Multiple Sclerosis (MS) management in individuals aged 55 and above presents unique challenges due to the complex interaction between aging, comorbidities, immunosenescence, and MS pathophysiology. This comprehensive review explores the evolving landscape of MS in older adults, including the increased incidence and prevalence of MS in this age group, the shift in disease phenotypes from relapsing-remitting to progressive forms, and the presence of multimorbidity and polypharmacy. We aim to provide an updated review of the available evidence of disease-modifying treatments (DMTs) in older patients, including the efficacy and safety of existing therapies, emerging treatments such as Bruton tyrosine kinase (BTKs) inhibitors and those targeting remyelination and neuroprotection, and the critical decisions surrounding the initiation, de-escalation, and discontinuation of DMTs. Non-pharmacologic approaches, including physical therapy, neuromodulation therapies, cognitive rehabilitation, and psychotherapy, are also examined for their role in holistic care. The importance of MS Care Units and advance care planning are explored as a cornerstone in providing patient-centric care, ensuring alignment with patient preferences in the disease trajectory. Finally, the review emphasizes the need for personalized management and continuous monitoring of MS patients, alongside advocating for inclusive study designs in clinical research to improve the management of this growing patient demographic.

Brain and Mind Center University of Sydney Sydney NSW Australia

Comprehensive Center for Clinical Neurosciences and Mental Health Medical University of Vienna Vienna Austria

Copenhagen and Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Danish Multiple Sclerosis Center Department of Neurology Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Departament of Pharmacology Faculty of Medicine; Institute of Biomedical Research of Malaga Regional University Hospital of Malaga Malaga Spain

Department of Medicine Faculty of Medicine Complutense University of Madrid Madrid Spain

Department of Neurology Hospital Clínico Universitario San Carlos IdISSC Madrid Spain

Department of Neurology Medical Faculty Heinrich Heine University Düsseldorf Germany

Department of Neurology Medical University of Vienna Vienna Austria

Department of Neurology Palacky University Olomouc Olomouc Czechia

Department of Neurorehabilitation Sciences Multiple Sclerosis Centre Casa di Cura Igea Milan Italy

Department of Pharmacology and Pediatry Faculty of Medicine University of Malaga Malaga Spain

Rehabilitation and Multiple Sclerosis Noorderhart Hospitals Pelt Belgium

Univ Lille Inserm U1172 LilNCog CHU Lille FHU Precise Lille France

University MS Centre Hasselt Pelt Belgium

University Vita Salute San Raffaele Milan Italy

Zobrazit více v PubMed

Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA, et al. . Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition. Mult Scler. (2020) 26:1816–21. doi: 10.1177/1352458520970841 PubMed DOI PMC

MS International Federation . 3rd edition of the Atlas of MS . Available online at: https://www.atlasofms.org/map/global/epidemiology/number-of-people-with-ms#about (Accessed September 11, 2023).

Koch-Henriksen N, Thygesen LC, Stenager E, Laursen B, Magyari M. Incidence of MS has increased markedly over six decades in Denmark particularly with late onset and in women. Neurology. (2018) 90:e1954–63. doi: 10.1212/wnl.0000000000005612 PubMed DOI

Solaro C, Ponzio M, Moran E, Tanganelli P, Pizio R, Ribizzi G, et al. . The changing face of multiple sclerosis: Prevalence and incidence in an aging population. Mult Scler. (2015) 21:1244–50. doi: 10.1177/1352458514561904 PubMed DOI

Marrie RA, Yu N, Blanchard J, Leung S, Elliott L. The rising prevalence and changing age distribution of multiple sclerosis in Manitoba. Neurology. (2010) 74:465–71. doi: 10.1212/WNL.0b013e3181cf6ec0 PubMed DOI

Sorensen PS, Sellebjerg F, Hartung HP, Montalban X, Comi G, Tintoré M. The apparently milder course of multiple sclerosis: changes in the diagnostic criteria, therapy and natural history. Brain. (2020) 143:2637–52. doi: 10.1093/brain/awaa145 PubMed DOI

Wallin MT, Culpepper WJ, Campbell JD, Nelson LM, Langer-Gould A, Marrie RA, et al. . The prevalence of MS in the United States: A population-based estimate using health claims data. Neurology. (2019) 92:e1029–40. doi: 10.1212/wnl.0000000000007035 PubMed DOI PMC

Kern DM, Cepeda MS. Treatment patterns and comorbid burden of patients newly diagnosed with multiple sclerosis in the United States. BMC Neurol. (2020) 20:296. doi: 10.1186/s12883-020-01882-2 PubMed DOI PMC

Grytten N, Aarseth JH, Lunde HM, Myhr KM. A 60-year follow-up of the incidence and prevalence of multiple sclerosis in Hordaland County, Western Norway. J Neurol Neurosurg Psychiatry. (2016) 87:100–5. doi: 10.1136/jnnp-2014-309906 PubMed DOI PMC

Lunde HMB, Assmus J, Myhr K-M, Bø L, Grytten N. Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study. J Neurology Neurosurg Psychiatry. (2017) 88:621–5. doi: 10.1136/jnnp-2016-315238 PubMed DOI PMC

Rotstein DL, Chen H, Wilton AS, Kwong JC, Marrie RA, Gozdyra P, et al. . Temporal trends in multiple sclerosis prevalence and incidence in a large population. Neurology. (2018) 90:e1435–41. doi: 10.1212/wnl.0000000000005331 PubMed DOI

Kingwell E, van der Kop M, Zhao Y, Shirani A, Zhu F, Oger J, et al. . Relative mortality and survival in multiple sclerosis: findings from British Columbia, Canada. J Neurol Neurosurg Psychiatry. (2012) 83:61–6. doi: 10.1136/jnnp-2011-300616 PubMed DOI

Rodríguez-Antigüedad Zarranz A, Mendibe Bilbao M, Llarena González C, Audicana C. Mortality and cause of death in multiple sclerosis: findings from a prospective population-based cohort in Bizkaia, Basque Country, Spain. Neuroepidemiology. (2014) 42:219–25. doi: 10.1159/000359971 PubMed DOI

Chalmer TA, Baggesen LM, Nørgaard M, Koch-Henriksen N, Magyari M, Sorensen PS. Early versus later treatment start in multiple sclerosis: a register-based cohort study. Eur J Neurol. (2018) 25:1262–e110. doi: 10.1111/ene.13692 PubMed DOI

Simonsen CS, Flemmen HØ, Broch L, Brunborg C, Berg-Hansen P, Moen SM, et al. . Early high efficacy treatment in multiple sclerosis is the best predictor of future disease activity over 1 and 2 years in a norwegian population-based registry. Front Neurol. (2021) 12:693017. doi: 10.3389/fneur.2021.693017 PubMed DOI PMC

Buron MD, Chalmer TA, Sellebjerg F, Barzinji I, Danny B, Christensen JR, et al. . Initial high-efficacy disease-modifying therapy in multiple sclerosis: A nationwide cohort study. Neurology. (2020) 95:e1041–51. doi: 10.1212/wnl.0000000000010135 PubMed DOI

Rommer PS, Eichstädt K, Ellenberger D, Flachenecker P, Friede T, Haas J, et al. . Symptomatology and symptomatic treatment in multiple sclerosis: Results from a nationwide MS registry. Multiple Sclerosis J. (2019) 25:1641–52. doi: 10.1177/1352458518799580 PubMed DOI

Soelberg Sorensen P, Giovannoni G, Montalban X, Thalheim C, Zaratin P, Comi G. The multiple sclerosis care unit. Mult Scler. (2019) 25:627–36. doi: 10.1177/1352458518807082 PubMed DOI PMC

Wills OC, Probst YC. Understanding lifestyle self-management regimens that improve the life quality of people living with multiple sclerosis: a systematic review and meta-analysis. Health Qual Life Outcomes. (2022) 20:153. doi: 10.1186/s12955-022-02046-1 PubMed DOI PMC

Amato MP, Derfuss T, Hemmer B, Liblau R, Montalban X, Soelberg Sørensen P, et al. . Environmental modifiable risk factors for multiple sclerosis: Report from the 2016 ECTRIMS focused workshop. Mult Scler. (2018) 24:590–603. doi: 10.1177/1352458516686847 PubMed DOI

Romero-Pinel L, Bau L, Matas E, León I, Muñoz-Vendrell A, Arroyo P, et al. . The age at onset of relapsing-remitting multiple sclerosis has increased over the last five decades. Mult Scler Relat Disord. (2022) 68:104103. doi: 10.1016/j.msard.2022.104103 PubMed DOI

Prosperini L, Lucchini M, Ruggieri S, Tortorella C, Haggiag S, Mirabella M, et al. . Shift of multiple sclerosis onset towards older age. J Neurology Neurosurg Psychiatry. (2022) 93:1137–9. doi: 10.1136/jnnp-2022-329049 PubMed DOI

Zinganell A, Göbel G, Berek K, Hofer B, Asenbaum-Nan S, Barang M, et al. . . doi: 10.1007/s00415-023-12041-1 DOI

Wallin MT, Culpepper WJ, Nichols E, Bhutta ZA, Gebrehiwot TT, Hay SI, et al. . Global, regional, and national burden of multiple sclerosis 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. (2019) 18:269–85. doi: 10.1016/S1474-4422(18)30443-5 PubMed DOI PMC

MSBase Neuro-immunology Registry . Patient demographics . Available online at: https://www.msbase.org/data-and-findings/patient-demographics (Accessed January 9, 2024).

Patti F, Vila C. Symptoms, prevalence and impact of multiple sclerosis in younger patients: a multinational survey. Neuroepidemiology. (2014) 42:211–8. doi: 10.1159/000360423 PubMed DOI

Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, et al. . Multiple sclerosis. Nat Rev Dis Primers. (2018) 4:43. doi: 10.1038/s41572-018-0041-4 PubMed DOI

Oreja-Guevara C, Alonso M, Calles MC, Cebolla S, Fernández Ó, Gich J, et al. . Síntomas Invisibles de la Esclerosis Múltiple. Barcelona: Permanyer; (2023).

Marrie RA, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. Comorbidity delays diagnosis and increases disability at diagnosis in MS. Neurology. (2009) 72:117–24. doi: 10.1212/01.wnl.0000333252.78173.5f PubMed DOI PMC

Kister I, Bacon T, Cutter GR. How multiple sclerosis symptoms vary by age, sex, and race/ethnicity. Neurol Clin Pract. (2021) 11:335–41. doi: 10.1212/cpj.0000000000001105 PubMed DOI PMC

Kister I, Bacon TE, Chamot E, Salter AR, Cutter GR, Kalina JT, et al. . Natural history of multiple sclerosis symptoms. Int J MS Care. (2013) 15:146–58. doi: 10.7224/1537-2073.2012-053 PubMed DOI PMC

Wood B, van der Mei I, Ponsonby A-L, Pittas F, Quinn S, Dwyer T, et al. . Prevalence and concurrence of anxiety, depression and fatigue over time in multiple sclerosis. Multiple Sclerosis J. (2013) 19:217–24. doi: 10.1177/1352458512450351 PubMed DOI

Buchanan RJ, Chakravorty BJ, Tyry T, Hatcher W, Vollmer T. Age-related comparisons of people with multiple sclerosis: demographic, disease, and treatment characteristics. NeuroRehabilitation. (2009) 25:271–8. doi: 10.3233/nre-2009-0525 PubMed DOI

Beal CC, Stuifbergen AK, Brown A. Depression in multiple sclerosis: a longitudinal analysis. Arch Psychiatr Nurs. (2007) 21:181–91. doi: 10.1016/j.apnu.2007.02.008 PubMed DOI PMC

Koch MW, Patten S, Berzins S, Zhornitsky S, Greenfield J, Wall W, et al. . Depression in multiple sclerosis: a long-term longitudinal study. Mult Scler. (2015) 21:76–82. doi: 10.1177/1352458514536086 PubMed DOI

Peres DS, Rodrigues P, Viero FT, Frare JM, Kudsi SQ, Meira GM, et al. . Prevalence of depression and anxiety in the different clinical forms of multiple sclerosis and associations with disability: A systematic review and meta-analysis. Brain Behav Immun Health. (2022) 24:100484. doi: 10.1016/j.bbih.2022.100484 PubMed DOI PMC

Mirmosayyeb O, Brand S, Barzegar M, Afshari-Safavi A, Nehzat N, Shaygannejad V, et al. . Clinical characteristics and disability progression of early- and late-onset multiple sclerosis compared to adult-onset multiple sclerosis. J Clin Med. (2020) 9(5):1326. doi: 10.3390/jcm9051326 PubMed DOI PMC

Lotti C. B., Oliveira A. S. B., Bichuetti D. B., de Castro I., Oliveira E. M. L. Late onset multiple sclerosis: concerns in aging patients. Arquivos Neuro-Psiquiatria. (2017) 75 (7). doi: 10.1590/0004-282x20170070 PubMed DOI

Shirani A, Zhao Y, Petkau J, Gustafson P, Karim ME, Evans C, et al. . Multiple sclerosis in older adults: the clinical profile and impact of interferon Beta treatment. BioMed Res Int. (2015) 2015:451912. doi: 10.1155/2015/451912 PubMed DOI PMC

Scalfari A, Neuhaus A, Daumer M, Ebers GC, Muraro PA. Age and disability accumulation in multiple sclerosis. Neurology. (2011) 77:1246–52. doi: 10.1212/WNL.0b013e318230a17d PubMed DOI PMC

