Sleep Disorders in Multiple Sclerosis

  • Tiffany J. Braley
  • Eilis Ann BoudreauEmail author
Demyelinating Disorders (DN Bourdette and M Cameron, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Demyelinating Disorders


Recent studies suggest that individuals with multiple sclerosis (MS) are at increased risk for sleep disturbances and that sleep disturbances contribute to fatigue and other chronic symptoms in MS. Although fatigue occurs commonly in people with MS, this symptom is often attributed to MS-specific pathology. Consequently, sleep disorders are often unrecognized and untreated in this population. Timely diagnosis and treatment of sleep problems in MS offer a new opportunity to ameliorate some of the daytime fatigue experienced by patients with MS. To increase this opportunity, the practitioner should be comfortable performing basic screening for common sleep complaints among patients with MS. The objectives of this review are to summarize the latest relevant data on sleep disorders in MS and offer a helpful approach to the identification and workup of the most common sleep problems in this population. Unexplored research avenues and opportunities to address important questions at the interface of sleep and MS are also discussed.


Obstructive sleep apnea Restless leg syndrome Insomnia Fatigue Multiple sclerosis 


Compliance with Ethical Standards

Conflict of Interest

Eilis Ann Boudreau declares no conflict of interest.

Tiffany J. Braley receives grant support from the National Multiple Sclerosis Society, the American Sleep Medicine Foundation, and the Michigan Translation and Commercialization (MTRAC) for Life Sciences Program to conduct her research. She is principal investigator on a clinical trial that receives material support, but no financial support, from Biogen. She is site principal investigator for several industry-funded studies of MS immunotherapeutics at the University of Michigan (sponsors include Genzyme-Sanofi and Genentech-Roche) but receives no direct compensation for any of this work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc. 2008;5:136–43.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Mai E, Buysse DJ. Insomnia: prevalence, impact, pathogenesis, differential diagnosis, and evaluation. Sleep Med Clin. 2008;3:167–74.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Winkelman JW, Finn L, Young T. Prevalence and correlates of restless legs syndrome symptoms in the Wisconsin Sleep Cohort. Sleep Med. 2006;7:545–52.CrossRefPubMedGoogle Scholar
  4. 4.
    Merlino G, Fratticci L, Lenchig C, Valente M, Cargnelutti D, Picello M, et al. Prevalence of ‘poor sleep’ among patients with multiple sclerosis: an independent predictor of mental and physical status. Sleep Med. 2009;10:26–34.CrossRefPubMedGoogle Scholar
  5. 5.•
    Braley TJ, Segal BM, Chervin RD. Obstructive sleep apnea and fatigue in patients with multiple sclerosis. J Clin Sleep Med. 2014;10:155–62. This study is of importance because it suggested that OSA is common in individuals with MS, especially when complaints of fatigue are present, and that OSA is under-recognized in this population.Google Scholar
  6. 6.
    Italian REMS Study Group, Manconi M, Ferini-Strambi L, Filippi M, Bonanni E, Iudice A, et al. Multicenter case–control study on restless legs syndrome in multiple sclerosis: the REMS study. Sleep. 2008;31:944–52.Google Scholar
  7. 7.
    Brass SD, Li CS, Auerbach S. The underdiagnosis of sleep disorders in patients with multiple sclerosis. J Clin Sleep Med. 2014;10:1025–31.PubMedPubMedCentralGoogle Scholar
  8. 8.••
