Narcolepsy. (Featured CME Topic: Narcolepsy).

Abstract: Narcolepsy is a severely debilitating neurologic disease that is not as rare as many believe, affecting an estimated 140,000 Americans. Despite the sometimes debilitating nature of narcolepsy symptoms, the disease may go undiagnosed without an organized method for evaluating patients with sleep complaints. Many of the classic symptoms of narcolepsy, such as excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations, may be mistakenly associated with other disease states and must be differentiated from other sleep disorders. The results of self-administered sleep-disorder questionnaires are useful and may increase the suspicion of narcolepsy; however, referral to an accredited sleep laboratory for a formal sleep study including overnight polysomnography is necessary for a positive narcolepsy diagnosis. A variety of medications may be used to successfully treat excessive daytime sleepiness and cataplexy, the two most debilitating symptoms of the disease. Primary-care physi cians who develop the proper diagnostic skills can play a pivotal role in the accurate diagnosis and long-term management of patients suffering from narcolepsy.

**********

Narcolepsy is a chronic neurologic disorder, mistakenly thought to occur only rarely. It is estimated that 1 in 2,000 Americans is afflicted with this disease. (1) The clinical symptoms of narcolepsy (see Table 1) profoundly affect the physical, mental, and social health of these individuals. Despite this, symptoms often go unrecognized, and patients may remain undiagnosed or misdiagnosed for years. Narcolepsy symptoms usually appear during adolescence and have even been noted in children; however, the diagnosis of narcolepsy is generally not made until adulthood. A secondary peak of onset occurs in the third decade of life. Increases in sleep disorder research and in the number of sleep disorder laboratories during the past decade have resulted in greater availability of testing and treatment. By distinguishing the sleepiness of a sleep disorder from the systemic fatigue occurring as a constitutional symptom of a non-sleep-related disorder, primary care physicians can play a pivotal role in screening patient s and making appropriate referrals for sleep disorders, including narcolepsy.

Pathophysiology 

Human narcolepsy may have multiple etiologies and may be at least partially genetic. There is a high incidence of human leukocyte antigen (HLA)-DR2 haplotypes among narcoleptics; however, it does not appear to be the sole determinant of the disease. (2) Experiments in well-established canine models of narcolepsy suggest an autosomal recessive pattern of inheritance. (3) An incidence of narcolepsy among first-degree relatives of narcoleptic patients that is higher than the general population has been demonstrated (1-2% versus 0.02-0.1 8%), (4) although a high rate of discordance in identical twins indicates that factors other than genetic determinants are involved. Thus, the development of narcolepsy may involve environmental factors acting on a genetically predisposed background. (3) In spite of the high frequency of HLADR2 haplotypes among narcoleptics, the incidence of the same HLA markers among normal individuals can lead to a large number of false-negatives, and HLA testing is not routinely performed for the diagnosis of narcolepsy.

Recently, a relationship between narcolepsy and a deficiency of the peptide neurotransmitter hypocretin has been suggested. Hypocretin-containing neurons are found in the lateral hypothalamus, where they project to various parts of the brain, including.nuclei, believed to regulate sleep. In canine models of narcolepsy, the receptor protein for hypocretin is absent. (3) Similarly, genetically engineered mice that do not produce hypocretin peptide display symptoms of narcolepsy. (5) These findings are supported by studies in narcoleptic patients. In 75% of narcoleptic patients, hypocretin is undetectable in cerebrospinal fluid. (6) Likewise, postmortem examination revealed deficiencies in hypocretin-producing neurons in the brains of narcoleptics. (7,8) Despite the strong association between hypocretin deficiency and narcolepsy, the primary cause remains unknown. Taken together, the available data suggest that the destruction of hypocretin-producing cells is consistent with an autoimmune process. (9,10)