Moura J, Duarte S, Oliveira V, Pereira D, Costa D, Samões R, et al. . Characterization of a late-onset multiple sclerosis Portuguese cohort. Mult Scler Relat Disord. (2023) 70:104506. doi: 10.1016/j.msard.2023.104506 PubMed DOI

Guillemin F, Baumann C, Epstein J, Kerschen P, Garot T, Mathey G, et al. . Older age at multiple sclerosis onset is an independent factor of poor prognosis: A population-based cohort study. Neuroepidemiology. (2017) 48:179–87. doi: 10.1159/000479516 PubMed DOI

Cortese M, Bjornevik K, Chitnis T, Ascherio A, Munger KL. Aging with multiple sclerosis: A longitudinal study of physical function, mental health, and memory in two cohorts of US women. Mult Scler. (2022) 28:121–31. doi: 10.1177/13524585211007739 PubMed DOI PMC

Lublin FD, Häring DA, Ganjgahi H, Ocampo A, Hatami F, Čuklina J, et al. . How patients with multiple sclerosis acquire disability. Brain. (2022) 145:3147–61. doi: 10.1093/brain/awac016 PubMed DOI PMC

Hosseini Z, Homayuni A, Etemadifar M. Barriers to quality of life in patients with multiple sclerosis: a qualitative study. BMC Neurol. (2022) 22:174. doi: 10.1186/s12883-022-02700-7 PubMed DOI PMC

Gil-González I, Martín-Rodríguez A, Conrad R, Pérez-San-Gregorio MÁ. Quality of life in adults with multiple sclerosis: a systematic review. BMJ Open. (2020) 10:e041249. doi: 10.1136/bmjopen-2020-041249 PubMed DOI PMC

Pike J, Jones E, Rajagopalan K, Piercy J, Anderson P. Social and economic burden of walking and mobility problems in multiple sclerosis. BMC Neurol. (2012) 12:94. doi: 10.1186/1471-2377-12-94 PubMed DOI PMC

Fernandez O, Costa-Frossard L, Martínez-Ginés ML, Montero P, Prieto-González JM, Ramió-Torrentà L. Integrated management of multiple sclerosis spasticity and associated symptoms using the spasticity-plus syndrome concept: results of a structured specialists’ Discussion using the workmat(®) methodology. Front Neurol. (2021) 12:722801. doi: 10.3389/fneur.2021.722801 PubMed DOI PMC

Williams AE, Vietri JT, Isherwood G, Flor A. Symptoms and association with health outcomes in relapsing-remitting multiple sclerosis: results of a US patient survey. Mult Scler Int. (2014) 2014:203183. doi: 10.1155/2014/203183 PubMed DOI PMC

Buhse M, Banker WM, Clement LM. Factors associated with health-related quality of life among older people with multiple sclerosis. Int J MS Care. (2014) 16:10–9. doi: 10.7224/1537-2073.2012-046 PubMed DOI PMC

Stromillo ML, Giorgio A, Rossi F, Battaglini M, Hakiki B, Malentacchi G, et al. . Brain metabolic changes suggestive of axonal damage in radiologically isolated syndrome. Neurology. (2013) 80:2090–4. doi: 10.1212/WNL.0b013e318295d707 PubMed DOI

Gärtner J, Chitnis T, Ghezzi A, Pohl D, Brück W, Häring DA, et al. . Relapse rate and MRI activity in young adult patients with multiple sclerosis: A post hoc analysis of phase 3 fingolimod trials. Mult Scler J Exp Transl Clin. (2018) 4:2055217318778610. doi: 10.1177/2055217318778610 PubMed DOI PMC

Tremlett H, Zhao Y, Joseph J, Devonshire V. and Neurologists* tUC, Relapses in multiple sclerosis are age- and time-dependent. J Neurology Neurosurg Psychiatry. (2008) 79:1368–74. doi: 10.1136/jnnp.2008.145805 PubMed DOI

Scalfari A, Lederer C, Daumer M, Nicholas R, Ebers GC, Muraro PA. The relationship of age with the clinical phenotype in multiple sclerosis. Mult Scler. (2016) 22:1750–8. doi: 10.1177/1352458516630396 PubMed DOI

Koch MW, Mostert J, Zhang Y, Wolinsky JS, Lublin FD, Strijbis EMM, et al. . Association of age with contrast-enhancing lesions across the multiple sclerosis disease spectrum. Neurology. (2021) 97:e1334–e1342. doi: 10.1212/WNL.0000000000012603 PubMed DOI PMC

Papadopoulos D, Magliozzi R, Mitsikostas DD, Gorgoulis VG, Nicholas RS. Aging, cellular senescence, and progressive multiple sclerosis. Front Cell Neurosci. (2020) 14:178. doi: 10.3389/fncel.2020.00178 PubMed DOI PMC

Frischer JM, Weigand SD, Guo Y, Kale N, Parisi JE, Pirko I, et al. . Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol. (2015) 78:710–21. doi: 10.1002/ana.24497 PubMed DOI PMC

Hemmer B, Kerschensteiner M, Korn T. Role of the innate and adaptive immune responses in the course of multiple sclerosis. Lancet Neurol. (2015) 14:406–19. doi: 10.1016/s1474-4422(14)70305-9 PubMed DOI

Eschborn M, Pawlitzki M, Wirth T, Nelke C, Pfeuffer S, Schulte-Mecklenbeck A, et al. . Evaluation of age-dependent immune signatures in patients with multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. (2021) 8(6):e1094. doi: 10.1212/nxi.0000000000001094 PubMed DOI PMC

Rommer PS, Bsteh G, Zrzavy T, Hoeftberger R, Berger T. Immunosenescence in neurological diseases-is there enough evidence? Biomedicines. (2022) 10(11):2864. doi: 10.3390/biomedicines10112864 PubMed DOI PMC

Macaron G, Larochelle C, Arbour N, Galmard M, Girard JM, Prat A, et al. . Impact of aging on treatment considerations for multiple sclerosis patients. Front Neurol. (2023) 14:1197212. doi: 10.3389/fneur.2023.1197212 PubMed DOI PMC

Perdaens O, van Pesch V. Molecular mechanisms of immunosenescene and inflammaging: relevance to the immunopathogenesis and treatment of multiple sclerosis. Front Neurol. (2021) 12:811518. doi: 10.3389/fneur.2021.811518 PubMed DOI PMC

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. (2023) 186:243–78. doi: 10.1016/j.cell.2022.11.001 PubMed DOI

Neumann B, Segel M, Chalut KJ, Franklin RJ. Remyelination and ageing: Reversing the ravages of time. Mult Scler. (2019) 25:1835–41. doi: 10.1177/1352458519884006 PubMed DOI PMC

Krysko KM, Henry RG, Cree BAC, Lin J, Caillier S, Santaniello A, et al. . Telomere length is associated with disability progression in multiple sclerosis. Ann Neurol. (2019) 86:671–82. doi: 10.1002/ana.25592 PubMed DOI PMC

Kuhlmann T, Moccia M, Coetzee T, Cohen JA, Correale J, Graves J, et al. . Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol. (2023) 22:78–88. doi: 10.1016/s1474-4422(22)00289-7 PubMed DOI PMC

Capkun G, Dahlke F, Lahoz R, Nordstrom B, Tilson HH, Cutter G, et al. . Mortality and comorbidities in patients with multiple sclerosis compared with a population without multiple sclerosis: An observational study using the US Department of Defense administrative claims database. Multiple Sclerosis Related Disord. (2015) 4:546–54. doi: 10.1016/j.msard.2015.08.005 PubMed DOI

Murtonen A, Kurki S, Hänninen K, Soilu-Hänninen M, Sumelahti ML. Common comorbidities and survival in MS: Risk for stroke, type 1 diabetes and infections. Mult Scler Relat Disord. (2018) 19:109–14. doi: 10.1016/j.msard.2017.10.019 PubMed DOI

Castelo-Branco A, Chiesa F, Bengtsson CE, Lee S, Minton NN, Niemcryk S, et al. . Non-infectious comorbidity in patients with multiple sclerosis: A national cohort study in Sweden. Mult Scler J Exp Transl Clin. (2020) 6:2055217320947761. doi: 10.1177/2055217320947761 PubMed DOI PMC

Laroni A, Signori A, Maniscalco GT, Lanzillo R, Russo CV, Binello E, et al. . Assessing association of comorbidities with treatment choice and persistence in MS: A real-life multicenter study. Neurology. (2017) 89:2222–9. doi: 10.1212/wnl.0000000000004686 PubMed DOI

Ostolaza A, Corroza J, Ayuso T. Multiple sclerosis and aging: comorbidity and treatment challenges. Mult Scler Relat Disord. (2021) 50:102815. doi: 10.1016/j.msard.2021.102815 PubMed DOI

Marrie RA, Maxwell C, Mahar A, Ekuma O, McClintock C, Seitz D, et al. . Colorectal cancer survival in multiple sclerosis. A Matched Cohort Study. (2021) 97:e1447–56. doi: 10.1212/wnl.0000000000012634 PubMed DOI PMC

GianFrancesco MA, Barcellos LF. Obesity and multiple sclerosis susceptibility: A review. J Neurol Neuromedicine. (2016) 1:1–5. doi: 10.29245/2572.942x/2016/7.1064 PubMed DOI PMC

Schreiner TG, Genes TM. Obesity and multiple sclerosis-A multifaceted association. J Clin Med. (2021) 10(12):2689. doi: 10.3390/jcm10122689 PubMed DOI PMC

Wingerchuk DM. Smoking: effects on multiple sclerosis susceptibility and disease progression. Ther Adv Neurol Disord. (2012) 5:13–22. doi: 10.1177/1756285611425694 PubMed DOI PMC

Manouchehrinia A, Huang J, Hillert J, Alfredsson L, Olsson T, Kockum I, et al. . Smoking attributable risk in multiple sclerosis. Front Immunol. (2022) 13:840158. doi: 10.3389/fimmu.2022.840158 PubMed DOI PMC

Kleerekooper I, Chua S, Foster PJ, Trip SA, Plant GT, Petzold A, et al. . Associations of alcohol consumption and smoking with disease risk and neurodegeneration in individuals with multiple sclerosis in the United Kingdom. JAMA Netw Open. (2022) 5:e220902. doi: 10.1001/jamanetworkopen.2022.0902 PubMed DOI PMC

Mokry LE, Ross S, Timpson NJ, Sawcer S, Davey Smith G, Richards JB. Obesity and multiple sclerosis: A mendelian randomization study. PloS Med. (2016) 13:e1002053. doi: 10.1371/journal.pmed.1002053 PubMed DOI PMC

Langford A, Langer-Gould A, Zhang J. Are obesity and tobacco smoke risk factors for conversion from clinically isolated syndrome to multiple sclerosis? Neurology. (2013) 80:P05.140–P05.140. doi: 10.1212/WNL.80.7_supplement.P05.140 DOI

Wu J, Olsson T, Hillert J, Alfredsson L, Hedström AK. Influence of oral tobacco versus smoking on multiple sclerosis disease activity and progression. J Neurology Neurosurg Psychiatry. (2023) 94:589–96. doi: 10.1136/jnnp-2022-330848 PubMed DOI PMC

Lutfullin I, Eveslage M, Bittner S, Antony G, Flaskamp M, Luessi F, et al. . Association of obesity with disease outcome in multiple sclerosis. J Neurology Neurosurg Psychiatry. (2023) 94:57–61. doi: 10.1136/jnnp-2022-329685 PubMed DOI PMC

Degelman ML, Herman KM. Smoking and multiple sclerosis: A systematic review and meta-analysis using the Bradford Hill criteria for causation. Mult Scler Relat Disord. (2017) 17:207–16. doi: 10.1016/j.msard.2017.07.020 PubMed DOI

Society M. Review of the evidence on smoking and MS . Available online at: https://www.mssociety.org.uk/sites/default/files/2021-11/Smoking%20and%20MS%20Evidence%20Review.pdf.

