Online ISSN : 1687-8329


Quick Search 

January2014 Vol.51 Issue:      1 Table of Contents
Full Text

Relation between Serum Vitamin D Levels and Activity of Multiple Sclerosis


Mamdouh Ali Kotb1,3, Sayed Sobhy Sayed2,4


Departments of Neurology, El-Minia University1, Fayoum University2; Egypt

National Hospital3, Al-Mousa Hospital4; Saudi Arabia


Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system. Vitamin D level affects the risk of MS onset. Objective: To evaluate the effect of vitamin D level on the clinical course of the disease. Methods: Twenty-two MS patients followed for one year. Clinical evaluation, serum 25 hydroxyvitamin D level measurement, and MRI evaluation were done for all patients. Results: Patients with MS had vitamin D insufficiency. Patients with confirmed relapses had significantly lower serum vitamin D compared to patients without relapses. Serum vitamin D level inversely correlates with the clinical severity of the disease. Conclusion: Vitamin D has a role in the clinical course and severity of MS disease. [Egypt J Neurol Psychiat Neurosurg.  2014; 51(1): 123-129]


Key Words: Vitamin D, multiple sclerosis, vitamin D deficiency.

Correspondence to Sayed Sobhy Sayed, Department of Neurology, Fayoum University, Egypt.

Tel: +201222190502      Email:



Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) that starts in most patients with a relapsing-remitting disease course. The etiology of MS is multifactorial. Both genetic susceptibility and environmental exposure contribute to the pathogenesis.1 One of the environmental factors associated with the development of MS is vitamin D.2

Vitamin D is produced in the skin by ultraviolet radiation (UVR), is found in certain foods, and may be taken as a supplement.3 The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25-OH-D), is critical for bone metabolism, but also has important immunomodulatory properties4, effecting a reduction in proinflammatory immune pathways.5,6 The major circulating form, and that used to measure vitamin D, is 25-hydroxyvitamin D (25-OH-D).7

There is substantial epidemiological evidence, including prospective cohort studies, indicating that higher levels of serum 25 (OH) D are associated with a lower risk of MS onset.8 However, the effect of vitamin D on clinical course is less clear. Here we examine whether decreasing levels of serum 25 (OH) D are associated with a higher risk of relapse of MS.


Aim of The Work

               The present study aims to evaluate the association between levels of serum 25 (OH) D, and the risk of relapse of MS.



The present study included 22 patients, aged 18-32 years with clinically definite MS using 2005 McDonald criteria9, and relapsing remitting disease course, presented to neurology clinic at National Hospital and Al-Mousa Hospital KSA from January 2011 to September 2012. Patients were excluded from participation if they suffered from other serious diseases. Verbal informed consent was obtained from all patients.

Exacerbation was defined as a worsening of existing symptoms or the appearance of new symptoms lasting for more than 24 hours, after a period of more than 30 days of improvement or stability, confirmed by neurologic examination10, in the absence of fever, known infection, concurrent steroid withdrawal, or externally derived increases in body temperature.11

All patients visited the outpatient clinic of the Hospital regularly every 2 months for one year. On every visit, disability was measured using the Kurtzke Expanded Disability Status Scale (EDSS).12 Blood samples for 25 (OH) D measurements were taken, and MRI brain and/or cervical with contrast were done at the first visit and at the end of one year, as well as at the time of relapse if present. Furthermore, patients were instructed to contact the hospital when they experienced symptoms of neurologic impairment.

Serum 25(OH) D was extracted using acetonitrile and concentrations measured with a commercially available radioimmunoassay (DiaSorin Inc., Stillwater, MN; detection range: 12.5–250 nmol/L; interbatch reproducibility: 4.6% at 32 nmol/L, 6.4% at 125 nmol/L). All samples were stored at -20 °C, shielded from light. Serum 25 (OH) D levels were referred to the internationally accepted norms.13 The official international standard for serum 25-hydroxyvitamin D levels has been established, with norms fall between 75 and 200 nmol/l, insufficiency existing below 75 nmol/l and deficiency below 25 nmol/l.(14-21)

The MRIs were performed according to a standardized protocol comprising T2 weighted and T1 weighted gadolinium-enhancing (Gd+) scans using a standard head coil with a 1.5 Tesla MRI unit.  Radiologist evaluated scans to determine gadolinium-enhancing (GE) lesions, and total volume of T2 lesions (baseline and follow up).


Statistical Analysis

All data were entered into a database for later analysis using the Statistical Package for the Social Sciences (SPSS version 11.0 for Windows). Statistical significance was established at p < 0.05. For group comparisons, a non-paired two-tailed t -test was performed. For correlations, a bivariate Pearson correlation coefficients was performed.




