Paul P. Doghramji, MD, FAAFP

Family Practice Physician

Collegeville Family Practice & Pottstown Medical Specialists, Inc.

Medical Director of Health Services, Ursinus College – Collegeville, PA

Attending Family Practice Physician, Pottstown Memorial Medical Center – Pottstown, PA

Sleep Medicine for the Primary Care Provider

Learning Objectives

▪ Explain the sleep/wake cycle and circadian rhythms

▪ Review common sleep disorders in primary care

▪ Use appropriate diagnostic tools to assess patients’

sleep health

▪ Identify medications and/or treatment options used for

various sleep disorders

Agenda

▪ What is sleep?

▪ Sleep stages

▪ Sleep physiology

▪ Dreaming

▪ Sleepiness

▪ Sleep disorders

▪ Insomnia and comorbidities

Sleep Perspectives

▪ Behavioral

▪ Reversible

▪ Perceptual disengagement from, and unresponsiveness to, the environment

▪ Neurophysiological

▪ Two distinct states: REM sleep and NREM

▪ Actively produced, not a result of passive inactivity

▪ Highly regulated by homeostatic and circadian processes

▪ Produces changes in the entire organism, not just the CNS

▪ Teleological

▪ Necessary for survival; deprivation leads to functional impairments and eventual death

▪ Important for clearance of neurotoxic waste products (e.g., beta amyloid) that accumulate in

the brain during wakefulness

NREM = non-rapid eye movement

Carskadon MA, Dement WC (2005), Normal human sleep: an overview. In: Principles and Practice of Sleep Medicine, 4th ed., Kryger MH et al., eds. Philadelphia: Elsevier/Saunders, pp13-23. Science vol 342, 18 Oct 2013.

What Does Sleep Do?The 4R’s of Sleep:

▪ Rest

▪ Restore

▪ Repair

▪ Rejuvenate

3 PROPER-ties of Sleep

▪ Proper duration

▪ Proper timing

▪ Proper quality

▪ Improper duration and/or timing and/or quality can lead

to insufficient rest/restore/rejuvenate/repair -> poor

health and decreased longevity

Why is Sleep Important?

▪ Cognition and performance

▪ Mood regulation

▪ Mental health

▪ Physical health

▪ Safety

Sleep Stages

SLEEP REST

Two States of Sleep

Rapid eye movement (REM) sleep

▪ When dreaming occurs

▪ “Active brain in a paralyzed body”

Hours 1

N 1

& REM

N 2

N3

2 3 4 5 6 7 8

Non-REM sleep

▪ 3 stages

▪ Based primarily on EEG

Typical Sleep Architectural Pattern of a Young Human Adult

Adapted from Hauri P. The Sleep Disorders. Kalamazoo, Mich: Upjohn;1982:8.

Stage I & REM sleep (red) are graphed on the same level because their EEG patterns are very similar

Sleep Architecture

▪ Sleep is entered through stage N1

▪ Orderly progression from stage N1 to N3 and, typically within 90

minutes of sleep onset, to the 1st REM period

▪ 90-minute cycle of REM-NREM repeats throughout sleep

▪ As the night progresses

▪ REM periods increase in duration and density of eye movements

▪ N3 sleep becomes less prominent in the 2nd half of the night

Sleep Stage Characteristics

NREM REM

Heart rate Steady Variable

Blood pressure Steady Labile

Respirations Regular Irregular

Skeletal muscle tone Normal Decreased

Thermoregulation Waking modes Decreased

Penile tumescence Infrequent Frequent

Mental activity Limited Dreaming

Brain O2 consumption Decreased Waking level

Lee-Chiong T, ed. Sleep: A Comprehensive Handbook. Hoboken, NJ: Wiley & Sons; 2006.

Sleep Across the Life Span

0

100

200

300

400

500

600

700

Tota

l Sle

ep T

ime

(min

)

Age (years)

Total Time in Bed

Awake in Bed

NREM N 1

REM

NREM N 2

NREM N 3

10 20 30 40 50 60 70 8050

Adapted from Williams RL, et al. Electroencephalography of Human Sleep: Clinical Applications. New York, NY: John Wiley & Sons; 1974.

Sleep Physiology

Brainstem Mechanisms Underlying Sleep and Arousal

Adapted from Saper CB, et al. Nature. 2005 Oct 27; 437(7063):1257-63.

Ascending

Arousal SystemSleep and

Arousal Centers

Orexin = Hypocretin

▪ Hypothalamic peptides (OX1 and OX2)

▪ Localized in the dorsolateral hypothalamus

▪ Wide projections throughout brain and spinal column

▪ Peptide neurotransmitters involved in

▪ Arousal

▪ Locomotion

▪ Metabolism (energy and appetite control)

▪ Increase blood pressure & heart rate

Peyron et al. J Neurosci. 1998;18:9996. Moore et al. Arch Ital Biol. 2001;139:195. Silber & Rye. Neurology. 2001;56:1616.

Flip Flop Switch Model of Arousal and Sleep

Modified from Saper CB, et al. Nature. 2005;437(7063):1257-1263.

Dreaming

When Do We Dream?

▪ Dreaming occurs in all stages of sleep

▪ 80% of persons who are awakened during REM sleep and

sleep onset (N1 & N2)

▪ 40% of persons who are awakened from a deep sleep

Foulkes D. Dreaming: a cognitive-psychological analysis. Hillsdale, N.J.: Erlbaum, 1985.

N1 & N2 N3 REM

Simpler, shorter

and have fewer

associations

than REM sleep

dreams

More diffuse

(e.g., about a

color or an

emotion)

Tend to be

bizarre and

detailed, with

storyline plot

associations

Highest recall during sleep stages with EEG patterns

most like those in the waking state

D

R

E

A

M

S

REM and Non-REM Dreams

Frightening Dreams

TYPE OF

DREAMINCIDENCE SYMPTOMS SLEEP STAGE

ASSOCIATED

FACTORSFrequent

nightmares in

children

20% to 30%,

declines with age

Frightening, detailed plots

Difficult return to sleep

REM sleep, usually

late in sleep (4 - 6

a.m.)

