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•	Narcolepsy

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Narcolepsy

Highlights

Is Narcolepsy Hereditary?

People whose close relatives have narcolepsy are more likely to have the sleep disorder themselves. The risk is highest for first-degree relatives (parents or siblings). According to a 2005 study in the Journal of Sleep Research, narcolepsy is 105 times higher among male first-degree relatives, and 54 times higher among female first-degree relatives, than the general population.

Narcolepsy in Children

Although narcolepsy typically begins in adolescence or young adulthood, it can occur at any age. Even young children can have narcolepsy. According to a small study in Pediatric Neurology, children who have headaches are more likely to have narcolepsy than their healthy peers. The researchers recommended that pediatricians ask patients with headaches whether they have experienced daytime sleepiness, narcolepsy, or insomnia.

Drug Treatments for Daytime Sleepiness

• Modafinil (Provigil) is the only drug approved to treat the daytime sleepiness associated with narcolepsy.
• At the time this report was written, the FDA was considering approving a similar drug, armodafinil (NuVigil). A 2006 study published in Current Medical Research and Opinion suggested that armodafinil helps improve wakefulness, memory, attention, and fatigue in patients with narcolepsy.

Drug Treatments for Cataplexy

• Sodium oxybate (Xyrem) is the only approved treatment for narcolepsy-associated cataplexy. (Cataplexy is the sudden muscle weakness that often accompanies narcolepsy; it is usually provoked by intense emotions.) Recent studies report that Xyrem is very helpful for treating this condition.
• Antidepressant drugs such as tricyclics, selective serotonin reuptake inhibitors (SSRIs), and selective serotonin and norepinephrine reuptake inhibitors (SSNRIs) are also prescribed for cataplexy. However, a 2006 review in the Cochrane Database found there was little medical evidence to support their use. The researchers called for more clinical trials to determine how well antidepressants work for narcolepsy treatment, and which types of antidepressants work the best.

Introduction

The word narcolepsy comes from two Greek words roughly translated as "seized by numbness". The two primary symptoms in narcolepsy reflect this phrase:

• Excessive daytime sleepiness, with frequent daily sleep attacks or a need to take several naps during the day.
• Temporary and sudden muscle weakness (called cataplexy), usually brought on by strong emotions.

Some, but not all patients experience other symptoms:

• Microsleep episodes, in which the patient behaves automatically but without conscious awareness.
• A sense of paralysis that occurs between wakefulness and sleep (called atonia).
• Dream-like states between waking and sleeping (called hypnagogic hallucinations).
• Periodic leg movements during sleep (periodic limb movement disorder).

REM (rapid eye movement) sleep is abnormal in narcolepsy. In fact, narcolepsy is sometimes defined as the loss of boundaries between wakefulness, non-REM sleep, and REM sleep. REM sleep is the active, dreaming phase of sleep.

Primary Symptoms of Narcolepsy

Excessive Sleepiness. All people with narcolepsy experience excessive sleepiness during the day with episodes of falling asleep rapidly and inappropriately, even when fully involved in an activity. These events may be characterized by the following behaviors:

• Periods of drowsiness may occur every 3 or 4 hours and usually end in short naps.
• Patients may sleep for a few minutes, particularly if they are in an awkward position or for a few hours if they are lying down.
• Patients often underestimate the duration of their drowsy periods and may not recall clearly their behavior during that time.

Cataplexy. Cataplexy is an abrupt loss of muscle tone or strength that results in an inability to move and always occurs during wakefulness. It occurs in about two-thirds of narcolepsy patients and may be triggered by the following events:

• Sudden emotion, usually anger or laughter (the most common trigger)
• Following a heavy meal
• During periods of stress

Muscle reflexes are completely absent during a cataplectic attack. Cataplectic attacks can be very minimal and appear as passing weakness or affecting only the eyelids and face. They may, on the other hand, be so severe that they weaken the whole body. The most severe form is called status cataplectics, which occurs repeatedly for hours or days. Abrupt withdrawal from certain drugs used to treat narcolepsy, notably clomipramine, can cause status cataplectics.

Cataplexy may have the following characteristics:

• Most attacks last less than 30 seconds and can be missed by even skilled observers. However, on severe cases, a person may fall and remain paralyzed for as long as several minutes.
• Typically the patient's head will suddenly fall forward, the jaw becomes slack, and the knees will buckle.
• Speech may become suddenly loud or broken and stutter-like.

