Venous blood flow and iron deposition in multiple sclerosis

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Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system. It  is believed to be primarily an autoimmune disorder with an initial trigger suspected among environmental factors (including viral infection and bacterial) impacting a genetic predisposition. The initial trigger facilitates the movement of T-cells and demyelinating antibodies from the blood into the brain through disruption of the blood–brain barrier.

Interestingly, from the time of the first histologic description by Charcot in 1868, MS plaques ( seen now on and MRI scan) were known to be venocentric. Additionally, and in common with several neurodegenerative disorders, the brain and spinal cord of MS-affected patients contain abnormally high levels of some metals, particularly iron. The advanced MRI and histologic studies show the peculiar deposition of the iron stores in MS constantly encircling the venous wall. These iron deposits, curiously, resemble iron stores commonly seen in peripheral venous disease.

It has been recently shown that MS is significantly associated with a condition defined as chronic cerebrospinal venous insufficiency (CCSVI) (Zamboni et al, 2009a, 2009b, 2009c). In CCSVI, put simply, there is a narrowing of the vessels draining blood away from the brain.Blocked venous blood outflow causes a high rate of cerebral venous reflux in MS patients.

This detected reflux, propagated from the chest and neck veins, may have an important function in explaining the mechanism of iron overload in MS. By contrast, venous reflux has not been found in patients affected by other neurodegenerative diseases with increased iron stores, such as Alzheimer’s and Parkinson’s diseases.

More specifically, the rate of venous reflux flow detected in the main cervical veins of MS patients was 70% as opposed to 0%  in the three control populations. It has been shown that extracranial reflux was also transmitted up to the deep cerebral venous system in 50% of MS cases, but was detected neither in healthy controls nor in patients with other neurologic diseases

Despite the strong association found between CCSVI and MS, it has not yet been clarified whether such venous obstructions can be considered a cause or an effect of MS.

How does this differ from other diseases?

Starting from histology, there is an impressive parallel between the inflammatory process activated in the course of chronic venous disorders (CVDs), and that studied in MS. However, two important things have happened in the past 2 years:

(1) a demonstration of altered venous flow in the cerebral venous system in the course of MS and (2) the development of advanced MRI techniques that have brought about an extraordinary improvement in the capacity to assess iron stores and cerebral veins.

There is thus a hypothesis that iron overload in MS is secondary to disturbed venous flow in the cerebral veins.

So when  does iron accumulate in the brain ?

With advancing age, iron accumulates in the brain and has been associated with senile dementia, many cognitive dysfunctions, and neurodegenerative disorders. The reason may include

• dysregulation of the proteins involved in iron influx and sensing of intracellular iron;
• iron accumulation in ventral motor neurons
• increased mitochondrial iron load .

This finding may pave the way to a better understanding of iron accumulation in the aged brain.

Iron Overload in Multiple Sclerosis

Although investigations into the role of iron in MS are still few, many high-resolution MR techniques have shown stored iron regions inside the brain and spinal cord.

If we look at experimental autoimmune encephalomyelitis (EAE), an animal model of MS, dietary modifications have revealed an incidence of EAE in 70% of mice with a normal iron level or iron overload, but 0% in iron-deficient mice. This is clear evidence that iron deficiency protects against the progress of MS in mice with induced EAE, with obvious clinical implications (Grant et al, 2003).

Authors have speculated that the failure of iron-deficient mice to develop EAE is impressive, but controversial as iron deficiency may lead to much more serious health hazards. However, they conclude that any of the pharmaceutical approaches to inhibiting EAE are less effective than iron deficiency.

At present, despite the intriguing mechanisms of iron deposition in CCSVI  we cannot definitely prove this hypothesis.

Tags:course of MS,ms treatment,research,susceptibility gene

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