Journal Volume 1 - January 2006
Article 12
Multiple Sclerosis I am going to present you with an overview of multiple sclerosis. As the topic of MS is very complicated and entails an enormous amount of information, I am going to focus my discussion on some of the new developments in the field. I will focus my paper on the diagnosis of MS; how we determine the risks of developing MS after the first demyelinating event; some new data indicating why it is important that we recognize this as early as possible and start treating it; and then, finally, some of the recent pathology developments regarding different types of MS. The McDonald Criteria The diagnosis of MS hinges on the ‘multiple’ part of multiple sclerosis. The diagnostic criteria require multiple areas in space within the nervous system and multiple in time. In other words, there needs to be at least two attacks at different times, and the attacks need to be in at least two different locations in the nervous system. The old criteria were the Poser criteria that were developed in the 1970s. MRI scans first came out in 1985. So, the earlier MS criteria were developed and used before the MRI existed. The new McDonald criteria incorporate MRI into the definition. The last criteria, and this is difficult, requires that there is no other explanation. Turning first to the criteria regarding attacks in time, the diagnosis requires two clinical attacks. If a person has an attack, a first attack, there needs to be a second attack in order to receive an MS diagnosis. The clinician can choose to wait to see if there is going to be a second clinical attack or the clinician can choose to use MRIs to identify attacks. There are definitions as to how these MRIs are to be performed. All of the inflammatory activity that occurs within the first three-month period is considered to be part of the same (first) attack. So, any new enhancing lesion after 3 months is an attack. Also, any new T2 MRI spot after 30 days is considered a new lesion. For many people who present with transverse myelitis, their physicians perform serial MRI’s trying to catch a second attack in time. The evidence has demonstrated that for every attack an MS patient is aware of, there are approximately ten silent ones that can be identified on an MRI. That evidence offers significant opportunity to identify subsequent attacks with MRIs. If a person has only one location, such as transverse myelitis, you do not yet have MS; the diagnosis requires a second location. Again, the physician can wait until there is another attack or they can begin looking for subsequent attacks by performing serial MRIs. The second criteria for an MS diagnosis concerns inflammatory attacks in more than one location. A significant challenge concerned the determination as to how much MRI change was needed to qualify for a MS diagnosis. A German scientist, Barkhoff, performed a particularly good study on this issue. Through his experiments, he determined that nine lesions were needed for the diagnosis. You need three out of these four to qualify for the MRI requirements:
Each spinal cord lesion counts as a separate lesion. Also, spinal cord lesions count as infratentorial lesions. Two or more of the following:
Even from a brief overview of these diagnostic criteria, it is readily apparent how difficult this issue is for physicians. It is a struggle to arrive at a correct diagnosis of MS; it is very hard to do. Because of the use of MRI and new diagnostic criteria, the time to diagnose MS has fallen from 3.9 to 0.61 years during the past decade. Conversion of CIS to MS by McDonald Criteria How do the McDonald criteria perform relative to the older Poser MS criteria? This was a study of 139 patients with CIS; clinically isolated syndrome (Figure 1). This means that they had one attack of something like transverse myelitis or optic neuritis, and at twelve months they got an MRI. Within those twelve months, thirty-seven percent of them had a new lesion and therefore met the McDonald criteria for multiple episodes in time. Within the first year on the old criteria only eleven percent of them had met the criteria by having a clinical attack. They took these people that met the McDonald criteria at a year, and saw how they did. The dark bars reflect those that met the McDonald criteria within the first year. By the third year, eighty percent of them had gone on to have a clinical attack. It seemed the MRI predicted quite well who was going to go on and have a more aggressive course. The light bars are the ones who had no change on the MRI at a year, and you can see only twenty percent of them had gone on to get MS. If you compare this eighty percent three-year rate to the Poser criteria where only forty-four percent had developed MS, we are getting almost twice the yield (correct diagnosis) with these new diagnostic criteria. How do we use this diagnostic information to determine a person’s risk of whether they have MS or whether they should be treated? There is a good five-year study published in 1993 that has generated a tremendous amount of information. As you can see from the chart (Figure 2), of those who presented with transverse myelitis and had an abnormal brain MRI, two-thirds had gone on to get MS within the five years. This has now been updated with a fourteen-year follow up on this group (Figure 3). Referring to the bolded line in the chart, if they had even between one and three spots on their brain MRI when they first presented fourteen years ago, even though they might have transverse myelitis, eighty-nine percent of those had CDMS; that is clinically definite MS. Another six percent had clinically probable MS. So, you are getting a ninety-five percent chance that they have MS. Because of this, if a person presents with a single episode like transverse myelitis and their brain MRI is abnormal, most MS specialists would recommend going ahead and treating those people, knowing that their risk of really having MS is extremely high.
