(See also Approach to the Patient With a Sleep or Wakefulness Disorder Approach to the Patient With a Sleep or Wakefulness Disorder Almost half of all people in the US report sleep-related problems. Disordered sleep can cause emotional disturbance, memory difficulty, poor motor skills, decreased work efficiency, and increased... read more .)
The cause of narcolepsy is unknown. In Europe, Japan, and the US, incidence is 0.2 to 1.6/1000. Narcolepsy is equally common in both sexes.
Narcolepsy is strongly associated with specific human leukocyte antigen (HLA) haplotypes, but the cause is not thought to be genetic. Concordance in twins is low (25%), suggesting a prominent role for environmental factors, which often trigger the disorder. The neuropeptide hypocretin-1 is deficient in cerebrospinal fluid (CSF) of narcoleptic animals and most human patients, suggesting that the cause may be HLA–associated autoimmune destruction of hypocretin-containing neurons in the lateral hypothalamus.
Narcolepsy features dysregulation of the timing and control of rapid eye movement (REM) sleep. Therefore, REM sleep intrudes into wakefulness and into the transition from wakefulness to sleep. Many symptoms of narcolepsy result from postural muscle paralysis and vivid dreaming, which characterize REM.
There are 2 types:
Type 1: Narcolepsy due to hypocretin deficiency and accompanied by cataplexy (momentary muscular weakness or paralysis evoked by sudden emotional reactions)
Type 2: Narcolepsy with normal hypocretin levels and without cataplexy
The Kleine-Levin syndrome, a very rare disorder in adolescent boys, resembles narcolepsy. The Kleine-Levin syndrome causes episodic hypersomnia (excessive daytime sleepiness) and hyperphagia. Etiology is unclear but may be an autoimmune response to an infection.
Symptoms and Signs of Narcolepsy
The main symptoms of narcolepsy are
Excessive daytime sleepiness (EDS)
Hypnagogic and hypnopompic hallucinations
Disturbed nocturnal sleep (due to increased arousals)
About 10% of patients have all 5 of these symptoms.
Symptoms usually begin in adolescents or young adults without prior illness, although onset can be precipitated by an illness, a stressor, or a period of sleep deprivation. Once established, narcolepsy persists throughout life; life span is unaffected.
Excessive daytime sleepiness
EDS is the primary symptom and can occur anytime. Sleep episodes vary from few to many per day, and each may last minutes or hours. Patients can resist the desire to sleep only temporarily but can be roused as readily as from normal sleep. Sleep tends to occur during monotonous conditions (eg, reading, watching television, attending meetings) but may also occur during complex tasks (eg, driving, speaking, writing, eating).
Patients may also experience sleep attacks—episodes of sleep that strike without warning. Patients may feel refreshed when they awaken yet fall asleep again in a few minutes.
Nighttime sleep may be unsatisfying with frequent arousals and interrupted by vivid, frightening dreams.
Consequences include low productivity, breaches in interpersonal relationships, poor concentration, low motivation, depression, a dramatic reduction in quality of life, and potential for physical injury (particularly due to motor vehicle collisions).
Momentary episodes of muscular weakness or paralysis occur without loss of consciousness and usually last < 2 minutes;they are evoked by sudden emotional reactions, such as laughter, anger, fear, joy, or, often, surprise.
Weakness may be confined to the limbs (eg, patients may drop the rod when a fish strikes their line) or may cause a limp fall during hearty laughter (as in “weak with laughter”) or sudden anger. Cataplexy can also affect other muscles: The jaw may droop, facial muscles may flicker, eyes may close, the head may nod, and speech may be slurred. Vision may be blurred. These attacks resemble the loss of muscle tone that occurs during REM sleep.
Clinically significant cataplexy occurs in about 20% of patients.
Patients are momentarily unable to move as they are just falling asleep or immediately after they awaken. These episodes may be very frightening. They resemble the motor inhibition that accompanies REM sleep.
Sleep paralysis occurs in about 25% of patients but also in some healthy children and, less commonly, in healthy adults.
Hypnagogic or hypnopompic hallucinations
Particularly vivid auditory or visual illusions or hallucinations may occur when just falling asleep (hypnagogic) or, less often, immediately after awakening (hypnopompic). They are difficult to distinguish from intense reverie and are somewhat similar to vivid dreams, which are normal in REM sleep.
Hypnagogic hallucinations occur in about 30% of patients, are common among healthy young children, and occasionally occur in healthy adults.
Disturbed nocturnal sleep
Sleep is often also disturbed by increased arousals in patients with narcolepsy, potentially worsening EDS.
