Narcolepsy

Kelly Carden, MD St Thomas Medical Partners – Sleep Specialists

September 30, 2017 TSS Annual Meeting

ConfliCt of interest DisClosures

Type of Potential Conflict Details of Potential Conflict

Grant/Research Support

Consultant FBI Speakers’ Bureaus Financial support

Other BOD – AASM, ASMF, ABSM, APSS. Sec/Tr – AASM, ASMF, ABSM. Reviewer - UpToDate

2. I wish to disclose the following potential conflicts of interest:

1. I do not have any potential conflicts of interest to disclose, OR

4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture:

X

X 3. The material presented in this lecture has no relationship with any of these potential conflicts, OR

Narcolepsy • The History

• Clinical presentation

• Prevalence

• Pathophysiology

• Diagnosis

• Treatment

History of Narcolepsy 1877/78 - Syndrome first described – Westphal and

Fisher (Germany)

1880 - Gelineau gave narcolepsy its name

1902 – Loewenfeld gave cataplexy its name

1935 – Stimulants introduced

Late 1950’s – TCAs introduced, useful in cataplexy

1960s – methylphenidate available

- Sleep-onset REM periods

1970 – MSLT described

History of Narcolepsy 1973 - Canine model described by Knecht & Mitler 1980s - Association with HLA-DR2 1992 – Association with HLA-DQB1*0602 1998 – Hypocretin/orexin identified almost

simultaneously by DeLecea and Sakurai 1990s - Hypocretin mutations in animals 2000s - Hypocretin deficiency in human

narcolepsy 2002 – Xyrem approved by the FDA

A Case To Ponder

A 23 year old woman is referred for evaluation of excessive sleepiness after having fallen asleep while driving. She reports that her sleepiness has been present since high school, and several times each day she struggles to remain awake. She is worried that this sleepiness is impacting on her job performance, and her boyfriend complains that she often dozes off on dates.

She occasionally feels weak in the knees when laughing. Once, she fell to the ground while laughing during a party and could not get up for 1-2 minutes. She gets about 8 hours of sleep each night. She wakes up 2 or 3 times each night and sometimes has trouble returning to sleep.

If she is sleepy while driving, she may imagine seeing an animal in the road. Sometimes when waking from sleep it feels like she is dreaming though she is sure she is awake.

Several times she has been terrified to find

herself unable to move for a minute after awakening.

Symptoms of Classic Narcolepsy (Narcolepsy Type I) 1) Excessive daytime sleepiness

• Variable patient to patient • Most evident under boring,

monotonous, or relaxing circumstances

• May vary over course of the day • EDS often transiently relieved with

brief naps

Clinical Presentation: EDS

• May feel the onset or experience “sleep attacks”

• Memory lapses and automatic behavior

• Impaired attention / concentration – Decreased work performance – Increased drowsy driving crashes

• Visual disturbances

Clinical Presentation: EDS

1-2/Day 3-4/Day >5Day

Frequency of Daytime Sleep Episodes

< 10 min 10-19 min 20-29 min

30-59 min 1-2 hrs > 2 hrs

Reported Duration of Daytime Naps

Adapted from Honda Y, Juji T, eds. HLA in Narcolepsy. Tokyo: Springer-Verlat, 1988

Clinical Presentation: Automobile Accidents

Sleepiness Related MVA in Patients with Sleep Disorders

0

10

20

30

40

50

60

OSA Narcolepsy Control

Men Women

*

*

*

*p

Symptoms of narcolepsy 2) Cataplexy

• Brief episodes of muscular weakness* • Twitches, esp of facial muscles may be seen • May be mild or partial, unilateral / bilateral • Consciousness is maintained • Usually precipitated by: laughter, anger,

amusement, excitement/surprise, elation, while fighting sleep attack

• DTRs are transiently absent • In children - facial hypotonia (droopy eyelids,

mouth opening, tongue protrusion)

0102030405060708090

100

Legs / knees Jaw Slurred speech Falling toground

Sites of Cataplexy

Adapted from Anic-Labat et al. SLEEP 1999;22.

