Management and prognosis of narcolepsy in children

INTRODUCTION — Narcolepsy is a rare, chronic neurologic disorder characterized by excessive daytime sleepiness. Many patients also have cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted nighttime sleep. Symptom onset in pediatric cases is typically between ages 5 and 15 years, but delays in symptom recognition (by parents/caregivers and healthcare providers alike) and misdiagnosis are common.

The management and prognosis of narcolepsy in children are reviewed here. The clinical features and diagnosis of narcolepsy and the approach to evaluating sleep disorders in children are presented separately. (See "Clinical features and diagnosis of narcolepsy in children" and "Assessment of sleep disorders in children".)

Diagnosis and management of narcolepsy in adults are also reviewed separately. (See "Clinical features and diagnosis of narcolepsy in adults" and "Treatment of narcolepsy in adults".)

BEHAVIORAL AND LIFESTYLE MODIFICATION — All children and families should receive education about behavioral strategies and lifestyle adjustments to reduce the impact of the disease [1].

Sleep habits and daytime naps — Parents/caregivers should encourage the child with narcolepsy to maintain regular sleep-wake schedules and receive adequate time for sleep at night (at least 10 hours for school-age children and at least 8 hours for adolescents). Although this is good advice for any child, it becomes especially important for a child with narcolepsy.

Short scheduled naps during the daytime can mitigate drowsiness for a small number of hours. Depending on the age of the child, naps may be planned at school or upon return home from school for 15 to 30 minutes, and most patients feel more alert afterwards.

Diet and exercise — To promote daytime alertness and aid sleep hygiene, we advise patients avoid heavy carbohydrate-rich meals, excessive sugar intake, and eating heavy meals before bedtime. In our experience, caffeine use does not produce a sustained alerting effect in people with narcolepsy, and side effects of anxious feeling or tachycardia can outweigh benefits. The effect of specific diets on daytime sleepiness and alertness has yet to be studied in narcolepsy.

Regular exercise during the daytime can enhance alertness.

Mental health care — Caregivers and clinicians should maintain heightened awareness for psychiatric comorbidities in children with narcolepsy. Depression, anxiety, obsessive compulsive disorder, and social phobia have been reported in up to 35 percent of patients [2]. (See "Clinical features and diagnosis of narcolepsy in children", section on 'Neuropsychiatric symptoms'.)

We also encourage psychological counseling from the time of diagnosis, including family counseling if needed to cope with this chronic disease. Cognitive behavior therapy for narcolepsy management is a useful complement to pharmacotherapy [3] and, in our experience, promotes treatment adherence and agency among patients.

School and career planning — Children may need special accommodations at school to promote an optimal learning environment. Clinicians and caregivers may find it helpful to work closely with a school guidance counselor to ensure the opportunity for one to two brief daytime naps. Schools can sometimes make other accommodations to improve a child's alertness, such as sitting at the front of the class, movement/stretch breaks, being allowed to chew gum or drink cold water in class, and/or taking "stop the clock" breaks during longer timed tests. In some instances, the diagnosis of narcolepsy may allow for extra time to take standardized tests.

Young people with narcolepsy can also benefit from advice regarding the choice of a career. In general, individuals with narcolepsy may be more at ease in occupations that allow for standing and moving about rather than sedentary jobs. Workplace accommodations may be needed to allow more frequent breaks, opportunities for brief naps, and flexible schedules.

●Professions like school teaching may allow for staying awake while standing and being mobile and physically active.

●Late-night shifts or frequent changes to work hours can be difficult for people with narcolepsy [1], so night shift work might need to be avoided.

●There are specific occupations that people with narcolepsy cannot pursue, such as commercial transportation (eg, airline pilot, city bus driver, or long-haul truck driver).

Support groups — Narcolepsy symptoms can contribute to social isolation and frustration due to stigma and lack of understanding about the disease. Local, national, and international support groups can help patients and their family/caregivers cope and learn useful life management skills. Support groups are offered through Narcolepsy Network, Project Sleep, Hypersomnia Foundation, and Wake-Up Narcolepsy.

Safety and driving — Safety considerations are important to review. Patients should consider avoiding heights or working near moving machinery if they have severe sleepiness or uncontrolled cataplexy in order to avoid falls and potential injury. Swimming with supervision is recommended if swimming triggers cataplexy.

People with narcolepsy have an increased risk of car accidents due to sleepiness. We caution adolescents against driving for more than 25 to 30 minutes at a time; highway driving should be avoided when possible. These recommendations may be modified depending on severity of symptoms, treatment adherence, and driving capabilities. Further considerations on driving safety are reviewed separately. (See "Treatment of narcolepsy in adults", section on 'Driving safety'.)

