Clinical features and diagnosis of narcolepsy in children

INTRODUCTION — Narcolepsy is a chronic neurologic disorder characterized by excessive and irresistible sleepiness, cataplexy (episodes of muscle weakness during periods of strong emotion), hypnagogic hallucinations (vivid dreams at sleep onset), and sleep paralysis (a momentary inability to move the body as one is drifting off to sleep or upon waking up).

Narcolepsy has two forms in both children and adults, depending on whether cataplexy is present [1]. Narcolepsy type 1, previously called narcolepsy with cataplexy, includes cataplexy as one of the earliest symptoms and is associated with low cerebrospinal fluid (CSF) orexin (also called hypocretin) levels. Narcolepsy type 2, or narcolepsy without cataplexy, shares all of the features of narcolepsy type 1 except cataplexy and low CSF orexin.

In children, narcolepsy is often overlooked as a cause of disabling sleepiness, and delays in the diagnosis are common. When narcolepsy starts in childhood, which it commonly can, it can have several unique features, including atypical cataplexy characterized by facial hypotonia or positive motor signs, precocious puberty, rapid unexplained weight gain, and daytime sleepiness manifesting primarily as habitual napping or irritability and hyperactivity.

This topic will review the clinical features and diagnosis of narcolepsy in children. Management in children, and diagnosis and treatment of narcolepsy in adults, are reviewed separately. (See "Management and prognosis of narcolepsy in children" and "Clinical features and diagnosis of narcolepsy in adults" and "Treatment of narcolepsy in adults".)

EPIDEMIOLOGY — The epidemiology of narcolepsy in children is not well characterized.

A European study estimated a pooled incidence rate of 0.83 per 100,000 person-years in children aged 5 to 19 years [2]. The overall prevalence of narcolepsy in Western countries has been estimated at 20 to 50 cases per 100,000 [3].

There are no studies that have examined the relative proportions of type 1 and type 2 narcolepsy in children.

ETIOLOGY — In the majority of cases, narcolepsy in children is sporadic and of unknown etiology. Genetic susceptibility and immune dysregulation likely play essential roles in narcolepsy type 1. (See 'Pathophysiology' below.)

Secondary narcolepsy can occur due to structural lesions affecting the hypothalamus and/or brainstem, perhaps via disruption of orexin signaling. Narcolepsy can also occur with genetic syndromes and acquired disorders such as autoimmune encephalitis. (See 'Pathophysiology' below.)

PATHOPHYSIOLOGY

●Loss of orexin (also known as hypocretin) neurons – Clinicopathologic studies in narcolepsy type 1 show selective loss of orexin-secreting neurons in the hypothalamus and little or no detectable orexin in the cerebrospinal fluid. An increase in histaminergic neurons of the tuberomammillary region has also been observed in people with narcolepsy type 1, but the clinical significance is unclear [4]. (See "Clinical features and diagnosis of narcolepsy in adults", section on 'Orexin/hypocretin'.)

Many of the clinical manifestations of narcolepsy type 1 result from loss of the neurons producing the orexin neuropeptides. Orexins suppress rapid eye movement (REM) sleep, and orexin neuron loss results in REM sleep disinhibition. Many narcolepsy symptoms, including dream-like hallucinations before falling asleep or upon waking, sleep paralysis, and cataplexy, relate to intrusions of the dream-like imagery and muscle atonia experienced in REM sleep [5,6]. Orexins also stabilize sleep and wake states; with orexin neuronal loss, people have trouble maintaining long periods of wake or sleep [7].

●Genetic and immune factors – Genetic factors likely play an important role in the predisposition for narcolepsy. There is a strong association between the DQB1*0602 human leukocyte antigen (HLA) haplotype and narcolepsy type 1. These and other factors are reviewed in more detail separately. (See "Clinical features and diagnosis of narcolepsy in adults", section on 'Genetic factors'.)

