Version July 2025
INTRODUCTION —
Narcolepsy is a clinical syndrome of chronic daytime sleepiness along with additional symptoms that may include cataplexy, disrupted nighttime sleep, sleep paralysis, and hypnogogic and hypnopompic hallucinations.
Two forms of narcolepsy are recognized: narcolepsy type 1 (NT1; narcolepsy with cataplexy), which is caused by orexin deficiency; and narcolepsy type 2 (NT2), which shares all features of NT1 except cataplexy and low orexin levels. Diagnosis of either NT1 or NT2 requires excluding other causes of daytime sleepiness, performing diagnostic sleep tests, and, in select cases, measuring orexin-A in cerebrospinal fluid (CSF).
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 "Management and prognosis of narcolepsy in children" and "Treatment of narcolepsy in adults".)
EPIDEMIOLOGY
Incidence and prevalence — Incidence and prevalence are best studied for narcolepsy type 1 (NT1). In population-based studies, the estimated incidence of NT1 is 0.74 per 100,000 person-years [1-3]. Peak incidence is in the second and third decades. Prevalence estimates range from 25 to 50 per 100,000 people [4]. Males and females are affected in equal proportions [4,5].
Narcolepsy type 2 (NT2) appears to be slightly less common than NT1, with prevalence estimates ranging from 20 to 34 per 100,000 people [5,6].
Risk factors — The best-studied risk factor for NT1 is the DQB1*0602 haplotype (a subtype of DQ1), which is present in 95 percent of narcolepsy patients with cataplexy and in 96 percent of those with orexin deficiency [7-12]. Some additional human leukocyte antigen (HLA) haplotypes may further increase the risk of narcolepsy, while others appear protective [13,14].
Though these and other genetic factors may predispose some people to develop narcolepsy, triggering environmental factors such as infection with streptococcus or influenza appear to be even more important [15,16]. Only approximately 25 percent of affected monozygotic twins are concordant for narcolepsy [17].
On rare occasions, narcolepsy runs in families. Affected individuals often lack DQB1*0602 and have normal orexin-A levels [7,18]. 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 [19-22]. Very rare individuals with variants in the gene coding for orexins have been reported to manifest narcolepsy with cataplexy in infancy [23,24].
ETIOLOGY AND PATHOPHYSIOLOGY —
Narcolepsy usually occurs sporadically in children, teenagers, and young adults. In people with narcolepsy type 1 (NT1), a genetically influenced autoimmune process likely kills the orexin-producing neurons. The cause of narcolepsy type 2 (NT2) is unknown, though some patients may have partial loss of the orexin neurons. In rare individuals, brain lesions can cause secondary narcolepsy by damaging the orexin neurons or their connections.
Loss of orexin signaling — NT1 results from the loss of the neuropeptide neurotransmitters orexin-A and orexin-B (also known as hypocretin-1 and hypocretin-2), which play a key role in the promotion of wakefulness (figure 1).
●Orexin physiology – Orexin-A and orexin-B are products of the hypocretin neuropeptide precursor (HCRT) gene, and they are made only by a cluster of neurons in the lateral hypothalamus [25,26]. They have excitatory effects when they bind the orexin 1 (OX1) and orexin 2 (OX2) receptors on postsynaptic neurons.
Orexins are released during wakefulness and increase the activity of many brain regions that promote wakefulness, including the locus coeruleus, raphe nuclei, tuberomammillary nucleus, basal forebrain, and cortex (figure 1) [27-31]. In healthy individuals, this orexin signaling normally stabilizes wakefulness and prevents inappropriate transitions into sleep [32-34]. However, loss of the orexin neurons in NT1 permits rapid transitions into sleep and intrusions of rapid eye movement (REM) sleep-related phenomena (eg, cataplexy, sleep paralysis, and hypnagogic and hypnopompic hallucinations) into wakefulness. (See "Stages and architecture of normal sleep".)
●Orexin deficiency in NT1 – Animal models first identified the importance of orexins in narcolepsy. Dogs with pathogenic variants in the OX2 receptor were found to have sleepiness and cataplexy very similar to human narcolepsy [35]. Mice lacking the orexin peptides or orexin-producing neurons also have severe narcolepsy [36-38]. Very similar behavior was seen in mice lacking both orexin receptors.
