Pediatr Drugs (2014) 16:363–372 DOI 10.1007/s40272-014-0083-3

REVIEW ARTICLE

Pharmacological Management of Narcolepsy and Cataplexy in Pediatric Patients Michel Lecendreux

Published online: 30 July 2014 Ó Springer International Publishing Switzerland 2014

Abstract Narcolepsy is a neurological disorder frequently occurring from childhood and persisting through adolescence and adulthood. Individuals suffering from narcolepsy exhibit excessive daytime somnolence, sleep attacks, cataplexy, dysomnia, metabolic perturbations including weight gain, and problems in social interaction and academic performance. The prevalence of narcolepsy in childhood is not known but can be estimated from adult studies to be greater than 20–60 per 100,000 in Western countries. The 2009 (A) H1N1 vaccination campaign led to an increase of narcoleptic cases both in children and in adults, supporting the autoimmune hypothesis of the disease. This article focuses on the epidemiology, etiology, and particularities of treatment in pediatric narcolepsy and details the effects of the drugs used to treat this condition, including recent trends in the field. Future therapeutic directions are also discussed. At present, medications used to treat children or adolescents have shown efficacy mostly based on clinical experience, given the lack of level 1 evidence-based studies in the pediatric population. Therefore, most compounds used in adult narcolepsy to target clinical symptoms such as wake-promoting or anticataplectic agents are prescribed off-label in pediatric patients. Published research shows the benefit of drug therapy for narcoleptic children, but these must be dispensed with caution in the absence of well conducted clinical trials.

M. Lecendreux (&) Pediatric Sleep Center and National Reference Center for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia and Kleine–Levin Syndrome, Robert Debre University Hospital, 48 Boulevard Serurier, 75019 Paris, France e-mail: [email protected]

Key Points Since onset of narcolepsy is generally in childhood or adolescence, there is a need for appropriate diagnosis and early initiation of treatment. Evidence-based treatment guidelines have not been developed for the management of narcolepsy in children by any of the relevant medical associations, and current treatment strategies are primarily based on empirical data and clinical experience. There are country-specific approvals of drugs for treatment of narcolepsy in the pediatric population and off-label use of other drugs is common, but randomized clinical trials are required to confirm efficacy and tolerability of these medications and to evaluate new therapeutic approaches.

1 Introduction Narcolepsy is a chronic and life-long condition characterized by the presence of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nighttime sleep. EDS is present in all patients with narcolepsy and is required for a diagnosis [1]; disturbed nighttime sleep, which is a frequent patient complaint, may be present in more than 80 % of patients [2]. In contrast, cataplexy is only present in approximately 70 % of patients even though it is a distinguishing characteristic of narcolepsy and is a strong diagnostic indicator [1]. Cataplexy is defined as a sudden loss of muscle tone, resulting in

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weakness and a loss of voluntary muscle control that is often triggered by emotions, including, in particular, laughter, anger, and excitement. Hypnagogic and hypnopompic hallucinations are less frequent than the other symptoms and consist of vivid sensory sensations, of which the former occur at sleep onset and the latter occur during the waking process. The estimated incidence of adult narcolepsy, approximately 1 per 100,000 individuals per year based on a regional study in the USA [3], would suggest that it is a rare condition. However, given that it is a chronic disorder, the overall prevalence is greater, and has been estimated to be 20–60 per 100,000 in Western countries, with the prevalence varying by country and ethnicity; the highest reported prevalence is in Japan (0.2–0.6 %) and the lowest is in Israel (\0.001 %) [4]. Accumulating evidence, including an association with specific genotypes, such as DQB1*0602 and various T-cell receptor polymorphisms, suggest an autoimmune basis for narcolepsy [5–7]. These autoimmune components are thought to contribute to the loss of hypocretin (orexin)producing neurons that characterizes the predominant form of narcolepsy and provides the basis, along with the presence of cataplexy, for recognition as type 1 narcolepsy according to the revised International Classification of Sleep Disorders (ICSD-3) diagnostic criteria [1]. Hypocretins, consisting of hypocretin-1 and hypocretin-2, are neuropeptides that function in the maintenance of sleepwakefulness, reward-seeking behavior, and autonomic regulation [8, 9]. Although narcolepsy has traditionally been considered to be a disease of adulthood, most cases have their onset in childhood or adolescence, typically during the second decade of life, with a peak age of onset of approximately 15 years [10, 11]. The prevalence of narcolepsy in the pediatric population remains unknown, but based upon the regional study conducted in the USA, it could affect 20–50 per 100,000 children [3]. Interestingly, multiple reports in Europe and Asia have suggested an association between childhood narcolepsy and exposure to seasonal streptococcus infections, H1N1 influenza, and H1N1 vaccination in genetically predisposed individuals [12]. While these observations support the proposed autoimmune mechanism for the etiopathogenesis of narcolepsy [13], the specific triggers and underlying pathways responsible for precipitating narcolepsy onset and the loss of hypocretin neurons have not been fully characterized. Pediatric narcolepsy may have some distinctions from adult presentation. As shown in a study by Pizza et al. [14], pediatric narcolepsy with cataplexy is characterized at onset by an abrupt increase of total sleep over the 24 h, and generalized hypotonia. Hypotonic phenomena and selected facial movements may decrease over time and evolve into

