- Email: [email protected]
Narcolepsy
Nurs Clin N Am 37 (2002) 675–692
Narcolepsy Ann E. Rogers, PhD, RN, FAANa,b,*, H. Michael Dreher, DNSc, RNa,b a
School of Nursing, University of Pennsylvania, 420 Guardian Drive Philadelphia, PA 19104, USA b Division of Sleep and Respiratory Neurobiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Narcolepsy is a chronic disorder characterized by excessive daytime sleepiness. All patients experience excessive daytime sleepiness. Other symptoms include cataplexy, sleep paralysis, hypnagogic hallucinations, and disrupted nocturnal sleep. Treatment, usually with stimulants and low doses of antidepressant medications, can dramatically improve the patient’s quality of life. Although only advanced practice nurses may be actively involved in the diagnosis and treatment of this disorder, all nurses can encourage their patients who complain of excessive daytime sleepiness to consult a specialist in sleep disorders medicine, provide emotional support after diagnosis, and educate patients and their families about narcolepsy and its treatment. Narcolepsy is a sleep disorder that is characterized by excessive daytime sleepiness (EDS). Although the origins of this syndrome are unknown, it is now theorized that the neuroexcitatory peptide hypocretin and its receptors may be central to its pathophysiology [1]. Persons with narcolepsy exhibit EDS and disturbed nocturnal sleep, cataplexy, sleep paralysis, hypnagogic hallucinations, and pathologic manifestations of rapid eye movement (REM) sleep. It is a chronic neurologic disorder that is more common than Huntington chorea, multiple sclerosis, or muscular dystrophy [2], affecting between 0.03% and 0.18% of the general population [3]. The onset of narcolepsy usually occurs during adolescence or during the early twenties with the onset of daytime sleepiness and sleep attacks. Recent research has suggested that there may be second, smaller peak in onset around age 35 [4,5], and approximately 25% of patients do not present for diagnosis until after age 40 [6]. * Corresponding author. E-mail address: [email protected] (A.E. Rogers). 0029-6465/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 9 - 6 4 6 5 ( 0 2 ) 0 0 0 3 5 - X
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The classic auxiliary symptoms of cataplexy, sleep paralysis, and hypnagogic hallucinations may occur almost immediately or may develop 5 to 10 or even 20 years later. Whereas the severity of the auxiliary symptoms may fluctuate throughout the patient’s life, EDS, once present, is chronic and unremitting. Untreated, EDS associated with narcolepsy persists into old age, but it is not exacerbated by the development of age-associated changes in nocturnal sleep (eg, poorer sleep efficiency, increased awakenings, and decreases in Stage 3/4 sleep) [7–9]. It is reported that some patients have less severe daytime sleepiness with increasing age [8,10,11], but whether this change represents improved coping with the illness or simply partial remission is not known. The symptoms of narcolepsy can be debilitating, and up to half of all narcoleptic patients experience difficulties at work, in marriage, or in their social lives related to symptom burden [12]. In one study, 80% of subjects reported falling asleep at work on at least several occasions. Narcolepsy can also cause impaired attention and poor concentration, which can interfere with education and employment [13–16]. The insidious nature of narcoleptic sleep attacks or cataplexy during meals, conversations, and even during sexual intercourse may negatively affect interpersonal relationships. The symptoms of narcolepsy may be cause friends and family members to mistakenly attribute excessive sleepiness to boredom, laziness, or psychological problems [13–15]. The symptoms of narcolepsy can interfere with activities of daily living and negatively affect quality of life. Narcoleptic subjects reported more impairment in their physical and emotional health (25%), social isolation (35%), and more severe family problems (21%) when compared with a normative sample of 2406 disabled persons [17]. Symptoms of narcolepsy seem to have a more serious impact on driving when compared with epilepsy, another chronic neurologic disease with episodic loss of consciousness. Except for the area of driver’s license maintenance, persons with narcolepsy had a similar or greater impact in all driving-related measures. Although far fewer epileptic subjects drove (31.7%) than subjects with narcolepsy (73.3%), those that did drive had significantly better driving records with fewer nearaccidents, episodes of falling asleep at the wheel, and actual accidents than narcoleptic subjects. These findings led Broughton et al [18] to suggest that the chronic pervasive daytime sleepiness experienced by narcoleptic patients may be particularly handicapping because persons with epilepsy are relatively alert between seizures. Finally, adverse effects were recently reported in a study using the 36-item Short Form Health Survey [19]. Patients with narcolepsy scored significantly lower on vitality and social functioning and reported more difficulty when performing their usual activities due to physical and emotional problems compared with normative scores for the general population. When compared with several patient populations, patients with narcolepsy also experienced equally severe or more severe effects (Fig. 1). Perhaps the most poignant illustrations of the effects narcolepsy has on quality of life come from e-mail messages from patients to AER. During the
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Fig. 1. Comparison of narcolepsy patients with the general population and other patient populations. (From Beusterien KM, Rogers AE, Walsleben JA, et al. Health-related quality of life effects of modafinil for treatment of narcolepsy. Sleep 1999;22:759; with permission.)
past 3 years, she has maintained a web site to recruit subjects for her current study (http://www.nursing.upenn.edu/narcolepsy), and she has received hundreds of e-mail messages like the following: I hate what is happening to me. I want to feel human again. I want to be able to drive without the fear that I will kill myself or someone else. I don’t know how much longer my boss will put up with this from me. I leave early…sometimes I am late because I fall asleep while dressing in the morning. If I am a few minutes later than usual getting back from a break they look for me because they know I fall asleep in the break room. Is there hope for me? Can anyone help me? (E-mail to [email protected], June 2001.) I was released from my job this past April because of my narcolepsy I was found sleeping twice and working as an electrician I almost fell from a 40 foot lift. …I have lost my right to drive and cannot find anyone to hire me. What should I do or what can I do when it’s so bad could I file for social security disability? (E-mail to [email protected], September 2001.) I have experienced all the symptoms of the illness throughout my life but daytime sleepiness with multiple sleep attacks have continued to be my biggest problem. The severity of it now has completely devastated my life, robbing me of everything I found meaningful. (E-mail to aerogers@ nursing.upenn.edu from a 53-year-old artist, January, 2002.)
Symptoms All patients with narcolepsy experience EDS, and many have one or more auxiliary symptoms (eg, cataplexy, sleep paralysis, hypnagogic
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hallucinations, and disturbed nocturnal sleep). The most disabling symptoms for most patients are sleep attacks and EDS. Sleep attacks are short episodes of sleep that may occur many times a day. They can occur at any time, including during times of physical inactivity or boredom or when not anticipated or expected (eg, during a test or business meeting, while waiting for a traffic light to change from red to green, or when skiing, examining patients, or eating a meal) [2,8,16]. Some occur suddenly without warning, whereas others are preceded by a cognitive awareness of drowsiness. Once aroused by even superficial touch, a sound, or even the cessation of a speaking voice, the narcoleptic individual usually feels refreshed and often has a refractory period of one to several hours before the onset of the next sleep attack. However, most narcoleptic patients are not fully cognizant alert individuals who simply suffer from sleep attacks. They also experience a persistent, abnormal daytime sleepiness that Mitler and Gujavarty [20] compared with the ‘‘sleepiness one feels when trying to complete a boring task at 3 AM after 72 hours of total sleep deprivation.’’ Cataplexy is a brief (seconds or minutes) abrupt loss or weakness of skeletal muscle tone without any loss of consciousness. This symptom can vary in severity with a range from a mild sensation of muscle weakness in the neck to a complete postural collapse, entailing a dangerous fall to the ground. The frequency of symptoms may vary in each individual. Some patients may experience only one or two episodes during a lifetime (which is less common), whereas others may have many episodes of cataplexy each day. Episodes of cataplexy are most commonly precipitated by a sudden emotional stimulus, such as laughter, anger, or surprise. To view a videotaped episode of cataplexy, visit Stanford University’s Center for Narcolepsy website (http://www.med.stanford.edu/school/Psychiatry/narcolepsy). Sleep paralysis occurs in some narcoleptics during the transition between sleep and waking. The individual experiences a sudden but temporary paralysis of all striated muscles. The person cannot move any muscles other than the muscles of respiration. Each episode of sleep paralysis usually lasts a few minutes and may also be accompanied by intense fear or hypnagogic hallucinations. The cessation of sleep paralysis ends spontaneously or terminates immediately when the individual is touched or spoken to by another person. Like cataplexy, the frequency of these episodes is highly variant. Sleep paralysis may occur daily, weekly, or once or twice in a lifetime. Hypnagogic hallucinations are vivid, life-like sensory dream-like experiences that appear as a person is falling asleep before loss of consciousness. The duration of these visual, auditory, or tactile hallucinations is usually approximately 1 to 15 minutes. Persons with narcolepsy may also complain of disturbed nocturnal sleep that is often fragmented and shortened. Whereas persistent or episodic fragmented nocturnal sleep might commonly contribute to EDS in someone without a sleep disorder, this is not the central cause of EDS in the individual with narcolepsy. Daytime sleepiness is usually the first symptom
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of narcolepsy, and it often develops several years before the individual becomes cognizant of their persistent nighttime sleep disruption. Moreover, studies indicate that improving the nocturnal sleep of these patients does not lead to any reduction in daytime sleepiness [21]. One recent study indicates that daytime sleepiness may contribute to nocturnal sleep disruptions [22]. Patients whose daytime sleepiness was eliminated by stimulant medications had nocturnal sleep patterns that corresponded with sleep patterns in normal sleepers, whereas subjects whose sleepiness was not controlled by stimulants had fragmented and shortened nocturnal sleep.
