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Clinical features and diagnosis of narcolepsy in adults

Clinical features and diagnosis of narcolepsy in adults
Author:
Thomas E Scammell, MD
Section Editor:
Ruth Benca, MD, PhD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Feb 2022. | This topic last updated: Aug 11, 2020.

INTRODUCTION — Narcolepsy is a clinical syndrome of daytime sleepiness with cataplexy, hypnagogic hallucinations, and sleep paralysis. It is one of the most common causes of disabling daytime sleepiness after obstructive sleep apnea [1,2]. Other diagnoses may be worth considering, and a general approach to the patient with chronic sleepiness is presented elsewhere. (See "Approach to the patient with excessive daytime sleepiness".)

The epidemiology, clinical features, etiology, and diagnosis of narcolepsy are reviewed here. Narcolepsy in children and the treatment of narcolepsy in adults are reviewed separately. (See "Clinical features and diagnosis of narcolepsy in children" and "Treatment of narcolepsy in adults".)

EPIDEMIOLOGY — Narcolepsy type 1 (narcolepsy with cataplexy) is estimated to have a prevalence of 25 to 50 per 100,000 people and an incidence of 0.74 per 100,000 person-years [3-5]. It is equally common in men and women [6-8]. Narcolepsy typically begins in the teens and early twenties, but occasionally occurs as early as five years of age or after 40 years of age. The prevalence of narcolepsy type 2 (narcolepsy without cataplexy) is uncertain because it is not as well studied and harder to diagnose; however, it has been estimated to be 20 to 34 per 100,000 people [8,9].

ETIOLOGY — Loss of orexin (hypocretin) signaling, genetic factors, and rare brain lesions can cause narcolepsy.

Orexin/hypocretin — Narcolepsy results from the loss of the neuropeptides, orexin-A and orexin-B (also known as hypocretin-1 and hypocretin-2). These neurotransmitters are products of the prepro-orexin gene and are made by neurons in the lateral hypothalamus [10,11]. Orexin-A and -B have excitatory effects when they bind the ox1 and ox2 receptors on postsynaptic neurons.

The orexins are released during wakefulness and increase the activity of many brain regions involved in the promotion of wakefulness, including the locus coeruleus, raphe nuclei, and tuberomammillary nucleus (figure 1) [12-16]. By increasing the activity of these wake-promoting aminergic neurons, orexins stabilize wakefulness, prevent inappropriate transitions into rapid eye movement (REM) or non-REM sleep, and inhibit REM sleep [17-19]. Loss of orexins may allow REM sleep-related phenomena (eg, cataplexy, hypnagogic hallucinations, and sleep paralysis) to intrude into wakefulness (figure 2). (See "Stages and architecture of normal sleep".)

Animal models first identified the importance of orexins in narcolepsy. Dogs with mutations in the ox2 receptor were found to have sleepiness and cataplexy very similar to human narcolepsy [20]. Mice lacking the orexin peptides or orexin-producing neurons also had severe narcolepsy [21-23]. Very similar behavior was seen in mice lacking both orexin receptors.

People with narcolepsy are typically classified as having either narcolepsy type 1 (narcolepsy with cataplexy) or narcolepsy type 2 (narcolepsy without cataplexy). Those with narcolepsy type 1 were subsequently shown to also have orexin deficiency. Whereas most animal models have a loss of orexin signaling due to mutations in the genes coding for orexins or their receptors [20-22], people who have narcolepsy type 1 have a roughly 90 percent reduction in the number of hypothalamic neurons producing orexins with little or no detectable orexin-A in their spinal fluid [24-33]. The neuronal loss appears to be selective since adjacent neurons containing melanin-concentrating hormone are preserved.

An increase in the number of histaminergic neurons in the tuberomammillary nucleus has been observed in the brains of patients with narcolepsy type 1 [34,35]. Most likely, this is a compensatory response to the loss of excitatory input from orexin neurons, and its physiological significance remains unclear.

The cause of narcolepsy type 2 is unknown, and these patients usually have normal cerebrospinal fluid (CSF) orexin-A levels [28,30,31]. It has been hypothesized that this disorder may result from less extensive loss of the orexin neurons [36], impaired orexin receptor signaling, or a completely separate mechanism. About 24 percent of patients who have narcolepsy type 2 have low CSF orexin-A levels, and about half of these individuals may later develop cataplexy, suggesting progression of the disease [37].

Genetic factors — Narcolepsy usually occurs sporadically, but genetic factors play an important role. The DQB1*0602 haplotype (a subtype of DQ1) is present in 95 percent of patients with cataplexy and in 96 percent of those with orexin deficiency [28,31,38-42]. Some additional human leukocyte antigen (HLA) haplotypes may further increase the risk of narcolepsy, while others appear protective [43,44]. Though these and other genetic factors may predispose some people to develop narcolepsy, environmental factors appear to be even more important, as only about 25 percent of affected monozygotic twins are concordant for narcolepsy [45]. (See "Human leukocyte antigens (HLA): A roadmap".)

On rare occasions, narcolepsy runs in families. Affected individuals often lack DQB1*0602 and have normal orexin-A levels [28,46]. Some family members lacking definite narcolepsy may have isolated sleepiness, hallucinations, or sleep paralysis, suggesting incomplete penetrance. The genes underlying these familial cases are generally unknown, but eight Japanese families with narcolepsy showed linkage to a site on chromosome 4p13-q21, which may act in concert with the HLA-influenced predisposition [47]. Other families have been reported with linkage to the myelin oligodendrocyte glycoprotein gene and sites on chromosome 6 (near the HLA region) and chromosome 21 [48-50].

Autoimmune hypothesis — Many researchers have hypothesized that the orexin neurons are selectively killed by an autoimmune process, since narcolepsy is strongly associated with a certain HLA haplotype, DQB1*0602 [51]. The onset of narcolepsy appears highest in the spring, suggesting that it may be triggered by a winter infection [52]. One possible trigger is streptococcal pharyngitis, because anti-streptolysin O (ASO) and anti-DNase B titers are sometimes elevated, especially in the first year after the onset of narcolepsy [53].

A T cell-mediated process is possible because narcolepsy is linked to a polymorphism in the T cell receptor alpha gene [54]. Supporting this idea, several studies have shown that patients with narcolepsy often have T cells that target multiple epitopes of the prepro-orexin protein [55-60]. A humoral mechanism may also contribute, as antibodies against tribbles homolog 2, a protein expressed in neurons, are increased in some patients soon after the onset of narcolepsy [61,62]. The number of astrocytes may be moderately increased in the orexin neuron region [32,63], which is consistent with an inflammatory or neurodegenerative process.

Individuals in several countries in Europe developed narcolepsy type 1 soon after receiving Pandemrix, an AS03-adjuvanted 2009 H1N1 influenza vaccine. Pandemrix was used in some European countries during the 2009-2010 H1N1 influenza pandemic, but it was not used in the United States. The risk of narcolepsy after Pandemrix was clearly greatest in children and adolescents with DQB1*0602. One proposed mechanism is cross-reactivity between the human orexin 2 receptor and influenza nucleoprotein A, a protein found in higher concentrations in Pandemrix compared with other H1N1 vaccines [60,64].

It appears likely that the orexin neurons are killed by an autoimmune mechanism, but the process must be subtle. Neuroimaging studies have found no consistent abnormalities [65-70], and CSF of patients close to narcolepsy onset lacks increased protein or oligoclonal bands [71,72].

