Narcolepsy Clinical Trials, Diagnosis, and Treatment

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Narcolepsy

Narcolepsy is a neurological condition most characterized by Excessive Daytime Sleepiness (EDS). A narcoleptic will most likely experience disturbed nocturnal sleep, confused with insomnia, and disorder of REM or rapid eye movement sleep. It is a type of dyssomnia.

Current Research

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Symptoms

The main characteristic of narcolepsy is overwhelming 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 with or 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 up. It may last a few seconds to minutes. This is often frightening but is not dangerous. Hypnagogic hallucinations are vivid, often frightening, dream-like 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. Daytime sleepiness, 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.

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) also suffer from insomnia for extended periods of time. This is most often from

An excess of sleep.

Use of self-medications such as energy drinks, or caffeinated drinks.

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.

Effects

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 rapid eye movement (REM) sleep, is when most remembered dreaming occurs.

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. 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:

Nighttime sleep does not include much deep sleep, so the brain tries to "catch up" during the day, hence EDS

May visibly fall asleep at any moment (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

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.

Epidemiology

It is estimated that there are as many as 3 million people worldwide affected by narcolepsy. In the United States it is estimated that narcolepsy afflicts as many as 200,000 Americans[citation needed], but fewer than 50,000 are diagnosed. It is as widespread as Parkinson's disease or multiple sclerosis and more prevalent than cystic fibrosis, but it is less well known. Narcolepsy is often mistaken for depression, epilepsy, or the side effects of medications.

Narcolepsy can occur in both men and women at any age, although its symptoms are usually first noticed in teenagers or young adults. There is strong evidence that narcolepsy may run in families; 8 to 12 percent of people with narcolepsy have a close relative with this neurologic disorder.

Narcolepsy has its typical onset in adolescence and young adulthood. There is an average 15-year delay between onset and correct diagnosis which may contribute substantially to the disabling features of the disorder. Cognitive, educational, occupational, and psychosocial problems associated with the excessive daytime sleepiness of narcolepsy have been documented. For these to occur in the crucial teen years when education, development of self-image, and development of occupational choice are taking place is especially damaging. While cognitive impairment does occur, it may only be a reflection of the excessive daytime somnolence.

The prevalence of narcolepsy is about 1 per 2,000 persons. It is a reason for patient visits to sleep disorder centers, and with its onset in adolescence, it is also a major cause of learning difficulty and absenteeism from school. Normal teenagers often already experience excessive daytime sleepiness because of a maturational increase in physiological sleep tendency accentuated by multiple educational and social pressures; this may be disabling with the addition of narcolepsy symptoms in susceptible teenagers. In clinical practice, the differentiation between narcolepsy and other conditions characterized by excessive somnolence may be difficult. Treatment options are currently limited. There is a paucity in the literature of controlled double-blind studies of possible effective drugs or other forms of therapy. Mechanisms of action of some of the few available therapeutic agents have been explored but detailed studies of mechanisms of action are needed before new classes of therapeutic agents can be developed.

Narcolepsy is an underdiagnosed condition in the general population. This is partly because its severity varies from obvious down to barely noticeable. Some narcoleptics do not suffer from loss of muscle control. Others may only feel sleepy in the evenings.

Diagnosis

Diagnosis is relatively easy when all the symptoms of narcolepsy are present. But if the sleep attacks are isolated and cataplexy is mild or absent, diagnosis is more difficult.

Two tests that are commonly used in diagnosing narcolepsy are the polysomnogram and the multiple sleep latency test. These tests are usually performed by a sleep specialist. The polysomnogram involves continuous recording of sleep brain waves and a number of nerve and muscle functions during nighttime sleep. When tested, people with narcolepsy fall asleep rapidly, enter REM sleep early, and may awaken often during the night. The polysomnogram also helps to detect other possible sleep disorders that could cause daytime sleepiness.

For the multiple sleep latency test, a person is given a chance to sleep every 2 hours during normal wake times. Observations are made of the time taken to reach various stages of sleep. This test measures the degree of daytime sleepiness and also detects how soon REM sleep begins. Again, people with narcolepsy fall asleep rapidly and enter REM sleep early.

