Narcolepsy

Narcolepsy is characterized by irresistible attacks of sleep during the day, resulting in brief but refreshing naps. In addition, several “accessory symptoms” can occur: cataplexy (brief episodes of sudden bilateral loss of muscle tone associated with intense emotion), sleep paralysis, and sleep-related hallucinations. By definition, these symptoms cannot occur during the use of or withdrawal from a medication. Also, narcolepsy has a genetic component. Although only 1%-2% of first-degree relatives of patients with narcolepsy have narcolepsy, this represents a 20- to 40-fold increase in prevalence compared with the general population. Human leukocyte antigen DQB1*0602 is present in 68% of the patients with the disorder (Mignot et al. 1997). Recent studies suggest that abnormalities of receptors for the peptide neurotransmitter orexin may be related to cataplexy (Chemelli et al. 1999; Lin et al. 1999).

Although narcolepsy is a neurological rather than a psychiatric disorder, it is included with Axis I disorders in order to facilitate the differential diagnosis of hypersomnia.

Behavioral/psychotherapeutic treatment Naps are useful as an adjunct to stimulant drugs in the clinical management of narcolepsy. Scheduling three to four 15-minute naps throughout the day can improve alertness (Roehrs et al. 1986a) and decrease the requirements for stimulant medications (Aldrich 1990). The alerting effect of naps is usually short lived (about 30 minutes) and is not prolonged even with naps of longer durations. Thus, it is preferable to recommend several short naps scheduled at strategic times (e.g., before driving). Because nocturnal sleep disturbances are common among patients with narcolepsy, it is also important for these individuals to maintain very regular sleep-wake schedules to ensure adequate night sleep duration.

Narcolepsy is a lifelong condition that often causes significant occupational, family, and psychosocial problems. Supportive group therapy may be very beneficial to patients in adjusting their lifestyles to the chronic nature of this disorder and in learning to cope with its disabling consequences.

Pharmacological treatment Stimulant medications constitute the mainstay of the pharmacological treatment of narcolepsy (Guilleminault 1993; Mitler et al. 1993, 1994; Parkes and Dahlitz 1993). The most commonly used agents are methylphenidate and dextroamphetamine, 15-100 mg/day; methamphetamine, 15-80 mg/day; and pemoline, 37.5-150 mg/day, in two to three divided doses (American Sleep Disorders Association 1994). More recent studies have documented the efficacy of modafinil, 200-400 mg/day, on both subjective and objective measures of daytime sleepiness (Broughton et al. 1997; U.S. Modafinil in Narcolepsy Multicenter Study Group 1998). Other stimulant medications, including mazindol, are used less frequently and offer no specific advantages. Finally, medications such as codeine, propranolol, and methysergide have been reported to be effective in some case series but are not widely used.

Accessory symptoms of cataplexy, sleep paralysis, and sleep-related hallucinations can be treated effectively with antidepressant medications. Tricyclic agents, such as protriptyline, 10-60 mg, and clomipramine or imipramine, 50-150 mg, have been most widely used. MAOIs are also effective in treating such symptoms, and reports have suggested the efficacy of fluoxetine as well (Frey and Darbonne 1994). Typically, the dose of antidepressant medication that is required for control of symptoms is one-fourth to one-half of the usual doses. Single daily doses are usually effective. Sedating cyclic antidepressants should be given at bedtime to avoid the potential for increased daytime sleepiness; SSRIs, MAOIs, and alerting tricyclics (protriptyline, desipramine) can be given during the day.

γ-Hydroxybutyrate, a putative neurotransmitter that can be administered orally, can decrease symptoms of sleepiness, hallucinations, and cataplexy in patients with narcolepsy (Lammers et al. 1993). However, this compound is not available clinically and has been misused as an intoxicant.

Finally, many patients with narcolepsy report disrupted nocturnal sleep. In such instances, the use of a short-acting benzodiazepine medication can improve subjective and objective measures of nighttime sleep (Thorpy et al. 1992).