Clinical Presentation: Cataplexy

0102030405060708090

100

Laughing Joking Anger Stress Sex

Adapted from Anic-Labat et al. SLEEP 1999;22.

Emotions Triggering Cataplexy Clinical Presentation: Cataplexy

Sleep 1999; 22:77-87.

Bassetti CL. Spectrum of narcolepsy. In: Baumann CR, Bassetti CL, Scammell TE, eds. Narcolepsy: Pathophysiology, Diagnosis, and Treatment. Springer Science+Business Media; 2011:309-319. Sturzenegger C, Bassetti CL. The clinical spectrum of narcolepsy with cataplexy: a reappraisal. J Sleep Res. 2004;13(4):395-406.

Swiss Narcolepsy Scale Measures frequency of 5 potential symptoms: Q1 – Inability to fall asleep Q2 – Feeling bad or not well rested in the morning Q3 – Taking a nap during the day Q4 – Weak knees/buckling of the knees during emotions such as laughing, happiness, or anger Q5 – Sagging of the jaw during emotions such as laughing, happiness, or anger

What do these three have in common?

Symptoms of Narcolepsy

3) Hypnagogic / hypnopomnic hallucinations • Vivid, dream-like hallucinations at the beginning

or end of sleep

4) Sleep paralysis • Inability to move upon awakening • Respiration ongoing but some patients c/o

abnormal breathing • Brief • Unsettling/unnerving

Symptoms of narcolepsy

5) Sleep maintenance insomnia • Spontaneous awakenings during the night

6) Automatic Behavior • Driving, writing incoherently • Poor memory • Inattention • Conversations

Clinical Presentation: Symptom Prevalence

0

10

20

30

40

50

60

70

80

90

100

Highest Reported Prevalence

%

EDS Cataplexy Hypnagogic Sleep Fragmented Hallucinations Paralysis Sleep

Adapted from Honda Y, Juji T, eds. HLA in Narcolepsy. Tokyo: Springer-Verlat, 1988

• Excessive daytime sleepiness (EDS)

• Cataplexy • Hypnagogic hallucinations • Sleep paralysis

• Fragmented nocturnal sleep

• Other associated features

Tetrad

Pentad

Clinical Presentation: Symptoms

Associated sleep disorders

– Obstructive sleep apnea – Periodic limb movements – REM behavior disorder – Sleepwalking & sleeptalking – C/o vivid dreaming – Nightmares

Age at Onset of Symptoms

Adapted from Handbook of Sleep Disorders, page 199 by courtesy of Marcel Dekker Inc.

N = 180

01020

30405060

708090

100

110120130

0-5

6-10

11-1

5

16-2

0

21-2

5

26-3

0

31-3

5

36-4

0

41-4

5

46-5

0

51-5

5

56-6

0

61-6

5

AGE OF ONSET (yrs)

AB

SO

LU

TE

FR

EQ

UE

NC

YVivid HypnagogicHallucinationsSleep Paralysis

Cataplexy

EDS/Sleep Attacks

Chart1

0-50-50-50-5

6-106-106-106-10

11-1511-1511-1511-15

16-2016-2016-2016-20

21-2521-2521-2521-25

26-3026-3026-3026-30

31-3531-3531-3531-35

36-4036-4036-4036-40

41-4541-4541-4541-45

46-5046-5046-5046-50

51-5551-5551-5551-55

56-6056-6056-6056-60

61-6561-6561-6561-65

EDS/Sleep Attacks

Cataplexy

Sleep Paralysis

Vivid Hypnagogic Hallucinations

AGE OF ONSET (yrs)

ABSOLUTE FREQUENCY

N = 180

2

1

0

1

5

4

2

3

27

15

10

10

45

32

20

20

17

19

15

13

27

27

23

20

19

18

13

13

14

15

10

10

10

9

8

9

5

10

4

6

4

3

0

2

0

1

0

0

0

1

0

0

Sheet1

EDS/Sleep AttacksCataplexySleep ParalysisVivid hypnagogic hallucinations

0-52101

6-105423

11-1527151010

16-2045322020

21-2517191513

26-3027272320

31-3519181313

36-4014151010

41-4510989

46-5051046

51-554302

56-600100

61-650100

Sheet1

EDS/Sleep Attacks

Cataplexy

Sleep Paralysis

Vivid Hypnagogic Hallucinations

AGE OF ONSET (yrs)

ABSOLUTE FREQUENCY

N = 180

Sheet2

Sheet3

Prevalence

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0.16

0.18

Western Europe& N. America

Japan Israel Multiple Sclerosis(US)

Narcolepsy with cataplexy

Minimal gender differences Adapted from Mignot E. Neurology 1998;50(Suppl 1).

