Patients with narcolepsy may have various combinations of cataplexy, hypnagogic hallucinations, and sleep paralysis, which are phenomena of REM, indicating an abnormal intrusion of REM sleep into wakefulness

By Taj M. Jiva, MD

Narcolepsy is a chronic neurological disorder of unknown etiology characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, and disrupted nocturnal sleep.1 After obstructive sleep apnea, it is the leading cause of excessive daytime sleepiness diagnosed by sleep specialists. Cataplexy, hypnagogic hallucinations, and sleep paralysis are phenomena of rapid–eye-movement (REM), indicating an abnormal intrusion of REM sleep into wakefulness.1 Individuals with narcolepsy may have various combinations of the associated features, but the presence of sleepiness is universal. Sleep attacks and excessive daytime sleepiness usually manifest themselves early; cataplexy may occur as much as 20 year later.2,3 Hypnagogic hallucinations and sleep paralysis are usually transitory.1

Historical Perspectives
In 1880, Gelineau4 first described a pathological condition characterized by irresistible and recurrent sleep attacks, at times accompanied by falls. The clinical tetrad of sleep attacks, cataplexy, sleep paralysis, and hypnagogic hallucinations were later described by Daniels5 in 1930. Subsequent sleep research confirmed the intrusion of sleep-onset REM (SOREM) period into awake states in patients with narcolepsy.1 Thus, cataplexy and sleep paralysis are pathologic manifestations of SOREM periods and the dissociated REM sleep inhibitory process.1

The Stanford University Sleep Clinic, Stanford, Calif, was the first medical clinic established to specialize in sleep disorders. It was founded in the early 1970s by William Dement, MD, PhD, to diagnose and treat narcolepsy. The Stanford Center for Narcolepsy, established in the 1980s, was the first to report that narcolepsy-cataplexy is caused by hypocretin abnormalities in both animals and humans.6-8

Narcolepsy affects 0.03% to 0.06% of individuals in North America and Western Europe, or approximately one in 2,000 people; this translates to approximately 125,000 people in the United States and about 20,000 people in the United Kingdom.9 These estimates may be unreliable because of the widespread underdiagnosis of narcolepsy. In many cases, diagnosis is not made until many years after the onset of symptoms. It may be mistaken for epilepsy, depression, or schizophrenia. Although narcolepsy is perceived as relatively rare, its incidence is similar to that of Parkinson disease or multiple sclerosis.9 The disorder begins in early adult life and affects both sexes equally.1-3

In most patients, the onset of narcolepsy symptoms often develops near puberty.1 The peak incidence of narcolepsy is seen in patients aged 15 to 30 years. Narcolepsy manifests itself before the age of 25 in 70% to 80% of patients.3 Bimodal incidence, beginning at 5 or 6 years of age with a second peak at 35 to 45 years of age, has also been reported, however.1 Although narcolepsy is thought to be rare in preadolescent children, symptoms of the disorder have been reported in this age group.3 About half of adults with narcolepsy experienced symptoms during childhood or early adolescence.1 The symptoms may level off in severity at about 30 years of age.1

Socioeconomic Impact
Considering the chronic course of the disease and its potentially devastating socioeconomic impact, underrecognition and undertreatment of narcolepsy represent a significant clinical problem.

Sleep attacks and excessive daytime sleepiness are the most disabling symptoms of narcolepsy, directly contributing to its psychological and economic consequences.10 Individuals are at increased risk for motor-vehicle, occupational, household, and smoking accidents.10,11 Narcolepsy developing during adolescence compromises academic performance.10-12 Sleep attacks may occur during meals, conversations, and even sexual intercourse, causing marital and interpersonal relationship problems. Occupational performance is also impaired because of excessive daytime sleepiness and poor concentration.10-12

Excessive daytime sleepiness is the most frequent (and, often, the most disabling) symptom of narcolepsy.1-3 Patients typically experience a repeating pattern of daytime sleepiness and involuntary napping; they will often fall asleep for less than a half hour and awaken feeling refreshed, but sleepiness will recur in a few hours.13 Conscious efforts to fight sleep, such as engaging in physical activity, can be temporarily successful, but the overpowering need for sleep is irresistible. These episodes are sometimes referred to as sleep attacks. They may occur during any type of activity (an examination, a business meeting, eating, walking, engaging in a sport, or waiting at a traffic light) and may last from a few minutes to an hour.12,13

