eMedicine Specialties > Neurology > Sleep-Related Diseases

Narcolepsy

Ali M Bozorg, MD, Clinical Fellow in Epilepsy & Sleep Medicine, Comprehensive Epilepsy Program, Department of Neurology, University of South Florida
Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital

Updated: Sep 12, 2008

Introduction

Background

Narcolepsy is characterized by the classic tetrad of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. Note that this tetrad is seen only rarely in children. The term "narcolepsy" is derived from Greek, "seized by somnolence." Gelineau was the first to delineate the syndrome in 1880.

Narcolepsy frequently is unrecognized, with a typical delay of 10 years between onset and diagnosis. Approximately 50% of adults with the disorder retrospectively report symptoms beginning in their teenage years. This disorder may lead to impairment of social and academic performance in otherwise intellectually normal children. The implications of the disease are often misunderstood by patients, parents, teachers, and health care professionals.

Narcolepsy is treatable. However, a multimodal approach is required for the most favorable outcome.

For a CME activity, see Updates in the Differential Diagnosis and Management of Narcolepsy (Slides With Transcript).

Pathophysiology

Narcolepsy is thought to result from genetic predisposition, abnormal neurotransmitter functioning and sensitivity, and abnormal immune modulation. Current data implicate certain human leukocyte antigen (HLA) subtypes and abnormalities in monoamine synaptic transmission, particularly in the pontine reticular activating system.

Understanding of the neurochemistry of narcolepsy stems primarily from research involving narcoleptic dogs (eg, special laboratory-bred Dobermans and Labradors). In these animal models, the disorder is transmitted in an autosomal recessive fashion with full penetrance and is characterized mainly by cataplexy.

• Muscarinic cholinergic stimulation increases cataplexy in these animals, and cholinergic blockade eliminates the symptom. Nicotinic agents have no effect on cataplexy.
• The muscarinic receptor subtype M2 is up-regulated in the pontine reticular formation in narcoleptic canines, especially in the nucleus reticularis, pontis caudalis, nucleus reticularis gigantocellularis, reticularis pontis parvi, tegmenti pontis, and interpeduncularis.
• Other receptor subtypes such as the alpha1-noradrenergic receptor appear to mediate cataplexy. Prazosin, an alpha1-antagonist, worsens symptoms in human and canine subjects.
• The alpha2-receptor also may be involved.
• The pons is not the only neuroanatomic site that is responsible for mediating cataplexy. Experiments in narcoleptic Dobermans with selective injections of a muscarinic agonist have demonstrated that the basal forebrain structures (ie, nucleus basalis, substantia innominata, diagonal band, medial septum) also induce status cataplecticus.
• The meso-cortico-limbic dopaminergic system also has been implicated. This connection with the limbic system in part explains the relationship of cataplexy to emotion.

Dysfunction and inappropriate regulation of rapid eye movement (REM) sleep are thought to cause narcolepsy.

• Neuroanatomic control of REM sleep appears to be localized to the pontine reticular activating system.
• The brain contains REM-on cells, which fire selectively during REM sleep periods, and REM-off cells, for which the converse holds true. Most REM-on cells function through cholinergic transmission, whereas REM-off cells are noradrenergic or serotonergic.
• In narcolepsy, monoamine-dependent inhibition of REM-on cells may be defective.
• Symptoms can be viewed as REM sleep components intruding into wakeful states. For example, cataplexy and sleep paralysis represent an intrusion of REM sleep atonia, whereas hallucinations represent an intrusion of dreams.

Narcolepsy-cataplexy is associated strongly with HLA DR2: 85-98% of Caucasian patients are DR2 positive. In other ethnic groups (particularly black populations), the DR2 allele is a poor marker for narcolepsy, whereas another allele, DQB1*0602, is associated with the disorder. DQB1*0602 positivity is associated more strongly with narcolepsy-cataplexy than with narcolepsy without cataplexy. In a recent clinical trial, 76% of DQB1*0602-positive patients with narcolepsy had cataplexy, while only 41% of those who were DQB1*0602 negative had narcolepsy with cataplexy. Homozygosity for this allele confers a higher relative risk of developing narcolepsy.  DQB1*0602 is found in 24% of normal healthy subjects.  HLA DQA1*0602 also has proven to be associated with increased susceptibility for developing narcolepsy.

