Dr. Brooks is staff physician and Dr. Kushida is assistant professor at the Stanford University Center of Excellence for Sleep Disorders in California. Reprinted from TEN. 2001;3(9):43-47. 



Narcolepsy is a potentially disabling neurologic disorder characterized by excessive daytime somnolence (EDS) and other symptoms, including cataplexy, sleep paralysis, hypnagogic hallucinations, and disrupted nocturnal sleep. The prevalence of narcolepsy is estimated to be .03% to .05% in the general population. The peak onset of symptoms occurs in adolescence, with a second peak at ~40 years of age. Even with treatment, narcolepsy can have a negative impact on health, social functioning, and performance at school or work. There are reasons to be optimistic that more effective treatments may be forthcoming.


History of Narcolepsy

The clinical manifestations of narcolepsy have been recognized for centuries and have been at times attributed to psychopathology, epilepsy, trauma, tumors, or infection. The history of narcolepsy has been extensively reviewed by Mignot,1 and will be summarized here. Willis described narcolepsy as early as 1672. However, Gélineau, in 1880, was the first to use the term “narcolepsy” (combining the Greek words for “somnolence” and “to seize”) to describe a clinical disorder that included irresistible sleep attacks and episodes of “astasia” (falling).

In 1902, Lowenfeld reported an association between excessive sleepiness and episodes of brief muscle weakness triggered by emotions. In 1926, Adie termed this muscle weakness “cataplexy.” In 1927, Lhermitte and Tournay described an association between narcolepsy and hypnagogic hallucinations. A short time later, Wilson reported an association between sleep paralysis and narcolepsy. Daniels, in 1934, noted the association of EDS, cataplexy, sleep paralysis, and hypnagogic hallucinations. Yoss and Daly termed this constellation of symptoms “narcoleptic tetrad” in 1957. In 1960, Vogel observed sleep-onset rapid eye movement periods (SOREMPs) in narcoleptics. Dement and Rechtschaffen later solidified the idea that disordered rapid eye movement (REM) sleep was of central importance in the pathophysiology of narcolepsy.

In the 1980s, Japanese workers discovered a link between narcolepsy and the human leukocyte antigen (HLA) DR2, suggesting that narcolepsy might represent a genetically determined autoimmune disorder.2 Although this idea remains unproven, further studies have established the concept of a genetic susceptibility to narcolepsy.

Clinical Features of Narcolepsy

Narcolepsy is a complex neurological disorder that disrupts sleep and wakefulness. In the majority of cases, symptoms of narcolepsy begin by the age of 25 years; onset occurs in approximately 10% of cases before age 10, and in 5% of cases after age 50. The disorder, affecting both genders equally, often begins gradually. EDS is usually the initial symptom, followed by other symptoms, including cataplexy, sleep paralysis, and hypnagogic hallucinations which occur over months to years. In a small number of cases, one of the other symptoms may precede excessive sleepiness. Once established, narcolepsy is not progressive, but usually persists for life, although symptoms may abate in some cases. Cataplexy, sleep paralysis, and hypnagogic hallucinations are more likely to disappear than excessive sleepiness.

The primary symptom of narcolepsy is EDS. Patients may report an ongoing feeling of drowsiness, or they may suffer from sleepiness episodes of variable duration. As in normal individuals, the sleepiness of the narcoleptic tends to be worse in the afternoon, in warm environments, and in passive or boring situations. Narcoleptic drowsiness, however, may become irresistible, leading to unwanted periods of sleep during the daytime, often at inappropriate times (such as during a meal, during a conversation, or while driving). This overwhelming urge to sleep may occur very suddenly, leading to what have been called “sleep attacks.” Periods of automatic behavior, a reflection of brief intrusions of sleep (“microsleeps”) into the drowsy state, may also occur. Suboptimal alertness may lead to secondary symptoms, such as difficulties with concentration and memory. Duration of daytime sleep episodes varies from minutes to an hour, and patients often feel transiently refreshed from even brief naps. Not only does excessive somnolence place the narcoleptic at increased risk of accidental injury, but it can also have a serious negative impact on family and social situations and on performance at school or work.