Changes in Sleep

Normally, sleep is comprised of two separate sleep states: rapid eye movement (REM) sleep and non-REM sleep. REM sleep is characterized by vivid dreaming, muscle atonia, desynchronized activity observed on an electroencephalogram (EEG), and episodic bursts of REM. In contrast, non-REM sleep is characterized by synchronized slow wave or delta wave activity, muscle relaxation, and less frequent dreaming. Normal sleep architecture begins with non-REM sleep, alternating with REM sleep at approximately 90-minute intervals throughout the night with REM period duration increasing as the night progresses. (11)

In narcolepsy, onset and offset of both REM and non-REM sleep are impaired. Narcoleptics are unable to maintain either REM or non-REM sleep, which causes frequent arousals and resulting in disturbed nocturnal sleep." Although narcoleptics fall asleep easily, they may paradoxically experience insomnia. As many as 90% of narcoleptics report severe disruption of nocturnal sleep. It is believed that the unmet need for REM sleep during the night causes abnormal REM sleep to intrude into wakefulness, causing the REMrelated symptoms of cataplexy, sleep paralysis, and hypnagogic hallucinations. (11,12)

Symptoms of Narcolepsy

Excessive Daytime Sleepiness. The excessive daytime sleepiness (EDS) of narcolepsy is a chronic symptom in which daytime sleep episodes occur at inappropriate or unexpected times. These attacks are inadvertent, difficult to avoid, and have major social implications because they can occur during active situations such as working, eating, talking, or driving. EDS is generally the first clinical symptom of narcolepsy to emerge. (11) Because it may appear gradually, and because there are many possible causes for EDS, it may be difficult to associate EDS with narcolepsy. Patients and their physicians may explain the symptom as a result of social or occupational demands.

Cataplexy. Cataplexy is an abrupt, reversible decrease in muscle tone elicited by emotion that is reported by approximately 75% of narcoleptics. (11) The frequency and severity of cataplexy attacks may be variable, but its presence is a clinical marker for narcolepsy. These attacks are usually triggered by emotions such as laughter, elation, or anger and most often affect the facial or neck muscles, characterized by a sagging jaw, inclined head, or slurred speech. (13) It may also affect the extremities, such as buckling of the knees. Attacks limited only to certain muscle groups are known as partial cataplexy. Although this is the most common presentation of cataplexy, partial cataplexy attacks may be ignored or discounted by patients and physicians.

About one-third of narcoleptics with cataplexy experience complete cataplexy, the sudden and severe loss of muscle tone causing collapse to the ground. (14) These cataplectics remain fully aware of their surroundings but cannot move and, by falling, risk serious injury. The duration of cataplexy attacks, whether partial or complete, is usually brief but can last up to 30 minutes. (14) When they occur, attacks of cataplexy may appear at disease onset or not until months or years following EDS onset.

Sleep Paralysis. Sleep paralysis is the inability to move for seconds to minutes during sleep onset or offset and is a frightening experience when it first occurs. (12) Although breathing is unaffected, patients are unable to move their extremities or to speak. They feel powerless despite being conscious of the situation and can recall the event afterwards. Up to 80% of individuals with narcolepsy report sleep paralysis episodes. (14) The frequency of sleep paralysis varies among narcoleptics from rare to daily, and it commonly occurs with frightening or unpleasant hallucinations.

Hypnagogic Hallucinations. Hypnagogic hallucinations also occur during the transition between waking and sleep and, in addition to nocturnal sleep onset, may occur during daytime naps or sleep attacks. They are often bizarre or frightening visual experiences but may also have auditory or other sensory involvement. An important distinguishing feature is that patients are aware they are hallucinating and remain conscious of their surroundings. Nearly 70% of narcoleptics experience hypnagogic hallucinations, (14) with many patients experiencing them frequently. Sadly, these symptoms sometimes lead to an incorrect diagnosis of mental illness. (15)

Automatic Behaviors. About 50% of narcoleptics experience automatic behavior. When automatic behaviors occur, sleep has partially overtaken the brain, but the body continues to perform familiar tasks with complete retrograde (16)

Patients experience brief lapses during conversation or routine activities such as walking or driving and may exhibit extremely inappropriate behavior resembling partial complex seizures.

