Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
Correspondence to Kyoung Jin Hwang Department of Neurology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea Tel: +82-2-958-8429 Fax: +82-2-958-8490 E-mail: jinie111@hanmail.net
• Received: July 28, 2025 • Revised: October 24, 2025 • Accepted: October 24, 2025
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Narcolepsy is a central disorder of hypersomnolence primarily characterized by excessive daytime sleepiness often accompanied by cataplexy, sleep paralysis, hypnagogic hallucinations, and disrupted nocturnal sleep. Pathophysiological mechanisms involve genetic predisposition, hypocretin deficiency, infectious and immune-related factor. Diagnosis is established through clinical evaluation, polysomnography, multiple sleep latency testing, and cerebrospinal fluid hypocretin measurement. Pharmacological treatment primarily aims to alleviate excessive daytime sleepiness (EDS) and cataplexy. Stimulants such as modafinil and solriamfetol are commonly used for managing EDS, while antidepressants are employed to control cataplexy. Pitolisant and sodium oxybate have demonstrated efficacy in treating both EDS and cataplexy. This review summarizes current understanding of the epidemiology, clinical features, pathophysiology, diagnostic approaches, and therapeutic options for narcolepsy.
Narcolepsy is classified as a central disorder of hypersomnolence, primarily characterized by excessive daytime sleepiness (EDS). According to the International Classification of Sleep Disorders, third edition (ICSD-3),1 central disorders of hypersomnolence encompass narcolepsy type 1 (with cataplexy), narcolepsy type 2 (without cataplexy), idiopathic hypersomnia, and Kleine-Levin syndrome. Among these, narcolepsy is distinguished by profound and persistent daytime sleepiness and may be accompanied by additional symptoms including cataplexy, sleep paralysis, hypnagogic hallucinations, and fragmented nocturnal sleep.
EPIDEMOLOGY OF NARCOLEPSY
The prevalence of narcolepsy is estimated to range from 0.02% to 0.018% in Western populations.2 In Asia, a prevalence of 0.0185% has been reported in Japan.3 In South Korea, the estimated prevalence among adolescents is 0.053% for type 1 narcolepsy and 0.015% for type 2.4 The onset of narcolepsy typically follows a bimodal distribution, with peak incidence occurring between the ages of 15 years and 25 years and a second, smaller peak between 30 years and 40 years of age.5 Both genders are equally affected.5
SYMPTOMS OF NARCOLEPSY
Excessive daytime sleepiness
EDS is often the first prominent symptom experienced by patient with narcolepsy. Patient with narcolepsy report pervasive and irresistible sleepiness during waking hours, which persists despite adequate or even prolonged nocturnal sleep. This persistent somnolence is often accompanied by cognitive slowing, decreased concentration, and diminished motivation.
The onset of symptoms most commonly occurs during adolescence, although cases with childhood or adult onset have also been reported.6 One of the hallmark features of EDS is the occurrence of sudden, uncontrollable episodes of sleep, often referred to as "sleep attacks". These episodes may occur in inappropriate or potentially dangerous situations, such as during conversations, meals, or while standing. Although brief naps may transiently alleviate symptoms, sleepiness typically recurs shortly thereafter. Despite appearing awake, most patients with narcolepsy experience significant difficulty maintaining alertness. Some patients exhibit automatic behaviors, such as continuing to speak or perform tasks without conscious awareness, often with no recollection of the episode. These can substantially impair academic performance, occupational functioning, and social relationships.7,8
Cataplexy
Cataplexy is a hallmark symptom of narcolepsy and is typically precipitated by strong emotional stimuli such as laughter, anger, or excitement.9 It is characterized by a sudden, transient loss of voluntary muscle tone, which may manifest as facial muscle weakness, head dropping, slurred speech, limb buckling, or, in severe cases, complete postural collapse. Consciousness is preserved during cataplectic episodes, and patients are generally able to recall the event in detail. These episodes are usually brief, lasting from a few seconds to several minutes, and resolve spontaneously without intervention.10
The presence of cataplexy is a key diagnostic criterion for narcolepsy type 1, as defined by the ICSD-3.1 In contrast, the absence of cataplexy in individuals with otherwise similar clinical features typically indicates a diagnosis of narcolepsy type 2.
The frequency of cataplexy episodes can vary widely, ranging from a few times per year to as many as 15 to 20 times per day. Cataplexy typically emerges several years after the onset of EDS. While symptoms may improve over time in approximately 10-20% of patients,11 many continue to experience intermittent episodes throughout their lives.