Almramhi MM, Storm CS, Kia DA, Coneys R, Chhatwal BK, Wood NW. The role of body fat in multiple sclerosis susceptibility and severity: A Mendelian randomisation study. Multiple Sclerosis J. (2022) 28:1673–84. doi: 10.1177/13524585221092644 PubMed DOI

Thelen J, Zvonarev V, Lam S, Burkhardt C, Lynch S, Bruce J. Polypharmacy in multiple sclerosis: current knowledge and future directions. Mo Med. (2021) 118:239–45. PubMed PMC

Chertcoff A, Ng HS, Zhu F, Zhao Y, Tremlett H. Polypharmacy and multiple sclerosis: A population-based study. Multiple Sclerosis J. (2023) 29:107–18. doi: 10.1177/13524585221122207 PubMed DOI PMC

Marrie RA, Fisk JD, Walld R, Bolton JM, Sareen J, Patten SB, et al. . Use of benzodiazepines and Z-drugs in multiple sclerosis. Front Neurol. (2022) 13:874724. doi: 10.3389/fneur.2022.874724 PubMed DOI PMC

Bakirtzis C, Nikolaidis I, Boziki MK, Grigoriadou E, Karakasi MV, Moysiadis T, et al. . Epidemiological insights on medication concurrency and polypharmacy in people with multiple sclerosis in Greece. Int J MS Care. (2023) 25:140–4. doi: 10.7224/1537-2073.2022-046 PubMed DOI PMC

Debus JL, Bachmann P, Frahm N, Mashhadiakbar P, Langhorst SE, Streckenbach B, et al. . Associated factors of potential drug-drug interactions and drug-food interactions in patients with multiple sclerosis. Ther Adv Chronic Dis. (2022) 13:20406223221108391. doi: 10.1177/20406223221108391 PubMed DOI PMC

Rawle MJ, Cooper R, Kuh D, Richards M. Associations between polypharmacy and cognitive and physical capability: A british birth cohort study. J Am Geriatr Soc. (2018) 66:916–23. doi: 10.1111/jgs.15317 PubMed DOI PMC

Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontology. (2003) 38:843–53. doi: 10.1016/S0531-5565(03)00133-5 PubMed DOI

Magyari M, Sorensen PS. Comorbidity in multiple sclerosis. Front Neurol. (2020) 11:851. doi: 10.3389/fneur.2020.00851 PubMed DOI PMC

Bove R, Okai A, Houtchens M, Elias-Hamp B, Lugaresi A, Hellwig K, et al. . Effects of menopause in women with multiple sclerosis: an evidence-based review. Front Neurol. (2021) 12:554375. doi: 10.3389/fneur.2021.554375 PubMed DOI PMC

Baroncini D, Annovazzi PO, Rossi ND, Mallucci G, Clerici VT, Tonietti S, et al. . Impact of natural menopause on multiple sclerosis: a multicentre study. J Neurology Neurosurg Psychiatry. (2019) 90:1201–6. doi: 10.1136/jnnp-2019-320587 PubMed DOI

Ladeira F, Salavisa M, Caetano A, Barbosa R, Sá F, Correia Ana S. The influence of menopause in multiple sclerosis course: A longitudinal cohort study. Eur Neurol. (2019) 80:223–7. doi: 10.1159/000496374 PubMed DOI

Bridge F, Butzkueven H, van der Walt A, Jokubaitis VG. The impact of menopause on multiple sclerosis. Autoimmun Rev. (2023) 22:103363. doi: 10.1016/j.autrev.2023.103363 PubMed DOI

Lorefice L, D’Alterio MN, Firinu D, Fenu G, Cocco E. Impact of menopause in patients with multiple sclerosis: current perspectives. Int J Women’s Health. (2023) 15:103–9. doi: 10.2147/IJWH.S334719 PubMed DOI PMC

Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, et al. . Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol. (1996) 39:285–94. doi: 10.1002/ana.410390304 PubMed DOI

Hartung H-P, Gonsette R, Konig N, Kwiecinski H, Guseo A, Morrissey SP, et al. . Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. (2002) 360:2018–25. doi: 10.1016/S0140-6736(02)12023-X PubMed DOI

Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. . A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. (2010) 362:387–401. doi: 10.1056/NEJMoa0909494 PubMed DOI

Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. . Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. New Engl J Med. (2012) 367:1087–97. doi: 10.1056/NEJMoa1206328 PubMed DOI

Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. . Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. (2010) 362:402–15. doi: 10.1056/NEJMoa0907839 PubMed DOI

Miller AE, Wolinsky JS, Kappos L, Comi G, Freedman MS, Olsson TP, et al. . Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. (2014) 13:977–86. doi: 10.1016/s1474-4422(14)70191-7 PubMed DOI

Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. . Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. (2012) 367:1098–107. doi: 10.1056/NEJMoa1114287 PubMed DOI

Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et al. . Ocrelizumab versus placebo in primary progressive multiple sclerosis. New Engl J Med. (2016) 376:209–20. doi: 10.1056/NEJMoa1606468 PubMed DOI

Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al. . Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. (2017) 376:221–34. doi: 10.1056/NEJMoa1601277 PubMed DOI

Comi G, Kappos L, Selmaj KW, Bar-Or A, Arnold DL, Steinman L, et al. . Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Lancet Neurol. (2019) 18:1009–20. doi: 10.1016/S1474-4422(19)30239-X PubMed DOI

Hauser SL, Bar-Or A, Cohen JA, Comi G, Correale J, Coyle PK, et al. . Ofatumumab versus teriflunomide in multiple sclerosis. New Engl J Med. (2020) 383:546–57. doi: 10.1056/NEJMoa1917246 PubMed DOI

The IFNB Multiple Sclerosis Study Group . Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology. (1993) 43:655–61. doi: 10.1212/WNL.43.4.655 PubMed DOI

Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. . Placebo-controlled trial of natalizumab for relapsing multiple sclerosis. New Engl J Med. (2006) 354:899–910. doi: 10.1056/NEJMoa044397 PubMed DOI

Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, et al. . The CAMMS223 trial investigators, alemtuzumab vs. Interferon beta-1a in early multiple sclerosis. New Engl J Med. (2008) 359:1786–801. doi: 10.1056/NEJMoa0802670 PubMed DOI

Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, et al. . Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. (2012) 380:1819–28. doi: 10.1016/s0140-6736(12)61769-3 PubMed DOI

Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, et al. . Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Copolymer 1 Multiple Sclerosis Study Group Neurol. (1995) 45:1268–76. doi: 10.1212/wnl.45.7.1268 PubMed DOI

Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, et al. . Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. (2018) 391:1263–73. doi: 10.1016/S0140-6736(18)30475-6 PubMed DOI

Ebers GC. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet. (1998) 352:1498–504. PubMed

Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, et al. . A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. (2006) 354:899–910. doi: 10.1056/NEJMoa044397 PubMed DOI

O'Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al. . Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. (2011) 365:1293–303. doi: 10.1056/NEJMoa1014656 PubMed DOI

Confavreux C, O'Connor P, Comi G, Freedman MS, Miller AE, Olsson TP, et al. . Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. (2014) 13:247–56. doi: 10.1016/s1474-4422(13)70308-9 PubMed DOI

Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, et al. . Alemtuzumab vs. Interferon beta-1a early multiple sclerosis. N Engl J Med. (2008) 359:1786–801. doi: 10.1056/NEJMoa0802670 PubMed DOI

Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Sørensen PS, et al. . A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. New Engl J Med. (2010) 362:416–26. doi: 10.1056/NEJMoa0902533 PubMed DOI

Comi G, Bermel R, Bar-Or A, McGinley M, Arnold D, Henry R, et al. . A multicentre, open label, single-arm, phase 3b study (CONSONANCE) to assess the effectiveness and safety of ocrelizumab in patients with primary and secondary progressive multiple sclerosis: year-1 interim analysis (P1-1.Virtual). Neurology. (2022) 98:652. doi: 10.1212/WNL.98.18_supplement.652 DOI

Kappos L, Fox RJ, Burcklen M, Freedman MS, Havrdová EK, Hennessy B, et al. . Ponesimod compared with teriflunomide in patients with relapsing multiple sclerosis in the active-comparator phase 3 OPTIMUM study: A randomized clinical trial. JAMA Neurol. (2021) 78:558–67. doi: 10.1001/jamaneurol.2021.0405 PubMed DOI PMC

Hutchinson M, Kappos L, Calabresi PA, Confavreux C, Giovannoni G, Galetta SL, et al. . The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL. J Neurol. (2009) 256:405–15. doi: 10.1007/s00415-009-0093-1 PubMed DOI

Giovannoni G, Cook S, Rammohan K, Rieckmann P, Sørensen PS, Vermersch P, et al. . Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. Lancet Neurol. (2011) 10:329–37. doi: 10.1016/S1474-4422(11)70023-0 PubMed DOI

Newsome SD, Kieseier BC, Arnold DL, Shang S, Liu S, Hung S, et al. . Subgroup and sensitivity analyses of annualized relapse rate over 2 years in the ADVANCE trial of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis. J Neurol. (2016) 263:1778–87. doi: 10.1007/s00415-016-8182-4 PubMed DOI PMC

Cohen JA, Gold R, de Sèze J, Robertson D, Wiendl H, Wray S, et al. . (2022). Efficacy of early ofatumumab versus late-switch from teriflunomide: subgroup analysis of the ALITHIOS open-label extension study by prior disease-modifying therapy exposure and age, in: 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, Amsterdam, Netherlands, 2022 Oct 26-28.

Bass AD, Arroyo R, Boster AL, Boyko AN, Eichau S, Ionete C, et al. . Alemtuzumab outcomes by age: Post hoc analysis from the randomized CARE-MS studies over 8 years. Mult Scler Relat Disord. (2021) 49:102717. doi: 10.1016/j.msard.2020.102717 PubMed DOI

Miller AE, O’Connor P, Wolinsky JS, Confavreux C, Kappos L, Olsson TP, et al. . Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. Mult Scler. (2012) 18:1625–32. doi: 10.1177/1352458512450354 PubMed DOI PMC

Turner B, Cree BAC, Kappos L, Montalban X, Papeix C, Wolinsky JS, et al. . Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis. J Neurol. (2019) 266:1182–93. doi: 10.1007/s00415-019-09248-6 PubMed DOI PMC

Signori A, Schiavetti I, Gallo F, Sormani MP. Subgroups of multiple sclerosis patients with larger treatment benefits: a meta-analysis of randomized trials. Eur J Neurol. (2015) 22:960–6. doi: 10.1111/ene.12690 PubMed DOI

Weideman AM, Tapia-Maltos MA, Johnson K, Greenwood M, Bielekova B. Meta-analysis of the age-dependent efficacy of multiple sclerosis treatments. Front Neurol. (2017) 8:577. doi: 10.3389/fneur.2017.00577 PubMed DOI PMC

Zhang Y, Gonzalez Caldito N, Shirani A, Salter A, Cutter G, Culpepper W. 2nd, et al. Aging efficacy disease-modifying therapies multiple sclerosis: meta-analysis Clin trials. Ther Adv Neurol Disord. (2020) 13:1756286420969016. doi: 10.1177/1756286420969016 PubMed DOI PMC

Wray S, Then Bergh F, Wundes A, Arnold DL, Drulovic J, Jasinska E, et al. . Efficacy and safety outcomes with diroximel fumarate after switching from prior therapies or continuing on DRF: results from the phase 3 EVOLVE-MS-1 study. Adv Ther. (2022) 39:1810–31. doi: 10.1007/s12325-022-02068-7 PubMed DOI PMC

Roche H-L. A study to evaluate ocrelizumab treatment in participants with progressive multiple sclerosis (CONSONANCE); NCT03523858 . Available online at: https://classic.clinicaltrials.gov/ct2/show/NCT03523858.

Roche H-L. This is an extension study of the roche P-trials to investigate safety and effectiveness of ocrelizumab in participants with multiple sclerosis (MS); NCT03599245 . Available online at: https://classic.clinicaltrials.gov/ct2/show/NCT03599245.

Comi G BR, Bar-Or A, McGinley M, Arnold D, Henry R, Benedict R, et al. . A multicentre, open-label, single-arm, phase 3b study (CONSONANCE) to assess the effectiveness and safety of ocrelizumab in patients with primary and secondary progressive multiple sclerosis: Year 2 interim analysis, in: 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS 2022), , 26–28 October 2022. Amsterdam, Netherlands.

Vollmer BL, Wolf AB, Sillau S, Corboy JR, Alvarez E. Evolution of disease modifying therapy benefits and risks: an argument for de-escalation as a treatment paradigm for patients with multiple sclerosis. Front Neurol. (2021) 12:799138. doi: 10.3389/fneur.2021.799138 PubMed DOI PMC

Ng HS, Graf J, Zhu F, Kingwell E, Aktas O, Albrecht P, et al. . Disease-modifying drug uptake and health service use in the ageing MS population. Front Immunol. (2022) 12:794075. doi: 10.3389/fimmu.2021.794075 PubMed DOI PMC

Amato MP, Fonderico M, Portaccio E, Pastò L, Razzolini L, Prestipino E, et al. . Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis. Brain. (2020) 143:3013–24. doi: 10.1093/brain/awaa251 PubMed DOI

Zanghì A, Avolio C, Amato MP, Filippi M, Trojano M, Patti F, et al. . First-line therapies in late-onset multiple sclerosis: An Italian registry study. Eur J Neurol. (2021) 28:4117–23. doi: 10.1111/ene.15006 PubMed DOI PMC

Coyle PK, Gorritz M, Wade RL, Zhou Z, Khalid S, Maiese EM, et al. . Real-world use of ofatumumab to treat multiple sclerosis 9 months post-FDA approval during COVID-19 pandemic. Multiple Sclerosis Related Disord. (2023) 78:104881. doi: 10.1016/j.msard.2023.104881 PubMed DOI

Patti F, Penaherrera JN, Zieger L, Wicklein E-M. Clinical characteristics of middle-aged and older patients with MS treated with interferon beta-1b: post-hoc analysis of a 2-year, prospective, international, observational study. BMC Neurol. (2021) 21:324. doi: 10.1186/s12883-021-02347-w PubMed DOI PMC

Chisari CG, Bianco A, Brescia Morra V, Calabrese M, Capone F, Cavalla P, et al. . Effectiveness of ocrelizumab in primary progressive multiple sclerosis: a multicenter, retrospective, real-world study (OPPORTUNITY). Neurotherapeutics. (2023) 20(6):1696–706. doi: 10.1007/s13311-023-01415-y PubMed DOI PMC

Epstein S, Fong KT, De Jager PL, Levine L, Riley C, Wesley S, et al. . Evaluation of ocrelizumab in older progressive multiple sclerosis patients. Mult Scler Relat Disord. (2021) 55:103171. doi: 10.1016/j.msard.2021.103171 PubMed DOI

Disanto G, Moccia M, Sacco R, Spiezia AL, Carotenuto A, Brescia Morra V, et al. . Monitoring of safety and effectiveness of cladribine in multiple sclerosis patients over 50 years. Mult Scler Relat Disord. (2022) 58:103490. doi: 10.1016/j.msard.2022.103490 PubMed DOI