Alcohol, marijuana, and other sedating substances should be strictly avoided due to potential adverse interactions with medications and their potential to worsen sleep quality.

PHARMACOTHERAPY

General principles — Narcolepsy is a lifelong disorder. There are no curative therapies, and management is symptomatic. In addition to nonpharmacologic strategies, pharmacotherapy is required in nearly all children to target sleepiness, cataplexy, and other bothersome symptoms.

At the time of diagnosis, nearly all children with narcolepsy are significantly impaired by sleepiness, consequent behavioral or cognitive difficulties, and/or by cataplexy. Approximately 50 to 80 percent of children also experience disrupted nighttime sleep due to sleep/wake instability, non-rapid eye movement (NREM) parasomnias, REM parasomnias, sleep-disordered breathing, restless legs syndrome, periodic limb movements of sleep, and nocturnal eating disorder [4,5]. Nonpharmacologic strategies are only partially effective, hence drug therapy is required in nearly all children.

Medications with regulatory approval — Medications used to treat narcolepsy in children are listed in the tables (table 1 and table 2). In the United States, the US Food and Drug Administration (FDA) has approved the following for pediatric narcolepsy:

●Traditional stimulants (methylphenidate and amphetamine) for treatment of daytime sleepiness associated with narcolepsy

●Sodium oxybate for treatment of excessive sleepiness and cataplexy (age ≥7 years)

●Mixed-salt oxybate for treatment of excessive sleepiness and cataplexy (age ≥7 years)

The European Medicines Agency has authorized traditional stimulants, sodium oxybate, mixed-salt oxybate, and pitolisant for treating children with narcolepsy age six years and above.

The 2021 American Academy of Sleep Medicine (AASM) clinical practice guidelines for treatment of central disorders of hypersomnolence include treatment recommendations for pediatric narcolepsy [6,7]. However, these recommendations were limited by a paucity of clinical trials specifically reporting risks and benefits in children and adolescents with narcolepsy. Thus, the treatment strategies provided below are based on clinical experience, case reports and case series in children, and indirect evidence of benefit and safety in adults with narcolepsy. (See 'Initial treatment' below.)

Target predominant symptoms first — The choice of first-line pharmacotherapy should be individualized according to symptoms that are most bothersome to the patient (eg, sleepiness, cataplexy, disrupted nighttime sleep), side effect profiles and risks, and patient and clinician preferences. For most patients, excessive daytime sleepiness is the most severe and bothersome symptom, whereas cataplexy and disrupted nighttime sleep can vary in severity and impact on quality of life.

Titrate and monitor — Medications are titrated with the goal of maximally controlling symptoms while minimizing side effects and toxicity. All children on drug therapy require careful and periodic monitoring to determine efficacy and adverse effects [8]. Newly diagnosed patients may initially require sleep clinic visits every two to three months, and then at longer intervals.

●Monitoring tools and tests – To monitor subjective sleepiness severity longitudinally and assess treatment response in clinic, we use the Epworth Sleepiness Scale for Children and Adolescents (form 1) [9] for patients ages 7 to 18 years or the Pediatric Daytime Sleepiness Scale (table 3) [10] for patients 11 to 18 years. The Ullanlinna Narcolepsy Scale is an 11-item scale that contains questions pertaining to both sleepiness and cataplexy, with higher scores indicating more impairment [11]. Although the Ullanlinna Narcolepsy Scale was not developed or validated in the pediatric population, it has been used in pediatric narcolepsy treatment trials [12,13].

In older teens, a maintenance of wakefulness test (MWT) can empirically help clinicians adjust the dose and timing of alerting medications to treat sleepiness [14]. Some clinicians use the MWT to assess efficacy of treatments before allowing patients with narcolepsy to drive. However, the MWT is not validated in the pediatric population and can be burdensome and costly to patients, limiting widespread use. (See "Quantifying sleepiness", section on 'Maintenance of wakefulness test (MWT)'.)

The multiple sleep latency test (MSLT) is an objective test of excessive daytime sleepiness used primarily for diagnostic testing for narcolepsy. The MSLT is frequently used as an outcome measure in research studies and used in clinical practice much more often than the MWT. However, the MSLT is not often used for treatment monitoring in the clinic. The required overnight sleep study and next-day MSLT is time consuming, and on average the improvement in daytime sleepiness on the MSLT is small, at least in comparison to improvement seen in subjective measures.