Secondary narcolepsy — In rare cases, lesions of the posterior hypothalamus and midbrain can cause narcolepsy. Tumors, vascular malformations, strokes, and inflammatory processes such as neurosarcoidosis have all been reported to cause secondary narcolepsy, most likely due to direct injury to the orexin neurons or their projections [73-84].

Narcolepsy can also occur with genetic syndromes such as Prader-Willi syndrome or Niemann-Pick disease type C, and sleepiness and cataplexy-like events are seen in some patients with Prader-Willi syndrome [85-88]. Paraneoplastic anti-Ma2 antibodies can produce hypothalamic encephalitis with sleepiness, cataplexy, and low orexin-A levels [89-91]. (See "Clinical features, diagnosis, and treatment of Prader-Willi syndrome", section on 'Sleep apnea' and "Overview of Niemann-Pick disease", section on 'Classification and clinical features' and "Paraneoplastic and autoimmune encephalitis", section on 'Ma2-associated encephalitis'.)

These processes damage much more than just the orexin neurons; thus, all patients with secondary narcolepsy have obvious neurologic deficits, with cognitive, emotional, motor, endocrine, or eye movement abnormalities. In contrast with typical narcolepsy, nearly all patients with secondary narcolepsy have an increase in their total amount of sleep, often sleeping 12 hours or more each day. Neuroimaging is unnecessary in narcolepsy patients with a normal bedside neurologic exam. (See "The detailed neurologic examination in adults".)

CLINICAL FEATURES

Clinical presentation — Narcolepsy can be conceptualized as a disorder of sleep-wake control in which elements of sleep intrude into wakefulness and elements of wakefulness intrude into sleep. The result is the classic tetrad of chronic daytime sleepiness with varying amounts of cataplexy, hypnagogic hallucinations, and sleep paralysis. All patients have sleepiness, but only one-third of patients will have all of these symptoms. Thus, the diagnosis of narcolepsy should be considered even among patients with chronic daytime sleepiness alone. The features of narcolepsy frequently worsen during the first few months to years and then persist for life [92].

Patients with narcolepsy type 1 (narcolepsy with cataplexy) typically present with moderate to severe daytime sleepiness, transient facial weakness or falls triggered by joking or laughter (partial or complete cataplexy), or the inability to move for one or two minutes immediately after awakening or just before falling asleep. While cataplexy should prompt immediate consideration of narcolepsy, other symptoms are less specific, including complaints of daytime sleepiness or hallucinations that occur as the patient is falling asleep or awakening. Patients with narcolepsy type 2 do not have cataplexy [93].

Daytime sleepiness — All patients with narcolepsy have chronic sleepiness, but they do not sleep more than healthy individuals during a 24-hour period [94,95]. They are prone to fall asleep throughout the day, often at inappropriate times. The sleepiness may be so severe that patients with narcolepsy can rapidly doze off with little warning; these episodes are commonly referred to as "sleep attacks." Sleepiness associated with narcolepsy usually improves temporarily after a brief nap, and most patients feel rested when they awake in the morning. Patients with narcolepsy typically have Epworth Sleepiness Scale scores >15 (calculator 1) [96,97]. (See "Quantifying sleepiness", section on 'Epworth Sleepiness Scale (ESS)'.)

Cataplexy — Cataplexy is emotionally-triggered transient muscle weakness. Most episodes are triggered by strong, generally positive emotions such as laughter, joking, or excitement [98]. Episodes may also be triggered by anger or grief in some individuals. Cataplexy develops within three to five years of the onset of sleepiness in 60 percent of people with narcolepsy [92].

The muscle weakness is often partial, affecting the face, neck, and knees. In both partial and generalized attacks, cataplexy almost always begins in the face, manifesting as ptosis and a slack, hypotonic face with an open mouth and interruption of smiling or other facial expression [99]. Severe episodes can induce bilateral weakness or paralysis, causing the patient to collapse [98]. Sometimes, the weakness can have an atypical appearance with persistent generalized weakness plus facial grimacing, tremor, or tongue protrusion, especially in children [100,101]. Consciousness remains intact during cataplexy, and the weakness usually resolves in less than two minutes [102,103].

Hypnagogic hallucinations — Hypnagogic hallucinations are vivid, often frightening visual, tactile, or auditory hallucinations that occur as the patient is falling asleep. They probably result from a mixture of wakefulness and the dreaming of rapid eye movement (REM) sleep. Hypnopompic hallucinations are similar hallucinations that occur upon awakening; they can also occur in narcolepsy, but are less common. (See "Approach to the patient with visual hallucinations", section on 'Narcolepsy'.)

Sleep paralysis — Sleep paralysis is the complete inability to move for one or two minutes immediately after awakening. It may also occur just before falling asleep. Episodes of sleep paralysis can be frightening because the immobility may be accompanied by hypnopompic hallucinations or a sensation of suffocation. The feeling of suffocation may be related to slight reductions in tidal volume that occur during sleep paralysis. Sleep paralysis can be distinguished from cataplexy because sleep paralysis occurs upon awakening, while cataplexy is triggered by positive emotions.

Sleep paralysis and hypnagogic hallucinations are common in patients with narcolepsy but not specific for the diagnosis. About 20 percent of the general population have a rare episode of sleep paralysis, perhaps once or twice over several years, but people with narcolepsy tend to have these symptoms much more frequently. (See 'Differential diagnosis' below.)

Other features — Many patients with narcolepsy also have fragmented sleep, other sleep disorders, and obesity, probably as a consequence of orexin deficiency. Depression, anxiety, and other psychiatric problems are also common, but whether they are a direct consequence of orexin deficiency or a complication of the disease is unknown.

Fragmented sleep – Patients with narcolepsy generally fall asleep rapidly but can spontaneously awaken several times during the night and have difficulty returning to sleep. This sleep maintenance insomnia seems paradoxical in a disorder characterized by daytime sleepiness, and it may reflect a low threshold to transition from sleep to wakefulness [104]. (See "Risk factors, comorbidities, and consequences of insomnia in adults".)

Other sleep disorders – People with narcolepsy have a higher than expected incidence of obstructive sleep apnea, periodic limb movements of sleep, restless legs syndrome, REM sleep behavior disorder, sleepwalking, and other sleep disorders [105-109]. This was illustrated by a single-center clinical and polysomnographic study that included 100 consecutive patients with narcolepsy, in which the most common comorbid sleep disorders were insomnia (28 percent), REM sleep behavior disorder (24 percent), restless legs syndrome (24 percent), obstructive sleep apnea (21 percent), and non-REM sleep parasomnias (10 percent) [110]. Identification and treatment of concurrent sleep disorders is important because such disorders may contribute to a patient's daytime sleepiness. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults" and "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

Obesity – Mild obesity is common, and weight gain at the onset of narcolepsy can be dramatic in children and sometimes accompanied by precocious puberty [111-114]. (See "Clinical features and diagnosis of narcolepsy in children", section on 'Obesity and precocious puberty'.)