●Secondary narcolepsy – While narcolepsy is idiopathic in the majority of cases, structural lesions affecting the diencephalon and/or brainstem occasionally precipitate secondary narcolepsy, perhaps via disruption of orexin secretion [8]. Hypothalamic glioma, craniopharyngioma, sarcoidosis, and head injury have all been associated with secondary narcolepsy in children [9,10]. Case reports and series report narcolepsy development with anti-N-methyl-D-aspartate (NMDA) receptor antibody encephalitis [11], multiple sclerosis, and neuromyelitis optica [12]. Narcolepsy can also occur with genetic syndromes such as Prader-Willi syndrome [13], Coffin-Lowry syndrome, Norrie disease [8,14], myotonic dystrophy [15], and Niemann-Pick disease type C [14,16-18].

●Association with H1N1 influenza A – The incidence of narcolepsy abruptly increased in the midst of the 2009 H1N1 influenza A pandemic, with most new cases in children and adolescents. The annual incidence increased about fourfold in China, which had low levels of vaccination against influenza [19], and 1.6-fold in the United States [20]. In northern Europe, vaccination with Pandemrix, an AS03-adjuvanted influenza vaccine, was associated with a 5- to 14-fold increase in incidence of narcolepsy in children and adolescents [21]. In studies that included HLA testing, all affected children were HLA DQB1*0602 haplotype positive [22].

Molecular mimicry and autoimmunity are likely implicated, related to an antigen in the Pandemrix vaccine, the influenza infection itself [23-26], or to both [27,28]. (See "Clinical features and diagnosis of narcolepsy in adults", section on 'Autoimmune hypothesis'.)

CLINICAL MANIFESTATIONS — Excessive daytime sleepiness (EDS) is an essential clinical feature of narcolepsy and is the most common presenting symptom in both children and adults.

The classic tetrad of narcolepsy type 1 symptoms is EDS, cataplexy, hypnagogic hallucinations, and sleep paralysis. However, only 10 to 25 percent of people with narcolepsy type 1 have this complete tetrad of symptoms [29,30], making diagnosis challenging. Sleep paralysis and other symptoms may gradually appear over time. Overall, survey data have shown that clinicians are unfamiliar with narcolepsy symptoms [31], and this lack of awareness likely contributes to delays in diagnosis [32].

Age of onset — Narcolepsy is a lifelong disorder that most commonly begins in the first, second, or early third decade of life. Approximately one-third of patients develop symptoms before 15 years of age, and up to 5 percent of cases begin before the age of five years [33]. Anecdotally, the age of onset of narcolepsy type 2 may be slightly later than narcolepsy type 1.

Daytime sleepiness — Daytime sleepiness is present in all children with narcolepsy and is usually the first symptom. The onset can be as early as five to six years of age, but in rare cases it may be apparent even in the preschool years.

The severity of daytime sleepiness ranges from waxing and waning drowsiness to irresistible, unintended lapses into sleep (often referred to as sleep attacks). Lapses into sleep can occur throughout the day but are most likely to occur during sedentary activities such as sitting in a classroom, reading a book, or being driven in a car. People with narcolepsy typically report that short naps (10 to 20 minutes) are refreshing.

Daytime sleepiness sometimes manifests as habitual napping that occurs after a child typically grows out of the need for daily naps. Specifically, habitual napping is uncommon in healthy children after five to six years of age, and when present, it should raise suspicion for pathologic sleepiness.

When sleepiness is mild or subtle, caregivers may instead report a history of irritability, poor concentration, or memory impairment, especially in younger children [34]. Children with daytime sleepiness can be mistaken for being "lazy" and may become the target of negative comments from their peers. These behavioral manifestations of sleepiness may also be perceived to be symptoms of attention deficit hyperactivity disorder (ADHD), although ADHD may also be a comorbidity of narcolepsy [35].

Daytime sleepiness in narcolepsy may be associated with automatic behaviors of which the child is unaware. This can manifest as a segment of sloppy handwriting in an assignment or performing routine tasks with little recollection of them afterwards.