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classic presentation (i.e. brief muscle weakness episodes triggered by emotions), whereas total sleep time across the 24 h decreases [14]. Furthermore, narcolepsy in children is frequently associated with both obesity and precocious puberty [15, 16]. While there is a general tendency toward overweight and obesity in narcolepsy [11], these weight problems are intrinsic to childhood narcolepsy and have been reported in up to 84 % of children [17–22]. They are manifested relatively early in the course of the disease, and occur quickly and suddenly after the onset of other symptoms. In contrast to narcoleptic adults, in whom weight gain and obesity may be associated with the presence of cataplexy [23], no significant differences in body mass index was observed between narcoleptic children with and without cataplexy [18]. The confluence of narcoleptic and associated symptoms has a profound effect in children, resulting in reduced function and a greater psychosocial impact, especially related to social and performance behavior, including decreased academic achievement [20, 24–26]. Indeed, the presence of associated symptoms, such as obesity conveys an additional burden, with obese narcoleptic children showing greater fatigue, lower sleep efficiency, and more school absences than non-obese children with narcolepsy [17]. High levels of depressive symptoms have also been observed among children with narcolepsy [27], as well as the presence of secondary schizophrenia [22], consistent with the higher prevalence of medical and psychiatric comorbidities that have been reported in narcolepsy relative to the general population [28]. Notably, while obesity was not associated with depressive symptoms [27], a higher body mass index was associated with the presence of schizophrenia (p = 0.002) [22]. The exact healthcare cost of pediatric narcolepsy is not known. Moreover, determination of healthcare cost is confounded by the problem of timely recognition and accurate diagnosis of narcolepsy, which may be delayed since there is often a long gap between symptom onset and diagnosis [29]. This delay may result, at least in part, from lack of symptom recognition and misdiagnosis in children [29]. Thus, on the one hand, costs might be overestimated if children are diagnosed inappropriately and receive treatment that may not benefit them, or on the other hand, cost might be underestimated if significant proportions of children go undiagnosed [30]. Appropriate diagnosis and treatment is integral to improving the function and quality of life of children with narcolepsy [31, 32], and primary care pediatricians are likely to play a major role in the care of these patients. Although formal evaluation of narcolepsy therapies in children and adolescents has been limited, some available treatments have shown evidence of efficacy and may be of

Management of Pediatric Narcolepsy

value in the clinical setting; lack of treatment results in a risk for impaired outcomes. Therefore, the purpose of this clinical review is to summarize what is currently known regarding the options for management of narcolepsy in the pediatric population, focusing on EDS and cataplexy, the two primary symptoms.

2 Pharmacologic Management of Pediatric Narcolepsy Hope for a cure of narcolepsy is very important in young patients with this disease, since the prospect and constraints of life-long treatment are major concerns. In the absence of a cure, pharmacotherapy should be initiated at disease onset in order to provide symptomatic relief and to restore a normal or sufficient level of alertness and function. However, because of specific issues of tolerability and toxicity, patient age is an important factor to take into consideration when therapy is initiated close to disease onset [33, 34]. These issues include reports that medications such as methylphenidate and amphetamine stimulants are associated with growth suppression when used for the treatment of attention-deficit hyperactivity disorder (ADHD) in children [35], a potential for hypersensitivity resulting in severe rashes with modafinil/armodafinil in young children [36–38], and poor tolerance of children to tricyclic antidepressants [39]. Evidence-based treatment guidelines have not been developed for narcolepsy treatment in children by any of

