Abstract
Multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system. It is a complex disease, with a pathogenesis not fully understood and multiple clinical presentations. MS is a chronic disease, represents a great cost to healthcare systems and is often associated with a high burden of disability in patients. Despite the absence of a cure, there are at least13 disease-modifying therapies that act on different targets of the pathogenic process. The main purpose of this review is to solve 16 controversial and current topics in MS. These 16 topics are analysed, and when there is enough evidence, we issue recommendations. The topics include diagnosis, treatment, use of new technologies in MS, and medication side effects. This paper is meant for neurologists, neurology residents, general physicians and any other healthcare personnel interested in demyelinating diseases.
References
Correale J, Farez MF, Gaitán MI. Environmental factors influencing multiple sclerosis in Latin America. Mult Scler J Exp Transl Clin. 2017;3(2):205521731771504.
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.
Belbasis L, Bellou V, Evangelou E, Ioannidis JPA, Tzoulaki I. Environmental risk factors and multiple sclerosis: An umbrella review of systematic reviews and meta-analyses. Lancet Neurol. 2015;14(3):263-73.
Toro J, Cárdenas S, Fernando Martínez C, Urrutia J, Díaz C. Multiple sclerosis in Colombia and other Latin American countries. Mult Scler Relat Disord. 2013;2(2):80-9.
Toro J, Sarmiento OL, Díaz Del Castillo A, Satizábal CL, Ramírez JD, Montenegro AC, et al. Prevalence of multiple sclerosis in Bogotá, Colombia. Neuroepidemiology. 2007;28(1):33-8.
Freedman MS, Rush CA. Severe, highly active, or aggressive multiple sclerosis. Contin Lifelong Learn Neurol. 2016;22(3):761-84.
Kaunzner U, Kumar G, Askin G, Gauthier S, Nealon S, Vartanian T, et al. A study of patients with aggressive multiple sclerosis at disease onset. Neuropsychiatr Dis Treat. 2016;12:1907-12.
Rush CA, Maclean HJ, Freedman MS. Aggressive multiple sclerosis: Proposed definition and treatment algorithm. Nat Rev Neurol. 2015;11(7):379-89.
Menon S, Shirani A, Zhao Y, Oger J, Traboulsee A, Freedman MS, et al. Characterising aggressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013;84(11):1192-8.
Edan G, Comi G, Le Page E, Leray E, Rocca MA, Filippi M. Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: A 3-year randomised trial. J Neurol Neurosurg Psychiatry. 2011;82(12):1344-50.
Weiner HL. Immunosuppressive treatment in multiple sclerosis. J Neurol Sci. 2004;223(1):1-11.
Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, 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.
Freedman MS. Multiple sclerosis: Does aggressive MS warrant aggressive treatment? Nat Rev Neurol. 2014;10(7):368-70.
Rush CA, Atkins HL, Freedman MS. Autologous hematopoietic stem cell transplantation in the treatment of multiple sclerosis. Cold Spring Harb Perspect Med. 2018;a029082.
Sormani MP, Muraro PA, Schiavetti I, Signori A, Laroni A, Saccardi R, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis. Neurology. 2017;88(22):2115-22.
Atkins HL, Freedman MS. Hematopoietic stem cell therapy for multiple sclerosis: top 10 lessons learned. Neurotherapeutics. 2013;10(1):68-76.
Foley FW, Zemon V, Campagnolo D, Marrie RA, Cutter G, Tyry T, et al. The Multiple Sclerosis Intimacy and Sexuality Questionnaire: Re-validation and development of a 15-item version with a large US sample. Mult Scler J. 2013;19(9):1197-203.
Schairer LC, Foley FW, Zemon V, Tyry T, Campagnolo D, Marrie RA, et al. The impact of sexual dysfunction on health-related quality of life in people with multiple sclerosis. Mult Scler J. 2014;20(5):610-6.
Lublin FD, Reingold SC, Cohen JA, Cutter GR, S0rensen PS, Thompson AJ, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014;83(3):278-86.
Correale J, Ysrraelit MC, Fiol MP. Benign multiple sclerosis: Does it exist? Curr Neurol Neurosci Rep. 2012;12(5):601-9.
