Pulmonary Medicine

Narcolepsy

What every physician needs to know:

Narcolepsy is a chronic sleep disorder caused by a dysfunction of the central nervous system's sleep-wake regulation.

The classic tetrad for narcolepsy consists of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, and hypnagogic hallucinations. Only some of the four symptoms may be present in an individual, and these symptoms may vary in frequency and severity over time. EDS, sleep paralysis, and hypnagogic hallucinations can be present in any individual who is sleep-deprived; these symptoms are not specific to narcolepsy. Only cataplexy is unique to narcolepsy.

Narcoleptic patients are able to achieve wakefulness, non-rapid eye movement (NREM) sleep, and REM sleep but are unable to maintain the state. These patients dissociate into various states of consciousness at inappropriate times. This dissociation is often incomplete, leading to a mixture of normal and abnormal states of consciousness.

Dysregulation of REM sleep is a key feature of narcolepsy. Unlike other individuals, narcoleptics exhibit short REM sleep latency (sleep-onset REM or SOREM), in which REM sleep is achieved immediately or very soon after sleep onset. The intrusion of REM sleep into wakefulness is the pathophysiologic phenomenon behind cataplexy, sleep paralysis, and hypnagogic hallucinations.

The cause of narcolepsy has yet to be determined, but there is evidence for both genetic and environmental factors. Human narcolepsy with cataplexy is due to a deficiency in the neuropeptide hypocretin (also known as orexin), a major wake-promoting neurotransmitter. Produced exclusively in the hypothalamus, the neuropeptides hypocretin-1 and -2 (orexin A and B) are intimately involved in wake-promoting mechanisms. Narcoleptic humans have very low or absent levels of cerebrospinal fluid (CSF) hypocretin-1. Hypocretin neurons are selectively damaged in patients with narcolepsy, but the cause of the damage is unknown.

Narcolepsy affects men and women equally, with a prevalence of approximately 1 in 2000 in the United States. It usually develops within the second or third decade of life (most commonly before age 25). It is very rare to develop narcolepsy in infancy or old age.

To date, there is no known cure.

Classification:

The International Classification of Sleep Disorders-2 (ICSD-2) divides narcolepsy into three categories: narcolepsy with cataplexy, narcolepsy without cataplexy, and secondary narcolepsy, discussed below. Narcolepsy without cataplexy has been a topic of debate since, without clear-cut cataplexy, symptoms of narcolepsy (without cataplexy) may be due to hypersomnia of unknown etiology.

For narcolepsy with cataplexy, excessive daytime sleepiness must be present almost daily for at least three months, along with a history of clear-cut cataplexy. The daytime sleepiness is not better explained by another sleep disorder, medical condition, or medication use. If a history of clear-cut cataplexy is present, the diagnosis need not be but should be confirmed by one of the following:

a) measurement of cerebrospinal fluid (CSF) hypocretin-1 [level < 110 pg/mL or 1/3 of mean normal control value is diagnostic for narcolepsy with cataplexy], or

b) nocturnal polysomnography (six hours of sufficient sleep and no other sleep disorders) followed by a Multiple Sleep Latency Test (mean sleep latency ≤ 8 min and ≥ 2 sleep-onset REM periods).

In narcolepsy without cataplexy, excessive daytime sleepiness must be present almost daily for at least three months, but there is either no history of clear-cut cataplexy or a history of atypical (questionable) cataplexy-like episodes. The daytime sleepiness is not better explained by another sleep disorder, medical condition, or medication use. The diagnosis must be confirmed by one of the following:

a) measurement of CSF hypocretin-1, or

b) confirmatory sleep studies (nocturnal polysomnogram followed by a Multiple Sleep Latency Test).

In secondary narcolepsy (narcolepsy that is due to a medical condition), excessive daytime sleepiness must be present almost daily for at least three months, and a significant underlying medical or neurological disorder that accounts for the daytime sleepiness must be present along with one of the following criteria:a) a definitive history of cataplexy, or

b) atypical (questionable) cataplexy plus confirmatory studies (CSF hypocretin-1 measurement or nocturnal polysomnogram followed by Multiple Sleep Latency Test), or

c) CSF hypocretin-1 level < 110 pg/mL (or 1/3 of normal control values).