The association of HLA subtypes with narcolepsy raises the question of whether narcolepsy is an autoimmune disease.

• HLA expression appears to be diffuse in the white matter of narcoleptic canines.
• Cytokines also have been implicated in inducing sleep.
• Between 12% and 35% of the population carry this gene, but only 0.02-0.18% have the disease.
• First-degree relatives have a 10- to 40-fold higher risk than the general population. Of first-degree relatives, 4.7% have excessive sleepiness.
• Monozygotic twin studies have only shown a 25-31% concordance for the disorder.  This suggests that both genetic and environmental factors may play a role in the etiology of narcolepsy.

Autosomal recessive canine narcolepsy has been linked to canarc-1. This gene is highly homologous to the human immunoglobulin switch gene, but it appears to be located on a different chromosome. A recent development in the pathogenesis of narcolepsy is identification of an abnormality in the hypocretin (orexin) receptor 2 gene (Hcrtr2) in the canine model. Hypocretins are neuropeptides that have been localized to the tuberis of the hypothalamus and appear to have an excitatory effect on this structure. Orexin knockout mice also have been engineered, resulting in a mouse model of narcolepsy.

The hypocretin system plays an important role in the pathophysiology of human narcolepsy as well. Low or absent levels of cerebrospinal fluid (CSF) hypocretin were demonstrated in patients with sporadic narcolepsy. This is especially the case for HLA DQB1*0602-positive patients suffering from narcolepsy with cataplexy. Postmortem pathological examination of narcoleptic brains have demonstrated dramatically reduced hypocretin neurons.

The close HLA association of narcolepsy has led to the theory that narcolepsy is caused by an autoimmune destruction of hypocretin cells in susceptible individuals. An interplay of genetics and environmental factors results in selective destruction of hypocretin neurons. Once enough hypocretin neurons are lost, the symptoms of narcolepsy emerge. Currently, the susceptibility model and selective loss of hypocretin neurons remains the most attractive theory.

Frequency

United States

Prevalence of narcolepsy has been studied in the following populations:

• North American blacks, 0.02%
• Northern Californians, 0.05%
• Southern California Caucasians, 0.07%
• First-degree relatives, 1-2% risk (10-40 times greater than general population)

International

Prevalence of narcolepsy has been studied in the following populations:

• Israeli Jews and Arabs, 0.002%
• Czech Caucasians, 0.02%
• Finnish Caucasians, 0.026%
• United Kingdom Caucasians, 0.04%
• French Caucasians, 0.05%
• Fujisawa Japanese teenagers, 0.16%
• Japanese general population, 0.18%

Mortality/Morbidity

• Adult patients often perceive narcoleptic symptoms as embarrassing, and social isolation may result.
  • They may encounter interpersonal stress in relationships, sexual dysfunction, and difficulty working due to the disease itself or its treatment.
  • They may experience job impairment from sleep attacks, memory problems, cataplexy, interpersonal problems, and personality changes. These symptoms may lead coworkers to perceive narcoleptics as lazy, inattentive, and lacking motivation.
  • Patients with narcolepsy sometimes are falsely suspected of illegal drug use. Patients should inform employers concerning their stimulant medications, because they may test positive for amphetamines on screening preemployment drug tests.
  • In one study, 24% of narcoleptic patients had to quit working and 18% were terminated from their jobs because of their disease.
  • Left untreated, narcolepsy may be psychosocially devastating.
• Morbidity in narcoleptic children includes poor school performance, social impairment, ridicule from peers, and dysfunction in other activities of normal childhood development.

Race

See Frequency.

Sex

The male-to-female ratio is 1.64:1.

