Narcolepsy Workup: Approach Considerations, Sleep Studies

Sections

Narcolepsy

Workup

Approach Considerations

Sleep studies are an essential part of the evaluation of patients with possible narcolepsy. The combination of an overnight polysomnogram (PSG) followed by a multiple sleep latency test (MSLT) can provide strongly suggestive evidence of narcolepsy while excluding other sleep disorders.

Human leukocyte antigen (HLA) typing may provide collateral data, but it is more useful for excluding the diagnosis by documenting that the patient does not have either DQB1*0602 or DQA1*0602. HLA typing is less valuable for confirming the diagnosis, in that HLA-DR2 and DQw1 are present in 20-30% of the general population.

Measurement of hypocretin (orexin) levels in the cerebrospinal fluid (CSF) may help establish the diagnosis.^[18]CSF hypocretin levels lower than 110 pg/mL are included in the diagnostic criteria for narcolepsy in the second edition of the International Classification of Sleep Disorders (ICSD-2). On the other hand, high CSF hypocretin levels do not exclude the diagnosis of narcolepsy.

In most cases, imaging studies are unrevealing. A few small studies have implicated magnetic resonance imaging (MRI) changes of the pons within the reticular activating system. Imaging studies such as MRI are useful for excluding rare causes of symptomatic narcolepsy. Structural abnormalities of the brain stem and diencephalon may present as idiopathic narcolepsy. In patients with secondary narcolepsy, MRI of the brain may show various abnormalities that correspond to the underlying cause.

Sleep Studies

An overnight PSG followed by an MSLT can exclude other causes of excessive daytime sleepiness (EDS), especially sleep apnea, and can provide information about EDS by measuring sleep latency and sleep-onset rapid eye movement periods (SOREMPs). The overnight PSG findings typically are normal in narcolepsy, though they may show sleep fragmentation. All central nervous system (CNS) stimulants and sedative-hypnotics should be discontinued 2 weeks before the PSG and MSLT.

The MSLT involves 5 opportunities to nap at 2-hour intervals over the day. More than 2 SOREMPs and a mean sleep latency of less than 8 minutes strongly suggest narcolepsy. These findings are not completely specific and also can be seen in patients with severe sleep deprivation, delayed sleep phase disorder, or severe sleep apnea. For these reasons, a PSG of the previous night is necessary for interpretation of the MSLT; MSLT cannot be used alone to confirm or rule out narcolepsy.

Diagnosing narcolepsy in children presents numerous difficulties. One study found that 85% of children with narcolepsy also suffered from sleep-disordered breathing. Serial MSLTs may be required, and usually multiple confounding factors are involved (eg, increased alertness in the novel environment of the sleep laboratory). Furthermore, normative MSLT values for children have not been established.

