Multiple Sclerosis Discovery -- Episode 28 with more from Dr. Brenda Banwell

[intro music]   Hello, and welcome to Episode Twenty-Eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features part two of an interview with Dr. Brenda Banwell in which we discuss pediatric MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Researchers recently put a simple measure of corpus callosum atrophy to the test in a 17-year-long study. The team measured the area of this inter-hemisphere highway in MS patients and found it correlated with their cognitive and physical disabilities over time. Corpus callosum area is faster, easier, and cheaper to measure than volume, since it requires no special equipment beyond the typical MRI machine. The researchers hope they will be able to demonstrate that this measurement can also predict disease course in future studies with larger cohorts.   Every Friday we curate research articles on all topics related to multiple sclerosis and highlight our favorites in the “Editors’ Pick.” Two weeks ago, the editors’ picks included a study on the HPV vaccine and MS and another about how cinnamon can ameliorate EAE. Last week we chose a study on heterogeneity among oligodendrocyte precursor cells and another on teasing out the causal variants in genetics association studies. You can see our weekly picks by going to our website, clicking on the “Papers” tab, and selecting “Editors’ Picks.” In addition to the Editors’ Picks, we link to every MS-related study found in PubMed.   Our senior science writer, Carol Morton, will be at the Keystone meeting on Neuroinflammation in Diseases of the Central Nervous System in Taos, New Mexico from January 25th through the 30th. She will be on the hunt for good stories and interviews for this podcast, so be sure to say “hi” and tell her all about your latest work.   [transition music]   Now to the interview. Dr. Brenda Banwell is Professor of Neurology and Pediatrics at the Perelman School of Medicine at the University of Pennsylvania and chief of the Division of Neurology at The Children’s Hospital of Philadelphia. Last week, we talked about a new journal called Multiple Sclerosis and Related Disorders, of which she is one of the co-editors-in-chief. This week we turn to her particular subspecialty.   [Interview]   Interviewer – Dan Keller I’m here at The Children’s Hospital of Philadelphia with Dr. Banwell, and someone from the public affairs office is here with us. Dr. Banwell, let’s talk about pediatric MS. What are some of the clinical features that you see that may distinguish it from adult?   Interviewee – Brenda Banwell Maybe walk you through a little bit of the journey that the pediatric multiple sclerosis field has taken over the last 10-12 years. When pediatric multiple sclerosis clinics were first being created which was in the late 1990s, the literature on pediatric multiple sclerosis was extremely brief; it was a mixture of patients that we now recognize have multiple sclerosis, some have what we call acute disseminated encephalomyelitis – ADEM – and still others had different demyelinating disorders. And there were no consensus criteria for the diagnosis of multiple sclerosis in children and the criteria for the diagnosis in adults did not include pediatric-onset patients formally. All of that has changed. And in the process of making the diagnosis of multiple sclerosis more clearly, we obviously had to look at the clinical features.   So, first of all, I would say that multiple sclerosis onset during childhood and teenage years is relapsing-remitting in character, so clear relapses and periods of clear remission. We have not seen children with primary progressive multiple sclerosis. Worldwide there are a very, very small number of children who may have that diagnosis; it’s extremely unlikely that there are very many, so for all intents and purposes it’s a relapsing-remitting disease during the pediatric age group.   The clinical features of attacks are generally very similar to adults with a few caveats. In children who are under about 10, there’s a likelihood that the children will present a little more atypically than adults. The younger children present with an episode with multiple neurological deficits, confusion, even impairment in level of consciousness which can make that first episode very difficult to distinguish from the more traditional acute disseminated encephalomyelitis, the important difference between the two being acute disseminated encephalomyelitis is a monophasic disease, so one attack almost always without any MRI evidence of new disease over time and no further clinical relapses in the vast majority of those children. So it’s a very important diagnosis to distinguish from the lifelong disease, multiple sclerosis, and one can distinguish them obviously on the basis of time but also on certain MRI features. And specifically when one looks at the first presentation, looking for risk determinants for multiple sclerosis are also important.   So in that vein, we’ve looked at things that are associated with the likelihood that a first attack is really multiple sclerosis, and those include prior exposure to Epstein-Barr virus, which gives one about a sixfold increased likelihood of having MS; low vitamin D levels which is a problem because low vitamin D levels are quite common in the community now across the board in certain parts of the world, but children who have very low levels are more likely to have multiple sclerosis compared to children whose vitamin D levels were higher when they present with an acute event.   If the MRI scan in the brain shows areas of what we call “T1 hypointensity”, which are black holes or really are indications of focal prior brain injury, then those patients are much more likely to have multiple sclerosis. And the reason for that is that in multiple sclerosis, the first attack when you first have the deficits, there’s likely been a period of time behind the scenes where the immune system has begun to attack and has had focal areas of injury that the patient didn’t recognize but are clearly visible on MRI, so MRI is our extraordinarily helpful guide. So areas of abnormality in the brain that are in the what we call periventricular white matter, and then these dark areas on these what are called T1 sequences are strongly indicative that this is a first attack of multiple sclerosis.   