Transcript The Differential Diagnosis and Treatment of Excessive

Differential Diagnosis and
Treatment of Excessive
Daytime Sleepiness
1
What is EDS?
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Excessive daytime sleepiness
 The tendency to fall asleep during normal
waking hours1
Contrast with “fatigue”
 A desire to rest due to feelings of
exhaustion1
 Symptom of underlying disorder
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.
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EDS – a common complaint
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Almost ½ of all Americans report a sleeprelated problem1
EDS is the primary complaint of 1 in 8 people
seen in sleep clinics2
More than 1 in 4 patients complain of EDS in
the primary care setting3
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Roth T & Roehrs
TA; Clin Ther.,1996; 3. Kushida CA, et al. Sleep Breath; 2000.
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EDS characteristics
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Number of daily
episodes vary
Occurs during passive
activities
 TV watching, sitting
on a plane
Occurs during more
active tasks
 Driving, eating,
speaking
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Bassetti C
& Aldrich MS. Neuro Clin;1996.
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The Consequences of EDS
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Consequences to Self
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 Productivity1,2
 Motivation2
 Interpersonal relationship problems2
 Depression + anxiety1, 3
 Insomnia1
 Quality of life1,2
1. Hasler G, et al. J Clin Psychiatry; 2005; 2. Daniels E, et al. J Sleep Res; 2001;
3. Theorell-Haglow J, et al. Sleep; 2006.
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Consequences to Health
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Sleepiness vs. blood pressure1
  EDS symptoms =
  Sleep BP
  Daytime systolic/diastolic variability
  Anger, depression, anxiety
 More likely to get a diagnosis of
hypertension
1. Goldstein IB, et al. Am J Hypertens; 2004.
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Consequences to Health
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Sleepiness vs. CVD in older adults1
  EDS symptoms =
  CVD mortality
• 200% in men; 40% in women
  CVD morbidity
• 35% more MI and CHF in men; 66%
more in women
1. Newman AB, et al. J Am Geriatr Soc; 2000.
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Consequences to Society
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Crashes when driver falls asleep1
 100,000 each year in U. S.
 1,500 deaths
 Death rate may exceed alcohol-related
crashes
~1/2 of all work-related accidents2
1 in 5 public accidents due to falls2
1. Mahowald MW. Postgrad Med; 2000; 2. Leger D. Sleep; 1994.
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Drivers beware: sleepiness
vs. drunkenness
Study compared effects on performance of
sleep deprivation and alcohol1
 Drivers who went 17-19 hours without
sleep = drivers with 0.05% BAC
 Sleepy drivers responded ~50% more
slowly/less accuracy than fully awake
drivers
 Sleepiness can compromise performance
needed for road and job safety
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1. Williamson AM & Feyer AM. Occup Environ Med; 2000.
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Patient assessment
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Is sleep the new vital sign?
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Growing evidence shows that sleep is an
important ingredient in good health1
Few MDs address sleep quality in their
practices
 <10% of patient charts document sleep
history2
Sleep disorders are underdiagnosed,
undertreated
1. Wilson JF. Am Coll Physicians; 2005; 2. Namen AM, et al. South Med J; 2001.
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Pathophysiology
of EDS
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EDS is not a disorder – but a symptom1
Causes2:
 CNS abnormalities, e. g. narcolepsy
 Sleep deficiency, e. g. sleep apnea
 Circadian imbalances, e. g. jet lag
 Drug side effects, e. g. marijuana
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Roth T & Roehrs
TA. Clin Ther; 1996.
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How does the patient report
symptoms?
 I’m tired
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I feel lazy
I have low energy
I feel drowsy
I feel sleepy
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Assess for other psychiatric
comorbidities
 Symptoms of depression?
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Mood or memory problems?
Does patient fall asleep suddenly?
Is the patient a “night owl”?
Does the patient drink or take drugs?
How many hours sleep per night, including
weekends and weekdays?
