Vitamin B reduces white matter hyperintensities progression in patients with severe cerebral small vessel disease

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Margherita Cavalieri, Department of Neurology, Medical University of Graz, Austria, and others reported in a study, published ahead of print in Stroke, that daily vitamin B supplementation in patients with severe cerebral small vessel disease (CSVD) significantly reduced white matter hyperintensities (WMH) progression.

Cavalieri et al wrote that elevated blood concentrations of total homocysteine have been associated with CSVD, which is shown as ischaemic lesions in the vascular territories of the deep perforating small arteries on MRI. As vitamin B supplementation can lower homocysteine, the aim of Cavalieri et al’s substudy of the VITATOPS (Vitamins to prevent stroke) trial was to assess whether vitamin B would reduce the progression of CSVD on MRI (potentially through the reduction of homocysteine). Patients were eligible for inclusion in the substudy, as with the main VITATOPS study, if they had had a stroke or a transient ischaemic attack within the past seven months. The primary endpoint was WMH progression and incident lacunes (consistent lesions not present at the baseline scan).

Of the 359 patients in the study, after randomisation, 174 received vitamin B supplementation (2mg folic acid, 25mg vitamin B6, and 0.5mg vitamin B12) and 185 received placebo. There were no significant differences in baseline MRI characteristics between the two groups. After two years, there were no significant differences in WMH progression or incident lacunes between the two groups: WMH mean change of 0.08 for the active treatment groups vs. WMH change of 0.13 for the placebo group (p=0.419); incident lacunes 14% for active treatment group vs. 11% for the placebo group (p=0.434). However a post-hoc analysis showed that in patients with severe CSVD at baseline (according to MRI evidence), vitamin B supplementation was associated with a significant reduction in WMH volume change compared with placebo—0.3 for the B vitamin group vs. 1.7 for the placebo group (0.039). There were no other significant differences between the groups.

Cavalieri et al reported: “Given the neutral outcome of the whole VITATOPS MRI substudy but also that of the whole VITATOPS trial [which did not find vitamin B supplementation to be significantly more effective than placebo at reducing the incidence of major vascular events], the results of our post-hoc analysis in patients with severe CSVD have to be interpreted with caution.”

They added that they could not determine whether homocysteine lowering in the active treatment group was responsible for slowing of the WHM progression as longitudinal measurements were not available but said: “It is known that vitamin supplementation in the entire VITATOPS cohort decreased the homocysteine concentration by approximately 4μmol/L in the treated group compared with the placebo.” According to the authors, homocysteine may slow WMH progression through several mechanisms, including reducing hyperhomocysteinemia-related endothelial dysfunction.

They concluded: “Our finding may have important clinical implications because white matter abnormalities have been reported to predict disability and mortality in elderly people. Larger trials in patients with MRI evidence for severe CSVD are required to confirm our results. If indeed vitamins slow progression of WMH, the effect will be seen most easily in patients with the most severe WMH where the control group’s WMH are progressing most rapidly.”

Co-author Reinhold Schmidt said: “Slowing progression of white matter damage in the elderly is an important healthcare issue given the unfavorable effects of small vessel disease related white matter changes on cognition, mood, gait and mortality. Currently there exists no approved therapy for these brain abnormalities. A small number of pilot studies showed that blood pressure lowering can delay the progression of lesions. Our results now indicate that vitamin B supplementation can exert similar positive effects. For any of these potential therapies larger trials using MRI to monitor white matter lesion progression and clinical endpoints are needed. Our results could help design such future studies in terms of number of patients, duration of follow-up, and patient stratification.”

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