Purpose of Review
The present review summarizes recent research on the association between sleep disturbance and cognitive dysfunction in MS. Assessment methodology, domain-specific associations between sleep disturbance and cognitive dysfunction, and implications for future research and treatment are discussed.
All 12 studies included in this review found significant associations between sleep disturbance and cognitive dysfunction; however, results varied considerably depending on the assessment method used and the cognitive domain assessed. Self-reported sleep disturbance generally predicted self-report but not objective measures of cognitive dysfunction. Objective sleep measures (e.g., polysomnography, actigraphy) generally predicted objective impairments in processing speed and attention; however, objective sleep disturbance was more variable in predicting performance in other cognitive domains (e.g., memory, executive function).
Sleep disturbance may help predict future cognitive decline in MS. Results highlight the need to integrate sleep assessment into routine MS care. Interventions aimed treating sleep disturbance may offer promise for improving cognitive dysfunction in MS.
This is a preview of subscription content,to check access.
Access this article
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Pugliatti M, Sotgiu S, Rosati G. The worldwide prevalence of multiple sclerosis. Clin Neurol Neurosurg. 2002;104(3):182–91. https://doi.org/10.1016/S0303-8467(02)00036-7.
Poser S, Raun N, Poser W. Age at onset, initial symptomatology and the course of multiple sclerosis. Acta Neurol Scand. 1982;66(3):355–62.
Amato M, Ponziani G, Rossi F, Liedl C, Stefanile C, Rossi L. Quality of life in multiple sclerosis: the impact of depression, fatigue and disability. Mult Scler. 2001;7(5):340–4. https://doi.org/10.1177/135245850100700511.
Jongen PJ, Ter Horst AT, Brands AM. Cognitive impairment in multiple sclerosis. Minerva Med. 2012;103(2):73–96.
Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol. 2008;7(12):1139–51. https://doi.org/10.1016/S1474-4422(08)70259-X.
Archibald CJ, Fisk JD. Information processing efficiency in patients with multiple sclerosis. J Clin Exp Neuropsychol. 2000;22(5):686–701. https://doi.org/10.1076/1380-3395(200010)22:5;1-9;ft686.
Bergendal G, Martola J, Stawiarz L, Kristoffersen-Wiberg M, Fredrikson S, Almkvist O. Callosal atrophy in multiple sclerosis is related to cognitive speed. Acta Neurol Scand. 2013;127(4):281–9. https://doi.org/10.1111/ane.12006.
Bergsland N, Zivadinov R, Dwyer MG, Weinstock-Guttman B, Benedict RH. Localized atrophy of the thalamus and slowed cognitive processing speed in MS patients. Mult Scler. 2016;22(10):1327–36. https://doi.org/10.1177/1352458515616204.
Demaree HA, DeLuca J, Gaudino EA, Diamond BJ. Speed of information processing as a key deficit in multiple sclerosis: implications for rehabilitation. J Neurol Neurosurg Psychiatry. 1999;67(5):661–3. https://doi.org/10.1136/jnnp.67.5.661.
Benedict RB, Weinstock-Guttman B, Fishman I, Sharma J, Tjoa CW, Bakshi R. Prediction of neuropsychological impairment in multiple sclerosis: comparison of conventional magnetic resonance imaging measures of atrophy and lesion burden. Arch Neurol. 2004;61(2):226–30. https://doi.org/10.1001/archneur.61.2.226.
Calabrese M, Agosta F, Rinaldi F, Mattisi I, Grossi P, Favaretto A, et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch Neurol. 2009;66(9):1144–50. https://doi.org/10.1001/archneurol.2009.174.
Rovaris M, Comi G, Filippi M. MRI markers of destructive pathology in multiple sclerosis-related cognitive dysfunction. J Neurol Sci. 2006;245(1–2):111–6. https://doi.org/10.1016/j.jns.2005.07.014.
Sanfilipo MP, Benedict RH, Weinstock-Guttman B, Bakshi R. Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis. Neurology. 2006;66(5):685–92. https://doi.org/10.1212/01.wnl.0000201238.93586.d9.
