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1 Differential Diagnosis and Treatment of Excessive Daytime Sleepiness.

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1 1 Differential Diagnosis and Treatment of Excessive Daytime Sleepiness

2 2 What is EDS? Excessive daytime sleepiness Excessive daytime sleepiness  The tendency to fall asleep during normal waking hours 1 Contrast with “fatigue” Contrast with “fatigue”  A desire to rest due to feelings of exhaustion 1  Symptom of underlying disorder 1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

3 3 EDS – a common complaint Almost ½ of all Americans report a sleep- related problem 1 Almost ½ of all Americans report a sleep- related problem 1 EDS is the primary complaint of 1 in 8 people seen in sleep clinics 2 EDS is the primary complaint of 1 in 8 people seen in sleep clinics 2 More than 1 in 4 patients complain of EDS in the primary care setting 3 More than 1 in 4 patients complain of EDS in the primary care setting 3 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.

4 4 EDS characteristics Number of daily episodes vary Number of daily episodes vary Occurs during passive activities Occurs during passive activities  TV watching, sitting on a plane Occurs during more active tasks 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.

5 5 1) Zeman, A. et al. BMJ; 2004; 2) Beers MH, et al. Merck Manual of Diagnosis and Therapy; Normal sleep stages 1,2

6 6 Comparative EDS prevalence Level II insomnia – inability staying asleep + daytime dysfunction 1 33% EDS 2 31% Chronic back pain 3 26% Age-related nocturia 4 25% Level I insomnia – difficulty falling asleep 1 14% Migraine 5 12% 1) Hatoum HT, et al. Am J Manag Care; 1998; 2) Roth T & Roehrs TA. Clin Ther; 1996; 3) Hillman M, et al. J Epidemiol Community Health; 1996; 4) Fultz NH & Herzog, Urol Clin North Am; 1996; 5) Hagen K. Cephalgia; 2000.

7 7 Factors associated with EDS 1 Age (Compared to age 50-59)  83% in  48% higher in  9% higher in Marital status (Compared to marrieds)  69% in unmarrieds Sleep duration (Compared to ≥7 h sleep)  371% if <6 h sleep  55% if 6-7 h sleep Sleep-wake schedule (Compared to regular schedule)  78% in weekly irregular  270% in daily irregular 1) Doi Y, et al. J Occup Health; 2003

8 8 Factors associated with EDS 1 Difficult falling/staying asleep ≥1/wk (Compared to <1/wk)  47% Depression  404% Asthma  261% Peptic ulcer  203% Muscle-joint pain  59% 1) Doi Y, et al. J Occup Health; 2003

9 9 The Consequences of EDS

10 10 Consequences to Self  Productivity  Productivity 1,2  Motivation 2  Motivation 2  Interpersonal relationship problems 2  Interpersonal relationship problems 2  Depression + anxiety 1, 3  Depression + anxiety 1, 3  Insomnia 1  Insomnia 1  Quality of life 1,2  Quality of life 1,2 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.

11 11 Consequences to Health Sleepiness vs. blood pressure 1 Sleepiness vs. blood pressure 1   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.

12 12 Consequences to Health Sleepiness vs. CVD in older adults 1 Sleepiness vs. CVD in older adults 1   EDS symptoms =   CVD mortality 200% in men; 40% in women 200% in men; 40% in women   CVD morbidity 35% more MI and CHF in men; 66% more in women35% more MI and CHF in men; 66% more in women 1. Newman AB, et al. J Am Geriatr Soc; 2000.

13 13 Consequences to Society Crashes when driver falls asleep 1 Crashes when driver falls asleep 1  100,000 each year in U. S.  1,500 deaths  Death rate may exceed alcohol-related crashes ~1/2 of all work-related accidents 2 ~1/2 of all work-related accidents 2 1 in 5 public accidents due to falls 2 1 in 5 public accidents due to falls 2 1. Mahowald MW. Postgrad Med; 2000; 2. Leger D. Sleep; 1994.

