Narcolepsy

Narcolepsy

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Narcolepsy is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Gelineau's syndrome
  • narcoleptic syndrome
  • paroxysmal sleep
  • hypnolepsy

Disorder Subdivisions

  • narcolepsy with cataplexy
  • narcolepsy without cataplexy

General Discussion

Narcolepsy is a neurological sleep disorder characterized by chronic, excessive attacks of drowsiness during the day, sometimes called excessive daytime sleepiness (EDS). Attacks of drowsiness may persist for only a few seconds or several minutes. These episodes vary in frequency from a few incidents to several during a single day. Nighttime (nocturnal) sleep patterns may also be disrupted. Three additional symptoms often associated with narcolepsy are sudden extreme muscle weakness (cataplexy), a specific type of hallucination that occurs just before falling asleep or upon awakening, and brief episodes of paralysis while waking up. Narcolepsy also may be associated with "automatic behavior", i.e. doing something automatically without any memory afterward. The incidence of narcolepsy is approximately 1 in 2,000 and most researchers believe that the disorder remains undiagnosed or misdiagnosed in many cases.



There is increasing evidence that narcolepsy is an autoimmune disorder. Autoimmune disorders are caused when the body's immune system mistakenly attacks healthy tissue or cells. In narcolepsy, the immune system destroys certain brain cells that produce a peptide called hypocretin. Hypocretin impacts on many brain functions, but the details of its actions are not yet understood. Why the immune system attacks healthy cells in narcolepsy is unknown and additional environmental and genetic factors may play a role in the development of the disorder.

Symptoms

The development and severity of symptoms associated with narcolepsy vary greatly from one person to another. The onset of symptoms initially occurs one at a time; appearance of new symptoms may be separated by years, with sleepiness generally preceding cataplexy. Narcolepsy usually begins in an adolescent whose initial symptoms are mild but worsen with age. Sometimes symptoms do not change for months, while at other times symptoms may change very quickly. Depending upon the severity of the disorder, narcolepsy can dramatically affect a person's daily routine, disrupting all aspects of a person's life.



Excessive daytime sleepiness (EDS) is usually the first symptom of narcolepsy. People with narcolepsy typically experience periods of drowsiness, tiredness, lack of energy, an irresistible urge to sleep ("sleep attack"), and/or an inability to resist sleep. This susceptibility to unending drowsiness and/or falling asleep may occur every day but the severity varies from day to day and throughout each day. These episodes are more likely to occur during monotonous, boring activities such as watching television. However, the episodes can occur at any time even when a person is walking, talking, eating or driving a car. Consequently, narcolepsy can profoundly disrupt a person's life. Affected individuals may fall asleep for brief periods ranging from a few seconds to several minutes. A characteristic finding of narcolepsy is that affected individuals often feel dramatically more awake and alert following short naps.



Narcolepsy can also disrupt nighttime sleeping patterns. Affected individuals may frequently awaken during the night and may be wide awake for significant periods during the night. Despite disrupted sleep patterns, the total sleep time for people with narcolepsy in every 24 hour period is generally normal because they sleep repeatedly for short periods during the day and night.



Many individuals with narcolepsy experience weakness and the sudden loss of voluntary muscle tone (cataplexy). This often occurs during times of intense emotions such as laughter, anger, elation, and/or surprise. Episodes of cataplexy may occur as short periods of partial muscle weakness and can vary in duration and severity. In some cases, a cataplectic attack may be barely noticeable. Affected individuals may experience very brief, mild episodes that may cause the knees to buckle, the jaws to sage, the eyelids to droop or the head to drop. Occasionally in severe cases, there may be an almost complete loss of muscle control that lasts for several minutes. During a severe cataplectic attack, speech and movement may become difficult or impossible although there is no loss of consciousness. Cataplexy may improve as affected individuals grow older.



Some people with narcolepsy do not have cataplexy, and cataplexy is not necessary for a diagnosis of narcolepsy. Cataplexy usually develops approximately several weeks to months after the development of excessive daytime sleepiness. In rare cases, cataplexy may precede the development of difficulties in maintaining alertness.



Some individuals with narcolepsy may experience hallucinations that may occur at the beginning or at the end of a sleep period. These are often vivid and frightening. Examples of hallucinations may include hearing a phone ring or a person walking nearby, seeing people or animals that aren't there, or having an out of body experience. When the hallucinations occur upon awakening, they are called hypnopompic hallucinations; when they occur when falling asleep, they are called hypnagogic hallucinations. Hallucinations often occur in conjunction with sleep paralysis.



People with narcolepsy may experience temporary "sleep paralysis". They may be briefly unable to move their limbs or heads or speak. Episodes of sleep paralysis are very short and typically coincide with falling asleep or waking up. Affected individuals regain all movements after these brief episodes.



