Document Type: Original Article

Authors

1 Iranian Center of Neurological Research, Neuroscience Institute, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran

3 Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

4 Adelaide Medical School, Faculty of Health and Sciences, University of Adelaide, Adelaide, Australia

Abstract

Background: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with the most common complaint of fatigue. A high number of patients with MS are interested in taking dietary supplements as a complementary therapy. We propose a specially formulated supplement for patients with MS and aim to evaluate its effects on fatigue.
Methods: This study was a triple-blind, randomized, placebo-controlled trial using a stratified randomization method according to sex. 46 eligible patients participated in the study, 23 in the placebo group and 23 in the intervention group. The intervention group received two capsules of multivitamin-mineral (MVM) daily for 3 months. 
Measurements of fatigue and cytokines were performed in all patients at the baseline and after the 3-month intervention
Results: Finally, information of 41 participants was used for data analysis. However, fatigue was decreased after supplementation than before, in the intervention group (P = 0.005). There was no significant difference (P = 0.090) between the change of fatigue score in the MVM group (-3.00 ± 4.42) and the control group (-0.40 ± 5.14). Among cytokines, Interleukin 4 (IL-4) significantly increased in the intervention group compared to the placebo (P = 0.030).
Conclusion: Our study showed that the present MVM probably could improve the inflammatory state and fatigue in patients with MS.

