Narcolepsy-cataplexy sleepiness

Willie, J. T. Yanagisawa, M. (2007). Lessons from sleepy mice narcolepsy-cataplexy and the orexin neuropeptide system. In Narcolepsy and Hypersomnia, ed. C. Bassetti, M. Billiard E. Mignot, New York, NY Informa Healthcare, pp. 257-78. 

Newman, J. and Bough ton, R., Pupillometric assessment of excessive daytime sleepiness in narcolepsy-cataplexy, Sleep, 14, 121, 1991. 

Broughton R, Valley V, Aguirre M, Roberts J, Suwalski W, Dunham W (1986) Excessive daytime sleepiness and the pathophysiology of narcolepsy-cataplexy a laboratory perspective. Sleep 9 205-215... 

The sleep disorder narcolepsy, which affects around 1 in every 2000 people, is characterized by a tetrad of symptoms excessive daytime sleepiness, cataplexy (loss of muscle tone triggered by emotional arousal), hypnagogic hallucinations,... 

Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy, may be caused by the lack of hypocretin mRNA and peptides in humans (Peyron et al., 2000) or a disruption of the hypocretin receptor 2 or its ligand in dogs and mice (Lin et al., 1999 Chemelli et al., 1999). Hypocretin-containing neurons are located exclusively in the dorsomedial, lateral, and perifornical hypothalamic areas (Peyron et al., 1998). Two hypocretin sequences, Hcrt-1 (orexin-A) and Hcrt-2 (orexin-B), are generated from a single preprohypocretin (De Lecea et al., 1998 Peyron et al, 1998 Sakurai et al, 1998). Axons from these neurons are found in the hypothalamus, locus coeruleus (LC), raphe nuclei, tuberomamillary nucleus, midline thalamus, all levels of spinal cord, sympathetic and parasympathetic centers, and many other brain regions... 

The essential features are sleep attacks, cataplexy, hypnagogic hallucinations, and sleep paralysis. Individuals with narcolepsy complain of excessive daytime sleepiness, sleep attacks that last up to 30 minutes, fatigue, impaired performance, and disturbed nighttime sleep. They have multiple arousals during the night. 

Medications used to treat narcolepsy are shown in Table 72-5. Pharmacotherapy focuses on excessive daytime sleepiness and cataplexy. 

One peculiar effect of GHB is that it seems to reduce the symptoms of narcolepsy, a relatively rare sleep disorder. People with narcolepsy are excessively sleepy all the time and often have a condition called cataplexy, in which the person can suddenly and unexpectedly lose all muscle tone and fall immediately into rapid eye movement (REM) sleep (the stage of sleep during which dreaming occurs). 

Other Hypersomnias. Narcolepsy is not the only hypersomnia, but it is by far the most common. Primary hypersomnia shares sleep attacks and excessive daytime sleepiness with narcolepsy but does not feature cataplexy or REM-associated abnormalities. Another rare hypersomnia is Kleine-Levin syndrome (KLS), which most often occurs in teenage boys. KLS consists of intermittent bouts of hypersomnia and bizarre behaviors including compulsive eating and sexual inappropriateness. Distinguishing these hypersomnias from narcolepsy may help clarify the patient s prognosis, but the treatment alternatives are very similar. 

Some stimulants are approved for treatment of narcolepsy. Stimulants mainly improve excessive daytime sleepiness, and the effects may be dose related (Mitler et al. 1990). However, cataplexy usually does not respond to stimulants (Hyman et al. 1995). Stimulants are often administered in divided daily doses, and doses are often titrated weekly on the basis of clinical response. 

One of the oldest uses for dextroamphetamines is in the treatment of narcolepsy, a sleep disorder characterized by constant daytime fatigue and sleepiness, with a disturbance in nighttime REM sleep (the period of sleep when dreams occur). During the day or other periods of time when they would normaly be awake, people with narcolepsy often experience sudden episodes of REM sleep. They may also suffer from sleep paralysis and/or cataplexy, an abmpt, total loss of muscle control. Central nervous system stimulants like dextroamphetamine help to relieve these symptoms. 

With no effective treatment for narcolepsy currently available, the approximately 100,000 to 125,000 people in the United States afflicted with the often debilitating disease are eager for this research to yield a therapeutic drug. Narcolepsy causes excessive daytime sleepiness often accompanied by cataplexy, a sudden... 

