Narcolepsy
What is narcolepsy?
Narcolepsy is a chronic (long lasting) disease of the brain (central nervous system). Excessive daytime sleepiness (EDS) is the main symptom and is present in 100% of patients with narcolepsy. The other primary symptoms of narcolepsy include loss of muscle tone (cataplexy), distorted perceptions ( hypnagogic hallucinations), and inability to move or talk ( sleep paralysis). Additional symptoms include disturbed nocturnal sleep and automatic behavior. All of the symptoms of narcolepsy may be present in various combinations and degrees of severity.
Narcolepsy begins (has its onset) usually in teenagers or young adults and affects both sexes equally. The first symptom to appear is EDS, which may remain unrecognized for a long time in that it develops gradually over time. The other symptoms can follow EDS by months or years.
How common is narcolepsy?
The frequency (prevalence) of narcolepsy is similar to that of Parkinson's disease and multiple sclerosis . In North America and Western Europe, narcolepsy occurs in 0.03 - 0.09% of the population. However, in some countries (e.g., Israel), the prevalence of narcolepsy is much lower while in other countries (e.g., Japan), it is much higher. It is estimated that approximately 125,000 to 200,000 Americans suffer from narcolepsy, but only fewer than 50,000 are properly diagnosed.
Narcolepsy often remains undiagnosed or misdiagnosed for several years. This may occur, in part, because physicians do not consider the diagnosis of narcolepsy frequently enough. For example, they may think of narcolepsy only in people who have the main symptom of EDS. Narcolepsy may not be considered in the evaluation of patients who come to their doctors complaining of fatigue, tiredness, or problems with concentration, attention, memory, and performance, and other illnesses (seizures, mental illness, etc.).
What causes narcolepsy?
Rapid advances have been made in the last few years in determining the cause of narcolepsy. The newest discovery has been the finding of abnormalities in the structure and function of a particular group of nerve cells, called hypocretin neurons, in the brains of patients with narcolepsy. These cells are located in a part of the brain called the hypothalamus and they normally secrete neurotransmitter substances called hypocretins. (Neurotransmitters are chemicals released by nerve cells to transmit messages to other cells.)
The hypocretin neurons and their connections with many different areas of the brain make up the hypocretin system, whose functions are not yet fully known. The abnormalities in the hypocretin system are thought to play a role in the development of narcolepsy. Thus, they may be responsible, both directly and by affecting other neurotransmitter systems, for the daytime sleepiness and abnormal REM sleep found in narcolepsy. (See the section below on sleep laboratory tests for a discussion of REM sleep.)
What's the evidence for involvement of the hypocretin system in narcolepsy? Experiments in dogs (Doberman pinschers and Labradors) with narcolepsy and in the mouse form of narcolepsy point to an abnormal hypocretin system as a cause for the development of their narcolepsy. Changes in this system have recently been found in people with narcolepsy. Recent reports showed that patients with narcolepsy have a markedly decreased number of hypocretin nerve cells in the brain. They also have a decreased level of hypocretins in the cerebrospinal fluid (the fluid that surrounds the brain and the spinal cord ).
It has been known for many years that narcolepsy is associated with a specific type of human leukocyte antigen (HLA). HLAs are genetically determined proteins on the surface of white blood cells. They are a part of the body's immune (defense) system. The finding of a very high HLA-association in narcolepsy led to the proposal (hypothesis) that narcolepsy is an autoimmune disease, similar to other HLA-associated diseases such as multiple sclerosis and ankylosing spondylitis.
In this hypothesis, an autoimmune reaction is proposed (theorized) to cause the loss of nerve cells (hypocretin and some other neurons in the brain) in patients with narcolepsy. An as yet unknown factor in the environment (e.g., infection or trauma) might initiate (trigger) the autoimmune reaction. In the autoimmune reaction, the normal brain cells are attacked by the body's own immune system, as though these neurons were foreign proteins. As a result, the neurons are damaged and deteriorate (degenerate). Ultimately, the involved neurons are destroyed and they and their neurotransmitter chemicals disappear. Whether narcolepsy is indeed an autoimmune disease , however, remains to be proven.