Pathophysiology Although the precise etiology of narcolepsy is unknown, recent discoveries suggest that human and animal narcolepsy is associated with the destruction of hypocretin (orexin)-secreting cells in the hypothalamus [1,23–25]. Despite normal serum levels of hypocretin-1 (Hcrt-1), CSF levels of Hcrt-1 are severely reduced or absent in narcoleptic patients [26,27]. Because serum levels are not abnormal, the deficit does not seem to be caused by damage to neuronal cells in the gut but rather seems associated with damage to the CNS. Additionally, several cases of well documented secondary cases of narcolepsy have involved damage to the hypothalamus, including two recent cases where symptoms of narcolepsy developed after a hypothalamic infarct and after damage to the hypothalamic area during resection of an astrocytoma [28–30]. Research using animal models suggests the importance of this system in the development of narcolepsy. For example, a deletion in the Hcrt receptor-2 gene causes cataplexy in dogs [31], and Hcrt knockout mice exhibit cataplexy or episodes of REM sleep while awake [32]. Recent work with narcoleptic dogs has shown decreased histamine content in the cortex and thalamus, two structures important for histaminemediated arousal [33]. Because histamine normally promotes arousal, decreases in histaminergic neurotransmission may account for some of the sleep abnormalities associated with narcolepsy. Although narcolepsy is transmitted through a single autosomal recessive gene (CANARC 1) in Doberman pinschers, the genetic basis for human narcolepsy is not that simple. Even though almost all narcoleptics are positive for DRB1*1501-DQA1*0102-DQB1*0602, this haplotype is neither sufficient nor necessary for the development of narcolepsy [34,35]. Most cases of narcolepsy are sporadic, and familial cases are the exception rather than the rule. For instance, despite sharing the same human leukocyte antigen (HLA) haplotype as the narcoleptic patient, family members do not necessarily develop the disorder [36–38]. An even stronger case against an absolute genetic predisposition to develop narcolepsy is suggested by studies that identify at least four pairs of monozygotic twins (established by HLA testing
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and DNA fingerprinting) who are discordant for narcolepsy [36,38,39]. These findings suggest that nongenetic factors may be associated with the development of narcolepsy. Despite the association of HLA and autoimmune disease, researchers have been unable to find evidence that narcolepsy is caused by an autoimmune process [37,40,41]. There is also no evidence that endocrine or viral causes are implicated in its etiology [42,43].
Diagnosis Although EDS is endemic in contemporary American society, not all sleepy individuals have narcolepsy. Patients presenting with a complaint of difficulty in maintaining desired wakefulness or EDS should be evaluated carefully. Because there are numerous causes of EDS, it is important that anyone with a complaint of daily or almost daily EDS for 3 months or more be referred to a sleep disorder center for evaluation (a list of accredited sleep disorders centers can be found at http://www.aasmnet.org/listing.htm). During the first visit, the sleep disorders specialist, who might be a physician, a psychologist, or a doctorally prepared nurse, obtains a health history and a detailed sleep history. Although classic cases of narcolepsy are easy to recognize, most individuals present with some but not all symptoms of the disorder. A nocturnal polysomnogram is necessary to rule out sleep apnea as a cause of the patient’s EDS. If sleep apnea is present, it must be successfully treated before diagnosing narcolepsy. All patients must also undergo a Multiple Sleep Latency Test (MSLT), which objectively measures the severity of daytime sleepiness. Patients with narcolepsy fall asleep very quickly during the MSLT (5.0 minutes) and have at least two sleep-onset REM periods.
Treatment Treatment of narcolepsy is usually multifaceted and focuses on the control of EDS and cataplexy. This section provides an overview of pharmacologic and nonpharmacologic treatments, discusses issues related to compliance, and suggests appropriate nursing interventions. Controlling EDS Pharmacologic treatment To ensure safe and adequate function at home, while driving, or at work, EDS must be controlled [44] (see Table 1). Pharmacologic treatment for narcolepsy includes older stimulant medications such as dextroamphetamine (Dexedrine) and methylphenidate (Ritalin) and the newer drug modafinil (Provigil). Adderall (a product containing a mixture of amphetamine salts)
5–100 mg
Methamphetamine-HCl (Desoxyn) Modafinil (Provigil)
37.5–300 mg
Pemoline (Cylert)
Variable duration of action, depending on whether using regular or sustained release form of medication More potent than dextroamphetamine Lower potency than amphetamines or methylphenidate. Long duration of action Less potent than amphetamines. Variable duration of action, depending on whether using regular or sustained release form of medication Less potent than other medications used to control daytime sleepiness. Long duration of action
Potency and duration of action
Can cause liver damage; patient must be monitored regularly
Sympathomimetic effects, mood alterations
Schedule IV
Schedule II Most frequently prescribed stimulant for treatment of narcolepsy in the United States
Schedule IV
Schedule II
Schedule II
Sympathomimetic effects, mood alterations
Sympathomimetic effects, mood alterations Fewest side effects of stimulant medications
Other information
Potential side effects
* Data from Narcolepsy, a teaching slide set prepared by the American Academy of Sleep Medicine, Rochester, MN.
10–100 mg
Methylphenidate-HCl (Ritalin/Ritalin-SR)
200–800 mg
5–100 mg
Usual daily dose*
Dextroamphetamine-sulfate (Dexadrine, Dextrostat, Dexadrine-SR)
Name
Table 1 Medications used to treat excessive daytime sleepiness A.E. Rogers, H.M. Dreher / Nurs Clin N Am 37 (2002) 675–692 681
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and Concerta (a new sustained-release form of methylphenidate) are also effective. Modafinil is usually the treatment of choice. It has fewer side effects than traditional stimulants and a longer duration of action [45–48]. Not all patients find modafinil effective for controlling their EDS, and some need to be switched to a traditional stimulant. Treatment is usually started with a low dose of a short-acting drug and is increased as necessary. Some patients benefit from a combination of short- and long-acting medications, such as modafinil and methylphenidate, or from a second dose of modafinil in the afternoon. Although the sustained-release formulations of dextroamphetamine and methylphenidate have longer half-lives than their short-acting forms, a second or even a third dose may be required to sustain alertness during the afternoon and evening hours. Nonpharmacologic approaches Many practitioners recommend behavioral approaches, particularly scheduled naps and sleep hygiene measures, for the treatment of narcolepsy. Patients are usually directed to take three to six 15-minute naps per day and to adopt a regular schedule for arising and retiring at night. Although napping can produce a transient improvement in alertness and performance [43,49–51], it does not reduce the number or duration of unscheduled daytime naps in untreated patients, nor is it clear that combining scheduled sleep periods and stimulant medications is more effective than the use of stimulants alone [52,53]. In one study, extending the nocturnal sleep period to 12 hours reduced subjective sleepiness and significantly improved mean sleep latencies the following day [54]. The mean sleep latency, however, increased only 3.6 minutes, resulting in a mean sleep latency of 7.8 minutes on the MSLT. Reducing or eliminating nocturnal sleep disruptions with benzodiazepines or gamma-hydroxybutyrate [21,55,56] has also not demonstrated any effect on daytime sleepiness. Although sleep schedule manipulations can produce statistically significant improvements in daytime alertness, the clinical utility of manipulating sleep schedules is limited. Extending or regularizing nocturnal sleep periods [54] or adding naps [43,51] can help increase alertness at least for short periods (generally less than 1 hour). Moreover, many of the suggested schedules are impractical for patients attending school or working. Patients may have difficulty taking one or two 15-minute naps during the workday, and a 120minute nap, which has been shown to be more effective than several short naps [51], is unlikely to be tolerated by most employers. Caffeine is sometimes recommended as an inefficient but safe alternative to traditional stimulant medications or as an adjuvant treatment [57]. Caffeine, which can improve alertness in sleep-deprived subjects [58,59], has not been investigated as a treatment for EDS in narcoleptic patients. Its alerting effects, however, are limited. For example, it takes six cups of strong
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coffee or approximately 750 mg of caffeine to obtain an effect comparable to 5 mg of dexamphetamine [44,60], and most persons in the United States consume only an average of 200 mg of caffeine per day [23]. Most patients do not find caffeine effective for controlling daytime sleepiness and can easily fall asleep after its ingestion [61]. Although dietary manipulations are popular among patients, the efficacy of restricting intake of simple sugars, the use of dietary supplements, or avoiding meals to be alert, for example, has not been supported by research. Numerous anecdotal reports describing postprandial drowsiness, increased drowsiness after consumption of sugars, carbohydrate cravings, sleep attacks triggered by ingestion of certain foods, or unusual eating patterns among narcoleptic patients [62–64] have not been substantiated. Pollack and Green’s [65] study of narcoleptic and control subjects living in a time-isolation laboratory demonstrated that most of these claims were spurious. In examining the relationship between sleep, eating behavior, and subjective alertness, they reported that, although naps were more likely to occur after a meal than preceding a meal, naps were no more likely to occur after larger meals or meals containing more of any one macronutrient. Meals followed by naps did not differ in size or macronutrient composition from meals that were not followed by naps. Nevertheless, even if dietary alterations have not been shown to increase daytime alertness, all narcoleptic patients should be counseled to consume only enough calories to maintain their weight within appropriate levels. Almost 20 years ago, it was reported there was a higher incidence of Type II diabetes and obesity among Japanese narcoleptic patients [66]. More recent studies indicate that patients with narcolepsy, on average, have a body mass index (BMI) 10% to 20% greater than matched control subjects [62,66,67]. The use of antidepressant medications for treatment of cataplexy has been ruled as a potential cause of increased BMI in narcoleptic patients [68]. Lower levels of physical activity associated with daytime napping have also been ruled out as a cause of increased BMI [69]. Five years ago, after studies showed that narcoleptic patients usually consume fewer calories and carbohydrates than control subjects, researchers began suggesting that patients may have lower than normal metabolic rates [68]. Until the recent discovery of altered hypocretin function in this population, no one could explain why patients had lower metabolic rates. The relationship between altered hypocretin function and altered metabolism is not completely understood, but researchers believe that hypocretin abnormalities may be linked to the lower metabolic rates in narcoleptic patients [70]. Dietary strategies for the treatment of narcolepsy are widely used by patients, although there is limited evidence to support their use. Nevertheless, despite a paucity of research, dietary manipulations continue to be recommended. For example, Garma and Marchand [57] state in their 1994 article, ‘‘good dietary practices are useful in insuring good sleep hygiene’’ and then recommend that ‘‘morning and midday avoidance of