14 14 Drivers beware: sleepiness vs. drunkenness Study compared effects on performance of sleep deprivation and alcohol 1 Study compared effects on performance of sleep deprivation and alcohol 1 Drivers who went hours without sleep = drivers with 0.05% BAC Drivers who went hours without sleep = drivers with 0.05% BAC Sleepy drivers responded ~50% more slowly/less accuracy than fully awake drivers Sleepy drivers responded ~50% more slowly/less accuracy than fully awake drivers Sleepiness can compromise performance needed for road and job safety Sleepiness can compromise performance needed for road and job safety 1. Williamson AM & Feyer AM. Occup Environ Med; 2000.

15 15 Asleep at the wheel Sleepiness – 1-3% of US vehicle crashes 1 Sleepiness – 1-3% of US vehicle crashes 1  96% involve drivers of passenger vehicles  3% involves drivers of large trucks NHTSA – 100K crashes/yr NHTSA – 100K crashes/yr  ~1500 or 4% of all traffic fatalities/yr 2  71,000 injured/yr  $12.5 billion lost Risk factors – young age, shift work, alcohol/drug use, sleep disorders. Risk factors – young age, shift work, alcohol/drug use, sleep disorders. 1. Lyznick JM, et al. JAMA; 1998; 2) NHTSA; 2000.

16 16 Drivers at high-risk for sleep-related crashes 60% of sleep-related crashes are caused by drivers <30 yr of age 1 60% of sleep-related crashes are caused by drivers <30 yr of age 1  School, job, socializing cuts into total sleep time Analysis of >4,000 crash reports shows: Analysis of >4,000 crash reports shows:  Drivers ≤25 yr in 55% sleep-related crashes 2  Men in more crashes than women 1). Knipling RR & Wang, S-S; NHTSA; 1994; 2) Pack AI, et al. Accid Anal Prev; 1995.

17 17 Drivers at high-risk for sleep-related crashes Truckers – 25% fell asleep at the wheel ≥1 last year 1 Truckers – 25% fell asleep at the wheel ≥1 last year 1  66% drove while sleepy in the preceding month In 4333 crashes where the driver was asleep, not intoxicated: 2 In 4333 crashes where the driver was asleep, not intoxicated: 2  Crashes were mostly driving-off-the-road (78%)  Took place at higher speeds (62% were >50 mph)  Fatality rate similar to that of alcohol-related crashes (1.4% vs. 2.1%)  Occurred mostly 12AM-7AM, mid-afternoon 3PM 1) McCartt AT, et al. Accid Anal Prev; 2000; 2) Pack AI. Accid Anal Prev.; 1995.

18 18 Patient assessment

19 19 Is sleep the new vital sign? Growing evidence shows that sleep is an important ingredient in good health 1 Growing evidence shows that sleep is an important ingredient in good health 1 Few MDs address sleep quality in their practices Few MDs address sleep quality in their practices  <10% of patient charts document sleep history 2 Sleep disorders are underdiagnosed, undertreated Sleep disorders are underdiagnosed, undertreated 1. Wilson JF. Am Coll Physicians; 2005; 2. Namen AM, et al. South Med J; 2001.

20 20 Pathophysiology of EDS EDS is not a disorder – but a symptom 1 EDS is not a disorder – but a symptom 1 Causes 2 : Causes 2 :  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.

21 21 How does the patient report symptoms? I’m tired I’m tired I feel lazy I feel lazy I have low energy I have low energy I feel drowsy I feel drowsy I feel sleepy I feel sleepy

22 22 Assess for other psychiatric comorbidities Symptoms of depression? Symptoms of depression? Mood or memory problems? Mood or memory problems? Does patient fall asleep suddenly? Does patient fall asleep suddenly? Is the patient a “night owl”? Is the patient a “night owl”? Does the patient drink or take drugs? Does the patient drink or take drugs? How many hours sleep per night, including weekends and weekdays? How many hours sleep per night, including weekends and weekdays?

