Can we prevent or treat multiple sclerosis by individualised vitamin D supply?

EPMA Journal

Friedemann Paul¹  Andrea Döring²  Jan Dörr¹ 

[1] Clinical and Experimental Research Center for Multiple Sclerosis, Charité - Universitätsmedizin Berlin, Berlin, Germany;Current address: Department of Neurology, DIAKO, Flensburg, Germany

关键词: Tailored therapy;    Targeted prevention;    Personalised medicine;    Supplementation;    Risk factor;    Therapy;    Prevention;    Cholecalciferol;    Vitamin D;    Multiple sclerosis;   

Others  :  801889
DOI  :  10.1186/1878-5085-4-4

 received in 2012-11-30, accepted in 2013-01-09,  发布年份 2013

【 摘 要 】

Apart from its principal role in bone metabolism and calcium homeostasis, vitamin D has been attributed additional effects including an immunomodulatory, anti-inflammatory, and possibly even neuroprotective capacity which implicates a possible role of vitamin D in autoimmune diseases like multiple sclerosis (MS). Indeed, several lines of evidence including epidemiologic, preclinical, and clinical data suggest that reduced vitamin D levels and/or dysregulation of vitamin D homeostasis is a risk factor for the development of multiple sclerosis on the one hand, and that vitamin D serum levels are inversely associated with disease activity and progression on the other hand. However, these data are not undisputable, and many questions regarding the preventive and therapeutic capacity of vitamin D in multiple sclerosis remain to be answered. In particular, available clinical data derived from interventional trials using vitamin D supplementation as a therapeutic approach in MS are inconclusive and partly contradictory. In this review, we summarise and critically evaluate the existing data on the possible link between vitamin D and multiple sclerosis in light of the crucial question whether optimization of vitamin D status may impact the risk and/or the course of multiple sclerosis.

【 授权许可】

   
2013 Dörr et al.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Compston A, Coles A: Multiple sclerosis. Lancet 2008, 372:1502-1517.
• [2]Weinges-Evers N, Brandt AU, Bock M, Pfueller CF, Dörr J, Bellmann-Strobl J, Scherer P, Urbanek C, Boers C, Ohlraun S, Zipp F, Paul F: Correlation of self-assessed fatigue and alertness in multiple sclerosis. Mult Scler 2010, 16:1134-1140.
• [3]Veauthier C, Radbruch H, Gaede G, Pfueller C, Dörr J, Bellmann-Strobl J, Wernecke K-D, Zipp F, Paul F, Sieb J: Fatigue in multiple sclerosis is closely related to sleep disorders: a polysomnographic cross-sectional study. Mult Scler 2011, 17:613-622.
• [4]Handel AE, Jarvis L, McLaughlin R, Fries A, Ebers GC, Ramagopalan SV: The epidemiology of multiple sclerosis in Scotland: inferences from hospital admissions. PLoS One 2011, 6:e14606.
• [5]Borisow N, Döring A, Pfueller CF, Paul F, Dörr J, Hellwig K: Expert recommendations to personalization of medical approaches in treatment of multiple sclerosis: an overview of family planning and pregnancy. EPMA J 2012, 3:9. BioMed Central Full Text
• [6]Ascherio A, Munger KL: Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol 2007, 61:288-299.
• [7]Ascherio A, Munger KL: Environmental risk factors for multiple sclerosis. Part II: noninfectious factors. Ann Neurol 2007, 61:504-513.
• [8]Handel AE, Giovannoni G, Ebers GC, Ramagopalan SV: Environmental factors and their timing in adult-onset multiple sclerosis. Nat Rev Neurol 2010, 6:156-166.
• [9]Goodin DS: The causal cascade to multiple sclerosis: a model for MS pathogenesis. PLoS One 2009, 4:e4565.
• [10]Ramagopalan SV, Dobson R, Meier UC, Giovannoni G: Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol 2010, 9:727-739.
• [11]McFarland HF, Martin R: Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 2007, 8:913-919.
