Narcolepsy Features in Young Patients

Abstract

Narcolepsy is a lifelong central hypersomnia characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations, and disrupted nocturnal sleep. Behavioral and psychiatric comorbidities are often associated clinical features. It is divided into two subtypes, narcolepsy type-1, and narcolepsy type-2, depending on the presence of cataplexy and the cerebrospinal fluid hypocretin-1 levels. An autoimmune process, along with environmental factors, has been hypothesized to cause the disease. Among children and adolescents, incidence in Europe falls between 0.14 and 0.3 in 100,000, with a reported increase in the incidence after the 2009 H1N1 pandemic influence and vaccination. Currently, specific pediatric diagnostic criteria and cut-off instrumental values are lacking. Clinical presentation of the disease may differ between children and adults, and misdiagnoses or diagnostic delays are still an issue. The treatment is based on behavioral and pharmacological therapy, but drugs in children are prescribed off-label. Overall, pathogenic mechanism of narcolepsy and data on drug efficacy in children are still limited: more research is needed to develop new drugs and to reach approval of current treatments in the pediatric population.

Keywords

children - sleep - sleepiness - cataplexy - cataplectic facies

• References

• 1 Gélineau J. De La Narcolepsie. Gazette des Hôpitaux Civils et Militaires. 1880; 53: 626-628
• 2 Westphal C. Eigentümliche mit Einschlafen verbundene Anfälle. Arch Psychiatr Nervenkr 1877; 7: 631-635
• 3 Yoss RE, Daly DD. Criteria for the diagnosis of the narcoleptic syndrome. Proc Staff Meet Mayo Clin 1957; 32 (12) 320-328
• 4 American Academy of Sleep Medicine. The International Classification of Sleep Disorders-Revised: Diagnostic and Coding Manual. 3rd ed. Rochester, MN: 2014
• 5 Berro LF, Tufik SB, Tufik S. A journey through narcolepsy diagnosis: From ICSD 1 to ICSD 3. Sleep Sci 2014; 7 (01) 3-4
• 6 American Academy of Sleep Medicine. International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual. Chicago, IL: 2001
• 7 American Academy of Sleep Medicine. The International Classification of Sleep Disorders-Revised: Diagnostic and Coding Manual. 2nd ed. Chicago, IL: 2005
• 8 Peyron C, Faraco J, Rogers W. , et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6 (09) 991-997
• 9 Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355 (9197): 39-40
• 10 Kornum BR, Faraco J, Mignot E. Narcolepsy with hypocretin/orexin deficiency, infections and autoimmunity of the brain. Curr Opin Neurobiol 2011; 21 (06) 897-903
• 11 Partinen M, Saarenpää-Heikkilä O, Ilveskoski I. , et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One 2012; 7 (03) e33723 . Doi: 10.1371/journal.pone.0033723
• 12 Nohynek H, Jokinen J, Partinen M. , et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One 2012; 7 (03) e33536
• 13 Han F, Lin L, Warby SC. , et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol 2011; 70 (03) 410-417
• 14 Han F, Lin L, Li J, Dong XS, Mignot E. Decreased incidence of childhood narcolepsy 2 years after the 2009 H1N1 winter flu pandemic. Ann Neurol 2013; 73 (04) 560
• 15 Aran A, Einen M, Lin L, Plazzi G, Nishino S, Mignot E. Clinical and therapeutic aspects of childhood narcolepsy-cataplexy: a retrospective study of 51 children. Sleep 2010; 33 (11) 1457-1464
• 16 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
