Current perspectives on Multiple Sclerosis

Yıl 2024, Cilt: 4 Sayı: 1, 34 - 52, 30.06.2024

Sema Çimen Kaan Küçükoğlu

https://doi.org/10.5281/zenodo.12547696

Öz

Multiple Sclerosis (MS) is a chronic, autoimmune disease that affects the central nervous system. It is characterised by inflammation, demyelination and axonal loss, and is typically manifested by relapses and remissions. It is the most prevalent neurological disorder worldwide, with a significant prevalence in many countries. It is the leading cause of non-traumatic neurological impairment in young adults. Although the etiology is not fully understood, genetic predisposition, environmental factors (exposure to inadequate sunlight and/or inadequate dietary intake of vitamin D, Epstein-Barr virus infection, etc.) Furthermore, an individual's lifestyle, including obesity, smoking, and other factors, plays a significant role in the development of the disease. The clinical subtypes of MS, as defined in 2013, are classified into four categories: The four main clinical subtypes of MS are: Isolated Syndrome, Relapsing-Remitting MS, Primary Progressive MS and Secondary Progressive MS. The clinical subtypes of MS are further subdivided according to the activity and progression of the disease.
MS is a heterogenous disease, with lesions affecting multiple systems. The most common clinical manifestations include fatigue, blurred vision, and ocular pain (optic neuritis), as well as weakness and sensory changes in specific body regions, such as the face, arms, and legs. Furthermore, the patient presented with symptoms including balance impairment, vertigo, memory and cognitive difficulties, and bladder control issues.
Although there is currently no cure for MS, existing treatments focus on alleviating acute attacks, improving symptoms, and reducing the impact of the disease through biological therapies. Modifying therapies for the disease (e.g., interferons, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, ocrelizumab, natalizumab, etc.) These drugs, which reduce the frequency of clinical attacks and slow the progression of the disease, also reduce the activity of MRI lesions, making them an important component of MS treatment. They are effective due to their diverse mechanisms of action, administration routes, and dosages.

Anahtar Kelimeler

Attack, Demyelination, Inflammation, Multiple sclerosis

Kaynakça

• 1. Dobson R, Giovannoni G. Multiple sclerosis–a review. Eur J Neurol. 2019;26, 1:27–40. 2. Filippi M, Bar-Or A, Piehl F, et al. Multiple sclerosis. Nat Rev Dis Prim. 2018;43.
• 3. Charcot JM. Leçons de, 1868. Manuscrits des leçons de JM Charcot. Fonds numérisé Charcot. Bibliothèque de l’Université Pierre & Marie Curie. Published online 1968.
• 4. Motl RW, Learmonth YC. Neurological disability and its association with walking impairment in multiple sclerosis: brief review. Neurodegener Dis Manag. 2014;4, 6:491–500.
• 5. Browne P, Chandraratna D, Angood C, et al. Atlas of Multiple Sclerosis 2013: A growing global problem with widespread inequity. Neurology. 2014;83(11):1022-1024.
• oi:10.1212/WNL.0000000000000768
• 6. M.S. International Federation. Atlas of MS. Access Date. 2023;22.
• 7. McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and Treatment of Multiple Sclerosis: A Review. JAMA. 2021;325, 8:765–79.
• 8. Simpson S, Wang W, Otahal P, Blizzard L, Mei IA, Taylor B V. Latitude continues to be significantly associated with the prevalence of multiple sclerosis: an updated meta-analysis. J Neurol Neurosurg Psychiatry. 2019;90, 11:1193–200.
• 9. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part II: Noninfectious factors. Ann Neurol Off J Am Neurol Assoc Child Neurol Soc. 2007;61, 6:504–13.
• 10. Gandhi R, Laroni A, Weiner HL. Role of the innate immune system in the pathogenesis of multiple sclerosis. J Neuroimmunol. 2010;221:1–2, 7–14.
• 11. Dedoni S, Scherma M, Camoglio C, et al. An overall view of the most common experimental models for multiple sclerosis. Neurobiol Dis. 2023;106230.
• 12. Brownlee WJ, Hardy TA, Fazekas F, Miller DH. Diagnosis of multiple sclerosis: progress and challenges. Lancet. 2017;389, 10076:1336–46.
• 13. Ömerhoca S, Akkaş SY, İçen NK. Multiple sclerosis: diagnosis and differential diagnosis. Arch Neuropsychiatry. 2018;55, Suppl:1.
• 14. Altunrende B, Birday E, Kasap M, Akman Demir G. Fingolimod for the treatment of relapsing-remitting multiple sclerosis. Turkish J Neurol. 2017;176-85.
• 15. Murray TJ. The history of multiple sclerosis: the changing frame of the disease over the centuries. J Neurol Sci. 2009;277:3– 8.
• 16. Eraksoy M, Bulut S, Alp R. Multipl Sklerosis. 1th ed. (Ed NTK,M E, eds.). Güneş Tıp Kitabevleri; 2013.
• 17. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502–17.
• 18. Sevim S. Multipl skleroz atakları üzerine güncelleme: Tanım, patofizyoloji, özellikler, taklitçiler ve tedavi. Turk J Neurol. 2016;22:99–108.
• 19. Chmielewska N, Szyndler J. Targeting CD20 in multiple sclerosis—review of current treatment strategies. Neurol Neurochir Pol. 2023;57:235–42.
