Circadian Rhythm Sleep Disorders Herbert Yue, MD Stanford

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Circadian Rhythm Sleep Disorders

• Herbert Yue, MD
• Stanford Sleep Medicine Center

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Introduction

• Two modular processes that govern sleep and
  wakefulness
• Referred to as two process model of sleep wake
  regulation
• Homeostatic drive for sleep
• Intrinsic circadian rhythm
• For each hour of wakefulness, homeostatic drive
  for sleep increases
• Typically after 14-16 hours, sufficient
  homeostatic sleep drive is obtain

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Introduction

• Circadian rhythm important regulator of
  wakefulness
• Allows synchronization of physiologic process to
  desired sleep wake cycle
• Exerts active promotion of wakefulness

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Introduction
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Circadian Rhythm Biology

• Circadian rhythms generated from superchiasmatic
  nucleus (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

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Circadian Rhythm Biology

• Photoreceptors in retina important signal
  collectors
• Receptors discovered in cells of retina
• Important for entrainment
• Contain photopigment melanopsin
• Most sensitive to blue wavelength of light

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Circadian Rhythm Biology
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Circadian Phase Markers

• Active investigation into markers of circadian
  phase in humans
• ?Clinical utility of markers
• Two currently utilized markers
• Core body temperature
• Dim light melatonin measurement (DLMO)

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Core Body temperature

• Drop in temp associated with stability in sleep
• Three dips in temp
• 800pm-1200am
• 300-500am
• 100-400pm

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Melatonin Secretion

• Increase in levels around 800pm
• Levels peak at approximately 300am and begin to
  decrease
• Lowest levels just before awakening

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Circadian Phase Markers

• Measurement of markers difficult
• Core body temperature altered by activity, food
  intake, and sleep
• Melatonin secretion very sensitive to light
  exposure, needs to be obtained under dim light
  conditions
• Dim light melatonin onset (DLMO)

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Circadian Rhythm

• Disruptions in the circadian rhythm physiology
  consequently can cause a number of circadian
  rhythm sleep disorders
• Disorders can be secondary to external inference
  with sleep wake mechanism
• Remainder of disorders are related to inherent
  disruption of the circadian rhythm

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Classification

• Six distinct circadian rhythm disorders
  recognized 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

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Classification

• Diagnostic criteria require impairment
• Social, occupational, etc
• Phase tolerance may exist i.e. sleep not
  disrupted by sleep alignment
• Diagnosis also must not be better explained by
  other sleep disorder
• Unconventional sleep cycle ? CRSD
• Persistent insomnia no matter timing of sleep
• Congruence of sleep timing and circadian rhythm

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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

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Prevalence

• Exact prevalence not known, although high numbers
  if shift workers/travelers considered
• One formal study using diagnostic criteria with
  epidemiologic sample looked at SWD
• 30 of night workers and 26 of rotating workers
  met minimal criteria for SWD
• Little data for other CRSDs

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Common Themes

• All dxs require 2 week actigraphy/sleep diary
• Goal is to create congruence
• Treatment
• Light in AM backward shift and vice versa
• Melatonin works in opposite manner from light
• Light, exercise in periods of activity

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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 gt 1 month

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Shift Work Disorder (SWD)
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Shift Work Disorder (SWD)
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Shift Work Disorder (SWD)
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Shift Work Disorder (SWD)

• Rotating shift workers show increased rates of
  impairment
• gt30 of rotating shift workers with reported
  sleep latencies of greater than 30 minutes
  compared to 10 of night and day shift workers
• Increased rates of absenteeism, accidents at work
  and poor job satisfaction

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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

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Shift Work Disorder (SWD)

• Non-pharmacologic treatment
• Sleep hygiene
• Scheduled naps
• Assessment of work schedule
• Exercise
• Light exposure

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Shift Work Disorder (SWD)

• Pharmacologic treatments include
  modafinil/stimulants
• Only modafinil or armodafinil currently FDA
  approved as tx for SWD
• Improvements in self reported sleepiness,
  objective sleep latencies, and accident rates
• Other stimulants, such as amphetamines not
  indicated
• Rebound insomnia

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Delayed Sleep Phase Disorder (DSPD)