Sleepiness is usually the first symptom to appear and is insidious in onset; it typically develops over the course of several weeks or months.1-3 The presence of excessive daytime sleepiness is universal in patients with narcolepsy, and remains a lifelong symptom. Daytime drowsiness, memory lapses, and speech automatism have also been described.13

Cataplexy, a symptom unique to narcolepsy, is an abrupt and reversible loss of skeletal muscle tone (REM sleep atonia) when the patient is emotional or excited.1 Cataplexy may be mild and result only in a drooping head, sagging jaw, arms drooping to the sides, or buckling knees.2 In more severe cases, cataplectic attacks may involve sudden paralysis of all skeletal muscles with complete postural collapse. The individual slumps to the floor and is unable to move. These individuals are at risk for injury from falling. Reflexes are absent during these episodes.1,2 The episodes may last for a few seconds or up to 30 minutes; they are almost always triggered by strong emotional stimuli such as laughter, surprise, excitement, or anger.1-3 Patients usually maintain consciousness, but they may have dreams or hallucinations. The frequency of cataplectic attacks varies among individuals, from happening very rarely to occurring several times per day. Blurred vision, impaired speech, and irregular respirations have been described when specific muscle groups are involved. The condition may be confused with seizure disorder.1-3 Not all patients with narcolepsy experience cataplexy; however, it occurs in at least 60% of patients who have the disease.2

Hallucinations associated with narcolepsy are vivid, dream-like experiences—visual (circles, objects, animals, or persons) or auditory (sounds or melodies)—that may precede sleep or occur during the sleep attacks.1-3 Such hallucinations are experienced by most, but not all, patients with narcolepsy. They have been reported in up to two thirds of patients with narcolepsy.2 Elementary cenesthopathic experiences are a form of frightening hallucination in which an individual has extracorporeal feelings such as floating above the bed (levitation).1 Hallucinations commonly occur at sleep onset and in association with sleep paralysis.2

Sleep paralysis is a sudden and transient inability to move the limbs, breathe, or speak (REM sleep atonia) that occurs in the transition zone between sleep and wakefulness.1-3 These episodes, which are of short duration (1 to several minutes), are usually terrifying, especially when accompanied by hypnagogic hallucinations. Individuals are fully conscious during such episodes, which rarely last longer than 10 minutes and resolve spontaneously. Sleep paralysis occurs in about 60% of patients with narcolepsy.3 Episodes of sleep paralysis may be precipitated by stress or sleep deprivation.3

Sleepiness also accounts for automatic behavior, episodes of semipurposeful activity accompanied by amnesia that are experienced by up to 80% of people with narcolepsy, as well as by patients with other disorders of excessive daytime sleepiness such as sleep apnea.3 Episodes of automatic behavior usually occur during monotonous or repetitive activities; they can last for seconds or up to 30 minutes or more and may be associated with brief lapses in speech, use of irrelevant words or phrases, or nonsensical actions (such as putting clothes in an oven).3

Nocturnal sleep may be disturbed by frequent awakenings, terrifying dreams, increased body movement, and apneic spells. This symptom may be exacerbated by commonly prescribed stimulant medications.3

Narcolepsy is conceptualized as multifactorial in origin, with polygenic and environmental factors involved.1,14 Narcolepsy is inherited and is statistically associated with subtypes of certain class 3 human leukocyte antigen (HLA) haplotypes on human chromosome 6: HLA DQB1*0602 and DQA1*0102.15,16 Furthermore, the frequency of the DQB1*0602 haplotype is higher in patients with cataplexy than in those without cataplexy.16 There is no clear evidence that HLA haplotypes and autoimmunity play a role in the pathogenesis of narcolepsy.17 Indeed, 25% of the population carries the HLA-DQB1*0602 haplotype without disposition to narcolepsy.18 The risk of narcolepsy to first-degree relatives is estimated at 1% to 2% in familial cases of narcolepsy.17 Both genetic and environmental factors may play a role in pathogenesis, however.14-16,18 Only 25% to 31% of monozygotic twins are concordant for narcolepsy.18