Diagnostic Features

The essential features of Narcolepsy are repeated irresistible attacks of refreshing sleep, cataplexy, and recurrent intrusions of elements of rapid eye movement (REM) sleep into the transition period between sleep and wakefulness. The individual’s sleepiness typically decreases after a sleep attack, only to return several hours later. The sleep attacks must occur daily over a period of at least 3 months to establish the diagnosis (Criterion A), although most individuals describe many years of sleep attacks prior to seeking clinical attention. In addition to sleepiness, individuals with Narcolepsy experience one or both of the following: cataplexy (i.e., episodes of sudden, bilateral, reversible loss of muscle tone that last for seconds to minutes and are usually precipitated by intense emotion) (Criterion B1) or recurrent intrusions of elements of rapid eye movement (REM) sleep into the transition between sleep and wakefulness as manifested by paralysis of voluntary muscles or dreamlike hallucinations (Criterion B2). Many sleep experts allow the diagnosis to be made in the absence of cataplexy or intrusions of REM sleep elements if the individual demonstrates pathological sleepiness and two or more sleep-onset REM periods during a Multiple Sleep Latency Test (MSLT). The symptoms must not be due to the direct physiological effects of a substance (including a medication) or another general medical condition (Criterion C). Although Narcolepsy is classified in the section of ICD devoted to neurological conditions, it is included in this section to assist in differential diagnosis in individuals with excessive sleepiness and is coded on Axis I.

Episodes of sleepiness in Narcolepsy are often described as irresistible, resulting in unintended sleep in inappropriate situations (e.g., while driving an automobile, attending meetings, or carrying on a conversation). Low-stimulation, low-activity situations typically exaggerate the degree of sleepiness (e.g., falling asleep while reading, watching television, or attending lectures). Sleep episodes generally last 10-20 minutes but can last up to an hour if uninterrupted. Dreaming is frequently reported. Individuals have varying abilities to “fight off” these sleep attacks. Some individuals take naps intentionally in order to manage their sleepiness. Individuals with Narcolepsy typically have 2-6 episodes of sleep (intentional and unintentional) per day when untreated. Sleep episodes are usually superimposed on a more normal degree of alertness, although some individuals describe constant sleepiness of some degree.

Cataplexy often develops several years after the onset of daytime sleepiness and occurs in approximately 70% of individuals with the disorder. The loss of muscle tone with cataplexy may be subtle, leading to a sagging jaw or drooping eyelids, head, or arms not noticeable to observers. Cataplexy can also be more dramatic, and the individual may drop objects being carried, buckle at the knees, or actually fall to the ground. Respiratory and eye muscles are not affected. The muscle weakness usually lasts only seconds, although periods of up to a half hour have been reported. Episodes are followed by a full return of normal muscle strength. Full consciousness and alertness are preserved during cataplectic episodes. Individuals can clearly describe events and have no confusion before or after the episode. Rarely, prolonged episodes of cataplexy may lead into sleep episodes. Cataplexy is usually triggered by a strong emotional stimulus (e.g., anger, surprise, laughter). Sleep deprivation typically increases the frequency and severity of episodes of cataplexy.

Approximately 20%-40% of individuals with Narcolepsy also experience intense dreamlike imagery just before falling asleep (hypnagogic hallucinations) or just after awakening (hypnopompic hallucinations). Most sleep-related hallucinations are visual and incorporate elements of the actual environment. For instance, individuals may describe objects appearing through cracks in the wall or describe objects moving in a picture on the wall. The hallucinations may also be auditory (e.g., hearing intruders in the home) or kinetic (e.g., sensation of flying). Although hypnagogic and hypnopompic hallucinations are important symptoms among individuals with Narcolepsy, these symptoms are also present in approximately 10%-15% of the general population. Approximately 30%-50% of individuals with Narcolepsy also experience sleep paralysis just on falling asleep or awakening. In this condition, individuals describe being awake but unable to move or speak. They may also complain of feeling unable to breathe, although the diaphragm is spared and respiration continues. It should be noted, however, that 40%-50% of normal sleepers report having had isolated episodes of sleep paralysis at least once during their lifetime. Sleep-related hallucinations and sleep paralysis may occur simultaneously, resulting in an often terrifying experience of seeing or hearing unusual things and being unable to move. Both sleep-related hallucinations and sleep paralysis last for seconds to a few minutes and terminate spontaneously. Both phenomena (vivid mental imagery and skeletal muscle atonia) are thought to result from dissociated elements of REM sleep intruding into wakefulness.

