Narcolepsy

For patient information click here

Narcolepsy
ICD-10	G47.4
ICD-9	347
OMIM	161400
DiseasesDB	8801
MedlinePlus	000802
MeSH	D009290

Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Muhammad Waleed Haider, M.D.[2] Kiran Singh, M.D. [3]

Synonyms and keywords: Narcolepsy, Cataplexy, Hypocretin, Modafinil, Gamma hydroxybutyrate

Overview

Narcolepsy is a debilitating lifelong rapid eye movement (REM) sleep disorder that has a typical onset during adolescence or early adulthood and is characterized by a classic tetrad of Excessive Daytime Sleepiness (EDS), cataplexy (sudden symmetric loss of muscle tone during wakefulness that is evoked by strong emotions), sleep paralysis and hypnagogic hallucinations (hallucinations while falling asleep). Other features include frequent irresistible sleep attacks, fragmented night sleep, loss of concentration and memory, hypnopompic hallucinations (hallucinations during waking up) and blurry vision. Narcolepsy is of two types: narcolepsy type 1 (formerly narcolepsy with cataplexy) and narcolepsy type 2 (formerly narcolepsy without cataplexy). Narcolepsy can have severe consequences for the patient with impairments in academic, social and occupational performances. Problems may include social stigma associated with the disease, reduced quality of life, difficulty in obtaining an education and keeping a job and socioeconomic consequences. It can restrict patients from having certain careers and activities. Narcolepsy is often under-diagnosed and 5-10 years of delay is common before making a firm diagnosis.

Historical Perspective

The term narcolepsy derives from the French word narcolepsie created in 1880 by the French physician Jean-Baptiste-Édouard Gélineau (1859-1928) by combining the Greek narke numbness, stupor and lepsis attack, seizure. [Source: entry Narcolepsy. in the Online Etymology Dictionary. Douglas Harper, Historian. 18 Sep 2007. [4]

Pathophysiology

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.

Differential Diagnosis

• Attention-deficit/hyperactivity disorder or other behavioral problems
• Brain tumor
• Cerebrovascular insufficiency
• Chorea and movement disorders
• Conversion disorder (functional neurological symptom disorder)
• Encephalopathy
• Head trauma
• Hereditary
• Insufficient nocturnal sleep
• Major depressive disorder
• Hypersomnolence
• Schizophrenia
• Seizures
• Sleep apnea syndrome
• Sleep deprivation

Epidemiology and Demographics

It is estimated that as many as 3 million people worldwide are affected by narcolepsy. In the United States, it is estimated that this condition afflicts as many as 200,000 Americans, 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 20-40 per 100,000 (0.02%-0.04%) of the overall population.. 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 under diagnosed 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.

Risk Factors

• Genetic predisposition

• Monozygotic twins with narcolepsy
• First-degree relatives with narcolepsy

• Group A streptococcal throat infection
• Head trauma
• Influenza
• Job changes
• Stress

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.

DSM-V Diagnostic Criteria for Narcolepsy

“

A. Recurrent periods of an irrepressible need to sleep, lapsing into sleep, or napping occurring within the same day.These must have been occurring at least three times per week over the past 3 months. AND B. The presence of at least one of the following: 1. Episodes of cataplexy, defined as either (a) or (b), occurring at least a few times per month: a. In individuals with long-standing disease, brief (seconds to minutes) episodes of sudden bilateral loss of muscle tone with maintained consciousness that are precipitated by laughter or joking. b. In children or in individuals within 6 months of onset, spontaneous grimaces or jaw-opening episodes with tongue thrusting or a global hypotonia, without any obvious emotional triggers. 2. Hypocretin deficiency, as measured using cerebrospinal fluid (CSF) hypocretin-1 immuno reactivity values (less than or equal to one-third of values obtained in healthy subjects tested using the same assay, or less than or equal to 110 pg/mL). Low CSF levels of hypocretin-1 must not be observed in the context of acute brain injury, inflammation, or infection. 3. Nocturnal sleep polysomnography showing rapid eye movement (REM) sleep latency less than or equal to 15 minutes, or a multiple sleep latency test showing a mean sleep latency less than or equal to 8 minutes and two or more sleep-onset REM periods. Specify whether: Narcolepsy without cataplexy but with hypocretin deficiency: Criterion B requirements of low CSF hypocretin-1 levels and positive polysomnography/ multiple sleep latency test are met, but no cataplexy is present (Criterion B1 not met). Narcolepsy with cataplexy but without hypocretin deficiency: In this rare subtype (less than 5% of narcolepsy cases), Criterion B requirements of cataplexy and positive polysomnography/multiple sleep latency test are met, but CS hypocretin-1 levels are normal (Criterion B2 not met). Autosomal dominant cerebellar ataxia, deafness, and narcolepsy: This subtype is caused by exon 21 DNA (cytosine-5)-methyltransferase-1 mutations and is characterized by late-onset (age 30-40 years) narcolepsy (with low or intermediate CSF hypocretin-1 levels), deafness, cerebellar ataxia, and eventually dementia. Autosomal dominant narcolepsy, obesity, and type 2 diabetes: Narcolepsy, obesity, and type 2 diabetes and low CSF hypocretin-1 levels have been described in rare cases and are associated with a mutation in the myelin oligodendrocyte glycoprotein gene. Narcolepsy secondary to another medical condition: This subtype is for narcolepsy that develops secondary to medical conditions that cause infectious(e.g., Whipple’s disease, sarcoidosis), traumatic, or tumoral destruction of hypocretin neurons. Specify current severity: Mild: Infrequent cataplexy (less than once per week), need for naps only once or twice per day, and less disturbed nocturnal sleep. Moderate: Cataplexy once daily or every few days, disturbed nocturnal sleep, and need for multiple naps daily. Severe: Drug-resistant cataplexy with multiple attacks daily, nearly constant sleepiness,and disturbed nocturnal sleep (i.e., movements, insomnia, and vivid dreaming).

”

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 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, 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. 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.

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:

• 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.

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.

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 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.

References

Sources

• Mitler, M M (1991). "Relative Efficacy of Drugs for the treatment of Sleepiness in Narcolepsy". Sleep. 14 (3): 218.
• Mayer, G (1995). "Selegiline Treatment in Narcolepsy". Clinical Neuropharmacology. 18 (4): 306.
• Chabas, D (2003). "The Genetics of Narcolepsy". Annual Review of Genomics & Human Genetics. 4: 459.
• Smith, A J; et al. (2004). "A functional autoantibody in narcolepsy". Lancet: 2122–2124. CS1 maint: Explicit use of et al. (link)

Template:WikiDoc Sources