The evidence that hypoxia is a precipitating factor in causing early MS lesions includes increased protein levels of hypoxia-inducible factor-1α; presence of the D-110 hypoxia-inducible protein; increased expression of hypoxia-inducible genes in lesions as well as in adjacent normal-appearing white matter (NAWM); loss of myelin-associated glycoprotein in myelin of early MS lesions; a 50% reduction of blood flow through NAWM with areas of lowest blood flow having the greatest probability of lesion development. Why MS-like lesions develop following hypoxemic insults in some individuals but not in others is likely dependent upon the presence of immune predisposing factors that are governed genetically. Hypoperfusion may be due to decreased arterial supply, restricted venous return, or a combination of these. There are clinical trials ongoing or planned to treat chronic cerebrospinal venous insufficiency (CCSVI) through angioplasty. I suggest that it is important that clinical trials addressing vascular issues in MS should examine how the vascular intervention affects white matter perfusion and determine whether the extent of perfusion recovery and maintenance of this recovery is related to functional recovery and maintenance of functional recovery. Consideration should also be given to the possibility of arterial problems playing a role in hypoperfusion in some MS patients. 1. Introduction Multiple sclerosis (MS) is a complex disease with both environmental and genetic factors playing a role in the disease [1]. Most of the current therapeutic approaches in treating MS are based upon the thinking that the primary disorder is in immune regulation [2]. This, however, does not take into account that the first identifiable feature of MS is a breakdown in the blood-brain barrier (BBB) and that this can also occur in the retina [3], a site that does not contain myelin. Considerable evidence has accumulated over the past few decades suggesting that the immune attack on myelin may be secondary to damage of oligodendrocytes and associated myelin [4, 5]. The question is what causes this oligodendrocyte damage? This paper reviews the evidences that suggest that hypoperfusion might be a causal factor in oligodendrocyte and myelin damage that results in a frank immune attack on these structures in individuals with specific genetic backgrounds. This might explain a possible linkage between chronic cerebrospinal venous insufficiency (CCSVI) and MS [6]. There is considerable controversy whether CCSVI is a predisposing factor for MS; nevertheless, due to patient demand,
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