Up to 70% of narcoleptics experience cataplexy, which represents sudden, transient loss or reduction of skeletal muscle tone. Attacks of cataplexy are often triggered by an emotional stimulus (especially joking, laughter, or anger) or even by a memory of an emotionally charged event. Other triggers include stress, meals, and fatigue, but episodes may also occur without obvious provocation. The phenomenon of cataplexy may be subtle or dramatic, ranging from brief sagging of the jaw or knee buckling, collapse, or even injury. The severity of the attack may be maximal at onset, or the weakness may evolve over seconds, sequentially affecting various body parts. The duration of cataplexy episodes varies from a few seconds to half an hour, with episodes commonly lasting no longer than a few seconds to minutes. Consciousness and memory are maintained, although patients may report hallucinations or dream-like imagery during prolonged episodes.

Sleep paralysis refers to episodes of voluntary muscle paralysis occurring at sleep onset or upon awakening. Up to 40% to 50%3 of normal individuals report isolated sleep paralysis at least once in a lifetime (recurring episodes are much less common). The phenomenon recurs in up to 40% of narcoleptics. Episodes of sleep paralysis last for 1 to several minutes and resolve spontaneously or in response to external stimulation, such as the touch of another person. Usually, all voluntary muscles are involved, except those controlling eye movements and respiration. Hypnagogic imagery may occur concomitantly, but the sensorium is generally clear. Understandably, the experience may provoke acute anxiety.

Narcoleptics commonly report hallucinations at sleep onset (hypnagogic) or sleep offset (hypnopompic). These are often described as “waking dreams.” Generally, the hallucinations are visual or auditory, but tactile hallucinations or feelings of movement (such as levitating) are not uncommon. The visual hallucinations may be elaborate (such as animals or people) or simple (changing shapes and colors). Auditory hallucinations may take the form of sounds, words (the perception of one’s name being called is a common experience), or music.

Although one might expect that patients with EDS would be able to sleep soundly at will, this is not the case in narcolepsy. The major sleep period is usually disrupted. Narcoleptics encounter difficulty with sleep initiation or, more commonly, sleep maintenance. The total amount of sleep per 24-hour period is not increased in narcolepsy. The problem is that sleep is inappropriately distributed across the period, with intrusions in the daytime and poor consolidation of nocturnal sleep.

Genetics of Narcolepsy

Honda and colleagues2 first described the associations between narcolepsy and HLA DR2 and HLA DQ6 in the Japanese population. The association has been confirmed in 96% of whites with narcolepsy.4 The incidence of HLA DR2 varies among ethnic groups, with a lower incidence in African Americans. HLA DQ6 (and more particularly DQB1*0602) is a more sensitive marker for narcolepsy across ethnic groups. DQB1*0602 occurs more often in narcoleptics with cataplexy than in those without cataplexy.4,5 There is also a positive correlation between DQB1*0602 positivity and severity of cataplexy.

Most cases of narcolepsy are sporadic, but there are numerous reports of familial occurrence of narcolepsy. The risk of development of narcolepsy with cataplexy in first-degree relatives is 1% to 2% (10–40 times that in the general population). A larger percentage (4% to 5%) of relatives have isolated daytime somnolence. Several DQB1*0602-negative families have been identified, in which narcolepsy with cataplexy appears to be transmitted in an autosomal-dominant pattern with high penetrance.6 These cases may stem from a genetic mutation. Sporadic cases of DQB1*0602-negative narcolepsy with clear-cut cataplexy have also been reported, but these are unusual.

Although the strong HLA associations suggest that an autoimmune process may be responsible for narcolepsy, this has not been established. Overall, the evidence suggests that DQB1*0602 and DQA1*0102 confer susceptibility to narcolepsy.4 It is likely that other predisposing genes will be identified.

The Discovery of the Hypocretin/Orexin Peptides

In 1998, de Lecea and colleagues7 reported finding a hypothalamic-specific mRNA encoding the precursor of a pair of peptides homologous to secretin. They named the peptides hypocretin 1 and hypocretin 2 (Hcrt1 and Hcrt2) to denote their hypothalamic specificity and their resemblance to secretin. In the same year, Sakurai and colleagues8 identified two neuropeptides that bound and activated two related orphan G protein-coupled receptors. These peptides were found to stimulate food intake when administered centrally to rats. Thus, the investigators called them orexin A and orexin B (from the Greek “orexis,” meaning “appetite”). Later, it became clear that the orexins and the hypocretins were identical. Both of the hypocretins bind to two G protein-coupled receptors (Hcrtr 1 and Hcrtr 2), although hypocretin 2 has low affinity for Hcrtr 1. The cell bodies of hypocretin-producing neurons reside in the hypothalamus. They have dense projections within the hypothalamus but project widely to many other brain areas as well, most densely to the locus ceruleus.9 Four major pathways of hypocretin projection have been identified, two projecting toward the cortex and two toward the brainstem. The two descending pathways impinge on structures well known to be involved in sleep-wake regulation and occurrence of rapid eye movement (REM) sleep. The generous distribution of the hypocretin system suggests that these neuropeptides contribute to multiple physiologic functions, such as food intake, thermoregulation, endocrine function, cardiovascular regulation, and the sleep-wake cycle.9 The neuronal group is small and may not contain more than 10,000–15,000 neurons, suggesting a regulatory role for this newly discovered brain system.