Sleep paralysis
Sleep paralysis is a transient episode of muscle atonia occurring during the transition between sleep and waking, during which patient keeps conscious but unable to initiate voluntary movements or speech. These episodes are often accompanied by vivid hypnagogic or hypnopompic hallucinations and a pronounced sense of fear or discomfort. Although typically self-limiting, they may resolve more rapidly with external sensory stimulation. Sleep paralysis is more frequently observed in of patient with cataplexy.12
Hypnagogic and hypnopompic hallucinations
Hypnagogic and hypnopompic hallucinations are vivid perceptual experiences that occur during the transition into sleep or upon awakening, respectively. These hallucinations are often described as highly realistic and may involve visual, auditory, or tactile components.13 Although the content is typically dreamlike, patient remains partially aware of their environment, which can make the experience particularly distressing. While such hallucinations can occur in the general population, they are significantly more prevalent in individuals with patient with cataplexy.14
Disturbed night sleep
Despite experiencing excessive daytime sleepiness, individuals with narcolepsy often report poor nocturnal sleep quality. Frequent nocturnal awakenings and fragmented sleep contribute to a reduction in deep, restorative sleep stages, thereby impairing the regulation of the sleep-wake cycle. Disturbed night sleep may exacerbate daytime symptoms and perpetuate a cycle of chronic fatigue and impaired alertness.
PATHOPHYSIOLOGY OF NARCOLEPSY
Genetic factors
Although narcolepsy is predominantly a sporadic disorder, genetic predisposition has been implicated.15 First-degree relatives of individuals with narcolepsy have an estimated 1-2% lifetime risk of developing the disorder,16 which is markedly higher than that of the general population. Moreover, concordance rates among monozygotic twins are approximately 25%,17 further supporting a genetic contribution. However, these findings also indicate that genetic factors alone are insufficient to cause the narcolepsy, suggesting the involvement of additional environmental or immunological triggers.
Loss of hypocretin (orexin)
Hypocretin, a neuropeptide neurotransmitter, is produced in the posterior and lateral hypothalamus. It projects extensively throughout the central nervous system (CNS), including aminergic and cholinergic regions such as locus coeruleus, raphe nuclei, tuberomammillary nucleus, basal forebrain, and cortex, which are critical for promoting arousal and maintaining stable wakefulness. Loss of hypocretin neurons leads to reduced and inconsistent firing of these wake-promoting neurons, resulting in excessive daytime sleepiness and unstable transitions between wakefulness and sleep.
In addition to promoting wakefulness, hypocretin neurons provide excitatory drive to rapid eye movement (REM)-off regions, such as the locus coeruleus, dorsal raphe nucleus, and ventrolateral periaqueductal gray, thereby suppressing inappropriate activation of REM-on neurons in the laterodorsal and pedunculopontine tegmental nuclei. In normal REM sleep, muscle atonia is generated by glutamatergic neurons in the sublaterodorsal nucleus (SLD), which activate glycinergic and gamma-aminobutyric acid (GABA)ergic interneurons in the ventromedial medulla (VMM) to inhibit spinal motor neurons.18,19
Cataplexy appears to result from the intrusion of this REM atonia circuitry into wakefulness. Strong emotional stimuli activate the medial prefrontal cortex and the amygdala. In narcolepsy, the loss of hypocretin neurons weakens excitatory drive to REM-off regions, thereby disinhibiting REMon circuitry. GABAergic neurons in the central nucleus of the amygdala inhibit REM-off regions, thereby disinhibiting the REM-on neurons in the SLD. This cascade allows the SLD-VMM pathway during wakefulness, leading to suppression of spinal motor neurons and transient muscle atonia, which clinically manifests as partial or complete cataplexy.18,19
These findings collectively indicate that the loss of hypocretin neurons destabilizes the functional boundaries between wake-promoting and REM-generating circuits, explaining both the excessive sleepiness and the REM-associated phenomena, such as cataplexy and hypnagogic hallucinations, that characterize narcolepsy.
