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Narcolepsy

Definition:
Narcolepsy is a chronic neurological disorder caused by the brain’s inability to regulate sleep-wake cycles normally. At various times throughout the day, people with narcolepsy experience fleeting urges to sleep. If the urge becomes overwhelming, patients fall asleep for periods lasting from a few seconds to several minutes. In rare cases, some people may remain asleep for an hour or longer.

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Narcoleptic sleep episodes can occur at any time, and thus frequently prove profoundly disabling. People may involuntarily fall asleep while at work or at school, when having a conversation, playing a game, eating a meal, or, most dangerously, when driving an automobile or operating other types of potentially hazardous machinery. In addition to daytime sleepiness, three other major symptoms frequently characterize narcolepsy: cataplexy, or the sudden loss of voluntary muscle tone; vivid hallucinations during sleep onset or upon awakening; and brief episodes of total paralysis at the beginning or end of sleep.

Contrary to common beliefs, people with narcolepsy do not spend a substantially greater proportion of their time asleep during a 24-hour period than do normal sleepers. In addition to daytime drowsiness and involuntary sleep episodes, most patients also experience frequent awakenings during nighttime sleep. For these reasons, narcolepsy is considered to be a disorder of the normal boundaries between the sleeping and waking states.

For most adults, a normal night’s sleep lasts about 8 hours and is composed of four to six separate sleep cycles. A sleep cycle is defined by a segment of non-rapid eye movement (NREM) sleep followed by a period of rapid eye movement (REM) sleep. The NREM segment can be further divided into stages according to the size and frequency of brain waves. REM sleep, in contrast, is accompanied by bursts of rapid eye movement (hence the acronym REM sleep) along with sharply heightened brain activity and temporary paralysis of the muscles that control posture and body movement. When subjects are awakened from sleep, they report that they were “having a dream” more often if they had been in REM sleep than if they had been in NREM sleep. Transitions from NREM to REM sleep are governed by interactions among groups of neurons (nerve cells) in certain parts of the brain.

Scientists now believe that narcolepsy results from disease processes affecting brain mechanisms that regulate REM sleep. For normal sleepers a typical sleep cycle is about 100 – 110 minutes long, beginning with NREM sleep and transitioning to REM sleep after 80 – 100 minutes. But, people with narcolepsy frequently enter REM sleep within a few minutes of falling asleep.

Who Gets Narcolepsy?
Narcolepsy is not rare, but it is an underrecognized and underdiagnosed condition. The disorder is estimated to affect about one in every 2,000 Americans. But the exact prevalence rate remains uncerntain, and the disorder may affect a larger segment of the population.

Narcolepsy appears throughout the world in every racial and ethnic group, affecting males and females equally. But prevalence rates vary among populations. Compared to the U.S. population, for example, the prevalence rate is substantially lower in Israel (about one per 500,000) and considerably higher in Japan (about one per 600).

Most cases of narcolepsy are sporadic-that is, the disorder occurs independently in individuals without strong evidence of being inherited. But familial clusters are known to occur. Up to 10 percent of patients diagnosed with narcolepsy with cataplexy report having a close relative with the same symptoms. Genetic factors alone are not sufficient to cause narcolepsy. Other factors-such as infection, immune-system dysfunction, trauma, hormonal changes, stress-may also be present before the disease develops. Thus, while close relatives of people with narcolepsy have a statistically higher risk of developing the disorder than do members of the general population, that risk remains low in comparison to diseases that are purely genetic in origin.

* Obstructive sleep apnea is a temporary cessation of breathing that occurs repeatedly during sleep and is caused by a narrowing of the airway. Restless legs syndrome is a neurological disorder characterized by unpleasant sensations-burning, creeping, tugging-in the legs and an uncontrollable urge to move when at rest


Symptoms:

The main characteristic of narcolepsy is excessive daytime sleepiness (EDS), even after adequate night time sleep. A person with narcolepsy is likely to become drowsy or to fall asleep, often at inappropriate times and places. Daytime naps may occur without warning and may be physically irresistible. These naps can occur several times a day. They are typically refreshing, but only for a few hours. Drowsiness may persist for prolonged periods of time. In addition, night time sleep may be fragmented with frequent awakenings.

