7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
1/48
Circadian Rhythm Sleep
Disorders
Herbert Yue, MD
Stanford Sleep Medicine Center
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
2/48
Introduction
Two modular processes that govern sleep andwakefulness
Referred to as two process model of sleepwake regulation Homeostatic drive for sleep
Intrinsic circadian rhythm
For each hour of wakefulness, homeostatic drivefor sleep increases Typically after 14-16 hours, sufficient homeostatic
sleep drive is obtain
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
3/48
Introduction
Circadian rhythm important regulator ofwakefulness
Allows synchronization of physiologic processto desired sleep wake cycle
Exerts active promotion of wakefulness
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
4/48
Introduction
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
5/48
Circadian Rhythm Biology
Circadian rhythms generated from superchiasmaticnucleus (SCN) of hypothalamus
Signals from SCN modulate daily rhythms in sleep and
alertness Core body temperature
Secretion of cortisol and melatonin
Intrinsic rhythm of clock slightly longer than 24 hours Synchronization occurs to 24hr schedule using external cues
Zeitgeibers: Temporal timing signals, light exposure
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
6/48
Circadian Rhythm Biology
Photoreceptors in retina important signalcollectors
Receptors discovered in cells of retina Important for entrainment
Contain photopigment melanopsin
Most sensitive to blue wavelength of light
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
7/48
Circadian Rhythm Biology
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
8/48
Circadian Phase Markers
Active investigation into markers ofcircadian phase in humans
?Clinical utility of markers Two currently utilized markers
Core body temperature
Dim light melatonin measurement (DLMO)
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
9/48
Core Body temperature
Drop in tempassociated with
stability in sleep Three dips in temp 8:00pm-12:00am
3:00-5:00am
1:00-4:00pm
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
10/48
Melatonin Secretion
Increase in levelsaround 8:00pm
Levels peak atapproximately3:00am and beginto decrease
Lowest levels justbefore awakening
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
11/48
Circadian Phase Markers
Measurement of markers difficult Core body temperature altered by activity, food
intake, and sleep
Melatonin secretion very sensitive to lightexposure, needs to be obtained under dim lightconditions Dim light melatonin onset (DLMO)
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
12/48
Circadian Rhythm
Disruptions in the circadian rhythmphysiology consequently can cause a
number of circadian rhythm sleepdisorders
Disorders can be secondary to externalinference with sleep wake mechanism
Remainder of disorders are related toinherent disruption of the circadian rhythm
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
13/48
Classification
Six distinct circadian rhythm disordersrecognized by the International
Classification of Sleep Disorders (ICSD-2) Essential feature: Persistent/recurrent
pattern of sleep disturbance
Alterations in circadian timekeeping system Misalignment between internal circadian
timing and exogenous influences
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
14/48
Classification
Diagnostic criteria require impairment Social, occupational, etc
Phase tolerance may exist; i.e. sleep not disrupted bysleep alignment
Diagnosis also must not be better explained byother sleep disorder
Unconventional sleep cycle CRSD Persistent insomnia no matter timing of sleep
Congruence of sleep timing and circadian rhythm
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
15/48
Classification
Six distinct CRSDs Delayed sleep phase disorder
Advanced sleep phase disorder Jet lag type
Shift work type
Irregular sleep wake cycle disorder
Free running type
ICSD also recognizes CRSD NOS Secondary to medical condition, etc
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
16/48
Prevalence
Exact prevalence not known, althoughhigh numbers if shift workers/travelers
considered One formal study using diagnostic criteriawith epidemiologic sample; looked at SWD 30% of night workers and 26% of rotating
workers met minimal criteria for SWD Little data for other CRSDs
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
17/48
Common Themes
All dxs require 2 week actigraphy/sleepdiary
Goal is to create congruence Treatment Light in AM = backward shift and vice versa
Melatonin works in opposite manner fromlight
Light, exercise in periods of activity
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
18/48
Shift Work Disorder (SWD)
Minimal criteria for diagnosis Work in shift work position, either night-shift
or rotating shift for the past 2 weeks Impairment in daytime functioning, typically
insomnia or excessive daytime sleepiness,present for > 1 month
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
19/48
Shift Work Disorder (SWD)
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
20/48
Shift Work Disorder (SWD)
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
21/48
Shift Work Disorder (SWD)
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
22/48
Shift Work Disorder (SWD)
Rotating shift workers show increasedrates of impairment
>30% of rotating shift workers with reportedsleep latencies of greater than 30 minutescompared to 10% of night and day shiftworkers
Increased rates of absenteeism, accidents atwork and poor job satisfaction
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
23/48
Shift Work Disorder (SWD)
Risk factors for SWD Increasing age; peak in sleep disturbances at
age 52 with decreases after age 62 Female gender; women with less sleep on
average then men and increase complaints
Intrinsic tolerance of individuals
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
24/48
Shift Work Disorder (SWD)
Non-pharmacologictreatment
Sleep hygiene
Scheduled naps
Assessment of workschedule
Exercise Light exposure
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
25/48
Shift Work Disorder (SWD)
Pharmacologic treatmentsinclude modafinil/stimulants
