insomnia and narcolepsy
TRANSCRIPT
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Insomnia and Narcolepsy- A walkthrough
By: Arya.M.J
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Narcolepsy
• Narcolepsy is a chronic disease of the central nervous system.
• Syndrome of abnormal sleep tendencies including excessive day time sleepiness.
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REM Abnormalities include
• Sleep onset REM periods• Dissociated REM sleep inhibitory processes,
cataplexy, sleep paralysis, and hypnagogic hallucinations
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Narcolepsy
• Syndrome of state of instability • Patients have capacity to achieve
wakefulness, non REM and REM sleep unable to maintain state
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Narcolepsy
• Lack of modulator responsible for maintaining active sleep state thus patients will dissociate into various states of consciousness at inappropriate times
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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
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Narcolepsy
• Primary symptoms of narcolepsy include:i. Excessive Daytime Sleepiness(EDS)ii. Loss of muscletone(Cataplexy)iii.Inablility to move or talk(Sleep Paralysis)iv.Distorted Perceptions(Hypnagogic
hallucinations)
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Narcolepsy
• Automatic behavior and disruptive night time sleep also occur commonly
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Narcolepsy
• All symptoms are not present in all patients
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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
• In almost all cases with cataplexy and in rare cases without cataplexy narcolepsy is associated with deficiency of hypothalamic neuropeptide hypocretin
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Narcolepsy
• Hypocretin neurons located in hypothalamus contribute to regulation of the activity of norepinephrine, serotonin, histamine and acetycholine cell groups
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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
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Narcolepsy Sleepiness
• Durations of sleepiness will last minutes or longer than one hour if recumbent
• Patients will wake up from nap feeling refreshed
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Narcolepsy Sleepiness
• May feel abnormally drowsy resulting in poor performance at work, memory lapses, ambulatory, gestural speech automatisms
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Cataplexy
• Abrupt reversible decrease or loss of muscle tone
• Elicited by emotional response such as laughter, anger or surprise
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Cataplexy
• This may occur in two thirds of patients with narcolepsy
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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
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Sleep Paralysis
• Experience on falling asleep or waking up where patients suddenly are unable to move limbs, speak or breathe deeply
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Sleep Paralysis
• Patient is aware of condition and able to recall completely later
• Episodes lasting rarely than few minutes
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Sleep Paralysis
• May occur as independent phenomenon in 3 to 5% of population
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Hallucinations
• Either on falling asleep- hypnagogic• Or awakening – hypnopompic• Hallucinations may accompany sleep paralysis
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Sleep Paralysis
• Usually simple forms such as colored circles or parts of objects
• Maybe formed images such as animals or persons
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Hallucinations
• Auditory are also common ranging from sounds to melody
• Or cestenopathic feelings such as picking, rubbing or light touching
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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%
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Diagnostic Procedures in Evaluation of Sleepiness
• Polysomnogram• MSLT• Epworth Sleepiness Scale• Sleep Diary
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Positive Diagnosis for Narcolepsy
• MSLT mean sleep latency less than 8 minutes with 2 REM onset periods
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Positive Diagnosis for Narcolepsy
• Need polysomnogram study prior to MSLT to rule out nonrestorative sleep
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Positive Diagnosis for Narcolepsy
• Nonrestorative sleep, insufficient sleep or circadian rhythm disturbance can also account for sleepiness on MSLT along with REM onset intrusions
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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
• HLA typing is very high more than 90% in narcolepsy with cataplexy for DQB1*0602
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Genetic Testing
• DQB1*0602 is 40% positive for narcolepsy without cataplexy
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Genetic Testing
HLAQB1*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
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Narcolepsy
• Presence of cataplexy solidifies diagnosis of narcolepsy
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Hypocretin
• Patients with cataplexy have undetectable amounts of hypocretin in cerebral spinal fluid
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Hypocretin
• Neuropathological studies indicate dramatic loss of hypocretin in brains and hypothalami in narcoleptic patients with cataplexy
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Hypocretin
• Using 110 pg/ml cutoff• CSF hypocretin measurements in patients with
cataplexy are 99% specificity 87% sensitive
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Hypocretin
• CSF measurements are more limited predicative power with narcolepsy without cataplexy
• Most patients have normal levels
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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%
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Treatment of Narcolepsy
Phamacologic treatments • Excessive daytime sleepiness• Cataplexy REM related symptomsBehavioral approaches
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Treatment of Narcolepsy
Excessive daytime sleepiness• Modafinil (Provigil)• Methylphenidate (Ritaline)• Dextroamphetamine • Gammahydroxybutyrate (Xyrem)
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Treatment of Excessive Sleepiness
Provigil • Histaminergic effect along with inhibiting
dopamine uptake • Relative lack of side effects • No blood pressure effects• Not addictive
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Treatment of Excessive Sleepiness
Ritalin• Wake promoting effect is secondary to
dopamine release stimulation and dopamine reuptake inhibition
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Treatment of Excessive Sleepiness
• Compounds selective for dopaminergic transmission have no effect on cataplexy
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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
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Treatment of Cataplexy
Tricyclic Antidepressants • Imipramine• Protripyline• DesipramineSSRI• FluoxitineGammahydroxybutyrate (Xyrem)
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Treatment of Cataplexy
Older Tricyclic Antidepressants• Cholinergic, histaminergic and alpha
adrenergic blocking propertiesSSRI’s • Monoamine uptake inhibition• Serotonin, norpinephrine, epinephrine and
dopamine
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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
• Fluoxitene and other SSRI’s are active agents against cataplexy at relatively high doses likely mediated by weak adrenergic effects
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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
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Treatment of Cataplexy
Gammahydroxybutyrate (Xyrem)• Short half life • Must be administered twice a night• Cataplexy and daytime alertness also improve
after several weeks
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Treatment of Cataplexy
Gammahydroxybutyrate (Xyrem)Mode of action• Will have major effect on dopamine
transmission raising brain content of dopamine
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Treatment of Narcolepsy
Non-drug treatments• Scheduled naps• Regular sleep wake schedule• Avoidance of frequent time zone changes• Good sleep hygiene
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Medical treatments
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The End