Treatment & Management

Vendrame M, Havaligi N, Matadeen-Ali C, Adams R, Kothare SV. Narcolepsy in children: a single-center clinical experience. Pediatr Neurol. 2008 May. 38(5):314-20. [Medline].
Plazzi G, Serra L, Ferri R. Nocturnal aspects of narcolepsy with cataplexy. Sleep Med Rev. 2008 Apr. 12(2):109-28. [Medline].
Palaia V, Poli F, Pizza F, Antelmi E, Franceschini C, Moghadam KK, et al. Narcolepsy with cataplexy associated with nocturnal compulsive behaviors: a case-control study. Sleep. 2011 Oct 1. 34(10):1365-71. [Medline]. [Full Text].
Plazzi G, Pizza F, Palaia V, Franceschini C, Poli F, Moghadam KK, et al. Complex movement disorders at disease onset in childhood narcolepsy with cataplexy. Brain. 2011 Dec. 134:3480-92. [Medline]. [Full Text].
Rogers AE, Aldrich MS, Lin X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep. 2001 Jun 15. 24(4):385-91. [Medline].
Benbadis SR. Effective treatment of narcolepsy with codeine in a patient receiving hemodialysis. Pharmacotherapy. 1996 May-Jun. 16(3):463-5. [Medline].
Szakacs Z, Dauvilliers Y, Mikhaylov V, Poverennova I, Krylov S, Jankovic S, et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017 Mar. 16 (3):200-207. [Medline].
Wakix (pitolisant) [package insert]. Plymouth Meeting, PA: Harmony Biosciences, LLC. August, 2019. Available at [Full Text].
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013. 372-78.
American Academy of Sleep Medicine. The International Classification of Sleep Disorders-Revised: Diagnostic and Coding Manual. 3rd ed. Rochester, MN: American Academy of Sleep Medicine; 2014.
Ruoff C, Rye D. The ICSD-3 and DSM-5 guidelines for diagnosing narcolepsy: clinical relevance and practicality. Curr Med Res Opin. 2016 Jul 20. 1-12. [Medline].
American Academy of Sleep Medicine. International Classification of Sleep Disorders,. 2nd ed. Darien, IL: American Academy of Sleep Medicine.; 2005.
Naumann A, Daum I. Narcolepsy: Pathophysiology and neuropsychological changes. Behav Neurol. 2003. 14(3,4):89-98. [Medline].
Burgess CR, Scammell TE. Narcolepsy: neural mechanisms of sleepiness and cataplexy. J Neurosci. 2012 Sep 5. 32(36):12305-11. [Medline]. [Full Text].
Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999 Aug 6. 98(3):365-76. [Medline].
Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999 Aug 20. 98(4):437-51. [Medline].
Diniz Behn CG, Klerman EB, Mochizuki T, Lin SC, Scammell TE. Abnormal sleep/wake dynamics in orexin knockout mice. Sleep. 2010 Mar. 33(3):297-306. [Medline]. [Full Text].
Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002 Oct. 59(10):1553-62. [Medline].
Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, Hublin C, Linna M, Olsén P, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One. 2012. 7(3):e33723. [Medline]. [Full Text].
Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012. 7(3):e33536. [Medline]. [Full Text].
Abad VC, Guilleminault C. Review of rapid eye movement behavior sleep disorders. Curr Neurol Neurosci Rep. 2004 Mar. 4(2):157-63. [Medline].
Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002 Oct. 59(10):1553-62. [Medline].
Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000 Sep. 27(3):469-74. [Medline].
Thannickal TC, Nienhuis R, Siegel JM. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep. 2009 Aug 1. 32(8):993-8. [Medline]. [Full Text].
Blouin AM, Thannickal TC, Worley PF, Baraban JM, Reti IM, Siegel JM. Narp immunostaining of human hypocretin (orexin) neurons: loss in narcolepsy. Neurology. 2005 Oct 25. 65(8):1189-92. [Medline].
Nishino S, Sakurai E, Nevsimalova S, Yoshida Y, Watanabe T, Yanai K. Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls. Sleep. 2009 Feb 1. 32(2):175-80. [Medline]. [Full Text].
Kanbayashi T, Kodama T, Kondo H, Satoh S, Inoue Y, Chiba S. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep. 2009 Feb 1. 32(2):181-7. [Medline]. [Full Text].
Overeem S, Black JL 3rd, Lammers GJ. Narcolepsy: immunological aspects. Sleep Med Rev. 2008 Apr. 12(2):95-107. [Medline].
Cvetkovic-Lopes V, Bayer L, Dorsaz S, Maret S, Pradervand S, Dauvilliers Y, et al. Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. J Clin Invest. 2010 Mar. 120(3):713-9. [Medline]. [Full Text].
Dauvilliers Y, Abril B, Mas E, Michel F, Tafti M. Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment. Neurology. 2009 Oct 20. 73(16):1333-4. [Medline].
Knudsen S, Mikkelsen JD, Bang B, Gammeltoft S, Jennum PJ. Intravenous immunoglobulin treatment and screening for hypocretin neuron-specific autoantibodies in recent onset childhood narcolepsy with cataplexy. Neuropediatrics. 2010 Oct. 41(5):217-22. [Medline].
