Anomalous Venous Blood Flow and Iron Deposition in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is primarily an autoimmune disorder of unknown origin. This review focuses iron overload and oxidative stress as surrounding cause that leads to immunomodulation in chronic MS. Iron overload has been demonstrated in MS lesions, as a feature common with other neurodegenerative disorders. However, the recent description of chronic cerebrospinal venous insufficiency (CCSVI) associated to MS, with significant anomalies in cerebral venous outflow hemodynamics, permit to propose a parallel with chronic venous disorders (CVDs) in the mechanism of iron deposition. Abnormal cerebral venous reflux is peculiar to MS, and was not found in a miscellaneous of patients affected by other neurodegenerative disorders characterized by iron stores, such as Parkinson's, Alzheimer's, amyotrophic lateral sclerosis. Several recently published studies support the hypothesis that MS progresses along the venous vasculature. The peculiarity of CCSVI-related cerebral venous blood flow disturbances, together with the histology of the perivenous spaces and recent findings from advanced magnetic resonance imaging techniques, support the hypothesis that iron deposits in MS are a consequence of altered cerebral venous return and chronic insufficient venous drainage.

Assessing Abnormal Iron Content in the Deep Gray Matter of Patients with Multiple Sclerosis versus Healthy Controls

“…It is just these regions that have increased iron content as seen with SWI and with conventional MR imaging. 4,9 The recent work of Haacke et al 18 suggests that the iron increase seen in MR imaging occurs at the confluence of the small draining veins out of the structures of interest such as the PUT, GP, and CN. Given the previous evidence that MS is a perivenular disease and that iron builds up in the venule wall, 12,30 it may be that these increases in iron represent venous endothelial damage.…”

“…2 Recently, the inter-relationship between venous abnormalities, obstructed flow, and a possible role for iron in tissue damage has been considered. 3,4 To a large degree but not exclusively, the imaging pathogenic landmarks of MS have been well documented mostly in WM. 5,6 To a lesser degree, investigators have noticed abnormalities in cortical regions as well, specifically near the GM/WM boundary and in GM as well.…”

Failure of the vascular hypothesis of multiple sclerosis in a rat model of chronic cerebrospinal venous insufficiency

“…Iron overload is hypothesized to act as a causal factor in the development of MS lesions [41], either directly via oxidative stress or indirectly by causing the primary activation of the autoimmune cascade [32].…”

Visualizing Iron Deposition in Multiple Sclerosis Cadaver Brains

“…Until recently, the focus of research into this complex disease has been on immunological 3,4 , neurological [5][6][7][8] , cellular 9 and molecular [10][11][12][13][14][15][16] events. A few early studies suggested that vascular anomalies may lead to MS [17][18][19][20] and this hypothesis is now being reexamined by Zamboni and others 14,[21][22][23][24][25][26][27][28][29] . Zamboni refers to the resulting vascular effects on the brain as "chronic cerebrospinal venous insufficiency" or CCSVI 28 that leads to iron deposition in the vessel walls 14 , in the venous drainage system 30 and in and around MS lesions 31 .…”