Four other “classic” symptoms of narcolepsy, which may not occur in all patients, are cataplexy, sleep paralysis, hypnogogic hallucinations, and automatic behavior. Cataplexy is an episodic condition featuring loss of muscle function, ranging from slight weakness (such as limpness at the neck or knees, sagging facial muscles, or inability to speak clearly) to complete body collapse. Episodes may be triggered by sudden emotional reactions such as laughter, anger, surprise, or fear, and may last from a few seconds to several minutes. The person remains conscious throughout the episode. Sleep paralysis is the temporary inability to talk or move when waking (or less often, falling asleep). It may last a few seconds to minutes. This is often frightening but is not dangerous. Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing, falling asleep and/or while awakening. Automatic behavior means that a person continues to function (talking, putting things away, etc.) during sleep episodes, but awakens with no memory of performing such activities. It is estimated that up to 40 percent of people with narcolepsy experience automatic behavior during sleep episodes. , sleep paralysis, and hypnagogic hallucinations also occur in people who do not have narcolepsy, more frequently in people who are suffering from extreme lack of sleep. Cataplexy is generally considered to be unique to narcolepsy and is analogous to sleep paralysis in that the usually protective paralysis mechanism occurring during sleep is inappropriately activated. The opposite of this situation (failure to activate this protective paralysis) occurs in rapid eye movement behavior disorder.

In most cases, the first symptom of narcolepsy to appear is excessive and overwhelming daytime sleepiness. The other symptoms may begin alone or in combination months or years after the onset of the daytime naps. There are wide variations in the development, severity, and order of appearance of cataplexy, sleep paralysis, and hypnagogic hallucinations in individuals. Only about 20 to 25 percent of people with narcolepsy experience all four symptoms. The excessive daytime sleepiness generally persists throughout life, but sleep paralysis and hypnagogic hallucinations may not.

Although these are the common symptoms of narcolepsy, many (although less than 40% of people with narcolepsy)[citation needed] also suffer from insomnia for extended periods of time.

The symptoms of narcolepsy, especially the excessive daytime sleepiness and cataplexy, often become severe enough to cause serious problems in a person’s social, personal, and professional life.

Normally, when an individual is awake, brain waves show a regular rhythm. When a person first falls asleep, the brain waves become slower and less regular. This sleep state is called non-rapid eye movement (NREM) sleep. After about an hour and a half of NREM sleep, the brain waves begin to show a more active pattern again. This sleep state, called REM sleep (rapid eye movement sleep), is when most remembered dreaming occurs. Associated with the EEG-observed waves during REM sleep, muscle atonia is present (called REM atonia).

In narcolepsy, the order and length of NREM and REM sleep periods are disturbed, with REM sleep occurring at sleep onset instead of after a period of NREM sleep. Thus, narcolepsy is a disorder in which REM sleep appears at an abnormal time. Also, some of the aspects of REM sleep that normally occur only during sleep — lack of muscular control, sleep paralysis, and vivid dreams — occur at other times in people with narcolepsy. For example, the lack of muscular control can occur during wakefulness in a cataplexy episode; it is said that there is intrusion of REM atonia during wakefulness. Sleep paralysis and vivid dreams can occur while falling asleep or waking up. Simply put, the brain does not pass through the normal stages of dozing and deep sleep but goes directly into (and out of) rapid eye movement (REM) sleep. This has several consequences:

*Night time sleep does not include as much deep sleep, so the brain tries to “catch up” during the day, hence EDS.
*People with narcolepsy may visibly fall asleep at unpredicted moments (such motions as head bobbing are common).
*People with narcolepsy fall quickly into what appears to be very deep sleep.
*They wake up suddenly and can be disoriented when they do (dizziness is a common occurrence).
*They have very vivid dreams, which they often remember in great detail.
*People with narcolepsy may dream even when they only fall asleep for a few seconds.

Causes:
While the cause of narcolepsy has not yet been determined, scientists have discovered conditions that may increase an individual’s risk of having the disorder. Specifically, there appears to be a strong link between narcoleptic individuals and certain genetic conditions. One factor that may predispose an individual to narcolepsy involves an area of Chromosome 6 known as the HLA complex. There appears to be a correlation between narcoleptic individuals and certain variations in HLA genes, although it is not required for the condition to occur.

Certain variations in the HLA complex are thought to increase the risk of an auto-immune response to protein-producing neurons in the brain. The protein produced, called hypocretin or orexin, is responsible for controlling appetite and sleep patterns. Individuals with narcolepsy often have reduced numbers of these protein-producing neurons in their brains.