People with NT1 were subsequently shown to have orexin deficiency. Whereas some animal models have a loss of orexin signaling due to variants in the genes coding for orexins or their receptors [35-37], people who have NT1 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 [7,8,23,39-45]. 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 NT1 [46-48]. Most likely, these are compensatory responses to the loss of excitatory input from orexin neurons, and their physiologic significance remains unclear.
●Role of orexins in NT2 – The pathophysiology of NT2 is unknown, and these patients usually have normal cerebrospinal fluid (CSF) orexin-A levels [7,8,43]. It has been hypothesized that this disorder may result from less extensive loss of the orexin neurons [49], impaired orexin receptor signaling, or a completely separate mechanism.
Approximately one-quarter of patients clinically diagnosed with NT2 due to their lack of cataplexy actually have low CSF orexin-A levels, and approximately half of these individuals may later develop cataplexy, suggesting progression of the disease [50]. If the CSF orexin level is low, a patient should be diagnosed with NT1 rather than NT2. (See 'Diagnosis' below.)
Autoimmune hypothesis — A growing body of evidence indicates that orexin neurons in the hypothalamus are selectively killed by an autoimmune process in patients with narcolepsy.
●HLA association – Narcolepsy is strongly associated with the human leukocyte antigen (HLA) haplotype DQB1*0602. This allele increases the risk of developing narcolepsy by approximately 200-fold, indicating involvement of the immune system [51]. In addition, the onset of narcolepsy appears highest in the spring, suggesting that it may be triggered by a winter infection in genetically susceptible individuals [52].
●Infectious triggers – 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 [15]. A second is influenza. In the winter of 2009 to 2010, the number of new cases of NT1 in China roughly tripled, possibly due to infection with H1N1 influenza [52]. Similarly, the number of new cases of NT1 increased 8- to 12-fold after vaccination with Pandemrix, an AS03-adjuvanted H1N1 vaccine used in some European countries during the 2009 to 2010 H1N1 influenza pandemic [53]. The risk of narcolepsy after Pandemrix was greatest in children and adolescents with DQB1*0602, and the onset of NT1 was usually a few months after receiving this vaccine.
●Immune response – 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 [53,55-59]. 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 [60,61]. The number of astrocytes may be moderately increased in the orexin neuron region [44,62], which is consistent with an inflammatory or neurodegenerative process.
While it appears likely that the orexin neurons are killed by an autoimmune mechanism, the process must be subtle. Neuroimaging studies have found no consistent abnormalities [63-68], and CSF of patients close to narcolepsy onset lacks increased protein or oligoclonal bands [69,70].
Secondary narcolepsy — Rarely, narcolepsy is a secondary manifestation of hypothalamic or midbrain pathology or a neurogenetic disorder. Examples include:
●Structural pathology (eg, tumors such as craniopharyngioma or glioma, vascular malformation, stroke, traumatic brain injury)
●Inflammatory processes (eg, neurosarcoidosis, multiple sclerosis, neuromyelitis optica spectrum disorder, paraneoplastic encephalitis due to anti-Ma2 antibodies) [71-85]
●Genetic syndromes (eg, Prader-Willi syndrome, Niemann-Pick disease type C, Norrie disease, myotonic dystrophy) [86-89]
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.
CLINICAL MANIFESTATIONS —
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 chronic daytime sleepiness with varying amounts of cataplexy, hypnagogic hallucinations, and sleep paralysis, as well as fragmented nocturnal sleep.
Clinical presentation — Narcolepsy has a peak age of onset in the teens and early twenties. Onset before age 5 years and after age 40 years is rare. (See "Clinical features and diagnosis of narcolepsy in children".)
The initial symptoms are usually excessive daytime sleepiness, hypnagogic hallucinations, sleep paralysis, and disrupted nighttime sleep. Cataplexy typically develops in the following weeks to months, although sometimes it does not develop for three to five years [90]. Symptoms are then generally stable and persist for life.
Core symptoms
Daytime sleepiness — All patients with narcolepsy have chronic daytime sleepiness, but they do not sleep more than healthy individuals during a 24-hour period [91,92]. They are prone to falling asleep throughout the day, often when sedentary and at inappropriate times. The sleepiness may be so severe that patients can rapidly doze off with little warning; these episodes are commonly referred to as "sleep attacks."