Clinical Presentation: Associated Features

• Psychosocial problems • Depression • Frequent Misdiagnoses

– Major depression – Thyroid disorder – Chronic fatigue syndrome – Schizophrenia

• Headaches • Weight gain (average BMI = 28) • Decreased Quality of Life

Narcolepsy: Disabling Disorder

0

10

20

30

40

50

60

70

80

90

100

PhysicalFunction

Role limitations-physical

Bodily Pain General Health Vitality Social Function Role limitations-emotional

Mental Health

General PopulationEpilepsyNarcolepsyParkinson's

Quality of Life Comparison

SF-3

6 Sc

ore

Adapted from Beusterien et al. SLEEP 1999; 22

Pathophysiology: What Causes Narcolepsy?

• Genetic Predisposition

• HLA DR2, DQB1*0602, DQA1*0102

• Possible autoimmune disease

• Loss of Hypocretin/Orexin neurons (in the hypothalamus)

• Instability of sleep/wake system

What causes narcolepsy?

• Most narcoleptics do not have mutations in the genes coding for hypocretin or its receptors, to date there is only one case of reported preprohypocretin mutation

• First degree relatives with 1-2% risk (10-40 x risk of average population)

• Only 1/3 of monozygotic twins will both develop narcolepsy

Orexin/Hypocretin & Narcolepsy in Canine and Murine models

• Dogs with nonsense mutations in the hypocretin receptor gene have narcolepsy

• Mice lacking hypocretin have narcolepsy • Mice lacking hypocretin neurons have

narcolepsy

Hypocretin/Orexin & Narcolepsy

• CSF levels of hypocretin are very low in most narcoleptics with cataplexy

• Narcoleptics with cataplexy have lost >90% of their hypothalamic hypocretin neurons

• Narcoleptics without cataplexy or with atypical cataplexy usually have normal CSF levels of hypocretin

Pathophysiology: Hypocretin Cell Loss in Human Narcolepsy

Courtesy J. Siegel, UCLA

Normal Narcolepsy

50 microns

10% 24%

CSF orexin useful in:

• Patients unable to discontinue psychotropic medications before MSLT

• False-negative MSLT • Atypical cataplexy

• If HLA typing negative, it is not recommended

to do CSF evaluation

2 Hit hypothesis

Some say we have supporting evidence in…..Finland (etc)

H1N1 Swine Flu Vaccination • Pandemrix is AS03, a

so-called adjuvant system, which is an agent added to a vaccine to boost its efficiency.

• AS03 contains squalene, which is extracted from shark liver oil.

Finland Experience In Finland, like other nations, an increase occurred only among the very young. Those older than 20 years did not experience an increase in narcolepsy above background levels

Nearly all of the Finnish children had narcolepsy with cataplexy, and all of them had the HLA DQB1*0602 subtype (Partinen, 2012).

H1N1 Vaccine

Three States of Being in Sleep Medicine

Can you name them?

Three States of Being

• Wake • NREM • REM

Ascending arousal regions

Control of NREM

Control of REM

My Analogy

3 position light switch Dimmer switch

Orexin activates arousal regions

REM-on neurons ( )

Orexin

TMN Raphe LC

PPT LDT

REM-on Neurons

Motor Neurons

Orexin stabilizes the flip-flop

Homeostatic Sleep Drive

Circadian Waking Drive

GAL GABA

NE 5-HT

Stabilizes Behavioral State

Glutamate Orexin

GABA?

