Patients with suspected narcolepsy who are referred to sleep clinics for definitive diagnosis can benefit from treatment including modafinil, traditional stimulants, or tricyclic antidepressants.

Narcolepsy is a chronic neurological disorder marked by sudden and uncontrollable drowsiness and attacks of sleep at unexpected and irregular intervals. The sleep attacks may last minutes or hours and vary in frequency from a few to many in a single day. In addition to sleep attacks, the majority of narcolepsy cases are accompanied by cataplexy, the loss of skeletal muscle tone without loss of consciousness. The cataplectic attacks of narcolepsy are frequently prompted by laughter; at other times, embarrassment, social interactions with strangers, sudden anger, athletic exertion, or sexual intercourse may trigger an episode. Historically, narcolepsy has been underdiagnosed. It is believed to affect roughly 5% of the population.^1,2

Narcoleptics may fall asleep at dangerous or inappropriate times. Untreated, they are at high risk for motor vehicle accidents and workplace injuries. Children with narcolepsy often have trouble reaching their potential in school. A person with narcolepsy also may suffer injuries at home; falls during cataplectic attacks and burns caused by falling asleep while smoking are common.

Many aspects of the daily life of a person with narcolepsy may be impaired by excessive daytime sleepiness. Although the diagnosis of narcolepsy usually is not made until adulthood, symptoms, particularly excessive daytime sleepiness, usually appear by adolescence,³ a time of increasing responsibility at school and work.

Besides daytime sleepiness and cataplexy, two other classic symptoms of narcolepsy include sleep paralysis and hypnagogic hallucinations. Sleep paralysis is an inability to move or to speak when falling asleep or awakening (when still conscious of one’s surroundings). Although normal individuals may have short periods of sleep paralysis a few times in their lives, it is a daily occurrence for many narcoleptics. Sleep paralysis associated with the transition from wake to sleep is termed sleep-onset paralysis, and should be differentiated from similar experiences occurring when waking from sleep (sleep-offset paralysis). Sleep paralysis may be brought on by several factors including stress, sleep deprivation, fever, or sleeping in the prone position.⁴ Associated symptoms include sweating, heart palpitations, and other autonomic symptoms.⁵

Hypnagogic hallucinations are dreamlike experiences during waking that often incorporate elements of the environment. They are vivid perceptual experiences that usually occur when narcoleptics are most sleepy. Hypnagogic hallucinations are most often visual or auditory, but they may also be tactile. The episodes are usually brief, rarely lasting more than 15 minutes. They may result in a sense of confusion if the patient is awakened from them.

Nocturnal sleep disturbances have also been identified as a prominent feature of narcolepsy. Narcoleptic sleep is characterized by frequent wakenings, increased number of arousals, rapid eye movement (REM) abnormalities, increased amount of stage 1 sleep, and reduced total sleep time.⁴ The combination of excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations is often referred to as the narcoleptic tetrad.

Prevalence
Prevalence studies suggest that narcolepsy affects about 200,000 persons in the United States every year.⁶ However, this figure is probably an underestimate because narcolepsy often is underrecognized and underdiagnosed.⁷ The average delay between symptom onset and the diagnosis of narcolepsy is enormous—approximately 15 years.⁸ Determining who is at risk for developing narcolepsy is difficult. Although some studies have suggested a link between narcolepsy and human leukocyte antigens DR2 and DQwl,^9,10 this association is not a reliable predictor of disease development.¹¹

Clues to the Cause
Narcolepsy is linked to a disruption of the sleep control mechanism. The sleep cycle normally consists of two primary phases: REM sleep and non-REM (NREM) sleep. NREM sleep is a quiet sleep state. The muscles are relaxed but maintain some tone, breathing is regular, the cerebral cortex generates high-voltage waves, and consumption of energy by the brain is minimal. Although REM sleep shares the loss of consciousness of the environment seen in NREM sleep, it is physiologically quite different. Breathing and heart rate are irregular; characteristic rapid eye movements occur; the cortex generates fast, irregular, low-voltage waves similar to those present in alert waking; vivid dreams take place; and brain metabolism often exceeds levels seen when the subject is awake. Tone in the postural muscles, such as those in the back and legs, is absent during REM sleep, although twitches occasionally break through the motor quiescence.