New Discoveries in Animal Models of Narcolepsy

There are strains of dogs affected with narcolepsy and/or cataplexy. The canine syndrome is similar to the one observed in humans, and symptoms begin during the equivalent of early adolescence. Systematic investigation of a large dog colony initially led to identification of the chromosome containing the gene responsible for canine narcolepsy. Later, it was demonstrated that canine narcolepsy is due to a mutation of the gene coding for the hypocretin 2 receptor.10 Around the same time, other researchers observed narcoleptic-like behavior in preprohypocretin knockout mice.11

Hypocretin/Orexin in Human Narcoleptics

Nishino and colleagues12 hypothesized that human narcolepsy involves a disruption in hypocretin neurotransmission. They measured cerebrospinal fluid hypocretin in nine narcoleptic patients with cataplexy and eight control subjects. Hcrt1 was detected in all control samples. In seven of nine patients, hypocretin levels were below the assay’s limits of detection. In two patients with unquestionable narcolepsy-cataplexy, hypocretin was detectable; one patient’s level was similar to that of the control subjects, and the other’s level was elevated. These results demonstrate a deficiency in hypocretin function in some patients with narcolepsy, possibly due to a defect in hypocretin production. The patients with detectable hypocretin levels were clinically indistinguishable from the other narcoleptic patients. These two cases may reflect an abnormality of the effector-receptor interaction rather than a lack of hypocretin production. More recently, pathologic studies of brains of narcoleptics (compared with those of age-matched control subjects), performed simultaneously at Stanford and UCLA, have demonstrated absence of hypocretin neurons in the hypothalamus.13,14

These observations in human narcoleptics establish obvious links between narcolepsy and the hypocretin system. These findings, along with the those from canine and murine models, suggest that the hypocretin system is of central importance in the development of narcolepsy and have opened new pathways of inquiry into its pathophysiology.

Pathophysiology of Narcolepsy

The pathogenesis of human narcolepsy remains unclear. It is apparent, however, that narcolepsy represents a complex process. Association with specific HLA alleles and increased prevalence in first-degree relatives suggests a genetic basis. That genetic factors alone are insufficient to explain the disorder, is supported by the infrequent familial cases and the low concordance rate (25% to 30%) of narcolepsy between identical twins.6 Although still attractive, the autoimmune hypothesis remains unproven. Narcolepsy is not associated with oligoclonal bands in cerebrospinal fluid or with typical peripheral markers of autoimmune disease, such as autoantibodies, or elevations of erythrocyte sedimentation rate or C-reactive protein. The clinical expression of the disorder likely depends on the interplay between one or more genetic factors and environmental triggers. There are also numerous case reports of secondary or “symptomatic” narcolepsy, including some with cataplexy. Such cases have been associated with head trauma, stroke, multiple sclerosis, brain tumor, neurodegenerative disorders, and central nervous system infections.

How might the hypocretin system fit into the clinical framework of narcolepsy? Although the neuroanatomic and neurophysiologic underpinnings of human narcolepsy are incompletely defined, one of the disorder’s primary features seems to be abnormal regulation of REM sleep. The phenomena of cataplexy, sleep paralysis, and hypnagogic hallucinations all appear to represent inappropriate intrusions of REM sleep physiology into wakefulness. REM sleep onset is generated by cholinergic neurons in the pons and opposed by monoaminergic neurons in the locus ceruleus and dorsal raphe. Normally, locus ceruleus cells are continuously active during wakefulness but cease firing prior to and during cataplexy and REM sleep. Hypocretin neurons project densely to the locus ceruleus and are excitatory. It is reasonable to suppose that a functional defect in hypocretin neurotransmission might diminish opposition of REM sleep onset, thereby allowing its initiation at inappropriate times.