The role of heredity in humans with narcolepsy is not completely understood. Most narcolepsy does not run in families. In some patients, however, the disease appears to be inherited. Still, no consistent pattern of heredity has been recognized in families so far. It is estimated that relatives of patients with narcolepsy may have a higher predisposition (tendency) to develop narcolepsy or some sleep related abnormalities, such as increased daytime sleepiness, increased REM sleep, or others. It is interesting that in dogs with narcolepsy, the disease is inherited in a predictable pattern. In these animals, the narcolepsy is caused by an abnormal change (mutation) in a particular gene that is normally responsible for producing a receptor (binder) in the brain for the hypocretin neurotransmitter.
What are the symptoms of narcolepsy?
Excessive daytime sleepiness (EDS)
The main symptom (clinical manifestation) of narcolepsy, excessive daytime sleepiness (EDS), is often the most disabling one. It causes the patient to tend to fall asleep or doze off easily. This happens not only in relaxed situations, but also at inappropriate times and places. For example, patients may fall asleep while watching TV, reading a book, driving a motor vehicle, attending a meeting, or engaging in a conversation. The daytime sleepiness is present even after normal nighttime sleep. Patients may refer to this symptom by any of the following descriptions: being tired, fatigued, or sleepy, feeling lazy, or having low energy.
EDS is present throughout the day but the patient, with extreme effort, may be able to resist the sleepiness for some time. Finally, however, it becomes overwhelming and results in a sleep episode of varied duration (seconds to minutes). In addition to the daytime sleepiness, repetitive, irresistible, and unintentional sleep attacks may occur throughout the day. EDS usually impairs a patient's functioning because it reduces motivation and vigilance, interferes with concentration and memory, and increases irritability.
Cataplexy
Cataplexy is a sudden, temporary (reversible) loss of muscle tone (the normal firmness of a muscle) in a person with narcolepsy. An attack of cataplexy usually is triggered by emotional stimuli such as laughter, excitement, surprise, or anger. Factors that might contribute (predispose) to the attacks of cataplexy include physical fatigue, stress , and sleepiness.
Severe attacks of cataplexy may involve all of the voluntarily controlled (skeletal) muscles, which can result in a complete body collapse with a fall to the ground and risk of injury. Milder forms of cataplexy are more common. These involve regional (focal) muscle groups and result in symptoms such as a dropping head, sagging jaw, slurred speech, buckling of the knees, or weakness in the arms. This muscle weakness (loss of tone) can be quite subtle. Consciousness is maintained throughout the episodes of cataplexy but the patient is usually unable to speak.
Cataplectic attacks may last from a few seconds to several minutes. They may vary from a few per year to numerous attacks per day that could disable the patient. Cataplexy is present in 65% to 70% of patients with narcolepsy. The onset of cataplexy may coincide with the onset of EDS. However, cataplexy often develops years later. Therefore, the absence of cataplexy should not rule out the diagnosis of narcolepsy.
Hypnagogic hallucinations
Hypnagogic hallucinations may be present in up to 50% of patients with narcolepsy. Hypnagogic hallucinations are dream-like experiences that occur during the transition (passage) from wakefulness to sleep, whereas hypnopompic hallucinations are those that occur during the transition from sleep to wakefulness. These hallucinations (distorted sensations or perceptions) may involve hearing, vision, touch, balance, or movement. They often incorporate images of the patient's environment into the dream-like images. The hallucinations are frequently vivid, bizarre, frightening, and disturbing for the patients. As a result, the patients may become fearful that they have or will develop a mental illness.
Sleep paralysis
Sleep paralysis may be present in up to 60% of patients with narcolepsy. Sleep paralysis is a temporary inability to move or talk that occurs during sleep-to-wake or wake-to-sleep transitions. The duration of these episodes of sleep paralysis may be from seconds to minutes. They can occur at the same time as hypnagogic (or hypnopompic) hallucinations. During sleep paralysis, breathing is maintained, although some patients may experience a frightening sensation of "not being able to breathe".
Cataplexy, hypnagogic hallucinations, and sleep paralysis in patients with narcolepsy are referred to as REM related abnormalities because they are caused by REM sleep intrusions into wakefulness. (See the discussion of REM sleep in the section on sleep laboratory tests below.)