The present study included 22 patients with RRMS followed for one year (Table 1). 10 (45%) patients were males, and 12 (55%) were females. Mean (±SD) age in year was 24.5 (±3.9). The mean (±SD) serum 25(OH) D at the time of inclusion to the study was 41.6 nmol/L (±17.3). The mean (±SD) baseline Expanded Disability Status Scale (EDSS) was 2.6 (±0.9). At the end of one year follow up, the mean (±SD) serum 25(OH) D was 43.4 nmol/L (±18.1), and that of EDSS was 2.7 (±0.8). Baseline and follow up serum 25 (OH) D were not significantly higher (P=0.655, and 0.862 respectively) in males (43.7±24.9, and 44.3±24.6) than females (39.9±7.5, and 42.8±11.5). Disability status scales at time of inclusion, and at the end of follow up period were higher in males (2.7±1.1, and 2.9±1.1) than females (2.5±0.6, and 2.5±0.6) but the differences were not significant (P=0.694, and P=0.429). A total of nine confirmed relapses occurred in nine participants (6 males, and 3 females) during one-year follow up.

In general patients with MS had vitamin D insufficiency (baseline serum 25 (OH) D 41.6±17.3, and follow up serum 25 (OH) D  43.4±18.1) according to the international standard for serum 25 (OH) D.14-21 Moreover patients with confirmed relapses (Figures 1 and 2) had significantly (P=0.001, and P<0.001) lower baseline serum 25(OH) D (28.9±5.4) and follow up serum 25(OH) D (28.4±7.6) compared to patients without relapses (50.5±17.2, and 53.8±15.9 respectively). Inverse correlations were observed between baseline serum 25 (OH) D (Figure 3) and baseline EDSS (P=0.000), and follow up EDSS (P=0.001) as well as between follow up serum 25 (OH) D (Figure 4) and baseline EDSS (P=0.000), and follow up EDSS (P=0.000).


Table 1. Characteristics of patients.


Variable (n = 22)

Mean  or %


Age, in year



Baseline EDSS



Follow up EDSS



Baseline serum vitamin D



Follow up serum vitamin D



Gender, female/male



Disease activity, relapse/no relapse



EDSS  Expanded Disability Status Scale


Table 2. Clinical and laboratory characteristics of patients with and without relapses.




No relapses






Age, in year






Baseline EDSS






Follow up EDSS






Baseline serum vitamin D






Follow up serum vitamin D






EDSS  Expanded Disability Status Scale, * Significant at P<0.05, ** Significant at P<0.01



Figure 1. Baseline serum 25 (OH) D level in patients with and without relapses.




Figure 2. Follow up serum 25 (OH) D level in patients with and without relapses.




Figure 3. Correlation between baseline serum 25 (OH) D level and Expanded Disability Status Scale.




Figure 4. Correlation between follow up serum 25 (OH) D level and Expanded Disability Status Scale





In this study, we found that patients with MS had lower serum levels of 25- hydroxyvitamin D than the official international standard for serum 25-hydroxyvitamin D levels. This was in accordance with the study of Soilu-Hannine and colleagues (2005) who found low serum levels of vitamin D in MS patients at the onset of the disease.22 Also,  Munger and colleagues (2006), reported a decreased  risk of MS with increasing serum levels of 25 (OH) D.38 At the same time, Kargt and colleagues (2009),  found  that,  higher levels of 25 (OH) D  inversely associated with MS in women.23 

Our results converge with a growing body of evidence supporting a protective role for vitamin D in MS development as we found that patients with MS had vitamin D insufficiency. Vitamin D is a potent immunomodulator24, and several studies have shown that administration of the biologically active hormone 1,25- dihydroxy vitamin D prevents experimental autoimmune encephalomyelitis (EAE) onset and progression in mice. 25,26. The exact mechanisms of this protection are unknown, but evidence suggests an indirect effect, possibly mediated by regulatory T cells.24,27 Of interest, regulatory T cells have been shown to be suppressed in individuals with MS.28 An inhibitory effect of levels of 25-hydroxyvitamin D in autoimmune reactions is consistent with the accelerated onset of EAE26, and experimental type 1 diabetes in vitamin D–deficient mice.29 This effect could be mediated by local synthesis of 1,25-dihydroxyvitamin D from 25-hydroxyvitamin D by activated macrophages expressing 1-α- hydroxylase. If sufficient 1,25- dihydroxyvitamin D is produced, it may exert paracrine effects on surrounding T lymphocytes, thereby regulating the tissue-specific immune responses.24

In the present study, we show that lower 25-OH-D levels were significantly associated with a higher relapse risk in patients with relapsing-remitting MS. This was in accordance with the study of Soilu-Hanninen and colleagues (2005) where the relative risk of remaining relapse-free within the previous 2 years before diagnosis increased by 51% for each 10 nmol/L increase of 25(OH) vitamin D level.(22) Similarly, in a large prospective longitudinal study in relapse-remitting MS an increase in serum 25(OH) vitamin D levels with 10 nmol/L was associated with a 9% to 12% risk reduction for relapses.30