Hypocretin neurons also project to brain regions known to be important in producing and sustaining arousal. Alteration of neurotransmission in these areas due to a defect in the hypocretin system might help to explain the excessive somnolence that is the hallmark of narcolepsy.

Diagnosis of Narcolepsy

In idiopathic narcolepsy, results of physical and neurologic examinations are normal. Neurologic abnormalities may be present in secondary forms of the disorder, depending on the responsible brain lesion, but findings are generally nonspecific. Taking a patient history is of crucial importance in diagnosing narcolepsy. Patients may relate symptoms in broad or imprecise terms, and it is important for the examiner to differentiate complaints of genuine sleepiness from other symptoms such as physical tiredness or fatigue. EDS is a common symptom encountered in medical practice and is not specific to narcolepsy. EDS may arise from many causes, including sleep deprivation, sleep disruption, licit and illicit drugs, and medical and psychiatric diseases. In most of these cases, the overwhelming “sleep attacks” common in narcolepsy do not occur. Unlike narcoleptics, patients with many of these other conditions do not find brief naps to be rejuvenating. Sleep paralysis and hypnagogic (or hypnopompic) hallucinations, common in narcoleptics, may also occur in normal individuals under certain conditions. The most helpful symptom in diagnosing narcolepsy is clear-cut cataplexy. Some experts even insist that the presence of cataplexy is a prerequisite for the diagnosis of narcolepsy.

Polysomnographic studies are also essential in confirming the diagnosis. Overnight recordings usually demonstrate shortening of REM sleep latency, as well as disruption of sleep architecture with multiple awakenings. Results of the Multiple Sleep Latency Test (MSLT) are abnormal, with mean sleep latencies usually less than 5 minutes and the occurrence of SOREMPs. According to the International Classification of Sleep Disorders,3 the minimal criteria for diagnosing narcolepsy in the absence of cataplexy include EDS, associated features (sleep paralysis, hypnagogic hallucinations, disrupted nocturnal sleep, automatic behavior), mean sleep latency on MSLT of less than 5 minutes, and at least two SOREMPs. Others15 recommend that in cases of EDS without cataplexy, a descriptive diagnosis (eg, “EDS with multiple SOREMPs”) is preferable to use of the term “narcolepsy.” It is important to remember that cataplexy may present up to several years after the onset of EDS; in such cases, the diagnosis becomes clear over time.

Overall, HLA typing is of limited usefulness in diagnosing narcolepsy, because the subtypes of interest occur not infrequently in normal individuals, and the HLA associations are strongest in individuals with cataplexy (who also pose the least diagnostic difficulty). Although uncommon, patients with cataplexy who are negative for HLA DQB1*0602 have been reported. Measurement of hypocretin in cerebrospinal fluid may prove to be useful in diagnosing difficult cases. At the present time, neuroimaging studies are not helpful in diagnosing idiopathic narcolepsy.

Treatment of Narcolepsy

The treatment of narcolepsy now consists of medications, education, support, and behavioral changes. The traditional medical treatment of narcolepsy includes the use of stimulants for excessive sleepiness and antidepressants for the manifestations of disordered REM sleep. The relationship between pharmacology and narcolepsy has been reviewed by some (see Nishino and Mignot16). Two new compounds have been extensively studied, and one of them, modafinil, is currently commercially available.

Modafinil is considered more of a “somnolytic” than a “stimulant” medication.17,18 In adults, it has been found to be less efficacious than amphetamine-like drugs, once subjects have already been treated with the latter, and it would be better to consider it for initial treatment in newly diagnosed cases.19 Modafinil does not control cataplexy and may need to be given with anticataplectic medications if this symptom is an important clinical problem. Because amphetamines have some anticataplectic activity, there may be some rebound cataplexy when switching from amphetamines to modafinil.19 The side effects of modafinil are usually mild at the recommended dosage. Headache is the most common and can generally be avoided if the drug is started at 100 mg in the morning and progressively increased for 3–4 days. The recommended daily dosage is 300–400 mg, given in two divided doses in the morning and at lunch time. Some sleep centers have prescribed modafinil in doses up to 600 mg daily, but the higher doses have produced increased side effects without any gain in alertness.