Usually no pathology

Frequent

nightmares in

adults

5% to 8%

Increased awakenings

Daytime memory

impairment and anxiety

REM sleep

“Thin-boundary” / creative

personality

May have associated

psychopathology

PTSD

8% - 68% of

veterans

>25% of trauma

victims

Stereotypic dreams of the

trauma

Intense rage, fear, grief

REM sleep and sleep

onset

Significant trauma

Daytime hyper-

arousability & anxiety

REM sleep

behavior

disorder

Most common in

late middle age and

in men

Acting out of dreams

Nocturnal injuries

REM sleep

REM EMG tone

Degenerative neurologic

illness in 50%

Night terrors

1% to 4% of

children

Declines with age

Rare in adults

Blood-curdling screams

Autonomic discharge

Limited recall

Deep sleep, early

(1- 3 a.m.)

Stages 3 & 4

arousals on PSG

No pathology in children

Psychiatric & neurologic

disorders in adults

PAGEL JF, Nightmares and Disorders of Dreaming. Am Fam Physician. 2000 Apr 1;61(7):2037-2042.

REM = rapid eye movement; EMG = electromyography

Sleepiness

Sleepiness: How Do Patients Describe It?

▪ “I’m tired all the time”

▪ “I have no energy”

▪ “I feel fatigued”

▪ “I feel depressed”

▪ “I don’t feel rested”

▪ “I don’t sleep well”

The International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.

Chervin RD. Chest 2000;118:372-379. Shen J, et al. Sleep Med Rev 2006;10:63-76.

Patients Also Mean Other Things“TIRED”

Sleepiness FatigueLack of

motivation

Tendency to fall

asleep or inability

to stay awake

Sensation of

weariness,

tiredness,

exhaustion,

loss of energy;

the desire to rest

“I don’t feel like

doing anything…”

Improved by sleep Improved by rest,

exertion makes it

worse

Sleepiness in America

37%

16%

0%

10%

20%

30%

40%

At least a few days per month At least a few days per week

% of US Adults Reporting that They Are So Sleepyit Interferes with Their Daily Activities

National Sleep Foundation. “Sleep in America” Poll. March 2002.

Assessment Options: Sleep Parameters

▪ Subjective: based on self-report

▪Epworth

▪ Insomnia Severity Scale

▪Diaries

▪Often do not reflect objective sleep measures

▪ Objective: Sleep lab or home sleep monitor

▪ Wearable technology (eg, Fitbit) increasingly capable of more

objective sleep assessment: eg, total sleep time, slow wave sleep,

REM sleep

▪Not reimbursable, not validated in clinical practice

Epworth Sleepiness Scale

Johns MW. Sleep. 1991;14:540-545.

Rate the chances of dozing in sedentary situations

Never Slight Moderate High

Sitting and reading 0 1 2 3

Watching television 0 1 2 3

Sitting, inactive in a public place (eg, a movie theater or a meeting)

0 1 2 3

As a passenger in a car for an hour without a break

0 1 2 3

Lying down to rest in the afternoon when circumstances permit

0 1 2 3

Sitting and talking to someone 0 1 2 3

Sitting quietly after lunch without alcohol

0 1 2 3

In a car, while stopped for a few minutes in the traffic

0 1 2 3

Score >=10 Prompts Further Evaluation

US women 20.8%,US men 29.7%2

South Africa1 24.5%

Japan1 12.4%

China1 6.2%

Austria1 17.5%

Belgium1 17.5%

Brazil1 14.3%

Germany1 7.2%

Portugal1 18.3%

Slovakia1 13.7%

Spain1 12.7%

Norway3 17.7%

N=35,327 survey respondents aged 39 ± 15.3 years.1

ESS, Epworth Sleepiness Scale

1. Soldatos CR, et al. Sleep Med. 2005;6:5-13; 2. Baldwin CM, et al. Sleep. 2004;27:305-311; 3. Pallesen S, et al. Sleep. 2007;30:619-624.

Worldwide Prevalence of ESS Scores >10

Categories of Sleepiness

▪ Insufficient sleep

▪ Factitious

▪ Insomnia

▪ Poor quality sleep

▪ Obstructive sleep apnea

▪ Restless Legs Syndrome

▪ Disturbed timing of sleep

▪ Circadian rhythm disorders

▪ Medications and substances

▪ Rx, OTC, herbals

▪ Illicit drugs, alcohol

▪ Brain “damage”

▪ MS, Parkinson’s, TBI, stroke,

Alzheimer's

▪ Narcolepsy

Sleep Disorders

Restless Legs Syndrome6

10%-15%

Comorbid Insomnias4

6%

Narcolepsy5

0.06%†

Obstructive Sleep Apnea1

3%-28%

Sleep-Wake Disorders: Prevalence in Adults

*Among night and rotating shift workers; †Prevalence of hypersomnias such as narcolepsy without cataplexy may be higher.

1. Young T, et al. Am J Respir Crit Care Med. 2002;165:1217-1239. 4. Ohayon MM. Sleep Med Rev. 2002;6:97-111.2. Drake CL, et al. Sleep. 2004;27:1453-1462. 5. Silber MH, et al. Sleep. 2002;25:197-202.3. Strine DP, et al. Sleep Med. 2005;6:23-27. 6. Merlino G et al. Neurol Sci. 2007;28:S37-S46. †Mignot E, et al. Brain. 2006;129:1609-1623. †Singh M, et al. Sleep. 2006;29:890-895.