ORX

Diagnosis: Evaluation • History

– Sleepiness, cataplexy, other dissociated REM sleep features

• Polysomnography (PSG) – Exclude other causes for EDS (sleep apnea) – Document sleep duration – Identify and treat associated conditions – SOREM on PSG*

• Multiple Sleep Latency Test (MSLT) – Objective sleepiness – Sleep onset REM periods (SOREMPs)

Diagnosis: Polysomnographic Findings

• Short sleep latency • Sleep onset REM period in 50% of

narcolepsy patients • Sleep fragmentation (REM and NREM)

– Increased number of arousals – Increased stage 1 sleep – Low(ish) sleep efficiency

• Frequently associated with periodic leg movements

Diagnosis: Polysomnographic Findings

Pathophysiology: Sleep / Wake Fragmentation

Normal and narcoleptic 24-hour PSG recordings

Con

trol

U

ntre

ated

Pa

tient

Adapted from Rogers AE et al. SLEEP 1994;17

New in the ICSD-3, 2014

• New classification system – Narcolepsy I (aka hypocretin deficiency

syndrome, narcolepsy-cataplexy, narcolepsy with cataplexy). ICD-10 code G47.411

– Narcolepsy II (aka narcolepsy without cataplexy). ICD-10 code G47.419. ~ 15-25% of cases reported

• New diagnostic criteria

Narcolepsy I – Diagnostic Criteria • A and B must be met:

– A. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring > 3 months

– B. One or both of the following: • Cataplexy + MSL of 2

SOREMPs. A SOREMP within 15 minutes of SO on preceding MSLT may replace on of the SOREPs on the MSLT

• Low CNS hypocretin (

Subtypes – Narcolepsy I

• Narcolepsy Type I due to a medical condition – Seen with lesions of the posterior hypothalamus,

midbrain, or pons – Lesions are usually due to tumors, strokes, trauma,

or multiple sclerosis. – May involve the orexin neurons or their

connections to REM- and wake-regulatory regions. • Narcolepsy without cataplexy with low CSF

Hypocretin-1 levels – If diagnostic criteria A and B2 are met.

Narcolepsy II – Diagnostic Criteria • A – E must be met:

– A. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring > 3 months

– B. MSL of 2 SOREMPs. A SOREMP within 15 minutes of SO on preceding MSLT may replace on of the SOREPs on the MSLT

– C. Cataplexy is absent (note 10% may develop changes their classification).

Narcolepsy II – Diagnostic Criteria • A –E must be met:

– D. Either CSF hypocretin – 1 concentration has not been measured or it is not low (it is >110 pg/mL or > 1/3 mean values of normal subjects).

– E. The hypersomnolence and/or MSLT findings are not better explained by other causes such as insufficient sleep, OSA, DSPS, meds or the withdrawal of meds.

Preparing for MSLT Step one: Discontinue sleep-altering/REM suppressant drugs 14 days before test (or more – five times the half life of drug/metabolites)

– Traditional stimulants – Modafinil & Armodafinil – SSRIs, exception need off Prozac 6 weeks! – TCAs and MAOIs – Benzodiazepines, sedatives and muscle

relaxers – Weight loss drugs, for example phentermine – AND…..ask about recreational drugs (e.g. MJ

is REM suppressant/rebound on w/d)

Preparing for MSLT Step two: Actigraphy and Sleep Diaries

– Actigraphy is “strongly recommended” in the ICDS-3 prior to PSG/MSLT

– 7 hours TIB (or more) x 7d

Practice Parameters

Clinical Practice Guideline for the use of the Multiple Sleep Latency

Test and Maintenance of Wakefulness Test

(Expected publication: Summer 2019)

Diagnosis: MSLT • Standardized protocol

– Always performed after a nocturnal polysomnogram, TST at least 6 hours (PP), goal at least 7 hours (ICSD-3)

– Five 20-minute naps. Four nap ok if 2 SOREMPs already.

– Naps every 2 hours.

– No smoking or vigorous activity 30 min before each nap. No napping in between.

– Measures sleep latency and REM sleep onset

Diagnosis: MSLT – Adults*

Adapted from Mitler et al. Psychiatric Clinics of North America, 1987;10.

