Narcolepsy By: E. Tomas Calderon M.D.. Narcolepsy Syndrome of abnormal sleep tendencies including excessive day time sleepiness Syndrome of abnormal sleep

NarcolepsyNarcolepsy

By: E. Tomas Calderon M.D.By: E. Tomas Calderon M.D.


Syndrome of abnormal sleep Syndrome of abnormal sleep tendencies including excessive day tendencies including excessive day time sleepinesstime sleepiness

Disturbed nocturnal sleep Disturbed nocturnal sleep Pathological Manifestations of REM Pathological Manifestations of REM

sleepsleep Prevalence close to 0.04% of Prevalence close to 0.04% of

populationpopulation

REM Abnormalities includeREM Abnormalities include

Sleep onset REM periodsSleep onset REM periods Dissociated REM sleep inhibitory Dissociated REM sleep inhibitory

processes, cataplexy, sleep paralysis, processes, cataplexy, sleep paralysis, and hypnagogic hallucinationsand hypnagogic hallucinations


Syndrome of state of instability Syndrome of state of instability Patients have capacity to achieve Patients have capacity to achieve

wakefulness, non REM and REM sleep wakefulness, non REM and REM sleep unable to maintain stateunable to maintain state


Lack of modulator responsible for Lack of modulator responsible for maintaining active sleep state thus maintaining active sleep state thus patients will dissociate into various patients will dissociate into various states of consciousness at states of consciousness at inappropriate times inappropriate times


This will lead to states of This will lead to states of consciousness that are mixture of consciousness that are mixture of normal statesnormal states

Such as:Such as:– Cataplexy which is waking state with Cataplexy which is waking state with

paralysis of REMparalysis of REM


Classic tetradClassic tetrad Excessive daytime sleepinessExcessive daytime sleepiness CataplexyCataplexy Sleep paralysisSleep paralysis Hypnagogic Hallucinations Hypnagogic Hallucinations


Automatic behavior and disruptive Automatic behavior and disruptive night time sleep also occur night time sleep also occur commonlycommonly


All symptoms are not present in all All symptoms are not present in all patientspatients


Many symptoms of narcolepsy can Many symptoms of narcolepsy can occur in any patient who is sleep occur in any patient who is sleep depriveddeprived

From insufficient or nonrestorative From insufficient or nonrestorative sleepsleep

Only cataplexy is unique to Only cataplexy is unique to narcolepsynarcolepsy


In almost all cases with cataplexy In almost all cases with cataplexy and in rare cases without cataplexy and in rare cases without cataplexy narcolepsy is associated with narcolepsy is associated with deficiency of hypothalamic deficiency of hypothalamic neuropeptide hypocretin neuropeptide hypocretin


Hypocretin neurons located in Hypocretin neurons located in hypothalamus contribute to hypothalamus contribute to regulation of the activity of regulation of the activity of norepinephrine, serotonin, histamine norepinephrine, serotonin, histamine and acetycholine cell groupsand acetycholine cell groups

Clinical Feature of Clinical Feature of NarcolepsyNarcolepsy

SleepinessSleepiness Unwanted episodes of sleep recur Unwanted episodes of sleep recur

several times a day during several times a day during monotonous sedentary activity but monotonous sedentary activity but also in situations when involved in a also in situations when involved in a tasktask

Narcolepsy SleepinessNarcolepsy Sleepiness

Durations of sleepiness will last Durations of sleepiness will last minutes or longer than one hour minutes or longer than one hour if recumbentif recumbent

Patients will wake up from nap Patients will wake up from nap feeling refreshedfeeling refreshed

Narcolepsy SleepinessNarcolepsy Sleepiness

May feel abnormally drowsy resulting May feel abnormally drowsy resulting in poor performance at work, in poor performance at work, memory lapses, ambulatory, gestural memory lapses, ambulatory, gestural speech automatismsspeech automatisms

CataplexyCataplexy

Abrupt reversible decrease or loss of Abrupt reversible decrease or loss of muscle tonemuscle tone

Elicited by emotional response such Elicited by emotional response such as laughter, anger or surpriseas laughter, anger or surprise

CataplexyCataplexy

This may occur in two thirds of This may occur in two thirds of patients with narcolepsypatients with narcolepsy

CataplexyCataplexy

Severity can vary from absolute Severity can vary from absolute powerlessness which seems to powerlessness which seems to involve entire voluntary musculature involve entire voluntary musculature

To limited involvement of certain To limited involvement of certain muscle groups or fleeting sensation muscle groups or fleeting sensation of weaknessof weakness

Sleep ParalysisSleep Paralysis

Experience on falling asleep or Experience on falling asleep or waking up where patients suddenly waking up where patients suddenly are unable to move limbs, speak or are unable to move limbs, speak or breathe deeplybreathe deeply