Additional symptoms
Disturbed nocturnal sleep with frequent awakenings and increased body movements may develop after the onset of the primary symptoms of narcolepsy. This additional symptom, along with EDS and the REM related abnormalities, form the so-called "narcolepsy pentad" (a set of five symptoms).
Automatic behavior may occur in 60% to 80% of patients with narcolepsy. Automatic behavior refers to the performance of routine activities with reduced awareness or to semi-purposeful behavior, often with the unusual use of words (irrelevant words, lapses in speech). The patient is unaware of this behavior, which occurs while she/he is fluctuating between sleep and wakefulness.
Other complaints associated with narcolepsy may include eye disturbances due to sleepiness, such as blurred vision, double vision, and droopy eyelids.
How is narcolepsy diagnosed?
The diagnosis of narcolepsy is based on a clinical evaluation, specific questionnaires, sleep logs or diaries, and the results of sleep laboratory tests. - The clinical evaluation includes a detailed medical history and physical examination by a physician.
- Several different questionnaires may be used in the assessment of patients with symptoms that suggest narcolepsy. The Stanford Narcolepsy Questionnaire is a very extensive questionnaire that can provide the physician with valuable information on all symptoms of narcolepsy, but especially on cataplexy. The Epworth Sleepiness Scale is a brief self-administered scale (questionnaire) that provides an estimate of the degree of daytime sleepiness.
- The use of sleep logs or sleep diaries for 2 to 3 weeks is recommended in the evaluation of any patient with EDS. Sleep diaries provide the physician with information about the patient's usual sleep patterns (sleep deprivation, irregular sleep/wake pattern, interrupted sleep), alcohol and/or drug use, and common waking behaviors (e.g., "Internet syndrome"). (The Internet syndrome is the habit of surfing the Internet until late at night, thereby causing sleep deprivation and daytime sleepiness.) All of this information may be helpful in the evaluation of a patient with EDS.
- Standard sleep laboratory tests ("sleep studies") for narcolepsy include polysomnography (PSG) and the multiple sleep latency test (MSLT). Polysomnography (PSG) is a full night recording of several different functional (physiological) factors (parameters) of a patient's sleep. The PSG is followed the next day by the multiple sleep latency test (MSLT), which is a recording of the patient's tendency to fall asleep during the day. These procedures (PSG and MSLT) provide objective measures of daytime sleepiness and REM sleep abnormalities.
Daytime sleepiness is measured in the MSLT by the sleep latency (SL) time. This is the time from the beginning of the recording to the onset of sleep. In healthy individuals, the SL time is more than 10 minutes, whereas in narcolepsy, it could be as short as 0.5 minutes (an almost immediate onset of sleep).
REM sleep is so named because of the rapid eye movements (REM) that characterize this phase of sleep. In REM sleep, dreams are vivid, muscle activity is suppressed, and brain activity is high. The REM sleep abnormality that is characteristic of narcolepsy is referred to as sleep onset REM periods. This means that in narcolepsy, the REM sleep begins soon after the onset of sleep. Thus, in healthy individuals, the first REM sleep period occurs about 80 to 120 minutes after the onset of sleep. By contrast, in narcolepsy, the initial REM sleep period usually occurs within 15 minutes of the onset of sleep. In addition, narcolepsy patients will have two or more sleep onset REM periods during the multiple sleep latency test (MSLT) in the daytime.
PSG is also helpful in excluding (ruling out) other causes of daytime sleepiness, such as sleep apnea syndrome (SAS), periodic limb movements in sleep (PLMS), and sleep disruptions. In some cases, a repeat PSG and MSLT may be recommended if there is worsening of the symptoms of narcolepsy despite the treatment and/or an additional sleep disorder is suspected (e.g., sleep apnea syndrome).
Another sleep laboratory test may be used to evaluate the effects of the treatment for narcolepsy - the maintenance of wakefulness test (MWT). This test is a recording that measures the ability of a subject to stay awake during the day.
The blood test for a particular type of HLA (Human Leukocyte Antigen) has been observed to have a very high association with narcolepsy. Certain types of HLA are part of an individual's genetic or hereditary makeup and can be characteristic of certain conditions, especially autoimmune diseases. We now know, however, that the particular HLA type associated with narcolepsy is not specific (unique) for this condition. Therefore, HLA typing should not be used for the diagnosis of narcolepsy. There are familial forms of narcolepsy without that HLA marker and there are sporadic or individual (not associated with a family history) forms that have the HLA marker.
