Narcolepsy during Childhood: An Update

Abstract

Narcolepsy type 1 (NT1) is a rare central disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations, and fragmented nocturnal sleep usually arising in adolescence or young adulthood. Recently, the childhood NT1 diagnoses have increased for improved disease awareness and for several cases occurring after the H1N1 pandemic influenza or vaccination. As in adults, the occurrence of NT1 in individuals with a genetic predisposition of the immune system (e.g., human leukocyte antigen, HLA-DQB1*0602) together with the role of environmental triggers (e.g., H1N1 influenza virus, streptococcus β hemolyticus) further supports the autoimmune pathogenesis. Children with NT1 close to disease onset show a peculiar cataplexy phenotype characterized by persistent hypotonia with prominent facial involvement (cataplectic facies) and by a complex mosaic of hyperkinetic movement abnormalities that increase during emotional stimulation. This phenotype progressively vanishes along the disease course leading to the typical picture of cataplexy (i.e., muscle weakness exclusively evoked by strong emotions). This possibly explains in part the misdiagnoses and diagnostic delay. Childhood NT1 also shows behavioral abnormalities and psychiatric disorders, encompassing depressive feelings, hyperactive/aggressive behavior, up to psychotic features. The association with obesity and precocious puberty strikingly suggests that NT1 arising in prepubertal children may reflect a wide hypothalamic derangement secondary to hypocretin neuronal loss. The complexity of the childhood NT1 phenotype claims a multidisciplinary assessment and management, taking behavioral and endocrinological features into account. NT1 indeed is a lifelong disorder with a devastating impact on quality of life, especially when arising across developmental age, and targeted school programs, medicolegal and psychological supports are essential for patients care. Controlled studies are mandatory to assess safety and efficacy of the current symptomatic off-label medications on which also relies the treatment for children with NT1, and hopefully future pathogenetic evidences will pave the way to better disease prevention and therapies to modify the disease course.

H1N1 infection of sleep/wake regions results in narcolepsy-like symptoms

“…The present results (1) suggest that H1N1 viral infection itself rather than an autoimmune response may have been responsible for the large increase in the number of new cases of narcolepsy in Chinese children, particularly because >94% of those children did not receive H1N1 vaccination (3). At disease onset, narcolepsy in children presents with an array of motoric behaviors that is not typically observed in adults (18). These differences between adults and children may be caused, at least in part, by different etiologies of narcolepsy, rather than because of developmental reasons.…”

Role of the Orexin System on the Hypothalamus-Pituitary-Thyroid Axis

“…Moreover, among narcoleptic patients, energy imbalance, eating disorders (Chabas et al, 2007), precocious puberty, obesity and changes in bicarbonate levels are more frequent than in healthy subjects, also during childhood (Poli et al, 2013; Rocca et al, 2015; Franco et al, 2016). …”

Efficiency of a Combination of Pharmacological Treatment and Nondrug Interventions in Childhood Narcolepsy

“…3 These neurotransmitters produce exclusively from the lateral hypothalamus, playing a major role in wakefulness and REM sleep. 2,[5][6][7] Narcolepsy is currently divided into narcolepsy type 1 and type 2 according to the revised International Classification of Sleep Disorders (ICSD-3). 8 Narcolepsy type 1 is characterized by excessive daytime sleepiness and cataplexy caused by hypocretin-1 deficiency.…”

“…The close association with HLA DQB1 Ã 06:02 haplotype and low or undetectable hypocretin-1 levels in the cerebrospinal fluid support the hypothesis of an autoimmune etiology in narcolepsy type 1. 1,[3][4][5][6][7] Narcolepsy type 2 is characterized by excessive daytime sleepiness without cataplexy and hypocretin deficiency, diagnosed based on patients' complaints and polysomnographic evidence in the absence of other causes of daytime sleepiness. ICSD-3 recognizes a pathophysiologic subtype-narcolepsy due to a medical condition, including brain pathologies (e.g., brain tumors or infiltrative disorders, such as sarcoidosis), Niemann-Pick disease type C, demyelinating disorders, and stroke or injury resulting in damage to the hypocretin pathways.…”

“…ICSD-3 recognizes a pathophysiologic subtype-narcolepsy due to a medical condition, including brain pathologies (e.g., brain tumors or infiltrative disorders, such as sarcoidosis), Niemann-Pick disease type C, demyelinating disorders, and stroke or injury resulting in damage to the hypocretin pathways. 1,4,5 We present the clinical and laboratory characteristics, and treatment outcomes of children with a typical presentation of narcolepsy to increase awareness of this disorder in pediatric practice and help guide its treatment.…”