insomnia and narcolepsy

Insomnia and Narcolepsy- A walkthrough

By: Arya.M.J

Narcolepsy

• Narcolepsy is a chronic disease of the central nervous system.

• Syndrome of abnormal sleep tendencies including excessive day time sleepiness.

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

• 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

• 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)

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

Narcolepsy

• 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

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

Genetic Testing

• 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

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

Narcolepsy

• 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

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 symptomsBehavioral 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• DesipramineSSRI• FluoxitineGammahydroxybutyrate (Xyrem)

Treatment of Cataplexy

Older Tricyclic Antidepressants• Cholinergic, histaminergic and alpha

adrenergic blocking propertiesSSRI’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

Treatment of Cataplexy

• 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

Non-drug treatments• Scheduled naps• Regular sleep wake schedule• Avoidance of frequent time zone changes• Good sleep hygiene

Medical treatments

The End