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ÔsweetsÕ and carbohydrates, especially simple sugars, and large meals will improve alertness in some narcoleptics.’’ Perhaps the perception shared by many narcoleptic patients—that stimulant drugs are ineffective for reducing the severity of daytime sleepiness—leads individuals to believe specious claims that dietary manipulations can control symptoms more effectively or more naturally [45,53,71]. Behavioral interventions are appealing to patients and providers alike because of their low cost and lack of potentially dangerous side effects. Whereas the majority of patients combine pharmacologic therapy and some form of self-initiated behavioral management regimen, an alarming number of patients (30% to 54%) report relying exclusively on nonpharmacologic measures to combat daytime sleepiness [4,72]. Reasons for noncompliance or eschewing stimulant therapy altogether vary widely. Some patients worry about getting ‘‘addicted’’ to stimulants, whereas others deem the side effects from medications worse than the symptoms of narcolepsy [73]. Some techniques recommended by patients with narcolepsy to manage their symptoms are fairly benign (eg, splashing cold water on the face, practicing deep breathing/meditation, and avoiding stress) [4,72]. Other techniques, such as driving a car with a manual transmission, using an alarm clock while driving, hurting themselves while driving to stay awake, avoiding social situations, and smoking cigarettes, have the potential for harm. Some behavioral strategies (eg, scheduling social and business activities to coincide with periods of peak alertness, restricting attendance at evening events, and giving in and sleeping) suggest a highly compromised quality of life where resignation to living with profound sleepiness has been accepted. Controlling cataplexy and other REM-related symptoms Small doses of antidepressant medications and other drugs that suppress REM sleep may be used to control cataplexy. Tricyclic antidepressants, such as clomipramine (Anafranil), imipramine (Tofranil), and protriptyline hydrochloride (Vivactil), are generally considered more effective than selective serotonin reuptake inhibitors (SSRIs) for the treatment of cataplexy (Table 2). Tricyclic antidepressants and SSRIs are powerful and effective REM sleep inhibitors; however, anticholinergic side effects, such as blurred vision, dry mouth, constipation, tachycardia, and urinary retention, may limit their use. The efficacy of sodium oxybate (Xyrem) or gamma hydroxybutyrate for controlling cataplexy has been documented by numerous small studies over the past 25 years [74–78]. Results of a recent clinical trial involving 136 patients confirmed that nightly administration of sodium oxybate produced a significant decrease in the frequency of cataplexy [79]. Sodium oxybate seems to be a unique endogenous neurotransmitter/neuromodulator that consolidates REM and nonREM sleep and decreases sleep fragmentation [75,77,80,81].
25–150 mg
25–100 mg
20–60 mg
10–100 mg
5–60 mg
Clonipramine (Anafranil)
Desimpramine (Norpramin/ Pertofran)
Fluoxetine (Prozac)
Impramine (Jaminime, Tofranil)
Protriptyline (Triptil, Vivactil)
Anticholinergic effects (dry mouth, blurred vision, and constipation) at high doses
Some anticholinergic effects (dry mouth, blurred vision, constipation) but less than clonipramine and desimpramine
Fewer side effects than other clonipramine, disimpramine, and impramine. Less weight gain than with other antidepressants
More anticholinergic effects (dry mouth, blurred vision, constipation) than impramine
Some anticholinergic effects (dry mouth, blurred vision, constipation)
Potential side effects
* Data from Narcolepsy, a teaching slide set prepared by the American Academy of Sleep Medicine, Rochester, MN.
Usual daily dose*
Name
Table 2 Medications used to treat cataplexy
May need higher doses to control cataplexy
Very effective against cataplexy; used more frequently in Europe
Other information
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Although there are few sides effects associated with sodium oxybate [79], it is difficult to use and cannot be prescribed in United States. The drug is available only in liquid form and must be taken in several divided doses at night. Because of its short half-life, patients are encouraged to use an alarm clock so that they are assured of awakening to take their second dose of medication 2.5 to 4 hours after going to bed. Sodium oxybate is an investigational drug and is not available to patients unless they are participating in a clinical trial. Not all patients require medications to control cataplexy. Patients with infrequent or minor symptoms may prefer to avoid medications, whereas others with similar symptoms request medication. The patient’s lifestyle may influence their decision or desire for medication. For example, patients may request medications to control cataplexy if they fear having an episode when holding a new grandchild, are highly embarrassed by episodes of cataplexy occurring in public settings, etc. Although pharmacologic treatment is rarely prescribed for the control of other REM dissociation phenomena, the treatment of cataplexy usually reduces the incidence and severity of hypnagogic hallucinations and sleep paralysis [70]. Occasionally, a short-acting hypnotic or sedating antidepressant may be prescribed for patients who are distressed by their fragmented nocturnal sleep. Compliance Because few patients rely exclusively on stimulant medications to control their EDS, all patients should be questioned about behavioral strategies used to manage their symptoms and the rationale for selecting these strategies. If patients report difficulties staying awake, especially when driving, their medication regime may need to be modified. Compliance with prescribed therapy should also be assessed because studies have shown that the majority of narcoleptic patients fail to take their prescribed dosage of stimulant medications [82,83]. Dosage reductions are often substantial, with patients taking less than one half the medication prescribed. Compliance with anti-cataplectic medications has not been studied. However, there is little evidence to suggest that compliance rates for anti-cataplectic medications would be higher than those for stimulant medications. Patients of all ages and from all educational and socioeconomic levels frequently choose to alter their prescribed medication regimens without consulting their health care provider, take their medications at different times than prescribed, and take more or less drug than prescribed [84–87]. Underdosing by frequently taking less medication than prescribed is common [85,88,89]. Patients also fail to fill their original prescription or do not refill their prescriptions in a timely fashion. Patients take ‘‘drug holidays’’ or completely stop taking their medications after a few months without consulting their physicians. Only approximately one third of all patients are
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estimated to be satisfactorily compliant, with another third partially compliant, and the remaining third not at all compliant to treatment [89]. Patient belief systems influence compliance [90,91]. Many patients express fears about ‘‘becoming addicted’’ to stimulant medications, whereas others express a desire for a ‘‘natural’’ remedy. Clinicians need to discuss the difference between ‘‘drug use’’ and ‘‘drug abuse’’ with their patients and to have frank discussions of appropriate uses of stimulants (particularly Ritalin) to combat frequent media claims of overprescribing. Rather than just seeking to get the patient to take the prescribed pills, the focus might be on the patient’s quality of life. For example, patients could be asked what would they like to do if they could remain awake for longer periods of time or if they were not worried about experiencing cataplexy. After the patient identifies a goal—for example, working full-time, keeping the house neater, or returning to school—the health care provider’s role would be to help the patient meet the goal in a safe manner. Strategies to incorporate pill taking into the patient’s usual activities should also be discussed, and long-acting stimulants should be prescribed if patients have difficulty remembering to take their afternoon dosages of medication. Nursing interventions Nursing interventions are mainly supportive. Referral to a sleep disorders specialist is critical if narcolepsy is suspected. When referring patients to a sleep disorder center, it is often helpful to provide some basic information about how long it might take to get an appointment, what tests might be involved, and whether or not the tests are covered by their medical insurance. In some areas of the United States, it is not unusual for patients to have to wait several months to be seen by a sleep disorders specialist or undergo diagnostic tests. Patients should be cautioned to avoid driving or operating heavy machinery when drowsy. After diagnosis, patients frequently crave information about their illness. Accurate information is available from the National Sleep Foundation website (http://www.sleepfoundation.org), the National Institute of Health (http://www.nhlbi.nih.gov/health/public/sleep/narcolepsy.htm), and many other websites maintained by sleep disorders centers (eg, Stanford University). However, not all information posted on the web is accurate, and patients should be cautioned about relying on other patients and vendors of various products for treatment information. Patients may also benefit from meeting other patients at local support group meetings or on line. A number of bulletin boards and newsgroups for patients are available through the web; some are moderated by professionals, but most are not. Most of the stimulants used to take medications are classified as Schedule II Narcotics in the United States. The number of tablets that can be prescribed at one time is limited, and prescriptions cannot be refilled. Only modafinil and pemoline, which are Schedule IV medications, can be refilled,
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and then only for a 6-month period. The cost of medication may be problematic for some patients. Modafinil is very expensive (approximately $6.00 per tablet), and some health insurance plans, particularly those using a formulary system, may restrict coverage to older, less expensive stimulants (eg, amphetamines and methylphenidate). If a patient complains about increasing daytime sleepiness despite treatment with stimulant medications, they should be referred back to a sleep disorders specialist for further evaluation. Do not waste your time (and the patient’s) by suggesting many of the behavioral measures advocated in some nursing publications. Obtaining proper nutrition, although desirable to prevent cardiovascular disease, does not reduce EDS, nor is there empiric basis for recommending that the patient awaken the same time each morning; abstain from food, caffeine, and alcohol after 8 PM; take a hot bath or shower before bed; find support for daily stressors; and ensure that the bedroom is dark, cool, and quiet [92,93]. These strategies, commonly recommended for patients with sleep-onset insomnia, do not reduce nocturnal sleep disruptions in patients with narcolepsy. Summary Narcolepsy is a chronic disorder of EDS. All patients experience EDS. Other symptoms include cataplexy, sleep paralysis, hypnagogic hallucinations, and disrupted nocturnal sleep. Treatment, usually with stimulants and low-doses of antidepressant medications, can dramatically improve the patient’s quality of life. Although only advanced practice nurses may be actively involved in the diagnosis and treatment of this disorder, all nurses can encourage their patients who complain of EDS to consult a specialist in sleep disorders medicine, provide emotional support after diagnosis, and educate patients and their families about narcolepsy and its treatment. References [1] Olafsdottir BR, Rye DB, Scammell TE, et al. Polymorphisms in hypocretin/orexin pathway genes and narcolepsy. Neurology 2001;57:1896–99. [2] National Commission on Sleep Disorders Research. Report of the National Commission on Sleep Disorders Research. DHHS Pub. No. 93-XXXX Washington, DC: US Government Printing Office; 1993. [3] Nishino S, Okura M, Mignot E. Narcolepsy: genetic predisposition and neuropharmacological mechanisms. Sleep Medicine Review 2000;4:57–59. [4] 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;57:2029–33. [5] Okun ML, Lin L, Pelin Z, et al. Clinical aspects of narcolepsy-cataplexy across ethnic groups. Sleep 2002;25:27–35. [6] Honda Y, Asaka A, Tanimura M, et al. A genetic study of narcolepsy and excessive daytime sleepiness in 308 families with a narcolepsy or hypersomnia proband. In: Guilleminault C, Lugaresi E, editors. Sleep/wake disorders: natural history, epidemiology, and long-term evolution. New York: Raven Press; 1983. p. 188–99.