Furthermore, results reproduced within a pediatric population study exhibit a 14% decrease in relapsing risk for each 10 nmol/L increase in vitamin D status.31 More recently Runia and colleagues (2012) reported a similar relation between lower 25-OH-D levels and the higher exacerbation risk in patients with relapsing-remitting MS32. There is biological plausibility for vitamin D as a protective factor against relapses. 1,25-OH-D shifts the immune response away from a proinflammatory profile and enhances anti-inflammatory pathways in multiple settings5,6,33; furthermore, a correlation between serum 25-OH-D concentrations and a more anti-inflammatory Th1/Th2 ratio has been found.34

In addition, we observed a negative correlation between 25(OH) D serum levels and EDSS. This was in agreement with the recent study of  Kragt and colleagues (2009), who found the same tendency.23 Also, the effect of vitamin D levels and disability status in MS was evaluated in cross-sectional studies reporting a negative correlation between vitamin D levels and the Expanded Disability Status Scale (EDSS), the most widely accepted disability scale in MS studies.35,36 This correlation may be mediated through a genetic regulation of vitamin D metabolism in patients with MS37,38, in particular in the HLA system39,40, and the influence of a vitamin D receptor gene polymorphism on disability.39,41



               The result of this study concludes that low vitamin D level is a risk for MS onset, more over low vitamin D level increased the incidence of relapses and associated with more severe disease.


[Disclosure: Authors report no conflict of interest]




1.      Compston A, Coles A. Multiple sclerosis. Lancet. 2008; 372(9648): 1502-17.

2.      Ascherio A, Munger KL, Simon KC. Vitamin D and multiple sclerosis. Lancet Neurol. 2010; 9(6): 599-612.

3.      Holick MF. Vitamin D deficiency. N Engl J Med. 2007; 357(3): 266-81.

4.      Tsoukas CD, Provvedini DM, Manolagas SC. 1,25-dihydroxyvitamin D3: a novel immunoregulatory hormone. Science. 1984; 224(4656): 1438-40.

5.      Lemire JM, Archer DC, Beck L, Spiegelberg HL. Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions. J Nutr. 1995; 125(6 Suppl): 1704S-8S.

6.      May E, Asadullah K, Zugel U. Immunoregulation through 1,25-dihydroxyvitamin D3 and its analogs. Curr Drug Targets Inflamm Allergy. 2004; 3(4): 377-93.

7.      Zerwekh JE. Blood biomarkers of vitamin D status. Am J Clin Nutr. 2008; 87(4): 1087S-91S.

8.      Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006; 296(23): 2832-8.

9.      Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005; 58(6): 840-6.

10.    Schumacker GA, Beebe G, Kibler RF, Kurland LT, Kurtzke JF, McDowell F, et al. Problems of Experimental Trials of Therapy in Multiple Sclerosis: Report by the Panel on the Evaluation of Experimental Trials of Therapy in Multiple Sclerosis. Ann N Y Acad Sci. 1965; 122: 552-68.

11.    McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001; 50(1): 121-7.

12.    Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983; 33(11): 1444-52.

13.    Pierrot-Deseilligny C. Clinical implications of a possible role of vitamin D in multiple sclerosis. J Neurol. 2009; 256(9): 1468-79.

14.    Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int. 2005; 16(7): 713-6.

15.    Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr. 2003;89(5):552-72.

16.    Grant WB, Holick MF. Benefits and requirements of vitamin D for optimal health: a review. Altern Med Rev. 2005; 10(2): 94-111.

17.    Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr. 2005; 135(2): 317-22.

18.    Vieth R. The role of vitamin D in the prevention of osteoporosis. Ann Med. 2005; 37(4): 278-85.

19.    Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006; 84(1): 18-28.

20.    Lips P. Vitamin D physiology. Prog Biophys Mol Biol. 2006;92(1):4-8.

21.    Roux C, Bischoff-Ferrari HA, Papapoulos SE, de Papp AE, West JA, Bouillon R. New insights into the role of vitamin D and calcium in osteoporosis management: an expert roundtable discussion. Curr Med Res Opin. 2008; 24(5): 1363-70.

22.    Soilu-Hanninen M, Airas L, Mononen I, Heikkila A, Viljanen M, Hanninen A. 25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosis. Mult Scler. 2005; 11(3): 266-71.

23.    Kragt J, van Amerongen B, Killestein J, Dijkstra C, Uitdehaag B, Polman C, et al. Higher levels of 25-hydroxyvitamin D are associated with a lower incidence of multiple sclerosis only in women. Mult Scler. 2009; 15(1): 9-15.