Benedict RH, Cookfair D, Gavett R, Gunther M, Munschauer F, Garg N, et al. Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). J Int Neuropsychol Soc. 2006;12(04):549–58.
Benedict RH, Amato MP, Boringa J, Brochet B, Foley F, Fredrikson S, et al. Brief International Cognitive Assessment for MS (BICAMS): international standards for validation. BMC Neurol. 2012;12(1):55. https://doi.org/10.1186/1471-2377-12-55.
Krupp LB, Christodoulou C, Melville P, Scherl WF, Pai LY, Muenz LR, et al. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology. 2011;76(17):1500–7. https://doi.org/10.1212/WNL.0b013e318218107a.
Shaygannejad V, Janghorbani M, Ashtari F, Zanjani HA, Zakizade N. Effects of rivastigmine on memory and cognition in multiple sclerosis. Can J Neurol Sci. 2008;35(4):476–81. https://doi.org/10.1017/S0317167100009148.
Goverover Y, Chiaravalloti ND, O’Brien A, DeLuca J. Evidenced based cognitive rehabilitation for persons with multiple sclerosis: an updated review of the literature from 2007-2016. Arch Phys Med Rehabil. https://doi.org/10.1016/j.apmr.2017.07.021.
Burke SL, Maramaldi P, Cadet T, Kukull W. Associations between depression, sleep disturbance, and apolipoprotein E in the development of Alzheimer’s disease: dementia. Int Psychogeriatr. 2016;28(9):1409–24. https://doi.org/10.1017/S1041610216000405.
Gunn DG, Naismith SL, Bolitho SJ, Lewis SJ. Actigraphically-defined sleep disturbance in Parkinson’s disease is associated with differential aspects of cognitive functioning. J Clin Neurosci. 2014;21(7):1112–5. https://doi.org/10.1016/j.jocn.2013.09.017.
• Bamer A, Johnson K, Amtmann D, Kraft G. Prevalence of sleep problems in individuals with multiple sclerosis. Mult Scler. 2008;14(8):1127–30. This study was among the first to characterize sleep disturbance in MS, determine an estimated prevalence (50%), and examine clinical correlates in a large cohort of community-dwelling individuals with MS. https://doi.org/10.1177/1352458508092807.
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(11):e49996. https://doi.org/10.1371/journal.pone.0049996.
Brass SD, Duquette P, Proulx-Therrien J, Auerbach S. Sleep disorders in patients with multiple sclerosis. Sleep Med Rev. 2010;14(2):121–9. https://doi.org/10.1016/j.smrv.2009.07.005.
Caminero A, Bartolomé M. Sleep disturbances in multiple sclerosis. J Neurol Sci. 2011;309(1):86–91. https://doi.org/10.1016/j.jns.2011.07.015.
Barun B. Pathophysiological background and clinical characteristics of sleep disorders in multiple sclerosis. Clin Neurol Neurosurg. 2013;115(Suppl 1):S82–5. https://doi.org/10.1016/j.clineuro.2013.09.028.
Melamud L, Golan D, Luboshitzky R, Lavi I, Miller A. Melatonin dysregulation, sleep disturbances and fatigue in multiple sclerosis. J Neurol Sci. 2012;314(1–2):37–40. https://doi.org/10.1016/j.jns.2011.11.003.
• Braley TJ, Segal BM, Chervin RD. Obstructive sleep apnea and fatigue in patients with multiple sclerosis. J Clin Sleep Med. 2014;10(2):155–62. https://doi.org/10.5664/jcsm.3442. This study was among the first to estimate the prevalence of sleep apnea and idenify a sleep apnea screening tool (STOP-BANG) as a primary contributor to self-reported fatigue.
Brass SD, Li CS, Auerbach S. The underdiagnosis of sleep disorders in patients with multiple sclerosis. J Clin Sleep Med. 2014;10(9):1025–31. https://doi.org/10.5664/jcsm.4044.
Veauthier C. Sleep disorders in multiple sclerosis. Review. Curr Neurol Neurosci Rep. 2015;15(5):21. https://doi.org/10.1007/s11910-015-0546-0.
