nightshift workers, bright light exposure rang-ing from 1000 lux to 10,000 lux either in

3- or 6-hour blocks or in 20-minute or1-hour blocks (ending 2 hours beforethe end of the shift) has been shown to

Case 7-2A 26-year-old female securityguard reported chronicfatigue and difficultykeeping up with her duties.She had started her job4 months ago and worked8- to 9-hour night shifts for4 to 5 consecutive days (from11:00 PM or midnight to7:00 AM). On days off sheusually went to bed whenher husband did at midnightand slept until late morning.She reported difficultystaying asleep during theday when off duty, andsleepiness and decreasedconcentration during hershift at night. She describedmalaise, anxiety, anddecreased libido. Whenworking, she consumedlarge amounts of caffeineand sugar to help her stayawake. Her sleep-wake diarybefore and after treatment isshown in Figure 7-6.

Comment. As shown inFigure 7-6, after appropriatetreatment the patientis sleeping in the ‘‘compromisedcircadian position’’ withsleep and wake timesthat allow time for somesocial activities during herdays off, yet the change insleep-wake times betweendays off and days on duty isnot dramatically different.This sleep-wake scheduleallows for more sleepconsolidation and longersleep duration throughoutthe week.

FIGURE 7-6 Sleep-wake diary of a patient with shift work disorder. A, Patient’s sleepdiary for 1 week before treatment. B, Patient’s sleep diary for 1 weekafter 1 month of treatment with a combination of intermittent naps

when possible before the shift, bright light exposure (yellow) during the shift, andavoidance of light on the morning commute (sunglasses) together with maintaining adark and quiet bedroom. In addition, 3 mg of melatonin (purple pill) was started toimprove 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 wasinstructed to maintain a compromised sleep and wake schedule so that she would havetime with her husband and friends, but not completely revert to a daytime schedule.



accelerate circadian adaptation to nightwork and improve both alertness andperformance (Case 7-2).40 Complemen-tary to light exposure during work, it isimportant to avoid bright light expo-sure during the morning commute byusing appropriate eyewear.17

Data on the use of melatonin, atvarious doses, have produced conflict-ing results. However, melatonin whentaken at bedtime does appear tomodestly improve daytime sleep, butwithout any significant impact onnighttime alertness or performance.All other pharmacologic modalities failto address the circadian misalignmentbut can be used for improving alert-ness during work hours or sleepduring the scheduled sleep time.Therefore, pharmacologic agentsshould be used in combination withlight and behavioral modalities. Hyp-notics are not specifically indicated forSWD but may be prescribed for thetreatment of insomnia that is oftenseen in these patients. Caffeine com-bined with timed naps improves per-formance and alertness during thenight shift.41 The wake-promotingagents modafinil (200 mg) and armo-dafinil (150 mg) have been shown toimprove performance and alertnesswhen taken at the beginning of thenight shift.17 Both modafinil and armo-dafinil are approved by the FDA for thetreatment of excessive sleepiness as-sociated with SWD. The AASM practiceparameters recommend planned nap-ping before and/or during thework shift,timed light exposure, and stimulantssuch as caffeine or modafinil during thenight shift to improve alertness.17

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Circadian Rhythm Abnormalities - L.S. Neurologylsneuro.org/files/c/mouvementdisorders/Circadian Rhythm... · Circadian Rhythm Abnormalities Phyllis C. Zee, MD, PhD; Hrayr Attarian,

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