Section I: Basic Science

DR. FOX: My name is Dr. Robert Fox, and welcome to this program, "The Multiple Sclerosis Highlights from the 2006 American Academy of Neurology." Joining me today are two experts in the multiple sclerosis field. Dr. Samia Khoury, a Codirector of the Partners' Multiple Sclerosis Center at the Brigham and Women's Hospital and Associate Professor of Neurology at Harvard Medical School. And Dr. Paul O'Connor, Director of the Multiple Sclerosis Center at St. Michael's Hospital and Associate Professor of Neurology at the University of Toronto. Welcome to you both.

DR. FOX: Let's start with the scientific highlights. Samia, what were the important papers that were presented at this meeting?

DR. KHOURY: Well, I'm going to talk about a few things that attracted my attention at this meeting. To start with, there was an interesting abstract [P02.080] on MS pathology looking at biopsies from MS patients. Dr. Lucchinetti and her colleagues looked at cortical demyelination. So there was evidence of cortical demyelination in these biopsies, which is quite prevalent, and I think that's an important thing that people have not been focusing on before, and I know that there are several groups that have been interested in looking at cortical demyelination by MRI also, and maybe you may want to touch up on this in later discussions. There were some other interesting things. For example, there were abstracts related to diagnosis of MS. There is an abstract [P02.081] on clinically-isolated syndromes. So if you take people with a first episode of demyelination, and you take their CSF and then you measure tau protein and neurofilament, these can help you increase the sensitivity and the specificity of the diagnosis. So you can predict which patients are going to convert to MS much better than just by relying on the MRI alone. A second abstract [P02.088] was by looking at a genomic approach to the MS diagnosis. So, if you look at microarray of peripheral blood lymphocytes of MS and other autoimmune diseases, there is a certain pattern of these genes that are expressed. So this group, what they did is they took nine genes, and they focused on these nine genes, and they developed a kind of a formula by looking at these nine genes, giving them a score. And they looked at the expression of these genes by QPCR, and after they put them in this formula, they have this score. And if you do this on MS patients versus control, versus other autoimmune diseases, this was able to differentiate the MS patients from the other controls and from the other autoimmune diseases very nicely just focusing on nine genes. So I thought that was very interesting.

DR. FOX: So by learning more about those genes, one might eventually figure out a little more of what's going on at the molecular basis with MS?

DR. KHOURY: Definitely, yes. That's one way to look at it. And the other way is just to think that by looking at the genes expressed, there may be a way to differentiate MS from other diseases. So it's just basically making the diagnosis a little bit more easy.

DR. O'CONNOR: If I could just interject, this is part of a longstanding effort to find a blood test that helps us to diagnosis MS, which so far has eluded us despite many previous efforts in this area. So, we'll see if this particular study stands the test of replication or not.

DR. KHOURY: Right. You know, that's been the problem with most of these assays, is when it comes to the time to replicate them, most of them have not been easy to replicate. Another area that I was interested in is the T-cell reactivities in MS, which is something that people have been working on for many years. One of the very interesting abstracts [S42.001] was related to looking at T-cell reactivity in pediatric patients. So, this is Amit Bor-Or's group, and they took pediatric MS and people with type 1 diabetes-again, pediatric patients-and they looked at reactivity against dietary antigens, and in particular to milk antigens. And what they found was that in MS patients, the reactivity is to myelin basic protein, for example, and also to BSA, which is bovine serum antigen, whereas in the diabetic patients, they reacted to the -- I forget which one it was, the insulin, I think, or some GAD protein particular to diabetes -- but also at the same time another milk antigen. So there was a different antigen profile for the reactivity, which I thought is very interesting. And that could be interpreted either as a cross-reactivity between the BSA and the myelin in these pediatric patients, or it also could be interpreted as an evidence of a particular T-cell receptor repertoire in these patients that makes them react to these two antigens versus not react to the other two.

DR. FOX: Now, is this something that is only seen in pediatrics, or is this something that's also seen in adults? Or has this not been looked at in that fashion?

DR. KHOURY: Well, I know there's been some studies before in MS patients regarding reactivity to milk antigens. But in this particular study, the focus was on pediatrics.

DR. O'CONNOR: So, in fact, this same study was done in adults several years ago, published by the same group in the Journal of Immunology. I was a co-author, so that's why I remember it. And it's the same story, it's that both diabetics and MS patients respond to bovine serum antigen, or BSA, as it's called, but they respond to different epitopes of the antigen. So the same antigen, different epitopes. And now the Banwell, Amit Bar-Or group has got the same findings in pediatric MS. Again, the reactivity to BSA among both diabetics and MS patients.

DR. KHOURY: There was also another abstract [S42.005] related to isolating T-cells from lesions, from MS lesions, and this was the group led by Markovic-Plese. And what they did is they isolated these T-cells, and they cloned them and checked their reactivity to myelin peptides, and what they found is that the majority of the cells were of CD8 type, and they reacted to PLP, one of the PLP antigens. So, I thought that was interesting, because this is the first time people have actually isolated the cells from the lesions and looking at their reactivity.

DR. FOX: So, we for years thought about CD4 cells being important in MS, and now there's more talk of CD8. Is that sort of the forgotten corner of the immune system that we're starting to recognize more?

