2. 1 Sleep Disorders Medicine Back to Basics April 10, 2015 Elliott K. Lee MD, FRCPC, Dip. ABPN, Dip. Amer. Board of Sleep Medicine Asst. Professor, Dept of Psychiatry, University of Ottawa Sleep Disorders Service, Royal Ottawa Hospital

3. Sleep disorders Insomnia Excessive Daytime Sleepiness Nocturnal Spells

4. Insomnia “Adjustment”/Psychophysiologic (Psychologic factors, Physiologic factors, Negative conditioning) INSOMNIA Circadian Psychiatric “Adjustment”/ Psychophysiologic Medical/Neurologic

5. Excessive Daytime Sleepiness Lack of sleep Insufficient time in bed Inadequate quality of sleep Sleep Apnea, PLMD Intrinsic sleepiness Narcolepsy; Idiopathic Hypersomnia Medical/psychiatric disorder Major Depression Medications, medical – thyroid, anemia etc. Circadian Rhythm Disturbance Shift work, delayed sleep phase, etc.

6. “Nocturnal Spells” NREM parasomnia Night Terrors, Sleepwalking REM parasomnia Nightmares, REM behavior disorder etc Seizure Disorder Psychiatric e.g. Panic attack etc.

7. Purpose of Sleep Restorative Function Energy Conservation Immune Function Regulation Ontogenetic Hypothesis Memory Consolidation Protective Mechanism

8. SLEEP ARCHITECTURE

9. STAGES OF SLEEP NREM & REM NREM = N1, N2 (light stages) N3 (SWS – slow wave sleep) Sleep Cycles REM increases as the night progresses Changes across the lifespan

10. SLEEP HYPNOGRAM REM N3 N2 N1 W 1 Hours 1 2 3 4 5 67

11. Table of Stg. %Table of Stg. % Stg%

12. Sleep Stage % by Age

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14. REM Sleep Rapid Eye Movements Muscle atonia (paralysis) Dream recall 90 minute latency “Paradoxical Sleep” – EEG mimics wakefulness Breathing irregular, heart rate fluctuates

15. Onset of REM R & K 1968 REM sleep onset

16. REM Control Nuclei

17. Orexin-Hypocretin projections

18. OREXIN (“Flip Flop switch) REM Off (REM On) Wake On (sleep fragmentation) Sleep On/(Wake off) (Sleep attacks) (Sleep paralysis, cataplexy, hypnagogic hallucinations)

19. Orexin Novel sleeping agent approved by FDA in US (Aug 2014) Belsomra (suvorexant) Orexin antagonist- for treatment of insomnia

20. Sleep waveform schematic

21. EEG TypeHz.Sleep Stg. Delta0.5 - 3SWS Theta3 - 7REM Alpha8 - 12Wake Beta16 - 25Wake Spindle12 - 14Stg. N2, N3 Gamma20 - 50REM, wake EEG Frequencies “Deep” “Awake” “Stage II”

22. SLEEP DISORDERS

23. Sleep Disorders Obstructive Sleep Apnea/hypopnea (OSA) Restless Legs Syndrome (RLS) Periodic Limb Movement Disorder (PLMD) REM behavior disorder (RBD) Narcolepsy

24. SLEEP APNEA Two Types: Obstructive & Central Pauses in breathing > 10 seconds in length Respiratory Disturbance Index: >5 hr =clinically significant ZZZZzzzzzz

25. OSA Clinical Symptoms

26. OBSTRUCTIVE SLEEP APNEA (OSA) Causes ▪ Narrow Upper Airway ▪ Elevated BMI ▪ Family Hx Exacerbated by: ▪ Medications – BDZs, Opioids ▪ Alcohol Consumption ▪ Supine sleep ▪ REM sleep ▪ **Supine + REM sleep

27. Normal vs. Collapsed Airway

28. “Kissing” Tonsils

29. TREATMENTS FOR OSA **CPAP – Continuous Positive Airway Pressure **CPAP – Continuous Positive Airway Pressure **Weight Loss - ↓ BMI = ↓ RDI Avoid Alcohol, Sedatives “Snoreball” Technique / Positional Therapy Oral Appliance Provent Upper Airway Surgery Tonsillectomy (pediatrics) Uvulopalatopharyngoplasty (UPPP) Tracheostomy

30. OSA Consequences Memory problems Irritability, mental illness e.g. depression Motor vehicle accidents Hypertension Heart attack and stroke Impaired glucose control