Why Treat MS Early Why are MS specialists interested in treating MS early as opposed to waiting for the next attack and a more definitive diagnosis? There are several lines of evidence supporting the importance of early treatment. I will go over each of these in turn. There is evidence from atrophy; changes in normal appearing white matter of the brain; functional MRI changes; and then data from three drug trials (Copaxone, Avonex and Rebif data). This diagram shows the atrophy data (Figure 4). Jack Simons’ work shows this evidence really well, but this is corroborated in numerous other studies. These are four different measures of brain atrophy; or shrinkage. They took people with an EDSS of between 1 and 3.5. EDSS is a disability rating scale, and 1 to 3.5 is the lowest end of the scale. With 3.5, they are not really even having trouble walking at that point. It is a very, very mild MS. Then they followed them. The white bars are the changes in atrophy at one year and the dark bars are what happened by two years. The two on the right; when it goes down, that’s bad. And the first two on the left, when it goes up, that’s bad. So basically, bad things happen to the atrophy, no matter how you looked at it. This was determined very early in the disease. Even over one or two years atrophy is occurring and we would like to jump in there early to try to prevent this. This graphic shows a MR Spectroscopy (Figure 5). This is a picture from our scanner at the University of Washington. The MR spectroscopy is a more sophisticated technology than an MRI. We are able to set the machine to get a picture of the anatomy, but we can also obtain a chemical footprint from a specific location in the anatomy. That is precisely what we are doing from within the white box in this image. This NAA peak is a chemical that is in axons and is a measure of axon integrity. The choline is in myelin, so we can actually measure how much damage there is on a chemical basis within that square. In this study by Fernando, they looked at clinically isolated syndrome (CIS) (Figure 6). Again, this is people who have had a single attack. They looked not at the spots on the MRI, but at the normal appearing white matter; totally normal looking areas of the brain. They found that looking at these various chemicals, they are pretty similar between a control group and the people that had a single attack. This is the case until you get down to the myo-inositol, and that is elevated in those with the prior attack. This chemical is a measure of the metabolism of oligodendrocytes. It looks like very early on, right after the first attack, even in the normal areas of the brain the oligodendrocytes are already suffering. We should, again, jump in early and try to prevent them from dying off. This is a functional MRI (Figure 7); these images are also from our machine at the University of Washington. We are able to have the person lie in the machine, get a regular MRI scan and then we have them do some activity. In this case, they were tapping the right index finger. We have them do that for thirty seconds, then we alternate between lying there doing nothing and doing the activity for thirty seconds. We can actually measure the difference in blood and oxygen extraction from the blood with them doing this. The bright areas on the scan are areas of the brain that are required for this person to tap their finger. The brain is cross-wired so that the left brain controls the right index finger. MRI’s are, however, cross-presented, so the left side of the brain is the one on the right. It is evident that this person has wide spread changes across a big area of the brain. This person has MS, but they have such a mild case that you would not be able to tell it seeing them walk down the street. They are very mildly affected, but yet at this very early stage, they are already having to use considerably more brain resources to do simple movements as compared to a person without MS (the control). This is another functional MRI study that was done by Rocca (Figure 8). He looked at clinically isolated syndromes (people who have had their first attack). He found that these three areas of the brain, were lighting up with functional MRI, and they shouldn’t be. Again, very early on, there are wider spread changes in the brain than the regular MRI would lead one to believe. This is the ETOMS (Early Treatment of MS) study that involved Rebif versus placebo (Figure 12). You can see there was a difference in the development of second attacks. So, this drug also works early on. This is the Prisms Long-Term Follow-Up, involving Rebif (Figure 13). For this study they put half of the patients on placebo and half on Rebif for two years and then they crossed everybody over to Rebif; it was similar to the Copaxone study design. The first and second bars (on the left) reflect the numbers of attacks people experience when they were treated for the entire length of the study. The bar (on the far right) shows what happens when you don’t treat them for the first two years, and then