• 20. Leray E, Moreau T, Fromont A, Edan G. Epidemiology of multiple sclerosis. Rev Neurol (Paris). 2016;172(1):3-13. doi:10.1016/j.neurol.2015.10.006
• 21. Walton C, King R, Rechtman L, et al. Rising prevalence of multiple sclerosis. Published online 2020:1816-1821.
• 22. Nicoletti A, Patti F, Lo Fermo S, et al. Possible increasing risk of multiple sclerosis in Catania, Sicily. Neurology. 2005;65, 8:1259–63.
• 23. Sellner J, Kraus J, Awad A, Milo R, Hemmer B, Stüve O. The increasing incidence and prevalence of female multiple sclerosis—a critical analysis of potential environmental factors. Autoimmun Rev. 2011;10, 8:495–502.
• 24. Stenager E. A global perspective on the burden of multiple sclerosis. Lancet Neurol. 2019;18, 3:227–8.
• 25. Orton S-M, Herrera BM, Yee IM, et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 2006;5, 11:932–6.
• 26. Padilha IG, Fonseca AP, Pettengill AL, et al. Pediatric multiple sclerosis: from clinical basis to imaging spectrum and differential diagnosis. Pediatr Radiol. 2020;50:776–92.
• 27. Pilotto S, Gencarelli J, Bova S, et al. Etiological research in pediatric multiple sclerosis: A tool to assess environmental exposures. Pediatr Ital Genet Environ Expo Quest Mult Scler Journal–Experimental, Transl Clin.
• 2021;7, 4:20552173211059050.
• 28. Yan K, Balijepalli C, Desai K, Gullapalli L, Druyts E. Epidemiology of pediatric multiple sclerosis: a systematic literature review and meta-analysis. Mult Scler Relat Disord. 2020;44:102260.
• 29. Immovilli P, Mitri P, Bazzurri V, et al. The Impact of Highly Effective Treatment in Pediatric-Onset Multiple Sclerosis: A Case Series. Children. 2022;9:11.
• 30. Jeong A, Oleske DM, Holman J. Epidemiology of pediatric- onset multiple sclerosis: a systematic review of the literature. J Child Neurol. 2019;34, 12:705–12.
• 31. Hemmer B, Cepok S, Nessler S, Sommer N. Pathogenesis of multiple sclerosis: an update on immunology. Curr Opin Neurol. 2002;15, 3:227–31.
• 32. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Medical progress. Mult Scler N Engl J Med. 2000;343:938–52.
• 33. Smolders J, Damoiseaux J, Menheere P, Hupperts R. Vitamin D as an immune modulator in multiple sclerosis, a review. J Neuroimmunol. 2008;194:1–2, 7–17.
• 34. Potemkowski A. Stwardnienie rozsiane w świecie iw Polsce–ocena epidemiologiczna. Aktual Neurol. 2009;2, 9:91–7.
• 35. Ramagopalan S, Valdar W, Criscuoli M, et al. Age of puberty and the risk of multiple sclerosis: a population based study. Eur J Neurol. 2010;16, 3:342–7.
• 36. Briggs FB, Gunzler DD, Ontaneda D, Marrie RA. Smokers with MS have greater decrements in quality of life and disability than non-smokers. Mult Scler J. 2014;23, 13:1772–81.
• 37. Khan Z, Gupta GD, Mehan S. Cellular and molecular evidence of multiple sclerosis diagnosis and treatment challenges. J Clin Med. 2023;12, 13:4274.
• 38. Van der Mei, I., Lucas RM, Taylor B, et al. Population attributable fractions and joint effects of key risk factors for multiple sclerosis. Mult Scler J. 2016;22, 4:461–9.
• 39. Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol. 2017;13, 1:25–36.
• 40. Jafari N. Risk Factors in Cause and Course of Multiple Sclerosis. Doktora Tezi, Erasmus Üniversitesi; 2011.
• 41. Cohen JA, Rae-Grant A. Handbook of Multiple Sclerosis. 2th ed. Springer Healthcare Ltd.; 2012. doi:10.1007/978-1- 907673-50-4
• 42. Brynedal B, Duvefelt K, Jonasdottir G, et al. HLA-A confers an HLA-DRB1 independent influence on the risk of multiple sclerosis. PLoS One. 2007;2, 7:664.
• 43. Sawcer S, Hellenthal G, Pirinen M, et al. International Multiple Sclerosis Genetics Consortium Wellcome Trust Case Control Consortium 2 Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476, 7359:214–9.
• 44. Beecham A, Patsopoulos N, Xifara D, et al. International Multiple Sclerosis Genetics Consortium (IMSGC). Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet. 2013;45, 11:1353–60.
• 45. Moutsianas L, Jostins L, Beecham AH, et al. Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat Genet. 2015;47:1107–1113.
• 46. Nouri H, Tabesh H, Saboori M, et al. Protective and risk factors in multiple sclerosis. Int J Med Rev. 2019;6, 2:51–8.
• 47. Zawada M. Potential pathogens in multiple sclerosis (MS. Adv Hyg Exp Med. 2012;66:758–70.
• 48. Huang J. Biomarkers and Viral Risk Factors in Multiple Sclerosis. Published online 2022. https://www.proquest.com/docview/2700374980?pq- origsite=gscholar&fromopenview=true&sourcetype=Disse rtations & Theses.
• 49. Gombash SE, Lee PW, Sawdai E, Lovett-Racke AE. Vitamin D as a risk factor for multiple sclerosis: immunoregulatory or neuroprotective? Front Neurol. 2022;13:796933.
• 50. Ascherio A, Munger KL, White R, et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol. 2014;71, 3:306–314.
• 51. Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology. 2009;73, 19:1543– 50.
