Pediatric Narcolepsy: Overcoming Challenges in Diagnosis and Management

Addressing the Challenges in its Recognition, Diagnosis, and Management
Michael J. Thorpy, MD and Anne Marie Morse, DO

Introduction:

While narcolepsy represents the same condition in both children and adults, the symptoms may present differently in children.¹ Half of children who develop narcolepsy do so before age 16, yet many do not receive a diagnosis in childhood. Because of the dissimilar presentation in children, pediatric patients with narcolepsy are often misdiagnosed and many are treated needlessly for unrelated conditions.¹ In this ECHO, Drs. Thorpy and Morse 1) delineate key differences among the clinical manifestations of narcolepsy symptoms in children versus adults; 2) define the physical, psychological, and social comorbidities associated with pediatric narcolepsy; and 3) define the benefits and risks of current and evolving pharmacologic therapies that can optimize treatment outcomes for pediatric narcolepsy.

Symptoms and Diagnosis of Pediatric Narcolepsy

In pediatric narcolepsy, the “pentad” of symptoms includes excessive daytime sleepiness (EDS), sleep-related hallucinations, sleep paralysis, cataplexy, and disturbed nocturnal sleep.^1,2 First and foremost, it is important to recognize EDS in children and adolescents who are inappropriately falling asleep.

There is a certain nuance to diagnosing pediatric narcolepsy, and seeking out other medical clues and comorbidities can be helpful. These include attention deficit hyperactivity disorder (ADHD), hyperactive type, in the prepubescent population; and ADHD, inattentive type in postpubescent teens, possibly combined with a moody/irrational demeanor leading to numerous arguments with their parents.³

Another pediatric-specific presentation of narcolepsy is a longer sleep duration within a 24-hour period (hypersomnia).¹ This is in contrast with the typical adult narcolepsy hypersomnolence disorder phenotype, in which the individual sleeps fewer hours within a 24-hour period.

Cataplexy may also be a distinguishing factor when diagnosing pediatric narcolepsy. While cataplexy generally refers to a transient episode of loss of muscle tone in children, such episodes can manifest as active motor phenomena, including eyebrow rising, tongue thrusting, and even dyskinetic movements with a persistent hypotonia.¹ Children can also have loss of tone and drop attacks, head drops, buckling knees, and hand drops from their sides. Notably, these symptoms may occur independent of any emotional reaction, such as a typical laughter-induced episode.⁴

Sleep-related hypnagogic hallucinations may be misdiagnosed as nightmare disorder or “night terrors.”¹ It is important to recognize that children may express both disorders daily, and that they are distinct from one another.¹ Hypnagogic hallucinations should not be simply interpreted as psychosis in children or adolescents.

One of the most striking signs of pediatric narcolepsy may be the sudden onset of significant weight gain, in which a child or adolescent goes from a normal weight percentile to obesity in a short time.^1,3 Being aware of this distinct somatic sign can help avoid a diagnostic delay as well allow for quicker intervention.

An important key to timely diagnosis of narcolepsy in children exhibiting EDS and abnormal behavior begins with reports from parents and teachers.¹ If a child is falling asleep in school, teachers should alert the parents so that the parents can catalog the symptoms and provide them to their pediatrician.

“If no clear cause for a child’s sleepiness is apparent, the clinician should investigate these symptoms more intensively.”

“Any atypical movement disorder associated with sleep disorder should also prompt further investigation.”

–Michael J. Thorpy, MD

Since so much of the sleep literature is based on adult testing, clinicians need to consider what is normal for a particular age group. Current diagnostic criteria—results from polysomnography and the multiple sleep latency test—are based on adult information. As sleep duration changes with a child’s developmental age, sleep latency is heavily influenced by Tanner staging, so clinical and laboratory findings need to be adjusted for children and adolescents.²

“A finding that may be considered inconsequential for adults may indeed be pathologic for children and adolescents.”

“It is critical for clinicians to use all of this information—not only collecting a child’s history—but to think through what the diagnostic workup may look like and what those results may yield.”

–Anne Marie Morse, DO

Comorbidities and Confounders in Pediatric Narcolepsy

Both physical and psychological comorbidities—significant weight gain, precocious puberty, ADHD, depressive syndrome, anxiety, suboptimal performance, poor quality of life, and suicidal thoughts—may manifest with pediatric narcolepsy, which may make a clear diagnosis more challenging. As mentioned, the somatic signs can include significant weight gain and precocious puberty, which are particularly interesting features associated with pediatric cataplexy. Moreover, psychological symptoms can include ADHD, depressive syndrome, and anxiety, which can occur as true comorbidities or part of the narcolepsy syndrome.¹ Clinicians should elicit how narcolepsy may be affecting a child’s/adolescent’s quality of life and social life, and whether any negative feelings are adversely impacting their consideration of self-harm or suicide.