• 17 Ponziani V, Gennari M, Pizza F, Balsamo A, Bernardi F, Plazzi G. Growing up with type 1 narcolepsy: its anthropometric and endocrine features. J Clin Sleep Med 2016; 12 (12) 1649-1657
• 18 Miyagawa T, Kawashima M, Nishida N. , et al. Variant between CPT1B and CHKB associated with susceptibility to narcolepsy. Nat Genet 2008; 40 (11) 1324-1328
• 19 Hallmayer J, Faraco J, Lin L. , et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genet 2009; 41 (06) 708-711
• 20 Kornum BR, Kawashima M, Faraco J. , et al. Common variants in P2RY11 are associated with narcolepsy. Nat Genet 2011; 43 (01) 66-71
• 21 Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998; 50 (02) (Suppl. 01) S16-S22
• 22 Aran A, Lin L, Nevsimalova S. , et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 2009; 32 (08) 979-983
• 23 Hartmann FJ, Bernard-Valnet R, Quériault C. , et al. High-dimensional single-cell analysis reveals the immune signature of narcolepsy. J Exp Med 2016; 213 (12) 2621-2633
• 24 Lecendreux M, Churlaud G, Pitoiset F. , et al. Narcolepsy type 1 is associated with a systemic increase and activation of regulatory T Cells and with a systemic activation of global T cells. PLoS One 2017; 12 (01) e0169836 Doi: 10.1371/journal.pone.0169836
• 25 Dauvilliers Y, Montplaisir J, Molinari N. , et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 2001; 57 (11) 2029-2033
• 26 Ohayon MM, Priest RG, Zulley J, Smirne S, Paiva T. Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology 2002; 58 (12) 1826-1833
• 27 Wilner A, Steinman L, Lavie P, Peled R, Friedmann A, Brautbar C. Narcolepsy-cataplexy in Israeli Jews is associated exclusively with the HLA DR2 haplotype. A study at the serological and genomic level. Hum Immunol 1988; 21 (01) 15-22
• 28 Honda Y. Census of narcolepsy, cataplexy and sleep life teenagers in Fujisawa city. Sleep Res 1979; 8: 191
• 29 Han F, Chen E, Wei H. , et al. Childhood narcolepsy in North China. Sleep 2001; 24 (03) 321-324
• 30 Wu H, Zhuang J, Stone WS. , et al. Symptoms and occurrences of narcolepsy: a retrospective study of 162 patients during a 10-year period in eastern China. Sleep Med 2014; 15 (06) 607-613
• 31 Longstreth Jr WT, Ton TG, Koepsell T, Gersuk VH, Hendrickson A, Velde S. Prevalence of narcolepsy in King County, Washington, USA. Sleep Med 2009; 10 (04) 422-426
• 32 Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep 2002; 25 (02) 197-202
• 33 Szakács A, Darin N, Hallböök T. Increased childhood incidence of narcolepsy in western Sweden after H1N1 influenza vaccination. Neurology 2013; 80 (14) 1315-1321
• 34 Oberle D, Drechsel-Bäuerle U, Schmidtmann I, Mayer G, Keller-Stanislawski B. Incidence of narcolepsy in Germany. Sleep 2015; 38 (10) 1619-1628
• 35 Wijnans L, Lecomte C, de Vries C. , et al. The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns. Vaccine 2013; 31 (08) 1246-1254
• 36 Thorpy MJ, Krieger AC. Delayed diagnosis of narcolepsy: characterization and impact. Sleep Med 2014; 15 (05) 502-507
• 37 Morrish E, King MA, Smith IE, Shneerson JM. Factors associated with a delay in the diagnosis of narcolepsy. Sleep Med 2004; 5 (01) 37-41
• 38 Poli F, Overeem S, Lammers GJ. , et al. Narcolepsy as an adverse event following immunization: case definition and guidelines for data collection, analysis and presentation. Vaccine 2013; 31 (06) 994-1007
• 39 Rocca FL, Pizza F, Ricci E, Plazzi G. Narcolepsy during childhood: An update. Neuropediatrics 2015; 46 (03) 181-198
