Main Article Content


Background: Multiple Sclerosis (MS) is a complex autoimmune neurodegenerative disorder that afflicts a significant number of individuals worldwide. This formidable disease, which is often life-threatening, imposes a lifelong impact on those diagnosed, altering their existence in profound ways.

Methods: The current review is meticulously crafted, drawing upon a multitude of scholarly articles previously disseminated in both national and international academic journals within the same discipline.

Results: This disease inflicts substantial damage to the Central Nervous System (CNS), predominantly affecting the myelin sheath of nerve fibers, spinal cord, and eyes, thereby leading to the development of muscle weakness, movement disorders, and visual impairments. Recent observations have unveiled a potential link between a gut bacterium, Clostridium perfringens, and the onset of MS in humans.

Conclusion: Given that the precise etiology of Multiple Sclerosis (MS) remains elusive and presents a formidable challenge, this paper endeavors to shed light on the current landscape of the disease. It provides an in-depth exploration of its epidemiology, clinical manifestations, diagnostic procedures, prognosis, and treatment modalities, all underpinned by the most recent advancements in the fields of immunology and medical microbiology about infectious diseases.


Multiple Sclerosis Autoimmune Disorder Clostridium perfringens Human Epsilon Toxicity Neurological Disease

Article Details

How to Cite


  1. Hatheway CL. Toxigenic Clostridia. Cliv. Microbiol. Rev. 1990; 3(1): 66-98.
  2. Gilden DH. 2005. Infectious causes of multiple sclerosis. The Lancet, Neurology 2005;4(3): 195-202.
  3. Li J, Sayeed S, Mc Clane BA. Prevalence of enterotoxigenic Clostridium perfringens isolates in Pittsburgh (Pennsylvania) area soils and home kitchens. Appl. Environ. Microbiol. 2007; 73(22): 7218-7224.
  4. Beranzini SE. Revealing the genetic basis of multiple sclerosis: Are we there Yet? Current Opinion, Genetics & Development 2011; 21(3): 317-324.
  5. Wekerle H. Nature, nurture and microbes: The development of multiple sclerosis. Acta Neurol Scand. 2017; 136 Suppl. 201: 22-25.
  6. Lassmann H. Multiple Sclerosis. Pathology. Cold Spring Harb Perspect Med 2018; 8(3): a028936.
  7. Finnie JW. Neurological disorders produced by Clostridium perfringens type D epsilon toxin. Anaerobe 2004; 10(2): 145-150.
  8. Wen Q, Mc Clane BA. Detection of enterotoxigenic Clostridium perfringens type A isolates in America retail foods. Appl. Environ. Microbiol. 2004; 70(5): 2685-2691.
  9. Wagley S, Bokori- Brown M, Morcrette H, Malaspina A, D Arcy C. Evidence of Clostridium perfringens epsilon toxin associated with multiple sclerosis. Mult. Scler. 2019; 25(5): 653-660.
  10. Goldstein J, Morris WE, Loidl CF, Mc Clane BA, Uzal FA. Clostridium perfringens epsilon toxin increases the small intestinal permeability in mice and rats. PLoS One 2009; 4(9): 7065.
  11. Popoff MR. Epsilon toxin: A fascinating pore-forming toxin. FEBS J. 2011;278(23): 4602-4615.
  12. Adler D, Linden JR, Shetty SV, Ma Y, Titball RW. Clostridium perfringens epsilon toxin compromises the blood-brain barrier in a humanized Zebrafish model. iScience 2019; 15: 39-54.
  13. Garcia JP, Adams V, Beingesser J, Hughes ML, Lyras D. Epsilon toxin essential for the virulence of Clostridium perfringens type D infection in sheep, goats, and mice. Infect. Immun. 2013; 81(7): 2405-2414.
  14. Savva CG, Clark AR, Naylor CE, Moss DS, Basak AK. The pore structure of Clostridium perfringens epsilon toxin. Nat. Commun. 2019; 10(1): 2641.
  15. Li J, Adams V, Bannam TL, Miyamoto K, Garcia JP. Toxin plasmids of Clostridium perfringens. Microbiol. Mol. Biol. Rev. 2013; 77(2): 208-233.
  16. Chen J, Chia N, Kalari KR, Yao JZ, Solden MM. Multiple sclerosis patients have distinct gut microbiota compared to healthy controls. Sci. Rep. 2016;6: 28484.
