InforMS: Winter 2016


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.


Exploring the Future of MS Research

Over the last thirty years, we’ve refined our understanding of MS. With each research study, another dot is added to our picture of the disease. It’s certainly not a straight line and it’s often messy and full of frustratingly slow twists and turns. But even those twists and turns can add to our collective bank of knowledge. And this ever-evolving understanding gives us a foundation for significant hope and optimism for the future of MS treatment and research.

To learn more about what’s on the horizon for MS research, we spoke with Dr. John Corboy, Co-Director of the Rocky Mountain MS Center at University of Colorado.

InforMS: What are the big remaining questions in the world of MS?

Dr. Corboy : The really big questions? What’s the cause? What’s the cure? One of the other big questions that patients have and that we aren’t yet able to answer is: “What’s going to happen to me?”

To answer that question, we need a better way to separate the individuals with a relatively good prognosis from those with a relatively poor one. If we had that ability, we could do two things. First, we could identify those patients who don’t need to be treated at all, or who could be treated with any of the therapies, and those patients with severe disease who we need to treat aggressively, upfront. Second, being able to better define patients’ trajectory would allow us to do what we really want to do, which is treat to a target. In MS, we need a better way to define our therapeutic goal and tell if we have achieved it.

InforMS: What exactly are we trying to measure and how could a marker help us measure it?

Dr. Corboy : We are trying to measure neuronal—grey matter—damage, because that type of nervous system damage is the most strongly associated with disability.

"We could eventually use neurofilament blood markers to give us predictive information about how severe someone’s MS is."
Dr. John Corboy
We know that if you damage a muscle such as your heart, you can see an increase in particular muscle proteins in blood – this marker is used as the basis of heart attack tests. Something similar happens in the brain. Neurofilament is a component of nerve cells. When a nerve cell is damaged it leaks, and you can identify the level of damage by measuring neurofilaments. It’s been known for years that you could measure neurofilaments in the spinal fluid. However, we have never incorporated this approach at the clinical level, because it is just not practical to perform repeated spinal taps in people. However, it was recently discovered that you could also measure neurofilaments in blood. The presence of neurofilament suggests that nerve cell damage is occurring. Hopefully we could eventually use neurofilament blood markers to give us predictive information about how severe someone’s MS is and to point us toward the best therapeutic approach.

Ultimately, the goal would be to use neurofilaments as response markers. We could measure whether or not the neurofilaments levels in your blood go back to normal levels if you’re treated with Drug X or Drug Y. That would tell us that nerve cell damage has slowed or been stopped, and would suggest that the drug is effective.

InforMS: I hear from patients all of the time that they feel like their MS is getting worse, but their neurologist tells them their MRI is fine. So it sounds like what you’re saying is there is a lot happening behind the scenes that our current tests or measurements can’t tell us?

Dr. Corboy : It is very important to convey that brain damage starts happening very early in MS. It simply isn’t the case that everyone is fine until they acquire disabling symptoms and develop progressive MS when they’re fifty. Brain damage and neuronal damage happen extremely early. The more evidence we have of this early, irreversible damage, the more we can stress that we have to treat patients differently. Not only do we have to try to address MS earlier and more aggressively, but also perhaps in completely different ways.

So, these sensitive biomarkers that show early nerve damage and brain atrophy, combined with volumetric MRIs, could allow us to powerfully reinforce the case for early and aggressive treatment.

InforMS: How do we know that this nerve damage is occurring early on in MS?

Dr. Corboy : There are people who get an MRI scan for other reasons and yet the MRIs look like MS. This is known as radiologically isolated syndrome. When you compare these patients to sex and age matched controls, they already have brain atrophy or brain volume loss, and yet they have not had a single clinical symptom. This means that the nerve damage was already happening before they had any clinical signs of MS.

There are also some fascinating studies of people who are newly diagnosed, that go back and look at what happened to them before they were diagnosed. One study examined whether or not low exercise levels led to a diagnosis of MS. They concluded that, no, it did not. But very interestingly, several years before the patients were diagnosed with MS, before they had symptoms, their exercise levels went down compared with age matched controls. So that tells us that something was already happening before they got diagnosed.

InforMS: What are some significant hindrances to progress in treating MS effectively?

Dr. Corboy : As a community, we still underestimate the significance of this disease. Everybody can see a heart attack – that is clearly severe. Cancer—that is clearly severe. But somehow, MS doesn’t count as severe for many people. Look at what is called “benign MS” by many: the definition of benign MS includes an Expanded Disability Status Scale (EDSS) of 3 at 10 years. That means moderate disability in one functional scale and mild disability in 3 to 4 functional scales, though still fully ambulatory.

