Iron stores and Cerebral Veins in MS Studied by Susceptibility Weighted Imaging (SWI)
E. Mark Haackea, James Garberna, Yanwei Miaob, Charbel Habiba, Manju Liua.
aDepartment of Radiology, Wayne State University, Detroit, MI 48202, USA
bDepartment of Radiology, the First Affiliated Hospital, Dalian Medical University, Dalian,
Liaoning 116011, China
E. Mark Haacke, PhD
Wayne State University
MR Research Facility
Department of Radiology
HUH—MR Research G030/Radiology
3990 John R Road
Detroit, MI 48201
Tel. (313) 745-1395
Fax (313) 745-9182
Aim: Multiple sclerosis (MS) is a disease whose etiology until recently has remained a mystery.
A possible explanation for MS has been put forward by Zamboni et al 1 that it is caused by a
chronic cerebrospinal venous insufficiency (CCSVI). In this paper, we show that the iron
deposition as seen by susceptibility weighted imaging (SWI) in the basal ganglia and thalamus is
consistent with this interpretation.
Methods: 14 MS patients were recruited for this study with a mean age of 38 ranging from 19
to 66 years old. A velocity compensated 3D gradient echo sequence was used to generate
susceptibility weighted images (SWI) with a high sensitivity to iron content. We evaluated iron
in the following structures: substantia nigra, red nucleus, globus pallidus, putamen, caudate
nucleus, thalamus and pulvinar thalamus. Each structure was broken into two parts, a high iron
content region and a low iron content region. The measured values were compared to previously
established baseline iron content in these structures as a function of age.
Results: Of the 14 cases, 12 revealed an increase in iron above normal levels and with a
particular pattern of iron deposition in the medial venous drainage system.
Conclusion: The backward iron accumulation pattern seen in the basal ganglia, thalamus and
midbrain of most MS patients is consistent with the hypothesis of venous hypertension.
Key words: brain iron deposition, susceptibility weighted imaging, iron changes in multiple
It has been suggested recently that multiple sclerosis (MS) may develop as a neurodegenerative
disease because of a venous vascular insufficiency 1 and the resulting venous hypertension
related directly to abnormalities (narrowing and restricted flow) in the jugular and azygous veins.
Although evidence of venous involvement has been known for a long time 2-4, pioneering efforts
in this direction have basically been ignored until Zamboni et al 1 demonstrated the presence of
stenoses in MS patients. This is truly a paradigm shift, where one must look outside the brain, in
this case the cardiovascular system, to understand the source of the brain’s problem in MS.
Evidently, the venous hypertension that leads to multiple sclerosis can have a damaging effect on
the vessel wall 5,6. This is best understood from research related to chronic venous disease where
it has been shown that changes in venous hemodynamics leads to a disruption of flow, a
reduction of the shear stress in the vessel wall, an inflammatory degenerative response and,
subsequently, a deterioration of the venous wall 7-9. Similar effects are known in atherosclerosis
when normal flow is disrupted. And even in multiple sclerosis research dating back to the work
of Adams 2, and later Trojano 10, venous wall breakdown in multiple sclerosis has been well
Following this argument a bit further, one might expect then local iron increases from the
damaged vessel wall, loss of vessel function, reduced transit times and reduced local blood flow
in the chronic stages of the disease. One might also expect that the vascular pathways most
closely associated with the hypertension and local reflux (especially in the areas of the internal
cerebral veins and vein of Galen) associated with obstructed venous flow would in turn lead to
local venous damage in multiple sclerosis 11-13. The areas most affected by this might well be the
thalamus and basal ganglia since they are associated with the medial venous drainage system 14.
Figure 3: Here, we show some example phase images for an age matched normal control (A, C)
and an MS patient (B,D) for the basal ganglia and thalamus (A and B) and the midbrain (C and
D). Note the heavy iron deposition (arrows): in the lower part of the caudate as well as in the
globus pallidus and at the boundaries of the putamen (B, black arrows). Also, iron content has
increased in the thalamus (and pulvinar thalamus B, white arrows) and in the substantia nigra (D,
Figure 4: Iron content as a function of age for: A) the pulvinar thalamus and B) the substantia
nigra. The squares and the dots represent the iron values measured in region II using phase
information, in the left and right hemispheres respectively, and the lines represent their linear
regression. The crosses and the triangles represent the iron values in the left and right hemisphere
of the studied 14 MS patients respectively.
Table 1. Number of MS patients revealing abnormal iron content in each structure for different
parameters. Counting all structures, 12 of 14 patients had at least one structure with abnormally
high iron content.
Parameters CN GP PUT
2 3 1
2 2 2
3 4 2
3 2 3
4 4 3
6 6 5
Note: WS-AI: Whole Structure - Average Iron; WS-TI: Whole Structure - Total Iron; RII-TA:
Region II - Total Area; RII-TI: Region II - Total Iron; RII-AI: Region II - Average Iron