Sleepiness associated with narcolepsy usually improves for one to two hours after a brief nap, and most patients feel rested when they awake in the morning. This history of restorative sleep is diagnostically helpful, since people with excessive daytime sleepiness due to other causes (eg, poor-quality sleep from sleep apnea, sedating medications) often do not feel rested in the morning or after naps.
The severity of sleepiness is commonly measured using the Epworth Sleepiness Scale, which asks patients to rate their likelihood of falling asleep during a range of low-stimulation situations (calculator 1). Patients with narcolepsy typically have Epworth Sleepiness Scale scores >15 [93,94]. (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 [95]. Episodes may also be triggered by intense anger or frustration in some individuals.
The muscle weakness in cataplexy 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 [96]. Severe episodes can induce bilateral weakness or paralysis, causing the patient to collapse [95]. Often in children and rarely in adults, the weakness can have an atypical appearance with persistent generalized weakness plus facial grimacing, tremor, or tongue protrusion [97,98]. (See "Clinical features and diagnosis of narcolepsy in children", section on 'Cataplexy'.)
Consciousness remains intact during cataplexy, and the weakness usually resolves in less than two minutes [99,100].
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. In a cohort of 100 individuals with narcolepsy, the frequency of hallucinations was approximately 10 times per month in people with NT1 and 3 times per month in those with narcolepsy type 2 (NT2) [101].
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 occurs in approximately two-thirds of patients with narcolepsy [102]. Healthy individuals can have occasional hypnagogic or hypnopompic hallucinations and sleep paralysis, often due to insufficient sleep and likely high REM sleep pressure, but the frequency of these events is higher in patients with narcolepsy. For example, sleep paralysis occurs at least once per month in most people with narcolepsy type 1 (NT1) and only in approximately 3 percent of the general population [90,103].
Other clinical 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 and fragmented sleep. (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 [115-118]. 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 [116]. The greatest excess in mood and anxiety disorders was observed in the youngest age group (age 18 to 24 years).
DIFFERENTIAL DIAGNOSIS —
A variety of alternative conditions must be considered whenever narcolepsy is suspected, particularly when cataplexy is not present. Taking a careful history is key as 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 (table 1). These include insufficient sleep, obstructive sleep apnea, central sleep apnea, periodic limb movements, circadian rhythm sleep-wake disorders (eg, rotating shift work, delayed sleep phase syndrome), 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".)
Use of a sleep diary and actigraphy to confirm adequate sleep and stable sleep patterns prior to conducting diagnostic sleep testing is particularly important in the evaluation of narcolepsy. Patients with delayed sleep phase disorder may show abnormal sleep propensity and sleep-onset rapid eye movement (REM) periods (SOREMPs) on a multiple sleep latency test (MSLT) 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' below.)
●Hypnagogic/hypnopompic 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) [119,120].
In contrast to the hallucinations of schizophrenia and other psychotic disorders, narcolepsy patients usually recognize hypnagogic/hypnopompic hallucinations as dream-like phenomena [101].
●Cataplexy – True cataplexy is highly specific for narcolepsy. Functional neurological symptom disorder (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 [121,122].
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 [96]. 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.)
DIAGNOSTIC EVALUATION
Clinical suspicion — All patients with narcolepsy have sleepiness, but only one-third will have the classic tetrad of sleepiness, cataplexy, hypnogogic hallucinations, and sleep paralysis at the time of diagnosis. Thus, the diagnosis of narcolepsy should be considered even among patients with chronic daytime sleepiness alone, especially when excessive sleepiness begins acutely in teenagers and young adults.
A history of cataplexy should prompt immediate consideration of narcolepsy, but other symptoms are less specific, including complaints of daytime sleepiness, sleep-related hallucinations, and sleep paralysis.
History and examination — The initial assessment consists of a routine history, sleep history, and physical and neurologic examination.
●History – All patients with chronic daytime sleepiness should have a thorough medical history and a sleep history specifically seeking evidence of cataplexy, hypnagogic or hypnopompic hallucinations, and sleep paralysis.
Questions that are helpful in detecting possible narcolepsy in patients who complain of sleepiness include the following (table 2):
•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?