What does that mean in practical terms? It may mean you’re not hiking; or you’re not doing 14ers; you may still be skiing, but probably not. You might not be working and you’re probably a little disorganized with your kids. And my question is: When did that become benign, and when did that become acceptable? We need to acknowledge that everyone has aggressive disease until proven otherwise. We are not able to make that distinction as well as we would like. And, of course, untreated or undertreated, many MS patients will develop disability.

InforMS: What other research is in the pipeline that gives you hope for the future?

Dr. Corboy : There is encouraging research on how to protect nerves from damage. It is important to alter or suppress the immune system—which is what DMTs do—but protecting against nerve damage is likely the key to preventing disability. We are looking at why cells die over time. One argument is that disruption in the energy mechanisms is what leads to cell damage and cell death over time.

"It is hypothesized that biotin may help slow, stop, or even reverse the progression of disability associated with demyelination."
Dr. John Corboy
Some of our research is focused on compounds that may be neuroprotective. Biotin is a water-soluble B vitamin that is critical in energy metabolism and production of fatty acids. It is hypothesized that biotin may help slow, stop, or even reverse the progression of disability associated with demyelination. Studies have shown some progressive MS patients improving with high dose Biotin. To further explore this, there is going to be a large 400 person study over the next 27 months.

Research in this area is very preliminary and all the studies have been very small. How these sorts of drugs might be helpful and how they might be used—perhaps as add-on therapies to improve the effects of disease modifying drugs—is unknown. But they are causing excitement because they provide indications that neuroprotective strategies are a real possibility for people with MS.

InforMS: What about the repair or remyelination of nerve cells that have already been damaged?

Dr. Corboy : Strategies to repair the nervous system are in their infancy. The human body, including the central nervous system, has a tremendous capacity to replace damaged cells and to repair itself. We heal from cuts, we (at least some of us) grow new hair when the old falls out, and we mend broken bones.

The brain can also repair damage, and routinely does so in MS. Oligodendrocytes are myelin-making cells and they repair MS damage all the time. This is one reason people have remissions after a relapse—because the brain has repaired the problem. LINGO-1 is a protein that inhibits the development of myelin-making cells, which, in turn, limits the natural ability of the brain to remyelinate damaged axons. Anti-LINGO-1 blocks LINGO-1, and by so doing may stimulate myelin growth. Phase II studies of this molecule in 82 people with a first attack of optic neuritis found a small but statistically significant improvement in the speed of nerve conduction in the optic nerve, which suggest that there was possibly remyelination of the optic nerve. There was no improvement in visual function however.

InforMS: What are your thoughts on stem cell research for MS?

Dr. Corboy : The area of stem cell research to treat diseases, including MS, is huge. The basic problem in MS is that the immune system is attacking the nervous system. One strategy to fix this would be to get rid of the old, poorly behaving immune cells and replace them -- or reboot -- with cells that have not been programmed to attack the nervous system. The most publicized stem cell approaches in MS reboot the immune system.

There are lots of different types of stem cells, and they have different qualities and characteristics. They have different abilities to enter the nervous system and to migrate to where you need them to go. They might have different abilities, either to replace cells that are damaged or to stimulate those cells that are already in the nervous system, or help them to function better.

Unfortunately, stem cells that are injected into a person’s body are not likely to enter the nervous system and induce repair. None of the stem cell studies have suggested that you would be able to regrow nerves. If you are going to do something to repair nerves, you will need preprogrammed cells that can go down the correct developmental path to become nerve cells, and then somehow get to the appropriate place where they can set up shop, create new connections, and stop reproducing.

It is important to recognize that these types of treatments are not approved for use in the United States. Recently the New England Journal of Medicine published a paper about an MS patient who went to three different stem cell clinics outside of the United States. The patient’s spinal fluid was injected with mesenchymal embryonic fetal neural stem cells. He later developed multiple complications including paraplegia with urinary incontinence. This is a cautionary tale for patients who are interested in stem cell research. Going somewhere and getting something randomly shot into your body is extremely risky. 

Although it’s a cautionary tale, that doesn’t diminish the interest in stem cell research, but it’s all very preliminary and there is a lot that we just don’t know.

InforMS: Are you hopeful about the future of MS treatment and research?

Dr. Corboy : Yes, I am very hopeful. The key is to change our collective mindset. We have some really good treatments and wellness approaches for MS right now. The problem is that, as a community, we are not always using them. We know a whole lot about this disease and we have a lot of ways to treat it. One of the most important things we can do is change how we think about this disease – it’s an aggressive disease that must be treated early and in the most effective way possible.