To the Editor We read with interest the article by Marshall et al.1 The authors assessed the cerebrovascular reactivity (CVR) in patients affected by multiple sclerosis (MS) and in healthy control individuals. They found a reduced ability to dilate of the brain arterioles in patients with MS in respect to control participants. Even a powerful hypercapnic vasodilator stimulus was unable to induce arteriolar dilation, ultimately affecting brain perfusion. Despite high levels of nitric oxide found in MS, hypoperfusion is a constant and overlooked problem in MS.2 Marshall et al1 further elucidated a mechanism contributing to reduced perfusion. The authors also showed how CVR is associated with both lesion volume and brain atrophy index, suggesting a role of perfusion in the complex pathogenesis of MS. Such a finding opens new intriguing questions about the reason for reduced CVR in patients affected by MS.