Information on the following diseases can be found in the Related Disorders section of this report:

• Familial Periodic Paralysis
• Sleep Apnea

The symptoms of narcolepsy generally begin between the ages of 10 to 20 years. The development and severity of symptoms vary greatly from case to case. The onset of narcolepsy symptoms initially occurs one at a time; appearance of new symptoms may be separated by years, and generally do not appear in any specific order. Narcolepsy usually begins in an adolescent whose initial symptoms are mild but become worse with age. Sometimes symptoms do not change for months or years, while at other times symptoms may change very quickly.

Excessive daytime sleepiness (ED) is usually the first symptom of narcolepsy. People with narcolepsy usually 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 throughout each day. 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.

Another symptom of narcolepsy is the sudden loss of voluntary muscle tone (cataplexy). This often occurs during times of intense emotions such as anger, elation, and/or surprise. Episodes of cataplexy may occur as short periods of partial muscle weakness. Occasionally, there may be an almost complete loss of muscle control that lasts for several minutes. This may result in sudden collapse. During a cataplectic attack, speech and movement become difficult or impossible although there is no loss of consciousness. People experiencing a cataplectic attack generally maintain partial awareness of their surroundings. Only some people with narcolepsy will also have cataplexy, and cataplexy is not necessary for a diagnosis of narcolepsy.

Hallucinations are frightening episodes that may occur during the beginning and/or end of a sleep period (hypnaogic hallucinations) in people with narcolepsy. Hallucinations may pertain to any or all of the senses (i.e., taste, touch, smell, hearing, and/or vision). These hallucinations may be so intense that it may be impossible for the person to distinguish reality from fantasy.

People with narcolepsy may experience "sleep paralysis." During sleep they may want to move but are unable to do so and as a result may experience panic. The occurrence of sleep paralysis typically coincides with falling asleep or waking up.

Only approximately 20 percent of people with narcolepsy experience all four symptoms mentioned above (i.e., excessive daytime sleepiness, cataplexy, hallucinations and sleep paralysis). Affected individuals may also experience fatigue, memory problems and disturbed sleep during the night (nocturnal sleep). Individuals may awaken during the night as a result of nightmares, the urge to urinate, and/or temporary, repeated interruptions of breathing (sleep apnea). At times there is no apparent reason for awakening, and frequently the awakenings are associated with a craving for food, especially something sweet. (For more information on sleep apnea, see the Related Disorders section of this report.)

The exact cause of narcolepsy is not known, but researchers believe that genetic, autoimmune, environmental and other factors all play a role in the development of the disorder.

Two separate studies published in September 2000 have linked narcolepsy to specific brain chemicals called hypocretins (also known as orexins), which play an important role in regulating sleep and appetite. The first study, from the University of California at Los Angeles, suggests that people who develop narcolepsy may have lost many of the nerve cells in the brain that contain hypocretins over the years. The second study, from Stanford University Medical Center, found a lack of hypocretins in the brains of narcoleptic individuals. Although both studies indicate that narcolepsy is linked to a lack of hypocretin-containing cells, additional research will be needed to determine what causes the loss of those cells. Some researchers believe the loss may be caused by an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses against "foreign" or invading organisms begin to attack healthy tissue for unknown reasons.

Narcolepsy is known to run in families and an association with the human leukocyte antigen (HLA-DR2) has been reported in some cases. HLAs are genetic markers that have been identified on human chromosome 6. Scientists suspect that inheritance of a gene makes a person susceptible to narcolepsy, but they do not know the pattern of inheritance and how the gene may be transferred from one generation to another.

In the August 6, 1999, issue of the journal Cell, researchers at Stanford University reported they have identified a gene that causes narcolepsy in dogs. They found that canine narcolepsy is caused by an autosomal recessive mutation in Hcrtr-2, the gene that encodes the receptor for the brain hormone (neuropeptide) hypocretin-2. These genes are on chromosome 12 in dogs, and scientists are trying to determine if they are located on the same chromosomes in humans.

In recessive disorders, the condition does not occur unless an individual inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

It has been shown that mice that do not manufacture enough hypocretins spontaneously fall asleep while exercising. The receptors for hypocretins are missing or diminished in the brains of narcoleptic dogs. Therefore, it was hypothesized following the study of canine narcolepsy that the cause of narcolepsy in humans may be the absence or low number of hypocretin receptors or abnormalities in the hypocretin in the brain.