The Pediatric Daytime Sleepiness Scale (PDSS) has been validated in children ages 11 to 15 years old and can be used to quantify subjective daytime sleepiness (table 1) [36]. Total PDSS scores range from 0 to 32, with higher scores indicative of more severe sleepiness. The median PDSS score in healthy teenagers is 16 [36]. In a cohort of 31 children with newly diagnosed narcolepsy (mean age 13 years), the mean PDSS score was 22 [37].

A version of the Epworth Sleepiness Scale (ESS) that has been modified for children and adolescents (ESS-CHAD) (form 1) is also used by some clinicians, with elevated scores indicating sleepiness [38]. The ESS-CHAD shows good validity and reliability for children 7 to 18 years [39,40]. Based on clinical experience, untreated pediatric narcolepsy patients typically have an ESS-CHAD score greater than 15, although reference values have not been firmly established in teenagers.

Cataplexy — Cataplexy is the most specific symptom of narcolepsy. It is seen in approximately 80 percent of children with narcolepsy [33]. It typically emerges around the same time as excessive sleepiness or in the months thereafter.

Typical cataplexy is characterized by sudden, transient, and symmetric loss of muscle tone; the weakness or paralysis usually arises in response to strong emotions such as laughter, surprise, anger, fright, or anticipation of reward. Consciousness is fully preserved. Episodes usually last <1 minute with full return of function thereafter. Cataplexy attacks rarely last >2 minutes, but if a particular trigger continues, consecutive attacks can merge to form what seems to be one long episode. The severity of attacks ranges from a slight head or shoulder drop (partial cataplexy) to buckling of the knees and sudden collapse to the floor (full cataplexy).

By contrast, the following characteristics are atypical for cataplexy:

●Attacks never triggered by laughing, mirth, or joking

●Prolonged attacks in adults (eg, >3 minutes) in the absence of an ongoing precipitant

●Absence of clear triggers of the episodes or negative emotions (such as anxiety, fear, or a sudden, startling noise) as the sole triggers

●Purely unilateral attacks

●Hyperacute generalized muscle weakness without build-up over seconds, leading to falls and injuries

●Prolonged recovery time (several minutes) needed to recover after a single attack

●Uncertainty regarding the preservation of consciousness

●Exclusively generalized attacks without a history of partial episodes

If two or more of these characteristics are present, the episodes should not be labeled as typical cataplexy. Patients with narcolepsy type 1 may report both typical and atypical cataplexy events. If only atypical cataplexy is reported, the patient should not be diagnosed at narcolepsy type 1 without cerebrospinal fluid (CSF) orexin testing confirmation. (See 'Diagnostic criteria' below.)

Young children often present with atypical positive or negative motor features, which later evolve into more typical cataplexy [41]. Persistent cataplexy characterized by facial weakness is common in children, manifested by the jaw dropping open, eyelid drooping (ptosis), head rolling, or tongue thrusting movements [42]. This has given rise to the term "cataplectic facies," which is a unique clinical feature of childhood narcolepsy [42,43]. This weakness is likely sustained, partial cataplexy that is not triggered by emotion. Other manifestations of atypical cataplexy in children may include positive motor signs such as eyebrow raising, perioral movements, and head/trunk swaying [41]. Over the first years, these signs evolve into the classic form of brief cataplexy triggered by emotions [41]. (See 'Differential diagnosis' below.)

The frequency of cataplexy is variable. Children can have dozens of cataplexy episodes in a day, producing a clumsy and uncoordinated appearance. When in doubt as to the nature of these episodes, a review of videos provided by caregivers can be very helpful.

Hypnagogic hallucinations and sleep paralysis — Hypnagogic hallucinations and sleep paralysis are seen in approximately 50 to 60 percent of children with narcolepsy. Like cataplexy, these phenomena may represent episodic intrusion of fragments of rapid eye movement (REM) sleep onto wakefulness.