Keywords

  1. Klotz L, Havla J, Schwab N, Hohlfeld R, Barnett M, Reddel S, et al. Risks and risk management in modern multiple sclerosis immunotherapeutic treatment. Ther Adv Neurol Disord 2019; 12: 1756286419836571.
  2. Tillery EE, Clements JN, Howard Z. What's new in multiple sclerosis? Ment Health Clin 2017; 7(5): 213-20.
  3. Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, et al. The natural history of multiple sclerosis: A geographically based study. I. Clinical course and disability. Brain 1989; 112 (Pt 1): 133-46.
  4. McFarland HF, Martin R. Multiple sclerosis: A complicated picture of autoimmunity. Nat Immunol 2007; 8(9): 913-9.
  5. Zajicek JP, Wing M, Scolding NJ, Compston DA. Interactions between oligodendrocytes and microglia. A major role for complement and tumour necrosis factor in oligodendrocyte adherence and killing. Brain 1992; 115 (Pt 6): 1611-31.
  6. Vartanian T, Li Y, Zhao M, Stefansson K. Interferon-gamma-induced oligodendrocyte cell death: Implications for the pathogenesis of multiple sclerosis. Mol Med 1995; 1(7): 732-43.
  7. Benveniste EN, Merrill JE. Stimulation of oligodendroglial proliferation and maturation by interleukin-2. Nature 1986; 321(6070): 610-3.
  8. Compston A, Coles A. Multiple sclerosis. Lancet 2008; 372(9648): 1502-17.
  9. Amedei A, Prisco D, D'Elios MM. Multiple sclerosis: The role of cytokines in pathogenesis and in therapies. Int J Mol Sci 2012; 13(10): 13438-60.
  10. Sacramento PM, Monteiro C, Dias ASO, Kasahara TM, Ferreira TB, Hygino J, et al. Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4(+) T-cell subsets in multiple sclerosis patients. Eur J Immunol 2018; 48(8): 1376-88.
  11. Rodgers JM, Miller SD. Cytokine control of inflammation and repair in the pathology of multiple sclerosis. Yale J Biol Med 2012; 85(4): 447-68.
  12. Kleinewietfeld M, Hafler DA. The plasticity of human Treg and Th17 cells and its role in autoimmunity. Semin Immunol 2013; 25(4): 305-12.
  13. Gumus H. Fatigue Can Be Objectively Measured in Multiple Sclerosis: Multipl Sklerozda Yorgunluk Objektif Olarak Olculebilir. Noro Psikiyatr Ars 2018; 55(Suppl 1): S76-S79.
  14. Masullo L, Papas MA, Cotugna N, Baker S, Mahoney L, Trabulsi J. Complementary and alternative medicine use and nutrient intake among individuals with multiple sclerosis in the United States. J Community Health 2015; 40(1): 153-60.
  15. Xue H, Ren H, Zhang L, Sun X, Wang W, Zhang S, et al. Alpha-tocopherol ameliorates experimental autoimmune encephalomyelitis through the regulation of Th1 cells. Iran J Basic Med Sci 2016; 19(5): 561-6.
  16. Bitarafan S, Saboor-Yaraghi A, Sahraian MA, Soltani D, Nafissi S, Togha M, et al. Effect of Vitamin A Supplementation on fatigue and depression in Multiple Sclerosis patients: A double-blind placebo-controlled clinical trial. Iran J Allergy Asthma Immunol 2016; 15(1): 13-9.
  17. Naghashpour M, Majdinasab N, Shakerinejad G, Kouchak M, Haghighizadeh MH, Jarvandi F, et al. Riboflavin supplementation to patients with multiple sclerosis does not improve disability status nor is riboflavin supplementation correlated to homocysteine. Int J Vitam Nutr Res 2013; 83(5): 281-90.
  18. Prins JB, Bleijenberg G, Bazelmans E, Elving LD, de Boo TM, Severens JL, et al. Cognitive behaviour therapy for chronic fatigue syndrome: A multicentre randomised controlled trial. Lancet 2001; 357(9259): 841-7.
  19. Jafarirad S, Siassi F, Harirchian MH, Sahraian MA, Eshraghian MR, Shokri F, et al. The effect of vitamin A supplementation on stimulated T-cell proliferation with myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. J Neurosci Rural Pract 2012; 3(3): 294-8.
  20. Wikstrom J, Westermarck T, Palo J. Selenium, vitamin E and copper in multiple sclerosis. Acta Neurol Scand 1976; 54(3): 287-90.
  21. Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev 1996; 54(12): 382-90.
  22. Johnson S. The possible role of gradual accumulation of copper, cadmium, lead and iron and gradual depletion of zinc, magnesium, selenium, vitamins B2, B6, D, and E and essential fatty acids in multiple sclerosis. Med Hypotheses 2000; 55(3): 239-41.
  23. Moore MM. Treatment of multiple sclerosis with nicotinic acid and vitamin b1 preliminary report. Arch Intern Med (Chic) 1940; 65(1): 1-20.
  24. Burton JM, Kimball S, Vieth R, Bar-Or A, Dosch HM, Cheung R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 2010; 74(23): 1852-9.
