While the search continues for a cure for narcolepsy, researchers are studying hypocretin neurotransmission and treating patients with the latest drug therapies.
Narcolepsy is a central nervous system disorder characterized by excessive daytime sleepiness (EDS) and frequently by rapid eye movement (REM) manifestations during normal awakening. Although not rare, narcolepsy is considerably less common than sleep apnea or periodic limb movement disorder. Its prevalence in the United States is 0.02% to 0.05% and is similar between males and females.1 Worldwide, it is been shown to range from 0.02% to 0.18%. Prevalence varies with ethnicity, being more common in Japan and least common in Israel.
Narcolepsy symptoms commence most frequently in the second and third decades. The onset of symptoms is rare after the fourth decade. It has been reported in children as early as 2 years of age. Although symptoms may begin early in life, actual diagnosis may not occur until many years later. Narcolepsy is often mistaken for other disorders characterized by daytime sleepiness and fatigue. A history of symptoms, generally EDS, can in many cases be traced back to puberty.
Narcolepsy consists of a “tetrad” of symptoms. The most common and most specific features are EDS and cataplexy. EDS usually precedes the onset of cataplexy and then develops and progresses over several weeks or months before it stabilizes. It is the primary clinical feature in all patients. It is generally irresistible and persistent. Although patients may be aware of sudden “sleep attacks” when hypersomnia peaks, they are physiologically sleepy all the time. They report feeling refreshed upon awakening in the morning and daytime naps of 15 to 30 minutes’ duration are usually refreshing; however, the benefit from daytime naps is limited, lasting only 2 to 3 hours.
Cataplexy (to strike down in fear) is the abrupt loss of muscle tone precipitated by intense emotion; most commonly, laughter, but emotions such as anger, surprise, excitement, and sexual arousal may also trigger cataplectic attacks. These attacks occur without the loss of consciousness, may be characterized by partial or complete loss of muscle tone (sagging of face, eyelid, or jaw; head drop; blurred vision; or buckling of the knees), and last anywhere from a few seconds to minutes. Cataplexy usually develops within a few months of EDS, but may develop years later. It is specific to narcolepsy and may occur several times a day or only a few times a year. It can be very stressful and socially embarrassing.
The remaining two features of the “tetrad” are sleep paralysis and hypnogogic hallucinations. Sleep paralysis is characterized by the inability to move (loss of muscle tone) for a few seconds or minutes at sleep onset (most common) or sleep offset. The paralysis usually ends spontaneously or after mild sensory stimulation. It is present in 70% to 80% of narcoleptics and varies in frequency throughout life. It can be present in other sleep disorders, most commonly in those disorders causing frequent disruptions in sleep. Hypnogogic hallucinations are vivid dreams that occur during transitions between sleep and wakefulness. They occur most commonly with sleep onset, but may be experienced upon awakening (hypnopompic). Patients may experience other types of hallucinations including sensory and auditory experiences. Hypnogogic hallucinations are present in about 50% of narcoleptics.
The cause of narcolepsy is unknown. It is a neurologic disorder with evidence pointing to altered a-adrenergic receptor functioning.2 The primary REM generator lies in the rostral pontine reticular formation. There is a reduction of discharge of monoaminergic neurons in the locus ceruleus and raphe nuclei and an enhancement of brainstem cholinergic activity. In cataplexy, there are changes in neurotransmitter levels with emotion. Excessive cholinergic stimulation and reduced noradrenergic activity lead to muscle atonia. Rarely, central nervous system (CNS) lesions are associated with narcolepsy symptoms.
|Sleep apnea syndrome
Periodic limb movement disorder
Withdrawal from stimulants
Circadian rhythm disorders
Table 1. Differential diagnosis in patients with excessive daytime sleepiness.
Recently, a neurotransmitter named hypocretin has been found to play a role in narcolepsy in dogs. This neurotransmitter has also been found to be undetectable in narcoleptic patients.3 Reduced numbers of hypocretin-containing neurons have been observed in hypothalamic areas of the human narcoleptic brain.