●Care coordination and referrals – Coordination among sleep specialists, primary care, and other subspecialists is particularly important for children with narcolepsy because the disorder is lifelong, involves multiple comorbidities (eg, obesity, anxiety, depression, precocious puberty, and autonomic dysfunction). As an example, we typically refer children with narcolepsy and precocious puberty to endocrinology for further assessment and possible gonadotropin-releasing hormone (GnRH) agonist therapy.

Monotherapy versus polytherapy — Once the most significant symptoms are well controlled, other manifestations can then be treated with additional medications, if necessary. Monotherapy is preferred but not always possible. As single agents, oxybates (sodium oxybate or mixed-salt oxybate) may offer a monotherapeutic approach to control sleepiness, cataplexy, and disrupted nighttime sleep. Based on clinical experience, oxybates also improve symptoms of hypnagogic/hypnopompic hallucinations and sleep paralysis as well. Pitolisant treats both excessive daytime sleepiness and cataplexy. All other medications have a narrower therapeutic profile.

Initial treatment

Selection of agent

●For children with predominant daytime sleepiness, initial treatment options include central nervous system stimulants, wake-promoting agents, pitolisant, and oxybates (table 1) [15-18]. Absent head-to-head studies comparing various medications in pediatric narcolepsy, we suggest starting with a central nervous system stimulant (methylphenidate or amphetamine) in most patients. This preference is based on extensive experience with the safety and tolerability of stimulants in children with attention-deficit/hyperactivity disorder (ADHD). (See 'Traditional stimulants (methylphenidate/amphetamine)' below.)

Due to lack of FDA approval for children, we less commonly start with modafinil, armodafinil, or solriamfetol as first-line wake-promoting agents. We consider these options when there is a contraindication to traditional stimulants or past intolerance. (See 'Modafinil and armodafinil' below and "Treatment of narcolepsy in adults", section on 'Solriamfetol'.)

●For children with problematic cataplexy and daytime sleepiness, we suggest an oxybate as first-line therapy to target both symptoms. This preference prioritizes monotherapy over polytherapy. Based on clinical experience, oxybates can also be helpful for treatment of disrupted nighttime sleep, sleep paralysis, and hypnagogic/hypnopompic hallucinations. Alternatively, a traditional stimulant can be combined with an antidepressant with anticataplexy effects (eg, fluoxetine or venlafaxine); this approach is sometimes better tolerated than oxybates and may be useful in patients with cataplexy or comorbid depression/anxiety (table 2). The choice may also be influenced by medication cost, insurance coverage, and medication availability. (See 'Sodium oxybate' below and 'Antidepressants with anticataplexy effects' below.)

In Europe, pitolisant is an additional first-line option, as it has both alerting and mild anticataplexy effects and has regulatory approval for use in children six years of age and older [19]. (See 'Pitolisant' below.)

●Therapy for disrupted nighttime sleep includes trazodone, baclofen, zolpidem, and temazepam, but evidence is based on case reports and case series mostly in adults with narcolepsy [4]. Based on clinical experience, treating periodic limb movements with iron supplementation (as suggested in people without narcolepsy) is not effective in patients with pediatric narcolepsy.

Administration and efficacy

Traditional stimulants (methylphenidate/amphetamine) — Traditional stimulants in a variety of formulations are used to treat daytime sleepiness in patients with pediatric narcolepsy (table 1).

●Mechanism of action – Amphetamines and methylphenidate inhibit dopamine reuptake from the synaptic cleft, and amphetamines also increase release of dopamine from presynaptic neurons [20]. To a lesser extent, methylphenidate and amphetamine can inhibit the reuptake of norepinephrine and serotonin.

●Agent, dosing, and titration – The choice among various traditional stimulants depends largely on individual preferences of the clinician and family, as well as considerations of duration of action, comorbidities, and whether or not the child can swallow pills.

We almost always use sustained-release formulations of stimulants to begin with, as optimizing daytime alertness for attendance at school is important. However, "booster" doses of immediate-release stimulants may be required in the afternoon or after school for homework management.

The recommended starting and maximum doses of stimulants for children with narcolepsy are the same as for more common indications (table 1). Stimulant medications are typically started at the lowest dose that may produce an effect and increased gradually (every three to seven days) until target symptoms improve. The same principles apply to the titration of dextroamphetamine.

●Side effects – Relatively common side effects of all stimulants include anorexia, weight loss due to appetite suppression, sleep disturbance, jitteriness, tachycardia, emotional lability, and the development of tics. Stimulants can worsen underlying anxiety and mood disorders, and the patient's psychiatrist/therapist should be involved in decision making and monitoring during treatment.