23 23 Epworth Sleepiness Scale A quick, in-office test 1 A quick, in-office test 1 Assesses whether a person will get sleepy in certain situations Assesses whether a person will get sleepy in certain situations Use this scale for each situation: 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.

24 24 Epworth Sleepiness Scale Sitting and reading 0 Watching TV 1 Sitting in a public place 1 Riding in a car as a passenger for ≥1 hour 2 Lying down in the afternoon 2 Sitting and talking to someone 0 Sitting quietly after lunch (no alcohol) 1 Stopped for a few minutes in traffic while driving 0 1. Johns MW. Sleep; 1991.

25 25 Rule out other medical conditions 1 Stroke Stroke Tumors/cysts Tumors/cysts Vascular malformations Vascular malformations Head trauma Head trauma CNS infections (sleeping sickness) CNS infections (sleeping sickness) Parkinsonism Parkinsonism Alzheimer's, other dementias Alzheimer's, other dementias 1. Black JE, et al. Neurol Clin; 2005.

26 26 Differential Diagnosis

27 27 Most frequent causes of EDS Insufficient sleep syndrome Insufficient sleep syndrome Obstructive sleep apnea Obstructive sleep apnea Substance/medication use Substance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndrome Delayed sleep-phase syndrome Narcolepsy Narcolepsy Periodic limb movement disorders Periodic limb movement disorders

28 28 Insufficient sleep syndrome Have patient keep a sleep log 1 Have patient keep a sleep log 1  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.

29 29 Falling asleep vs. staying asleep Difficulty falling asleep 1 Difficulty falling asleep 1  Suggests delayed sleep phase syndrome  Chronic psychophysiologic insomnia  Inadequate sleep hygiene  Restless legs syndrome Difficulty staying asleep Difficulty staying asleep  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.

30 30 Most frequent causes of EDS Insufficient sleep syndrome Insufficient sleep syndrome Obstructive sleep apnea Obstructive sleep apnea Substance/medication use Substance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndrome Delayed sleep-phase syndrome Narcolepsy Narcolepsy Periodic limb movement disorders Periodic limb movement disorders

31 31 Obstructive sleep apnea Absence of breathing during sleep Absence of breathing during sleep Obstruction of airways  snoring, decrease in oxygen saturation of hemoglobin, arousal 1 Obstruction of airways  snoring, decrease in oxygen saturation of hemoglobin, arousal 1 Result is disturbed sleep and EDS Result is disturbed sleep and EDS Most common diagnosis of patients with complaint of EDS who seek care at US sleep centers 2 Most common diagnosis of patients with complaint of EDS who seek care at US sleep centers 2  Almost 7 out of 10 patients 1. Victor LD. Am Fam Physician; 1999; 2. Punjabi NM, et al. Sleep; 2000.

32 32 Obstructive sleep apnea Associated with: Associated with:  Not only CVD and obesity, but also:  Metabolic syndrome 1 Untreated OSA  Direct/deleterious effects on CV function and structure 3 Untreated OSA  Direct/deleterious effects on CV function and structure 3  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.

33 33 Obstructive sleep apnea  Systolic BP and heart rate 1  Systolic BP and heart rate 1  CRP concentrations 1  CRP concentrations 1  May contribute to ischemia, CHF, arrhythmia, cerebrovascular disease, stroke  Atrial fibrillation can predict OSA 2  Atrial fibrillation can predict OSA 2  49% vs. 32% who do not have OSA 1 in 15 has moderate to severe OSA 3 1 in 15 has moderate to severe OSA 3  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.

34 34 Obstructive sleep apnea – Airflow decrease

35 35 Physical exam for OSA Check for: 1 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.