DR. KHOURY: Absolutely. I think CD8 cells play an important role in the disease pathogenesis, and now, people are focusing more on the CD8 cells. And the next abstract [S29.005] that I'm going to talk about, actually, again relates to CD8 cells. This was in the EAE model, and they found that CD8 T-cells are the ones that mediate the occurrence of black holes. So they looked at animals with EAE, and they generated the disease in different knockout animals, so animals that lack all T-cells or animals that lack CD4 cells or perforin or FAS. And they found that if you knock out the CD8 cells or perforin, then you don't get the black holes on an MRI of these mice. So it's interesting and again it suggests that the CD8 T-cells play an important role in the pathogenesis. The next section that I'm going to talk about is immune mechanisms in MS therapies. There was an abstract related to the action of glatiramer acetate. Now, you know that glatiramer acetate-it's been suggested that its mode of action is by generating TH2-type cells that cross-react with myelin. In this abstract [S29.003] ,and, yes, this was by Dr. Zamvil's group, this was in EAE, and what they demonstrated is actually, at least in EAE, this was not the mechanism of action of glatiramer acetate. Instead, they showed that the antigen-presenting cells are modified by the glatiramer acetate, causing them to become tolerogenic or suppressive. So, if you transfer antigen-presenting cells from the treated animals into a new recipient animal, you can suppress their disease and treat their disease. So again, it's an interesting new look at how glatiramer acetate might be working.

DR. FOX: Yes, it's always been a bit of a mystery as to how all these drugs work and in certainly multiple mechanisms. And the idea that the glatiramer acetate just works through suppressor cell generation is probably not correct.

DR. KHOURY: Yes. Another abstract [P03.180], again relatied to glatiramer acetate, and it shows that patients who are responders to the glatiramer acetate treatment had a decrease in IL-18 in their serum. So interleukin-18 is one of the proinflammatory cytokines. And, at the same time, caspase-1, which is the molecule that cleaves the IL-18 from a procytokine to an active cytokine is also decreased. So there is a correlation between people who have a decrease in their response to glatiramer acetate and their decrease in IL-18 and and Caspase-1. And this was by Dhib-Jalbut's group. There was also an interest now in dendritic cells in MS, and I think we're seeing more and more people interested in that particular aspect of dendritic cells.

DR. FOX: I'm sorry. Remind us of what dendritic cells are, and what they do in the brain.

DR. KHOURY: Sure. Dendritic cells are the immune system's most powerful antigen-presenting cells. So they present antigens to the T-cells and increase reactivity. And there's different kinds of dendritic cells, and one of the abstracts [S42.006] by Dr. Balashov and Weiner showed that dendritic cells, plasma cytodendritic cells, a subset of these dendritic cells, have increased production of interferon-alfa and that when you treat these patients with interferon-beta, there is a decrease in the production of this interferon-alfa by dendritic cells. Also, I wanted to mention a couple of abstracts from the disease model-again, the experimental autoimmune encephalomyelitis. We had several abstracts, [S29.002] but some of the interesting ones relate to the estrogen, you know, which has been promoted as a possible way of downregulating MS in the animals treated with estrogen or in pregnant mice. There was an increase in regulatory T-cells related to the treatment with estrogen. So this was the mechanism of how this might work in animals. And another very interesting abstract by Dr. Weiner [S29.001] was a novel way to use a molecule that is being used for other autoimmune diseases. This is an anti-CD3 antibody treatment which is in clinical trials for diabetes, for example, in an intravenous form. But in this abstract, Dr. Weiner shows that if you give this antibody orally- so you feed it to mice-there is a generation of regulatory T-cells in the gut, in the mesenteric lymph nodes, that migrate to the spleen and suppress disease. And these cells are LAP-positive, which is a marker of TGF-beta. And this is an interesting new way of treating the disease in mice, at least, and potentially in humans.

DR. FOX: Well, thanks very much, Samia. That sounds like a lot of exciting things going on at this year's Academy.

REFERENCES [P02.080] Cortical Demyelination Is Present in Early Multiple Sclerosis
Shanu Roemer, Christine Stadelmann, Wolfgang Bruck, Gottingen, Germany, Yazmin Morales, Chicago, IL, Joseph E. Parisi, Claudia F. Lucchinetti, Rochester, MN

[P02.081] Axonal Damage Markers in Cerebrospinal Fluid of Patients with Clinically Isolated Syndrome and Early Multiple Sclerosis
Hayrettin Tumani, Ulm, BW, Germany, Axel Petzold, London, United Kingdom, Johannes Brettschneider, Ulm, Germany

[P02.088] Genomic Approaches to the Diagnosis of Multiple Sclerosis
Thomas M. Aune, Sallyanne C. Fossey, Phillip S. Crooke, Kelley A. Richardson, Jessica P. Aune, Xinqing Deng, Subraminiam Sriram, Nancy J. Olsen, Dallas, TX, Cindy L. Vnencak-Jones, Nashville, TN

[S42.001] T Cell Proliferation against Myelin, Pancreatic, and Dietary Antigens in Children: Autoimmunity Is Detectable Early in CNS Demyelination and Type I Diabetes
Brenda Banwell, Amit Bar-Or, Montreal, QC, Canada, Julia Kennedy, Roy Cheung, Hans-Michael Dosch, Toronto, ON, Canada

[S42.005] Characterization of T-Cells Derived from Acute and Chronic Multiple Sclerosis Lesions
Monica Montes, Valerie Jewells, Diane Armao, Jennifer Smrtka, Yunan Tang, Danuta Sujkowska, Silva Markovic-Plese, Chapel Hill, NC

[S29.005] CD8+ T-Cells Mediate "T1 Black Hole" Formation in an Animal Model of Multiple Sclerosis
Istvan Pirko, Tifany Nolan, Scott K. Holland, Scott Dunn, Aaron J. Johnson, Cincinnati, OH