Other Symptoms of Narcolepsy

Atonia. Atonia is a sense of paralysis that occurs between wakefulness and sleep, usually upon waking or sometimes at the onset of sleep. The person is conscious but cannot speak, move (cannot even open the eyes), and cannot breathe deeply. Atonia rarely lasts beyond 20 minutes, but when it first occurs, this experience can be terrifying, particularly if the patient also develops hallucinations.

Hypnagogic Hallucinations. Hypnagogic hallucinations are dreams that intrude on wakefulness, which can cause visual, auditory, or touchable sensations. They occur between waking and sleeping, usually at the onset of sleep, and can also occur about 30 seconds after a cataplectic attack.

• Visual hallucinations have been described as a "film running through the head" or as a waking dream with strong emotional content. Images can be intrusive. More commonly they may involve seeing colored forms that shift in size and shape.
• Auditory hallucinations may include random sounds or elaborate melodies.
• A person may also hallucinate feelings of rubbing or light touches, even levitation.

Such symptoms may also appear in other sleep disorders and are probably related to extreme sleepiness. In general, cataplexy must also be present for a clear diagnosis of narcolepsy. Some experts believe, however, that some patients with narcolepsy may experience hypnagogic hallucinations and daytime sleepiness and not cataplexy.

Microsleep and Automatic Behavior. In some cases, patients have so-called microsleep episodes, in which they behave automatically without conscious awareness. Such automatic behavior may not be recognized as part of a disorder by either patients or the people around them. Some examples include:

• People with narcolepsy can be driving or walking competently but end up in a location different from the intended one.
• A narcolepsy patient can be carrying on a conversation and jump from one unrelated topic to another or just trail off and stop talking altogether.
• The patient may suddenly perform bizarre actions, such as putting socks in the refrigerator.
• Patients may experience severe forgetfulness.
• Their movements may suddenly become slow or clumsy.
• In some cases, their behavior may resemble some forms of epileptic seizures.

Disturbed Sleep. Nighttime sleep is often disturbed in narcolepsy, but it is usually mild to moderate and does not account for the daytime sleepiness experienced by people with narcolepsy.

Periodic Limb Movement Disorder. Many patients with narcolepsy experience periodic limb movement disorder, also called PLMD (formerly known as nocturnal myoclonus). In PLMD, the leg muscles involuntarily contract every 20 to 40 seconds during sleep, occasionally arousing the patient. The patient is usually unaware of the cause of the interruption.

The hypothalamus is a highly complex structure in the brain that regulates many important brain chemicals. Malfunction of this area of the brain may give rise to cluster headaches.

Click the icon to see an image of sleep patterns.

Causes

Narcolepsy is a neurological sleep disorder. It is not caused by mental illness or psychological problems. It is most likely the end result of a number of genetic abnormalities that affect specific biologic factors in the brain, coupled with an environmental trigger such as a virus.

Researchers are attempting to come up with a unifying theory involving genetic factors, autoimmunity, and deficiencies in hypocretin, a brain peptide that is important in regulating sleep. Most of the research conducted on narcolepsy uses dogs that have genetic factors that cause narcolepsy, but such studies are helping researchers find the biologic bases to this strange and distressing condition.

Hypocretin and Other Chemicals in the Brain

Hypocretin. Hypocretin (also called orexin) is a peptide that modulates activity in the hypothalamus (the region in the brain associated with sleep, well being, and appetite). Hypocretin specifically has properties that promote wakefulness and inhibits REM sleep. Hypocretin may also have other actions that affect feeding behavior and increase activity in the autonomic (sympathetic) nervous system and systems that regulate motor control. Deficiencies in this peptide have been observed in most patients with narcolepsy who also have cataplexy. Deficiencies might set off the following chemical responses that may produce sleep attacks:

• Lower levels of histamine, a chemical that promotes wakefulness
• Low levels of epinephrine (commonly known as adrenaline), a hormone important in alertness and arousal
• Increase in acetylcholine, which affects REM sleep
• Changes in the enzyme monoamine oxidase, which is believed to be important in preventing arousal
• Changes in dopamine, an important neurotransmitter (chemical messenger in the brain) that helps regulate sleep
• Lower levels of leptin, a hormone associated with obesity when levels decline; (people with narcolepsy tend to be overweight.
• Higher-than-normal secretion of growth-hormone during the day, which may play a role in sudden falling-asleep episodes