Sehgal A, Mignot E. Genetics of sleep and sleep disorders. Cell. 2011 Jul 22. 146(2):194-207. [Medline]. [Full Text].
Mignot E. Sleep, sleep disorders and hypocretin (orexin). Sleep Med. 2004 Jun. 5 Suppl 1:S2-8. [Medline].
Weiner Lachmi K, Lin L, Kornum BR, Rico T, Lo B, Aran A, et al. DQB1*06:02 allele-specific expression varies by allelic dosage, not narcolepsy status. Hum Immunol. 2012 Apr. 73(4):405-10. [Medline]. [Full Text].
Hor H, Kutalik Z, Dauvilliers Y, Valsesia A, Lammers GJ, Donjacour CE, et al. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat Genet. 2010 Sep. 42(9):786-9. [Medline].
Hallmayer J, Faraco J, Lin L, Hesselson S, Winkelmann J, Kawashima M, et al. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genet. 2009 Jun. 41(6):708-11. [Medline]. [Full Text].
Kornum BR, Kawashima M, Faraco J, Lin L, Rico TJ, Hesselson S, et al. Common variants in P2RY11 are associated with narcolepsy. Nat Genet. 2011 Jan. 43(1):66-71. [Medline]. [Full Text].
Shimada M, Miyagawa T, Kawashima M, Tanaka S, Honda Y, Honda M, et al. An approach based on a genome-wide association study reveals candidate loci for narcolepsy. Hum Genet. 2010 Oct. 128(4):433-41. [Medline].
Longstreth WT Jr, Koepsell TD, Ton TG, Hendrickson AF, van Belle G. The epidemiology of narcolepsy. Sleep. 2007 Jan 1. 30(1):13-26. [Medline].
Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep. 2002 Mar 15. 25(2):197-202. [Medline].
Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet. 2007 Feb 10. 369(9560):499-511. [Medline].
Doherty L, Crowe C, Sweeney B. National narcolepsy survey. Ir Med J. 2010 Apr. 103(4):110, 112-3. [Medline].
Douglas NJ. The psychosocial aspects of narcolepsy. Neurology. 1998 Feb. 50(2 Suppl 1):S27-30. [Medline].
Pakola SJ, Dinges DF, Pack AI. Review of regulations and guidelines for commercial and noncommercial drivers with sleep apnea and narcolepsy. Sleep. 1995 Nov. 18(9):787-96. [Medline].
Prasad M, Setty G, Ponnusamy A, Hussain N, Desurkar A. Cataplectic facies: clinical marker in the diagnosis of childhood narcolepsy-report of two cases. Pediatr Neurol. 2014 May. 50 (5):515-7. [Medline].
Guilleminault C, Pelayo R. Narcolepsy in prepubertal children. Ann Neurol. 1998 Jan. 43(1):135-42. [Medline].
Bassetti C, Aldrich MS, Quint DJ. MRI findings in narcolepsy. Sleep. 1997 Aug. 20(8):630-1. [Medline].
Melberg A, Hetta J, Dahl N, et al. Autosomal dominant cerebellar ataxia deafness and narcolepsy. J Neurol Sci. 1995 Dec. 134(1-2):119-29. [Medline].
Dauvilliers Y, Baumann CR, Carlander B, Bischof M, Blatter T, Lecendreux M, et al. CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry. 2003 Dec. 74(12):1667-73. [Medline].
Vossler DG, Wyler AR, Wilkus RJ, et al. Cataplexy and monoamine oxidase deficiency in Norrie disease. Neurology. 1996 May. 46(5):1258-61. [Medline].
Maeda M, Tamaoka A, Hayashi A, et al. [A case of HLA-DR2, DQw1 negative post-traumatic narcolepsy]. Rinsho Shinkeigaku. 1995 Jul. 35(7):811-3. [Medline].
Fry JM. Treatment modalities for narcolepsy. Neurology. 1998 Feb. 50(2 Suppl 1):S43-8. [Medline].
US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy. Neurology. 2000 Mar 14. 54(5):1166-75. [Medline].
Golicki D, Bala MM, Niewada M, Wierzbicka A. Modafinil for narcolepsy: systematic review and meta-analysis. Med Sci Monit. 2010 Aug. 16(8):RA177-86. [Medline].
The Nuvigil website. Available at http://www.nuvigil.com/. Accessed: 12/8/2009.
Thorpy MJ, Shapiro C, Mayer G, Corser BC, Emsellem H, Plazzi G, et al. A randomized study of solriamfetol for excessive sleepiness in narcolepsy. Ann Neurol. 2019 Mar. 85 (3):359-370. [Medline].
Xyrem Web site. Available at https://www.xyrem.com/.
Lockrane B, Bhatia P, Gore R. Successful treatment of narcolepsy and cataplexy: A review. Can Respir J. 2005 May-Jun. 12(4):225-7. [Medline].
Black J, Pardi D, Hornfeldt CS, Inhaber N. The nightly use of sodium oxybate is associated with a reduction in nocturnal sleep disruption: a double-blind, placebo-controlled study in patients with narcolepsy. J Clin Sleep Med. 2010 Dec 15. 6(6):596-602. [Medline]. [Full Text].
Vignatelli L, D'Alessandro R, Candelise L. Antidepressant drugs for narcolepsy. Cochrane Database Syst Rev. 2005 Jul 20. CD003724. [Medline].
[Guideline] Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep. 2007 Dec. 30(12):1705-11. [Medline]. [Full Text].
Spencer TJ, Madras BK, Bonab AA, Dougherty DD, Clarke A, Mirto T, et al. A positron emission tomography study examining the dopaminergic activity of armodafinil in adults using [¹¹C]altropane and [¹¹C]raclopride. Biol Psychiatry. 2010 Nov 15. 68(10):964-70. [Medline].