Other Manifestations. It is generally accepted that the symptoms of narcolepsy have a negative impact on the quality of life of these patients. (17) The risk of serious automobile or machine accidents is very real. Narcoleptic patients are fearful of public embarrassment and injury resulting from episodes of cataplexy, causing patients to suppress emotions in an effort to lessen these attacks. Consequently, narcoleptics may be viewed as poorly motivated or depressed, making school challenging and the workplace a difficult and uncomfortable environment. Such adversity often leads to psychological symptoms secondary to their illness, such as alienation, shame, low self-esteem, or depression. (15,17)

When Is Narcolepsy Clinically Suspect?

That fatigue and sleepiness are a common complaint while narcolepsy is a relatively uncommon disease makes diagnosing narcolepsy difficult. It is important that primary care physicians not allow patients to rationalize complaints of sleepiness, fatigue, or sleep disturbances without screening them for potential sleep disorders such as narcolepsy. A detailed sleep history including the duration, severity, and consistency of the problem is the first step in the differential diagnosis. When evaluating a patient who complains of fatigue or excessive sleepiness, a key question to ask is, "Do you fall asleep inadvertently in inappropriate settings?"

To help determine the severity of EDS, a brief self-administered questionnaire called the Epworth Sleepiness Scale (ESS) can be completed by patients while in the office. The ESS consists of eight questions that subjectively assess the severity of daytime sleepiness based the subject's dozing behavior in everyday situations. (18) After the severity of EDS has been determined, additional tests can be ordered to determine the cause. A sample ESS questionnaire is shown in Figure 1.

A history of cataplexy may be revealed by asking the patient whether strong emotion (usually laughter, anger, or excitement) elicits muscle weakness. (13) The presence of this symptom should create a high suspicion for the diagnosis of narcolepsy. Other historic facts supporting a diagnosis of narcolepsy include sleep fragmentation or disturbed nocturnal sleep, sleep paralysis, hypnagogic hallucinations, and family history. Unless cataplexy or inadvertent sleep episodes are actually observed, however, a physical examination will not detect these symptoms. A cataplexy questionnaire developed by the Stanford Center for Narcolepsy may be helpful in assessing the presence of cataplexy. (13)

Differential Diagnosis

Other sleep disorders to consider in the differential diagnosis are obstructive sleep apnea (OSA), upper airway resistance syndrome, idiopathic central nervous system (CNS) hypersomnolence, and periodic limb movements during sleep (Fig. 2).

Obstructive Sleep Apnea. As with narcolepsy, OSA is associated with EDS resulting from highly fragmented sleep. In OSA, the upper airway becomes occluded during sleep. This causes increased upper airway resistance, increased respiratory muscle effort, and episodes of oxygen desaturation. The repeated decreases in oxygenation are associated with frequent arousals throughout the night. Loud snoring, a classic symptom of OSA, may be reported by a sleep partner. Other clinical markers for OSA include male gender, obesity, and hypertension. (19)

Upper-airway Resistance Syndrome. A more subtle form of sleep-disordered breathing is known as upper airway resistance syndrome. (20) Patients experience syndrome. perience recurring partial up per airway closure, but not severe enough to cause apnea, hypopnea, or oxygen desaturation. However, the increased respiratory effort that ensues also causes frequent arousals and sleep fragmentation.