Shift Work Disorder2

8%-32%* Insufficient Sleep

Syndrome3

26%

How to Diagnose the Cause of Sleepiness

▪ Get detailed sleep/wake history

▪ Determine whether sleepy, fatigue, or depression

▪ Quantify degree of sleepiness: ESS

▪ Start probing for the causes, looking for clues

▪ Insufficient Sleep Syndrome: doesn’t get enough sleep

▪ OSA: loud snoring, waking up choking, witnesses apneas, waking with sore throat,

headache, enuresis, nocturia

▪ RLS: uncomfortable feelings in legs prevent sleep, need to move them to relieve

symptoms

▪ PLMD: no clues except excessive sleepiness

▪ Narcolepsy: hypnogogic/hypnopompic hallucinations, sleep paralysis, cataplexy

Obstructive Sleep Apnea (OSA)

Symptoms

▪ Loud Snoring

▪ Gasping, choking

▪ Witnessed apneas

▪ Morning headaches, sore throat

▪ Enuresis/nocturia

Physical Findings

▪ Large neck

▪ Crowded pharynx

▪ Obesity

▪ Micrognathia, short chin

Treatment

▪ CPAP/BiPAP/Auto-AP

▪ Oral appliance

▪ Surgery

▪ Weight loss

▪ Positioning

▪ “Bongo” nasal valves

▪ “Inspire”

OSA is a Highly Prevalent Medical Condition1

▪ OSA prevalence varies based on patient demographics and definitions used for

respiratory events2

▪ US prevalence of moderate to severe OSA (AHI ≥15) is estimated at 10%4,b

▪ Prevalence in men (13.0%) is approximately twice that in women (5.6%)4

The Wisconsin Sleep Cohort estimates overall OSA (AHI ≥5) prevalence to be3,a

24%

in men

9%

in women

1. Franklin KA, Lindberg E. J Thor Dis. 2015;7(8):1311-1322. 2. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd

ed. Darien, IL: American Academy of Sleep Medicine; 2014. 3. Garvey JF et al. J Thorac Dis. 2015;7(5):920-929. 4. Peppard PE et al. Am J Epidemiol.

2013;177(9):1006-1014.

AHI=apnea-hypopnea indexaAges 30-60 years3

bAges 30-70 years4

Predisposing Conditions

▪ Age (40 to 70 years)

▪ Commercial motor vehicle driver

▪ Family history of obstructive sleep apnea

▪ Male sex

▪ Obesity (body mass index > 35 kg per m2)

▪ Postmenopausal woman not taking hormone therapy

▪ Preoperative for bariatric surgery

▪ Retrognathia

Semelka M, et.al. Am Fam Physician. 2016 Sep 1;94(5):355-360.

OSA is Associated with Negative Health Consequences

1. Somers VK et al. Circulation. 2008;118(10):1080-1111. 2. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed.

Darien, IL: American Academy of Sleep Medicine; 2014. 3. White DP. Am J Respir Crit Care Med. 2005;172(11):1363-1370. 4. Knauert M et al. World J

Otorhinolaryngol Head Neck Surg. 2015;1(1):17-27. 5. Dempsey JA et al. Physiol Rev. 2010; 90((1):47-112. 6. Lal C et al. Chest. 2012;141(6):1601-1610.

7. Semelka M, et.al. Am Fam Physician. 2016 Sep 1;94(5):355-360.

Systemic Inflammation

Airway opens & reoxygenation1,3

Reduced pharyngeal muscle tone2

Sleep onset1

Arousalfrom sleep1,3

Increasedpharyngeal

muscle tone1,3

Airway narrowingor collapse;reduction in airflow2

Increasedventilatory effort1,3

Hypoxemia &hypercapnia1,3

IntermittentHypoxemia

Stroke Hypertension

Diabetes

Depression OSA can lead to significant health

consequences, including4,5,6 7:

Neurocognitive impairment

SleepFragmentation

CAD

AtrialFibrillation

CHF

Prevalence of OSA in Co-morbidities

Schafer et al.

Cardiology 1999

83%

76%

37%

48%Diabetes

Obesity

All Hypertension

Atrial Fibrillation

Congestive HeartFailure

Drug-ResistantHypertension

49%

77%

Coronary Artery Disease

59%Pacemakers

Sjostrom et al.

Thorax 2002

Logan et al.

J Hypertens 2001

Oldenburg et al.

Eur J Heart Fail 2007

O'Keeffe & Patterson.

Obes Surg 2004

Einhorn et al.

Endocr Pract 2007

Gami et al.

Circulation 2004

Garrigue et al.

Circulation 2007

30%

74%

Benefits of CPAP Treatment

▪ In patients with obstructive sleep apnea, continuous positive airway pressure (CPAP)…

▪ Lowers blood pressure

▪ Reduces rates of arrhythmia and stroke

▪ Improves left ventricular ejection fraction in patients with heart failure

▪ Reduces fatal and nonfatal cardiovascular events

▪ A recent meta-analysis demonstrated similar rates of blood pressure lowering between continuous positive airway pressure and mandibular advancement devices

Semelka M, et.al. Diagnosis and Treatment of Obstructive Sleep Apnea in Adults. Am Fam Physician. 2016 Sep 1;94(5):355-360.

Screening for OSA: STOP-BANG Method

STOP Questionnaire*

▪ Snoring

▪ Tiredness (daytime)

▪ Observed you stop

breathing during sleep

▪ High blood Pressure

BANG†

▪ BMI > 35

▪ Age > 50 years

▪ Neck circumference

> 40 cm (~ 16 in)

▪ Gender: Male

* High risk = Yes to > 2 of 4 STOP items

† High risk = Yes to > 3 of 8 STOP-BANG items

Chung F, et al. Anesthesiology 2008;108:812-821.

OSA is Measured by:

▪ Apnea/Hypopnea Index (AHI), the average number of apnea/hypopneas per hour

▪ Apnea: cessation of airflow for at least 10 sec

▪ Hypopnea: partial obstruction that is either severe enough, and/or causes desaturation, and/or arousal

▪ AHI

▪ 5-15: mild OSA

▪ 16-30: moderate OSA

▪ >30 severe OSA

Airway Assessment: OSA Mallampati Scale

Nuckton TJ, et al. Sleep. 2006;29:903-908.

Odds of OSA increase >2-fold for every 1-point increase

Class I Class II Class III Class IV

Testing for OSA

▪ Overnight polysomnogram is gold standard

▪ Split night acceptable for those with AHI >20 in first few hours

▪ Home sleep study

▪ More accurate in identifying patients with a higher pretest probability of OSA and can rule out OSA in low-risk patients

▪ Not recommended in patients with comorbidities

▪ Less expensive

▪ More patient friendly

Semelka M, et.al. Am Fam Physician. 2016 Sep 1;94(5):355-360.

