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Anomalous venous blood flow and iron deposition in multiple sclerosis

link to abstract

Ajay Vikram Singh1 and Paolo Zamboni2

1Department of Physics, European School of Molecular Medicine (SEMM), IFOM-IEO Campus, Centro Interdisciplinare Materiali e Interfacce Nanostrutturati (CIMAINA), University of Milan, Milan, Italy
2Vascular Diseases Center, University of Ferrara, Ferrara, Italy
Correspondence: Professor P Zamboni, Director Vascular Diseases Center, University of Ferrara, Milan, Italy. E-mail: zmp@unife.it

Received 27 April 2009; Revised 27 July 2009; Accepted 29 July 2009; Published online 2 September 2009.

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.

This was the focus of Dr Haacke's presentation as well...he showed SWI MRI images of severe iron deposition and hypoxia (lack of oxygen) and loss of gray matter in the MS brain as measured by new technologies he has developed. Read his presentation again from my notes for further detail. Looks like Dr. Zamboni is sticking to this as the mechanism of injury in brain tissue, and after seeing Dr. Haacke's presentation, I understand why. And as we've been discussing for awhile here, this kind of injury can set the immune system off...but the reflux comes first.
cheer

Thanks for the heads-up. I hope this paper will give some insight in the question of whether there is any causation between the iron and disease activity, or whether it is just a byproduct. Reminds me a little of the Aluminum-Altzheimer connection, which to the best of my knowledge at this point is just a correlation, not a causation. I posted this question as well in your "finalized notes" thread, sorry for the re-post here...

zinc status affects iron handling in the body. i've posted on this before here at TIMS.
on the oxidation concern, zinc improves liver function, which boosts uric acid, which is a powerful antioxidant.
zinc is low in ms. optimal is 18.2 umol/L.

Bump...
for those who missed it. Zamboni's new paper outlines his theory for mechanism of disease process in MS-and his order is:
1. CCSVI (congenital cerebral venous outflow abnormality)
2. iron deposition and oxygen deprivation into brain tissue
3. hypoxia and cellular death
4. Activation of immune system
cheer

You have to pay for the paper....BUT the figures and tables are public domain.

link
Figure 1 is the history of a lesion, showing how a vein sits at the center of each lesion, and a "streak of blood" surrounds the lesion.
Figure 2 shows the immune cascade which attacks myelin
Figure 3 shows the physiology of cerebral venous return
Figure 4 shows the venous stenosis being found
Figure 5 shows Collateral circles being formed
Figure 6 shows reflux mapping

Well worth a peek....shows how the pieces fit together-
cheer

http://www.jbc.org/content/283/8/5168.full
Zinc Deficiency-induced Iron Accumulation, a Consequence of Alterations in Iron Regulatory Protein-binding Activity, Iron Transporters, and Iron Storage Proteins*
One consequence of zinc deficiency is an elevation in cell and tissue iron concentrations.

http://www.journals.elsevierhealth.com/ ... 8/abstract
Treatment of symptomatic heterozygous aceruloplasminemia with oral zinc sulphate
Aceruloplasminemia is an autosomal recessive and phenotypically primarily neurodegenerative disease caused by a homozygous mutation of the ceruloplasmin gene. The absence of ceruloplasmin and its ferroxidase activity leads to pathological iron overload in the brain and other organs. While heterozygous carriers of ceruloplasmin gene mutations have been believed to be asymptomatic, a number of cases with neurological deficits have recently been described. To date, an effective treatment has not been established for either aceruloplasminemia or symptomatic heterozygous aceruloplasminemia. The present report concerns the beneficial treatment of an 18-year-old girl with extrapyramidal and cerebellar-mediated movement disorder caused by a heterozygous mutation of the ceruloplasmin gene using oral zinc sulphate.

This is wonderful, wow see that great table showing the similarities between CVI and MS lesions.... It is stunning. Remember that CVI is a proven venous disease, so these similarities are more than academic.

I added these both to the research link.......

I have the full paper. I don't have the ability to host it on line, but if you would like a copy, please PM me.

Now that I'm reading the paper I'm a bit more confused about the role iron plays in all this. I.e. is it simply deposited while the immune-system is trying to clean up the mess or is it exacerbating the problem? I know I mentioned this before, but the authors explicitly state that "iron is instrumental in myelination and oligodendrocyte development", something direly needed in an MS brain.

Also, I don't follow the logic of the EAE example, because if CCSVI is true the relationship between EAE and MS is shallow at best. Iron is essential in building cells, so could is simply be that the immune-cells responding to immunization with myelin protein in EAE can not be built as effectively in anemic animals?