Treatment

Several treatments are available for narcolepsy. These treat the symptoms, not the underlying cause. The drowsiness is normally treated using stimulants such as methylphenidate, amphetamines, dextroamphetamine, methamphetamine, modafinil, etc. Other medications used are codeine and selegiline. Another drug that is used is atomoxetine (Strattera), a non-stimulant and Norepinephrine uptake inhibhitor (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 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 to optimal management of narcolepsy.

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.

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 if they are provided with proper medical care.
If possible, individuals with narcolepsy should avoid jobs that require driving long distances or handling hazardous equipment or that require alertness for lengthy periods.
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, coworkers 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.

Narcolepsy In Popular Culture

Narcolepsy has been used by some as a form of humor. Depictions of the disorder can range greatly in accuracy.

The band Third Eye Blind wrote a song called Narcolepsy, describing the narcoleptic narrator's uncontrollable nightmares and sleep paralysis.
In the episode "Best Man for the GOB" of Arrested Development, George Sr. hires a narcoleptic stripper in order to convince his accountant Ira Gilligan that he has killed the stripper in order to get him to leave town.
The lead character in Gus Van Sant's moving hustler drama My Own Private Idaho, played by River Phoenix, experiences narcolepsy frequently. A dictionary definition of the condition is presented in the opening sequence. The acceptance and support he receives through these episodes by Keanu Reeves' character illustrates their humanity and counterpoints their dehumanizing work.
In the movie Rat Race, one of the main characters (Enrico Pollini, played by Rowan Atkinson) has narcolepsy as well as being very eccentric.
In the movie Moulin Rouge!, the Argentinian has narcolepsy, and it is because of this that Ewan McGregor's character becomes involved in the overall plot.
In the movie Deuce Bigalow: Male Gigolo, a woman with narcolepsy was shown as the cause of several slap-stick accidents.
In the animated sitcom The Simpsons, Abe often falls asleep randomly, usually whilst conversing with others.
In the movie Death Race 2000, the navigator Joe Seasly was later diagnosed with narcolepsy at age 29
In the Korean Drama 'Loveholic', Yul-ju, a main character, has narcolepsy.
Singer and pianist Ben Folds wrote a song called Narcolepsy describing the singer's tendency to fall asleep emotionally.
In the anime movie The Place Promised In Our Early Days, the female lead develops narcolepsy and eventually sleeps for a few years at a time, having dreams of a parallel world.
In the anime and manga One Piece, Portgas D. Ace and Monkey D. Garp are both narcoleptic, falling asleep during meals or fights.
In the medical sitcom Scrubs, a narcoleptic patient's episodes are brought on by sexual arousal.
In the movie Kontroll, one of the inspectors has a severe case of narcolepsy. The other inspectors play tricks on him while he's asleep.
The band Placebo wrote a song called "Narcoleptic", on their album Black Market Music.
Narcoleptic pornographic film actor Ron Jeremy is shown falling asleep while driving in an outtake on the Porn Star: The Legend of Ron Jeremy DVD.
In the video game Destroy All Humans!, the scientist Sleepy Ernst suffers from narcolepsy, constantly sleeping under a tree, which leaves him open to be killed by Crypto.
The West Chester punk outfit Plow United's third and final full length album was entitled Narcolepsy
A recurring guest character on The Sopranos was Aaron Arkaway, a devout fundamentalist Christian who suffered from narcolepsy. He was dating Janice Soprano, who explained to her bemused family (when Aaron fell asleep at the dinner table) that "narcolepsy is an AMA-recognized dyssomnia."
In the film Patch Adams, Robin Williams, portraying Patch Adams himself, is seen with a puppet speaking to a group, saying something like this: "Good day, everyone, my name is Patty O'Lantern, and I am here today to speak about narcolepsy. Now, narcolepsy..." *makes snoring sound, flops puppet.*
It is thought that St. John may have had narcolepsy, as he is seen in a sleep like pose in "The Last Supper", or it is possible that he ingested his namesake, "St. John's Wort", a plant which is known to cause drowsiness and dozing episodes.
In the American sitcom "Frasier", Frasier Crane's brother Niles develops narcolepsy brought about by the stress of speaking to his ex-wife Marris' lawyers.
In Shrek the Third, Sleeping Beauty is a narcoleptic, hence her name. She is often found dozing off or waking with a start.
In Sharkboy and Lavagirl, the main character, Max, appears to have narcolepsy... so may his classmates, Linus and Marissa. Max tends to dream immediately after falling asleep. He becomes a day dreamer later, seemingly overcoming it.
The name of Australian band The Sleepy Jackson was inspired by a former drummer who was narcoleptic