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Epworth Sleepiness
Scale
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A quick, in-office test1
Assesses whether a person will get sleepy in
certain situations
Use this scale for each situation:
 0 = would never doze or sleep
 1 = slight chance of dozing or sleeping
 2 = moderate chance of dozing or sleeping
 3 = high chance of dozing or sleeping
1. Johns MW. Sleep; 1991.
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Epworth Sleepiness
Scale
Sitting and reading
Watching TV
Sitting in a public place
Riding in a car as a passenger for ≥1 hour
Lying down in the afternoon
Sitting and talking to someone
Sitting quietly after lunch (no alcohol)
Stopped for a few minutes in traffic
while driving
0
1
1
2
2
0
1
0
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1. Johns MW. Sleep; 1991.
Rule out other medical
conditions1
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Stroke
Tumors/cysts
Vascular malformations
Head trauma
CNS infections (sleeping sickness)
Parkinsonism
Alzheimer's, other dementias
1. Black JE, et al. Neurol Clin; 2005.
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Differential Diagnosis
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Most frequent causes of
EDS
Insufficient sleep syndrome
 Obstructive sleep apnea
 Substance/medication use
 Shift-work sleep disorder
 Delayed sleep-phase syndrome
 Narcolepsy
 Periodic limb movement disorders
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Insufficient sleep
syndrome
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Have patient keep a sleep log1
 Bedtimes
 Number/time of awakenings
 Arising times
 Frequency/duration of naps
 Bedtime events (food, alcohol, physical
activity)
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.
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Falling asleep vs.
staying asleep
Difficulty falling asleep1
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Suggests delayed sleep phase syndrome
Chronic psychophysiologic insomnia
Inadequate sleep hygiene
Restless legs syndrome
Difficulty staying asleep
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Suggests advanced sleep phase syndrome
Major depression
Sleep apnea
Limb movement disorder
Aging
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.
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Most frequent causes of
EDS
Insufficient sleep syndrome
 Obstructive sleep apnea
 Substance/medication use
 Shift-work sleep disorder
 Delayed sleep-phase syndrome
 Narcolepsy
 Periodic limb movement disorders
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Obstructive sleep
apnea
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Absence of breathing during sleep
Obstruction of airways  snoring, decrease
in oxygen saturation of hemoglobin, arousal1
Result is disturbed sleep and EDS
Most common diagnosis of patients with
complaint of EDS who seek care at US sleep
centers2
 Almost 7 out of 10 patients
1. Victor LD. Am Fam Physician; 1999; 2. Punjabi NM, et al. Sleep; 2000.
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Obstructive sleep
apnea
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Associated with:
 Not only CVD and obesity, but also:
1
 Metabolic syndrome
Untreated OSA  Direct/deleterious effects
on CV function and structure3
 Sympathetic activation
 Oxidative stress
 Inflammation
 Endothelial dysfunction
1. Vgontzas AN, et al. Sleep Med Rev; 2005; 2. Shamsuzzaman AS, et al. JAMA;
2003; 3. Narkiewicz K, et al. Curr Cardiol Rep; 2005.
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Obstructive sleep
apnea
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 Systolic BP and heart rate1
 CRP concentrations1
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May contribute to ischemia, CHF, arrhythmia,
cerebrovascular disease, stroke
 Atrial fibrillation can predict OSA2
 49% vs. 32% who do not have OSA
1 in 15 has moderate to severe OSA3
 1 in 5 has mild OSA
1. Meier-Ewert HK, et al. J Am Coll Cardiol; 2004; 2. Gami AS, et al. Circulation;
2004; 3. Shamsuzzaman AD, et al. JAMA; 2003.
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Physical exam
for OSA
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Check for: 1
 Obesity, especially at midriff & neck
 Jaw and tongue abnormalities
 Nasal obstruction; enlarged tonsils
 Expiratory wheezing
 Spinal curvature
 Note signs of R ventricular failure
 Edema, abdominal distention
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.
