The program focuses on management, diagnosis and a detailed understanding of the overall impact of pediatric narcolepsy. Experts discuss early sign and symptom recognition with timely diagnoses and management of pediatric narcolepsy.
Pediatric Narcolepsy: Timely Diagnosis, Treatment, and Outcome Optimization
Introduction
Narcolepsy is a chronic debilitating neurologic condition that typically has onset in childhood or adolescence, and is characterized by a pentad of symptoms that represent both daytime and nighttime dysfunction. Excessive daytime sleepiness (EDS) is present in all people with narcolepsy (PWN), but can have variable features based on age. Other pentad symptoms that may be present include sleep related hallucinations, sleep paralysis, disturbed nocturnal sleep, and cataplexy. Despite these well-defined pentad symptoms, the burden of narcolepsy invades all aspects of life and can be devastating to psychological and social health and development.1-4
Presentation, Symptoms, And Diagnosis
Narcolepsy is categorized into two types: narcolepsy type 1 (NT1), which includes cataplexy or the reduction or absence of the neurotransmitter orexin (hypocretin) in the cerebrospinal fluid (CSF); and narcolepsy type 2 (NT2), without cataplexy and normal CSF orexin. Most pediatric patients with narcolepsy also exhibit at least one additional symptom beyond excessive daytime sleepiness (EDS) and cataplexy, though the prevalence of these symptoms varies.5 Typically, the classic quintet of narcolepsy symptoms – which includes EDS, cataplexy, sleep paralysis, hypnagogic and/or hypnopompic hallucinations, and disturbances in nocturnal sleep – does not emerge all at once at the start of the condition in children. Epidemiologic studies have shown this rare disease to have a global average prevalence of between 20 and 50 per 100,000 children.1-4 Most PWN experience an onset before the second decade of life, but may not be diagnosed until adulthood.
In general, narcolepsy comes with significant delays in diagnosis which creates its own unique contributory burden of the disease. A cross-sectional study in the United States involving nearly 1,700 participants, 92% of whom were older than 18, with self-reported narcolepsy revealed that symptoms beginning in childhood were the most significant indicator of a diagnosis being delayed by over a year.6 This delay in diagnosis may result from inadequate recognition and incorrect attribution of symptoms by HCPs, often leading to a range of misdiagnoses. Symptoms of narcolepsy in children and adolescents may be experienced or interpreted differently. Variability in symptoms is common, with initial signs typically appearing before 20 years of age in 50%-65% of those affected.7-9 EDS is the primary and essential symptom for diagnosing narcolepsy, despite not being exclusive to this condition.10 However, EDS in children and adolescents may be interpreted as “normal” puberty related sleepiness, mood disorder or even ADHD. Insufficient sleep and circadian rhythm disorders are common in adolescents and frequently present with EDS and may potentially further confound consideration of the diagnosis of narcolepsy.11 Cataplexy is typically defined as a transient abrupt reduction or loss of muscle tone that can be triggered by strong emotions like laughter, and is considered a highly specific symptom of narcolepsy. In pediatric and new onset narcolepsy, an active motor phenomena can be observed with features of eyebrow raising, tongue thrusting and even dyskinetic movements being observed, and occurring with or without emotional trigger.11 Cataplexy typically appears either concurrently with the first instance of EDS or within one to three years thereafter. A comparative study of narcolepsy symptoms between 31 children aged 10 to 19 and 117 adults aged 20 and above showed that nearly half of the children did not display symptoms of cataplexy, resulting in a diagnosis of narcolepsy type 2 (NT2); this contrasts with only 20.5% of adults receiving the same diagnosis (P < 0.01). Despite this, the average delay from symptom onset to diagnosis was significantly shorter for children at 1.8 years compared to 26.5 years for adults (P < 0.001), suggesting that cataplexy symptoms could still emerge over time in children who are at risk. Over time, these symptoms generally evolve into the more classic form of cataplexy triggered primarily by emotional responses.