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[7] Broughton WA, Broughton RJ. Psychosocial impact of narcolepsy. Sleep 1994;17:S45–47. [8] Parkes JD. Sleep and its disorders. London: W.B. Saunders; 1985. [9] Stepanski E, Lamphere J, Badiz P, et al. Sleep fragmentation and daytime sleepiness. Sleep 1984;7:18–26. [10] Billiard M, Besset A, Cadihac J. The clinical and polygraphic development of narcolepsy. In: Guilleminault C, Lugaresi E, editors. Sleep/wake disorders: natural history, epidemiology, and long-term evolution. New York: Raven Press; 1983. p. 171–85. [11] Broughton RJ. Narcolepsy. In: Thorpy MJ, editor. Handbook of sleep disorders. New York: Marcel Dekker; 1990. p. 197–216. [12] Roy A. Psychiatric aspects of narcolepsy. Br J Psychiatry 1976;128:562–65. [13] Broughton R, Ghanem Q. The impact of compound narcolepsy on the life of the patient. In: Guilleminault C, Dement WC, Passouant P, editors. Narcolepsy: advances in sleep research, vol. 3. New York: Spectrum Publications; 1976. p. 201–20. [14] Broughton R, Ghanem Q, Hishikawa Y, et al. Life effects of narcolepsy in 180 patients from North America, Asia, and Europe compared to matched controls. Can J Neurol Sci 1981;8:199–204. [15] Passouant P, Billiard M. The evolution of narcolepsy with age. In: Guilleminault C, Dement WC, Passouant P, editors. Narcolepsy: advances in sleep research, vol. 3. New York: Spectrum Publications; 1976. p. 179–96. [16] Rogers AE. Problems and coping strategies identified by narocleptic subjects. J Neurosurg Nurs 1984;16:326–34. [17] McMahon BT, Walsh JK, Sexton K, et al. Need satisfaction in narcolepsy. Rehabil Lit 1982;43:82–85. [18] Broughton RJ, Guberman A, Roberts J. Comparison of the psychosocial effects of epilepsy and narcolepsy/cataplexy: a controlled study. Epilepsia 1984;25:423–33. [19] Buesterien KM, Rogers AE, Walsleben JA, et al. Health-related quality of life effects of modafinil for the treatment of narcolepsy. Sleep 1999;22:757–67. [20] Mitler MM, Gujavarty KS. Narcolepsy: when to suspect it and how to help. Consultant 1982;4:215–24. [21] Thorpy MJ, Snyder M, Aloe FS, et al. Short-term triazolam use improves nocturnal sleep of narcoleptics. Sleep 1992;15:212–16. [22] Rogers AE, Aldrich MS, Caruso CC. Patterns of sleep and wakefulness in treated narcoleptic subjects. Sleep 1994;17:590–7. [23] International Food Council. IFIC review: caffeine and health. July 1998. Available at: http://www.ific.org/proactive/newsroom/release.vtml?id=17784. Accessed January 29, 2002. [24] Melberg A, Ripley B, Lin L, et al. Hypocretin deficiency in familial symptomatic narcolepsy. Ann Neurol 2001;49:136–7. [25] Silber MH, Rye DB. Solving the mysteries of narcolepsy: the hypocretin story. Neurology 2001;56:1616–18. [26] Dalal MA, Schuld A, Haack M, et al. Normal plasma levels of orexin A (hypocretin-1) in narcoletic patients. Neurology 2001;56:1749–50. [27] Nishino S, Ripley B, Overeem S, et al. Low CSF hypocretin (orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 2001;50:381–8. [28] Arii J, Kanbayashi T, Tanabe Y, et al. A hypersomnolent girl with decreased CSF hypocretin level after removal of a hypothalamic tumor. Neurology 2001;56:1775. [29] Malik S, Boeve BF, Krahn LE, et al. Narcolepsy associated with other central nervous system disorders. Neurology 2001;57:539–41. [30] Scammell TE, Nishino S, Mignot E, et al. Narcolepsy and low CSF orexin (hypocretin) concentration after diencephalic stroke. Neurology 2001;56:1751–3. [31] Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (Orexin) receptor 2 gene. Cell 1999;98:365–76. [32] Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999;98:437–57.
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[33] Nishino S, Fujiki N, Sakurai E, et al. Decreased brain histamine content in hypocretin/ orexin receptor-2 mutated narcoleptic dogs. Neurosci Lett 2001;313:125–8. [34] Honda Y, Takahaski Y, Honda M, et al. Genetic aspects of narcolepsy. In: Hayaishi O, Inoue S, editors. Sleep and sleep disorders: from molecule to behavior. Tokyo: Takeda Science Foundation; 1997. p. 341–58. [35] Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998;50(Suppl 1):S16–22. [36] Guilleminault C, Mignot E, Grumet C. Family study of narcolepsy. Lancet 1989;11:1376–80. [37] Matsuki K, Honda Y, Satake M, et al. HLA in narcolepsy in Japan. In: Honda Y, Juju T, editors. HLA in narcolepsy. Berlin: Springer-Verlag; 1988. p. 58–76. [38] Montplaisir J, Poirier G. HLA in narcolepsy in Canada. In: Honda Y, Juju T, editors. HLA in narcolepsy. Berlin: Springer-Verlag; 1988. p. 97–107. [39] Partinen M, Hublin C, Kaprio J, et al. Twin studies in narcolepsy. Sleep 1994;17:S13–16. [40] Carlander B, Eliaou JF, Billiard M. Autoimmune hypothesis in narcolepsy. Neurophysiol Clin 1993;23:15–22. [41] Mignot E, Tafti M, Dement WC, et al. Narcolepsy and immunity. Adv Neuroimmunol 1995;5:23–37. [42] Anch AM, Browman CP, Mitler MM, et al. Sleep: a scientific perspective. Englewood Cliffs, NJ: Prentice Hall; 1988. [43] Roehrs R, Zorick F, Wittig R, et al. Alerting effects of naps in patients with narcolepsy. Sleep 1986;9:191–94. [44] Mitler MM, Aldrich MS, Koob GF, et al. Narcolepsy and its treatment with stimulants. Sleep 1994;17:352–71. [45] Broughton RJ, Fleming JAE, George CFP, et al. Randomized, double-blind, placebocontrolled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology 1997;49:444–51. [46] Fry JM. Treatment modalities for narcolepsy. Neurology 1998;50(Suppl 1):S43–48. [47] Nishino S, Mignot E. Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol 1997;52:27–8. [48] US Modafinil in narcolepsy multicenter study group. Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol 1998;43:88–97. [49] Godbout R, Montplaisir J. All-day performance variations in normal and narcoleptic subjects. Sleep 1986;9:200–4. [50] Helmus T, Rosenthal L, Bishop C, et al. The alerting effects of short and long naps in narcoleptic, sleep-deprived, and alert individuals. Sleep 1997;20:251–7. [51] Mullington J, Broughton R. Scheduled naps in the management of daytime sleepiness in narcolepsy-cataplexy. Sleep 1993;16:444–56. [52] Rogers AE, Aldrich MS. Do regularly scheduled naps reduce sleep attacks and excessive daytime sleepiness associated with narcolepsy? Nurs Res 1993;42:111–7. [53] Rogers AE, Aldrich MS, Lin X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep 2001;24:1–7. [54] Yuchiyama M, Mayer G, Meirer-Ewart K. Differential effects of extended sleep in narcoleptic patients. Electroencephalogr Clin Neurophysiol 1994;91:212–8. [55] Montplaisir J, Godbout R. Nocturnal sleep of narcoleptics: revisited. Sleep 1986;9:159–61. [56] Scrima L, Hartman PG, Johnson FR Jr, et al. Efficacy of gamma-hydroxybutyrate versus placebo in treating narcolepsy-cataplexy: double blind subjective measures. Biol Psychiatry 1985;26:331–41. [57] Garma L, Marchand F. Non-pharmacological approaches to the treatment of narcolepsy. Sleep 1994;17:S97–102. [58] Panetar D, McCann U, Kamimori G, et al. Caffeine reversal of sleep deprivation effects on alertness and mood. Psychopharmacology (Berlin) 1993;112:359–65. [59] Wright KP Jr, Badia P, Myers BL, et al. Combination of bright light and caffeine as a countermeasure for impaired alertness and performance during extended sleep deprivation. J Sleep Res 1997;6:26–35.