• Stanton BR, Barnes F, Silber E. Sleep and fatigue in multiple sclerosis. Mult Scler. 2006;12(4):481–6. https://doi.org/10.1191/135248506ms1320oa. This study was among the first to distinguish sleep-onset, middle, and terminal insomnia characteristics in a sample of MS patients. Specific MS symptom contributions to sleep disturbance (e.g., nocturia) were explored as well as which types of insomnia best predict daytime fatigue (middle insomnia).
• Strober LB, Arnett PA. An examination of four models predicting fatigue in multiple sclerosis. Arch Clin Neuropsychol. 2005;20(5):631–46. https://doi.org/10.1016/j.acn.2005.04.002. This study identified sleep and depression as independent and bi-directional mediators of fatigue in MS.
Bakshi R. Fatigue associated with multiple sclerosis: diagnosis, impact and management. Mult Scler. 2003;9(3):219–27. https://doi.org/10.1191/1352458503ms904oa.
Bamer AM, Johnson KL, Amtmann DA, Kraft GH. Beyond fatigue: assessing variables associated with sleep problems and use of sleep medications in multiple sclerosis. Clin Epidemiol. 2010;2010(2):99–106. https://doi.org/10.2147/clep.s10425.
Ben Ari Shevil E, Johansson S, Ytterberg C, Bergstrom J, von Koch L. How are cognitive impairment, fatigue and signs of depression related to participation in daily life among persons with multiple sclerosis? Disabil Rehabil. 2014;36(23):2012–8. https://doi.org/10.3109/09638288.2014.887797.
Thelen JM, Lynch SG, Bruce AS, Hancock LM, Bruce JM. Polypharmacy in multiple sclerosis: relationship with fatigue, perceived cognition, and objective cognitive performance. J Psychosom Res. 2014;76(5):400–4. https://doi.org/10.1016/j.jpsychores.2014.02.013.
Clancy M, Drerup M, Sullivan AB. Outcomes of cognitive-behavioral treatment for insomnia on insomnia, depression, and fatigue for individuals with multiple sclerosis: a case series. Int J MS Care. 2015;17(6):261–7. https://doi.org/10.7224/1537-2073.2014-071.
Majendie CMA, Dysch L, Carrigan N. Cognitive behavioral therapy for insomnia (CBT-I) for an adult with multiple sclerosis. Clin Case Stud. 2016;16(2):115–31. https://doi.org/10.1177/1534650116674594.
•• Aldughmi M, Huisinga J, Lynch SG, Siengsukon CF. The relationship between fatigability and sleep quality in people with multiple sclerosis. Mult Scler J. 2016;2:10.1177/2055217316682774. This study identified depression as a significant mediator in the relationship between sleep and cognitive dysfunction.
•• Braley TJ, Kratz AL, Kaplish N, Chervin RD. Sleep and cognitive function in multiple sclerosis. Sleep. 2016;39(8):1525–33. https://doi.org/10.5665/sleep.6012. This study is among the few studies to date to use objective sleep measures (polysomnography) to examine sleep distubance in MS. Results support that both sleep apnea and total sleep time are significant contributors to diminished attention and processing speed in MS.
•• Hare CJ, Crangle CJ, Carney CE, Hart TL. Insomnia symptoms, subjective appraisals, and fatigue: a multiple mediation model. Behav Sleep Med. 2017:1–12. https://doi.org/10.1080/15402002.2017.1342167. This study examined potential mediators of the relationship between insomnia and cognitive fatigue. Catastrophic thinking, but not rumination, about fatigue mediated this relationship.
•• AEW H, Bol Y, Lobbestael J, Hupperts R, van Heugten CM. Mindfulness-based cognitive therapy for severely fatigued multiple sclerosis patients: a waiting list controlled study. J Rehabil Med. 2017;49(6):497–504. https://doi.org/10.2340/16501977-2237. An intervention designed to address negative reactions to fatigue had positive effects on self-reported fatigue but no effects on sleep.
