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Previous studies reported that patients with multiple sclerosis may have low serum vitamin B12. The aim of this study was to evaluate if multiple sclerosis is associated with vitamin B12 deficiency.
Methods: This study was conducted from 2008 to 2009 in Isfahan, central Iran. Consecutive patients with multiple sclerosis were invited from three neurology clinics to participate. Controls were recruited from healthy blood donors. None of the participants had received B12 or folate supplementation within the preceding year. Clinical disability was evaluated according to the Extended Disability Status Scale (EDSS) and serum B12 concentration was measured with Radioimmunoassay Dual Isotope method.
Results: There were 13 (21.6%) multiple sclerosis patients and 10 (26.3%) controls with low serum B12 concentration with no significant difference between the groups; p = 0.385. The mean serum vitamin B12 concentration in multiple sclerosis patients (108.99 ± 45.29 pg/mL) was not significantly different compared with controls (98.94 ± 44.37 pg/mL); p = 0.282. There was no correlation between concentration of serum vitamin B12 and disease age of onset (r = -0.013, p = 0.926), EDSS scores (r = -0.225, p = 0.084), or duration (r = 0.212, p = 0.132) or type of the disease (p = 0.551).
Conclusion: In contrast to some previous reports, our findings did not support association between vitamin B12 deficiency and multiple sclerosis.
Keywords: Cobalamin, homocysteine, methylmalonic acid, multiple sclerosis, vitamin B12
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) with progressive process leading to chronic disability in many cases. Disease onset usually occurs in young adults, more common in females, and has a prevalence ranges between 2 and 150 per 100,000 1. The prevalence of MS in Iran is about 20 to 30 per 100,000 2. The etiology of MS is complex and multi-factorial involving both genetic and environmental factors but, the main etiology is still unknown 1.
Vitamin B12, also known as Cobalamin, plays important structural and functional roles in the nervous system and its deficiency leads to demyelination followed by axonal degeneration and eventually irreversible damage due to axonal death. Accordingly, B12 deficiency can result in some clinical and paraclinical characteristics similar to what is seen in MS patients 3. The association between B12 deficiency and MS has been investigated by several studies with different results. Some studies have demonstrated significantly reduced serum B12 as well as macrocytosis in MS patients while others did not show such an association 3.
The nature of the relation between MS and B12 deficiency is unclear and multiple levels of inter-relationship can be suggested. The association could be the result of overlapping autoimmune disorders or it may reflect an increased demand for B12 for myelin repair 3. Anyway, if a subgroup of MS patients should prove to have decreased concentrations of B12, irrespective of the cause, treatment is easy and important to prevent permanent disability as there are reports of MS patients improving with B12 therapy 4.
The only dietary source of Cobalamin is animal products (e.g. meat, dairy products) and inadequate intake is one of the main causes of B12 deficiency 4. According to the considerable prevalence of MS and nutritional deficiency in our society 2,5 we decided to determine the association between MS and B12 deficiency in our population. Our objectives were to analyze serum B12 of patients with MS and to evaluate if there is any correlation with clinical disability or disease age of onset.
METHODS AND MATERIALS
This case-control study was conducted from 2007 to 2008 in city of Isfahan, central Iran. According to reports, Isfahan could be considered as an area with a medium to high risk of MS 2. Consecutive MS patients were invited from three neurology clinics to participate. All patients fulfilled the clinical definite criteria for MS 6. None of the patients had history of atrophic gastritis or gastrectomy and none of them had anaemia or malnutrition. Controls were recruited from healthy persons went to the blood transfusion organization of Isfahan for blood donation. None of the patients or controls had received B12 or folate supplementation within the preceding year. The ethics committee of Isfahan University of Medical Sciences approved the study and consent was obtained from participants.
Clinical disability was evaluated according to the Extended Disability Status Scale (EDSS). Serum B12 concentration was measured with Radioimmunoassay Dual Isotope method [DiaSorin S.p.A., Italy]. The cutoff value for low serum vitamin B12 concentrations was 75 pg/mL.