Associated Features and Disorders

Associated descriptive features and mental disorders. Some individuals with Narcolepsy experience generalized daytime sleepiness between the discrete sleep attacks. They may describe being able to sleep at any time in any situation. Automatic behavior, in which the individual engages in activity without full awareness, can occur as a result of profound sleepiness. Individuals may drive, converse, or even work during episodes of automatic behavior. Frequent, intense, and vivid dreams may occur during nocturnal sleep. Individuals with Narcolepsy often experience fragmented nighttime sleep as a result of spontaneous awakenings or periodic limb movements. Rarely, individuals may present with a chief complaint of insomnia rather than hypersomnia.

Individuals with Narcolepsy may hesitate to engage in social activities because they fear falling asleep or having an episode of cataplexy. They may also strive to prevent attacks of cataplexy by exerting control over their emotions, which may lead to a generalized lack of expressiveness that interferes with social relations. Narcolepsy can severely limit daytime functioning because of repeated, uncontrollable sleep attacks, automatic behavior, and episodes of cataplexy. Individuals with Narcolepsy are at risk for accidental injury to themselves or others because of falling asleep in dangerous situations (e.g., while driving an automobile or operating machinery).

A concurrent mental disorder or history of another mental disorder can be found in approximately 40% of individuals with Narcolepsy. The most common associated disorders are Mood Disorders (primarily Major Depressive Disorder and Dysthymic Disorder), followed by Substance-Related Disorders and Generalized Anxiety Disorder. A history of Parasomnias such as Sleepwalking Disorder, bruxism (clenching of the jaw and grinding teeth), rapid eye movement (REM) sleep behavior disorder, and Enuresis appears to be more common in individuals with Narcolepsy.

Associated laboratory findings. Findings from the daytime Multiple Sleep Latency Test (MSLT) include an average sleep latency of less than 5 minutes and the appearance of REM sleep during two or more naps on a five-nap MSLT. These MSLT criteria will correctly identify approximately two out of three individuals with Narcolepsy. Nocturnal polysomnographic studies frequently demonstrate sleep latencies of less than 10 minutes and sleep-onset REM periods. Additional findings on polysomnography may include frequent transient arousals, decreased sleep efficiency, increased stage 1 sleep, increased REM sleep, and an increase in the frequency of eye movements within the REM periods (“REM density”). Periodic limb movements and episodes of sleep apnea are often noted, but the latter occur less frequently than in Breathing-Related Sleep Disorder. Individuals with Narcolepsy may demonstrate differences in the amplitude or timing of circadian functioning as measured by core body temperature and motor activity.

Human leukocyte antigen (HLA) typing of individuals with Narcolepsy often shows the presence of HLA-DQB1*0602. This marker is present in almost all individuals with Narcolepsy and cataplexy and is independent of racial ethnicity. However, HLA-DQB1*0602 is present in only 40% of individuals with Narcolepsy without cataplexy and is present in 20%-25% of the general population. Other HLA markers vary in terms of their sensitivity and specificity in different racial groups.

Associated physical examination findings and general medical conditions. Individuals with Narcolepsy may appear sleepy during the clinical interview and examination and may actually fall asleep in the waiting area or examination room. During episodes of cataplexy, individuals may slump in the chair and have slurred speech or drooping eyelids.