• 52. Cortese M, Riise T, Bjørnevik K, et al. Timing of use of cod liver oil, a vitamin D source, and multiple sclerosis risk: The EnvIMS study. Mult Scler J. 2015;21, 14:1856–64.
• 53. Bjørnevik K, Riise T, Casetta I, et al. Sun exposure and multiple sclerosis risk in Norway and Italy: The EnvIMS study. Mult Scler J. 2014;20, 8:1042–9.
• 54. Giovannoni G, Ebers G. Multiple sclerosis: the environment and causation. Curr Opin Neurol. 2007;20, 3:261–8.
• 55. Hawkes C. Smoking is a risk factor for multiple sclerosis: a metanalysis. Mult Scler J. 2007;13, 5:610–5.
• 56. Handel AE, Williamson AJ, Disanto G, Dobson R, Giovannoni G, Ramagopalan S V. Smoking and multiple sclerosis: an updated meta-analysis. PLoS One. 2011;6, 1:16149.
• 57. O’Gorman C, Broadley S. Smoking and multiple sclerosis: evidence for latitudinal and temporal variation. J Neurol. 2014;261:1677–83.
• 58. Zhang P, Wang R, Li Z, et al. The risk of smoking on multiple sclerosis: a meta-analysis based on 20,626 cases from case- control and cohort studies. PeerJ. 2016;4:1797.
• 59. Poorolajal J, Bahrami M, Karami M, Hooshmand E. Effect of smoking on multiple sclerosis: a meta-analysis. J Public Health (Bangkok). 2017;39, 2:312–20.
• 60. Hedström AK, Hillert J, Olsson T, Alfredsson L. Smoking and multiple sclerosis susceptibility. Eur J Epidemiol. 2013;28:867–74.
• 61. 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.
• 62. Rosiak K. Czynniki ryzyka i wybrane aspekty psychospołeczne w stwardnieniu rozsianym. Badanie kliniczno-kontrolne, Rozprawa doktorska. Gdańsk. 2016;2016:3–11.
• 63. Hedström AK, Ryner M, Fink K, et al. Smoking and risk of treatment-induced neutralizing antibodies to interferon β- 1a. Mult Scler J. 2014;20, 4:445–50.
• 64. Hedström AK, Lima Bomfim I, Barcellos L, et al. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. Neurology. 2014;82, 10:865– 72.
• 65. Hernán MA, Jick SS, Logroscino G, Olek MJ, Ascherio A, Jick H. Cigarette smoking and the progression of multiple sclerosis. Brain. 2005;128, 6:1461–5.
• 66. O’Gorman C, Lucas R, Taylor B. Environmental Risk Factors for Multiple Sclerosis: A Review with a Focus on Molecular Mechanisms. Int J Mol Sci. 2012;13, 9:11718–52.
• 67. Baskara I, Kerbrat S, Dagouassat M, et al. Cigarette smoking induces human CCR6+ Th17 lymphocytes senescence and VEGF-A secretion. Sci Rep. 2020;10, 1:6488.
• 68. Alrouji M, Manouchehrinia A, Gran B, Constantinescu CS. Effects of cigarette smoke on immunity, neuroinflammation and multiple sclerosis. J Neuroimmunol. 2019;329:24–34.
• 69. Smith KJ, Lassmann H. The role of nitric oxide in multiple sclerosis. Lancet Neurol. 2002;1, 4:232–41.
• 70. Lauer K. Environmental risk factors in multiple sclerosis. Expert Rev Neurother. 2010;10, 3:421–40.
• 71. Shirani A, Tremlett H. The effect of smoking on the symptoms and progression of multiple sclerosis: a review. J Inflamm Res. Published online 2010:115–26.
• 72. Ammitzbøll C, Essen MR, Börnsen L, et al. GPR15+ T cells are Th17 like, increased in smokers and associated with multiple sclerosis. J Autoimmun. 2019;97:114–21.
• 73. Gao Z, Nissen JC, Ji K, Tsirka SE. The experimental autoimmune encephalomyelitis disease course is modulated by nicotine and other cigarette smoke components. PLoS One. 2014;9, 9:107979.
• 74. Nizri E, Irony-Tur-Sinai M, Lory O, Orr-Urtreger A, Lavi E, Brenner T. Activation of the cholinergic anti-inflammatory system by nicotine attenuates neuroinflammation via suppression of Th1 and Th17 responses. J Immunol. 2009;183, 10:6681–8.
• 75. Alfredsson L, Olsson T. Lifestyle and environmental factors in multiple sclerosis. Cold Spring Harb Perspect Med. 2019;9:4.
• 76. Hedström A, Olsson T, Alfredsson L. Smoking is a major preventable risk factor for multiple sclerosis. Mult Scler J. 2016;22(8):1021-1026. doi:10.1177/1352458515609794
• 77. Munger KL. Childhood obesity is a risk factor for multiple sclerosis. Mult Scler J. 2013;19:13.
• 78. Wesnes K, Riise T, Casetta I, et al. Body size and the risk of multiple sclerosis in Norway and Italy: the EnvIMS study. Mult Scler J. 2015;21, 4:388–95.
• 79. De Rosa, V., Procaccini C, Calì G, et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity. 2007;26, 2:241–55.
• 80. Cheung CC, Thornton JE, Kuijper JL, Weigle DS, Clifton DK, Steiner RA. Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology. 1997;138, 2:855– 8.
• 81. Matkovic V, Ilich JZ, Skugor M, et al. Leptin is inversely related to age at menarche in human females. J Clin Endocrinol Metab. 1997;82, 10:3239–45.