• Characterized as bedtimes that are 3-6 hours
  later than conventional times
• Typically problems sleeping before 200am and
  waking up earlier than 1000am
• Subjective sleepiness worst in the mornings, with
  highest levels of alertness during the late
  evening

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Delayed Sleep Phase Disorder (DSPD)

• Difficulty with sleep onset at desired time, but
  sleep once initiated is normal
• Most common CRSD referral, although population
  data lacking
• Population estimates of prevalence of 0.17
• Prevalence increases to gt15 amongst adolescents
• Positive family history

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Delayed Sleep Phase Disorder (DSPD)
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Delayed Sleep Phase Disorder (DSPD)

• Most patients present for treatment as they are
  unable to conform to societal bed/wake times
• Treatment primarily light exposure and melatonin
  administration

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Delayed Sleep Phase Disorder (DSPD)

• Bright light therapy generally given in the early
  morning for 1-2 hours
• Induces phase shift backwards
• Typically takes upwards of 2 weeks to see effects
• Compliance often limited

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Melatonin Secretion
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Delayed Sleep Phase Disorder (DSPD)

• Melatonin may also be given, typically 5-7 hours
  before the DLMO
• DLMO typically occurs 2-3 hours before sleep
  onset in healthy individuals
• Effects of melatonin may not be long lived
• Some studies show reversion to DSPD after
  medication stopped

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Advanced Sleep Phase Disorder (ASPD)

• Habitual and undesired sleep/wake up times
  several hours earlier than desired
• Sleep onset 600-900pm and wake up times
  200-500am
• Symptoms of early morning awakenings, sleep
  maintenance problems, or excessive daytime
  sleepiness

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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

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Advanced Sleep Phase Disorder (ASPD)

• Treatment typically light exposure in early
  evening
• Usually in the hours of 700-900pm
• Delays DLMO
• Compliance limited in the few studies performed
• No current role for hypnotics or stimulants

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Melatonin Secretion
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Jet Lag Disorder (JLD)

• Defined as disruption in sleep after travel
  across 2-3 time zones
• Typically benign and self limited, although can
  be distressing to patients productivity
• Circadian rhythm resets
• Approx 90 minutes later for westward flights
• 60 minutes earlier for eastward flights
• Treatment typically involves
• Light administration
• Melatonin administration

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Jet Lag Disorder (JLD)

• Treatment with light or melatonin usually
  involves corresponding exposure
• Light exposure
• Maximize exposure in the morning for westward
  flights, exposure in evening for eastward flight
• Melatonin admin
• Most studies evaluated 5mg dose at bedtime,
  typically for eastward travel

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Melatonin Secretion
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Jet Lag Disorder (JLD)

• Hypnotics
• 3-4 day course of Ambien associated with improved
  sleep quality
• Short acting hypnotic such as Sonata may be
  helpful for an overnight flight
• Armodafanil
• Recent data showing improved subjective alertness
  and reduced jet lag sx
• Current pending application as FDA approved
  treatment for JLD

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Free Running Disorder (FRD)

• Characterized as gradual drift of major sleep
  period by 1-2 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 with conventional sleep/wake times
• Majority of cases in the blind
• Lack of photic entrainment
• Estimated 50 have free running disorder, 70
  with chronic sleep disturbances
• Cases described for non-blind, usually after head
  trauma

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Free Running Disorder (FRD)
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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)

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Irregular Sleep Wake Disorder (ISWD)

• Characterized as absence of clear circadian
  rhythm
• Although total amount of sleep normal, sleep
  periods scattered throughout the day
• Napping prevalent, with sleep episodes gt 3 per
  day
• Rare condition
• Likely secondary to primary disturbance of
  circadian rhythm
• Lack of external time cues, such as light and
  activity
• Seen most commonly in dementia, developmentally
  disabled children, and with severe brain trauma

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Irregular Sleep Wake Disorder (ISWD)
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Irregular Sleep Wake Disorder (ISWD)

• Treatment primarily restoring external time cues
• Scheduled social and physical activities
• Timed bright light
• Some role for hypnotics to improve sleep

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Conclusion

• CRSD occur secondary to incongruence of sleep
  time and circadian rhythm or intrinsic disruption
  in circadian rhythm
• Light and melatonin are useful adjuncts in tx
• Zeitgebers are critically important
• Growing literature demonstrating genetic basis
  for these conditions

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