Mark Freedman, MD: Hello. I'm Dr. Mark Freedman, professor of neurology at the University of Ottawa in Ottawa, Ontario, Canada. I would like to welcome you to this Medscape Great Debate, entitled "Radiologically Isolated Syndrome: To Treat or Not to Treat." Joining with me are 2 other panelists, Dr. Bruce Cree, assistant professor of neurology at the University of California, San Francisco, and Dr. Fred Lublin, professor of neurology at the Mount Sinai School of Medicine in New York. Gentleman, radiologically isolated syndrome [RIS], is it MS and should we be treating it? Bruce?I think the first thing we have to decide is what are we talking about -- what is radiologically isolated syndrome? I think the key point here is that we are talking about a patient who has had brain MRI [magnetic resonance imaging] done for some other reason and you see what looks like typical MS [multiple sclerosis] on the brain MRI -- periventricular plaques; contrast enhancement. And those are the cases that are defined as radiologically isolated syndrome. We are not talking about tiny little spots in the brain that you might see associated with migraine or age-related changes. These are patients who have had an imaging study done and who have a brain MRI that looks like MS, but no signs or symptoms, and no relapses that would tell you this is a clinically isolated syndrome [CIS]. So Dr. Lublin, would you treat or not treat a patient?
Dr. Freedman: Let me just interfere for a minute, because why would a patient [being seen] for a migraine get enhancement? Are we doing enhancing scans on patients who don't have curious neurologic symptoms? Is there not a suspicion that they might have something going on there and does that not make them more likely to have MS? Why would we be doing MRIs like that? What sort of patient populations are we talking about, because I see lots of people with that nonspecific stuff?
Fred Lublin, MD: There is no suspicion here. What we are talking about is people who had an MRI for some other reason completely unrelated to anything that could be construed as MS. Every once in a while you dig a little deeper and you may come up with something, but mostly we are talking about ones with a bad headache or pituitary abnormalities, workups for hormonal imbalances and things of that sort -- [even] a bump on the head. So if there is a suspicion there, that is not what we are talking about. We are talking about truly surprising findings on the MRI.
Dr. Freedman: But surely there are other things that can look exactly like MS. We have seen it repeatedly that there are many, many mimics of other diseases that show up with lesions identical to [those of] people with multiple sclerosis. How do you differentiate these?
Dr. Cree: I think there are relatively few things that look absolutely identical to MS. I have a pretty short list of things that I look for. Sarcoidosis is possible. I suppose CNS [central nervous system] lupus is possible, although that is pretty rare and I really don't see CNS lupus in my practice. Lyme disease can certainly present with lesions that look exactly like MS. [Also] other infectious etiologies, syphilis for example. So there are other things that can look like MS, but there is a way to go ahead and tease these things apart.
Dr. Freedman: So how would you do that? Before we could even consider treatment, I think we need to know what we are treating.
Dr. Cree: I think the point here is that these radiologically isolated syndromes look like MS, but we have no other causative etiology to explain the lesions on the brain MRI. I think the other point here, which is very interesting to me, is that it extends beyond the brain MRI and goes into the spinal cord. There was a study presented at this congress by Darin Okuda,[1] who showed that some of these patients who had brain MRIs also had some cervical spinal cord imaging. It was very interesting that of those patients who had cervical spinal cord imaging, a number of those patients also had lesions within the cervical cord. The key piece of data that he showed was that a majority of those patients -- 84% of the patients who had cervical cord lesion -- go on to develop the first attack of multiple sclerosis, the so-called clinically isolated syndrome. So the odds ratio of having a CIS or progression to primary-progressive MS [PPMS] -- because 2 of the patients ultimately went on to have PPMS -- was about 1 in 128, a very, very high odds ratio.
Dr. Lublin: This is with brain lesions?
Dr. Cree: This is with brain lesions as well.
Dr. Lublin: So they looked at the spine because the brain was abnormal?
Dr. Cree: The brain was abnormal and then the spine was looked at. So of those patients who had lesions in the cord, the odds ratio of going on and having a first attack is extremely high.
Dr. Freedman: So if this is the case Fred, why wouldn't you treat this?
