NarcolepsyWHAT IS NARCOLEPSY?The word narcolepsy comes from two Greek words that can be roughly translated as seized by numbness. The two primary symptoms in narcolepsy reflect this phrase:
Some, but not all patients experience other symptoms:
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. Interestingly, one study observed that narcolepsy produces intense emotional states during REM phases at the onset of sleep. [For a full definition of REM and nonREM sleep, see box Healthy Sleep.] Primary Symptoms of NarcolepsyExcessive 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:
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:
Muscle reflexes are completely absent during a cataleptic attack. Cataleptic attacks can range from very minimal and be experienced as passing weakness or affecting only the eyelids and face or they may be so severe that they weaken the whole body. Status catapleticus is severe cataplexy, which occurs repeatedly for hours or days. It can be triggered by abrupt withdrawal from certain agents used to treat narcolepsy, notably clomipramine.Catalepsy may have the following characteristics:
Other Symptoms of NarcolepsyAtonia. 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 cataleptic attack.
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 the patient has so-called microsleep episodes, in which the person behaves automatically without conscious awareness. Such automatic behavior may not be recognized as part of a disorder by either the patients or the people around them. Some examples are as follows:
In some cases, their behavior may resemble some forms of epileptic seizures. Disturbed Sleep. Although in the narcolepsy, nighttime sleep is often disturbed, 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.
WHAT CAUSES NARCOLEPSY?In the past, some people believed that narcolepsy was caused by repressed sexual drives, which caused guilt so intense that the patient would false asleep to escape it. It now becoming very clear that narcolepsy is a physical condition, 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. Some 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 BrainHypocretin. 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. They 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 now been observed in most patients with narcolepsy, who also have cataplexy. Deficiencies might set off the following chemical responses that may produce sleep attacks:
Genetic FactorsThe risk for narcolepsy in someone with close relatives is very small, about 1% to 2%. Even in identical twins, the risk for the other twin is only 10% to 20%. A combination of genetic factors along with an environmental trigger, then, is most likely involved with this sleep disorder. Some, but not all, cases involved inheriting genetic defects. Researchers are looking for specific genetic mutations that might be make individuals susceptible to this disorder. AutoimmunityIt 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.) 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, 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. It should be noted, however, that between 20% and 40% of people without narcolepsy carry these HLA types. Evidence to date has also failed to identify any specific cytokines or other immune factors that might play such a role in narcolepsy. WHO HAS NARCOLEPSY?Estimates of prevalence of narcolepsy in the US range from as low as 40,000 to as high as 140,000. Experts who endorse the larger number believe that only 15% to 30% of actual cases are recognized, most often in people with cataplexy--the most apparent symptom. Patients with less obvious symptoms may be diagnosed with other causes, usually psychiatric or emotional problems. Ethnic DifferencesGenetic factors may influence its prevalence in different populations, however. 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. AgeNearly half of patients with narcolepsy are first diagnosed after age 40, although excessive sleepiness usually becomes apparent in a person's twenties or thirties. Growing evidence suggests, in fact, that the disorder may also emerge in early childhood in many patients. People who develop it in the younger age group often have a family history of the disease and a severe condition, suggesting that genetic factors are important in this group. HOW SERIOUS IS NARCOLEPSY?Long-Term OutlookNarcolepsy is a life-long problem but it is not progressive. Symptoms may even lessen over time but they never completely disappear. In one 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 AccidentsPerhaps the most serious consequence of narcolepsy is the high risk for accidents. Almost 75% of narcoleptic patients 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 FunctioningSome, 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 has found that narcoleptics had trouble with short-term memory, although if given time to repeat memory tasks their response became normal. Emotional and Social DifficultiesThe 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% to 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). Accompany Physical ProblemsHeadaches. 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 44.4% of women and 28.3% 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 now 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. One study, for example, also observed that relatives of people with narcolepsy also had a higher incidence of greater weight, suggesting that there may be some common component. HOW IS NARCOLEPSY DIAGNOSED?Medical and Personal HistoryAlthough narcolepsy is now clearly known to be a physical disorder, physicians are still very likely to misdiagnose these 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 physician 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:
Diagnosis based only on symptoms, however, is often problematic for various reasons:
In some cases, the patient may need to consult a sleep specialist or go to a sleep disorders center for accurate diagnosis of a sleep disorder. About 250 centers are accredited by the American Sleep Disorders Associations. [ See Where Else Can Help for Narcolepsy be Obtained? below.] Patients should investigate centers carefully, being sure that they offer full sleep studies. One night at a sleep clinic can be very costly and is not usually covered by insurance. At most, sleep disorders centers' patients undergo an in-depth analysis, usually supervised by a multi-disciplinary team of consultants who can provide both physical and psychiatric evaluations. QuestionnairesA physician 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) employs a machine that measures the time it takes to fall asleep lying in a quiet room during the day. The patient takes four or five scheduled naps two 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 eight minutes) from wakefulness into sleep. At least two 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. PolysomnographyIn some cases overnight polysomnography is 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:
These instruments record activity in these organs as the patient passes, or fails to pass, through the various sleep stages. One study using polysomnography reported that normal and narcoleptic patients perform equally during the first five to 10 minutes of the test, but after that, patients with narcolepsy showed 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 HypocretinTesting the patient's spinal fluid to detect deficiencies in hypocretin is proving to be a useful method for diagnosing narcolepsy. Low levels have occurred in small studies in around 85% of patients. (Low levels, however, can also occur with brain injury and Guillain-Barre syndrome.) Nevertheless, 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 of problems, such as epilepsy or psychosis, which require potent drugs that have significant side effects and are not helpful for patients with narcolepsy. Investigative Diagnostic ProceduresTranscranial 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 DisordersRuling out Psychologic Disorders. In one study, 40% of patients who actually had narcolepsy had been diagnosed incorrectly with some psychological or psychiatric problem. In one study, 16% were diagnosed with depression and 17% with neurotic disorders. 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.