• [12]Nylander A, Hafler DA: Multiple sclerosis. J Clin Invest 2012, 122:1180-1188.
• [13]Haegert DG: Multiple sclerosis: a disorder of altered T-cell homeostasis. Mult Scler Int 2011, 2011:461304.
• [14]Trapp BD, Peterson J, Ransohoff RM, Rudick RA, Mork S, Bo L: Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998, 338:278-285.
• [15]Peterson JW, Bo L, Mork S, Chang A, Trapp BD: Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001, 50:389-400.
• [16]De Stefano N, Matthews PM, Fu L, Narayanan S, Stanley J, Francis GS, Antel JP, Arnold DL: Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain 1998, 121(Pt 8):1469-1477.
• [17]Vogt J, Paul F, Aktas O, Muller-Wielsch K, Dörr J, Dörr S, Bharathi BS, Glumm R, Schmitz C, Steinbusch H, Raine CS, Tsokos M, Nitsch R, Zipp F: Lower motor neuron loss in multiple sclerosis and experimental autoimmune encephalomyelitis. Ann Neurol 2009, 66:310-322.
• [18]Kutzelnigg A, Lucchinetti CF, Stadelmann C, Brück W, Rauschka H, Bergmann M, Schmidbauer M, Parisi JE, Lassmann H: Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005, 128:2705-2712.
• [19]Sinnecker T, Mittelstaedt P, Dörr J, Pfueller CF, Harms L, Niendorf T, Paul F, Wuerfel J: Multiple sclerosis lesions and irreversible brain tissue damage: a comparative ultrahigh-field strength magnetic resonance imaging study. Arch Neurol 2012, 69:739-745.
• [20]Sinnecker T, Dörr J, Pfueller CF, Harms L, Ruprecht K, Jarius S, Brück W, Niendorf T, Wuerfel J, Friedemann P: Distinct lesion morphology at 7-T MRI differentiates neuromyelitis optica from multiple sclerosis. Neurology 2012, 79:708-714.
• [21]Bock M, Brandt AU, Dörr J, Kraft H, Weinges-Evers N, Gaede G, Pfueller CF, Herges K, Radbruch H, Ohlraun S, Bellmann-Strobl J, Kuchenbecker J, Zipp F, Paul F: Patterns of retinal nerve fiber layer loss in multiple sclerosis patients with or without optic neuritis and glaucoma patients. Clin Neurol Neurosurg 2010, 112:647-652.
• [22]Oberwahrenbrock T, Schippling S, Ringelstein M, Kaufhold F, Zimmermann H, Keser N, Young KL, Harmel J, Hartung H-P, Martin R, Paul F, Aktas O, Brandt AU: Retinal damage in multiple sclerosis disease subtypes measured by high-resolution optical coherence tomography. Mult Scler Int 2012, 2012:530305.
• [23]Dörr J, Wernecke KD, Bock M, Gaede G, Wuerfel JT, Pfueller CF, Bellmann-Strobl J, Freing A, Brandt AU, Friedemann P: Association of retinal and macular damage with brain atrophy in multiple sclerosis. PLoS One 2011, 6:e18132.
• [24]Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS: Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011, 69:292-302.
• [25]Río J, Comabella M, Montalban X: Multiple sclerosis: current treatment algorithms. Curr Opin Neurol 2011, 24:230-237.
• [26]Buck D, Hemmer B: Treatment of multiple sclerosis: current concepts and future perspectives. J Neurol 2011, 258:1747-1762.
• [27]Jain N, Bhatti MT: Fingolimod-associated macular edema: incidence, detection, and management. Neurology 2012, 78:672-680.
• [28]Paul F, Dörr J, Wurfel J, Vogel HP, Zipp F: Early mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2007, 78:198-200.
• [29]Sorensen PS, Bertolotto A, Edan G, Giovannoni G, Gold R, Havrdova E, Kappos L, Kieseier BC, Montalban X, Olsson T: Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler 2012, 18:143-152.