Idiopathic Central Nervous System Hypersomnia. Although less common than narcolepsy, idiopathic hypersomnia is characterized by lifelong EDS but with no REM sleep abnormality. Chronic sleep deprivation and upper airway resistance syndrome must be aggressively ruled out because idiopathic hypersomnia is a diagnosis of exclusion, and the results of formal sleep studies, discussed below, are normal. (19)

Periodic Limb Movement Disorder. Periodic limb movement disorder may be associated with restless legs syndrome. Patients with restless legs syndrome experience a "creepy crawly" or aching discomfort between the knee and ankle that is brought on by rest. It is associated with an irresistible urge to move the legs that interferes with the onset or return to sleep. The resulting fragmented sleep leads to chronic EDS. (21) Although the patient may be unaware of movements during sleep, formal sleep studies will detect these leg movements.

Understanding Sleep Evaluations

A formal sleep study is necessary for a positive narcolepsy diagnosis and usually requires referral to a sleep specialist or neurologist. These studies normally include overnight polysomnography followed by a multiple sleep latency test (MSLT).

Polysomnography. The polysomnogram continuously records normal and abnormal physiologic activity during an entire night. A typical polysomnogram montage includes an EEG, electrooculogram, and electromyogram and may include measurement of airflow, respiratory effort, EGG (electrocardiogram), oximetry, and leg movements. It documents the adequacy of sleep, including the frequency, duration, and total amount of stage 1 to 2, stage 3 to 4 (slow wave sleep), and REM sleep. It will also indicate whether other etiologies of EDS, such as sleep apnea, are present.

Multiple Sleep Latency Test. The MSLT is the primary test for the diagnosis of narcolepsy. This test assesses two major components of narcolepsy: hypersomnolence and sleep onset REM periods, which occur in narcolepsy but are otherwise uncommon. The mean sleep latency, or time to sleep onset, provides evidence for hypersomnolence. It is measured with an EEG during normal waking hours and consists of providing the patient with four or five 20-minute nap opportunities at 2-hour intervals. Normally, sleep latency is greater than 10 minutes, and REM sleep does not occur. Patients with narcolepsy typically fall asleep in 5 minutes or less and will display sleep onset REM periods during at least two of the five daytime nap periods. (11)

Treatment

Common Treatments. Narcolepsy is a debilitating and lifelong illness, but treatment with proper pharmacological agents can make a significant difference in the lives of these patients. The primary objective of drug therapy is alleviating the two most troubling symptoms of narcolepsy: EDS and cataplexy.

EDS is primarily treated with CNS stimulants, improving alertness and increasing daytime performance. (22) The stimulant agents most commonly prescribed are dextroamphetamine and methylphenidate. Each can increase alertness, elevate mood, and prevent sleep. (22'23) Although many patients take stimulants with enduring benefit and without significant side effects, they can cause insomnia, hypertension, palpitations, and irritability. (23) Tolerance to long-term stimulant therapy also may occur, necessitating an increase in dosage to achieve the same control of symptoms. Compliance with stimulants is generally poor, especially among patients with severe EDA requiring high doses. (24)

Modafinil (Provigil), recently approved for the treatment of EDS associated with narcolepsy, is effective in reducing daytime sleepiness with fewer side effects. (25,26) Because of its safety profile compared with amphetamines and its Schedule IV labeling, many experienced clinicians consider modafinil to be the drug of first choice for treating EDS in newly diagnosed narcolepsy patients.

Unfortunately, stimulants do not treat cataplexy effectively. The most common drug therapy for cataplexy involves prescribing antidepressants of the tricyclic or serotonin-selective reuptake inhibitor classes. Tricyclics include protripty-line, imipramine, and clomipramine whereas serotonin-selective reuptake inhibitors include fluoxetine and paroxetine. (23) Although these drugs are known to suppress REM sleep, their exact mechanism of action in alleviating cataplexy is unknown. Anticataplectic doses are generally lower than antidepressant doses; however, patients may experience dry mouth, sweating, constipation, and sexual dysfunction, which may lead to discontinuation. (23)