Genetic Factors

Narcolepsy has a genetic component and tends to run in families. Experts estimate that around 8 – 10% of people with narcolepsy have a close relative who has the disorder. A 2006 study reported that the risk for narcolepsy among male first-degree relatives (parents or sibling) was 105 times higher than the general population; the risk for female first-degree relatives was 54 times higher. Other studies suggest that people who have a first-degree relative with narcolepsy are 20 – 40 times more likely to have narcolepsy than other people.

However, most experts agree that genetics are not the only factor involved in narcolepsy. Narcolepsy most likely involves a combination of genetics and one or more environmental triggers such as infection, trauma, hormonal changes, immune system problems or stress. Researchers are looking for specific genetic mutations that may make individuals susceptible to this disorder.

Autoimmunity

It has been theorized that narcolepsy may be an autoimmune disease, in which the immune system may be tricked into perceiving its own proteins to be antigens. (Antigens are foreign substances targeted for attack by immune factors in the body.)

An antigen is a substance that can provoke an immune response.

Important autoimmune diseases include multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. In such diseases, the immune system overproduces potent factors called cytokines, which cause inflammation and injury in the susceptible cells and tissues affected by the disease. Most autoimmune diseases also tend to afflict those with particular genetically determined molecules of the immune system called human leukocyte antigens (HLAs).

Experts suggest that an immune attack in narcolepsy may occur against cells containing the brain peptide hypocretin (orexin), resulting in deficiencies that are now believed to be major components of the narcolepsy process. HLAs, particularly a subgroup known as (HLA)DQB1-0602, have been strongly associated with narcolepsy and low levels of hypocretin. Narcolepsy patients who carry this HLA group tend to have a specific syndrome of symptoms that include cataplexy and periodic limb movement disorder. However, between 20% and 40% of people without narcolepsy carry these HLA types.

An important research report, published in 2004 in The Lancet, provided the first concrete evidence that autoimmunity may play a role in narcolepsy. The study’s research team seem to have identified an autoantibody associated with narcolepsy. The researchers injected mice with antibodies taken from patients with narcolepsy. All patients carried the (HLA)DQB1-0602 genotype. Mice were also injected with antibodies from healthy patients. Only the antibodies from patients with narcolepsy produced narcolepsy-type neuromuscular responses.

The results suggested that the antibodies triggered an autoimmune response that affected the hypocretin system. Scientists hope that this autoantibody may prove to be a diagnostic biomarker and that a blood test can eventually be developed to accurately diagnose narcolepsy. In addition to new diagnostic tests, this research may pave the way for immunomodulatory drugs that could prevent hypocretin depletion. However, other research has yet to conclusively establish a link between narcolepsy and autoimmunity.

Risk Factors

Narcolepsy affects around 1 in 2,000 people. Experts estimate that around 135,000 – 200,000 Americans have narcolepsy, but the number may be higher. Only about 25% of people who have narcolepsy are actually diagnosed with the disorder. Patients are often mistakenly diagnosed with other causes such as psychiatric or emotional problems. Many patients wait decades before they are properly diagnosed.

Ethnic Differences

Genetic factors may influence narcolepsy's prevalence in different populations. For example, studies have found much higher rates among Japanese and much lower rates among people in Israel. A 2002 study suggested, however, that the disease is very consistent among all ethnic groups and does not vary in severity or symptoms.

Age

Narcolepsy symptoms usually first appear in adolescence or young adulthood. However, narcolepsy can begin at any age. Growing evidence suggests that the disorder may emerge in early childhood in many patients. People who develop it at a young age often have a family history of the disease and a severe condition, suggesting that genetic factors are important in this group. A 2006 study found that children with frequent headaches are more likely to develop narcolepsy and excessive daytime sleepiness than other children. The researchers recommended that pediatricians ask about narcolepsy symptoms when treating children with chronic headaches.

Prognosis

Narcolepsy is a life-long problem but it is not progressive. Symptoms may even lessen over time but they never completely disappear. In a 2001 study comparing older adults (over 65 years old) and younger adults, the older group had less cataplexy although there was no difference in excessive daytime sleepiness. In fact, another study suggested that sleep disturbances at night often worsen as a person ages.

