|Year : 2016 | Volume
| Issue : 3 | Page : 174-178
Effects of vitamin D deficiency on the relapse, severity, and disability of multiple sclerosis
Ahmed Esmael1, Mohammed El-Sherif1, Ayman A Elazzouny2
1 Department of Neurology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
2 Department of Neurology, Misr University for Sciences and Technology, Giza, Egypt
|Date of Submission||02-Mar-2015|
|Date of Acceptance||13-Jun-2015|
|Date of Web Publication||27-Oct-2016|
Department of Neurology, Faculty of Medicine, Mansoura University, Mansoura 35516, Dakahlia
Source of Support: None, Conflict of Interest: None
Background Multiple sclerosis (MS) is a long-standing inflammatory disease of the white matter and affects more than two million people worldwide. Upcoming evidence proposed that 25-hydroxy-vitamin D3 (25HVD3) deficiency could be one of the most crucial environmental elements for the pathogenesis of MS.
Objective The aim of this study was to compare 25HVD3 levels in MS patients and controls and to detect the association with relapse, severity, and disability in MS patients.
Patients and methods Mansoura Neurology Department data sheet was collected and all patients were assessed using the Expanded Disability Status Scale (EDSS) at the onset. 25HVD3 levels in the blood were evaluated for all patients and controls using the chemiluminescent immunoassay test.
Results A total of 50 MS patients were included in this work and matched with 25 controls. There was a statistically significantly lower mean serum 25HVD3 level in MS patients in comparison with the controls (20.5 ± 16.8 and 42.9 ± 17.9 ng/ml, respectively; P = 0.002). In addition, there was a statistically significantly lower level of 25HVD3 (18.4 ± 17.7) in severe cases of MS (EDSS ≥ 6; P < 0.05) with certain significant clinical features such as older age (P < 0.001) and longer disease duration (P < 0.001). The incidence of 25HVD3 deficiency (<20 ng/ml) in MS patients was 60%.
Conclusion Our results showed that there is an inverse correlation between 25HVD3 level and EDSS score. In addition, lower 25HVD3 levels are associated with increased relapse risk in MS.
Keywords: Expanded Disability Status Scale, 25-hydroxy-vitamin D3, multiple sclerosis
|How to cite this article:|
Esmael A, El-Sherif M, Elazzouny AA. Effects of vitamin D deficiency on the relapse, severity, and disability of multiple sclerosis. Egypt J Neurol Psychiatry Neurosurg 2016;53:174-8
|How to cite this URL:|
Esmael A, El-Sherif M, Elazzouny AA. Effects of vitamin D deficiency on the relapse, severity, and disability of multiple sclerosis. Egypt J Neurol Psychiatry Neurosurg [serial online] 2016 [cited 2017 Aug 16];53:174-8. Available from: http://www.ejnpn.eg.net/text.asp?2016/53/3/174/193086
| Introduction|| |
Multiple sclerosis (MS) is a long-standing, demyelinating with immune-mediated basis, and disabling central nervous system disease affecting predisposed patients with assertive genetic susceptibility alongside specific environmental circumstances exposure. The highest incidence is in those between 20 and 30 years of age. The female population has two times greater risk for MS compared with the male population .
Fundamentally, there is a negative association between the decrease in the sunlight exposure [mainly, decreased ultraviolet radiation exposure and subsequently decreased 25-hydroxy-vitamin D3 (25HVD3) level] and occurrence of MS. Thus, MS prevalence differs with geographic coordinate system (latitude) and it is high in districts after the 40th parallels (both south and north) ,,.
There are many observations – for example, during fetal life, 25HVD3 assists in the formation of the immunological tolerance, leading to the removal of self-reactive lymphocytes . Moreover, 25HVD3 receptors were discovered in the rat brain and spinal cord regions . Moreover, the intake of 25HVD3 by the mother during pregnancy is associated with a subsequent lower risk for MS of the child .