[S29.003] Immune Modulation by Glatiramer Acetate Is Driven by Antigen Presenting Cells and Is Not T Cell Antigen Specific
Martin S. Weber, Thomas E. Prod´homme, Cynthia D. Rundle, Olaf Stüve, Dallas, TX, Scott S. Zamvil, San Francisco, CA

[P03.180] Modulation of IL-18 and Caspase-1 Expression Correlates with the Clinical Response to Glatiramer Acetate (GA) in Multiple Sclerosis
Reuben M. Valenzuela, Horea Rus, Baltimore, MD, Kouichi Ito, Piscataway, NJ, Suhayl Dhib-Jalbut, New Brunswick, NJ

[S42.006] Plasmacytoid Dendritic Cells in Multiple Sclerosis: Loss of IFN-alpha Production after Treatment with IFN-beta
Konstantin E. Balashov, New Brunswick, NJ, Adi Dembinsky-Vaknin, Leonilda Santos, Howard L. Weiner, Boston, MA

[S29.002] Enhanced FoxP3 Expression and Treg Cell Function in Pregnant and Estrogen-Treated Mice
Magdalena J. Polanczyk, Corwyn Hopke, Michael Afentoulis, Arthur Vandenbark, Halina Offner, Portland, OR

[S29.001] Suppression of Experimental Allergic Encephalomyelitis by Oral Administration of Anti-CD3 Monoclonal Antibody
Howard L. Weiner, Hirofumi Ochi, Michal Abraham, Jerusalem, Israel, Hiroki Ishikawa, Dan Frenkel, Kaiyong Yang, Alexandre Basso, Henry Wu, Mei-Ling Chen, Roopali Gandhi, Ariel Miller, Haifa, Israel, Ruth Maron, Boston, MA

Section II: Clinical Trials

DR. FOX: My name is Dr. Dr. Fox and welcome to this program, joining me are Dr. Samia Khoury and Paul O'Connor. Paul, let's turn to you. What were the highlights from the clinical trials section from this year's meeting?

DR. O'CONNOR: Well, this year I'd like to highlight four different clinical trials that I thought were of particular importance to the audience. The first is the BENEFIT trial. Now, the BENEFIT trial is a trial of Betaseron in patients who had a first demyelinating event. Patients were treated with either Betaseron or placebo and followed over two years for the development of either MacDonald's MS or clinically definite MS. Dr. Mark Freedman [S02.001] presented the results of this trial, showing that the use of the medication delayed the conversion to MacDonald's MS at six months by about 50% and delayed the conversion to clinically definite MS by about 50%, as well, using a two-year time horizon.

DR. FOX: And just to be clear, the clinically definite is another clinical relapse and the MacDonald criteria bring in MRI into the diagnostic process. Is that right?

DR. O'CONNOR: Absolutely. And in so doing, we accelerate the ability to diagnose MS, which is why the 50% difference in rate was seen at six months rather than the two years which was seen for clinically definite MS. Dr. Chris Polman [S02.002] then presented a subgroup analysis from this trial looking at patients who had a number of different clinical or MRI characteristics, and interestingly, the drug appeared to be most effective for patients who had a monofocal versus a multifocal clinical presentation, most effective for patients who did not have gadolinium enhancement. So it seems as if it was the patients with less active disease who benefited most from the treatment.

DR. FOX: Now, that's a little surprising. One would have thought, or at least I would have thought, that if you didn't have gad lesions to start, and you were less likely to go on and to have more activity later, the therapy wouldn't have as much of an impact because you were milder. So was this a surprising finding?

DR. O'CONNOR: I found this somewhat surprising. Certainly, it's different from what we've seen with natalizumab, where more active patients tend to get more of a benefit from treatment. In terms of what happened in the other interferon trials, we don't really know because the data hasn't been presented in this fashion. But it's an interesting finding, and it certainly bears further investigation.

DR. KHOURY: Do you know if this was a planned analysis, or is it just a post-hoc evaluation?

DR. O'CONNOR: This is a post-hoc analysis. So the primary endpoint of the trial was the development of clinically definite MS, and in that regard the trial was successful in that there was about a 50% reduction in risk of CD-MS conversion.

DR. FOX: So how do we compare this trial result to the other first attack trials that use other preparations of interferon?

DR. O'CONNOR: Well, if we look at the ETOMS study, which was Rebif 22 micrograms once per week, the trial that I'm discussing, the BENEFIT trial results seem superior. If we look at the CHAMPS trial data, which was Avonex interferon IM 6, 22 or 30 micrograms once per week, the results seem comparable, although a detailed analysis has not yet been done.

DR. FOX: So how well can we compare these trials? They obviously use different patients. They were done in different places. How much caution do we need when we compare one study to another?

DR. O'CONNOR: Well, I think we do need to be cautious because the three different trials that I just mentioned did in fact have slightly different inclusion criteria. The CHAMPS trial did not allow patients in who had a multifocal presentation. The time from symptom onset to trial entry varied between the ETOMS versus the CHAMPS versus the BENEFIT trial. Patients had to be entered into the CHAMPS trial a shorter time after the onset of the initial event. So there's a different proportion of patients who received steroids in the three different trials, so there are some points that make it difficult to make a direct trial-to-trial comparison, even though everybody does that.