If the answer to any of these questions is "yes," narcolepsy should be considered and both a polysomnogram (PSG) and a multiple sleep latency test (MSLT) should be performed [123]. An Epworth Sleepiness Score should also be measured (calculator 1), with scores higher than 10 indicative of excessive daytime sleepiness. (See 'Polysomnography and MSLT' below.)
●Examination – The physical examination is usually unrevealing aside from obesity, which is common in people with narcolepsy. The neurologic examination in patients with typical narcolepsy is normal. Patients with narcolepsy secondary to hypothalamic or midbrain pathology may have neurocognitive dysfunction, emotional dysregulation, eye movement abnormalities, or focal weakness due to involvement of local structures. (See 'Secondary narcolepsy' above.)
Polysomnography and MSLT — All patients with clinical suspicion for narcolepsy on initial assessment should undergo sleep testing. Testing for suspected narcolepsy consists of both an overnight, in-laboratory PSG and an MSLT, which is performed the morning after the PSG.
The MSLT in particular requires preparation beginning at least two weeks in advance so that results of the test are not confounded by sleep deprivation and effects of medications on rapid eye movement (REM) sleep (table 3). Preparation, protocol details, and interpretation are reviewed in detail separately. (See "Quantifying sleepiness", section on 'Multiple sleep latency test (MSLT)'.)
Findings specific to the diagnosis of narcolepsy are reviewed here:
●PSG – The purpose of the overnight PSG in the evaluation of narcolepsy is twofold: to exclude alternative and coexisting causes of chronic daytime sleepiness warranting specific treatment and to evaluate for findings supportive of a diagnosis of narcolepsy.
Patients with narcolepsy typically demonstrate spontaneous awakenings, mildly reduced sleep efficiency, and increased light non-REM sleep on PSG. Such findings are supportive but nonspecific. In addition, patients with narcolepsy type 1 (NT1) and occasionally those with narcolepsy type 2 (NT2) may show REM sleep within 15 minutes of the onset of sleep, which is diagnostic of narcolepsy in the appropriate clinical context [124-128]. By contrast, healthy individuals do not enter REM sleep until 80 to 100 minutes after the onset of sleep. (See 'Diagnosis' below.)
Polysomnographic characteristics of alternative disorders warranting further treatment before reconsidering a diagnosis of narcolepsy, including obstructive sleep apnea, 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 'Evaluation' and "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults", section on 'Periodic limb movements of sleep'.)
●MSLT – The purpose of the MSLT is to measure mean sleep latency (the time it takes to fall asleep) during a series of five daytime nap opportunities and to measure the time elapsed from sleep onset to the first REM sleep period. Patients with narcolepsy fall asleep faster than normal, and they enter REM sleep more often than healthy individuals. These characteristics are quantified during the MSLT as follows:
•Mean sleep latency – Patients with narcolepsy have a mean sleep latency (averaged over all nap opportunities) of less than 8 minutes, providing objective evidence of sleep propensity. On average, healthy subjects fall asleep in approximately 10 to 15 minutes.
•Sleep-onset REM periods (SOREMPs) – Each nap session continues for 15 minutes after sleep onset to detect REM sleep. In healthy individuals, REM sleep during a 15-minute nap is rare. The naps of patients with narcolepsy often contain REM sleep, and the presence of two or more naps containing REM sleep (known as SOREMPs) is an essential feature of narcolepsy.
Alternatives to the MSLT, such as continuous 24-hour PSG during which patients can nap as much as they would like, are being explored but require further validation [128].
●Important limitations – The MSLT has several limitations in the diagnostic evaluation of narcolepsy that should be considered [129]:
•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 (who typically require more sleep than adults) and adults with long sleep times [130]. (See "Clinical features and diagnosis of narcolepsy in children", section on 'Multiple sleep latency test'.)
•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 [131,132]. 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 [133].
•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 or undertreated sleep apnea, or circadian phase delay [134]. In fact, 5 to 10 percent of the general population may have two or more SOREMPs [135] and up to 20 percent have a mean sleep latency ≤8 minutes [136]. SOREMPs that immediately follow stage N1 sleep may be more specific for narcolepsy than those that follow stage N2 or N3 sleep [137,138].
•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 [139].