Patient is aware of condition and able Patient is aware of condition and able to recall completely laterto recall completely later

Episodes lasting rarely than few Episodes lasting rarely than few minutesminutes


May occur as independent May occur as independent phenomenon in 3 to 5% of population phenomenon in 3 to 5% of population

HallucinationsHallucinations

Either on falling asleep- hypnagogicEither on falling asleep- hypnagogic Or awakening – hypnopompicOr awakening – hypnopompic Hallucinations may accompany sleep Hallucinations may accompany sleep

paralysisparalysis


Usually simple forms such as colored Usually simple forms such as colored circles or parts of objectscircles or parts of objects

Maybe formed images such as Maybe formed images such as animals or personsanimals or persons

HallucinationsHallucinations

Auditory are also common ranging Auditory are also common ranging from sounds to melodyfrom sounds to melody

Or cestenopathic feelings such as Or cestenopathic feelings such as picking, rubbing or light touchingpicking, rubbing or light touching


Onset of clinical symptoms usually Onset of clinical symptoms usually 15 to 25 years of age15 to 25 years of age

On occasion may occur earlier On occasion may occur earlier Second smaller peak between 35 to Second smaller peak between 35 to

45 years of age45 years of age


Familial aspect of narcolepsy with Familial aspect of narcolepsy with cataplexycataplexy

Risk of development of narcolepsy Risk of development of narcolepsy with cataplexy in first degree with cataplexy in first degree relatives is 1 to 2%. This is 10 to 40 relatives is 1 to 2%. This is 10 to 40 times higher than general populationtimes higher than general population

Larger proportion of relatives may Larger proportion of relatives may have isolated sleepiness 4 to 5%have isolated sleepiness 4 to 5%

Diagnostic Procedures in Diagnostic Procedures in Evaluation of SleepinessEvaluation of Sleepiness

PolysomnogramPolysomnogram MSLTMSLT Epworth Sleepiness ScaleEpworth Sleepiness Scale Sleep DiarySleep Diary

Positive Diagnosis for Positive Diagnosis for NarcolepsyNarcolepsy

MSLT mean sleep latency less than 8 MSLT mean sleep latency less than 8 minutes with 2 REM onset periodsminutes with 2 REM onset periods


Need polysomnogram study prior to Need polysomnogram study prior to MSLT to rule out nonrestorative sleepMSLT to rule out nonrestorative sleep


Nonrestorative sleep, insufficient Nonrestorative sleep, insufficient sleep or circadian rhythm sleep or circadian rhythm disturbance can also account for disturbance can also account for sleepiness on MSLT along with REM sleepiness on MSLT along with REM onset intrusionsonset intrusions

Genetic TestingGenetic Testing

Genetic testing has been used to aid Genetic testing has been used to aid clinical diagnosis of narcolepsyclinical diagnosis of narcolepsy

Mignot showed that 40% of subjects Mignot showed that 40% of subjects with two or more sleep onset REM with two or more sleep onset REM periods were positive for DQB1*0602periods were positive for DQB1*0602


HLA typing is very high more than HLA typing is very high more than 90% in narcolepsy with cataplexy for 90% in narcolepsy with cataplexy for DQB1*0602DQB1*0602


DQB1*0602 is 40% positive for DQB1*0602 is 40% positive for narcolepsy without cataplexynarcolepsy without cataplexy


HLAQB1*0602HLAQB1*0602

CaucasiansCaucasians 85-100%85-100% 22%22%

African African AmericanAmerican

90-95%90-95% 34%34%

JapaneseJapanese 100%100% 12%12%

With Cataplexy Control Subjects


Presence of cataplexy solidifies Presence of cataplexy solidifies diagnosis of narcolepsy diagnosis of narcolepsy

HypocretinHypocretin

Patients with cataplexy have Patients with cataplexy have undetectable amounts of hypocretin undetectable amounts of hypocretin in cerebral spinal fluidin cerebral spinal fluid


Neuropathological studies indicate Neuropathological studies indicate dramatic loss of hypocretin in brains dramatic loss of hypocretin in brains and hypothalami in narcoleptic and hypothalami in narcoleptic patients with cataplexy patients with cataplexy


Using 110 pg/ml cutoffUsing 110 pg/ml cutoff CSF hypocretin measurements in CSF hypocretin measurements in

patients with cataplexy are 99% patients with cataplexy are 99% specificity 87% sensitive specificity 87% sensitive


CSF measurements are more limited CSF measurements are more limited predicative power with narcolepsy predicative power with narcolepsy without cataplexywithout cataplexy

Most patients have normal levelsMost patients have normal levels


HLA typing would be useful first step HLA typing would be useful first step than a lumbar puncture to assess than a lumbar puncture to assess hypocretin levelshypocretin levels