If anybody can help me out in the decision process of whether I should blood-let or not, that would be great

I suppose one other reason to loose a bit of blood every once in a while is that this also gets rid of 10% or so of the harmful T and B cells that exacerbate early MS. Now that I think about this I'm actually surprised that nobody has looked into this: phlebotomy as a means of treating relapsing-remittent MS. This could at least in principle be more effective than plasma exchange, which only gets rid of bad antibodies. This is way off topic, and I'm sure it doesn't work because it seems to obvious for nobody to have tried it...

With regards to iron, I don't know about bloodletting but the main points of the paper seem to me to be
1. The trigger for the auto-immune attack in MS is unknown, but in EAE an induced autoimmune disease deficient levels protect against damage.

(I think what this means is that an immune attack in the brain, induced by EAE or not, has iron as a role of the injury to tissue)

(It appears to me that what they mean by auto immune is simply activation of immune cells against self antigens...even if the cells in question were damaged and such attack is "normal" vs the kind of auto immune attack in EAE where the immune system is set up to attack HEALTHY tissue. An important difference, but they seem to be calling all immune activity against self antigens, healthy or not, "autoimmune".)

2. the initial trigger causes the immune system to come in and primarily attack oligodendrocytes.

3. iron may be that trigger; it has been shown that blood leaks out at times of relapse (perivascular extravasation).

Also the iron is itself attractive to macrophages--they are drawn to it and there is research showing macrophages filled with iron in MS. Macrophages devour dead tissue and foreign bodies...and the body always recycles iron because it is important for many physiological activities. So the immune system is the way the body does this iron recycling, it is a "prime directive" so to speak...conserve iron.

this process produces gamma interferon which is the MAIN thing that causes degeneration of the nerves. Ordinarily, the t cells are induced to die when they come in contact with gam. int., BUT in the presence of iron, the cells do NOT die, they hang around and cause more clean up and "standby damage"...like the fact that gamma interferon is a normal part of this process but it degenerates nerves. Those poor nerves do not have a chance with the iron having leaked in there.

Those are the main points as they pertain to iron, very watered down and simplified as I understand them.
marie

The paper is now available for download at:

http://youriluken.homestead.com/multipl ... _in_MS.pdf

I saw the doctor who has been seeing me for hemochromatosis for the past ten years yesterday and he was extremely interested in this article. He even asked if it would be OK if he shared my case with some friends who are neurologists and hematologists to get their opinions and discuss it (my neuro is neutral on the matter so far, maybe my hemo doctor can puch him to look a little closer as he does want to talk with him). He even wondered aloud if phlebotomy has ever been looked at as a therapy for MS. Basically, my ferritin level is very high but all of my other blood work is fine including iron saturation which is not a normal presentation for hemochromatosis. Also, when I first started phlebotomy a slid dangerously anemic which, in his words, I am the only hemochromatosis patient that he has seen that with. To back up my original diagnosis, I did have a liver biopsy done about ten years ago and it showed a lot of accumulated iron (but thankfully no damage) which is highly indicitive of hemochromatosis. This article suggests that the ferritin levels can be elevated due to MS which I was diagnosed with this past spring. I just finished giving blood for a genetics test for hemochromatosis and should have my results in a week or so. If that is negative, I could possibly be a good case for ferritin as a marker of MS disease activity as when I first went to the doctor ten years ago, it was because I felt extremely fatigued, foggy, etc. (this first signs of MS?). After a fairly intense phlebotomy regimen (1 unit every two weeks for almost a year), my ferritin levels were in the low normal range, I was basically anemic, and I felt much better. Did removing the iron (which I became somewhat lax about the past few years) stop any progression for a while until the levels came back up? I had a number of nonenhancing leisions when I was MRI'd this spring which suggests that I have had MS for a while. This is especially interesting if my hemochromatosis tests come back negative. If they are positive, maybe the hemochromatosis is a exacerbating factor that when coupled with CCSVI (which I should know about my status there in the not too distant future) is enough to start the CNS damage cascade. Either way, I'll be back on the "every two week blood letting" starting this week to drop the ferritin to safe levels. It is too bad the blood bank throws it all away due to the Betaseron. Looking at my case in particular, this article makes a lot of sense and ties together a number of loose ends.

i have wondered about this for a while. my uncle died of hemachromatosis a number of years ago. my father (and the other brothers) all then had to have the genetic test. my father came back negative so i did not end up getting tested.

jay123 wrote:i have wondered about this for a while. my uncle died of hemachromatosis a number of years ago. my father (and the other brothers) all then had to have the genetic test. my father came back negative so i did not end up getting tested.

As parents can be carriers and not have it, it is worth getting checked, especially if it is anywhere in your family.

It's odd, the only time I have ever been anemic was during my pregnancies (all with MS). I wonder how pregnancy/less MS symptoms/iron deficiency tie in with this finding, if at all? I definately felt better during pregnancy and had barely any notice of MS.