Hypnagogic hallucinations consist of vivid, dream-like imagery at sleep onset; the same phenomena can more occasionally occur on awakening, when they are then referred to as hypnopompic hallucinations. Sleep paralysis is a momentary inability to move the body, most commonly on awakening in the morning or during the night, but occasionally as one is drifting off to sleep.

Children below the age of five to six years are usually unable to provide a reliable history for hypnagogic hallucinations and sleep paralysis. Children may find the experiences frightening, such that symptoms are initially attributed to nightmares, sleep terrors, or other parasomnias. (See "Parasomnias of childhood, including sleepwalking", section on 'Sleep terrors'.)

Other common features

Awakenings and movements during sleep — Disrupted nighttime sleep is a core symptom of narcolepsy in both children and adults [44]. Children with narcolepsy often have frequent, brief awakenings, which may or may not be associated with periodic leg movements. (See "Clinical features and diagnosis of narcolepsy in adults", section on 'Other features'.)

In addition to awakenings, complex motor behaviors may arise during REM sleep due to incomplete muscle paralysis [45,46]. In a series of 40 children with type 1 narcolepsy who underwent video polysomnography (PSG), 32 percent of patients exhibited complex motor behaviors during REM sleep consistent with REM sleep behavior disorder (RBD), compared with none of 22 age- and sex-matched controls [47]. Movements included both vigorous dream enactment motions (eg, vivid gestures, throwing something, raising the head and reaching or grabbing) and pantomime-like events characterized by slow, calm, and repetitive gesturing. Events were more common among children with impaired nighttime sleep, worse daytime sleepiness, and cataplectic facies/status cataplecticus.

Neuropsychiatric symptoms — Depression is common in both children and adults with narcolepsy [48]. Children are also at risk for aggressive behavior, symptoms of ADHD, social and emotional distress, and decreased school performance and engagement [49-52]. Cognitive deficits have also been reported [53].

Obesity and precocious puberty — One of the unique features of childhood narcolepsy type 1 is its association with obesity, which is often present at the onset of daytime sleepiness [54,55]. The mechanism of weight gain, which is often sudden, is not yet clear; decreased energy expenditure as well as a decrease in basal metabolic rate have each been observed [55,56].

Within a few years of diagnosis, approximately two-thirds of children with narcolepsy are overweight or obese [41,55,57]. The age of onset of narcolepsy symptoms seems to be earlier in children with obesity compared with those who are not obese [58].

Precocious puberty also occurs with increased frequency in children with narcolepsy, affecting 17 percent of children with narcolepsy compared with 2 percent of similarly aged control children with obesity [58]. In one study, all children with narcolepsy type 1 and precocious puberty were obese, but their body mass index (BMI) was not significantly higher than those with narcolepsy type 1 without precocious puberty [58].

DIFFERENTIAL DIAGNOSIS — Narcolepsy is a rare cause of excessive daytime sleepiness (EDS) in children; however, the more severe the sleepiness, the more important it is to consider narcolepsy as a potential cause.

Other causes of sleepiness — Particularly when there is no history of cataplexy, alternative and more common causes of EDS should be considered, including insufficient sleep due to poor sleep hygiene and fragmented sleep due to disorders such as obstructive sleep apnea (table 2). Other causes of sleepiness to consider are medication side effects, substance abuse, delayed sleep-wake phase disorder (in teenagers), depression, and underlying medical conditions. (See "Assessment of sleep disorders in children", section on 'Excessive daytime sleepiness'.)

Most of these causes of EDS can be differentiated from narcolepsy by history and the absence of additional clinical features of narcolepsy (ie, cataplexy, sleep attacks, hypnagogic hallucinations, and sleep paralysis). Notably, however, hypnagogic hallucinations, sleep paralysis, and sleep attacks are not specific to narcolepsy and can occur as isolated phenomena, precipitated by insufficient or fragmented sleep. Wrist actigraphy and sleep logs maintained for two to three weeks can help exclude insufficient sleep and delayed sleep phase syndrome.

