A recent hypothesis1 implicated chronic cerebrospinal venous insufficiency (CCSVI) in the etiology of multiple sclerosis (MS). The postulated mechanism states that iron accumulation in the brains of patients with MS was caused by blockade of the cerebral veins, resulting in reduced blood flow, extravasation of erythrocytes, and iron deposition leading to oxidative tissue damage. This hypothesis left patients in a quandary: Should they pursue diagnosis and amelioration of vein blockade for treatment of MS, and must they avoid iron in order to improve their quality of life?

In this issue of Neurology®, Worthington et al. 2 challenge this proposal, reasoning that if parenchymal brain iron deposition were present in MS, it should be reflected by increased CSF ferritin (the iron storage protein). Their study showed that while CSF ferritin levels were pathologically raised in patients with superficial siderosis and subarachnoid hemorrhage, a significantly lower number of patients with MS were affected by high ferritin levels. Furthermore, CSF ferritin did not increase in patients with MS over a 3-year follow-up period (arguing against a gradual buildup of iron) and, unexpectedly, in patients with secondary progressive MS, the relative increase of CSF ferritin from baseline to follow-up was related to improvement of lower limb function and reduction of the T1 lesion volume. There is no evidence in the literature to support systemic iron overload in MS; most studies report normal iron levels. Iron overload (ferritin levels higher than 200 μg/L for women and 300 μg/L for men, or transferrin saturation over 45%) does not occur at a higher frequency in patients with MS in comparison to the general population. Furthermore, evidence of accumulation of iron in liver, heart, or spleen is lacking in MS. 3, 4 Studies have yet to be published that assess measures of iron status or iron in the tissues by evaluating soluble transferrin receptor concentrations together with ferritin or log ferritin values (the sTfR-F index).