Cognitive impairment (CI) is a common and disabling symptom in people with multiple sclerosis (PwMS), significantly affecting employment outcomes and quality of life. Despite its prevalence, routine assessment of CI is often hindered by limited access to comprehensive neuropsychological evaluations and challenges in interpreting subjective concerns. The relationship between objective and subjective measures of cognition is complex and often discordant. This review provides an overview focused on patient-reported CI, emphasizing on the association with objective measures of CI, the role of confounding factors, and the limitations of current screening approaches. Regardless of the underlying processes driving these concerns, patient-reported CI has a significant impact on day-to-day quality of life of PwMS and needs to be efficiently evaluated and addressed as several reversible causes can be managed efficiently when detected.
KobeltGThompsonAJBergJ, et al. New insights into the burden and costs of multiple sclerosis in Europe. Mult Scler2017; 23(8): 1123–1136. DOI: 10.1177/1352458517694432.
2.
BenedictRHDrakeASIrwinLN, et al. Benchmarks of meaningful impairment on the MSFC and BICAMS. Mult Scler2016; 22(14): 1874–1882. DOI: 10.1177/1352458516633517.
3.
RaoSMLeoGJBernardinL, et al. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology1991; 41(5): 685–691.
4.
BenedictRHBAmatoMPDeLucaJ, et al. Cognitive impairment in multiple sclerosis: Clinical management, MRI, and therapeutic avenues. Lancet Neurol2020; 19(10): 860–871. DOI: 10.1016/S1474-4422(20)30277-5.
5.
OhJSuthiphosuwanSSatiP, et al. Cognitive impairment, the central vein sign, and paramagnetic rim lesions in RIS. Mult Scler2021; 27(14): 2199–2208. DOI: 10.1177/13524585211002097.
6.
DamascenoAPimentel-SilvaLRDamascenoBP, et al. Cognitive trajectories in relapsing—remitting multiple sclerosis: A longitudinal 6-year study. Mult Scler2020; 26(13): 1740–1751. DOI: 10.1177/1352458519878685.
7.
BenedictRHPolJYasinF, et al. Recovery of cognitive function after relapse in multiple sclerosis. Mult Scler2021; 27(1): 71–78. DOI: 10.1177/1352458519898108.
8.
De MeoEPortaccioEGiorgioA, et al. Identifying the distinct cognitive phenotypes in multiple sclerosis. JAMA Neurol. 2021; 78(4): 414–425. DOI: 10.1001/jamaneurol.2020.4920.
9.
CotterJFirthJEnzingerC, et al. Social cognition in multiple sclerosis: A systematic review and meta-analysis. Neurology2016; 87: 1727–1736.
10.
BoraEÖzakbaSVelakoulisD, et al. Social cognition in multiple sclerosis: A meta-analysis. Neuropsychol Rev2016; 26: 160–172. DOI: 10.1007/s11065-016-9320-6.
11.
KalbRBeierMBenedictRH, et al. Recommendations for cognitive screening and management in multiple sclerosis care. Mult Scler2018; 24(13): 1665–1680. DOI: 10.1177/1352458518803785.
12.
CharestKTremblayALangloisR, et al. Detecting subtle cognitive impairment in multiple sclerosis with the Montreal cognitive assessment. Can J Neurol Sci2020; 47(5): 620–626. DOI: 10.1017/cjn.2020.97.
13.
GaliotoRMacaronGLaceJW, et al. Is computerized screening for processing speed impairment sufficient for identifying MS-related cognitive impairment in a clinical setting?Mult Scler Relat Disord2021; 54: 103106. DOI: 10.1016/j.msard.2021.103106.
14.
BenedictRHMunschauerFLinnR, et al. Screening for multiple sclerosis cognitive impairment using a self-administered 15-item questionnaire. Mult Scler2003; 9(1): 95–101.
15.
