Narcolepsy: an interface among neurology, immunology, sleep, and genetics

 

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Abstract

Narcolepsy is a primary disorder of the central nervous system resulting from genetic, environmental, and immunological interactions defined as excessive daytime sleepiness plus cataplexy, hallucinations, sleep paralysis, and sleep fragmentation. The pathophysiology is not entirely known, but the interaction among genetic predisposition, environmental exposition, and immune component with consequent hypocretin-1 deficiency is the model to explain narcolepsy type I. The mechanism of narcolepsy type II is less understood. There is a delay of over ten years for the diagnosis of narcolepsy around the world. Patients with narcolepsy have many comorbidities with a negative impact on quality of life. The treatment of narcolepsy must contain an educational approach for the family, coworkers, and patients. Scheduled naps and sleep hygiene are essential to minimize the dose of medications. Much progress has been seen in the pharmacological treatment of narcolepsy with new stimulants, different presentations of oxybate, and recent studies with orexin agonists. Narcolepsy is a rare disease that needs to be more understood and highlighted to avoid delayed diagnosis and severe disabilities in patients.

Resumo

A narcolepsia é um distúrbio primário do sistema nervoso central resultante das interações genéticas, ambientais e imunológicas definidas como sonolência diurna excessiva mais cataplexia, alucinações, paralisia do sono e fragmentação do sono. A fisiopatologia não é completamente conhecida, mas a interação entre predisposição genética, exposição ambiental e componente imunológico com consequente deficiência de hipocretina-1 é o modelo para explicar a narcolepsia tipo I. O mecanismo da narcolepsia tipo II é menos compreendido. Há um atraso de mais de dez anos para o diagnóstico da narcolepsia em todo o mundo. Pacientes com narcolepsia apresentam muitas comorbidades com impacto negativo na qualidade de vida. O tratamento da narcolepsia deve conter uma abordagem educativa para a família, colegas de trabalho e pacientes. Cochilos programados e higiene do sono são importantes para minimizar a dose dos medicamentos. Muito progresso foi observado no tratamento farmacológico da narcolepsia com novos estimulantes, diferentes apresentações de oxibato e estudos recentes com agonistas de orexina. A narcolepsia é uma doença rara que precisa ser mais compreendida e destacada para evitar atrasos no diagnóstico e incapacidades graves nos pacientes.

Publication History

Received: 10 November 2023

Accepted: 01 December 2023

Article published online:
02 April 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/)