Children with obstructive sleep apnea usually have snoring or other indications on history of abnormal breathing during sleep, and polysomnography (PSG) is needed to confirm the diagnosis. (See "Evaluation of suspected obstructive sleep apnea in children", section on 'Evaluation'.)

Mimics of cataplexy — Cataplexy in children is sometimes confused with atonic seizures. Unlike cataplexy, however, seizures are not typically triggered by strong emotions, and seizures that cause falls usually include loss of consciousness and are followed by confusion and obtundation. Cataplexy also can be confused with syncope. Unlike cataplexy, syncope is preceded by vision and/or hearing changes and lightheadedness and is associated with loss of consciousness.

With persistent cataplexy (cataplectic facies), ptosis and a slack jaw are common, mimicking myasthenias gravis (MG). However, unlike in MG, a history of excessive sleepiness is almost always present before, or concurrent with facial symptoms. (See "Clinical manifestations of myasthenia gravis".)

Other central disorders of hypersomnolence — More rare central disorders of hypersomnolence can cause severe daytime sleepiness beginning in childhood, including the following:

●Idiopathic hypersomnia – Patients with idiopathic hypersomnia do not have cataplexy, but on rare occasions they may exhibit features such as hypnagogic hallucinations, sleep paralysis, or sleep attacks. They often have increased amounts of sleep over a 24-hour period. Idiopathic hypersomnia is typically considered only after other causes of sleepiness have been ruled out by both history and PSG. PSG followed by a multiple sleep latency test (MSLT) is required for the diagnosis of idiopathic hypersomnia. These tests show characteristic findings that are distinct from narcolepsy (ie, a shortened mean sleep latency but fewer than two sleep-onset REM periods [SOREMPs]). (See "Idiopathic hypersomnia".)

●Kleine-Levin syndrome (KLS) – KLS is unique for its episodic course of hypersomnia lasting days to weeks followed by periods of normal daytime alertness and sleep. During these episodes of hypersomnia, patients commonly have cognitive disturbances, anorexia or hyperphagia, memory impairment, derealization, and severe apathy. They may also exhibit disinhibition in the form of hypersexuality. The strikingly episodic nature of EDS in KLS and the prominent cognitive and behavioral disturbances distinguish it from narcolepsy, which manifests with daily, nonremitting symptoms. (See "Kleine-Levin syndrome (recurrent hypersomnia)".)

●Rapid-onset Obesity, Hypoventilation, Hypothalamic and Autonomic Dysfunction (ROHHAD) – ROHHAD is a rare cause of acquired sleepiness in children [59]. It generally begins in the first decade and shows a slight female predominance. There is abrupt onset of obesity and sleep-related hypoventilation. Other common signs include altered thermoregulation, hyponatremia or hypernatremia, hyperprolactinemia, and neurobehavioral disturbances. No specific etiology has been found, and the condition is progressive. Noninvasive ventilation or tracheostomy combined with a home ventilator may be required. (See "Congenital central hypoventilation syndrome and other causes of sleep-related hypoventilation in children", section on 'Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD)'.)

EVALUATION AND REFERRAL — Narcolepsy should be suspected in children presenting with the subacute onset of severe daytime sleepiness leading to sleep attacks and daytime naps, particularly when there is also a history of cataplexy, sleep paralysis, or new obesity. Cataplexy in young children can be subtle with mainly persistent facial weakness. (See 'Clinical manifestations' above.)

The initial evaluation consists of a history directed at identifying potential causes of sleepiness and recognizing other characteristic features of narcolepsy that may be overlooked by the child and caregivers. The sleep history should be structured, systematic, and detailed. An approach to the initial evaluation is presented separately. (See "Assessment of sleep disorders in children", section on 'Excessive daytime sleepiness' and "Assessment of sleep disorders in children".)

