Featured CME Topic: Narcolepsy Narcolepsy

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 physicians 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. 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 patients 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. Experiments in well-established canine models of narcolepsy suggest an autosomal recessive pattern of inheritance. An incidence of narcolepsy among first-degree relatives of narcoleptic patients that is higher than the general population has been demonstrated (1–2% versus 0.02–0.18%), 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. 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. Similarly, genetically engineered mice that do not produce hypocretin peptide display symptoms of narcolepsy. These findings are supported by studies in narcoleptic patients. In 75% of narcoleptic patients, hypocretin is undetectable in cerebrospinal fluid. Likewise, postmortem examinaFrom 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: nfeld@msn.com Accepted November 20, 2002. Copyright © 2003 by The Southern Medical Association 0038-4348/03/9603-0277 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. Southern Medical Journal • Volume 96, Number 3, March 2003 277 tion revealed deficiencies in hypocretin-producing neurons in the brains of narcoleptics. 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.