Neuropsychiatric comorbidities – Individuals with narcolepsy are at increased risk for depression, anxiety, attention deficit hyperactivity disorder, and other psychiatric comorbidities [115-119]. In a population-based, case-control study that included 9312 patients with narcolepsy and more than 45,000 age- and gender-matched controls, a broad range of psychiatric disorders were more common in patients with narcolepsy compared with controls; the most prevalent were depression and anxiety, which were three to four times more common than in controls [117]. The greatest excess in mood and anxiety disorders was observed in the youngest age group (age 18 to 24 years). Occasional children with narcolepsy may have psychotic disorders, often with auditory hallucinations, although whether these are a consequence of the disease itself or medications such as amphetamines remains unclear [120,121].

DIAGNOSTIC EVALUATION

Clinical assessment — All patients with chronic daytime sleepiness should have a thorough history, sleep history, physical exam, and neurologic exam seeking evidence of cataplexy, hypnagogic or hypnopompic hallucinations, or sleep paralysis. Questions that are helpful in detecting possible narcolepsy include the following (table 1):

Are you sleepy most of the day?

Do you feel rested on waking in the morning?

Are your naps refreshing?

Do you ever see, feel, or hear things that you know aren’t there as you are falling asleep?

Are you ever unable to move when you first awake or as you are falling asleep?

Do you have muscle weakness when you laugh or tell a joke?

Over the last two weeks, how often have you fallen asleep when you did not intend to?

If the answer to any of these questions is "yes," narcolepsy should be considered and both a polysomnogram and a multiple sleep latency test should be performed [122]. Further information on the evaluation of a sleepy patient and when to refer a patient to a sleep specialist can be found separately. (See "Approach to the patient with excessive daytime sleepiness".)

Sleep studies — The purpose of the polysomnogram is to exclude alternative and coexisting causes of chronic daytime sleepiness, which may warrant specific treatment [106,123,124]. The purpose of the multiple sleep latency test is to measure the mean sleep latency and identify sleep onset rapid eye movement periods (SOREMPs). Stimulants and other psychoactive medications should be stopped one week before testing, and antidepressants should be stopped at least three weeks before testing (four weeks for fluoxetine) to avoid rapid eye movement (REM) sleep rebound effects.

Polysomnography (PSG) evaluates sleep architecture, sleep quality, and other physiological parameters. Patients who have narcolepsy typically demonstrate spontaneous awakenings, mildly reduced sleep efficiency, and increased light non-REM sleep. Patients with narcolepsy type 1 and occasionally those with narcolepsy type 2 may show REM sleep within 15 minutes of the onset of sleep [125-127]. In contrast, healthy individuals enter REM sleep 80 to 100 minutes after the onset of sleep. Polysomnographic characteristics of alternative disorders are described separately. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on 'Diagnosis' and "Central sleep apnea: Risk factors, clinical presentation, and diagnosis", section on 'Diagnostic evaluation' and "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults", section on 'Periodic limb movements of sleep'.)

The Multiple Sleep Latency Test (MSLT) generally begins in the morning, 1.5 to three hours after the PSG. The patient is placed in a sleep-inducing environment (ie, dark, quiet room) and instructed to try to sleep. Monitoring includes electroencephalography (EEG), electrooculography, mental or submental electromyography, and electrocardiography (ECG). Each nap session continues for 15 minutes after sleep onset to detect REM sleep. The sleep latency is documented for each nap session. If the patient does not fall asleep, the nap session is terminated after 20 minutes and the sleep latency is documented as being 20 minutes. This is repeated at two hour intervals until the patient has had four or five opportunities to nap [128]. (See "Quantifying sleepiness", section on 'Multiple sleep latency test (MSLT)'.)

On average, healthy subjects fall asleep in about 10 to 15 minutes, whereas people with narcolepsy fall asleep in less than 8 minutes, providing objective evidence of their sleep propensity [129,130]. The naps of patients with narcolepsy often include REM sleep, and the presence of two or more naps containing REM sleep (known as SOREMPs) are an essential feature of narcolepsy [131,132].

The MSLT has several limitations in the diagnostic evaluation of narcolepsy that should be considered [133]:

An MSLT is valid only if the PSG demonstrated at least six hours of sleep during the preceding night. Greater amounts of sleep may be needed to be considered adequate in children and adults with long sleep times.

The MSLT has poor test-retest reliability and can be falsely negative or positive 20 to 30 percent of the time, especially in narcolepsy patients who lack cataplexy [134,135]. For negative studies, the test should be repeated if the history is strongly suggestive of narcolepsy.

The MSLT may be less sensitive for the diagnosis of narcolepsy in older adults because sleep latency increases and SOREMPs become less frequent with age [136].

An increased number of SOREMPs is not specific for a diagnosis of narcolepsy. SOREMPs are common in shift workers and can occur with other disorders that increase REM sleep pressure, such as insufficient sleep, untreated sleep apnea, or circadian phase delay [137]. In fact, 5 to 10 percent of the general population may have two or more SOREMPs [138] and up to 20 percent have a mean sleep latency ≤8 minutes [139]. SOREMPs that immediately follow stage N1 sleep may be more specific for narcolepsy than those that follow stage N2 or N3 sleep [140].

REM sleep-suppressing medications (eg, antidepressants, stimulants) can prevent the appearance of SOREMPs, and withdrawal from these drugs can produce SOREMPs, for up to several weeks after discontinuation.

Other laboratory tests — Measurement of orexin-A (hypocretin-1) in cerebrospinal fluid (CSF) is useful in certain clinical situations [37,133,141]. Examples include when the MSLT is difficult to interpret due to either poor nighttime sleep (eg, insomnia, sleep apnea, circadian rhythm sleep disorders); the inability to discontinue antidepressants or other sleep-modulating medications prior to testing; when the patient is a young child (the MSLT has not been standardized in young children and, thus, is difficult to interpret) (see "Clinical features and diagnosis of narcolepsy in children", section on 'Polysomnography and MSLT'); or when the patient has atypical cataplexy (90 percent of patients with true cataplexy have low orexin levels) [28]. A commercially available assay for CSF orexin is available in the United States through Mayo Clinic Laboratories.

HLA testing is not routine for diagnosing narcolepsy. Most people with narcolepsy are DQB1*0602 positive, but this finding is not specific because the haplotype also occurs in 12 to 40 percent of healthy Americans, and more than 99 percent of DQB1*0602 positive individuals do not have narcolepsy. Still, some clinicians find HLA testing useful in individuals with cataplexy, as over 90 percent of patients with narcolepsy with cataplexy carry DQB1*0602 [41,42]. Conversely, in patients with atypical cataplexy, lack of DQB1*0602 provides support against a diagnosis of narcolepsy with cataplexy.

DIAGNOSTIC CRITERIA — Narcolepsy type 1 (narcolepsy with cataplexy) is highly likely in a patient with symptoms of chronic daytime sleepiness and cataplexy, since all patients with narcolepsy have chronic daytime sleepiness and cataplexy occurs in almost no other disorder. Narcolepsy type 2 (narcolepsy without cataplexy) is more difficult to diagnose because sleepiness can occur with a variety of sleep disorders, and hypnagogic hallucinations and sleep paralysis can occur with any condition that increases REM sleep pressure.

The diagnosis of narcolepsy type 1 (narcolepsy with cataplexy) requires both of the following (table 2) [93]:

Daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least three months

One or both of the following:

Cataplexy and a mean sleep latency of ≤8 minutes and two or more sleep onset REM sleep periods (SOREMPs) on a multiple sleep latency test (MSLT). A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal polysomnogram may replace one of the SOREMPs on the MSLT.

Cerebrospinal fluid (CSF) orexin-A concentration is low.