Other studies have demonstrated that narcolepsy may be inherited as an autosomal dominant genetic trait. In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.

The exact number of people with narcolepsy in the United States is unknown. The American Narcolepsy Association has estimated that narcolepsy affects approximately 200,000 Americans but other estimates are lower. One estimate places the prevalence at .03%-.16% of the general population.

Approximately 5 percent of people with narcolepsy experience symptoms by the age of 10 years; 5 percent of people develop symptoms after the age of 20 years, and 18 percent of people with narcolepsy develop symptoms after the age of 30 years. Symptoms rarely begin after the age 40. Some researchers believe that narcolepsy is under-diagnosed in children. Narcolepsy tends to remain a lifelong condition. Slightly more males are affected by this disorder than females.

Symptoms of the following disorders can be similar to those of Narcolepsy. Comparisons may be useful for a differential diagnosis:

Symptoms resembling those of narcolepsy may occur after brain tumors (intracranial), head trauma, hardening of the arteries in the brain (cerebral arteriosclerosis), psychosis, and/or excessive amounts of protein in the blood due to kidney failure (uremia).

Episodes of sudden extreme muscle weakness (cataplexy) may also occur because of familial periodic paralysis. This disorder is characterized by periods of cataplexy that last for prolonged periods of time as compared with cataplexy associated with narcolepsy. Familial periodic paralysis is a result of an inborn error of potassium metabolism that causes abnormally high levels of this mineral in the blood.

Sleep apnea is a common sleep disorder characterized by temporary, recurrent interruptions of breathing during sleep. Symptoms of the disorder include wakefulness during the night, excessive sleepiness during the day, loud snoring, and/or obesity. In obstructive apnea, the most common form of sleep apnea, labored breathing is interrupted by airway tightening (constriction). The muscles of the diaphragm and chest build up sufficient pressure to force the airway open; partial awakening may then occur and the person may gasp for air. Sleep is resumed as breathing begins again. Untreated sleep apnea may be associated with high blood pressure, irregular heart beats, swelling in the arms and/or legs, hallucinations, anxiety, and/or irritability. (For more information on this disorder, choose "Apnea, Sleep" as your search term in the Rare Disease Database.)

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 that may document abnormalities in REM sleep regulation. (Sleep typically cycles through four progressively deeper stages of sleep as well as REM or "rapid eye movement" sleep. REM sleep is characterized by increased brain activity, a rapid breathing rate, rapid eye movements, dreaming, and involuntary muscle jerks. Evidence suggests that the hallucinations, sleep paralysis, and cataplexy associated with narcolepsy may be manifestations of abnormal REM sleep regulation.)

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 those who experience excessive sleepiness and sleep attacks, therapy may include administration of certain stimulants, such as methylphenidate (Ritalin), pemoline (Cylert), methamphetamine, or dextroamphetamine. Methylphenidate has often been considered the preferred therapy for sleep attacks and drowsiness in association with narcolepsy, and pemoline has been a frequent second choice. For those who have an inadequate response to such therapies, treatment may be provided with methamphetamine, dextroamphetamine, or other stimulants. 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.

On December 20, 2002, the FDA approved the use of Methylin (methylphenidate) in solution form for the treatment of narcolepsy in adults and for children over the age of 6 years.

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 manufactured by:

Orphan Medical
13911 Ridgedale Drive
Minnetonka, MN 55305

The orphan drug modafinil (Provigil), manufactured by Cephalon, Inc., was approved by the Food and Drug Administration (FDA) in 1998 for the treatment of excessive daytime sleepiness in individuals with narcolepsy. 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. For example, during a multicenter trial, researchers evaluated 271 affected individuals who received modafinil or an inactive substance (placebo) daily over nine weeks. They were then taken off therapy and evaluated for two weeks to assess potential withdrawal effects. Those who received modafinil therapy experienced no withdrawal symptoms when such therapy was discontinued and returned to former levels of daytime sleepiness.