Age

• Narcolepsy has been reported in children as young as 2 years.
• The age-of-onset distribution is bimodal. The highest peak occurs at 15 years, while a less pronounced peak occurs at 36 years.

Clinical

History

The classic tetrad consists of excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Children rarely manifest all 4 symptoms.

• EDS is the primary symptom of narcolepsy and must be present for at least 3 months in all patients.
  • Sleepiness is a normal experience that cycles and invariably occurs after prolonged wakefulness. In healthy persons, mild sleepiness is apparent only during boring situations (eg, falling asleep while watching TV).
  • In patients with narcolepsy, severe EDS leads to involuntary somnolence during more active conditions such as driving, eating, or talking. Sleepiness in narcolepsy may be severe and constant, with paroxysms during which patients may fall asleep without warning (ie, sleep attacks).
  • Patients with narcolepsy tend to take short and refreshing naps (ie, REM type naps) during the day. Their daytime naps may be accompanied by dreams.
  • Several questionnaires evaluate sleepiness. The most commonly used is the 8-question Epworth Sleepiness Scale (1991).
    • Patients respond to each question on a scale from 0 (not at all likely to fall asleep) to 3 (very likely to fall asleep).
    • The resulting total score is between 0 and 24.
    • Although what score constitutes abnormal sleepiness is controversial, total scores above 10 generally warrant investigation.
• Cataplexy (Latin, "to strike down with fear") is a brief and sudden loss of muscle tone and represents REM intrusion during wakefulness.
  • If severe and generalized, it may cause a fall.
  • More subtle forms exist with only partial loss of tone (eg, head nod and knee buckling).
  • Respiratory and extraocular movements are preserved.
  • The most characteristic feature of cataplexy is that it usually is triggered by emotions (usually laughter and anger).
  • Cataplexy is seen in about 70% of patients with narcolepsy, and its presence with EDS strongly suggests the diagnosis of narcolepsy.
• Sleep paralysis is the inability to move upon awakening or less commonly upon falling asleep with consciousness intact.
  • It often is accompanied by hallucinations.
  • Respiratory and extraocular muscles are spared.
  • Sleep paralysis can be relieved by sensory stimuli such as touching or speaking to the patient.
  • Sleep paralysis occurs less frequently when patients sleep in uncomfortable positions.
• Sleep-related hallucinations may occur at sleep onset (ie, hypnagogic) or awakening (ie, hypnopompic) and are usually vivid (dreamlike) visual, auditory, or tactile in nature.
• Disrupted nocturnal sleep is also a common feature of narcolepsy. Consequently, total sleep time in 24 hours in narcoleptic patients is essentially unchanged due to daytime naps.
• Obesity is another common feature of narcolepsy and may lead to the coexistence of obstructive sleep apnea.
• The classic picture of narcolepsy may be somewhat different in young children.
  • Children may deny EDS because of embarrassment.
  • Sometimes restlessness and motor overactivity may predominate.
  • Academic deterioration, inattentiveness, and emotional lability are common.
  • In one study of 51 prepubertal patients with narcolepsy¹ , the following initial complaints were noted:
    • Children younger than 5 years presented with unexplained falls and "drop attacks," aggressive behavior, sudden irritability, and abrupt dropping of objects. Atonic seizures are the most common misdiagnosis in this age group.
    • In children aged 5-10 years, the most common initial complaint was inattentiveness, repetitive sleepiness, followed by difficulty with morning arousal associated with aggressive behavior and abrupt falls in school. These children often were misdiagnosed as having attention deficit hyperactivity disorder (ADHD), learning disability, depression, or another neurologic disorder.
    • In children aged 10-12 years, poor academic performance was a common complaint. Other presenting symptoms included inappropriate low level of alertness, falling asleep in class, and inability to wake up in the morning.

Physical

• Perform a careful neurologic examination to exclude other causes, including an underlying structural abnormality.
• No specific findings on physical examination suggest narcolepsy, although obesity may be associated with the disorder.
• Examining the patient during cataplexy shows appendicular muscle atonia and loss of deep tendon reflexes.