In canine models, mutations in the hypocretin receptor 2 gene result in symptoms characteristic of EDS and cataplexy.20 Similarly, mice with targeted ablation of hypocretin-producing neurons exhibit phenotypes closely resembling human narcolepsy.21,22
Neuroimaging studies using magnetic resonance imaging have demonstrated significantly reduced gray matter volume in the hypothalamus and nucleus accumbens of patients with narcolepsy.23 Additionally, fluorine-18 positron emission tomography study have reported decreased cerebral glucose metabolism in the hypothalamus, thalamus, and anterior frontal regions.24
Cerebrospinal fluid (CSF) analysis shows markedly reduced hypocretin levels in approximately 70-80% of patients with narcolepsy.25 Notably, in narcolepsy type 1 patients with cataplexy, about 90% exhibit CSF hypocretin concentrations below 110 pg/mL.26
Human leukocyte antigen (HLA) typing
A strong genetic association exists between narcolepsy and a specific immune-related gene: HLA-DQB1*0602.27 More than 85% of patients with narcolepsy accompanied by cataplexy test positive for the HLA-DQB10602 allele, regardless of ethnicity. This allele is strongly associated with cataplexy in narcolepsy and is thought to contribute to the disorder through an autoimmune mechanism that selectively destroys hypocretin neurons in the brain, resulting in decreased hypocretin levels. However, since HLA-DQB10602 is also present in 13-35% of the general population,28 its presence alone is not sufficient for diagnosing narcolepsy. Nonetheless, because most patients with hypocretin deficiency are positive for this allele, HLA-DQB1*0602 typing may be a useful preliminary screening tool prior to performing more invasive procedures such as CSF hypocretin measurement.
Immunologic factor
Streptococcal pharyngitis has been proposed as potential environmental triggers for narcolepsy,29 particularly in cases where the onset of symptoms closely follows the illness and is accompanied by elevated immune markers such as antistreptolysin O or anti-DNase B titers.
Another significant environmental factor emerged during the 2009-2010 H1N1 influenza pandemic. A marked increase in narcolepsy incidence was observed among children and adolescents who had either been infected with H1N1 or received the Pandemrix vaccine.30,31 It has been hypothesized that the immune response elicited by the vaccine, particularly against influenza antigens with molecular mimicry to hypocretin, may have triggered an autoimmune attack on hypocretin-producing neurons in genetically susceptible individuals, especially those carrying the HLA-DQB1*0602 allele.
Secondary narcolepsy
Although rare, certain neurological disorders and structural brain lesions can cause narcolepsy. Secondary narcolepsy has been associated with conditions such as Prader-Willi syndrome,32 Niemann-Pick disease,33 and hypothalamus or midbrain lesions such as tumors, vascular malformations, or strokes.34
DIAGNOSIS OF NARCOLEPSY
Persistent and severe EDS lasting longer than 3 months warrants a thorough evaluation for narcolepsy, given the increased likelihood of diagnosis. A comprehensive clinical assessment is imperative to exclude alternative etiologies of EDS, including obstructive sleep apnea syndrome, circadian rhythm sleep-wake disorders, affective disorders such as depression, and drug-induced hypersomnolence secondary to medications like certain antidepressants or antiseizure medications.
Subjective evaluations of EDS can be achieved through validated questionnaire such as the Epworth Sleepiness Scale and the Stanford Sleepiness Scale. Additionally, objective evaluations including sleep diaries and actigraphy facilitate detailed characterization of sleep-wake patterns, identification of insufficient sleep or circadian misalignment.
Diagnostic confirmation of narcolepsy involves overnight polysomnography to assess sleep architecture and to exclude other sleep disorders contributing to EDS, followed by a multiple sleep latency test (MSLT) conducted on the subsequent day.35 The MSLT quantifies physiologic sleep propensity and detects the occurrence of sleep-onset rapid eye movement periods (SOREMPs). According to established diagnostic criteria, narcolepsy is confirmed when the mean sleep latency is less than 8 minutes and at least two SOREMPs are observed across the five nap opportunities. While MSLT remains the cornerstone of narcolepsy diagnosis, its sensitivity is approximately 85% in patients exhibiting cataplexy.36,37 In cases where clinical suspicion remains high despite negative MSLT findings and progressive symptoms, repeat testing after 6 months to 12 months is advisable, as subsequent MSLT may yield positive results.
Inconclusive MSLT results may be supplemented by CSF hypocretin-1 quantification. Patients with narcolepsy accompanied by cataplexy typically demonstrate CSF hypocretin-1 concentrations ≤110 pg/mL or less than one-third of normative values, reflecting high diagnostic specificity (99%) and sensitivity (87%).37 However, in patients lacking cataplexy or presenting atypically, hypocretin-1 measurement demonstrates reduced sensitivity.25
According to the ICSD-3, narcolepsy is classified into type 1 (characterized by cataplexy and/or low CSF hypocretin-1 levels) and type 2 (characterized by EDS without cataplexy and with normal hypocretin-1 concentrations; Table 1).1
TREATMENT OF NARCOLEPSY
Non-pharmacologic treatment of narcolepsy
The primary goal of narcolepsy treatment is to manage symptoms effectively, thereby enabling patients to participate in daily home and occupational activities. While pharmacologic treatment remains the mainstay of therapy, patient education regarding the nature of the disorder, symptom specific lifestyle considerations, and appropriate behavioral strategies is also essential.
