Transcript Narcolepsy

Narcolepsy
By: E. Tomas Calderon M.D.
Narcolepsy
Syndrome of abnormal sleep tendencies
including excessive day time sleepiness
 Disturbed nocturnal sleep
 Pathological Manifestations of REM sleep
 Prevalence close to 0.04% of population

REM Abnormalities include
Sleep onset REM periods
 Dissociated REM sleep inhibitory
processes, cataplexy, sleep paralysis, and
hypnagogic hallucinations

Narcolepsy
Syndrome of state of instability
 Patients have capacity to achieve
wakefulness, non REM and REM sleep
unable to maintain state

Narcolepsy
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Lack of modulator responsible for
maintaining active sleep state thus
patients will dissociate into various states
of consciousness at inappropriate times
Narcolepsy
This will lead to states of consciousness
that are mixture of normal states
 Such as:

– Cataplexy which is waking state with paralysis
of REM
Narcolepsy
Classic tetrad
 Excessive daytime sleepiness
 Cataplexy
 Sleep paralysis
 Hypnagogic Hallucinations
Narcolepsy

Automatic behavior and disruptive night
time sleep also occur commonly
Narcolepsy

All symptoms are not present in all
patients
Narcolepsy
Many symptoms of narcolepsy can occur
in any patient who is sleep deprived
 From insufficient or nonrestorative sleep
 Only cataplexy is unique to narcolepsy
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Narcolepsy
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In almost all cases with cataplexy and in
rare cases without cataplexy narcolepsy is
associated with deficiency of hypothalamic
neuropeptide hypocretin
Narcolepsy

Hypocretin neurons located in
hypothalamus contribute to regulation of
the activity of norepinephrine, serotonin,
histamine and acetycholine cell groups
Clinical Feature of Narcolepsy
Sleepiness
 Unwanted episodes of sleep recur several
times a day during monotonous sedentary
activity but also in situations when
involved in a task
Narcolepsy Sleepiness
 Durations
of sleepiness will last
minutes or longer than one hour if
recumbent
 Patients will wake up from nap feeling
refreshed
Narcolepsy Sleepiness

May feel abnormally drowsy resulting in
poor performance at work, memory
lapses, ambulatory, gestural speech
automatisms
Cataplexy
Abrupt reversible decrease or loss of
muscle tone
 Elicited by emotional response such as
laughter, anger or surprise

Cataplexy

This may occur in two thirds of patients
with narcolepsy
Cataplexy
Severity can vary from absolute
powerlessness which seems to involve
entire voluntary musculature
 To limited involvement of certain muscle
groups or fleeting sensation of weakness

Sleep Paralysis

Experience on falling asleep or waking up
where patients suddenly are unable to
move limbs, speak or breathe deeply
Sleep Paralysis
Patient is aware of condition and able to
recall completely later
 Episodes lasting rarely than few minutes

Sleep Paralysis

May occur as independent phenomenon in
3 to 5% of population
Hallucinations
Either on falling asleep- hypnagogic
 Or awakening – hypnopompic
 Hallucinations may accompany sleep
paralysis

Sleep Paralysis
Usually simple forms such as colored
circles or parts of objects
 Maybe formed images such as animals or
persons

Hallucinations
Auditory are also common ranging from
sounds to melody
 Or cestenopathic feelings such as picking,
rubbing or light touching

Narcolepsy
Onset of clinical symptoms usually 15 to
25 years of age
 On occasion may occur earlier
 Second smaller peak between 35 to 45
years of age
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Narcolepsy
Familial aspect of narcolepsy with cataplexy
 Risk of development of narcolepsy with
cataplexy in first degree relatives is 1 to
2%. This is 10 to 40 times higher than
general population
 Larger proportion of relatives may have
isolated sleepiness 4 to 5%
Diagnostic Procedures in Evaluation
of Sleepiness
Polysomnogram
 MSLT
 Epworth Sleepiness Scale
 Sleep Diary

Positive Diagnosis for Narcolepsy

MSLT mean sleep latency less than 8
minutes with 2 REM onset periods
Positive Diagnosis for Narcolepsy

Need polysomnogram study prior to MSLT
to rule out nonrestorative sleep
Positive Diagnosis for Narcolepsy