Fabis-Pedrini MJ, James I, Seewann A, Yau WY, van de Bovenkamp AA, Sanders FRK, et al. Natural history of benign multiple sclerosis: Clinical and HLA correlates in a Western Australian cohort. J Neurol Sci. 2018;388:12-8.
Sartori A, Abdoli M, Freedman MS. Can we predict benign multiple sclerosis? Results of a 20-year long-term follow-up study. J Neurol. 2017;264(6):1068-75.
Correale J, Peirano I, Romano L. Benign multiple sclerosis: A new definition of this entity is needed. Mult Scler J. 2012;18(2):210-8.
Hawkins SA, McDonnell G V. Benign multiple sclerosis? Clinical course, long term follow up, and assessment of prognostic factors. J Neurol Neurosurg Psychiatry. 1999;67(2):148-52.
Sayao AL, Devonshire V, Tremlett H. Longitudinal follow-up of "benign" multiple sclerosis at 20 years. Neurology. 2007;68(7):496-500.
Doshi A, Chataway J. Multiple sclerosis, a treatable disease. Clin Med J R Coll Physicians London. 2017;17(6):530-6.
Dargahi N, Katsara M, Tselios T, Androutsou ME, De Courten M, Matsoukas J, et al. Multiple sclerosis: Immunopathology and treatment update. Brain Sci. 2017;7(7):1-27.
Deleu D, Mesraoua B, El Khider H, Canibano B, Melikyan G, Al Hail H, et al. Optimization and stratification of multiple sclerosis treatment in fast developing economic countries: a perspective from Qatar. Curr Med Res Opin. 2017;33(3):439-58.
Kappos L, Edan G, Freedman MS, Montalbán X, Hartung HP, Hemmer B, et al. The 11-year long-term follow-up study from the randomized BENEFIT CIS trial. Neurology. 2016;87(10):978-87.
Madsen C. The innovative development in interferon beta treatments of relapsing-remitting multiple sclerosis. Brain Behav. 2017;7(6):1-8.
Tramacere I, Del Giovane C, Salanti G, Amico R, Filippini G. Immunomodulators and immunosuppressants for relaps-ing-remmiting multiple sclerosis : a network meta-analysis (Review). Cochrane Database Syst Rev. 2015;(9).
Hartung DM, Bourdette DN, Ahmed SM, Whitham RH. The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: Too big to fail? Neurology. 2015;84(21):2185-92.
Annovazzi P, Bertolotto A, Brescia Morra V, Gasperini C, Montanari E, Navarra P, et al. A comprehensive review on Copemyl®. Neurol Ther. 2017;6(2):161-73.
Romero M, Arango C, Alvis N, Suarez JC, Duque A. Costos de la esclerosis múltiple en Colombia. Value Health. 2011;14(5 SUPPL.):S48-50.
Skromne-Eisenberg E, Ordoñez-Boschetti L, Treviño-Frenk I. Disease-modifying therapies in multiple sclerosis in Latin America. Mult Scler J Exp Transl Clin. 2017;3(3):205521731772336.
Hua LH, Cohen JA. Considerations in the development of generic disease therapies for multiple sclerosis. Neurol Clin Pract. 2016;6(4):369-76.
Selmaj K, Barkhof F, Belova AN, Wolf C, van den Tweel ER, Oberyé JJ, et al. Switching from branded to generic glatiramer acetate: 15-month GATE trial extension results. Mult Scler J. 2017;23(14):1909-17.
Lysandropoulos AP, Absil J, Metens T, Mavroudakis N, Guisset F, Van Vlierberghe E, et al. Quantifying brain volumes for multiple sclerosis patients follow-up in clinical practice - comparison of 1.5 and 3 Tesla magnetic resonance imaging. Brain Behav. 2016;6(2):1-8.
George IC, Sati P, Absinta M, Cortese ICM, Sweeney EM, Shea CD, et al. Clinical 3-tesla FLAIR MRI improves diagnostic accuracy in multiple sclerosis. Mult Scler. 2016;22(12):1578-86.
