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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: Dec 2022. | This topic last updated: Jul 12, 2022.

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 males and females [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 monoaminergic 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 also allows REM sleep-related phenomena (eg, cataplexy, hypnagogic hallucinations, and sleep paralysis) to intrude into wakefulness. (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 neurons making histamine and a reduction in neurons making corticotropin-releasing hormone have been observed in the brains of patients with narcolepsy type 1 [34-36]. Most likely, these are a compensatory response to the loss of excitatory input from orexin neurons, and their 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 [37], 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 [38].

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 [28,31,39-43]. Some additional human leukocyte antigen (HLA) haplotypes may further increase the risk of narcolepsy, while others appear protective [44,45]. 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 [46]. (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 [28,47]. 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 [48]. 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 [49-51].

Autoimmune hypothesis — Researchers hypothesize that the orexin neurons are selectively killed by an autoimmune process, since narcolepsy is strongly associated with a certain HLA haplotype, DQB1*0602 [52]. The onset of narcolepsy appears highest in the spring, suggesting that it may be triggered by a winter infection [53]. 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 [54].

A T cell-mediated process is possible because narcolepsy is linked to a polymorphism in the T cell receptor alpha gene [55]. Supporting this idea, several studies have shown that patients with narcolepsy often have T cells that target multiple epitopes of the prepro-orexin protein [56-61]. 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 [62,63]. The number of astrocytes may be moderately increased in the orexin neuron region [32,64], 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 [61,65].

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 [66-71], and CSF of patients close to narcolepsy onset lacks increased protein or oligoclonal bands [72,73].

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 [74-85].

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 [86-89]. Paraneoplastic anti-Ma2 antibodies can produce hypothalamic encephalitis with sleepiness, cataplexy, and low orexin-A levels [90-92]. (See "Overview of Niemann-Pick disease", section on 'Classification and clinical features' and "Paraneoplastic and autoimmune encephalitis", section on 'Ma2-associated encephalitis' and "Prader-Willi syndrome: Management".)

These disorders 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 [93].

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 [94].

Daytime sleepiness — All patients with narcolepsy have chronic sleepiness, but they do not sleep more than healthy individuals during a 24-hour period [95,96]. 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) [97,98]. (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 [99]. Episodes may also be triggered by intense anger or frustration in some individuals. Cataplexy develops within three to five years of the onset of sleepiness in 60 percent of people with narcolepsy [93].

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 [100]. Severe episodes can induce bilateral weakness or paralysis, causing the patient to collapse [99]. Sometimes, the weakness can have an atypical appearance with persistent generalized weakness plus facial grimacing, tremor, or tongue protrusion, especially in children [101,102]. Consciousness remains intact during cataplexy, and the weakness usually resolves in less than two minutes [103,104].

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 when awakening or when 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 at the edges of sleep, while cataplexy is triggered by positive emotions when fully awake.

Sleep paralysis and hypnagogic hallucinations are common in patients with narcolepsy but are 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 [105]. (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 [106-110]. 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) [111]. 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 [112-115]. (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 [116-120]. In a population-based, case-control study that included 9312 patients with narcolepsy and more than 45,000 age- and sex-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 [118]. 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 [121,122].

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 [123]. 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 [107,124,125]. The purpose of the multiple sleep latency test (MSLT) 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. The patient should also have actigraphy or complete a sleep log for one to two weeks prior to the MSLT to document adequate amounts and timing of sleep.

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 [126-128]. 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 MSLT 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 [129]. (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 [130,131]. 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 [132,133].

The MSLT has several limitations in the diagnostic evaluation of narcolepsy that should be considered [134]:

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 [135,136]. 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 [137].

More than two 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 [138]. In fact, 5 to 10 percent of the general population may have two or more SOREMPs [139] and up to 20 percent have a mean sleep latency ≤8 minutes [140]. SOREMPs that immediately follow stage N1 sleep may be more specific for narcolepsy than those that follow stage N2 or N3 sleep [141].

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 [38,134,142]. 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-A 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 this 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 [42,43]. 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) [94]:

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 [134,143,144]. 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? (See "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 are 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) [145,146]. 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 [100]. A transient loss of deep tendon reflexes during cataplexy is a very helpful observation, as these reflexes are still present during pseudocataplexy.

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

What is narcolepsy? – 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.)

Etiology – Narcolepsy results from the loss of the neuropeptides, orexin-A and orexin-B (also known as hypocretin-1 and hypocretin-2), made by neurons in the lateral hypothalamus. In sporadic cases, an autoimmune etiology is likely. Rare secondary cases are seen in association with structural lesions of the hypothalamus or midbrain. (See 'Etiology' above.)

Clinical features – 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. (See 'Clinical presentation' above.)

Cardinal symptoms of narcolepsy include:

Moderate to severe daytime sleepiness (see 'Daytime sleepiness' above)

Transient facial weakness or falls caused by episodes of cataplexy (ie, emotionally-triggered muscle weakness) (see 'Cataplexy' above)

Hallucinations when falling asleep or awakening (see 'Hypnagogic hallucinations' above)

Inability to move for one or two minutes immediately after awakening (see 'Sleep paralysis' above)

Evaluation – 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. (See 'Diagnostic evaluation' above.)

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 'Clinical assessment' above.)

Diagnosis – 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.)

Differential diagnosis – 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".)

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