Blood pressure should be monitored with stimulants to check for elevated blood pressure. Stimulants should generally not be prescribed in patients with personal history or family history of serious heart problems such as cardiac arrhythmias; when therapy is deemed necessary, it should be managed in consultation with a cardiologist. (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Stimulants' and "Cardiac evaluation of patients receiving pharmacotherapy for attention deficit hyperactivity disorder".)

●Efficacy – While traditional stimulants are commonly used in clinical practice, their efficacy for excessive daytime sleepiness has not been studied in a randomized controlled trial in pediatric narcolepsy. In a retrospective observational study of 51 pediatric patients with narcolepsy with cataplexy, those taking methylphenidate reported less subjective daytime sleepiness [16]. Nonetheless, based on robust clinical experience, methylphenidate and amphetamine substantially improve daytime sleepiness in most pediatric patients with narcolepsy types 1 and 2.

Sodium oxybate — Sodium oxybate treats both sleepiness and cataplexy in patients with narcolepsy and has regulatory approval for use in children in Europe and, in the United States, through the Risk Evaluation and Mitigation (REMS) program. It may be used as a first- or second-line agent depending on clinical characteristics. (See 'Selection of agent' above and 'Inadequate response to first-line therapy' below.)

●Mechanism of action – Sodium oxybate is the sodium salt of gamma hydroxybutyrate (GHB). Mixed-salt oxybate is comprised of calcium, magnesium, potassium, and sodium oxybate (see 'Mixed-salt oxybate' below). GHB is a metabolite of gamma-aminobutyric acid (GABA) and may act as a GABA-B and GHB receptor agonist. It stabilizes nocturnal sleep architecture, which is often disrupted in patients with narcolepsy, but the mechanism through which it reduces daytime sleepiness and cataplexy is unknown.

●Dosing – Sodium oxybate must be given in two divided doses at night. The first dose is administered at bedtime, and the second dose is given 2.5 to 4 hours after initial sleep onset (table 1). Twice nightly dosing is necessary due to the drug's short half-life (0.5 to 2 hours) and rapid absorption.

We typically start with 2 g per night in divided doses and titrate gradually (eg, increments of 1 g per night [0.5 g/dose] no faster than once per week) according to effect and tolerability. In one pediatric series, the mean daily dose of sodium oxybate was 5 g [21]. Per manufacturer labeling, the maximum recommended daily dose in children (≥7 years of age) is 6 g per night in divided doses for children weighing 20 to <30 kg, 7.5 g per night in divided doses for those weighing 30 to <45 kg, and 9 g per night in divided doses for those weighing ≥45 kg [22].

Of note, an extend-release form of sodium oxybate, which is dosed once nightly, has been approved for adults with narcolepsy. (See "Treatment of narcolepsy in adults", section on 'Oxybates'.)

●Side effects and precautions – In the randomized trial of sodium oxybate in 104 children, the most common adverse events attributed to treatment were enuresis (18 percent), nausea and vomiting (17 and 16 percent, respectively), headache (16 percent), and weight loss (12 percent) [23]. There were two serious adverse events (acute psychosis and suicidal ideation), both of which improved with discontinuation of drug. Open-label follow-up of 85 participants in the trial showed maintenance of efficacy for both cataplexy and sleepiness over 48 weeks; by the end of the study, 77 percent of patients had experienced at least one treatment-emergent adverse event, but the types of concerns were not different from those previously reported [24].

More serious side effects (including respiratory depression with concomitant alcohol or sedating substance/medication use) should be disclosed and monitored per the required Risk Evaluation and Mitigation Strategies (REMS) program.

Caution is advised in patients with pre-existing anxiety or depression due to the potential for depression to worsen on sodium oxybate. In the clinical trial in children, baseline depression and anxiety scales were in the normal range in the two subjects who developed suicidality or psychosis [23]; hence, ongoing screening for changes in mood or suicidality is recommended.

As oxybates are often intensely sedating, it can be hard to wake to a phone or smoke alarm, so precaution is advised when patients live with college roommates or in other potentially vulnerable or dangerous situations. Oxybates should never be used with alcohol and other sedating substances. Cases of central sleep apnea have been reported with sodium oxybate, and monitoring for symptoms of pauses in breathing, gasping at night, and/or new snoring should be performed at clinical visits.

Due to the potential for drug diversion (GHB was known as a "date rape drug" before the medical indication for cataplexy was first confirmed), oxybates are made available to patients via a centralized pharmacy, and in the United States, prescribers must register with the REMS program. We recommend patients living in dorms keep oxybates, stimulants, and other potentially abusable medications in locked storage.