Hagens MHJ, Burggraaff J, Kilsdonk ID, de Vos ML, Cawley N, Sbardella E, et al. Three-Tesla MRI does not improve the diagnosis of multiple sclerosis. Neurology. 2018;91(3):e249-57.
Lamirel C, Newman NJ, Biousse V. Optical coherence tomography (OCT) in optic neuritis and multiple sclerosis. Rev Neurol (París). 2010;166(12):978-86.
Pulicken M, Gordon-Lipkin E, Balcer LJ, Frohman E, Cutter G, Calabresi PA. Optical coherence tomography and disease subtype in multiple sclerosis. Neurology. 2007;69(22):2085-92.
Frohman EM, Racke MK, Raine CS. Multiple sclerosis - the plaque and its pathogenesis. N Engl J Med. 2006;354(9):942-55.
Sepulcre J, Murie-Fernandez M, Salinas-Alaman A, García-Layana A, Bejarano B, Villoslada P. Diagnostic accuracy of retinal abnormalities in predicting disease activity in MS. Neurology. 2007;68(18):1488-94.
Toledo J, Sepulcre J, Salinas-Alaman A, García-Layana A, Murie-Fernandez M, Bejarano B, et al. Retinal nerve fiber layer atrophy is associated with physical and cognitive disability in multiple sclerosis. Mult Scler J. 2008;14(7):906-12.
Lambe J, Murphy OC, Saidha S. Can Optical coherence tomography be used to guide treatment decisions in adult or pediatric multiple sclerosis? Curr Treat Options Neurol. 2018;20(4):9.
Petzold A, Balcer LJ, Calabresi PA, Costello F, Frohman TC, Frohman EM, et al. Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol. 2017;16(10):797-812.
Alonso R, Gonzalez-Moron D, Garcea O. Optical coherence tomography as a biomarker of neurodegeneration in multiple sclerosis: A review. Mult Scler Relat Disord. 2018;22:77-82.
Outteryck O, Majed B, Defoort-Dhellemmes S, Vermersch P, Zéphir H. A comparative optical coherence tomography study in neuromyelitis optica spectrum disorder and multiple sclerosis. Mult Scler. 2015;21(14):1781-93.
Kuhle J, Barro C, Andreasson U, Derfuss T, Lindberg R, Sandelius Á, et al. Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa. Clin Chem Lab Med. 2016;54(10):1655-61.
Barro C, Benkert P, Disanto G, Tsagkas C, Amann M, Naegelin Y, et al. Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis. Brain. 2018;141(8):2382-91.
Bhan A, Jacobsen C, Myhr KM, Dalen I, Lode K, Farbu E. Neurofilaments and 10-year follow-up in multiple sclerosis. Mult Scler J. 2018;24(10):1301-7.
Dubuisson N, Puentes F, Giovannoni G, Gnanapavan S. Science is 1 % inspiration and 99 % biomarkers. Mult Scler J. 2017;1-111.
Teunissen CE, Khalil M. Neurofilaments as biomarkers in multiple sclerosis. Mult Scler J. 2012;18(5):552-6.
Khalil M, Teunissen CE, Otto M, Piehl F, Sormani MP, Gattringer T, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018;4(10):577-89.
Sellebjerg F, Royen L, Soelberg S0rensen P, Oturai AB, Jensen PEH. Prognostic value of cerebrospinal fluid neurofilament light chain and chitinase-3-like-1 in newly diagnosed patients with multiple sclerosis. Mult Scler J. 2018;135245851879430.
Broadley SA, Barnett MH, Boggild M, Brew BJ, Butzkueven H, Heard R, et al. A new era in the treatment of multiple sclerosis. Med J Aust. 2015;203(3):139-41.
Wingerchuk DM, Weinshenker BG. Disease modifying therapies for relapsing multiple sclerosis. BMJ. 2016;i3518.
Longbrake EE, Naismith RT, Parks BJ, Wu GF, Cross AH. Dimethyl fumarate-associated lymphopenia : Risk factors and clinical significance. Mult Scler J Exp Transl Clin. 2015;1. pii: 2055217315596994.