Abnormalities in the mesocorticolimbic dopaminergic systems could explain the excessive somnolence of narcolepsy.17 The cholinoceptive hypersensitivity of the basal forebrain and brainstem may explain the impaired REM sleep patterns seen.17 Neurochemical studies of human narcolepsy and canine and feline models by Mitler et al19 detected a widespread underrelease of dopamine, a brainstem-specific proliferation of muscarinic acetylcholine receptors, and hypersensitivity to acetylcholine. During normal sleep, REM sleep is tightly regulated; REM periods occur at approximately 90-minute intervals, with the increasing duration of each period as the night progresses. In narcolepsy, SOREM occurs at, or within 20 minutes of, the onset of sleep.3 Dreaming and skeletal muscle paralysis occur during normal REM sleep, which may explain the hypnagogic hallucinations, cataplexy, and sleep paralysis of narcolepsy (the pathological equivalent of REM sleep). Narcolepsy, therefore, is thought to be a dysregulation of the central nervous system (CNS) mechanisms that are involved in wakefulness and REM sleep.1 People with narcolepsy often experience nighttime sleep disruption. Their sleep is often fragmented throughout the 24-hour day.

Lin et al6 were the first researchers to implicate the hypocretin system in narcolepsy. Their investigations revealed that canine narcolepsy is caused by a mutation of the hypocretin (orexin) receptor 2 gene6. Nishino et al7 subsequently implicated the hypocretin system in human narcolepsy. Human narcolepsy is associated with undetectable hypocretin-1 levels in the cerebrospinal fluid. Hypocretin neurotransmission was deficient in seven of nine patients with narcolepsy.7

Most cases of human narcolepsy are not caused by hypocretin gene mutations. Only one hypocretin mutation was found, in a case with an unusually early onset (at 6 months of age). This finding demonstrates that hypocretin mutations can cause narcolepsy in humans, as they do in animals. Peyron et al8 also demonstrated that the brain tissues of narcoleptic humans have no hypocretin-1 and hypocretin-2 peptides. These authors also reported that human narcolepsy patients have no preprohypocretin transcripts in their hypothalami. This is the first research work that implies that human narcolepsy is caused by the destruction of hypocretin-containing cells.8 Loss of the hypocretin system could increase sleepiness by inhibiting the cholinergic and aminergic arousal systems or reducing excitatory output to the forebrain’s hypnogenic systems. Similarly, a deficiency in the hypocretin system could cause cataplexy through inhibition of the brainstem’s motor excitatory system or through reduced excitatory output to the motor inhibitory system.17,20 These studies are fascinating because future identification of the narcolepsy gene in humans is possible; because hypocretins may be the major sleep-modulating neurotransmitters; because there is hope for a novel approach to the therapy of narcolepsy with the use of hypocretin agonists and antagonists; and because of the relationship or association between HLA haplotypes and hypocretins.17

Despite the chronic and serious nature of narcolepsy, it remains largely underdiagnosed and undertreated.1 People with narcolepsy may hide their symptoms out of fear or embarrassment. Often, the symptoms of dissociated REM sleep (such as cataplexy) are mild or appear at a later stage, making the diagnosis of narcolepsy difficult.1-3 Physicians’ recognition of narcolepsy is low, and narcolepsy may be misdiagnosed as depression, schizophrenia, or hypothyroidism. Increased awareness of this neurological disorder by primary care physicians is needed to stimulate more frequent referrals to sleep specialists for evaluation and diagnosis of narcolepsy.

A clinical diagnosis of narcolepsy is based primarily on a patient’s history and presentation. Diagnostic tests are used to confirm the diagnosis or rule out other conditions. Nocturnal polysomnography, followed by the daytime multiple sleep latency test (MSLT), is indicated.1 The MSLT provides an objective evaluation of daytime sleepiness. A mean sleep latency of (usually) less than 5 minutes, two or more SOREM periods, or both will clinch the diagnosis of narcolepsy.1,17,21 It is recommended that the MSLT be performed on the day after a nocturnal polysomnographic recording to anchor the daytime findings to the quality and quantity of the previous night’s sleep, to exclude other causes of excessive daytime sleepiness such as sleep apnea or periodic leg movements. A short sleep latency, a SOREM period (in 40% to 50% of cases), frequent awakenings and arousals, and excessive body movements are noted in individuals with narcolepsy and may complement this diagnosis.2,17