• 82. Ramagopalan S V, Dobson R, Meier UC, Giovannoni G. Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol. 2009;9, 7:727–39.
• 83. Chitnis T. Role of puberty in multiple sclerosis risk and course. Clin Immunol. 2013;149, 2:192–200.
• 84. Lee JM, Appugliese D, Kaciroti N, Corwyn RF, Bradley RH, Lumeng JC. Weight status in young girls and the onset of puberty. Pediatrics. 2007;119, 3:624– 30.
• 85. Gianfrancesco MA, Barcellos LF. Obesity and multiple sclerosis susceptibility: a review. J Neurol neuromedicine. 2016;1, 7:1.
• 86. Abna Z, Fazeli SA, Mirhashemi S, et al. A narrative review study on the effects of obesity and bariatric surgery on multiple sclerosis. Ann Indian Acad Neurol. 2021;24, 5:664.
• 87. Matarese G, Carrieri PB, Cava A, et al. Leptin increase in multiple sclerosis associates with reduced number of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci. 2005;102, 14:5150–5.
• 88. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117, 1:175–84.
• 89. Procaccini C, Pucino V, Mantzoros CS, Matarese G. Leptin in autoimmune diseases. Metabolism. 2015;64, 1:92–104.
• 90. Matarese G, Carrieri PB, Montella S, Rosa V, Cava A. Leptin as a metabolic link to multiple sclerosis. Nat Rev Neurol. 2010;6, 8:455–61.
• 91. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72(3):690–693.
• 92. 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, 6:1002053.
• 93. Locke AE, Kahali B, Berndt SI, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518, 7538:197–206.
• 94. Gianfrancesco MA, Stridh P, Rhead B, et al. Evidence for a causal relationship between low vitamin D, high BMI, and pediatric-onset MS. Neurology. 2017;88, 17:1623–9.
• 95. Handel AE, Giovannoni G, Ebers GC, Ramagopalan S V. Environmental factors and their timing in adult-onset multiple sclerosis. Nat Rev Neurol. 2010;6, 3:156–66.
• 96. DeLuca H, Plum L. UVB radiation, vitamin D and multiple sclerosis. Photochem Photobiol Sci. 2017;16:411–5.
• 97. Gale CR, Martyn CN. Migrant studies in multiple sclerosis. Prog Neurobiol. 1995;47:4–5, 425–48.
• 98. Sabel CE, Pearson JF, Mason DF, Willoughby E, Abernethy DA, Taylor B V. The latitude gradient for multiple sclerosis prevalence is established in the early life course. Brain. 2021;144, 7:2038–46.
• 99. Tao C, Simpson S, Mei I, et al. Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87, 12:1343– 9.
• 100. Hucke S, Eschborn M, Liebmann M, et al. Sodium chloride promotes pro-inflammatory macrophage polarization thereby aggravating CNS autoimmunity. J Autoimmun. 2016;67:90–101.
• 101. Farez MF, Fiol MP, Gaitán MI, Quintana FJ, Correale J. Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86, 1:26–31.
• 102. Wu C, Yosef N, Thalhamer T, et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature. 2013;496, 7446:513–7.
• 103. Kleinewietfeld M, Manzel A, Titze J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496, 7446:518–22.
• 104. Chen J, Chia N, Kalari KR, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep. 2016;6, 1:1–10.
• 105. Galluzzo P, Capri FC, Vecchioni L, et al. Comparison of the intestinal microbiome of Italian patients with multiple sclerosis and their household relatives. Life. 2021;11, 7:620.
• 106. Lin X, Liu Y, Ma L, et al. Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice. J Transl Med. 2021;19:1–16.
• 107. Haase S, Haghikia A, Wilck N, Müller DN, Linker RA. Impacts of microbiome metabolites on immune regulation and autoimmunity. Immunology. 2018;154, 2:230–8.
• 108. Zmora N, Suez J, Elinav E. You are what you eat: diet, health and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019;16, 1:35–56.
• 109. Krautkramer KA, Fan J, Bäckhed F. Gut microbial metabolites as multi-kingdom intermediates. Nat Rev Microbiol. 2021;19, 2:77–94.
• 110. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4+ CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199, 7:971–9.
• 111. Tomé‐Carneiro J, Gonzálvez M, Larrosa M, et al. Resveratrol in primary and secondary prevention of cardiovascular disease: a dietary and clinical perspective. Ann N Y Acad Sci. 2013;1:37–51.
• 112. Andersen C, Søndergaard HB, Bang Oturai D, et al. Alcohol consumption in adolescence is associated with a lower risk of multiple sclerosis in a Danish cohort. Mult Scler J. 2019;25, 12:1572–9.
• 113. Berer K, Gerdes LA, Cekanaviciute E, et al. Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Natl Acad Sci. 2017;114, 40:10719–24.
• 114. Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444, 7117:337–42.
• 115. Fonseca-Kelly Z, Nassrallah M, Uribe J, et al. Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis. Front Neurol. 2012;3:84.
• 116. Imler Jr TJ PTM. Decreased severity of experimental autoimmune encephalomyelitis during resveratrol administration is associated with increased IL-17+ IL-10+ T cells, CD4− IFN-γ+ cells, and decreased macrophage IL-6 expression. Int Immunopharmacol. 2009;9, 1:134–43.
• 117. Hedström A, Mowry E, Gianfrancesco M, et al. High consumption of coffee is associated with decreased multiple sclerosis risk; results from two independent studies. J Neurol Neurosurg Psychiatry. 2016;87, 5:454–60.