DR. O'CONNOR: So I thought I'd move on next to discussing some of the natalizumab information. This is the drug that's been very much in the news in the last little while, and we heard some presentations from the AFFIRM and SENTINEL pivotal phase III trials of this drug. Dr. Ted Phillips [S02.005] reviewed some of the disability data related to the AFFIRM study, pointing out that on multiple measures of disability, including EDSS change, proportional change, time to EDSS change, change on the multiple sclerosis functional composite and certain MRI markers that are surrogates, if you will, for disability, like T1 black holes or T2 lesion burden, in all these different measures there is a pronounced effect in favor of the natalizumab therapy. So that was interesting to hear.

DR. FOX: So it sounds like it does work. It works in a wide array of measures, both on the MRI and the disability.

DR. O'CONNOR: Right. There was a great deal of convergent validity, I would say, in the sense that no matter how you seemed to look at it, the drug reduces relapses, and the drug delays disability progression.

DR. FOX: Did we learn anything more about the safety of natalizumab?

DR. O'CONNOR: There was a poster on this subject [P01.086]. All the patients that have been on natalizumab for any duration have been assessed, and to date there are only the two cases of PML. Both those cases emerged in patients who were also treated with Avonex previously as part of the SENTINEL study. There have been no other significant opportunistic infections that have been identified. There was one case of cryptosporidial enteritis that was identified, but this was not a particularly serious case. So we are left with the two cases of PML, and what looks like an approximate risk of 1 in 1,000 over 18 months of therapy for contracting this condition. And I think that's a conservative way to interpret the data.

DR. KHOURY: There was actually an interesting abstract that was related to CSF findings in the natalizumab patients [S32.001].

DR. O'CONNOR: Right. Go ahead and discuss it, if you would.

DR. KHOURY: So this was the patients who during the treatment with natalizumab had a decrease in CD4:CD8 ratios down to levels that are seen with HIV patients. There's a very strong decrease in CD4:CD8 ratios. And these normalized six months after stopping therapy. However, even though the ratio has normalized, the number of cells recovered from the CSF was still low. So I thought that was interesting.

DR. O'CONNOR: Yes, I think that's a fascinating presentation. That's by Olaf Stuve and colleagues. And it certainly shows that the drug has a pronounced effect on CSF cell count, and as you said, CD4:CD8 ratios. And indeed, even in peripheral blood on therapy, CD4:CD8 ratios go down. They don't go down below normal levels, but they tend to go down, and these effects, as you pointed out, are reversible, and after six months, the CSF CD4:CD8 ratio is back to normal.

DR. FOX: So does this suggest why PML may have developed in those two patients with MS who were treated with natalizumab, because you've created an immunodeficient brain, if you will, even if it is reversible?

DR. O'CONNOR: I mean, I think it could be a factor. There's other factors at work, as well, such as the theory by Rancehoff and colleagues that this agent causes the flushing out of the JC virus from the bone marrow, which might, therefore, affect the risk of its subsequent entry into the central nervous system. But the notion that the CNS is short of active immune cells is certainly consistent with what was just discussed.

DR. FOX: So where do we go from here with this drug? What sort of patients might wonder if they are appropriate for this drug?

DR. O'CONNOR: Yes, it's a very difficult question to answer. I think the first and most obvious group of patients for therapy, if the drug were back on the market, would be those patients who have active disease and who have failed on other conventional disease-modifying therapies. So that, to me, would be the most obvious first treatment group. With the greater use of the drug, a greater feel for its safety, it might become possible to extend the use to fully informed patients with less serious disease who want to be on the drug. In fact, one of the presentations by Rudick [S52.005] touched on the effect of this drug on quality of life. And quite remarkably, in both the AFFIRM monotherapy trial and the SENTINEL combination trial, patients reported a beneficial effect on quality of life, both in terms of their mental and physical composite scores using the SF-36, as well using a global overall sense of well-being score, a visual analog scale score, in both studies patients reported if they were on therapy that they felt better than if they were on placebo. And to get these clearcut beneficial quality of life measures in an MS disease-modifying trial is most unusual. In fact, I would say it's unprecedented. And I can say from personal experience that the many patients at our center who are in this trial are very anxious to get back on the drug.

DR. FOX: So it's some tough decisions. A good drug, but some serious risks and some tough, hard discussions to have with patients about how it all balances out.

DR. O'CONNOR: Yes, risk and benefit. That's right. A couple of other points on natalizumab before I move on to other trials. Dr. Balcer [S32.004] did a presentation regarding visual function with natalizumab and was able to show that using low-contrast visual acuity testing, there is a delay in visual worsening in patients on natalizumab as compared to placebo. So that's another disability-type endpoint, if you will.

DR. FOX: Now, Paul, I hadn't really heard about this much before used in a trial. Is this a new outcome measure that we're using to measure vision in MS?

DR. O'CONNOR: Well, it is, and part of the motivation behind this is that the multiple sclerosis functional composite does not have a good visual component. And low-contrast visual acuity may be, in fact, that missing part of the component for visual function. Another very important presentation related to the drug was Dr. Calabresi's antibody talk [S42.007]. And what he showed us is that with patients on natalizumab, 6% develop persistently positive antibodies. Those patients who are antibody-positive experience a loss of efficacy of the drug, both in terms of relapses and disability progression, and those patients who are antibody-positive are most likely to have significant infusion reactions. So, if you are antibody-positive and you're on this drug, you should get off it. Antibody-positive in this sense means persistently positive, so that's positive over two subsequent tests separated by 42 days. Interestingly, most patients turn antibody-positive by about 12 weeks of therapy, and so that would be an ideal time to start testing patients. If you're a clinician and you're using the drug, if a patient has an infusion reaction, that's a clue, of course, that they may be antibody positive, because in the clinical trial, the infusion reactions were disproportionately occurring in antibody-positive patients.

