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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

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Narcolepsy

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

  2. 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

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

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

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

  6. 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

  7. Narcolepsy Classic tetrad • Excessive daytime sleepiness • Cataplexy • Sleep paralysis • Hypnagogic Hallucinations

  8. Narcolepsy • Automatic behavior and disruptive night time sleep also occur commonly

  9. Narcolepsy • All symptoms are not present in all patients

  10. 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

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

  12. Narcolepsy • Hypocretin neurons located in hypothalamus contribute to regulation of the activity of norepinephrine, serotonin, histamine and acetycholine cell groups

  13. 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

  14. Narcolepsy Sleepiness • Durations of sleepiness will last minutes or longer than one hour if recumbent • Patients will wake up from nap feeling refreshed

  15. Narcolepsy Sleepiness • May feel abnormally drowsy resulting in poor performance at work, memory lapses, ambulatory, gestural speech automatisms

  16. Cataplexy • Abrupt reversible decrease or loss of muscle tone • Elicited by emotional response such as laughter, anger or surprise

  17. Cataplexy • This may occur in two thirds of patients with narcolepsy

  18. 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

  19. Sleep Paralysis • Experience on falling asleep or waking up where patients suddenly are unable to move limbs, speak or breathe deeply

  20. Sleep Paralysis • Patient is aware of condition and able to recall completely later • Episodes lasting rarely than few minutes

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

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

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

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

  25. 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

  26. 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%

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

  28. Positive Diagnosis for Narcolepsy • MSLT mean sleep latency less than 8 minutes with 2 REM onset periods

  29. Positive Diagnosis for Narcolepsy • Need polysomnogram study prior to MSLT to rule out nonrestorative sleep

  30. Positive Diagnosis for Narcolepsy • Nonrestorative sleep, insufficient sleep or circadian rhythm disturbance can also account for sleepiness on MSLT along with REM onset intrusions

  31. 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

  32. Genetic Testing • HLA typing is very high more than 90% in narcolepsy with cataplexy for DQB1*0602

  33. Genetic Testing • DQB1*0602 is 40% positive for narcolepsy without cataplexy

  34. Genetic Testing HLAQB1*0602 With Cataplexy Control Subjects

  35. Narcolepsy • Presence of cataplexy solidifies diagnosis of narcolepsy

  36. Hypocretin • Patients with cataplexy have undetectable amounts of hypocretin in cerebral spinal fluid

  37. Hypocretin • Neuropathological studies indicate dramatic loss of hypocretin in brains and hypothalami in narcoleptic patients with cataplexy

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

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

  40. 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

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

  42. Treatment of Narcolepsy Phamacologic treatments • Excessive daytime sleepiness • Cataplexy REM related symptoms Behavioral approaches

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

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

  45. Treatment of Excessive Sleepiness Ritalin • Wake promoting effect is secondary to dopamine release stimulation and dopamine reuptake inhibition

  46. Treatment of Excessive Sleepiness • Compounds selective for dopaminergic transmission have no effect on cataplexy

  47. 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

  48. Treatment of Cataplexy Tricyclic Antidepressants • Imipramine • Protripyline • Desipramine SSRI • Fluoxitine Gammahydroxybutyrate (Xyrem)

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

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