●Efficacy – The AASM clinical practice guidelines suggest sodium oxybate as an option for treatment of pediatric narcolepsy based on results of one randomized trial in pediatric narcolepsy as well as a few observational studies showing clinically significant improvements in cataplexy, disease severity, and excessive daytime sleepiness [6,23,25-27]. Preliminary data also suggest that sodium oxybate can improve rapid eye movement REM sleep behavior disorder in children with narcolepsy type 1 [28].

The multisite, double-blind, placebo-controlled, randomized withdrawal controlled study included 106 participants with narcolepsy type 1 (ages 7 to 16 years) who were either oxybate naïve or were on stable doses of sodium oxybate [23]. Those randomized to placebo and withdrawn from sodium oxybate had significantly more weekly cataplexy attacks (median increase of 12.7 attacks per week) and increased sleepiness on the Epworth Sleepiness Scale for Children and Adolescents (median increase 3 points) versus those randomized to stay on sodium oxybate. Other efficacy outcomes also favored sodium oxybate including improvement in overall narcolepsy severity scores.

Mixed-salt oxybate — A lower-sodium version of GHB (calcium, magnesium, potassium, and sodium oxybates; mixed-salt oxybate) received FDA approval in 2020 for treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy as young as seven years old. Mixed-salt oxybate contains 131 mg of sodium at the maximum recommended dose (4.5 grams twice nightly for patients >45 kg); sodium oxybate contains 1640 mg of sodium at this dose. Insurance coverage is variable, and guidelines were published before FDA approval of mixed-salt oxybate [6]. Like sodium oxybate, prescription in the United States requires participation in the REMS program.

We prioritize use of mixed-salt oxybate instead of sodium oxybate if there is concern about the high sodium content of sodium oxybate in an individual child. Dietary guidelines for Americans recommend that children ≥14 years old eat less than 2300 mg of sodium per day, and targets are even lower for younger children [29,30]. In the United States, average salt intake in children exceeds targets for both males and females in all age groups. Among children with narcolepsy, we advise even lower targets (eg, less than 1500 mg sodium per day) for those with prehypertension or hypertension (table 4), diabetes, or chronic kidney disease.

Overall, pediatric narcolepsy patients might benefit from mixed-salt oxybate over sodium oxybate treatment to reduce risk of long-term cardiovascular comorbidities, but longitudinal studies are needed for confirmation.

Inadequate response to first-line therapy

Approach — For patients who do not respond adequately to first-line pharmacotherapy, our approach depends on the problematic symptom and the initial therapy. Combination medication use requires close blood pressure monitoring for hypertension (table 4) and follow-up for symptoms of a mood disorder, appetite suppression, weight loss, and headache.

●Problematic sleepiness despite a stimulant – If sleepiness remains poorly controlled, wake-promoting agents like modafinil or armodafinil should be added to the stimulant regimen [31]. We use modafinil or armodafinil as second-line therapies for patients with intolerance of stimulants (eg, worsening of anxiety, elevations in blood pressure, or weight loss) or a contraindication to stimulant use (table 1). We suggest pitolisant for adjunctive therapy in patients with an inadequate response to either drug class. We often use sodium oxybate or mixed-salt oxybate for treatment of severe daytime sleepiness unresponsive to traditional stimulants and/or wake-promoting therapies.

●Problematic sleepiness despite an oxybate – If sleepiness remains problematic on an oxybate despite adequate control of cataplexy, we suggest adding back or optimizing dosing of a stimulant or a wake-promoting agent for daytime use. Pitolisant could also be used in conjunction with or instead of oxybates, but there is limited clinical experience with this approach in the United States. (See 'Pitolisant' below.)

●Problematic cataplexy despite an oxybate – As discussed above, oxybates are used as first-line therapy in patients with problematic cataplexy and sleepiness. In Europe, pitolisant can be used for daytime sleepiness and cataplexy control instead of an oxybate if symptoms are mild or moderate in severity. If an oxybate is not effective enough for cataplexy, we suggest adding fluoxetine or venlafaxine (table 2). (See 'Antidepressants with anticataplexy effects' below.)

Administration and efficacy

Modafinil and armodafinil — Neither modafinil nor armodafinil is approved by the FDA in the pediatric population (<17 years old) because of risk of serious cutaneous hypersensitivity (Stevens-Johnson syndrome) and psychiatric adverse reactions. Nonetheless, the AASM clinical practice guidelines concluded that there is sufficient safety and efficacy based on observational data on modafinil to support use in pediatric narcolepsy [6].

●Mechanism of action – The exact mechanism is unclear, but research suggests modafinil binds to the dopamine transporter and inhibits dopamine reuptake [32-34].

