Sleep Disorders

Spring 1999
Volume 10, Number 1

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Narcolepsy, a chronic disorder that usually begins during adolescence, is characterized by excessive sleepiness, daytime sleep episodes, cataplexy, and abnormalities of REM sleep. It has prevalence of about 1 in 3000, and affects men and women equally. Chronic sleepiness often leads to impaired work performance, psychosocial problems, and increases the risk of accidents. Treatment with stimulant medications for sleepiness and tricyclic antidepressants for cataplexy leads to substantial improvement in symptoms for most patients.

Introduction. Narcolepsy was the first primary sleep disorder to be identified and is characterized by excessive daytime sleepiness, daytime sleep episodes, cataplexy, and rapid eye movement (REM) sleep abnormalities.1,2 It is a chronic disorder with a prevalence of about .03% that affects men and women equally.3 Idiopathic hypersomnia, a clinically uncommon related variant, is associated with excessive sleepiness, but not REM sleep abnormalities nor cataplexy. The disorders may lead to psychosocial problems, poor work performance, and accidents. With treatment, most patients have substantial improvement, but not complete alleviation of symptoms.

Clinical Aspects. Symptoms usually begin in the second decade of life and rarely as late as age 60. Excessive sleepiness and brief daytime sleep episodes are the usual presenting symptoms. The daytime sleep episodes, sometimes called sleep attacks, are not unique to narcolepsy. They can occur with any disorder that causes chronic severe sleepiness including chronic sleep deprivation and obstructive sleep apnea syndrome. Narcoleptic sleepiness does not differ qualitatively from the sleepiness that occurs in normal persons after sleep deprivation. It is most apparent in monotonous sedentary situations and is relieved by movement. It differs in that no amount of nighttime nor daytime sleep produces full alertness. In some patients, chronic sleepiness leads to reduced awareness of drowsiness. Many narcoleptics, however, are aware of their drowsiness and do not have sleep attacks without warning. Once established, the sleepiness associated with narcolepsy usually remains stable. The majority of narcoleptics have fallen asleep driving and while at work. They have poorer driving records and greater work impairments than epileptics.4

Chronic sleepiness can lead to automatic behavior, memory complaints, and visual disturbances. Automatic behavior — amnestic episodes associated with semi-purposeful activity — may occur in narcoleptics and in other patients with chronic sleepiness. The episodes usually happen during monotonous activities, last for seconds to an hour, and may be accomplished by brief lapses in speech or nonsensical activities. Memory problems are caused by drowsiness with impaired attention and concentration. Blurred vision is probably due to failure of fusion induced by drowsiness.

Cataplexy refers to weakness without altered awareness that is precipitated by emotion or excitement and lasts seconds to minutes. Severe attacks produce almost complete paralysis; patients may stagger and fall, or slump into a chair. Twitching around the face or eyelids may accompany the weakness. More common milder episodes may cause sagging of the face, eyelids, or jaw; dysarthria; momentary head drop; or buckling of the knees. Laughter and humor, such as when hearing a joke, are the usual precipitants, along with anger, excitement, and fear. Cataplexy usually develops within a few months of the onset of sleepiness. However, some patients develop it years or decades after the onset of sleepiness.

Sleep paralysis refers to episodes of complete inability to move at the onset of sleep or upon awakening. The episodes last a few seconds or minutes and are often accompanied by a sensation of struggling to move, they end spontaneously or with mild sensory stimulation. Hypnagogic and hypnopompic hallucinations also occur at the interface between wakefulness and sleep. They may accompany sleep paralysis or occur independently. The hallucinations, which may be visual, auditory, or somatosensory, differ from dreams because some awareness of the surroundings is preserved. Cataplexy, sleep paralysis, and hypnagogic hallucinations, sometimes improve with age.

Many narcoleptics also suffer from disturbed nocturnal sleep with frequent awakenings. This is a prominent complaint in some older narcoleptics.

Idiopathic hypersomnia. Patients with idiopathic hypersomnia have sleepiness without cataplexy or REM sleep abnormalities. Some patients have prolonged nighttime sleep, grogginess upon awakening (sleep drunkenness), and long unrefreshing naps. Others have normal nighttime sleep lengths and normal awakening with sleepiness that is clinically indistinguishable from narcolepsy. Sleep paralysis and hypnogogic hallucinations may occur in patients with idiopathic hypersomnia, but cataplexy does not.5, 6 The course varies; some patients have a stable course while others improve after a few years.

