Getting to the Bottom of MS

At the Rocky Mountain MS Center we periodically survey people in the MS community to find out what they want from us. A frequent, frustrated response is, “A cure for MS.” We would love to find the cure—we’ve been looking for it for more than three decades, but unfortunately, finding a cure is not a straightforward process. It is rare, in medicine, to have a “Eureka!” moment, where one minute there wasn’t a cure and, suddenly, there is one. A cure evolves out of an understanding of the disease and quite often, we don’t understand the disease. That has certainly been the case with MS. However, our knowledge has grown tremendously in the last few decades and this has certainly helped us to develop increasingly effective treatments for MS. To learn more about our evolving understanding MS, we talked with neurologist and MS researcher Dr. Timothy Vollmer, our Medical Director and Co-Director of the Rocky Mountain MS Center at University of Colorado.

InforMS: In Happy Accidents, a book about the haphazard nature of medical breakthroughs, the author says, “We present science as a set of facts and strong beliefs that have been set in stone . . . and the history of scientific advances as a sequence of events that have led to more-or-less direct progress. The reality is different. Progress has resulted only after many false starts and despite widespread misconceptions held over long periods of time.” Were there false starts and misconceptions in our quest to understand multiple sclerosis?

"When the MRI came on board, we found people were actually having 10-20 inflammatory events per year with only one clinical relapse."
Dr. Timothy Vollmer
Dr. Vollmer: Thirty years ago, we believed patients were having MS relapses maybe once a year. We thought we could “see” disease activity pretty well by simply looking at a patient in clinic and could tell how much damage they had and where they were headed in terms of the disease course. But when the MRI came on board, we found people were actually having 10-20 inflammatory events in the brain per year with only one clinical relapse. So, today we know that most of the disease that occurs in MS is sub-clinical. The patient doesn’t know it’s going on and the physicians don’t know either, unless they do an MRI. That’s because the brain does a remarkable job of repairing and rewiring itself to overcome this ongoing, sub-clinical damage.

Another important advance in our understanding of MS is that the current classification system we use (relapsing-remitting MS, secondary-progressive MS, primary-progressive MS) isn’t very useful and doesn’t actually predict whether a patient will respond to therapy. When you look at all the clinical trial and imaging data, the things that determine whether a patient responds to immunological therapy is not which MS classification they are in—it’s their age and whether they are having active inflammation. If they are having relapses, or they are developing new T2 lesions, or gadolinium-enhancing lesions, they respond to the therapies more or less.

InforMS: How did that classification system come about?

Dr. Vollmer: The early studies in MS were focused on drugs like azathioprine and we enrolled anyone with MS—we didn’t stratify people according to disease severity. The drugs had modest effects, but we couldn’t get statistical significant results. To fix that problem, the field began to sub-classify MS in the way that has come back to haunt us. To try to get patient populations that were more homogenous and more likely to respond to therapy, we began to use terms like relapsing-remitting MS, primary progressive MS, secondary progressive MS.

Unfortunately, when humans give two different names to the same object, they begin to assume they are different and then start to act as if they really are. As a result, researchers started looking for differences between progressive and relapsing patients. Recently my colleagues and I reviewed of all of the immunological studies that had been done in PPMS and RRMS. There were about 27 papers that reported differences, but of those 27 papers, not a single one reported the same finding. And none of them corrected for age.

InforMS: What is the significance of a patient’s age?

Dr. Vollmer: MS is the most inflammatory during the early phases. As patients age the intensity of the inflammatory attack decreases and may even shut off in the late 50’s and early 60’s. In the early clinical trials, we fail to show benefit from the anti-inflammatory therapies in the older primary progressive and secondary progressive patients. Those studies were biased towards patients who were no longer in the inflammatory phase, so using an anti-inflammatory therapy wasn’t going to be of any benefit. Patients who are secondary progressive show less treatment effect to therapies than those who are early relapsing-remitting, but it’s important to understand that it’s not related to the term RRMS or SPMS, or the pattern of worsening—it’s related to age. The fact is that if you are older, you are more likely to be called secondary progressive. That’s when the inflammatory attack is less intense and, therefore, you get less response to therapy.

Another change is in our thinking about the biology of MS. The term “remission” is quite inaccurate. We think of remission as the time when symptoms have improved and the disease has subsided. But now we know the disease is actually still very active during this phase but it’s clinically invisible. Because it is invisible, we don’t recognize that damage is still occurring. Improvement happens during “remissions” not because the MS has stopped, but because of cortical remodeling and rewiring, functions have been shifted around, and the brain has compensates for the injury caused by the relapse. The most likely explanation for progressive disease is the inability of those compensatory mechanisms to continue to mask the disease activity that’s been going on all along. So, progressive disease doesn’t represent a fundamental change in the biology of MS and it isn’t the onset of neurodegeneration. Rather, the brain has used up its reserve capacity and can no longer compensate for the sub-clinical disease activity.