If there is clinical suspicion for narcolepsy type 2 in a patient with chronic daytime sleepiness, the diagnosis should be confirmed with (table 3):

An overnight polysomnogram followed the next day by an MSLT that demonstrates a mean sleep latency ≤8 minutes and at least two SOREMPs.

The diagnosis of narcolepsy type 2 hinges upon the MSLT, yet the MSLT has several limitations and poor reproducibility in narcolepsy type 2 patients. Consequently, it is sometimes hard to be certain if a patient has narcolepsy type 2 or idiopathic hypersomnia [133,142]. In the absence of a specific biomarker, clinical judgment is crucial: Does the patient have symptoms suggestive of REM sleep dysfunction (eg, frequent sleep paralysis or hypnagogic hallucinations) indicative of narcolepsy, or nonrestorative, long sleep with troublesome morning sleep inertia indicative of idiopathic hypersomnia?  

DIFFERENTIAL DIAGNOSIS — A variety of alternative conditions must be considered whenever narcolepsy is suspected, particularly when cataplexy is not present. The correct differential diagnosis depends upon which symptom or sign has prompted suspicion of narcolepsy:

Chronic daytime sleepiness – Many conditions can cause daytime sleepiness because they disrupt the duration or quality of sleep. These include insufficient sleep, obstructive sleep apnea, central sleep apnea, periodic limb movements, circadian rhythm sleep-wake disorders (eg, rotating shift work), mood disorders, and idiopathic hypersomnia. It is common for more than one such condition to exist. (See "Approach to the patient with excessive daytime sleepiness".)

Sleep logs and actigraphy can be helpful when a circadian disorder is suspected or to provide evidence for chronic sleep deprivation. In patients with delayed sleep phase disorder, a multiple sleep latency test (MSLT) may show an increased number of sleep-onset REM periods (SOREMPs) even after six hours of sleep the night before if the habitual sleep period extends into the late morning. Similarly, uncorrected sleep deprivation may result in an increased number of SOREMPs on an MSLT that are not specific for a diagnosis of narcolepsy. (See 'Diagnostic evaluation' above.)

Hypnagogic hallucinations and sleep paralysis – These symptoms often occur in narcolepsy, but can also occur as isolated phenomena, often precipitated by insufficient sleep, circadian rhythm sleep disorders, obstructive sleep apnea, and anxiety. They can also occur as a rebound phenomenon in patients who abruptly stop taking REM sleep-suppressing substances (eg, alcohol, amphetamines, antidepressants) [143,144]. About 20 percent of healthy individuals may have infrequent hypnagogic hallucinations or sleep paralysis (eg, one to two times per year), but many individuals with narcolepsy experience these symptoms more often (eg, two to three times per month). In contrast to the hallucinations of schizophrenia and other psychotic disorders, narcolepsy patients usually recognize hypnagogic hallucinations as dream-like phenomena.

Cataplexy – Cataplexy is highly diagnostic of narcolepsy. Conversion disorder occasionally manifests with cataplexy-like attacks, sometimes referred to as "pseudocataplexy," which can be difficult to distinguish from true cataplexy by history alone. Video recordings with careful attention to the presence of facial features during the attacks can be helpful, as abrupt facial hypotonia, neck weakness, and sometimes buckling of the knees are fairly reliable markers of genuine cataplexy [99]. A transient loss of deep tendon reflexes during cataplexy is a very helpful observation.

On rare occasions, true cataplexy can occur with lesions of the hypothalamus or brainstem, Prader-Willi syndrome, or other rare disorders discussed above. (See 'Secondary narcolepsy' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Parasomnias, hypersomnias, and circadian rhythm disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Narcolepsy (The Basics)")

SUMMARY AND RECOMMENDATIONS

Narcolepsy is a clinical syndrome of chronic daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. Only about one-third of patients will have all four symptoms; thus, the diagnosis of narcolepsy should be considered even in patients with chronic daytime sleepiness alone. (See 'Introduction' above and 'Clinical features' above.)

Narcolepsy typically begins in the teens and early twenties, but may occur as early as five years of age or after 40 years of age. Patients typically present with moderate to severe daytime sleepiness, transient facial weakness or falls caused by episodes of cataplexy (ie, emotionally-triggered muscle weakness), hallucinations when falling asleep or awakening, or the inability to move for one or two minutes immediately after awakening. (See 'Epidemiology' above and 'Clinical presentation' above.)

All patients with chronic daytime sleepiness, cataplexy, hypnagogic hallucinations, or sleep paralysis should have a thorough medical history, sleep history, physical exam, and neurologic exam seeking additional evidence of narcolepsy. Questions that are helpful in detecting possible narcolepsy in patients with chronic daytime sleepiness are listed in the table (table 1). If the answer to any of these questions is "yes," narcolepsy should be considered, and both a polysomnogram and a multiple sleep latency test (MSLT) should be performed. (See 'Diagnostic evaluation' above.)

The diagnosis of narcolepsy is confirmed with a polysomnogram that rules out other sleep disorders and a MSLT that demonstrates an average sleep latency ≤8 minutes and/or at least two sleep onset rapid eye movement periods (SOREMPs) (table 2 and table 3). Cataplexy is highly suggestive of narcolepsy. (See 'Diagnostic criteria' above.)

Since chronic sleepiness, hypnagogic hallucinations, and sleep paralysis can occur in other conditions, alternative etiologies should be excluded whenever narcolepsy is considered (eg, untreated sleep apnea, periodic limb movements of sleep, insufficient sleep, or sedating medications), particularly when cataplexy is not present. (See 'Differential diagnosis' above and "Approach to the patient with excessive daytime sleepiness".)