Differential Diagnoses

Other Problems to Be Considered

Idiopathic hypersomnia: This is similar in presentation to narcolepsy but the patient has no sleep-onset REM period and naps are unrefreshing. This entity is difficult to differentiate from narcolepsy, although the advent of the modern sleep laboratory has aided in making a diagnosis in these challenging cases. Like narcolepsy, the treatment is amphetamines.
Prader-Willi syndrome
Kasabach-Merritt syndrome
Autosomal dominant cerebellar ataxia, deafness, and narcolepsy
Delayed sleep-phase syndrome
Autism
Depression
Diencephalic lesions
Drug abuse
Insufficient sleep syndrome
Kleine-Levin syndrome
Medication effect
Norrie disease
Poor sleep hygiene
Posttraumatic narcolepsy
Increased intracranial pressure

Workup

Laboratory Studies

• HLA typing
  • DQB1*0602
  • DQA1*0602
  • In general, HLA typing is clinically useful to exclude narcolepsy. It is less valuable to confirm the diagnosis, since HLA-DR2 and DQw1 are present in 20-30% of the general population.
• CSF hypocretin levels below 110 pg/mL is indicative of narcolepsy. On the other hand, high CSF hypocretin levels do not exclude the diagnosis of narcolepsy.

Imaging Studies

• In most cases, imaging studies are unrevealing.
• A few small studies have implicated MRI changes of the pons within the reticular activating system. Structural abnormalities of the brain stem and diencephalon may present as idiopathic narcolepsy; however, the concept of "symptomatic" narcolepsy remains controversial.

Other Tests

• An overnight polysomnogram followed by a multiple sleep latency test (MSLT) is essential in the workup. All central nervous stimulants and sedative-hypnotics should be discontinued 2 weeks prior to the PSG and MSLT.
  • These tests allow exclusion of other causes of EDS, especially sleep apnea.
  • They provide information about daytime sleepiness by measuring sleep latency and sleep-onset REM periods (SOREMPs).
  • The MSLT involves 5 opportunities to nap at 2-hour intervals over the day.
  • More than 2 SOREMPs and a mean sleep latency of less than 8 minutes strongly suggest narcolepsy. These findings are not completely specific and also can be seen in patients with severe sleep deprivation or severe sleep apnea.
  • For these reasons, a polysomnogram of the previous night is necessary to interpret the MSLT.
  • The overnight polysomnogram findings typically are normal in narcolepsy, although they may show sleep fragmentation
  • MSLT cannot be used alone to confirm or rule out narcolepsy.
• Diagnosing narcolepsy in children presents numerous difficulties.
  • One study found that 85% of children with narcolepsy also suffered from sleep-disordered breathing.
  • Serial MSLTs may be required, and usually multiple confounding factors are involved (eg, increased alertness in the novel environment of the sleep laboratory).
  • Normative MSLT values for children have not been established.
  • HLA typing may provide collateral data but is more useful in excluding the diagnosis.
  • Measurement of CSF hypocretin levels may aide in the diagnosis.
  • Imaging studies such as MRI are useful to exclude rare causes of symptomatic narcolepsy.