Some affected individuals may also experience additional symptoms including fatigue, depression, difficulty concentrating, and memory problems. Periodic leg movements and sleep apnea have also been reported in individuals with narcolepsy.

Causes

Narcolepsy with cataplexy has been linked to low levels of a specific brain chemical called hypocretin (also known as orexin). This chemical plays an important role in regulating sleep and other functions. Hypocretin also functions as a neurotransmitter, a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another, enabling nerve cells to communicate. Researchers have determined that the number of neurons that produce hypocretin is significantly reduced in individuals with narcolepsy. Hypocretin-producing neurons are found in the hypothalamus, the area of the brain that regulates many functions including sleep, appetite and body temperature. In some individuals as many as 80-90 percent of hypocretin-producing neurons in the hypothalamus are lost. Individuals who have narcolepsy with cataplexy have the lowest levels of hypocretin.



In 2009, researchers discovered that individuals with narcolepsy have changes in a gene known as a T cell receptor gene. (T cells are specialized immune cells that play a role in all immune system responses). This variant T cell receptor gives individuals a genetic predisposition to developing narcolepsy. A genetic predisposition means that a person carries a gene or genes for a disease, but that it may not be expressed unless other additional factors are present. The genetic factors associated with narcolepsy are insufficient to cause the disorder by themselves.



Many cases of narcolepsy are strongly associated with a group of genes known as the human leukocyte antigen (HLA) complex located on human chromosome 6. These genes play a role in regulating the proper function of the immune system. Affected individuals often have variants of some of these genes. The exact role and significance of these HLAs in narcolepsy are not fully understood. Most disorders associated with the HLA complex have an immunological component to the disorder, either through autoimmunity or because of an improper immune system response to a foreign substance. Researchers believe that HLA and the variant T cell found in individuals with narcolepsy interact in a manner that causes the destruction of brain cells that produce hypocretin.



The exact cause of narcolepsy without cataplexy is unknown.

Affected Populations

The exact number of people with narcolepsy in the United States is unknown. One estimate places the prevalence at .03 percent to .16 percent of the general population in various ethnic groups worldwide. One U.S. study placed the incidence of new cases of narcolepsy at .74 per 100,000 person-years in the general population in the United States. The disorder has also been estimated to affect 1 in 2,000 people in the general population. However, because narcolepsy often goes unrecognized or misdiagnosed, determining its true frequency in the general population is difficult.



The onset of narcolepsy can occur anytime between early childhood and 50 years of age. Two peak time periods have been identified; one around 15 years of age and another around 36 years of age. Some researchers believe that narcolepsy is under-diagnosed in children. Narcolepsy tends to remain a lifelong condition. Although the nature and severity of symptoms experienced by an affected person may varying over time, the disorder is not progressive.



Narcolepsy was first described in the medical literature in 1880 by Gelineau and in 1887 by Westphal.

Standard Therapies

Diagnosis

Narcolepsy is diagnosed based upon a thorough clinical evaluation; a careful patient and family history; objective verification of characteristic symptoms (i.e., excessive daytime drowsiness, potentially in association with cataplexy, hypnagogic hallucinations, and/or sleep paralysis); and specialized sleep studies.



Two main tests used to diagnose narcolepsy are an overnight polysomnogram (PSG) followed by a multiple sleep latency test (MSLT). A PSG is a test done during sleep and continually measures a variety of things including brain wave changes, heart rate, eye movements, limb movements, muscle tone and respiration. A PSG is usually followed by a MSLT, which measures how quickly someone falls asleep for a nap every two hours during the day (4 or 5 nap opportunities). Individuals with narcolepsy fall asleep during the day more easily than people without narcolepsy. In addition, they will enter dreaming sleep (rapid eye movement sleep) even during a brief nap; something a healthy well-slept individual will not do.



Individuals with narcolepsy often have extremely low levels of hypocretin in their cerebrospinal fluid. Testing cerebrospinal fluid for hypocretin levels may be able to assist in a diagnosis of narcolepsy.



Treatment

The treatment of narcolepsy is directed toward the specific symptoms that are present in each individual. Various medications may help to alleviate certain symptoms associated with narcolepsy.



For individuals who experience excessive daytime sleepiness and sleep attacks, therapy may include administration of certain stimulants, such as modafinil (Provigil). Modafinil was approved by the Food and Drug and Administration (FDA) for the treatment of excessive daytime sleepiness in narcolepsy in 1999. Modafinil is now the most widely prescribed drug for excessive daytime sleepiness. The drug's mechanism of action appears to differ from that of other stimulants and does not appear to affect alertness or memory. In addition, evidence suggests that modafinil therapy is not associated with dependency or symptoms of withdrawal and therefore may be an effective alternative to other treatments for excessive daytime sleepiness. Modafinil is generally associated with fewer side effects than previous drugs used to treat this condition.