(adapted from Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Narcolepsy)

Findings From Current Research

A Double-Blind, Placebo-Controlled Study Demonstrates Sodium Oxybate is Effective for the Treatment of Excessive Daytime Sleepiness in Narcolepsy

Xyrem International Study Group.

STUDY OBJECTIVE: Assess the efficacy of sodium oxybate for the treatment of narcolepsy with an emphasis on excessive daytime sleepiness. DESIGN: Eight-week, multicenter, double-blind, placebo-controlled trial. SETTING: Forty-two sleep clinics in the United States, Canada, and Europe. PARTICIPANTS: Two hundred twenty-eight adults with narcolepsy with cataplexy. INTERVENTIONS: Patients were withdrawn from antidepressant treatment and then randomly assigned to receive 4.5 g, 6 g, or 9 g of sodium oxybate nightly or placebo for 8 weeks. Six-gram and 9-g doses were titrated in weekly 1.5-g increments. Patients who were receiving placebo underwent a mock dose-titration schedule. Stimulant use continued unchanged. Excessive daytime sleepiness was measured using the Epworth Sleepiness Scale and Maintenance of Wakefulness Test. The Clinical Global Impression of Change was used to measure changes in disease severity. Changes in narcolepsy symptoms and adverse events were recorded in daily diaries. RESULTS: After 8 weeks, patients treated with 9 g of sodium oxybate nightly displayed a significant median increase of > 10 minutes in the Maintenance of Wakefulness Test (p < .001). Patients displayed dose-related decreases in median Epworth Sleepiness Scale scores and frequency of weekly inadvertent naps, which were significant at the 6-g and 9-g doses (for each, p < .001). The improvements in excessive daytime sleepiness were incremental to those achieved by concomitant stimulants alone. Significant improvements in the Clinical Global Impression of Change were noted for each group treated with sodium oxybate (p < or = .001). Adverse events were consistent with the known safety profile of sodium oxybate. CONCLUSIONS: When combined with its previously demonstrated anticataplectic effects, the results of the current study indicate sodium oxybate is the first drug to demonstrate efficacy for the 2 major symptoms of narcolepsy.

Journal: J Clin Sleep Med. 2005 Oct 15;1(4):391-7.
Adapted from PubMed; click here to access full journal article.

Cataplexy Emotional Trigger Questionnaire (CETQ)--A Brief Patient Screen to Identify Cataplexy in Patients with Narcolepsy

Authors: Moore WR, Silber MH, Decker PA, Heim-Penokie PC, Sikkink VK, Slocumb N, Richardson JW, Krahn LE.

Sleep Disorders Center, Department of Nursing, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. moore.wendy@mayo.edu

STUDY OBJECTIVES: This pilot study explored the sensitivity and specificity of a brief survey to determine the presence of cataplexy. We hypothesized that the brief questionnaire could provide a quick, sensitive, and specific screening tool to identify those patients with cataplexy, which would result in more timely referrals for further diagnostic testing. DESIGN: The pilot study utilized a brief questionnaire that was developed by including 5 questions that were found to be strong positive predictors of cataplexy from a previous 51-item cataplexy questionnaire. SETTING: Participants with a laboratory-confirmed diagnosis completed the questionnaire via mail correspondence or at the time of scheduled appointments in the Mayo Clinic Sleep Disorder Center, Rochester, Minn. PARTICIPANTS: Seventy-eight patients with narcolepsy and cataplexy and 78 patients with obstructive sleep apnea completed the questionnaire. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: The sensitivity, specificity, area under the curve, positive predictive value, and negative predictive value/were computed for each question individually, along with appropriate 95% confidence intervals. CONCLUSIONS: The first item of the cataplexy emotional trigger questionnaire (CETQ) discriminates patients with cataplexy from controls with excellent sensitivity and specificity. The addition of the other 4 questions, in the context of question 1, did not improve specificity, area under the curve, positive predictive value, or negative predictive value but did provide useful confirmatory data. Thus, a single question provides a brief practical tool that could improve the recognition of cataplexy in the clinical setting. Depending on the circumstance, users may be interested in utilizing 1 or all 5 questions.