• 40 Pizza F, Vandi S, Liguori R. , et al. Primary progressive narcolepsy type 1: the other side of the coin. Neurology 2014; 83 (23) 2189-2190
• 41 Luca G, Haba-Rubio J, Dauvilliers Y. , et al; European Narcolepsy Network. Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J Sleep Res 2013; 22 (05) 482-495
• 42 Pizza F, Franceschini C, Peltola H. , et al. Clinical and polysomnographic course of childhood narcolepsy with cataplexy. Brain 2013; 136 (Pt 12): 3787-3795
• 43 Wise MS. Childhood narcolepsy. Neurology 1998; 50 (02) (Suppl. 01) S37-S42
• 44 Guilleminault C, Mignot E, Partinen M. Controversies in the diagnosis of narcolepsy. Sleep 1994; 17 (8, Suppl) S1-S6
• 45 Young D, Zorick F, Wittig R, Roehrs T, Roth T. Narcolepsy in a pediatric population. Am J Dis Child 1988; 142 (02) 210-213
• 46 Dauvilliers Y, Gosselin A, Paquet J, Touchon J, Billiard M, Montplaisir J. Effect of age on MSLT results in patients with narcolepsy-cataplexy. Neurology 2004; 62 (01) 46-50
• 47 Nevsimalova S, Buskova J, Kemlink D, Sonka K, Skibova J. Does age at the onset of narcolepsy influence the course and severity of the disease?. Sleep Med 2009; 10 (09) 967-972
• 48 Nevsimalova S. Narcolepsy in childhood. Sleep Med Rev 2009; 13 (02) 169-180
• 49 Wise MS, Lynch J. Narcolepsy in children. Semin Pediatr Neurol 2001; 8 (04) 198-206
• 50 Lecendreux M, Lavault S, Lopez R. , et al. Attention-deficit/hyperactivity disorder (ADHD) symptoms in pediatric narcolepsy: a cross-sectional study. Sleep 2015; 38 (08) 1285-1295
• 51 Modestino EJ, Winchester J. A retrospective survey of childhood ADHD symptomatology among adult narcoleptics. J Atten Disord 2013; 17 (07) 574-582
• 52 Guilleminault C, Pelayo R. Narcolepsy in prepubertal children. Ann Neurol 1998; 43 (01) 135-142
• 53 Broughton WA, Broughton RJ. Psychosocial impact of narcolepsy. Sleep 1994; 17 (8, Suppl) S45-S49
• 54 Hayes Jr D. Narcolepsy with cataplexy in early childhood. Clin Pediatr (Phila) 2006; 45 (04) 361-363
• 55 Dorris L, Zuberi SM, Scott N, Moffat C, McArthur I. Psychosocial and intellectual functioning in childhood narcolepsy. Dev Neurorehabil 2008; 11 (03) 187-194
• 56 Peterson PC, Husain AM. Pediatric narcolepsy. Brain Dev 2008; 30 (10) 609-623
• 57 Fortuyn HA, Lappenschaar MA, Furer JW. , et al. Anxiety and mood disorders in narcolepsy: a case-control study. Gen Hosp Psychiatry 2010; 32 (01) 49-56
• 58 Pizza F, Magnani M, Indrio C, Plazzi G. The hypocretin system and psychiatric disorders. Curr Psychiatry Rep 2014; 16 (02) 433 . Doi: 10.1007/s11920-013-0433-9
• 59 Inocente CO, Gustin MP, Lavault S. , et al. Depressive feelings in children with narcolepsy. Sleep Med 2014; 15 (03) 309-314
• 60 Huang YS, Guilleminault C, Chen CH, Lai PC, Hwang FM. Narcolepsy-cataplexy and schizophrenia in adolescents. Sleep Med 2014; 15 (01) 15-22
• 61 Zamarian L, Högl B, Delazer M. , et al. Subjective deficits of attention, cognition and depression in patients with narcolepsy. Sleep Med 2015; 16 (01) 45-51
• 62 Naumann A, Bellebaum C, Daum I. Cognitive deficits in narcolepsy. J Sleep Res 2006; 15 (03) 329-338
• 63 Bayard S, Croisier Langenier M, Cochen De Cock V, Scholz S, Dauvilliers Y. Executive control of attention in narcolepsy. PLoS One 2012; 7 (04) e33525 . Doi: 10.1371/journal.pone.0033525
• 64 Posar A, Pizza F, Parmeggiani A, Plazzi G. Neuropsychological findings in childhood narcolepsy. J Child Neurol 2014; 29 (10) 1370-1376
• 65 Plazzi G, Parmeggiani A, Mignot E. , et al. Narcolepsy-cataplexy associated with precocious puberty. Neurology 2006; 66 (10) 1577-1579