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Most frequent causes of
EDS
Insufficient sleep syndrome
 Obstructive sleep apnea
 Substance/medication use
 Shift-work sleep disorder
 Delayed sleep-phase syndrome
 Narcolepsy
 Periodic limb movement disorders
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Substance/medication use
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EDS can be a sign of drug-dependent and
drug-induced sleep disorders1
 Chronic use of stimulants
 Hypnotics, sedatives
 Antimetabolite therapy
 OCs; thyroid medications
 Withdrawal from CNS depressants
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.
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Substance/medication use
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Review the patient’s Rx drug use
 Check for interactions,high doses
Inquire about OTC medications
 Diphenhydramine, anticholinergics
Take alcohol history
 Interaction with Rx or OTCs?
Ask about recreational drug use
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.
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Most frequent causes of
EDS
Insufficient sleep syndrome
 Obstructive sleep apnea
 Substance/medication use
 Shift-work sleep disorder
 Delayed sleep-phase syndrome
 Narcolepsy
 Periodic limb movement disorders
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Shift-work disorder
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Circadian rhythm sleep disorder1
 Internal/environmental sleep-wake
cadence out of synch
Insomnia, EDS, or both1
~10% of the night and rotating shift work
population2
 4-fold  in sleepiness-related accidents,
absenteeism, depression2
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Drake CL,
et al. Sleep; 2004.
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Shift-work disorder
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Resolves as body clock realigns1
Fixed-shift work is preferable
 Full-time night or evening
Rotating shifts should go clockwise
 Day  Evening  Night
Helpful: Bright light, masks, white noise
Short t1/2 hypnotics, wake-promoting drugs
used judiciously
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.
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Most frequent causes of
EDS
Insufficient sleep syndrome
 Obstructive sleep apnea
 Substance/medication use
 Shift-work sleep disorder
 Delayed sleep-phase syndrome
 Narcolepsy
 Periodic limb movement disorders
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Delayed-sleep phase
syndrome
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Sleep cycle out of synch with desired wake
times1
Problem: Going to sleep and awakening late
(3AM and 10AM)
If earlier wake times are necessary, then EDS
can result
 Poor performance in work/school
Improved sleep hygiene is key
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.
35
Most frequent causes of
EDS
Insufficient sleep syndrome
 Obstructive sleep apnea
 Substance/medication use
 Shift-work sleep disorder
 Delayed sleep-phase syndrome
 Narcolepsy
 Periodic limb movement disorders
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Narcolepsy
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Pathologic sleepiness, sudden loss of muscle
tone (cataplexy), fragmented sleep, sleep
paralysis1
Affects 1 out of 2,000 people2
 140,000 Americans2
Delay of 10 yr from onset to diagnosis is
common1
The cause is unknown
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Ohayon MM, et al. Neurology; 2002.
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Narcolepsy Pathophysiology
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Cause? –  hypocretin-secreting neurons1,2
 Regulate arousal state in hypothalamus
Marker – REM sleep during ≥2 daytime naps3
Dysfunctional switching to REM sleep 
wakefulness during sleep3
 Patients are mentally awake but physically
in REM sleep – sleep paralysis syndrome.
1. Thannickal TC, et al. Neuron; 2000; 2. Sutcliffe JG & de Lecea. Nat Rev Neurosci; 2002; 3. Scammell
T. Ann Neurol; 2003.
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Narcolepsy Pathophysiology
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Genetic predisposition1
 Familial clustering
 10- to 40-fold  vs. general population
Hallmark symptom – cataplexy
2
 Bilateral weakness
 Prevalence ~ 75%2
1. Nishino S, et al. Sleep Med Rev; 2000; 2. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.
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Narcolepsy –
Diagnosis
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Diagnostic for narcolepsy1
 History of cataplexy
 Nocturnal polysomnography
 MSLT
Differential diagnosis1
 Lesions of brain stem, hypothalamus
 Encephalitis, metabolic disorders
Urine and blood exams can confirm nonnarcoleptic EDS1
1.Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.