Grebenciucova E, Berger JR. Immunosenescence: the role of aging in the predisposition to neuro-infectious complications arising from the treatment of multiple sclerosis. Curr Neurol Neurosci Rep. (2017) 17:61. doi: 10.1007/s11910-017-0771-9 PubMed DOI

Goldman MD, Dwyer L, Coleman R, Sohn MW, Stuve O. Patient-specific factors modulate leukocyte response in dimethyl fumarate treated MS patients. PloS One. (2020) 15:e0228617. doi: 10.1371/journal.pone.0228617 PubMed DOI PMC

Vaughn CB, Jakimovski D, Kavak KS, Ramanathan M, Benedict RHB, Zivadinov R, et al. . Epidemiology and treatment of multiple sclerosis in elderly populations. Nat Rev Neurol. (2019) 15:329–42. doi: 10.1038/s41582-019-0183-3 PubMed DOI

Schweitzer F, Laurent S, Fink GR, Barnett MH, Reddel S, Hartung HP, et al. . Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis. Curr Opin Neurol. (2019) 32:305–12. doi: 10.1097/wco.0000000000000701 PubMed DOI

Jordan AL, Yang J, Fisher CJ, Racke MK, Mao-Draayer Y. Progressive multifocal leukoencephalopathy in dimethyl fumarate-treated multiple sclerosis patients. Mult Scler. (2022) 28:7–15. doi: 10.1177/1352458520949158 PubMed DOI PMC

Prosperini L, Scarpazza C, Imberti L, Cordioli C, De Rossi N, Capra R. Age as a risk factor for early onset of natalizumab-related progressive multifocal leukoencephalopathy. J NeuroVirology. (2017) 23:742–9. doi: 10.1007/s13365-017-0561-9 PubMed DOI

Schwab N, Schneider-Hohendorf T, Hoyt T, Gross CC, Meuth SG, Klotz L, et al. . Anti-JCV serology during natalizumab treatment: Review and meta-analysis of 17 independent patient cohorts analyzing anti-John Cunningham polyoma virus sero-conversion rates under natalizumab treatment and differences between technical and biological sero-converters. Multiple Sclerosis J. (2018) 24:563–73. doi: 10.1177/1352458517728814 PubMed DOI

Nakahara J, Tomaske L, Kume K, Takata T, Kamada M, Deguchi K, et al. . Three cases of non-carryover fingolimod-PML: Is the risk in Japan increased? Neurol Neuroimmunol Neuroinflamm. (2019) 6:e559. doi: 10.1212/nxi.0000000000000559 PubMed DOI PMC

Berger JR, Cree BA, Greenberg B, Hemmer B, Ward BJ, Dong VM, et al. . Progressive multifocal leukoencephalopathy after fingolimod treatment. Neurology. (2018) 90:e1815–21. doi: 10.1212/wnl.0000000000005529 PubMed DOI PMC

Prosperini L, de Rossi N, Scarpazza C, Moiola L, Cosottini M, Gerevini S, et al. . Natalizumab-related progressive multifocal leukoencephalopathy in multiple sclerosis: findings from an italian independent registry. PloS One. (2016) 11:e0168376. doi: 10.1371/journal.pone.0168376 PubMed DOI PMC

Jakimovski D, Eckert SP, Zivadinov R, Weinstock-Guttman B. Considering patient age when treating multiple sclerosis across the adult lifespan. Expert Rev Neurother. (2021) 21:353–64. doi: 10.1080/14737175.2021.1886082 PubMed DOI

Grebenciucova E, Reder AT, Bernard JT. Immunologic mechanisms of fingolimod and the role of immunosenescence in the risk of cryptococcal infection: A case report and review of literature. Mult Scler Relat Disord. (2016) 9:158–62. doi: 10.1016/j.msard.2016.07.015 PubMed DOI

Habek M, Piskač D, Gabelić T, Barun B, Adamec I, Krbot Skorić M. Hypogammaglobulinemia, infections and COVID-19 in people with multiple sclerosis treated with ocrelizumab. Mult Scler Relat Disord. (2022) 62:103798. doi: 10.1016/j.msard.2022.103798 PubMed DOI PMC

Fuchs TA, Wattengel BA, Carter MT, El-Solh AA, Lesse AJ, Mergenhagen KA. Outcomes of multiple sclerosis patients admitted with COVID-19 in a large veteran cohort. Mult Scler Relat Disord. (2022) 64:103964. doi: 10.1016/j.msard.2022.103964 PubMed DOI PMC

Simpson-Yap S, Brouwer ED, Kalincik T, Rijke N, Hillert JA, Walton C, et al. . Associations of disease-modifying therapies with COVID-19 severity in multiple sclerosis. Neurology. (2021) 97:e1870–85. doi: 10.1212/wnl.0000000000012753 PubMed DOI PMC

Louapre C, Collongues N, Stankoff B, Giannesini C, Papeix C, Bensa C, et al. . Clinical characteristics and outcomes in patients with coronavirus disease 2019 and multiple sclerosis. JAMA Neurol. (2020) 77:1079–88. doi: 10.1001/jamaneurol.2020.2581 PubMed DOI PMC

Zecca C, Gobbi C. Long-term treatment with anti-CD20 monoclonal antibodies is untenable because of risk: YES. Multiple Sclerosis J. (2022) 28:1173–1175. doi: 10.1177/13524585221088734 PubMed DOI

Prosperini L, Haggiag S, Tortorella C, Galgani S, Gasperini C. Age-related adverse events of disease-modifying treatments for multiple sclerosis: A meta-regression. Mult Scler. (2021) 27:1391–402. doi: 10.1177/1352458520964778 PubMed DOI

Buscarinu MC, Reniè R, Morena E, Romano C, Bellucci G, Marrone A, et al. . Late-onset MS: disease course and safety-efficacy of DMTS. Front Neurol. (2022) 13:829331. doi: 10.3389/fneur.2022.829331 PubMed DOI PMC

Negroski D, Sellers D, Khiabani A, Khiabani D. Real-world experience switching from high-efficacy infusions to cladribine tablets (EP1055). ECTRIMS; 2022. Amsterdam: Multiple Sclerosis J. (2022) 28:692–945. doi: 10.1016/j.msard.2022.104491 DOI

Giovannoni G, Coyle PK, Vermersch P, Walker B, Aldridge J, Nolting A, et al. . Integrated lymphopenia analysis in younger and older patients with multiple sclerosis treated with cladribine tablts. Front Immunol. (2021) 12:763433. doi: 10.3389/fimmu.2021.763433 PubMed DOI PMC

Talwar A, Earla JR, Hutton GJ, Aparasu RR. Prescribing of disease modifying agents in older adults with multiple sclerosis. Mult Scler Relat Disord. (2022) 57:103308. doi: 10.1016/j.msard.2021.103308 PubMed DOI

Filippi M, Amato MP, Centonze D, Gallo P, Gasperini C, Inglese M, et al. . Early use of high-efficacy disease−modifying therapies makes the difference in people with multiple sclerosis: an expert opinion. J Neurol. (2022) 269:5382–94. doi: 10.1007/s00415-022-11193-w PubMed DOI PMC

Hartung H-P, Meuth SG, Thompson AJ. Paradigm shifts: Early initiation of high-efficacy disease-modifying treatment in multiple sclerosis. Multiple Sclerosis J. (2021) 27:1473–6. doi: 10.1177/13524585211033190 PubMed DOI

Freeman L, Longbrake EE, Coyle PK, Hendin B, Vollmer T. High-efficacy therapies for treatment-naïve individuals with relapsing–remitting multiple sclerosis. CNS Drugs. (2022) 36:1285–99. doi: 10.1007/s40263-022-00965-7 PubMed DOI PMC

Wiendl H, Gold R, Zipp F, Berger T, Deisenhammer F, Di Pauli F, et al. . Multiple sclerosis therapy consensus group (MSTCG): answers to the discussion questions. Neurological Res Pract. (2021) 3:44. doi: 10.1186/s42466-021-00140-1 PubMed DOI PMC

Trojano M, Kalincik T, Iaffaldano P, Amato MP. Interrogating large multiple sclerosis registries and databases: what information can be gained? Curr Opin Neurol. (2022) 35:271–7. doi: 10.1097/wco.0000000000001057 PubMed DOI

Selmaj K, Cree BAC, Barnett M, Thompson A, Hartung H-P. Multiple sclerosis: time for early treatment with high-efficacy drugs. J Neurol. (2024) 271(1):105–15. doi: 10.1007/s00415-023-11969-8 PubMed DOI PMC

Iaffaldano P, Lucisano G, Caputo F, Paolicelli D, Patti F, Zaffaroni M, et al. . Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies. Ther Adv Neurological Disord. (2021) 14:17562864211019574. doi: 10.1177/17562864211019574 PubMed DOI PMC

Buron MD, Chalmer TA, Sellebjerg F, Barzinji I, Bech D, Christensen JR, et al. . Initial high-efficacy disease-modifying therapy in multiple sclerosis. A nationwide cohort study. (2020) 95:e1041–51. doi: 10.1212/wnl.0000000000010135 PubMed DOI

Filippi M, Rocca MA. Rethinking multiple sclerosis treatment strategies. Lancet Neurol. (2020) 19:281–2. doi: 10.1016/S1474-4422(20)30063-6 PubMed DOI

Sorensen PS, Kopp TI, Joensen H, Olsson A, Sellebjerg F, Magyari M. Age and sex as determinants of treatment decisions in patients with relapsing-remitting MS. Mult Scler Relat Disord. (2021) 50:102813. doi: 10.1016/j.msard.2021.102813 PubMed DOI

Hartung HP, Meuth SG, Miller DM, Comi G. Stopping disease-modifying therapy in relapsing and progressive multiple sclerosis. Curr Opin Neurol. (2021) 34:598–603. doi: 10.1097/wco.0000000000000960 PubMed DOI

Bsteh G, Feige J, Ehling R, Auer M, Hegen H, Di Pauli F, et al. . Discontinuation of disease-modifying therapies in multiple sclerosis - Clinical outcome and prognostic factors. Mult Scler. (2017) 23:1241–8. doi: 10.1177/1352458516675751 PubMed DOI

Corboy JR, Fox RJ, Kister I, Cutter GR, Morgan CJ, Seale R, et al. . Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial. Lancet Neurol. (2023) 22:568–77. doi: 10.1016/s1474-4422(23)00154-0 PubMed DOI

Jakimovski D, Kavak KS, Vaughn CB, Goodman AD, Coyle PK, Krupp L, et al. . Discontinuation of disease modifying therapies is associated with disability progression regardless of prior stable disease and age. Multiple Sclerosis Related Disord. (2022) 57:103406. doi: 10.1016/j.msard.2021.103406 PubMed DOI

Coerver EME, Bourass A, Wessels MHJ, van Kempen ZLE, Jasperse MMS, Tonino BAR, et al. . Discontinuation of first-line disease-modifying therapy in relapse onset multiple sclerosis. Mult Scler Relat Disord. (2023) 74:104706. doi: 10.1016/j.msard.2023.104706 PubMed DOI

Kaminsky AL, Omorou AY, Soudant M, Pittion-Vouyovitch S, Michaud M, Anxionnat R, et al. . Discontinuation of disease-modifying treatments for multiple sclerosis in patients aged over 50 with disease Inactivity. J Neurol. (2020) 267:3518–27. doi: 10.1007/s00415-020-10029-9 PubMed DOI

Chappuis M, Rousseau C, Bajeux E, Wiertlewski S, Laplaud D, Le Page E, et al. . Discontinuation of second- versus first-line disease-modifying treatment in middle-aged patients with multiple sclerosis. J Neurol. (2023) 270:413–22. doi: 10.1007/s00415-022-11341-2 PubMed DOI

Fagius J, Feresiadou A, Larsson EM, Burman J. Discontinuation of disease modifying treatments in middle aged multiple sclerosis patients. First line Drugs vs natalizumab. Mult Scler Relat Disord. (2017) 12:82–7. doi: 10.1016/j.msard.2017.01.009 PubMed DOI

Bonenfant J, Bajeux E, Deburghgraeve V, Le Page E, Edan G, Kerbrat A. Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis? Eur J Neurol. (2017) 24:237–44. doi: 10.1111/ene.13181 PubMed DOI

Goldschmidt CH, Glassman J, Ly B, Harvey T, Hua LE. A Retrospective Study on the Effects of De-Escalation of Disease-Modifying Therapy in Patients With Multiple Sclerosis. Presented at: 2023 CMSC Annual Meeting; May 31 to June 3; Aurora, CO. DMT01.

Montalban X, Gold R, Thompson AJ, Otero-Romero S, Amato MP, Chandraratna D, et al. . ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Eur J Neurol. (2018) 25:215–37. doi: 10.1111/ene.13536 PubMed DOI

Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS, et al. . Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis. Rep Guideline Development Dissemination Implementation Subcommittee Am Acad Neurol. (2018) 90:789–800. doi: 10.1212/wnl.0000000000005345 PubMed DOI

Krämer J, Bar-Or A, Turner TJ, Wiendl H. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat Rev Neurol. (2023) 19:289–304. doi: 10.1038/s41582-023-00800-7 PubMed DOI PMC

Ringheim GE, Wampole M, Oberoi K. Bruton's tyrosine kinase (BTK) inhibitors and autoimmune diseases: making sense of BTK inhibitor specificity profiles and recent clinical trial successes and failures. Front Immunol. (2021) 12:662223. doi: 10.3389/fimmu.2021.662223 PubMed DOI PMC

Montalban X, Arnold DL, Weber MS, Staikov I, Piasecka-Stryczynska K, Willmer J, et al. . Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med. (2019) 380:2406–17. doi: 10.1056/NEJMoa1901981 PubMed DOI

Reich DS, Arnold DL, Vermersch P, Bar-Or A, Fox RJ, Matta A, et al. . Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol. (2021) 20:729–38. doi: 10.1016/S1474-4422(21)00237-4 PubMed DOI PMC

group M . Merck provides update on phase III results for evobrutinib in relapsing multiple sclerosis . Available online at: https://www.merckgroup.com/en/news/evobrutinib-phase-lll.html (Accessed December 18, 2023).

