Clinical Review

Narcolepsy Bashir A. Chaudhary, MD, and Iftekhar Husain, MD Augusta, Georgia

Narcolepsy afflicts more than 200,000 Americans. In still not being used for diagnostic purposes, the associ­ most cases the first symptom o f the disease, excessive ation between narcolepsy and the human leukocyte davtime sleepiness, develops during childhood or ado­ group A (HLA) antigen D R 2 is the strongest so far lescence. This initial presentation is followed by cata­ described for any disease. With the help o f psychoso­ plexy or other auxiliary symptoms several years later. cial support, therapeutic naps, and medications, the pa­ Not infrequently, many years pass before the proper tient with narcolepsy may be able to lead a normal life. diagnosis of narcolepsy is made. Narcolepsy is a Methylphenidate and imipramine are the two most chronic lifelong disease without periods of remission. widely used drugs for the treatment of daytime somno­ Excessive davtime sleepiness, inappropriate sleep at­ lence and cataplexy, respectively. tacks, and the pathognomonic symptom of cataplexy, Key words. Sleep, REM; narcolepsy; hallucination; cat­ are diagnostic of narcolepsy. Confirmation of the dis­ aplexy; sleep disorders. ease is made by a multiple sleep latency test. Although J Fam Proa 1993; 36:207-213.

The awareness o f sleep disorders has greatly increased Prevalence during the past two decades.1”6 Sleep apnea and narco­ Narcolepsy is not a rare disease. In one survey, physicians lepsy are the two most frequently encountered causes of reported narcolepsy in 0.5% of their adult patients.20 excessive daytime somnolence in sleep disorder centers. Several large studies have reported an incidence o f 1 per Sleep apnea is a potentially life-threatening disorder with 1000 with both sexes affected equally.21-23 It has been many complications including cardiac arrhythmias and estimated that 100,000 to 200,000 people in the United systemic and pulmonary hypertension leading to right­ States have narcolepsy. sided heart failure.7’8 On the other hand, narcolepsy is a chronic, nonfatal, but often debilitating disease, causing difficulty throughout life: problems at work, broken mar­ riages, low self-esteem, psychological and emotional dis­ Clinical Features turbances, and industrial and automobile accidents.9-11 Narcolepsy can be diagnosed clinically by its typical Gelineu first used the term narcolepsy in 1880, and symptoms (Table 1). The two primary symptoms are Yoss and Daly described the tetrad of narcolepsy, cata­ excessive daytime sleepiness, with irresistible sleep at­ plexy, hypnagogic hallucinations, and sleep paralysis in tacks, and cataplexy. Auxiliary symptoms occur in 70% 1957.12 Narcolepsy is now characterized by dysfunction to 80% of patients with narcolepsy, the most important of rapid eye movement (REM ) sleep.13-14 In narcolepsy, being hypnagogic hallucinations, sleep paralysis, dis­ REM sleep occurs suddenly during the awake state. The rupted nocturnal sleep, and automatic behavior. Those neurophysiologic mechanisms o f R EM sleep cause the patients exhibiting no auxiliary symptoms are considered symptoms o f narcolepsy.15-19 to have so-called independent narcolepsy.24-26 In one study of 170 patients, all had daytime hypersomnolence, 10% experienced daytime sleepiness alone, 20% to 25% had daytime sleepiness and one auxiliary symptom, and 50% had davtime sleepiness and all three auxiliary symp­

Submitted, revised, A pril 1, 1992. toms.27 The major symptoms o f narcolepsy are caused by an From the Department o f Medicine, Sleep Disorders Center, M edical College o f Georgia, inappropriate intrusion of REM sleep into a person’s Augusta. Requests for reprints should be addressed to Bashir A . Chaudhary, MD, Sleep Disorders Center, M edical College o f Georgia, Augusta, GA 30912-3135. waking hours. The sleep attacks are complete REM sleep

© 1993 Appleton & Lange ISSN 0094-3509 The Journal of Family Practice, Vol. 36, No. 2, 1993 207 Narcolepsy Chaudharv and Husain