• [30]Giovannoni G, Southam E, Waubant E: Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis: tolerability and adherence. Mult Scler 2012, 18:932-946.
• [31]Limmroth V, Putzki N, Kachuck NJ: The interferon beta therapies for treatment of relapsing-remitting multiple sclerosis: are they equally efficacious? A comparative review of open-label studies evaluating the efficacy, safety, or dosing of different interferon beta formulations alone or in combination. Ther Adv Neurol Disord 2011, 4:281-296.
• [32]Fox RJ: Primary neuroprotection: the Holy Grail of multiple sclerosis therapy. Neurology 2010, 74:1018-1019.
• [33]Holick MF: Vitamin D: a millenium perspective. J Cell Biochem 2003, 88:296-307.
• [34]Ascherio A, Munger KL, Simon KC: Vitamin D and multiple sclerosis. Lancet Neurol 2010, 9:599-612.
• [35]Holick MF: Vitamin D deficiency. N Engl J Med 2007, 357:266-281.
• [36]Hagenau T, Vest R, Gissel TN, Poulsen CS, Erlandsen M, Mosekilde L, Vestergaard P: Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: an ecologic meta-regression analysis. Osteoporos Int 2009, 20:133-140.
• [37]Database of the German Institut für Ernährungsinformation, Freudenstadt, Germany. [http://www.ernaehrung.de/lebensmittel webcite]
• [38]White JH: Regulation of intracrine production of 1,25-dihydroxyvitamin D and its role in innate immune defense against infection. Arch Biochem Biophys 2012, 523:58-63.
• [39]Haussler MR, Jurutka PW, Mizwicki M, Norman AW: Vitamin D receptor (VDR)-mediated actions of 1α, 25(OH)2 vitamin D3: genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab 2011, 25:543-559.
• [40]Carlberg C, Molnar F: Current status of vitamin D signaling and its therapeutic applications. Curr Top Med Chem 2012, 12:528-547.
• [41]Holick MF: Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol 2009, 19:73-78.
• [42]Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, Bischoff-Ferrari HA, Cavalier E, Ebeling PR, Fardellone P, Gandini S, Gruson D, Guérin AP, Heickendorff L, Hollis BW, Ish-Shalom S, Jean G, Von Landenberg P, Largura A, Olsson T, Pierrot-Deseilligny C, Pilz S, Tincani A, Valcour A, Zittermann A: Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev 2010, 9:709-715.
• [43]Bischoff-Ferrari HA: Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol 2008, 624:55-71.
• [44]Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS: Hypovitaminosis D in medical inpatients. N Engl J Med 1998, 338:777-783.
• [45]Holick MF: High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006, 81:353-373.
• [46]Hintzpeter B, Mensink GBM, Thierfelder W, Müller MJ, Scheidt-Nave C: Vitamin D status and health correlates among German adults. Eur J Clin Nutr 2008, 62:1079-1089.
• [47]Peelen E, Knippenberg S, Muris AH, Thewissen M, Smolders J, Tervaert JWC, Hupperts R, Damoiseaux J: Effects of vitamin D on the peripheral adaptive immune system: a review. Autoimmun Rev 2011, 10:733-743.
• [48]Fleet JC, DeSmet M, Johnson R, Li Y: Vitamin D and cancer: a review of molecular mechanisms. Biochem J 2012, 441:61-76.
• [49]Grant WB: An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr 2011, 65:1016-1026.
• [50]Deluca HF, Cantorna MT: Vitamin D: its role and uses in immunology. FASEB J 2001, 15:2579-2585.
• [51]Correale J, Ysrraelit MC, Gaitán MI: Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain 2009, 132:1146-1160.
• [52]Di Rosa M, Malaguarnera M, Nicoletti F, Malaguarnera L: Vitamin D3: a helpful immuno-modulator. Immunology 2011, 134:123-139.
• [53]Almerighi C, Sinistro A, Cavazza A, Ciaprini C, Rocchi G, Bergamini A: 1Alpha,25-dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes. Cytokine 2009, 45:190-197.