Risk for Accidents

Perhaps the most serious consequence of narcolepsy is the high risk for accidents. Almost 75% of patients with narcolepsy reported falling asleep while driving in one survey and 56% reported near accidents. Other common narcolepsy-related accidents include burns from touching hot objects, cuts from sharp objects, and breaking things.

Effects on Mental Functioning

Some, but not all, studies report that people with narcolepsy have problems with memory and attention. Some research suggests that problems may be due to the abnormalities in the brain that cause the narcolepsy itself. Problems in thinking, however, are more likely to be due to tiredness and episodes of sleepiness. One study found that patients with narcolepsy had trouble with short-term memory, although if given time to repeat memory tasks their response became normal.

Emotional and Social Difficulties

The patient suffers emotional and social difficulties from the uncontrollable sleep episodes and cataplexy. Studies have reported rates of depression in people with narcolepsy ranging from 30 - 57%. (In the general population, prevalence of depression is 8%.) Studies have shown severe emotional and social dysfunction in all areas, including work, relationships, and leisure activities. One study reported that 25% of men with narcolepsy suffered sexual problems. Some experts believe that the psychological and social effects are more serious than those caused by epilepsy (which narcolepsy can be mistaken for).

Accompanying Physical Problems

Headaches. Studies report a very high incidence of headaches in general, and migraines in particular. In one study, 81% of narcolepsy patients had headaches, with 57% of them reporting migraines. In another study, migraines were reported in 44% of women and 28% of men with narcolepsy. Narcolepsy developed more than a decade before the migraines did, suggesting some common disease pathway in both disorders.

Obesity. Evidence suggests that people with narcolepsy are at high risk for obesity compared to the general population. This could be a consequence of low activity level, but research also indicates that deficiencies in the brain peptide hypocretin may play a role in both narcolepsy and feeding behavior, which could increase the risk for obesity.

Diagnosis

Although narcolepsy is a physical disorder, doctors are still very likely to misdiagnose patients as having psychologic problems. It often takes a year or longer for a patient with narcolepsy to receive a correct diagnosis. To determine specific sleep disorders, the doctor will take a medical and family history and should be told of any medications being taken. The symptoms of narcolepsy are sometimes undeniable if the patient reports all of the major symptoms:

• Excessive daytime sleepiness with a tendency for frequent naps. (These frequent naps should occur every day for at least 6 months to serve as a diagnosis of narcolepsy.) Narcolepsy is usually diagnosed in adolescence and young adulthood when falling asleep suddenly in school brings the problem to attention.
• Cataplexy (abrupt loss of muscle tone or weakness that causes a person to stop all motor activity).
• Hypnagogic hallucinations (vivid visual or auditory phenomena) experienced at the onset of sleep.
• Sleep paralysis (an inability to move on first awakening).

Diagnosis based only on symptoms, however, is often problematic for various reasons:

• Patients often seek medical help for single symptoms (sleep paralysis or hypnagogic hallucinations) that might be associated with other disorders, particularly epilepsy.
• Symptoms are sometimes not dramatically apparent for years, even to the patient or a skilled observer. In one study, the average number of years between onset of symptoms and diagnosis was 14. Another study conducted in a sleep clinic reported that more than half of patients were diagnosed when they were over 40 and had not realized they had narcolepsy until they experienced a bout of cataplexy.

In some cases, the patient may need to consult a sleep specialist or go to an accredited sleep disorders center for accurate diagnosis of a sleep disorder. Patients should carefully investigate centers to make sure that they offer full sleep studies. Patients who visit a sleep center undergo an in-depth analysis, usually supervised by a multidisciplinary team of consultants who can provide both physical and psychiatric evaluations.

Questionnaires

A doctor may administer certain questionnaires on sleeping habits.

The Epworth Sleepiness Scale. The Epworth sleepiness scale (ESS) uses a simple questionnaire to measure excessive sleepiness. It is proving to be a very accurate measure for assessing narcolepsy.