●Dosing – Modafinil is the racemic mixture of R- and S-enantiomers of the compound. The S-enantiomer is inactive, and armodafinil contains only the active R-enantiomer. Doses are typically titrated so efficacy and side effects can be closely monitored (table 1).

•Modafinil has a shorter half-life (approximately seven hours) in children compared with adults, and thus most children with narcolepsy will typically require a dose in the morning and again after lunch/early afternoon. The usual effective dose of modafinil ranges from 50 to 100 mg twice daily for children and 100 to 200 mg twice daily for adolescents.

•Armodafinil is longer acting than modafinil, typically dosed once in the morning, with a usual effective dose range of 50 to 250 mg depending on age and weight.

●Side effects – Reported side effects of modafinil and armodafinil include headache, nervousness and irritability, dry mouth, nausea, and loss of appetite. Given the potential for Stevens-Johnson syndrome, modafinil/armodafinil should be stopped if any unexplained rash is observed with treatment.

Importantly, modafinil and armodafinil can impair the effectiveness of steroidal contraceptives due to induction of CYP3A4/5. Also, exposure to modafinil and armodafinil during pregnancy has been associated with an increased risk of major congenital anomalies [35]. Guidance on alternative or concomitant methods of contraception, including barrier methods (condoms), is recommended for adolescent females to prevent pregnancy. (See "Treatment of narcolepsy in adults", section on 'Pregnancy and lactation'.)

●Efficacy – Limited observational data support the efficacy and safety of modafinil in pediatric narcolepsy [6]. In an observational case series of 10 patients with narcolepsy with cataplexy (mean age 11.8 +/- 3.3 years) treated with modafinil 200 mg/day, there was a significant reduction lasting over 6 to 12 months in subjective sleepiness measured using the Epworth Sleepiness Score and objective sleepiness based on the MSLT [36].

Pitolisant — Pitolisant is a newer agent for narcolepsy with both alerting and anticataplexy effects. Access and payor coverage in the United States can be difficult because it has not been approved for use in children and adolescents. When available, it is a reasonable first- or second-line agent depending on clinical characteristics. (See 'Selection of agent' above and 'Inadequate response to first-line therapy' above.)

●Mechanism of action – Pitolisant is an inverse agonist of the histamine H3 receptor. The H3 receptor inhibits histaminergic neurons, and pitolisant reduces this inhibition, enabling more histamine release. The H3 receptor has similar effects in other wake-promoting neurons in the locus coeruleus, dorsal raphe, and basal forebrain, so pitolisant can also increase release of norepinephrine, serotonin, and acetylcholine [37].

●Dosing – In the pediatric trials, doses of 4 to 20 mg were used in those <40 kg, and the dose was titrated up to 40 mg in those 40 kg and higher [12]. In our clinical experience, we typically start at 4.45 to 8.9 mg in the morning, depending on weight and concurrent medications (table 2). The dose can be titrated up to 17.8 to 35.6 mg over four to five weeks if needed.

●Side effects – Pitolisant was associated with a higher incidence of insomnia and headache compared with placebo in one pediatric study [12]. Pitolisant has the potential to prolong the QT interval, and we recommend checking an electrocardiogram (ECG) once the patient is on a stable dose. In patients taking strong CYP2D6 inhibitors such as fluoxetine, lower pitolisant doses are recommended. Pitolisant can also impair the effectiveness of steroidal contraceptives due to induction of CYP3A4/5, and clinicians should provide guidance on alternative or concomitant methods of contraception, including barrier methods (condoms), for adolescent females to prevent pregnancy. (See "Treatment of narcolepsy in adults", section on 'Pregnancy and lactation'.)

●Efficacy – Supporting evidence for pitolisant in children includes results of an eight-week multicenter randomized trial in which 110 pediatric patients with narcolepsy type 1 or type 2 were randomly assigned to pitolisant (uptitrated from 5 mg up to 40 mg) or placebo [12]. Compared with the placebo group, patients in the pitolisant group showed improved subjective daytime sleepiness based on the Pediatric Daytime Sleepiness Scale, narcolepsy symptoms based on Ullanlinna Narcolepsy Scale, and cataplexy based on the Ullanlinna Narcolepsy Scale-cataplexy subscore from baseline. A multicenter open-label study of pitolisant among 55 patients with narcolepsy type 1 or 2 ages 6 to 18 years also showed improvement in daytime sleepiness and weekly cataplexy compared with baseline levels [38].

Supporting evidence for pitolisant in adults is reviewed separately. (See "Treatment of narcolepsy in adults", section on 'Pitolisant'.)