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[60] Parkes JD, Dahlitz M. Amphetamine prescription. Sleep 1993;16:201–3. [61] Thorpy MJ, Goswami M. Treatment of narcolepsy. In: Thorpy MJ, editor. Handbook of sleep disorders. New York: Dekker; 1990. p. 235–58. [62] Bell IR. Diet history in narcolepsy. In: Guilleminault C, Dement WC, Passouant P, editors. Narcolepsy. New York: Spectrum; 1976. p. 221–8. [63] Kales A, Kales J. Sleep disorders: recent findings in the diagnosis and treatment of disturbed sleep. New Engl J Med 1974;290:487. [64] Zarcone V. Narcolepsy. New Engl J Med 1973;288:1156–66. [65] Pollak CP, Green J. Eating and its relationships with subjective alertness and sleep in narcoleptic subjects living without temporal cues. Sleep 1990;13:467–78. [66] Honda Y, Doi Y, Ninomiya C, et al. Increased frequency of non-insulin-dependent diabetes mellitus among narcoleptic patients. Sleep 1986;9:254–9. [67] Schuld A, Hebebrand J, Geller F, et al. Increased body-mass index in patients with narcolepsy. Lancet 2000;355:1274–5. [68] Lammers GJ, Pijl H, Iestra J, et al. Spontaneous food choice in narcolepsy. Sleep 1996; 19:75–6. [69] Middlekoop HA, Lammers GJ, Van Hilten BJ, et al. Circadian distribution of motor activity and immobility in narcolepsy: assessment with continuous motor activity monitoring. Psychophysiology 1995;32:286–91. [70] Overeem S, Mignot E, van Dijk JG, et al. Narcolepsy: clinical features, new pathophysiological insights, and future perspectives. J Clin Neurophysiol 2001;18:78–105. [71] Daniels E, King MA, Smith IE, et al. Health-related quality of life in narcolepsy. J Sleep Res 2001;10:75. [72] Cohen FL, Nehring WM, Cloninger L. Symptom description and management in narcolepsy. Holist Nurs Pract 1996;10:45–53. [73] Alaia SL. Life effects of narcolepsy: measures of negative impact, social support and psychological well-being. Loss, grief, and care 1992;5:1–22. [74] Broughton R, Mamelak M. The treatment of narcolepsy-cataplexy with nocturnal gammahydroxybutyrate. Can J Neurol Sci 1979;6. [75] Lammers GJ, Arends J, Declerck AC, et al. Gammahydroxybutyrate and narcolepsy: a double-blind placebo-controlled study. Sleep 1993;16:216–20. [76] Mamelak M, Escriu JM, Stokan O. The effects of gamma-hydroxybutrate on sleep. Biol Psychiatry 1977;12:273–88. [77] Scrima L, Hartman PG, Johnson FH Jr, et al. Efficacy of gamma-hydroxybutyrate versus placebo in treating narcolepsy-cataplexy; double blind subjective measures. Biol Psychiatry 1989;26:331–43. [78] Scrima L, Hartman PG, Johnson FH Jr, et al. The effects of gamma-hydroxybutyrate on the sleep of patients with narcolepsy: a double blind study. Sleep 1990;13:479–90. [79] The 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 treatment of narcolepsy. Sleep 2002;25:43–9. [80] Broughton R, Mamelak M. Effects of nocturnal gamma-hydroxybutyrate on sleep/waking patterns in narcolepsy-cataplexy. Can J Neurol Sci 1980;7:23–31. [81] Scharf MB, Brown D, Woods M, et al. The effects and effectiveness of gamma-hydroxybutyrate in patients with narcolepsy. J Clin Psychiatry 1985;46:222–5. [82] Rogers AE, Aldrich MS, Berrios AM, et al. Compliance with stimulant medications in narcolepsy. Sleep 1997;20:28–33. [83] Rogers AE, Cantor C, Marcus S. Compliance with stimulant medications in patients with narcolepsy: measurement with a MEMS TrackCap [abstract]. Sleep 2001;24(Supp). [84] Firestone P. Factors associated with children’s adherence to stimulant medication. Am J Orthopsychiat 1982;52:447–57. [85] Kauffman RE, Smith-Wright D, Reese CA, et al. Medication compliance in hyperactive children. Pediatr Pharmacol (New York) 1981;1:231–7.
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[86] Simons MR. Nursing interventions related to compliance. Nurs Clin North Am 1992; 27:477–85. [87] Sleator EK. Measurement of compliance. Psychopharmacol Bull 1985;21:1089–93. [88] Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel assessment technique. JAMA 1989;261:3273–7. [89] Urquhart J. Variable patient compliance in ambulatory trials-nuisance, threat, opportunity. J Antimicrob Chemother 1993;32:643–9. [90] The working group on health education and high blood pressure control. The physician’s guide; improving adherence among hypertensive patients. Washington, DC: US Department of Health and Human Services, Public Health Service, National Institute of Health; 1987. [91] Ward GW. How misconceptions deter maintenance. Urban Health 1977;6:28–9. [92] MacLeod V, Shneerson J. Narcolepsy: nursing the sleeping sickness. Nurs Times 1998; 94:48–50. [93] Stansberry TT. Narcolepsy: uunveiling a mystery. Am J Nurs 2001;101:50–3.
Narcolepsy Ann E. Rogers, PhD, RN, FAANa,b,*, H. Michael Dreher, DNSc, RNa,b a
School of Nursing, University of Pennsylvania, 420 Guardian Drive Philadelphia, PA 19104, USA b Division of Sleep and Respiratory Neurobiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Narcolepsy is a chronic disorder characterized by excessive daytime sleepiness. All patients experience excessive daytime sleepiness. Other symptoms include cataplexy, sleep paralysis, hypnagogic hallucinations, and disrupted nocturnal sleep. Treatment, usually with stimulants and low doses of antidepressant medications, can dramatically improve the patient’s quality of life. Although only advanced practice nurses may be actively involved in the diagnosis and treatment of this disorder, all nurses can encourage their patients who complain of excessive daytime sleepiness to consult a specialist in sleep disorders medicine, provide emotional support after diagnosis, and educate patients and their families about narcolepsy and its treatment. Narcolepsy is a sleep disorder that is characterized by excessive daytime sleepiness (EDS). Although the origins of this syndrome are unknown, it is now theorized that the neuroexcitatory peptide hypocretin and its receptors may be central to its pathophysiology [1]. Persons with narcolepsy exhibit EDS and disturbed nocturnal sleep, cataplexy, sleep paralysis, hypnagogic hallucinations, and pathologic manifestations of rapid eye movement (REM) sleep. It is a chronic neurologic disorder that is more common than Huntington chorea, multiple sclerosis, or muscular dystrophy [2], affecting between 0.03% and 0.18% of the general population [3]. The onset of narcolepsy usually occurs during adolescence or during the early twenties with the onset of daytime sleepiness and sleep attacks. Recent research has suggested that there may be second, smaller peak in onset around age 35 [4,5], and approximately 25% of patients do not present for diagnosis until after age 40 [6]. * Corresponding author. E-mail address: [email protected] (A.E. Rogers). 0029-6465/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 9 - 6 4 6 5 ( 0 2 ) 0 0 0 3 5 - X
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The classic auxiliary symptoms of cataplexy, sleep paralysis, and hypnagogic hallucinations may occur almost immediately or may develop 5 to 10 or even 20 years later. Whereas the severity of the auxiliary symptoms may fluctuate throughout the patient’s life, EDS, once present, is chronic and unremitting. Untreated, EDS associated with narcolepsy persists into old age, but it is not exacerbated by the development of age-associated changes in nocturnal sleep (eg, poorer sleep efficiency, increased awakenings, and decreases in Stage 3/4 sleep) [7–9]. It is reported that some patients have less severe daytime sleepiness with increasing age [8,10,11], but whether this change represents improved coping with the illness or simply partial remission is not known. The symptoms of narcolepsy can be debilitating, and up to half of all narcoleptic patients experience difficulties at work, in marriage, or in their social lives related to symptom burden [12]. In one study, 80% of subjects reported falling asleep at work on at least several occasions. Narcolepsy can also cause impaired attention and poor concentration, which can interfere with education and employment [13–16]. The insidious nature of narcoleptic sleep attacks or cataplexy during meals, conversations, and even during sexual intercourse may negatively affect interpersonal relationships. The symptoms of narcolepsy may be cause friends and family members to mistakenly attribute excessive sleepiness to boredom, laziness, or psychological problems [13–15]. The symptoms of narcolepsy can interfere with activities of daily living and negatively affect quality of life. Narcoleptic subjects reported more impairment in their physical and emotional health (25%), social isolation (35%), and more severe family problems (21%) when compared with a normative sample of 2406 disabled persons [17]. Symptoms of narcolepsy seem to have a more serious impact on driving when compared with epilepsy, another chronic neurologic disease with episodic loss of consciousness. Except for the area of driver’s license maintenance, persons with narcolepsy had a similar or greater impact in all driving-related measures. Although far fewer epileptic subjects drove (31.7%) than subjects with narcolepsy (73.3%), those that did drive had significantly better driving records with fewer nearaccidents, episodes of falling asleep at the wheel, and actual accidents than narcoleptic subjects. These findings led Broughton et al [18] to suggest that the chronic pervasive daytime sleepiness experienced by narcoleptic patients may be particularly handicapping because persons with epilepsy are relatively alert between seizures. Finally, adverse effects were recently reported in a study using the 36-item Short Form Health Survey [19]. Patients with narcolepsy scored significantly lower on vitality and social functioning and reported more difficulty when performing their usual activities due to physical and emotional problems compared with normative scores for the general population. When compared with several patient populations, patients with narcolepsy also experienced equally severe or more severe effects (Fig. 1). Perhaps the most poignant illustrations of the effects narcolepsy has on quality of life come from e-mail messages from patients to AER. During the
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Fig. 1. Comparison of narcolepsy patients with the general population and other patient populations. (From Beusterien KM, Rogers AE, Walsleben JA, et al. Health-related quality of life effects of modafinil for treatment of narcolepsy. Sleep 1999;22:759; with permission.)