The diagnostic criteria for narcolepsy are described in the International Classification of Sleep Disorders. These criteria indicate that the diagnosis may be based on clinical symptoms alone if both EDS and cataplexy are present. If cataplexy is not present, however, the diagnosis should be based on the clinical symptoms and polysomnographic findings.
How is narcolepsy treated?
The treatment of narcolepsy includes drug (pharmacological) and non-drug, or behavioral, therapies. Treatment options should be individualized depending on the severity of the symptoms, life conditions (e.g., type of work or responsibilities) of the patients, and the specific goals (e.g., relief of certain symptoms) of therapy. Optimal management usually takes weeks to months to achieve and requires continued communication among the physician, narcoleptic patient, family members, employer, teachers, and others. Good treatment management typically produces significant improvement of the symptoms rather than a resolution of all symptoms.
Medications
The types, number, and severity of the symptoms determine which drugs are used to treat the narcolepsy. Severe daytime sleepiness may require treatment with high doses of stimulant medication, and sometimes a combination of stimulants may be needed. Rare or infrequent cataplexy and other associated symptoms may not require any drug treatment, or treatment on an "as needed regimen" may be adequate. Trouble sleeping ( insomnia ) and depression may also require treatment. Therapy should be catered to the individual needs of the patient. For example, improved alertness may be critical throughout the day for most students and working adults, but may be critical only at certain times of the day (e.g., driving times) for other people.
Alerting medications are used for the treatment of EDS. Amphetamines (e.g., Dexedrine, Desoxyn, DextroStat, Adderall) and methylphenidate (Ritalin) are generalized brain (central nervous system) stimulants. These medications are the traditional stimulants used in narcolepsy to decrease sleepiness and improve alertness. However, they also increase the activity of the so-called sympathetic part of the nervous system, which can produce undesirable side effects. These side effects include elevation of blood pressure, nervousness, irritability, and rarely, fearful distrust (paranoid) reactions. These alerting medications can also lead to drug dependency due to the feeling of great happiness ( euphoria ) that they can cause. Drug dependency, however, has rarely been described in individuals with narcolepsy.
Pemoline (Cylert) is also used as an alerting medication. However, it is less effective than the traditional stimulants. Moreover, this drug has the potential risk of toxic side effects on the liver. Therefore, if pemoline is used, liver blood tests need to be monitored frequently.
Modafinil (Provigil), which was approved by the Food and Drug Administration (FDA) in 1999, has alerting effects similar to those of the traditional stimulants. This medication has been evaluated in several multicenter trials using the objective sleep studies (polysomnography - PSG and the maintenance of wakefulness test - MWT) as well as the subjective sleepiness scales. The results showed a positive impact of the drug on both the objective and the subjective measures of sleepiness. This medication, however, does not affect cataplexy and the other REM sleep symptoms.
Modafinil is not a general CNS stimulant like the amphetamines, but the way it works is unknown. This drug has a much lower risk for high blood pressure and mental side effects because it acts in a different way than the classic stimulants. It does not have significant effects on the sympathetic nervous system and does not cause mood changes, euphoria, or dependence. Furthermore, this drug does not develop tolerance (modafinil does not become ineffective with prolonged use). Headache and nausea are the most commonly reported side effects, and they are usually mild and temporary (transient). These side effects can be reduced, however, by a slow increase from a low initial dose up to the desired dose.
Modafinil is usually used in a single daily dose. It could become the drug of choice for newly diagnosed narcoleptic patients or for patients with significant side effects from other alerting medications. Switching patients from amphetamines to modafinil may cause the reappearance of cataplexy in patients previously well controlled. Increasing the dose or adding an anticataplectic medication usually solves this problem. Although relatively new in the U.S., modafinil has been used to treat narcolepsy for many years in other countries (e.g., France).
Drugs in a class called monoamine oxidase inhibitors (MAOIs), such as phenelzine (Nardil) and selegiline (Eldepryl), can also be used for treatment of EDS.
