Andrew N. Wilner, MD; Michael G. Dwyer, PhD


July 09, 2014

Editor's Note: While on site at the 6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), held in Dallas, Texas, May 28-31, 2014, Medscape correspondent Andrew N. Wilner, MD, spoke with Michael G. Dwyer, PhD, Assistant Professor of Neurology and Biomedical Informatics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, about the implications of pseudoatrophy in multiple sclerosis.

Dr. Wilner: You gave a presentation[1] just a few minutes ago about MRI measures, with particular attention to the phenomenon of pseudoatrophy. Could you explain what "pseudoatrophy" means?

Dr. Dwyer: "Pseudoatrophy" is the name that has been given to the observation that when we start patients initially on an anti-inflammatory therapy, we see a relatively rapid short-term drop in brain volume over about a 3-month period. The ultimate question is whether that brain-volume reduction represents an actual loss of tissue, which is what we usually expect atrophy in multiple sclerosis to represent in the long term -- such changes as neurodegeneration, loss of axons, loss of myelin, and loss of cell bodies. But in the case of pseudoatrophy, many people (myself included) believe that the short-term rapid changes are a resolution of long-term low-level inflammation, so that the brain is returning to the volume it would have had without the inflammation that is artificially increasing the brain volume.

Dr. Wilner: Inflammation, in this case, that is caused by multiple sclerosis.

Dr. Dwyer: Yes. The critical question is if we are measuring brain volume changes -- we always claim to be measuring atrophy, but what we are really measuring directly are brain-volume changes -- are we conflating "good" brain-volume changes, which would signal resolution of disease activity, with "bad" brain-volume changes, which would represent actual loss of cells and tissue matrix? It's very difficult.

Many people assume that the pseudoatrophy effect is water-related, because we see it happen very quickly and then it levels off after about 3 months. We found the same thing in this study. The challenge has always been that to put the issue to rest, we have to somehow show that it really isn't tissue loss -- that it is related to these inflammatory changes. Does that make sense so far?

Dr. Wilner: Perfect sense.

Dr. Dwyer: In this study, we had the opportunity to look at immunologic markers for proinflammatory and anti-inflammatory cytokines specifically. Commensurate with these short-term brain-volume changes, we saw same-direction changes in these proinflammatory cytokines, specifically interleukin (IL)-17F. In patients whose brain volumes dropped more (presumably more of this pseudoatrophy effect), we saw at the same time a greater drop in IL-17F -- more reduction in proinflammatory cytokines.

Dr. Wilner: Less inflammation.

Dr. Dwyer: Presumably less inflammation; on the basis of what we were looking at. It's very difficult to say anything with certainty.

Everybody would love to have some sort of in vivo method with MRI to quantify water content separately. Unfortunately, there isn't a good clinically viable method out there yet for that. I know that some groups are working in that area, and that would hopefully answer many questions and let us separate the good volume-change component from the bad volume-change component.

In the short term, we need to decide. Many investigators and companies are looking at neuroprotection. If we want to evaluate neuroprotection, we have to be sure that we have a good measure of neuroprotection.

Dr. Wilner: When we look at drug efficacy and the many MRI measures, it's becoming clear that one of the most important measures in terms of a drug's efficacy is its ability to prevent brain atrophy.

Dr. Dwyer: Exactly.

Dr. Wilner: Are you suggesting that maybe we shouldn't start that measure on day 1?

Dr. Dwyer: Exactly. I'm not the first to suggest that, but to do that evaluation in an honest way, we have to be sure that we are not missing some important, real brain change in the first 3 months. Our study looked at that and added more evidence to say that yes, it probably is best to skip those first 3 months. Until we have a perfect technique to separate "good" and "bad" volume changes out, skipping the first 3 months makes sense.

Dr. Wilner: Starting the measure of effectiveness or lack of effectiveness of a new drug at about 3 months, when the pseudoatrophy has stabilized, and then going forward for the next 6 months or 1 year (or as long as the study progresses) might give a truer reflection of the drug's efficacy in neuroprotection?

Dr. Dwyer: Exactly. Very roughly, and depending on who you ask, we see about 0.1% of brain atrophy or brain volume change in healthy control individuals per year. It depends on age and a lot of other factors, but it's on the order of 0.1%. In multiple sclerosis, we see on the order of a 1% change per year.

Dr. Wilner: Ten times normal.

Dr. Dwyer: Yes. It's a substantially faster atrophy rate. In an absolute sense, the difference is small, but relatively, it's large. The key point is that in our study, if what we saw is pseudoatrophy, we saw a 1% change in white matter and a 1.5% change in gray matter. That's almost a year's worth of atrophy.

Now imagine that instead of looking at 1 drug, you are trying to compare 2 drugs head-to-head that may both have some efficacy, and you want to know which one has more. You can't be 1% off on this measurement.

Dr. Wilner: What are you doing next?

Dr. Dwyer: In the short term, I would recommend trials to skip the first 3 months -- to start with the 3 months as a baseline. In the long term, my interest is MRI metrics, and I'm interested in collaborating with people on better metrics that can tease out these 2 different components of atrophy. We are doing some work with some animal models on a scanner we have at Buffalo. Hopefully we will be able to measure water within the next 10 years.


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