Sleepiness Scale helps to evaluate the severity of narcolepsy. This is a subjective measurement of sleepiness requiring patients to evaluate the likelihood of falling asleep while performing everyday activities. This scale is not diagnostic, taken alone, but may indicate a sleep disorder.1

The diagnosis of narcolepsy often requires ruling out other hypersomnias. Idiopathic CNS hypersomnia often mimics the excessive daytime sleepiness of narcolepsy, but is without other characteristic symptoms of narcolepsy.1 Other causes of excessive daytime sleepiness include sleep apnea, periodic limb movement disorder, and circadian rhythm disorders. Other possible differential diagnoses include hypothyroidism, epilepsy, hypoglycemia, fugue states, myasthenia gravis, multiple sclerosis, and various psychiatric disorders.1

There is no known cure for narcolepsy. Its symptoms can be ameliorated using stimulant medications.17,22 Current approaches to the management of narcolepsy combine behavioral and pharmacologic therapies including CNS stimulants, REM suppressants, and hypnotic medications. The broad objective of behavioral therapies is scheduled daytime naps, adequate sleep hygiene, greater stimulation during waking hours (such as exercising regularly and avoiding repetitive or sedentary tasks), and avoiding heavy meals and alcohol.1,17

Drug treatment of narcolepsy focuses on the management of two symptoms: excessive daytime sleepiness and cataplexy.9 CNS stimulants such as amphetamines and methylphenidate have been the mainstay of pharmacological therapy for excessive daytime sleepiness in narcolepsy since the 1950s.23 These indirect sympathomimetics enhance the release of norepinephrine, dopamine, and serotonin (and also block their reuptake).23 Their main action is on the central dopaminergic system.17,22 Methylphenidate has similar efficacy and a better therapeutic index than dextroamphetamine.3,17 These agents are schedule II controlled substances. Moreover, these stimulants are not consistently effective in long-term therapy (drug tolerance may develop) and they are associated with significant cardiovascular adverse effects (palpitations), gastrointestinal adverse effects (anorexia and gastric upset), nervous-system adverse effects (nervousness, irritability, tremor, and insomnia), and the potential for abuse.23,24

Because of their REM-suppressive activity, tricyclic antidepressants have been used for the management of cataplexy and other symptoms for more than 30 years.1,23 These drugs have adverse anticholinergic effects.9 Their mode of action is correlated with the inhibition of serotonin reuptake.17 Hence, selective serotonin reuptake inhibitors such as fluoxetine are used for cataplexy.17 Newer nontricyclic antidepressants (such as venlafaxine) inhibit both norepinephrine and serotonin reuptake and have fewer anticholinergic side effects.17

In December 1998, the US Food and Drug Administration approved the marketing of modafinil (schedule IV), the first nonamphetamine drug in 40 years to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy.25

Modafinil is a novel wakefulness-promoting agent that is pharmacologically distinct from the stimulant drugs.17,25 Its exact mechanism of action is unknown; however, it requires an intact central adrenergic system.26,27 The effect of modafinil cannot be explained by the type of dopaminergic activation seen with stimulants. Modafinil has little or no effect on dopaminergic activity26 and has highly selective activity in the nervous system relative to amphetamine and methylphenidate.28 In animal models of narcolepsy, modafinil increases wakefulness with no increase in locomotor activity.27

The wakefulness-promoting and safety properties of modafinil in humans were assessed in an 18-center, double blind, placebo-controlled clinical trial.25 Study outcome showed that modafinil taken once daily was a very well tolerated and effective agent for the treatment of excessive daytime sleepiness associated with narcolepsy. It demonstrated an excellent safety profile for up to 40 weeks of open-label treatment, and its efficacy was maintained.25

A study on the health-related quality of life (HQL) associated with modafinil use for the treatment of narcolepsy demonstrated that narcolepsy causes significant adverse effects on HQL.29 The modafinil treatment group had more energy, fewer difficulties performing the usual activities of life, less interference with social activities, improved psychological well-being, higher productivity, improved attention, and better self-esteem, compared with placebo subjects (P<.05). These improvements in HQL were maintained over an extended period.29

Taj M. Jiva, MD, is clinical assistant professor of medicine, State University of New York at Buffalo.

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