The diagnosis of “secondary progressive MS” has long been thought to mark a shift in the course of the disease from a primarily inflammatory process to a neurodegenerative one. Although the majority of people with MS are initially diagnosed as “relapsing-remitting,” about half of them, after about ten years, will transition to a secondary progressive disease course. This progressive phase is characterized by gradual loss of function and thought by some to herald a shift in MS pathology — from inflammation to some other process that causes neurons to die in the absence of inflammation. The nature of this “neurodegenerative process” has never been well understood.
An important study, published in March of 2009, in the journal Brain, has provided some surprising new information on this topic. A group of researchers examined brain tissue from 67 people who had MS. What they discovered was evidence of “pronounced inflammation” not only in the brain tissue of people with acute and relapsing MS, but also in the brains of people with secondary and primary progressive disease. Evidence of demyelination and axonal degeneration was only found when there was also evidence of acute inflammation. These data strongly suggest that there is not a transition to a secondary disease process and challenge the notion that, in MS, the inflammation stops and then the neurodegenerative process takes over. When neurodegeneration was found in the absence of acute inflammation, the levels were similar to those of healthy, age-matched controls which suggests the degeneration was a consequence of the aging process.
This study challenges the increasingly prevalent notion that MS is partially or even primarily a neurodegenerative disease. It is also significant because, if the inflammation is indeed the primary culprit in the MS disease process, it has implications for how we treat the disease. What follows is a conversation with Dr. Timothy Vollmer, neurologist, MS researcher and Medical Director of the Rocky Mountain MS Center.
Q: It would be helpful to begin our conversation by establishing a few definitions. For the purpose of this discussion, what is inflammation?
Dr. Vollmer: Inflammation is certainly an imprecise term. For what we’re talking about here, inflammation should be understood to mean “an immune attack on the brain.” When we look at patients as they go through the life-stages of MS, the majority of them seem to have an inflammatory process that is very brisk at first, and then it decreases over time until, for reasons we don’t understand, it generally shuts off when patients reach their late 50s or early 60s.
Q: What is neurodegeneration?
Dr. Vollmer: Neurodegeneration means “death of nerve cells.” There are two fundamental ways that can happen. In primary neurodegeneration there is a process going on inside the neuron that leads ultimately to its death and destruction. Any inflammation is thought to be a reaction to this primary process because treating that inflammation does not change the disease. Parkinson’s disease and ALS are primary neurodegenerative diseases.
There is another type of neurodegeneration that is secondary to the inflammation—that is, it only occurs as a consequence of inflammation. In this case, the inflammation causes the cell death. It can do this in a number of different ways–by a direct attack with antibodies or T cells; or by creating an environment that is ultimately toxic to nerve cells; or by transecting fibers and preventing interneurons from firing, which deletes them from the system, because the brain doesn’t keep non-functioning neurons around.
What the article in Brain suggests is a shift in thinking about this process in multiple sclerosis from this first type of neurodegeneration to the second.
Q: How has your thinking about MS evolved over the past 20 years?
Dr. Vollmer: I believe there have been four really important advances in our understanding of MS. The first is that the majority of disease activity is sub-clinical. Our understanding of the tempo of the disease has been changed by what we have learned from the MRI. Twenty-five years ago, we thought MS was a disease that caused inflammation to occur in the brain but we didn’t think this inflammation was occurring all that often. We also thought we could see the disease activity pretty well, that by looking at a patient in clinic, we could tell how much damage they had and where they were headed in terms of the disease course. People were having relapses maybe once a year and we thought those relapses were due to these new local areas of inflammation. But, when the MRI came on board, we found people were actually having 10-20 inflammatory events per year but only one clinical relapse.
So, today we know that the clinical activity we see, at least in the relapsing stage of the disease, is just the tip of the iceberg. Most of the disease that occurs in MS is sub-clinical. When you are using standard MRI approaches, most gadolinium-enhancing lesions (90-95%) are clinically silent and are not associated with relapse. The patient doesn’t know they are going on and the physician doesn’t know they are going on, unless they do an MRI. That’s why we use MRI as a primary outcome measure in Phase I and Phase II studies because we see 10 to 20 times as much clinical activity as we would if we only counted clinically evident relapses.
