LATE ONSET MULTIPLE SCLEROSIS
Keywords:
multiple sclerosis (MS), late onset, disease modifying terapies (DMT)
Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) that usually occurs between the ages of 20 and 40.
Less often, the diagnosis of MS can be made in children and adolescents, before the age of 18, as well as in people aged 50 and over. If the symptoms of MS appear in people aged 50 and over, this form of the disease is called late onset MS (LOMS). Compared to the classic onset of MS, people with LOMS are characterized by a more frequent occurrence of a progressive course of the disease, a delay in establishing a diagnosis in relation to the time since the appearance of initial neurological disorders, as well as a higher prevalence of motor disability. The older the person, the greater the risk of comorbidity, which negatively affects the course of the disease and potentially limits therapeutic options. There are limited data on the effectiveness and safety of therapy that modifies the natural course of the disease, for people with MS in this age group.
It is particularly interesting how the aging process affects the pathophysiology of MS, the clinical course and the treatment approach of people with LOMS.
References
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25. Tremlett, H.; Devonshire, V. Is late-onset multiple sclerosis associated with a worse outcome? Neurology 2006; 67, 954–959.
26. Buscarinu, M.C.; Reniè, R.; Morena, E.; Romano, C.; Bellucci, G.; Marrone, A.; Bigi, R.; Salvetti, M.; Ristori, G. Late-Onset MS: Disease Course and Safety-Efficacy of DMTS. Front. Neurol. 2022; 13, 829331.
27. 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.
28. Andersen, M.A.; Buron, M.D.; Magyari, M. Late-onset MS is associated with an increased rate of reaching disability milestones. J. Neurol. 2021, 268, 3352–3360.
29. Wang, B.; Li, X.; Li, H.; Xiao, L.; Zhou, Z.; Chen, K.; Gui, L.; Hou, X.; Fan, R.; Chen, K.; et al. Clinical, Radiological and Pathological Characteristics between Cerebral Small Vessel Disease and Multiple Sclerosis: A Review. Front. Neurol. 2022; 13, 841521.
30. Wattjes, M.P.; Ciccarelli, O.; Reich, D.S.; Banwell, B.; de Stefano, N.; Enzinger, C.; Fazekas, F.; Filippi, M.; Frederiksen, J.; Gasperini, C.; et al. 2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis. Lancet Neurol. 2021; 20, 653–670.
31. Rice, C.M.; Scolding, N.J. The diagnosis of primary central nervous system vasculitis. Pract. Neurol. 2020; 20, 109–114.
32. Jewells, V.L.; Latchaw, R.E. CNS Vasculitis—An Overview of This Multiple Sclerosis Mimic: Clinical and MRI Implications. Semin. Ultrasound CT MRI 2020; 41, 296–308.
33. McCormick, J.R.; Sama, A.J.; Schiller, N.C.; Butler, A.J.; Donnally, C.J., 3rd. Cervical Spondylotic Myelopathy: A Guide to Diagnosis and Management. J. Am. Board. Fam. Med. 2020; 33, 303–313.
34. Cacciaguerra, L.; Sechi, E.; Rocca, M.A.; Filippi, M.; Pittock, S.J.; Flanagan, E.P. Neuroimaging features in inflammatory myelopathies: A review. Front. Neurol. 2022; 13, 993645.
35. Kraker, J.A.; Chen, J.J. An update on optic neuritis. J. Neurol. 2023, 270, 5113–5126.
36. Bennett, J.L.; Costello, F.; Chen, J.J.; Petzold, A.; Biousse, V.; Newman, N.J.; Galetta, S.L. Optic neuritis and autoimmune optic neuropathies: Advances in diagnosis and treatment. Lancet Neurol. 2023; 22, 89–100.
37. Bradshaw, M.J.; Pawate, S.; Koth, L.L.; Cho, T.A.; Gelfand, J.M. Neurosarcoidosis: Pathophysiology, Diagnosis, and Treatment. Neurol. Neuroimmunol. Neuroinflamm. 2021; 8, e1084.
38. Berrigan, L.I.; Fisk, J.D.; Patten, S.B.; Tremlett, H.; Wolfson, C.; Warren, S.; Fiest, K.M.; McKay, K.A.; Marrie, R.A. Health-related quality of life in multiple sclerosis: Direct and indirect effects of comorbidity. Neurology 2016; 86, 1417–1424.
39. Maric G, Pekmezovic T, Tamas O, Veselinovic N, Jovanovic A, Lalic K, Mesaros S, Drulovic J. Impact of comorbidities on the disability progression in multiple sclerosis. Acta Neurol Scand. 2022;145(1):24-29.
40. Ostolaza A, Corroza J, Ayuso T. Multiple sclerosis and aging: comorbidity and treatment challenges. Mult Scler Relat Disord. 2021; 50:102815.
41. 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.
42. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontology. 2003; 38:843–53.
43. 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.