• 118. Reich DS, Lucchinetti CF, Calabresi PA. Multiple Sclerosis. N Engl J Med. 2018;378:169–180.
• 119. Peschl P, Bradl M, Höftberger R, Berger T, Reindl M. Myelin oligodendrocyte glycoprotein: deciphering a target in inflammatory demyelinating diseases. Front Immunol. 2017;8:529.
• 120. McCreary M, Mealy M, Wingerchuk D, Levy M, DeSena A, Greenberg B. Updated diagnostic criteria for neuromyelitis optica spectrum disorder: Similar outcomes of previously separate cohorts. Mult Scler Journal–Experimental, Transl Clin. 2018;4, 4:2055217318815925.
• 121. Milo R, Miller A. Revised diagnostic criteria of multiple sclerosis. Autoimmun Rev. 2014;13:4–5, 518–24.
• 122. McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol Off J Am Neurol Assoc Child Neurol Soc. 2001;50, 1:121–7.
• 123. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17, 2:162–73.
• 124. Brownlee WJ, Swanton JK, Altmann DR, Ciccarelli O, Miller DH. Earlier and more frequent diagnosis of multiple sclerosis using the McDonald criteria. J Neurol Neurosurg Psychiatry. 2015;86, 5:584–5.
• 125. Friedrich A. Multiple Sklerose erkennen. Heilberufe. 2021;73, 10:26–9.
• 126. Crayton H, Heyman RA, Rossman HS. A multimodal approach to managing the symptoms of multiple sclerosis.Neurology. 2004;63, 11 sup:12– 8.
• 127. Deangelis TM, Miller A. Diagnosis of multiple sclerosis. In: Goodin DS, ed. Handbook of Clinical Neurology: Multiple Sclerosis and Related Disorders. 3rd series. The; 2014:317– 342.
• 128. Brownell B, Hughes JT. The distribution of plaques in the cerebrum in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1962;25, 4:315.
• 129. Arrambide G, Rovira A, Sastre-Garriga J, et al. Spinal cord lesions: a modest contributor to diagnosis in clinically isolated syndromes but a relevant prognostic factor. Mult Scler J. 2018;24, 3:301–12.
• 130. Riederer I, Mühlau M, Hoshi M-M, Zimmer C, Kleine JF. Detecting optic nerve lesions in clinically isolated syndrome and multiple sclerosis: double-inversion recovery magnetic resonance imaging in comparison with visually evoked potentials. J Neurol. 2019;266:148–56.
• 131. Kuhlmann T, Lassmann H, Brück W. Diagnosis of inflammatory demyelination in biopsy specimens: a practical approach. Acta Neuropathol. 2008;115:275–87.
• 132. Inglese M. Multiple sclerosis: new insights and trends. Am J Neuroradiol. 2006;27, 5:954–7.
• 133. Ma X, Ma R, Zhang M, Qian B, Wang B, Yang W. Recent progress in multiple sclerosis treatment using immune cells as targets. Pharmaceutics. 2023;15, 3:728.
• 134. Lublin FD. New multiple sclerosis phenotypic classification.Eur Neurol. 2014;72, Suppl.:1–5.
• 135. Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol. 2005;4, 5:281–8.
• 136. Wiendl H, Gold R, Berger T, et al. No Title. 2021;14:17562864211039648.
• 137. National Multiple Sklerosis Society. Access Date, 27 February 2024. Link, https://www.nationalCNSociety.org/What-is-MS/Types-of-MS/Primary-progressive-MS. Published online 2024.
• 138. MS Australia Research Advocacy Cure. Access Date, 26 February 2024. Link, https://www.msaustralia.org.au/types-of-ms/. Published online 2024.
• 139. National Multiple Sklerosis Society. Link, https://www.nationalCNSociety.org/What-is-MS/Types- of-MS/Secondary-progressive-MS. Published online 2024.
• 140. Koch M, Kingwell E, Rieckmann P, Tremlett H. The natural history of primary progressive multiple sclerosis. Neurology. 2009;73, 23:1996–2002.
• 141. Okuda D, Mowry E, Beheshtian A, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology. 2009;72, 9:800–5.
• 142. Klineova S, Lublin FD. Clinical course of multiple sclerosis.Cold Spring Harb Perspect Med. 2018;8, 9:28928.
• 143. Metaxakis A, Petratou D, Tavernarakis N. Molecular interventions towards multiple sclerosis treatment. BrainSci. 2020;10:5,299.
• 144. Cudalba D, Gica N, Peltecu G, Botezatu R, Panaitescu AM. Multiple sclerosis in pregnancy. Treatment options and outcomes: a review. Rom J Neurol. 2022;21, 2:119.
• 145. Johnson B, Maves T, Mazanec WJ, Miller JR. Stepped-care approach to treating MS: a managed care treatment algorithm. J Manag Care Pharm. 2004;10, 3:26– 32.
• 146. Faissner S, Plemel JR G, R Y, V.W. Progressive multiple sclerosis: from pathophysiology to therapeutic strategies.Nat Rev drug Discov. 2019;18, 12:905–22.
• 147. Brummer T, Zipp F, Bittner S. T cell–neuron interaction in inflammatory and progressive multiple sclerosis biology. Curr Opin Neurobiol. 2022;75:102588.
• 148. Hauser SL, Cree BA. Treatment of multiple sclerosis: a review. Am J Med. 2020;133, 12:1380–90.
• 149. Yang JH, Rempe T, Whitmire N, Dunn-Pirio A, Graves JS. Therapeutic advances in multiple sclerosis. Front Neurol. 2022;13:824926.