Multiple Sleep Latency Test. The multiple sleep latency test (MSLT) uses a machine that measures the time it takes to fall asleep lying in a quiet room during the day. The patient takes 4 or 5 scheduled naps 2 hours apart. People with healthy sleep habits fall asleep in about 10 to 20 minutes. In patients with narcolepsy, polysomnography plus MSLT will show a much shorter duration of time (less than 8 minutes) from wakefulness into sleep. At least 2 of the naps are REM-onset (the active sleep phase associated dreaming). The test has limitations, however, and is most useful for measuring the severity of the problem. The Epworth sleepiness scale may be more accurate in differentiating narcolepsy from normal daytime sleepiness.

Polysomnography

An overnight polysomnography (sleep study) can be a valuable means for determining the basic cause of sleepiness. The patient arrives at the sleep center about two hours before bedtime without having made any changes in daily habits. The patient is hooked up to a battery of monitoring devices:

• Electroencephalogram, or EEG (monitors the electrical activity of the brain)
• Electrocardiogram or ECG (monitors the heart)
• Electromyogram (monitors the movements of muscles)
• Electrooculogram (monitors eye movements)

These instruments record activity as the patient passes, or fails to pass, through the various sleep stages. One study using polysomnography reported that both healthy patients and those with narcolepsy perform equally during the first 5 to 10 minutes of the test, but after that, patients with narcolepsy show evidence of drowsiness and even indications of sleep. In general, however, polysomnography is most useful for ruling out other disorders, such as sleep apnea, in people with narcolepsy.

Testing Spinal Fluid for Hypocretin

Testing the patient's spinal fluid to detect deficiencies in hypocretin may be a useful method for diagnosing narcolepsy. Low levels may indicate narcolepsy. (Low levels, however, can also occur with brain injury or Guillain-Barre syndrome.) Some researchers believe that measuring hypocretin levels may identify people with early or mild symptoms of narcolepsy (such as cataplexy without altered consciousness). This would help avoid inaccurate diagnoses such as epilepsy or psychosis, which require potent drugs that have significant side effects and are not helpful for patients with narcolepsy.

Investigative Diagnostic Procedures

Transcranial Magnetic Stimulation. An investigative test uses an instrument that magnetically stimulates part of the brain to produce cataplexy. In one study of patients with narcolepsy, such stimulation caused loss of muscle tone in certain areas when patients were off their medication, but had no effect when they were in treatment.

Ruling out Other Disorders

Ruling out Psychologic Disorders. In one study, 40% of patients who actually had narcolepsy had been diagnosed incorrectly with some psychological or psychiatric problem. Certainly, patients with narcolepsy have emotional difficulties because of the condition and it is often difficult, particularly for a nonspecialist, to detect the physical problem. Even worse, hypnagogic hallucinations may result in diagnoses of schizophrenia or bipolar disorder, which are treated with potent antipsychotic drugs that have severe side effects and are useless for narcolepsy.

Ruling out Epilepsy. Narcolepsy can easily be mistaken for epilepsy, a group of disorders that cause seizures. Case studies have reported a misdiagnosis of epilepsy in patients who were actually experiencing cataplexy and sleep paralysis.

Other Causes of Persistent Fatigue. A number of conditions can cause persistent fatigue and should be ruled out:

• Obstructive sleep apnea. This is a major sleep disorder that causes fatigue and afternoon sleepiness and must be ruled out before a diagnosis of narcolepsy can be established. (A person may also suffer sleep apnea and narcolepsy at the same time.)
• Chronic fatigue syndrome
• Head trauma
• Infectious mononucleosis

Swollen lymph nodes, sore throat, fatigue and headache are some of the symptoms of mononucleosis, which is caused by the Epstein-Barr virus. It is generally self-limiting and most patients can recover in 4 to 6 weeks without medications.

• Guillain-Barre syndrome
• Hepatitis
• Atypical pneumonia, particularly those involving echoviruses

Other Causes of Sleep Paralysis. Sleep paralysis may be triggered by certain conditions, such as:

• Irregular sleep habits
• Sleep deprivation
• Shift work
• Jet lag
• Psychologic stress

These conditions may also worsen sleep paralysis in narcolepsy. Narcolepsy sleep paralysis usually occurs at the onset of sleep and is chronic.

Treatment

Lifestyle treatment of narcolepsy includes taking three or more scheduled sleep-times throughout the day. One study suggested that the best approach is a combination of scheduled nighttime sleep and two 15-minute naps (for example one before lunch and another before dinner). Patients should also avoid heavy meals and alcohol, which can interfere with sleep.