  25. Ho SY, Catalanotto FA, Lisak RP, Dore-Duffy P. Zinc in multiple sclerosis. II: Correlation with disease activity and elevated plasma membrane-bound zinc in erythrocytes from patients with multiple sclerosis. Ann Neurol 1986; 20(6): 712-5.
  26. Melo TM, Larsen C, White LR, Aasly J, Sjobakk TE, Flaten TP, et al. Manganese, copper, and zinc in cerebrospinal fluid from patients with multiple sclerosis. Biol Trace Elem Res 2003; 93(1-3): 1-8.
  27. Bloem L. Iron and multiple sclerosis [PhD Thesis]; Stellenbosch, South Africa: University of Stellenbosch; 2007.
  28. Sheykhansari S, Kozielski K, Bill J, Sitti M, Gemmati D, Zamboni P, et al. Redox metals homeostasis in multiple sclerosis and amyotrophic lateral sclerosis: A review. Cell Death Dis 2018; 9(3): 348.
  29. Sadaka Y, Verhey LH, Shroff MM, Branson HM, Arnold DL, Narayanan S, et al. 2010 McDonald criteria for diagnosing pediatric multiple sclerosis. Ann Neurol 2012; 72(2): 211-23.
  30. Embry AF, Snowdon LR, Vieth R. Vitamin D and seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol 2000; 48(2): 271-2.
  31. Faridar A, Eskandari G, Sahraian MA, Minagar A, Azimi A. Vitamin D and multiple sclerosis: A critical review and recommendations on treatment. Acta Neurol Belg 2012; 112(4): 327-33.
  32. Sanoobar M, Eghtesadi S, Azimi A, Khalili M, Jazayeri S, Reza GM. Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with relapsing-remitting multiple sclerosis. Int J Neurosci 2013; 123(11): 776-82.
  33. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 1983; 33(11): 1444-52.
  34. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989; 46(10): 1121-3.
  35. Beck AT, Steer RA, Brown GK. BDI-II, Beck Depression Inventory: Manual. New York, NY: Psychological Corporation; 1996. p. 2.
  36. Stroud NM, Minahan CL. The impact of regular physical activity on fatigue, depression and quality of life in persons with multiple sclerosis. Health Qual Life Outcomes 2009; 7: 68.
  37. Braley TJ, Chervin RD. Fatigue in multiple sclerosis: Mechanisms, evaluation, and treatment. Sleep 2010; 33(8): 1061-7.
  38. Chalah MA, Ayache SS. Is there a link between inflammation and fatigue in multiple sclerosis? J Inflamm Res 2018; 11: 253-64.
  39. Heesen C, Nawrath L, Reich C, Bauer N, Schulz KH, Gold SM. Fatigue in multiple sclerosis: An example of cytokine mediated sickness behaviour? J Neurol Neurosurg Psychiatry 2006; 77(1): 34-9.
  40. Flachenecker P, Bihler I, Weber F, Gottschalk M, Toyka KV, Rieckmann P. Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Mult Scler 2004; 10(2): 165-9.
  41. Schwid SR, Covington M, Segal BM, Goodman AD. Fatigue in multiple sclerosis: current understanding and future directions. J Rehabil Res Dev 2002; 39(2): 211-24.
  42. De Riccardis L., Buccolieri A, Muci M, Pitotti E, De Robertis F, Trianni G, et al. Copper and ceruloplasmin dyshomeostasis in serum and cerebrospinal fluid of multiple sclerosis subjects. Biochim Biophys Acta Mol Basis Dis 2018; 1864(5 Pt A): 1828-38.
  43. Nashmi AD, Hassan AF, Hammady MM. Estimation the level of metals (Lead, Cadmium, Copper and Zinc) in multiple sclerosis patients in BasraIraq. Indian J Forensic Med Toxicol 2020; 14(3): 1029-35.
  44. Bredholt M, Frederiksen JL. Zinc in multiple sclerosis: A systematic review and meta-analysis. ASN Neuro 2016; 8(3): 1759091416651511.
  45. Maric D, Brkic S, Tomic S, Novakov MA, Cebovic T, Turkulov V. Multivitamin mineral supplementation in patients with chronic fatigue syndrome. Med Sci Monit 2014; 20: 47-53.
  46. Wang SM, Yin LY, Zhang Y, Fan JH, Chang IJ, Dawsey SM, et al. Multivitamin and mineral supplementation is associated with the reduction of fracture risk and hospitalization rate in Chinese adult males: A randomized controlled study. J Bone Miner Metab 2015; 33(3): 294-302.
  47. Harris E, Macpherson H, Pipingas A. Improved blood biomarkers but no cognitive effects from 16 weeks of multivitamin supplementation in healthy older adults. Nutrients 2015; 7(5): 3796-812.
  48. Long SJ, Benton D. Effects of vitamin and mineral supplementation on stress, mild psychiatric symptoms, and mood in nonclinical samples: A meta-analysis. Psychosom Med 2013; 75(2): 144-53.
  49. Jansen E, Beekhof P, Tamosiunas A, Luksiene D, Baceviciene M. Biomarkers of oxidative stress and redox status in a short-term low-dosed multivitamin and mineral supplementation study in two human age groups. Biogerontology 2015; 16(5): 645-53.
  50. Hussain T, Tan B, Yin Y, Blachier F, Tossou MC, Rahu N. Oxidative Stress and inflammation: What polyphenols can do for us? Oxid Med Cell Longev 2016; 2016: 7432797.