CSF orexin-A testing — Low cerebrospinal fluid (CSF) orexin-A (≤110 picograms/mL or one-third the normal value) obtained via routine lumbar puncture has high sensitivity and specificity for the diagnosis of NT1 (89 and 99 percent, respectively) [7,41]. Nonetheless, testing is not required or indicated in most patients with suspected narcolepsy, as the diagnosis of NT1 or NT2 can be made with a thorough history plus PSG and MSLT.
Testing is useful in the following clinical situations, and the test is available in the United States through Mayo Clinic Laboratories [7,50,129,140]:
●Unreliable MSLT results – When NT1 is suspected but the MSLT is negative or difficult to interpret, a low CSF orexin-A provides convincing evidence of NT1, independent of sleep study findings. The most common reasons for an unreliable MSLT in this setting are:
•Poor nighttime sleep (eg, insomnia, sleep apnea, circadian rhythm sleep disorders)
•Antidepressants or other sleep-modulating medications cannot be discontinued prior to testing
•Very young age (see "Clinical features and diagnosis of narcolepsy in children", section on 'Polysomnography')
●Atypical cataplexy – In patients who have events that are atypical for cataplexy and for whom a functional neurologic disorder is suspected, a normal CSF orexin-A level can help rule out NT1.
Measurement of CSF orexin-A is generally unhelpful in people who fulfill diagnostic criteria for NT2, as they usually have orexin-A levels in the normal range (>200 pg/mL) and occasionally in the intermediate range (110 to 200 pg/mL).
Of note, if the CSF orexin level is low in an individual with suspected narcolepsy but no history of cataplexy, the patient should be diagnosed with NT1 rather than NT2; approximately half of such patients go on to develop cataplexy in subsequent years [50].
Other testing — Neuroimaging is unnecessary in patients with suspected narcolepsy who have a normal bedside neurologic examination. Patients with focal neurologic findings should undergo magnetic resonance imaging (MRI) of the brain to exclude structural pathology. The urgency of imaging depends on the severity and time course of symptoms. (See 'Secondary narcolepsy' above.)
Human leukocyte antigen (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 [10,11]. Conversely, in patients with atypical cataplexy, lack of DQB1*0602 provides support against a diagnosis of narcolepsy with cataplexy.
DIAGNOSIS —
The diagnosis of narcolepsy is established based on characteristic clinical features, sleep testing, and cerebrospinal fluid (CSF) orexin-A testing in select patients. Diagnosis also rests on exclusion of alternative causes of daytime sleepiness, especially when cataplexy is absent.
Narcolepsy type 1 — Narcolepsy type 1 (NT1; 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.
The diagnosis of NT1 requires all of the following (table 4) [124]:
●Daily periods of irrepressible need to sleep or daytime lapses into drowsiness or sleep
●One or both of the following:
•Cataplexy and either:
-Mean sleep latency of ≤8 minutes and two or more sleep-onset rapid eye movement (REM) periods (SOREMPs) on a multiple sleep latency test (MSLT)
-A SOREMP (within 15 minutes of sleep onset) on nocturnal polysomnogram (PSG)
•CSF orexin-A (hypocretin-1) concentration, measured by radioimmunoassay, is ≤110 picograms/mL or less than one-third of mean values obtained in normal subjects with the same standardized assay
●Symptoms and signs are not better explained by chronic insufficient sleep, a circadian rhythm sleep-wake disorder or other current sleep disorder, mental disorder, or medication/substance use or withdrawal
Narcolepsy type 2 — Narcolepsy type 2 (NT2) 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.
If there is clinical suspicion for NT2 in a patient with chronic daytime sleepiness, the diagnosis requires all of the following (table 5):
●Daily periods of irrepressible need to sleep or daytime lapses into drowsiness or sleep.
●Mean sleep latency of ≤8 minutes and two or more SOREMPs on an MSLT. A SOREMP (within 15 minutes of sleep onset) on the preceding nocturnal PSG may replace one of the SOREMPs on the MSLT.
●Symptoms and signs are not better explained by chronic insufficient sleep, a circadian rhythm sleep-wake disorder or other current sleep disorder, mental disorder, or medication/substance use or withdrawal.