• [54]Piemonti L, Monti P, Sironi M, Fraticelli P, Leone BE, Dal Cin E, Allavena P, Di Carlo V: Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol 2000, 164:4443-4451.
• [55]Griffin MD, Lutz W, Phan VA, Bachman LA, McKean DJ, Kumar R: Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci USA 2001, 98:6800-6805.
• [56]Lemire JM, Adams JS, Sakai R, Jordan SC: 1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest 1984, 74:657-661.
• [57]Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE: Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007, 179:1634-1647.
• [58]Bhalla AK, Amento EP, Serog B, Glimcher LH: 1,25-dihydroxyvitamin D3 inhibits antigen-induced T cell activation. J Immunol 1984, 133:1748-1754.
• [59]Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HF, O'Garra A: 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol 2001, 167:4974-4980.
• [60]Yu S, Cantorna MT: Epigenetic reduction in invariant NKT cells following in utero vitamin D deficiency in mice. J Immunol 2011, 186:1384-1390.
• [61]Smolders J, Thewissen M, Peelen E, Menheere P, Tervaert JWC, Damoiseaux J, Hupperts R: Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS One 2009, 4:e6635.
• [62]Döring A, Paul F, Dörr J: Vitamin D and multiple sclerosis: the role for risk of disease and treatment. Nervenarzt 2012.
• [63]Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ: Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 2005, 29:21-30.
• [64]Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D: New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab 2002, 13:100-105.
• [65]de Abreu DAF, Eyles D, Féron F: Vitamin D, a neuro-immunomodulator: implications for neurodegenerative and autoimmune diseases. Psychoneuroendocrinology 2009, 34(Suppl 1):S265-S277.
• [66]Dyment DA, Sadovnick AD, Ebers GC, Sadnovich AD: Genetics of multiple sclerosis. Hum Mol Genet 1997, 6:1693-1698.
• [67]Sadovnick AD: Genetic background of multiple sclerosis. Autoimmun Rev 2012, 11:163-166.
• [68]Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton S-M, Dyment DA, Deluca GC, Herrera BM, Chao MJ, Sadovnick AD, Ebers GC, Knight JC: Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet 2009, 5:e1000369.
• [69]Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM, Berlanga-Taylor AJ, Handel A, De Luca GC, Sadovnick AD, Lepage P, Montpetit A, Ebers GC: Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol 2011, 70:881-886.
• [70]Torkildsen Ø, Knappskog PM, Nyland HI, Myhr KM: Vitamin D-dependent rickets as a possible risk factor for multiple sclerosis. Arch Neurol 2008, 65:809-811.
• [71]Ramagopalan SV, Hanwell HEC, Giovannoni G, Knappskog PM, Nyland HI, Myhr K-M, Ebers GC, Torkildsen O: Vitamin D-dependent rickets, HLA-DRB1, and the risk of multiple sclerosis. Arch Neurol 2010, 67:1034-1035.
• [72]Lemire JM, Archer DC: 1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J Clin Invest 1991, 87:1103-1107.
• [73]Cantorna MT, Hayes CE, DeLuca HF: 1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis. Proc Natl Acad Sci USA 1996, 93:7861-7864.
• [74]Pedersen LB, Nashold FE, Spach KM, Hayes CE: 1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking. J Neurosci Res 2007, 85:2480-2490.
• [75]Spach KM, Hayes CE: Vitamin D3 confers protection from autoimmune encephalomyelitis only in female mice. J Immunol 2005, 175:4119-4126.
• [76]Becklund BR, Severson KS, Vang SV, DeLuca HF: UV radiation suppresses experimental autoimmune encephalomyelitis independent of vitamin D production. Proc Natl Acad Sci USA 2010, 107:6418-6423.
• [77]Wergeland S, Torkildsen O, Myhr KM, Aksnes L, Mørk SJ, Bø L: Dietary vitamin D3 supplements reduce demyelination in the cuprizone model. PLoS One 2011, 6:e26262.