• 66 Poli F, Pizza F, Mignot E. , et al. High prevalence of precocious puberty and obesity in childhood narcolepsy with cataplexy. Sleep 2013; 36 (02) 175-181
• 67 Inocente CO, Lavault S, Lecendreux M. , et al. Impact of obesity in children with narcolepsy. CNS Neurosci Ther 2013; 19 (07) 521-528
• 68 Dahl RE, Holttum J, Trubnick L. A clinical picture of child and adolescent narcolepsy. J Am Acad Child Adolesc Psychiatry 1994; 33 (06) 834-841
• 69 Tsujino N, Sakurai T. Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacol Rev 2009; 61 (02) 162-176
• 70 Russell SH, Small CJ, Kennedy AR. , et al. Orexin A interactions in the hypothalamo-pituitary gonadal axis. Endocrinology 2001; 142 (12) 5294-5302
• 71 Ferguson AV, Samson WK. The orexin/hypocretin system: a critical regulator of neuroendocrine and autonomic function. Front Neuroendocrinol 2003; 24 (03) 141-150
• 72 Ohno K, Sakurai T. Orexin neuronal circuitry: role in the regulation of sleep and wakefulness. Front Neuroendocrinol 2008; 29 (01) 70-87
• 73 Barateau L, Lopez R, Dauvilliers Y. Treatment options for narcolepsy. CNS Drugs 2016; 30 (05) 369-379
• 74 Alóe F, Alves RC, Araújo JF. , et al. Brazilian guidelines for the treatment of narcolepsy [in Portuguese]. Rev Bras Psiquiatr 2010; 32 (03) 305-314
• 75 Proctor A, Bianchi MT. Clinical pharmacology in sleep medicine. ISRN Pharmacol 2012; 2012: 914168 . Doi: 10.5402/2012/914168
• 76 Lecendreux M, Bruni O, Franco P. , et al. Clinical experience suggests that modafinil is an effective and safe treatment for paediatric narcolepsy. J Sleep Res 2012; 21 (04) 481-483
• 77 Briars L, Todd T. A review of pharmacological management of attention-deficit/hyperactivity disorder. J Pediatr Pharmacol Ther 2016; 21 (03) 192-206
• 78 Roth T, Dauvilliers Y, Guinta D, Alvarez-Horine S, Dynin E, Black J. Effect of sodium oxybate on disrupted nighttime sleep in patients with narcolepsy. J Sleep Res 2016 . Doi: 10.1111/jsr.12468
• 79 Nishino S, Okuro M. Emerging treatments for narcolepsy and its related disorders. Expert Opin Emerg Drugs 2010; 15 (01) 139-158
• 80 Billiard M, Bassetti C, Dauvilliers Y. , et al; EFNS Task Force. EFNS guidelines on management of narcolepsy. Eur J Neurol 2006; 13 (10) 1035-1048
• 81 Lopez R, Dauvilliers Y. Pharmacotherapy options for cataplexy. Expert Opin Pharmacother 2013; 14 (07) 895-903
• 82 Thorpy MJ, Dauvilliers Y. Clinical and practical considerations in the pharmacologic management of narcolepsy. Sleep Med 2015; 16 (01) 9-18
• 83 Bymaster FP, Katner JS, Nelson DL. , et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 2002; 27 (05) 699-711
• 84 Mignot E, Nishino S. Emerging therapies in narcolepsy-cataplexy. Sleep 2005; 28 (06) 754-763
• 85 Inocente C, Arnulf I, Bastuji H. , et al. Pitolisant, an inverse agonist of the histamine H3 receptor: an alternative stimulant for narcolepsy-cataplexy in teenagers with refractory sleepiness. Clin Neuropharmacol 2012; 35 (02) 55-60
• 86 Lin L, Bassetti CL, Lammers GJ. , et al. Guidelines for the appropriate use of CSF measurements to diagnose narcolepsy. In: Bassetti CL, Billiard M, Mignot E. , eds. Narcolepsy and Hypersomnia. 1st ed. New York, NY: Informa Healthcare; 2006: 663-670
• 87 Nevsimalova S, Vankova J, Stepanova I, Seemanova E, Mignot E, Nishino S. Hypocretin deficiency in Prader-Willi syndrome. Eur J Neurol 2005; 12 (01) 70-72
• 88 Littner MR, Kushida C, Wise M. , et al; Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005; 28 (01) 113-121