Conversely, most children with transient illness either have a normal brain MRI and maybe have inflammation in the back of the eye, the optic nerve, or the spinal cord, or they have this ADEM – acute disseminated encephalomyelitis picture – which gives you these hazy, widespread, large, ill-defined changes in the brain MRI that are at least visually quite different from multiple sclerosis. The key subsequent to that is that in patients with multiple sclerosis, by definition there will be new disease over time both on serial MRI scans and clinically. And that is also the case in young adults with relapsing-remitting multiple sclerosis.   Genetically, pediatric MS patients do have – at least those from northern European heritage – a higher likelihood of having what we call the HLA-DRB*1501 locus, which is a gene that is important in immune system development or at least immune system recognition of self. And that relationship is true in adult-onset MS as well, and over the last few years the number of genes that have been linked to multiple sclerosis risk overall, and that panel of genes is similar in pediatric-onset MS.   So I think the overall message is that relapsing-remitting multiple sclerosis in children and adults is very likely to be the same disease. There are some subtle differences relating to the age of the patient, but if you follow people over time the relapsing-remitting character and the changes on imaging and these clinical feature of kids are really quite similar to relapsing-remitting MS in young adults.   MSDF When you mentioned exposure to Epstein-Barr virus as a risk factor, if you looked at adults about 90% of people have antibody. Do kids generally not have such a proportion of antibody and it’s more indicative there? Does it tell you more if they are positive than in an adult?   Dr. Banwell There’s a lot of evidence that suggests that your multiple sclerosis risk is determined by where you grow up in your childhood years. You may not manifest with the disease until you’re 20 or 30, but all sort of studies, particularly immigration studies, strongly suggest it’s where you grow up that determines your risk. Therefore, if something is a risk factor, one ought to have it if your onset is a 6-year-old or an 8-year-old or a 10-year-old, if it’s important in causing the disease. So when we looked at Epstein-Barr virus exposure in pediatric-onset MS patients, about 80-85% are positive, which compares to only about 35-40% of regional, age, and sex-matched healthy children. So our power to make the relationship is very high. What the Epstein-Barr virus means to the person may be very similar in kids and adults. Certainly in adult-onset MS patients, about 97-98% are positive, which compares to about 90% of the healthy population. So it’s still higher but, of course, you’re sampling the adult patients way past when the exposure may have occurred, and so there’s been time for people who don’t have the disease to also experience the exposure, it just doesn’t matter – presumably – to them; they’re not manifesting with MS.   In children, though, when we’re looking at patients who are presenting very, very close to when they presumably had the key risk exposure. So we think that’s biologically important. We’ve also looked at viral shedding. So Epstein-Barr virus is an interesting infection because once you acquire it, it lives in your B-cell population so you have EBV-infected B cells, and about 20% of the year you shed the virus in saliva, which is why it’s so easily spread, particularly in adolescence, which is when it’s particularly acquired. So we looked in our pediatric MS patients at how many times in the course of a year, so with a sample done with most swabs once a month, were they shedding the virus, and looked at Epstein-Barr virus-exposed healthy kids. Healthy children shed the virus 20% of the year, as has been previously reported; MS patients, it was 66-70% of the year.   So one of our hypotheses that we’re currently exploring further is whether maybe part of what Epstein-Barr virus might do in MS is, first of all, shed more often so you’re controlling it less well. Every time you shed the virus, your immune system has to turn itself back on and put the virus back into its latent state. If you don’t you can end up with all sorts of complications including lymphoma. And so if part of Epstein-Barr virus’ role in MS is turning the immune system on multiple months per year, that isn’t probably what you want when you have an autoimmune disease; you don’t want your immune system being turned on multiple times a year, particularly if unfortunately you turn on a component of the immune system that may then be directed at the brain. So that’s an interesting phenomenon that we’re currently doing further research on.   MSDF So it sounds like the EBV is something of a polyclonal activator of B cells which then cross-react in the brain, or do react in the brain?   Dr. Banwell Well, that’s the next stage is to see if you look at what immune cells are responding to the challenge of this reactivated EBV, is it that there are specific T-cell clones, and if so are those T-cells specifically looking at proteins expressed both by EBV and by proteins in the central nervous system, sort of a molecular mimicry model, which might be true? Or is it just unfortunate that you’ve turned the whole immune system on, or a large number of aspects of the immune system on, which is more of a general immune process? We don’t know the answer to that.   MSDF Considering these patients start out with relapsing-remitting MS earlier, do they progress to secondary-progressive earlier or at the same age as someone who gets it as an adult?   Dr. Banwell Good question. So the only really good paper on that question, keeping in mind that if we go from prospective studies that are really only started in 1999 to 2000, we don’t have a lot of prospectively rigorously studied pediatric patients. But Dr. Renaud in the New England Journal of Medicine published a paper from the French database where they looked at patients who reported pediatric-onset MS. And what they found was that from first attack until the point at which 50% of their pediatric-onset patients had started into secondary disease progression, that time interval was about 20 years, which is about 10 years longer than one would report on average in adult-onset MS. So if you look at adult-onset MS patients, 50% of them will have entered into secondary disease progression after 10 years from first attack. This is all untreated patients, which of course now is no longer really much the case in developed parts of the world.   