Narcolepsy By: E. Tomas Calderon M.D.

Narcolepsy Syndrome of abnormal sleep tendencies including excessive day time sleepiness Syndrome of abnormal sleep tendencies including excessive day time sleepiness Disturbed nocturnal sleep Disturbed nocturnal sleep Pathological Manifestations of REM sleep Pathological Manifestations of REM sleep Prevalence close to 0.04% of population Prevalence close to 0.04% of population

REM Abnormalities include Sleep onset REM periods Sleep onset REM periods Dissociated REM sleep inhibitory processes, cataplexy, sleep paralysis, and hypnagogic hallucinations Dissociated REM sleep inhibitory processes, cataplexy, sleep paralysis, and hypnagogic hallucinations

Narcolepsy Syndrome of state of instability Syndrome of state of instability Patients have capacity to achieve wakefulness, non REM and REM sleep unable to maintain state Patients have capacity to achieve wakefulness, non REM and REM sleep unable to maintain state

Narcolepsy Lack of modulator responsible for maintaining active sleep state thus patients will dissociate into various states of consciousness at inappropriate times 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 This will lead to states of consciousness that are mixture of normal states Such as: Such as: –Cataplexy which is waking state with paralysis of REM

Narcolepsy Classic tetrad Excessive daytime sleepiness Excessive daytime sleepiness Cataplexy Cataplexy Sleep paralysis Sleep paralysis Hypnagogic Hallucinations Hypnagogic Hallucinations

Narcolepsy Automatic behavior and disruptive night time sleep also occur commonly Automatic behavior and disruptive night time sleep also occur commonly

Narcolepsy All symptoms are not present in all patients All symptoms are not present in all patients

Narcolepsy Many symptoms of narcolepsy can occur in any patient who is sleep deprived Many symptoms of narcolepsy can occur in any patient who is sleep deprived From insufficient or nonrestorative sleep From insufficient or nonrestorative sleep Only cataplexy is unique to narcolepsy Only cataplexy is unique to narcolepsy

Narcolepsy In almost all cases with cataplexy and in rare cases without cataplexy narcolepsy is associated with deficiency of hypothalamic neuropeptide hypocretin 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 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 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 Durations of sleepiness will last minutes or longer than one hour if recumbent Patients will wake up from nap feeling refreshed 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 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 Abrupt reversible decrease or loss of muscle tone Elicited by emotional response such as laughter, anger or surprise Elicited by emotional response such as laughter, anger or surprise

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

Cataplexy Severity can vary from absolute powerlessness which seems to involve entire voluntary musculature 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 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 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 Patient is aware of condition and able to recall completely later Episodes lasting rarely than few minutes Episodes lasting rarely than few minutes

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

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

Sleep Paralysis Usually simple forms such as colored circles or parts of objects Usually simple forms such as colored circles or parts of objects Maybe formed images such as animals or persons Maybe formed images such as animals or persons

Hallucinations Auditory are also common ranging from sounds to melody Auditory are also common ranging from sounds to melody Or cestenopathic feelings such as picking, rubbing or light touching Or cestenopathic feelings such as picking, rubbing or light touching

Narcolepsy Onset of clinical symptoms usually 15 to 25 years of age Onset of clinical symptoms usually 15 to 25 years of age On occasion may occur earlier On occasion may occur earlier Second smaller peak between 35 to 45 years of age Second smaller peak between 35 to 45 years of age

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

Diagnostic Procedures in Evaluation of Sleepiness Polysomnogram Polysomnogram MSLT MSLT Epworth Sleepiness Scale Epworth Sleepiness Scale Sleep Diary Sleep Diary

Positive Diagnosis for Narcolepsy MSLT mean sleep latency less than 8 minutes with 2 REM onset periods 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 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 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 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 Mignot showed that 40% of subjects with two or more sleep onset REM periods were positive for DQB1*0602

Genetic Testing HLA typing is very high more than 90% in narcolepsy with cataplexy for DQB1*0602 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 DQB1*0602 is 40% positive for narcolepsy without cataplexy

