The goal of therapy for narcolepsy is controlling its underlying symptoms.
Gelineau, a French physician, coined the term “narcolepsy” in 1880. This disorder is often inherited and is of unknown etiology. Narcolepsy is a distinctive but underdiagnosed disorder of sleep and waking. Its cardinal manifestations are excessive daytime sleepiness (EDS), with a tendency to nap repeatedly through the day; cataplexy, a loss of muscle tone triggered by emotion, causing immobility for seconds to minutes; hypnagogic hallucinations, vivid visual or auditory phenomena experienced at the onset of sleep; and sleep paralysis, an inability to move on first awakening. Perhaps as many as 5% of adults are excessively sleepy to a clinically relevant extent.1 The comparable figure for children is not known.2 It is the second leading cause of EDS diagnosed by sleep centers after obstructive sleep apnea (OSA). Pathophysiologically, rapid eye movement (REM) dysregulation is believed to play a crucial role. In narcolepsy, these aspects become dissociated and intrude into wakefulness; however, the physiopathogenesis of narcolepsy seems to be more complicated than this, with evidence of non-REM (NREM) sleep and possibly circadian sleep wake rhythm abnormalities. Basic neurochemical mechanisms are not yet well defined.3
Narcolepsy has a prevalence of around 1:2,000 in the United States.4,5 Narcolepsy appears throughout the world in every racial and ethnic group, affecting males and females equally. It can present at any age, most often in the second and third decades of life. The age at diagnosis has a mean delay of more than 10 years because of the frequent misdiagnosis with other neurologic or psychiatric conditions.6
EDS is almost universal with narcolepsy. People with EDS describe it as a persistent sense of mental cloudiness, a lack of energy, a depressed mood, or extreme exhaustion. School problems, including academic deterioration, inattentiveness, and emotional lability, are very common in children, and school personnel often initiate referral to the child’s primary care physician for evaluation.7-9 The clinical picture may sometimes be dominated by restlessness and motor overactivity rather than the expected hypoactivity. About 40% of all patients with narcolepsy are prone to involuntary brief sleep episodes with automatic behavior. They fall asleep for a few seconds while performing a task but continue carrying it through to completion without any apparent interruption. During these episodes, people are usually engaged in habitual, essentially “second nature” activities such as taking notes in class, typing, or driving. They cannot recall their actions, and their performance is almost always impaired during a microsleep. If an episode occurs while driving, patients may get lost or have an accident.
Estimates for the occurrence of the nonsleepiness components of the syndrome are: cataplexy (all cases where cataplexy is required for the diagnosis of narcolepsy; however, others accept that in about 20% of cases cataplexy is not present), hypnagogic or hypnopompic hallucinations (50%-60%); and sleep paralysis (40%). These symptoms occur in various combinations. In narcolepsy, overnight sleep is generally disrupted, causing some degree of persistent tiredness.
All four symptoms of the narcoleptic tetrad—EDS, cataplexy, hypnagogic hallucinations, and sleep paralysis—are rarely present at onset. Cataplexy may not be present during the initial years of the disease, but most patients eventually develop this symptom. Ascertaining whether cataplexy is present is an important and often difficult element of the history. The classical association of EDS and cataplexy (narcolepsy with cataplexy subtype) recurs in about 80% of cases and is sufficient for a definite diagnosis, because cataplexy is a specific symptom.10 The bizarre nature of hypnagogic hallucinations and sleep paralysis may confuse children; parents must sometimes be asked to clarify the child’s experiences. Some children are too embarrassed to discuss their symptoms. When only EDS is present (narcolepsy without cataplexy subtype), the diagnosis is possible if specific pathological polysomnographic sleep onset rapid eye movement periods (SOREMPs) findings are demonstrated.10
Additional symptoms can include automatic behavior, poor memory and concentration, and visual disturbances such as blurred vision and diplopia. Obesity may occur as a coexisting problem in childhood narcolepsy. Although the reason for obesity is not known, one can speculate that a contributing factor is inactivity associated with hypersomnia.
The diagnosis of narcolepsy should be based on a thorough clinical history, coupled with characteristic findings on the multiple sleep latency test (MSLT) and overnight polysomnography (PSG). Overnight PSG is performed to identify intrinsic sleep disorders, such as sleep-disordered breathing and periodic limb movement disorder (PLMD), and to document sleep-wake architecture. The MSLT generally shows reduced mean sleep latency and, usually, the occurrence of episodes of SOREMPs; however, the presence of clinically significant respiratory disturbances or periodic limb movements does not rule out the diagnosis of narcolepsy. These disorders coexist in a significant minority of narcolepsy patients.8,11,12 The MSLT is an objective, well-validated method of confirming the presence of pathologic daytime sleepiness and assessing abnormal entry into REM sleep.