People with mild narcolepsy symptoms that do not require medication may be able to maintain alertness with sleep scheduling. In a 2001 study, scheduled sleep periods were also helpful for patients who were extremely sleepy in spite of medications. The benefits of scheduled naps, however, are not clear for patients whose condition responds to medication. In the same study, patients who took stimulants and were able to maintain alertness or were only moderately sleepy derived no additional benefit from the naps.

Medications for narcolepsy target the major symptoms of sleepiness and cataplexy. Stimulant drugs are used to manage excessive daytime sleepiness while antidepressants and other compounds address cataplectic symptoms. The FDA has approved two drugs specifically for the treatment of narcolepsy. They are now the first-line treatments:

• Modafinil (Provigil): For excessive daytime sleepiness
• Sodium oxybate (Xyrem): For cataplexy

Drug Treatments for Sleepiness

Modafinil. Modafinil (Provigil) is a drug used to treat the excessive sleepiness associated with narcolepsy and other sleep disorders. (Modafinil does not treat cataplexy.) The FDA approved modafinil in 1998. Since that time, it has largely replaced methylphenidate (Ritalin) and other stimulants for treatment of narcolepsy sleepiness. Patients who switch to modafinil from stimulants such as methylphenidate experience few problems if they gradually taper off the stimulant dose.

Modafinil helps patients with narcolepsy stay awake during the day. In one study, patients who had not yet taken modafinil were able to stay awake only an average of 6 out of 20 minutes. After taking the medication, awake time increased to 12 - 14 of every 20 minutes, and some patients had normal wake times. In another study, modafinil increased the ability to stay awake by 50% and reduced the number of involuntary sleep episodes by about 25%.

Some of its additional benefits include what it does not do:

• Modafinil does not appear to affect natural hormones important in sleep, including cortisol (the major stress hormone), melatonin, and growth hormone. Therefore, studies suggest that it does not interfere with voluntary naps during the day or with the quantity or quality of nighttime sleep.
• It does not cause anxiety to the degree that the standard stimulants do.
• It does not cause a rebound effect as stimulants do. In other words, people who take modafinil do not usually "crash" when the drug wears off.
• It has less potential for abuse than stimulant drugs. In one trial, no patients developed dependence on the drug after 9 weeks of daily use. However, modafinil can still be habit-forming. Patients may need to gradually lower the dose before stopping treatment.

Side effects may include:

• Headache (the most commonly reported side effect)
• Nausea
• Diarrhea
• Dry mouth
• Nasal and throat congestion
• Nervousness and anxiety
• Dizziness
• Back pain
• Difficulty sleeping
• Decreases the effects of hormonal methods of birth control, including the pill. (Women of childbearing age who take modafinil should switch to another form of birth control.)

A new drug, armodafinil (NuVigil), which is related to modafinil, is being investigated for treatment of narcolepsy-associated excessive sleepiness. In clinical trials comparing it with placebo, armodafinil improved wakefulness, memory, attention, and fatigue in patients with narcolepsy.

Stimulants. Medications that act as stimulants are standard treatments for narcolepsy. They include:

• Methylphenidate (Ritalin)
• Dextroamphetamine (Dexedrine)
• Methamphetamine (Desoxyn)

Methylphenidate and dextroamphetamine last for 2 - 5 hours and are the standard drugs for excessive daytime sleepiness. These drugs are useful for people who can manage wakefulness with a night's sleep and scheduled naps. They can improve mood, mental acuity, and other aspects of mental functioning. An older drug, pemoline (Cylert), is now prescribed less frequently due to its risks for liver damage.

Stimulants can have unpleasant side effects, including:

• Weight loss
• Dizziness
• Nausea
• Changes in blood pressure and rapid heartbeat
• Headache

There are some differences between these drugs:

• Methylphenidate, which is the standard drug for treating attention deficit hyperactivity disorder, is safer than dextroamphetamine. Small studies suggest that high doses may help avert cataplexy, although more research is needed to confirm this effect. Psychosis from overdose is very rare. Psychologic dependence can occur, but abuse has not been reported in children who have taken it for years.
• Dextroamphetamine has more severe side effects than methylphenidate. These include mood changes and jerky muscle movements. Prolonged use may cause serious depression. Overdose, which can occur at doses of only 100 to 500 mg, can cause psychosis and even death. This drug should not be used during pregnancy. There is also a risk for addiction and abuse.