Children with suspected narcolepsy should be referred to a sleep medicine clinician with pediatric training or experience for evaluation prior to formal diagnostic sleep testing. The diagnosis of narcolepsy rests heavily on polysomnography (PSG) and a multiple sleep latency test (MSLT), which require an overnight stay in a sleep laboratory and meticulous planning to avoid confounding effects of sleep insufficiency and medications. Lumbar puncture for measurement of cerebrospinal fluid (CSF) orexin levels should be considered in some patients. (See 'CSF orexin (hypocretin-1) testing' below.)

DIAGNOSIS — The diagnosis of narcolepsy is established on the basis of characteristic clinical features combined with nocturnal polysomnography (PSG) and a multiple sleep latency test (MSLT).

Diagnostic criteria — Diagnostic criteria for narcolepsy are identical for children and adults [1].

A diagnosis of narcolepsy type 1 requires all of the following (table 3):

●Daily periods of irrepressible need to sleep or daytime lapses into sleep. In young children, narcolepsy sometimes presents as excessively long night of sleep or resumption of previously discontinued daytime napping.

●The presence of one or both of the following:

•Cataplexy and either:

-Mean sleep latency of ≤8 minutes and two or more sleep-onset rapid eye movement periods (SOREMPs) on an MSLT performed according to standard techniques.

-A SOREMP (within 15 minutes of sleep onset) on nocturnal PSG.

•Cerebrospinal fluid (CSF) orexin (hypocretin-1) concentration is ≤110 picograms/mL (or less than one-third of mean values obtained in normal subjects) with a standardized radioimmunoassay.

●The 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.

If a patient lacks cataplexy or if the CSF orexin level is >110 picograms/mL, narcolepsy type 2 is diagnosed, assuming other criteria are met (table 4). If cataplexy emerges later, the disorder is reclassified as narcolepsy type 1. The validity of a SOREMP on the nocturnal PSG for diagnosis of narcolepsy type 2 is unknown.

Sleep studies

Polysomnography — All children with suspected narcolepsy require nocturnal PSG, and most children also require MSLT the following day.

The main purpose of PSG in the diagnostic evaluation of narcolepsy is to exclude alternative or coexisting causes of chronic daytime sleepiness, and to ensure that an adequate amount of sleep has been obtained before the MSLT. However, based on updated diagnostic criteria reflected in the International Classification of Sleep Disorders, third edition, text revision (ICSD-3-TR), the nocturnal PSG should also be scrutinized for the presence of a SOREMP within 15 minutes of sleep onset [1]. This is a highly specific finding associated with narcolepsy type 1 in adults and children [60]. Its presence is now sufficient to diagnose narcolepsy type 1 in the setting of typical symptoms of narcolepsy with cataplexy.

In some cases, patients have had a prior PSG to rule out sleep-disordered breathing, with normal results or mild OSA thought not severe enough to account for the presence of severe daytime sleepiness. Such testing should be reviewed for the presence of a nocturnal SOREMP. If found and the patient has severe daytime sleepiness and cataplexy, further diagnostic testing may be unnecessary.

In addition to scrutiny for a SOREMP within 15 minutes of sleep onset, we also review the nocturnal PSG for other markers of narcolepsy type 1, including rapid eye movement (REM) sleep without atonia, objective measures of disrupted nighttime sleep (eg, wake/N1 index [number of transitions from sleep to wake or N1 sleep per hour of sleep time]), and frequent transitions from REM sleep to wake or N1 [44,61-63].

Multiple sleep latency test — Diagnostic PSG and MSLT require meticulous preparation to avoid confounding effects of sleep insufficiency and medications [64-66]. Children, including teenagers, need more sleep than adults, so the amount of sleep on the PSG the night before the MSLT should meet age-based needs [67].