DR. KHOURY: What kind of reactions were these?

DR. O'CONNOR: Well, an infusion reaction could range from anything such as a mild rash to urticaria, headache, some mild breathlessness. The vast majority of the infusion reactions in the trial were minor events, not major events. Only percentages less than one of patients actually had urticaria.

DR. O'CONNOR: Another trial I wanted to briefly discuss was a presentation by Dr. Jeff Cohen [S61.001] related to Copaxone, a trial of patients who received either the regular dose, 20 mg/day, or double the dose, which is 40 mg/day. In this trial, which lasted nine months, patients were allowed in if they had had one attack in the previous year and if their MRI showed an enhancing lesion. What was shown in the trial of a relatively small number of patients, about 90, was that patients on the higher dose had fewer relapses and fewer enhancing lesions. Now, these numbers don't reach statistical significance because the sample size is somewhat small. We have to be cautious. But it is interesting that strong trends towards greater efficacy were shown in this double dose trial of Copaxone.

DR. FOX: Now, up to this point there haven't been many studies that have looked at the dose of Copaxone. Isn't that right? Hasn't it always been 20.

DR. O'CONNOR: There have been none. It's always been 20.

DR. FOX: Just, that's always what's been done.

DR. O'CONNOR: Is there nothing other than 20? So we've always wondered, could you lower the dose, could you increase the dose, and what would happen? So this is the first step to seeing what a higher dose might do. Again, we have to be cautious, because it was a highly selected population of patients who had both a prestudy relapse and an enhancing lesion at baseline. In fact, about 300-odd patients were screened to get the 90 for the study. And the next trial I want to discuss briefly is the FTY-720 phase II results. Now, FTY-720, otherwise known as fingolimod, is an oral agent. It's a sphingosine-1 phosphate receptor antagonist. So it binds to these receptors which are widely present on white blood cells, particularly lymphocytes, and actually prevents their exiting from lymph node-type tissue. So patients on the medication will experience a reduction in their lymphocyte count as these lymph cells, as I said, are in the lymph nodes and the spleen. Now, what was presented was phase II data of a trial involving about 280 patients [S12.003]. Patients either received placebo, 1.25 or 5 mg of fingolimod over six months with monthly MRI. The primary endpoint was the cumulative number of enhancing lesions, and this drug reduced the number of enhancing lesions by more than 50% in both dose groups. As well, and quite gratifyingly, relapse rates were also reduced by more than 50% in both dose groups. At the end of the six-month placebo-controlled phase of the trial, placebo patients were re-randomized to either low- or high-dose fingolimod, and what was shown was, once the placebo patients were switched, they too had a very significant reduction in their number of enhancing lesions over the subsequent year, and they also experienced a significant reduction in their relapse rate. So this is an interesting agent. It's an oral agent, which would be, of course, popular with patients. This is a phase II, study, however. We need to be cautious, and a phase III trial is being planned, and in fact has started in certain areas of the world.

DR. KHOURY: Do you know if there has been any decrease in number of T-cells in the CSF of these patients?

DR. O'CONNOR: No, I don't. I don't know what the CSF cell count does, and that's an interesting point. Certainly, we do know that this drug does enter into the CNS. It's lipid soluble. We would like to know that. In terms of adverse events of this agent, it has a known propensity to cause a transient decrease in heart rate in the first six hours after taking the medication. It slightly increases blood pressure by about 5 mmHg, and it's slightly bronchospastic, so it's in some ways a bit like a beta blocker in that it can slow the heart rate and cause some mild bronchoconstriction. There have been no major adverse events related to this drug, so far. In the renal transplant literature, it occasionally caused macular edema, but that has not been seen in the MS studies to date. But again, it's early days yet.

DR. FOX: So if this drug works by retaining white blood cells in the lymph nodes, and what happens? Do the lymph nodes get large? Do you get lymphadenopathy? I mean, do you just get this ever-growing lymph node?

DR. O'CONNOR: That's a good question, and kind of a logical expectation. But in fact, within a lymph node, the volume of cells per se is, as a proportion of everything else in the lymph node, very small. So even though you have many, many more cells in the lymph node, you don't notice a difference. And certainly, clinically there's absolutely no lymph adenopathy with the use of this agent, nor is there any splenomegaly.

DR. FOX: So the studies that are underway now, are these phase III trials? Is this moving this forward?

DR. O'CONNOR: Yes, the phase III trial is getting underway. It's called the FREEDOMS trial, and it's occurring in Europe, Canada and discussions are underway with the FDA to have it occur in the United States. But it is not yet approved for initiation in the United States.

DR. FOX: Well, that's all the time we have today, so thank you, Paul, for reviewing the highlights of the clinical trial section.

DR. O'CONNOR: My pleasure.