•• Hughes AJ, Parmenter BA, Haselkorn JK, Lovera JF, Bourdette D, Boudreau E, et al. Sleep and its associations with perceived and objective cognitive impairment in individuals with multiple sclerosis. J Sleep Res. 2017;26(4):428–35. https://doi.org/10.1111/jsr.12490. This study demonstrated that self-reported measures of sleep correlate moderately with self-reported but not objective cognitive function. The study included only individuals with congitive impairment.
•• Hughes AJ, Turner AP, Alschuler KN, Atkins DC, Beier M, Amtmann D, et al. Association between sleep problems and perceived cognitive dysfunction over 12 months in individuals with multiple sclerosis. Behav Sleep Med. 2016;16(1):1–13. https://doi.org/10.1080/15402002.2016.1173553. This was the only study to examine longitudinal relationships between sleep and cognitive dysfunction. Associations between sleep and cognitive dysfunction were mediated by fatigue.
•• Lehmann P, Eling P, Kastrup A, Grothues O, Hildebrandt H. Self-reported sleep problems, but not fatigue, lead to decline in sustained attention in MS patients. Mult Scler. 2013;19(4):490–7. https://doi.org/10.1177/1352458512457719. This study used a novel sustained attentional task and demonstrated a relationship between self-reported poor sleep and performance on the task.
•• Patel VP, Walker LA, Feinstein A. Processing speed and distractibility in multiple sclerosis: the role of sleep. Mult Scler Relat Disord. 2017;11:40–2. https://doi.org/10.1016/j.msard.2016.11.012. Adding a distractor task to the SDMT effectively differentiated people with and without excessive daytime sleepiness, suggesting that executive dysfunction, rather than processing speed, is more related to daytime sleepiness.
•• Sater R, Gudesblatt M, Kresa-Reahl K, Brandes D, Sater P. The relationship between objective parameters of sleep and measures of fatigue, depression, and cognition in multiple sclerosis. MSJ-ETC. 2015;1:205521731557782. https://doi.org/10.1177/2055217315577828. In addition to Braley et al. 2016, this was one of the few studies to incorporate objective sleep assessment. This study also used a novel computerized cognitive tests, for which performance correlated with SE%, SOL, and WASO.
•• Shahrbanian S, Duquette P, Kuspinar A, Mayo NE. Contribution of symptom clusters to multiple sclerosis consequences. Qual Life Res. 2015;24(3):617–29. https://doi.org/10.1007/s11136-014-0804-7. This study demonstrated associations between self-reported sleep disturbance and general perceived cognitive dysfunction in a diverse sample of individuals with MS and clinically isolated syndrome.
•• Siengsukon CF, Aldughmi M, Kahya M, Lynch S, Bruce J, Glusman M, et al. Individuals with mild MS with poor sleep quality have impaired visuospatial memory and lower perceived functional abilities. Disabil Health J. 2017;11(1):116–21. https://doi.org/10.1016/j.dhjo.2017.04.011. Self-reported poor sleep quality was associated with objective visuospatial but not verbal memory.
•• van Geest Q, Westerik B, van der Werf YD, Geurts JJ, Hulst HE. The role of sleep on cognition and functional connectivity in patients with multiple sclerosis. J Neurol. 2017;264(1):72–80. https://doi.org/10.1007/s00415-016-8318-6. This study featured Dutch versions of tests commonly used to assess cognitive function in MS. Results were consistent with other studies in the review that subjective measures of sleep more strongly correlated with subjective than objective cognitive dysfunction.
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(2):193–213. https://doi.org/10.1016/0165-1781(89)90047-4.
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540–5. https://doi.org/10.1093/sleep/14.6.540.
Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001;2(4):297–307. https://doi.org/10.1016/S1389-9457(00)00065-4.
Hays RD, Martin SA, Sesti AM, Spritzer KL. Psychometric properties of the medical outcomes study sleep measure. Sleep Med. 2005;6(1):41–4. https://doi.org/10.1016/j.sleep.2004.07.006.
Derogatis LR, Lipman R, Covi L. SCL-90. Administration, scoring and procedures manual-I for the R (revised) version and other instruments of the Psychopathology Rating Scales Series Chicago: Johns Hopkins University School of Medicine; 1977.