Structured behavioral interventions, particularly the implementation of regular nocturnal sleep schedules and strategically timed daytime naps, have demonstrated efficacy in attenuating EDS. Scheduled naps of about 20 minutes can significantly reduce the frequency of unintended sleep episodes during waking hours.38 Moreover, a combined approach involving pharmacologic agents alongside two scheduled 15-minute naps per day and consistent nocturnal sleep hygiene has been shown to yield superior outcomes in mitigating subjective EDS and the frequency of sleep attacks when compared to pharmacotherapy alone.39 Thus, promoting patient awareness and supporting the integration of brief naps during work or school hours may contribute to more effective management of EDS.
For patients whose daily functioning is significantly impaired by cataplexy, education on managing emotion-triggering situations can be beneficial. Behavioral strategies such as systematic desensitization,40,41 which involves gradual exposure to cataplexy-inducing stimuli, and stimulus control,40 aimed at reducing sensitivity through repeated exposure, may help patients gain better control over emotional triggers and reduce cataplexy.
Of particular concern is the elevated risk of motor vehicle accidents among patient with narcolepsy, who are reported to be three to four times more likely to be involved in such incidents compared to the general population.42,43 Notably, one-third of these accidents are directly attributable to sleep attacks during driving. It is therefore imperative to provide comprehensive education to patients and their families regarding the potential safety hazards associated with EDS and cataplexy in the context of driving and other high-risk activities.
Adherence to optimal sleep hygiene practices, including maintaining adequate and regular nighttime sleep, is essential in minimizing symptom exacerbation. Insufficient nocturnal sleep has been shown to disproportionately intensify daytime somnolence in patients with narcolepsy,39 surpassing the effects observed in general population, despite equivalent total sleep duration.
Pharmacologic treatment of narcolepsy
Pharmacologic treatment of narcolepsy is determined by the predominant symptoms that interfere with daily functioning. Therapeutic agents are typically selected to specifically address either EDS or cataplexy (Table 2).
Treatment for EDS only
CNS stimulants are primarily used in the treatment of EDS. The most commonly used agents include modafinil, armodafinil, methylphenidate, and, more recently, solriamfetol.
Modafinil is widely considered the first-line treatment due to its efficacy in promoting wakefulness and its relatively favorable side effect profile compared to traditional stimulants. Although its precise mechanism of action remains unclear, modafinil presumed to enhance arousal through modulation of dopaminergic, adrenergic, and histaminergic pathways, particularly in the hypothalamus.44 It is typically administered in divided doses ranging from 100 mg/day to 400 mg/day, which may offer improved symptom control and tolerability.45 Common adverse effects include headache, dry mouth, insomnia, nausea, and anxiety. Cardiac side effects such as tachycardia, palpitations, and chest discomfort may occur in some cases.46,47 Rarely, hypersensitivity reactions including rash or serious dermatologic conditions such as Stevens-Johnson syndrome have been reported. Divided dosing has been shown to be more effective than a single daily dose.48
Armodafinil, the R-enantiomer of modafinil, has a longer half-life of approximately 10-14 hours and demonstrates similar efficacy and tolerability compared to modafinil. It is initiated at 50-150 mg/day and be titrated up to a maximum of 250 mg/day.49,50
Methylphenidate, a dopamine reuptake inhibitor that also promotes dopamine release, is effective for EDS but is generally considered a second-line treatment.51 Immediate-release formulations are commonly preferred due to their short duration of action, allowing flexible dosing. Treatment typically begins at 10 mg twice daily and may be titrated to a maximum of 60 mg/day. However, tolerance and the potential for dependence limit its long-term use. Adverse effects are decrement of appetite, sympathetic nervous system activation, palpitations and insomnia.
Solriamfetol is a dual dopamine and norepinephrine reuptake inhibitor that received Food and Drug Administration approval in 2019 for the treatment of EDS in narcolepsy. Clinical trials have demonstrated its efficacy in improving wakefulness. 52 The recommended starting dose is 75 mg/day, with titration up to a maximum of 150 mg/day. Adverse effects are headache, nausea, reduced appetite, and anxiety.53 Although widely approved in several countries, it has not yet been approved for clinical use in South Korea.