The neural control of normal sleep states and the relationship to narcolepsy are only partially understood. In humans, narcoleptic sleep is characterized by a tendency to go abruptly from a waking state to REM sleep with little or no intervening non-REM sleep. The changes in the motor and proprioceptive systems during REM sleep have been studied in both human and animal models. During normal REM sleep, spinal and brainstem alpha motor neuron depolarization produces almost complete atonia of skeletal muscles via an inhibitory descending reticulospinal pathway. Acetylcholine may be one of the neurotransmitters involved in this pathway. In narcolepsy, the reflex inhibition of the motor system seen in cataplexy is believed identical to that seen in normal REM sleep.

In 2004 researchers in Australia induced narcolepsy-like symptoms in mice by injecting them with antibodies from narcoleptic humans. The research has been published in the Lancet providing strong evidence suggesting that some cases of narcolepsy might be caused by autoimmune disease.

Narcolepsy is strongly associated with HLA DQB1*0602 genotype. There is also an association with HLA DR2 and HLA DQ1. This may represent linkage disequilibrium.

Despite the experimental evidence in human narcolepsy that there may be an inherited basis for at least some forms of narcolepsy, the mode of inheritance remains unknown.

Some cases are associated with genetic diseases such as Niemann-Pick disease or Prader-Willi syndrome.

Diagnosis:

Narcolepsy is not definitively diagnosed in most patients until 10 to 15 years after the first symptoms appear. This unusually long lag-time is due to several factors, including the disorder’s subtle onset and the variability of symptoms. As important, however, is the fact that the public is largely unfamiliar with the disorder, as are many health professionals. When symptoms initially develop, people often do not recognize that they are experiencing the onset of a distinct neurological disorder and thus fail to seek medical treatment.

A clinical examination and exhaustive medical history are essential for diagnosis and treatment. However, none of the major symptoms is exclusive to narcolepsy. EDS-the most common of all narcoleptic symptoms-can result from a wide range of medical conditions, including other sleep disorders such as sleep apnea, various viral or bacterial infections, mood disorders such as depression, and painful chronic illnesses such as congestive heart failure and rheumatoid arthritis that disrupt normal sleep patterns. Various medications can also lead to EDS, as can consumption of caffeine, alcohol, and nicotine. Finally, sleep deprivation has become one of the most common causes of EDS among Americans.

This lack of specificity greatly increases the difficulty of arriving at an accurate diagnosis based on a consideration of symptoms alone. Thus, a battery of specialized tests, which can be performed in a sleep disorders clinic, is usually required before a diagnosis can be established.

Two tests in particular are considered essential in confirming a diagnosis of narcolepsy: the polysomnogram (PSG) and the multiple sleep latency test (MSLT). The PSG is an overnight test that takes continuous multiple measurements while a patient is asleep to document abnormalities in the sleep cycle. It records heart and respiratory rates, electrical activity in the brain through electroencephalography (EEG), and nerve activity in muscles through electromyography (EMG). A PSG can help reveal whether REM sleep occurs at abnormal times in the sleep cycle and can eliminate the possibility that an individual’s symptoms result from another condition.

The MSLT is performed during the day to measure a person’s tendency to fall asleep and to determine whether isolated elements of REM sleep intrude at inappropriate times during the waking hours. As part of the test, an individual is asked to take four or five short naps usually scheduled 2 hours apart over the course of a day. As the name suggests, the sleep latency test measures the amount of time it takes for a person to fall asleep. Because sleep latency periods are normally 10 minutes or longer, a latency period of 5 minutes or less is considered suggestive of narcolepsy. The MSLT also measures heart and respiratory rates, records nerve activity in muscles, and pinpoints the occurrence of abnormally timed REM episodes through EEG recordings. If a person enters REM sleep either at the beginning or within a few minutes of sleep onset during at least two of the scheduled naps, this is also considered a positive indication of narcolepsy.

Treatment:
The drowsiness is normally treated using amphetamine-like stimulants such as methylphenidate, racemic amphetamine, dextroamphetamine, and methamphetamine, or modafinil, a new stimulant with a different pharmacologic mechanism. In Fall 2007 an alert for severe adverse reactions to modafinil was issued by the FDA .