Of note, the diagnosis of NT2 hinges upon the MSLT, yet the MSLT has several limitations and poor reproducibility in patients with NT2. Consequently, it is sometimes hard to be certain if a patient has NT2 or idiopathic hypersomnia [129,141,142]. In the absence of a specific biomarker, clinical judgment is crucial. For patients who have symptoms suggestive of REM sleep dysfunction (eg, frequent sleep paralysis or hypnagogic hallucinations), the correct diagnosis is likely NT2; for those with nonrestorative, long sleep with troublesome morning sleep inertia, the correct diagnosis is likely idiopathic hypersomnia. (See "Idiopathic hypersomnia".)
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
●Definitions – Narcolepsy is a clinical syndrome of chronic daytime sleepiness and varying combinations of cataplexy, hypnagogic hallucinations, and sleep paralysis. Two forms of narcolepsy are recognized (see 'Introduction' above):
•Narcolepsy type 1 (NT1; narcolepsy with cataplexy), resulting from loss of orexin signaling in the hypothalamus
•Narcolepsy type 2 (NT2), sharing all features of NT1 except cataplexy and low orexin levels
●Epidemiology – Narcolepsy has a peak age of onset in the teens and early twenties. Males and females are affected in equal proportions. The best-studied risk factor is the human leukocyte antigen (HLA) DQB1*0602 haplotype, which is present in nearly all patients with NT1. (See 'Risk factors' above.)
●Etiology – Narcolepsy usually occurs sporadically. NT1 is likely due to an autoimmune process that kills the orexin-producing neurons (figure 1). The cause of NT2 is unknown. Rarely, brain lesions can cause secondary narcolepsy. (See 'Etiology and pathophysiology' above.)
●Clinical manifestations – Cardinal symptoms of narcolepsy include:
•Moderate to severe daytime sleepiness, with daily periods of irrepressible need to sleep or daytime lapses into drowsiness or sleep (see 'Daytime sleepiness' above)
•Cataplexy, manifesting as transient facial weakness or falls triggered by strong, generally positive emotions, such as laughing at a joke (see 'Cataplexy' above)
•Hallucinations when falling asleep (hypnagogic) or awakening (hypnopompic) (see 'Hypnagogic hallucinations' above)
•Inability to move for one or two minutes immediately after awakening (see 'Sleep paralysis' above)
All patients with narcolepsy have sleepiness, but only one-third will have the classic tetrad of sleepiness, cataplexy, hypnogogic hallucinations, and sleep paralysis at the time of diagnosis.
●Differential diagnosis – Alternative causes of daytime sleepiness should be excluded whenever narcolepsy is being considered, particularly when cataplexy is not present. Common causes in adults include insufficient sleep; other sleep disorders (eg, untreated sleep apnea); medical, neurologic, and psychiatric disorders; and sedating medications (table 1). (See "Approach to the patient with excessive daytime sleepiness".)
●Evaluation – Patients with chronic daytime sleepiness should have a thorough history and sleep history seeking evidence of cataplexy, hypnagogic or hypnopompic hallucinations, and sleep paralysis. (See 'Clinical suspicion' above.)
Testing for suspected narcolepsy consists of both an overnight, in-laboratory polysomnogram (PSG) and a multiple sleep latency test (MSLT), which is performed the morning after the PSG. MSLT findings supportive of narcolepsy include a mean sleep latency ≤8 minutes and ≥2 sleep-onset rapid eye movement (REM) sleep periods (SOREMPs). (See 'Polysomnography and MSLT' above.)
Lumbar puncture for measurement of cerebrospinal fluid (CSF) orexin-A levels is not routinely indicated but can be useful when results of diagnostic sleep testing are unreliable or difficult to interpret. Neuroimaging is unnecessary in patients with suspected narcolepsy who have a normal bedside neurologic examination. (See 'CSF orexin-A testing' above and 'Other testing' above.)
●Diagnosis – The diagnosis of narcolepsy is established based on characteristic clinical features, diagnostic sleep testing, and exclusion of alternative causes of daytime sleepiness. In the proper clinical context, a mean sleep latency ≤8 minutes and ≥2 SOREMPs on PSG/MSLT are diagnostic of narcolepsy (table 4 and table 5). Cataplexy or low CSF orexin-A confirm the diagnosis of NT1 (table 4). (See 'Diagnosis' above.)