Table 1 Oral pharmacotherapies used for the treatment of pediatric narcolepsy. Dosing is based on empirical data derived from medications used in adults and reports in the pediatric literature. All drugs are used off-label for narcolepsy in the pediatric population except for Medication

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the relevant medical associations. Established guidelines primarily focus on management of adults with narcolepsy and emphasize the limited evidence for the use of currently available pharmacologic therapies in the pediatric population [40, 41]. Consequently, over the past years, several best practice recommendations have been published that include a clinically relevant approach to pediatric management based on empirical data derived from medications used in adults [42–44]. These recommendations generally acknowledge a preference for monotherapy when possible (lack of evidence for treatment synergy) and sufficiently long-term administration of a treatment at effective doses, which may vary among individuals. Importantly, it should be emphasized that market-authorized medications for the treatment of narcolepsy in pediatric populations are limited and country-specific. In the USA, only amphetamines and methylphenidate stimulants have been approved by the US FDA for the treatment of narcolepsy in children; in Europe, the European Medicines Agency has only approved methylphenidate immediate release for the pediatric population. In the absence of published randomized, placebo-controlled trials in pediatric populations, the medical literature is rife with case reports, chart reviews, and open-label studies suggesting that various pharmacotherapies, especially wake-promoting agents and anticataplectics, can improve symptoms and outcomes in children and adolescents. These therapies are discussed below, and suggested dose ranges are shown in Table 1.

amphetamines and methylphenidate stimulants that have been approved in the USA, and methylphenidate immediate release in Europe

Symptoms for which efficacy has been demonstrated or suggested

Suggested pediatric daily dose range

Modafinil

Excessive daytime sleepiness

100–400 mg

Armodafinil

Excessive daytime sleepiness

50–250 mg

Methylphenidate

Excessive daytime sleepiness

10–40 mg

Dextroamphetamine

Excessive daytime sleepiness

5–60 mg

Methamphetamine

Excessive daytime sleepiness

20–25 mg

Atomoxetine

Excessive daytime sleepiness, cataplexy

10–25 mg

Mazindol

Excessive daytime sleepiness, cataplexy

1–4 mg

Pitolisant

Excessive daytime sleepiness, cataplexy

10–40 mg

Sodium oxybate

Excessive daytime sleepiness, cataplexy, disturbed nocturnal sleep, hypnagogic hallucinations, sleep paralysis

2–6 g

Venlafaxine

Cataplexy, hypnagogic hallucinations, sleep paralysis

37.5–150 mg

Fluoxetine

Cataplexy, hypnagogic hallucinations, sleep paralysis

20–40 mg

Clomipramine

Cataplexy, hypnagogic hallucinations, sleep paralysis

10–75 mg

Wake-promoting agents

Stimulants

Antidepressants

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2.1 Excessive Daytime Sleepiness (EDS) EDS is experienced in patients with narcolepsy, including children and adolescents. It is reported to be one of the most disabling symptoms of the disease due to the detrimental impact on daytime activities and academic performance [17, 26]. In the majority of cases, EDS is the first symptom to occur in narcoleptic children and appears to be relatively stable across the life span of the individual. Several therapies that represent first-line treatment for EDS may be useful in children and adolescents. 2.1.1 Wake-Promoting Agents Modafinil and armodafinil, which is the biologically active r-enantiomer of modafinil, are wake-promoting agents that have demonstrated efficacy for EDS in narcolepsy [45, 46] and are generally considered a first-line therapy [40, 41]. Their mode of action is complex, but several functions have been proposed, including alpha-1 adrenergic activity, direct and indirect actions on the dopaminergic system, and a role in serotoninergic and gamma-aminobutyric acid (GABA) pathways [37, 38]. Modafinil is effective at increasing daytime wakefulness at dosages between 100 and 400 mg/ day taken in one to two doses in the morning and at midday, and its use has been reported at up to 600 mg/day [47]. The side effects are generally mild, represented by headaches, nervousness, anxiety, nausea, and insomnia at the start of treatment. No cases of long-term dependence or tolerance have been reported. In view of its enzymatic inducing effect on cytochrome P450, sexually active young women must be advised to use normal-dose contraception containing 50 lg ethinylestradiol. In pediatric patients, the favorable effect of modafinil on EDS was reported in a small case series of 13 children with narcolepsy [48], and an unpublished double-blind, randomized study was conducted in 26 children (6–16 years of age) suffering from excessive sleepiness or sleep apnea syndrome [49]. This latter study reported satisfactory tolerance and efficacy among the 19 patients in the modafinil treatment arm at dosages ranging from 100 to 400 mg/day. Additionally, a letter based on the clinical experience of an international group of pediatric sleep specialists suggested that modafinil was an effective and safe treatment for pediatric narcolepsy [50]. A total of 205 children and adolescents (99 males and 106 females; age range 4–18 years) with narcolepsy were treated with modafinil at a daily dose that varied from 50 to 600 mg. Patients were treated for more than 10 years in the majority of the centers, and modafinil was found to be effective in more than 85 % of patients. For the remaining 15 % of cases lack of efficacy, habituation, or mild adverse effects led to drug

