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Disorders of Sleep and Wakefulness Timothy J Walter MD Capitol Sleep Medicine Columbus, OH.

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Presentation on theme: "Disorders of Sleep and Wakefulness Timothy J Walter MD Capitol Sleep Medicine Columbus, OH."— Presentation transcript:

1 Disorders of Sleep and Wakefulness Timothy J Walter MD Capitol Sleep Medicine Columbus, OH

2 Excessive Sleepiness Normal Sleepiness Normal Sleepiness vs Excessive Sleepiness

3 Definitions and Terminology NORMAL SLEEPINESS A biological drive state of decreased ability to maintain wakefulness or increased propensity to fall asleep Physiologic determinants of normal sleepiness –Sleep drive Time since sleep Duration and continuity of sleep –Circadian phase (biological time of day)

4 3 pm9 pm3 am9 am AsleepAwake worksleep Physiologic Determinants of Sleepiness 9 am Circadian Drive for Wakefulness Normal Sleepiness Sleep Drive Wake Propensity

5 Definitions and Terminology EXCESSIVE SLEEPINESS A symptom of difficulty in maintaining wakefulness and increased propensity to fall asleep even in inappropriate circumstances and in situations which interfere with activities of daily living DETERMINANTS OF EXCESSIVE SLEEPINESS Increased sleep drive Sleep disruption

6 Reduced Activity in the Cortex in Normal Volunteers With Acute Sleep Deprivation Thomas M, et al. J Sleep Res

7 Behavioral Morbidity of Excessive Sleepiness Undesired sleep episodes Lapses of attention Decreased work productivity Accidents Irritability Fatigue Depressed mood Loss of energy Lack of motivation

8 Behavioral Morbidity of Excessive Sleepiness..\MPEG\Sleepy cabbie.wmv

9 Measuring Excessive Sleepiness Objective measures –Physiologic Multiple Sleep Latency Test (MSLT) Maintenance of Wakefulness Test (MWT) Subjective measures –Patient-rated Epworth Sleepiness Scale (ESS) Karolinska Sleepiness Scale (KSS)

10 Epworth Sleepiness Scale (ESS) SituationChance of dozing (0-3) Sitting and reading0123 Watching television0123 Sitting inactive in a public place—for example, a theater or meeting 0123 As a passenger in a car for an hour without a break0123 Lying down to rest in the afternoon0123 Sitting and talking to someone0123 Sitting quietly after lunch (when you’ve had no alcohol)0123 In a car, while stopped in traffic0123 Total Score 0 = would never doze 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing Johns MW. Sleep Reprinted with permission from the American Academy of Sleep Medicine. ESS total score >10 indicates possible excessive daytime sleepiness or sleep disorder.

11 Epworth Sleepiness Scale (ESS) Adapted from: Johns MW. Sleep. 1991; Adler et al, Mov Disord 2003 ESS Mean Score Narcolepsy* Idiopathic Hypersomnia* Severe OSA* ( RDI=49.5) Periodic Limb Movement Syndrome (PLMS)* Normal Subjects* Normal Subjects (2–10) *Untreated patients **Patients pre-selected w/ ES [ESS>10]) 16.9 Parkinson’s Disease**

12 Measuring the Impact of Excessive Sleepiness Neurobehavioral measures –Psychomotor Vigilance Task (PVT) –Steer Clear Performance Test (SCPT) Quality of life or functional status ratings –Short-Form Health Survey (SF-36) –Functional Outcomes of Sleep Questionnaire (FOSQ) Overall clinical condition –Clinical Global Impression of Severity (CGI-S) or Change (CGI-C) - Clinician-rated –Patient diaries

13 Conditions Associated With Excessive Sleepiness Disorders of Sleep & Wakefulness Other Medical, Neurological, or Psychiatric Conditions Normal Sleepiness

14 Disorders of Sleep and Wakefulness Associated With Excessive Sleepiness Sleep-Wake Dysregulation Sleep Disruption Circadian Misalignment Disorders of Sleep and Wakefulness

15 1. Dyssomnias (Disorders of Sleep or Wakefulness) A. Intrinsic Sleep Disorders B. Extrinsic Sleep Disorders C. Circadian Rhythm Sleep Disorders 2. ParasomniasA. Arousal Disorders B. Sleep-Wake Transition Disorders C. Parasomnia Associated with REM Sleep D. Other Parasomnia 3. Sleep Disorders Associated with Mental, Neurologic or Other Medical Disorder A. Associated with Mental Disorders B. Associated with Neurologic Disorders C. Associated with Other Medical Disorders 4. Proposed Sleep Disorders International Classification of Sleep Disorders (ICSD)