36 36 Most frequent causes of EDS Insufficient sleep syndrome Insufficient sleep syndrome Obstructive sleep apnea Obstructive sleep apnea Substance/medication use Substance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndrome Delayed sleep-phase syndrome Narcolepsy Narcolepsy Periodic limb movement disorders Periodic limb movement disorders

37 37 Substance/medication use EDS can be a sign of drug-dependent and drug-induced sleep disorders 1 EDS can be a sign of drug-dependent and drug-induced sleep disorders 1  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.

38 38 Substance/medication use Review the patient’s Rx drug use Review the patient’s Rx drug use  Check for interactions,high doses Inquire about OTC medications Inquire about OTC medications  Diphenhydramine, anticholinergics Take alcohol history Take alcohol history  Interaction with Rx or OTCs? Ask about recreational drug use Ask about recreational drug use 1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

39 39 Most frequent causes of EDS Insufficient sleep syndrome Insufficient sleep syndrome Obstructive sleep apnea Obstructive sleep apnea Substance/medication use Substance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndrome Delayed sleep-phase syndrome Narcolepsy Narcolepsy Periodic limb movement disorders Periodic limb movement disorders

40 40 Shift-work disorder Circadian rhythm sleep disorder 1 Circadian rhythm sleep disorder 1  Internal/environmental sleep-wake cadence out of synch Insomnia, EDS, or both 1 Insomnia, EDS, or both 1 ~10% of the night and rotating shift work population 2 ~10% of the night and rotating shift work population 2 4-fold  in sleepiness-related accidents, absenteeism, depression 2 4-fold  in sleepiness-related accidents, absenteeism, depression 2 1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Drake CL, et al. Sleep; 2004.

41 41 Shift-work disorder Resolves as body clock realigns 1 Resolves as body clock realigns 1 Fixed-shift work is preferable Fixed-shift work is preferable  Full-time night or evening Rotating shifts should go clockwise Rotating shifts should go clockwise  Day  Evening  Night Helpful: Bright light, masks, white noise Helpful: Bright light, masks, white noise Short t 1/2 hypnotics, wake-promoting drugs used judiciously Short t 1/2 hypnotics, wake-promoting drugs used judiciously 1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

42 42 Most frequent causes of EDS Insufficient sleep syndrome Insufficient sleep syndrome Obstructive sleep apnea Obstructive sleep apnea Substance/medication use Substance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndrome Delayed sleep-phase syndrome Narcolepsy Narcolepsy Periodic limb movement disorders Periodic limb movement disorders

43 43 Delayed-sleep phase syndrome Sleep cycle out of synch with desired wake times 1 Sleep cycle out of synch with desired wake times 1 Problem: Going to sleep and awakening late (3AM and 10AM) Problem: Going to sleep and awakening late (3AM and 10AM) If earlier wake times are necessary, then EDS can result If earlier wake times are necessary, then EDS can result  Poor performance in work/school Improved sleep hygiene is key Improved sleep hygiene is key 1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

44 44 Most frequent causes of EDS Insufficient sleep syndrome Insufficient sleep syndrome Obstructive sleep apnea Obstructive sleep apnea Substance/medication use Substance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndrome Delayed sleep-phase syndrome Narcolepsy Narcolepsy Periodic limb movement disorders Periodic limb movement disorders

45 45 Narcolepsy Pathologic sleepiness, sudden loss of muscle tone (cataplexy), fragmented sleep, sleep paralysis 1 Pathologic sleepiness, sudden loss of muscle tone (cataplexy), fragmented sleep, sleep paralysis 1 Affects 1 out of 2,000 people 2 Affects 1 out of 2,000 people 2  140,000 Americans 2 Delay of 10 yr from onset to diagnosis is common 1 Delay of 10 yr from onset to diagnosis is common 1 The cause is unknown The cause is unknown 1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Ohayon MM, et al. Neurology; 2002.