Nave K-A. Myelination and the trophic support of long axons. Nat Rev Neurosci. (2010) 11:275–83. doi: 10.1038/nrn2797 PubMed DOI

Duncan ID, Radcliff AB, Heidari M, Kidd G, August BK, Wierenga LA. The adult oligodendrocyte can participate in remyelination. Proc Natl Acad Sci U.S.A. (2018) 115:E11807–e11816. doi: 10.1073/pnas.1808064115 PubMed DOI PMC

Boyd A, Zhang H, Williams A. Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models. Acta Neuropathol. (2013) 125:841–59. doi: 10.1007/s00401-013-1112-y PubMed DOI PMC

Franklin RJM, Frisén J, Lyons DA. Revisiting remyelination: Towards a consensus on the regeneration of CNS myelin. Semin Cell Dev Biol. (2021) 116:3–9. doi: 10.1016/j.semcdb.2020.09.009 PubMed DOI

Cadavid D, Balcer L, Galetta S, Aktas O, Ziemssen T, Vanopdenbosch LJ, et al. . Predictors of response to opicinumab in acute optic neuritis. Ann Clin Transl Neurol. (2018) 5:1154–62. doi: 10.1002/acn3.620 PubMed DOI PMC

Heß K, Starost L, Kieran NW, Thomas C, Vincenten MCJ, Antel J, et al. . Lesion stage-dependent causes for impaired remyelination in MS. Acta Neuropathol. (2020) 140:359–75. doi: 10.1007/s00401-020-02189-9 PubMed DOI PMC

Sim FJ, Zhao C, Penderis J, Franklin RJ. The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. J Neurosci. (2002) 22:2451–9. doi: 10.1523/jneurosci.22-07-02451.2002 PubMed DOI PMC

Franklin RJM. Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci. (2002) 3:705–14. doi: 10.1038/nrn917 PubMed DOI

Lubetzki C, Zalc B, Williams A, Stadelmann C, Stankoff B. Remyelination in multiple sclerosis: from basic science to clinical translation. Lancet Neurol. (2020) 19:678–88. doi: 10.1016/S1474-4422(20)30140-X PubMed DOI

Cree BAC, Cutter G, Wolinsky JS, Freedman MS, Comi G, Giovannoni G, et al. . Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. (2020) 19:988–97. doi: 10.1016/S1474-4422(20)30347-1 PubMed DOI

Tourbah A, Gout O, Vighetto A, Deburghgraeve V, Pelletier J, Papeix C, et al. . MD1003 (High-dose pharmaceutical-grade biotin) for the treatment of chronic visual loss related to optic neuritis in multiple sclerosis: A randomized, double-blind, placebo-controlled study. CNS Drugs. (2018) 32:661–72. doi: 10.1007/s40263-018-0528-2 PubMed DOI PMC

Tourbah A, Lebrun-Frenay C, Edan G, Clanet M, Papeix C, Vukusic S, et al. . MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler. (2016) 22:1719–31. doi: 10.1177/1352458516667568 PubMed DOI PMC

Newsome SD, Tian F, Shoemaker T, Fitzgerald KC, Cassard SD, Fiol J, et al. . A phase 1b, open-label study to evaluate the safety and tolerability of the putative remyelinating agent, liothyronine, in individuals with MS. Neurotherapeutics. (2023) 20:1263–74. doi: 10.1007/s13311-023-01402-3 PubMed DOI PMC

Pelletier J, Ranjeva J-P, Tourbah A, Edan G, Barillot C, Mer SLL, et al. . Results of a Phase 1b study to confirm safety and tolerability of olesoxime in multiple sclerosis patients. Neurology. (2015) 84:P7.282. doi: 10.1212/WNL.84.14 DOI

Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, et al. . Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet. (2017) 390:2481–9. doi: 10.1016/S0140-6736(17)32346-2 PubMed DOI

Metz LM, Cerchiaro G, Almalik Y, Makkawi SO, Zedde A. Quetiapine is not tolerable to people with MS in doses potentially required to enhance myelin repair. Am Acad Neurology. (2020) 94 (15_supplement). doi: 10.1212/WNL.94.15_supplement.2868 DOI

Cadavid D, Mellion M, Hupperts R, Edwards KR, Calabresi PA, Drulović J, et al. . Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. (2019) 18:845–56. doi: 10.1016/s1474-4422(19)30137-1 PubMed DOI

Biogen . Efficacy and safety of BIIB033 (Opicinumab) as an add-on therapy to disease-modifying therapies (DMTs) in relapsing multiple sclerosis (MS) (AFFINITY). Available online at: https://clinicaltrials.gov/study/NCT03222973?tab=results.

Greenberg BM, Bowen JD, Alvarez E, Rodriguez M, Caggiano AO, Warrington AE, et al. . placebo-controlled, single-ascending-dose intravenous infusion study of rHIgM22 in subjects with multiple sclerosis immediately following a relapse. Mult Scler J Exp Transl Clin. (2022) 8:20552173221091475. doi: 10.1177/20552173221091475 PubMed DOI PMC

Metz L. Pilot trial of domperidone in relapsing-remitting multiple sclerosis (RRMS) . Available online at: https://clinicaltrials.gov/study/NCT02493049#collaborators-and-investigators (Accessed October 2, 2023).

Chataway J, De Angelis F, Connick P, Parker RA, Plantone D, Doshi A, et al. . Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. Lancet Neurol. (2020) 19:214–25. doi: 10.1016/S1474-4422(19)30485-5 PubMed DOI PMC

Cree BA, Ziemann A, Pfleeger K, Schwefel B, Wundes A, Freedman MS, et al. . Safety and efficacy of elezanumab in relapsing and progressive forms of multiple sclerosis: results from two phase 2 studies, RADIUS-R and RADIUS-P. Mult Scler J. (2021) 27(2 SUPPL):92–3. doi: 10.1177/13524585211044647 DOI

Willekens B. Metformin add-on clinical study in multiple sclerosis to evaluate brain remyelination and neurodegeneration. Available online at: https://clinicaltrials.gov/study/NCT05893225?cond=Multiple%20Sclerosis&intr=%E2%80%9Cremyelination%E2%80%9D&rank=3#collaborators-and-investigators (Accessed October 2, 2023).

Jones CD, Motl R, Sandroff BM. Depression in multiple sclerosis: Is one approach for its management enough? Multiple Sclerosis Related Disord. (2021) 51:102904. doi: 10.1016/j.msard.2021.102904 PubMed DOI

Raissi A, Bulloch AGM, Fiest KM, McDonald K, Jetté N, Patten SB. Exploration of undertreatment and patterns of treatment of depression in multiple sclerosis. Int J MS Care. (2015) 17:292–300. doi: 10.7224/1537-2073.2014-084 PubMed DOI PMC

Zhang E, Tian X, Li R, Chen C, Li M, Ma L, et al. . Dalfampridine in the treatment of multiple sclerosis: a meta-analysis of randomised controlled trials. Orphanet J Rare Dis. (2021) 16:87. doi: 10.1186/s13023-021-01694-8 PubMed DOI PMC

Shi J, Wu X, Chen Y. Study on Dalfampridine in the treatment of Multiple Sclerosis Mobility Disability: A meta-analysis. PloS One. (2019) 14:e0222288. doi: 10.1371/journal.pone.0222288 PubMed DOI PMC

Valet M, Quoilin M, Lejeune T, Stoquart G, Van Pesch V, El Sankari S, et al. . Effects of fampridine in people with multiple sclerosis: A systematic review and meta-analysis. CNS Drugs. (2019) 33:1087–99. doi: 10.1007/s40263-019-00671-x PubMed DOI

Ghorbanpour S, Rahimibarghani S, Rohani S, Rastkar M, Ghajarzadeh M. Fampridine for gait imbalance in patients with multiple sclerosis (MS): a systematic review and meta-analysis. Neurol Sci. (2023) 44:3059–69. doi: 10.1007/s10072-023-06795-9 PubMed DOI

Fu X, Wang Y, Wang C, Wu H, Li J, Li M, et al. . A mixed treatment comparison on efficacy and safety of treatments for spasticity caused by multiple sclerosis: a systematic review and network meta-analysis. Clin Rehabil. (2018) 32:713–21. doi: 10.1177/0269215517745348 PubMed DOI

Torres-Moreno MC, Papaseit E, Torrens M, Farré M. Assessment of efficacy and tolerability of medicinal cannabinoids in patients with multiple sclerosis: A systematic review and meta-analysis. JAMA Netw Open. (2018) 1:e183485. doi: 10.1001/jamanetworkopen.2018.3485 PubMed DOI PMC

da Rovare VP, Magalhães GPA, Jardini GDA, Beraldo ML, Gameiro MO, Agarwal A, et al. . Cannabinoids for spasticity due to multiple sclerosis or paraplegia: A systematic review and meta-analysis of randomized clinical trials. Complement Ther Med. (2017) 34:170–85. doi: 10.1016/j.ctim.2017.08.010 PubMed DOI

Kleiner D, Horváth IL, Bunduc S, Gergő D, Lugosi K, Fehérvári P, et al. . Nabiximols is efficient as add-on treatment for patients with multiple sclerosis spasticity refractory to standard treatment: A systematic review and meta-analysis of randomised clinical trials. Curr Neuropharmacol. (2023) 21:2505–15. doi: 10.2174/1570159x21666230727094431 PubMed DOI PMC

Hajebrahimi S, Darvishi A, HajEbrahimi R, Asadi N, Jafari Shendi Z, Asiaban N, et al. . Efficacy and safety of desmopressin in nocturia and nocturnal polyuria control of neurological patients: A systematic review and meta-analysis. Neurourol Urodyn. (2024) 43(1):167–82. doi: 10.1002/nau.25291 PubMed DOI

Perez DQ, Espiritu AI, Jamora RDG. Efficacy and safety of amantadine for the treatment of fatigue in multiple sclerosis: a systematic review and meta-analysis. Neurodegener Dis Manag. (2020) 10:383–95. doi: 10.2217/nmt-2020-0030 PubMed DOI

Yang TT, Wang L, Deng XY, Yu G. Pharmacological treatments for fatigue in patients with multiple sclerosis: A systematic review and meta-analysis. J Neurol Sci. (2017) 380:256–61. doi: 10.1016/j.jns.2017.07.042 PubMed DOI

Motavalli A, Majdi A, Hosseini L, Talebi M, Mahmoudi J, Hosseini SH, et al. . Pharmacotherapy in multiple sclerosis-induced cognitive impairment: A systematic review and meta-analysis. Mult Scler Relat Disord. (2020) 46:102478. doi: 10.1016/j.msard.2020.102478 PubMed DOI

Zheng X, Wei W, Liu P, Wu C, Lu L, Tang C. Botulinum toxin type A for hand tremor: a meta-analysis of randomised controlled trials. Neurol Neurochir Pol. (2020) 54:561–7. doi: 10.5603/PJNNS.a2020.0079 PubMed DOI

Pourmohammadi A, Riahi R, Hosseini SM, Adibi I. Pharmacological treatment of tremor in multiple sclerosis; a systematic review. Mult Scler Relat Disord. (2022) 60:103722. doi: 10.1016/j.msard.2022.103722 PubMed DOI

Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage. (2004) 28:140–75. doi: 10.1016/j.jpainsymman.2004.05.002 PubMed DOI

Pöllmann W, Feneberg W, Steinbrecher A, Haupts MR, Henze T. [Therapy of pain syndromes in multiple sclerosis – an overview with evidence-based recommendations]. Fortschr Neurol Psychiatr. (2005) 73:268–85. doi: 10.1055/s-2004-830193 PubMed DOI

Otero-Romero S, Sastre-Garriga J, Comi G, Hartung HP, Soelberg Sørensen P, Thompson AJ, et al. . Pharmacological management of spasticity in multiple sclerosis: Systematic review and consensus paper. Mult Scler. (2016) 22:1386–96. doi: 10.1177/1352458516643600 PubMed DOI

Oreja-Guevara C, Montalban X, de Andrés C, Casanova-Estruch B, Muñoz-García D, García I, et al. . Consensus document on spasticity in patients with multiple sclerosis. Grupo de Enfermedades Desmielinizantes de la Sociedad Española de Neurología. Rev Neurol. (2013) 57:359–73. PubMed

Vollmer TL, Robinson MJ, Risser RC, Malcolm SK. A randomized, double-blind, placebo-controlled trial of duloxetine for the treatment of pain in patients with multiple sclerosis. Pain Pract. (2014) 14:732–44. doi: 10.1111/papr.12127 PubMed DOI

Prnjavorac B, Kunic S, Pejanovic-Skobic N, Gorana NP, Zirojevic D, Vukas SK, et al. . Pregabalin in the treatment of peripheral and central chronic neuropathic pain. Mater Sociomed. (2023) 35:42–7. doi: 10.5455/msm.2023.35.42-47 PubMed DOI PMC

