1 Sleep Disorders Medicine Back to Basics April 9, 2014 Elliott K. Lee MD, FRCPC, Dip. ABPN, Dip....

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Sleep Disorders MedicineBack to BasicsApril 9, 2014

Elliott K. LeeMD, FRCPC, Dip. ABPN, Dip. Amer. Board of Sleep MedicineAsst. Professor, Dept of Psychiatry, University of Ottawa

Sleep Disorders Service, Royal Ottawa Hospital

Sleep disorders

Insomnia Excessive Daytime Sleepiness Nocturnal Spells

Insomnia

“Adjustment”/Psychophysiologic

(Psychologic factors,Physiologic factors,

Negative conditioning)

INSOMNIA

Circadian Psychiatric “Adjustment”/

Psychophysiologic

Medical/Neurologic

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 parasomniaNight Terrors, Sleepwalking

REM parasomniaNightmares, 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

1 2 3 4 5 6 7

Table of 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

Onset of REMR & K 1968

REM sleep onset

REM Control Nuclei

SCNclock

DA (+)

Histamine (+)

NA (+)

5HT (+)

Orexin / Hypocretin

Monoamines controlled by Orexin

Orexin-Hypocretin projections

Sleep waveform schematic

EEG Type Hz. Sleep Stg.

Delta 0.5 - 3 SWS

Theta 3 - 7 REM

Alpha 8 - 12 Wake

Beta 16 - 25 Wake

Spindle 12 - 14 Stg. N2, N3

Gamma 20 - 50 REM, wake

EEG Frequencies

“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

ZZZZzzzzzzZZZZzzzzzz

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

Memory problemsIrritability, mental illness e.g. depression

Motor vehicle accidents

Hypertension

Heart attack and stroke

Impaired

glucose control

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 legsR – est – symptoms worsened at restG – ets better with movementE – 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

Dopaminergic Agents Intermittent

(<2x/week)- Levodopa (Sinemet)eg. Sinemet CR 25/100 1 tab po qhs prntake as abortive therapy when symptoms arise

Daily or almost daily (>3x/week)- Pramipexole (Mirapex)- Ropinirole

(Requip)eg Pramipexole 0.25-0.5 mg po qpmtake 2 hours before symptoms are worst

Silber MH et al. Mayo Clin ProcSilber 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)

SLEEPWALKING vs. RBD

SleepwalkingSleepwalking

▪ ▪ Stage N3 (NREM)Stage N3 (NREM)

▪ ▪ No dream recallNo dream recall

▪ ▪ ChildrenChildren

▪ ▪ Not easily Not easily awakenedawakened

REM Behaviour REM Behaviour DisorderDisorder

▪ ▪ REM sleepREM sleep

▪ ▪ Dream recallDream recall

▪ ▪ Adults (elderly)Adults (elderly)

▪ ▪ Easily awakenedEasily 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”Narcolepsy “Pentad”

EExcessive Daytime Sleepinessxcessive Daytime Sleepiness– May fall asleep without warning, unusual situationsMay fall asleep without warning, unusual situations

Cataplexy (75%)Cataplexy (75%)– Flaccid muscle paralysis; eyes and diaphragm OK; pt. remains Flaccid muscle paralysis; eyes and diaphragm OK; pt. remains

awake but paralyzed.awake but paralyzed.

Hypnagogic / pompic hallucinations (50-60%)Hypnagogic / pompic hallucinations (50-60%)– ““Multimodal”. Often highly emotional, sexual, frighteningMultimodal”. Often highly emotional, sexual, frightening

Sleep Paralysis (50-66%)Sleep Paralysis (50-66%)

– – Awakes unable to move anything but eyes. Can’t Awakes unable to move anything but eyes. Can’t breathe breathe voluntarily or talk. HH often occur. voluntarily or talk. HH often occur.