• [78]Acheson ED, Bachrach CA, Wright FM: Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatr Scand Suppl 1960, 35:132-147.
• [79]Kurtzke JF: An evaluation of the geographic distribution of multiple sclerosis. Acta Neurol Scand 1966, 42(Suppl 19):91.
• [80]Swank RL, Lerstad O, Strom A, Backer J: Multiple sclerosis in rural Norway its geographic and occupational incidence in relation to nutrition. N Engl J Med 1952, 246:722-728.
• [81]Kurtzke JF, Beebe GW, Norman JE Jr: Epidemiology of multiple sclerosis in US veterans: III. Migration and the risk of MS. Neurology 1985, 35:672-678.
• [82]Willer CJ, Dyment DA, Sadovnick AD, Rothwell PM, Murray TJ, Ebers GC: Timing of birth and risk of multiple sclerosis: population based study. BMJ 2005, 330:120.
• [83]Sotgiu S, Pugliatti M, Sotgiu MA, Fois ML, Arru G, Sanna A, Rosati G: Seasonal fluctuation of multiple sclerosis births in Sardinia. J Neurol 2006, 253:38-44.
• [84]Salzer J, Svenningsson A, Sundström P: Season of birth and multiple sclerosis in Sweden. Acta Neurol Scand 2010, 122:70-73.
• [85]Dobson R, Giovannoni G, Ramagopalan S: The month of birth effect in multiple sclerosis: systematic review, meta-analysis and effect of latitude. J Neurol Neurosurg Psychiatr 2012.
• [86]Van der Mei IAF, Ponsonby AL, Dwyer T, Blizzard L, Simmons R, Taylor BV, Butzkueven H, Kilpatrick T: Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case–control study. BMJ 2003, 327:316.
• [87]Islam T, Gauderman WJ, Cozen W, Mack TM: Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology 2007, 69:381-388.
• [88]Dalmay F, Bhalla D, Nicoletti A, Cabrera-Gomez JA, Cabre P, Ruiz F, Druet-Cabanac M, Dumas M, Preux PM: Multiple sclerosis and solar exposure before the age of 15 years: case–control study in Cuba, Martinique and Sicily. Mult Scler 2010, 16:899-908.
• [89]Kampman MT, Wilsgaard T, Mellgren SI: Outdoor activities and diet in childhood and adolescence relate to MS risk above the Arctic Circle. J Neurol 2007, 254:471-477.
• [90]McDowell TY, Amr S, Culpepper WJ, Langenberg P, Royal W, Bever C, Bradham DD: Sun exposure, vitamin D and age at disease onset in relapsing multiple sclerosis. Neuroepidemiology 2011, 36:39-45.
• [91]McDowell TY, Amr S, Culpepper WJ, Langenberg P, Royal W, Bever C, Bradham DD: Sun exposure, vitamin D intake and progression to disability among veterans with progressive multiple sclerosis. Neuroepidemiology 2011, 37:52-57.
• [92]Van der Mei IAF, Blizzard L, Ponsonby AL, Dwyer T: Validity and reliability of adult recall of past sun exposure in a case–control study of multiple sclerosis. Cancer Epidemiol Biomarkers Prev 2006, 15:1538-1544.
• [93]Lucas RM, Ponsonby AL, Dear K, Valery PC, Pender MP, Taylor BV, Kilpatrick TJ, Dwyer T, Coulthard A, Chapman C, Van der Mei I, Williams D, McMichael AJ: Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology 2011, 76:540-548.
• [94]Hart PH, Gorman S, Finlay-Jones JJ: Modulation of the immune system by UV radiation: more than just the effects of vitamin D? Nat Rev Immunol 2011, 11:584-596.
• [95]Jin Y, De Pedro-Cuesta J, Söderström M, Stawiarz L, Link H: Seasonal patterns in optic neuritis and multiple sclerosis: a meta-analysis. J Neurol Sci 2000, 181:56-64.