However more than affected children is impacted, as the delays and burden include, stress and compromised relationships with family, friends and school faculty. Unfortunately, when narcolepsy is not diagnosed in a timely fashion, children may be mislabeled as disobedient, combative or given an alternative medical diagnosis like ADHD or depression. These mistaken labels or diagnoses can compromise time to appropriate diagnosis while also contributing to poor self-esteem, lower likelihood for academic success and compromised socialization.
Comorbidities Associated With Pediatric Narcolepsy
Pediatric narcolepsy is also associated with comorbidities including rapid weight gain, precocious puberty12, and attention deficit hyperactivity disorder, as well as increased risk for deficits in social functioning, depression, and anxiety.13 Notably, rapid weight gain often coincides with the appearance of narcolepsy symptoms like excessive daytime sleepiness (EDS), leading to obesity, which is a persistent and widely observed comorbidity in these patients.5,12,14,15 Obesity rates in children with narcolepsy vary from 25% to 75%, and their BMI is significantly elevated compared to controls.14,15,16 Although weight gain and obesity are predominantly seen in narcolepsy type 1 (NT1), they are also observed in narcolepsy type 2 (NT2), albeit at lower rates.14Some studies indicate that obese children with narcolepsy may experience poorer sleep efficiency, increased risk of sleep apnea, higher fatigue levels, and more school absences compared to their nonobese counterparts.17
Early puberty, occurring sooner than typical developmental timelines for both girls and boys, has been linked to NT1 in various studies.15,18,19 One particular study found that 17% of children with NT1 experienced early puberty, compared to only 1.9% in obese controls, with no clear association between weight gain and higher risks of early puberty.15 Another study suggested a correlation between early puberty and weight gain but found no independent association between them.12
Psychological comorbidities in pediatric narcolepsy include conditions such as attention deficit hyperactivity disorder (ADHD), major depression, and anxiety disorder.14 A 2015 study assessing ADHD in children under 18 with NT1 or NT2 reported significantly higher ADHD rating scale scores in narcolepsy patients compared to healthy controls, with no marked difference between NT1 and NT2 groups. Moreover, a Swedish study on 38 pediatric narcolepsy patients revealed an ADHD prevalence about four times higher than in the general population and increased rates of major depression, anxiety, and oppositional defiant disorder. These cognitive and psychiatric issues may stem from the sleep disruptions or neurological impairments associated with narcolepsy, as suggested by another Danish study showing significantly higher rates of psychiatric disorders in narcolepsy patients under 19 years of age, both pre- and post-diagnosis, compared to matched controls.20
Social impacts of narcolepsy on pediatric patients have been less studied, but available data provide insights into the personal and caregiving challenges posed by the condition. One study involving 40 prepubertal patients reported that 90% of participants wanted to conceal their symptoms from peers, and the same percentage felt ashamed of these symptoms. Additionally, 80% felt helpless about their condition, 83% saw their symptoms as barriers to social acceptance, and 20% showed signs of reactive depression, such as appetite loss and social withdrawal. Another qualitative study with young adults diagnosed with narcolepsy described negative experiences like being awakened abruptly in class, physical collapses during social activities due to cataplexy, and social teasing.
Though few studies have directly assessed the impact of narcolepsy on intellectual and learning capabilities using neuropsychological tests, observational data suggest that narcolepsy negatively affects academic performance, a situation worsened by the complexities of misdiagnosis and delayed diagnosis. The challenges escalate as academic demands increase, and since academic and life success often correlates with interpersonal relationships, the psychosocial issues associated with narcolepsy raise significant concerns.