Treatment of Pediatric Narcolepsy

Treating pediatric narcolepsy is especially challenging as therapeutic options are limited. Many medications that treat excessive sleepiness are not approved for pediatric use. Approved traditional stimulants for children include methylphenidate and select amphetamines; clinicians who prefer to prescribe on label need to check medication indications.⁵ Medications used to treat adults with narcolepsy include solriamfetol, modafinil, and armodafinil, but none of these agents are approved by the FDA for pediatric use.^5,6 As such, they would be considered only when presented with unusual and special circumstances. Additionally, for children and adolescents with cataplexy, the evidence is weak that methylphenidate and amphetamines will be effective.⁵

The most effective agents for children with narcolepsy with or without cataplexy are the oxybate formulations that treat all symptoms of the disorder—sleepiness, abnormal rapid eye movement (REM) sleep phenomena such as cataplexy, sleep paralysis, hypnagogic hallucinations, and vivid dreaming.^5,6 The oxybates have demonstrated clinically significant improvement in EDS, cataplexy, and disease severity.⁶

While the first two agents described below (Xyrem and Xywav), are approved for children aged 7 years and older,^7,8 they need to be taken before bedtime and during the night, which may not be practical for most families. This dosing may limit adherence to the regimen because children often have difficulty waking during the night to take the second dose.^7,8

Lumryz requires only a once-nightly dose and can be given to a child before going to bed, so neither the child nor the caregiver need to wake up for the second dose. Unlike the first two oxybate formulations, Lumryz is currently only approved for adults.⁹

• Xyrem, sodium oxybate, is taken twice at night.⁷
• Xywav, a formulation of mixed oxybates, has 92% less sodium, and also requires twice-nightly dosing.⁸
• Lumryz is an extended-release formulation of sodium oxybate taken once-nightly. The active oxybate agent in Lumryz is the same as in Xyrem and Xywav.⁹

The oxybate formulations are available only through their respective Risk Evaluation and Mitigation Strategy (REMS) programs, a restricted access regime to ensure safe use of the medications.¹⁰ All the oxybates have boxed warnings about central nervous system depression, abuse, and misuse.^7-9 In pediatric patients, the most common adverse effects of the oxybates are nausea, enuresis, vomiting, headache, weight decrease, decreased appetite, dizziness, and sleepwalking.^7,8

It is important to recognize that although clinicians might be limited by some of the medications that may be available on label, they can incorporate behavioral strategies, such as cognitive behavioral therapy for hypersomnolence, to assist their pediatric patients in coping with the disorder.⁶ Other interventions might include offering a 504 plan or an Individualized Education Plan that details the type of assistance that children require during their school day to function optimally and achieve their academic goals.

Concluding Comments

As the presentations differ between the adult phenotype of narcolepsy and pediatric narcolepsy, the diagnosis of pediatric narcolepsy warrants a detailed evaluation to achieve its timely diagnosis. The assessment should determine whether or not EDS is present, and whether it is being masked by a prior misdiagnosis or an Rx for essentially unneeded medication. Ideally, any suggestion that a child or adolescent is experiencing atypical sleep, with sudden onset weight gain and behavior disturbances, should prompt caregivers to seek a sleep specialist—preferably a pediatric sleep specialist—who can thoroughly assess the child and provide appropriate treatment.

References:

1. Plazzi G, Clawges HM, Owens JA. Clinical characteristics and burden of illness in pediatric patients with narcolepsy. Pediatr Neurol. 2018;85:21-32.
2. Pizza F, Franceschini C, Peltola H, et al. Clinical and polysomnographic course of childhood narcolepsy with cataplexy. Brain. 2013;136(Pt 12):3787-3795.
3. Lecendreux M, Lavault S, Lopez R, et al. Attention-deficit/hyperactivity disorder (ADHD) symptoms in pediatric narcolepsy: a cross-sectional study. Sleep. 2015;38(8):1285-1295.
4. Plazzi G, Pizza F, Palaia V, et al. Complex movement disorders at disease onset in childhood narcolepsy with cataplexy. Brain. 2011;134(Pt 12):3477-3489.
5. Bassetti CLA, Kallweit U, Vignatelli L, et al. European guideline and expert statements on the management of narcolepsy in adults and children. J Sleep Res. 2021;30(6):e13387.
6. Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(9):1881-1893.
7. Xyrem. Prescribing information. Jazz Pharmaceuticals, Inc.; 2023. Accessed January 24, 2024. https://pp.jazzpharma.com/pi/xyrem.en.USPI.pdf
8. Xywav. Prescribing information. Jazz Pharmaceuticals, Inc.; 2023. Accessed January 24, 2024. https://pp.jazzpharma.com/pi/xywav.en.USPI.pdf
9. Lumryz. Prescribing information. Avadel CNS Pharmaceuticals, LLC; 2023. Accessed January 24, 2024. https://www.avadel.com/lumryz-prescribing-information.pdf
10. US Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies (REMS). Accessed January 25, 2024. https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm