Narcolepsy Differential Diagnoses

Sections

Narcolepsy

DDx

Diagnostic Considerations

Idiopathic hypersomnia is similar in presentation to narcolepsy, but patients with this condition have no sleep-onset rapid eye movement (REM) period, and naps are unrefreshing.^[49]In addition, idiopathic hypersomnia is not associated with cataplexy. Idiopathic hypersomnia can be difficult to distinguish from narcolepsy, though the advent of the modern sleep laboratory has aided in diagnosing these challenging cases.

Differentiation of these two disorders can provide valuable insight for therapy. Although amphetamines are used for treatment of both idiopathic hypersomnia and narcolepsy, the excessive daytime sleepiness (EDS) in patients with idiopathic hypersomnia is often resistant to stimulant treatments. In addition, sodium oxybate, which is very costly, is not approved for use in idiopathic hypersomnia.

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

Prader-Willi syndrome
Kasabach-Merritt syndrome
Syndrome of autosomal dominant cerebellar ataxia, deafness, and narcolepsy^[50]
Delayed sleep-phase syndrome
Autism
Depression
Diencephalic lesions
Drug abuse
Insufficient sleep syndrome
Kleine-Levin syndrome^[51]
Medication effect
Norrie disease^[52]
Poor sleep hygiene
Posttraumatic narcolepsy^[53]
Increased intracranial pressure
Conversion disorder, factitious disorder, and malingering

Differential Diagnoses

Workup

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. [QxMD MEDLINE Link].
Plazzi G, Serra L, Ferri R. Nocturnal aspects of narcolepsy with cataplexy. Sleep Med Rev. 2008 Apr. 12(2):109-28. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link].
Benbadis SR. Effective treatment of narcolepsy with codeine in a patient receiving hemodialysis. Pharmacotherapy. 1996 May-Jun. 16(3):463-5. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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, Text Revision. Washington, DC: American Psychiatric Association; 2022.
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Burgess CR, Scammell TE. Narcolepsy: neural mechanisms of sleepiness and cataplexy. J Neurosci. 2012 Sep 5. 32(36):12305-11. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link]. [Full Text].
Abad VC, Guilleminault C. Review of rapid eye movement behavior sleep disorders. Curr Neurol Neurosci Rep. 2004 Mar. 4(2):157-63. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Thannickal TC, Nienhuis R, Siegel JM. Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy. Sleep. 2009 Aug 1. 32(8):993-8. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link]. [Full Text].
Overeem S, Black JL 3rd, Lammers GJ. Narcolepsy: immunological aspects. Sleep Med Rev. 2008 Apr. 12(2):95-107. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Sehgal A, Mignot E. Genetics of sleep and sleep disorders. Cell. 2011 Jul 22. 146(2):194-207. [QxMD MEDLINE Link]. [Full Text].
Mignot E. Sleep, sleep disorders and hypocretin (orexin). Sleep Med. 2004 Jun. 5 Suppl 1:S2-8. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link]. [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. [QxMD MEDLINE Link].
Longstreth WT Jr, Koepsell TD, Ton TG, Hendrickson AF, van Belle G. The epidemiology of narcolepsy. Sleep. 2007 Jan 1. 30(1):13-26. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet. 2007 Feb 10. 369(9560):499-511. [QxMD MEDLINE Link].
Doherty L, Crowe C, Sweeney B. National narcolepsy survey. Ir Med J. 2010 Apr. 103(4):110, 112-3. [QxMD MEDLINE Link].
Douglas NJ. The psychosocial aspects of narcolepsy. Neurology. 1998 Feb. 50(2 Suppl 1):S27-30. [QxMD MEDLINE Link].
Godbout R, Montplaisir J. All-day performance variations in normal and narcoleptic subjects. Sleep. 1986. 9 (1 Pt 2):200-4. [QxMD MEDLINE Link].
McCall CA, Watson NF. Therapeutic Strategies for Mitigating Driving Risk in Patients with Narcolepsy. Ther Clin Risk Manag. 2020. 16:1099-1108. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Guilleminault C, Pelayo R. Narcolepsy in prepubertal children. Ann Neurol. 1998 Jan. 43(1):135-42. [QxMD MEDLINE Link].
Bassetti C, Aldrich MS, Quint DJ. MRI findings in narcolepsy. Sleep. 1997 Aug. 20(8):630-1. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Vossler DG, Wyler AR, Wilkus RJ, et al. Cataplexy and monoamine oxidase deficiency in Norrie disease. Neurology. 1996 May. 46(5):1258-61. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
Fry JM. Treatment modalities for narcolepsy. Neurology. 1998 Feb. 50(2 Suppl 1):S43-8. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link]. [Full Text].
Xywav [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc. July 2020. Available at [Full Text].
Dauvilliers Y, Lecendreux M, Lammers GJ, Franco P, Poluektov M, Caussé C, et al. Safety and efficacy of pitolisant in children aged 6 years or older with narcolepsy with or without cataplexy: a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2023 Apr. 22 (4):303-311. [QxMD MEDLINE Link].
Vignatelli L, D'Alessandro R, Candelise L. Antidepressant drugs for narcolepsy. Cochrane Database Syst Rev. 2005 Jul 20. CD003724. [QxMD MEDLINE Link].
[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. [QxMD MEDLINE Link]. [Full Text].
Maski K, Trotti LM, Kotagal S, Robert Auger R, Rowley JA, Hashmi SD, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021 Sep 1. 17 (9):1881-1893. [QxMD MEDLINE Link].
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. [QxMD MEDLINE Link].

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, Catalyst, Ceribell, Eisai, Jazz, LivaNova, Neurelis, Neuropace, SK Life Science Science, Sunovion, Takeda, UCB<br/>Serve(d) as a speaker or a member of a speakers bureau for: Catalyst, Jazz, LivaNova, Neurelis, SK Life Science, Stratus, UCB<br/>Received research grant from: Cerevel Therapeutics; Ovid Therapeutics; Neuropace; Jazz; SK Life Science, Xenon Pharmaceuticals, UCB, Marinus, Longboard.

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 Differential Diagnoses

Diagnostic Considerations

Differential Diagnoses

References

Tables

Contributor Information and Disclosures

What would you like to print?