MillerDMBethouxFVictorsonD, et al. Validating Neuro-QoL short forms and targeted scales with people who have multiple sclerosis. Mult Scler2015; 22(6): 830–841. DOI: 10.1177/1352458515599450.
16.
O’BrienAGaudino-GoeringEShawarynM, et al. Relationship of the multiple sclerosis neuropsychological questionnaire (MSNQ) to functional, emotional, and neuropsychological outcomes. Arch Clin Neuropsychol2007; 22(8): 933–948. DOI: 10.1016/j.acn.2007.07.002.
17.
TunmoreJKontouEMoghaddamN, et al. The association between the multiple sclerosis neuropsychological questionnaire and objective measures of cognition: A systematic literature review and meta-analysis. J Clin Exp Neuropsychol2023; 45(2): 197–217. DOI: 10.1080/13803395.2023.2213847.
18.
MacaronGBaldassariLENakamuraK, et al. Cognitive processing speed in multiple sclerosis clinical practice: Association with patient-reported outcomes, employment, and MRI metrics. Eur J Neurol. 2020; 27(7): 1238–1249. DOI: 10.1111/ene.14239.
19.
ThomasGARieglerKEBradsonML, et al. Relationship between subjective report and objective assessment of neurocognitive functioning in persons with multiple sclerosis. J Int Neuropsychol Soc2023; 29(3): 266–273. DOI: 10.1017/S1355617722000212.
20.
LaethemDVan CockADe SchependomJ, et al. Correlates of patient reported cognitive performance with regard to disability. Sci Rep. 2022; 12(1): 13489. DOI: 10.1038/s41598-022-17649-3.
21.
BenedictRHCoxDThompsonLL, et al. Reliable screening for neuropsychological impairment in multiple sclerosis. Mult Scler2004; 10(6): 675–678. DOI: 10.1191/1352458504ms1098oa.
22.
SumowskiJFSandryJ. Multiple sclerosis cognitive scale (MSCS): A Brief psychometrically-robust metric of patient-reported cognitive difficulty. Mult Scler2025; 31(3): 352–362. DOI: 10.1101/2024.04.29.24306587.
23.
DemersMRouleauIScherzerP, et al. Impact of the cognitive status on the memory complaints in MS patients. Can J Neurol Sci2011; 38(5): 728–733. DOI: 10.1017/S031716710005410X.
24.
MarrieRACheluneGJMillerDM, et al. Subjective cognitive complaints relate to mild impairment of cognition in multiple sclerosis. Mult Scler2005; 11(1): 69–75. DOI: 10.1191/1352458505ms1110oa.
25.
ShermanTERapportLJRyanKA. Awareness of deficit in multiple sclerosis. J Clin Exp Neuropsychol2008; 30(3): 301–311. DOI: 10.1080/13803390701380617.
26.
KobeltGLangdonDJönssonL. The effect of self-assessed fatigue and subjective cognitive impairment on work capacity: The case of multiple sclerosis. Mult Scler2019; 25(5): 740–749. DOI: 10.1177/1352458518769837.
27.
D’hoogheMBDe CockABenedictRHB, et al. Perceived neuropsychological impairment inversely related to self- reported health and employment in multiple sclerosis. Eur J Neurol2019; 26(12): 1447–1454. DOI: 10.1111/ene.14012.
28.
EspirituAISolimanYBlairM, et al. Self-reported cognitive function mediates the relationship between employment status and cognitive functioning in persons with multiple sclerosis. Mult Scler Relat Disord2024; 87: 105645. DOI: 10.1016/j.msard.2024.105645.
29.
WegenJVan EgmondEEAVan BenedictRHB, et al. IBRO neuroscience reports subjective cognitive impairment is related to work status in people with multiple sclerosis. IBRO Neurosci Rep2022; 13(July): 513–522. DOI: 10.1016/j.ibneur.2022.10.016.
30.
