1. Sleep Disorders Medicine Back to Basics April 9, 2014
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

2. Sleep disorders
Insomnia
Excessive Daytime Sleepiness
Nocturnal Spells

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

4. 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.

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

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

7. Sleep Architecture

8. 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

9. SLEEP HYPNOGRAM W N1 N2 1 N3
REM 1 2 3 4 5 6 7
Hours

10. Table of Stg. %
Stg%

11. Sleep Stage % by Age

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

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

14. REM Control Nuclei

15. Monoamines controlled by Orexin
SCN clock
DA (+) ~
Orexin /
Hypocretin
Histamine (+)
5HT (+)
Monoamines controlled by Orexin
NA (+)

16. Orexin-Hypocretin projections

17. Sleep waveform schematic

18. EEG Frequencies EEG Type Hz. Sleep Stg. Delta 0.5 - 3 SWS Theta 3 - 7
REM
Alpha
8 - 12
Wake
Beta
Spindle
Stg. N2, N3
Gamma
REM, wake
“Deep”
“Awake”
“Stage II”

19. Sleep disorders

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

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

22. OSA Clinical Symptoms

23. 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

24. Normal vs. Collapsed Airway

25. “Kissing” Tonsils

26. TREATMENTS FOR OSA **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

27. Provent

29. Continuous Positive Airway Pressure (CPAP)

30. Uvulopalatopharyngoplasty (UP3)

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

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

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

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

35. PLMs 2 MIN

37. Restless Leg Syndrome “URGE” U – rge to move legs
R – est – symptoms worsened at rest
G – ets better with movement
E – vening – symptoms worse in evening

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

40. RLS – PLMD: neurochemistry
Likely due to iron deficiency in basal ganglia (Fe is co-factor in enzymes that synthesize DA).
May predict onset of “syn-nucleinopathies” (REM behaviour disorder, Parkinson’s, Lewy Body dementia).

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

42. Check Iron (Ferritin)! Intake – food? Absorption - GI difficulties
Blood loss? - Anemia – Cough? Poop? - Menstrual Periods/Pregnancy - Blood donations
Target ferritin > 50 μg/L
May replace e.g. FeSO4 with vitamin C tid 2 hours before or after meals

43. Silber MH et al. Mayo Clin Proc (2004) 79(7) : 916-22
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 mg po qpm take 2 hours before symptoms are worst
Silber MH et al. Mayo Clin Proc (2004) 79(7) :

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

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

46. REM Behaviour disorder (RBD)

47. 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

48. 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)

49. REM Behaviour Disorder
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

50. Narcolepsy

51. 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

52. 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
Cataplexy takes an average of 1-4 years to develop after excessive daytime sleepiness, but sometimes it can even be decades.

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

54. MSLT interpretation BOB Bob’s Avg. SOL = 12.8 mins, 1 REM period JANE
Nap 1 Nap 2 Nap 3 Nap Nap 5
5.0 mins 10 mins 9 mins 20 mins mins
REM No REM No REM No REM No REM
Bob’s Avg. SOL = 12.8 mins, 1 REM period
JANE
Nap 1 Nap 2 Nap 3 Nap 4
1.5 mins 2 mins 1 min 3 mins
REM No REM REM No REM
Jane’s Avg. SOL = 1.9 mins, 2 REM periods
CAROL
20 mins 20 mins 20 mins 20 mins
Carol’s Avg. SOL = 20 mins, no sleep, no REM periods

55. 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

56. 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

59. 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

60. INSOMNIA

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

62. 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

63. 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

64. 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.
Talk about adenosine – accumulates – helps us sleep – why exercise may be helpful for sleep

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

66. 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

67. BDZ and Non BDZ half lives
Drug
Half life (hours)
Ultra short half life
Zaleplon (Starnoc)
Zolpidem (Ambien)
Zopiclone (Imovane)
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

68. Antipsychotics and sleep
Tmax (h)
Total Sleep Time
SWS (Slow wave Sleep)
Sleep latency
Clozapine 3
+++ ++ +
Quetiapine 1
Ziprasidone 5
Olanzapine
Risperidone
Haloperidol
4-6
Krystal, A.D., H.W. Goforth, and T. Roth, Effects of antipsychotic medications on sleep in schizophrenia. Int Clin Psychopharmacol, (3): p

69. Now for some questions, if there’s timex

70. The most common cause of excessive daytime sleepiness in the general population is:
Narcolepsy
Sleep Apnea
Nocturnal myoclonus
Sleep deprivation
Idiopathic hypersomnia

71. The most common cause of excessive daytime sleepiness in the general population is:
Narcolepsy
Sleep Apnea
Nocturnal myoclonus
Sleep deprivation
Idiopathic hypersomnia

72. Which of the following is necessary for the rate-limiting step in the biosynthesis of dopamine?
Magnesium
Copper
Zinc
Iron
None of the above

73. Which of the following is necessary for the rate-limiting step in the biosynthesis of dopamine?
Magnesium
Copper
Zinc
Iron
None of the above

74. Which of the following drugs is not indicated for the treatment of Restless Leg Syndrome (RLS)
Venlafaxine
Propoxyphene
Gabapentin
Ropinirole
Pramipexole

75. Which of the following drugs is not indicated for the treatment of Restless Leg Syndrome (RLS)
Venlafaxine
Propoxyphene
Gabapentin
Ropinirole
Pramipexole

76. A 72 year old man presents with a 3 year history of cognitive decline
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:
Alzheimer’s dementia
Lewy body dementia
Frontotemporal dementia
Malingering
The wife has a dementing illness

77. A 72 year old man presents with a 3 year history of cognitive decline
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:
Alzheimer’s dementia
Lewy body dementia
Frontotemporal dementia
Malingering
The wife has a dementing illness

78. The wakefulness promoted by caffeine is mediated by its effect upon which neurotransmitter:
Histamine
Dopamine
Adenosine
Acetylcholine
Serotonin

79. The wakefulness promoted by caffeine is mediated by its effect upon which neurotransmitter:
Histamine
Dopamine
Adenosine
Acetylcholine
Serotonin

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

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

82. Which of the following best describe the narcolepsy tetrad?
cataplexy, sleep paralysis, nocturnal myoclonus, sleepiness
epilepsy, sleepiness, hypnagogic hallucinations, cataplexy
sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis
sleep onset REM periods, sleepiness, enuresis, cataplexy
sleep paralysis, sleepiness, cataplexy, sleep apnea

83. Which of the following best describe the narcolepsy tetrad?
cataplexy, sleep paralysis, nocturnal myoclonus, sleepiness
epilepsy, sleepiness, hypnagogic hallucinations, cataplexy
sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis
sleep onset REM periods, sleepiness, enuresis, cataplexy
sleep paralysis, sleepiness, cataplexy, sleep apnea

84. Zzzzzz QUESTIONS?? Zzzzzz
Special thanks to Chief Technologist Lisa Orr for her enormous assistance in assembling these slides.