Sleepiness is a primary symptom of narcolepsy, often preceding the onset of the other well-known symptoms of the disease, namely cataplexy, sleep paralysis, and hypnagogic hallucinations (44). Evaluation of the MSLT of narcoleptic patients has demonstrated a short sleep latency (<5 min) and multiple sleep-onset REM periods (SOREMPs). The more specific finding in the MSLT of narcoleptic patients is more than 2 SOREMPs, shown to reach a specificity of 99% by Amira et al. (45), which further increased to 99.2% if 3 SOREMPs were recorded (46). On the other hand, more than one SOREMP can occur in nonnarcoleptic patients, such as those with sleep apnea, sleep deprivation, depression, periodic limb movements, circadian rhythm disruption, or withdrawal from REM-suppressing medications (5,47). Thus, the findings of the MSLT, which is always performed for suspected narcoleptic patients, must be interpreted in view of the clinical history and nocturnal PSG. 

The prevalence of narcolepsy with cataplexy is 1 in 10,000 or 0.02% to 0.16% worldwide (69). Patients usually present with complaints of excessive daytime sleepiness before the onset of hypnogogic/hypnopompic hallucinations, sleep... 

The word narcolepsy refers to a syndrome of unknown origin that is characterized by abnormal sleep tendencies, including excessive daytime sleepiness and often disturbed nocturnal sleep and pathological manifestations of REM sleep. The REM sleep abnormalities include sleep onset REM periods and the dissociated REM sleep inhibitory processes, cataplexy and sleep paralysis. Excessive daytime sleepiness, cataplexy, and less often sleep paralysis and hypnagogic hallucinations are the major symptoms of the disease [12]. 

Narcolepsy genetic characteristics. Rare, disabling sleep disorder of unknown origin. Characterized by sudden attacks of flaccid paralysis (cataplexy), extensive daytime sleepiness, sleep paralysis, hypnagogic hallucinations and rapid onset of rapid eye movement (REM) phase of sleep. 

Narcolepsy is a rare disease characterized by excessive daytime sleepiness. It has a prevalence of 0.05% in the general population and affects an estimated 140,000 people in the United States. In 2002, the FDA approved sodium oxybate (Xyrem ) for the treatment of cataplexy in patients with narcolepsy. The active ingredient in this drug is gamma hydroxybutyrate, or GHB. The development and marketing of sodium oxybate was permitted after a revision of the Date Rape Prevention Act of 2000 (see Chapter 5) that allowed GHB to be legally administered for medical purposes. 

In a double-blind, randomized, placebo-controlled, crossover study in 24 patients with narcolepsy, gammahydroxybutyrate 60 mg/kg in a single night-dose for 4 weeks reduced the daily number of hypnagogic hallucinations, daytime sleep attacks, and the severity of subjective daytime sleepiness, and tended to reduce the number of daily attacks of cataplexy (2). It reduced the percentage of wakefulness during REM sleep and the number of awakenings out of REM sleep, and tended to increase slow wave sleep. Adverse events were few and mild. 

Monitoring parameters for pharmacotherapy of narcolepsy include reduction in daytime sleepiness, cataplexy, hypnagogic and hypnopompic hallucinations, and sleep paralysis. Patients should be evaluated regularly during medication titration, then every 6 to 12 months to assess adverse drug events (e.g., mood changes, sleep disturbances, and cardiovascular abnormalities). If symptoms increase during therapy, PSG should be done. 

Narcolepsy is a chronic neurological disorder and is characterised by excessive daytime sleepiness (EDS), usually accompanied by cataplexy (attacks of weakness on emotional arousal). These symptoms are often associated with the intrusion into wakefulness of other elements of rapid eye movement (REM) sleep, such as sleep paralysis and hypnagogic hallucinations, i.e. in a transient state preceding sleep. 

Doses of medications used to treat narcolepsy are summarized in Table 71-5. Pharmacologic management of narcolepsy is focused on two primary areas treatment of excessive daytime sleepiness (EDS) and treatment of cataplexy. 

The primary objective of pharmacologic treatment of narcolepsy is to reduce symptoms that adversely impact the quality of life. This includes alleviating daytime sleepiness with modaflnil or stimulants. The goal is to produce the fullest possible return of normal function for patients at work, school, home, and socially. Cataplexy, hypnagogic hallucinations, and sleep paralysis should be treated when they are present and troublesome. The health care provider should consider... 

Some clinicians believe that combinations of long- and shortacting stimulants are effective for the treatment of narcolepsy. Some stimulants have a short effective period, while others have a longer duration of activity and slower onset of action. By combining stimulants with different activities it may be possible to achieve alertness more rapidly and for a longer period. In addition, although published evidence is limited, combinations of stimulants and antidepressants may be of benefit for treatment of sleepiness and cataplexy. 

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