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• References

• 1 International Classification of Sleep Disorders – Third edition (ICSD-3). III ed:. American Academy of Sleep Medicine; 2014
  Google Scholar
• 2 Overeem S, van Nues SJ, van der Zande WL, Donjacour CE, van Mierlo P, Lammers GJ. The clinical features of cataplexy: a questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency. Sleep Med 2011; 12 (01) 12-18 DOI: 10.1016/j.sleep.2010.05.010.
  CrossrefPubMedGoogle Scholar
• 3 Scheer D, Schwartz SW, Parr M, Zgibor J, Sanchez-Anguiano A, Rajaram L. Prevalence and incidence of narcolepsy in a US health care claims database, 2008–2010. Sleep 2019; 42 (07) zsz091 DOI: 10.1093/sleep/zsz091.
  CrossrefPubMedGoogle Scholar
• 4 Wing YK, Li RH, Lam CW, Ho CK, Fong SY, Leung T. The prevalence of narcolepsy among Chinese in Hong Kong. Ann Neurol 2002; 51 (05) 578-584 DOI: 10.1002/ana.10162.
  CrossrefPubMedGoogle Scholar
• 5 Longstreth Jr WT, Koepsell TD, Ton TG, Hendrickson AF, van Belle G. The epidemiology of narcolepsy. Sleep 2007; 30 (01) 13-26 DOI: 10.1093/sleep/30.1.13.
  CrossrefPubMedGoogle Scholar
• 6 Scammell TE. Narcolepsy. N Engl J Med 2015; 373 (27) 2654-2662 DOI: 10.1056/NEJMra1500587.
  CrossrefPubMedGoogle Scholar
• 7 Hong SC, Lin L, Jeong JH. et al. A study of the diagnostic utility of HLA typing, CSF hypocretin-1 measurements, and MSLT testing for the diagnosis of narcolepsy in 163 Korean patients with unexplained excessive daytime sleepiness. Sleep 2006; 29 (11) 1429-1438 DOI: 10.1093/sleep/29.11.1429.
  CrossrefPubMedGoogle Scholar
• 8 Gerashchenko D, Murillo-Rodriguez E, Lin L. et al. Relationship between CSF hypocretin levels and hypocretin neuronal loss. Exp Neurol 2003; 184 (02) 1010-1016 DOI: 10.1016/S0014-4886(03)00388-1.
  CrossrefPubMedGoogle Scholar
• 9 Lima FCB, do Nascimento Junior EB, Teixeira SS, Coelho FM, Oliveira GDP. Thinking outside the box: cataplexy without narcolepsy. Sleep Med 2019; 61 (x): 118-121
  CrossrefPubMedGoogle Scholar
• 10 Bassetti CLA, Adamantidis A, Burdakov D. et al. Narcolepsy - clinical spectrum, aetiopathophysiology, diagnosis and treatment. Nat Rev Neurol 2019; 15 (09) 519-539 DOI: 10.1038/s41582-019-0226-9.
  CrossrefPubMedGoogle Scholar
• 11 Cremaschi RC, Hirotsu C, Tufik S, Coelho FM. Health-related quality of life in patients with narcolepsy types 1 and 2 from a Sleep Center in Brazil. Arq Neuropsiquiatr 2020; DOI: 10.1590/0004-282X20200032.
  Article in Thieme ConnectPubMedGoogle Scholar
• 12 Gélineau JBE. De la narcolepsie. Surgères, Charente-Inférieure: Imprimerie de Surgères 1881;64(1881.1889).
• 13 Fromherz S, Mignot E. Narcolepsy research: past, present, and future perspectives. Arch Ital Biol 2004; https://www.ncbi.nlm.nih.gov/pubmed/15493549 142 (04) 479-486
  PubMedGoogle Scholar
• 14 Von Ecônomo C. Sleep as a problem of localization. J Nerv Ment Dis 1930; 3: 249-259
  CrossrefGoogle Scholar
• 15 Gulyani S, Wu MF, Nienhuis R, John J, Siegel JM. Cataplexy-related neurons in the amygdala of the narcoleptic dog. Neuroscience 2002; 112 (02) 355-365 DOI: 10.1016/s0306-4522(02)00089-1.
  CrossrefPubMedGoogle Scholar