(Note, both head trauma and syndrome Guillain-Barre syndrome can also produce test results showing low levels of hypocretin in spinal fluid, just as narcolepsy can.) Other Causes of Sleep Paralysis. Sleep paralysis may be triggered by certain conditions, such as the following:
These conditions may also exacerbate sleep paralysis in narcolepsy, although in the sleep disorder, narcolepsy sleep paralysis usually occurs at the onset of sleep and is chronic. WHAT ARE THE TREATMENTS FOR NARCOLEPSY?Scheduled Sleep PeriodsNonmedical treatment of narcolepsy includes taking three or more scheduled sleep-times throughout the day. One study suggested that the optimal sleep pattern is a combination of scheduled nighttime sleep (e.g., from 11:00 to 7:30) 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 one 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. StimulantsBrands. Medications that act as stimulants are standard treatments for narcolepsy. The include the following:
Methylphenidate and dextroamphetamine last for two to five hours and are the standard agents for excessive daytime sleepiness. Pemoline is effective for eight to 10 hours. These agents 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. Side Effects. Stimulants can have significant side effects, including the following:
There are some differences between these agents:
Stimulants should be avoided or taken only under a physician's guidance in people with heart disease, hyperthyroidism, glaucoma, anxiety disorder, and high blood pressure. Drug Holidays. 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. ModafinilModafinil (Provigil, Alertec) is a novel drug that promotes long-lasting wakefulness. It is now approved for narcolepsy. Before treatment, patients in one study were able to stay awake only an average of six minutes out of twenty. After taking the medication, awake time increased to 12 to 14 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 reduce cataplexy. Some evidence suggests that taking it along with Ritalin may help prevent cataplexy attacks and does not appear to have any harmful interactions. It should be noted, however, that long-term safety and effectiveness of modafinil is not yet known. In one study, modafinil appeared safe for at least 16 weeks of use, but longer studies are needed. Although most current research suggests that modafinil poses less of a risk for abuse than many of the stimulants used for narcolepsy, some evidence suggests that it might have stimulant properties that could lead to abuse. Side Effects. Side effects include the following:
Patients who switch to modafinil from stimulants, such as methylphenidate (Ritalin), experience few problems if they taper the stimulant dose gradually. Gamma-Hydroxybutyrate (GHB)Gamma hydroxybutyrate (Xyrem), also referred to as sodium oxybate or GHB, is proving to reduce the frequency of cataplexy attacks and to improve daytime sleepiness. It takes about four weeks for significant benefits, which reach their peak at about eight weeks. Food intake can affect its activity, so patients are advised to take it at a regular time after the evening meal. Xyrem has been approved by the FDA for narcolepsy, but with tight restrictions on its use. Although the drug appears to be effective and safe when used for narcolepsy, it has a history of illegal 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 in 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 (Selegiline)Selegiline (Eldepryl, Movergan), also known as deprenyl, is an antioxidant drug that blocks monoamine oxidase B, an enzyme that degrades dopamine and may play a role in narcolepsy. Adverse Effects. Selegiline has side effects that are important:
AntidepressantsAntidepressants have been very useful in controlling symptoms of narcolepsy, particularly cataplexy. Tricyclic Antidepressants. The tricyclic antidepressants protriptyline (Vivactil), clomipramine (Anafranil), imipramine (Janimine, Tofranil), and viloxazine appear to suppress REM sleep and may be added to the stimulant regimen in severe cases. These antidepressants do not cause sedation and are useful in managing cataplexy, sleep paralysis, and hypnagogic hallucinations (the hallucinations that occur between sleep and wakefulness). Side effects are fairly common with these medications and many people cannot tolerate them. The most often reported include the following:
Tricyclics can have serious, although rare, side effects.
Selective Serotonin Reuptake Inhibitors (SSRI). Selective serotonin reuptake inhibitors (SSRIs) may also be helpful in combination with stimulants. For example, fluoxetine (Prozac), the standard SSRI, and citalopram (Celexa), another SSRI, have been reported to be effective in treating cataplexy that does not respond to standard treatments. Side effects include the following:
Designer Antidepressants. Reboxetine (Edronax) is a unique antidepressant, known as a selective noradrenaline reuptake inhibitor. A 2001 study reported that it reduced sleepiness and increased the time it took to fall asleep by about 50%. WHERE ELSE CAN HELP FOR NARCOLEPSY BE OBTAINED?American Sleep Disorders Association (www.asda.org National Sleep Foundation (www.sleepfoundation.org National Center for Sleep Disorders Research (http://rover2.nhlbi.nih.gov/about/ncsdr/index.htm Narcolepsy Network (www.websciences.org/narnet Stanford Center For Narcolepsy (www-med.stanford.edu/school/Psychiatry/narcolepsy). The Sleep Well (www.sleepquest.com UCLA Sleep Home Page (www.sleephomepages.org World Federation of Sleep Research Societies (www.wfsrs.org/newsletter.html) Narcolepsy & Sleep Disorders (www.narcolepsy.com) Center for Narcolepsy Research (www.uic.edu/depts/cnr) Young Adults With Narcolepsy (www.yawn.org) National Narcolepsy Registry (www.narcolepsyregistry.org) Narcolepsy Research Project (www.nursing.upenn.edu/Narcolepsy) Review Date: 7/11/2003
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