Anticataplectic medication is the general name for drugs that are used to treat cataplexy. These drugs may also be used for the other REM related symptoms, such as hypnagogic hallucinations and sleep paralysis. Tricyclic antidepressants (TCAs), used in lower than antidepressant doses, are often effective in controlling cataplexy. These medications act on some neurotransmitter systems to produce suppression of REM sleep and consequently improve the symptoms of cataplexy.
In some cases, the side effects may limit the use of TCAs, although in most cases the side effects are temporary. The most frequent side effects are so called "anticholinergic side effects," including dry mouth, dry eyes, blurred vision, urine retention, constipation , impotence , increased appetite, drowsiness, nervousness, confusion, restlessness, headache, etc. In addition, some of the TCAs may increase periodic limb movements in sleep, which could further disrupt already disturbed nighttime sleep in narcoleptic subjects. If TCAs are abruptly discontinued, a significant worsening of the cataplexy and other REM related symptoms could occur. This "rebound phenomenon" may appear in 72 hours after discontinuation of the medication and peak in approximately 10 days from the withdrawal.
The most frequently used TCAs for the treatment of cataplexy and other REM related symptoms are protriptyline (Vivactil), imipramine (Tofranil), clomipramine (Anafranil), desipramine (Norpramine), and amitriptyline (Elavil). Sedating TCAs such as clomipramine, amitriptyline , and imipramine , should be prescribed for evening use, whereas the alerting ones (protriptyline and desipramine ) should be used during the day.
Selective serotonin reuptake inhibitors (SSRIs) are also useful in treating cataplexy at doses that are comparable to those used to treat depression . The most frequently used SSRIs for treatment of cataplexy and REM related symptoms are fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), and venlafaxine (Effexor). The SSRIs may not be as effective as the TCAs (although direct comparative data are lacking), but they have fewer side effects. The most frequently reported side effects are dizziness , lightheadedness, nausea, and mild tremor . Rarely, in some patients, mild constipation or diarrhea may occur. Fluoxetine (Prozac) given late in the day may cause insomnia.
Sodium oxybate (Xyrem), also known as gamma-hydroxybutyrate or GHB, is another medication with anticataplectic effects. This drug is usually administered in two doses; the first is given at bedtime and the second 4 hours later. It consolidates (unifies) sleep and improves the disturbed nocturnal (nighttime) sleep that is characteristic of narcolepsy. Further, this nighttime benefit may help decrease daytime drowsiness and cataplexy. Sodium oxybate is unrelated to drugs that are known to be sleep-inducing (hypnotic) and is not used for insomnia (trouble sleeping). However, it can cause drowsiness and should only be taken at night. This drug has been used for some time in Europe for the treatment of narcolepsy. In the U.S., FDA approval for Xyrem is expected in 2002.
Non-drug treatments
Non-drug treatments include the disease-specific education of the patient and family members and modification of behavior patterns. Understanding the symptoms of narcolepsy may help relieve some of the frustrations, fears, anger, depression, and resentment of the patients and family members. These emotional reactions are responses to both the unusual nature of the symptoms and society's ignorance of this disease. National organizations and local narcolepsy support groups are additional sources of information and assistance.
Behavioral approaches include establishing a regular, structured sleep-wake schedule. Planned naps of 15 to 30 minutes or longer are usually refreshing and may be beneficial in reducing the patient's daytime sleepiness. Certain dietary restrictions should be observed (e.g., avoidance of large meals and alcohol). Regular exercise and exposure to bright light can improve alertness. Occupational, marriage, and family counseling may help improve the patient's quality of life .
Special considerations are needed for school schedules and working conditions. Occupations that require working in different shifts, changing the work schedule, or driving should be avoided. The dangers of driving while sleepy and/or experiencing cataplexy need to be addressed and the patients should be advised to avoid driving with these symptoms. However, many patients with narcolepsy are able to drive for short distances at certain times of the day and after taking their stimulant medications. Reporting requirements to the Department of Motor Vehicles (DMV) differ from state to state. Some states require that individuals who have any lapses of consciousness or sleepiness be reported to the DMV.
What is the outcome (prognosis) for patients with narcolepsy?