24.    Hayes CE, Nashold FE, Spach KM, Pedersen LB. The immunological functions of the vitamin D endocrine system. Cell Mol Biol (Noisy-le-grand). 2003; 49(2): 277-300.

25.    Lemire JM, Archer DC. 1,25-dihydroxyvitamin D3 prevents the in vivo induction of murine experimental autoimmune encephalomyelitis. J Clin Invest. 1991; 87(3): 1103-7.

26.    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 U S A. 1996; 93(15): 7861-4.

27.    Nashold FE, Hoag KA, Goverman J, Hayes CE. Rag-1-dependent cells are necessary for 1,25-dihydroxyvitamin D(3) prevention of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2001; 119(1): 16-29.

28.    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.

29.    Giulietti A, Gysemans C, Stoffels K, van Etten E, Decallonne B, Overbergh L, et al. Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice. Diabetologia. 2004; 47(3): 451-62.

30.    Simpson S, Jr., Taylor B, Blizzard L, Ponsonby AL, Pittas F, Tremlett H, et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol. 2010; 68(2): 193-203.

31.    Mowry EM, Krupp LB, Milazzo M, Chabas D, Strober JB, Belman AL, et al. Vitamin D status is associated with relapse rate in pediatric-onset multiple sclerosis. Ann Neurol. 2010; 67(5): 618-24.

32.    Runia TF, Hop WC, 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(3): 261-6.

33.    Lemire JM. Immunomodulatory actions of 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol. 1995;53(1-6):599-602.

34.    Smolders J, Thewissen M, Peelen E, Menheere P, Tervaert JW, Damoiseaux J, et al. Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis. PLoS One. 2009; 4(8): e6635.

35.    van der Mei IA, Ponsonby AL, Dwyer T, Blizzard L, Taylor BV, Kilpatrick T, et al. Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia. J Neurol. 2007; 254(5): 581-90.

36.    Smolders J, Menheere P, Kessels A, Damoiseaux J, Hupperts R. Association of vitamin D metabolite levels with relapse rate and disability in multiple sclerosis. Mult Scler. 2008; 14(9): 1220-4.

37.    Orton SM, Morris AP, Herrera BM, Ramagopalan SV, Lincoln MR, Chao MJ, et al. Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis. Am J Clin Nutr. 2008;88(2):441-7.

38.    Smolders J, Damoiseaux J, Menheere P, Tervaert JW, Hupperts R. Fok-I vitamin D receptor gene polymorphism (rs10735810) and vitamin D metabolism in multiple sclerosis. J Neuroimmunol. 2009; 207(1-2): 117-21.

39.    Mamutse G, Woolmore J, Pye E, Partridge J, Boggild M, Young C, et al. Vitamin D receptor gene polymorphism is associated with reduced disability in multiple sclerosis. Mult Scler. 2008; 14(9): 1280-3.

40.    Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton SM, Dyment DA, et al. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genet. 2009; 5(2): e1000369.

41.    Tajouri L, Ovcaric M, Curtain R, Johnson MP, Griffiths LR, Csurhes P, et al. Variation in the vitamin D receptor gene is associated with multiple sclerosis in an Australian population. J Neurogenet. 2005; 19(1): 25-38.

الملخص العربي


العلاقة بين فيتامين د ونشاط التصلب اللويحى


يعتبر التصلب اللويحى المتعدد الإنتكاسى الخمودى من الأمراض المزمنة التي تصيب الجهاز العصبي المركزي. من العوامل البيئية التي قد تصاحب الإصابة بالتصلب اللويحى هي نقص فيتامين د. تهدف هذه الدراسة إلى دراسة العلاقة بين مستوى فيتامين د ونشاط وحدة المرض. وقد اشتملت هذه الدراسة على اثنين وعشرين مريضا. تمت متابعة المرضى كل شهرين على مدار عام لتحديد مدى الإعاقة العصبية كما تم اخذ عينة دم لتحديد مستوى فيتامين د وكذلك عمل رنين مغناطيسي بالصبغة على المخ والحبل الشوكي عند أول زيارة ثم بعد عام وعند وجود انتكاسة. وقد لوحظ أن مرضى التصلب اللويحى لديهم نقص في مستوى فيتامين د. كما أن مستوى فيتامين د اقل لدى المرضى الذين تعرضوا لانتكاسات مقارنة بالمرضى الذين لم يتعرضوا لانتكاسات، وان مستوى فيتامين د يتناسب عكسيا مع شدة الإعاقة الناتجة عن المرض. وهذه النتائج ترجح وجود علاقة بين فيتامين د والجهاز المناعي للجسم وبالتالي خطر الإصابة بالتصلب اللويحى ونشاط وحدة المرض.



2008 � Copyright The Egyptian Journal of Neurology,
Psychiatry and Neurosurgery. All rights reserved.

Powered By DOT IT