Excessive Daytime Sleepiness (EDS) is Common in Patients with OSA

▪ In a multicenter trial using the MSLT,a

among 136 patients with OSA (AHI

≥15) across 7 sleep clinics before

CPAP treatment1:

▪ 62.5% (n=85) of patients had ES (mean

sleep latency <7.5 min)

▪ Prevalence estimates of objective

EDS in OSA may vary with differences

in thresholds used across studies

>60%had objective EDSb prior to

CPAP treatment2

bMean MLST sleep latency <7.5 min.

Evaluated in 136 OSA patients (AHI ≥15) across 7 sleep clinics.

MSLT=Multiple Sleep Latency TestaThe MSLT is a laboratory-based, objective tool that uses mean sleep latency (eg, time from lights out to first epoch of sleep) and number of sleep-

onset REM periods to characterize the patient’s ability to fall asleep.1,2

1. Weaver TE et al. Sleep. 2007;30(6):711-719. 2. Littner MR, et al. Sleep. 2005;28(1):113-121.

Excessive Daytime Sleepiness May Persist Despite ≥6 Hours CPAP Use per Night1-3

▪ EDS is among the most frequently reported

complaints in patients with OSA4

▪ In a multicenter trial (n=128 patients with AHI

≥15) patients with OSA were treated with

CPAP for 3 months and assessed for

sleepiness before and after airway treatment

using2:

▪ Self-reported ESS and FOSQ

▪ Clinically-derived MSLT

FOSQ=Functional Outcomes of Sleep Questionnaire

1. Qaseem A et al. Ann Intern Med. 2013;159(7):471-483. 2. Weaver TE et al. Sleep. 2007;30(6):711-719. 3. Antic N et al. Sleep. 2011;34(1):111-119.

4. American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.

aEvaluated in patients with pre- and post-treatment

assessments who had abnormal pretreatment values2

bSubjective EDS defined as ESS (>10)2

cObjective EDS according to MSLT sleep latency <7.5 min2

dFunctional impairment defined as FOSQ <17.92

For patients reporting ≥6 hours of CPAP use per night,

based on MSLT (n=23), more than half of participants

continued to experience EDS2

0

10

20

30

40

50

60

ESS MSLT FOSQ

Percent Patients Failing to Achieve a Normal Score With ≥6 h CPAP Use per

Night for 3 Months2,a

n=11/23 n=25/37n=28/36

% P

atie

nts

22b

52c

32d

Neurologic Regulation of Sleep/Wake Cycle

CNS=central nervous system

1. Schwartz JR, Roth T. Curr Neuropharmacol. 2008;6(4):367-378. 2. Slater G, Steier J. J Thorac Dis. 2012;4(6):608-616. 3. Saper CB et al. Nature.

2005;437(7063):1257-1263. 4. España RA, Scammell TE. Sleep. 2011;34(7):845-858.

ES may result from injury to neurons involved in

promoting wakefulness1,3,4

Increased Sleep Drive1,2

▪ Sleep disruption

▪ Insufficient sleep duration

▪ Comorbid sleep disorders

▪ Sedative hypnotics,

opiates

Inadequate Wake Drive1,2

▪ CNS disruption of

wake-promoting neurons

▪ Comorbid sleep-wake

disorders (eg, narcolepsy)

Emerging Research Suggests OSA May Cause Neuronal Injury and Brain Alterations Resulting in EDS

In Experimental Animal

Models of OSA

1. Zhu Y et al. Front Neurol. 2015;6:109. 2. Zhu Y et al. J Neurosci. 2007;27(37):10060-10071. 3. Joo EY et al. Sleep. 2010;33(2):235-241. 4. Lal C et al.

Chest. 2012;141(6):1601-1610. 5. Xiong Y et al. J Magn Reson Imaging. 2017;45(5):1371-1378. 6. Slater G, Steier J. J Thorac Dis. 2012;4(6):608-616.

Chronic intermittent hypoxia has been

associated with injury to certain wake-

promoting neurons (eg, noradrenergic,

dopaminergic)2

Chronic sleep fragmentation has been

associated with loss of certain wake-

promoting neurons (eg, noradrenergic,

orexigenic)1

In Patients With OSA

ES in patients adherent to CPAP was associated

with structural changes to white matter5:

▪ Potentially indicative of compromised neuronal connectivity

▪ Some structural changes correlated with clinical measures of EDS (ESS)

Diagnosis of EDS in OSA is based on a clinical assessment, which must be made by the treating physician after airway treatment is implemented and all other

causative disorders have been ruled out including other untreated sleep disorders, mental disorder, or the effects of medication.6

OSA was associated with reduced gray

matter volume in brain regions involved

in wakefulness and neurocognitive

performance compared with healthy

volunteers3,4

EDS in OSA May Lead to Involuntary Sleep Episodes

▪ Among 822 patients with newly diagnosed moderate to severe OSA,

43% (n=350) reported high levels of subjective EDS, including involuntary

sleep episodes1,b

aInvoluntary episodes of sleep can occur during walking, talking, and driving1; bIcelandic Sleep Apnea Cohort.

1. Ye L et al. Eur Respir J. 2014;44(6):1600-1607. 2. Weaver EM et al. Arch Otolaryngol Head Neck Surg. 2004;130(4):453-458.

Involuntary Sleep Episodesa Reported by Patients

With Moderate to Severe OSA1

n=350

Relaxing

(eg, watching TV)

99%

During the Day

65%

Driving

38%

Self-reported EDS does not

necessarily correlate with

polysomnographic measures

(eg, AHI), and can persist

despite improvement in the

AHI, the primary measure of

OSA severity2

Self-Report Measures Can Be Used in Clinical Practice

1. Miglis MG, Kushida CA. Sleep Med Clin. 2014;9(4):491-498. 2. Johns MW. Sleep. 1991;14(6):540-545. 3. Ahmed IM, Thorpy MJ. In: Sleepiness: Causes,

Consequences and Treatment. Cambridge, UK: Cambridge University Press; 2011:36-49. 4. Chapman JL et al. Sleep Med Clin. 2016;11(3):353-363. 5. Chasens

ER, Ratcliffe SJ et al. Sleep. 2009;32(7):915-919.