Because of the potential for side effects associated with stimulant and antidepressant use, careful titration and monitoring are important in the long-term management of narcolepsy patients. Nonpharmacologic treatment of narcolepsy includes maintaining a regular sleep-wake schedule and creating a comfortable sleep environment that promotes unintermpted sleep. Nicotine, caffeine, and other stimulating medications should be avoided in the evening because they may disrupt and fragment sleep. A schedule of brief planned naps throughout the day may be recommended as part of the overall treatment plan. (24)

Promising New Treatment

Among the newer agents currently being studied for the treatment of narcolepsy, sodium oxybate shows the most promise. Sodium oxybate ([gamma]-hydroxybutyrate) is a putative neurotransmitter found in the brain. Early investigations demonstrated that the nightly administration of sodium oxybate changed sleep architecture to more closely approximate that of normal sleep. Sodium oxybate has been shown by EEG to increase slow-wave sleep, decrease the number of nighttime awakenings, and increase REM efficiency. (27,28) The improved quality of nighttime sleep associated with sodium oxybate appears to have a positive effect on other REM-related manifestations because there is a substantial reduction in the auxiliary symptoms of narcolepsy including cataplexy. (26) FDA approval of sodium oxybate (Xyrem, Orphan Medical, Inc., Minnetonka, MN) was granted in 2002. (29)

Support Strategies

Improving the quality of life for patients with narcolepsy depends not only on effective management of the clinical symptoms but also on providing psychosocial support. A study of narcoleptics identified the need for information, referral, and group counseling services as the most important psychosocial needs of these patients. (17) Several organizations to contact for information and assistance include the following:

The Narcolepsy Network

10921 Reed Hartman Highway

Cincinnati, OH 45242

Email: [e-mail]

American Academy of Sleep Medicine 

6301 Bandel Road NW, Suite 101

Rochester, MN 55901

URL: http://www.asda.org/

Narcolepsy Sleep Disorder Association Online Newsletter

URL: http://www.narcolepsy.com/

The National Sleep Foundation

1522 K Street, NW, Suite 500

Washington DC 20005

URL: http://www.sleepfoundation.org/publications/livingnarcolepsy.html

Conclusion

Narcolepsy can produce symptoms that cause severe physical and emotional suffering for these patients. By encouraging patients to discuss any sleep problems and adopting this approach as part of an overall review of systems, primary care physicians can play a critical role in providing an initial diagnosis and making appropriate referrals. Although a strong suspicion of narcolepsy may be made by patient history, the definitive diagnosis is best made with a formal sleep study and MSLT performed in an accredited sleep laboratory.

[FIGURE 2 OMITTED]

Table 1

Frequency of symptoms occuring in patients with nacrolepsy (a)

Symptom                       % of patients

Excessive daytime sleepiness      100%
Fragmented nightime sleep          90%
Cataplexy                          80%
Hypnagogic hallucinations          70%
Sleep paralysis                    60%
Automatic behaviors                50%

(a)From Chaudhary BA, Husain I. Narcolepsy. J Fam Pract
1993;36:207-213. (16)

Accepted November 20, 2002.

References

(1.) Hublin C, Partinen M, Kaprio J, Koskenvuo M, Guilleminault C. Epidemiology of narcolepsy. Sleep 1994; 17(Suppl 8):S7-S12.

(2.) Moscovitch A, Partinen M, Guilleminault C. The positive diagnosis of narcolepsy and narcolepsy's borderland. Neurology 1993;43:55-60.

(3.) Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (Orexin) receptor 2 gene. Cell 1999;98:365-376.

(4.) Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998; 50(2 Suppl 1):S16-S22.

(5.) Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in Orexin knockout mice: Molecular genetics of sleep regulation. Cell 1999;98:437-451.

(6.) Nishino S, Ripley B, Overeem S, Nevsimalova S, Lammers GJ, Vankova J, et al. Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 2001;50:381-388.

(7.) Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000;6:991-997.

(8.) Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000;27:469-474.

(9.) Lin L, Hungs M, Mignot E. Narcolepsy and the HLA region. J Neuroimmunol 2001;117:9-20.