Other medications used are codeine and selegiline. Another drug that is used is atomoxetine (Strattera), a non-stimulant and Norepinephrine reuptake inhibitor (NRI), that has little or no abuse potential. In many cases, planned regular short naps can reduce the need for pharmacological treatment of the EDS to a low or non-existent level. Cataplexy is frequently treated with tricyclic antidepressants such as clomipramine, imipramine, or protriptyline. Venlafaxine, a newer antidepressant which blocks the reuptake of serotonin and norepinephrine, has shown usefulness in managing symptoms of cataplexy. Gamma-hydroxybutyrate (GHB), a medication recently approved by the US Food and Drug Administration, is the only medication specifically indicated for cataplexy. Gamma-hydroxybutyrate has also been shown to reduce symptoms of EDS associated with narcolepsy. While the exact mechanism of action is unknown, GHB is thought to improve the quality of nocturnal sleep.

Treatment is tailored to the individual based on symptoms and therapeutic response. The time required to achieve optimal control of symptoms is highly variable, and may take several months or longer. Medication adjustments are also frequently necessary, and complete control of symptoms is seldom possible. While oral medications are the mainstay of formal narcolepsy treatment, lifestyle changes are also important. The main treatment of excessive daytime sleepiness in narcolepsy is with a group of drugs called central nervous system stimulants. For cataplexy and other REM-sleep symptoms, antidepressant medications and other drugs that suppress REM sleep are prescribed.

In addition to drug therapy, an important part of treatment is scheduling short naps (10 to 15 minutes) two to three times per day to help control excessive daytime sleepiness and help the person stay as alert as possible. Daytime naps are not a replacement for nighttime sleep.

Ongoing communication between the health care provider, patient, and the patient’s family members is important for optimal management of narcolepsy.

Finally, a recent study reported that transplantation of hypocretin neurons into the pontine reticular formation in rats is feasible, indicating the development of alternative therapeutic strategies in addition to pharmacological interventions.

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Coping with narcolepsy:
Learning as much about narcolepsy as possible and finding a support system can help patients and families deal with the practical and emotional effects of the disorder, possible occupational limitations, and situations that might cause injury. A variety of educational and other materials are available from sleep medicine or narcolepsy organizations.

Support groups exist to help persons with narcolepsy and their families.

To imagine what a person with narcolepsy copes with daily, keep in mind that while many are not sleep-deprived (in the classical sense), a major symptom of narcolepsy is akin to sleep deprivation in a normal person; as a normal person, imagine going years functioning off just 3-4 hours of sleep per night. While lifestyle changes and drug therapy can help largely mitigate many symptoms of narcolepsy, there currently exists no complete and permanent solution, therefore patience, empathy and self-education are excellent coping tools.

Individuals with narcolepsy, their families, friends, and potential employers should know that:

Narcolepsy is a life-long condition that may require continuous medication.
Although there is no cure for narcolepsy at present, several medications can help reduce its symptoms.
People with narcolepsy can lead productive lives with proper medical care and lifestyle changes.
A major physiological and physical effect of narcolepsy is roughly akin to the effects of sleep deprivation; such effects can often be controlled and minimized through a combination of lifestyle changes and drug therapy.
Individuals with narcolepsy should avoid jobs that require driving long distances or handling hazardous equipment or that require alertness for lengthy periods (especially where the consequences of falling asleep are dangerous to themselves or others).
Parents, teachers, spouses, and employers should be aware of the symptoms of narcolepsy. This will help them avoid the mistake of confusing the person’s behavior with laziness, hostility, rejection, or lack of interest and motivation. It will also help them provide essential support and cooperation.
Employers can promote better working opportunities for individuals with narcolepsy by permitting special work schedules and nap breaks.
Doctors generally agree that lifestyle changes can be very helpful to those suffering with narcolepsy. Suggested self-care tips, from the National Sleep Foundation, University at Buffalo, and Mayo Clinic, include:

Take several short daily naps (10-15 minutes) to combat excessive sleepiness and sleep attacks.
Develop a routine sleep schedule – try to go to sleep and awaken at the same time every day.
Alert your employers, co-workers and friends in the hope that others will accommodate your condition and help when needed.
Do not drive or operate dangerous equipment if you are sleepy. Take a nap before driving if possible. Consider taking a break for a nap during a long driving trip.
Join a support group.
Break up larger tasks into small pieces and focusing on one small thing at a time.
Take several short walks during the day.
Carry a tape recorder, if possible, to record important conversations and meetings.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.