Muñoz MA, Kulick CG, Kortepeter CM, Levin RL, Avigan MI. Liver injury associated with dimethyl fumarate in multiple sclerosis patients. Mult Scler J. 2017;23(14):1947-9.
Pavlovic D, Patera AC, Nyberg F, Gerber M, Liu M. Progressive multifocal leukoencephalopathy: Current treatment options and future perspectives. Ther Adv Neurol Disord. 2015;8(6):255-73.
Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, et al. PML diagnostic criteria. Neurology. 2013;80:1430-8.
Epstein DJ, Dunn J, Deresinski S. Infectious complications of multiple sclerosis therapies: implications for screening, prophylaxis, and management. Open Forum Infect Dis. 2018;5(8):1-8.
Blessing MM, Raghunathan A, Erickson LA. Progressive Multifocal leukoencephalopathy. Mayo Clin Proc. 2018;93(1):123-5.
Ho PR, Koendgen H, Campbell N, Haddock B, Richman S, Chang I. Risk of natalizumab-associated progressive multifo-cal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-33.
Sintzel MB, Rametta M, Reder AT. Vitamin D and multiple sclerosis: A comprehensive review. Neurol Ther. 2018;7(1):59-85.
Pierrot-Deseilligny C, Souberbielle JC. Vitamin D and multiple sclerosisAn update. Mult Scler Relat Disord. 2017;14:35-45.
Ascherio A, Munger KL. Epidemiology of multiple sclerosis: from risk factors to prevention - an update. Semin Neurol. 2016;36(2):103-14.
Shoemaker TJ, Mowry EM. A review of vitamin D supplementation as disease-modifying therapy. Mult Scler. 2018;24(1):6-11.
Rolf L, Muris AH, Bol Y, Damoiseaux J, Smolders J, Hupperts R. Vitamin D3 supplementation in multiple sclerosis: Symptoms and biomarkers of depression. J Neurol Sci. 2017;378:30-5.
Jagannath VA, Filippini G, Di Pietrantonj C, Asokan G V, Robak EW, Whamond L, et al. Vitamin D for the management of multiple sclerosis. Cochrane Database of Systematic Reviews. 2018.
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 J. 2017;23(9):1241-8.
Hua LH, Fan TH, Conway D, Thompson N, Kinzy TG. Discontinuation of disease-modifying therapy in patients with multiple sclerosis over age 60. Mult Scler J. 2018;1-10.
Kister I, Spelman T, Alroughani R, Lechner-Scott J, Duquette P, Grand'Maison F, et al. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: A propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016;87(10):1133-7.
Gajofatto A, Benedetti MD. Treatment strategies for multiple sclerosis: When to start, when to change, when to stop? World J Clin Cases. 2015;3(7):545-55.
Tobin WO, Weinshenker BG. Stopping immunomodulatory medications in MS: Frequency, reasons and consequences. Mult Scler Relat Disord. 2015;4(5):437-43.
De Angelis F, Plantone D, Chataway J. Pharmacotherapy in secondary progressive multiple sclerosis: an overview. CNS Drugs. 2018;32(6):499-26.
Ciotti JR, Cross AH. Disease-modifying treatment in progressive multiple sclerosis. Curr Treat Options Neurol. 2018;20(5):12.
Gajofatto A. Spotlight on siponimod and its potential in the treatment of secondary progressive multiple sclerosis: The evidence to date. Drug Des Devel Ther. 2017;11:3153-7.
Tur C, Montalban X. Progressive MS trials: Lessons learned. Mult Scler. 2017;23(12):1583-92.
Kapoor R, Ho PR, Campbell N, Chang I, Deykin A, Forrestal F, et al. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol. 2018;17(5):405-15.
Gholamzad M, Ebtekar M, Ardestani MS, Azimi M, Mahmodi Z, Mousavi MJ, et al. A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future. Inflamm Res. 2019;68(1):25-38.
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(10127):1263-73.
Cohen M, Maillart E, Tourbah A, De Sèze J, Vukusic S, Brassat D, et al. Switching from natalizumab to fingolimod in multiple sclerosis: A French prospective study. JAMA Neurol. 2014; 71(4):436-41.