Narcolepsy is a life-long disease. The symptoms may vary in severity during the patient's lifespan, but they never disappear completely. In fact, the symptoms usually gradually worsen over time, and then tend to become stable. Even then, however, the EDS sometimes may become more pronounced and require additional medication. At other times, cataplexy and/or the other symptoms may decrease or even disappear for a time.
Many different factors can contribute to these changes in a patient's symptoms, including an irregular sleep/wake schedule, the use of substances or drugs that affect the central nervous system , infections of the brain, and the development of additional sleep disorders, such as sleep apnea syndrome (SAS), periodic limb movements in sleep syndrome (PLMS), or others. However, regular check-ups with the doctor and adherence to the plan of drug (pharmacological) and behavioral treatment should diminish these fluctuations and improve the patients' symptoms and quality of life. A primary care physician, usually in collaboration with a sleep medicine specialist, can recognize the symptoms of narcolepsy, initiate the proper evaluation, and manage the treatment that is recommended by the specialist. In addition, the primary care physician has a significant role in managing the impact of narcolepsy on a patient's quality of life, just as for any other complex, chronic (long lasting) condition.
What's in the future for narcolepsy?
The recent discovery that a lack of hypocretins in the cerebrospinal fluid (CSF) may be related to the cause of narcolepsy could lead to the development of tests to determine the level of hypocretins in the CSF. Such tests could help in the diagnosis of narcolepsy. The expectation is that these tests will be simple (drawing blood) and not complicated (drawing CSF), and will reflect the level of hypocretins in the CSF. In addition, the discovery of the role of hypocretins in the development of narcolepsy may lead to the development of new compounds for the treatment of narcolepsy. For example, hypocretin agonists (compounds that have the effect of hypocretins) could be used to treat narcolepsy. Also, hypocretin antagonists (compounds that have the opposite effect of hypocretins) can be developed to treat other sleep disorders, such as insomnia. - Narcolepsy is a chronic disease of the central nervous system (the brain). The symptoms include excessive daytime sleepiness (EDS), loss of muscle tone (cataplexy), distorted perceptions (hypnagogic hallucinations), inability to move or talk (sleep paralysis), disturbed nocturnal sleep, and automatic behavior.
- Narcolepsy usually begins in teenagers or young adults and affects both sexes equally.
- The frequency (prevalence) of narcolepsy is similar to that of Parkinson's disease and multiple sclerosis. Approximately 125,000 to 200,000 Americans are estimated to suffer from narcolepsy, but only fewer than 50,000 are actually properly diagnosed.
- Abnormalities in the structure and function of a particular group of nerve cells in the brain called hypocretin neurons are thought to play a role in the development of narcolepsy.
- The diagnosis of narcolepsy is based on a clinical evaluation, specific questionnaires, sleep logs or diaries, and the results of sleep laboratory tests (polysomnography and multiple sleep latency test).
- Treatment options for narcolepsy include drug and behavioral modification therapies and disease-specific education of the patient and family members. The treatment should be individualized, depending on the types and severity of the symptoms, the life conditions of the patients, and the specific goals of therapy.
- Optimal management usually takes weeks to months to achieve and requires continued communication among the physician, narcoleptic patient, family members, employer, and teachers.
- Alerting medications are used for the treatment of EDS. Amphetamines and methylphenidate (Ritalin) are general CNS stimulants that decrease sleepiness and improve alertness. Modafinil (Provigil) has alerting effects similar to those of the traditional stimulants but has less undesirable side effects.
- Anticataplectic medications are used to treat cataplexy, hypnagogic hallucinations, and sleep paralysis. Tricyclic antidepressants (TCAs) are often effective in controlling cataplexy, but also frequently produce side effects that could limit their use.
- Selective serotonin reuptake inhibitors (SSRIs) are also useful in the treatment of cataplexy and their side effects are milder. Sodium oxybate (Xyrem) is a medication with anticataplectic effects that also improves disturbed nocturnal sleep.
- Behavioral approaches to treating narcolepsy include establishing a structured sleep-wake cycle and planned naps, and involve diet, exercise, and occupational, marriage, and family counseling.
Medical Author: Roza Hayduk, M.D.
Medical Editor: Leslie J. Schoenfield, M.D., Ph.D.
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