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Most frequent causes of
EDS
Insufficient sleep syndrome
 Obstructive sleep apnea
 Substance/medication use
 Shift-work sleep disorder
 Delayed sleep-phase syndrome
 Narcolepsy
 Periodic limb movement disorders
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Periodic limb
movement disorders
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Abnormal twitching/kicking of legs during
sleep1
 Interferes with nocturnal sleep  EDS
 ~10% of adults2
 Restless legs syndrome
 More common in middle/later years
 Creeping/crawling sensations
Abnormalities in dopamine transmission2
1.Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Hornyak M, et al. Sleep Med Rev; 2006.
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Periodic limb
movement disorders
Often occurs in narcolepsy and OSA1
 Seen in pregnancy, renal/hepatic failure,
anemia and other disorders
 Sleep history/partner’s testimony
 Test: Iron, anemia, kidney/liver function
 Dopamine agonists can be helpful
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1.Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Hornyak M, et al. Sleep Med Rev; 2006.
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When to refer?
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Know when to treat
and when to refer
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Can condition be treated via sleep hygiene?
 Insufficient sleep syndrome
 Substance/medication use
 Delayed sleep-phase syndrome
 Shift-work sleep disorder
Counsel on sleep architecture
Do blood work, RFTs/LFTs
Prescribe sedatives prudently
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Know when to treat
and when to refer
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Refer when diagnosis appears to be:
 Obstructive sleep apnea
 Pulmonologist, sleep clinic, surgeon
 Narcolepsy
 Neurologist, sleep clinic
 Periodic limb movement disorders
 Internist, endocrinologist, sleep clinic
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The sleep clinic
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Sleep studies evaluate EDS as well as OSA,
narcolepsy, periodic limb movement disorders
Polysomnography1
 Data accumulated from patient as s/he
sleeps
 Quantifies sleep adequacy
 Determines what causes EDS
1. AARC-APT. Respir Care; 1995.
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The sleep clinic Polysomnography
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Measures1:
 EEG
 Eye movements
 Heart rate
 O2 saturation
 Muscle tone & activity
All-night test
1. AARC-APT. Respir Care; 1995; 2. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.
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The sleep clinic –
MSLT
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Multiple Sleep Latency Test
 Complimentary test for narcolepsy1
 Assesses speed of sleep onset
 REM sleep is monitored
 All-day test: 8-10 hours
 High ESS scores ~ Low MSLT scores2
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Chervin RD, et al. J Psychosom
Res; 1997.
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Treatment
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Non-pharmacologic
treatment
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Rationale – To improve natural sleep
Counsel patients on good sleep hygiene1
 Regular sleep schedule
 Restrict time in bed
 Sleep-conductive environment
 Exercise
 Avoid stimulants
 Incorporate relaxation techniques
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006
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Pharmacotherapy –
Hypnotics
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Rationale – To treat insomnia
Sleep-onset insomnia
 Use drugs with shorter t1/2
 Zalepon, zolpidem, triazolam
Sleep-maintenance insomnia
 Use drugs with longer t1/2
 Temazepam, eszopiclone
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006
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Pharmacotherapy –
Hypnotics
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Use with caution in elderly, pulmonary
insufficiency
To  tolerance, use lower doses for brief
periods; taper off slowly
In patients who continue to have EDS, stop or
switch the drug
Monitor for amnesia, hallucinations,
incoordination, falls
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006
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Pharmacotherapy –
Stimulants
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Rationale – To improve alertness