Solaro C, Bergamaschi R, Rezzani C, Mueller M, Trabucco E, Bargiggia V, et al. . Duloxetine is effective in treating depression in multiple sclerosis patients: an open-label multicenter study. Clin Neuropharmacol. (2013) 36:114–6. doi: 10.1097/WNF.0b013e3182996400 PubMed DOI

Carta MG, Paribello P, Anastasia A, De Berardis D, Nardi AE, Fornaro M. Pharmacological management of depression in patients with multiple sclerosis. Expert Opin Pharmacotherapy. (2018) 19:1533–40. doi: 10.1080/14656566.2018.1516207 PubMed DOI

Baghbanian SM, Khalili B, Bakhshi A, Azizi H, Ghazaeian M. The effects of bupropion on sexual dysfunction in female patients with multiple sclerosis: A double-blind randomized clinical trial. Mult Scler Relat Disord. (2023) 69:104399. doi: 10.1016/j.msard.2022.104399 PubMed DOI

Schneider SA, Deuschl G. The treatment of tremor. Neurotherapeutics. (2014) 11:128–38. doi: 10.1007/s13311-013-0230-5 PubMed DOI PMC

Panicker JN, Fowler CJ, Kessler TM. Lower urinary tract dysfunction in the neurological patient: clinical assessment and management. Lancet Neurol. (2015) 14:720–32. doi: 10.1016/s1474-4422(15)00070-8 PubMed DOI

Bapir R, Bhatti KH, Eliwa A, García-Perdomo HA, Gherabi N, Hennessey D, et al. . Efficacy of overactive neurogenic bladder treatment: A systematic review of randomized controlled trials. Arch Ital Urol Androl. (2022) 94:492–506. doi: 10.4081/aiua.2022.4.492 PubMed DOI

Brucker BM, Jericevic D, Rude T, Enemchukwu E, Pape D, Rosenblum N, et al. . Mirabegron versus solifenacin in multiple sclerosis patients with overactive bladder symptoms: A prospective comparative nonrandomized study. Urology. (2020) 145:94–9. doi: 10.1016/j.urology.2020.08.008 PubMed DOI

Horstmann M, Schaefer T, Aguilar Y, Stenzl A, Sievert KD. Neurogenic bladder treatment by doubling the recommended antimuscarinic dosage. Neurourol Urodyn. (2006) 25:441–5. doi: 10.1002/nau.20289 PubMed DOI

Amend B, Hennenlotter J, Schäfer T, Horstmann M, Stenzl A, Sievert K-D. Effective treatment of neurogenic detrusor dysfunction by combined high-dosed antimuscarinics without increased side-effects. Eur Urol. (2008) 53:1021–8. doi: 10.1016/j.eururo.2008.01.007 PubMed DOI

Aharony SM, Lam O, Corcos J. Treatment of lower urinary tract symptoms in multiple sclerosis patients: Review of the literature and current guidelines. Can Urol Assoc J. (2017) 11:E110–e115. doi: 10.5489/cuaj.4059 PubMed DOI PMC

Mills RJ, Yap L, Young CA. Treatment for ataxia in multiple sclerosis. Cochrane Database Syst Rev. (2007) 24(1):Cd005029. doi: 10.1002/14651858.CD005029.pub2 PubMed DOI

Nicholas RS, Friede T, Hollis S, Young CA. Anticholinergics for urinary symptoms in multiple sclerosis. Cochrane Database Syst Rev. (2009) 21(1):Cd004193. doi: 10.1002/14651858.CD004193.pub2 PubMed DOI

Mücke M, Cuhls H, Peuckmann-Post V, Minton O, Stone P, Radbruch L. Pharmacological treatments for fatigue associated with palliative care. Cochrane Database Syst Rev. (2015) 2015):Cd006788. doi: 10.1002/14651858.CD006788.pub3 PubMed DOI PMC

Miller P, Soundy A. The pharmacological and non-pharmacological interventions for the management of fatigue related multiple sclerosis. J Neurol Sci. (2017) 381:41–54. doi: 10.1016/j.jns.2017.08.012 PubMed DOI

Koch MW, Glazenborg A, Uyttenboogaart M, Mostert J, De Keyser J. Pharmacologic treatment of depression in multiple sclerosis. Cochrane Database Syst Rev. (2011) 16(2):Cd007295. doi: 10.1002/14651858.CD007295.pub2 PubMed DOI

Gil-Sanchez A, Canudes M, Valcheva P, Nogueras L, González-Mingot C, Hervás JV, et al. . Effects of vortioxetine on cognition and fatigue in patients with multiple sclerosis and depression: a case series study. CNS Neurol Disord Drug Targets. (2024) 23(3):395–401. doi: 10.2174/1871527322666230321093133 PubMed DOI

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

Seppala LJ, Wermelink A, de Vries M, Ploegmakers KJ, van de Glind EMM, Daams JG, et al. . Fall-risk-increasing drugs: A systematic review and meta-analysis: II. Psychotropics. J Am Med Dir Assoc. (2018) 19:371.e11–371.e17. doi: 10.1016/j.jamda.2017.12.098 PubMed DOI

Cruce R, Vosoughi R, Freedman MS. Cognitive impact of anticholinergic medication in MS: Adding insult to injury? Mult Scler Relat Disord. (2012) 1:156–61. doi: 10.1016/j.msard.2012.05.002 PubMed DOI

Meza R, Peña J, García K, Corsi O, Rada G. Are cannabinoids effective in multiple sclerosis? Medwave. (2017) 17:e6865. doi: 10.5867/medwave.2017.6865 PubMed DOI

Selph S, Carson S, Fu R, Thakurta S, Low A, McDonagh M. Drug class reviews, drug class review: neuropathic pain: final update 1 report. [Internet]. Portland (OR): Oregon Health & Science University; (2011). PubMed

Otero-Romero S, Rodríguez-García J, Vilella A, Ara JR, Brieva L, Calles C, et al. . Recommendations for vaccination in patients with multiple sclerosis who are eligible for immunosuppressive therapies: Spanish consensus statement. Neurología (English Edition). (2021) 36:50–60. doi: 10.1016/j.nrleng.2020.02.010 PubMed DOI

Byrnes KL, Whillier S. Effects of nonpharmaceutical treatments on symptom management in adults with mild or moderate multiple sclerosis: ;Meta-analysis. J Manipulative Physiol Ther. (2019) 42:514–31. doi: 10.1016/j.jmpt.2018.12.010 PubMed DOI

Asano M, Finlayson ML. Meta-analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education, and medication. Mult Scler Int. (2014) 2014:798285. doi: 10.1155/2014/798285 PubMed DOI PMC

Zielińska-Nowak E, Włodarczyk L, Kostka J, Miller E. New strategies for rehabilitation and pharmacological treatment of fatigue syndrome in multiple sclerosis. J Clin Med. (2020) 9:3592. doi: 10.3390/jcm9113592 PubMed DOI PMC

Gitman V, Moss K, Hodgson D. A systematic review and meta-analysis of the effects of non-pharmacological interventions on quality of life in adults with multiple sclerosis. Eur J Med Res. (2023) 28:294. doi: 10.1186/s40001-023-01185-5 PubMed DOI PMC

Döring A, Pfueller CF, Paul F, Dörr J. Exercise in multiple sclerosis – an integral component of disease management. Epma J. (2011) 3:2. doi: 10.1007/s13167-011-0136-4 PubMed DOI PMC

Binshalan T, Nair KPS, McNeill A. The effectiveness of physiotherapy interventions for mobility in severe multiple sclerosis: A systematic review and meta-analysis. Mult Scler Int. (2022) 2022:2357785. doi: 10.1155/2022/2357785 PubMed DOI PMC

Etoom M, Khraiwesh Y, Lena F, Hawamdeh M, Hawamdeh Z, Centonze D, et al. . Effectiveness of physiotherapy interventions on spasticity in people with multiple sclerosis: A systematic review and meta-analysis. Am J Phys Med Rehabil. (2018) 97:793–807. doi: 10.1097/phm.0000000000000970 PubMed DOI

Amedoro A, Berardi A, Conte A, Pelosin E, Valente D, Maggi G, et al. . The effect of aquatic physical therapy on patients with multiple sclerosis: A systematic review and meta-analysis. Mult Scler Relat Disord. (2020) 41:102022. doi: 10.1016/j.msard.2020.102022 PubMed DOI

Gopal A, Sydow R, Block V, Allen DD. Effectiveness of physical therapy in addressing sexual dysfunction in individuals with multiple sclerosis: A systematic review and meta-analysis. Int J MS Care. (2021) 23:213–22. doi: 10.7224/1537-2073.2020-039 PubMed DOI PMC

Abou L, Qin K, Alluri A, Du Y, Rice LA. The effectiveness of physical therapy interventions in reducing falls among people with multiple sclerosis: A systematic review and meta-analysis. J Bodyw Mov Ther. (2022) 29:74–85. doi: 10.1016/j.jbmt.2021.09.015 PubMed DOI

García-Muñoz C, Cortés-Vega MD, Heredia-Rizo AM, Martín-Valero R, García-Bernal MI, Casuso-Holgado MJ. Effectiveness of vestibular training for balance and dizziness rehabilitation in people with multiple sclerosis: A systematic review and meta-analysis. J Clin Med. (2020) 9(2):590. doi: 10.3390/jcm9020590 PubMed DOI PMC

Alphonsus KB, Su Y, D’Arcy C. The effect of exercise, yoga and physiotherapy on the quality of life of people with multiple sclerosis: Systematic review and meta-analysis. Complementary Therapies Med. (2019) 43:188–95. doi: 10.1016/j.ctim.2019.02.010 PubMed DOI

Veneri D, Gannotti M, Bertucco M, Fournier Hillman SE. Using the international classification of functioning, disability, and health model to gain perspective of the benefits of yoga in stroke, multiple sclerosis, and children to inform practice for children with cerebral palsy: A meta-analysis. J Altern Complement Med. (2018) 24:439–57. doi: 10.1089/acm.2017.0030 PubMed DOI

Castellano-Aguilera A, Biviá-Roig G, Cuenca-Martínez F, Suso-Martí L, Calatayud J, Blanco-Díaz M, et al. . Effectiveness of virtual reality on balance and risk of falls in people with multiple sclerosis: A systematic review and meta-analysis. Int J Environ Res Public Health. (2022) 19(21):14192. doi: 10.3390/ijerph192114192 PubMed DOI PMC

Kajbafvala M, Ashnagar Z, Lucio A, Firoozeh F, Salehi R, Pashazadeh F, et al. . Pelvic floor muscle training in multiple sclerosis patients with lower urinary tract dysfunction: A systematic review and meta-analysis. Mult Scler Relat Disord. (2022) 59:103559. doi: 10.1016/j.msard.2022.103559 PubMed DOI

Vecchio M, Chiaramonte R. and P DIB, Management of bladder dysfunction in multiple sclerosis: a systematic review and meta-analysis of studies regarding bladder rehabilitation. Eur J Phys Rehabil Med. (2022) 58:387–96. doi: 10.23736/s1973-9087.22.07217-3 PubMed DOI PMC

Cortés-Pérez I, Osuna-Pérez MC, Montoro-Cárdenas D, Lomas-Vega R, Obrero-Gaitán E, Nieto-Escamez FA. Virtual reality-based therapy improves balance and reduces fear of falling in patients with multiple sclerosis. systematic Rev meta-analysis randomized Controlled trials. J Neuroeng Rehabil. (2023) 20:42. doi: 10.1186/s12984-023-01174-z PubMed DOI PMC

Learmonth YC, Ensari I, Motl RW. Physiotherapy and walking outcomes in adults with multiple sclerosis: Systematic review and meta-analysis. Phys Ther Rev. (2016) 21:160–72. doi: 10.1080/10833196.2016.1263415 DOI

Mura G, Carta MG, Sancassiani F, MaChado S, Prosperini L. Active exergames to improve cognitive functioning in neurological disabilities: a systematic review and meta-analysis. Eur J Phys Rehabil Med. (2018) 54:450–62. doi: 10.23736/s1973-9087.17.04680-9 PubMed DOI

Ensari I, Motl RW, Pilutti LA. Exercise training improves depressive symptoms in people with multiple sclerosis: results of a meta-analysis. J Psychosom Res. (2014) 76:465–71. doi: 10.1016/j.jpsychores.2014.03.014 PubMed DOI

Dalgas U, Stenager E, Sloth M, Stenager E. The effect of exercise on depressive symptoms in multiple sclerosis based on a meta-analysis and critical review of the literature. Eur J Neurol. (2015) 22:443–e34. doi: 10.1111/ene.12576 PubMed DOI

Torres-Costoso A, Martínez-Vizcaíno V, Reina-Gutiérrez S, Álvarez-Bueno C, Guzmán-Pavón MJ, Pozuelo-Carrascosa DP, et al. . Effect of exercise on fatigue in multiple sclerosis: A network meta-analysis comparing different types of exercise. Arch Phys Med Rehabil. (2022) 103:970–987.e18. doi: 10.1016/j.apmr.2021.08.008 PubMed DOI

Razazian N, Kazeminia M, Moayedi H, Daneshkhah A, Shohaimi S, Mohammadi M, et al. . The impact of physical exercise on the fatigue symptoms in patients with multiple sclerosis: a systematic review and meta-analysis. BMC Neurol. (2020) 20:93. doi: 10.1186/s12883-020-01654-y PubMed DOI PMC