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discontinuation. The most frequent side effects were headache (13.7 %), nervousness and irritability (6.5 %), and loss of appetite (2.2 %). The fact that no severe hypersensitivity reactions were reported in any patient, and in particular no serious skin reactions, is especially important to note because of the previously mentioned risk for severe rash, including Stevens Johnson syndrome that may occur with modafinil use [36]. 2.1.2 Stimulants Sodium oxybate, the sodium salt of gamma-hydroxybutyrate, is a drug that has demonstrated significant benefit in adults with narcolepsy [51] and is recommended as a firstline treatment for EDS as well as for cataplexy [40, 41], both indications for which it has received registration approval in several countries. Published guidelines also suggest potential benefits for the treatment of all other core symptoms of narcolepsy [40, 41]. However, it has not been approved by the FDA nor by the EMA for the treatment of pediatric narcolepsy; the safety and effectiveness of sodium oxybate have not been established in pediatric patients, nor have its pharmacokinetics been studied in patients younger than 18 years of age. Sodium oxybate has been shown to be effective against daytime sleepiness, cataplexy, and disrupted nighttime sleep in adults with narcolepsy [52]. It acts on the GABA complex, particularly by stimulating the GABA-B receptors and produces a more physiological action than benzodiazepines on sleep architecture, as it increases slowwave sleep and preserves paradoxical sleep. It is difficult to say whether the improvements in EDS and the anti-cataplectic effects achieved with this drug are direct or secondary to the improvement of sleep quality. As in adults, the treatment is initiated in children with 1.5 g in two doses taken at night approximately 4 h apart (in view of its very brief half-life of 40–60 min). In contrast to adults, in whom the dose may be increased progressively to not more than 9 g per night, pediatric dosing should be limited to 6 g per night. Sodium oxybate is also associated with a high sodium load, suggesting the need for surveillance for sodium-related side effects, especially in individuals who may be sodium restricted. The most common side effects with sodium oxybate are headaches, dizziness, depression, sleepwalking, enuresis, and terminal insomnia (the patient wakes up very early at around 4–5 am and is unable to get back to sleep). Alcohol consumption is strictly contraindicated as it may increase the risk of respiratory depression, hypotension, and profound sedation, which may be especially relevant for patients in late adolescence and early adulthood. Due to the risk of misuse, it is subject to strict dispensing conditions.

Management of Pediatric Narcolepsy

Although clinical reports on the efficacy and tolerability of sodium oxybate in children and adolescents have been encouraging, safety data are lacking and await more extensive studies in the pediatric population [53]. However, young patients presenting with severe narcolepsy have been successfully treated for several years with sodium oxybate, which has shown good efficacy for daytime and nighttime symptoms as well as good tolerability. In a retrospective analysis of 51 children and adolescents treated for narcolepsy in the USA, sodium oxybate was effective for EDS as well as all other self-reported narcolepsy symptoms, including insomnia, hypnagogic hallucinations and sleep paralysis [20]. Efficacy across the range of symptoms did not differ between subgroups of patients stratified by puberty status with the exception that sodium oxybate had less effect on hypnagogic hallucinations in pre-pubertal children than in other peri- and postpubertal individuals (p \ 0.01). In contrast, modafinil and methylphenidate were effective only for reducing sleepiness. Interestingly, venlafaxine was reported to be primarily effective for reducing cataplexy, with only minor effects on reducing sleepiness, sleep paralysis, and hypnagogic hallucinations. No effects were observed on the subsequent development of puberty among pre-pubertal children treated with sodium oxybate. A more recent retrospective study in 27 children who had narcolepsy with cataplexy and had been treated with sodium oxybate and followed in a clinical setting in France and Italy [54] used a semi-structured interview to evaluate the tolerability and efficacy. The mean daily dose of sodium oxybate administered was 5.0 ± 1.6 g. Among these patients, 82.2 % reported improvement in EDS, and there was also improvement for the core symptoms of cataplexy (81.5 %), disturbed nocturnal sleep (94.7 %), sleep paralysis (18.2 %), and hypnagogic hallucinations (5.9 %), as well as improvements in attention symptoms and learning ability at school. The main side effects included weight loss, headache, nausea, disrupted nocturnal sleep, irritability, parasomnias, and daily episodes of sleep drunkenness; 25.9 % of patients reported no side effects. No patients discontinued sodium oxybate for reasons of lack of efficacy. Only one of the 23 patients who continued sodium oxybate considered time of administration to be a problem. More pediatric clinical trials of sodium oxybate should be conducted, including evaluation in a greater number of young patients. There is a lack of data concerning the time to response to sodium oxybate in children. In adults, a post hoc analysis of a randomized, placebo-controlled trial found that onset of therapeutic response, assessed as clinically meaningful improvements in EDS and cataplexy, was observed in C50 % of patients within 2 months, indicating that the time course to initial and maximum response may take weeks or months [55].