Human narcolepsy has been strongly associated with positive HLA-DR2 typing. The halotype found to be consistent across most ethnic groups is HLA DQB1*0602. This genotype occurs in 90% to 100% of Japanese and Caucasian patients with narcolepsy, while its occurrence is 12% in the Japanese general population and 22% in the Caucasian general population.2
The diagnosis of narcolepsy is usually made through a detailed clinical history, physical examination, and specific testing. A detailed clinical history and physical examination are required to establish possible differential diagnoses of the patient’s EDS (Table 1). The presence of cataplexy is the most specific clinical finding for narcolepsy; however, it may be poorly perceived by the patient and unrecognized by the physician or family members. EDS can be assessed using several approaches. The Epworth Sleepiness Scale is a rating scale assessing the likelihood that a patient would fall asleep in a number of different situations.4 Each situation is scored on a scale of 0-3 and total scores greater than 10 are suggestive of pathological sleepiness. The scale is limited in that it is a subjective assessment of the patient’s degree of sleepiness. It may be useful in following a patient’s response to treatment. Specific testing includes polysomnography (PSG) and multiple sleep latency testing (MSLT). These tests are required to substantiate clinical findings as the lifelong management of narcolepsy involves drugs with considerable addictive and abuse potential.
PSG is used to assess the quality and quantity of nighttime sleep. It allows the identification of sleep-related breathing disorders or movement disorders that could result in fragmented sleep leading to the patient’s complaint of daytime sleepiness. Narcoleptic patients generally demonstrate a short sleep latency and the early onset of REM sleep, frequently within minutes of turning the lights out. Patients generally have excessive sleep disruption with frequent arousals and awakenings and excessive movements in non-REM and REM sleep.
|Protriptyline 5-60 mg
Imipramine 10-100 mg
Desipramine 25-100 mg
Clomipramine 10-150 mg
Fluoxetine 20-60 mg
Venlafaxine 75-225 mg
Reboxetine 2-10 mg
Sodium oxybate 4.5-9 g
Table 2. Drugs used to treat cataplexy with the usual range of daily dosage.
The MSLT is performed following the nighttime PSG to objectively assess the degree of daytime sleepiness.5 It consists of polygraphic monitoring of sleep parameters for a period of 20 minutes in a quiet, dark, and comfortable bedroom. The patient is given four or five nap opportunities to fall asleep at 2-hour intervals throughout the day. Both the time to sleep onset and the presence of a sleep onset REM period are documented. REM sleep that occurs within 15 minutes of sleep onset is considered a sleep onset REM period. A mean sleep latency of <8 minutes and the presence of REM sleep in at least two naps are considered diagnostic for narcolepsy. If other sleep disorders are recognized on the PSG, then results of the MSLT are not valid. If, for example, obstructive sleep-disordered breathing is observed on the PSG, then this disorder must be treated first. If daytime sleepiness persists or if cataplexy is suspected after the effective treatment of other sleep disorders, then an MSLT is indicated. To be clinically relevant, the MSLT must be performed under specific conditions. Patients should be off medications for a period of 2 weeks to avoid possible drug interactions. The patient should fill out a sleep diary for the 2-week period prior to testing to ensure that the patient’s sleep schedule has been stable.
As there is no cure for narcolepsy, treatment is aimed at reducing the EDS and related REM dissociated features (cataplexy, sleep paralysis, and hypnogogic hallucinations). There are a number of social and economic costs of untreated narcolepsy including poor school performance, avoidance of social interactions, workplace mishaps, automobile accidents, interpersonal difficulty, and depression. Treatment is individualized relative to the presence and degree of symptoms and involves both nonpharmacological and pharmacological interventions. The American Academy of Sleep Medicine has published practice parameters for the treatment of narcolepsy.6
Patient education is paramount in maximizing treatment benefit. Patients should be instructed on good sleep hygiene practices, avoidance of irregular sleep patterns, or sleep deprivation. Patients with narcolepsy should avoid working shift work. It is generally beneficial for the patient to take short naps of 10 to 15 minutes two or three times a day; however, this may be impractical in many settings such as school or work. The patient and family should be aware of the hazards of driving as well as possible hazards in the workplace.
Pharmacological Treatment of EDS
For many years, the mainstay of drug treatment of EDS associated with narcolepsy has been amphetamine-like drugs. These stimulants are indirect sympathomimetics that increase levels of monoamines within the synaptic cleft by enhancing the release of norepinephrine, dopamine, and serotonin, and by blocking their reuptake. These stimulants include dextroamphetamine, methamphetamine, methylphenidate, pemoline, and mazindol. The amphetamine-like drugs have significant side effects including nervousness, headaches, irritability, tremor, insomnia, anorexia, gastrointestinal upset, and heart palpitations. Methylphenidate has been the drug of choice since its discovery in the 1950s. Its efficacy is similar to that of dextroamphetamines and methamphetamines, but with fewer side effects. Pemoline is the weakest of these agents and has a high potential for liver toxicity. If used, it is recommended that liver function tests be performed on a regular basis. The use of pemoline has decreased greatly since the recognition of the potential for liver toxicity. Increasing the dose of stimulant medication is generally done with great caution among physicians who are concerned about inducing tolerance and dependence; however, dependence is acknowledged to be rare among narcoleptics even when using high doses.