Diagnosis. For many years, the first step in diagnosis is to determine whether the patient has excessive daytime sleepiness or whether the complaint is a less specific one of fatigue or tiredness. Sleepiness is associated with falling asleep or fighting sleep in appropriate times. On the other hand, fatigue associated with endocrine disorders, viral illnesses, cardiac disease, neuromuscular diseases, and chronic fatigue syndrome are usually not accompanied by drowsiness and fighting to stay awake unless disturbed sleep is present.

Sudden sleep episodes are sometimes described as loss of consciousness, suggesting seizures or syncope, and automatic behavior may be misdiagnosed as an automatism accompanying a partial complex or absence seizures. The association with sedentary situations and drowsiness preceding the episode are useful distinguishing features.

Brief duration, preserved consciousness, and emotional precipitants differentiate cataplexy from myasthenia gravis, atonic seizures, periodic paralysis, and drop attacks associated with vertebro-basilar insufficiency. While cataplexy is virtually pathognomonic for narcolepsy, up to 30% of the general population has experienced a feeling of weakness with emotion. Thus, a feeling of weakness is not specific. Actual bilateral weakness involving the face or axial muscle is more likely to represent true cataplexy. Sleep paralysis and hypnagogic hallucinations are not specific. Fifteen percent of adolescents and young adults have had sleep paralysis, often precipitated by sleep deprivation or disruption of normal sleep patterns.

Diagnosis of idiopathic hypersomnia is difficult because other causes of sleepiness must be excluded. Patients with sleep apnea may not have positive findings on an initial polysomnogram, particularly if the apnea occurs only in the supine position. Patients with insufficient sleep syndrome may present with complaints of sleepiness. These persons spend inadequate amounts of time in bed and have a tendency to spend more time in bed on weekends. If sleepiness resolves with a trial of increased time asleep at night, the diagnosis is probably insufficient sleep syndrome.

Sleep studies are indicated for most patients with suspected narcolepsy. Nocturnal polysomnography — performed with the patient medication-free, on a regular schedule, and obtaining sufficient sleep for at least 10 days — assesses the presence and severity of sleep apnea, periodic limb movements, and nocturnal sleep disturbance. A Multiple Sleep Latency Test (MSLT), generally performed the following day, assesses the mean time to fall asleep (mean sleep latency), and the propensity to enter REM sleep prematurely during 4 or 5 nap opportunities. Narcoleptics fall asleep much more quickly in this setting than controls and tend to enter REM sleep during about half of the opportunities to do so.

Although the MSLT is the most useful test for the diagnosis of narcolepsy, false positives and negatives do occur and the test must be interpreted in the clinical context. Two or more sleep-onset REM periods (SOREMPs) during the MSLT are the usual criterion for pathological REM sleep and is the usual result in patients with narcolepsy. However, the absence of SOREMPs on MSLT does not exclude narcolepsy and their presence does not confirm the diagnosis. In a series of narcoleptics, 20% had < 2 SOREMPs.7 SOREMPs also can occur with sleep-wake schedule disturbances, drug and alcohol withdrawal, REM sleep deprivation from sleep apnea, and depression. In a series of patients with sleep apnea, 7% had SOREMPs.7

Thus, for patients with excessive daytime sleepiness and short latency to REM sleep who do not have cataplexy, other possible diagnoses should be considered before establishing a definitive diagnosis of narcolepsy. These include periodic limb movement disorder, upper airway resistance syndrome, position-dependent sleep apnea, alcohol-dependent or allergy-dependent sleep apnea, or a sleep-wake schedule disturbance. If suspicion is high for sleep apnea, a repeat polysomnogram may be indicated.

Polysomnography is usually normal in patients with idiopathic hypersomnia, while the MSLT is likely to show short sleep latencies without sleep-onset REM periods. These findings are nonspecific and rule out insufficient sleep syndrome. A repeat study should be obtained after a 1-month trial of increased sleep.