REFERENCES

[S02.001] Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): Clinical Outcomes
Mark S. Freedman, Ottawa, ON, Canada, Ludwig Kappos, Basel, Switzerland, Chris H. Polman, Gilles Edan, Rennes, Cedex, France, Hans P. Hartung, Dusseldorf, Germany, David Miller, London, United Kingdom, Xavier Montalban, Barcelona, Spain, Frederik Barkhof, Amsterdam, Netherlands, Lars Bauer, Peter Jakobs, Rupert Sandbrink, Berlin, Germany, for the BENEFIT Study Group, Germany

[S02.002] Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): Subgroup Analyses
Chris H. Polman, Amsterdam, Netherlands, Ludwig Kappos, Basel, Switzerland, Mark S. Freedman, Ottawa, ON, Canada, Gilles Edan, Rennes, Cedex, France, Hans P. Hartung, Dusseldorf, Germany, David Miller, London, United Kingdom, Xavier Montalban, Barcelona, Spain, Frederik Barkhof, Amsterdam, Netherlands, Lars Bauer, Peter Jakobs, Christoph Pohl, Rupert Sandbrink, Berlin, Germany, for the BENEFIT Study Group, Germany

[S02.005] The Effects of Natalizumab Monotherapy on Multiple Measures of Disability Progression in MS Patients
J. Theodore Phillips, Dallas, TX, Ludwig Kappos, Basel, Switzerland, Paul W. O'Connor, Toronto, ON, Canada, Eva Havrdova, Prague, Czech Republic, Michael Hutchinson, Dublin, Ireland, David H. Miller, Chris H. Polman, Amsterdam, Netherlands, Fred D. Lublin, New York, NY, Gavin Giovannoni, London, United Kingdom, Andrzej Wajgt, Katowice-Ligota, Poland, Frances Lynn, Michael A. Panzara, Alfred W. Sandrock, Cambridge, MA

[P01.086] The Safety and Tolerability of Natalizumab: Results from the Safety-Extension Study in Patients with Multiple Sclerosis
Paul W. O'Connor, Toronto, ON, Canada, Andrew Goodman, Rochester, NY, Ludwig Kappos, Basel, Switzerland, Fred D. Lublin, New York, NY, David H. Miller, London, United Kingdom, Chris H. Polman, Amsterdam, Netherlands, Richard A. Rudick, Cleveland, OH, Frances Lynn, Michael A. Panzara, Alfred W. Sandrock, Cambridge, MA

[S32.001] Immune Surveillance in Multiple Sclerosis Patients Treated with Natalizumab
Olaf Stuve, Christina Marra, Keith R. Jerome, Linda Cook, Seattle, WA, Petra D. Cravens, Sabine Cepok, Elliot Frohman, Ted Phillips, Gabriele Arendt, Dusseldorf, Germany, Bernhard Hemmer, Marburg, Germany, Nancy Monson, Michael K. Racke, Dallas, TX

[S52.005] Natalizumab Improves Health-Related Quality of Life in Patients with Relapsing Multiple Sclerosis
Richard A. Rudick, Cleveland, OH, Michael Hutchinson, Dublin, Ireland, Paul W. O'Connor, Toronto, ON, Canada, Eva Havrdova, Prague, Czech Republic, Ludwig Kappos, David H. Miller, J. Theodore Phillips, Dallas, TX, Chris H. Polman, Amsterdam, Netherlands, William H. Stuart, Atlanta, GA, Peter A. Calabresi, Baltimore, MD, Christian Confavreux, Lyon, France, Steven L. Galetta, Philadelphia, PA, Ernst-Wilhelm Radue, Basel, Switzerland, Fred D. Lublin, New York, NY, Gavin Giovannoni, London, United Kingdom, Andrzej Wajgt, Katowice-Ligota, Poland, Bianca Weinstock-Guttman, Buffalo, NY, Daniel R. Wynn, Northbrook, IL, Frances Lynn, Michael A. Panzara, Alfred W. Sandrock, Cambridge, MA, The AFFIRM and SENTINEL Investigators

[S32.004] Natalizumab Reduces Loss of Visual Function in Patients with Relapsing Multiple Sclerosis
Laura Balcer, Steven L. Galetta, Philadelphia, PA, Paul W. O'Connor, Toronto, ON, Canada, Eva Havrdova, Prague, Czech Republic, Michael Hutchinson, Dublin, Ireland, Ludwig Kappos, David H. Miller, J. Theodore Phillips, Dallas, TX, Chris H. Polman, Amsterdam, Netherlands, William H. Stuart, Atlanta, GA, Peter A. Calabresi, Baltimore, MD, Christian Confavreux, Lyon, France, Ernst-Wilhelm Radue, Basel, Switzerland, Richard A. Rudick, Cleveland, OH, Fred D. Lublin, New York, NY, Gavin Giovannoni, London, United Kingdom, Andrzej Wajgt, Katowice-Ligota, Poland, Bianca Weinstock-Guttman, Buffalo, NY, Daniel R. Wynn, Northbrook, IL, Frances Lynn, Michael A. Panzara, Alfred W. Sandrock, Cambridge, MA, The AFFIRM and SENTINEL Investigators

[S42.007] The Incidence and Clinial Significance of Antibodies to Natalizumab over 2 Years of Treatment in Patients with Multiple Sclerosis
Peter A. Calabresi, Baltimore, MD, Gavin Giovannoni, Paul W. O'Connor, Toronto, ON, Canada, Eva Havrdova, Prague, Czech Republic, Michael Hutchinson, Dublin, Ireland, Ludwig Kappos, David H. Miller, London, United Kingdom, J. Theodore Phillips, Dallas, TX, Chris H. Polman, Amsterdam, Netherlands, William H. Stuart, Atlanta, GA, Christian Confavreux, Lyon, France, Steven L. Galetta, Philadelphia, PA, Ernst-Wilhelm Radue, Basel, Switzerland, Richard A. Rudick, Cleveland, OH, Fred D. Lublin, New York, NY, Andrzej Wajgt, Katowice-Ligota, Poland, Bianca Weinstock-Guttman, Buffalo, NY, Daniel R. Wynn, Northbrook, IL, Frances Lynn, Michael A. Panzara, Alfred W. Sandrock, Cambridge, MA, The AFFIRM and SENTINEL Investigators

[S61.001] "Results of a Randomized, Double-Blind, Parallel-Group Study Assessing Safety and Efficacy of 40 mg vs. 20 mg of Glatiramer Acetate on MRI-Measured Disease Activity in RRMS."
J. A. Cohen, Cleveland, Ohio.

