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Gadolinium: highlighting MRI: key to revelation?


Clinicians have known for some time that in multiple sclerosis the breakdown of myelin is associated with the breakdown of the blood-brain barrier. This barrier is a "wall" of tiny endothelial cells in the blood vessels that permeate the brain tissue, nourishing it and providing oxygen.

If there is damage to the blood vessel wall, the blood and its contents may start leaking through the endothelial cells, through the blood-brain barrier, and into the perivascular space--that area around the blood vessels in the brain tissue. Among the substances which may thus invade the brain are cells and antibodies of the immune system; inflammation then begins in the perivascular space. It appears that breakdown of the blood-brain barrier and inflammation are nearly simultaneous events.

Now, physicians from the National Hospital in London report that when they use magnetic resonance imaging (MRI) to scan patients who have been injected with gadolinium, a contrast-enhancing agent, they see that the blood-brain barrier breach is a very early event in the evolution of the new MS lesions and may even be pivotal in their formation.

"When we inject the gadolinium it generally flow through the blood cells and stays in them," Dr. Alan Thompson, lecturer in clinical neurology, told the American Academy of Neurology in Miami last May. "But when there is leakage it goes through the blood vessel walls into the perivascular space and pools there. You can see it readily on the scan." (See illustration.)

In a six-month clinical study Dr. Thompson's group, including Dr. Allan Kermode, who is now in Perth, Australia, injected gadolinium and did MRI scans every two weeks on 24 patients with multiple sclerosis. The combined technology produced a very clear picture at the site of active MS lesions.

"There must be active lesions to be visualized," Dr. Thompson stressed. "That's crucial." The fact that the imaging was done so frequently made it possible to see the lesions almost as they formed.

"About 87% of the new lesions became enhanced with gadolinium," the London neurologist said. "But in four patients we actually saw leakage occuring in early lesions before any other abnormalities could be seen on the MRI. In other words, the blood-brain barrier breakdown with inflammation is a very early event, and may show up on the scan before the expected MRI abnormalities appear."

The early event was seen in only four patients, he explained, because it is a very fleeting occurrence and has to be captured quickly. "We would have had to be scanning the whole group of patients 24 hours a day to catch the leakage every time in all of them."

It had generally been thought that inflammation might simply occur as a result of the demyelinating process, in the same way inflammation follows any kind of trauma or insult to the body, Dr. Thompson said. "But with gadolinium we found it happening very, very early in lesion formation. This suggests the blood-brain barrier breakdown may occur before demyelination begins."

Because it is possible to monitor the evolution of lesions so accurately, Dr. Thompson thinks this may have profound implications for clinical trials. "Because you can see change evolving so quickly with frequent scanning, you may be able to deal with much smaller numbers of patients over a short period of time when you test drug effects on patients in clinical studies," he says.

The British findings highlight some questions that have puzzled investigators: is it possible that inflammation itself could cause some of the symptoms of MS? Could a condition of inflammation which does not move on to demyelination perhaps be responsible for some of the more transient MS symptoms or those that reverse themselves very quickly? And what in fact triggers the inflammation?

Dr. Thompson is now trying to work out the exact relationship between inflammation and demyelination. "We have the bility to do it using gadolinium, which of course we never had before. We always had to rely on autopsy tissue, which is hopelessly inadequate if you're looking at an everchanging disease."

Translating the British finding into therapy directed at the blood-brain barrier of patients with multiple sclerosis will be a major task. Dr. Celia Brosnan of Albert Einstein College of Medicine observes that the barrier could conceivably provide a target for treatment that would prevent the entry of immune products into the brain, thus deflecting the course of MS. In fact, she says, this very approach is being taken in some animal studies using antibodies against molecules involved in the adhesion of inflammatory cells to blood vessel walls.

Early breaching of the blood-brain barrier has been confirmed by other investigators, notably Drs. Henry McFarland and Dale McFarlin at the National Institute of Neurological Disorders and Stroke. They plan to report their latest work at the American Neurological Association meeting in Atlanta this fall.

As Dr. McFarlin told INSIDE MS, "I think the recent discoveries we have made with the help of gadolinium are probably the most important advances in MS research seen in the last decade."
COPYRIGHT 1990 National Multiple Sclerosis Society
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Copyright 1990, Gale Group. All rights reserved. Gale Group is a Thomson Corporation Company.

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Title Annotation:includes information on whether MS is actually two diseases; contrast-enhancing agent used with magnetic resonance imaging
Author:Shaw, Phyllis
Publication:Inside MS
Date:Jun 22, 1990
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