Soldatos CR, Dikeos DG, Paparrigopoulos TJ. Athens Insomnia Scale: validation of an instrument based on ICD-10 criteria. J Psychosom Res. 2000;48(6):555–60. https://doi.org/10.1016/S0022-3999(00)00095-7.
Vickrey BG. Multiple sclerosis quality of life (MSQOL)-54 instrument. Los Angeles: University of California; 1995.
Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray T. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci. 1994;21(1):9–14. https://doi.org/10.1017/S0317167100048691.
Broadbent DE, Cooper PF, FitzGerald P, Parkes KR. The cognitive failures questionnaire (CFQ) and its correlates. Br J Clin Psychol. 1982;21(1):1–16. https://doi.org/10.1111/j.2044-8260.1982.tb01421.x.
Cella D, Lai JS, Nowinski CJ, Victorson D, Peterman A, Miller D, et al. Neuro-QOL: brief measures of health-related quality of life for clinical research in neurology. Neurology. 2012;78(23):1860–7. https://doi.org/10.1212/WNL.0b013e318258f744.
Stewart AL, Greenfield S, Hays RD, Wells K, Rogers WH, Berry SD, et al. Functional status and well-being of patients with chronic conditions: results from the Medical Outcomes Study. JAMA. 1989;262(7):907–13. https://doi.org/10.1001/jama.1989.03430070055030.
Delis D, Kramer J, Kaplan E, Ober B. The California verbal learning test-II. 2nd ed. San Antonio: The Psychological Corporation; 2000.
Benedict RB, Schretlen D, Groninger L, Dobraski M, Shpritz B. Revision of the Brief Visuospatial Memory Test: studies of normal performance, reliability, and validity. Psychol Assess. 1996;8(2):145–53. https://doi.org/10.1037/1040-3522.214.171.124.
Smith A. Symbol digit modalities test (SDMT): manual (revised). Los Angeles: Western Psychological Services; 1982.
Gronwall D. Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills. 1977;44(2):367–73. https://doi.org/10.2466/pms.19126.96.36.1997.
Golden CJ. Stroop color and word test: A manual for clinical and experimental uses. Chicago IL: Stoelting Co; 1978.
Benedict RH, Schretlen D, Groninger L, Brandt J. Hopkins Verbal Learning Test–Revised: normative data and analysis of inter-form and test-retest reliability. Clin Neuropsychol. 1998;12(1):43–55. https://doi.org/10.1076/clin.188.8.131.526.
Benton AL, Varney NR, Hamsher KD. Visuospatial judgment. A clinical test. Arch Neurol. 1978;35(6):364–7. https://doi.org/10.1001/archneur.1978.00500300038006.
Delis DC, Kaplan E, Kramer JH. Delis-Kaplan executive function system (D-KEFS): Psychological Corporation; 2001.
Corners C. CPT: Conners’ continuous performance test. Multi-Health Systems: North Tonawanda; 1995.
Dwolatzky T, Whitehead V, Doniger GM, Simon ES, Schweiger A, Jaffe D, et al. Validity of a novel computerized cognitive battery for mild cognitive impairment. BMC Geriatr. 2003;3(1):4. https://doi.org/10.1186/1471-2318-3-4.
Wechsler D. WAIS-III: Wechsler adult intelligence scale. Psychological Corporation; 1997.
Bucks R, Willison J. Development and validation of the location learning test (LLT): a test of visuo-spatial learning designed for use with older adults and in dementia. Clin Neuropsychol. 1997;11(3):273–86. https://doi.org/10.1080/13854049708400456.
Conflict of Interest
Katherine M. Dunn and Trisha Chaffee declare no conflict of interest.
Abbey J. Hughes reports grants from the National Institutes of Health.
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.
This article is part of the Topical Collection on Sleep
About this article
Cite this article
Hughes, A.J., Dunn, K.M. & Chaffee, T. Sleep Disturbance and Cognitive Dysfunction in Multiple Sclerosis: a Systematic Review. Curr Neurol Neurosci Rep 18, 2 (2018). https://doi.org/10.1007/s11910-018-0809-7