• 150. Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003;61, 11:1528–32.
• 151. Frohman EM, Shah A, Eggenberger E, Metz L, Zivadinov R, Stüve O. Corticosteroids for multiple sclerosis: I. Appl Treat exacerbations Neurother. 2007;4:618–26.
• 152. Repovic P, Lublin FD. Treatment of multiple sclerosis exacerbations. Neurol Clin. 2011;29, 2:389–400.
• 153. Berkovich R. Treatment of acute relapses in multiple sclerosis. In: Translational Neuroimmunology in Multiple Sclerosis. ; 2016:307–26.
• 154. Citterio A, Mantia L, Ciucci G, et al. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane database Syst Rev. Published online 1996:11.
• 155. Diebold M, Derfuss T. Immunological treatment of multiple sclerosis. In: Seminars in Hematology. ; 2016:54– 7.
• 156. Havrdova E, Zivadinov R, Krasensky J, et al. Randomized study of interferon beta-1a, low-dose azathioprine, and low-dose corticosteroids in multiple sclerosis. Mult Scler J. 2009;15, 8:965–76.
• 157. Morrow S, Metz L, Kremenchutzky M. High dose oral steroids commonly used to treat relapses in Canadian MS clinics. Can J Neurol Sci. 2009;36, 2:213–5.
• 158. Myhr K, Mellgren S. Corticosteroids in the treatment of multiple sclerosis. Acta Neurol Scand. 2009;120:73–80.
• 159. Van Der Voort LF, Visser A, Knol DL, Oudejans CBM, Polman CH, Killestein J. Lack of interferon‐beta bioactivity is associated with the occurrence of relapses in multiple sclerosis. Eur J Neurol. 2009;16(9):1049-1052. doi:10.1111/j.1468-1331.2009.02649.x
• 160. Inglese M, Petracca M. Therapeutic strategies in multiple sclerosis: a focus on neuroprotection and repair and relevance to schizophrenia. Schizophr Res. 2015;161, 1:94– 101.
• 161. Durelli L, Cocito D, Riccio A, et al. High‐dose intravenous methylprednisolone in the treatment of multiple sclerosis: Clinical‐immunologic correlations. Neurology. 1986;36, 2:238. 162. Beck RW, Cleary PA, Anderson JMM, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med. 1992;326, 9:581–8.
• 163. Milligan N, Newcombe R, Compston D. A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1. Clinical effects. J Neurol Neurosurg Psychiatry. 1987;50, 5:511–6.
• 164. Goodin DS, Reder AT, Bermel RA, et al. Relapses in multiple sclerosis: Relationship to disability. Mult Scler Relat Disord. 2016;6:10–20.
• 165. Gold R, Buttgereit F, Toyka K V. Mechanism of action of glucocorticosteroid hormones: possible implications for therapy of neuroimmunological disorders. J Neuroimmunol. 2001;117:1–2, 1–8.
• 166. Henze T, Rieckmann P, Toyka K. Symptomatic Treatment of Multiple Sclerosis: Multiple Sclerosis Therapy Consensus Group (MSTCG) of the German Multiple Sclerosis Society1. Eur Neurol. 2006;56, 2:78–105.
• 167. Cutter NC, Scott DD, Johnson JC, Whiteneck G. Gabapentin effect on spasticity in multiple sclerosis: a placebo- controlled, randomized trial. Arch Phys Med Rehabil. 2000;81, 2:164–9.
• 168. Paisley S, Beard S, Hunn A, Wight J. Clinical effectiveness of oral treatments for spasticity in multiple sclerosis: a systematic review. Mult Scler J. 2002;8, 4:319–29.
• 169. Shakespeare D, Boggild M, Young CA, Sclerosis CM, RDotC G. Anti‐spasticity agents for multiple sclerosis. Cochrane Database Syst Rev. 2003;1.
• 170. Krupp LB. Mechanisms, measurement, and management of fatigue in multiple sclerosis. In: Eds TAJ, C P, R H, eds. Multiple Sclerosis: Clinical Challenges and Controversies. 1th ed. Martin Dunitz; 1997:283–94.
• 171. Edgley K, Sullivan MJ, Dehoux E. A survey of multiple sclerosis: II. Determ Employ status Can J Rehabil. 1991;4(3):127–132.
• 172. Rammohan K, Rosenberg J, Lynn D, Blumenfeld A, Pollak C, Nagaraja H. Efficacy and safety of modafinil (Provigil®) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry. 2002;72, 2:179–83.
• 173. Krupp LB, Rizvi SA. Symptomatic therapy for underrecognized manifestations of multiple sclerosis. Neurology. 2002;58, 8_supp:32– 9.
• 174. Chwastiak L, Ehde DM, Gibbons LE, Sullivan M, Bowen JD, Kraft GH. Depressive symptoms and severity of illness in multiple sclerosis: epidemiologic study of a large community sample. Am J Psychiatry. 2002;159, 11:1862–8.
• 175. National Multiple Sklerosis Society. Disease-modifying therapies for MS. Access Date, 25 April 2024. Link, https://nms2cdn.azureedge.net/cCNSite/nationalCNSociet y/media/msnationalfiles/brochures/brochure-the-ms- disease-modifying-medications.pdf. Published online 2023.
• 176. Brancati S, Gozzo L, Longo L, Vitale DC, Drago F. Rituximab in multiple sclerosis: are we ready for regulatory approval? Front Immunol. 2021;12:661882.
