COGNITIVE IMPAIRMENT IN MULTIPLE SCLEROSIS: FROM PATHOPHYSIOLOGY TO TREATMENT - A LITERATURE REVIEW

Małgorzata Leśnik; Rafał Kuśmider; Hubert Kostka; Damian Dolata; Adrian Zagórski; Patrycja Wierzbowska; Jadwiga Kleinrok; Anna Bereta-Kostaś

doi:10.31435/ijitss.4(48).2025.4313

Authors

Małgorzata Leśnik Medical University of Silesia, Katowice, Poland https://orcid.org/0009-0004-4798-6302
Rafał Kuśmider Medical University of Silesia, Katowice, Poland https://orcid.org/0009-0003-3580-3495
Hubert Kostka 5 Military Clinical Hospital with Polyclinic SPZOZ, Kraków, Poland https://orcid.org/0009-0003-4419-5364
Damian Dolata Independent Public Healthcare Institution of the Ministry of the Interior and Administration, Kraków, Poland https://orcid.org/0009-0006-9165-8212
Adrian Zagórski 5 Military Clinical Hospital with Polyclinic SPZOZ, Kraków, Poland https://orcid.org/0000-0002-5420-8101
Patrycja Wierzbowska Gabriel Narutowicz Municipal Specialist Hospital, Kraków, Poland https://orcid.org/0009-0005-5201-0512
Jadwiga Kleinrok University Hospital in Kraków, Kraków, Poland https://orcid.org/0009-0005-2132-9299
Anna Bereta-Kostaś University Hospital in Kraków, Kraków, Poland https://orcid.org/0009-0007-5664-3119

DOI:

https://doi.org/10.31435/ijitss.4(48).2025.4313

Keywords:

Multiple Sclerosis, Cognitive Dysfunction, Cognition, Processing Speed, Quality of Life, Risk Factors

Abstract

Introduction and Purpose: Cognitive impairment (CI) is a frequent and often overlooked symptom of multiple sclerosis (MS). It significantly affects patients' quality of life, limiting daily functioning, independence, and social and professional engagement. While it can appear at any stage of the disease, it is particularly prevalent in progressive forms. The aim of this review is to present a comprehensive overview of cognitive dysfunction in MS, including its origins, clinical presentation, assessment, and management strategies.

Description of the State of Knowledge: CI in MS arises from complex interactions involving immune-mediated inflammation, neurodegeneration, and structural and functional brain changes. It typically affects information processing speed, attention, memory, and executive functions. Various risk factors contribute to its severity, including disease phenotype, age, comorbidities, and lifestyle factors. Despite its high prevalence, CI is underdiagnosed due to limited routine screening. Standardized cognitive assessment tools are increasingly used in clinical practice to support timely diagnosis and monitoring of cognitive decline. Both pharmacological and non-pharmacological approaches, particularly cognitive rehabilitation, have demonstrated beneficial effects.

Conclusions: Cognitive impairment should be recognized as a core symptom of MS and addressed through regular screening and individualized treatment. Early detection, interdisciplinary care, and patient education are key to reducing its impact and improving long-term outcomes.

References

Benedict, R. H. B., Amato, M. P., DeLuca, J., & Geurts, J. J. G. (2020). Cognitive impairment in multiple sclerosis: clinical management, MRI, and therapeutic avenues. The Lancet Neurology, 19(10), 860–871. https://doi.org/10.1016/s1474-4422(20)30277-5

Lisak M, Špiljak B, Pašić H, Trkanjec Z. (2021). Cognitive Aspects in Multiple Sclerosis. Psychiatr Danub., 33(Suppl 13):177-182.

Mitolo, M., Venneri, A., Wilkinson, I. D., & Sharrack, B. (2015). Cognitive rehabilitation in multiple sclerosis: A systematic review. Journal of the Neurological Sciences, 354(1–2), 1–9. https://doi.org/10.1016/j.jns.2015.05.004

Oset, M., Stasiolek, M., & Matysiak, M. (2020). Cognitive Dysfunction in the Early Stages of Multiple Sclerosis—How Much and How Important? Current Neurology and Neuroscience Reports, 20(7), 22. https://doi.org/10.1007/s11910-020-01045-3

Miller, E., Morel, A., Redlicka, J., Miller, I., & Saluk, J. (2018). Pharmacological and Non-pharmacological Therapies of Cognitive Impairment in Multiple Sclerosis. Current Neuropharmacology, 16(4), 475–483. https://doi.org/10.2174/1570159x15666171109132650

Jellinger, K. A. (2024). Cognitive impairment in multiple sclerosis: from phenomenology to neurobiological mechanisms. Journal of Neural Transmission, 131(8), 871–899. https://doi.org/10.1007/s00702-024-02786-y

López-Gómez, J., Enciso, B. S., Miró, M. C., & Pascual, Q. (2023). Clinically isolated syndrome: Diagnosis and risk of developing clinically definite multiple sclerosis. Neurología (English Edition), 38(9), 663–670. https://doi.org/10.1016/j.nrleng.2021.01.010

Olek MJ, Howard J, González-Scarano F, Dashe JF. (2024). Evaluation and diagnosis of multiple sclerosis in adults. UpToDate.