GlukhovskyLBrandstadterRLeavittVM, et al. Hippocampal volume is more related to patient-reported memory than objective memory performance in early multiple sclerosis. Mult Scler2021; 27(4): 568–578. DOI: 10.1177/1352458520922830.
31.
KletenikIAlvarezEHonceJM, et al. Subjective cognitive concern in multiple sclerosis is associated with reduced thalamic and cortical gray matter volumes. Mult Scler J Exp Transl Clin2019; 5(1):2055217319827618. DOI: 10.1177/2055217319827618.
32.
PeriniGCotta RamusinoMSinforianiE, et al. Cognitive impairment in depression: Recent advances and novel treatments. Neuropsychiatr Dis Treat2019; 15: 1249–1258.
33.
HughesAJBhattaraiJJPaulS, et al. Depressive symptoms and fatigue as predictors of objective- subjective discrepancies in cognitive function in multiple sclerosis. Mult Scler Relat Disord2019; 30: 192–197. DOI: 10.1016/j.msard.2019.01.055.Hughes.
34.
KinsingerSWLattieEMohrDC. Relationship between depression, fatigue, subjective cognitive impairment, and objective neuropsychological functioning in patients with multiple sclerosis. Neuropsychology2010; 24(5): 573–580. DOI: 10.1037/a0019222.Relationship.
35.
RabinowitzARArnettPA. A longitudinal analysis of cognitive dysfunction, coping, and depression in multiple sclerosis. Neuropsychology2009; 23(5): 581–591. DOI: 10.1037/a0016064.
36.
HonanCABrownRFBatchelorJ. Perceived cognitive difficulties and cognitive test performance as predictors of employment outcomes in people with multiple sclerosis. J Int Neuropsychol Soc2015; 21(2): 156–168. DOI: 10.1017/S1355617715000053.
37.
WilskiMGabryelskiJBrolaW, et al. Health-related quality of life in multiple sclerosis: Links to acceptance, coping strategies and disease severity. Disabil Health J2019; 12(4): 608–614. DOI: 10.1016/j.dhjo.2019.06.003.
38.
YoungCAMillsRJLangdonD, et al. Measuring coping in multiple sclerosis: The coping index-MS. Mult Scler2022; 28(14): 2274–2284. DOI: 10.1177/13524585221114004.
39.
ScherderRJPrinsAJVan DorpMJ, et al. Pain, cognition and disability in advanced multiple sclerosis. Scand J Pain2021; 21(4): 754–765. DOI: 10.1515/SJPAIN-2021-0067/ASSET/GRAPHIC/J_SJPAIN-2021-0067_FIG_002.JPG.
40.
BrownFSGlasmacherSATaylorD, et al. Pain and cognitive performance in adults with multiple sclerosis: A systematic review. Mult Scler Relat Disord2023; 71: 104584. DOI: 10.1016/j.msard.2023.104584.
41.
BrassSDDuquettePProulx-TherrienJ, et al. Sleep disorders in patients with multiple sclerosis. Sleep Med Rev2010; 14(2): 121–129. DOI: 10.1016/j.smrv.2009.07.005.
42.
SaterRAGudesblattMKresa-ReahlK, et al. The relationship between objective parameters of sleep and measures of fatigue, depression, and cognition in multiple sclerosis. Mult Scler J Exp Transl Clin2015; 1: 2055217315577828. DOI: 10.1177/2055217315577828.
43.
HughesAJDunnKMChaffeeT. Sleep disturbance and cognitive dysfunction in multiple sclerosis: A systematic review. Curr Neurol Neurosci Rep2018; 18(1): 2. DOI: 10.1007/S11910-018-0809-7.
44.
HughesAJTurnerAPAlschulerKN, et al. Association between sleep problems and perceived cognitive dysfunction over 12 months in individuals with multiple sclerosis. Behav Sleep Med2018; 16(1): 79–91. DOI: 10.1080/15402002.2016.1173553.
45.