Data were analyzed using SPSS version 16.0. Comparisons between the two groups were done using Independent t-Test and Chi-Square Test. Spearman and Pearson Correlation Coefficients were used to test the relationship of B12 concentration with disease age of onset, clinical status, and MS type. A p value of less than 0.05 was considered significant
During the study period, 60 MS patients (54 women and 6 men, age 18-57 years, mean 33.00 ± 9.77 years) and 38 controls were evaluated. There was no significant difference between the MS and control groups in age (p = 0.623) or gender (p = 0.531). Age of onset of the disease was 15 to 39 years, mean 23.42 ± 4.82 years. Duration of disease, from first symptom to the present sampling occasion, was 0 to 33 years, mean 9.40 ± 7.89 years. Fifteen (15%) patients had remitting-relapsing MS (RR-MS), 37 (61.6%) had secondary progressive MS (SP-MS), and eight (13.3%) had primary progressive MS (PP-MS). EDSS scores were 0 to 6 with a mean of 1.7 ± 1.39. Control subjects were 33 women and five men with the mean age of 31.97 ± 10.2 years (18-51 years).
According to the cut-off value of the diagnostic kit (75 pm/mL), there were 13 (21.6%) MS patients and 10 (26.3%) controls with low serum B12 concentration with no significant difference between the groups; p = 0.385. There was also not significant difference in the mean plasma B12 concentration between MS patients and controls (p = 0.282). No correlation was found between concentration of serum vitamin B12 and disease age of onset (r = -0.013, p = 0.926), EDSS scores (r = -0.225, p = 0.084), or duration (r = 0.212, p = 0.132) or type of the disease (p = 0.551).
The debate concerning the possible role of vitamin B12 in MS is long lasting and several studies with different results have been done since 1950s and early 1960s 3. Although demyelination is a prominent feature of both MS and B12 deficiency, these two entities are usually distinguishable based on clinical and pathological characteristics. Neurological presentations of B12 deficiency usually occur in middle or late life and a few patients can present before the age 40 years 7. The majority of patients with MS do not have detectable B12 deficiency. However, there is evidence of an overlap of the two disorders and a subgroup of patients with this association. But, our results did not show any association between serum B12 concentration and MS, disease age of onset, or clinical disability which is similar to some 8,9 but in contrast to other reports 10-13. Njist et al. reported that B12 concentrations in CSF and serum of MS patients were lower than in control subjects. There was also a significant correlation between serum and CSF vitamin concentrations 13. Recently, Kocer et al. also found a significant relationship between MS and B12 deficiency 12. Another study reported that serum B12 concentration in MS patients is related to the age of onset of the disease 14. According to that report, B12 concentration was significantly lower in those who experienced the onset of first neurological symptoms prior to age 18 years compared to patients in whom the disease first manifested after age 18. However, our results did not support these findings.
The prevalence of low serum B12 concentration in our MS patients and controls was about the same as the results of a population study on 1214 people aged 25 to 64 years in Tehran, Iran 5. Normal serum B12 concentrations in our MS patients, however, can not rule out B12 deficiency. There is evidence that patients with MS may be functionally deficient in vitamin B12, as indicated by elevated levels of homocysteine 10. Homocysteine is a potentially neurotoxic metabolite that its concentration rises in the absence of adequate amounts of B12, folic acid, and pyridoxine. In the study by Besler and Comoglu on 24 MS patients and controls, plasma total homocysteine concentrations were significantly higher in MS patients whose plasma B12 and folate concentrations were lower but not statistically significant, than controls 15. In another study by Ramsaransing et al., plasma homocysteine concentration was higher in MS patients, but serum concentrations of vitamin B6, vitamin B12, and folate were not different between patients with MS and controls 16. If the serum B12 concentration is borderline, total plasma homocysteine (tHcy) or methylmalonic acid (MMA) concentrations may be useful guides to functional B12 deficiency 7. Indeed, increased serum MMA and plasma tHcy concentrations indicate an intracellular B12 deficiency and are regarded as more sensitive variables than serum B12 for the diagnosis of B12 deficiency 9. However, studies did not show relation between elevated plasma homocysteine and B12 in MS patients and further studies are needed in this field 16,17.
In conclusion, despite an association between B12 deficiency and MS had been reported in some previous studies, as the same as some other reports we found no relationship between B12 deficiency and MS. Accordingly, we do not recommend routine assessment of vitamin B12 in patients with known MS. If having other neurological disorders is suspected, more sensitive measures such as total plasma homocysteine or methylmalonic acid concentrations may be more useful.