Haki, M., Al-Biati, H. A., Al-Tameemi, Z. S., Ali, I. S., & Al-Hussaniy, H. A. (2024). Review of multiple sclerosis: Epidemiology, etiology, pathophysiology, and treatment. Medicine, 103(8), e37297. https://doi.org/10.1097/md.0000000000037297

Cree, B. A., Arnold, D. L., Chataway, J., Chitnis, T., Fox, R. J., Ramajo, A. P., Murphy, N., & Lassmann, H. (2021). Secondary progressive multiple sclerosis. Neurology, 97(8), 378–388. https://doi.org/10.1212/wnl.0000000000012323

Antel, J., Antel, S., Caramanos, Z., Arnold, D. L., & Kuhlmann, T. (2012). Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity? Acta Neuropathologica, 123(5), 627–638. https://doi.org/10.1007/s00401-012-0953-0

Eijlers, A. J. C., Van Geest, Q., Dekker, I., Steenwijk, M. D., Meijer, K. A., Hulst, H. E., Barkhof, F., Uitdehaag, B. M. J., Schoonheim, M. M., & Geurts, J. J. G. (2018). Predicting cognitive decline in multiple sclerosis: a 5-year follow-up study. Brain, 141(9), 2605–2618. https://doi.org/10.1093/brain/awy202

Meca-Lallana, V., Gascón-Giménez, F., Ginestal-López, R. C., Higueras, Y., Téllez-Lara, N., Carreres-Polo, J., Eichau-Madueño, S., Romero-Imbroda, J., Vidal-Jordana, Á., & Pérez-Miralles, F. (2021). Cognitive impairment in multiple sclerosis: diagnosis and monitoring. Neurological Sciences, 42(12), 5183–5193. https://doi.org/10.1007/s10072-021-05165-7

Roheger, M., Grothe, L., Hasselberg, L., Grothe, M., & Meinzer, M. (2024). A systematic review and meta-analysis of socio-cognitive impairments in multiple sclerosis. Scientific Reports, 14(1), 7096. https://doi.org/10.1038/s41598-024-53750-5

Barros, C., & Fernandes, A. (2020). Linking Cognitive Impairment to Neuroinflammation in Multiple Sclerosis using neuroimaging tools. Multiple Sclerosis and Related Disorders, 47, 102622. https://doi.org/10.1016/j.msard.2020.102622

Dendrou, C. A., Fugger, L., & Friese, M. A. (2015). Immunopathology of multiple sclerosis. Nature Reviews. Immunology, 15(9), 545–558. https://doi.org/10.1038/nri3871

Kappus, N., Weinstock-Guttman, B., Hagemeier, J., Kennedy, C., Melia, R., Carl, E., Ramasamy, D. P., Cherneva, M., Durfee, J., Bergsland, N., Dwyer, M. G., Kolb, C., Hojnacki, D., Ramanathan, M., & Zivadinov, R. (2015). Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis. Journal of Neurology Neurosurgery & Psychiatry, 87(2), jnnp-2014. https://doi.org/10.1136/jnnp-2014-31051

Margoni, M., Preziosa, P., Rocca, M. A., & Filippi, M. (2023). Depressive symptoms, anxiety and cognitive impairment: emerging evidence in multiple sclerosis. Translational Psychiatry, 13(1), 264. https://doi.org/10.1038/s41398-023-02555-7

Schoonheim, M. M., Vigeveno, R. M., Lopes, F. C. R., Pouwels, P. J., Polman, C. H., Barkhof, F., & Geurts, J. J. (2013). Sex‐specific extent and severity of white matter damage in multiple sclerosis: Implications for cognitive decline. Human Brain Mapping, 35(5), 2348–2358. https://doi.org/10.1002/hbm.22332

Reia, A., Petruzzo, M., Falco, F., Costabile, T., Conenna, M., Carotenuto, A., Petracca, M., Servillo, G., Lanzillo, R., Morra, V. B., & Moccia, M. (2021). A retrospective exploratory analysis on cardiovascular risk and cognitive dysfunction in multiple sclerosis. Brain Sciences, 11(4), 502. https://doi.org/10.3390/brainsci11040502