Treatment for cataplexy only
The mechanism by which antidepressants suppress cataplexy is not fully understood; however, it is presumed to involve enhanced serotonergic and noradrenergic neurotransmission, which in turn suppresses REM sleep. This suppression prevents REM intrusion during wakefulness, thereby reducing REM-related symptoms such as cataplexy, sleep paralysis, and hypnagogic hallucinations.
Venlafaxine is the most commonly used antidepressant for cataplexy and is generally well tolerated. The initial recommended dose is 37.5 mg/day, with maintenance doses typically ranging from 75 mg/day to 150 mg/day.54 Fluoxetine and duloxetine have also showed efficacy in the treatment of cataplexy.55,56
Tricyclic antidepressants (TCAs) including protriptyline, desipramine, imipramine, and clomipramine is also used management of cataplexy.57 However, used of TCAs is limited due to anticholinergic and cardiovascular side effects, such as headache, urinary retention, orthostatic hypotension, constipation, and sexual dysfunction.58 Abrupt discontinuation of TCAs is not recommended, as it can lead to significant withdrawal symptoms and a rebound worsening of cataplexy.
Treatment for both EDS and cataplexy
Pitolisant is an oral histamine H₃ receptor inverse agonist approved for the treatment of both EDS and cataplexy in patients with narcolepsy.59,60 Histaminergic neurons promote wakefulness by activating wake-promoting regions, including the locus coeruleus, pons, dorsal raphe nucleus, and forebrain. Pitolisant enhances histamine synthesis and release by blocking presynaptic H₃ autoreceptors, thereby increasing histaminergic tone. Pitolisant has a long half-life of approximately 20 hours and is taken once daily in the morning. The starting dose is 8.9 mg/day, which may be titrated up to a maximum of 35.6 mg/day. Common adverse effects are headache, insomnia, irritability, anxiety, and nausea. Pitolisant exhibit a low abuse potential.61,62
Sodium oxybate, the sodium salt of gamma-hydroxybutyrate, has demonstrated efficacy in managing EDS, cataplexy, and disrupted nocturnal sleep in adult patients with narcolepsy. Although widely approved in several countries, it has not yet been approved for clinical use in South Korea. Sodium oxybate acts as an agonist at GABA type B receptors. While its precise mechanism remains unclear, one hypothesis suggests that it suppresses noradrenergic neurons in the locus coeruleus during sleep, thereby enhancing wakefulness through a rebound effect during the day.63 Common adverse events are nausea, headache, dizziness, weight loss, urinary incontinence, mood changes, sleepwalking, and psychotic symptoms. Sodium oxybate has a high risk of dependence, misuse, and withdrawal.64,65 It is contraindicated with other CNS depressants and alcohol due to synergistic effects that can lead to profound CNS depression.64,66 Overdose of sodium oxybate may result in serious adverse events, including respiratory depression, bradycardia, seizures and death.65 It has not yet been approved for clinical use in South Korea.
CONCLUSION
Narcolepsy is a lifelong disorder that significantly impairs daytime functioning and quality of life. Despite its relatively low prevalence, its clinical impact is substantial due to early onset and chronic progression. A combination of pharmacologic treatment and behavioral strategies has shown efficacy in mitigating core symptoms such as EDS and cataplexy. Further research into the underlying mechanisms and development of novel therapeutics remains essential to enhance long-term outcomes and quality of life for patients with narcolepsy.
The diagnosis of narcolepsy type 1 requires the presence of one or both of the following: cataplexy combined with characteristic MSLT or CSF hypocretin-1 deficiency.
ICSD-3, International Classification of Sleep Disorders, third edition; MSLT, multiple sleep latency test; SOREMPs, sleep-onset rapid eye movement periods; CSF, cerebrospinal fluid.
aA SOREMP on preceding overnight polysomnography may replace on of the SOREMP on the MSLT.
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Table 1. Diagnostic criteria for narcolepsy (ICSD-3)1
The diagnosis of narcolepsy type 1 requires the presence of one or both of the following: cataplexy combined with characteristic MSLT or CSF hypocretin-1 deficiency.
ICSD-3, International Classification of Sleep Disorders, third edition; MSLT, multiple sleep latency test; SOREMPs, sleep-onset rapid eye movement periods; CSF, cerebrospinal fluid.
A SOREMP on preceding overnight polysomnography may replace on of the SOREMP on the MSLT.