Media Gallery

of 0

Author

Sagarika Nallu, MD Assistant Professor, Pediatric Neurologist and Epileptologist, Adult and Pediatric Sleep Specialist, Department of Pediatrics, University of South Florida, Morsani College of Medicine

Sagarika Nallu, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Epilepsy Society, Child Neurology Society

Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Bioserenity (DigiTrace), Brain Sentinel, Cavion, Ceribell, Eisai, Greenwich, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion<br/>Serve(d) as a speaker or a member of a speakers bureau for: Bioserenity (DigiTrace), Brain Sentinel, Cavion, Ceribell, Eisai, Greenwich, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion<br/>Received research grant from: LivaNova, Greenwich, SK biopharmaceuticals, Takeda,.

Additional Contributors

Ali M Bozorg, MD Assistant Professor, Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida College of Medicine

Ali M Bozorg, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Academy of Sleep Medicine

Disclosure: Received honoraria from Cyberonics for speaking and teaching; Received honoraria from UCB, Inc. for speaking and teaching.

Dani J Thomas, DO Fellow in Sleep Medicine, University of South Florida College of Medicine

Dani J Thomas, DO is a member of the following medical societies: American Thoracic Society, Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Carmel Armon, MD, MSc, MHS Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center

Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Movement Disorders Society, and Sigma Xi

Disclosure: Nothing to disclose.

Matthew J Baker, MD Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital

Disclosure: Nothing to disclose.

Jose E Cavazos, MD, PhD, FAAN Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, University of Texas Health Science Center at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center; Director of the Epilepsy Center, Audie L Murphy Veterans Affairs Medical Center

Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American Neurological Association, and Society for Neuroscience

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

Narcolepsy Workup

Approach Considerations

Sleep Studies

About

Membership

Apps

WebMD Network

Editions

What to Read Next on Medscape

Narcolepsy Workup

Approach Considerations

Sleep Studies

References

Tables

Contributor Information and Disclosures

What would you like to print?

Find Us On

About

Membership

Apps

WebMD Network

Editions

What to Read Next on Medscape

Related Conditions and Diseases

Medscape Consult

News & Perspective

Tools

Slideshow

Most Popular Articles

Recommended