31. Sleep Deprivation and Children Not the same as adults May be “hyperactive” - fidget - poor attention - cranky Undiagnosed OSA may be mistaken for ADHD

32. Periodic Limb Movements (PLMs) & Restless Legs Syndrome (RLS)

33. Periodic Limb Movements (PLMs) Repetitive leg (limb) movements DURING SLEEP Typically 20-40 seconds apart Cause awakenings and fragmentation Patient often unaware. Bedpartner reports “kicking” c/o frequent awakenings, light sleep aka Nocturnal Myoclonus

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35. Restless Legs Syndrome – DSM-5 “URGE” Unpleasant sensation U – rge to move legs R – est – symptoms worsened at rest G – ets better with movement E – vening – symptoms worse in evening ≥ 3x/week, ≥ 3months Significant distress Not due to medical condition, substance

36. RLS/PLMD Periodic Limb Movement Disorder (PLMD) Restless Leg Syndrome (RLS) 80% 20%

37. RLS – PLMD: neurochemistry Likely due to iron deficiency in basal ganglia (Fe is co-factor in enzymes that synthesize DA).

38. Address Exacerbating Factors IRON DEFICIENCY Caffeine Tobacco Alcohol Medications - dopamine blockers – antipsychotics, GI motility agents - antidepressants (SSRI’s)

39. Dopaminergic Agents Intermittent (<2x/week) - Levodopa (Sinemet) eg. Sinemet CR 25/100 1 tab po qhs prn take as abortive therapy when symptoms arise Daily or almost daily (>3x/week) - Pramipexole (Mirapex) - Ropinirole (Requip) eg Pramipexole 0.25- 0.5 mg po qpm take 2 hours before symptoms are worst Silber MH et al. Mayo Clin Proc Silber MH et al. Mayo Clin Proc (2004) 79(7) : 916-22

40. Side Effects Nausea Nasal stuffiness Constipation Leg swelling Insomnia Sleepiness/sleep attacks (caution driving) *Pathological gambling and compulsive behaviors

41. Second and Third Line Agents Gabapentin (Neurontin) - anticonvulsant Benzodiazepines (sedative hypnotics) - Clonazepam (rivotril / klonopin) - Lorazepam (ativan) - Diazepam (valium) Opioids - Codeine - Hydrocodone - Methadone* (Quinine obsolete)

42. REM BEHAVIOUR DISORDER (RBD)

43. REM Behaviour Disorder (RBD) No muscle atonia during REM sleep Ability to act out complex dream behaviour Bedpartner often the “victim” Age of onset: 50 – 60yrs. Males (90%) Usually opposite of waking personality Strongly associated with synucleinopathies - Parkinsonism/Parkinson’s - Lewy Body Dementia

44. Treatments for RBD Full EEG montage during PSG CT Scan, MRI – r/o lesions Securing the environment (mattress on floor, bed rails, restraints) Bedpartner sleeps in another room Rx – Clonazepam * (Melatonin) * (Pramipexole)

45. SLEEPWALKING vs. RBD Sleepwalking ▪ Stage N3 (NREM) ▪ No dream recall ▪ Children ▪ Not easily awakened REM Behaviour Disorder ▪ REM sleep ▪ Dream recall ▪ Adults (elderly) ▪ Easily awakened

46. NARCOLEPSY

47. Narcolepsy - DSM-5 Recurrent periods of irrepressible need to sleep, ≥ 3x/wk, ≥3 months Cataplexy* Hypocretin deficiency (CSF Hcrt- 1<110pg/mL) PSG – REM latency ≤ 15 min, or MSLT with SL ≤ 8 min and ≥ 2 SOREMPs

48. Narcolepsy “Pentad” Excessive Daytime Sleepiness –May fall asleep without warning, unusual situations Cataplexy (75%) –Flaccid muscle paralysis; eyes and diaphragm OK; pt. remains awake but paralyzed. Hypnagogic / pompic hallucinations (50-60%) –“Multimodal”. Often highly emotional, sexual, frightening Sleep Paralysis (50-66%) – Awakes unable to move anything but eyes. Can’t breathe voluntarily or talk. HH often occur. Disturbed nocturnal sleep