44. Schweitzer, F.; Laurent, S.; Fink, G.R.; Barnett, M.H.; Reddel, S.; Hartung, H.P.; Warnke, C. Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis. Curr. Opin. Neurol. 2019; 32, 305–312.
45. 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, 1391–1402.
46. 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.
47. 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.
48. 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
49. 135. 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
50. ChisariCG, BiancoA, Brescia MorraV, Calabrese M,CaponeF, CavallaP,et al. Effectiveness of ocrelizumab in primary progressive multiple sclerosis: a multicenter, retrospective, real-world study (OPPORTUNITY). Neurotherapeutics. 2023; 20 (6):1696–706.
51. EpsteinS,FongKT,DeJagerPL,LevineL,RileyC,WesleyS,etal.Evaluationof ocrelizumab in older progressive multiple sclerosis patients. Mult Scler Relat Disord. 2021; 55:103171.
52. 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.
53. 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. Neurovirol. 2017; 23, 742–749.
54. 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.
55. 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.
56. 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.
2. 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
3. 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.
4. Fernández Ó, Sörensen PS, Comi G, Vermersch P, Hartung HP, Leocani L, Berger T, Van Wijmeersch B, Oreja-Guevara C. Managing multiple sclerosis in individuals aged 55 and above: a comprehensive review. Front Immunol. 2024;15:1379538.
5. 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.
6. Mirmosayyeb O, Brand S, Barzegar M, Afshari-Safavi A, Nehzat N, Shaygannejad V, Sadeghi Bahmani D. 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.
7. 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.
8. ZhangY,GonzalezCalditoN,ShiraniA,SalterA,CutterG,CulpepperW.2nd, et al. Aging efficacy disease-modifying therapies multiple sclerosis: meta-analysis Clin trials. Ther Adv Neurol Disord. 2020; 13:1756286420969016.
9. Zinganell A, Göbel G, Berek K, Hofer B, Asenbaum-Nan S, Barang M, Böck K, Bsteh C, Bsteh G, Eger S, Eggers C, Fertl E, Joldic D, Khalil M, Langenscheidt D, Komposch M, Kornek B, Kraus J, Krendl R, Rauschka H, Sellner J, Auer M, Hegen H, Pauli FD, Deisenhammer F. Multiple sclerosis in the elderly: a retrospective cohort study. J Neurol. 2024; 271(2):674-687.
10. 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.
11. 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.
12. 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.
13. Lunde HMB,Assmus J, Myhr K-M, BøL, Grytten N. Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study. J Neurology Neurosurg Psychiatry. 2017; 88:621–5.
14. Eschborn M, Pawlitzki M, Wirth T, et al. Evaluation of Age-Dependent Immune Signatures in Patients With Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021; 8(6):e1094.
15. Kuhlmann, T.; Moccia, M.; Coetzee, T.; Cohen, J.A.; Correale, J.; Graves, J.; Marrie, R.A.; Montalban, X.; Yong, V.W.; Thompson, A.J.; et al. Multiple sclerosis progression: Time for a new mechanism-driven framework. Lancet Neurol. 2023, 22, 78–88
16. Rawji KS, Mishra MK, Michaels NJ, Rivest S, Stys PK, Yong VW. Immunosenescence of microglia and macrophages: impact on the aging central nervous system. BRAIN. 2016; 139:653–61.
17. 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;8:577-612.
18. Nociti, V.; Romozzi, M.; Mirabella, M. Challenges in Diagnosis and Therapeutic Strategies in Late-Onset Multiple Sclerosis. J. Pers. Med. 2024, 14, 400.
19. Alroughani, R.; Akhtar, S.; Ahmed, S.; Behbehani, R.; Al-Hashel, J. Is Time to Reach EDSS 6.0 Faster in Patients with Late-Onset versus Young-Onset Multiple Sclerosis? PLoS ONE 2016, 11, e0165846.
20. 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.
21. Lublin FD, Häring DA, Ganjgahi H, Ocampo A, Hatami F, Č uklina J, et al. How patients with multiple sclerosis acquire disability. Brain. 2022; 45:3147–61.
22. Roohani, P.; Emiru, T.; Carpenter, A.; Luzzio, C.; Freeman, J.; Scarberry, S.; Beaver, G.; Davidson, L.; Parry, G. Late onset multiple sclerosis: Is it really late onset? Mult. Scler. Relat. Disord. 2014; 3, 444–449.
23. Naseri, A.; Nasiri, E.; Sahraian, M.A.; Daneshvar, S.; Talebi, M. Clinical Features of Late-Onset Multiple Sclerosis: A Systematic Review and Meta-analysis. Mult. Scler. Relat. Disord. 2021; 50, 102816.
24. Alroughani, R.; Akhtar, S.; Ahmed, S.; Behbehani, R.; Al-Hashel, J. Is Time to Reach EDSS 6.0 Faster in Patients with Late-Onset versus Young-Onset Multiple Sclerosis? PLoS ONE. 2016; 11, e0165846.