REFERENCES

  1. Scammell TE. Narcolepsy. N Engl J Med 2015; 373:2654.
  2. Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet 2007; 369:499.
  3. Longstreth WT Jr, Koepsell TD, Ton TG, et al. The epidemiology of narcolepsy. Sleep 2007; 30:13.
  4. Nohynek H, Jokinen J, Partinen M, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One 2012; 7:e33536.
  5. Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One 2012; 7:e33723.
  6. Ohayon MM, Priest RG, Zulley J, et al. Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology 2002; 58:1826.
  7. Coleman RM, Roffwarg HP, Kennedy SJ, et al. Sleep-wake disorders based on a polysomnographic diagnosis. A national cooperative study. JAMA 1982; 247:997.
  8. Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep 2002; 25:197.
  9. Shin YK, Yoon IY, Han EK, et al. Prevalence of narcolepsy-cataplexy in Korean adolescents. Acta Neurol Scand 2008; 117:273.
  10. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92:573.
  11. de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 1998; 95:322.
  12. Hagan JJ, Leslie RA, Patel S, et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci U S A 1999; 96:10911.
  13. Bayer L, Eggermann E, Serafin M, et al. Orexins (hypocretins) directly excite tuberomammillary neurons. Eur J Neurosci 2001; 14:1571.
  14. Yamanaka A, Tsujino N, Funahashi H, et al. Orexins activate histaminergic neurons via the orexin 2 receptor. Biochem Biophys Res Commun 2002; 290:1237.
  15. Eriksson KS, Sergeeva O, Brown RE, Haas HL. Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci 2001; 21:9273.
  16. Brown RE, Sergeeva O, Eriksson KS, Haas HL. Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat. Neuropharmacology 2001; 40:457.
  17. España RA, Scammell TE. Sleep neurobiology from a clinical perspective. Sleep 2011; 34:845.
  18. Burgess CR, Scammell TE. Narcolepsy: neural mechanisms of sleepiness and cataplexy. J Neurosci 2012; 32:12305.
  19. Scammell TE, Arrigoni E, Lipton JO. Neural Circuitry of Wakefulness and Sleep. Neuron 2017; 93:747.
  20. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98:365.
  21. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; 98:437.
  22. Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001; 30:345.
  23. Tabuchi S, Tsunematsu T, Black SW, et al. Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function. J Neurosci 2014; 34:6495.
  24. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6:991.
  25. Olafsdóttir BR, Rye DB, Scammell TE, et al. Polymorphisms in hypocretin/orexin pathway genes and narcolepsy. Neurology 2001; 57:1896.
  26. Hungs M, Lin L, Okun M, Mignot E. Polymorphisms in the vicinity of the hypocretin/orexin are not associated with human narcolepsy. Neurology 2001; 57:1893.
  27. Dauvilliers Y, Baumann CR, Carlander B, et al. CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry 2003; 74:1667.
  28. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002; 59:1553.
  29. Nishino S, Ripley B, Overeem S, et al. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355:39.
  30. Kanbayashi T, Inoue Y, Chiba S, et al. CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia. J Sleep Res 2002; 11:91.
  31. Bourgin P, Zeitzer JM, Mignot E. CSF hypocretin-1 assessment in sleep and neurological disorders. Lancet Neurol 2008; 7:649.
  32. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000; 27:469.
  33. Crocker A, España RA, Papadopoulou M, et al. Concomitant loss of dynorphin, NARP, and orexin in narcolepsy. Neurology 2005; 65:1184.
  34. Valko PO, Gavrilov YV, Yamamoto M, et al. Increase of histaminergic tuberomammillary neurons in narcolepsy. Ann Neurol 2013; 74:794.
  35. John J, Thannickal TC, McGregor R, et al. Greatly increased numbers of histamine cells in human narcolepsy with cataplexy. Ann Neurol 2013; 74:786.
  36. Thannickal TC, Nienhuis R, Siegel JM. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep 2009; 32:993.
  37. Andlauer O, Moore H 4th, Hong SC, et al. Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy. Sleep 2012; 35:1247.
  38. Hayduk R, Flodman P, Spence MA, et al. HLA haplotypes, polysomnography, and pedigrees in a case series of patients with narcolepsy. Sleep 1997; 20:850.
  39. Mignot E, Hayduk R, Black J, et al. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients. Sleep 1997; 20:1012.
  40. Taheri S, Mignot E. The genetics of sleep disorders. Lancet Neurol 2002; 1:242.
  41. Tafti M, Hor H, Dauvilliers Y, et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep 2014; 37:19.
  42. Capittini C, De Silvestri A, Terzaghi M, et al. Correlation between HLA-DQB1*06:02 and narcolepsy with and without cataplexy: approving a safe and sensitive genetic test in four major ethnic groups. A systematic meta-analysis. Sleep Med 2018; 52:150.
  43. Hor H, Kutalik Z, Dauvilliers Y, et al. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat Genet 2010; 42:786.
  44. Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 2001; 68:686.
  45. Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998; 50:S16.
  46. Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 2001; 57:2029.
  47. Nakayama J, Miura M, Honda M, et al. Linkage of human narcolepsy with HLA association to chromosome 4p13-q21. Genomics 2000; 65:84.
  48. Miyagawa T, Hohjoh H, Honda Y, et al. Identification of a telomeric boundary of the HLA region with potential for predisposition to human narcolepsy. Immunogenetics 2000; 52:12.
  49. Dauvilliers Y, Blouin JL, Neidhart E, et al. A narcolepsy susceptibility locus maps to a 5 Mb region of chromosome 21q. Ann Neurol 2004; 56:382.
  50. Hor H, Bartesaghi L, Kutalik Z, et al. A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy. Am J Hum Genet 2011; 89:474.
  51. Mahlios J, De la Herrán-Arita AK, Mignot E. The autoimmune basis of narcolepsy. Curr Opin Neurobiol 2013; 23:767.
  52. Han F, Lin L, Warby SC, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol 2011; 70:410.
  53. Aran A, Lin L, Nevsimalova S, et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 2009; 32:979.
  54. Hallmayer J, Faraco J, Lin L, et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genet 2009; 41:708.
  55. Latorre D, Kallweit U, Armentani E, et al. T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature 2018; 562:63.
  56. Kornum BR, Burgdorf KS, Holm A, et al. Absence of autoreactive CD4+ T-cells targeting HLA-DQA1*01:02/DQB1*06:02 restricted hypocretin/orexin epitopes in narcolepsy type 1 when detected by EliSpot. J Neuroimmunol 2017; 309:7.
  57. Lecendreux M, Churlaud G, Pitoiset F, et al. Narcolepsy Type 1 Is Associated with a Systemic Increase and Activation of Regulatory T Cells and with a Systemic Activation of Global T Cells. PLoS One 2017; 12:e0169836.
  58. Cogswell AC, Maski K, Scammell TE, et al. Children with Narcolepsy type 1 have increased T-cell responses to orexins. Ann Clin Transl Neurol 2019; 6:2566.
  59. Pedersen NW, Holm A, Kristensen NP, et al. CD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens. Nat Commun 2019; 10:837.
  60. Luo G, Ambati A, Lin L, et al. Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy. Proc Natl Acad Sci U S A 2018; 115:E12323.
  61. Cvetkovic-Lopes V, Bayer L, Dorsaz S, et al. Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. J Clin Invest 2010; 120:713.
  62. Kawashima M, Lin L, Tanaka S, et al. Anti-Tribbles homolog 2 (TRIB2) autoantibodies in narcolepsy are associated with recent onset of cataplexy. Sleep 2010; 33:869.
  63. Thannickal TC, Siegel JM, Nienhuis R, Moore RY. Pattern of hypocretin (orexin) soma and axon loss, and gliosis, in human narcolepsy. Brain Pathol 2003; 13:340.
  64. Ahmed SS, Volkmuth W, Duca J, et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med 2015; 7:294ra105.
  65. Frey JL, Heiserman JE. Absence of pontine lesions in narcolepsy. Neurology 1997; 48:1097.
  66. Bassetti C, Aldrich MS, Quint DJ. MRI findings in narcolepsy. Sleep 1997; 20:630.
  67. Kwen PL, Pullicino P. Pontine lesions in idiopathic narcolepsy. Neurology 1998; 50:577.
  68. Overeem S, Steens SC, Good CD, et al. Voxel-based morphometry in hypocretin-deficient narcolepsy. Sleep 2003; 26:44.
  69. Kaufmann C, Schuld A, Pollmächer T, Auer DP. Reduced cortical gray matter in narcolepsy: preliminary findings with voxel-based morphometry. Neurology 2002; 58:1852.
  70. Draganski B, Geisler P, Hajak G, et al. Hypothalamic gray matter changes in narcoleptic patients. Nat Med 2002; 8:1186.
  71. Fredrikson S, Carlander B, Billiard M, Link H. CSF immune variables in patients with narcolepsy. Acta Neurol Scand 1990; 81:253.
  72. Overeem S, Geleijns K, Garssen MP, et al. Screening for anti-ganglioside antibodies in hypocretin-deficient human narcolepsy. Neurosci Lett 2003; 341:13.
  73. Schwartz WJ, Stakes JW, Hobson JA. Transient cataplexy after removal of a craniopharyngioma. Neurology 1984; 34:1372.
  74. Aldrich MS, Naylor MW. Narcolepsy associated with lesions of the diencephalon. Neurology 1989; 39:1505.
  75. Arii J, Kanbayashi T, Tanabe Y, et al. A hypersomnolent girl with decreased CSF hypocretin level after removal of a hypothalamic tumor. Neurology 2001; 56:1775.
  76. Scammell TE, Nishino S, Mignot E, Saper CB. Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke. Neurology 2001; 56:1751.
  77. Malik S, Boeve BF, Krahn LE, Silber MH. Narcolepsy associated with other central nervous system disorders. Neurology 2001; 57:539.
  78. Clavelou P, Tournilhac M, Vidal C, et al. Narcolepsy associated with arteriovenous malformation of the diencephalon. Sleep 1995; 18:202.