Treatment

Medical Care

• Nonpharmacologic treatment
  • Sleep hygiene is important. Most patients improve if they maintain a regular sleep schedule, usually 7.5-8 hours of sleep per night.
  • Scheduled naps during the day also may help.
  • Provide emotional support and career/vocational counseling to the patient and parent.
  • Assist with documentation for special academic needs, insurance, disability forms, and attaining a driver's license.
  • Question patients about high-risk behaviors such as alcohol and drug use, which may exacerbate symptoms.
  • Inquiries into depression, family conflict, and other psychosocial problems are also important.
  • Encourage children to participate in after-school activities and sports. A well-designed exercise program can be beneficial and stimulating. School personnel should have the child with narcolepsy refrain from activities if he or she appear drowsy.
  • Avoidance of foods high in refined sugars may improve daytime sleepiness.
• Pharmacologic treatment
  • CNS stimulants such as methylphenidate, dextroamphetamine sulfate, methamphetamine, and amphetamine are used for treatment of narcolepsy.
    • Older stimulants are thought to act primarily through brainstem dopamine, nigrostriatal, and mesocorticolimbic pathways. These medications help reduce daytime sleepiness, improving the symptom in 65-85% of patients.
    • Methylphenidate, the most frequently used stimulant, improves sleep tendency in a dose-related fashion.
    • Undesirable side effects include headache, irritability, nervousness, and gastrointestinal complaints.
    • Nocturnal sleep may be impaired, thus decreasing total sleep time.
  • Modafinil was discovered recently as a novel wake-promoting agent.
    • The mechanism of action is not understood, but it does not appear to alter levels of dopamine or norepinephrine.
    • Modafinil's safety and efficacy have been evaluated in a multicenter, double-blind, placebo-controlled trial. The treatment group experienced both subjective and objective improvement in sleepiness.
    • Unlike traditional medications, modafinil does not appear to affect total sleep time or suppress REM sleep.
    • The most common adverse effect is headache. Its safety in children has not been established.
  • Sodium oxybate is the only FDA-approved treatment for cataplexy. It is also used to treat EDS. Sodium oxybate is a CNS depressant and should not be used with alcohol or other CNS depressants.
  • Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRI) have also been used to treat cataplexy.
  • Currently, no FDA-approved pharmacotherapy is available for children with narcolepsy. However, the medications used to treat narcolepsy in adults have been used off-label in the pediatric population with positive results.

Consultations

A child in whom narcolepsy is suspected must be evaluated by a pediatric neurologist. Further evaluation at a sleep disorders clinic is also imperative.

Diet

Patients with narcolepsy should avoid heavy meals and alcohol.

Activity

• Recommendations
  • Scheduled short naps
  • Exercise program
  • Restrict driving when sleepy (Patients with narcolepsy should avoid driving or operating heavy machinery when sleepy.)

Medication

The main focus is symptomatic treatment of excessive somnolence and cataplexy with CNS stimulants and antidepressants. Stimulants improve wakefulness, while antidepressants such as clomipramine and fluoxetine reduce cataplectic attacks.

CNS stimulants

These stimulants increase wakefulness, vigilance, and performance. They are thought to alter midbrain dopaminergic activity, but the precise mechanism of action is unknown. Interpatient variability in dose required to alleviate EDS is considerable and unpredictable. Some patients are relieved of daytime sleepiness completely with 5 mg of methylphenidate daily; others require higher doses. Initiate treatment at low doses and individualize the therapy.

Pemoline (Cylert)

Initial drug of choice in children younger than 7 y with narcolepsy; has relatively little effect on blood pressure. The United States FDA concluded that the overall risk of liver toxicity from pemoline outweighs the benefits. In May 2005, Abbott chose to stop sales and marketing of their brand of pemoline (Cylert) in the United States. In October 2005, all companies that produced generic versions of pemoline also agreed to stop sales and marketing of pemoline.

Dosing

Adult

60-200 mg PO qd

Pediatric

<7 years: Not established
>7 years: 18.75 mg PO bid titrated to symptoms; average daily dose, 187 mg/d

Interactions

May cause decreased seizure threshold in patients receiving antiepileptic drugs

Contraindications

Documented hypersensitivity; impaired hepatic function

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May exacerbate symptoms in psychotic children, tics, or Tourette syndrome; liver enzyme levels may increase—check liver function prior to starting therapy and periodically thereafter

Methylphenidate (Ritalin)

Piperidine derivative most commonly prescribed; efficacy has been demonstrated in randomized, double-blind, dose-response, and placebo-controlled trials.