46 46 Narcolepsy - Pathophysiology Cause? –  hypocretin-secreting neurons 1,2 Cause? –  hypocretin-secreting neurons 1,2  Regulate arousal state in hypothalamus Marker – REM sleep during ≥2 daytime naps 3 Marker – REM sleep during ≥2 daytime naps 3 Dysfunctional switching to REM sleep  wakefulness during sleep 3 Dysfunctional switching to REM sleep  wakefulness during sleep 3  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.

47 47 Narcolepsy - Pathophysiology Genetic predisposition 1 Genetic predisposition 1  Familial clustering  10- to 40-fold  vs. general population Hallmark symptom – cataplexy Hallmark symptom – cataplexy  Bilateral weakness 2  Prevalence ~ 75% 2 1. Nishino S, et al. Sleep Med Rev; 2000; 2. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

48 48 Narcolepsy – Neurophysiology Show EEG/EMG recording during a narcoleptic episode Show EEG/EMG recording during a narcoleptic episode Use Figure 4 “E” in Chemelli, 1999 Use Figure 4 “E” in Chemelli, Nishino S, et al. Sleep Med Rev; 2000; 2. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

49 49 Narcolepsy – Diagnosis Diagnostic for narcolepsy 1 Diagnostic for narcolepsy 1  History of cataplexy  Nocturnal polysomnography  Wrist actigraphy  MSLT Differential diagnosis 1 Differential diagnosis 1  Lesions of brain stem, hypothalamus  Encephalitis, metabolic disorders Urine/blood confirm non-narcoleptic EDS 1 Urine/blood confirm non-narcoleptic EDS 1 1.Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

50 50 Narcolepsy – Diagnosis Narcolepsy without cataplexy - phenotypic variant of narcolepsy with cataplexy. Narcolepsy without cataplexy - phenotypic variant of narcolepsy with cataplexy.  Clinical diagnostic criteria are similar Narcoleptics with cataplexy have low levels of CSF hypocretin whereas those without cataplexy had normal levels 1. Narcoleptics with cataplexy have low levels of CSF hypocretin whereas those without cataplexy had normal levels Kanbayashi T, et al. J Sleep Res

51 51 Most frequent causes of EDS Insufficient sleep syndrome Insufficient sleep syndrome Obstructive sleep apnea Obstructive sleep apnea Substance/medication use Substance/medication use Shift-work sleep disorder Shift-work sleep disorder Delayed sleep-phase syndrome Delayed sleep-phase syndrome Narcolepsy Narcolepsy Periodic limb movement disorders Periodic limb movement disorders

52 52 Periodic limb movement disorders Abnormal twitching/kicking of legs during sleep 1 Abnormal twitching/kicking of legs during sleep 1  Interferes with nocturnal sleep  EDS  ~10% of adults 2  Restless legs syndrome  More common in middle/later years  Creeping/crawling sensations Abnormalities in dopamine transmission 2 Abnormalities in dopamine transmission 2 1.Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Hornyak M, et al. Sleep Med Rev; 2006.

53 53 Periodic limb movement disorders Often occurs in narcolepsy and OSA 1 Often occurs in narcolepsy and OSA 1 Seen in pregnancy, renal/hepatic failure, anemia and other disorders Seen in pregnancy, renal/hepatic failure, anemia and other disorders Sleep history/partner’s testimony Sleep history/partner’s testimony Test: Iron, anemia, kidney/liver function Test: Iron, anemia, kidney/liver function Dopamine agonists can be helpful Dopamine agonists can be helpful 1.Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Hornyak M, et al. Sleep Med Rev; 2006.

54 54 When to refer?

55 55 Know when to treat and when to refer Can condition be treated via sleep hygiene? 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 Counsel on sleep architecture Do blood work, RFTs/LFTs Do blood work, RFTs/LFTs Prescribe sedatives prudently Prescribe sedatives prudently

56 56 Know when to treat and when to refer Refer when diagnosis appears to be: 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

57 57 Which physicians refer to sleep clinics? 1 Make as bar chart Make as bar chart  38% internists  17% pulmonologists  14% otolaryngologists  10% family physicians/GPs  6% neurologists  4% cardiologists  3% psychiatrists 1. Punjabi NM, et al. Sleep; 2000.