    Veauthier C, Gaede G, Radbruch H, Gottschalk S, Wernecke KD, Paul F. Treatment of sleep disorders may improve fatigue in multiple sclerosis. Clin Neurol Neurosurg. 2013;115:1826–30. This study was of major importance because it demonstrated that treatment of sleep disorders in individuals with MS, could decrease fatigue, one of the most frequent and disabling symptoms associated with MS.Google Scholar
  9. 9.
    Young T, Shahar E, Nieto FJ, Redline S, Newman AB, Gottlieb DJ, et al. Predictors of sleep-disordered breathing in community-dwelling adults: the Sleep Heart Health Study. Arch Intern Med. 2002;162:893–900.CrossRefPubMedGoogle Scholar
  10. 10.
    Braley TJ, Segal BM, Chervin RD. Sleep-disordered breathing in multiple sclerosis. Neurology. 2012;79:929–36.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Brown DL, McDermott M, Mowla A, De Lott L, Morgenstern LB, Kerber KA, et al. Brainstem infarction and sleep-disordered breathing in the BASIC sleep apnea study. Sleep Med. 2014;15:887–91.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Losurdo A, Dittoni S, Testani E, Di Blasi C, Scarano E, Mariotti P, et al. Sleep disordered breathing in children and adolescents with Chiari malformation type I. J Clin Sleep Med. 2013;9:371–7.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Gabbay IE, Lavie P. Age- and gender-related characteristics of obstructive sleep apnea. Sleep Breath. 2012;16:453–60.CrossRefPubMedGoogle Scholar
  14. 14.
    Dewan NA, Nieto FJ, Somers VK. Intermittent hypoxemia and OSA: implications for comorbidities. Chest. 2015;147:266–74.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Peppard PE. Is obstructive sleep apnea a risk factor for hypertension?—differences between the Wisconsin Sleep Cohort and the Sleep Heart Health Study. J Clin Sleep Med. 2009;5:404–5.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Gottlieb DJ, Yenokyan G, Newman AB, O’Connor GT, Punjabi NM, Quan SF, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation. 2010;122:352–60.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;353:2034–41.CrossRefPubMedGoogle Scholar
  18. 18.
    Epstein LJ, Kristo D, Strollo Jr PJ, Friedman N, Malhotra A, Patil SP, et al. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009;5:263–76.PubMedGoogle Scholar
  19. 19.
    Ramar K, Dort LC, Katz SG, Lettieri CJ, Harrod CG, Thomas SM, et al. Clinical practice guideline for the treatment of obstructive sleep apnea and snoring with oral appliance therapy: an update for 2015. J Clin Sleep Med. 2015;11:773–827.PubMedPubMedCentralGoogle Scholar
  20. 20.
    American Academy of Sleep Medicine. International Classification of Sleep Disorders (ICSD-3): diagnostic and coding manual, 3rd ed. American Academy of Sleep Medicine, 2014.Google Scholar
  21. 21.
    Zaslavsky O, LaCroix AZ, Hale L, Tindle H, Shochat T. Longitudinal changes in insomnia status and incidence of physical, emotional, or mixed impairment in postmenopausal women participating in the Women’s Health Initiative (WHI) study. Sleep Med. 2015;16:364–71.CrossRefPubMedGoogle Scholar
  22. 22.
    Taylor DJ, Mallory LJ, Lichstein KL, Durrence HH, Riedel BW, Bush AJ. Comorbidity of chronic insomnia with medical problems. Sleep. 2007;30:213–8.PubMedGoogle Scholar
  23. 23.
    Hurwitz BJ, Jeffery D, Arnason B, Bigley K, Coyle P, Goodin D, et al. Tolerability and safety profile of 12- to 28-week treatment with interferon beta-1b 250 and 500 microg QOD in patients with relapsing-remitting multiple sclerosis: a multicenter, randomized, double-blind, parallel-group pilot study. Clin Ther. 2008;30:1102–12.CrossRefPubMedGoogle Scholar
  24. 24.
    Byerley WF, Reimherr FW, Wood DR, Grosser BI. Fluoxetine, a selective serotonin uptake inhibitor, for the treatment of outpatients with major depression. J Clin Psychopharmacol. 1988;8:112–5.CrossRefPubMedGoogle Scholar
  25. 25.