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Immediate-release methylphenidate or sustained- or extended-release methylphenidate represent second-line treatments for EDS. Well known by clinicians in the context of treatment of ADHD in children and adolescents, these substances block dopamine and/or norepinephrine reuptake but do not inhibit monoaminergic vesicle transporters. The dosages vary according to the form used and, in the case of immediate-release methylphenidate, are between 0.5 and 1 mg/kg/day. The most frequent side effects are loss of appetite, nervousness, tics, headaches, and sleep-onset insomnia. The slow-release forms enable better coverage of daytime requirements while reducing side effects. The pharmacokinetics of methylphenidate has a major influence on the clinical effects of the drug, and several formulations of methylphenidate are available across different countries. Combined use of both immediate- and slow-release forms of methylphenidate might be helpful when both immediate and long-lasting effects are required. Of relevance, the methylphenidate preparations EquasymÒ and MedikinetÒ contain both immediate- and slow-release components within the same formulation and could, therefore, be particularly useful in some patients with narcolepsy. Although immediate-release methylphenidate is approved in the EU for the treatment of narcolepsy in children over 6 years of age, a study by Aran et al. [20] reported that it had a low rate of adherence (\20 %). Amphetamine-type drugs (e.g. dextroamphetamine) have long been used for their wake-promoting properties. They are considered effective for the treatment of narcolepsy-associated EDS, although it should also be noted that marketing authorization has not been issued for these treatments, either for adults or for children. Nevertheless, the extensive use of amphetamines as a treatment for ADHD in children provides experience that can be extrapolated to the pediatric narcolepsy population. However, it should also be noted that the use of amphetamines in patients with ADHD may mask the symptoms of narcolepsy; ADHD has been reported to be a comorbid condition in some narcolepsy patients [28, 56]. Amphetamines are associated with well recognized side effects, including insomnia, irritability, high blood pressure, and psychotic reactions, and they are also controlled substances due to their risk of tolerance and dependence. Amphetamines also result in rebound hypersomnia, which has been defined as ‘‘an intense interval of compensatory sleep after druginduced waking’’ [57]. This rebound hypersomnia occurs likely as a result of the ability of amphetamines to promote dopamine release [58], and this effect may actually lead to dose increase. Thus, patients should be monitored for treatment-related hypersomnia, and the reasons necessitating increased dosing should be considered prior to making the dose change.