58 58 Why do physicians refer to sleep clinics? 1 Make as bar chart Make as bar chart  Apnea – 57%  Sleepiness – 48%  Fatigue – 17%  Insomnia – 16%  Snoring – 12%  Sleep walking – 1% 1. Punjabi NM, et al. Sleep; 2000.

59 59 The sleep clinic Sleep studies evaluate EDS as well as OSA, narcolepsy, periodic limb movement disorders Sleep studies evaluate EDS as well as OSA, narcolepsy, periodic limb movement disorders Polysomnography 1 Polysomnography 1  Data accumulated from patient as s/he sleeps  Quantifies sleep adequacy  Determines what causes EDS 1. AARC-APT. Respir Care; 1995.

60 60 The sleep clinic - Polysomnography Measures 1 : Measures 1 :  EEG  Eye movements  Heart rate  O 2 saturation  Muscle tone & activity All-night test All-night test 1. AARC-APT. Respir Care; 1995; 2. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006.

61 61 The sleep clinic – MSLT Multiple Sleep Latency Test Multiple Sleep Latency Test  Complimentary test for narcolepsy 1  Assesses speed of sleep onset  REM sleep is monitored  All-day test: 8-10 hours  High ESS scores ~ Low MSLT scores 2 1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006; 2. Chervin RD, et al. J Psychosom Res; 1997.

62 62 Treatment

63 63 Non-pharmacologic treatment Rationale – To improve natural sleep Rationale – To improve natural sleep Counsel patients on good sleep hygiene 1 Counsel patients on good sleep hygiene 1  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

64 64 Pharmacotherapy – Hypnotics Rationale – To treat insomnia Rationale – To treat insomnia Sleep-onset insomnia Sleep-onset insomnia  Use drugs with shorter t 1/2  Zalepon, zolpidem, triazolam Sleep-maintenance insomnia Sleep-maintenance insomnia  Use drugs with longer t 1/2  Temazepam, eszopiclone 1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006

65 65 Pharmacotherapy – Hypnotics Use with caution in elderly, pulmonary insufficiency Use with caution in elderly, pulmonary insufficiency To  tolerance, use lower doses for brief periods; taper off slowly To  tolerance, use lower doses for brief periods; taper off slowly In patients who continue to have EDS, stop or switch the drug In patients who continue to have EDS, stop or switch the drug Monitor for amnesia, hallucinations, incoordination, falls Monitor for amnesia, hallucinations, incoordination, falls 1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006

66 66 Pharmacotherapy – Stimulants Rationale – To improve alertness Rationale – To improve alertness Methylphenidate, amphetamines Methylphenidate, amphetamines Indirect-acting sympathomimetics 1 Indirect-acting sympathomimetics 1  Produce behavioral activation and increased arousal, motor activity, alertness Used mostly for EDS; ineffective for cataplexy 1, 2 Used mostly for EDS; ineffective for cataplexy 1, 2 Immediate- or extended-release forms 1 Immediate- or extended-release forms 1 1. Mitler MM & Hayduk R. Drug Saf; 2002; 2. Littner M, et al. Sleep; 2001.

67 67 Pharmacotherapy – Stimulants MPH and the amphetamines are Schedule II MPH and the amphetamines are Schedule II  Carry the risk of substance abuse/illicit use Rebound hypersomnia or tolerance to alerting agent can occur 1 Rebound hypersomnia or tolerance to alerting agent can occur 1  Switch to a different drug class or provide drug holiday 1. Black JE, et al. Neuro Clin; 2005.