O'Connor PW, Goodman A, Kappos L, Lublin FD, Miller DH, Polman C, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology. 2011;76(22):1858-65.
Giovannoni G, Marta M, Davis A, Turner B, Gnanapavan S, Schmierer K. Switching patients at high risk of PML from natalizumab to another disease-modifying therapy. Pract Neurol. 2016;16(5):389-93.
Leurs CE, van Kempen Z LE, Dekker I, Balk LJ, Wattjes MP, Rispens T, et al. Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients. Mult Scler J. 2018;24(11):1453-60.
Coyle PK. Switching therapies in multiple sclerosis. CNS Drugs. 2013;27(4):239-47.
Von Geldern G, Mowry EM. The influence of nutritional factors on the prognosis of multiple sclerosis. Nat Rev Neurol. 2012;8(12):678-89.
Esposito S, Bonavita S, Sparaco M, Gallo A, Tedeschi G. The role of diet in multiple sclerosis: A review. Nutr Neurosci. 2018;21(6):377-90.
Lundin KEA, Wijmenga C. Coeliac disease and autoimmune disease - Genetic overlap and screening. Nat Rev Gastroenterol Hepatol. 2015;12(9):507-15.
Mische LJ, Mowry EM. The evidence for dietary interventions and nutritional supplements as treatment options in multiple sclerosis: a review. Curr Treat Options Neurol. 2018;20(4):8.
Hadjivassiliou M, Sanders DS, Grünewald RA, Woodroofe N, Boscolo S, Aeschlimann D. Gluten sensitivity: from gut to brain. Lancet Neurol. 2010;9(3):318-30.
Kaufman M, Pardo G, Rossman H, Sweetser MT, Forrestal F, Duda P. Natalizumab treatment shows no clinically meaningful effects on immunization responses in patients with relapsing-remitting multiple sclerosis. J Neurol Sci. 2014;341(1-2):22-7.
Kappos L, Mehling M, Arroyo R, Izquierdo G, Selmaj K, Curovic-Perisic V, et al. Randomized trial of vaccination in fingolimod-treated patients "with multiple sclerosis. Neurology. 2015;84(9):872-9.
Baror A, Freedman MS, Bauer D, Jodl S, Truffinet P, Benamor M, et al. Teriflunomide effect on immune response to influenza vaccine in patients with multiple sclerosis. Neurology. 2013;81(6):552-8.
Rotstein DL, Bharatha A, Selchen D. Severe aseptic temporal lobe encephalitis on fingolimod. Mult Scler Relat Disord. 2018;23:4-6.
Williamson EML, Chahin S, Berger JR. Vaccines in multiple sclerosis. Curr Neurol Neurosci Rep. 2016;16(4):1-8.
Mailand MT, Frederiksen JL. Vaccines and multiple sclerosis: a systematic review. J Neurol. 2017;264(6):1035-50.
Confavreux C, Suissa S, Saddier P, Bourdès V, Vukusic S. Vaccinations and the risk of relapse in multiple sclerosis. N Engl J Med. 2001;344(5):319-26.
McNicholas N, Chataway J. Relapse risk in patients with multiple sclerosis after H1N1 vaccination, with or without seasonal influenza vaccination. J Neurol. 2011;258(8):1545-7.
De Keyser J, Zwanikken C, Boon M. Effects of influenza vaccination and influenza illness on exacerbations in multiple sclerosis. J Neurol Sci. 1998;159(1):51-3.
Farez MF, Correale J. Immunizations and risk of multiple sclerosis: Systematic review and meta-analysis. J Neurol. 2011;258(7):1197-206.
Miller AE, Morgante LA, Buchwald LY, Nutile SM, Coyle PK. A multicenter, randomized, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis. Neurology. 1997;48(2):312-4.
Von Hehn C, Howard J, Liu S, Meka V, Pultz J, Mehta D, et al. Immune response to vaccines is maintained in patients treated with dimethyl fumarate. Neurol Neuroimmunol NeuroInflammation. 2017;5(1):e409.
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