1 able 1. Common Symptoms of Narcolepsy temporary loss o f muscle tone and an inability to move If both occur simultaneously, patients are unable to move Symptoms Patients Affected, % or cry out in response to the hallucinatory' danger; how­ Excessive daytime 100 somnolence ever, either type o f episode may be interrupted if the patient is touched. Disturbed sleep 90 About 50% of narcoleptic patients have automatic

Cataplexy 80 behavior with complete retrograde amnesia.32 There mav be brief lapses in the middle o f conversation or during Hypnagogic hallucinations 70 more complex behavior such as walking, driving, or Sleep paralysis 60 continuing routine work for a period o f time. The lapses most often occur during the late afternoon and evening. Automatic behavior 50 Patients with narcolepsy fall asleep easily but usually report frequent nighttime awakenings. The total wake episodes. The muscle weakness o f cataplexy and sleep time and number o f awakenings during sleep increase paralysis appear to be identical to the muscle inhibition linearly with age. Sleep efficiency, a measurement of the occurring during REM sleep, and the hallucinations are time a patient actually sleeps while in bed, is decreased dreamlike experiences during partial wakefulness.28 early in life and shows a more rapid decline compared The sleep attacks appear as clinically normal sleep, with that o f the general population.27 The incidence of arc characteristically brief, but may last from a few sec­ periodic leg movements during nocturnal sleep is also onds to 30 minutes, and are usually refreshing.29'30 The higher than in the general population. Approximately attacks are often precipitated by passive recreation such 80% o f narcoleptic patients have periodic hunger pangs as reading or watching television, which may induce and cravings for sweet foods, and these symptoms may sleepiness even in normal people. Patients with narco­ awaken them during the night.15 lepsy, however, may experience attacks in situations con­ Blurred vision was reported as the third most com­ sidered to be stimulating such as playing games or during mon complaint among one group o f narcoleptic patients conversation. The patients can be easily awakened from seen by ophthalmologists. Intermittent diplopia also oc­ these sleep episodes by auditory or tactile stimulation. A curs in these patients.33- 36 refractory period o f alertness o f 1 to 4 hours follows each Approximately one half of the patients with narco­ attack. lepsy have memory problems, particularly loss o f recent Cataplexy, the pathognomonic symptom of narco­ memory.37’38 It is hypothesized that “microsleep” occur­ lepsy, is present in 80% o f patients. Cataplexy is a sudden ring during the daytime interferes with perception and brief loss o f muscle control usually precipitated by strong acquisition of information.39 Objective evaluations have emotions such as laughter, surprise, elation, or anger, shown that narcoleptics do have more difficulty in main­ although in rare instances it may occur without an iden­ taining attention, although the results of tests of concen­ tifiable cause.6 Many narcoleptics develop a flat affect in tration and memory are not significantly different from an attempt to suppress the emotions that trigger cata- those of controls.40 However, normal results on concen­ plectic attacks.30 Thus, many narcoleptics find it difficult tration and memory' tests have been attributed to the use to interact normally in social situations. Cataplexy gen­ of stimulants by an estimated 77% o f narcolepsy patients. erally involves only the voluntary muscles, usually spar­ ing extraocular and respiratory muscles. Patients typically remain fully conscious during the attack and have com­ plete recall o f the episodes. Onset of Symptoms I wenty-fivc percent to 50% o f patients with narco­ lepsy exhibit sleep paralysis and hypnagogic hallucina­ Although narcolepsy may occur at any age, onset com­ tions that occur during the transition periods between monly occurs during the second decade o f life.27-41'42 The sleeping and waking.31 Hypnagogic hallucinations are highest incidence is among people 15 to 25 years o f age. vivid, usually frightening experiences occurring at the Excessive daytime sleepiness and sleep attacks are the onset of sleep. These episodes usually incorporate ele­ initial symptoms o f narcolepsy, with auxiliary symptoms ments of the patient’s environment; therefore, they are generally appearing several years after the onset o f sleep labeled hallucinations rather than dreams. The hallucina­ attacks. A gap o f over 40 years has been reported be­ tions are usually visual or auditory but may be tactile and tween the onset of daytime sleepiness and the first attack arc often quite complex. With sleep paralysis, there is a o f cataplexy.43