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Lisdexamfetamine dimesylate is the first long-acting stimulant prodrug. It undergoes a rate-limiting enzymatic bioconversion to d-amfetamine in the bloodstream [59] and was shown to provide a daily duration of efficacy of at least 13 h post-dose in children in a laboratory school study [60, 61]. The efficacy of once-daily lisdexamfetamine dimesylate in relieving the symptoms of ADHD compared with placebo has been demonstrated in a series of 4-week USbased clinical trials in children [62], adolescents [63], and adults [64], and more recently in a 7-week European study in children and adolescents with ADHD [65]. Thus, along with the other amphetamine stimulants, it is well recognized as a medication that may be appropriate for use in pediatric narcolepsy, although there is little information on the efficacy of these drugs within the clinical setting of pediatric narcolepsy. Because of the potential sensitivity of the pediatric population to changes in metabolism and endocrine function, it is also important to consider the effects of treatment on these functions. Studies by Donjacour et al. [66–68] have evaluated the endocrine effects of sodium oxybate and stimulants in narcoleptic adults and children. Stimulants may increase growth hormone secretion, decrease testosterone and total and free thyroxine. Sodium oxybate increases growth hormone and prolactin secretion, may change insulin sensitivity in adults, and may have a profound effect on weight. Thus, children who are prescribed these medications should be monitored with regard to metabolic/endocrine function and growth. 2.1.3 Third-Line Agents for EDS Mazindol is an imidazoline-derived, tricyclic, nonamphetamine stimulant with anorectic properties that has been used in narcolepsy and obesity since 1970. Mazindol blocks dopamine and norepinephrine reuptake and has been shown to improve EDS and cataplexy in adults [69]. The dosage is from 1 to 4 mg/day, taken in two doses, in the morning and at midday. The side effects are gastrointestinal and heart rate disorders, headaches, and dizziness. A retrospective chart review of 94 patients with narcolepsy (13 of whom were children) and 45 patients with hypersomnia showed that mazindol had a long-term, favorable benefit/risk ratio in 60 % of drug-resistant adult hypersomniacs, and a clear benefit on cataplexy [70]. While the benefits were also observed in the children, there are no other available data on use of this drug in the pediatric population. 2.2 Cataplexy Even though cataplexy is the most specific symptom of narcolepsy, it is usually not the first symptom to appear.

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Cataplexy in children is not only disabling, since it can result in unexpected falls or inability to walk without support, but it may also be a source of embarrassment, adding to the psychosocial problems already prevalent among children with narcolepsy. Based on class 1 evidence, sodium oxybate is recommended as first-line pharmacological treatment of cataplexy [41]. In an open-label pilot study in a small number of pediatric patients suffering from severe narcolepsy (n = 8; age 9–16 years), 88 % showed improvement in cataplexy episode frequency and severity, and the Epworth Sleepiness Score (ESS) decreased from 19 to 12.5 [53]; concomitant treatment with medications for sleepiness or cataplexy were allowed. The treatment effects were maintained among the three patients who continued therapy for 10–28 months. Although their use is off-label, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (20–60 mg/ day) and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine (75–300 mg) are recommended as second-line treatment for cataplexy, hypnagogic hallucinations, and sleep paralysis in adults [40, 41]. Tricyclic antidepressants are also suggested, particularly clomipramine starting at low doses of 10–20 mg, increasing to 75 mg/day if required. Use is limited by anticholinergic side effects and potential cardiovascular effects (QT prolongation in particular). A rebound increase in cataplexy symptoms is frequently experienced when tricyclic antidepressants are discontinued abruptly. However, these recommendations lack class 1 evidence and are based on expert opinion only. While there is limited information on the use of these medications for narcolepsy in the pediatric population, two case reports suggest the efficacy of venlafaxine in children. In one study, six children were effectively treated for their cataplexy symptoms at venlafaxine doses of up to 113.5 mg daily, with successful reduction of hypnagogic hallucinations in the two patients who reported that this was their most troubling symptom [71]. No serious or severe side effects were reported, although there was an increase of disturbed nocturnal sleep when venlafaxine was taken after 2:00 pm. In the other study, a 3-year-old child was successfully treated for cataplexy, including a 2-year follow-up without any remarkable safety findings [72]. The selective norepinephrine reuptake inhibitor atomoxetine is mentioned as a potential treatment for cataplexy in European narcolepsy guidelines [40] but not in the US guidelines [41], although it is available as an off-label option. While it may be associated with increased heart rate and blood pressure, it is used in children for the treatment of ADHD, and thus may also be worth considering in pediatric narcolepsy, although clinical evaluation of its efficacy and safety in children with narcolepsy would be welcome.