On 29th of October, 2007 the FDA announced a warning about the potential for serious rashes and psychiatric symptoms were added to the prescribing information for the wakefulness-promoting agent Provigil (modafinil), by the FDA.

Although rare, serious rashes including Stevens-Johnson syndrome, toxic epidermal necrolysis, and rash with eosinophilia and systemic symptoms have been reported in children and adults on the drug. In addition, multiorgan hypersensitivity reactions have occurred.

Some patients also report experiencing anxiety, mania, hallucinations, and suicidality on the drug. Thus, "caution should be exercised when Provigil is given to patients with a history of psychosis, depression, or mania," the label states.

Finally, the label reminds providers that Provigil is not approved for use in children for any indication.



For those with cataplexy, sleep paralysis, and/or hypnagogic hallucinations, treatment may include administration of certain antidepressants, such as imipramine, desimipramine, protriptyline, and clomipramine. Close monitoring by a physician is necessary for those taking such medications and is also required if such therapy is withdrawn.

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. Affected individuals should consider speaking with their physicians concerning the establishment of appropriate sleep schedules. Those who also have sleep apnea may benefit from the use of a device called a Continuous Positive Airway Pressure (CPAP). This medical device enables individuals to breathe normally during sleep so they are not deprived of oxygen and may achieve a more normal sleep pattern.
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The National Sleep Foundation, in collaboration with the Narcolepsy Network, has established a confidential "National Narcolepsy Registry." The registry's goal is to develop a better understanding of narcolepsy and to improve treatments through the identification of the gene or genes responsible for the disorder. For more information, contact:

Narcolepsy Network, Inc.
P.O. Box 42460
Cincinnati, OH 45242
(513) 891-3522
e-mail: narnet@aol.com

or

National Sleep Foundation
Narcolepsy Coordinator Stephanie Capalbo
(202) 785-2300
(202) 785-2880 (fax)
e-mail: NATSLEEP@HAVEN.IOS.COM

The National Institute of Mental Health (NIMH) and National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health support research on sleep disorders, including narcolepsy. Information regarding studies they sponsor, as well as other narcolepsy research, is listed at www.clinicaltrials.gov. People who do not have Internet access may find contact:

National Institute of Neurological Disorders and Stroke (NINDS)
9000 Rockville Pike,
Bethesda, MD 20892
Phone: (800) 411-1222
TTY: (800) 411-1010
Email: prpl@mail.cc.nih.gov

An investigational drug for treating narcolepsy, CEP-10953, manufactured by Cephalon, is in stage III trials (2004) at a variety of U.S. locations. Cephalon is seeking volunteers of both genders between the ages of 18 through 65. For information, go to www.clinicaltrials.gov or contact:

Cephalon, Inc.
145 Brandywine Parkway
West Chester, PA. 19380
Phone: (610) 344-0200
Fax: (610) 738-6590
Website: www.cephalon.com

Scientists are studying human brain tissue from individuals with narcolepsy. Preliminary reports suggest that, in those with the disorder, the brain may have abnormally increased numbers of specialized chemical sites (receptors) on the surfaces of certain nerve cells (neurons) that are sensitive to stimulation by the neurotransmitter dopamine. Neurotransmitters are natural chemicals in the brain that regulate the transmission of messages between certain neurons. These dopamine receptors are located deep within the brain in the basal ganglia, which plays a role in regulating movements and emotions. This abnormality of dopamine receptors may be associated with the fact that emotional extremes can trigger attacks of cataplexy. More study of brain tissue is needed to confirm these findings.

Genetic studies are underway to locate the gene(s) that may be involved in the onset of narcolepsy. Researchers at Stanford University have identified in dogs that gene that causes narcolepsy.

For information about the National Narcolepsy Registry at Montefiore Medical Center in New York, contact:

Helen M. Temple, M.S.
National Narcolepsy Registry
Tel: (718) 920-4841
E-mail: HMTemple@aol.com

Various additional investigational medicines are being studied for the treatment of narcolepsy including fluvoxamine, zimeldine, gamma-hydroxybuterate, monamine oxidase inhibitors, and femoxitine. With the discovery of the role of hypocretin in narcolepsy, researchers are now studying hypocretin agonists and immunosuppressors for the treatment of narcolepsy. 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

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 161400; 12/3/99. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?161400.

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