[S12.003] Oral FTY720 in Relapsing MS: Results of the Dose-Blinded, Active Drug Extension Phase of a Phase II Study
Paul O'Connor, Toronto, ON, Canada, Jack Antel, Westmount, QC, Canada, Giancarlo Comi, Milan, Italy, Xavier Montalban, Barcelona, Spain, Tomas Haas, Ana De Vera, Goeril Karlsson, Ludwig Kappos, Basel, Switzerland

Section III: Imaging

DR. FOX: My name is Dr. Robert Fox, and joining me is Dr. Paul O'Connor. Paul, let's focus on the MRI abstracts at this year's meeting.

DR. O'CONNOR: Well, there were a number of interesting ones presented. The first area that was touched on was the use of MRI composite scores. Both Dr. Traboulsee [S10.001] and Dr. Wolinsky [S22.001] had presentations on this subject, the main idea being to come up with a single composite score that puts together the various different MRI measures that are used in clinical trials.

DR. FOX: So we do this now with the clinical side with the MS functional composite, where we take ambulation and we take arm function and we take cognitive function and we boil them all into one score so we can get a number of other measures added together into one. So it sounds like this is trying to take different MRI measures which seem to be looking at different things, looking at new inflammation, looking at serious damage and trying to integrate them together. Is that right?

DR. O'CONNOR: That's my understanding of it. The idea is to have a single summary score just as we have with the EDSS or the MSFC. It's convenient to have that. The issues always are is the composite score telling you everything that you can actually learn from knowing the individual component scores? And I think that issue is unsettled at present.

DR. FOX: But ideally it would allow us to more accurately characterize the radiologic disease activity of a patient. And I suppose that in the ideal sense-and we'll have to see how these studies play out over the years-will help us develop more sensitive radiologic measure of how therapies work. Is that how you see it?

DR. O'CONNOR: That's how I see it. Ideally, the summary score would tell us information that individual scores didn't tell us. Ideally, the summary score would correlate in a more meaningful way with clinical measures such as the EDSS and MSFC. I'm not certain, however, that the summary scores, because they merge such disparate types of information, will ultimately be the way to go. I think the jury is out on that point.

DR. FOX: We'll have to see.

DR. O'CONNOR: Another area I wanted to discuss was a presentation by Dr. Pittock [S22.004] on lesion location in Devic's disease, neuromyelitis optica. Now, as you know, in neuromyelitis optica, some patients have antibodies to aquaporin-4 channels, which are water channels that are in the brain in a subependymal location. And Dr. Pittock was able to show us some interesting MRIs of brains where the lesions were around or co-localizing to the aquaporin-4 channel locations. So these are atypical lesions for MS, but characteristic of a localization that would fit with aquaporin channels. So these images were very interesting.

DR. FOX: So just remind us of what aquaporin does, and what are aquaporin channels, and why are they important in MS?

DR. O'CONNOR: So aquaporin channels are important in Devic's disease, in any event, and it seems to be that the antibody that's associated with Devic's disease is an antibody to the aquaporin-4 channel. And these channels are involved in regulating water input or output to glial cells and neurons. And whether the antibody, the NMO antibody IG, that Dr. Vanda Lennon from the Mayo Clinic has developed and discovered, is pathogenic in Devic's remains to be proven. But certainly, the presence of this antibody is associated with Devic's disease, and this antibody is potentially affecting the function of these channels in the central nervous system.

DR. FOX: So that would explain to us why patients with Devic's disease, who we typically think about as having only optic neuritis and transverse myelitis, we are learning now that they have occasionally very extensive lesions in the brain, typically involving the brainstem and the cerebellum and big, confluent lesions going up into the cerebral hemispheres, as well. So it sounds like this gives us an explanation as to why we see those atypical-looking lesions.

DR. O'CONNOR: Right. I think that's true. It's important to remember, though, that it's only a minority of Devic's patients that one sees the lesions in the brain and brain stem. So it was interesting to see these images. Another interesting paper was from the fMRI domain by Dr. Melanie Burke and colleagues [S22.005], and in this very interesting study, patients who had very mild disability with no cognitive or arm disability were evaluated on two different types of tasks. One was a finger-tapping task, and one was a logical reasoning task. And what Dr. Burke was able to show was that when the arm function was normal in these patients, there was no evidence of overactivity of brain motor areas when doing the finger-tapping task. However, during the logical reasoning task, when looking at the orbital frontal areas, she was able to show that MS patients use both sides of the brain and more of the brain than do control normals, the idea being that the MS brain has to work harder to perform a fairly simple logical reasoning task, even when there's no obvious cognitive deficit.

DR. FOX: So they can still perform a task, they just need more brain to do it?

DR. O'CONNOR: Right. But this in turn brings up the issue as to whether this has anything to do with patients' perceptions of fatigability and reduced endurance, both cognitively and physically in MS.

DR. FOX: Because when you have to use so many different brain regions instead of the original, very expedient brain pathways that were before MS, it's going to take more energy and it's going to take more effort, perhaps, and leave patients more fatigued later. Is that how it's thought to be?

DR. O'CONNOR: That's what I'm thinking, is that if you have to use more of your brain to do any given task, then you are going to fatigue more easily. In turn, this is going to make your job performance likely subpar if you're being compared to someone who doesn't have these problems.