(10.) Mignot E, Thorsby E. Narcolepsy and the HLA system. N Engl J Med 2001;344:692 (letter).

(11.) Krahn LE, Black JL, Silber MH. Narcolepsy: New understanding f irresistible sleep. Mayo Clin Proc 2001;76:185-194.

(12.) Aldrich MS. Diagnostic aspects of narcolepsy. Neurology 1998;50(2 Suppl l):S2-S7.

(13.) Anic-Labat S, Guilleminault C, Kraemer HC, Meehan J, Arrigoni J, Mignot E. Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep 1999;22:77-87.

(14.) Bassetti C, Aldrich MS. Narcolepsy. Neural Clin 1996;14:545-571.

(15.) Broughton WA, Broughton RJ. Psychosocial impact of narcolepsy. Sleep 1994;17(Suppl 8):S45-S49.

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

(17.) Goswami M. The influence of clinical symptoms on quality of life in patients with narcolepsy. Neurology 1998;50(2 Suppl 1):S31-S36.

(18.) Johns MW. A new method for measuring daytime sleepiness: The Epworth Sleepiness Scale. Sleep 1991;14:540-545.

(19.) Mahowald MW. What is causing excessive daytime sleepiness? Evaluation to distinguish sleep deprivation from sleep disorders. Postgrad Med 2000;107:108-110, 115-118, 123.

(20.) Guilleminault C, Kim YD, Palombini L, Li K, Powell N. Upper airway resistance syndrome and its treatment. Sleep 2000;23(Suppl 4):S197-S200.

(21.) Allen RP, Earley CJ. Restless legs syndrome: A review of clinical and pathophysiologic features. J Clin Neurophysiol 2001;8:128-147.

(22.) Littner M, Johnson SF, McCall WV, Anderson WM, Davila D, Hartse SK, et al; Standards of Practice Committee. Practice parameters for the treatment of narcolepsy: An update for 2000. Sleep 2001;24:451-466.

(23.) Hublin C. Narcolepsy: Current ding treatment options. CNS Drugs 1996;6:426-436.

(24.) Rogers AE, Aldrich MS, Lin X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep 2001;24:385-391.

(25.) Broughton RJ, Fleming JA, George CF, Hill JD, Kiyger MH, Moldofsky H, et al. Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of excessive daytime sleepiness in narcolepsy. Neurology 1997;49:444-451.

(26.) Fry JM. Treatment modalities for narcolepsy. Neurology 1998;50(2 Suppl l):S43-S48.

(27.) Scrima L, Hartman. PG, Johnson FH Jr, Thomas EE, Hiller FC. The effects of [gamma]-hydroxybutyrate on the sleep of narcolepsy patients: A double-blind study. Sleep 1990;13:479-490.

(28.) Lammers GJ, Arends J, Declcrck AC, Ferrari MD, Schouwink G, Troost J. [gamma]-hydroxybutyrate and narcolepsy: A double-blind placebo-controlled study. Sleep 1993;16:216-220.

(29.) US Xyrem Multicenter Study Group. A randomized, double blind, placebo-controlled multicenter trial comparing the effects of three doses of orally administered sodium oxybate with placebo for the treatment of narcolepsy. Sleep 2002;25:42-49.

RELATED ARTICLE: Key Points

* Narcolepsy is a deficiency of the neurotransmitter hypocretin.

* The Epworth Sleepiness Scale provides a subjective assessment of the severity of excessive daytime sleepiness.

* Modafinil and sodium oxybate are important new drugs for the treatment of narcolepsy/cataplexy.

From the St. Petersburg Sleep Disorders Center, St. Petersburg, FL.

Reprint requests to Neil T. Feldman, MD, St. Petersburg Sleep Disorders Center, 2525 Pasadena Avenue S., Suite P, St. Petersburg, FL 33707. Email: [e-mail]

Copyright [C] 2003 by The Southern Medical Association

0038-4348/03/9603-0277