Specific Age Features

Hyperactivity may be one of the presenting signs in children with daytime sleepiness. The core clinical features and laboratory findings in Narcolepsy in children are similar to those in adults. However, cataplexy and mild daytime sleepiness may be more difficult to identify in children than in adults.

Prevalence

Epidemiological studies indicate a prevalence of 0.02%-0.16% for Narcolepsy in the adult population, with equal rates in females and males.

Course

Daytime sleepiness is almost always the first symptom of Narcolepsy and usually becomes clinically significant during adolescence. However, on careful review, some degree of sleepiness may have been present even during preschool and early school ages. Onset after age 40 is unusual. However, some individuals with Narcolepsy may not identify excessive sleepiness as a symptom of an illness. This may explain why many individuals are first diagnosed with Narcolepsy many years after the first onset of symptoms. Acute psychosocial stressors or acute alterations in the sleep-wake schedule herald the onset in roughly half of cases. Cataplexy may develop concurrently with sleepiness but often appears months, years, or even decades after the onset of sleepiness. Sleep-related hallucinations and sleep paralysis are more variable symptoms of the disorder and may not occur in some individuals. Disrupted nocturnal sleep usually develops later in the course of the disorder, often when individuals are in their 40s or 50s.

The excessive sleepiness of Narcolepsy has a stable course over time. The development of other Sleep Disorders (e.g., periodic limb movements or Breathing-Related Sleep Disorder) may worsen the degree of sleepiness, whereas treatment with stimulant medications may improve it. Cataplexy usually has a stable course as well, although some individuals report decreased symptoms or even complete cessation of symptoms after many years. Similarly, the sleep-related hallucinations and sleep paralysis may go into remission while the daytime sleepiness and sleep attacks persist.

Familial Pattern

Data from HLA studies and family studies strongly suggest a role for genetic factors in the development of Narcolepsy. The mode of inheritance has not been determined but is likely multifactorial. Approximately 5%-15% of first-degree biological relatives of probands with Narcolepsy have the disorder. Approximately 25%-50% of the first-degree biological relatives of individuals with Narcolepsy have other disorders characterized by excessive sleepiness (such as Primary Hypersomnia).

Differential Diagnosis

Narcolepsy must be differentiated from normal variations in sleep, sleep deprivation, other primary Sleep Disorders, and Sleep Disorder Related to Another Mental Disorder, Hypersomnia Type. Many individuals feel some sleepiness during the day, particularly in the afternoon hours when an increase in physiological sleepiness occurs. However, such individuals do not have irresistible sleep at other times of the day and can “fight through” their sleepiness with increased mental and physical effort. They generally do not experience cataplexy, sleep-related hallucinations, or sleep paralysis. Episodes of muscle weakness may occur in individuals without Narcolepsy. Although joking and laughing are the most typical triggers of cataplexy, episodes that are exclusively triggered by stress or tension or that occur in the context of physical exertion are less likely to represent true cataplexy.

Sleep deprivation from any cause produces daytime sleepiness. Narcolepsy should be diagnosed only if the individual has demonstrated a regular sleep-wake schedule with an adequate amount of nocturnal sleep. Sleep deprivation and irregular sleep schedules may rarely lead to sleep-related hallucinations or sleep paralysis, but not to cataplexy.

The degree of daytime sleepiness may be similar in individuals with Narcolepsy and Primary Hypersomnia. Compared with individuals with Narcolepsy, individuals with Primary Hypersomnia generally describe prolonged and less disrupted nocturnal sleep. Daytime sleepiness in Primary Hypersomnia consists of more prolonged, unrefreshing sleep periods, which have less urgency than the sleep “attacks” of Narcolepsy and are less often associated with dreaming. Individuals with Primary Hypersomnia do not manifest cataplexy, sleep-related hallucinations, or sleep paralysis. Nocturnal polysomnography confirms less disrupted sleep and normal REM latency in individuals with Primary Hypersomnia, and the MSLT does not show sleep-onset REM periods.