past 3 years, she has maintained a web site to recruit subjects for her current study (http://www.nursing.upenn.edu/narcolepsy), and she has received hundreds of e-mail messages like the following: I hate what is happening to me. I want to feel human again. I want to be able to drive without the fear that I will kill myself or someone else. I don’t know how much longer my boss will put up with this from me. I leave early…sometimes I am late because I fall asleep while dressing in the morning. If I am a few minutes later than usual getting back from a break they look for me because they know I fall asleep in the break room. Is there hope for me? Can anyone help me? (E-mail to [email protected], June 2001.) I was released from my job this past April because of my narcolepsy I was found sleeping twice and working as an electrician I almost fell from a 40 foot lift. …I have lost my right to drive and cannot find anyone to hire me. What should I do or what can I do when it’s so bad could I file for social security disability? (E-mail to [email protected], September 2001.) I have experienced all the symptoms of the illness throughout my life but daytime sleepiness with multiple sleep attacks have continued to be my biggest problem. The severity of it now has completely devastated my life, robbing me of everything I found meaningful. (E-mail to aerogers@ nursing.upenn.edu from a 53-year-old artist, January, 2002.)
Symptoms All patients with narcolepsy experience EDS, and many have one or more auxiliary symptoms (eg, cataplexy, sleep paralysis, hypnagogic
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hallucinations, and disturbed nocturnal sleep). The most disabling symptoms for most patients are sleep attacks and EDS. Sleep attacks are short episodes of sleep that may occur many times a day. They can occur at any time, including during times of physical inactivity or boredom or when not anticipated or expected (eg, during a test or business meeting, while waiting for a traffic light to change from red to green, or when skiing, examining patients, or eating a meal) [2,8,16]. Some occur suddenly without warning, whereas others are preceded by a cognitive awareness of drowsiness. Once aroused by even superficial touch, a sound, or even the cessation of a speaking voice, the narcoleptic individual usually feels refreshed and often has a refractory period of one to several hours before the onset of the next sleep attack. However, most narcoleptic patients are not fully cognizant alert individuals who simply suffer from sleep attacks. They also experience a persistent, abnormal daytime sleepiness that Mitler and Gujavarty [20] compared with the ‘‘sleepiness one feels when trying to complete a boring task at 3 AM after 72 hours of total sleep deprivation.’’ Cataplexy is a brief (seconds or minutes) abrupt loss or weakness of skeletal muscle tone without any loss of consciousness. This symptom can vary in severity with a range from a mild sensation of muscle weakness in the neck to a complete postural collapse, entailing a dangerous fall to the ground. The frequency of symptoms may vary in each individual. Some patients may experience only one or two episodes during a lifetime (which is less common), whereas others may have many episodes of cataplexy each day. Episodes of cataplexy are most commonly precipitated by a sudden emotional stimulus, such as laughter, anger, or surprise. To view a videotaped episode of cataplexy, visit Stanford University’s Center for Narcolepsy website (http://www.med.stanford.edu/school/Psychiatry/narcolepsy). Sleep paralysis occurs in some narcoleptics during the transition between sleep and waking. The individual experiences a sudden but temporary paralysis of all striated muscles. The person cannot move any muscles other than the muscles of respiration. Each episode of sleep paralysis usually lasts a few minutes and may also be accompanied by intense fear or hypnagogic hallucinations. The cessation of sleep paralysis ends spontaneously or terminates immediately when the individual is touched or spoken to by another person. Like cataplexy, the frequency of these episodes is highly variant. Sleep paralysis may occur daily, weekly, or once or twice in a lifetime. Hypnagogic hallucinations are vivid, life-like sensory dream-like experiences that appear as a person is falling asleep before loss of consciousness. The duration of these visual, auditory, or tactile hallucinations is usually approximately 1 to 15 minutes. Persons with narcolepsy may also complain of disturbed nocturnal sleep that is often fragmented and shortened. Whereas persistent or episodic fragmented nocturnal sleep might commonly contribute to EDS in someone without a sleep disorder, this is not the central cause of EDS in the individual with narcolepsy. Daytime sleepiness is usually the first symptom
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of narcolepsy, and it often develops several years before the individual becomes cognizant of their persistent nighttime sleep disruption. Moreover, studies indicate that improving the nocturnal sleep of these patients does not lead to any reduction in daytime sleepiness [21]. One recent study indicates that daytime sleepiness may contribute to nocturnal sleep disruptions [22]. Patients whose daytime sleepiness was eliminated by stimulant medications had nocturnal sleep patterns that corresponded with sleep patterns in normal sleepers, whereas subjects whose sleepiness was not controlled by stimulants had fragmented and shortened nocturnal sleep.
Pathophysiology Although the precise etiology of narcolepsy is unknown, recent discoveries suggest that human and animal narcolepsy is associated with the destruction of hypocretin (orexin)-secreting cells in the hypothalamus [1,23–25]. Despite normal serum levels of hypocretin-1 (Hcrt-1), CSF levels of Hcrt-1 are severely reduced or absent in narcoleptic patients [26,27]. Because serum levels are not abnormal, the deficit does not seem to be caused by damage to neuronal cells in the gut but rather seems associated with damage to the CNS. Additionally, several cases of well documented secondary cases of narcolepsy have involved damage to the hypothalamus, including two recent cases where symptoms of narcolepsy developed after a hypothalamic infarct and after damage to the hypothalamic area during resection of an astrocytoma [28–30]. Research using animal models suggests the importance of this system in the development of narcolepsy. For example, a deletion in the Hcrt receptor-2 gene causes cataplexy in dogs [31], and Hcrt knockout mice exhibit cataplexy or episodes of REM sleep while awake [32]. Recent work with narcoleptic dogs has shown decreased histamine content in the cortex and thalamus, two structures important for histaminemediated arousal [33]. Because histamine normally promotes arousal, decreases in histaminergic neurotransmission may account for some of the sleep abnormalities associated with narcolepsy. Although narcolepsy is transmitted through a single autosomal recessive gene (CANARC 1) in Doberman pinschers, the genetic basis for human narcolepsy is not that simple. Even though almost all narcoleptics are positive for DRB1*1501-DQA1*0102-DQB1*0602, this haplotype is neither sufficient nor necessary for the development of narcolepsy [34,35]. Most cases of narcolepsy are sporadic, and familial cases are the exception rather than the rule. For instance, despite sharing the same human leukocyte antigen (HLA) haplotype as the narcoleptic patient, family members do not necessarily develop the disorder [36–38]. An even stronger case against an absolute genetic predisposition to develop narcolepsy is suggested by studies that identify at least four pairs of monozygotic twins (established by HLA testing
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and DNA fingerprinting) who are discordant for narcolepsy [36,38,39]. These findings suggest that nongenetic factors may be associated with the development of narcolepsy. Despite the association of HLA and autoimmune disease, researchers have been unable to find evidence that narcolepsy is caused by an autoimmune process [37,40,41]. There is also no evidence that endocrine or viral causes are implicated in its etiology [42,43].