People who are not narcoleptic begin their nighttime rest with NREM sleep, with REM sleep following roughly 90 minutes later. Narcoleptics, on the other hand, frequently go straight into REM sleep. Because of this trait, and because narcoleptics experience loss of muscle tone and dreamlike hallucinations that normally occur only during REM sleep, researchers have hypothesized that these symptoms of narcolepsy result from the inappropriate triggering of some aspects of REM sleep.

Although sleep problems are the most common symptoms of narcolepsy, much of the basic research on the disease has used cataplexy as a starting point. Sleepiness is a normal phenomenon; it is the amount of sleepiness that is abnormal in narcolepsy. Therefore, it is difficult to know if particular episodes of sleepiness seen in narcoleptics are abnormal. Cataplexy, however, never occurs in normal individuals. It is easily quantified and has an abrupt onset that allows scientists to determine the time course of the neural events that trigger it. By observing and manipulating cataplexy, investigators hope to gain a more clear insight into the pathogenesis of narcolepsy.

Clinical Implications of Under-Recognition
People unfamiliar with narcoleptic symptoms may label the narcoleptic patient as lazy or psychologically disturbed, which can have severe consequences, including low self-esteem, depression, and social problems. These problems are compounded because the disorder is frequently misdiagnosed as hypothyroidism, hypoglycemia, epilepsy, or multiple sclerosis. A delayed diagnosis typically worsens the narcoleptic’s psychological and social problems, while early diagnosis facilitates treatment, and better enables the patient to cope with the problem.

Because the onset of narcolepsy can be triggered by emotional stress, psychiatric misdiagnoses are common. Narcoleptics may be misdiagnosed as having depression, conduct and oppositional defiant disorders, attention-deficit/hyperactivity disorder, conversion disorder, and even psychosis if hypnagogic hallucinations are misinterpreted. Medical misdiagnoses include epilepsy and other neurologic disorders capable of causing excessive daytime sleepiness.

Children with narcolepsy may be subject to inaccurate interpretation by teachers and parents. Teachers and parents may perceive the child with narcolepsy as being lazy, inattentive, and poorly motivated. Sometimes use of illicit drugs is suspected. Narcoleptic children may be referred to special education programs because of the mistaken belief that they are intellectually limited. Such misunderstanding may persist even after the diagnosis of narcolepsy is made, indicating a need for better appreciation for the nature of the condition. Child health professionals should be aware that narcolepsy in young children is not a rare condition, and they should be familiar with the clinical manifestations of the disorder. Narcolepsy should be suspected if a child’s excessive sleepiness cannot be explained.

Diagnosis
Patients suspected of having narcolepsy based on the clinical presentation should be referred to a sleep clinic for definitive evaluation. The first step in the evaluation process is the interview. During the interview, the sleep clinician determines the patient’s chief complaint and the frequency and duration of any symptoms. It is also important to understand the patient’s sleep and wake schedule—important features include the usual time of going to bed, the total amount of nocturnal sleep, the number of naps taken daily, and any change in sleep patterns.

A number of scales have been validated for use in the quantification and qualification of narcoleptic symptoms. Use of these scales is beyond the scope of most primary care practices, but sleep clinicians may use them to facilitate the diagnosis of narcolepsy. The Sleep Wake Activity Inventory (SWAI) is a multidimensional questionnaire that includes a scale that evaluates excessive daytime sleepiness. Patients are asked to determine how often certain statements about sleepiness apply to them by circling a response on a visual analogue scale. A lower score on the scale indicates more pathologic levels of sleepiness.^12,13 The Epworth Sleepiness Scale (ESS) primarily measures excessive daytime sleepiness. Patients are asked to quantify their chance of dozing in several different situations. A higher score indicates greater levels of excessive daytime sleepiness.^14,15