• 177. Samjoo IA, Worthington E, Drudge C, et al. Efficacy classification of modern therapies in multiple sclerosis. J Comp Eff Res. 2021;10, 6:495–507.
• 178. Kappos L, Polman C, Freedman M, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67, 7:1242–9.
• 179. Kieseier BC. The mechanism of action of interferon-β in relapsing multiple sclerosis. CNS Drugs. 2011;25:491–502.
• 180. Dhib-Jalbut S, Marks S. Interferon-β mechanisms of action in multiple sclerosis. Neurology. 2010;74, 1_supp:17– 24.
• 181. Jakimovski D, Kolb C, Ramanathan M, Zivadinov R, Weinstock-Guttman B. Interferon β for multiple sclerosis. Cold Spring Harb Perspect Med. 2018;8, 11:32003.
• 182. Callegari I, Derfuss T, Galli E. Update on treatment in multiple sclerosis. Presse Med. 2021;50, 2:104068.
• 183. Calabresi PA. Diagnosis and management of multiple sclerosis. Am Fam Physician. 2004;70, 10:1935–44.
• 184. Arnon R, Aharoni R. Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc Natl Acad Sci. 2004;101, suppl:14593–8.
• 185. Teitelbaum D, Meshorer A, Hirshfeld T, Arnon R, Sela M. Suppression of experimental allergic encephalomyelitis by a synthetic polypeptide. Eur J Immunol. 1971;1, 4:242–8.
• 186. Comi G, Cohen JA, Arnold DL, Wynn D, Filippi M, Group FS. Phase III dose‐comparison study of glatiramer acetate for multiple sclerosis. Ann Neurol. 2011;69, 1:75–82.
• 187. Johnson K, Brooks B, Cohen J, 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. Neurology. 1995;45, 7:1268–76.
• 188. Johnson K, Brooks B, Cohen J, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on multiple sclerosis relapse rate and degree of disability. Neurology. 1998;50, 3:701–8.
• 189. Brenner T, Arnon R, Sela M, et al. Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone®. J Neuroimmunol. 2001;115:1–2, 152–60.
• 190. Lee D-H, Gold R, Linker RA. Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. Int J Mol Sci. 2012;13, 9:11783–803.
• 191. Lukashev M, Zeng W, Goelz S, et al. Activation of Nrf2 and modulation of disease progression in EAE models by BG00012 (dimethyl fumarate) suggests a novel mechanism of action combining anti-inflammatory and neuroprotective modalities. Mult Scler. Published online 2007:149–.
• 192. Sorensen PS, Sellebjerg F. Oral fumarate for relapsing- remitting multiple sclerosis. Lancet. 2008;372, 9648:1447–8.
• 193. Gerdes S, Shakery K, Mrowietz U. Dimethylfumarate inhibits nuclear binding of nuclear factor κB but not of nuclear factor of activated T cells and CCAAT/enhancer binding protein β in activated human T cells. Br J Dermatol. 2007;156, 5:838–42.
• 194. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367, 12:1098–107.
• 195. Havrdova E, Hutchinson M, Kurukulasuriya NC, et al. Oral BG-12 (dimethyl fumarate) for relapsing–remitting multiple sclerosis: a review of DEFINE and CONFIRM: Evaluation of: Gold. RJ F, DH M, JT P, eds. N Engl J Med. 2013;367:1098– 107.
• 196. Mills EA, Mao-Draayer Y. Aging and lymphocyte changes by immunomodulatory therapies impact PML risk in multiple sclerosis patients. Mult Scler J. 2018;24, 8:1014–22.
• 197. Naismith RT, Wundes A, ZieCNSen T, et al. Diroximel fumarate demonstrates an improved gastrointestinal tolerability profile compared with dimethyl fumarate in patients with relapsing–remitting multiple sclerosis: results from the randomized, double-blind, phase III EVOLVE-MS-2 study. CNS Drugs. 2020;34:185–96.
• 198. Wynn D, Lategan TW, Sprague TN, Rousseau FS, Fox EJ. Monomethyl fumarate has better gastrointestinal tolerability profile compared with dimethyl fumarate. Mult Scler Relat Disord. 2020;45:102335.
• 199. Bar-Or A, Pachner A, Menguy-Vacheron F, Kaplan J, Wiendl H. Teriflunomide and its mechanism of action in multiple sclerosis. Drugs. 2014;74:659–74.
• 200. US Food and Drug Administration Medication Guide. Published online 2013.
• 201. O’Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365, 14:1293–303.
• 202. O’Connor P, Comi G, Freedman MS, et al. Long-term safety and efficacy of teriflunomide: nine-year follow-up of the randomized TEMSO study. Neurology. 2016;86, 10:920–30.
• 203. Beutler E. Cladribine (2-chlorodeoxyadenosine. Lancet. 1992;340, 8825:952–6.
• 204. Rice GP, Filippi M, Comi G, Group CCS, FtCMS G. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Neurology. 2000;54, 5:1145–55.
• 205. Kawasaki H, Carrera C, Piro L, Saven A, Kipps T, Carson D. Relationship of deoxycytidine kinase and cytoplasmic 5’- nucleotidase to the chemotherapeutic efficacy of 2- chlorodeoxyadenosine. Blood. 1993;81(3):597-601. doi:10.1182/blood.V81.3.597.597
• 206. Giovannoni G, Comi G, Cook S, et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362, 5:416–26.
• 207. Giovannoni G. Cladribine to treat relapsing forms of multiple sclerosis. Neurotherapeutics. 2017;14, 4:874–87.