Previous drugs that have been used to treat excessive daytime sleepiness in narcolepsy include methylphenidate (Ritalin, Methylin), methamphetamine, or dextroamphetamine. These drugs stimulate the central nervous system and are still used when modafinil is unsuccessful. Because such medications may be associated with certain side effects, including nervousness, insomnia, or irritability, careful monitoring by physicians is required to ensure appropriate dosage adjustments and effectiveness of such therapy. In addition, close monitoring and long-term follow-up by physicians may be required if therapy is withdrawn.



Additional stimulants that have been used to treat excessive daytime sleepiness and narcolepsy include manzindol, selegiline, and pemoline.



A variety of drugs have been used to treat cataplexy. The orphan drug sodium oxybate (Xyrem) has been approved by the FDA to treat cataplexy, the sudden loss of muscular control and weakness that is associated with narcolepsy. Xyrem is also known as gamma hydroxybutyrate (GHB).



Xyrem has also been effective in improving nighttime sleep in individuals with narcolepsy. Some individuals with narcolepsy treated with high doses of the drug showed improved of daytime sleepiness. However, Xyrem is potentially associated with serious side effects. The drug is manufactured by:



Jazz Pharmaceuticals

3180 Porter Drive

Palo Alto, CA 94304



Individuals with cataplexy, sleep paralysis and/or hypnagogic hallucinations may be treated with certain antidepressants. Specifically, doctors often prescribe selective serotonin reuptake inhibitors, which suppress rapid eye movement sleep, to help alleviate these symptoms. These drugs include for example, fluoxetine (Prozac, Serafem, others), sertraline (Zoloft), atomoxetine (Strattera) and venlafaxine (Effexor). The most common side effects are decreased sexual desire and delayed orgasm. Other side effects can include digestive problems, restlessness, headache and insomnia. Older tricyclic antidepressants such as imipramine, desimipramine, protriptyline, and clomipramine may also be effective in reducing cataplexy, sleep paralysis and/or hallucinations, but many people are bothered by side effects, including dry mouth and constipation. Close monitoring by a physician is necessary for those taking antidepressant medications and is also required if such therapy is withdrawn.



In addition to drug therapy, many individuals have benefited from behavioral modification. Regular sleep habits are important for individuals with narcolepsy, including ensuring regular bedtime hours and preventing sleep interruptions. If possible, taking regular naps during the day may help to control excessive daytime sleepiness. Regular exercise is also recommended. Affected individuals should consider speaking with their physicians concerning the establishment of appropriate sleep schedules.

Investigational Therapies

The discovery that hypocretin plays a role in the development of narcolepsy has opened new avenues of research. Ongoing studies are investigating the implantation of cells that produce hypocretin (cell transplantation); implantation of a gene that promotes the expression of hypocretin (gene therapy); and the direct administration of hypocretin through the nose (intranasal), through the blood (intravenously) or through an opening (cistern) in the subarachnoid space of the brain (intracisternally).



At this time, many technical difficulties exist that must be resolved before gene therapy can succeed.



Researchers are also studying the role and implications of the immune system in the development of narcolepsy. Therapies that modify the response of the immune system including steroids, intravenous immunoglobulin and plasmapheresis have all been studied. So far, results from the study of these therapies have been inconsistent and inconclusive.



Various additional medications are being studied for the treatment of narcolepsy including fluvoxamine, zimelidine, monamine oxidase inhibitors, and femoxitine. More research is necessary to determine the long-term safety and effectiveness of these various potential treatment options for individuals with narcolepsy.



Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



Contact for additional information about narcolepsy:



David W. Carley, Ph.D.

Professor of Biobehavioral Health Sciences, Medicine and Bioengineering

Director, Center for Narcolepsy, Sleep and Health Research (CNSHR)



University of Illinois at Chicago

Suite 215, M/C 802

845 S. Damen Avenue

Chicago, IL 60612



Phone: (312)996-3827

Fax: (312)996-7008

http://www.uic.edu/nursing/CNSHR

References

TEXTBOOKS

Goswami M. Narcolepsy. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:561-2.



Fauci AS, et al., eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill Companies, Inc.; 1998:155.



Wyngaarden JB, et al., eds. Cecil Textbook of Medicine. 19th ed. Philadelphia, PA: W.B. Saunders Company; 1992:2065-2066.



Adams RD, et al., eds. Principles of Neurology. 4th ed. New York, NY: McGraw-Hill Companies, Inc.; 1989:314-317.