|Methylphenidate 10-60 mg
Dextroamphetamine 5-60 mg
Methamphetamine 5-60 mg
Pemoline 20-115 mg
Mazindol 0.5-6 mg
Modafinil 100-400 mg
Table 3. Drugs used in the treatment of excessive daytime sleepiness with the usual range of daily dosage.
A new wake-promoting drug, modafinil, has been approved by the Food and Drug Administration (FDA) for the treatment of narcolepsy. Modafinil is structurally unrelated to the amphetamine-like drugs and its mode of action is unknown. It has a half-life of 9 to 14 hours, thus permitting once-daily dosing. It is considered to be less potent than the amphetamine-like drugs, but because it has fewer side effects and a lower abuse potential, it has become the preferred drug for the treatment of EDS in narcoleptics. However, switching patients to modafinil who are stabilized on amphetamine-like stimulants may be difficult.7 These patients frequently find modafinil to be less effective, especially if they were on high doses of these stimulants. Switching from pemoline to modafinil is generally well tolerated. In addition, amphetamine-like stimulants have a mild anticataplectic effect. Switching to modafinil may be associated with an increase in the frequency of cataplectic attacks requiring the addition of or an increase in anticataplectic medications (see Table 2, page 27). There is a high incidence of headaches with the initiation of treatment with modafinil that can usually be avoided by a progressive increase in dosage over an 8- to 10-day period to the common dosage of 300 mg to 400 mg.
Stimulant medication is best administered in divided doses, generally upon awakening and at noon. A later dose may be given if indicated, but should not be given after 3 pm. Table 3 shows the normal daily range of dosing for the commonly used stimulants. The combination of long-acting and short-acting stimulants may be possible to achieve alertness quickly and for extended periods of time. Hypnotic medications may be given at bedtime if the patient reports problems with sleep maintenance. Benzodiazepine is the hypnotic of choice, as it generally does not have carry-over sedation the next morning.
Treatment of Cataplexy
When cataplexy is present, it is usually controlled by the use of medications that have a noradrenergic reuptake blocker action (Table 2, page 27). Cataplexy has been traditionally controlled by tricyclic antidepressant medications. Due to the anticholinergic adverse side effects (dry mouth, tachycardia, urinary retention, constipation, and blurred vision) associated with this class of medications, selective serotonin-reuptake inhibitors are gaining in popularity and are less sedating; however, this drug class is believed to have weaker anticataplectic effects.1 Tricyclic antidepressants are also effective in the treatment of hypnogogic hallucinations and sleep paralysis through their REM-suppressing effects.
A recent FDA-approved treatment for cataplexy is sodium oxybate, a central nervous system depressant. This drug can have serious side effects that include CNS and respiratory depression, confusion, depression, urinary incontinence, and sleepwalking. It is a form of gamma-hydroxybutyrate, which is a known drug of abuse and is generally known as the “date-rape” drug. As a result, it is a schedule class III drug. The manufacturer, in cooperation with the FDA, has established a program to ensure the safe and effective use of sodium oxybate (Xyrem Success ProgramSM). Dosing usually starts at 4.5 g per night given in two equally divided doses to a maximum of 9.0 g. The patient usually takes one dose at bedtime and the second dose 3 hours later.
The Future of Narcolepsy
Although there is no cure for narcolepsy and the treatment of narcolepsy has relied mostly on drug therapies that have been around for decades, the search for new treatments continues. This effort has led to the discovery of modafinil, a wake-promoting drug with fewer side effects than traditional stimulant medications, and sodium oxybate, an effective drug for the treatment of cataplexy. Sodium oxybate also appears to have wake-promoting and sleep-consolidating properties as well and this is currently under investigation.8 The recent discovery that hypocretin neurotransmission and hypocretin cells are reduced in patients with narcolepsy may provide future options for the management of narcolepsy.
Robert A. Whitman, PhD, ABSM, RRT, RPFT, is director of the Sleep Disorders Center and Pulmonary Diagnostics Services at the University of Kansas Medical Center, Kansas City, Kan; he is also a member of Sleep Review’s Editorial Advisory Board.
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