49. Excessive Daytime Sleepiness (EDS) Measure: Multiple Sleep Latency Test (MSLT) Measure: Multiple Sleep Latency Test (MSLT) Following an Nocturnal Polysomnogram (PSG) Following an Nocturnal Polysomnogram (PSG) Four or five 20 minutes naps at 2 hour intervals Four or five 20 minutes naps at 2 hour intervals Example: 9am, 11am, 1pm, 3pm Example: 9am, 11am, 1pm, 3pm Check for: 1) Avg. SOL & 2) REM sleep x2 Check for: 1) Avg. SOL & 2) REM sleep x2 Pathological Sleepiness = fall asleep < 8 mins + 2 or more SOREMPS Pathological Sleepiness = fall asleep < 8 mins + 2 or more SOREMPS * SOL = sleep onset latency * SOREMP = Sleep Onset REM period

50. MSLT interpretation BOB Nap 1Nap 2Nap 3Nap 4 Nap 5 5.0 mins10 mins9 mins20 mins 20 mins REMNo REMNo REMNo REM No REM Bob’s Avg. SOL = 12.8 mins, 1 REM period JANE Nap 1Nap 2Nap 3Nap 4 1.5 mins2 mins1 min3 mins REMNo REMREM No REM Jane’s Avg. SOL = 1.9 mins, 2 REM periods CAROL Nap 1Nap 2Nap 3Nap 4 20 mins20 mins20 mins20 mins Carol’s Avg. SOL = 20 mins, no sleep, no REM periods

51. Markers of Narcolepsy Hypocretin/Orexin 90-95% of narcolepsy with cataplexy – are CSF hypocretin deficient HLA DQB1*0602 – strongly associated with hypocretin deficiency (95%) HLA DQA1*0102 HLA DRB1*1503

52. Cataplexy Sudden onset of full or partial skeletal muscle weakness or paralysis Is preceded by heightened emotion such as laughter, anger or excitement Lasts seconds to minutes Results from abnormality of the REM sleep system

53. Narcolepsy Treatment Rx: Stimulant medication - Modafinil (Alertec) - Methylphenidate (Ritalin) - Dexedrine Education: EDS is not their fault Therapeutic napping REM suppressant medications for cataplexy - SSRI – e.g. Fluoxetine *Sodium Oxybate (GHB) - Xyrem

54. INSOMNIA

55. INSOMNIA DISORDER (DSM-5) Dissatisfaction with quality/quantity of sleep, ≥1 of following symptoms: - Problems initiating sleep - Difficulty maintaining sleep - Early morning wakenings Dissatisfaction with quality/quantity of sleep, ≥1 of following symptoms: - Problems initiating sleep - Difficulty maintaining sleep - Early morning wakenings Clinically significant distress Clinically significant distress ≥3 nights/week, ≥3 months ≥3 nights/week, ≥3 months Not due to substance, medical condition, inadequate sleep time. Not due to substance, medical condition, inadequate sleep time.

56. Insomnia Sleep Deprivation – “Hypoarousal” - decreased metabolism - decreased body temperature - lethargy - short sleep onset times Insomnia – “HYPER-arousal” night + day - increased metabolism - increased body temperature - anxiety, agitation

57. Suggestions Elucidate CAUSE/contributing factors - Stressor? - Substances – Caffeine? Alcohol? Nicotine? - Circadian factors? - Medical/Sleep – thyroid? RLS? Meds? - Psychiatric – Depression? Anxiety? Stress Behavioral factors/Sleep hygiene

58. Treating insomnia: Personal Sleep Hygiene Maintain a regular wake/sleep schedule. Refrain from taking naps. Avoid caffeine after mid-afternoon. Exercise - but not within 3 hours of bedtime. Establish a relaxing routine before bedtime. Use the bedroom for sleep activities. Avoid clock watching Set environment (light, noise, temperature) at comfortable levels.

59. Insomnia Treatments Cognitive Behavioural Therapy Sleep Restriction Therapy Relaxation Techniques Sleep Hygiene

60. Suggestions Stressor/short term relief - most evidence – non benzodiazepine benzo receptor agonists – Zopiclone (Imovane) Trazodone – reasonable –but little evidence Circadian factors - melatonin Comorbid psychiatric factors - Anxiety/Depression - BDZs – ultra short to medium T1/2 - Mirtazapine - Atypical antipsychotics – selected cases

61. BDZ and Non BDZ half lives DrugHalf life (hours) Ultra short half life Zaleplon (Starnoc)0.9-1.1 Zolpidem (Sublinox)1.4-4.5 Zopiclone (Imovane)3.5-6.5 Triazolam (Halcion)2-5 Short to medium half life Lorazepam (Ativan)10-20 Temazepam (Restoril)8-24 Oxazepam (Serax)6-24 Alprazolam (Xanax)6-20 Long half life Clonazepam (Rivotril)5-30 Diazepam (Valium)20-80 Chlorodiazepoxide (Librium)7-30 Chouinard, 2004 Bain, 2006 Fernandez, C et al, 1995