The use of modafinil combined with traditional stimulants has not been well studied. A review of 22 such cases in our clinic (modafinil 400–500 mg/day and methylphenidate 20 mg in divided doses) suggested a better response with combined medications than with one drug alone. We have not seen the combination of amphetamine with modafinil, and we believe that such a combination is unwise until the mechanism of action of modafinil is better defined. The drug has some effect on dopamine reuptake20,21 and may also act at hypothalamic sites subserving wakefulness.22 More definitive work is needed to define modafinil’s mode of action. The advantages of using low doses of methylphenidate are its quick onset of action and rapid elimination.

None of the therapeutic trials of amphetamines, methylphenidate, or modafinil have demonstrated levels of alertness, as measured by the MSLT or the Maintenance of Wakefulness Test (MWT), similar to those in control subjects.23 The great advantage of modafinil is that it does not produce the many side effects seen with amphetamines, including the vasopressor effect, at the recommended dosage.24 None of the regulatory agencies or drug companies have sponsored a study in children despite the fact that the peak age of onset of narcolepsy is around puberty, and that the combination of puberty, hormonal changes, and narcolepsy places young teenagers at the greatest jeopardy with respect to sleepiness. Teenagers with narcolepsy do not respond to treatment as well as older adults. While it may be tempting to treat teenaged narcoleptics with amphetamines, it is better to avoid this approach, considering the long-term side effects.

For many years, γ-hydroxybutyrate (GHB), also known as sodium oxybate, has been reported to be helpful in patients with narcolepsy.25-27 However, GHB’s mode of action is unclear. Initial work was done in France and Canada, and for years, narcoleptic patients have traveled from the United States to Canada to obtain the medication. GHB has been used recreationally and may be abused, as is the case with some other agents used to treat narcolepsy.28 This has delayed the drug’s approval by US regulatory agencies. Orphan Medical has performed clinical trials with doses of 3–9 g/day. In the patients studied at Stanford, GHB produced increased slow-wave sleep, a finding observed previously in narcoleptic patients who were obtaining the drug in Canada. GHB’s duration of action is short; it is given at bedtime, and a second dose must be taken during the night.

Prior investigations of GHB have demonstrated improved nocturnal sleep with decreased fragmentation in adult narcoleptic subjects.26 Although US drug trials have focused on its beneficial effect on cataplexy, results obtained in foreign countries have indicated a slow but progressive improvement in daytime alertness, which narcoleptic patients regard as the drug’s most important benefit. This may not occur until the agent has been used for several weeks, suggesting that there is a slow reorganization of sleep-wake control over time. Although narcolepsy has been described as a “disease of REM sleep,” there is ample evidence that nonrapid eye movement (NREM) sleep is drastically affected in narcoleptics, and restoration of a normal balance of nocturnal NREM and REM sleep may be one of the benefits of GHB. Preliminary studies performed at Stanford indicate that a small group of patients scored better on MSLT and MWT following daily use of GHB for at least 1 month, than with use of other currently used medications. These interesting preliminary results will require confirmation with larger studies.

Side effects of GHB are partially dose  dependent. Over time, there also appears to be adaptation over time to some side effects. Confusion and disorientation have been reported on awakening within 2 hours of nocturnal drug intake, raising concerns about risk of falling in elderly narcoleptics who awake to urinate during the night. Short-term enuresis has been observed, and abnormal levels of excitation have been associated with high dosage and chronic intake. Publication of the results of the large US trial performed during the past several months will provide important information about GHB. At present, it is not known if, or when, the Food and Drug Administration will approve the use of GHB. In any event, it is likely that physicians will encounter increasing numbers of narcoleptic patients taking the medication on their own, with supplies obtained from foreign countries or Internet sources.

Future Directions

As our understanding of narcolepsy continues to deepen, new and more effective methods for its treatment are likely to develop. Based on recent findings, the development of hypocretin agonists offers theoretical promise. There are potential problems with this approach, however, considering the broad and numerous physiologic roles that the hypocretin system appears to play. Perhaps hypocretin-receptor subtypes will be discovered, which might allow for fine-tuning of the system with more specific hypocretin analogues. Implants of hypocretin-producing cells might also be possible. An understanding of the process responsible for the loss of hypocretin cells in the first place would undoubtedly be helpful. In any event, one cannot help but be optimistic about the prospects for improved narcolepsy treatments, considering the recent dramatic advances in our understanding of this disorder.  PP


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