(AND IN REAL LIFE)

WITH ACKNOWLEDGMENT TO DR. BARBARA PHILIPS FOR SLIDE

CONTENT

1870’s - First descriptions of narcolepsy/ cataplexy

1920’s - Description of post encephalitic narcolepsy

1950’s - Treatment with methylphenidate; description of

the tetrad; description of idiopathic hypersomnia

1960’s - Use of TCA’s for cataplexy; discovery of

SOREM’s; first reports of OSA

1970’s - Consensus definition of narcolepsy; first

sleep nosology

1990 - International Classification of Sleep Disorders

(ICSD)

The Narcolepsy “Tetrad” Excessive daytime sleepiness (EDS)

Cataplexy

Hypnogogic hallucinations

Sleep paralysis

(Disrupted nocturnal sleep)

Excessive Daytime Sleepiness

Sleep attacks” are neither sensitive nor specific markers of narcolepsy

EDS is the sine qua non of narcolepsy

“monosymptomatic” narcolepsy

Sleepiness of narcolepsy is no different from other kinds of sleepiness

Cataplexy Episodic (bilateral) weakness without altered

consciousness lasting seconds to minutes and precipitated by excitement or emotion

May occur several times/day or a few times/year

Sagging of face, eyelid, or jaw; dysarthria; head drop; blurred vision; knee buckling; “drop attack”

Laughter is most common precipitator

Usually develops within a few months of EDS symptoms, but may develop 10-30 years later

6

Hypnogogic Hallucinations Vivid, “waking dreams” that occur during

transitions between sleep and wakefulness

Hypnogogic @ sleep onset

Hypnopompic @ awakening

May accompany sleep paralysis or occur independently

Neither sleep paralysis nor hypnagogic hallucinations are specific for narcolepsy

7

Making the Diagnosis History

Physical examination

Specific testing

Measuring Sleepiness Subjective scales

Stanford sleepiness scale

Epworth sleepiness scale

Objective testing

Multiple sleep latency testing (MSLT)

Maintenance of wakefulness test (MWT)

9

In-Lab Testing for Narcolepsy Polysomnography (PSG)

Multiple Sleep Latency Testing (MSLT)

10

MSLT Protocol Drug testing advisable (urine drug screen)

Should follow an overnight PSG

4 or 5 naps, 2 hours apart

naps last 20 minutes, or 15 minutes after onset of sleep (longest can be 35 mins)

unit of measure:

minutes to sleep onset (stage 1)

minutes to REM sleep onset (beginning with stage 1)

11

MSLT Findings

Mean sleep latency

Normal is > 10 minutes

8.5-10 minutes is “gray zone”

<8.5 minutes is pathological sleepiness

REM-onset sleep periods

Normal is < 2

If there is only one, it is most likely to be in first nap

One SOREMP obligates you to 5th nap or second SOREMP

Patient #3 26 Y.O. female

Chronic excessive daytime sleepiness

Multiple awakenings

(+)cataplexy, sleep paralysis, hypnagogic

hallucinations

History of hyperparathyroidism

15

Epidemiology of Narcolepsy M=F

1/10,000 1/2000 1/200?

Prevalence varies with ethnicity

1/600 in Japan

1/4000 in North America and Europe

1/500,000 in Israel

Symptoms usually appear in in teens or 20’s, but diagnosis may be delayed by decades.

16

Pathophysiology Sleep-onset REM accounts for associated

symptoms (intrusion of REM atonia)

Impaired sleep/wake regulation is the primary problem

Autoimmune-mediated neuronal damage?

17

Dysfunction of the hpocretin (AKA orexin) peptide system is associated with narcolepsy in dogs and in mice

Hypocretins affect gamma amino butyric acid (GABA) and glutamate secretion

Hypocretins also have a role in appetite stimulation

So what?

Genetics

HLA testing – useful?

DQB1-0602 subtype is most strongly associated with narcolepsy (90% in Caucasians)

Children of narcoleptics have 1% risk.