As regards the Middle East, there is little evidence in the literature about the relationship between MS disease and serum 25HVD3 levels. Hashem et al.  observed that the prevalence of MS in Egypt was in the range 1.41–14.1% per 1000 other neurological diseases. Moreover, El-Ghoneimy et al.  stated that the prevalence of 25HVD3 deficiency among MS patients was 86.7%.
| Aim|| |
The aim of this study was to compare 25HVD3 levels in MS patients and healthy controls, and to detect the association with relapse, severity, and disability in MS patients.
| Patients and methods|| |
Fifty patients with MS were included in this study and admitted in the Neurology Department of Mansoura University Hospital (Mansoura, Egypt). Inclusion criteria were as follows: definite MS according to Poser et al.  criteria, or brain MRI-supported definite MS according to Paty and Li  criteria. Patients were diagnosed as having relapsing remitting multiple sclerosis (RRMS), primary progressive multiple sclerosis (PPMS), or secondary progressive multiple sclerosis (SPMS) according to the classification of Lublin and Reingold  and with normal routine laboratory investigations (complete blood count, blood glucose level, and renal and liver functions). Patients with any associated medical or neurological diseases were excluded from this study. As regards the control group, 25 healthy individuals were selected as the control group and were matched for age and sex. The control group was free of neurological or chronic disease, and did not have any family member with MS. They underwent MRI of the brain to exclude white matter lesions. The study protocol was approved by the Local Ethical Committee at the hospital. All enrolled patients had signed written fully informed consent to participate in the study.
Patients were evaluated clinically, especially for age of onset, duration of illness, precipitating factors, whether active, course of MS (either relapsing or progressive), first signs and symptoms, family history of MS, other diseases, current use of corticosteroids, and rehabilitation treatments. The Expanded Disability Status Scale (EDSS) is a functional scale to determine the degree of disability and monitor disease progression. The EDSS includes eight functional systems, visual, sensory, cerebellar, brainstem, pyramidal, bowel and bladder, mental, and other functions. The scores range from 0 (neurologically free) to 10 (death). Patients were classified according to the severity of MS as follows: mild (0–3 EDSS), moderate (3.5–5.5 EDSS), and severe (≥6 EDSS) . Blood samples were obtained from patients and controls after overnight fasting. Blood samples were examined using the chemiluminescent immunoassay test (DiaSorin Liaison Kit; DiaSorin S.P.A, Saluggia, Italy) for 25HVD3 levels, all in the same laboratory. The 25HVD3 levels were categorized into low (<20 ng/ml = 50 nmol/l), medium (20–40 ng/ml), and high (>40 ng/ml) levels .
SPSS, version 15, 2006 for Windows statistical package (SPSS Inc., Chicago, Illinois, USA) was used for statistical analysis. Collected data were presented as mean ± SD, ranges, numbers, and ratios. Pearson’s χ2-test was used for comparisons. The result was considered statistically significant if P value was less than 0.05. The Mann–Whitney U-test was used to compare 25HVD3 levels of MS cases and healthy controls. Pearson’s correlation analysis was performed to evaluate the correlation of 25HVD3 level with severity of MS. The relationships between serum 25HVD3 concentrations for the incidence of relapse and severity of MS were assessed using Poisson regression models with the geometric mean individual serum levels.
| Results|| |
A total of 50 MS patients were included in this work and matched with 25 healthy individuals as controls. The mean age was 35.1 ± 9.1 (range: 19–55) years for patients and 34.8 ± 8.9 (range: 18–56) years for controls (P = 0.920). The most common age group of MS patients was from 20 to 40 (74% of patients) years. RRMS was the most common type, constituting 72% of patients, followed by SPMS (22%) and PPMS (6%). Most of the controls and MS patients were female (female to male ratio: 2.5: 1). The mean EDSS score of MS patients was 2.5 ± 4.5 and the mean duration of disease was 6.3 ± 0.2 years. The mean relapse number in the previous 2 years was 2.4 ± 1.6. The mean serum 25HVD3 levels was 20.5 ± 16.8 ng/ml in patients with MS versus 42.9 ± 17.9 ng/ml in controls with high statistical significance (P = 0.002) [Table 1] and [Table 2].
|Table 1: Baseline demographic data and vitamin D level of the patient group and the control group|
Click here to view
Comparison of subgroups of MS patient’s severity showed a statistically significantly lower serum level of 25HVD3 (18.4 ± 17.7) in severe cases of MS (EDSS≥6) (P < 0.05). Moreover, there was a significant association of older age (P < 0.001) and longer disease duration (P < 0.001) with severe cases of MS. Moreover, female sex (32; 78%) was significantly associated with mild-to-moderate severity of MS (EDSS between 0 and 5.5; P = 0.042) [Table 3].
|Table 3: Relation of 25-hydroxy-vitamin D3 level, Expanded Disability Status Scale, disease duration, age, and sex with the severity of multiple sclerosis|
Click here to view
As regards the association between serum 25HVD3 concentrations and severity of MS, the severity of MS was significantly increased in the group with low serum 25HVD3 concentrations (<20 ng/ml) compared with the group with high serum concentration medium (>40 ng/ml). Rate ratios for the low and the medium group were 2.0 and 1.5, respectively (P value for the lower level group was 0.007). The incidence of 25HVD3 deficiency (<20 ng/ml) in MS patients was 60% [Table 4].