Diagnosis of Narcolepsy
Multiple sleep latency testing
A delay of 10 years from onset of symptoms to diagnosis of narcolepsy is common.
A history of cataplexy strongly suggests narcolepsy in patients with EDS.
In patients with EDS, nocturnal polysomnography, followed by multiple sleep latency testing (MSLT), can confirm a diagnosis of narcolepsy when the findings include the following:
Sleep-onset REM episodes during at least 2 of 5 daytime nap opportunities or one during daytime nap opportunities plus one during the preceding nocturnal polysomnogram
Average sleep latency (time to fall asleep) of ≤ 8 minutes
No other diagnostic abnormalities on nocturnal polysomnography
Narcolepsy type 1 is diagnosed if patients also have cataplexy; type 2 is diagnosed if patients do not have cataplexy. EDS occurs in patients with narcolepsy type 1 or type 2.
The maintenance of wakefulness test does not help with diagnosis but does help monitor treatment efficacy.
Other disorders that can cause chronic EDS are usually suggested by the history and physical examination; brain imaging and blood and urine tests can confirm the diagnosis. These disorders include space-occupying lesions affecting the hypothalamus or upper brain stem, increased intracranial pressure, and certain forms of encephalitis. Hypothyroidism Hypothyroidism Hypothyroidism is thyroid hormone deficiency. Symptoms include cold intolerance, fatigue, and weight gain. Signs may include a typical facial appearance, hoarse slow speech, and dry skin. Diagnosis... read more , hyperglycemia, hypoglycemia Hypoglycemia Hypoglycemia, or low plasma glucose level can result in sympathetic nervous system stimulation, and central nervous system dysfunction. In patients with diabetes who take insulin or antihyperglycemic... read more , anemia, uremia, hypercapnia Ventilatory Failure Ventilatory failure is a rise in PaCO2 (hypercapnia) that occurs when the respiratory load can no longer be supported by the strength or activity of the system. The most common causes are severe... read more , hypercalcemia Hypercalcemia Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism... read more , hepatic failure Acute Liver Failure Acute liver failure is caused most often by drugs and hepatitis viruses. Cardinal manifestations are jaundice, coagulopathy, and encephalopathy. Diagnosis is clinical. Treatment is mainly supportive... read more , and seizure disorders Seizure Disorders A seizure is an abnormal, unregulated electrical discharge that occurs within the brain’s cortical gray matter and transiently interrupts normal brain function. A seizure typically causes altered... read more can also cause EDS with or without hypersomnia. Acute, relatively brief EDS and hypersomnia commonly accompany acute systemic disorders such as influenza. Hypersomnia also occurs in patients with meningoencephalitis due to African trypanosomiasis (sleeping sickness), which is transmitted by the tsetse fly.
Treatment of Narcolepsy
Modafinil or armodafinil
Narcolepsy may not require treatment if patients have occasional episodes of sleep paralysis or hypnagogic and hypnopompic hallucinations, infrequent and partial cataplexy, and mild EDS. For others, wake-promoting drugs and anticataplectic drugs are used. Patients should also get enough sleep at night and take brief naps (< 30 minutes) at the same time every day (typically afternoon). Patients with cataplexy should avoid precipitating factors (eg, laughter, anger, fear).
For type 1 narcolepsy, oxybates (sodium oxybate or a combination drug that contains calcium, magnesium, potassium, and sodium oxybates) or pitolisant should be used for cataplexy, and if EDS persists, modafinil should be added.
For type 2 narcolepsy, modafinil should be first-line treatment, with solriamfetol as 2nd-line for EDS. Pitolisant can also be used to treat EDS.
Modafinil, a long-acting wake-promoting drug, can help patients with EDS. The mechanism of action is unclear. Typically, modafinil 100 to 200 mg orally is given in the morning. Dose is increased to 400 mg as needed. If effects do not last into the evening, a small 2nd dose (eg, 100 mg) at noon or 1 pm may be used, although this dose sometimes interferes with nocturnal sleep.
Adverse effects of modafinil include nausea and headache, which are mitigated by lower initial doses and slower titration. Modafinil can lower the effectiveness of oral contraceptives and has abuse potential, although it is low. Rarely, serious rashes and Stevens-Johnson syndrome Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous hypersensitivity reactions. Drugs, especially sulfa drugs, antiseizure drugs, and antibiotics, are the most common... read more have developed in patients taking modafinil. If serious reactions develop, the drug should be stopped permanently. Modafinil should not be used during pregnancy because it may cause severe fetal congenital anomalies, including cardiac anomalies.
Armodafinil, the R-enantiomer of modafinil, has similar benefits and adverse effects but is longer-acting; dosage is 150 or 250 mg orally once in the morning.