25. Tremlett, H.; Devonshire, V. Is late-onset multiple sclerosis associated with a worse outcome? Neurology 2006; 67, 954–959.
26. Buscarinu, M.C.; Reniè, R.; Morena, E.; Romano, C.; Bellucci, G.; Marrone, A.; Bigi, R.; Salvetti, M.; Ristori, G. Late-Onset MS: Disease Course and Safety-Efficacy of DMTS. Front. Neurol. 2022; 13, 829331.
27. 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.
28. Andersen, M.A.; Buron, M.D.; Magyari, M. Late-onset MS is associated with an increased rate of reaching disability milestones. J. Neurol. 2021, 268, 3352–3360.
29. Wang, B.; Li, X.; Li, H.; Xiao, L.; Zhou, Z.; Chen, K.; Gui, L.; Hou, X.; Fan, R.; Chen, K.; et al. Clinical, Radiological and Pathological Characteristics between Cerebral Small Vessel Disease and Multiple Sclerosis: A Review. Front. Neurol. 2022; 13, 841521.
30. Wattjes, M.P.; Ciccarelli, O.; Reich, D.S.; Banwell, B.; de Stefano, N.; Enzinger, C.; Fazekas, F.; Filippi, M.; Frederiksen, J.; Gasperini, C.; et al. 2021 MAGNIMS-CMSC-NAIMS consensus recommendations on the use of MRI in patients with multiple sclerosis. Lancet Neurol. 2021; 20, 653–670.
31. Rice, C.M.; Scolding, N.J. The diagnosis of primary central nervous system vasculitis. Pract. Neurol. 2020; 20, 109–114.
32. Jewells, V.L.; Latchaw, R.E. CNS Vasculitis—An Overview of This Multiple Sclerosis Mimic: Clinical and MRI Implications. Semin. Ultrasound CT MRI 2020; 41, 296–308.
33. McCormick, J.R.; Sama, A.J.; Schiller, N.C.; Butler, A.J.; Donnally, C.J., 3rd. Cervical Spondylotic Myelopathy: A Guide to Diagnosis and Management. J. Am. Board. Fam. Med. 2020; 33, 303–313.
34. Cacciaguerra, L.; Sechi, E.; Rocca, M.A.; Filippi, M.; Pittock, S.J.; Flanagan, E.P. Neuroimaging features in inflammatory myelopathies: A review. Front. Neurol. 2022; 13, 993645.
35. Kraker, J.A.; Chen, J.J. An update on optic neuritis. J. Neurol. 2023, 270, 5113–5126.
36. Bennett, J.L.; Costello, F.; Chen, J.J.; Petzold, A.; Biousse, V.; Newman, N.J.; Galetta, S.L. Optic neuritis and autoimmune optic neuropathies: Advances in diagnosis and treatment. Lancet Neurol. 2023; 22, 89–100.
37. Bradshaw, M.J.; Pawate, S.; Koth, L.L.; Cho, T.A.; Gelfand, J.M. Neurosarcoidosis: Pathophysiology, Diagnosis, and Treatment. Neurol. Neuroimmunol. Neuroinflamm. 2021; 8, e1084.
38. Berrigan, L.I.; Fisk, J.D.; Patten, S.B.; Tremlett, H.; Wolfson, C.; Warren, S.; Fiest, K.M.; McKay, K.A.; Marrie, R.A. Health-related quality of life in multiple sclerosis: Direct and indirect effects of comorbidity. Neurology 2016; 86, 1417–1424.
39. Maric G, Pekmezovic T, Tamas O, Veselinovic N, Jovanovic A, Lalic K, Mesaros S, Drulovic J. Impact of comorbidities on the disability progression in multiple sclerosis. Acta Neurol Scand. 2022;145(1):24-29.
40. Ostolaza A, Corroza J, Ayuso T. Multiple sclerosis and aging: comorbidity and treatment challenges. Mult Scler Relat Disord. 2021; 50:102815.
41. 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.
42. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontology. 2003; 38:843–53.
43. 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.
44. Schweitzer, F.; Laurent, S.; Fink, G.R.; Barnett, M.H.; Reddel, S.; Hartung, H.P.; Warnke, C. Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis. Curr. Opin. Neurol. 2019; 32, 305–312.
45. 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, 1391–1402.
46. 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.
47. 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.
48. 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
49. 135. 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
50. ChisariCG, BiancoA, Brescia MorraV, Calabrese M,CaponeF, CavallaP,et al. Effectiveness of ocrelizumab in primary progressive multiple sclerosis: a multicenter, retrospective, real-world study (OPPORTUNITY). Neurotherapeutics. 2023; 20 (6):1696–706.
51. EpsteinS,FongKT,DeJagerPL,LevineL,RileyC,WesleyS,etal.Evaluationof ocrelizumab in older progressive multiple sclerosis patients. Mult Scler Relat Disord. 2021; 55:103171.
52. 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.
53. 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. Neurovirol. 2017; 23, 742–749.
54. 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.
55. 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.
56. 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.