Another advance in our thinking is that we now believe the major target of the immune attack on the brain is not myelin—it’s the central nervous system—it’s neurons. MS doesn’t just attack white matter in the brain—it attacks gray matter as well. It is not the number of lesions patients have—it is the decrease in the population of neurons, that is, decrease in the cortical gray matter and deep gray matter—that ultimately determines disability and probably the onset of secondary progressive disease.

InforMS: There have been tremendous advances in technology in the past 30 years. Have these changed how we understand MS?

Dr. Vollmer: MRI has been critical to the advances in MS. It was MRIs that demonstrated that the disease is really mostly subclinical, and that it damages neurons as well as myelin. We’ve used routine MRI for years, to 

monitor treatment response and disease progression, but recently we’ve begun to change what we focus on. We now know that the best predictor of disability isn’t damage to myelin, it is damage to the neural compartment. That has led to a number of studies that demonstrated that brain volume—which is a reflection of how many neurons you have—is actually a very powerful predictor of disability. And rate of brain volume loss—brain atrophy—is a key consequence of MS and can be modified by the DMTs.

We are also changing how we use scans because it has become apparent that just looking at white spots on an MRI is not a very sensitive way to determine whether disease activity is occurring. Volumetric MRI is a measure that we’ve used in clinical trials for 15 years that allows us to assess brain volume. We have recently started to do volumetric MRIs on all of our patients in clinic, and there are at least three other major centers that are starting to do the same thing.

"Volumetric MRI provides a much more sensitive measure of treatment response and it’s also quicker and easier for patients."
Dr. Timothy Vollmer
Volumetric MRI provides a much more sensitive measure of treatment response and it’s also quicker and easier for patients. A patient can get an MRI without getting contrast (gadolinium) and we can cut down the number of sequences—they can be in the MRI for 30 minutes instead of an hour or two. We get back a two-page assessment that includes the patient’s brain volume compared with age-matched controls, the ventricular size, and the size of the thalamus. Right now we are following patients on an annual basis with these volumetric MRIs and we’ll try to validate our ability to see change over time. My sense is that you’ll need to do the volumetric MRI every two years so you have enough time to see what kind of change has occurred. But what you can do, right now, with these numbers is see where a patient’s brain volume is, normalized for their skull, compared to healthy people.
Another advance is how we use MRI to diagnose MS. We have used MRI

to diagnose MS since the 1980s, but we didn’t actually accept it as a way to identify lesions separated by time and space until about three years ago, when the second version of the Macdonald criteria for diagnosis of MS came out. Now, when you do an MRI, if you see old lesions that aren’t enhancing and new lesions that are enhancing, that gives you—right at that point—separation in time and space. That means that you don’t have to wait for the second clinical event—because you have MRI evidence of two separate MS attacks—and you can diagnose someone much sooner.

InforMS: Whenever you read anything, anywhere, about MS, the first sentence is always, “MS is a chronic neurological disease with no known cause or cure...” I recently read an article about why we don’t have cures for all sorts of diseases, written by physician David Shaywitz. His assessment is that “most diseases aren’t well enough understood to enable the rational development of truly transformative therapies.” So, are we making strides in our understanding about how MS works?

Dr. Vollmer: For decades we have used the animal model of MS—experimental autoimmune encephalomyelitis, or EAE— to study MS. EAE is similar to the human disease, and it gave us a place to start. The animal model told us that MS was primarily a problem with T lymphocytes (T cells). The first DMTs helped us test that theory. The interferon betas were developed because researchers hypothesized, based on EAE, that viruses were causing MS. The hypothesis was wrong, but the drugs still worked—more or less—and figuring out why helped us begin to understand that the animal model of the disease is different from the disease in humans.

That was our first real inkling that the basic immunology that we thought we understood was wrong. Therapies that are effective in EAE don’t tend to work in MS because they primarily target T-cells. It is becoming clear that B-cells—not T cells—are the primary players in MS.

B cell involvement is unique to humans but is not important in EAE. The MS community thought B cells were superfluous. Then we tested a specific therapy—rituximab—that only targeted B cells and didn’t affect anything else in the body and it was highly effective. The key message here is that MS is a different disease in mice and rats than it is in humans. That has really changed our thinking.

InforMS: And, what about that cure...?

Dr. Vollmer: When we talk about the cure, there are two concepts we have to be aware of. One is fixing the inflammatory process in the brain. If you do that early enough in the disease process, that’s the only thing you need to do. But, for patients who have already developed disability, we have to focus on recovery and repair, and we are just getting started on that.

But what’s really changed and what the world doesn’t understand, yet, is we have the ability, right now, to take newly diagnosed patients and potentially put them in complete remission of the disease. So if you argue that a cure means you treat them once and then they’re fine, we don’t have that. But if you argue that a cure is something that prevents them from developing a disability, then we have that. We can do that now. What we don’t have is the ability to repair the brain. So if we allow patients to accumulate disability unfortunately there’s a limit in how much they are going to be able to get back. Whereas if we treat them very early, before they have disability, the data right now suggests that they’re going to remain in long-term remission.