DR. FOX: So when our patients say that their brain is tired, now we know why, because we're using a heck of a lot more than others.

DR. O'CONNOR: And they're telling us the truth. They're telling us the truth.

DR. FOX: That's interesting.

DR. O'CONNOR: There were also some interesting papers presented, looking at neuropsychological and MRI correlations at this meeting. I would be interested in your comments on those.

DR. FOX: There were. There were several papers that were trying to understand how specifically targeted regions of the brain correlated with atrophy in those regions. So one paper [P02.101] looked at specific lesions in brain regions and whether the amount of those lesions, the lesion load in those areas, correlated with the amount of atrophy in those areas. And surprisingly, it did not. We think that where there's lesions, there's injury, and that should lead to loss of tissue from the axonal transection that we've come to appreciate in MS. But it didn't seem to do that. Those lesions correlated with overall brain atrophy, but not within that small region. It may be because those regional measures aren't measuring exactly what we want, and they may not be as reproducible as they need to be. It could also relate to where you have one lesion, you're cutting fibers not only that subserve that particular brain region, but also fibers that are going elsewhere. So a single lesion is going to affect fibers that are going to a wide variety of areas, not just that one, single, left orbital frontal lobe, or whichever area you happen to be looking at. So I think the next step is to try to bunch these regions together-maybe not entire brain, but into logically connected areas-to ask if the legion load in areas where fibers are known to connect to specific brain regions are correlated with atrophy of those more extensive brain regions.

DR. O'CONNOR: I think that's a good idea. And one of the other issues is whether this is a technical problem in detecting gray matter lesions. So our concept of lesion load in MS is often tied up with white matter lesion load, and atrophy, of course, affects both gray and white matter so that it's not clear that you can detect gray matter atrophy on a conventional MRI, and that may be a factor in contributing to this discordance that you're describing.

DR. FOX: Well, not only gray matter atrophy, but the gray matter lesions. We can't see the gray matter lesions very well on MRI. We know that they're there on pathology, but they don't show up as bright spots on our typical T2-weighted images. And so by just looking at the white matter lesion load, which we do see, if we don't also measure the gray matter because we're not able to, that is going to lead to problems with the correlation with atrophy in those areas. So coming up with ways to image the lesion load in gray matter is really what we need to focus on and is a challenge in the field.

DR. O'CONNOR: It's a real challenge, and particularly as the pathology papers are coming out emphasizing how much gray matter atrophy there is in MS, both in the cerebral hemispheres, and one interesting paper presented at this meeting [P06.179] stated that in the spinal cord there is as much or as more gray matter demyelination as there is white matter demyelination. And yet we have no really good way of imaging the gray matter, per se, in the cord.

DR. FOX: Well, certainly the cord has been the forgotten area of MS all this time. We've known it was there, but it's so much easier to image the brain than the cord, and the cord is such a small area, it's tough to get good, high-quality images because it's tough to get a homogeneous magnetic field in the spinal cord, where around the brain it's much easier. But the spinal cord is where such a large proportion of disability comes from in our patients, where their arm dysfunction and their walking dysfunction and their bowel and bladder. Not to take anything away from cognitive dysfunction, which is most certainly subserved by damage up in the brain, but the cord is an area where I think MRI is going to help us in the future, and imaging the gray matter with the white matter is going to be important. I agree.

DR. O'CONNOR: Great. And that's about all I have to report on MRI for this meeting.

DR. FOX: Great. Well, thanks, Paul. I appreciate that.

DR. O'CONNOR: My great pleasure.

REFERENCES

[S10.001] Composite MRI Score as a Biomarker in Clinical Trials in Multiple Sclerosis
Anthony Traboulsee, Yinshan Zhao, David Li, Vancouver, BC, Canada

[S22.001] A Composite MRI Score (Z4) Predicts Disability over the Next 4.5 Years in a Prospectively Followed Cohort of Subjects on Glatiramer Acetate
Jerry S. Wolinsky, Ponnada A. Narayana, Houston, TX, Kenneth Johnson, Baltimore, MD, David Ladkani, Petach Tikva, Israel, Frederic Deutsch, Netanya, Israel, The Copolymer 1 Multiple Sclerosis Study Group

[S22.004] MRI Brain Lesions Characteristic of Neuromyelitis Optica (NMO) Colocalize with Sites of High Aquaporin Protein Concentrations
Sean J. Pittock, Brian G. Weinshenker, Claudia F. Lucchinetti, Dean M. Wingerchuk, Scottsdale, AZ, John R. Corby, Denver, CO, Vanda A. Lennon, Rochester, MN

[S22.005] Brain Compensation for Cognitive Processes in Multiple Sclerosis: A fMRI Study
Melanie A. Burke, Roderick K. Mahurin, James D. Bowen, Seattle, WA

[P02.101] Regional Lesion Volume Predicts Total and Then Regional Gray Matter Atrophy in MS
Dominic A. Carone, Syracuse, NY, Jared Bruce, Providence, RI, Ralph Benedict, Vritha Yella, Michael G. Dwyer, Christopher W. Tjoa, Robert Zivadinov, Buffalo, NY

[P06.179] Spinal Cord Gray Matter Is a Predilection Site for Demyelination in Multiple Sclerosis
Christopher P. Gilmore, Nottingham, Nottinghamshire, United Kingdom, Lars Bo, Amsterdam, Netherlands, Trudy Owens, Margaret M. Esiri, Oxford, United Kingdom, James Lowe, Nikos Evangelou, Nottingham, United Kingdom