The brain does a remarkable job of repairing and rewiring itself to overcome this ongoing, sub-clinical damage. But, all the time the brain is compensating, the brain is losing its substance—it is losing nerve cells, it is losing oligodendrocytes and incurring injury that, for a while, it can get around.
Another important advance in our understanding is that the current classification system we use (relapsing-remitting MS, secondary-progressive MS, primary-progressive MS) isn’t very useful and doesn’t 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 patients are having active inflammation — by virtue of the fact that they are having relapses, or they are developing new T2 lesions, or they are having gad-enhancing lesions— then they respond to the therapies more or less.
The third advance in our thinking about MS 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. In most patients neurons are included but in some patients they are the dominant targets. So, MS doesn’t just attack white matter in the brain—it attacks gray matter as well. It is not the number of white spots (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.
Finally, the term “remission” is quite inaccurate. The disease is actually very active during this phase but it’s clinically invisible, and because it is invisible, we are missing the damage that is occurring. What we think of as remission (that time when symptoms improve) is actually cortical remodeling and rewiring, when functions are being shifted around and the brain is compensating for the injury caused by the immune attacks. The most likely explanation for the clinical onset of progressive disease is the inability of those compensatory mechanisms to continue to mask the disease activity that’s been going on all along. The onset of progressive disease may not represent a fundamental change in the biology of MS. It isn’t the onset of neurodegeneration, but rather, the brain has used up its reserve capacity and can no longer compensate for the sub-clinical disease activity.
Q: Why are 90 percent of all lesions clinically silent?
Dr. Vollmer: We probably overestimate our ability to understand this. It is probably a combination of factors. As previously mentioned, the ability of the brain to accommodate and repair itself is critical.
Location is also important. Most lesions on brain MRI are in the deep cerebral white matter where there are a large number of fibers from different systems. A lesion in that area might affect a small number of fibers from a large number of systems. Most of those systems have a large enough reserve capacity that, unless we are working at peak performance, (and very few of us are) we wouldn’t notice a change in them, and in fact, we don’t. A lesion occurring in the brain stem or spinal cord is much more likely to be symptomatic but — even in the spinal cord, where we thought any damage would be evident —we still don’t see clinical evidence of about half to two-thirds of the disease occurring there.
An inflammatory event can have a variable impact on the ability of nerve signals to get through an affected area. Demylination can transiently affect the signal in a particular fiber and axonal transection can terminate it, but remember, nerve fibers aren’t unitary structures. They work as a sum total of all the firing that’s going on and they work in sequence with other pathways. So, some pathways may be more symptomatic because they are more sensitive and some may be less so because they are part of redundant systems.
It’s not just the location. The probability that a lesion will be clinically apparent also depends on whether it occurs in an eloquent pathway and has the kind of immune attack that actually destroys nerve fibers, so that it has a big effect. If it’s just destroying myelin, it may not have that effect—when we measure myelin destruction specifically, there is a pretty low correlation with disability.
And finally, you have to look at what the patient is doing that day. If someone is sitting at a desk and not moving much, they may not notice that something isn’t working 100 percent because they aren’t pushing 100 percent.
Q: Why is it, in MS, that two patients have the same disease but one ends up with disability and the other with mild disease?
Dr. Vollmer: You would predict that patients who have more inflammation would have a worse outcome. In general that’s true, but it turns out not to be the only factor. If you follow patients with MRI and you measure the amount of injury that’s occurring in the brain (by using T2 or FLAIR), you can compare patients who have the same amount of white spot damage in the brain stem, spinal cord and cerebral hemispheres. What you find is that one of them is very disabled and the other is not. We used to think that the variable outcomes were because the nervous system was being hit in a random sort of way—it was a matter of luck that your spots resulted in more disability because they occurred in a critical pathway. That’s probably not true.