▪ The FOSQ (or shorter FOSQ-10)

assesses the effect of sleepiness on

daily functioning4,5

▪ Evaluates 5 domains4,5

1. General productivity

2. Activity level

3. Vigilance

4. Social outcomes

5. Intimate/sexual relationships

▪ The ESS is the most frequently used,

validated self-report assessment of a

patient’s sleepiness1

▪ On a 4-point scale, patients rate their

likelihood of falling asleep during

8 different situations (reading,

driving, etc)2

▪ The ESS can also be used to monitor

the progression of or improvement in

sleepiness over time3

Epworth Sleepiness Scale (ESS)Functional Outcomes of Sleep

Questionnaire (FOSQ)

▪ Subjective measures rely on patients to accurately report their own sleepiness, however, they are4

▪ Practical for monitoring progression or improvement in EDS

▪ Simple to administer

Objective Measures Can Be Used in a Laboratory Setting to Detect Excessive

Daytime Sleepiness and Other Sleep Disorders

1. Littner MR, et al. Sleep. 2005;28(1):113-121. 2. Weaver TE et al. Sleep. 2007; 30(6):711-719. 3. Chapman JL et al. Sleep Med Clin. 2016;11(3):353-363.

▪ Measures the ability to stay awake

using mean sleep latency

▪ Experimental measure useful for

detecting response to interventions

intended to maintain wakefulness

▪ Measures physiologic sleep tendencies

using latency to sleep

▪ Diagnostic test traditionally used to

assess narcolepsy and other sleep

disorders

Multiple Sleep Latency Test (MSLT)1 Maintenance of Wakefulness (MWT)1

▪ Objective measures may detect a greater percentage of patients with EDS than subjective patient

reporting2

▪ However, time and cost constraints make these tests impractical for routine use in monitoring EDS in OSA3

Management of EDS in OSA

Re-examine Treatment Objectives

▪ Adequate sleep duration and optimized airway therapy1

▪ First-line treatment of choice for OSA is typically CPAP

1. Santamaria J et al. Sleep Med Rev. 2007;11(3):195-207. 2. Provigil tablets [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc; 2015.

3. Nuvigil tablets [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc; 2017. 4. Iftikhar IH et al. Lung. 2014;192(1):175-184. 5. Aurora RN et

al. J Clin Sleep Med. 2015;11(3):357-383.

Rx

Reinforce Behavioral Interventions

▪ Weight management2,3

▪ Exercise2

▪ Cardiovascular fitness3

Consider Pharmacotherapies

▪ Wake-promoting agents (eg, modafinil, armodafinil, solriamfetol)4,5

▪ Indicated for EDS associated with narcolepsy and CPAP-adherent patients with OSA

▪ Modafinil and armodafinil also indicated for shift-work disorder

Restless Legs Syndrome

Movement disorder with sensory and motor components; Clinical diagnosis with 4 criteria

Rest or inactivity

precipitates or worsens

symptoms

Getting up or moving

improves the sensation

Evening or nighttime

appearance or worsening

of symptoms

Restless Legs Syndrome (RLS): Diagnostic Criteria

Allen RP, et al. Sleep Med. 2003;4:101-119.

Urge to move with

uncomfortable, unpleasant sensations

in legs

Supportive criteria: Family history, positive response to

dopaminergic therapy, and periodic limb movements in sleep

RLS: Most Common Presenting Complaints

▪ Insomnia: trouble getting to sleep, 88%

▪ Tiredness: drowsiness or daytime sleepiness, 90%

1. Gamaldo CE, Earley CJ. Chest. 2006;130(5):1596-1604. 2. Allen RP, et al. Arch Intern Med. 2005;165:1286-1292. 3. Allen RP, et al. Sleep Med.

2003;4:101-119. 4. Allen RP, Earley CJ. J Clin Neurophysiol. 2001;18:128-147. 5. Turjanski N, et al. Neurology. 1999;52:932-937.

Restless Legs Syndrome: Assessment and Diagnosis

▪ 7%-10% prevalence (US, northern Europe)1

▪ Female predominance 2:12

▪ Increases with age2

▪ Mostly occurs BEFORE going to sleep but can be all day

▪ Totally a clinical diagnosis, no sleep testing needed

▪ Differentiate primary RLS from RLS secondary (25%) to:4

▪ Pregnancy, CKD, iron deficiency, medications (ALL anti-depressants except bupropion)

▪ Primary more frequent in younger patients, with family history

▪ May be associated with dopaminergic dysfunction4,5

**consider iron absorption issues; *FDA-approved.

1. Allen RP, et al. Sleep Med. 2003;4:101-109. 2. Manconi M, et al. Sleep Med. 2004;5:305-308. 3. Hening WA. Am J Med. 2007;120(1 Suppl 1):S22-S27. 4. Panossian LA, Avidan AY. Med Clin North Am. 2009;93:407-425.

Restless Legs Syndrome: Diagnostic/Treatment Strategies

Nonpharmacologic

▪ Relaxing exercise before bedtime may reduce symptoms3

▪ Avoid medications and substances that may aggravate symptoms (SSRIs, antihistamines, caffeine, nicotine)3

Pharmacologic

▪ Iron replacement therapy if ferritin level <50 μg/L

▪ Management of symptoms3,4

▪ Meds

Laboratory Testing

▪ Low Ferritin (< 50) –highly associated with RLS**1

▪ CKD: check GFR

▪ HCG (if pregnancy is suspected) –Pregnancy raises risk of RLS by 2- to 3-fold2

Management of RLS

Kannan, R. et. A. Am Fam Physician. August 15, 2013; Volume 88, Number 4.