    Jankovic SM. Injectable interferon beta-1b for the treatment of relapsing forms of multiple sclerosis. J Inflamm Res. 2010;3:25–31.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mendozzi L, Tronci F, Garegnani M, Pugnetti L. Sleep disturbance and fatigue in mild relapsing remitting multiple sclerosis patients on chronic immunomodulant therapy: an actigraphic study. Mult Scler. 2010;16:238–47.CrossRefPubMedGoogle Scholar
  27. 27.
    Edinger JD, Wohlgemuth WK, Radtke RA, Marsh GR, Quillian RE. Cognitive behavioral therapy for treatment of chronic primary insomnia: a randomized controlled trial. JAMA. 2001;285:1856–64.CrossRefPubMedGoogle Scholar
  28. 28.
    Morin CM, Vallieres A, Guay B, Ivers H, Savard J, Merette C, et al. Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial. JAMA. 2009;301:2005–15.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Pigeon WR, Bishop TM, Marcus JA. Advances in the management of insomnia. F1000Prime Rep 2014;6:48,48. eCollection 2014.Google Scholar
  30. 30.
    Rothdach AJ, Trenkwalder C, Haberstock J, Keil U, Berger K. Prevalence and risk factors of RLS in an elderly population: the MEMO study. Memory and Morbidity in Augsburg Elderly. Neurology. 2000;54:1064–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Li Y, Munger KL, Batool-Anwar S, De Vito K, Ascherio A, Gao X. Association of multiple sclerosis with restless legs syndrome and other sleep disorders in women. Neurology. 2012;78:1500–6.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Auger C, Montplaisir J, Duquette P. Increased frequency of restless legs syndrome in a French-Canadian population with multiple sclerosis. Neurology. 2005;65:1652–3.CrossRefPubMedGoogle Scholar
  33. 33.
    Lutz EG. Restless legs, anxiety and caffeinism. J Clin Psychiatry. 1978;39:693–8.PubMedGoogle Scholar
  34. 34.
    Aldrich MS, Shipley JE. Alcohol use and periodic limb movements of sleep. Alcohol Clin Exp Res. 1993;17:192–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. J Psychosom Res. 2002;53:547–54.CrossRefPubMedGoogle Scholar
  36. 36.
    Pigeon WR, Yurcheshen M. Behavioral sleep medicine interventions for restless legs syndrome and periodic limb movement disorder. Sleep Med Clin. 2009;4:487–94.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Hoque R, Chesson Jr AL. Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: literature review, qualitative scoring, and comparative analysis. J Clin Sleep Med. 2010;6:79–83.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Littner MR, Kushida C, Anderson WM, Bailey D, Berry RB, Hirshkowitz M, et al. Practice parameters for the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 2004;27:557–9.PubMedGoogle Scholar
  39. 39.
    Wilt TJ, MacDonald R, Ouellette J, Khawaja IS, Rutks I, Butler M, et al. Pharmacologic therapy for primary restless legs syndrome: a systematic review and meta-analysis. JAMA Int Med. 2013;173:496–505.CrossRefGoogle Scholar
  40. 40.
    Allen RP, Chen C, Garcia-Borreguero D, Polo O, DuBrava S, Miceli J, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med. 2014;370:621–31.CrossRefPubMedGoogle Scholar
  41. 41.
    Krupp L. Fatigue is intrinsic to multiple sclerosis (MS) and is the most commonly reported symptom of the disease. Mult Scler. 2006;12:367–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC. Fatigue in multiple sclerosis. Arch Neurol. 1988;45:435–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Lerdal A, Celius EG, Krupp L, Dahl AA. A prospective study of patterns of fatigue in multiple sclerosis. Eur J Neurol. 2007;14:1338–43.CrossRefPubMedGoogle Scholar
  44. 44.
    Janardhan V, Bakshi R. Quality of life in patients with multiple sclerosis: the impact of fatigue and depression. J Neurol Sci. 2002;205:51–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Roelcke U, Kappos L, Lechner-Scott J, Brunnschweiler H, Huber S, Ammann W, et al. Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18F-fluorodeoxyglucose positron emission tomography study. Neurology. 1997;48:1566–71.CrossRefPubMedGoogle Scholar