In addition to these and other scales, several other instruments are available to aid the sleep clinician in the diagnosis. The sleep log is a useful tool for monitoring patients outside the sleep clinic. The patient is asked to keep a daily record (usually for 1 week) of the number and length of naps taken, amount of alcohol consumed, amount of prescription and nonprescription drugs taken, caffeine consumption, bedtime, number of awakenings, and waketime. Another diagnostic instrument is the actigraph, a device that looks like a wristwatch and translates physical motion into numeric representation based on miniaturized acceleration sensors. Movement is sampled every tenth of a second and aggregated into a constant interval. The actigraph can store more than a week’s worth of data, which can be downloaded into a computer for analysis. Actigraph data can be used to identify nocturnal sleep duration and frequency of daytime sleep attacks, though not with the accuracy of a polysomnogram.

An integral component of the assessment of a patient with suspected narcolepsy is the sleep laboratory evaluation. Prior to the evaluation, there should be a wash-out phase during which the patient is taken off any drugs that directly affect the central nervous system, if it is judged safe to do so. The phase should be long enough to wash these drugs out of the system.

On the night of the polysomnogram, the patient is asked to arrive at the sleep laboratory 2 hours before bedtime. The patient is placed in a dark, quiet room and monitored throughout the night with central and occipital electroencephalogram (EEG), submental electromyogram (EMG), and two electro-oculogram (EOG) devices. The EEGs, EMG, and EOGs together provide the information necessary to determine the patient’s sleep parameters, including sleep latency, total sleep time, sleep efficiency, number of arousals, and sleep architecture. In addition, an electrocardiogram (ECG) is obtained to monitor heart rate during sleep, and a tibialis anterior EMG monitors leg movement. Additional assessments during the night at the sleep laboratory include a pulse oximeter to measure blood oxygen concentration, position monitoring, a snoring microphone, a thermistor at the nose and mouth to detect airflow, and a thoraco-abdominal belt to detect respiratory effect. These devices enable the clinician to rule out sleep apnea from the differential diagnosis.

If narcolepsy is suspected after the polysomnogram, a multiple sleep latency test (MSLT) may be performed the following day. Using the standard electrode array (EEGs, EMG, EOGs, ECG), the patient is recorded during four or five naps, and a MSLT score is calculated. A mean MSLT score of 5 minutes or less corroborates the complaint of excessive daytime sleepiness.⁴

A maintenance of wakefulness test (MWT) may be used instead of or in addition to a MSLT. This test consists of four 40-minute trials at 2-hour intervals. During the trials, patients are instructed to sit up in bed and remain awake for as long as possible instead of taking a nap.

Treatment
Stimulants such as amphetamine, methylphenidate, and pemoline are the primary treatment for narcolepsy. Amphetamine and methylphenidate appear to work by enhancing catecholaminergic function, thereby decreasing the incidence of daytime sleepiness. However, they are associated with a number of potentially troublesome side effects, including increased blood rate and tachycardia. Amphetamine psychosis may occur in a small percentage of patients treated on a long-term basis. Furthermore, tolerance to amphetamine may develop after patients take it for long periods of time. Because of their potential for abuse, amphetamine and methylphenidate are classified as Schedule II drugs. Pemoline, which has a lower potential for abuse and is categorized as a Schedule IV drug, is also the least effective of the stimulants used to treat narcolepsy.

Antidepressants, mainly tricyclic antidepressants (TCAs), are often used for the treatment of cataplexy, hypnagogic hallucinations, and sleep paralysis because they suppress REM sleep. The selective serotonin reuptake inhibitor (SSRI) fluoxetine has also been reported to be useful for the management of narcolepsy.

Modafinil, a wakefulness-promoting agent, is the newest agent for the treatment of excessive daytime sleepiness associated with narcolepsy. Modafinil is structurally distinct from amphetamine and methylphenidate. The precise mechanism of modafinil is unknown; it exerts catecholaminergic effects through a mechanism that differs from traditional catecholaminergic and dopaminergic stimulants. There is little or no potential for abuse with modafinil; hence, it has been categorized as a Schedule IV drug.