Dauwan M, Begemann MJH, Slot MIE, Lee EHM, Scheltens P, Sommer IEC. Physical exercise improves quality of life, depressive symptoms, and cognition across chronic brain disorders: a transdiagnostic systematic review and meta-analysis of randomized controlled trials. J Neurol. (2021) 268:1222–46. doi: 10.1007/s00415-019-09493-9 PubMed DOI PMC

Gascoyne C, Karahalios A, Demaneuf T, Marck C. Effect of exercise interventions on anxiety in people with multiple sclerosis: A systematic review and meta-analysis. Int J MS Care. (2020) 22:103–9. doi: 10.7224/1537-2073.2019-009R PubMed DOI PMC

Sánchez-Lastra MA, Martínez-Aldao D, Molina AJ, Ayán C. Pilates for people with multiple sclerosis: A systematic review and meta-analysis. Mult Scler Relat Disord. (2019) 28:199–212. doi: 10.1016/j.msard.2019.01.006 PubMed DOI

Cramer H, Lauche R, Azizi H, Dobos G, Langhorst J. Yoga for multiple sclerosis: a systematic review and meta-analysis. PloS One. (2014) 9:e112414. doi: 10.1371/journal.pone.0112414 PubMed DOI PMC

Munari D, Fonte C, Varalta V, Battistuzzi E, Cassini S, Montagnoli AP, et al. . Effects of robot-assisted gait training combined with virtual reality on motor and cognitive functions in patients with multiple sclerosis: A pilot, single-blind, randomized controlled trial. Restor Neurol Neurosci. (2020) 38:151–64. doi: 10.3233/rnn-190974 PubMed DOI

Cortés-Pérez I, Sánchez-Alcalá M, Nieto-Escámez FA, Castellote-Caballero Y, Obrero-Gaitán E, Osuna-Pérez MC. Virtual reality-based therapy improves fatigue, impact, and quality of life in patients with multiple sclerosis. A systematic rev meta-analysis. Sensors (Basel). (2021) 21(21):7389. doi: 10.3390/s21217389 PubMed DOI PMC

Giovannelli M, Borriello G, Castri P, Prosperini L, Pozzilli C. Early physiotherapy after injection of botulinum toxin increases the beneficial effects on spasticity in patients with multiple sclerosis. Clin Rehabil. (2007) 21:331–7. doi: 10.1177/0269215507072772 PubMed DOI

Heine M, van de Port I, Rietberg MB, van Wegen EE, Kwakkel G. Exercise therapy for fatigue in multiple sclerosis. Cochrane Database Syst Rev. (2015) 2015(9):CD009956. doi: 10.1002/14651858.CD009956.pub2 PubMed DOI PMC

Adamson BC, Ensari I, Motl RW. Effect of exercise on depressive symptoms in adults with neurologic disorders: a systematic review and meta-analysis. Arch Phys Med Rehabil. (2015) 96:1329–38. doi: 10.1016/j.apmr.2015.01.005 PubMed DOI

Reina-Gutiérrez S, Cavero-Redondo I, Martínez-Vizcaíno V, Núñez de Arenas-Arroyo S, López-Muñoz P, Álvarez-Bueno C, et al. . The type of exercise most beneficial for quality of life in people with multiple sclerosis: A network meta-analysis. Ann Phys Rehabil Med. (2022) 65:101578. doi: 10.1016/j.rehab.2021.101578 PubMed DOI

Faíl LB, Marinho DA, Marques EA, Costa MJ, Santos CC, Marques MC, et al. . Benefits of aquatic exercise in adults with and without chronic disease-A systematic review with meta-analysis. Scand J Med Sci Sports. (2022) 32:465–86. doi: 10.1111/sms.14112 PubMed DOI

Kinnett-Hopkins D, Adamson B, Rougeau K, Motl RW. People with MS are less physically active than healthy controls but as active as those with other chronic diseases: An updated meta-analysis. Mult Scler Relat Disord. (2017) 13:38–43. doi: 10.1016/j.msard.2017.01.016 PubMed DOI

Horton S, MacDonald DJ, Erickson K MS. exercise, and the potential for older adults. Eur Rev Aging Phys Activity. (2010) 7:49–57. doi: 10.1007/s11556-010-0062-9 DOI

Baird JF, Cutter GR, Motl RW. Do physical activity, cardiorespiratory fitness, and subcortical brain structures explain reduced walking performance in older adults with multiple sclerosis? Multiple Sclerosis Related Disord. (2022) 60:103702. doi: 10.1016/j.msard.2022.103702 PubMed DOI

Klaren RE, Sebastiao E, Chiu CY, Kinnett-Hopkins D, McAuley E, Motl RW. Levels and rates of physical activity in older adults with multiple sclerosis. Aging Dis. (2016) 7:278–84. doi: 10.14336/ad.2015.1025 PubMed DOI PMC

Kim Y, Mehta T, Lai B, Motl RW. Immediate and sustained effects of interventions for changing physical activity in people with multiple sclerosis: meta-analysis of randomized controlled trials. Arch Phys Med Rehabil. (2020) 101:1414–36. doi: 10.1016/j.apmr.2020.03.017 PubMed DOI PMC

Reina-Gutiérrez S, Meseguer-Henarejos AB, Torres-Costoso A, Álvarez-Bueno C, Cavero-Redondo I, Núñez de Arenas-Arroyo S, et al. . Effect of different types of exercise on fitness in people with multiple sclerosis: A network meta-analysis. Scand J Med Sci Sports. (2023) 33:1916–28. doi: 10.1111/sms.14407 PubMed DOI

Motl RW, Baird JF. Cardiorespiratory fitness and moderate-to-vigorous physical activity in older adults with multiple sclerosis. Mult Scler J Exp Transl Clin. (2021) 7:20552173211057514. doi: 10.1177/20552173211057514 PubMed DOI PMC

Hötting K, Röder B. Beneficial effects of physical exercise on neuroplasticity and cognition. Neurosci Biobehav Rev. (2013) 37:2243–57. doi: 10.1016/j.neubiorev.2013.04.005 PubMed DOI

Colcombe SJ, Kramer AF, Erickson KI, Scalf P, McAuley E, Cohen NJ, et al. . Cardiovascular fitness, cortical plasticity, and aging. Proc Natl Acad Sci U.S.A. (2004) 101:3316–21. doi: 10.1073/pnas.0400266101 PubMed DOI PMC

Hortobágyi T, Vetrovsky T, Balbim GM, Sorte Silva NCB, Manca A, Deriu F, et al. . The impact of aerobic and resistance training intensity on markers of neuroplasticity in health and disease. Ageing Res Rev. (2022) 80:101698. doi: 10.1016/j.arr.2022.101698 PubMed DOI

Miller L, McFadyen A, Lord AC, Hunter R, Paul L, Rafferty D, et al. . Functional electrical stimulation for foot drop in multiple sclerosis: A systematic review and meta-analysis of the effect on gait speed. Arch Phys Med Rehabil. (2017) 98:1435–52. doi: 10.1016/j.apmr.2016.12.007 PubMed DOI

Brandmeir NJ, Murray A, Cheyuo C, Ferari C, Rezai AR. Deep brain stimulation for multiple sclerosis tremor: A meta-analysis. Neuromodulation. (2020) 23:463–8. doi: 10.1111/ner.13063 PubMed DOI PMC

Zali A, Khoshnood RJ, Motavaf M, Salimi A, Akhlaghdoust M, Safari S, et al. . Deep brain stimulation for multiple sclerosis tremor: A systematic review and meta-analysis. Mult Scler Relat Disord. (2021) 56:103256. doi: 10.1016/j.msard.2021.103256 PubMed DOI

Hanna JA, Scullen T, Kahn L, Mathkour M, Gouveia EE, Garces J, et al. . Comparison of elderly and young patient populations treated with deep brain stimulation for Parkinson's disease: long-term outcomes with up to 7 years of follow-up. J Neurosurg. (2018) 131:807–12. doi: 10.3171/2018.4.Jns171909 PubMed DOI

Hsu W-Y, Cheng C-H, Zanto TP, Gazzaley A, Bove RM. Effects of transcranial direct current stimulation on cognition, mood, pain, and fatigue in multiple sclerosis: A systematic review and meta-analysis. Front Neurol. (2021) 12:626113. doi: 10.3389/fneur.2021.626113 PubMed DOI PMC

Rapisarda A, Ioannoni E, Izzo A, D'Ercole M, Montano N. Is there a place for spinal cord stimulation in the management of patients with multiple sclerosis? A systematic review of the literature. Minim Invasive Surg. (2021) 2021:9969010. doi: 10.1155/2021/9969010 PubMed DOI PMC

Goodwin BJ, Mahmud R, TomThundyil S, Rivera-Colon G, Murray VW, O'Donnell K. The efficacy of spinal cord stimulators in the reduction of multiple sclerosis spasticity: A narrative systematic review. Brain Neurorehabil. (2023) 16:e19. doi: 10.12786/bn.2023.16.e19 PubMed DOI PMC

Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, et al. . Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018). Clin Neurophysiol. (2020) 131:474–528. doi: 10.1016/j.clinph.2019.11.002 PubMed DOI

Chen X, Yin L, An Y, Yan H, Zhang T, Lu X, et al. . Effects of repetitive transcranial magnetic stimulation in multiple sclerosis: A systematic review and meta-analysis. Mult Scler Relat Disord. (2022) 59:103564. doi: 10.1016/j.msard.2022.103564 PubMed DOI

Fiest KM, Walker JR, Bernstein CN, Graff LA, Zarychanski R, Abou-Setta AM, et al. . Systematic review and meta-analysis of interventions for depression and anxiety in persons with multiple sclerosis. Multiple Sclerosis Related Disord. (2016) 5:12–26. doi: 10.1016/j.msard.2015.10.004 PubMed DOI

Kidd T, Carey N, Mold F, Westwood S, Miklaucich M, Konstantara E, et al. . A systematic review of the effectiveness of self-management interventions in people with multiple sclerosis at improving depression, anxiety and quality of life. PloS One. (2017) 12:e0185931. doi: 10.1371/journal.pone.0185931 PubMed DOI PMC

Ghielen I, Rutten S, Boeschoten RE, Houniet-de Gier M, van Wegen EEH, van den Heuvel OA, et al. . The effects of cognitive behavioral and mindfulness-based therapies on psychological distress in patients with multiple sclerosis, Parkinson's disease and Huntington's disease: Two meta-analyses. J Psychosom Res. (2019) 122:43–51. doi: 10.1016/j.jpsychores.2019.05.001 PubMed DOI

Pöttgen J, van de Vis W, van Nunen A, Rose A, Engelbrecht J, Pirard M, et al. . Psychobehavioral treatment options for sexual dysfunction in multiple sclerosis: A systematic review. Int J MS Care. (2020) 22:276–84. doi: 10.7224/1537-2073.2020-012 PubMed DOI PMC

Proctor BJ, Moghaddam N, Vogt W, das Nair R. Telephone psychotherapy in multiple sclerosis: A systematic review and meta-analysis. Rehabil Psychol. (2018) 63:16–28. doi: 10.1037/rep0000182 PubMed DOI

Montañés-Masias B, Bort-Roig J, Pascual JC, Soler J, Briones-Buixassa L. Online psychological interventions to improve symptoms in multiple sclerosis: A systematic review: Online psychological interventions in Multiple Sclerosis. Acta Neurol Scand. (2022) 146:448–64. doi: 10.1111/ane.13709 PubMed DOI PMC

Kiropoulos L. Early intervention for depressive symptoms in multiple sclerosis. Lancet Digital Health. (2023) 5:e637–8. doi: 10.1016/S2589-7500(23)00162-0 PubMed DOI

van den Akker LE, Beckerman H, Collette EH, Twisk JW, Bleijenberg G, Dekker J, et al. . Cognitive behavioral therapy positively affects fatigue in patients with multiple sclerosis: Results of a randomized controlled trial. Multiple Sclerosis J. (2017) 23:1542–53. doi: 10.1177/1352458517709361 PubMed DOI

van den Akker LE, Beckerman H, Collette EH, Eijssen IC, Dekker J, de Groot V. Effectiveness of cognitive behavioral therapy for the treatment of fatigue in patients with multiple sclerosis: A systematic review and meta-analysis. J Psychosom Res. (2016) 90:33–42. doi: 10.1016/j.jpsychores.2016.09.002 PubMed DOI

Hind D, Cotter J, Thake A, Bradburn M, Cooper C, Isaac C, et al. . Cognitive behavioural therapy for the treatment of depression in people with multiple sclerosis: a systematic review and meta-analysis. BMC Psychiatry. (2014) 14:5. doi: 10.1186/1471-244x-14-5 PubMed DOI PMC

Moss-Morris R, Harrison AM, Safari R, Norton S, van der Linden ML, Picariello F, et al. . Which behavioural and exercise interventions targeting fatigue show the most promise in multiple sclerosis? A systematic review with narrative synthesis and meta-analysis. Behav Res Ther. (2021) 137:103464. doi: 10.1016/j.brat.2019.103464 PubMed DOI

Taylor P, Dorstyn DS, Prior E. Stress management interventions for multiple sclerosis: A meta-analysis of randomized controlled trials. J Health Psychol. (2020) 25:266–79. doi: 10.1177/1359105319860185 PubMed DOI