Antidepressants with anticataplexy effects — Several antidepressants have anticataplexy effects in patients with narcolepsy, possibly through suppression of rapid eye movement (REM) sleep neural pathways (table 2). These agents are useful as add-on therapy for problematic cataplexy, especially in patients with comorbid mood and behavioral problems.

●Agent selection and efficacy – In case series, fluoxetine, citalopram, sertraline, and venlafaxine all have some evidence of benefit in patients with narcolepsy [16,17,39-42]. Based on clinical experience, fluoxetine and venlafaxine are superior to other selective serotonin or serotonin-norepinephrine inhibitors (SSRIs/SNRIs) for effective cataplexy control.

Tricyclic antidepressants (TCAs) such as clomipramine or protriptyline can also be considered but often have more adverse side effects than SSRIs/SNRIs. Careful monitoring of mood is required, given the potential for increased suicidal ideation with antidepressants (table 2).

●Mechanism of action – Norepinephrine and serotonin inhibit REM sleep-promoting pathways in the brain, and consequently reduce cataplexy, which is thought to be similar to the muscle paralysis of REM sleep. Thus, SSRIs and SNRIs can substantially reduce cataplexy. TCAs are monoamine reuptake inhibitors that prevent reuptake of norepinephrine, serotonin, and dopamine to some degree as well as produce central anticholinergic effects.

●Dosing – Fluoxetine is typically dosed once in the morning (10 to 60 mg) given its long-half life. Venlafaxine dosing ranges from 37.5 to 225 mg and is typically dosed as extend-release formulation once in the morning. In our experience, immediate-release venlafaxine may still be needed in the afternoon for cataplexy that may occur after school. Use of higher doses depends on clinical judgment and the ability to maintain adequate safety monitoring (table 2).

●Side effects – Side effects of SSRI/SNRI medications include mood alterations, increased risk for suicidality, sleep disturbances, and weight gain. TCAs generally produce more side effects, including anticholinergic effects including dry mouth, orthostatic hypotension, tremor, and constipation.

Other options — Atomoxetine, an SNRI, is used rarely alone or in combination with other agents for sleepiness in children with narcolepsy [16,43]. Potential side effects include headache, elevation of blood pressure, tachycardia, and weight loss (table 1). (See "Pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents", section on 'Atomoxetine'.)

Emerging therapies — Emerging treatments for children with narcolepsy include one newer medication approved for narcolepsy treatment in adults (solriamfetol) and several medications are still in development or testing in clinical trials [44]. A few of these agents are reviewed below.

●Alternative wake-promoting agents – Solriamfetol, a selective dopamine and norepinephrine reuptake inhibitor, has received regulatory approval in the United States for treatment of excessive daytime sleepiness in adults with narcolepsy [45,46] but has not yet been studied in children. We use solriamfetol as a third- or fourth-line treatment option for adolescents with problematic daytime sleepiness unresponsive to traditional stimulants or modafinil/armodafinil. (See "Treatment of narcolepsy in adults", section on 'Approach to pharmacotherapy'.)

●Immunotherapies – Immunotherapies such as intravenous immunoglobulin (IVIG) and glucocorticoids are of interest in narcolepsy given the postulated autoimmune-mediated etiology of narcolepsy type 1. However, available evidence is limited and insufficient to support routine use. In a single-center retrospective study of 52 consecutive patients (≤18 years) referred to a tertiary care center for treatment of pediatric narcolepsy, patients who received IVIG (n = 22) showed similar patterns of symptom control over a two-year period compared with those who did not receive IVIG [13]. In adjusted time-to-event analyses, IVIG was associated with more rapid achievement of symptom remission in the subset of patients with severe symptoms at baseline. These findings require prospective confirmation in a population of patients where immunotherapies can be tested close to symptom onset.

Case reports have shown inconsistent success of glucocorticoid therapy given soon after narcolepsy onset in children [47,48], and one adult patient showed no improvement in narcolepsy symptoms with natalizumab [49].

●Mazindol – Mazindol is a tricyclic compound and nonamphetamine stimulant that blocks dopamine and norepinephrine reuptake. In a retrospective study of narcolepsy in patients ages 9 to 74 years refractory to modafinil, methylphenidate, and sodium oxybate, patients taking mazindol reported a reduction in daytime sleepiness and cataplexy [50]. Common adverse reactions were dry mouth, palpitation, anorexia, nervousness, and headaches. In the literature, mazindol is associated with development of pulmonary hypertension, but no cases were reported among the narcolepsy patients undergoing cardiac echocardiograms in this study.

●Orexin agonists – Phase 2 trials of an oral hypocretin/orexin 2 receptor-selective agonist, TAK-994, showed improvements in sleepiness and cataplexy measures but were halted due to clinically important elevations in liver enzymes and drug-induced liver injury in several patients [51]. Other agents are also being studied [50,51].