Neurologic insults or medical conditions associated with secondary narcolepsy can be localized to the hypothalamus or they can be global. These conditions include but are not limited to brain tumors, head trauma, traumatic brain injury, multiple sclerosis, encephalomyelitis, vascular disorders, strokes, degenerative diseases, and inherited diseases (e.g., Neimann-Pick type C, myotonic dystrophy, Prader-Willi).

Are you sure your patient has narcolepsy? What should you expect to find?

Excessive daytime sleepiness (EDS) and cataplexy are considered the main symptoms of narcolepsy.

Excessive daytime sleepiness is typically the first symptom that comes on, and other symptoms of narcolepsy may or may not develop later. Narcoleptics complain of chronic daytime sleepiness and fatigue and describe an irresistible or overwhelming urge to sleep throughout the day, whether they are sedentary or active.

These urges, known as sleep attacks, may come on at inappropriate times, such as when driving or conversing. They usually occur several times a day and can last from several minutes to a few hours. Narcoleptics wake up from these sleep episodes feeling refreshed, and there is a refractory period of one to several hours before the next episode occurs.

It is important to differentiate sleep attacks from cataplexy.

Cataplexy is an abrupt and reversible decrease or loss of bilateral skeletal muscle tone (occasionally unilateral) that is provoked by intense emotional experiences, most commonly humor, laughter, or anger. Rarely, a cataplectic attack comes on due to sudden surprise, stress, embarrassment, or sexual arousal. Cataplexy may involve certain muscles or the entire musculature, but the diaphragm and ocular muscles are unaffected. In a typical cataplectic attack, the jaw sags, the head falls forward, the arms drop to the side, and the knees buckle.

Rarely, a cataplectic attack involves complete loss of all muscle tone, leading to total body collapse that can result in serious injury. Speech may be slurred, and the patient may complain of being clumsy or uncoordinated during these times. The attack usually lasts from thirty seconds to two minutes, but in rare situations, known as status catplecticus, the cataplectic attack can last for hours. Awareness is preserved throughout the cataplectic attack, so the patient remains awake and aware of his/her surroundings. If the attack is prolonged, rapid eye movement (REM) sleep may follow.

During normal sleep, an individual goes into NREM sleep and then REM sleep, and this cycle alternates as the night goes on. During normal REM sleep, the individual loses skeletal muscle tone (with the exception of the diaphragm), also known as REM sleep paralysis, and dreaming occurs. In narcoleptics, there is dissociation of certain components of REM sleep, so the individual may experience parts of REM sleep during wakefulness (i.e., sleep paralysis, cataplexy, hypnagogic hallucinations).

Sleep paralysis is best described as a terrifying experience that occurs upon falling asleep or awakening, when individuals find themselves paralyzed, suddenly unable to move arms and legs, speak, or even breathe deeply. During the event the individual is fully aware of what is happening and afterwards is able to recall the event vividly. With time, the individual learns that such episodes are brief and benign, rarely lasting longer than a few minutes and always ending spontaneously.

Unlike cataplexy, these episodes are not provoked by intense emotion. Sleep paralysis commonly occurs with hypnagogic/hypnopompic hallucinations and may occur as an independent and isolated phenomenon, especially after sleep deprivation. Between 3 percent and 5 percent of the general population may experience this phenomenon.

Abnormal vivid auditory or visual hallucinations that occur while falling asleep are known as hypnagogic hallucinations, but the more common hypnopompic hallucinations occur upon awakening. These hallucinations are intense dream-like states that are associated with feelings of fear or major threat, so they are frightening and disturbing to the individual who experiences them. The hallucinations may be visual, auditory, or (less commonly) tactile or vestibular.

Visual hallucinations, which may be in color or black and white, consist of simple forms and shapes or more intricate manifestations, such as people or animals. Auditory hallucinations, which may manifest as simple or complex sounds that may be threatening or derogatory, leave the patient terrified. Less commonly, patients report a sense of falling from the air or that someone is touching them. Hypnagogic hallucinations are often associated with sleep attacks.

In conjunction with symptoms of excessive daytime sleepiness, a definitive diagnosis of narcolepsy can be made if a positive history of clear-cut cataplexy is present. Without cataplexy, the symptoms described above (i.e., excessive daytime sleepiness, sleep paralysis, hypnagogic/hypnopompic hallucinations) may be seen in any individual who is sleep deprived as well as in other sleep-related disorders; therefore, confirmatory studies must be performed in order to establish the diagnosis.