Phyo AZZ, Demaneuf T, De Livera AM, Jelinek GA, Brown CR, Marck CH, et al. . The efficacy of psychological interventions for managing fatigue in people with multiple sclerosis: A systematic review and meta-analysis. Front Neurol. (2018) 9:149. doi: 10.3389/fneur.2018.00149 PubMed DOI PMC

Sesel AL, Sharpe L, Naismith SL. Efficacy of psychosocial interventions for people with multiple sclerosis: A meta-analysis of specific treatment effects. Psychother Psychosom. (2018) 87:105–11. doi: 10.1159/000486806 PubMed DOI

Klein OA, Drummond A, Mhizha-Murira JR, Mansford L, dasNair R. Effectiveness of cognitive rehabilitation for people with multiple sclerosis: a meta-synthesis of patient perspectives. Neuropsychol Rehabil. (2019) 29:491–512. doi: 10.1080/09602011.2017.1309323 PubMed DOI

das Nair R, Martin KJ, Lincoln NB. Memory rehabilitation for people with multiple sclerosis. Cochrane Database Syst Rev. (2016) 3:Cd008754. doi: 10.1002/14651858.CD008754.pub3 PubMed DOI

Dardiotis E, Nousia A, Siokas V, Tsouris Z, Andravizou A, Mentis AA, et al. . Efficacy of computer-based cognitive training in neuropsychological performance of patients with multiple sclerosis: A systematic review and meta-analysis. Mult Scler Relat Disord. (2018) 20:58–66. doi: 10.1016/j.msard.2017.12.017 PubMed DOI

Taylor LA, Mhizha-Murira JR, Smith L, Potter KJ, Wong D, Evangelou N, et al. . Memory rehabilitation for people with multiple sclerosis. Cochrane Database Syst Rev. (2021) 10:Cd008754. doi: 10.1002/14651858.CD008754.pub4 PubMed DOI PMC

Mhizha-Murira JR, Drummond A, Klein OA, dasNair R. Reporting interventions in trials evaluating cognitive rehabilitation in people with multiple sclerosis: a systematic review. Clin Rehabil. (2018) 32:243–54. doi: 10.1177/0269215517722583 PubMed DOI

Muñoz San José A, Oreja-Guevara C, Cebolla Lorenzo S, Carrillo Notario L, Rodríguez Vega B, Bayón Pérez C. Psychotherapeutic and psychosocial interventions for managing stress in multiple sclerosis: The contribution of mindfulness-based interventions. Neurología (English Edition). (2016) 31:113–20. doi: 10.1016/j.nrleng.2015.07.003 PubMed DOI

Ulrichsen KM, Kaufmann T, Dørum ES, Kolskår KK, Richard G, Alnæs D, et al. . Clinical utility of mindfulness training in the treatment of fatigue after stroke, traumatic brain injury and multiple sclerosis: A systematic literature review and meta-analysis. Front Psychol. (2016) 7:912. doi: 10.3389/fpsyg.2016.00912 PubMed DOI PMC

Simpson R, Posa S, Langer L, Bruno T, Simpson S, Lawrence M, et al. . A systematic review and meta-analysis exploring the efficacy of mindfulness-based interventions on quality of life in people with multiple sclerosis. J Neurol. (2023) 270:726–45. doi: 10.1007/s00415-022-11451-x PubMed DOI PMC

Zhang L, Lopes S, Lavelle T, Jones KO, Chen L, Jindal M, et al. . Economic evaluations of mindfulness-based interventions: a systematic review. Mindfulness (N Y). (2022) 13:2359–78. doi: 10.1007/s12671-022-01960-1 PubMed DOI PMC

Han A. Mindfulness- and acceptance-based interventions for symptom reduction in individuals with multiple sclerosis: A systematic review and meta-analysis. Arch Phys Med Rehabil. (2021) 102:2022–2031.e4. doi: 10.1016/j.apmr.2021.03.011 PubMed DOI

Simpson R, Simpson S, Ramparsad N, Lawrence M, Booth J, Mercer SW. Effects of Mindfulness-based interventions on physical symptoms in people with multiple sclerosis - a systematic review and meta-analysis. Mult Scler Relat Disord. (2020) 38:101493. doi: 10.1016/j.msard.2019.101493 PubMed DOI

Carletto S, Cavalera C, Sadowski I, Rovaris M, Borghi M, Khoury B, et al. . Mindfulness-based interventions for the improvement of well-being in people with multiple sclerosis: A systematic review and meta-analysis. Psychosom Med. (2020) 82:600–13. doi: 10.1097/psy.0000000000000819 PubMed DOI

Simpson R, Simpson S, Ramparsad N, Lawrence M, Booth J, Mercer SW. Mindfulness-based interventions for mental well-being among people with multiple sclerosis: a systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. (2019) 90:1051–8. doi: 10.1136/jnnp-2018-320165 PubMed DOI

Guarnaccia JB, Njike VY, Dutton A, Ayettey RG, Treu JA, Comerford BP, et al. . A pilot, randomized, placebo-controlled study of mindfulness meditation in treating insomnia in multiple sclerosis. BMC Neurol. (2023) 23:263. doi: 10.1186/s12883-023-03309-0 PubMed DOI PMC

Sahar P, Mohsen M, Ali akbar P, Ali akbar F. The effectiveness of mindfulness-integrated cognitive-behavioral therapy on sleep quality, anxiety, and fatigue in patients with multiple sclerosis: A randomized clinical trial. J Sleep Sci. (2019) 4(1-2):1–8.

Pagnini F, Cavalera C, Rovaris M, Mendozzi L, Molinari E, Phillips D, et al. . Longitudinal associations between mindfulness and well-being in people with multiple sclerosis. Int J Clin Health Psychol. (2019) 19:22–30. doi: 10.1016/j.ijchp.2018.11.003 PubMed DOI PMC

Baker NA, Tickle-Degnen L. The effectiveness of physical, psychological, and functional interventions in treating clients with multiple sclerosis: a meta-analysis. Am J Occup Ther. (2001) 55:324–31. doi: 10.5014/ajot.55.3.324 PubMed DOI

Quinn É, Hynes SM. Occupational therapy interventions for multiple sclerosis: A scoping review. Scandinavian J Occup Ther. (2021) 28:399–414. doi: 10.1080/11038128.2020.1786160 PubMed DOI

De-Bernardi-Ojuel L, Torres-Collado L, García-de-la-Hera M. Occupational therapy interventions in adults with multiple sclerosis or amyotrophic lateral sclerosis: A scoping review. Int J Environ Res Public Health. (2021) 18:1432. doi: 10.3390/ijerph18041432 PubMed DOI PMC

Kos D, Eijssen I, Bekkering GE, De Coninck L, O'Meara C, Koen M, et al. . Occupational therapy in multiple sclerosis. Cochrane Database Syst Rev. (2023) 2023:CD015371. doi: 10.1002/14651858.CD015371 DOI

Aghaz A, Alidad A, Hemmati E, Jadidi H, Ghelichi L. Prevalence of dysphagia in multiple sclerosis and its related factors: Systematic review and meta-analysis. Iran J Neurol. (2018) 17:180–8. PubMed PMC

Plotas P, Nanousi V, Kantanis A, Tsiamaki E, Papadopoulos A, Tsapara A, et al. . Speech deficits in multiple sclerosis: a narrative review of the existing literature. Eur J Med Res. (2023) 28:252. doi: 10.1186/s40001-023-01230-3 PubMed DOI PMC

Alali D, Ballard K, Bogaardt H. Treatment effects for dysphagia in adults with multiple sclerosis: A systematic review. Dysphagia. (2016) 31:610–8. doi: 10.1007/s00455-016-9738-2 PubMed DOI

Johansson K, Schalling E, Hartelius L. Self-reported changes in cognition, communication and swallowing in multiple sclerosis: data from the swedish multiple sclerosis registry and from a national survey. Folia Phoniatrica Logopaedica. (2020) 73:50–62. doi: 10.1159/000505063 PubMed DOI

Kaltsatou A, Flouris AD. Impact of pre-cooling therapy on the physical performance and functional capacity of multiple sclerosis patients: A systematic review. Multiple Sclerosis Related Disord. (2019) 27:419–23. doi: 10.1016/j.msard.2018.11.013 PubMed DOI

Stevens CJ, Singh G, Peterson B, Vargas NT, Périard JD. The effect of cooling garments to improve physical function in people with multiple sclerosis: A systematic review and meta-analysis. Mult Scler Relat Disord. (2023) 78:104912. doi: 10.1016/j.msard.2023.104912 PubMed DOI

Bilgin A, Kesik G, Ozdemir L. The effects of cooling therapies on fatigue, physical activity, and quality of life in multiple sclerosis: A meta-analysis. Rehabil Nurs. (2022) 47:228–36. doi: 10.1097/rnj.0000000000000388 PubMed DOI

Snetselaar LG, Cheek JJ, Fox SS, Healy HS, Schweizer ML, Bao W, et al. . Efficacy of diet on fatigue and quality of life in multiple sclerosis: A systematic review and network meta-analysis of randomized trials. Neurology. (2023) 100:e357–66. doi: 10.1212/wnl.0000000000201371 PubMed DOI

McLaughlin L, Clarke L, Khalilidehkordi E, Butzkueven H, Taylor B, Broadley SA. Vitamin D for the treatment of multiple sclerosis: a meta-analysis. J Neurol. (2018) 265:2893–905. doi: 10.1007/s00415-018-9074-6 PubMed DOI

López-Muñoz P, Torres-Costoso AI, Fernández-Rodríguez R, Guzmán-Pavón MJ, de Arenas-Arroyo SN, Basco-López J, et al. . Effect of vitamin D supplementation on fatigue in multiple sclerosis: A systematic review and meta-analysis. Nutrients. (2023) 15(13):2861. doi: 10.3390/nu15132861 PubMed DOI PMC

Guerrero Aznar MD, Villanueva Guerrero MD, Cordero Ramos J, Eichau Madueño S, Morales Bravo M, López Ruiz R, et al. . Efficacy of diet on fatigue, quality of life and disability status in multiple sclerosis patients: rapid review and meta-analysis of randomized controlled trials. BMC Neurol. (2022) 22:388. doi: 10.1186/s12883-022-02913-w PubMed DOI PMC

Jiang J, Chu C, Wu C, Wang C, Zhang C, Li T, et al. . Efficacy of probiotics in multiple sclerosis: a systematic review of preclinical trials and meta-analysis of randomized controlled trials. Food Funct. (2021) 12:2354–77. doi: 10.1039/D0FO03203D PubMed DOI

Atabilen B, Akdevelioğlu Y. Effects of different dietary interventions in multiple sclerosis: a systematic review of evidence from 2018 to 2022. Nutr Neurosci. (2023) 26(12):1279–91. doi: 10.1080/1028415x.2022.2146843 PubMed DOI

Abboud M, AlAnouti F, Georgaki E, Papandreou D. Effect of ketogenic diet on quality of life in adults with chronic disease: A systematic review of randomized controlled trials. Nutrients. (2021) 13(12):4463. doi: 10.3390/nu13124463 PubMed DOI PMC

Bahr LS, Bock M, Liebscher D, Bellmann-Strobl J, Franz L, Prüß A, et al. . Ketogenic diet and fasting diet as Nutritional Approaches in Multiple Sclerosis (NAMS): protocol of a randomized controlled study. Trials. (2020) 21:3. doi: 10.1186/s13063-019-3928-9 PubMed DOI PMC

Koutsogeorgou E, Chiesi AM, Leonardi M. Social capital components and social support of persons with multiple sclerosis: a systematic review of the literature from 2000 to 2018. Disabil Rehabil. (2020) 42:3437–49. doi: 10.1080/09638288.2019.1597182 PubMed DOI

Gerritzen EV, Lee AR, McDermott O, Coulson N, Orrell M. Online peer support for people with multiple sclerosis: A narrative synthesis systematic review. Int J MS Care. (2022) 24:252–9. doi: 10.7224/1537-2073.2022-040 PubMed DOI PMC

Kokas Z, Sandi D, Fricska-Nagy Z, Füvesi J, Biernacki T, Köves Á, et al. . Do Hungarian multiple sclerosis care units fulfil international criteria? PloS One. (2022) 17:e0264328. doi: 10.1371/journal.pone.0264328 PubMed DOI PMC

Cristiano E, Abad P, Becker J, Carrá A, Correale J, Flores J, et al. . Multiple sclerosis care units in Latin America: Consensus recommendations about its objectives and functioning implementation. J Neurological Sci. (2021) 429:118072. doi: 10.1016/j.jns.2021.118072 PubMed DOI

Finlayson M. Concerns about the future among older adults with multiple sclerosis. Am J Occup Ther. (2004) 58:54–63. doi: 10.5014/ajot.58.1.54 PubMed DOI

Walter HAW, Seeber AA, Willems DL, de Visser M. The role of palliative care in chronic progressive neurological diseases-A survey amongst neurologists in the Netherlands. Front Neurol. (2018) 9:1157. doi: 10.3389/fneur.2018.01157 PubMed DOI PMC

Golla H, Galushko M, Strupp J, Karbach U, Pfaff H, Ostgathe C, et al. . Patients feeling severely affected by multiple sclerosis:Addressing death and dying. OMEGA - J Death Dying. (2016) 74:275–91. doi: 10.1177/0030222815598443 DOI

Solari A, Giordano A, Sastre-Garriga J, Köpke S, Rahn A, Kleiter I, et al. . EAN guideline on palliative care of people with severe, progressive multiple sclerosis. J Palliative Med. (2020) 23:1426–43. doi: 10.1089/jpm.2020.0220 PubMed DOI PMC