• 16 Schuld A, Beitinger PA, Dalal M. et al. Increased body mass index (BMI) in male narcoleptic patients, but not in HLA-DR2-positive healthy male volunteers. Sleep Med 2002; https://www.ncbi.nlm.nih.gov/pubmed/14592196 3 (04) 335-339
  CrossrefPubMedGoogle Scholar
• 17 Fernandes GB, Cremaschi RC, Mangueira CLP, Tufik S, Coelho FM. Cataplexy plus presence of HLA-DQB1*0602 allele can predict Hypocretin-1 deficiency. Sleep Med 2018; 45: 146-147 DOI: 10.1016/j.sleep.2017.09.013.
  CrossrefPubMedGoogle Scholar
• 18 International Classification of Sleep Disorders – Second edition (ICSD-2). III ed.. American Academy of Sleep Medicine; 2005
  Google Scholar
• 19 Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol 2014; 13 (06) 600-613 DOI: 10.1016/S1474-4422(14)70075-4.
  CrossrefPubMedGoogle Scholar
• 20 Sarkanen TO, Alakuijala APE, Dauvilliers YA, Partinen MM. Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis. Sleep Med Rev 2018; 38: 177-186 DOI: 10.1016/j.smrv.2017.06.006.
  CrossrefPubMedGoogle Scholar
• 21 Luo G, Ambati A, Lin L. et al. Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy. Proc Natl Acad Sci U S A 2018; 115 (52) E12323-E12332 DOI: 10.1073/pnas.1818150116.
  CrossrefPubMedGoogle Scholar
• 22 Mignot E. Genetic and familial aspects of narcolepsy. Neurology 1998; 50 (2, Suppl 1) https://www.ncbi.nlm.nih.gov/pubmed/9484418 S16-S22
  CrossrefPubMedGoogle Scholar
• 23 Zhu M, Huang H. The Underlying Mechanisms of Sleep Deprivation Exacerbating Neuropathic Pain. Nat Sci Sleep 2023; 15: 579-591 DOI: 10.2147/NSS.S414174.
  CrossrefPubMedGoogle Scholar
• 24 Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355 (9197): 39-40 DOI: 10.1016/S0140-6736(99)05582-8.
  CrossrefPubMedGoogle Scholar
• 25 Sakurai T, Amemiya A, Ishii M. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998;92(05): 1 page following 696. ( https://www.ncbi.nlm.nih.gov/pubmed/9527442 )
  Google Scholar
• 26 Coelho FM, Pradella-Hallinan M, Alves GR. et al. A study of T CD4, CD8 and B lymphocytes in narcoleptic patients. Arq Neuropsiquiatr 2007; 65 (2B): https://www.ncbi.nlm.nih.gov/pubmed/17665008 423-427
  CrossrefPubMedGoogle Scholar
• 27 Coelho FM, Pradella-Hallinan M, Alves GR, Bittencourt LR, Tufik S. Report of two narcoleptic patients with remission of hypersomnolence following use of prednisone. Arq Neuropsiquiatr 2007; 65 (2A): https://www.ncbi.nlm.nih.gov/pubmed/17607439 336-337
  CrossrefPubMedGoogle Scholar
• 28 Ruppert E, Zagala H, Chambe J. et al. Intravenous Immunoglobulin Therapy Administered Early after Narcolepsy Type 1 Onset in Three Patients Evaluated by Clinical and Polysomnographic Follow-Up. Behav Neurol 2018; 2018: 1671072 DOI: 10.1155/2018/1671072.
  CrossrefPubMedGoogle Scholar
• 29 Coelho FM, Pradella-Hallinan M, Pedrazzoli M. et al. Low CD40L levels and relative lymphopenia in narcoleptic patients. Hum Immunol 2011; 72 (10) 817-820 DOI: 10.1016/j.humimm.2011.05.024.
  CrossrefPubMedGoogle Scholar
• 30 Campos JHC, Aguilar ACR, Antoneli F. et al. Whole-genome analysis of monozygotic Brazilian twins discordant for type 1 narcolepsy: a case report. BMC Neurol 2022; 22 (01) 439 DOI: 10.1186/s12883-022-02921-w.