Diagnosis Although EDS is endemic in contemporary American society, not all sleepy individuals have narcolepsy. Patients presenting with a complaint of difficulty in maintaining desired wakefulness or EDS should be evaluated carefully. Because there are numerous causes of EDS, it is important that anyone with a complaint of daily or almost daily EDS for 3 months or more be referred to a sleep disorder center for evaluation (a list of accredited sleep disorders centers can be found at http://www.aasmnet.org/listing.htm). During the first visit, the sleep disorders specialist, who might be a physician, a psychologist, or a doctorally prepared nurse, obtains a health history and a detailed sleep history. Although classic cases of narcolepsy are easy to recognize, most individuals present with some but not all symptoms of the disorder. A nocturnal polysomnogram is necessary to rule out sleep apnea as a cause of the patient’s EDS. If sleep apnea is present, it must be successfully treated before diagnosing narcolepsy. All patients must also undergo a Multiple Sleep Latency Test (MSLT), which objectively measures the severity of daytime sleepiness. Patients with narcolepsy fall asleep very quickly during the MSLT (5.0 minutes) and have at least two sleep-onset REM periods.
Treatment Treatment of narcolepsy is usually multifaceted and focuses on the control of EDS and cataplexy. This section provides an overview of pharmacologic and nonpharmacologic treatments, discusses issues related to compliance, and suggests appropriate nursing interventions. Controlling EDS Pharmacologic treatment To ensure safe and adequate function at home, while driving, or at work, EDS must be controlled [44] (see Table 1). Pharmacologic treatment for narcolepsy includes older stimulant medications such as dextroamphetamine (Dexedrine) and methylphenidate (Ritalin) and the newer drug modafinil (Provigil). Adderall (a product containing a mixture of amphetamine salts)
5–100 mg
Methamphetamine-HCl (Desoxyn) Modafinil (Provigil)
37.5–300 mg
Pemoline (Cylert)
Variable duration of action, depending on whether using regular or sustained release form of medication More potent than dextroamphetamine Lower potency than amphetamines or methylphenidate. Long duration of action Less potent than amphetamines. Variable duration of action, depending on whether using regular or sustained release form of medication Less potent than other medications used to control daytime sleepiness. Long duration of action
Potency and duration of action
Can cause liver damage; patient must be monitored regularly
Sympathomimetic effects, mood alterations
Schedule IV
Schedule II Most frequently prescribed stimulant for treatment of narcolepsy in the United States
Schedule IV
Schedule II
Schedule II
Sympathomimetic effects, mood alterations
Sympathomimetic effects, mood alterations Fewest side effects of stimulant medications
Other information
Potential side effects
* Data from Narcolepsy, a teaching slide set prepared by the American Academy of Sleep Medicine, Rochester, MN.
10–100 mg
Methylphenidate-HCl (Ritalin/Ritalin-SR)
200–800 mg
5–100 mg
Usual daily dose*
Dextroamphetamine-sulfate (Dexadrine, Dextrostat, Dexadrine-SR)
Name
Table 1 Medications used to treat excessive daytime sleepiness A.E. Rogers, H.M. Dreher / Nurs Clin N Am 37 (2002) 675–692 681
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and Concerta (a new sustained-release form of methylphenidate) are also effective. Modafinil is usually the treatment of choice. It has fewer side effects than traditional stimulants and a longer duration of action [45–48]. Not all patients find modafinil effective for controlling their EDS, and some need to be switched to a traditional stimulant. Treatment is usually started with a low dose of a short-acting drug and is increased as necessary. Some patients benefit from a combination of short- and long-acting medications, such as modafinil and methylphenidate, or from a second dose of modafinil in the afternoon. Although the sustained-release formulations of dextroamphetamine and methylphenidate have longer half-lives than their short-acting forms, a second or even a third dose may be required to sustain alertness during the afternoon and evening hours. Nonpharmacologic approaches Many practitioners recommend behavioral approaches, particularly scheduled naps and sleep hygiene measures, for the treatment of narcolepsy. Patients are usually directed to take three to six 15-minute naps per day and to adopt a regular schedule for arising and retiring at night. Although napping can produce a transient improvement in alertness and performance [43,49–51], it does not reduce the number or duration of unscheduled daytime naps in untreated patients, nor is it clear that combining scheduled sleep periods and stimulant medications is more effective than the use of stimulants alone [52,53]. In one study, extending the nocturnal sleep period to 12 hours reduced subjective sleepiness and significantly improved mean sleep latencies the following day [54]. The mean sleep latency, however, increased only 3.6 minutes, resulting in a mean sleep latency of 7.8 minutes on the MSLT. Reducing or eliminating nocturnal sleep disruptions with benzodiazepines or gamma-hydroxybutyrate [21,55,56] has also not demonstrated any effect on daytime sleepiness. Although sleep schedule manipulations can produce statistically significant improvements in daytime alertness, the clinical utility of manipulating sleep schedules is limited. Extending or regularizing nocturnal sleep periods [54] or adding naps [43,51] can help increase alertness at least for short periods (generally less than 1 hour). Moreover, many of the suggested schedules are impractical for patients attending school or working. Patients may have difficulty taking one or two 15-minute naps during the workday, and a 120minute nap, which has been shown to be more effective than several short naps [51], is unlikely to be tolerated by most employers. Caffeine is sometimes recommended as an inefficient but safe alternative to traditional stimulant medications or as an adjuvant treatment [57]. Caffeine, which can improve alertness in sleep-deprived subjects [58,59], has not been investigated as a treatment for EDS in narcoleptic patients. Its alerting effects, however, are limited. For example, it takes six cups of strong
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coffee or approximately 750 mg of caffeine to obtain an effect comparable to 5 mg of dexamphetamine [44,60], and most persons in the United States consume only an average of 200 mg of caffeine per day [23]. Most patients do not find caffeine effective for controlling daytime sleepiness and can easily fall asleep after its ingestion [61]. Although dietary manipulations are popular among patients, the efficacy of restricting intake of simple sugars, the use of dietary supplements, or avoiding meals to be alert, for example, has not been supported by research. Numerous anecdotal reports describing postprandial drowsiness, increased drowsiness after consumption of sugars, carbohydrate cravings, sleep attacks triggered by ingestion of certain foods, or unusual eating patterns among narcoleptic patients [62–64] have not been substantiated. Pollack and Green’s [65] study of narcoleptic and control subjects living in a time-isolation laboratory demonstrated that most of these claims were spurious. In examining the relationship between sleep, eating behavior, and subjective alertness, they reported that, although naps were more likely to occur after a meal than preceding a meal, naps were no more likely to occur after larger meals or meals containing more of any one macronutrient. Meals followed by naps did not differ in size or macronutrient composition from meals that were not followed by naps. Nevertheless, even if dietary alterations have not been shown to increase daytime alertness, all narcoleptic patients should be counseled to consume only enough calories to maintain their weight within appropriate levels. Almost 20 years ago, it was reported there was a higher incidence of Type II diabetes and obesity among Japanese narcoleptic patients [66]. More recent studies indicate that patients with narcolepsy, on average, have a body mass index (BMI) 10% to 20% greater than matched control subjects [62,66,67]. The use of antidepressant medications for treatment of cataplexy has been ruled as a potential cause of increased BMI in narcoleptic patients [68]. Lower levels of physical activity associated with daytime napping have also been ruled out as a cause of increased BMI [69]. Five years ago, after studies showed that narcoleptic patients usually consume fewer calories and carbohydrates than control subjects, researchers began suggesting that patients may have lower than normal metabolic rates [68]. Until the recent discovery of altered hypocretin function in this population, no one could explain why patients had lower metabolic rates. The relationship between altered hypocretin function and altered metabolism is not completely understood, but researchers believe that hypocretin abnormalities may be linked to the lower metabolic rates in narcoleptic patients [70]. Dietary strategies for the treatment of narcolepsy are widely used by patients, although there is limited evidence to support their use. Nevertheless, despite a paucity of research, dietary manipulations continue to be recommended. For example, Garma and Marchand [57] state in their 1994 article, ‘‘good dietary practices are useful in insuring good sleep hygiene’’ and then recommend that ‘‘morning and midday avoidance of
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ÔsweetsÕ and carbohydrates, especially simple sugars, and large meals will improve alertness in some narcoleptics.’’ Perhaps the perception shared by many narcoleptic patients—that stimulant drugs are ineffective for reducing the severity of daytime sleepiness—leads individuals to believe specious claims that dietary manipulations can control symptoms more effectively or more naturally [45,53,71]. Behavioral interventions are appealing to patients and providers alike because of their low cost and lack of potentially dangerous side effects. Whereas the majority of patients combine pharmacologic therapy and some form of self-initiated behavioral management regimen, an alarming number of patients (30% to 54%) report relying exclusively on nonpharmacologic measures to combat daytime sleepiness [4,72]. Reasons for noncompliance or eschewing stimulant therapy altogether vary widely. Some patients worry about getting ‘‘addicted’’ to stimulants, whereas others deem the side effects from medications worse than the symptoms of narcolepsy [73]. Some techniques recommended by patients with narcolepsy to manage their symptoms are fairly benign (eg, splashing cold water on the face, practicing deep breathing/meditation, and avoiding stress) [4,72]. Other techniques, such as driving a car with a manual transmission, using an alarm clock while driving, hurting themselves while driving to stay awake, avoiding social situations, and smoking cigarettes, have the potential for harm. Some behavioral strategies (eg, scheduling social and business activities to coincide with periods of peak alertness, restricting attendance at evening events, and giving in and sleeping) suggest a highly compromised quality of life where resignation to living with profound sleepiness has been accepted. Controlling cataplexy and other REM-related symptoms Small doses of antidepressant medications and other drugs that suppress REM sleep may be used to control cataplexy. Tricyclic antidepressants, such as clomipramine (Anafranil), imipramine (Tofranil), and protriptyline hydrochloride (Vivactil), are generally considered more effective than selective serotonin reuptake inhibitors (SSRIs) for the treatment of cataplexy (Table 2). Tricyclic antidepressants and SSRIs are powerful and effective REM sleep inhibitors; however, anticholinergic side effects, such as blurred vision, dry mouth, constipation, tachycardia, and urinary retention, may limit their use. The efficacy of sodium oxybate (Xyrem) or gamma hydroxybutyrate for controlling cataplexy has been documented by numerous small studies over the past 25 years [74–78]. Results of a recent clinical trial involving 136 patients confirmed that nightly administration of sodium oxybate produced a significant decrease in the frequency of cataplexy [79]. Sodium oxybate seems to be a unique endogenous neurotransmitter/neuromodulator that consolidates REM and nonREM sleep and decreases sleep fragmentation [75,77,80,81].