  46. 46.
    Flachenecker P, Bihler I, Weber F, Gottschalk M, Toyka KV, Rieckmann P. Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Mult Scler. 2004;10:165–9.CrossRefPubMedGoogle Scholar
  47. 47.
    Tartaglia MC, Narayanan S, Francis SJ, Santos AC, De Stefano N, Lapierre Y, et al. The relationship between diffuse axonal damage and fatigue in multiple sclerosis. Arch Neurol. 2004;61:201–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Veauthier C, Radbruch H, Gaede G, Pfueller CF, Dorr J, Bellmann-Strobl J, et al. Fatigue in multiple sclerosis is closely related to sleep disorders: a polysomnographic cross-sectional study. Mult Scler. 2011;17:613–22.CrossRefPubMedGoogle Scholar
  49. 49.
    Kaminska M, Kimoff R, Benedetti A, Robinson A, Bar-Or A, Lapierre Y, et al. Obstructive sleep apnea is associated with fatigue in multiple sclerosis. Mult Scler. 2012;18:1159–69.CrossRefPubMedGoogle Scholar
  50. 50.••
    Cote I, Trojan DA, Kaminska M, Cardoso M, Benedetti A, Weiss D, et al. Impact of sleep disorder treatment on fatigue in multiple sclerosis. Mult Scler. 2013;19:480–9. This study was of significant importance because the authors demonstrated that the standard treatment of obstructive sleep apnea in patients with MS resulted in improvement in their symptoms of fatigue and sleep quality. Because symptoms of fatigue are so common in patients with MS, this study supports the screening for and treating sleep apnea in this population.Google Scholar
  51. 51.
    Braley TJ, Segal BM, Chervin RD. Hypnotic use and fatigue in multiple sclerosis. Sleep Med. 2015;16:131–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Neau JP, Paquereau J, Auche V, Mathis S, Godeneche G, Ciron J, et al. Sleep disorders and multiple sclerosis: a clinical and polysomnography study. Eur Neurol. 2012;68:8–15.CrossRefPubMedGoogle Scholar
  53. 53.
    Trojan DA, Kaminska M, Bar-Or A, Benedetti A, Lapierre Y, Da Costa D, et al. Polysomnographic measures of disturbed sleep are associated with reduced quality of life in multiple sclerosis. J Neurol Sci. 2012;316:158–63.CrossRefPubMedGoogle Scholar
  54. 54.
    Boe Lunde HM, Aae TF, Indrevag W, Aarseth J, Bjorvatn B, Myhr KM, et al. Poor sleep in patients with multiple sclerosis. PLoS One. 2012;7, e49996.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Amtmann D, Askew RL, Kim J, Chung H, Ehde DM, Bombardier CH, et al. Pain affects depression through anxiety, fatigue, and sleep in multiple sclerosis. Rehabil Psychol. 2015;60:81–90.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Braley TJ, Kratz AL, Kaplish N, Chervin RD. Cognitive dysfunction in multiple sclerosis is associated with obstructive sleep apnea. Assoc Profess Sleep Soc, SLEEP, 2014.Google Scholar
  57. 57.
    Braley TJ, Kratz AL. Polysomnographic predictors of visuospatial functioning in multiple sclerosis. Assoc Profess Sleep Societies, SLEEP, 2015.Google Scholar
  58. 58.
    Chung F, Subramanyam R, Liao P, Sasaki E, Shapiro C, Sun Y. High STOP-Bang score indicates a high probability of obstructive sleep apnoea. Br J Anaesth. 2012;108:768–75.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Buysse DJ. Reynolds CF,3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28:193–213.CrossRefPubMedGoogle Scholar
  60. 60.
    Ferri R, Lanuzza B, Cosentino FI, Iero I, Tripodi M, Spada RS, et al. A single question for the rapid screening of restless legs syndrome in the neurological clinical practice. Eur J Neurol. 2007;14:1016–21.CrossRefPubMedGoogle Scholar
  61. 61.