Narcoleptics also complain of insomnia, disrupted sleep, and cognitive dysfunction, such as trouble with concentration, focus, and memory. Several sleep disorders are commonly seen with narcolepsy, including obstructive sleep apnea, REM sleep behavioral disorder, and periodic limb movement disorder.

Beware: there are other diseases that can mimic narcolepsy:

Symptoms of narcolepsy overlap with many other medical and psychiatric disorders, as well as other sleep disorders. With the exception of cataplexy, other symptoms of narcolepsy (i.e., hypnagogic/hypnopompic hallucinations, excessive daytime sleepiness, sleep paralysis) can be seen with sleep deprivation or other sleep disorders (e.g., OSA). Obstructive sleep apnea (OSA) is the most common disorder in the category of sleep-related breathing disorders. Obstructive sleep apnea patients present with chronic excessive daytime sleepiness and are commonly misdiagnosed with narcolepsy. Idiopathic hypersomnia can also be mistakenly diagnosed as narcolepsy, as these individuals present with excessive daytime sleepiness.

Other sleep disorders that may present with abnormal daytime sleepiness include circadian rhythm disorders and movement disorders, such as restless legs syndrome and periodic limb movement disorder. In the latter two, patients experience sleep fragmentation as a result of electroencephalographic arousals caused by limb movements, resulting in daytime hypersomnolence.

Neurologic disorders or lesions of the hypothalamus, such as multiple sclerosis, brain injury, encephalomyelitis, tumors, and cerebrovascular accidents, can also present with narcolepsy symptoms. Congenital disorders like Prader-Willi, myotonic dystrophy, and Neimann-Picks have also been associated with narcolepsy.

How and/or why did the patient develop narcolepsy?

Narcolepsy with cataplexy is associated with postnatal loss of hypocretin-containing neurons in the hypothalamus. The cause is unknown; while an autoimmune process is thought to be responsible for the loss of postnatal hypocretin neurons, antibodies to hypocretin and its receptors have not been found.

The discovery that human narcolepsy is associated with the tissue-type human leukocyte antigen HLA-DQB1*0602 led to the hypothesis that narcolepsy may be autoimmune-mediated since many autoimmune diseases are associated with class II HLA haplotypes. A genome-wide association study in white populations of North America and Europe led to the discovery that narcolepsy is strongly associated with polymorphisms in the T-cell receptor α locus, which encodes a major receptor for the HLA-peptide presentation of any disease. This finding suggests that postnatal cell death of hypocretin neurons in human narcolepsy occurs by organ-specific autoimmune targeting with HLA-TCR interactions.7

Which individuals are at greatest risk of developing narcolepsy?

Narcolepsy affects men and women equally. Although there is a greater incidence of narcolepsy among first-degree relatives, it occurs less frequently than would be predicted based on normal patterns of inheritance. Sporadic and familial forms of narcolepsy exist in humans, with the sporadic form being dominant (95%). Familial and twin studies have suggested that several genes and HLA are involved in human narcolepsy.

There is a predisposition for narcolepsy based on race and ethnicity. The prevalence of narcolepsy with cataplexy ranges from 0.002 percent among Israeli Jews to 0.15 percent among Japanese general population. A general-population-based study with a representative sample of more than eighteen thousand individuals in five European countries estimated a prevalence of 0.047 percent.

Narcolepsy with cataplexy is closely associated with the human leukocyte antigen (HLA) haplotype, specifically subtypes DR2 (DRB1*1501) and DQ (DQB1*0602). Both of these subtypes are present in most narcoleptics, but DQB1*0602 is more specifically associated in African Americans with narcolepsy with cataplexy. The most common HLA marker associated with narcolepsy with cataplexy is the DQB1*0602, with a prevalence ranging from 85-95 percent. Patients with this HLA marker may have a genetic susceptibility to some event that leads to development of narcolepsy. Environmental insults, such as infections and head trauma, have been associated with the onset of narcolepsy.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Blood testing for HLA DQB1*0602:

The HLA DQB1*0602 is found in 95 percent of narcoleptic patients with cataplexy, 41 percent of patients with narcolepsy without cataplexy, and 18-35 percent of the general population. HLA testing is not a useful screening or diagnostic test because the prevalence is also high in the general population, but it may be helpful in atypical (questionable) narcolepsy with cataplexy-like presentation. A negative HLA test should encourage the clinician to exclude other sleep disorders first before assigning a diagnosis of narcolepsy.