Other pharmacologic agents are being investigated for use in narcolepsy. These include selegiline, a drug used to treat Parkinson disease, and gamma-hydroxybutyrate (GHB). With regard to GHB, it will be important to ascertain through well-designed clinical trials if the efficacy and safety of the drug outweigh its potential for abuse.

Nonpharmacologic coping strategies include therapeutic naps of 15 to 30 minutes in duration. Nap therapy may alleviate the severity of daytime sleepiness and may permit the reduction of stimulant dosages in some patients. Other strategies—often employed by narcoleptics for safe driving—include applying cold packs, singing along with the radio, stopping for naps, and exercising at periodic stops.

Perhaps the most important component of narcolepsy management is the maintenance of a regular sleep-wake cycle. Patients should go to sleep and wake up at the same times every day, including weekends. Finally, nicotine and caffeine should be avoided because they can result in fragmented sleep.

Conclusion
Patients with narcolepsy, who for years have been underdiagnosed or misdiagnosed, may benefit from the relatively recent establishment of sleep medicine as a distinct subspecialty. The greater awareness of narcolepsy as a medical problem has provided an impetus for research that may lead to newer and more effective pharmacologic agents. In the meantime, patients with suspected narcolepsy should be referred to a sleep clinic for definitive diagnosis, and can benefit from treatment with modafinil, traditional stimulants, or TCAs if these agents can be tolerated.

John D. Zoidis, MD, is a contributing writer for RT Magazine.

References
1. Billiard M, Alperovitch A, Perot C, Jammes A. Excessive daytime somnolence in young men: prevalence and contributing factors. Sleep. 1987;10:297-305.

2. Stores G. Recognition and management of narcolepsy. Arch Dis Child. 1999;81:519-524.

3 Dahl RE, Holttum J, Trubnick L. A clinical picture of child and adolescent narcolepsy. J Am Acad Child Adolesc Psychiatry. 1994;33:834-841.

4. Gerhardstein R, Day R, Rosenthal L. Narcolepsy and other causes of excessive daytime sleepiness. Respir Care Clin North Am. 1999;5:427-446.

5. Bassetti C, Aldrich MS. Narcolepsy. Neurol Clin. 1996;14:545-550.

6. Chaudhary BA, Husain I. Narcolepsy. J Fam Pract. 1993;36:207-213.

7. Green PM, Stillman MJ. Narcolepsy. Signs, symptoms, differential diagnosis, and management. Arch Fam Med. 1998;7:472-478.

8. Scharf MB, Brown D, Woods M, Brown L, Hirschowitz J. The effects and effectiveness of gamma-hydroxybutyrate in patients with narcolepsy. J Clin Psychiatry. 1985;46:222-225.

9. Billiard M, Seignalet J. Extraordinary association between HLA-DR2 and narcolepsy [letter.] Lancet. 1985;2:226-227.

10. Matsuki K, Grumet FC, Lin X, et al. DQ (rather than DR) gene marks susceptibility to narcolepsy [letter.] Lancet. 1992;339:1052.

11. Mignot E, Lin X, Kalil J, et al. DQB1-0602 (DQw1) is not present in most nonDR2 Caucasian narcoleptics. Sleep. 1992;15:415-422.

12. Flores-Valencia M, Rosenthal L, Castano VA, et al. A factor replication of the sleep-wake activity inventory (SWAI) in a Mexican population. Sleep. 1997;20:111-118.

13. Rosenthal L, Roehrs TA, Roth T. The sleep-wake activity inventory: a self-report measure of daytime sleepiness. Biol Psychiatry. 1993;34:810-818.

14. Chervin R, Aldrich M, Pickett R, et al. Comparison of the results of the Epworth sleepiness scale and the multiple sleep latency test. J Psychosom Res. 1997;42:145-150.

15. Johns M. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;15:540-546.

16. Guilleminault C. Narcolepsy syndrome. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 2nd ed. Philadelphia: WB Saunders Co; 1994:549-561.

17. Mitler MM, Hajdukovic RM, Erman M, Koziol JA. Narcolepsy. J Clin Neurophysiol. 1990;7:93-118.