What Research is Being Done?
Within the Federal government, the National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health (NIH), has primary responsibility for sponsoring research on neurological disorders. As part of its mission, the NINDS supports research on narcolepsy and other sleep disorders with a neurological basis through grants to major medical institutions across the country.

Within the National Heart, Lung, and Blood Institute, also a component of the NIH, the National Center on Sleep Disorders Research (NCSDR) coordinates Federal government sleep research activities and shares information with private and nonprofit groups. NCSDR staff also promote doctoral and postdoctoral training programs, and educates the public and health care professional about sleep disorders. For more information, go to the NCSDR website at http://www.nhlbi.nih.gov/about/ncsdr/index.htm.

NINDS-sponsored researchers are conducting studies devoted to further clarifying the wide range of genetic factors-both HLA genes and non-HLA genes-that may cause narcolepsy. Other scientists are conducting investigations using animal models to identify neurotransmitters other than the hypocretins that may contribute to disease development. A greater understanding of the complex genetic and biochemical bases of narcolepsy will eventually lead to the formulation of new therapies to control symptoms and may lead to a cure. Researchers are also investigating the modes of action of wake-promoting compounds to widen the range of available therapeutic options.

Scientists have long suspected that abnormal immunological processes may be an important element in the cause of narcolepsy, but until recently clear evidence supporting this suspicion has been lacking. NINDS-sponsored scientists have recently uncovered evidence demonstrating the presence of unusual, possibly pathological, forms of immunological activity in narcoleptic dogs. These researchers are now investigating whether drugs that suppress immunological processes may interrupt the development of narcolepsy in this animal model.

Recently there has been a growing awareness that narcolepsy can develop during childhood and may contribute to the development of behavior disorders. A group of NINDS-sponsored scientists is now conducting a large epidemiological study to determine the prevalence of narcolepsy in children aged 2 to 14 years who have been diagnosed with attention-deficit hyperactivity disorder.

Finally, the NINDS continues to support investigations into the basic biology of sleep, including the brain mechanisms involved in generating and regulating REM sleep. Scientists are now examining physiological processes occurring in a portion of the hindbrain called the amygdala in order to uncover novel biochemical processes underlying REM sleep. A more comprehensive understanding of the complex biology of sleep will undoubtedly further clarify the pathological processes that underlie narcolepsy and other sleep disorders.

How Can you Help Research?
The NINDS contributes to the support of the Human Brain and Spinal Fluid Resource Center in Los Angeles. This bank supplies investigators around the world with tissue from patients with neurological and other disorders. Tissue from individuals with narcolepsy is needed to enable scientists to study this disorder more intensely. Prospective donors may contact:

Human Brain and Spinal Fluid Resource Center
Neurology Research (127A)
W. Los Angeles Healthcare Center
11301 Wilshire Blvd. Bldg. 212
Los Angeles, CA 90073
310-268-3536
24-hour pager: 310-636-5199
Email: RMNbbank@ucla.edu
http://www.loni.ucla.edu/~nnrsb/NNRSB

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Where you can get more information?

For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute’s Brain Resources and Information Network (BRAIN) at:

BRAIN
P.O. Box 5801
Bethesda, MD 20824
(800) 352-9424
http://www.ninds.nih.gov

Information also is available from the following organizations:

Narcolepsy Network, Inc.
79 Main Street
North Kingstown, RI 02852
narnet@narcolepsynetwork.org

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Tel: 888-292-6522 401-667-2523
Fax: 401-633-6567

National Sleep Foundation
1522 K Street NW
Suite 500
Washington, DC 20005
nsf@sleepfoundation.org
http://www.sleepfoundation.org
Tel: 202-347-3472
Fax: 202-347-3472

National Heart, Lung, and Blood Institute (NHBLI)
National Institutes of Health, DHHS
31 Center Drive, Rm. 4A21 MSC 2480
Bethesda, MD 20892-2480
http://www.nhlbi.nih.gov
Tel: 301-592-8573/240-629-3255 (TTY) Recorded Info: 800-575-WELL (-9355)

Resources:
http://www.ninds.nih.gov/disorders/narcolepsy/detail_narcolepsy.htm#109043201
http://en.wikipedia.org/wiki/Narcolepsy

2 replies on “Narcolepsy”

Thanks for the information. A few weeks ago my son was diagnosed with narcolepsy. As a mother, I feel so overwhelmed and so helpless. I’m having a hard time soaking in all the information I probably need to have to try and help him. Your article gives some really good insight into this disease. So, thanks.

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