Cerebrospinal fluid (CSF) hypocretin measurement:

Because narcolepsy with cataplexy lacks CSF hypocretin-1, a lumbar puncture may be performed to evaluate the CSF hypocretin level. A very low or undetectable CSF hypocretin level (< 110 pg/mL) is diagnostic for the disease. Based on prior data, the association between low CSF hypocretin level and narcolepsy is clear when there is a history of clear-cut cataplexy and HLA positivity. When cataplexy is absent or atypical (questionable), only about 20-40 percent of narcoleptic patients have low hypocretin levels. This patient group (the non-cataplectic narcoleptics with normal hypocretin levels) may represent an entirely different disease entity with different pathology.

What imaging studies will be helpful in making or excluding the diagnosis of narcolepsy?

Imaging studies are not routinely indicated in the evaluation for narcolepsy. When secondary narcolepsy is in question, brain magnetic resonance imaging (MRI) and/or computed tomography (CT) of the head may be helpful in evaluating lesions of the hypothalamus that may account for symptoms suggestive of narcolepsy.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of narcolepsy?

Non-invasive pulmonary diagnostic studies are not indicated and are unlikely to be useful in the evaluation of narcolepsy.

What diagnostic procedures will be helpful in making or excluding the diagnosis of narcolepsy?

CSF hypocretin measurement:

A diagnosis of narcolepsy can be made if a history of clear-cut cataplexy is present in a patient with abnormal daytime sleepiness. If cataplexy is not present or is atypical (questionable), then measurement of cerebrospinal fluid (CSF) hypocretin-1 should be performed to definitively diagnose narcolepsy with cataplexy. CSF hypocretin-1 concentration greater than 200 pg/mL is seen in controls and in patients with other sleep disorders, whereas concentration less than 110 pg/mL is 94 percent predictive of narcolepsy with cataplexy. Currently, CSF hypocretin-1 measurement is the most accurate diagnostic technique.

Attended polysomnogram (PSG) followed by multiple sleep latency testing (MSLT):

Alternatively, the diagnosis of narcolepsy requires a clinical history of excessive daytime sleepiness and a positive multiple sleep latency test (MSLT). A positive MSLT requires a mean sleep-onset latency of no more than eight minutes and two or more sleep-onset REM periods. A required polysomnogram that documents at least six hours of sleep and no other sleep-related disorders is performed the night before the MSLT.

The MSLT is the accepted standard for obtaining objective information regarding abnormal daytime sleepiness. An overnight polysomnogram performed the night before that documents at least six hours of sleep and no other sleep disorders is required. The MSLT consists of five scheduled naps, each lasting twenty minutes, scheduled every two hours during the day. Following each nap, the patient is asked to stay awake until the next scheduled nap. The test measures the time it takes to fall asleep (i.e., sleep onset latency, or SOL) as well as the presence or absence of REM sleep during each nap (i.e., sleep onset REM, or SOREM).

Prior to the availability of hypocretin-1 measurement, SOL of no more than eight minutes plus two SOREMs on an MSLT was considered diagnostic for narcolepsy, provided that the overnight PSG was negative for a sleep-related disorder and at least six hours was achieved. However, data has shown that these findings can also be seen in patients who are sleep-deprived, as well as in obstructive sleep apnea and other sleep-related disorders. The MSLT measures objective sleepiness but does not determine what causes sleepiness.

Patients with narcolepsy who do not have a history of cataplexy or who have atypical (questionable) cataplexy-like events require confirmatory overnight polysomnogram followed by MSLT. Prior to performing these tests, other sleep disorders should be ruled out or treated. Alternatively, CSF hypocretin levels can be obtained to make the diagnosis.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of narcolepsy?

There are no genetic or blood tests available for clinical use to make a positive diagnosis of narcolepsy. The genetic marker HLA DQB1*0602 can be helpful in the evaluation for narcolepsy, but it does not make a diagnosis. Almost all narcoleptics with deficient hypocretin-1 are also positive for this HLA. The HLA DQB1*0602 is found in 95 percent of narcoleptic patients with cataplexy, 41 percent of patients with narcolepsy without cataplexy, and 18-35 percent of the general population. Therefore, a negative test essentially rules out narcolepsy with cataplexy, but a positive test neither rules it out nor rules it in. The HLA DQB1*0602 can be useful when evaluating a patient with suspected narcolepsy who has a history of atypical (questionable) cataplexy. A negative HLA test should encourage the clinician to exclude other sleep disorders before assigning a diagnosis of narcolepsy.