So the patients with pediatric-onset take longer to start into secondary disease progression, but if you’re only 6 or 7 or 8 when you have your first attack, you’re 28 when you start to develop disability, which is about 10 years younger than most of the adult-onset patients. So the take-home message is it is certainly not more benign based on this particular data, the age at which patients are at-risk of becoming disabled is actually younger, but the time interval from the beginning of their disease until that time point is longer. And we hope that the current therapies and the new emerging therapies will change that outcome, but of course we only are just beginning to have a chance to see that.   MSDF What are some of the challenges in doing clinical trials with a pediatric population?   Dr. Banwell So in adult-onset MS patients, the clinical trial models have been very large; they’ve been randomized, double-blind, placebo-controlled, rigorously done studies that have often employed 200-400 individuals per study arm. And that is often quite feasible because the large MS programs around in North America and in many parts of Europe, an average adult MS clinic where MS is a common can have 3,000 patients alone. There are probably fewer than 3,000 pediatric-onset MS patients available for clinical trials worldwide total, and even that number may be inaccurate. So most pediatric MS programs in the world, of which there are still relatively few that have anything more than five or six patients, are really, really few and far between. So there just simply is a markedly reduced number of pediatric MS patients available for clinical trials.   Also challenging the current environment is that there are multiple trials all coming forward at the same time. So the FDA and the European’s Medicine Agency in particular require what they call “Pediatric Investigation Plans” – or PIPs – for all new drugs that are coming to market. In the MS field there are multiple new drugs coming to market. All of them have filed these Pediatric Investigation Plans. So even if we had the number of patients to power one study, we certainly don’t have enough patients to power five or six concurrently, therefore we run the risk of a given trial failing because it doesn’t reach its enrollment numbers.   We have families facing choices between multiple potential clinical trials at the same time and centers facing the challenge of launching multiple trials at the same time and the inherent difficulty with all of the work that goes into getting a study up and running at a given center. Pediatric MS patients have never previously been offered pediatric trial opportunities, so the culture of being in a trial is new so it’s a learning curve for everyone. And the medications that are being put forward have varying priorities. So some of the medications are oral, which may be quite appealing to children who are not, understandably, very keen on injections; some are given by infusion and that has varying challenges.   A clinical trial is not just an enormous time commitment on the behalf of the patient, in which our case is a child, but also their parents who have work and other commitments and other children. So being part of a clinical trial is an enormous commitment for a family, which is different than the commitment experienced by an individual who’s making that decision on their own behalf. And then adding to all of those challenges is the safety aspects of all these new medications, and of course our top priority amongst anything else is to make sure that our patients stay safe.   And so where there may be marked similarity in relapsing-remitting MS as a disease between children and adults, these therapies are being administered at a different time in terms of brain maturation, to a lesser worry but still important in terms of different levels of immune maturation, and certainly – very importantly – at a different stage of life in terms of acquisition of infection. And so many of the new medications that are coming online are more powerful than the medicines that are currently available, many are more capable of suppressing immune responses which puts a significant burden on making sure that everybody is fully vaccinated to the various things we can vaccinate against, but still kids are going to acquire their first infections during the window of time they may be on some of these medications. And so it’s really quite similar to some extent to some of the pediatric oncology care plans that we have to be very, very aware of.   MSDF It looks like the Canadian database of pediatric MS patients is one of the largest; I think when I talked to Amit Bar-Or, it was about 420 or 450. It sounds like there’s a real vying here for patients in terms of clinical trials, and is it even feasible; is it something that you should just discuss with the FDA and say how is this possible to do?   Dr. Banwell So I am one of four members of a clinical trials advisory group on behalf of the International Pediatric Multiple Sclerosis Study Group, which is an international group of about 150 physicians from 40 countries, so I do serve on an advisory to FDA and EMA under that umbrella. And the group of us have very much expressed this concern to FDA and EMA and have articulated our worry about underpowered trials. It’s a difficult environment, there’s a lot of discussion still to be had. The general statement from the regulatory authorities for each of the individual medications that are coming forward is that they are required to have a pediatric plan. And that was a hard-fought battle over many years to try to increase high-quality evidence for treatment of children, which all of us who treat children endorse.   So it’s not that we don’t want there to be good trials, it’s just, unfortunately, the reality is that it’s going to be very difficult to do traditional study designs with large arms and placebo-controlled, randomized, double-blinded models are not always going to be suited for all of the therapies. They’re not possible to do for every therapy that’s coming forward, and there’s going to need to be some discussion at a minimum on trial design and potentially on which trials are being done in what order, although that, of course, is certainly not my purview to decide, but it isn’t feasible to run multiple trials in this rare disease at the same time. So we’re going to need to look at rare disease models of therapy that have been put forward for perhaps some of the rare childhood cancers, for example, and other diseases, and we’re going to need the regulatory authorities to recognize we can’t use adult MS study designs for pediatric MS patients.   MSDF Very good, I appreciate it. Thank you.   Dr. Banwell Oh, you’re welcome.   [transition music]   Thank you for listening to Episode Twenty-Eight of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected].    [outro music]