  79. Rosenfeld MR, Eichen JG, Wade DF, et al. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 2001; 50:339.
  80. Melberg A, Dahl N, Hetta J, et al. Neuroimaging study in autosomal dominant cerebellar ataxia, deafness, and narcolepsy. Neurology 1999; 53:2190.
  81. Bjornstad B, Goodman SH, Sirven JI, Dodick DW. Paroxysmal sleep as a presenting symptom of bilateral paramedian thalamic infarctions. Mayo Clin Proc 2003; 78:347.
  82. Marcus CL, Trescher WH, Halbower AC, Lutz J. Secondary narcolepsy in children with brain tumors. Sleep 2002; 25:435.
  83. Gledhill RF, Bartel PR, Yoshida Y, et al. Narcolepsy caused by acute disseminated encephalomyelitis. Arch Neurol 2004; 61:758.
  84. Mayo MC, Deng JC, Albores J, et al. Hypocretin Deficiency Associated with Narcolepsy Type 1 and Central Hypoventilation Syndrome in Neurosarcoidosis of the Hypothalamus. J Clin Sleep Med 2015; 11:1063.
  85. Manni R, Politini L, Nobili L, et al. Hypersomnia in the Prader Willi syndrome: clinical-electrophysiological features and underlying factors. Clin Neurophysiol 2001; 112:800.
  86. Kandt RS, Emerson RG, Singer HS, et al. Cataplexy in variant forms of Niemann-Pick disease. Ann Neurol 1982; 12:284.
  87. Vossler DG, Wyler AR, Wilkus RJ, et al. Cataplexy and monoamine oxidase deficiency in Norrie disease. Neurology 1996; 46:1258.
  88. Vankova J, Stepanova I, Jech R, et al. Sleep disturbances and hypocretin deficiency in Niemann-Pick disease type C. Sleep 2003; 26:427.
  89. Overeem S, Dalmau J, Bataller L, et al. Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. Neurology 2004; 62:138.
  90. Landolfi JC, Nadkarni M. Paraneoplastic limbic encephalitis and possible narcolepsy in a patient with testicular cancer: case study. Neuro Oncol 2003; 5:214.
  91. Dauvilliers Y, Bauer J, Rigau V, et al. Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy. JAMA Neurol 2013; 70:1305.
  92. Okun ML, Lin L, Pelin Z, et al. Clinical aspects of narcolepsy-cataplexy across ethnic groups. Sleep 2002; 25:27.
  93. American Academy of Sleep Medicine. International Classification of Sleep Disorders, 3rd ed, American Academy of Sleep Medicine, 2014.
  94. Broughton R, Dunham W, Newman J, et al. Ambulatory 24 hour sleep-wake monitoring in narcolepsy-cataplexy compared to matched controls. Electroencephalogr Clin Neurophysiol 1988; 70:473.
  95. Dantz B, Edgar DM, Dement WC. Circadian rhythms in narcolepsy: studies on a 90 minute day. Electroencephalogr Clin Neurophysiol 1994; 90:24.
  96. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991; 14:540.
  97. Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep 1992; 15:376.
  98. Overeem S, van Nues SJ, van der Zande WL, et al. The clinical features of cataplexy: a questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency. Sleep Med 2011; 12:12.
  99. Pizza F, Antelmi E, Vandi S, et al. The distinguishing motor features of cataplexy: a study from video-recorded attacks. Sleep 2018; 41.
  100. Pizza F, Franceschini C, Peltola H, et al. Clinical and polysomnographic course of childhood narcolepsy with cataplexy. Brain 2013; 136:3787.
  101. Serra L, Montagna P, Mignot E, et al. Cataplexy features in childhood narcolepsy. Mov Disord 2008; 23:858.
  102. Guilleminault C, Gelb M. Clinical aspects and features of cataplexy. Adv Neurol 1995; 67:65.
  103. Anic-Labat S, Guilleminault C, Kraemer HC, et al. Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep 1999; 22:77.
  104. Schoch SF, Werth E, Poryazova R, et al. Dysregulation of Sleep Behavioral States in Narcolepsy. Sleep 2017; 40.
  105. Chokroverty S. Sleep apnea in narcolepsy. Sleep 1986; 9:250.
  106. Schenck CH, Mahowald MW. Motor dyscontrol in narcolepsy: rapid-eye-movement (REM) sleep without atonia and REM sleep behavior disorder. Ann Neurol 1992; 32:3.
  107. Dauvilliers Y, Pennestri MH, Petit D, et al. Periodic leg movements during sleep and wakefulness in narcolepsy. J Sleep Res 2007; 16:333.
  108. Cipolli C, Franceschini C, Mattarozzi K, et al. Overnight distribution and motor characteristics of REM sleep behaviour disorder episodes in patients with narcolepsy-cataplexy. Sleep Med 2011; 12:635.
  109. Plazzi G, Ferri R, Antelmi E, et al. Restless legs syndrome is frequent in narcolepsy with cataplexy patients. Sleep 2010; 33:689.
  110. Frauscher B, Ehrmann L, Mitterling T, et al. Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the innsbruck narcolepsy cohort. J Clin Sleep Med 2013; 9:805.
  111. Schuld A, Hebebrand J, Geller F, Pollmächer T. Increased body-mass index in patients with narcolepsy. Lancet 2000; 355:1274.
  112. Dahmen N, Bierbrauer J, Kasten M. Increased prevalence of obesity in narcoleptic patients and relatives. Eur Arch Psychiatry Clin Neurosci 2001; 251:85.
  113. Aran A, Einen M, Lin L, et al. Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children. Sleep 2010; 33:1457.
  114. Poli F, Pizza F, Mignot E, et al. High prevalence of precocious puberty and obesity in childhood narcolepsy with cataplexy. Sleep 2013; 36:175.
  115. Jara CO, Popp R, Zulley J, et al. Determinants of depressive symptoms in narcoleptic patients with and without cataplexy. J Nerv Ment Dis 2011; 199:329.
  116. Dimitrova A, Fronczek R, Van der Ploeg J, et al. Reward-seeking behavior in human narcolepsy. J Clin Sleep Med 2011; 7:293.
  117. Ruoff CM, Reaven NL, Funk SE, et al. High Rates of Psychiatric Comorbidity in Narcolepsy: Findings From the Burden of Narcolepsy Disease (BOND) Study of 9,312 Patients in the United States. J Clin Psychiatry 2017; 78:171.
  118. Kim J, Lee GH, Sung SM, et al. Prevalence of attention deficit hyperactivity disorder symptoms in narcolepsy: a systematic review. Sleep Med 2020; 65:84.
  119. Barateau L, Lopez R, Chenini S, et al. Depression and suicidal thoughts in untreated and treated narcolepsy: Systematic analysis. Neurology 2020; 95:e2755.
  120. Canellas F, Lin L, Julià MR, et al. Dual cases of type 1 narcolepsy with schizophrenia and other psychotic disorders. J Clin Sleep Med 2014; 10:1011.
  121. Plazzi G, Fabbri C, Pizza F, Serretti A. Schizophrenia-like symptoms in narcolepsy type 1: shared and distinctive clinical characteristics. Neuropsychobiology 2015; 71:218.
  122. Morgenthaler TI, Kapur VK, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007; 30:1705.
  123. Mayer G, Meier-Ewert K. Motor dyscontrol in sleep of narcoleptic patients (a lifelong development?). J Sleep Res 1993; 2:143.
  124. Harsh J, Peszka J, Hartwig G, Mitler M. Night-time sleep and daytime sleepiness in narcolepsy. J Sleep Res 2000; 9:309.
  125. Andlauer O, Moore H, Jouhier L, et al. Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA Neurol 2013; 70:891.
  126. Cairns A, Bogan R. Prevalence and Clinical Correlates of a Short Onset REM Period (SOREMP) during Routine PSG. Sleep 2015; 38:1575.
  127. Reiter J, Katz E, Scammell TE, Maski K. Usefulness of a Nocturnal SOREMP for Diagnosing Narcolepsy with Cataplexy in a Pediatric Population. Sleep 2015; 38:859.
  128. Carskadon MA, Dement WC, Mitler MM, et al. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 1986; 9:519.
  129. Roehrs T, Roth T. Multiple Sleep Latency Test: technical aspects and normal values. J Clin Neurophysiol 1992; 9:63.
  130. Moscovitch A, Partinen M, Guilleminault C. The positive diagnosis of narcolepsy and narcolepsy's borderland. Neurology 1993; 43:55.
  131. Mitler MM, Van den Hoed J, Carskadon MA, et al. REM sleep episodes during the Multple Sleep Latency Test in narcoleptic patients. Electroencephalogr Clin Neurophysiol 1979; 46:479.
  132. Richardson GS, Carskadon MA, Flagg W, et al. Excessive daytime sleepiness in man: multiple sleep latency measurement in narcoleptic and control subjects. Electroencephalogr Clin Neurophysiol 1978; 45:621.
  133. Baumann CR, Mignot E, Lammers GJ, et al. Challenges in diagnosing narcolepsy without cataplexy: a consensus statement. Sleep 2014; 37:1035.
  134. Trotti LM, Staab BA, Rye DB. Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. J Clin Sleep Med 2013; 9:789.
  135. Lopez R, Doukkali A, Barateau L, et al. Test-Retest Reliability of the Multiple Sleep Latency Test in Central Disorders of Hypersomnolence. Sleep 2017; 40.
  136. Dauvilliers Y, Gosselin A, Paquet J, et al. Effect of age on MSLT results in patients with narcolepsy-cataplexy. Neurology 2004; 62:46.
  137. Chervin RD, Aldrich MS. Sleep onset REM periods during multiple sleep latency tests in patients evaluated for sleep apnea. Am J Respir Crit Care Med 2000; 161:426.
  138. Mignot E, Lin L, Finn L, et al. Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults. Brain 2006; 129:1609.
  139. Goldbart A, Peppard P, Finn L, et al. Narcolepsy and predictors of positive MSLTs in the Wisconsin Sleep Cohort. Sleep 2014; 37:1043.
  140. Drakatos P, Suri A, Higgins SE, et al. Sleep stage sequence analysis of sleep onset REM periods in the hypersomnias. J Neurol Neurosurg Psychiatry 2013; 84:223.
  141. Overeem S, Scammell TE, Lammers GJ. Hypocretin/orexin and sleep: implications for the pathophysiology and diagnosis of narcolepsy. Curr Opin Neurol 2002; 15:739.
  142. Ruoff C, Pizza F, Trotti LM, et al. The MSLT is Repeatable in Narcolepsy Type 1 But Not Narcolepsy Type 2: A Retrospective Patient Study. J Clin Sleep Med 2018; 14:65.
  143. Szklo-Coxe M, Young T, Finn L, Mignot E. Depression: relationships to sleep paralysis and other sleep disturbances in a community sample. J Sleep Res 2007; 16:297.
  144. Ohayon MM. Prevalence of hallucinations and their pathological associations in the general population. Psychiatry Res 2000; 97:153.
Topic 7689 Version 44.0