16 Increased Sleep Drive Sleep Disruption Circadian Misalignment Circadian Misalignment Sleep-Wake Dysregulation Sleep-Wake Dysregulation ES in Shift Work Sleep Disorder Delayed Sleep Phase Syndrome Advanced Sleep Phase Syndrome Non-24-Hr Sleep-Wake Syndrome Time Zone Change Syndrome Circadian Rhythm Sleep Disorder Irregular Sleep Wake Pattern ES in Narcolepsy Idiopathic Hypersomnia Recurrent Hypersomnia Posttraumatic Hypersomnia ES in OSA Restless Legs Syndrome Periodic Limb Movement Disorder Central Sleep Apnea Syndrome Central Alveolar Hypoventilation Syndrome Determinants of Excessive Sleepiness in Disorders of Sleep and Wakefulness

17 Disorders of Sleep-Wake Dysregulation Increased Sleep Drive Sleep Disruption Circadian Misalignment Circadian Misalignment Sleep-Wake Dysregulation Sleep-Wake Dysregulation ES in Narcolepsy (ICSD 347) Idiopathic Hypersomnia Recurrent Hypersomnia Posttraumatic Hypersomnia ES in Narcolepsy (ICSD 347) Idiopathic Hypersomnia Recurrent Hypersomnia Posttraumatic Hypersomnia

18 Narcolepsy Characterized by irresistible, unintended attacks of sleep which can occur in inappropriate situations Symptoms –Excessive sleepiness –Cataplexy –Hypnagogic hallucinations –Sleep paralysis –Disrupted nighttime sleep Prevalence = 5 in 10,000 Onset typically in teen years, sometimes earlier

19 Diagnostic Criteria: Narcolepsy (ICSD † ) A.Excessive sleepiness or sudden muscle weakness B.Recurrent daytime sleep episodes for at least 3 months C.Cataplexy: sudden loss of muscle tone D.Associated features: Sleep paralysis; hypnagogic hallucinations; disrupted major sleep episode E.PSG findings: sleep latency <10 minutes, REM sleep latency <20 minutes; MSLT findings: mean <5 minutes, 2 or more sleep-onset REM periods F.Positive HLA-DR2 G.Medical or psychiatric disorders and other sleep disorders are not the primary cause of symptoms B + C or A + D + E + G Minimal Criteria † ICSD = International Classification of Sleep Disorders

20 Disorders of Sleep Disruption Increased Sleep Drive Sleep Disruption Circadian Misalignment Circadian Misalignment Sleep-Wake Dysregulation Sleep-Wake Dysregulation ES in OSA (ICSD ) Restless Legs Syndrome Periodic Limb Movement Disorder Central Sleep Apnea Syndrome Central Alveolar Hypoventilation Syndrome ES in OSA (ICSD ) Restless Legs Syndrome Periodic Limb Movement Disorder Central Sleep Apnea Syndrome Central Alveolar Hypoventilation Syndrome

21 Obstructive Sleep Apnea/Hypopnea Syndrome (OSA/HS*) Loss of airway tone which results in airway obstruction, cessation of breathing, arousal to increase airway patency during sleep –Results in interruption of the normal sleep cycle Symptoms –Excessive sleepiness –Loud snoring, snorting, and gasping reported by bed partner –Restless, nonrestorative sleep –Problems with memory –Depressed mood 2% of women, 4% of men meet criteria for OSA * OSA will be used throughout

22 Diagnostic Criteria Obstructive Sleep Apnea (ICSD ) A.A complaint of excessive sleepiness or insomnia. Occasionally, the patient may be unaware of clinical features that are observed by others. B.Frequent episodes of obstructed breathing occur during sleep. C.Associated features include: 1. Loud snoring; 2. Morning headaches; 3. A dry mouth upon awakening D.Polysomnographic monitoring demonstrates 1. >5 obstructive apneas, >10 sec in duration, per hour of sleep and one or more of the following: AFrequent arousals from sleep associated with the apneas BBradytachycardia CArterial oxygen desaturation in association with the apneic events 2. MSLT may or may not demonstrate mean sleep latency of <10 minutes. E.The symptoms can be associated with other medical disorders (eg, tonsilare enlargement) F.Other sleep disorders can be present (eg, PLMD or narcolepsy) Minimal Criteria: A plus B plus C

23 ES Associated With OSA The primary treatment for OSA is nCPAP nCPAP use significantly reduces ES –Patel et al, 2003 meta-analysis* Mean improvement in MSLT/MWT 0.93 minutes Mean improvement in ESS 2.87 In some patients, regular nCPAP therapy fails to fully resolve the symptom of ES ES associated with OSA can cause moderate impairment in social and occupational function *Patel SR, et al. Arch Intern Med

24 Disorders of Circadian Misalignment Increased Sleep Drive Sleep Disruption Circadian Misalignment Circadian Misalignment Sleep-Wake Dysregulation Sleep-Wake Dysregulation ES in Shift Work Sleep Disorder (ICSD ) Delayed Sleep Phase Syndrome Advanced Sleep Phase Syndrome Non-24-Hr Sleep-Wake Syndrome Time Zone Change Syndrome Circadian Rhythm Sleep Disorder Irregular Sleep Wake Pattern ES in Shift Work Sleep Disorder (ICSD ) Delayed Sleep Phase Syndrome Advanced Sleep Phase Syndrome Non-24-Hr Sleep-Wake Syndrome Time Zone Change Syndrome Circadian Rhythm Sleep Disorder Irregular Sleep Wake Pattern