  17. Jangi S, Gandhi R, Cox LM, Li N, Yan R. Alterations of the human gut microbiome in multiple sclerosis. Nat. Commun. 2016; 7: 12015.
  18. Thompson AJ, Hemmer B, Ciccarelli O. Multiple sclerosis. Lancet 2018; 391(10130): 1622-1636.
  19. Mirza A, Forbes JD, Zhu F, Bernstein CN, Graham M. The multiple sclerosis gut microbiota: A systematic review. Mult. Scler. Relat Disord. 2020; 37: 101427.
  20. Cantoni C, Lin Q, Dorsett Y, Liu Z, Pan Y. Alterations of host-gut microbiome interactions in multiple sclerosis. EBioMedicine 2022; 76: 10378.
  21. MSIF. MS Int. Federation, Atlas of MS, 2020. Multiple Sclerosis International Federation, 3rd Floor, Skyline House, 200 Union Street, London, SE1 OLX.
  22. Pugliathi M, Sotgiu S, Rosati G. The worldwide prevalence of multiple sclerosis. Clinical Neurology & Neurosurgery 2002; 104(3): 182-191.
  23. Hassan- Smith G, Douglas MR. Epidemiology and diagnosis of multiple sclerosis. British Journal of Hospital Medicine 2011;72(10): 146-151.
  24. Leray E, Moreau T, Fromont A, Edan G. Epidemiology of multiple sclerosis. Revue Neurologique 2016; 172(1): 3-13.
  25. Marrie RA. Mounting evidence for a multiple sclerosis prodrome. Nature Reviews, Neurology 2019;15(12): 689-690.
  26. Makhani N, Tremlett H. The multiple sclerosis prodrome. Nature Reviews, Neurology 2021; 17(8): 515-521.
  27. Marrie RA, Mark A, Helen T. From the prodromal stage of multiple sclerosis to disease prevention. Nature Reviews Neurology 2022; 18: 559-572.
  28. Trojano M, Paolicelli D. The differential diagnosis of multiple sclerosis: classification and clinical features of relapsing and progressive neurological syndrome. Neurological Sciences 2011;22 (Suppl 2): 98-102.
  29. Cree BA, Spencer CM, Varrin-Doyer M, Baranzini SE, Zamvil SS. Gut microbiome analysis in neuromyelitis optica reveals an overabundance of Clostridium perfringens. Ann. Neurol. 2016; 80(3): 443-447.
  30. Zamvil SS, Spencer CM, Baranzini SE, Cree BAC. The gut-microbiome in neuromyelitis optica. Neurotherapeutics 2018; 15(1): 92-101.
  31. Cameron MH, Nilsagard Y. Balance, gait and falls in multiple sclerosis. Handbook of Clinical Neurology 2018; 159: 237-250.
  32. Hayes S, Galvin R, Kennedy C, Finlayson M, Walsh CD, Coote S. Interventions for preventing falls in people with multiple sclerosis. The Cochrane Database of Systematic Reviews 2019; 11(11): CD012475.
  33. Andravizou A, Dardiotis E, Artemiadis A, Sokratous M, Siokas V. Brain atrophy in multiple sclerosis: mechanisms, clinical relevance, and treatment options. Auto-Immunity Highlights 2019; 10(1): 7.
  34. Oh J, Vidal-Jordana A, Montalban X. Multiple sclerosis: Clinical aspects. Curr. Opin. Neurol. 2018; 31(6): 752-759.
  35. Benedict RH, Amato MP, De Luca J, Geurts JJ. Cognitive impairment in multiple sclerosis: Clinical management, MRI and therapeutic avenues. The Lancet, Neurology 2020; 19(10): 860-871.
  36. Portaccio E, Amato MP. Cognitive impairment in multiple sclerosis: An update on assessment and management. Naturosci. 2022; 3(4): 667-676.
  37. Thomas PW, Thomas S, Hillier C, Galvin K, Baker R. Psychological interventions for multiple sclerosis. The Cochrane Database of Systematic Reviews 2006 (1): CD004431.
  38. Chwastiak LA, Dawn ME. Psychiatric issues in multiple sclerosis. Psychiatr. Clin. North Am. 2007; 30(4): 803-817.
  39. Paparrigopoulos T, Ferentinos P, Kouzoupis A, Koutsis G, Papadimitriou GN. The neuropsychiatry of multiple sclerosis: focus on disorders of mood, affect, and behavior. Int. Rev. Psychiatry 2010; 22(1): 14-21.
  40. Silveira C, Renato G, Diana M, Rosario C, Rui C. Neuropsychiatric symptoms of multiple sclerosis: Stat of the art. Psychiatry Investigation 2019; 16(12): 877- 888.
  41. Turner AP, Lindsey MK. Behavioral interventions in multiple sclerosis. Fed. Pract. 2020; 37(1): 31-35.
  42. Liu Z, Liao Q, Wen H, Zhang Y. Disease modifying therapies in relapsing-remitting multiple sclerosis: A Systematic review and network meta-analysis. Autoimmunity Review 2021;20(6): 102826.