|Table 4: Association between serum level of 25-hydroxy-vitamin D3 and severity of multiple sclerosis|
Click here to view
There was a strong significant inverse linear relationship between the relapse incidence in the previous 2 years and the 25HVD3 level (P < 0.005), indicating that vitamin D level influences the relapse of MS [Table 5].
|Table 5: Association between serum level of 25-hydroxy-vitamin D3 and relapse in the previous 2 years|
Click here to view
As shown in [Figure 1], an inverse correlation was observed between 25HVD3 level and EDSS score (P < 0.001). [Figure 2] shows the comparison of the level of 25HVD3 in MS patients with different severities of disease showing a significant increase in the severity of MS with lower levels of 25HVD3 (P < 0.05).
|Figure 1: Relationship of the level of 25-hydroxy-vitamin D3 with Expanded Disability Status Scale (EDSS) score.|
Click here to view
|Figure 2: 2 25-Hydroxy-vitamin D3 level in multiple sclerosis (MS) patients with different severities of disease.|
Click here to view
| Discussion|| |
Previous studies found that serum 25HVD3 levels of less than 20 ng/ml (50 nmol/l) indicate vitamin D deficiency. However, the levels below 30 ng/ml indicate insufficiency, and levels between 30 and 60 ng/ml (75 and 150 nmol/l) represent normal values . This is in agreement with the present study results, as the normal value in the control group was 42.9 ± 17.9 ng/ml, whereas the MS group showed decreased levels (20.5 ± 16.8 ng/ml).
As regards the relation between MS and 25HVD3, there were many observations. Munger et al.  stated that the high circulating levels of 25HVD3 were associated with a lower risk for MS (every 50 nmol/l increase in serum 25HVD3 led to a 41% decrease in MS risk). Moreover, Mirzaei et al.  reported that MS risk was lower among women born to mothers with high milk or vitamin D intake during pregnancy. Furthermore, Mowry et al.  found that each 10 ng/ml increase in 25HVD3 level was associated with a 15% lower risk for a new T2 lesion and a 32% lower risk for a gadolinium-enhancing lesion. Each 10 ng/ml increase in vitamin D level was associated with lower subsequent disability, suggesting that higher vitamin D levels were associated with lower relapse risk .
Although the link between vitamin D supplementation and decreased risk for MS has been widely assumed, present vitamin D repletion therapies have not yet shown a significant effect on the progress of MS. Kampman et al.  found that supplementation with 20 000 IU vitamin D weekly did not result in beneficial effects on MS-related outcomes.
The course of MS disease in Egyptian studies was found to be 65, 12, and 9% in RRMS, SPMS, and PPMS, respectively . However, in the present study it was 72, 22, and 6%, respectively.
El-Ghoneimy et al.  stated that the prevalence of 25HVD3 deficiency (<20 ng/ml) among MS patients was 86.7%. However, in the study by Ozgocmen et al. , Weinstock-Guttman et al. , and Nieves et al. , the prevalence was 61, 37.5, and 23%, respectively. In the present study, it was 60%. The difference in the prevalence rates may be due to many limitations of previous studies or different sample sizes and these factors need more Egyptian research studies to clarify it.
In the present study, lower 25HVD3 levels are significantly associated with a higher exacerbation risk in MS patient of about two times higher than that in the category of high levels, and this result is similar to the finding of Runia et al. . Simpson et al.  concluded that exacerbation risk was significantly decreased with higher vitamin D levels.
Our results reported a negative correlation between serum 25HVD3 levels and EDSS and severity of MS. In the study by van der Mei et al.  on 136 MS patients and 272 community controls in Tasmania, Australia, cases of lower vitamin D level had higher disability (EDSS > 3). The similar significant inverse correlation was reported by Smolders et al.  in their study on 267 patients. This is not in accordance with the findings of Gelfand et al. , who stated that there was no apparent association between 25HVD3 and MS disease severity, and they predisposed this to the sample size limitations, smaller effect sizes in darker pigmented populations, or the use of the MS severity scale, and not using the relapse rate, as a marker of disease severity ,.