• [96]Handel AE, Disanto G, Jarvis L, McLaughlin R, Fries A, Ebers GC, Ramagopalan SV: Seasonality of admissions with multiple sclerosis in Scotland. Eur J Neurol 2011, 18:1109-1111.
• [97]Meier DS, Balashov KE, Healy B, Weiner HL, Guttmann CRG: Seasonal prevalence of MS disease activity. Neurology 2010, 75:799-806.
• [98]Auer DP, Schumann EM, Kümpfel T, Gössl C, Trenkwalder C: Seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol 2000, 47:276-277.
• [99]Tremlett H, Van der Mei IAF, Pittas F, Blizzard L, Paley G, Mesaros D, Woodbaker R, Nunez M, Dwyer T, Taylor BV, Ponsonby AL: Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology 2008, 31:271-279.
• [100]Mirzaei F, Michels KB, Munger K, O'Reilly E, Chitnis T, Forman MR, Giovannucci E, Rosner B, Ascherio A: Gestational vitamin D and the risk of multiple sclerosis in offspring. Ann Neurol 2011, 70:30-40.
• [101]Banwell B, Bar-Or A, Arnold DL, Sadovnick D, Narayanan S, McGowan M, O'Mahony J, Magalhaes S, Hanwell H, Vieth R, Tellier R, Vincent T, Disanto G, Ebers G, Wambera K, Connolly MB, Yager J, Mah JK, Booth F, Sebire G, Callen D, Meaney B, Dilenge ME, Lortie A, Pohl D, Doja A, Venketaswaran S, Levin S, Macdonald EA, Meek D, et al.: Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. Lancet Neurol 2011, 10:436-445.
• [102]Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A: Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006, 296:2832-2838.
• [103]Munger KL, Zhang SM, O'Reilly E, Hernán MA, Olek MJ, Willett WC, Ascherio A: Vitamin D intake and incidence of multiple sclerosis. Neurology 2004, 62:60-65.
• [104]Soilu-Hänninen M, Airas L, Mononen I, Heikkilä A, Viljanen M, Hänninen A: 25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosis. Mult Scler 2005, 11:266-271.
• [105]Simpson S Jr, Taylor B, Blizzard L, Ponsonby AL, Pittas F, Tremlett H, Dwyer T, Gies P, Van der Mei I: Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol 2010, 68:193-203.
• [106]Pierrot-Deseilligny C, Rivaud-Péchoux S, Clerson P, De Paz R, Souberbielle JC: Relationship between 25-OH-D serum level and relapse rate in multiple sclerosis patients before and after vitamin D supplementation. Ther Adv Neurol Disord 2012, 5:187-198.
• [107]Runia TF, Hop WCJ, De Rijke YB, Buljevac D, Hintzen RQ: Lower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosis. Neurology 2012, 79:261-266.
• [108]Mowry EM, Krupp LB, Milazzo M, Chabas D, Strober JB, Belman AL, McDonald JC, Oksenberg JR, Bacchetti P, Waubant E: Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol 2010, 67:618-624.
• [109]Mowry EM, Waubant E, McCulloch CE, Okuda DT, Evangelista AA, Lincoln RR, Gourraud P-A, Brenneman D, Owen MC, Qualley P, Bucci M, Hauser SL, Pelletier D: Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol 2012, 72:234-240.
• [110]Løken-Amsrud KI, Holmøy T, Bakke SJ, Beiske AG, Bjerve KS, Bjørnarå BT, Hovdal H, Lilleås F, Midgard R, Pedersen T, Benth JS, Sandvik L, Torkildsen O, Wergeland S, Myhr K-M: Vitamin D and disease activity in multiple sclerosis before and during interferon-β treatment. Neurology 2012, 79:267-273.
• [111]Holmøy T, Moen SM, Gundersen TA, Holick MF, Fainardi E, Castellazzi M, Casetta I: 25-hydroxyvitamin D in cerebrospinal fluid during relapse and remission of multiple sclerosis. Mult Scler 2009, 15:1280-1285.