Management of Pediatric Narcolepsy

3 New and Experimental Approaches Several novel approaches to narcolepsy treatment, evaluated in case studies and/or currently undergoing more formal clinical assessment, have provided results showing symptomatic benefits for narcolepsy in general and for pediatric patients in particular. 3.1 Intravenous Immunoglobulin A case study of an 8-year-old boy with acute-onset hypocretin-deficiency initiated on high-dose intravenous immunoglobulin (IVIg) 5 months after the onset of first narcolepsy symptoms reported positive results with regard to both cataplexy and EDS [73]. Since then, other case studies in children [34, 74] and adults [75–78] have reported mixed efficacy of IVIg, suggesting that additional studies of this treatment may be warranted. 3.2 Pitolisant Pitolisant is an H3 receptor inverse agonist that enhances histamine signaling through inhibition of the H3 autoreceptor [79]. Given that histamine neurons are crucial in the maintenance of wakefulness, and the demonstrated mediation of wakefulness by inverse H3 agonists [80], evaluation of pitolisant in preclinical models demonstrated its stimulant properties [81]. This property of promoting wakefulness was confirmed in orexin knock-out mice and narcolepsy patients [82], and the potential for anti-cataplectic effects was also observed in the orexin knock-out mice [82]. In these mice, pitolisant reduced the periods of direct transition from wakefulness to REM sleep, which have been suggested to correspond to cataplexy in humans and dogs [83]. The ability to reduce the direct transition from wakefulness to REM sleep was also reported in adult narcoleptic patients with cataplexy in a randomized, double-blind clinical trial of pitolisant [84]. However, direct effects on cataplexy could not be assessed since the patients were allowed to continue anti-cateplectic antidepressants. In this trial, pitolisant at doses up to 40 mg also demonstrated efficacy for EDS compared with placebo, and was well tolerated relative to the active comparator modafinil [84]. In pediatric patients, pitolisant was evaluated in a case series of four adolescents (12.5 ± 3 years) suffering from severe narcolepsy with cataplexy and who were being treated with stimulants (modafinil, methylphenidate, mazindol, sodium oxybate, dextroamphetamine) [85]. The stimulants resulted in poor efficacy or generated side effects, and pitolisant was initiated after cessation of the other treatments, which were re-initiated at low doses in three patients who did not adequately respond to pitolisant

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alone. Pitolisant was increased from 10 to 40 mg per day, and patients achieved significant reductions in the adapted ESS from 14.3 ± 1.1 to 9.5 ± 2.9 (p = 0.03) when used alone, with a further decrease to 7 ± 3.5 with concomitant stimulants. A non-significant increase in mean sleep onset latency was also observed, from 31 ± 14 min to 36 ± 8 min (p = 0.21) on the maintenance of wakefulness test, and the frequency and the intensity of cataplectic attacks decreased in three of the patients. Side effects were minor and transitory, except for insomnia, which persisted in the long term. Thus, in these patients refractory to stimulants, the synergistic effect obtained with pitolisant when combined with other medications represented an added benefit. Based on these results, pitolisant could constitute an additional option for the treatment of refractory sleepiness in adolescents with narcolepsy, either as monotherapy or as adjunctive to psychostimulants. Randomized clinical trials of pitolisant are ongoing, and it should also be noted that, in France, this drug can be obtained from the French Drug Agency on an individual basis for patients with EDS refractory to other stimulants. 3.3 Intranasal Hypocretin A novel approach to narcolepsy treatment that is currently under evaluation is intranasal administration of hypocretin1, based on the rationale of hypocretin-replacement therapy to compensate for the loss of hypocretin-producing neurons. Two studies have confirmed that this treatment modality may be appropriate, with positive effects on sleep structure that are likely to translate into improved daytime sleepiness [86, 87]. Additional studies are needed to fully evaluate this therapy, including its potential for use in the pediatric population.

4 Conclusions In the absence of curative or disease-modifying therapies, a pharmacological approach to symptom management is an essential strategy for the treatment of children with narcolepsy. However, this approach requires further evaluation and the development of evidence-based guidelines, since current strategies have been mostly based on empirical data and clinical experience, with only limited availability of drugs that are not used off-label in the pediatric population. The implementation of well designed, randomized, controlled clinical trials in the pediatric population is critical to confirm the clinical efficacy and tolerability of existing medications and to evaluate newly developed pharmacotherapies. New therapies target the underlying immunopathology and include the use of immune-based therapies at early stages of the disease and

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hypocretin-replacement therapy. In addition, non-pharmacological interventions, including exercise and cognitive behavioral therapies should be systematically evaluated, especially in young children. The ultimate aim of these endeavors should be to improve prognosis and outcomes for children and adolescents presenting with narcolepsy with cataplexy. Conflicts of interest Michel Lecendreux is a consultant for UCB Pharma, Jazz, Bioprojet, and Shire. He has no shares and no conflicts of interests with Cephalon, Teva, or Midy. No sources of funding were used to assist with the preparation of this review.

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