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

Sleep disorders Insomnia Excessive Daytime Sleepiness Nocturnal Spells

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

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.

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

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

Sleep Architecture

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

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

Table of Stg. % Stg%

Sleep Stage % by Age

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

REM sleep onset Onset of REM R & K 1968

REM Control Nuclei

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

Orexin-Hypocretin projections

Sleep waveform schematic

EEG Frequencies EEG Type Hz. Sleep Stg. Delta 0.5 - 3 SWS Theta 3 - 7 REM Alpha 8 - 12 Wake Beta 16 - 25 Spindle 12 - 14 Stg. N2, N3 Gamma 20 - 50 REM, wake “Deep” “Awake” “Stage II”

Sleep disorders

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

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

OSA Clinical Symptoms

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

Normal vs. Collapsed Airway

“Kissing” Tonsils

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

Provent

Continuous Positive Airway Pressure (CPAP)

Uvulopalatopharyngoplasty (UP3)

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

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

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

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

PLMs 2 MIN

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

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

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).

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

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

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 0.25-0.5 mg po qpm take 2 hours before symptoms are worst Silber MH et al. Mayo Clin Proc (2004) 79(7) : 916-22

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

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

REM Behaviour disorder (RBD)

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

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)

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

Narcolepsy

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

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.

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

MSLT interpretation BOB Bob’s Avg. SOL = 12.8 mins, 1 REM period JANE Nap 1 Nap 2 Nap 3 Nap 4 Nap 5 5.0 mins 10 mins 9 mins 20 mins 20 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

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

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

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

INSOMNIA

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.

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

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

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

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

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

BDZ and Non BDZ half lives Drug Half life (hours) Ultra short half life Zaleplon (Starnoc) 0.9-1.1 Zolpidem (Ambien) 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

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, 2008. 23(3): p. 150-60.

Now for some questions, if there’s time x

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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