  CrossrefPubMedGoogle Scholar
• 31 Cvetkovic-Lopes V, Bayer L, Dorsaz S. et al. Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. J Clin Invest 2010; 120 (03) 713-719 DOI: 10.1172/JCI41366.
  CrossrefPubMedGoogle Scholar
• 32 Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991; 14 (06) 540-545 DOI: 10.1093/sleep/14.6.540.
  CrossrefPubMedGoogle Scholar
• 33 Fernandes GB, Cremaschi RC, Poyares D, Tufik S, Coelho FM. Prevalence of nocturnal sleep onset rapid movement sleep period (SOREMP) in narcolepsy type 1 and type 2. Sleep Med 2017; 38: 162-163 DOI: 10.1016/j.sleep.2017.08.004.
  CrossrefPubMedGoogle Scholar
• 34 Coelho FM, Pradella-Hallinan M, Pedrazzoli M. et al. Traditional biomarkers in narcolepsy: experience of a Brazilian sleep centre. Arq Neuropsiquiatr 2010; https://www.ncbi.nlm.nih.gov/pubmed/21049180 68 (05) 712-715
  CrossrefPubMedGoogle Scholar
• 35 Fernandes GB, Cremaschi RC, Tufik S, Coelho FM. Grey zone between narcolepsy type 1 and type 2. Arq Neuropsiquiatr 2017; 75 (09) 682-683 . Doi: 10.1590/0004-282. Doi: X20170106
  Article in Thieme ConnectPubMedGoogle Scholar
• 36 Thorpy MJ, Krieger AC. Delayed diagnosis of narcolepsy: characterization and impact. Sleep Med 2014; 15 (05) 502-507 DOI: 10.1016/j.sleep.2014.01.015.
  CrossrefPubMedGoogle Scholar
• 37 Pimentel Filho LH, Gomes ACD, Frange C, Tufik S, Coelho FMS. Validation of the Brazilian Portuguese version of the narcolepsy severity scale. Sleep Med 2020; 76: 134-139 DOI: 10.1016/j.sleep.2020.10.016.
  CrossrefPubMedGoogle Scholar
• 38 Dias Gomes AC, Pimentel Filho LH, Aguilar ACR, Truzzi GM, Tufik S, Coelho FMS. Validation of the Brazilian Portuguese version of the Stanford cataplexy questionnaire. Sleep Med 2023; 111: 101-104 DOI: 10.1016/j.sleep.2023.09.010.
  CrossrefPubMedGoogle Scholar
• 39 Matoulek M, Tuka V, Fialová M, Nevšímalová S, Šonka K. Cardiovascular fitness in narcolepsy is inversely related to sleepiness and the number of cataplexy episodes. Sleep Med 2017; 34: 7-12 DOI: 10.1016/j.sleep.2017.02.017.
  CrossrefPubMedGoogle Scholar
• 40 Truzzi GM, Naufel MF, Tufik S, Coelho FM. Narcolepsy: the impact of aging, hypocretin deficiency, and years of formal education in olfactory function and abdominal obesity. Arq Neuropsiquiatr 2021; 79 (09) 808-815 DOI: 10.1590/0004-282X-anp-2020-0352.
  Article in Thieme ConnectPubMedGoogle Scholar
• 41 Adda C, Lefévre B, Reimão R. Narcolepsy and depression. Arq Neuropsiquiatr 1997; 55 (3A): https://www.ncbi.nlm.nih.gov/pubmed/9629359 423-426
  CrossrefPubMedGoogle Scholar
• 42 de Martin Truzzi G, Naufel MF, Tufik S, Coelho FM. The influence of narcolepsy on olfactory function: a review. Sleep Med 2020; 72: 75-81 DOI: 10.1016/j.sleep.2020.03.023.
  CrossrefPubMedGoogle Scholar
• 43 Li B, Gao Z, He Y. et al. Narcolepsy and psychiatric disorders: A bidirectional Mendelian randomization study. J Psychiatr Res 2023; 169: 42-48 DOI: 10.1016/j.jpsychires.2023.11.034.
  CrossrefPubMedGoogle Scholar
• 44 Cremaschi RC, Hirotsu C, Tufik S, Coelho FM. High fatigue frequency in narcolepsy type 1 and type 2 in a Brazilian Sleep Center. Sleep Med 2018; 52: 234 DOI: 10.1016/j.sleep.2018.08.013.