Methylphenidate, amphetamines
Indirect-acting sympathomimetics1
 Produce behavioral activation and
increased arousal, motor activity, alertness
Used mostly for EDS; ineffective for
cataplexy1, 2
Immediate- or extended-release forms1
1. Mitler MM & Hayduk R. Drug Saf; 2002; 2. Littner M, et al. Sleep; 2001.
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Pharmacotherapy –
Stimulants
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MPH and the amphetamines are Schedule II
 Carry the risk of substance abuse/illicit use
Rebound hypersomnia or tolerance to alerting
agent can occur1
 Switch to a different drug class or provide
drug holiday
1. Black JE, et al. Neuro Clin; 2005.
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Pharmacotherapy –
Modafanil
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Rationale – To promote wakefulness
Approved for narcolepsy-associated EDS
Ill-defined MOA (not a stimulant)1
 Activates hypocretin-secreting neurons1,2
1
 Does not control cataplexy
Long-acting – once-daily dosing
3
 Peak plasma concentrations – 2-4 hr
4
 Small afternoon booster dose can be used
1. US Modafinil. Ann Neurol; 1998; 2. Willie JT, et al. Neuroscience; 2005; 3. Provigil PI; 2004; 4. Beers
MH, et al. Merck Manual of Diagnosis and Therapy; 2006.
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Pharmacotherapy –
Modafanil isomer
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Isomer formulation – r-modafanil or
armodafanil – also being evaluated
Once daily for EDS2
 r-isomer T1/2 = 10-14 hr vs. 3-4 hr for sisomer
 Higher peak concentrations vs. racemic
mixture
No efficacy/safety advantage over modafainil2
1. Harsh JR, et al. Curr Med Res Opin; 2006; 2. Dinges DF, et al. Curr Med Res Opin; 2006.
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Pharmacotherapy –
Sodium oxybate
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Rationale – To treat EDS, narcolepsy
FDA-approved for treatment of EDS and
cataplexy in narcolepsy1
MOA largely unknown2
Rapidly acting hypnotic (Tmax 0.5-1.25 hr)2
Short t½ (0.5-1 hr)2
 duration of stages 3, 4 sleep
 First REM sleep , then with continued
use, REM sleep 
1. FDA. FDA Talk Paper; 2002; 2006; 2. Xyrem PI; 2005.
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Pharmacotherapy –
Sodium oxybate
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Studies show efficacy in  cataplexy and
EDS1, 2, 3
  cataplexy attacks, ESS scores
Can be used with modafinil4
  nightly awakenings
Dosing: twice nightly
 Taken HS, then at 2.5-4 hrs after the sleep
begins
1. Xyrem. Sleep Med. 2005; 2. Xyrem. Sleep; 2003; 3. Xyrem. Sleep; 2002; 4. Xyrem. Sleep Med; 2004;
5. Bogan RK. Sleep. 2005; 6. Xyrem PI, 2005.
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Pharmacotherapy –
Sodium oxybate
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Potential drug of abuse (CIII)1
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Enforced as Schedule I
Special distribution requirements2
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Use of a central pharmacy
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Registration of prescribing MD
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Pharmacy verification of MD’s eligibility
to prescribe
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Registration/required reading of
materials by patient
1. FDA. FDA Talk Paper; 2002; 2006; 2. Xyrem PI; 2005.
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Continuous positive
airway pressure
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Rationale – To correct OSA
Reverses EEG slowing for both REM sleep
and wakefulness1
Improves symptoms of EDS1

 MSLT scores
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Persistent EDS 2° to obesity
Used at home but pressure is set in sleep
clinic first
1. Morisson F, et al. Chest; 2001.
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Surgery
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Rationale – To correct anatomical flaws
UPPP is the most common procedure
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Enlarges airways
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Submucosal tissue resection from
tonsillar pillars; adenoid resection
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Not suitable for obese patients
Trachestomy – last resort
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May take ≥1 year to heal
1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006
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Conclusions
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EDS  quality of life; can cause serious
consequences
EDS may be a sign of sleep apnea,
narcolepsy or a symptom of another condition
Patients who complain of EDS should be
assessed in a step-wise manner to rule out
the various conditions that can cause it
Know when to treat and when to refer
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