Management
Despite educational efforts and pharmacologic advances, many clinicians remain uncertain about optimal strategies to effectively treat, manage, and communicate with patients about narcolepsy. In the context of pediatric narcolepsy, educating and empowering the child’s participation is as critical as the involvement of the patient's parents or caregivers in the treatment process. Treatment for narcolepsy includes lifestyle, behavioral and pharmacologic therapies. Behavioral approaches focus on maintaining good sleep hygiene, which includes a consistent sleep schedule and planned daytime naps. Pharmacologic therapies include wake-promoting agents and stimulants such as modafinil, armodafinil, methylphenidate and amphetamines, in addition to oxybate medications. However, most of these medications are used off-label in the pediatric population.21,22 Only methylphenidate, amphetamines, and twice nightly oxybates (Xywav®/Xyrem®) are FDA-approved for the treatment of EDS in the pediatric population.23-25
Sodium oxybate and mixed salt oxybate formulations - Xywav®/Xyrem® - are currently the only FDA-approved medications for the treatment of EDS and cataplexy in pediatric patients 7 years of age and older.26 A third formulation of sodium oxybate with once-a-night-dosing - Lumryz™ - is currently under FDA review for use in pediatric narcolepsy.27 An approval decision is expected the second half of 2024. The safety and adverse event profiles of the above noted pharmacologic therapies are well-defined in their clinical trial literature and are addressed in the AASM clinical practice guidelines.24
In 2021, The European Academy of Neurology (EAN), European Sleep Research Society (ESRS) and European Narcolepsy Network (EU-NN) published guidelines on the management of narcolepsy in adults and children. Sodium oxybate was strongly recommended for the management of EDS and cataplexy in both adults and children.28 Also in 2021, the AASM, along with the aforementioned European societies, published updated clinical practice guidelines for the management of adults and children with narcolepsy. Both modafinil and sodium oxybate were recommended “conditionally” (ie, “the clinician use clinical knowledge and experience and strongly consider the individual patient’s values and preferences to determine the best course of action”) for treating narcolepsy in the pediatric population.
Once patients are diagnosed with narcolepsy, the challenge of treatment is reduced if an appropriate and careful clinical approach is used. Symptom experience and burden is an important driver of treatment decisions. However, optimal disease management must also involve a balanced clinical perspective that encourages patient involvement in a shared decision-making process. It is critical for clinicians to account for any comorbid conditions and their management. Treatment plans and dosing schedules should be clearly communicated, and tailored to align with each patient's goals and lifestyle. Clinicians must periodically assess patients to see if treatment adjustments are necessary, whether to continue, adjust, or switch medications, ensuring the treatment goals concerning efficacy and safety are met, and supporting effective long-term management.29
Patients have reported dissatisfaction with treatment options for narcolepsy, citing a range of factors, including suboptimal efficacy, troublesome side effects, drug tolerance development, and inconvenience.30 Clinicians and patients need to work together to make shared decisions regarding individualized diagnostic and treatment choices, as suggested in best-practice recommendations.31
FDA Approval and Change of Landscape
The FDA has approved the supplemental New Drug Application (sNDA) for pitolisant (Wakix) and has prioritized its review.32 This decision was based on the findings of a phase 3 clinical trial led by Bioprojet. The trial, which was a multicenter, randomized, placebo-controlled study, evaluated the safety and efficacy of pitolisant in treating narcolepsy in children aged 6 to 17 years, including those with potential cataplexy.33 As a result of the favorable outcomes from this study, the European Medicines Agency granted approval in 2023 for extending the use of pitolisant to include children aged 6 years and older with narcolepsy, with or without cataplexy. Pitolisant stands out as a first-of-its-kind medication that operates by inhibiting H3 autoreceptors and boosting histamine transmitter levels at synapses. This action enhances the activity of histaminergic neurons, thereby promoting alertness.34 The FDA has sanctioned its use for the treatment of symptoms such as excessive daytime sleepiness and cataplexy in adult narcolepsy patients. Pitolisant has been commercially available in the United States since late 2019.
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In support of improving patient care, Global Learning Collaborative (GLC) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team.