All cases of narcolepsy with low CSF All cases of narcolepsy with low CSF hypocretin are HLADQB1*0602 hypocretin are HLADQB1*0602 positivepositive


Estimates of observing low levels of Estimates of observing low levels of CSF hypocretin in HLA negative CSF hypocretin in HLA negative primary narcolepsy is less than 1%primary narcolepsy is less than 1%

Treatment of NarcolepsyTreatment of Narcolepsy

Phamacologic treatments Phamacologic treatments Excessive daytime sleepinessExcessive daytime sleepiness Cataplexy REM related symptomsCataplexy REM related symptoms

Behavioral approachesBehavioral approaches


Excessive daytime sleepinessExcessive daytime sleepiness Modafinil (Provigil)Modafinil (Provigil) Methylphenidate (Ritaline)Methylphenidate (Ritaline) Dextroamphetamine Dextroamphetamine Gammahydroxybutyrate (Xyrem) Gammahydroxybutyrate (Xyrem)

Treatment of Excessive Treatment of Excessive SleepinessSleepiness

Provigil Provigil Histaminergic effect along with Histaminergic effect along with

inhibiting dopamine uptake inhibiting dopamine uptake Relative lack of side effects Relative lack of side effects No blood pressure effectsNo blood pressure effects Not addictiveNot addictive


RitalinRitalin Wake promoting effect is secondary Wake promoting effect is secondary

to dopamine release stimulation and to dopamine release stimulation and dopamine reuptake inhibitiondopamine reuptake inhibition


Compounds selective for Compounds selective for dopaminergic transmission have no dopaminergic transmission have no effect on cataplexyeffect on cataplexy


AmphetaminesAmphetamines Will have cojoint dopaminergic and Will have cojoint dopaminergic and

adrenergic effects and have adrenergic effects and have cataplectic properties at high dosescataplectic properties at high doses

Abuse and dose escalation can occur Abuse and dose escalation can occur

Treatment of CataplexyTreatment of Cataplexy

Tricyclic Antidepressants Tricyclic Antidepressants ImipramineImipramine ProtripylineProtripyline DesipramineDesipramine

SSRISSRI FluoxitineFluoxitine

Gammahydroxybutyrate (Xyrem)Gammahydroxybutyrate (Xyrem)


Older Tricyclic AntidepressantsOlder Tricyclic Antidepressants Cholinergic, histaminergic and alpha Cholinergic, histaminergic and alpha

adrenergic blocking propertiesadrenergic blocking properties

SSRI’s SSRI’s Monoamine uptake inhibitionMonoamine uptake inhibition Serotonin, norpinephrine, Serotonin, norpinephrine,

epinephrine and dopamineepinephrine and dopamine


Adrenergic uptake blockers are Adrenergic uptake blockers are excellent anticataplectic agents with excellent anticataplectic agents with potent inhibitory effects in REM sleeppotent inhibitory effects in REM sleep

Protriptiline, imipramine, Protriptiline, imipramine, desipramine are adrenergic uptake desipramine are adrenergic uptake blockers with no effect on serotonin blockers with no effect on serotonin transmission transmission

And are potent anticataplectic agentsAnd are potent anticataplectic agents


Fluoxitene and other SSRI’s are Fluoxitene and other SSRI’s are active agents against cataplexy at active agents against cataplexy at relatively high doses likely mediated relatively high doses likely mediated by weak adrenergic effectsby weak adrenergic effects


Gammahydroxybutyrate (Xyrem)Gammahydroxybutyrate (Xyrem) Is a sedative anesthetic compound Is a sedative anesthetic compound Increasing slow wave and to lesser Increasing slow wave and to lesser

extent REM sleepextent REM sleep It will consolidate sleep improving It will consolidate sleep improving

daytime functiondaytime function


Gammahydroxybutyrate (Xyrem)Gammahydroxybutyrate (Xyrem) Short half life Short half life Must be administered twice a nightMust be administered twice a night Cataplexy and daytime alertness also Cataplexy and daytime alertness also

improve after several weeksimprove after several weeks


Gammahydroxybutyrate (Xyrem)Gammahydroxybutyrate (Xyrem)

Mode of actionMode of action Will have major effect on dopamine Will have major effect on dopamine

transmission raising brain content of transmission raising brain content of dopaminedopamine


Behavioral approachesBehavioral approaches Scheduled napsScheduled naps Regular sleep wake scheduleRegular sleep wake schedule Avoidance of frequent time zone Avoidance of frequent time zone

changeschanges Good sleep hygiene Good sleep hygiene

The End

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Narcolepsy By: E. Tomas Calderon M.D.. Narcolepsy Syndrome of abnormal sleep tendencies including excessive day time sleepiness Syndrome of abnormal sleep