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Table 2. Diagnostic Tests for Narcolepsy ity to remain awake in a quiet room.51 This test has been used to evaluate the efficacy o f various drugs in maintain­ Multiple Sleep Latency Test (MSLT) ing wakefulness. Browman et al52 evaluated the M SLT Variants o f M SLT and the maintenance-of-wakefulness test by continuous Single 45-minute test 48-hour polysomnographic recordings, and found that Tw o 1-hour tests Maintenance-of-wakefulness test both tests differentiated narcolepsy patients from con­ trols. Evoked potential Broughton et al53 have suggested using auditory evoked potentials for the evaluation of sleepiness. This Pupillometry test may be helpful in evaluating pharmacologic agents; however, in a follow-up study,54 Broughton found evoked potentials to be less sensitive and less accurate Laboratory Diagnosis than M SLT. History and physical examination are helpful in establish­ Pupillometry measures the ability o f the subjects to ing the clinical diagnosis of narcolepsy and ruling out remain alert in the dark.55 The pupillary diameter is related disorders.44'45 A nocturnal polysomnogram is measured by an infrared pupillograph. The alert, well- usually done initially to document the adequacy o f sleep rested person has pupils o f larger diameter that vary little and for evaluation o f sleep apneas, which are more com­ in size during a 15-minute tracing. In patients with mon causes o f daytime somnolence. hypersomnolence, the pupils show progressive constric­ A number of laboratory tests have been used in tion. Pupillometry is relatively inexpensive and less time confirming the diagnosis of narcolepsy (Table 2). The consuming than MSLT; however, it has not been stan­ Multiple Sleep Latency Test (MSLT) is the primary test dardized in normal subjects nor compared with other used for diagnosis.46"18 This test assesses two major tests for accuracy. In a recent study, pupil size showed a components of narcolepsy: hypersomnolcnce and REM- significantly greater number of spontaneous oscillations onset sleep. Usually, five 20-minute nap periods, each per minute in narcoleptics compared with controls; how­ separated by 2 hours, are monitored. Hypersomnolence ever, a variety o f methodological and statistical short­ is established if the patient falls asleep within 5 minutes. comings remain with pupillometric tests.56 In normal people, sleep latency (the time required to fall asleep) is usually more than 10 minutes; and REM , which usually begins 75 to 90 minutes after going to Narcolepsy and HLA-DR2 sleep, does not occur during these short nap periods. It the mean sleep latency is less than 5 minutes (ie, patients Recently a strong association between narcolepsy and the fall asleep quickly) and REM sleep is seen in two of the HLA antigens has been demonstrated. The HLA region five nap studies (ie, patients go quickly into REM sleep), is located on the short arm of human chromosome 6. The a diagnosis o f narcolepsy is strongly suggested. Sleep- association between narcolepsy and H LA -D R2 and onset REM periods, though characteristic of narcolepsy, HLA-DW1 antigens is the strongest association so tar have been described in other diseases. These periods described for any disease.57 Reports from Japan, France, occur quite frequently in patients with sleep apnea, in and England show a near 100% association between patients experiencing drug withdrawal, and in normal narcolepsy and the major histocompatibility complex subjects with irregular sleep schedules. class II gene product, H LA -D R 2.58-63 Other studies Many variants o f the standard M SLT have been show the association ranging from 90% to 98%.64'65 suggested. The degree o f excessive daytime somnolence About one third o f the normal healthy individuals are can be assessed by a single 4 5 -minute recording to de­ also positive for HLA-DR2; therefore the specificity of termine the latencies o f various sleep stages.49 This test this test is low. Because o f the low specificity, tissue establishes the degree of hypersomnolence, but does not typing is not helpful in making the diagnosis. Because of differentiate from other disorders that can cause hyper­ this high sensitivity, a negative test practically rules out somnolence. The use o f two 1-hour polysomnographic the diagnosis of narcolepsy. Narcolepsy with negative recordings has been suggested as an alternative diagnos­ HLA-DR2 has been described66-67; however, the possi­ tic test.50 Abnormally short sleep latency or REM onset bility exists that the patient with negative HLA-DR2 of less than 10 minutes on either of the two recordings may actually have some other disease. has both high diagnostic sensitivity (84%) and high Individuals with H LA -D R2 are at a higher risk of specificity (80% ). Another variant o f M SLT is the main- developing narcolepsy than the general population.65 tcnance-of-wakcfiilness test, measuring the patient’s abil­ Identification of a specific submolecular fraction or epit-