• 208. Mehling M, Kappos L, Derfuss T. Fingolimod for multiple sclerosis: mechanism of action, clinical outcomes, and future directions. Curr Neurol Neurosci Rep. 2011;11:492– 7.
• 209. Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002;277, 24:21453–7.
• 210. Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002;296, 5566:346–9.
• 211. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod orintramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362, 5:402–15.
• 212. Kappos L, Radue E-W, O’Connor P, et al. A placebo- controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362, 5:387–401.
• 213. Calabresi PA, Radue E-W, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13, 6:545–56.
• 214. Kappos L, Cohen J, Collins W, et al. Fingolimod in relapsing multiple sclerosis: an integrated analysis of safety findings. Mult Scler Relat Disord. 2014;3, 4:494–504.
• 215. Laroni A, Brogi D, Morra V, et al. Safety of the first dose of fingolimod for multiple sclerosis: results of an open-label clinical trial. BMC Neurol. 2014;14:65.
• 216. Hatcher SE, Waubant E, Nourbakhsh B, Crabtree-Hartman E, Graves JS. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol. 2016;73, 7:790–4.
• 217. Barry B, Erwin AA, Stevens J, Tornatore C. Fingolimod rebound: a review of the clinical experience and management considerations. Neurol Ther. 2019;8:241–50.
• 218. Subei AM, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis. CNS Drugs. 2015;29, 7:565–75.
• 219. Gergely P, Nuesslein‐Hildesheim B, Guerini D, et al. The selective sphingosine 1‐phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species‐ specific effects on heart rate. Br J Pharmacol. 2012;167, 5:1035–47.
• 220. Derfuss T, Mehling M, Papadopoulou A, Bar-Or A, Cohen JA, Kappos L. Advances in oral immunomodulating therapies in relapsing multiple sclerosis. Lancet Neurol. 2020;19, 4:336– 47.
• 221. Kappos L, Bar-Or A, Cree BA, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391, 10127:1263–73.
• 222. Cao L, Li M, Yao L, et al. Siponimod for multiple sclerosis. Cochrane Database Syst Rev. 2021;11:13647.
• 223. Yaldizli Ö, Putzki N. Natalizumab in the treatment of multiple sclerosis. Ther Adv Neurol Disord. 2009;2, 2:115– 28.
• 224. Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354, 9:899–910.
• 225. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354, 9:911–23.
• 226. Ryerson LZ, Foley J, Chang I, et al. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology. 2019;93, 15:1452–62.
• 227. Beum P V, Lindorfer MA, Beurskens F, et al. Complement activation on B lymphocytes opsonized with rituximab or ofatumumab produces substantial changes in membrane structure preceding cell lysis. J Immunol. 2008;181, 1:822– 32.
• 228. Montalvao F, Garcia Z, Celli S, et al. The mechanism of anti- CD20–mediated B cell depletion revealed by intravital imaging. J Clin Invest. 2013;123, 12:5098–103.
• 229. Sorensen PS, Blinkenberg M. The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects. Ther Adv Neurol Disord. 2016;9, 1:44–52.
• 230. Sabatino Jr JJ, Pröbstel, A-K., Zamvil SS. B cells in autoimmune and neurodegenerative central nervous system diseases. Nat Rev Neurosci. 2019;20, 12:728–45.
• 231. Li R, Patterson KR, Bar-Or A. Reassessing B cell contributions in multiple sclerosis. Nat Immunol. 2018;19, 7:696–707.
• 232. Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376, 3:221–34.
• 233. Klein C, Lammens A, Schäfer W, et al. Epitope interactions of monoclonal antibodies targeting CD20 and their relationship to functional properties. MAbs. Published online 2013:22–33.
• 234. Feng JJ, Ontaneda D. Treating primary-progressive multiple sclerosis: potential of ocrelizumab and review of B-cell therapies. Degener Neurol Neuromuscul Dis. 2017;7:31–45.
• 235. Gelfand JM, Cree BA, Hauser SL. Ocrelizumab and other CD20+ B-cell-depleting therapies in multiple sclerosis. Neurotherapeutics. 2017;14, 4:835–41.
• 236. Hartung H-P. Ocrelizumab shorter infusion: primary results from the ENSEMBLE PLUS substudy in patients with MS. Neurol Neuroimmunol Neuroinflammation. 2020;7:807.
• 237. Hauser SL, Kappos L, Montalban X, et al. Safety of ocrelizumab in multiple sclerosis: updated analysis in patients with relapsing and primary progressive multiple sclerosis. Mult Scler Relat Disord. 2018;26:264.
• 238. Hauser SL, Bar-Or A, Cohen JA, et al. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med. 2020;383, 6:546–57.
• 239. Cohen JA, Coles AJ, Arnold DL, 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, 9856:1819–28.
• 240. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease- modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380, 9856:1829–39.
• 241. Dargahi N, Katsara M, Tselios T, et al. Multiple sclerosis: immunopathology and treatment update. Brain Sci. 2017;7, 7:78.
• 242. Jeffery DR, Herndon R. Review of mitoxantrone in the treatment of multiple sclerosis. Neurology. 2004;63, 12_sup:19– 24.
• 243. Eckstein C, Bhatti MT. Currently approved and emerging oral therapies in multiple sclerosis: An update for the ophthalmologist. Surv Ophthalmol. 2016;61, 3:318–32.
• 244. National Multiple Sklerosis Society. Access Date, 26 ebruary 2024. Link, https://www.nationalCNSociety.org/What-is-MS/Typesof-MS/Relapsing-remitting-MS. Published online 2023.