Individuals with Breathing-Related Sleep Disorder often experience excessive sleepiness that is equal in magnitude to that of individuals with Narcolepsy. Furthermore, many individuals with Narcolepsy may develop some degree of sleep apnea. Breathing-Related Sleep Disorder is distinguished from Narcolepsy by a history of loud snoring; breathing pauses that disrupt nocturnal sleep; lengthy, unrefreshing daytime sleep episodes; and the absence of accessory symptoms such as cataplexy. Polysomnography can identify breathing pauses (apneas) in individuals with Breathing-Related Sleep Disorder. If an individual presents with an unambiguous history of Narcolepsy together with confirmatory polysomnographic findings (sleep-onset REM) and also has evidence of Breathing-Related Sleep Disorder during polysomnography, both diagnoses can be made. If an individual has sleep-onset REM and sleep apnea activity during polysomnography but does not have the full clinical syndrome of Narcolepsy, then only a diagnosis of Breathing-Related Sleep Disorder should be made.

Individuals with Hypersomnia Related to Another Mental Disorder may report excessive sleepiness and intense dreams. In particular, Major Depressive Episodes With Atypical Features and Bipolar Disorder, Most Recent Episode Depressed, often involve an intense need for sleep during the daytime. However, individuals with Mood Disorders typically have prolonged albeit disturbed nocturnal sleep in contrast to the short, fragmented sleep of Narcolepsy. Daytime naps are not refreshing in individuals with Mood Disorders. Furthermore, these individuals do not have the accessory symptoms that are characteristic of Narcolepsy (e.g., cataplexy), although individuals who have Major Depressive Disorder, With Psychotic Features, may complain of hallucinations near sleep and at other times. Polysomnographic studies of individuals with Mood Disorders may reveal short REM latency, but typically not as short as that seen in Narcolepsy. Nocturnal sleep latency is also longer in individuals with Mood Disorders. Finally, daytime testing with the MSLT shows a much lower degree of physiological sleepiness and infrequent sleep-onset REM periods in individuals with Mood Disorders. Thus, the “sleepiness” in these individuals appears to be more a manifestation of psychomotor retardation and anergy.

The use of, or withdrawal from, substances (including medications) may produce some symptoms of Narcolepsy. Cholinergic agonists (including anticholinesterase pesticides) can disrupt sleep continuity and enhance REM sleep. Similar effects can result from the abrupt discontinuation of anticholinergic agents, including tricyclic antidepressants. Reserpine and methyldopa can enhance REM sleep and produce sleepiness. Withdrawal from stimulants can produce severe somnolence. A diagnosis of Substance-Induced Sleep Disorder, Hypersomnia Type, might be warranted if the symptoms are judged to be due to the direct physiological effects of a substance. Conversely, a diagnosis of Narcolepsy should not be made if the individual is taking or has recently discontinued taking such substances.

Narcolepsy must be distinguished from Sleep Disorder Due to a General Medical Condition, Hypersomnia Type. The diagnosis is Sleep Disorder Due to a General Medical Condition when the symptoms are judged to be the direct physiological consequence of a specific general medical condition (e.g., closed Head injury or hypothalamic tumor).

Relationship to the International Classification of Sleep Disorders

The International Classification of Sleep Disorders (ICSD) diagnosis of Narcolepsy includes the same essential features as the DSM-IV diagnosis.

Diagnostic criteria for 347 Narcolepsy

A. Irresistible attacks of refreshing sleep that occur daily over at least 3 months.
B. The presence of one or both of the following:
(1) cataplexy (i.e., brief episodes of sudden bilateral loss of muscle tone, most often in association with intense emotion)
(2) recurrent intrusions of elements of rapid eye movement (REM) sleep into the transition between sleep and wakefulness, as manifested by either hypnopompic or hypnagogic hallucinations or sleep paralysis at the beginning or end of sleep episodes

C. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or another general medical condition.

Provided by ArmMed Media
Revision date: June 18, 2011
Last revised: by Amalia K. Gagarina, M.S., R.D.