●Medications that can impact sleep-wake function (eg, stimulants, antidepressants) should be stopped for at least two weeks prior to the study, provided it is safe to do so. Longer washout of medications may be needed for drugs with a very long half-life (eg, fluoxetine) [68]. This may require input and advice from the patient's primary care physician and/or child psychiatrist. Stimulants and antidepressants suppress REM sleep and can prevent the appearance of SOREMPs; conversely, abrupt discontinuation can result in REM rebound effects that include the appearance of SOREMPs.

●Urine drug screen for drugs of abuse is routinely performed during the MSLT test and commonly includes screening of substances such as amphetamines and marijuana [69]. In one study, caffeine was the most commonly reported positive result in a pediatric sleep laboratory conducting PSG-MSLT testing [70]. Clinicians are advised to ask about sedating/alerting substances including caffeine use when ordering PSG-MSLT testing and provide instructions about discontinuation based on their half-lives.

●Sleep logs and ideally wrist actigraphy should be obtained for at least two weeks before the MSLT [66], as insufficient sleep or circadian rhythm disturbances (most commonly delayed sleep phase syndrome) can produce false positive MSLT results specifically for narcolepsy type 2 [71]. Actigraphy reliably estimates total time in bed, total sleep time, and sleep efficiency. (See "Actigraphy in the evaluation of sleep disorders".)

The MSLT is started the morning after the PSG and consists of five 20-minute nap opportunities at two-hour intervals across the day. The latency until sleep onset is measured for each nap opportunity, and multichannel sleep recordings are analyzed to detect sleep stage transitions and the presence or absence of REM sleep during each nap. (See "Assessment of sleep disorders in children", section on 'Multiple sleep latency test'.)

Diagnostic accuracy — If a nocturnal PSG alone is conducted, the presence of a nocturnal SOREMP (REM sleep onset latency of ≤15 minutes) is highly specific for pediatric narcolepsy type 1 (97 percent) but has low sensitivity (55 percent) [60]. A child with a mean sleep latency >8 minutes may still have excessive daytime sleepiness, but age-specific criteria for diagnosis of narcolepsy have not yet been established.

The MSLT diagnostic criteria for narcolepsy are currently the same in children as they are in adults, despite the fact that normal mean sleep latency for children is likely considerably higher than for adults [72]. Pediatric-specific MSLT protocol recommendations are in development by the American Academy of Sleep Medicine.

In children as young as three years of age, a validation study identified alternative cutoffs for narcolepsy type 1 diagnosis. The study authors found that either ≥2 SOREMPs or a mean sleep latency ≤8.2 minutes had high sensitivity and specificity for the diagnosis of narcolepsy type 1 (against a gold standard of CSF orexin <110 pg/mL) [73]. A combination of the two measures did not improve diagnostic accuracy. On the other hand, when both of these measures were negative, narcolepsy type 1 could be ruled out in 99.5 percent of cases. The study did not address test performance for narcolepsy type 2. Further research to assess results compared with other sleep disorders such as obstructive sleep apnea and to explore generalizability of these findings is needed.

The diagnosis of narcolepsy in young children can be difficult and sometimes requires delaying testing until a child is at least six years of age or obtaining CSF orexin to make a definitive diagnosis.

CSF orexin (hypocretin-1) testing — A low cerebrospinal fluid (CSF) orexin level (<110 pg/mL) is highly sensitive and specific for a diagnosis of narcolepsy type 1, and a commercially available assay for CSF orexin is available in the United States through Mayo Clinic Laboratories.

Measurement of orexin is most useful when the diagnosis of narcolepsy type 1 is equivocal [74]. Examples include a child below the age of five years, in whom the MSLT is not validated, and instances in which the patient is already on an antidepressant medication, which cannot be safely stopped for diagnostic sleep tests. Up to 95 percent of patients with narcolepsy with cataplexy and orexin deficiency are also positive for the human leukocyte antigen (HLA) DQB1*0602 [75,76], so testing for presence of this haplotype is recommended before proceeding to lumbar puncture for the orexin assay.