25–150 mg
25–100 mg
20–60 mg
10–100 mg
5–60 mg
Clonipramine (Anafranil)
Desimpramine (Norpramin/ Pertofran)
Fluoxetine (Prozac)
Impramine (Jaminime, Tofranil)
Protriptyline (Triptil, Vivactil)
Anticholinergic effects (dry mouth, blurred vision, and constipation) at high doses
Some anticholinergic effects (dry mouth, blurred vision, constipation) but less than clonipramine and desimpramine
Fewer side effects than other clonipramine, disimpramine, and impramine. Less weight gain than with other antidepressants
More anticholinergic effects (dry mouth, blurred vision, constipation) than impramine
Some anticholinergic effects (dry mouth, blurred vision, constipation)
Potential side effects
* Data from Narcolepsy, a teaching slide set prepared by the American Academy of Sleep Medicine, Rochester, MN.
Usual daily dose*
Name
Table 2 Medications used to treat cataplexy
May need higher doses to control cataplexy
Very effective against cataplexy; used more frequently in Europe
Other information
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Although there are few sides effects associated with sodium oxybate [79], it is difficult to use and cannot be prescribed in United States. The drug is available only in liquid form and must be taken in several divided doses at night. Because of its short half-life, patients are encouraged to use an alarm clock so that they are assured of awakening to take their second dose of medication 2.5 to 4 hours after going to bed. Sodium oxybate is an investigational drug and is not available to patients unless they are participating in a clinical trial. Not all patients require medications to control cataplexy. Patients with infrequent or minor symptoms may prefer to avoid medications, whereas others with similar symptoms request medication. The patient’s lifestyle may influence their decision or desire for medication. For example, patients may request medications to control cataplexy if they fear having an episode when holding a new grandchild, are highly embarrassed by episodes of cataplexy occurring in public settings, etc. Although pharmacologic treatment is rarely prescribed for the control of other REM dissociation phenomena, the treatment of cataplexy usually reduces the incidence and severity of hypnagogic hallucinations and sleep paralysis [70]. Occasionally, a short-acting hypnotic or sedating antidepressant may be prescribed for patients who are distressed by their fragmented nocturnal sleep. Compliance Because few patients rely exclusively on stimulant medications to control their EDS, all patients should be questioned about behavioral strategies used to manage their symptoms and the rationale for selecting these strategies. If patients report difficulties staying awake, especially when driving, their medication regime may need to be modified. Compliance with prescribed therapy should also be assessed because studies have shown that the majority of narcoleptic patients fail to take their prescribed dosage of stimulant medications [82,83]. Dosage reductions are often substantial, with patients taking less than one half the medication prescribed. Compliance with anti-cataplectic medications has not been studied. However, there is little evidence to suggest that compliance rates for anti-cataplectic medications would be higher than those for stimulant medications. Patients of all ages and from all educational and socioeconomic levels frequently choose to alter their prescribed medication regimens without consulting their health care provider, take their medications at different times than prescribed, and take more or less drug than prescribed [84–87]. Underdosing by frequently taking less medication than prescribed is common [85,88,89]. Patients also fail to fill their original prescription or do not refill their prescriptions in a timely fashion. Patients take ‘‘drug holidays’’ or completely stop taking their medications after a few months without consulting their physicians. Only approximately one third of all patients are
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estimated to be satisfactorily compliant, with another third partially compliant, and the remaining third not at all compliant to treatment [89]. Patient belief systems influence compliance [90,91]. Many patients express fears about ‘‘becoming addicted’’ to stimulant medications, whereas others express a desire for a ‘‘natural’’ remedy. Clinicians need to discuss the difference between ‘‘drug use’’ and ‘‘drug abuse’’ with their patients and to have frank discussions of appropriate uses of stimulants (particularly Ritalin) to combat frequent media claims of overprescribing. Rather than just seeking to get the patient to take the prescribed pills, the focus might be on the patient’s quality of life. For example, patients could be asked what would they like to do if they could remain awake for longer periods of time or if they were not worried about experiencing cataplexy. After the patient identifies a goal—for example, working full-time, keeping the house neater, or returning to school—the health care provider’s role would be to help the patient meet the goal in a safe manner. Strategies to incorporate pill taking into the patient’s usual activities should also be discussed, and long-acting stimulants should be prescribed if patients have difficulty remembering to take their afternoon dosages of medication. Nursing interventions Nursing interventions are mainly supportive. Referral to a sleep disorders specialist is critical if narcolepsy is suspected. When referring patients to a sleep disorder center, it is often helpful to provide some basic information about how long it might take to get an appointment, what tests might be involved, and whether or not the tests are covered by their medical insurance. In some areas of the United States, it is not unusual for patients to have to wait several months to be seen by a sleep disorders specialist or undergo diagnostic tests. Patients should be cautioned to avoid driving or operating heavy machinery when drowsy. After diagnosis, patients frequently crave information about their illness. Accurate information is available from the National Sleep Foundation website (http://www.sleepfoundation.org), the National Institute of Health (http://www.nhlbi.nih.gov/health/public/sleep/narcolepsy.htm), and many other websites maintained by sleep disorders centers (eg, Stanford University). However, not all information posted on the web is accurate, and patients should be cautioned about relying on other patients and vendors of various products for treatment information. Patients may also benefit from meeting other patients at local support group meetings or on line. A number of bulletin boards and newsgroups for patients are available through the web; some are moderated by professionals, but most are not. Most of the stimulants used to take medications are classified as Schedule II Narcotics in the United States. The number of tablets that can be prescribed at one time is limited, and prescriptions cannot be refilled. Only modafinil and pemoline, which are Schedule IV medications, can be refilled,
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and then only for a 6-month period. The cost of medication may be problematic for some patients. Modafinil is very expensive (approximately $6.00 per tablet), and some health insurance plans, particularly those using a formulary system, may restrict coverage to older, less expensive stimulants (eg, amphetamines and methylphenidate). If a patient complains about increasing daytime sleepiness despite treatment with stimulant medications, they should be referred back to a sleep disorders specialist for further evaluation. Do not waste your time (and the patient’s) by suggesting many of the behavioral measures advocated in some nursing publications. Obtaining proper nutrition, although desirable to prevent cardiovascular disease, does not reduce EDS, nor is there empiric basis for recommending that the patient awaken the same time each morning; abstain from food, caffeine, and alcohol after 8 PM; take a hot bath or shower before bed; find support for daily stressors; and ensure that the bedroom is dark, cool, and quiet [92,93]. These strategies, commonly recommended for patients with sleep-onset insomnia, do not reduce nocturnal sleep disruptions in patients with narcolepsy. Summary Narcolepsy is a chronic disorder of EDS. All patients experience EDS. Other symptoms include cataplexy, sleep paralysis, hypnagogic hallucinations, and disrupted nocturnal sleep. Treatment, usually with stimulants and low-doses of antidepressant medications, can dramatically improve the patient’s quality of life. Although only advanced practice nurses may be actively involved in the diagnosis and treatment of this disorder, all nurses can encourage their patients who complain of EDS to consult a specialist in sleep disorders medicine, provide emotional support after diagnosis, and educate patients and their families about narcolepsy and its treatment. References [1] Olafsdottir BR, Rye DB, Scammell TE, et al. Polymorphisms in hypocretin/orexin pathway genes and narcolepsy. Neurology 2001;57:1896–99. [2] National Commission on Sleep Disorders Research. Report of the National Commission on Sleep Disorders Research. DHHS Pub. No. 93-XXXX Washington, DC: US Government Printing Office; 1993. [3] Nishino S, Okura M, Mignot E. Narcolepsy: genetic predisposition and neuropharmacological mechanisms. Sleep Medicine Review 2000;4:57–59. [4] 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;57:2029–33. [5] Okun ML, Lin L, Pelin Z, et al. Clinical aspects of narcolepsy-cataplexy across ethnic groups. Sleep 2002;25:27–35. [6] Honda Y, Asaka A, Tanimura M, et al. A genetic study of narcolepsy and excessive daytime sleepiness in 308 families with a narcolepsy or hypersomnia proband. In: Guilleminault C, Lugaresi E, editors. Sleep/wake disorders: natural history, epidemiology, and long-term evolution. New York: Raven Press; 1983. p. 188–99.
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