Ayromlou, H., Hosseini, S., Khalili, M., Ayromlou, S., Khamudchiyan, S., Farajdokht, F., Hassannezhad, S., & Moghadam, S. A. (2023). Insulin resistance is associated with cognitive dysfunction in multiple sclerosis patients: A cross‐sectional study. Journal of Neuroendocrinology, 35(6), e13288. https://doi.org/10.1111/jne.13288

Pavisian, B., MacIntosh, B. J., Szilagyi, G., Staines, R. W., O’Connor, P., & Feinstein, A. (2014). Effects of cannabis on cognition in patients with MS. Neurology, 82(21), 1879–1887. https://doi.org/10.1212/wnl.0000000000000446

De Giglio, L., Marinelli, F., Barletta, V. T., Pagano, V. A., De Angelis, F., Fanelli, F., Petsas, N., Pantano, P., Tomassini, V., & Pozzilli, C. (2016). Effect on Cognition of Estroprogestins Combined with Interferon Beta in Multiple Sclerosis: Analysis of Secondary Outcomes from a Randomised Controlled Trial. CNS Drugs, 31(2), 161–168. https://doi.org/10.1007/s40263-016-0401-0

Della Corte, M., Santangelo, G., Bisecco, A., Sacco, R., Siciliano, M., D’Ambrosio, A., Docimo, R., Cuomo, T., Lavorgna, L., Bonavita, S., Tedeschi, G., & Gallo, A. (2018). A simple measure of cognitive reserve is relevant for cognitive performance in MS patients. Neurological Sciences, 39(7), 1267–1273. https://doi.org/10.1007/s10072-018-3422-2

Grant, J. G., Rapport, L. J., Darling, R., Waldron-Perrine, B., Lumley, M. A., Whitfield, K. E., & Bernitsas, E. (2023). Cognitive enrichment and education quality moderate cognitive dysfunction in black and white adults with multiple sclerosis. Multiple Sclerosis and Related Disorders, 78, 104916. https://doi.org/10.1016/j.msard.2023.104916

Kalb, R., Beier, M., Benedict, R. H., Charvet, L., Costello, K., Feinstein, A., Gingold, J., Goverover, Y., Halper, J., Harris, C., Kostich, L., Krupp, L., Lathi, E., LaRocca, N., Thrower, B., & DeLuca, J. (2018). Recommendations for cognitive screening and management in multiple sclerosis care. Multiple Sclerosis Journal, 24(13), 1665–1680. https://doi.org/10.1177/1352458518803785

Benedict, R. H., Cookfair, D., Gavett, R., Gunther, M., Munschauer, F., Garg, N., & Weinstock-Guttman, B. (2006). Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). Journal of the International Neuropsychological Society, 12(4), 549–558. https://doi.org/10.1017/s1355617706060723

Diamond, B., Johnson, S., Kaufman, M., & Graves, L. (2007). Relationships between information processing, depression, fatigue and cognition in multiple sclerosis. Archives of Clinical Neuropsychology, 23(2), 189–199. https://doi.org/10.1016/j.acn.2007.10.002

Goretti, B., Viterbo, R. G., Portaccio, E., Niccolai, C., Hakiki, B., Piscolla, E., Iaffaldano, P., Trojano, M., & Amato, M. P. (2013). Anxiety state affects information processing speed in patients with multiple sclerosis. Neurological Sciences, 35(4), 559–563. https://doi.org/10.1007/s10072-013-1544-0

Taranu, D., Balz, L. T., Holbrook, J., Tumani, V., Schreiber, H., Tumani, H., & Uttner, I. (2025). Cognitive impairment, mood, and fatigue in various multiple sclerosis subtypes: a one-year follow-up study. Journal of Neurology, 272(6), 398. https://doi.org/10.1007/s00415-025-13115-y

Planche, V., Gibelin, M., Cregut, D., Pereira, B., & Clavelou, P. (2015). Cognitive impairment in a population‐based study of patients with multiple sclerosis: differences between late relapsing−remitting, secondary progressive and primary progressive multiple sclerosis. European Journal of Neurology, 23(2), 282–289. https://doi.org/10.1111/ene.12715

Morrow, S. A. (2024). Cognitive impairment in multiple sclerosis. Neuroimaging Clinics of North America, 34(3), 469–479. https://doi.org/10.1016/j.nic.2024.03.010

Morrow, S. A., Jurgensen, S., Forrestal, F., Munchauer, F. E., & Benedict, R. H. B. (2011). Effects of acute relapses on neuropsychological status in multiple sclerosis patients. Journal of Neurology, 258(9), 1603–1608. https://doi.org/10.1007/s00415-011-5975-3