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ome of the whole DR2 molecule might permit more Table 3. Drug Therapy for Narcolepsy accurate confirmation of the diagnosis than polysomnog­ Usual 24-Hour raphy, and prenatal diagnosis of narcolepsy by amnio­ Drug Dose centesis might be possible in the future.9 For hypersomnolence Methylphenidate 1 0 -6 0 mg Dextroamphetamine 10—60 mg Pemoline 18.75-112.5 mg Differential Diagnosis Mazindol 1 -6 mg Propranolol 4 0 -1 2 0 mg Inadequate sleep is a common cause o f excessive daytime sleepiness. Other than narcolepsy, the principal causes of For cataplexy Imipramine 2 5 -1 0 0 mg excessive daytime sleepiness are sleep apnea syndromes, Protriptyline 5 -6 0 mg narcolepsy with sleep apnea, idiopathic CNS hypersom­ Clomipramine 1 0 -1 0 0 mg nolence, and periodic movements in sleep. Other consid­ Desipramine 25—100 mg Fluoxetine 2 0 -6 0 mg erations are hypothyroidism, hypoglycemia, abuse o f Gammahydroxvbutvrate 5 - 7 g sedative drugs, metabolic encephalopathy, encephalitis, Viloxazine 5 0 -1 0 0 mg and brain tumor. Occasionally, narcolepsy is confused with petit mal or psychomotor seizures, depending on whether cataplexy or automatic behavior is exhibited. At overall functioning. Hypersomnolence is treated with times patients have been considered schizophrenic be­ CNS stimulants (eg, methylphenidate), and cataplexy is cause o f bizarre mentation and visual or auditory hallu­ treated with REM-suppressing antidepressants (eg, imi- cinations at the onset o f sleep. Klcine-Levin syndrome pramine) (Table 3).72-73 Despite recent advances in drug and hypersomnia linked to menstruation are two rare therapy of narcolepsy, methylphenidate and imipramine causes to keep in mind when evaluating a confusing case are still the most widely used and effective drugs. o f hypersomnia.68-69 Occasionally, because o f certain Methylphenidate at a dose of 20 mg/day (range 5 to common features, multiple sclerosis may be labeled 60 mg) is the drug of choice for hypersomnolence be­ falsely as narcolepsy, or vice versa.70 cause of its prompt action and low incidence of side effects.74-75 Late afternoon or evening doses should be avoided so as not to interfere with nighttime sleep. Other Treatment stimulants frequently in use are pemoline and dextroam­ phetamine.28 Pemoline has behavioral effects similar to The aim o f treating a narcoleptic patient is to relieve the those o f methylphenidate. Because o f its 12-hour half- symptoms that interfere with day-to-day functioning and life, pemoline (18.75 to 112.5 mg) may be given once to reassure the patient and family. With the help o f psycho­ daily. It has a slower onset o f action, and both its degree social counseling, therapeutic naps, and medication, the o f stimulation and its side effects seem to be lower than patient may be able to perform at an optimal level. those o f methylphenidate and amphetamines. Occasion­ Narcolepsy is frequently misunderstood.31-38 Par­ ally pemoline initially worsens sleepiness for several ents, teachers, spouses, and coworkers often assign mo­ hours after ingestion. Tolerance to pemoline usually does tivational causes, further dampening patient self-esteem. not develop.76 Dextroamphetamine (10 to 60 mg daily) It must be explained to the patient and his or her family is often used and preferred by some. Drug dependence, members, friends, and coworkers that narcolepsy is a amphetamine psychosis,31 and even paradoxical sleepi­ physical illness which the patient cannot voluntarily con­ ness6 can occur, but many patients can take stimulants trol. Family and group therapy may be valuable in help­ without significant side effects. ing patients accept the illness and establish reasonable Mitler et al75 recently reported on the comparative expectations. efficacy o f methylphenidate, pemoline, and protriptyline For milder cases o f narcolepsy, a schedule o f several in patients with narcolepsy. Methylphenidate improved short naps during the day will improve alertness consid­ wakefulness but pemoline did not; however, pemoline erably and reduce daytime sleepiness. Increasing the improved performance ability more reliably than meth­ length of the nap produces no increase in alertness.71 ylphenidate. Protriptyline improved neither wakefulness The objective of pharmacologic treatment of narco­ nor performance. Propranolol, a /3-adrenergic blocker, lepsy is to alleviate the two most troublesome symptoms, has been reported to be effective in treating daytime sleep attacks and cataplexy. Although cataplexy is present hypersomnolence and sleep attacks, but tolerance devel­ in 80% o f patients with narcolepsy, often only one symp­ ops rapidly.7 Anecdotal reports suggest that codeine tom, either sleep attacks or cataplexy, interferes with improves daytime hypersomnolence.78