Neurologic disorders that can cause excessive sleepiness should be ruled out such as hydrocephalus, mass lesions, and hypothalamic or brainstem lesions.
The goal of therapy for narcolepsy is to control the symptoms underlying the disability. The cornerstone of management is to educate and provide supportive counseling to the patient, family, and school personnel. Modafinil, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, selegiline, pemoline, tricyclic antidepressants, and fluoxetine are effective treatments for narcolepsy, but the quality of published clinical evidence supporting them varies. Their effect on cataplexy is reported to be absent or uncertain.10 The stimulant medications most clinicians use are methylphenidate or pemoline initially, with titration of daily dosage based on clinical response and side effects. Stimulants can cause central nervous system (CNS), cardiovascular, or gastrointestinal adverse experiences (anxiety, palpitations, and nausea). Additionally, amphetamine and methylphenidate are often associated with an increased liability for abuse. Another concern relates to the potential for dependence characterized by withdrawal symptoms on discontinuation. Modafinil, 2-[(diphenylmethyl)-sulphinyl] acetamide, is an effective treatment for EDS in narcolepsy and shows continued efficacy with up to 9 weeks of daily use.13 The major risks of withdrawal symptoms and abuse potential characterizing currently prescribed agents such as amphetamine and methylphenidate do not appear to be an issue with modafinil.13 An appropriate goal is to maintain optimal alertness during the most important hours of the day, such as during school or key social situations.
Sodium oxybate (gamma-hydroxybutyrate [GHB]) is another effective and well-tolerated treatment for narcolepsy and is approved in the United States for the treatment of cataplexy in patients with narcolepsy. In a multicenter, 12-month, open-label trial, sodium oxybate, in doses of 3 g to 9 g nightly, produced overall improvements in narcolepsy symptoms, which were significant at 4 weeks and maximal after 8 weeks.14 Reported improvements included a significant decrease in frequency of cataplexy attacks (P<0.001); diminished daytime sleepiness (P<0.001); and patient descriptions of nocturnal sleep quality, level of alertness, and ability to concentrate (for each, P<0.001). Another randomized, double blind, placebo-controlled multicenter trial,19 comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy, showed that compared to placebo, weekly cataplexy attacks were decreased by sodium oxybate at the 6-g dose (P=0.0529) and significantly at the 9-g dose (P=0.0008). The Epworth Sleepiness Scale was reduced at all doses, becoming significant at the 9-g dose (P=0.0001). The Clinical Global Impression of Change demonstrated a dose-related improvement, significant at the 9-g dose (P=0.0002). The frequency of inadvertent naps/sleep attacks and nighttime awakenings showed similar dose-response trends, becoming significant at the 9-g dose (P=0.0122 and P=0.0035, respectively). In a double-blind, placebo-controlled study,15 GHB reduced the daily number of hypnagogic hallucinations (P=0.008), daytime sleep attacks (P=0.001), and the severity of subjective daytime sleepiness (P= 0.028). GHB stabilized nocturnal REM sleep; it reduced the percentage of wakefulness during REM sleep (P=0.007) and the number of awakenings out of REM sleep (P=0.016), and tended to increase slow wave sleep (P=0.053).
Adverse events were generally mild, and patients showed no evidence of tolerance. There is minimal evidence of withdrawal symptoms following abrupt cessation of chronic sodium oxybate dosing in the therapeutic range.16 Food significantly alters the bioavailability of oxybate by decreasing mean peak plasma concentration, increasing median time-to-peak concentration, and decreasing the area under the plasma concentration-time curve.17 Food does not affect elimination and urinary excretion of unchanged drug. No dose adjustment of sodium oxybate based on sex is indicated.17 Although significant food effects were observed, these are minimized in patients by the nocturnal dosing of sodium oxybate hours after the evening meal at a consistent time interval following food ingestion.
Recommended first-line intervention for cataplexy is therapy with antidepressant drugs like tricyclic or serotonin selective reuptake inhibitors.18
Several nonpharmacologic interventions may contribute to the overall quality of life of the child with narcolepsy. The establishment of regular sleep-wake schedules, including adequate nocturnal sleep, is important to children with narcolepsy. Narcolepsy patients should be monitored closely for the emergence of coexisting sleep disorders, such as OSA and PLMD. These problems tend to increase in occurrence over time and may require specific intervention.