  43. Rice GP, Incorvaia B, Munari L. Interferon in relapsing–remitting multiple sclerosis. Cochrane Database Syst. Rev. 2001; (4): CD002002.
  44. La Mantia L, Tramacere I, Firwana B. Fingolimod for relapsing-remitting multiple sclerosis. Cochrane Database Syst. Rev. 2016; 4: CD009371.
  45. Roviro A. Diagnosis of multiple sclerosis. Journal of the Belgian Society of Radiology 2017; 101(S 1): 12.
  46. Nagpal R, Ogata K, Tsuji H, Matsuda K, Nomoto K. Sensitive quantification of Clostridium perfringens in human feces by quantitative real-time PCR targeting alpha-toxin and enterotoxin genes. BMC Microbiol. 2015; 15:219.
  47. Al- Zandi SH, Fayadh NA, Al-Waely NK. Central vein sign detected by SWI at 3T MRI as a discriminator between multiple sclerosis and leukoaraiosis. The Egyptian Journal of Radiology & Nuclear Medicine 2018;49(1): 158-164.
  48. Mc Ginley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and treatment of multiple sclerosis: A Review. JAMA 2021; 325(8): 765-779.
  49. Marrie RA. Environmental risk factors in multiple sclerosis etiology. The Lancet Neurology 2004;3(12): 709-718.
  50. Bar OA, Pender MP, Khanna R, Steinman L, Hartung HP. Epstein- Barr virus in multiple sclerosis: Theory and emerging immunotherapies. Trends in Molecular Medicine 2020;26(3):296-310.
  51. Tarlinton RE, Martynovva E, Albert AR, Svetlana K, Verma S. Role of viruses in the pathogenesis of multiple sclerosis. Viruses 2020;12 (6): 643.
  52. Jessica W, Daniele ZR, Ligia CFG, Elisa VR. Viral infection and their relationship to neurological disorders. Archives of Virology 2021; 166: 733-753.
  53. Aloisi F, Cross AH. Mini review of Epstein Barr virus involvement in multiple sclerosis etiology and pathogenesis. J. Neuroimmunol. 2022; 371: 577935.
  54. Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ. Longitudinal analysis reveals a high prevalence of Epstein- Barr virus associated with multiple sclerosis. Science 2022; 375(6578): 296-301.
  55. Soldan SS, Lieberman PM. Epstein Barr virus and multiple sclerosis. Nature Reviews, Microbiol. 2023; 21(1): 51-64.
  56. Ziemssen T, Katja A, Wolfgang B. Molecular biomarkers in multiple sclerosis J. Neuroinflammation 2019; 16(272): 1-11.
  57. Filippi M, Rocca MA, Barkhof F, Bruck W, Chen JT. Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol. 2012; 11: 349-360.
  58. Pascal B, Stephanie M, Sabine S, Ali M, Aleksandra M. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modeling and validation study. The Lancet Neurology 2022; 21(3): 246-257.
  59. Uzal FAG, Finnie JW, Garcia JP. In: Uzal FAS, Prescott JF, Popoff MR, (Eds). Clostridial diseases of animals. Ames, IA, USA: Wiley- Blackwell, 2016: 157-172.
  60. Talukdar PK, Hossain A, Sarkar MR. Inactivation strategies for Clostridium perfringens spores and vegetative cells. Appl. Environ. Microbiol. 2017; 83(1): 225-235.
  61. Wingerchuk DM, Disease modifying therapies for relapsing multiple sclerosis. British Medical Journal 2016; doi:10.1136/bmj.i3518.
  62. Hauser SL, Bar OA, Comi G, Hartung HP, Hammer B. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. The New England Journal of Medicine 2017; 376(3): 221-234.
  63. Hauser SL, Cree BA. Treatment of multiple sclerosis: A review. Am. J. Med. 2020; 133(12): 1380-1390.
  64. Ghezzi L, Cantoni C, Pinget GV, Zhou Y, Piccio L. Targeting the gut to treat multiple sclerosis. J. Clin. Invest. 2021; 131(13).
  65. Comi G. Treatment of multiple sclerosis: role of natalizumab. Neurological Sciences. 2009; 30: 30(S 2): 155-158.
  66. He D, Zhang C, Zhao X, Zhang Y, Li Y. Teriflunomide for multiple sclerosis. The Cochrane Database of Systematic Reviews 2016; 3: CD009882.
  67. Xu Z, Zhang F, Sun F. Dimethyl fumarate for multiple sclerosis. Cochrane Database Syst. Rev. 2015; 4: CD011076.
  68. Cree BA, Hartung HP, Barnett M. New drugs for multiple sclerosis: New treatment algorithms. Curr. Opin. Neurol. 2022; 35(3): 262-270.