Other aspects of running the MSLT

• First nap begins 2-3 hours after morning wake-up

• Each nap opportunity lasts 20 min after lights out OR 15 min after onset of sleep

• Sleep environment must be quiet and comfortable. If not (sirens, construction, etc), note it and maybe repeat the nap

• Toxicology screen to check for illicit drugs / medications that can alter the MSLT

• HLA testing in some centers

It is ok to run a MSLT after a split night study.

Quiz - Question 1 (true or false):

It is ok to run a MSLT after a split night study.

NO!

Quiz - Question 1 (true or false):

Quiz - Question 2 (true or false):

The conventional recording montage for the MSLT includes central EEG (C3-A2, C4-A1) and occipital (O1-A2, O2-A1) derivations, left and right eye electrooculograms (EOGs), mental/submental electromyogram (EMG), and electrocardiogram (EKG).

Quiz - Question 2 (true or false):

The conventional recording montage for the MSLT includes central EEG (C3-A2, C4-A1) and occipital (O1-A2, O2-A1) derivations, left and right eye electrooculograms (EOGs), mental/submental electromyogram (EMG), and electrocardiogram (EKG).

TRUE!

Quiz - Question 3 (true or false):

Sleep onset for the clinical MSLT is determined by the time from lights out to the first epoch of any stage of sleep.

Quiz - Question 3 (is true):

Sleep onset for the clinical MSLT is determined by the time from lights out to the first epoch of any stage of sleep. including stage 1 sleep. Sleep onset is defined as the first epoch of greater than 15 sec of cumulative sleep in a 30-sec epoch.

Quiz - Question 4:

In order to assess for the occurrence of REM sleep, in the clinical MSLT the test continues for 15 minutes from after the first epoch of sleep. Is this duration of 15 minutes determined by “clock time” or determined by a sleep time of 15 minutes?

Quiz - Question 4:

In order to assess for the occurrence of REM sleep, in the clinical MSLT the test continues for 15 minutes from after the first epoch of sleep. The duration of 15 minutes determined by “clock time”

Scoring the MSLT • Score sleep stages of each nap • Sleep latency - Good alpha helps a lot. Normal

is > 10 min. • REM latency is taken as the time of the first

epoch of sleep to the beginning of the first epoch of REM sleep regardless of the intervening stages of sleep or wakefulness.”

• REM sleep - It needs to be definite (scoring manual) REM sleep. Transient atonia or eye movements during NREM sleep are common in narcolepsy but don’t count. Can see REM without atonia as well.

Short MSLT latencies • Acute or chronic sleep deprivation (Did

the patient get at least 6 hours of sleep on the prior night?)

• Actigraphy data? • Disorders that produce sleepiness:

OSA, PLMS, sedating drugs, circadian phase delay/rhythm disorders, etc (Should you even run a MSLT if the prior night’s baseline study revealed OSA? What if pt was just begun on CPAP?)

Sleep-onset REM periods

• About 20% of normal young people may have REM sleep in one nap (usually in the AM)

• REM sleep in >2 naps is suggestive of narcolepsy, but can be caused by by other things that increase REM pressure (e.g. OSA, withdrawal from REM-suppressing drugs, REM sleep deprivation, etc)

Treatment of Excessive Sleepiness - Examples

Methylphenidate (Ritalin, Concerta) Dextroamphetamine (Dexedrine, Adderall) Modafinil (Provigil) Armodafinil (Nuvigil) Gamma Hydroxybutyrate (Xyrem)

Typical dose 20 mg SR 1-2x/day and/or 10-30 mg 2x/day 10 mg SR each AM or 5-30 mg 2x/day 100-400 mg each AM or 200 mg 2x/day 150 – 250 mg per day 1.5-4.5 g at bedtime and 3-4 hours later

Side effects Restlessness, hallucinations, tachycardia, hypertension Insomnia, tachycardia, dry mouth, decreased appetite Headache (34%), nausea (11%), nervousness (7%) Headache (17%), nausea (7%), dizziness (5%), insomnia (5%) AM sedation, nausea, dizzyness