Pathophysiology and pathogenesis. The tendency for REM sleep to occur within minutes of falling asleep, the electrophysiologic hallmark of narcolepsy, probably accounts for hypnagogic hallucinations and sleep paralysis, which reflects the intrusion of dream imagery and REM sleep atonia into the waking state. In addition, the muscle atonia that accompanies cataplexy appears to be identical to the atonia of REM sleep. However, total sleep time and REM sleep time are not increased over the 24-hour period as the increase in daytime sleep is offset by frequent nocturnal awakenings. Thus, the REM sleep abnormality appears to be part of a broader problem of impaired sleep/wake regulation. The occurrence of the REM sleep behavior disorder in some narcoleptic patients supports the concept that sleep/wake state boundaries are impaired.8

Abnormal control of REM sleep suggests that abnormal function of neural generators and modulators of REM sleep contributes to the pathogenesis of narcolepsy. The rostral pons contain cholinergic neurons that are essential for REM sleep expression. Serotonergic neurons of the raphe nuclei and noradrenergic neuron of the locus coeruleus that inhibit these cholinergic neurons become inactive at the onset of REM sleep and thereby facilitate its occurrence. A defect in monoaminergic regulation and cholinergic REM sleep mechanisms could therefore contribute to narcolepsy.

Idiopathic hypersomnia. Idiopathic hypersomnia is a heterogeneous disorder. Some cases appear to be triggered by specific antecedents, such as relatively minor viral illnesses, while others are idiopathic. Still, others may be phenotypic variants of narcolepsy.

Genetics and family studies. A familial tendency for narcolepsy has been recognized for years. However, while up to 1/2 of the narcoleptics have one or more first degree relatives with complaints of sleepiness; only 3% have a first degree relative with definitive narcolepsy-cataplexy.9 Thus, most sleepy relatives of narcoleptics do not have narcolepsy as their sleep complaints are due to other causes. In children of narcoleptics, the risk of developing narcolepsy is about 1%, 30 times greater than the risk in the general population.

Studies in Class II human leukocyte antigens (HLA) have clarified the genetic basis of the disease. HLA-DR2 and -DQ1 are present in more than 90% of Japanese and Caucasian narcoleptics, while in African-Americans, -DQ1 is present in more than 90%, but -DR2 is present in about 65%. Although the genes that control the expression of these antigens are clearly important, they are not sufficient or necessary for disease expression as some narcoleptics are negative for DR2 and DQ1. Although the association with the HLA-D region suggests an immunologic pathogenesis, clear immunologic abnormalities have not been detected. Monozygotic twins are often discordant for narcolepsy, indicating that environmental factors also play an important role.

Management. As narcolepsy is a chronic disorder, counseling and support are important aspects of management. Patient and family education about the syndrome, good sleep hygiene, the risks associated with sleepiness while driving and in the workplace, and about the role of medications are also important. Adequate sleep at night is important as insufficient sleep can exacerbate symptoms.

Stimulants, particularly methylphenidate (Ritalin), dextroamphetamine (Dexadrine), and pemoline (Cylert), are the usual treatment for sleepiness (Table 1).10 For most patients, the goal should be to achieve optimal alertness when it is most needed (work, school, and driving) through the use of medications and good sleep hygiene. Naps can be useful adjuncts to medications. Their beneficial effect in some patients is due at least in part to relief of insufficient sleep. Regular naps also reduce the daily requirements for stimulants, thereby reducing the risk of side effects. For a teenage patient, a typical program is a dose of methylphenidate (Ritalin) in the morning, a nap at lunch, a second dose of methylphenidate, a nap after school, and then a third dose of methylphenidate. When sleepiness fails to respond to medications, especially if it has responded in the past, other possible contributors should be considered, such as sleep apnea, insufficient sleep, or medication effects. Modafinil (Provigil) a non-amphetamine that has alerting properties, is now available in the US. As it has few side effects, it may be preferable as initial treatment for many patients.

Complications of chronic stimulant use include irritability, insomnia, and headaches.10 Most of these side effects are dose related and generally can be avoided if total daily doses do not exceed recommended guidelines. With appropriate management, most patients can take stimulants regularly for years without serious side effects.

Tricyclic antidepressants effectively control cataplexy and sleep paralysis in most patients. The inhibition of cataplexy occurs through the blockade of serotonin and norepinephrine reuptake. Selective serotonin reuptake inhibitors are also sometimes effective, especially in patients who cannot tolerate anticholinergic side effects of tricyclics.
 

Address comments and questions to:

Michael S Aldrich, MD
University of Michigan Sleep Disorders Center
UH 8D8707, Box 1007
1500 E. Medical Center Dr.
Ann Arbor, MI 48109-0117

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