Disturbed nocturnal sleepDisturbed nocturnal sleep

Excessive Daytime Excessive Daytime Sleepiness (EDS)Sleepiness (EDS)

Measure: Measure: Multiple Sleep Latency TestMultiple Sleep Latency Test (MSLT)(MSLT) Following an Nocturnal Polysomnogram Following an Nocturnal Polysomnogram

(PSG)(PSG) Four or five 20 minutes naps at 2 hour Four or five 20 minutes naps at 2 hour

intervalsintervals Example: 9am, 11am, 1pm, 3pmExample: 9am, 11am, 1pm, 3pm Check for: 1) Avg. SOL & 2) REM sleep x2Check for: 1) Avg. SOL & 2) REM sleep x2 Pathological Sleepiness = Pathological Sleepiness =

fall asleep < 8 mins + 2 or more SOREMPSfall asleep < 8 mins + 2 or more SOREMPS

* SOL = sleep onset latency* SOREMP = Sleep Onset REM period

MSLT interpretation

BOBNap 1 Nap 2 Nap 3 Nap 4 Nap 55.0 mins 10 mins 9 mins 20 mins 20

minsREM No REM No REM No REM No

REMBob’s Avg. SOL = 12.8 mins, 1 REM period

JANENap 1 Nap 2 Nap 3 Nap 41.5 mins 2 mins 1 min 3 minsREM No REM REM No REMJane’s Avg. SOL = 1.9 mins, 2 REM periods

CAROLNap 1 Nap 2 Nap 3 Nap 420 mins 20 mins 20 mins 20 minsCarol’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 Dissatisfaction with quality/quantity of sleep, ≥1 of following symptoms:sleep, ≥1 of following symptoms:- Problems initiating sleep- Problems initiating sleep- Difficulty maintaining sleep- Difficulty maintaining sleep- Early morning wakenings- Early morning wakenings

Clinically significant distressClinically significant distress ≥≥3 nights/week, ≥3 months3 nights/week, ≥3 months Not due to substance, medical Not due to substance, medical

condition, inadequate sleep time.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.

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 livesDrug 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)

Chouinard, 2004Bain, 2006Fernandez, C et al, 1995

Antipsychotics and sleepTmax (h)

Total Sleep Time

SWS(Slow wave Sleep)

Sleep latency

Clozapine 3 +++ ++ +

Quetiapine 1 +++ 0 +++

Ziprasidone 5 +++ +++ +

Olanzapine 5 +++ +++ +

Risperidone 1 + +++ +

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

The most common cause of excessive daytime sleepiness in the general population is:

A. NarcolepsyB. Sleep ApneaC. Nocturnal myoclonusD. Sleep deprivationE. Idiopathic hypersomnia

The most common cause of excessive daytime sleepiness in the general population is:

A. NarcolepsyB. Sleep ApneaC. Nocturnal myoclonusD. Sleep deprivationE. Idiopathic hypersomnia

Which of the following is necessary for the rate-limiting step in the biosynthesis of dopamine?

A. MagnesiumB. CopperC. ZincD. IronE. None of the above

Which of the following is necessary for the rate-limiting step in the biosynthesis of dopamine?

A. MagnesiumB. CopperC. ZincD. IronE. None of the above

Which of the following drugs is not indicated for the treatment of Restless Leg Syndrome (RLS)

A. VenlafaxineB. PropoxypheneC. GabapentinD. RopiniroleE. Pramipexole

Which of the following drugs is not indicated for the treatment of Restless Leg Syndrome (RLS)

A. VenlafaxineB. PropoxypheneC. GabapentinD. RopiniroleE. Pramipexole

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 dementiaB. Lewy body dementiaC. Frontotemporal dementiaD. MalingeringE. The wife has a dementing illness

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 dementiaB. Lewy body dementiaC. Frontotemporal dementiaD. MalingeringE. The wife has a dementing illness

The wakefulness promoted by caffeine is mediated by its effect upon which neurotransmitter:

A. HistamineB. DopamineC. AdenosineD. AcetylcholineE. Serotonin

The wakefulness promoted by caffeine is mediated by its effect upon which neurotransmitter:

A. HistamineB. DopamineC. AdenosineD. AcetylcholineE. Serotonin

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

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

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