25 Shift Work Sleep Disorder (SWSD) Circadian sleep disorder characterized by excessive sleepiness at night and/or insomnia during the day –Temporally associated with night work Symptoms –Excessive sleepiness –Insomnia

26 Nonstandard Work Schedules (Shift Work) Approximately 2% to 5% of the adult population report a sleep-related difficulty associated with working nonstandard hours Approximately 20 million Americans regularly work nonstandard schedules Working nonstandard hours is associated with increased morbidity: –Sleep-related difficulties (eg, ES and insomnia) These individuals are at significantly greater risk for errors, near misses, and accidents, especially during the commute home This risk has been reported to be significantly greater in those with a diagnosis of SWSD Partinen M, et al. Sleep Gold DR, et al. Am J Public Health Ohayon MM, et al. Sleep Med

27 Diagnostic Criteria: Shift Work Sleep Disorder (ICSD ) A.A primary complaint of insomnia or excessive sleepiness. B.The primary complaint is temporally associated with a work period (usually night work) that occurs during the habitual sleep phase. C.Evidence of disturbed chronobiological rhythmicity by demonstration of the loss of a normal sleep-wake pattern by polysomnography and by the MSLT. D.Absence of a psychiatric or medical disorder that could account for the symptoms. E.Does not meet criteria for any other sleep disorder producing insomnia or excessive sleepiness. Minimal Criteria: A plus B

28 Excessive Sleepiness Is A Result of Decreased Cortical Activity Increased sleep drive and/or poor quality of sleep results in decreased cortical activity This decreased cortical activity results in excessive sleepiness

29 modafinil Activates the Cortex in a Preclinical Model *P<.05 vs vehicle-treated during wake Ant. Cingulate Cortex Wake Vehicle modafinil 75 mg/kg (midnight) * Fos Immunoreactive Neuron Count Scammell T, et al. J Neuroscience

30 Efficacy

31 Modafinil for Excessive Sleepiness: Controlled Trials, Principal Studies 6 randomized, double-blind, placebo-controlled studies –Sleep/wake dysregulation (ES associated with narcolepsy) 18 center: 9-week safety and efficacy 21 center: 9-week safety and efficacy –Sleep disruption (residual ES associated with OSA) 4-week safety and efficacy 12-week safety and efficacy –Circadian misalignment (ES associated with SWSD) 12-week safety and efficacy 12-week safety and quality of life 1431 patients treated and assessed in these 6 studies

32 NarcolepsyOSASWSD 18 center21 center12 week4 week12 week Double-blind, placebo- controlled, parallel group Duration (wks)99124 Doses (mg)200, Dosingdaily am 1 hour prior to shift Study Descriptions

33 Characteristic Narcolepsy (N = 530) OSA (N = 446) SWSD (N = 455) Sex, N (%)Male239 (45)340 (76)243 (53) Female291 (55)106 (24)212 (47) Race, N (%)White434 (82)396 (89)321 (71) Black77 (15)29 (7)99 (22) Asian06 (1)2 (<1) Other19 (4)15 (3)32 (7) Age, yMean SD CGI-S rating, N (%) Not recorded043 (10)0 Normal, mildly, or slightly ill91 (17)121 (27)0 Moderately ill237 (45)199 (45)280 (62) Markedly, severely, or extremely ill202 (38)83 (19)175 (38) Baseline Characteristics Data on file. Cephalon, Inc. CGI-S: Clinical Global Impression of Severity

34 Baseline Sleep Latency MSLT (Minutes) NarcolepsyOSASWSD Baseline MSLT Mean MSLT (in minutes) Normal >15 minutes

35 Baseline Sleep Latency MWT (Minutes) Not Measured NarcolepsyOSASWSD Baseline MWT Mean MWT (in minutes) Normal >15 minutes

36 Summary and Conclusions ES is caused by increased sleep drive and/or disrupted sleep Patients with ES have reduced cortical activity Activity of the cortex is essential to achieving wakefulness and cognitive function ES manifests itself in similar ways regardless of the underlying cause ES can be measured objectively and subjectively using standardized, validated, and clinically relevant instruments Disorders of sleep and wakefulness can be defined based upon the underlying pathophysiology: –Sleep-Wake Dysregulation –Sleep Disruption –Circadian Misalignment

37 Summary and Conclusions (cont’d) Narcolepsy, OSA, and SWSD are disorders of sleep and wakefulness with ES as a primary complaint Excessive sleepiness is a prominent and disabling symptom of disorders of sleep and wakefulness Modafinil significantly and consistently improved wakefulness across the disorders, and across both objective and subjective efficacy measures Generally well tolerated, the safety profile of PROVIGIL was comparable across all disorders studied, with no population-specific safety concerns noted

38 Thank You! Timothy J Walter MD


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