If you decide the patient has narcolepsy, how should the patient be managed?

There is no known cure for narcolepsy, so treatment is primarily targeted at managing symptoms (e.g., daytime sleepiness, cataplexy). Non-pharmacologic treatments include patient education, sleep hygiene, daytime naps, and changes in lifestyle as necessary. Patients are advised to keep a consistent sleep schedule and to avoid sleep deprivation or irregular sleep patterns. Short daytime naps (20 minutes) two or three times a day have been shown to help in improving daytime sleepiness. Patients should be warned about the potential dangers of driving or operating machinery while drowsy or sleepy and the need to take necessary precautions to avoid accidents. Non-pharmacologic treatments are helpful in improving quality of life but should not be the only treatments provided.

Pharmacologic treatment for narcolepsy is divided into two categories: treatment for excessive daytime sleepiness (EDS) and treatment for cataplexy.

Treatment for combined excessive daytime sleepiness and cataplexy:

Sodium Oxybate (GHB)

Sodium oxybate is the treatment of choice for narcolepsy with cataplexy. The improvement in cataplexy is more rapid than the improvement in daytime sleepiness, which can take six to eight weeks. Therefore, supplementation with a different alerting medication (e.g., modafinil) in the first two months of treatment is recommended to improve daytime sleepiness. Sodium oxybate, which is taken at bedtime and a second dose 2.5–4 hours later while in bed, has a short half-life of 90-120 minutes. The drug is gradually increased over six to eight weeks to a goal of 6-9 grams per night, which is the effective dose.

Side effects of sodium oxybate include disorientation when awakened in the middle of the night, enuresis, nausea, and morning grogginess. The advantage of sodium oxybate is its significant impact on daytime sleepiness and cataplexy, and that patients need to take only one medication to treat narcolepsy with cataplexy. Sodium oxybate may cause respiratory depression and should be used with caution in patients with co-morbid narcolepsy and OSA, especially when OSA is not being treated.

Treatment for excessive daytime sleepiness:

Modafinil and Armodafinil

Modafinil and armodafinil are first-line pharmacologic treatments for abnormal daytime sleepiness and irresistible episodes of sleep in patients with narcolepsy. It has low to no abuse potential and no development of tolerance and it does not cause rebound hypersomnolence when stopped. Modafinil and armodafinil have no effect on cataplexy or other REM-related sleep phenomena (i.e., sleep paralysis, cataplexy).

Common side effects include headache, nervousness, nausea, and dry mouth. These symptoms can be reduced or avoided by a slow increase in dosage. Blood pressure should be monitored, as the medications may cause elevated blood pressure, and they should be used with caution in hypertensive patients whose blood pressure is not well controlled. Modafinil is taken once in the morning, or twice--once in the morning and once at lunchtime. Its elimination half-life is ten to twelve hours. Armodafinil, the R-enantiomer of modafinil, has a longer half-life of ten to fourteen hours and is administered once daily in the morning.

Both medications can reduce the efficacy of oral contraceptives, so patients should be advised about additional forms of contraception.

Amphetamine and Amphetamine-like CNS Stimulants

These central nervous system stimulants include methylphenidate, dextroamphetamine, and methamphetamine. They all have significant side effect profiles, including cardiovascular complications, high abuse potential, and development of tolerance. These medications are no longer recommended for the treatment of abnormal daytime sleepiness when better options are available.

Treatment for cataplexy:

Selective Norepinephrine/Serotoninergic Uptake Inhibitors

These medications, also known as antidepressants, are used to treat cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations. The most commonly used drug in this class is venlafaxine at a dosage of 75-150mg twice a day for adults and children. It is a potent inhibitor of serotonin and norepinephrine. The advantages of this class of medications are its improved side-effect profile, greater efficacy, and that it can be taken during wakefulness.

Atomoxetine

Atomoxetine is a highly specific noradrenergic reuptake inhibitor that has been shown to be effective in improving cataplexy and daytime sleepiness in children. It is given as 18-100mg once a day or in two divided doses. Its advantage is the use of one medication to treat both daytime sleepiness and cataplexy, but it is less effective than modafinil and sodium oxybate in adults.