Periodic Limb Movement Disorder (PLMD) vs. RLS

▪ Substantial overlap

▪ Up to 85% of RLS patients have PLMD

▪ 30% of PLMD patients have RLS

▪ RLS diagnosis is made clinically after suspicion of patient with

EDS and nighttime symptoms

▪ PLMD diagnosis is made via PSG

▪ Treatments are the same

Characteristics

▪ Stereotyped leg movements

▪ Involve one or both limbs

▪ Triple flexion with leg flexion, ankle dorsiflexion, and great toe

extension

▪ Lasts approximately 2 seconds

▪ Periodicity ranges from 20-40 seconds with a variable duration

▪ Mainly in non-rapid eye movement (REM) sleep

▪ Occasionally, a bed partner may provide the history of limb

movements

Narcolepsy

Clinical Features

▪ Chronic, debilitating condition with a prevalence of around 0.02%

▪ Clinical features begin in the teens or twenties. Onset after 50 years of age is unusual

▪ Average time to diagnosis is 10 years

▪ The classic tetrad of narcolepsy:

▪ Excessive sleepiness

▪ Cataplexy (if present is called type 1 narcolepsy; if not, is called type 2)

▪ Hallucinations upon falling asleep (hypnagogic) and/or upon awakening (hypnopompic)

▪ Sleep paralysis (generalized, transient inability to move or speak during sleep-wake transitions)

Kannan, R et. al Am Fam Physician. 2013 Aug 15;88(4):231-238.

Cataplexy

▪ Sudden decrease or loss of voluntary muscle tone following

an emotional trigger – usually laughter, but sometimes anger

or surprise

▪ Manifests as jaw dropping, head nodding, arms dropping to

the side, knees sagging, or the patient collapsing to the floor

▪ May last from a few seconds to a few minutes, and the

patient's conscious awareness is preserved

▪ The presence of cataplexy is highly specific for narcolepsy

Kannan, R et. al Am Fam Physician. 2013 Aug 15;88(4):231-238.

Diagnosis

▪ Referral to a sleep clinic

▪ Two weeks of a sleep log or actigraphy to document sleep duration

▪ Polysomnography to evaluate for other sleep disorders and document

adequate sleep time

▪ Next day multiple sleep latency test

▪ Daytime nap test to objectively assess for sleepiness and for onset of rapid eye

movement (REM) sleep during naps

▪ The combination of a mean sleep latency of less than eight minutes plus at least

two naps with early onset REM sleep supports a diagnosis of narcolepsy

The International Classification of Sleep Disorders: Diagnostic and Coding Manual. 2nd ed. Westchester, Ill.: American Academy of Sleep Medicine; 2005.

Treatment

▪ REM-suppressing antidepressants

▪ Venlafaxine (Effexor)

▪ Selective serotonin reuptake inhibitors

▪ Sleepiness

▪ Adequate sleep hygiene and scheduled daytime naps

▪ Medications

▪ Wake promoting medications: modafinil (Provigil), armodafinil (Nuvigil), solriamfetol (Sunosi), pitolisant (Wakix)

▪ Stimulants such as methylphenidate or dextroamphetamine

▪ Gamma hydroxybutyric acid (sodium oxybate [Xyrem, or Xywave])

Kannan, R et. al Am Fam Physician. 2013 Aug 15;88(4):231-238.

Insomnia

Insomnia

As a disorder:

▪ Trouble getting to sleep and/or

▪ Trouble staying asleep and/or

▪ Waking up too early and/or

▪ Occurring more days of the week than not

▪ Ongoing for over 3 months

Why Should PCP’s be Proactive about Insomnia?

▪ Very prevalent in primary care

▪ But patients don’t tell you

▪ Serious consequences

▪ Day to day life

▪ Poor outcome on mental and

physical health

▪ Insomnia is a clue

▪ Most insomnia is co-morbid

▪ Easy to identify

Treatment

▪ Relieves an upsetting symptom

▪ Improves next day

consequences

▪ Improves outcome of

co-morbidity

▪ Psychiatric

▪ Medical

▪ Majority is done by PCP

Insomnia Risk Factors

▪ Age (older)

▪ Sex (especially post-1 and perimenopausal2 females)

▪ Divorce / separation / widowhood

▪ Psychiatric illness (mood and anxiety disorders)

▪ Medical conditions

▪ Cigarette smoking

▪ Alcohol and coffee consumption

▪ Certain prescription drugs

1. NIH Consens State Sci Statements. 2005;22:1-30.

2. Young T, et al. Sleep. 2003;26:667-672.

Insomnia Screening and Follow-up

▪ Sleep Schedule: Do you have trouble getting to sleep, staying asleep, or waking

up too early?

▪ Daytime consequences: Do you feel like you have slept well throughout the day?

▪ Sleep timing: When do you go to bed? …Wake up? …Middle of the night

awakening? …How long does it take you to fall back to sleep?

▪ Treatments: What remedies have you tried? Any previous Rx’s?

▪ Sleep hygiene/lifestyle issues: Alcohol? Smoking? Exercise? Medications that

cause insomnia?

▪ Duration, frequency, prior: How long has this been going on?...How often?...

Have you had it before?...

Sateia MJ, Doghramji K, Hauri PJ, Morin MM. Sleep. 2000;23:1-66.

Erman MK. In: Sleep Disorders: Diagnosis and Treatment. Totowa, NY: Humana Press; 1998:21-51.

How Frequent are Comorbidities?

Terzano MG, et al. Sleep Med. 2004;5:67-75. Katz DA, McHorney CA. (1998).

Clinical correlates of insomnia in patients with chronic illness. Arch Intern Med 158(10):1099-1107.

35

28

19 17 15 1411

0

10

20

30

40

50

30

47

37 39

50

3842

106

17

2522

1215

0

10

20

30

40

50

InsomniaSevere insomnia

Pre

vale

nce

%Medical Conditions in Primary

Care Patients with InsomniaInsomnia with Medical Conditions

How Does Inadequate Sleep Increase CVD?

▪ Total sleep time (TST) < 5 hours compared to TST > 5 hours

▪ Higher glucose & cortisol levels

▪ HPA-associated endocrine & metabolic imbalances

▪ Hypercholesterolemia even after controlling for other risk factors

▪ Night-time BP: Nighttime SBP higher and day-to-night SBP dipping was lower

(-8% vs -15%, P < 0.01) in insomniacs

▪ Atherosclerosis: Total sleep time (P = 0.005), and sleep quality (P = 0.05)

contributed to increased carotid intima-media thickness

▪ Inflammation: Serum CRP levels higher and increased at a steeper rate

Lanfranchi, PA, et al. (2009). Nighttime blood pressure in normotensive subjects with chronic insomnia: implications for cardiovascular risk. Sleep 32(6): 760-766.