19

Differential Diagnosis of EDS Sleep deprivation

Another sleep disorder (OSA, RLS)

Poor sleep quality due to illness (CHF)

Medications, drugs, toxins

Depression

Delayed sleep-phase syndrome

Idiopathic hypersomnia

20

Comparison of Narcolepsy and IH Narcolepsy Sleepiness

Naps are frequent and restorative

Cataplexy(+/-)

Disrupted nocturnal sleep

Associated symptoms

Never remits

IH Prolonged or deep

sleep Naps n0n-restorative

No cataplexy

Reports of remission

May follow viral infection, head trauma

Other associated symptoms/signs

Periodic limb movements of sleep are frequently seen on PSG in narcoleptics (as they are in all patients, in general). RLS symptoms are rare.

REM behavior disorder occurs frequently in narcoleptics, and is not associated with increased risk of developing Parkinson’s or other neurologic disorders.

Problems with MSLT

Circadian rhythm

Effects of medications

P atient anxiety

Frequent false negatives, even in patients with cataplexy

Patient #1 31 Y.O. male

EDS since mononucleosis at age 18

Has been told he snores loudly

Possible sleep paralysis and hypnagogic

hallucinations

Also has episodes of onset and maintenance

insomnia, multiple awakenings

AHI TST: 2.9

RDI: 17.4/hr.

Total Sleep Time: 8.5 hrs.

Sleep Efficiency: 90%

REM: 22%

AHI REM: 3.7

Sleep Onset: 6.0 min.

REM latency: 94 minutes

Total Number of PLMS: 0

Sleep logs indicated an average of 8.75 hours of sleep per night for previous week. Bedtimes varied between 10:00 pm and 2:00 am, with wake times between 8:00 am and 10:00 am. (18 months after diagnosis, patient reports episodes of muscle weakness triggered by strong emotion)

There was one sleep onset REM period in Nap 2 with two epochs of REM

Number of Naps 5 Number of Naps with sleep 5 Number of Naps with REM 1 Nap 1 Nap 2 Nap 3 Nap 4 Nap 5 Mean

Lights Out 10:58 AM 1:06 PM 3:06 PM 5:14 PM 7:04 PM ---

Sleep Onset 11:06 AM 1:13 PM 3:12 PM 5:22 PM 7:15 PM ---

Lights On 11:22 AM 1:29 PM 3:29 PM 5:39 PM 7:31 PM ---

Time In Bed 24.0 min. 22.5 min. 23.0 min. 24.5 min. 27.5 min. 24.3 min.

Sleep Time 13.5 min. 14.0 min. 16.5 min. 12.0 min. 13.5 min. 13.9 min.

Sleep Latency 8.5 min. 7.0 min. 6.0 min. 8.0 min. 11.0 min. 8.1 min.

REM Latency --- 9.5 min. --- --- --- 9.5 min.

TREAT THE PATIENT, NOT THE TEST!

• Narcolepsy is ultimately a clinical diagnosis.

• The diagnosis of narcolepsy CANNOT be ruled out by sleep studies alone

• Most patients with a diagnosis of idiopathic hypersomnia have narcolepsy.

• Many narcoleptics are inaccurately diagnosed with chronic fatigue syndrome or fibromyalgia.

• While narcolepsy and depression often coexist, depression is probably over-diagnosed in narcoleptics, diagnosed and undiagnosed.

*opinion

Sleep Academic Award 29

Management of Narcolepsy Patient and family education

Sleep hygiene

Napping

Safety issues

Medications

Sleep Academic Award 30

Drug Treatment for Narcolepsy EDS-stimulants

Amphetamines, Modafinil, Desmodafinil, others

REM-associated phenomena-TCA’s, SSRIs, other REM-suppressing antidepressants.

Sodium Oxybate (Xyrem) – cataplexy AND EDS

31

Drug Therapy Issues

Abuse (not!)

Compliance

Drug holidays

Patient #2 19 Y.O. female college student

Severe excessive daytime sleepiness beginning 7 months before referral

No cataplexy, etc.

Less sleepy if she sleeps 10 hours/night