Dr. Lublin: Well let's not get into treatment yet -- let's stick with "is this MS?" So I think that what Dr. Cree brings up in this study of Okuda's[1] is actually a very clever thing to do. Because of all of the mimics you mentioned -- and there are a few that have come up at this congress too -- one that is a mitochondrial disorder and a few others, the finding of lesions in the brain and the spinal cord significantly narrows the differential diagnosis and makes it much more likely to be MS. So for example when people get older [they may] get white dots in the brain, but you don't get white dots in the spinal cord. So I put increased weight on lesions in the spinal cord and I am not surprised at the result of them switching.
Whether it becomes MS or not -- when you call something MS -- gets into whether you want to talk about a clinical definition, a radiologic definition, which doesn't yet exist, or a biological definition. So we know that biologically people have MS who never ever have a clinical attack, and were it not for MRI scans we would never pick them up. The Danes did this study years ago with everybody getting autopsies and 1 in 1000 had the neuropathologic features of multiple sclerosis. When they went back into their centralized medical records, they couldn't find anything neurologic in those folks. So we know they exist. It's to the left of benign MS. Now because we have these scans and the MRI is so sensitive to picking up the lesions of MS, we are picking these folks up when they get a bump on the head or a bad headache or whatever. So biologically some of these people are MS.
But then you have to say when are you willing to tell them that it is MS? Does it matter if they never would have had another clinical event ever?
Dr. Cree: But Fred, this gets right into the issue of CIS as well. So we know from longitudinal studies that patients who have a single attack and an abnormal brain MRI have a great likelihood of having further events. But not everybody. There are about 10% of patients who don't have another event over the next 14 years if you believe the Queen Square data.[2] So the vast majority do have another event and based on that we often wind up recommending treatment for those patients.
The newest set of [MS] diagnostic criteria that have been proposed, the MAGNIMS [Magnetic Resonance Imaging in MS] criteria,[3] [include] patients who have an abnormal brain MRI with evidence of dissemination in time by a contrast-enhanced lesion as well as other lesions that do not enhance with contrast, along with some other criteria for dissemination in space. [These criteria] are actually just as good as the McDonald criteria or the International Panel criteria from 2001 and 2005, where you show dissemination in time by serial MRI imaging. So I know you have sat on both of those panels and presumably are going to be reviewing the MAGNIMS criteria. Aren't you convinced that in the case of CIS with an abnormal MRI that meets MAGNIMS criteria that this is the same thing as MS?
Dr. Lublin: So CIS is not the issue here yet. I mean we are again moving to the left. You have established MS, clinically isolated syndrome, and here to the left you have radiologically isolated syndrome. Then you have all the people who have MS who we will never find out about because they never come to clinical or radiological attention. The CIS story is very compelling, and it is even more compelling than you laid out in the sense that all you need is 2 lesions. So the Queen Square data[2] [suggest that] if you have 1 lesion, [you have an] 80% chance in 14 years of converting to definite MS or having another attack. All of the clinical trials starting with CHAMPS [Controlled High-risk Avonex Multiple Sclerosis][4] and moving forward took 2 MS-looking lesions; MS as judged by people who know how to read MRI scans and pick out what looks like an MS lesion. They all showed highly significant benefit. It took us awhile and we still haven't convinced everyone that those folks ought to be treated. But back in 1993 when we came out with the first treatment for relapsing MS it took us a while to convince people that they ought to treat for that -- we moved past that. CIS I think most people treat -- [although] there are still debates and there are areas around the world where you can't get treated -- but that is based on well-established criteria and clinical trials.
For RIS we don't have that information. We do have a few studies now: we have LeBrun,[5] we have Okuda.[1] LeBrun did a follow-up,[6] and the conversion rate of those people ranged from 25% to 30% over 5 years clinically and higher, maybe double that, radiologically. But we don't know what the impact is of treating at that stage. You can by extension say, well why not? It is not unreasonable, which is why we could have flipped a coin as to how to sort out which side we were going to be on. I don't think it is necessarily unreasonable, but you have to recognize that as difficult as it is to say [to a patient] with CIS "we are going to treat you for something that I can't diagnose yet, but I know you will do better this way," [with RIS] you are talking about at least another exponential change: "you don't really have clinical MS and you have never had an attack, but we want you to take one of these therapies, which at best is going to be annoying -- and by the way I don't know when to stop it and you are now at risk for MS so you have to think about that, too." It is just tough.
I don't think there is a knee-jerk answer to this. I think that a changing MRI would bother me. I think it probably bothers you and I think that is what your colleague is showing, but I am not sure whether all of these people ought to be treated or if it will do any good. Saying that, I recognize that it's our work and the work of others [to recognize] that every exacerbation potentially counts, with 50% of individuals having something residual.