Nonrestorative sleep, insufficient sleep or
circadian rhythm disturbance can also
account for sleepiness on MSLT along with
REM onset intrusions
Genetic Testing
Genetic testing has been used to aid
clinical diagnosis of narcolepsy
 Mignot showed that 40% of subjects with
two or more sleep onset REM periods
were positive for DQB1*0602
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Genetic Testing
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HLA typing is very high more than 90% in
narcolepsy with cataplexy for DQB1*0602
Genetic Testing

DQB1*0602 is 40% positive for narcolepsy
without cataplexy
Genetic Testing
HLAQB1*0602
With Cataplexy
Control Subjects
Caucasians
85-100%
22%
African
American
90-95%
34%
Japanese
100%
12%
Narcolepsy
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Presence of cataplexy solidifies diagnosis
of narcolepsy
Hypocretin

Patients with cataplexy have undetectable
amounts of hypocretin in cerebral spinal
fluid
Hypocretin

Neuropathological studies indicate
dramatic loss of hypocretin in brains and
hypothalami in narcoleptic patients with
cataplexy
Hypocretin
Using 110 pg/ml cutoff
 CSF hypocretin measurements in patients
with cataplexy are 99% specificity 87%
sensitive

Hypocretin
CSF measurements are more limited
predicative power with narcolepsy without
cataplexy
 Most patients have normal levels

Hypocretin
HLA typing would be useful first step than
a lumbar puncture to assess hypocretin
levels
 All cases of narcolepsy with low CSF
hypocretin are HLADQB1*0602 positive
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Hypocretin

Estimates of observing low levels of CSF
hypocretin in HLA negative primary
narcolepsy is less than 1%
Treatment of Narcolepsy
Phamacologic treatments
 Excessive daytime sleepiness
 Cataplexy REM related symptoms
Behavioral approaches
Treatment of Narcolepsy
Excessive daytime sleepiness
 Modafinil (Provigil)
 Methylphenidate (Ritaline)
 Dextroamphetamine
 Gammahydroxybutyrate (Xyrem)
Treatment of Excessive Sleepiness
Provigil
 Histaminergic effect along with inhibiting
dopamine uptake
 Relative lack of side effects
 No blood pressure effects
 Not addictive
Treatment of Excessive Sleepiness
Ritalin
 Wake promoting effect is secondary to
dopamine release stimulation and
dopamine reuptake inhibition
Treatment of Excessive Sleepiness

Compounds selective for dopaminergic
transmission have no effect on cataplexy
Treatment of Excessive Sleepiness
Amphetamines
 Will have cojoint dopaminergic and
adrenergic effects and have cataplectic
properties at high doses
 Abuse and dose escalation can occur
Treatment of Cataplexy
Tricyclic Antidepressants
 Imipramine
 Protripyline
 Desipramine
SSRI
 Fluoxitine
Gammahydroxybutyrate (Xyrem)
Treatment of Cataplexy
Older Tricyclic Antidepressants
 Cholinergic, histaminergic and alpha
adrenergic blocking properties
SSRI’s
 Monoamine uptake inhibition
 Serotonin, norpinephrine, epinephrine and
dopamine
Treatment of Cataplexy
Adrenergic uptake blockers are excellent
anticataplectic agents with potent
inhibitory effects in REM sleep
 Protriptiline, imipramine, desipramine are
adrenergic uptake blockers with no effect
on serotonin transmission
 And are potent anticataplectic agents
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Treatment of Cataplexy
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Fluoxitene and other SSRI’s are active
agents against cataplexy at relatively high
doses likely mediated by weak adrenergic
effects
Treatment of Cataplexy
Gammahydroxybutyrate (Xyrem)
 Is a sedative anesthetic compound
 Increasing slow wave and to lesser extent
REM sleep
 It will consolidate sleep improving daytime
function
Treatment of Cataplexy
Gammahydroxybutyrate (Xyrem)
 Short half life
 Must be administered twice a night
 Cataplexy and daytime alertness also
improve after several weeks
Treatment of Cataplexy
Gammahydroxybutyrate (Xyrem)
Mode of action
 Will have major effect on dopamine
transmission raising brain content of
dopamine
Treatment of Narcolepsy
Behavioral approaches
 Scheduled naps
 Regular sleep wake schedule
 Avoidance of frequent time zone changes
 Good sleep hygiene
The End