  CrossrefPubMedGoogle Scholar
• 45 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 DOI: 10.5665/sleep.2366.
  CrossrefPubMedGoogle Scholar
• 46 Zhang M, Thieux M, Arvis L. et al. Metabolic disturbances in children with narcolepsy: a retrospective study. Sleep 2023; 46 (07) zsad076 DOI: 10.1093/sleep/zsad076.
  CrossrefPubMedGoogle Scholar
• 47 Cremaschi RC, Hirotsu C, Tufik S, Coelho FM. Health-related quality of life in patients with narcolepsy types 1 and 2 from a Sleep Center in Brazil. Arq Neuropsiquiatr 2020; 78 (08) 488-493 . Doi: 10.1590/0004-282. Doi: X20200032
  Article in Thieme ConnectPubMedGoogle Scholar
• 48 Cremaschi RC, Hirotsu C, Tufik S, Coelho FM. Chronic pain in narcolepsy type 1 and type 2 - an underestimated reality. J Sleep Res 2019; 28 (03) e12715 DOI: 10.1111/jsr.12715.
  CrossrefPubMedGoogle Scholar
• 49 Cremaschi RC, Hirotsu C, Tufik S, Coelho FM. The sensory pain of Dante's Inferno - Semantics of chronic pain in patients with narcolepsy. Sleep Sci 2019; 12 (01) 49-52 DOI: 10.5935/1984-0063.20190055.
  Article in Thieme ConnectPubMedGoogle Scholar
• 50 Chang ET, Lin CL, Chen SF, Hsu CY, Shen YC. Risk of bone fractures in patients with narcolepsy: a nationwide population-based cohort study. Sleep Med 2020; 70: 55-59 DOI: 10.1016/j.sleep.2020.02.015.
  CrossrefPubMedGoogle Scholar
• 51 da Paz Oliveira G, Elias RM, Peres Fernandes GB. et al. Decreased concentration of klotho and increased concentration of FGF23 in the cerebrospinal fluid of patients with narcolepsy. Sleep Med 2021; 78: 57-62 DOI: 10.1016/j.sleep.2020.11.037.
  CrossrefPubMedGoogle Scholar
• 52 Oliveira GP, Coelho FMS. Narcolepsy and bone metabolism: is there any association?. Sleep Med 2020; 74: 297 DOI: 10.1016/j.sleep.2020.07.036.
  CrossrefPubMedGoogle Scholar
• 53 Blattner M, Maski K. Central Disorders of Hypersomnolence. Continuum (Minneap Minn) 2023; 29 (04) 1045-1070 DOI: 10.1212/CON.0000000000001265.
  CrossrefPubMedGoogle Scholar
• 54 Bassetti CLA, Kallweit U, Vignatelli L. et al. European guideline and expert statements on the management of narcolepsy in adults and children. Eur J Neurol 2021; 28 (09) 2815-2830 DOI: 10.1111/ene.14888.
  CrossrefPubMedGoogle Scholar
• 55 Frange C, Franco AM, Brasil E. et al. Practice recommendations for the role of physiotherapy in the management of sleep disorders: the 2022 Brazilian Sleep Association Guidelines. Sleep Sci 2022; 15 (04) 515-573 DOI: 10.5935/1984-0063.20220083.
  Article in Thieme ConnectPubMedGoogle Scholar
• 56 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 (06) e13387 DOI: 10.1111/jsr.13387.
  CrossrefPubMedGoogle Scholar
• 57 Aguilar AC, Frange C, Pimentel Filho LH, Reis MJ, Tufik S, Coelho FMS. Lisdexamfetamine to improve excessive daytime sleepiness and weight management in narcolepsy: a case series. Br J Psychiatry 2020; 42 (03) 314-316 DOI: 10.1590/1516-4446-2019-0544.
  CrossrefPubMedGoogle Scholar
• 58 Lin JS, Gervasoni D, Hou Y. et al. Effects of amphetamine and modafinil on the sleep/wake cycle during experimental hypersomnia induced by sleep deprivation in the cat. J Sleep Res 2000; https://www.ncbi.nlm.nih.gov/pubmed/10733694 9 (01) 89-96