Morrow, S. A., Weinstock, Z. L., Mirmosayyeb, O., Conway, D., Fuchs, T., Jaworski, M. G., Eckert, S., Hojnacki, D. H., Dwyer, M. G., Zivadinov, R., Weinstock-Guttman, B., & Benedict, R. H. B. (2023). Detecting isolated cognitive relapses in persons with MS. Multiple Sclerosis Journal, 29(14), 1786–1794. https://doi.org/10.1177/13524585231201219

Benedict, R. H., DeLuca, J., Phillips, G., LaRocca, N., Hudson, L. D., & Rudick, R. (2017). Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis. Multiple Sclerosis Journal, 23(5), 721–733. https://doi.org/10.1177/1352458517690821

Langdon, D., Amato, M., Boringa, J., Brochet, B., Foley, F., Fredrikson, S., Hämäläinen, P., Hartung, H., Krupp, L., Penner, I., Reder, A., & Benedict, R. (2011). Recommendations for a brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). Multiple Sclerosis Journal, 18(6), 891–898. https://doi.org/10.1177/1352458511431076

Potticary, H., & Langdon, D. (2023). A Systematic Review and Meta-Analysis of the Brief Cognitive Assessment for Multiple Sclerosis (BICAMS) International Validations. Journal of Clinical Medicine, 12(2), 703. https://doi.org/10.3390/jcm12020703

Freedman, M. S. (2006). Disease-modifying drugs for multiple sclerosis: current and future aspects. Expert Opinion on Pharmacotherapy, 7(sup1), S1–S9. https://doi.org/10.1517/14656566.7.1.s1

Bellinvia, A., Portaccio, E., & Amato, M. P. (2022). Current advances in the pharmacological prevention and management of cognitive dysfunction in multiple sclerosis. Expert Opinion on Pharmacotherapy, 24(4), 435–451. https://doi.org/10.1080/14656566.2022.2161882

Branger, P., Parienti, J., Sormani, M. P., & Defer, G. (2016). The Effect of Disease-Modifying Drugs on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: A Meta-Analysis. PLoS ONE, 11(3), e0149685. https://doi.org/10.1371/journal.pone.0149685

Sormani, M. P., Arnold, D. L., & De Stefano, N. (2013). Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Annals of Neurology, 75(1), 43–49. https://doi.org/10.1002/ana.24018

Chen, M. H., Goverover, Y., Genova, H. M., & DeLuca, J. (2020). Cognitive Efficacy of pharmacologic Treatments in Multiple sclerosis: a Systematic review. CNS Drugs, 34(6), 599–628. https://doi.org/10.1007/s40263-020-00734-4

Cotter, J., Muhlert, N., Talwar, A., & Granger, K. (2018). Examining the effectiveness of acetylcholinesterase inhibitors and stimulant-based medications for cognitive dysfunction in multiple sclerosis: A systematic review and meta-analysis. Neuroscience & Biobehavioral Reviews, 86, 99–107. https://doi.org/10.1016/j.neubiorev.2018.01.006

DeLuca, J., Chiaravalloti, N. D., & Sandroff, B. M. (2020). Treatment and management of cognitive dysfunction in patients with multiple sclerosis. Nature Reviews Neurology, 16(6), 319–332. https://doi.org/10.1038/s41582-020-0355-1

Taylor, L. A., Mhizha-Murira, J. R., Smith, L., Potter, K., Wong, D., Evangelou, N., Lincoln, N. B., & Nair, R. D. (2021). Memory rehabilitation for people with multiple sclerosis. Cochrane Database of Systematic Reviews, 2021(10). https://doi.org/10.1002/14651858.cd008754.pub4

Sharbafshaaer, M., Trojsi, F., Bonavita, S., & Azimi, A. (2022). Integrated Cognitive Rehabilitation Home-Based Protocol to improve Cognitive functions in multiple sclerosis patients: a randomized controlled study. Journal of Clinical Medicine, 11(12), 3560. https://doi.org/10.3390/jcm11123560

Rayegani, S. M., Heidari, S., Seyed-Nezhad, M., Kiyani, N., & Moradi-Joo, M. (2024). Effectiveness of cognitive rehabilitation in comparison with routine rehabilitation methods in patients with multiple sclerosis: A systematic review and meta-analysis. Multiple Sclerosis Journal - Experimental Translational and Clinical, 10(3), 20552173241272561. https://doi.org/10.1177/20552173241272561

Klein, O. A., Drummond, A., Mhizha-Murira, J. R., Mansford, L., & dasNair, R. (2017). Effectiveness of cognitive rehabilitation for people with multiple sclerosis: a meta-synthesis of patient perspectives. Neuropsychological Rehabilitation, 29(4), 491–512. https://doi.org/10.1080/09602011.2017.1309323