68 68 Pharmacotherapy – Modafanil Rationale – To promote wakefulness Rationale – To promote wakefulness Approved for narcolepsy-associated EDS Approved for narcolepsy-associated EDS Ill-defined MOA (not a stimulant) 1 Ill-defined MOA (not a stimulant) 1  Activates hypocretin-secreting neurons 1,2  Does not control cataplexy 1 Long-acting – once-daily dosing Long-acting – once-daily dosing  Peak plasma concentrations – 2-4 hr 3  Small afternoon booster dose can be used 4 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.

69 69 Pharmacotherapy – Modafanil isomer Isomer formulation – r-modafanil or armodafanil – also being evaluated Isomer formulation – r-modafanil or armodafanil – also being evaluated Once daily for EDS 2 Once daily for EDS 2  r-isomer T 1/2 = hr vs. 3-4 hr for s- isomer  Higher peak concentrations vs. racemic mixture No efficacy/safety advantage over modafainil 2 No efficacy/safety advantage over modafainil 2 1. Harsh JR, et al. Curr Med Res Opin; 2006; 2. Dinges DF, et al. Curr Med Res Opin; 2006.

70 70 Pharmacotherapy – Sodium oxybate Rationale – To treat EDS, narcolepsy Rationale – To treat EDS, narcolepsy FDA-approved for treatment of EDS and cataplexy in narcolepsy 1 FDA-approved for treatment of EDS and cataplexy in narcolepsy 1 MOA largely unknown 2 MOA largely unknown 2 Rapidly acting hypnotic (T max hr) 2 Rapidly acting hypnotic (T max hr) 2 Short t ½ (0.5-1 hr) 2 Short t ½ (0.5-1 hr) 2  duration of stages 3, 4 sleep  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.

71 71 Pharmacotherapy – Sodium oxybate Studies show efficacy in  cataplexy and EDS 1, 2, 3 Studies show efficacy in  cataplexy and EDS 1, 2, 3   cataplexy attacks, ESS scores Can be used with modafinil 4 Can be used with modafinil 4   nightly awakenings Dosing: twice nightly Dosing: twice nightly  Taken HS, then at 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.

72 72 Pharmacotherapy – Sodium oxybate Potential drug of abuse (CIII) 1 Potential drug of abuse (CIII) 1  Enforced as Schedule I Special distribution requirements 2 Special distribution requirements 2  Use of a central pharmacy  Registration of prescribing MD  Pharmacy verification of MD’s eligibility to prescribe  Registration/required reading of materials by patient 1. FDA. FDA Talk Paper; 2002; 2006; 2. Xyrem PI; 2005.

73 73 Median percent change in cataplexy attacks per week 1 Use Figure 2 of US Xyrem study, 2002 Use Figure 2 of US Xyrem study, week double-blind phase Frequency of cataplexy attacks decreases over time Dose-related effect 1. Xyrem. Sleep; 2002.

74 74 Continuous positive airway pressure Rationale – To correct OSA Rationale – To correct OSA Reverses EEG slowing for both REM sleep and wakefulness 1 Reverses EEG slowing for both REM sleep and wakefulness 1 Improves symptoms of EDS 1 Improves symptoms of EDS 1   MSLT scores  Persistent EDS 2° to obesity Used at home but pressure is set in sleep clinic first Used at home but pressure is set in sleep clinic first 1. Morisson F, et al. Chest; 2001.

75 75 Surgery Rationale – To correct anatomical flaws Rationale – To correct anatomical flaws UPPP is the most common procedure UPPP is the most common procedure  Enlarges airways  Submucosal tissue resection from tonsillar pillars; adenoid resection  Not suitable for obese patients Trachestomy – last resort Trachestomy – last resort  May take ≥1 year to heal 1. Beers MH, et al. Merck Manual of Diagnosis and Therapy; 2006

76 76 Conclusions EDS  quality of life; can cause serious consequences EDS  quality of life; can cause serious consequences EDS may be a sign of sleep apnea, narcolepsy or a symptom of another condition 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 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 Know when to treat and when to refer


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