Nakazaki, C, et al. (2012). Association of insomnia and short sleep duration with atherosclerosis risk in the elderly."Am J Hypertens 25(11): 1149-1155. Parthasarathy,

S, et al. (2015). Persistent insomnia is associated with mortality risk. Am J Med 128(3): 268-275 e262. Lin, CL, et al. (2016). The relationship between insomnia with short

sleep duration is associated with hypercholesterolemia: a cross-sectional study. J Adv Nurs 72(2): 339-347. Farina, B., et al. (2014). Heart rate and heart rate variability

modification in chronic insomnia patients. Behav Sleep Med 12(4): 290-306. de Zambotti, M., et al. (2011). Sleep onset and cardiovascular activity in primary insomnia.

J Sleep Res 20(2): 318-325.

Does Insomnia Contribute to Development of Hypertension?

Lewis, P. E., et al. (2014). Risk of type II diabetes and hypertension associated with chronic insomnia among active component, U.S. Armed Forces,

1998-2013. MSMR 21(10): 6-13.

Prospective Follow-up

▪ Active duty in US Military

▪ Excluded: Chronic

insomnia prior to

1/1/1998

▪ Without hypertension at

baseline

▪ Chronic insomnia led to

higher risk of

hypertension (aHR 2.00)

Rate of Developing

Hypertension(per 10,000 person-years)

46.2

95.6

0

20

40

60

80

100

Controls Insomnia

Does Insomnia Increase Risk of CVDs?

1.681.85

1.4 1.3

0

0.5

1

1.5

2

aOR of CV Event

0.961.35

4.53

0

1

2

3

4

5

1 2 3

aOR for CHF

1st CV Event

# Insomnia Symptoms

Hsu, CY, et al. (2015). The Association Between Insomnia and Increased Future Cardiovascular Events: A Nationwide Population-Based Study.

Psychosom Med 77(7): 743-751. Laugsand, LE, et al. (2014). Insomnia and the risk of incident heart failure: a population study. Eur Heart J 35(21):

1382-1393. Canivet, C, et al. (2014). Insomnia increases risk for cardiovascular events in women and in men with low SES: a longitudinal, register-

based study. J Psychosom Res 76(4): 292-299.

How Much Does Insomnia Contribute to CV Mortality?

Health Professionals Follow-Up Study

▪ US men free of cancer

▪ Insomnia symptoms in 2004, followed through 2010

▪ Adjusted for age, lifestyle factors, and common chronic conditions

Metaanalysis of 13 Prospective Studies

▪ 122,501 subjects followed for 3-20 yrs

▪ Insomnia increased risk by 45% of developing or dying from CVD ▪ (RR 1.45, 1.29-1.62; p < 0.00001)

Li, Y, et al. (2014). "Association between insomnia symptoms and mortality: a prospective

study of U.S. men." Circulation 129(7): 737-746. Sofi, F, et al. (2014). Insomnia and risk of

cardiovascular disease: a meta-analysis. Eur J Prev Cardiol 21(1): 57-64.

1.25

1.091.04

1

1.25

1.5

Total Mortality CVD MortalityDifficulty Initiating & Nonrestorative

Difficulty initiatingDifficulty maintainingEarly-morning awakenings

1.55 (1.19-2.04)

1.32 (1.02-1.72)

Health Professionals Follow-Up Study

Adjusted Hazards Ratio

How Does Insomnia Contribute to Diabetes Risk?

Insulin Resistance Associated with

Subjective Sleep Complaints In

Those without Diabetes

ORs

Adjusted

for

InsomniaDaytime

Sleepiness

Sex and age1.68

(1.09–2.58)

1.80

(1.22–2.66)

Fully*1.24

(0.74–2.09)

1.75

(1.10–2.77)

*Adjusting for sex, age, alcohol consumption,

smoking, exercise, occupational status, BMI,

and family history of diabetes

Pykkönen A-J, et al. (2012) Subjective Sleep Complaints Are

Associated With Insulin Resistance in Individuals Without Diabetes.

Diabetes Care 35:2271–8.

aORs for HbA1c >= 6.0%

6.79

3.96

2.33

0

2

4

6

8

Kachi, Y., et al. (2011). Association between insomnia symptoms and

hemoglobin A1c level in Japanese men. PLoS One 6(7): e21420.

Males 22-69 years old with no hx of diabetes

Difficulty maintaining

sleep

Lasting 2+wks

Early AM

awakening

Some-times

Some-times

Japanese company annual health check-up

Does Treating Insomnia Lower Blood Pressure?

Standard BP treatment + estazolam

vs.

Standard BP treatment + placebo

▪ Insomnia treatment efficacy

▪ Estazolam: 67.3% (P < 0.001)

▪ Placebo: 14.0%

▪ Goal BP(< 140/90 mmHg)

▪ Estazolam: 74.8% (P < 0.001)

▪ Placebo: 50.5%

Li, Y, et al. (2017). "The impact of the improvement of insomnia on blood

pressure in hypertensive patients." J Sleep Res 26(1): 105-114.

Blood Pressure Reduction

from Baseline

-2.6 -2.8-2.5

-3.4

0

-2.3-2

-2.5 -2.7

-0.7

-2.8

-5

-7.1

0

-2.5

-3.7

-5.4

-8

-6

-4

-2

07 14 21 28 7 14 21 28

Placebo Estazolam

Systolic Diastolic

N = 202N = 200

Days of Treatment

Does Insomnia Increase Risk of Psychiatric Disorders?

31.1

35.9

30

14.4

5

21

18

10

0

5

10

15

20

25

30

35

40

Pa

tie

nts

(%

)

Incidence (%) over 3.5 years

Insomnia (n=240)

No Insomnia (n=739)

Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry. 1996;39:411-418.