Other tests — Neuroimaging in patients with narcolepsy is typically normal but may be indicated to rule out alternative causes of excessive sleepiness, particularly in the presence of focal neurologic findings or a history suggestive of increased intracranial pressure.

Although the HLA DQB1*0602 haplotype is present in the majority of individuals with narcolepsy type 1 (85 to 95 percent) [77], it is not sufficiently specific to be useful as a routine diagnostic test. However, given high prevalence among people with narcolepsy type 1, it is helpful as a screening test for narcolepsy type 1 in patients with atypical events suggestive of possible cataplexy.

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 5^th to 6^th 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 10^th to 12^th 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 topic (see "Patient education: Narcolepsy (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Etiology – Narcolepsy in children is mostly sporadic and, for narcolepsy type 1, caused by loss of orexin neurons in the hypothalamus. Rare cases of secondary narcolepsy are usually due to structural lesions in the hypothalamus or brainstem. The cause of narcolepsy type 2 is unknown. (See 'Etiology' above.)

●Pathophysiology – Genetic susceptibility and immune dysregulation likely play a central role in narcolepsy type 1, resulting in selective loss of orexin-secreting neurons in the hypothalamus. Orexin deficiency in turn causes sleep-state instability and inappropriate intrusions of rapid eye movement (REM) sleep into wakefulness. (See 'Pathophysiology' above.)

●Age of onset – In about one-third of patients, narcolepsy symptoms begin before the age of 15 years. Narcolepsy can present in children as young as six years of age, rarely even younger. (See 'Epidemiology' above.)

●Excessive daytime sleepiness (EDS) – All children with narcolepsy have EDS. The severity ranges from waxing and waning drowsiness to irresistible, unintended, frequent lapses into sleep (sleep attacks). When sleepiness is mild or subtle, caregivers may instead report a history of irritability, poor concentration, or memory impairment. (See 'Daytime sleepiness' above.)

●Cataplexy – Cataplexy involves sudden, transient loss of muscle tone, usually in response to strong emotions. In young children, cataplexy often involves the buccofacial muscles, with jaw opening, eyelid drooping (ptosis), head rolling, or tongue thrusting movements early in the disease course. (See 'Cataplexy' above.)

●Other key features – Additional core features of narcolepsy seen in adults, such as hypnagogic hallucinations and sleep paralysis, may be absent or difficult to elicit in young children. (See 'Hypnagogic hallucinations and sleep paralysis' above.)

●Obesity – Obesity is common in children with narcolepsy and tends to happen suddenly, near the onset of other symptoms. (See 'Obesity and precocious puberty' above.)

●Differential diagnosis – The differential diagnosis of narcolepsy in children includes insufficient or fragmented sleep due to poor sleep hygiene, obstructive sleep apnea, medication side effects, depression, and underlying medical conditions, among many others (table 2). Mimics of cataplexy in children, such as atonic seizures, are important to recognize. (See 'Differential diagnosis' above.)

●Evaluation and referral – The initial evaluation consists of a history to identify potential causes of sleepiness and recognize other characteristic features of narcolepsy that may be subtle or overlooked by the child and caregivers. Children with suspected narcolepsy should be referred to a sleep medicine clinician with pediatric training or experience for evaluation prior to formal diagnostic sleep testing. (See 'Evaluation and referral' above.)

●Diagnosis – Narcolepsy is diagnosed by clinical features and supported by a nocturnal polysomnography (PSG) plus a multiple sleep latency test (MSLT). In the proper clinical context, two or more sleep-onset REM periods (SOREMPs) and a mean sleep latency of ≤8 minutes on MSLT are diagnostic of narcolepsy (table 3 and table 4).

Cerebrospinal fluid (CSF) orexin testing is an option in selected children who are human leukocyte antigen (HLA) DQB1*0602 positive and cannot comply with PSG-MSLT testing. (See 'Polysomnography' above and 'CSF orexin (hypocretin-1) testing' above.)