• [112]Goldberg P, Fleming MC, Picard EH: Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Med Hypotheses 1986, 21:193-200.
• [113]Kimball SM, Ursell MR, O'Connor P, Vieth R: Safety of vitamin D3 in adults with multiple sclerosis. Am J Clin Nutr 2007, 86:645-651.
• [114]Burton JM, Kimball S, Vieth R, Bar-Or A, Dosch H-M, Cheung R, Gagne D, D'Souza C, Ursell M, O'Connor P: A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 2010, 74:1852-1859.
• [115]Mahon BD, Gordon SA, Cruz J, Cosman F, Cantorna MT: Cytokine profile in patients with multiple sclerosis following vitamin D supplementation. J Neuroimmunol 2003, 134:128-132.
• [116]Stein MS, Liu Y, Gray OM, Baker JE, Kolbe SC, Ditchfield MR, Egan GF, Mitchell PJ, Harrison LC, Butzkueven H, Kilpatrick TJ: A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology 2011, 77:1611-1618.
• [117]Grimaldi L, Barkhof F, Beelke M, Burton J, Holmoy T, Hupperts R, Killestein J, Rieckmann P, Schluep M, Smolders J: A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology 2012, 78:841.
• [118]Shaygannejad V, Janghorbani M, Ashtari F, Dehghan H: Effects of adjunct low-dose vitamin d on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized placebo-controlled trial. Mult Scler Int 2012, 2012:452541.
• [119]Soilu-Hänninen M, Aivo J, Lindström B-M, Elovaara I, Sumelahti M-L, Färkkilä M, Tienari P, Atula S, Sarasoja T, Herrala L, Keskinarkaus I, Kruger J, Kallio T, Rocca MA, Filippi M: A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2012, 83:565-571.
• [120]Aivo J, Lindsröm B-M, Soilu-Hänninen M: A randomised, double-blind, placebo-controlled trial with vitamin D3 in MS: subgroup analysis of patients with baseline disease activity despite interferon treatment. Mult Scler Int 2012, 2012:802796.
• [121]Kampman MT, Steffensen LH, Mellgren SI, Jørgensen L: Effect of vitamin D3 supplementation on relapses, disease progression and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial. Mult Scler 2012, 18:1144-1151.
• [122]Smolders J, Hupperts R, Barkhof F, Grimaldi LME, Holmoy T, Killestein J, Rieckmann P, Schluep M, Vieth R, Hostalek U, Ghazi-Visser L, Beelke M: Efficacy of vitamin D(3) as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon beta-1a: a Phase II, multicenter, double-blind, randomized, placebo-controlled trial. J Neurol Sci 2011, 311:44-49.
• [123]Dörr J, Ohlraun S, Skarabis H, Paul F: Efficacy of Vitamin D Supplementation in Multiple Sclerosis (EVIDIMS Trial): study protocol for a randomized controlled trial. Trials 2012, 13:15. BioMed Central Full Text
• [124]Marcus JF, Shalev SM, Harris CA, Goodin DS, Josephson SA: Severe hypercalcemia following vitamin D supplementation in a patient with multiple sclerosis: a note of caution. Arch Neurol 2012, 69:129-132.
• [125]Wingerchuk DM, Lesaux J, Rice GPA, Kremenchutzky M, Ebers GC: A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatr 2005, 76:1294-1296.
• [126]Jagannath VA, Fedorowicz Z, Asokan GV, Robak EW, Whamond L: Vitamin D for the management of multiple sclerosis. Cochrane Database Syst Rev 2010, 12:CD008422.
• [127]Hathcock JN, Shao A, Vieth R, Heaney R: Risk assessment for vitamin D. Am J Clin Nutr 2007, 85:6-18.
• [128]Golubnitschaja O, Costigliola V, EPMA: General report & recommendations in predictive, preventive and personalised medicine 2012: white paper of the European Association for Predictive, Preventive and Personalised Medicine. EPMA J 2012, 3:14. BioMed Central Full Text