Dosing

Adult

30-60 mg PO qd

Pediatric

Average pediatric dose similar to that of adults, approximately 50 mg PO qd

Interactions

May inhibit metabolism of coumarin anticoagulants, anticonvulsants, phenylbutazone, and tricyclic drugs (eg, imipramine, clomipramine, desipramine)

Contraindications

Documented hypersensitivity; marked anxiety, tension, and agitation (may aggravate these symptoms); glaucoma; motor tics; family history or diagnosis of Tourette syndrome

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution with hypertensive patients; check periodic CBC, differential, and platelet counts during prolonged therapy; high abuse potential (schedule II)

Modafinil (Provigil)

Pharmacologically distinct from other stimulants, does not appear to act via dopaminergic system.

Dosing

Adult

200-400 mg PO qd in single morning dose or divided doses

Pediatric

<16 years: Not established
>16 years: Administer as in adults

Interactions

May decrease levels of cyclosporine or steroidal contraceptives and, to lesser degree, theophylline; may increase concentrations of diazepam, propranolol, and phenytoin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor patients closely for signs of misuse or abuse, especially those with history of abuse of drugs or stimulants such as methylphenidate, amphetamine, and cocaine

Armodafinil (Nuvigil)

R-enantiomer of modafinil (mixture of R- and S-enantiomers). Elicits wake-promoting actions similar to sympathomimetic agents, although pharmacologic profile is not identical to sympathomimetic amines. In vitro, binds dopamine transporter and inhibits dopamine reuptake. Not a direct- or indirect-acting dopamine receptor agonist. Indicated to improve wakefulness in individuals with excessive sleepiness associated with narcolepsy, obstructive sleep apnea-hypopnea syndrome (OSAHS), or shift-work sleep disorder.

Dosing

Adult

150-250 mg PO qam

Pediatric

<17 years: Not established
>17 years: Administer as in adults

Interactions

Weakly induces CYP1A2 and CYP3A; may decrease levels of drugs metabolized by CYP1A2 (eg, theophylline) and CYP3A (eg, cyclosporine, midazolam, triazolam, steroidal contraceptives); may inhibit CYP2C19 activity, thereby increasing serum levels of CYP2C19 substrates (eg, omeprazole, phenytoin, propranolol)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic impairment and decrease dose with severe hepatic impairment; serious rash, including Stevens-Johnson syndrome, has been reported; other serious hypersensitivity reactions include angioedema, anaphylactoid reactions, and multiorgan hypersensitivity reactions; psychiatric adverse events (eg, mania, delusions, hallucinations, suicidal ideation) have been reported with modafinil; may increase blood pressure; monitor patients closely for signs of misuse or abuse, especially those with a history of drug or stimulant abuse (eg, methylphenidate, amphetamine, or cocaine)

Anticataplectic agents

Clomipramine, fluoxetine, and sodium oxybate treat cataplexy in patients with narcolepsy.

Clomipramine (Anafranil)

Dibenzazepine compound belonging to family of tricyclic antidepressants, reduces frequency of cataplexy and other auxiliary symptoms in narcolepsy.

Dosing

Adult

75-125 mg/d PO

Pediatric

1 mg/kg/d PO

Interactions

Haldol and possibly methylphenidate increase levels; increases level of phenobarbital; metabolized through P450 2D6 enzyme system

Contraindications

History of hypersensitivity to clomipramine HCl or other tricyclic antidepressants; recent myocardial infarction; MAOI within last 14 d

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause seizures, orthostatic hypotension, occasional elevation of liver enzymes, possible cardiac toxicity, rare cases of bone marrow suppression, hyperthermia

Fluoxetine (Prozac)

SSRI that treats cataplexy. Fewer side effects than tricyclic antidepressants. Its toxicity profile is also lower.