EnokaRMAlmuklassAMAlenazyM, et al. Distinguishing between fatigue and fatigability in multiple sclerosis. Neurorehabil Neural Repair2021; 35(11): 960–973. DOI: 10.1177/15459683211046257.
46.
HeesenCNawrathLReichC, et al. Fatigue in multiple sclerosis: An example of cytokine mediated sickness behaviour?J Neurol Neurosurg Psychiatry2006; 77(1): 34–39. DOI: 10.1136/jnnp.2005.065805.
47.
LoyBDTaylorRLFlingBW, et al. Relationship between perceived fatigue and performance fatigability in people with multiple sclerosis: A systematic review and meta-analysis. J Psychosom Res2018; 100: 1–7. DOI: 10.1016/j.jpsychores.2017.06.017.Relationship.
48.
MackayLJohnsonAMMoodieST, et al. Predictors of cognitive fatigue and fatigability in multiple sclerosis. Mult Scler Relat Disord2021; 56: 103316. DOI: 10.1016/j.msard.2021.103316.
49.
Claros-SalinasDBratzkeDGreitemannG, et al. Fatigue-related diurnal variations of cognitive performance in multiple sclerosis and stroke patients. J Neurol Sci2010; 295(1-2): 75–81. DOI: 10.1016/j.jns.2010.04.018.
50.
TommasinSDe LucaFFerranteI, et al. Cognitive fatigability is a quantifiable distinct phenomenon in multiple sclerosis. J Neuropsychol2020; 14(3): 370–383. DOI: 10.1111/jnp.12197.
51.
FrahmNHeckerMZettlUK. Polypharmacy among patients with multiple sclerosis: A qualitative systematic review. Expert Opin Drug Saf2020; 19(2): 139–145. DOI: 10.1080/14740338.2020.1720646.
52.
ChertcoffANgHSZhuF, et al. Polypharmacy and multiple sclerosis: A population-based study. Mult Scler2023; 29(1): 107–118.
53.
ThelenJMLynchSGBruceAS, et al. Polypharmacy in multiple sclerosis: Relationship with fatigue, perceived cognition, and objective cognitive performance. J Psychosom Res2014; 76(5): 400–404. DOI: 10.1016/j.jpsychores.2014.02.013.
54.
OkenBSFlegalKZajdelD, et al. Cognition and fatigue in multiple sclerosis: Potential effects of medications with central nervous system activity. J Rehabil Res Dev2006; 43(1): 83–90. DOI: 10.1682/jrrd.2004.11.0148.
55.
WeberEGoveroverYDeLucaJ. Beyond cognitive dysfunction: Relevance of ecological validity of neuropsychological tests in multiple sclerosis. Mult Scler2019; 25(10): 1412–1419. DOI: 10.1177/1352458519860318.
56.
MacaronGMossBPLiH, et al. Technology-enabled assessments to enhance multiple sclerosis clinical care and research. Neurol Clin Pract2020; 10(3): 222–231. DOI: 10.1212/CPJ.0000000000000710.
57.
van DongenLWesterikBvan der HieleK, et al. Introducing multiple screener: An unsupervised digital screening tool for cognitive deficits in MS. Mult Scler Relat Disord2020; 38: 101479. DOI: 10.1016/j.msard.2019.101479.
58.
WaskowiakPTRuitenbergMFHulstHE. Neuropsychological assessment in MS is outdated and is in need for innovation: Yes. Mult Scler2024; 30(2): 150–151. DOI: 10.1177/13524585241230184.
59.
DobsonRRiceDRD’hoogheM, et al. Social determinants of health in multiple sclerosis. Nat Rev Neurol2022; 18(12): 723–734. DOI: 10.1038/S41582-022-00735-5.
60.
GrantJGRapportLJDarlingR, et al. Cognitive enrichment and education quality moderate cognitive dysfunction in black and white adults with multiple sclerosis. Mult Scler Relat Disord2023; 78: 104916. DOI: 10.1016/J.MSARD.2023.104916.
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