Journal: J Clin Sleep Med. 2007 Feb 15;3(1):37-40.
Adapted from PubMed; click here to access full journal article.

The Epidemiology of Narcolepsy

Authors: Longstreth WT Jr, Koepsell TD, Ton TG, Hendrickson AF, van Belle G.

Neuroepidemiology Research Group, University of Washington, Seattle, WA, USA. wl@u.washington.edu

Much has been learned about the pathophysiology of narcolepsy over the last several decades. It is likely that hypocretin-producing cells in the lateral hypothalamus are selectively destroyed in genetically susceptible individuals carrying 1 or more alleles of HLA DQB1*0602. Despite advances, the causes of narcolepsy and how to prevent it remain elusive. Classic epidemiology aims not only to enumerate occurrence of disease in populations, but also to identify etiologic risk factors. This review details what the application of classic epidemiology has taught us so far about narcolepsy and suggests directions for future studies to clarify its etiology. The prevalence of narcolepsy with cataplexy has been examined in many studies and falls between 25 and 50 per 100,000 people. Information on incidence is limited, with 1 study finding the incidence of narcolepsy with cataplexy to be 0.74 per 100,000 person-years. The search for etiologic risk factors has yet to yield important associations. Factors most thoroughly examined include body mass index, immune responses, and stressful life events. Such associations may reflect a consequence rather than a cause of disease. As with other diseases characterized by selective cell loss, such as Parkinson's disease or type 1 diabetes mellitus, narcolepsy is likely caused by environmental exposures before the age of onset in genetically susceptible individuals. Matching efforts in these other diseases and using large well-designed epidemiologic studies of narcolepsy, investigators must intensify the search for these exposures, focusing on the first 2 decades of life. Identification of modifiable risk factors will help to prevent this disease.

Journal: Sleep. 2007 Jan 1;30(1):13-26.
Adapted from PubMed; click here to access full journal article.

The Psychosocial Problems of Children with Narcolepsy and Those with Excessive Daytime Sleepiness of Uncertain Origin

Authors: Stores G, Montgomery P, Wiggs L.

Department of Psychiatry, University of Oxford, Oxford, United Kingdom. gregory.stores@psych.ox.ac.uk

BACKGROUND: Narcolepsy is a predominantly rapid eye movement sleep disorder with onset usually in the second decade but often in earlier childhood. Classically it is characterized by combinations of excessive sleepiness especially sleep attacks, cataplexy, hypnagogic hallucinations, and sleep paralysis. The psychosocial effects of this lifelong condition are not well documented, especially in children. This study aims to describe the psychosocial profile of a large group of children with narcolepsy compared with other excessively sleepy children and controls. METHODS: We used an international cross-sectional questionnaire survey of children aged from 4 to 18 years who had received from a physician a diagnosis of narcolepsy compared with age- and gender-matched controls. Assessments were made of behavior, mood, quality of life, and educational aspects. RESULTS: Recruited children were separated into those who met conventional criteria for narcolepsy (n = 42) and those whose primary complaint was excessive daytime sleepiness without definite additional features of narcolepsy (excessive daytime sleepiness group; n = 18). Compared with controls, children with narcolepsy and also those with excessive daytime sleepiness alone showed significantly higher rates of behavioral problems and depression. Again, to a significant extent, their quality of life was poorer and they had more educational problems. The children with narcolepsy and the excessive daytime sleepiness group were indistinguishable from each other on these measures. CONCLUSIONS: A range of psychosocial problems can be identified in children with narcolepsy. The origins of these problems are unclear. The similar profiles of difficulties in the narcolepsy and excessive daytime sleepiness groups suggest that excessive sleepiness is the main cause. Clinicians and others responsible for the care of such children need to be mindful of the importance of early detection, intervention, and, ideally, the prevention of these problems.