Only modafinil or armodafinilcurrently FDA approved as tx
for SWD Improvements in self reported
sleepiness, objective sleeplatencies, and accident rates
Other stimulants, such asamphetamines not indicated Rebound insomnia
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
26/48
Delayed Sleep Phase Disorder(DSPD)
Characterized as bedtimes that are 3-6 hours later thanconventional times Typically problems sleeping before 2:00am and waking up earlier
than 10:00am
Subjective sleepiness worst in the mornings, with highest
levels of alertness during the late evening
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
27/48
Delayed Sleep Phase Disorder(DSPD)
Difficulty with sleep onset at desired time, butsleep once initiated is normal
Most common CRSD referral, althoughpopulation data lacking Population estimates of prevalence of 0.17%
Prevalence increases to >15% amongst adolescents
Positive family history
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
28/48
Delayed Sleep Phase Disorder(DSPD)
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
29/48
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
30/48
Delayed Sleep Phase Disorder(DSPD)
Bright light therapygenerally given inthe early morning for
1-2 hours Induces phase shift
backwards
Typically takesupwards of 2 weeksto see effects Compliance often
limited
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
31/48
Melatonin Secretion
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
32/48
Delayed Sleep Phase Disorder(DSPD)
Melatonin may also begiven, typically 5-7hours before the DLMO
DLMO typically occurs 2-3
hours before sleep onsetin healthy individuals
Effects of melatonin maynot be long lived
Some studies showreversion to DSPD aftermedication stopped
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
33/48
Advanced Sleep Phase Disorder(ASPD)
Habitual and undesired sleep/wake up times severalhours earlier than desired Sleep onset 6:00-9:00pm and wake up times 2:00-5:00am
Symptoms of early morning awakenings, sleep
maintenance problems, or excessive daytime sleepiness
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
34/48
Advanced Sleep Phase Disorder(ASPD)
Associated with increasing age Non age associated cases rare
Prevalence approx 1% of middle aged adults Genetic markers identified, ?autosomal dominant
transmission
-Missense mutation in Period 2 gene
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
35/48
Advanced Sleep Phase Disorder(ASPD)
Treatment typically lightexposure in earlyevening
Usually in the hours of7:00-9:00pm
Delays DLMO
Compliance limited in thefew studies performed
No current role forhypnotics or stimulants
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
36/48
Melatonin Secretion
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
37/48
Jet Lag Disorder (JLD)
Defined as disruption in sleep after travel across2-3 time zones
Typically benign and self limited, although can
be distressing to patients productivity Circadian rhythm resetsApprox 90 minutes later for westward flights 60 minutes earlier for eastward flights
Treatment typically involves: Light administration Melatonin administration
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
38/48
Jet Lag Disorder (JLD)
Treatment with light or melatonin usuallyinvolves corresponding exposure
Light exposure: Maximize exposure in the morning for westwardflights, exposure in evening for eastward flight
Melatonin admin
Most studies evaluated 5mg dose at bedtime, typicallyfor eastward travel
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
39/48
Melatonin Secretion
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
40/48
Jet Lag Disorder (JLD)
Hypnotics 3-4 day course of Ambien associated with improved
sleep quality
Short acting hypnotic such as Sonata may be helpfulfor an overnight flight
Armodafanil Recent data showing improved subjective alertness
and reduced jet lag sx Current pending application as FDA approved
treatment for JLD
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
41/48
Free Running Disorder (FRD)
Characterized as gradual drift of major sleep period by1-2 hours daily
If scheduled sleep/wake times attempted, pts report
insomnia and excessive daytime sleepiness Sx occur when non-entrained circadian rhythm out of phase withconventional sleep/wake times
Majority of cases in the blind Lack of photic entrainment
Estimated 50% have free running disorder, 70% with chronicsleep disturbances
Cases described for non-blind, usually after head trauma
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
42/48
Free Running Disorder (FRD)
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
43/48
Free Running Disorder (FRD)
Treatment in sighted individuals Scheduled sleep and wake cycles
Timed bright light Melatonin admin
Treatment in blind individuals
Regular work/sleep schedule non photic cue Melatonin admin (1 hr before bedtime)
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
44/48
Irregular Sleep Wake Disorder(ISWD)
Characterized as absence of clear circadianrhythm
Although total amount of sleep normal, sleep
periods scattered throughout the day Napping prevalent, with sleep episodes > 3 per day Rare condition
Likely secondary to primary disturbance of circadianrhythm
Lack of external time cues, such as light and activity Seen most commonly in dementia, developmentally
disabled children, and with severe brain trauma
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
45/48
Irregular Sleep Wake Disorder(ISWD)
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
46/48
Irregular Sleep Wake Disorder(ISWD)
Treatment primarily restoring externaltime cues
Scheduled social and physical activities Timed bright light
Some role for hypnotics to improve sleep
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
47/48
Conclusion
CRSD occur secondary to incongruence ofsleep time and circadian rhythm orintrinsic disruption in circadian rhythm
Light and melatonin are useful adjuncts intx
Zeitgebers are critically important Growing literature demonstrating genetic
basis for these conditions
7/31/2019 Circadian Rhythm Sleep Disorders 04-'10 (1)
48/48
http://www.facebook.com/photo.php?pid=3671936&id=585720673