References

1 : Narcolepsy.

2 : Narcolepsy with cataplexy.

3 : The epidemiology of narcolepsy.

4 : AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland.

5 : Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland.

6 : Prevalence of narcolepsy symptomatology and diagnosis in the European general population.

7 : Sleep-wake disorders based on a polysomnographic diagnosis. A national cooperative study.

8 : The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study.

9 : Prevalence of narcolepsy-cataplexy in Korean adolescents.

10 : Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.

11 : The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity.

12 : Orexin A activates locus coeruleus cell firing and increases arousal in the rat.

13 : Orexins (hypocretins) directly excite tuberomammillary neurons.

14 : Orexins activate histaminergic neurons via the orexin 2 receptor.

15 : Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus.

16 : Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat.

17 : Sleep neurobiology from a clinical perspective.

18 : Narcolepsy: neural mechanisms of sleepiness and cataplexy.

19 : Neural Circuitry of Wakefulness and Sleep.

20 : The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene.

21 : Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation.

22 : Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity.

23 : Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function.

24 : A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains.

25 : Polymorphisms in hypocretin/orexin pathway genes and narcolepsy.

26 : Polymorphisms in the vicinity of the hypocretin/orexin are not associated with human narcolepsy.

27 : CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions.

28 : The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias.

29 : Hypocretin (orexin) deficiency in human narcolepsy.

30 : CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia.

31 : CSF hypocretin-1 assessment in sleep and neurological disorders.

32 : Reduced number of hypocretin neurons in human narcolepsy.

33 : Concomitant loss of dynorphin, NARP, and orexin in narcolepsy.

34 : Increase of histaminergic tuberomammillary neurons in narcolepsy.

35 : Greatly increased numbers of histamine cells in human narcolepsy with cataplexy.

36 : Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy.

37 : Predictors of hypocretin (orexin) deficiency in narcolepsy without cataplexy.

38 : HLA haplotypes, polysomnography, and pedigrees in a case series of patients with narcolepsy.

39 : HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients.

40 : The genetics of sleep disorders.

41 : DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe.

42 : Correlation between HLA-DQB1*06:02 and narcolepsy with and without cataplexy: approving a safe and sensitive genetic test in four major ethnic groups. A systematic meta-analysis.

43 : Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy.

44 : Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups.

45 : Genetic and familial aspects of narcolepsy.

46 : Age at onset of narcolepsy in two large populations of patients in France and Quebec.

47 : Linkage of human narcolepsy with HLA association to chromosome 4p13-q21.

48 : Identification of a telomeric boundary of the HLA region with potential for predisposition to human narcolepsy.

49 : A narcolepsy susceptibility locus maps to a 5 Mb region of chromosome 21q.