switch them over. They have a higher relapse rate. Again, what you lose the first two years, you don’t gain back by treating them later. Those are the reasons why there is an emphasis on trying to recognize MS early and get on with treatment. Pathology Types of MS The last section of my paper will briefly address some of the pathology changes that have really revolutionized our way of thinking about MS. We used to think MS was one disease, but it now it turns out that there are four pathology types. This work was done by Claudia Lucchinetti at Mayo; Hans Lassman and Wolfgang Bruck were the European counterparts who participated in these studies. There are four types of acute MS lesions; this is type II. Type I and type II look the same, which is why I am not presenting a graphic of type I. There are T-lymphocytes and macrophages. The large white spot is missing myelin. With a stain for myelin on the right hand panel, the dark spot is a macrophage stain. The area that is missing myelin is chock full of macrophages. Macrophages are the garbage disposal units of the immune system. They are in there cleaning up debris. The bottom panel is a measure of complement. Antibodies and complement often go together to cause damage. The difference between type I and type II MS is that type I does not have complement or antibodies and type II does. There is nothing really new about these findings, and this is pretty much what we expected to find. Type III, however, was a surprise. The right hand panel is the missing myelin. You can see the macrophages involved there. The borders of this one are not as crisp as the previous one (Type II), because the line of inflammation is not as well demarcated. The bottom panels are very interesting; these are pictures of dying oligodendrocytes. You can see in the middle their nucleus is black. This is stained with a TUNEL stain. This is something called apoptosis. Apoptosis is like a suicide pill that we are preprogrammed to have. We use it a lot. Cells that are infected by viruses will trigger apoptosis and kill themselves off rather than bringing down your entire body. During formation of the fetus, we grow ten times as many nerve cells as we need and kill off ninety percent of them by apoptosis, leaving us with, hopefully, the best ten percent. These cells are dying. And they are dying by killing themselves. They do die right within the lesion, but they also die out away from the lesion in areas where there is no inflammation going on. They also have a preferential loss of MAG. MAG is a protein within the myelin, but it is on the inside of the myelin. So, they are dying from the inside out. If it were an immune system attack on the myelin, they would die from the outside in. So, these findings are curious. Type IV is also curious. The two top panels and the bottom left panel present good pictures of a lesion; on the bottom of each of these panels. Out away from the lesion (above the lesion) there are these white holes. Those are holes left by dying oligodendrocytes. Again, oligodendrocytes are dying away from the lesion. They are dying a regular death; they are not dying through apoptosis. It is interesting that there are four types of MS. These findings are very important. We don’t know if MS is one disease that has four stages, or if it is four diseases that are all masquerading as the same? We don’t know. Type III and type IV have never been associated with any known autoimmune processes; it raises the question as to whether autoimmunity is involved in type III and type IV? It is clear that the immune system is up to no good even in those types, because it is involved in cleaning up the debris and other functions; it is possible that you could get collateral damage from those activities. But it has made us rethink our approach to the whole disease. Type III and IV have only been seen in virus infections, toxins, or diseases where the oligodendrocytes get ill of their own accord. We don’t know which of these illnesses are contributing to type III and IV. Type III and IV, by the way, make up probably about thirty or thirty- five percent - somewhere in that range - of the MS realm. Each patient only has one type. These pathology studies were mostly done from autopsies, so, of course, they are done at only one point in time. In the few cases that we have more than one time point (from biopsy), they seem to maintain the same pathology, which suggests that maybe it is four diseases masquerading as one. With the McDonald criteria, we are now able to diagnose MS earlier and arrive at a more accurate diagnosis. Early diagnosis and treatment is important as widespread brain changes occur early in the disease process. It is so important that when a person presents with transverse myelitis that we are able to assess the risks of this developing into MS in order to prevent these early changes. Our understanding of MS is complicated by the different pathology types. We do not know what causes MS, and these new and recent findings from pathology have challenged how we think about MS. |