Selective Serotonin Reuptake Inhibitors (SSRIs):

SSRIs block presynaptic reuptake of catecholamines with selectivity towards serotonin. The prototype of this class is fluoxetine. SSRIs also inhibit REM sleep. Because of the availability and improved efficacy of newer drugs, SSRIs are no longer recommended as the first-line treatment for cataplexy.

Tricyclic Antidepressants (TCAs)

The three most common TCAs--imipramine, clomipramine, and protriptyline--are similar to SSRIs in that they increase muscle tone and inhibit REM sleep. Rebound cataplexy that may occur upon abrupt discontinuation of these medications can be severe. Because of their significant side-effect profile, TCAs are not recommended as a first-line treatment for cataplexy and are used only as a last resort.

What is the prognosis for patients managed in the recommended ways?

Narcolepsy is a life-long disorder that begins early in life, usually within the second or third decade of life. Although there is no cure, appropriate treatment will allow the patient to lead a normal, healthy, and productive lifestyle.

What other considerations exist for patients with narcolepsy?

Although familial forms of narcolepsy exist in humans, the sporadic form is dominant (95%). Family genetic counseling is not recommended in narcoleptic patients. Non-pharmacologic treatments, including advance care planning and education on the disease process, are important in improving the quality of life in narcoleptics. Narcoleptic patients can be directed toward several websites that are dedicated to narcolepsy and related topics on sleep disorders.

  • American Academy of Sleep Medicine, for patients and professionals.

  • Cataplexic offers a variety of resources, including a chat room and a message board developed by a narcoleptic patient.

  • Fact Sheet on Narcolepsy, prepared by the National Heart, Lung, and Blood Institute (NHLBI) at NIH.

  • Narcolepsy Network

  • The American Sleep Apnea Association

  • Provigil, developed by Cephalon, Inc. to treat excessive daytime sleepiness associated with narcolepsy.

  • Talk About Sleep provides information, news, and support for the whole range of sleep disorders.

What’s the evidence?

Mignot, E, Kryger, MH, Roth, T, Dement, WC. "Narcolepsy: pathophysiology and genetic predisposition". Principles and practice of sleep medicine. Elsevier Saunders. 2011. pp. 938-956.

(An up-to-date, authoritative, and comprehensive review of the underlying pathophysiology of narcolepsy.)

Guilleminault, C, Cao, M, Kryger, MH, Roth, T, Dement, WC. "Narcolepsy: diagnosis and management". Principles and practice of sleep medicine. Elsevier Saunders. 2011. pp. 957-968.

(The diagnosis and management of narcolepsy is reviewed in this recent evidence-based summary.)

Cao, M. "Advances in narcolepsy". Med Clin North Am. vol. 94. 2010. pp. 541-555.

(A general overview of narcolepsy geared for the general physician.)

Ahmed, I, Thorpy, M. "Clinical features, diagnosis and treatment of narcolepsy". Clin Chest Med.. vol. 31. 2010. pp. 371-381.

(This overview of narcolepsy has specialized information for the sleep medicine and pulmonary physician.)

Dauvilliers, Y, Arnulf, I, Mignot, E. "Narcolepsy with cataplexy". Lancet. vol. 369. 2007. pp. 499-511.

"International classification of sleep disorders: diagnostic and coding manual". American Academy of Sleep Medicine. 2005.

Hallmayer, J, Faraco, J, Lin, L. "Narcolepsy is strongly associated with the T-cell receptor alpha locus". Nat Genet. vol. 41. 2009. pp. 708-711.

Mignot, E, Hayduk, R, Grumet, FC. "HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients". Sleep. vol. 20. 1997. pp. 1012-1020.

Nishino, S, Okuro, M, Kotorii, N. "Hypocretin/orexin and narcolepsy: new basic and clinical insights". Acta Physiol (Oxf). vol. 198. 2010. pp. 209-222.

Nishino, S, Ripley, B, Overeem, S. "Hypocretin (orexin) deficiency in human narcolepsy". Lancet. vol. 35. 2000. pp. 39-40.

Mignot, E, Lammers, GJ, Ripley, B. "The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias". Arch Neurol. vol. 59. 2002. pp. 1553-1562.

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