Bäärnhielm et al.  reported that MS patients who had 25HVD3 levels less than 20 ng/ml (50 nmol/l) had an increased risk for MS. This is in agreement with the present study as severe MS cases (EDSS ≥ 6) showed lower 25HVD3 levels (<20 ng/ml) with marked relapse severity.
| Conclusion|| |
Our results showed that there is an inverse correlation between the 25HVD3 level and EDSS score; thus, the severity of MS increases with lower levels of 25HVD3. Lower vitamin D levels are associated with increased relapse risk in MS.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Miller JRRowland LPMultiple sclerosisMerrits’ neurology20003rd edPhiladelphia, PALippincott-Williams and Wilkins773791
Cantorna MTVitamin D and multiple sclerosis: an updateNutr Rev200866Suppl 2S135S138
Hayes CEVitamin D: a natural inhibitor of multiple sclerosisProc Nutr Soc200059531535
Soilu-Hänninen M, Airas L, Mononen I, Heikkilä A, Viljanen M, Hänninen A25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosisMult Scler200511266271
Mackay IRScience, medicine, and the future: tolerance and autoimmunityBMJ20003219396
Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM et al.
Extrarenal expression of 25-hydroxyvitamin D (3)-1 alpha-hydroxylaseJ Clin Endocrinol Metab200186888894
Mirzaei F, Michels KB, Munger K, O’Reilly E, Chitnis T, Forman MR et al.
Gestational vitamin D and the risk of multiple sclerosis in offspringAnn Neurol2011703040
Hashem S, El-Tamawy M, Hamdy S, Elmasry TEpidemiology of multiple sclerosis in EgyptEgypt J Neurol Psychiat Neurosurg201047625632
El-Ghoneimy AT, Gad AH, Samir H, Shalaby NM, Ramzy GH, Farghaly M, Hegazy MIContribution of vitamin D to the pathogenesis of multiple sclerosis and its effect on boneEgypt J Neurol Psychiat Neurosurg200946209222
Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC et al.
New diagnostic criteria for multiple sclerosis: guidelines for research protocolsAnn Neurol198313277231
Paty DW, Li DBKSiva A, Kesselring J, Thompson JADiagnosis of MS: do we need new diagnostic criteria?Frontiers in multiple sclerosis19992London, UKMartin Dunitz4750
Lublin FD, Reingold SCDefine the clinical course of multiple sclerosis: results of an international surveyNeurology199646907911
Kurtzke JFRating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS)Neurology19833314441452
Runia TF, Hop WC, de Rijke YB, Buljevac D, Hintzen RQLower serum vitamin D levels are associated with a higher relapse risk in multiple sclerosisNeurology201279261
Rosen CJClinical practice. Vitamin D insufficiencyN Engl J Med2011364248254
Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio ASerum 25-hydroxy vitamin D levels and risk of multiple sclerosisJAMA200629628322838
Mowry EM, Waubant E, McCulloch CE, Okuda DT, Evangelista AA, Lincoln RR et al.
Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosisAnn Neurol201272234240
Kampman MT, Steffensen LH, Mellgren SI, Jørgensen LEffect 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 trialMult Scler20121811441151
Hamdy SEpidemiology of multiple sclerosis in Egypt. 5th
Magrebian Congress of Neurology and 15th
National Congress of Neurology; Yasmin Hammamet, Tunisia200913
Ozgocmen S, Bulut S, Ilhan N, Gulkesen A, Ardicoglu O, Ozkan YVitamin D deficiency and reduced bone mineral density in multiple sclerosis: effect of ambulatory status and functional capacityJ Bone Miner Metab200523309313
Weinstock-Guttman B, Gallagher E, Baier M, Green L, Feichter J, Patrick K et al.
Risk of bone loss in men with multiple sclerosisMult Scler200410170175
Nieves J, Cosman F, Herbert J, Shen V, Lindsay RHigh prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosisNeurology19944416871692
Simpson SJr, Taylor B, Blizzard L, Ponsonby AL, Pittas F, Tremlett H et al.
Higher 25-hydroxy vitamin D is associated with lower relapse risk in multiple sclerosisAnn Neurol201068193203
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, AustraliaJ Neurol2007254581590
Smolders J, Menheere P, Kessels A, Damoiseaux J, Hupperts RAssociation of vitamin D metabolite levels with relapse rate and disability in multiple sclerosisMult Scler20081412201224
Gelfand JM, Cree BA, McElroy J, Oksenberg J, Green R, Mowry EM et al.
Vitamin D in African Americans with multiple sclerosisNeurology20117618241830
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 sclerosisAnn Neurol201067618624
Bäärnhielm M, Hedström AK, Kockum I, Sundqvist E, Gustafsson SA, Hillert J et al.
Sunlight is associated with decreased multiple sclerosis risk: no interaction with human leukocyte antigen-DRB1 *15Eur J Neurol201219955962
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]