JOURNAL ARTICLES

Hallmayer J, Faraco J, Lin L, et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genet. 2009;41:708-711.



Billiard M. Narcolepsy: current treatment options and future approaches. Neuropsychiatr Dis Treat. 2008;4:557-566.



Alaez C, Lin L, Flore A-H, et al. Association of narcolepsy-cataplexy with HLA-DRB1 and DQB1 in Mexican patients: a relationship between HLA and gender is suggested. BMC Med Genet. 2008;9:79.



Black J, Duntley SP, Bogan RK, O'Malley MB. Recent advances in the treatment and management of excessive daytime sleepiness. CNS Spectr. 2007;12:1-14.



Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet. 2007;369:499-511.



Wise MS, Arand DL, Auger RR, Brooks SN, Watson NF. Treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007;30:1712-1727.



Nishino S. Clinical and neurobiological aspects of narcolepsy. Sleep Med. 2007;8:373-399.



Longstreth Jr. WT, Koepsell TD, Ton TG, Hendrickson AF, van Belle G. The epidemiology of narcolepsy. Sleep. 2007;30:13-26.



Dauvilliers Y, Carlander B, Billiard M. Narcolepsy, from Westphal to hypocretin. Presse Med. 2004;33:1593-600.



Dauvilliers Y, Carlander B, Rivier F, Touchon J, Tafti M. Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset. Ann Neurol. 2004;56:905-8.



Mignot E. Sleep, sleep disorders and hypocretin (orexin). Sleep Med. 2004;5:S2-8.



McKenna L, McNicholas F, Childhood onset narcolepsy. A case report. Eur Child Adolesc Psychiatry. 2003;12:43-7.



Hood Bm, Harbord MG, Paediatric narcolepsy: complexities of diagnosis. J Paediatr Child Health. 2002;38:618-21.



Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group. Neurology. 2000;54:1166-1175.



Lin L, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999;98:365-376. [See comment in Cell. 1999;98:409-412.]



INTERNET

Bozorg AM, Benbadis SR. Narcolepsy. Emedicine Journal. http://emedicine.medscape.com/article/1188433-overview. Updated: February 19, 2010. Accessed February 8, 2012.



National Institute of Neurological Disorders and Stoke. Narcolepsy Fact Sheet. http://www.ninds.nih.gov/disorders/narcolepsy/detail_narcolepsy.htm. Updated December 28, 2011. Accessed February 8, 2012.



Mayo Clinic for Medical Education and Research. Narcolepsy. http://www.mayoclinic.com/health/narcolepsy/DS00345. Updated August 2, 2011. Accessed February 8, 2012.

Resources

National Sleep Foundation

1010 N. Glebe Road

Suite 310

Arlington, VA 22201

Tel: (703)243-1697

Email: nsf@sleepfoundation.org

Internet: http://www.sleepfoundation.org



Narcolepsy Network, Inc.

129 Waterwheel Lane

North Kingstown, RI 02852

USA

Tel: (401)667-2523

Fax: (401)633-6567

Tel: (888)292-6522

Email: narnet@narcolepsynetwork.org

Internet: http://www.narcolepsynetwork.org



American Sleep Association

1610 14th Street NW

Suite 300

Rochester, MN 55901

Tel: (507)287-6006

Fax: (507)287-6008

Email: asda@millcomm.com

Internet: http://www.sleepassociation.org/



Tri-State Sleep Disorders Center

1275 E. Kemper Rd.

Cincinnati, OH 45246

Tel: (513)671-3101

Fax: (513)671-4159

Tel: (800)838-4322

TDD: (311)111-6111

Email: ggaz@tristatesleep.com

Internet: http://www.tristatesleep.com



Narcolepsy Institute

Montefiore Medical Center

111 East 210th Street

Bronx, NY 10467

Tel: (718)920-6799

Fax: (718)654-9580

Email: MGoswami@NarcolepsyInstitute.org

Internet: http://www.narcolepsyinstitute.org



NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



MedicAlert Foundation International

2323 Colorado Avenue

Turlock, CA 95382

USA

Tel: (209)669-2401

Fax: (209)669-2456

Tel: (888)633-4298

Email: Inquiries@medicalert.org

Internet: http://www.medicalert.org



Center for Narcolepsy, Sleep and Health Research

College of Nursing, Suite 215

University of Illinois at Chicago

845 South Damen Avenue (M/C 802)

Chicago, IL 60612

Tel: (312)996-5176

Fax: (312)996-7008

Email: CNSHR@listserv.uic.edu

Internet: http://www.uic.edu/orgs/cnshr/



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

This information does not replace the advice of a doctor. Healthwise, Incorporated disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use . How this information was developed to help you make better health decisions.

Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.