Genetic Testing HLAQB1*0602 Caucasians85-100%22% African American 90-95%34% Japanese100%12% With Cataplexy Control Subjects

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

Hypocretin Patients with cataplexy have undetectable amounts of hypocretin in cerebral spinal fluid 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 Neuropathological studies indicate dramatic loss of hypocretin in brains and hypothalami in narcoleptic patients with cataplexy

Hypocretin Using 110 pg/ml cutoff Using 110 pg/ml cutoff CSF hypocretin measurements in patients with cataplexy are 99% specificity 87% sensitive CSF hypocretin measurements in patients with cataplexy are 99% specificity 87% sensitive

Hypocretin CSF measurements are more limited predicative power with narcolepsy without cataplexy CSF measurements are more limited predicative power with narcolepsy without cataplexy Most patients have normal levels Most patients have normal levels

Hypocretin HLA typing would be useful first step than a lumbar puncture to assess hypocretin levels 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 All cases of narcolepsy with low CSF hypocretin are HLADQB1*0602 positive

Hypocretin Estimates of observing low levels of CSF hypocretin in HLA negative primary narcolepsy is less than 1% 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 Excessive daytime sleepiness Cataplexy REM related symptoms Cataplexy REM related symptoms Behavioral approaches

Treatment of Narcolepsy Excessive daytime sleepiness Modafinil (Provigil) Modafinil (Provigil) Methylphenidate (Ritaline) Methylphenidate (Ritaline) Dextroamphetamine Dextroamphetamine Gammahydroxybutyrate (Xyrem) Gammahydroxybutyrate (Xyrem)

Treatment of Excessive Sleepiness Provigil Histaminergic effect along with inhibiting dopamine uptake Histaminergic effect along with inhibiting dopamine uptake Relative lack of side effects Relative lack of side effects No blood pressure effects No blood pressure effects Not addictive Not addictive

Treatment of Excessive Sleepiness Ritalin Wake promoting effect is secondary to dopamine release stimulation and dopamine reuptake inhibition 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 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 Will have cojoint dopaminergic and adrenergic effects and have cataplectic properties at high doses Abuse and dose escalation can occur Abuse and dose escalation can occur

Treatment of Cataplexy Tricyclic Antidepressants Imipramine Imipramine Protripyline Protripyline Desipramine DesipramineSSRI Fluoxitine Fluoxitine Gammahydroxybutyrate (Xyrem)

Treatment of Cataplexy Older Tricyclic Antidepressants Cholinergic, histaminergic and alpha adrenergic blocking properties Cholinergic, histaminergic and alpha adrenergic blocking propertiesSSRI’s Monoamine uptake inhibition Monoamine uptake inhibition Serotonin, norpinephrine, epinephrine and dopamine Serotonin, norpinephrine, epinephrine and dopamine

Treatment of Cataplexy Adrenergic uptake blockers are excellent anticataplectic agents with potent inhibitory effects in REM sleep 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 Protriptiline, imipramine, desipramine are adrenergic uptake blockers with no effect on serotonin transmission And are potent anticataplectic agents And are potent anticataplectic agents

Treatment of Cataplexy Fluoxitene and other SSRI’s are active agents against cataplexy at relatively high doses likely mediated by weak adrenergic effects 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 Is a sedative anesthetic compound Increasing slow wave and to lesser extent REM sleep Increasing slow wave and to lesser extent REM sleep It will consolidate sleep improving daytime function It will consolidate sleep improving daytime function

Treatment of Cataplexy Gammahydroxybutyrate (Xyrem) Short half life Short half life Must be administered twice a night Must be administered twice a night Cataplexy and daytime alertness also improve after several weeks 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 Will have major effect on dopamine transmission raising brain content of dopamine

Treatment of Narcolepsy Behavioral approaches Scheduled naps Scheduled naps Regular sleep wake schedule Regular sleep wake schedule Avoidance of frequent time zone changes Avoidance of frequent time zone changes Good sleep hygiene Good sleep hygiene

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