Dr. Cree: Every cubic millimeter of brain tissue that is acutely demyelinating has about 10,000 axons being transected based on Bruce Trapp's work, and once those axons are transected, they don't grow back. Once they die, the neurons die and I think that although we are still waiting for proof that neurodegeneration is caused by neuroinflammation, I am pretty swayed by these data and really think that is the key issue at stake here. If we go ahead and imagine a scenario where we have a treatment trial in RIS and we stratify that treatment trial where we are just looking at the patients who have spinal cord lesions and we find that we are able, with anti-inflammatory therapies, to delay the time significantly until the first actual clinical event, then we have done our patients a service. So from the extension of knowing what we know about MS, knowing what we know from the MAGNIMS study,[3] knowing what we know by putting up all of these MRI scans over the years and seeing more lesions than the patient presented with. Say a patient comes in with optic neuritis and the brain is chalk full of lesions; we know those lesions showed up at some point beforehand. Doesn't it make sense to actually consider treatment in such a patient?
Dr. Lublin: It makes sense, but you would want to have evidence.
Dr. Cree: Absolutely.
Dr. Lublin: The Bruce Trapp information is interesting. What is not clear to me is whether that is the case with every patient. What he is showing are the patients who came to his biopsy table [and there was] evidence of axonal degradation in some of them. One of the challenges that we now have is to phenotype people as to whether they are demyelinators or axon degenerators or both, and I don't know the answer to that. The pathologists haven't been able to answer the question for me either. They are interested in looking at a number of different things, but no one has answered the simple question as to whether someone is more degenerative or more inflammatory or demyelinated. We know there are people who have bad demyelination who get a fever, [become] septic and go from walking to plegic. You hydrate them and you treat their fever and they are back to walking again. Well they can't be degenerators. They have to be demyelinators. So there is a difference there, and I think these are the kinds of things we need to sort out. What we need to convince people is evidence. The other thing we need to deal with is what is the threshold under which you can put out a general recommendation to the neurologic community to treat, because it is a little different when your colleagues are looking at these scans and making decisions and when we put it out as a general recommendation for everybody.
Dr. Cree: Sure, of course. I would agree entirely at this point. I don't think we can make general recommendations. I think even in the subgroup of patients who really look like they probably have MS, we still don't know for sure whether treatment should be done or not, but I certainly would consider it. I have in my personal practice only treated one RIS patient and that patient had contrast-enhancing lesions and I also found evidence of subtle asymmetry on her neurological examination. I discussed treatment with her and she ultimately went on to treatment and ultimately went on to have CIS despite treatment and ultimately went on to have RRMS [relapsing-remitting MS] despite treatment. We now finally have her stabilized. It is a very interesting dilemma about what to do when you are faced with a real-life patient who is high functioning, who is active at work, young, and wants everything done for them. The question is, what do you do?
Dr. Freedman: If we had a treatment that was a simple pill with virtually no side effects and a long safety record, would you hesitate?
Dr. Lublin (to Dr. Cree): Did you make that decision on one scan or a follow-up?
Dr. Cree: She actually came in with a single scan and on the scan she would have met MAGNIMS criteria with a couple of contrast-enhancing lesions and other lesions that were T2 bright and a couple of T1 dark, again suggesting that some of the lesions had a more chronic nature. On the exam there were some very subtle findings that were there, but I was able to convince myself and we entered into a discussion and she ultimately decided to move forward with therapy.
Dr. Lublin: So I would disagree with that. I have treated some as well, but I always look for change over time. I want to see the enhancing lesions get better in the sense of not enhancing and I want to see something new. It doesn't matter if it is gad[olinium-enhancing] or T2. With that sort of picture, I would have a discussion with the patient about potential treatment, with all of the various caveats.
Dr. Cree: Sure.
Dr. Freedman: So if I could sum up, general recommendations are very hard to make at this point without the evidence. There are cases that, discussed individually with an intelligent individual who has read [the literature] and is very anxious and knows the pros and cons of taking the medication, it might be reasonable to consider treatment in such individuals. But it is case by case until we have the evidence that treating RIS makes a difference in the long run. I think, gentlemen, you have put all the important facts on the table and certainly for you the viewers this is something that you will be facing in your practices. The decisions are not clear, but we look forward to new evidence and that evidence should help us deal with the RIS syndrome. Thank you for your attention today.
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