    Benes H, Kohnen R. Validation of an algorithm for the diagnosis of restless legs syndrome: the Restless Legs Syndrome-Diagnostic Index (RLS-DI). Sleep Med. 2009;10:515–23.CrossRefPubMedGoogle Scholar
  62. 62.
    Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003;4:121–32.CrossRefPubMedGoogle Scholar
  63. 63.
    Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46:1121–3.CrossRefPubMedGoogle Scholar
  64. 64.
    Fisk JD, Ritvo PG, Ross L, Haase DA, Marrie TJ, Schlech WF. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. 1994;18 Suppl 1:S79–83.CrossRefPubMedGoogle Scholar
  65. 65.
    Tellez N, Rio J, Tintore M, Nos C, Galan I, Montalban X. Does the Modified Fatigue Impact Scale offer a more comprehensive assessment of fatigue in MS? Mult Scler. 2005;11:198–202.CrossRefPubMedGoogle Scholar
  66. 66.
    Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14:540–5.PubMedGoogle Scholar
  67. 67.
    Hedstrom AK, Akerstedt T, Hillert J, Olsson T, Alfredsson L. Shift work at young age is associated with increased risk for multiple sclerosis. Ann Neurol. 2011;70:733–41.CrossRefPubMedGoogle Scholar
  68. 68.
    Archibald CJ, McGrath PJ, Ritvo PG, Fisk JD, Bhan V, Maxner CE, et al. Pain prevalence, severity and impact in a clinic sample of multiple sclerosis patients. Pain. 1994;58:89–93.CrossRefPubMedGoogle Scholar
  69. 69.
    Ehde DM, Osborne TL, Hanley MA, Jensen MP, Kraft GH. The scope and nature of pain in persons with multiple sclerosis. Mult Scler. 2006;12:629–38.CrossRefPubMedGoogle Scholar
  70. 70.
    Stanton BR, Barnes F, Silber E. Sleep and fatigue in multiple sclerosis. Mult Scler. 2006;12:481–6.CrossRefPubMedGoogle Scholar
  71. 71.
    Newland PK, Naismith RT, Ullione M. The impact of pain and other symptoms on quality of life in women with relapsing-remitting multiple sclerosis. J Neurosci Nurs. 2009;41:322–8.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Finan PH, Goodin BR, Smith MT. The association of sleep and pain: an update and a path forward. J Pain. 2013;14:1539–52.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Ehde DM, Gibbons LE, Chwastiak L, Bombardier CH, Sullivan MD, Kraft GH. Chronic pain in a large community sample of persons with multiple sclerosis. Mult Scler. 2003;9:605–11.CrossRefPubMedGoogle Scholar
  74. 74.
    O’Connor AB, Schwid SR, Herrmann DN, Markman JD, Dworkin RH. Pain associated with multiple sclerosis: systematic review and proposed classification. Pain. 2008;137:96–111.CrossRefPubMedGoogle Scholar
  75. 75.
    Buysse DJ, Yu L, Moul DE, Germain A, Stover A, Dodds NE, et al. Development and validation of patient-reported outcome measures for sleep disturbance and sleep-related impairments. Sleep. 2010;33:781–92.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Martin JL, Hakim AD. Wrist actigraphy. Chest. 2011;139:1514–27.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Mullaney DJ, Kripke DF, Messin S. Wrist-actigraphic estimation of sleep time. Sleep. 1980;3:83–92.PubMedGoogle Scholar
  78. 78.
    Jean-Louis G, Kripke DF, Cole RJ, Assmus JD, Langer RD. Sleep detection with an accelerometer actigraph: comparisons with polysomnography. Physiol Behav. 2001;72:21–8.CrossRefPubMedGoogle Scholar
  79. 79.
    Buysse DJ, Ancoli-Israel S, Edinger JD, Lichstein KL, Morin CM. Recommendations for a standard research assessment of insomnia. Sleep. 2006;29:1155–73.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2016

Authors and Affiliations

  1. 1.University of Michigan Department of Neurology, Multiple Sclerosis and Sleep Disorders CentersAnn ArborUSA
  2. 2.Department of NeurologyOregon Health & Science UniversityPortlandUSA
  3. 3.Department of Medical Informatics and Clinical EpidemiologyOregon Health & Science UniversityPortlandUSA
  4. 4.Portland VA Medical CenterPortlandUSA

Personalised recommendations