  69. Burton JM, O’ Conner PW, Hohol M, Beyene J. Oral versus intravenous steroids for treatment of relapsing in multiple sclerosis. The Cochrane Database of Systematic Reviews 2012; 12: CD006921.
  70. Kesselring J, Beer S. Symptomatic therapy and neurorehabilitation in multiple sclerosis. The Lancet Neurology 2005; 4(10): 643-652.
  71. Shachar MA, Lam O, Jacques C. Treatment of lower urinary tract symptoms in multiple sclerosis patients: Review of the literature and current guidelines. Can. Urol. Assoc. J. 2017; 11(3-4): 110-115.
  72. Lui CT, Fung HT. A case of tolterodine poisoning. Hong Kong J. Emergency Medicine 2010; 17:168-172.
  73. Jure T, Jalesh NP. The management of lower urinary tract dysfunction in multiple sclerosis. Current Neurology and Neuroscience Reports 2018; 18(54): 1-11.
  74. Elsie EG. Neurogenic bowel dysfunction throughout multiple sclerosis: A review. Int. J. of MS Care 2022; 24(5): 209-217.
  75. Rebecca L. Potential antibiotic treatment for multiple sclerosis? The Lancet 2002; 359(9300): 50.
  76. Stamoula E, Siafis S, Dardalas I, Papazisis G. Antidepressants on multiple sclerosis: A review of in vitro and in vivo models. Front. Immunol. 2021; 12: 677879.
  77. Raimo S, Santangelo G, Trojano L. The emotional disorders associated with multiple sclerosis: Handb.Clin. Neurol. 2021; 183: 197-220.
  78. Pollmann W, Feneberg W. Current management of pain associated with multiple sclerosis. CNS Drugs 2008; 22(4): 291- 324.
  79. Jing S, Lingyu Y, Xia X, Rui L, Jhong J. Pruritus: Progress toward pathogenesis and treatment. Biomed. Res. Int. 2018; 2018: 9625936.
  80. Giuseppe I, Leticia T, Andrew B, Silvia D, Gil Y. Chronic pruritus in multiple sclerosis and clinical correlates. J. European Academy of Dermatology and Venereology 2022; 37(1): 154-159.
  81. Allart E, Benoit A, Tiffreau V, Thevenon A, Zephir H. Sustained – released fampridine in multiple sclerosis: effected on gait parameters, arm function, fatigue and quality of life. J. Neurol. 2015; 262(8): 1936-1945.
  82. Pavsic K, Pelicon K, Ledinek AH, Sega S. Short-term impact of fampridine on motor and cognitive functions, mood quality of life among multiple sclerosis patients. Clin. Neurol. Neurosurg. 2015; 139: 35- 40.
  83. Enyao Z, Xin T, Li R, Li M, Ma L. Dalfampridine in the treatment of multiple sclerosis: A meta-analysis of randomized controlled trials. Orphanet Journal of Rare Diseases 2021; 16(87): 1-12.
  84. Chari DM. Remyelination in multiple sclerosis. Int. Rev. Neurology 2007; 79: 589-620.
  85. Jagannath AV, Filippini G, Asokan GV, Robak EW, Robinson SA. Vitamin D for the management of multiple sclerosis. The Cochrane Database of Systematic Reviews 2018; 9(9): CD008422.
  86. Goldschmidt CH, Cohen JA. The rise and fall of high-dose biotin to treat progressive multiple sclerosis. Neurotherapeutics 2020; 17(3): 968-970.
  87. Ruth AN, John DF, Alexander S, Alan K, Charles NB. Prescription opioid use in multiple sclerosis. J. Neurology, Neurosurgery, and Psychiatry 2023; 94(2): 167-169.
  88. Torres- Moreno MC, Papaseit E, Torrens M, Farre M. Assessment of efficacy and tolerability of medicinal cannabinoids in patients with multiple sclerosis: A systematic review and meta-analysis. JAMA Network Open 2018; 1(6): 183485.
  89. Filippi M, Rocca MA, Enzinger C, Fisher E, Comi G. Magnetic resonance techniques in multiple sclerosis: the present and future. Archives of Neurology 2011; 68(12): 1514-1520.
  90. Heine M, Rietberg MB, Van Wegen EE, Kwakkel G. Exercise therapy for failure in multiple sclerosis. The Cochrane Database of Systematic Reviews 2015; (9): CD009956.
  91. Etoom M, Khraiwesh Y, Lena F. Effectiveness of physiotherapy interventions on spasticity in people with multiple sclerosis. A systematic review and meta-analysis. Am. J. Med. Rehabil. 2018; 97 (11): 793-807.
  92. Skinner S, Guimond C, Butler R, Dwosh E, Traboulsee AL, Sadovnick AD. An assessment of genetic counseling services for individuals with multiple sclerosis. J. Genet. Couns. 2015; 24(1): 46-57.