Treatment of cataplexy - Examples

Venlafaxine (Effexor) Fluoxetine (Prozac) Clomipramine (Anafranil) Gamma Hydroxybutyrate (Xyrem)

Typical dose 75-150 mg XR each AM 20-80 mg each AM 10-150 mg at bedtime 1.5-4.5 g at bedtime and 3-4 hours later

Side effects Few side effects, nausea Same, dry mouth Anticholinergic effects, somnolence, weight gain AM sedation, nausea, dizzyness

Pharmacotherapy: Fragmented Nocturnal Sleep

• Variable clinical practice, often not treated • If treated, does not normalize daytime alertness • Can use sedative/hypnotics or sedating

antidepressants • Avoid hypnotics with daytime carryover • GHB is also effective*

Behavioral Interventions • Limited effectiveness as only therapy

– e.g. napping, improving sleep habits • Sleepiness/fragmented sleep exacerbated

by: – Poor sleep hygiene – Shift work – Alcohol & recreational drugs

• Drowsy driving precautions

Conclusions • Narcolepsy is a disabling and prevalent

disorder • Narcolepsy is an impaired ability to

maintain wakefulness and a tendency for elements of REM sleep such as paralysis and hallucinations to intrude into wakefulness.

• Narcolepsy is due to impaired signaling by orexin (hypocretin)

Conclusions • The disorder can be reliably and

objectively diagnosed • Diagnosis often aided by the

PSG/MSLT with the appropriate protocol

• Treatment is effective and improves quality of life

• Understanding of narcolepsy is advancing rapidly

Thank You!!

NarcolepsyConflict of Interest Disclosures �NarcolepsyHistory of NarcolepsyHistory of NarcolepsyA Case To PonderSlide Number 7Slide Number 8Symptoms of Classic Narcolepsy (Narcolepsy Type I)Clinical Presentation: EDSClinical Presentation: EDSClinical Presentation: Automobile AccidentsSymptoms of narcolepsyClinical Presentation: CataplexyClinical Presentation: CataplexySlide Number 16What do these three have in common?Symptoms of NarcolepsySymptoms of narcolepsyClinical Presentation: Symptom PrevalenceClinical Presentation: SymptomsAssociated sleep disordersSlide Number 23PrevalenceClinical Presentation: Associated Features Narcolepsy: Disabling DisorderPathophysiology: �What Causes Narcolepsy?What causes narcolepsy?Orexin/Hypocretin & Narcolepsy�in Canine and Murine modelsHypocretin/Orexin & NarcolepsyPathophysiology: Hypocretin Cell Loss in Human NarcolepsySlide Number 32CSF orexin useful in:2 Hit hypothesis��Some say we have supporting evidence in…..Finland (etc)H1N1 Swine Flu VaccinationFinland ExperienceH1N1 VaccineThree States of Being�in Sleep MedicineThree States of BeingAscending arousal regionsMy AnalogyOrexin activates arousal regionsOrexin stabilizes the flip-flopDiagnosis: EvaluationDiagnosis:�Polysomnographic FindingsSlide Number 46Pathophysiology:�Sleep / Wake FragmentationNew in the ICSD-3, 2014Narcolepsy I – Diagnostic Criteria��Subtypes – Narcolepsy I��Narcolepsy II – Diagnostic CriteriaNarcolepsy II – Diagnostic CriteriaPreparing for MSLTPreparing for MSLTPractice ParametersSlide Number 56Diagnosis: MSLTDiagnosis: MSLT – Adults*Other aspects of running the MSLTQuiz - Question 1 (true or false): �Quiz - Question 1 (true or false): �Quiz - Question 2 (true or false): �Quiz - Question 2 (true or false): �Quiz - Question 3 (true or false): �Quiz - Question 3 (is true): �Quiz - Question 4: �Quiz - Question 4: �Scoring the MSLTShort MSLT latenciesSleep-onset REM periodsTreatment of Excessive Sleepiness - ExamplesTreatment of cataplexy - ExamplesPharmacotherapy: �Fragmented Nocturnal SleepBehavioral InterventionsConclusionsConclusionsThank You!!