●Reboxetine – Reboxetine is a selective inhibitor of norepinephrine reuptake that is being tested in a phase 3 trial in adults with narcolepsy (NCT05059223).

PROGNOSIS — There are limited longitudinal studies of pediatric narcolepsy, but it is a lifelong disorder. Generally, disease severity is often maximal in the first two years. Symptoms can improve from symptom onset and then generally stabilize thereafter. There are no longitudinal studies following pediatric narcolepsy patients across adulthood, but symptom management typically improves with time in our experience. Though not established, early recognition and management of comorbidities like anxiety and depression may enhance long-term outcome.

One study conducted over three years showed that children with narcolepsy slept more at disease onset, but the amount of sleep then normalized across the two-year study period [52]. In this study, pediatric patients with a more static form of cataplexy presenting as persistent facial weakness (cataplectic facies) at a younger age evolved to having the classic cataplexy triggered by strong emotions by the end of the study.

In our experience, symptom severity can fluctuate based on life experiences (eg, pregnancy, changes in school/college schedules), stress, changes in sleep schedule/habits, social triggers that induce cataplexy, and sometimes puberty.

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

●Overview – Narcolepsy in children often results in severe daytime sleepiness with broad impacts on physical, psychological, social, and emotional health. Management involves both behavioral and lifestyle modifications as well as symptomatic pharmacotherapy to target excessive daytime sleepiness and cataplexy. (See 'Introduction' above.)

●Behavioral and lifestyle modifications – Behavioral and lifestyle adjustments to reduce the impact of the disease include:

•Sleep-wake scheduling – Patients should maintain regular sleep-wake schedules and receive adequate time for sleep at night (at least 10 hours for school-age children and at least 8 hours for adolescents). Scheduled naps during the daytime can partially mitigate drowsiness. (See 'Sleep habits and daytime naps' above.)

•Diet and exercise – We advise patients to engage in regular exercise and avoid heavy carbohydrate-rich meals, excessive sugar intake, and eating heavy meals before bedtime. (See 'Diet and exercise' above.)

•Mental health care – We encourage psychological counseling from the time of diagnosis, including family counseling if needed to cope with new chronic disease. Anxiety, obsessive compulsive disorder, social phobia, and/or depression are common comorbidities that require appropriate psychiatric referral and care. Social supports from patient advocacy groups can be very helpful to promote wellbeing and coping. (See 'Mental health care' above.)

•School support – Children should receive necessary accommodations at school to promote an optimal learning environment. Interventions may include scheduled time for one or two brief daytime naps and breaks during long classes and tests to improve alertness. (See 'School and career planning' above.)

•Safety and driving – People with narcolepsy have an increased risk of car accidents due to sleepiness. We caution adolescents against driving for more than 25 to 30 minutes at a time, and highway driving should be avoided when possible. (See 'Safety and driving' above.)

●Initial pharmacotherapy – Pharmacotherapy is required in nearly all children to target disabling sleepiness, cataplexy, and other bothersome symptoms. Selection of initial pharmacotherapy should be individualized based on the symptom that is most bothersome to the patient (table 1 and table 2).

•Patients with predominant sleepiness – For children whose predominant symptom is daytime sleepiness, we suggest initial therapy with a stimulant medication such as methylphenidate (Grade 2C). Wake-promoting agents such as modafinil and armodafinil are a reasonable first-line alternative to stimulants, although experience with these drugs in children is more limited, and rare severe adverse reactions, including Stevens-Johnson syndrome and severe psychiatric events, have been reported. (See 'Selection of agent' above and 'Administration and efficacy' above.)

•Patients with problematic cataplexy and sleepiness – For children with narcolepsy type 1 who have problematic cataplexy and sleepiness, we suggest initial therapy with an oxybate (Grade 2C). The combination of a stimulant and an antidepressant with anticataplexy effects (eg, fluoxetine or venlafaxine) is a reasonable alternative, particularly in children with comorbid depression. (See 'Sodium oxybate' above and 'Traditional stimulants (methylphenidate/amphetamine)' above and 'Antidepressants with anticataplexy effects' above.)

●Inadequate response to initial therapy – Treatment is individualized based on the predominant symptom and medication history. In most cases, we try add-on therapy targeted to the predominant uncontrolled symptom. (See 'Approach' above.)

●Prognosis – Narcolepsy is considered a lifelong disorder. Disease severity is typically maximal in the first two years. Symptoms generally stabilize thereafter. (See 'Prognosis' above.)