Eugene Ahn

University of South Carolina

School of Medicine
Narcolepsy: Introduction

 CNS disorder characterized by excessive

sleepiness, cataplexy, hypnagogic
hallucinations, and sleep paralysis.
 First described in 1876
 Until recently, cause of narcolepsy was
largely unknown.
 Thought to be a disorder where elements of
sleep intrude into wakefulness, and
wakefulness intrudes into sleep.
Narcolepsy: Overview

 Epidemiology
 Clinical Features
 Etiology
 Genetic Factors
 Neuropathology
 Clinical Evaluation
 Differential Diagnosis
 Treatment
Epidemiology

 Second most common cause of disabling

daytime sleepiness after sleep apnea
 Affects 1:2000 people in United States
(0.05% of general population)
 Onset: 5-40 years but typically seen in teens
and early twenties
 Male to Female ratio 1:1
 No racial predominance
 Lifelong persistence
Clinical Features

 Excessive Daytime Sleepiness

 Hypnagogic Hallucinations
 Sleep Paralysis
 Cataplexy
 Insomnia
 Other Symptoms
Excessive Daytime
Sleepiness
 Seen in all patients with narcolepsy
 Prone to sleep throughout the day, often at
inappropriate times
 Patients sleep no more than normal in a 24-
hour period
 Also seen in other disorders associated with
poor sleep
 In contrast with sleep apnea, a short nap is
refreshing
 Can assess with the Epworth Sleepiness
Scale (ESS)
Epworth Sleepiness Scale
 Patients rank on scale of 0-3 likelihood of
dozing in certain situations, with 0 being
least likely and 3 being most likely.
– Sitting and reading
– Watching TV
– Sitting in a meeting or theater
– As a passenger in car for 1 hour
– Lying down to rest in daytime
– Sitting and talking to someone
– Sitting quietly after lunch
– In a car stopped few minutes in traffic
Hypnagogic Hallucinations

 Vivid, distressing hallucinations

 Occur just as the patient falls asleep
 Results as an intrusion of REM sleep
dreaming into wakefulness
 Described as someone entering room
frequently
 Also described as out-of-body
experiences
 Not a sign of psychiatric disease
Sleep Paralysis

 Terrifying experience where patient is

transiently unable to move just before sleep
onset or just after awakening
 Often associated with sense of impending
death, sense of inability to breathe
 Duration can be a few seconds to a couple
of minutes
 Can be terminated spontaneously or by
stimulation to rapidly bring on full
wakefulness
Cataplexy
 Sudden episodes of bilateral muscle
weakness leading to partial or complete
collapse
 Not associated with impairment of
consciousness
 True cataplexy triggered by strong
emotions, anger, excitement lasting 1-2
minutes
 Phenomenon due to atonia of disrupted
REM sleep – inhibition of spinal alpha motor
neurons by abnormally activated cells in
medial medulla.
 Seen in about 60% of narcoleptic individuals
Insomnia

 Seen in some narcoleptic patients

 Spontaneous awakening several times
at night with difficulty returning to
sleep
 Reflects low transition between
wakefulness and sleep
Other Symptoms

 Narcoleptic patients have higher

incidence of other sleep disorders
– Obstructive sleep apnea
– Periodic limb movements of sleep
– REM sleep behavior disorder
 Lower metabolic rate leading to mild
obesity
 Higher incidence of Type II DM
 Migraine headaches
Etiology: Narcolepsy with
Cataplexy
 Due to decrease in functional neuropeptide orexin.
 Orexin-A and orexin-B
– Excitatory effects on postsynaptic neurons
– Released during wakefulness, increases activity of many
brain regions involved in promotion of wakefulness – locus
coeruloeus, raphe nuclei, tuberomammillary nucleus
 90% of narcoleptic patients with cataplexy often
show decreased levels in CSF
 Decreased orexin possibly due to autoimmune
destruction of orexin releasing cells or due to loss
of receptor function
Etiology: Narcolepsy
without Cataplexy
 Patients show normal levels of Orexin
in CSF
 Likely due to different mechanism than
narcolepsy with cataplexy
 Role of abnormal orexin signaling
currently unknown
Genetics

 50-90% of narcoleptics have HLA DR2

and DQ1 antigens
 Strong association with DQB1*0602
haplotype
 Only 25% concordance in monzygotic
twins
– Genetics not likely to play major role
– Environmental factors predominate
Neuropathology
 Selective loss of orexin neurons
 Inflammatory or autoimmune?
 Despite association of narcolepsy and specific HLA
alleles, no change in immune function identified
 Not yet evidence of autoimmune based destruction
of orexin neurons
 No evidence of autoantibodies against orexin in
serum
 No evidence of ongoing inflammation
 However astrocytosis identified, consistent with
chronic neurodegenerative process
Secondary Narcolepsy

 Trauma and insults identified to cause

secondary narcolepsy
– Lesions in posterior hypothalamus
– Midbrain injuries – can lead to narcolepsy-like
presentation without full blown narcolepsy
– Tumors
– Vascular malformations
– Stroke
 Obvious abnormal neurologic exam
associated with secondary narcolepsy
Clinical Evaluation
 Nocturnal PSG (Polysomnography)
 MSLT (Multiple Sleep Latency Test)
 NPSG often demonstrates spontaneous
awakenings, reduced sleep efficiency, and
onset of REM sleep within 20 minutes of
sleep (normal 80-100 minutes)
 MSLT with mean onset of sleep < 8 minutes
(normal 10-15 minutes)
 SOREMs (sleep onset REMs)
 CSF orexin assay
 HLA testing
Diagnosis

 Chronic daytime sleepiness, normal

neurologic exam with:
– Definite cataplexy
– Sleep studies used to confirm diagnosis:
 MSLT < 8 minutes
 2+ SOREMs
 If without cataplexy (Narcolepsy variant):
– Must have definitely abnormal MSLT
 MSLT < 8 minutes
 2+ SOREMs
Differential Diagnosis

 With cataplexy:
– Hypothalamic lesions, Prader-Willi,
Niemann-Pick type C. Will have obvious
neurologic deficits
 Without cataplexy:
– Consider sleep apnea, periodic limb
movements, insufficient sleep,
medications, idiopathic hypersomnia (no
cataplexy, less than 2 SOREMs by
definition)
Treatment

 Pharmacotherapy targeting:
– Daytime sleepiness
 Modafinil (Provigil) – Start 100mg qAM max
400mg qAM
 Amphetamines (Concerta, Ritalin, Metadate,
Methylin, dextroamphetamine) – May require
high doses in some patients. Start 5-20mg
bid/tid, begin with immediate release then
transition to SR preparations.
 Pemoline – Last line drug, fatal hepatotoxicity.
Start 50mg qd, d/c if ALT > 2x normal.
Treatment

 Pharmacotherapy targeting:
– Cataplexy and other REM symptoms
 REM suppressing drugs
– Noradrenergic/serotonergic antidepressants. TCA’s,
SSRI’s/SNRI’s.
 Abrupt withdrawal can lead to status
cataplecticus.
 Gamma hydroxybutyrate (GHB, Xyrem)
– Binds to GABA-B receptors. Dose between 2,250-
4,000mg at bedtime, with 2nd dose 2-4h later.
– “Date rape” drug
– Can result in respiratory depression, coma, death
with overdose/abuse
Treatment

 Nonpharmacologic Approaches
– Planned napping
 Improves daytime sleepiness
 May be inappropriate in school/work settings

 Some require extended naps

– Psychosocial support
 Support groups, encouragement
 Misconceptions about poor motivation,
laziness, irresponsibility