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The most common treatment for cataplexy is the irregular sleep-wake cycle or drug use is not the cause o f tricyclic antidepressant imipramine. Antidepressants the somnolence, then the main possibilities remaining are probably act by suppressing REM sleep. The efFect o f sleep apnea and narcolepsy. Since narcolepsy is a lifelong imipramine on REM sleep and on cataplexy is immediate disease and the treatment often includes stimulant med­ and requires a lower dose than when it is used as an ications, the diagnosis must be firmly established before antidepressant.6 Tricyclics with sedating properties such starting drug therapy. The initial diagnostic test is usually as imipramine should be given in the evening so as not to a nocturnal polysomnogram to rule out sleep apnea. The interact with the effect o f stimulant medications. Usually reference standard in making a diagnosis o f narcolepsy at 50 to 75 mg of imipramine can effectively control cata­ the present time is the MSLT. HLA typing alone cannot plexy, sleep paralysis, and hypnagogic hallucinations. be relied upon because of the high prevalence of DR2 in Protriptyline (10 to 20 mg at night) has been reported to the general population. Therapeutic naps and medica­ control both cataplexy and sleep attacks.79 Protriptyline tions can usually control the symptoms o f narcolepsy. has become popular because o f its effectiveness in treat­ Many times additional effort is required to educate the ing cataplexy; and because it does not cause drowsiness, family, employers, and coworkers about the disease and it can be given during the daytime. It is usually better the therapy. tolerated than stimulant drugs by the elderly.80 Anti­ cholinergic side effects such as dry mouth, anorexia, sweating, hypotension, tachycardia, blurred vision, and Acknowledgments sexual dysfunction can occur with the use of tricyclic The authors arc grateful to Dr W .A. Speir for helpful review of the compounds. When tricyclics are suddenly withdrawn, manuscript and to Kay McCoy for expert secretarial assistance. there can be a marked increase in cataplexy. When cataplexy and sleepiness are both severe, ana­ leptics and antidepressants may be combined, but careful References titration and monitoring is mandatory in view o f serious 1. Kales A, Kales JD. Sleep disorders: recent findings in the diagnosis side effects.31 Methylphenidate can potentiate the effect and treatment o f disturbed sleep. N Engl J Med 1974; 2 9 0 :4 8 7 - of tricyclics by interfering with hepatic metabolism. 99. 2. Gastaut H, Lugares IE, Berti-Ceroni G, Coceagna G, cds. The Among the newer treatments for narcolepsy, the abnormalities o f sleep in man. Bologna: Auloe Gaggi Editore, most promising is gamma hydroxybutyrate (GHB), 1968. which occurs naturally in the hypothalamus and basal 3. Bixler EO , Kales A, Soldotos CR. Sleep disorders encountered in medical practice: a national survey o f physicians. 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