50 : A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy.

51 : The autoimmune basis of narcolepsy.

52 : Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China.

53 : Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset.

54 : Narcolepsy is strongly associated with the T-cell receptor alpha locus.

55 : T cells in patients with narcolepsy target self-antigens of hypocretin neurons.

56 : Absence of autoreactive CD4+ T-cells targeting HLA-DQA1*01:02/DQB1*06:02 restricted hypocretin/orexin epitopes in narcolepsy type 1 when detected by EliSpot.

57 : Narcolepsy Type 1 Is Associated with a Systemic Increase and Activation of Regulatory T Cells and with a Systemic Activation of Global T Cells.

58 : Children with Narcolepsy type 1 have increased T-cell responses to orexins.

59 : CD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens.

60 : Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy.

61 : Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients.

62 : Anti-Tribbles homolog 2 (TRIB2) autoantibodies in narcolepsy are associated with recent onset of cataplexy.

63 : Pattern of hypocretin (orexin) soma and axon loss, and gliosis, in human narcolepsy.

64 : Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2.

65 : Absence of pontine lesions in narcolepsy.

66 : MRI findings in narcolepsy.

67 : Pontine lesions in idiopathic narcolepsy.

68 : Voxel-based morphometry in hypocretin-deficient narcolepsy.

69 : Reduced cortical gray matter in narcolepsy: preliminary findings with voxel-based morphometry.

70 : Hypothalamic gray matter changes in narcoleptic patients.

71 : CSF immune variables in patients with narcolepsy.

72 : Screening for anti-ganglioside antibodies in hypocretin-deficient human narcolepsy.

73 : Transient cataplexy after removal of a craniopharyngioma.

74 : Narcolepsy associated with lesions of the diencephalon.

75 : A hypersomnolent girl with decreased CSF hypocretin level after removal of a hypothalamic tumor.

76 : Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke.

77 : Narcolepsy associated with other central nervous system disorders.

78 : Narcolepsy associated with arteriovenous malformation of the diencephalon.

79 : Molecular and clinical diversity in paraneoplastic immunity to Ma proteins.

80 : Neuroimaging study in autosomal dominant cerebellar ataxia, deafness, and narcolepsy.

81 : Paroxysmal sleep as a presenting symptom of bilateral paramedian thalamic infarctions.

82 : Secondary narcolepsy in children with brain tumors.

83 : Narcolepsy caused by acute disseminated encephalomyelitis.

84 : Hypocretin Deficiency Associated with Narcolepsy Type 1 and Central Hypoventilation Syndrome in Neurosarcoidosis of the Hypothalamus.

85 : Hypersomnia in the Prader Willi syndrome: clinical-electrophysiological features and underlying factors.

86 : Cataplexy in variant forms of Niemann-Pick disease.

87 : Cataplexy and monoamine oxidase deficiency in Norrie disease.

88 : Sleep disturbances and hypocretin deficiency in Niemann-Pick disease type C.

89 : Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis.

90 : Paraneoplastic limbic encephalitis and possible narcolepsy in a patient with testicular cancer: case study.

91 : Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy.

92 : Clinical aspects of narcolepsy-cataplexy across ethnic groups.

93 : Clinical aspects of narcolepsy-cataplexy across ethnic groups.

94 : Ambulatory 24 hour sleep-wake monitoring in narcolepsy-cataplexy compared to matched controls.

95 : Circadian rhythms in narcolepsy: studies on a 90 minute day.

96 : A new method for measuring daytime sleepiness: the Epworth sleepiness scale.

97 : Reliability and factor analysis of the Epworth Sleepiness Scale.

98 : The clinical features of cataplexy: a questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency.

99 : The distinguishing motor features of cataplexy: a study from video-recorded attacks.

100 : Clinical and polysomnographic course of childhood narcolepsy with cataplexy.

101 : Cataplexy features in childhood narcolepsy.

102 : Clinical aspects and features of cataplexy.

103 : Validation of a cataplexy questionnaire in 983 sleep-disorders patients.

104 : Dysregulation of Sleep Behavioral States in Narcolepsy.

105 : Sleep apnea in narcolepsy.

106 : Motor dyscontrol in narcolepsy: rapid-eye-movement (REM) sleep without atonia and REM sleep behavior disorder.

107 : Periodic leg movements during sleep and wakefulness in narcolepsy.

108 : Overnight distribution and motor characteristics of REM sleep behaviour disorder episodes in patients with narcolepsy-cataplexy.

109 : Restless legs syndrome is frequent in narcolepsy with cataplexy patients.

110 : Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the innsbruck narcolepsy cohort.

111 : Increased body-mass index in patients with narcolepsy.

112 : Increased prevalence of obesity in narcoleptic patients and relatives.

113 : Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children.

114 : High prevalence of precocious puberty and obesity in childhood narcolepsy with cataplexy.

115 : Determinants of depressive symptoms in narcoleptic patients with and without cataplexy.

116 : Reward-seeking behavior in human narcolepsy.

117 : High Rates of Psychiatric Comorbidity in Narcolepsy: Findings From the Burden of Narcolepsy Disease (BOND) Study of 9,312 Patients in the United States.

118 : Prevalence of attention deficit hyperactivity disorder symptoms in narcolepsy: a systematic review.

119 : Depression and suicidal thoughts in untreated and treated narcolepsy: Systematic analysis.

120 : Dual cases of type 1 narcolepsy with schizophrenia and other psychotic disorders.

121 : Schizophrenia-like symptoms in narcolepsy type 1: shared and distinctive clinical characteristics.

122 : Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin.

123 : Motor dyscontrol in sleep of narcoleptic patients (a lifelong development?).

124 : Night-time sleep and daytime sleepiness in narcolepsy.

125 : Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency.

126 : Prevalence and Clinical Correlates of a Short Onset REM Period (SOREMP) during Routine PSG.

127 : Usefulness of a Nocturnal SOREMP for Diagnosing Narcolepsy with Cataplexy in a Pediatric Population.

128 : Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness.

129 : Multiple Sleep Latency Test: technical aspects and normal values.

130 : The positive diagnosis of narcolepsy and narcolepsy's borderland.

131 : REM sleep episodes during the Multple Sleep Latency Test in narcoleptic patients.

132 : Excessive daytime sleepiness in man: multiple sleep latency measurement in narcoleptic and control subjects.

133 : Challenges in diagnosing narcolepsy without cataplexy: a consensus statement.

134 : Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia.

135 : Test-Retest Reliability of the Multiple Sleep Latency Test in Central Disorders of Hypersomnolence.

136 : Effect of age on MSLT results in patients with narcolepsy-cataplexy.

137 : Sleep onset REM periods during multiple sleep latency tests in patients evaluated for sleep apnea.

138 : Correlates of sleep-onset REM periods during the Multiple Sleep Latency Test in community adults.

139 : Narcolepsy and predictors of positive MSLTs in the Wisconsin Sleep Cohort.

140 : Sleep stage sequence analysis of sleep onset REM periods in the hypersomnias.

141 : Hypocretin/orexin and sleep: implications for the pathophysiology and diagnosis of narcolepsy.

142 : The MSLT is Repeatable in Narcolepsy Type 1 But Not Narcolepsy Type 2: A Retrospective Patient Study.

143 : Depression: relationships to sleep paralysis and other sleep disturbances in a community sample.

144 : Prevalence of hallucinations and their pathological associations in the general population.