  CrossrefPubMedGoogle Scholar
• 59 Darwish M, Kirby M, Hellriegel ET, Robertson Jr P. Armodafinil and modafinil have substantially different pharmacokinetic profiles despite having the same terminal half-lives: analysis of data from three randomized, single-dose, pharmacokinetic studies. Clin Drug Investig 2009; 29 (09) 613-623 DOI: 10.2165/11315280-000000000-00000.
  CrossrefPubMedGoogle Scholar
• 60 Calik MW. Update on the treatment of narcolepsy: clinical efficacy of pitolisant. Nat Sci Sleep 2017; 9: 127-133 DOI: 10.2147/NSS.S103462.
  CrossrefPubMedGoogle Scholar
• 61 Dauvilliers Y, Shapiro C, Mayer G. et al. Solriamfetol for the Treatment of Excessive Daytime Sleepiness in Participants with Narcolepsy with and without Cataplexy: Subgroup Analysis of Efficacy and Safety Data by Cataplexy Status in a Randomized Controlled Trial. CNS Drugs 2020; 34 (07) 773-784 DOI: 10.1007/s40263-020-00744-2.
  CrossrefPubMedGoogle Scholar
• 62 Dauvilliers Y, Mignot E, Del Río Villegas R. et al. Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1. N Engl J Med 2023; 389 (04) 309-321 DOI: 10.1056/NEJMoa2301940.
  CrossrefPubMedGoogle Scholar
• 63 Rosenberg R, Braceras R, Macfadden W, Candler S, Black J, Ruoff C. Implications of Oxybate Dosing Regimen for Sleep, Sleep Architecture, and Disrupted Nighttime Sleep in Patients with Narcolepsy: A Commentary. Neurol Ther 2023; 12 (06) 1805-1820 DOI: 10.1007/s40120-023-00543-z.
  CrossrefPubMedGoogle Scholar
• 64 Huang YS, Guilleminault C. Narcolepsy: action of two gamma-aminobutyric acid type B agonists, baclofen and sodium oxybate. Pediatr Neurol 2009; 41 (01) 9-16 DOI: 10.1016/j.pediatrneurol.2009.02.008.
  CrossrefPubMedGoogle Scholar
• 65 Calvo-Ferrandiz E, Peraita-Adrados R. Narcolepsy with cataplexy and pregnancy: a case-control study. J Sleep Res 2018; 27 (02) 268-272 DOI: 10.1111/jsr.12567.
  CrossrefPubMedGoogle Scholar
• 66 Barros F, Aguilar ACR, Tufik S, Coelho FM. Oral L–Carnitine used to treat narcoleptic type 1 patient during pregnancy - A case report. Sleep Sci 2018; 11 (04) 215-216 DOI: 10.5935/1984-0063.20180035.
  Article in Thieme ConnectPubMedGoogle Scholar
• 67 Salles C, Freitas MC, Cruz MME. Impact of L-carnitine in narcolepsy treatment: a systematic review on the effectiveness and safety. Sleep Sci 2022; 15 (Spec 1): 278-284 DOI: 10.5935/1984-0063.20220004.
  Article in Thieme ConnectPubMedGoogle Scholar
• 68 Miyagawa T, Kawamura H, Obuchi M. et al. Effects of oral L-carnitine administration in narcolepsy patients: a randomized, double-blind, cross-over and placebo-controlled trial. PLoS One 2013; 8 (01) e53707 DOI: 10.1371/journal.pone.0053707.
  CrossrefPubMedGoogle Scholar
• 69 Dauvilliers Y, Carlander B, Rivier F, Touchon J, Tafti M. Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset. Ann Neurol 2004; 56 (06) 905-908 DOI: 10.1002/ana.20339.
  CrossrefPubMedGoogle Scholar
• 70 Aldosari MS, Olaish AH, Nashwan SZ, Abulmeaty MMA, BaHammam AS. The effects of caffeine on drowsiness in patients with narcolepsy: a double-blind randomized controlled pilot study. Sleep Breath 2020; 24 (04) 1675-1684 DOI: 10.1007/s11325-020-02065-6.
  CrossrefPubMedGoogle Scholar