Journal: Pediatrics. 2006 Oct;118(4):e1116-23.
Adapted from PubMed; click here to access full journal article.

Narcolepsy and the Hypocretin System--Where Motion Meets Emotion

Authors: Siegel JM, Boehmer LN.

Brain Research Institute, University of California, Los Angeles (UCLA), and VA Greater Los Angeles Healthcare System, CA, USA. jsiegel@ucla.edu

Narcolepsy is a neurological disorder that is characterized by excessive daytime sleepiness and cataplexy--a loss of muscle tone generally triggered by certain strong emotions with sudden onset. The underlying cause of most cases of human narcolepsy is a loss of neurons that produce hypocretin (Hcrt, also known as orexin). These cells normally serve to drive and synchronize the activity of monoaminergic and cholinergic cells. Sleepiness results from the reduced activity of monoaminergic, cholinergic and other cells that are normally activated by Hcrt neurons, as well as from the loss of Hcrt itself. Cataplexy is caused by an episodic loss of activity in noradrenergic cells that support muscle tone, and a linked activation of a medial medullary cell population that suppresses muscle tone. Current treatments for narcolepsy include stimulants to combat sleepiness and antidepressants to reduce cataplexy. Sodium oxybate produces both reductions in cataplexy and improved waking alertness. Future treatments are likely to include Hcrt or Hcrt agonists to reverse the underlying neurochemical deficit.

Journal: Nat Clin Pract Neurol. 2006 Oct;2(10):548-56.
Adapted from PubMed; click here to access full journal article.

Narcolepsy and the Hypocretins

Authors: Wurtman RJ.

Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. dick@mit.edu

Narcolepsy is a chronic neurologic disease characterized by excessive daytime sleepiness and one or more of three additional symptoms (cataplexy, or sudden loss of muscle tone; vivid hallucinations; and brief periods of total paralysis) related to the occurrence of rapid eye movement (REM) sleep at inappropriate times. The daytime sleepiness typically presents as a sudden overwhelming urge to sleep, followed by periods of sleep that last for seconds or minutes, or even longer. During daytime sleep episodes, patients may exhibit "automatic behavior," performing conventionalized functions (eg, taking notes), but not remembering having done so once they are awake. About 10% of narcoleptics are members of familial clusters; however, genetic factors alone are apparently insufficient to cause the disease, inasmuch as the most common genetic disorder, a mutation in chromosome 6 controlling the HLA antigen immune complex, although seen in 90% to 100% of patients, also occurs in as many as 50% of people without narcolepsy. A dog model of narcolepsy exhibits a mutation on chromosome 12 that disrupts the processing of the peptide neurotransmitter hypocretin. No such mutation characterizes human narcolepsy; however, cerebrospinal fluid (CSF) hypocretin levels are profoundly depressed in narcoleptic patients, and a specific reduction in hypocretin-containing neurons has been described. One hypothesis concerning the pathophysiology of narcolepsy proposes that the HLA subtype resulting from the mutation on chromosome 6 increases the susceptibility of hypocretin-containing brain neurons to immune attack. Because hypocretin may normally participate in the maintenance of wakefulness, the loss of neurons that release this peptide might allow REM sleep to occur at inappropriate times, ie, while the patient is awake, in contrast to its normal cyclic appearance after a period of slow-wave sleep. The cataplexy, hallucinations, and/or paralysis associated with REM episodes normally are unnoticed-or, at least, not remembered-when the transition to REM follows slow wave sleep, as is normally the case; however, they are remembered when, in people with narcolepsy, the REM episode starts during a period of wakefulness. The association of narcolepsy with a deficiency in a specific neurotransmitter, in this case, hypocretin, is reminiscent of the associations between Parkinson's disease and dopamine, or early Alzheimer Disease and acetylcholine.

Journal: Metabolism. 2006 Oct;55(10 Suppl 2):S36-9.
Adapted from PubMed; click here to access full journal article.

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