Does Treating Insomnia Improve Comorbidities?

0

20

40

60

80

100

4 Months 16 Months

Poor Good

0

20

40

60

80

100

4 Months 16 MonthsControl Tai Chi

By Sleep Quality

%

4 months

CBT .21 (.03-1.47) p<.10

TCC NS

16 months

CBT .06 (.005-.669) p<.01

TCC .10 (.008-1.29) p<.05

ORs of Remaining

at High Risk

2-hour group sessions

weekly for 4 mo with a

16-mo evaluationRisk score based on 8 biomarkers: HDL, LDL, triglycerides,

C-reactive protein, fibrinogen, HA1c, glucose, insulin• High risk = 4 or more abnormal

By Intervention

% Remaining at High Risk

Carroll, JE, et al. (2015). Improved sleep quality in older adults with insomnia reduces biomarkers of disease risk: pilot results from a randomized controlled comparative

efficacy trial. Psychoneuroendocrinology 55: 184-192.

How is Insomnia Best Conceptualized to Guide Treatment?

▪ Genetic: heritability 42% - 57% in chronic insomnia

▪ Final common pathway: Autonomic and CNS hyperarousal

▪ Greater whole-brain metabolism during both sleep and wake periods

▪ Increased secretion of corticotropin and cortisol throughout sleep-wake cycle

▪ Sleep-wake regulation imbalance

▪ Overactivity of arousal systems

▪ Hypoactivity of sleep-inducing systems

▪ Both

▪ Failure of wake-promoting structures to deactivate during the transition

from waking to sleep states

Riemann D., et al. (2015). The neurobiology, investigation, and treatment of chronic insomnia. Lancet Neurol 14(5): 547-558. Vgontzas, AN, et al. (2013).

Insomnia with objective short sleep duration: the most biologically severe phenotype of the disorder. Sleep Med Rev 17(4): 241-254. Vgontzas et al.

Nofzinger et al. Am J of Psychiatry. 2004;161:2126-2128.

1. Kupfer DJ, Reynolds CF III. N Engl J Med. 1997;336:341-346.

2. Consensus Conference. JAMA. 1984;251:2410-2414.

Stepwise Approach for Managing Insomnia

Discuss With

Patient How They Sleep

Diagnosis1, 2

Education,

Including

Good Sleep

Practices1, 2

Nonpharma-

cologic

and/or

Pharma-

cologic

Therapy1, 2

Referral to

Sleep

Specialist

(In Cases of

Treatment

Failure)1

Patient Education: Most Powerful Tool

▪ Inform WHY management is so important

▪ Consequences

▪ Emphasize keeping regimented sleep schedule

▪ Wake up same time every day

▪ Naps usually not a good idea

▪ Emphasize sleeping long enough

▪ Can’t catch up on weekends

▪ Emphasize lifestyle measures

▪ Alcohol, exercise, smoking, caffeine, diet (no large meals)

Treatments: Cognitive Behavioral Therapy (CBT) and/or Medications?

▪ Address the co-morbid condition as well as the insomnia

▪ Discuss with patient pros and cons of meds and CBT

▪ Medications:

▪ Which are best applicable?

▪ Habit forming?

▪ How long to use?

▪ Side effects?

▪ CBT: at your discretion—ability, time, interest

▪ Allow patient to voice his/her concerns, fears, and needs

How Does Cognitive Behavioral Therapy Compare To Pharmacotherapy?

Adapted from: Jacobs GD, et al. Arch Intern Med. 2004;164:1888-1896.

Schutte-Rodin S et al. J Clin Sleep Med. 2008;4(5):487-504. Morin CM, et al. Sleep 1999;22:1134-56.

CBT-I Components

▪ Sleep hygiene education

▪ Cognitive therapy

▪ Sleep restriction therapy

▪ Stimulus control therapy

▪ Relaxation training

Sleep Hygiene

▪ Regular wake time

▪ Limit time awake and in bed

▪ Limit napping during the day

▪ Avoid clock watching if awake

▪ Avoid caffeine (after 2 PM),

alcohol after dinner, or eating

dinner just before bedtime

▪ Avoid stressful activities in

the evening

Treating Insomnia: Choosing the Right Pharmacotherapy

▪ Trouble with sleep initiation only: rapid and short acting

▪ Ramelteon, triazolam, zaleplon, zolpidem

▪ Trouble staying asleep with sleep initiation problems: rapid and long acting (can use these for sleep initiation only if you so choose)

▪ Eszopiclone, temazepam, zolpidem ER, zolpidem, suvorexant, lemborexant

▪ Trouble staying asleep withOUT sleep initiation problems

▪ Doxepin (taken at sleep onset), sublingual zolpidem (taken if one awakens)

▪ Issues with controlled substances: both of these unscheduled

▪ Ramelteon, doxepin

▪ Generic medications

▪ Temazepam, triazolam, zaleplon, zolpidem, eszopiclone

When to Consider Referral to a Sleep Expert

▪ Suspected obstructive sleep apnea or narcolepsy1-3

▪ Violent behaviors or unusual parasomnias1-3

▪ Daytime tiredness (sleepiness) that you can’t figure out1

▪ Insomnia fails to respond to behavioral and/or pharmacologic

therapy after an appropriate interval1,3

▪ You don’t feel comfortable treating the condition

1. Doghramji P. J Clin Psychiatry. 2001;62(suppl 10):18-26.

2. Sateia MJ, Owens J, Dube C, Goldberg R. Sleep. 2000;23:243-308.

3. Kushida CA, Littner MR, Morgenthaler T, et al. Sleep. 2005;28:499-521.

Summary

▪ Sleep is a necessary function of life. The absence and/or

disruption of which has serious consequences with quality and

quantity of life

▪ Most patients don’t volunteer sleep symptoms, so the PCP

must extract this information from them

▪ Patients with EDS have to be assessed and diagnosed to be

managed adequately

▪ Most sleep problems that patients present with can be fully

addressed and managed by the PCP

Additional Resources

▪ For additional resources, visit:

▪ TheNSF.org

▪ TheNSF.org/continuing-medical-education/

▪ Sleephealthjournal.org