All adolescents with narcolepsy must be counseled not to drive, use alcohol, or engage in dangerous activities while drowsy. Decisions about driving are made on an individual basis, taking into account the adolescent’s response to stimulants, medication compliance, and judgment. Many patients with narcolepsy limit their own driving, and others continue to drive only when necessary and only for short trips. Lengthy or boring drives should be avoided.
Narcolepsy is a lifelong disorder of the CNS characterized by uncontrollable daytime sleepiness and intermittent abnormal manifestations of REM sleep during wake or sleep-wake transition. There is evidence that symptoms of narcolepsy may adversely impact on people’s quality of life. The goal of therapy for narcolepsy is to control the symptoms underlying the disability. Successful treatment of narcolepsy requires an accurate diagnosis to exclude patients with other sleep disorders, and to avoid unnecessary complications of drug treatment. Treatment objectives should be tailored to individual circumstances. Regular follow-up of patients with narcolepsy is necessary to educate patients and their families, monitor for complications of therapy and emergence of other sleep disorders, and help the patient adapt to the disease.
Naseer Masoodi, MD, is a fellow in geriatric medicine, SUNY at Buffalo, NY; and Taj M. Jiva, MD, is a diplomate of the American Board of Sleep Medicine, and director of the Sleep Disorders Clinic, Orchard Park, NY.
1. Billiard M, Alperovitch A, Perot C, Jammes A. Excessive daytime somnolence in young men: prevalence and contributing factors. Sleep. 1987;10:297-305.
2. Anders TF, Carskadon MA, Dement WC, Harvey K. Sleep habits of children and the identification of pathologically sleepy children. Child Psychiatry Hum Dev. 1978;9:56-63.
3. Broughton RJ. Narcolepsy. In: Thorpy MJ, ed. Handbook of Sleep Disorders. New York: Marcell Dekker; 1990:197-216.
4. Robinson A, Guilleminault C. Narcolepsy. In: Chokroverty S, Daroff RB, eds. Sleep Disorders Medicine. Boston: Butterworth Heinemann; 1999.
5. Dement W. The prevalence of narcolepsy II. Sleep Res. 1973;2:147.
6. Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology. 2001;57:2029-2033.
7. Brown L, Billiard M. Narcolepsy, Kleine-Levin syndrome, and other causes of sleepiness in children. In: Ferber R, Kryger M, eds. Principles and Practice of Sleep Medicine in the Child. Philadelphia: WB Saunders; 1995:125-134.
8. Kotagal S. Narcolepsy in children. Semin Pediatr Neurol. 1996;3:36-43.
9. Wise M, Gillespie S. Clinical features of childhood narcolepsy [abstract]. Sleep Res. 1996;25:390.
10. American Academy of Sleep Medicine. International Classification of Sleep Disorders, Revised. Diagnostic and Coding Manual. Rochester, Minn: American Academy of Sleep Medicine; 2001.
11. Young D, Zorick F, Wittig R, Roehrs T, Roth T. Narcolepsy in a pediatric population. Am J Dis Child. 1988;142:210-213.
12. Wise M. Polysomnographic and MSLT results in childhood narcolepsy [abstract]. Sleep Res. 1996;25:389.
13. Becker PM, Jamieson AO, Jewel CE, et al. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology. 2000;54:1166-1175.
14. US Xyrem® Multicenter Study Group. A 12-month, open-label, multicenter extension trial of orally administered sodium oxybate for the treatment of narcolepsy. Sleep. 2003;26:31-35.
15. Lammers GJ, Arends J, Declerck AC, Ferrari MD, Schouwink G, Troost J. Gammahydroxybutyrate and narco-
lepsy: a double-blind placebo-controlled study. Sleep. 1993;16:216-220.
16. US Xyrem® Multi-Center Study Group. The abrupt cessation of therapeutically administered sodium oxybate (GHB) does not cause withdrawal symptoms. J Toxicol Clin Toxicol. 2003;41:131-135.
17. Borgen LA, Okerholm R, Morrison D, Lai A. The influence of gender and food on the pharmacokinetics of sodium oxybate oral solution in healthy subjects. J Clin Pharmacol. 2003;43:59-65.
18. Littner M, Johnson SF, Vaughn McCall W, et al. Practice parameters for the treatment of narcolepsy: an update for 2000. Sleep. 2001;24:451-466.
19. US Xyrem® Multicenter Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep. 2002;25:42-49.