  51. Meneghini R. Iron homeostasis, oxidative stress, and DNA damage. Free Radic Biol Med 1997; 23(5): 783-92.
  52. Nowak A, Boesch L, Andres E, Battegay E, Hornemann T, Schmid C, et al. Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial. Medicine (Baltimore) 2016; 95(52): e5353.
  53. Azzi A. The role of alpha-tocopherol in preventing disease. Eur J Nutr 2004; 43(Suppl 1): I/18-I/25.
  54. Dobryakova E, Genova HM, DeLuca J, Wylie GR. The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders. Front Neurol 2015; 6: 52.
  55. Hoe E, Nathanielsz J, Toh ZQ, Spry L, Marimla R, Balloch A, et al. Anti-Inflammatory effects of vitamin d on human immune cells in the context of bacterial infection. Nutrients 2016; 8(12): 806.
  56. Kaneko I, Sabir MS, Dussik CM, Whitfield GK, Karrys A, Hsieh JC, et al. 1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: Implication for behavioral influences of vitamin D. FASEB J 2015; 29(9): 4023-35.
  57. Yamamoto S, Ouchi Y, Onoe H, Yoshikawa E, Tsukada H, Takahashi H, et al. Reduction of serotonin transporters of patients with chronic fatigue syndrome. Neuroreport 2004; 15(17): 2571-4.
  58. Zemel MB, Sun X. Dietary calcium and dairy products modulate oxidative and inflammatory stress in mice and humans. J Nutr 2008; 138(6): 1047-52.
  59. Zhu Y, Mahon BD, Froicu M, Cantorna MT. Calcium and 1 alpha,25-dihydroxyvitamin D3 target the TNF-alpha pathway to suppress experimental inflammatory bowel disease. Eur J Immunol 2005; 35(1): 217-24.
  60. Syburra C, Passi S. Oxidative stress in patients with multiple sclerosis. Ukr Biokhim Zh (1999) 1999; 71(3): 112-5.
  61. Ford ES, Liu S, Mannino DM, Giles WH, Smith SJ. C-reactive protein concentration and concentrations of blood vitamins, carotenoids, and selenium among United States adults. Eur J Clin Nutr 2003; 57(9): 1157-63.
  62. Mai J, Sorensen PS, Hansen JC. High dose antioxidant supplementation to Patients with MS. Effects on glutathione peroxidase, clinical safety, and absorption of selenium. Biol Trace Elem Res 1990; 24(2): 109-17.
  63. Cohen ME, Meyer DM. Effect of dietary vitamin E supplementation and rotational stress on alveolar bone loss in rice rats. Arch Oral Biol 1993; 38(7): 601-6.
  64. Han SN, Wu D, Ha WK, Beharka A, Smith DE, Bender BS, et al. Vitamin E supplementation increases T helper 1 cytokine production in old mice infected with influenza virus. Immunology 2000; 100(4): 487-93.
  65. Early RG, Carlson BR. Water-soluble vitamin therapy in the delay of fatigue from physical activity in hot climatic conditions. Int Z Angew Physiol 1969; 27(1): 43-50.
  66. Costantini A, Nappo A, Pala MI, Zappone A. High dose thiamine improves fatigue in multiple sclerosis. BMJ Case Rep 2013; 2013.
  67. Reynolds EH. Multiple sclerosis and vitamin B12 metabolism. J Neuroimmunol 1992; 40(2-3): 225-30.
  68. Bitarafan S, Harirchian MH, Nafissi S, Sahraian MA, Togha M, Siassi F, et al. Dietary intake of nutrients and its correlation with fatigue in multiple sclerosis patients. Iran J Neurol 2014; 13(1): 28-32.
  69. Yasui M, Ota K. Experimental and clinical studies on dysregulation of magnesium metabolism and the aetiopathogenesis of multiple sclerosis. Magnes Res 1992; 5(4): 295-302.
  70. Cruciani RA, Dvorkin E, Homel P, Culliney B, Malamud S, Shaiova L, et al. L-carnitine supplementation for the treatment of fatigue and depressed mood in cancer patients with carnitine deficiency: A preliminary analysis. Ann N Y Acad Sci 2004; 1033: 168-76.
  71. Steen G, Axelsson H, Bowallius M, Holthuis N, Molander BM. Isoprenoid biosynthesis in multiple sclerosis. Acta Neurol Scand 1985; 72(3): 328-35.
  72. Sanoobar M, Dehghan P, Khalili M, Azimi A, Seifar F. Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: A double blind randomized clinical trial. Nutr Neurosci 2016; 19(3): 138-43.
  73. Soleimani M, Jameie SB, Barati M, Mehdizadeh M, Kerdari M. Effects of coenzyme Q10 on the ratio of TH1/TH2 in experimental autoimmune encephalomyelitis model of multiple sclerosis in C57BL/6. Iran Biomed J 2014; 18(4): 203-11.
  74. Sorgun MH, Yucesan C, Tegin C. Is malnutrition a problem for multiple sclerosis patients? J Clin Neurosci 2014; 21(9): 1603-5.
  75. Pooyandjoo M, Nouhi M, Shab-Bidar S, Djafarian K, Olyaeemanesh A. The effect of (L-)carnitine on weight loss in adults: A systematic review and meta-analysis of randomized controlled trials. Obes Rev 2016; 17(10): 970-6.