62. Antipsychotics and sleep Tmax (h)Total Sleep Time SWS (Slow wave Sleep) Sleep latency Clozapine3++++++ Quetiapine1+++0 Ziprasidone5+++ + Olanzapine5+++ + Risperidone1+++++ Haloperidol4-6++++++++ Krystal, A.D., H.W. Goforth, and T. Roth, Effects of antipsychotic medications on sleep in schizophrenia. Int Clin Psychopharmacol, 2008. 23(3): p. 150-60.

63. Zzzzzz QUESTIONS?? Zzzzzz Special thanks to Chief Technologist Lisa Orr for her enormous assistance in assembling these slides, and for my twins Isaac and Jacob for letting me sleep.

64. Now for some questions, if there’s time x

65. The most common cause of excessive daytime sleepiness in the general population is: A. Narcolepsy B. Sleep Apnea C. Nocturnal myoclonus D. Sleep deprivation E. Idiopathic hypersomnia

66. The most common cause of excessive daytime sleepiness in the general population is: A. Narcolepsy B. Sleep Apnea C. Nocturnal myoclonus D. Sleep deprivation E. Idiopathic hypersomnia

67. A 72 year old man presents with a 3 year history of cognitive decline. His wife notes that during the night he may flail his arms, and lash out at her during sleep. Upon awakening, he often vaguely recalls being chased and fighting off “the animals that were trying to get me”. The most likely diagnosis is: A. Alzheimer’s dementia B. Lewy body dementia C. Frontotemporal dementia D. Malingering E. The wife has a dementing illness

68. A 72 year old man presents with a 3 year history of cognitive decline. His wife notes that during the night he may flail his arms, and lash out at her during sleep. Upon awakening, he often vaguely recalls being chased and fighting off “the animals that were trying to get me”. The most likely diagnosis is: A. Alzheimer’s dementia B. Lewy body dementia C. Frontotemporal dementia D. Malingering E. The wife has a dementing illness

69. The wakefulness promoted by caffeine is mediated by its effect upon which neurotransmitter: A. Histamine B. Dopamine C. Adenosine D. Acetylcholine E. Serotonin

70. The wakefulness promoted by caffeine is mediated by its effect upon which neurotransmitter: A. Histamine B. Dopamine C. Adenosine D. Acetylcholine E. Serotonin

71. What two laboratory signs on the Multiple Sleep Latency Test are diagnostic of narcolepsy? A. mean sleep latency > 15 minutes and one sleep onset REM period B. mean sleep latency <8 minutes and no sleep onset REM periods C. mean sleep latency >20 minutes and two sleep onset REM periods D. mean sleep latency <8 minutes and two sleep onset REM periods E. mean sleep latency >15 minutes and no sleep onset REM periods

72. What two laboratory signs on the Multiple Sleep Latency Test are diagnostic of narcolepsy? A. mean sleep latency > 15 minutes and one sleep onset REM period B. mean sleep latency <8 minutes and no sleep onset REM periods C. mean sleep latency >20 minutes and two sleep onset REM periods D. mean sleep latency <8 minutes and two sleep onset REM periods E. mean sleep latency >15 minutes and no sleep onset REM periods

73. Which of the following best describe the narcolepsy tetrad? A. cataplexy, sleep paralysis, nocturnal myoclonus, sleepiness B. epilepsy, sleepiness, hypnagogic hallucinations, cataplexy C. sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis D. sleep onset REM periods, sleepiness, enuresis, cataplexy E. sleep paralysis, sleepiness, cataplexy, sleep apnea

74. Which of the following best describe the narcolepsy tetrad? A. cataplexy, sleep paralysis, nocturnal myoclonus, sleepiness B. epilepsy, sleepiness, hypnagogic hallucinations, cataplexy C. sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis D. sleep onset REM periods, sleepiness, enuresis, cataplexy E. sleep paralysis, sleepiness, cataplexy, sleep apnea

75. Continuous Positive Airway Pressure (CPAP)

76. Uvulopalatopharyngoplasty (UP3)

77. Oral Appliances (Mandibular Repositioning Devices (MRDs) Silencer- Johns Dental Labs Klearway- Great Lakes Orthodontics