The thing that seems to correlate better on the MRI with whether or not you are disabled is whether those white spots are associated with T1 black holes and whether they are associated with marked loss of gray matter in the brain—loss of neurons. So, the more important factor is not simply the amount of inflammation, but how damaging it is to the neural component—not to the myelin component but to the nerve component. In some patients the immune attack on the brain is much more destructive to the neurons and axons: those are the patients who will have the higher level of disability.
Q: You have several times referred to the “ different kinds of immune attacks in MS.” What do you mean?
Dr. Vollmer: The immune attack on the brain in one MS patient is not necessarily the same as that in another MS patient. The immune system has a number of different ways that it can damage the brain and those different mechanisms may or may not be employed in a given patient. For example, T cells can move in and recruit other T cells that can directly kill neurons, or oligodendrocytes or other cells in the brain. Or, they can release toxic molecules that can just sort of damage everything in the area. Or they can recruit macrophages, monocytes, and dendritic cells that can move in and begin to strip myelin.
Differences in the type of immune attack can be determined by genetics, or by the type of brain antigens targeted in your immune attack or by your environment and what kinds of things you’ve been exposed to. There is an interaction between your environment and your genetics: how that works is not clear. What influences this variation in the clinical expression of MS is an area of research that is not receiving as much attention as it should given that the immune response is usually pretty similar in patients.
Q: Sometimes, although patients report that their MS is getting worse, the neurologist will tell them that the MRI has not changed. Do MRIs always detect disease activity?
Dr. Vollmer: For reasons that are not fully clear, when an area of the brain is injured once, it becomes a preferred target of subsequent attacks and has a higher rate of repeat inflammation. So, any lesion we see in a patient may be the sum of multiple inflammatory attacks in the same spot that have accumulated over time. When you look at an MRI, and it looks the same as the last MRI, it may be over-interpreting the data to say that there is no change. New lesions may appear in the bed of old lesions, and may be buried under old disease where you can’t see them MRIs are insensitive and can’t see the gradual progression of that lesion over time. There is no perfect MRI sequence that can detect all disease activity.
Q: You talk about “patients who are at a high risk for disability.” Can you only identify them from MRI or are there indications in their clinical presentation as well?
Dr. Vollmer: You do get hints. Patients who have serious attacks, with a high level of disability and poor recovery at the onset of the disease are at a higher risk to have major disability down the road. However, that’s only a minority of patients. Initially, patients often have serious attacks, but then they have pretty much have full recovery.
There are broadly three factors that determine your outcome: one is the amount of inflammation you are having, the second is how destructive that inflammation is, and the third is how much reparative capacity your brain inherently has. These three factors all interact and the common final denominator is the loss of gray matter. However these three factors interact, you can see their consequence in terms of how fast the gray matter is disappearing from the brain.
Q: How does this recent study, which suggests the disease process in MS is primarily inflammatory, change how you think about treating MS patients?
Dr. Vollmer: It’s an important issue when we think about long-term management of MS. Given that the only process that we can identify right now is an inflammatory process—if we want to change the outcome, we need to shut off that inflammatory process early. And that’s not what we do—we only suppress it slightly, and over the long term that has not resulted in a major change in outcomes for patients. Clinicians are treating patients in the clinic based on what they look like right now. They only use aggressive treatment when patients are clearly failing with the first-line therapies and accumulating more disability.
The model we are trying to promote now says: don’t wait for them to develop disability. Use the MRI to determine how active they are and be willing to take the risks upfront, before they get disability, by selecting patients based on what’s happening to their brains, particularly in terms of TI black holes and ventricular size.
If we wait until patients have fixed disability, we have waited too long. They have lost so much neural tissue that we can’t restore function. What I think is critical for everyone to understand is this: it’s not where patients are now that is important. It’s where they may be when they are 55 or 65 years of age.
What we are trying to do is protect their brains for their futures. That’s a different paradigm.
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