Stimulants should be avoided or only taken under a doctor's guidance in people with heart disease, hyperthyroidism, glaucoma, anxiety disorder, and high blood pressure.

These drugs become ineffective if used continuously, and patients are advised to take a drug holiday one day a week or to withdraw gradually and resume treatment at a lower dose. Patients should not engage in activities that require being awake (such as driving) during withdrawal.

Drug Treatments for Cataplexy

Sodium oxybate (Xyrem). Sodium oxybate (Xyrem), also referred to as gamma hydroxybutyrate (GHB), helps reduce the frequency of cataplexy attacks and improve daytime sleepiness. It takes about 4 weeks for significant benefits, which reach their peak at about 8 weeks. Food intake can affect it, so patients are advised to take it at a regular time after the evening meal.

In 2002, the FDA approved Xyrem for treatment of cataplexy associated with narcolepsy. However, the FDA placed tight restrictions on its use. Although the drug appears to be effective and safe when used for narcolepsy, it has a history of illegal and "date-rape" use, with street names such as "Grievous Bodily Harm" or "Liquid Ecstasy." (The last term is not to be confused with "Ecstasy," another street drug with different effects.) In high doses, it can cause dependence over time. In addition, very serious side effects -- including seizures, coma, respiratory arrest, and death -- have been reported in people who abused it. Trials of Xyrem, however, have not reported these effects with the doses used in treatment for cataplexy. Patients still report side effects, although they tend to be mild. They include nausea, headache, dizziness, urine leakage, and sleepwalking.

Monoamine Oxidase Inhibitors (MAOIs). Selegiline (Eldepryl, Movergan), also known as deprenyl, is an MAOI that blocks monoamine oxidase B, an enzyme that degrades dopamine and may play a role in narcolepsy.

Adverse Effects. Selegiline has significant side effects:

• It interacts with nearly every antidepressant. Patients suffering from depression should discuss all treatment options with their doctor.
• People taking any monoamine oxidase inhibitor are at risk for high blood pressure if they consume tyramine-containing foods or beverages, including aged cheeses, most red wines, vermouth, dried meats and fish, canned figs, fava beans, and concentrated yeast products.

Antidepressants. Antidepressant drugs are not approved for treatment of cataplexy, but they are commonly used to manage this condition. Unfortunately, there have been few studies conducted on antidepressant treatment of cataplexy and there are little data on which type of antidepressant work bests. A 2005 review of antidepressants for narcolepsy noted the lack of good quality evidence to support their use and urged for more clinical trials.

Antidepressants used for cataplexy and management of REM symptoms include:

• Tricyclic antidepressants: Protriptyline (Vivactil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and desipramine (Norpramin, Pertofran)
• Selective serotonin reuptake inhibitors (SSRIs): Fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft)
• Newer antidepressants: Venlafaxine (Effexor)

Tricyclics were the first antidepressants used for cataplexy; they were also one of the first treatments for cataplexy. They can be helpful for some patients but have many unpleasant side effects, including dry mouth, constipation, and weight gain. Tricyclics can also lower blood pressure and cause disturbances in heart rhythm.

SSRIs have fewer side effects than tricyclics but may not work as well for cataplexy control. The most common side effects include nausea, drowsiness or insomnia, headache, weight gain, and sexual dysfunction.

Venlafaxine (Effexor) is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) that has shown promising results for treatment of cataplexy. Some patients with narcolepsy, and their doctors, report that venlafaxine seems to work best of all the antidepressants.

[For more information on antidepressants, see In-Depth Report #8: Depression.]

Resources

• www.aasmnet.org -- American Academy of Sleep Medicine
• www.sleepfoundation.org -- National Sleep Foundation
• www.narcolepsynetwork.org -- Narcolepsy Network
• www.wfsrs.org -- World Federation of Sleep Research Societies
• www.med.stanford.edu/school/psychiatry/narcolepsy -- Stanford Center For Narcolepsy
• www.nhlbi.nih.gov/sleep -- National Center on Sleep Disorders Research
• www.ninds.nih.gov -- National Institute on Neurological Disorders and Stroke

References

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