Dosing

Adult

20-40 mg/d PO

Pediatric

Average daily dose: 30 mg/d PO

Interactions

Interacts with flecainide, vinblastine, tricyclics, and drugs metabolized by P450 2D6; may cause occasional elevation of phenytoin and carbamazepine levels; may cause shift in protein binding of warfarin and digoxin

Contraindications

Documented hypersensitivity; hypersensitivity to SSRIs; MAOI within last 14 d

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use with caution in patients with hepatic impairment or history of seizures; discontinue MAOIs at least 14 d before initiating fluoxetine

Sodium oxybate (Xyrem)

Also known as gamma hydroxybutyrate (GHB). It is a central nervous system depressant used to treat patients with EDS and cataplexy. The precise mechanism by which sodium oxybate produces an effect on cataplexy is unknown.
Because of sodium oxybate's history of abuse as a recreational drug, the FDA approved it as a Schedule III Controlled Substance. A limited distribution program that includes physician education, patient education, a patient and physician registry, and detailed patient surveillance has been established. Under the program, prescribers and patients will be able to obtain the product only through the Xyrem Success Program, using a single centralized pharmacy 1-866-997-3688. Available as an oral solution 500 mg/mL.

Dosing

Adult

Initial dose: 2.25 g PO hs (while in bed), then repeat dose 2.5-4 h following first dose (total initial dose 4.5 g)
May increase dose by 1.5 g/d (ie, 0.75 g/dose) q2wk; not to exceed 9 g/d
Take on empty stomach at least 2 h after eating

Pediatric

Not established

Interactions

Coadministration with other CNS depressants or sedative hypnotics may increase toxicity; food significantly reduces bioavailability

Contraindications

Succinic semialdehyde dehydrogenase deficiency; coadministration with other CNS depressants or sedative hypnotic agents

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause confusion, depression, nausea, vomiting, dizziness, loss of consciousness, headache, incontinence, sleep dyspnea, or sleepwalking; abuse may lead to dependence and severe withdrawal symptoms; decrease initial dose by 50% with hepatic impairment; administer only at bedtime and while in bed; for at least 6 h after ingesting, do not engage in hazardous occupations or activities requiring complete mental alertness or motor coordination

Follow-up

Further Outpatient Care

• Both the primary pediatrician and pediatric neurologist should monitor children with narcolepsy.
• A sleep medicine specialist, if available, also should see the patient regularly.
• Patients should contact narcolepsy support groups.

Prognosis

• With proper management and treatment, patients with narcolepsy usually lead meaningful and productive personal and professional lives.

Patient Education

• Advise patients with narcolepsy about driving responsibilities.
• Educate patients, parents, teachers, and other care providers concerning the symptoms, prognosis, and safety precautions.
• For excellent patient education resources, visit eMedicine's Sleep Disorders Center. Also, see eMedicine's patient education article Narcolepsy.

Miscellaneous

Medicolegal Pitfalls

• Advise patients of the increased risk for sleep-related driving accidents.
• As of March 1994, only 6 states in the United States (California, Maryland, North Carolina, Oregon, Texas, and Utah) had guidelines for narcoleptic drivers.
• In contrast, most Canadian provinces and the United Kingdom have guidelines, but their effectiveness on reducing traffic-related morbidity is unknown.

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Keywords

narcolepsy, excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, hypersomnolence, sleep disorder, hypocretin

Contributor Information and Disclosures

Author

Ali M Bozorg, MD, Clinical Fellow in Epilepsy & Sleep Medicine, Comprehensive Epilepsy Program, Department of Neurology, University of South Florida
Ali M Bozorg, MD is a member of the following medical societies: American Academy of Neurology and American Society of Neuroimaging
Disclosure: Nothing to disclose.

Coauthor(s)

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Carmel Armon, MD, MSc, MHS, Professor of Neurology, Tufts University School of Medicine, Chief, Division of Neurology, Baystate Medical Center, Springfield, Massachusetts
Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Movement Disorders Society, and Sigma Xi
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Jose E Cavazos, MD, PhD, Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, University of Texas Health Science Center at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center; Director of the Epilepsy Center, Audie L Murphy Veterans Affairs Medical Center
Jose E Cavazos, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and Society for Neuroscience
Disclosure: Glaxo-SmithKline Honoraria Consulting; Ortho-McNeil Neurologics Honoraria Consulting; UCB Pharma Honoraria Consulting

CME Editor

Paul E Barkhaus, MD, Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center
Paul E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Matthew J Baker, MD, to the development and writing of this article.

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