Solriamfetol is a norepinephrine-dopamine reuptake inhibitor. It is indicated to treat EDS (but not cataplexy) in patients with narcolepsy or obstructive sleep apnea (OSA). The starting dose is 75 mg orally once a day, which can be doubled every 3 days to a maximum 150 mg once a day. Dose adjustment is required for patients with renal impairment, and solriamfetol should not be used in patients with end-stage renal disease. In clinical trials, solriamfetol was well-tolerated and significantly relieved symptoms of excessive sleepiness (documented by the Epworth Sleepiness Scale and maintenance of wakefulness testing) in adults with narcolepsy and in those with OSA and EDS. The most common adverse effects are insomnia, headache, nausea, decreased appetite, and diarrhea. There are no interactions with oral contraceptives.
Pitolisant is a histamine-3 receptor inverse agonist, which is indicated for treatment of EDS and cataplexy in patients with narcolepsy. The dosage varies between 8.9 to 35.6 mg in the morning. Pitolisant is started at 8.9 mg orally once a day (taken on awakening) and increased to 17.8 mg once a day at week 2. The dose may be increased to a maximum of 35.6 mg once a day if needed. Dose adjustment is required for patients with renal or hepatic impairment, and pitolisant should not be used in patients with end-stage renal disease. Adverse effects include headache, irritability, anxiety, and nausea. It interacts with oral contraceptives, making them less effective.
Sodium oxybates or a combination drug that contains calcium, magnesium, potassium, and sodium oxybate salts can also be used to treat EDS and cataplexy. The dose of both drugs is 2.25 g taken orally at bedtime while in bed, followed by the same dose 2.5 to 4 hours later. The maximum dose is 9 g a night. Adverse effects include headache, nausea, dizziness, nasopharyngitis, somnolence, vomiting, urinary incontinence, and sometimes sleepwalking. Oxybates are schedule III drugs and have the potential for abuse and dependence. They are contraindicated in patients with succinic semialdehyde dehydrogenase deficiency. Sodium oxybate should be used cautiously in patients with untreated respiratory disorders, hypertension, or heart failure (because sodium oxybate contains more sodium than the combination drug that contains several different oxybate salts).
Tricyclic antidepressants (particularly clomipramine, imipramine, and protriptyline) and SSRIs (eg, venlafaxine, fluoxetine) have been used in the past to treat cataplexy, sleep paralysis, and hypnagogic and hypnopompic hallucinations; however, data about the effectiveness of these drugs are limited. These drugs should be used only if pitolisant and oxybates are ineffective.
Methylphenidate or amphetamine derivatives can be used if patients do not respond to or cannot tolerate wake-promoting drugs. However, all stimulants should be considered 3rd- or 4th line after modafinil, armodafinil, solriamfetol, and pitolisant. If stimulants are prescribed for patients > 40 years, an exercise stress test should be done to determine whether patients have underlying cardiovascular disease.
Methylphenidate: 5 to 15 mg orally 2 or 3 times a day
Methamphetamine: 5 to 20 mg orally 2 times a day
Dextroamphetamine 5 mg orally 2 times a day to 20 mg orally 3 times a day
Methylphenidate and amphetamine derivatives are available in long-acting preparations and therefore can be dosed once a day in many patients. However, these stimulants have significant adverse effects, including agitation, hypertension, tachycardia, myocardial infarction (secondary to vasoconstriction), changes in appetite, and mood changes (eg, manic reactions). Abuse potential is high.
Narcolepsy may be caused by autoimmune destruction of hypocretin-containing neurons in the lateral hypothalamus.
The main symptoms are excessive daytime sleepiness (EDS), cataplexy, hypnagogic and hypnopompic hallucinations, sleep paralysis, and disturbed nocturnal sleep.
Confirm the diagnosis by polysomnography and multiple sleep latency testing.
EDS usually responds to modafinil or another wake-promoting drug; cataplexy responds to pitolisant or oxybates.
Drugs Mentioned In This Article
|Drug Name||Select Trade|
|Effexor, Effexor XR, Venlafaxine|
|Prozac, Prozac Weekly, Sarafem, Selfemra|
|Adhansia XR, Aptensio XR, Concerta, Cotempla XR, Daytrana, Jornay, Metadate CD, Metadate ER, Methylin, QuilliChew ER, Quillivant XR, RELEXXII, Ritalin, Ritalin LA, Ritalin SR|
|Adzenys, Adzenys XR, Dyanavel XR, Evekeo|
|Dexedrine, Dexedrine Spansule, DextroStat, Liquadd , ProCentra , XELSTRYM, Zenzedi|