Podcasts about edss

Last week, thousands of clinicians, nurses, physician's assistants, rehabilitation experts, and others traveled to Nashville to attend the Consortium of Multiple Sclerosis Centers 38th Annual Meeting. Welcome to Part 1 of our coverage from that meeting. In this episode, I'm talking with Dr. Kathy Zackowski, Associate Vice-President for Research at the National MS Society, and Dr. Zackowski is sharing some of the presentations that caught her attention. Next, you'll hear my conversation with Dr. Stephen Krieger, a neurologist at the Corinne Goldsmith Dickinson Center for Multiple Sclerosis. Dr. Krieger explains the hidden side of MS, why, when it comes to treating MS, "detecting only what we measure" isn't enough, and why an EDSS of 0 is not normal. We have a lot to talk about! Are you ready for RealTalk MS??! This Week: We're reporting from the CMSC Annual Meeting  :22 Dr. Kathy Zackowski shares some of the presentations that caught her attention  1:14 Dr. Stephen Krieger discusses the hidden side of MS, why, when it comes to treating MS,  "detecting only what we measure" isn't enough, and why an EDSS of 0 is not normal   18:56 Share this episode  33:36 Next Week: Part 2 of our coverage from the CMSC Annual Meeting  33:56 Have you downloaded the free RealTalk MS app?  34:30 SHARE THIS EPISODE OF REALTALK MS Just copy this link & paste it into your text or email: https://realtalkms.com/353 ADD YOUR VOICE TO THE CONVERSATION I've always thought about the RealTalk MS podcast as a conversation. And this is your opportunity to join the conversation by sharing your feedback, questions, and suggestions for topics that we can discuss in future podcast episodes. Please shoot me an email or call the RealTalk MS Listener Hotline and share your thoughts! Email: jon@realtalkms.com Phone: (310) 526-2283 And don't forget to join us in the RealTalk MS Facebook group! LINKS If your podcast app doesn't allow you to click on these links, you'll find them in the show notes in the RealTalk MS app or at www.RealTalkMS.com Join the RealTalk MS Facebook Group https://facebook.com/groups/realtalkms Download the RealTalk MS App for iOS Devices https://itunes.apple.com/us/app/realtalk-ms/id1436917200 Download the RealTalk MS App for Android Deviceshttps://play.google.com/store/apps/details?id=tv.wizzard.android.realtalk Give RealTalk MS a rating and review http://www.realtalkms.com/review Follow RealTalk MS on Twitter, @RealTalkMS_jon, and subscribe to our newsletter at our website, RealTalkMS.com. RealTalk MS Episode 353 Guests: Dr. Kathy Zackowski and Dr. Stephen Krieger Privacy Policy  

Recent studies show that people with MS are slightly more likely to have a seizure or develop epilepsy than the general population. The more physical disability a person has from MS (as assessed using the EDSS disability scale for MS), the more likely they are to develop seizures. Also, the longer duration someone has MS, the more likely they are to develop seizures. Join Dr. Marissa Kellogg to learn about seizures and epilepsy.

If you've listened to this podcast before, you already know that we avoid hype, and we stick to talking about evidence-based science. So, let me say right up front -- today, the cause of multiple sclerosis is unknown. However, a research team has identified a bacterial toxin that may prove to be the cause of MS onset as well as MS relapses. Joining me for an exclusive conversation about this discovery is Dr. Timothy Vartanian, who leads the team that made the discovery, and Dr. Richard Rudick, whose career has focused on experimental therapeutics for MS, playing a key role in the development of both Avonex and Tysabri. We're also talking about a stem cell therapy called MSC-NP that, in a Phase 1 clinical trial, delivered positive outcomes among people living with progressive MS. We'll tell you about a study that demonstrated why EDSS alone does not accurately define an individual's MS journey. We're sharing news from the International Progressive MS Alliance about a new research pipeline that will focus on improving well-being for people living with progressive MS. And we'll tell you where you can catch a replay of the International Progressive MS Alliance's latest webcast, Developing Treatments to End MS Progression. We have a lot to talk about! Are you ready for RealTalk MS??! This Week: Is this the cause of MS?  :22 STUDY: MSC:NP, a stem cell therapy for MS, delivers a positive outcome among people living with progressive MS  1:33 STUDY: Does EDSS tell the whole story of your MS status?   5:03 The International Progressive MS Alliance funds a research pipeline focused on improving well-being among people living with progressive MS  8:42 Webcast Replay: Developing Treatments to End MS Progression   10:24 Dr. Richard Rudick and Dr. Timothy Vartanian discuss a new discovery that may lead scientists to the cause of MS   11:36 Share this episode  29:25 Have you downloaded the free RealTalk MS app?  29:46 SHARE THIS EPISODE OF REALTALK MS Just copy this link & paste it into your text or email: https://realtalkms.com/292 ADD YOUR VOICE TO THE CONVERSATION I've always thought about the RealTalk MS podcast as a conversation. And this is your opportunity to join the conversation by sharing your feedback, questions, and suggestions for topics that we can discuss in future podcast episodes. Please shoot me an email or call the RealTalk MS Listener Hotline and share your thoughts! Email: jon@realtalkms.com Phone: (310) 526-2283 And don't forget to join us in the RealTalk MS Facebook group! LINKS If your podcast app doesn't allow you to click on these links, you'll find them in the show notes in the RealTalk MS app or at www.RealTalkMS.com STUDY: Epsilon Toxin-Producing Clostridium Perfringens Colonize the MS Gut and Epsilon Toxin Overcomes Immune Privilege https://www.jci.org/articles/view/163239 STUDY: Mesenchymal Stem Cell-Derived Neural Progenitors Attenuate Proinflammatory Microglial Activation Via Paracine Mechanisms https://futuremedicine.com/doi/10.2217/rme-2023-0005 STUDY: Cognitive Impairment, Fatigue and Depression in Multiple Sclerosis: Is There a Difference Between Benign and Non-Benign MS? https://msard-journal.com/article/S2211-0348(23)00134-7/fulltext#%20 International Progressive MS Alliance: Well-Being in Multiple Sclerosis Research Funding Opportunity https://progressivemsalliance.org/2023/03/15/well-being-in-multiple-sclerosis-research-funding-opportunity Prioritizing Progressive MS Rehabilitation Research: A Call from the International Progressive MS Alliance https://journals.sagepub.com/doi/pdf/10.1177/1352458521999970 Webcast Replay: Developing Treatments to End MS Progression https://www.facebook.com/watch/live/?ref=watch permalink&v=748824966910470 Join the RealTalk MS Facebook Group https://facebook.com/groups/realtalkms Download the RealTalk MS App for iOS Devices https://itunes.apple.com/us/app/realtalk-ms/id1436917200 Download the RealTalk MS App for Android Deviceshttps://play.google.com/store/apps/details?id=tv.wizzard.android.realtalk Give RealTalk MS a rating and review http://www.realtalkms.com/review Follow RealTalk MS on Twitter, @RealTalkMS_jon, and subscribe to our newsletter at our website, RealTalkMS.com. RealTalk MS Episode 292 Guests: Dr. Richard Rudick and Dr. Timothy Vartanian Tags: MS, MultipleSclerosis, MSResearch, MSSociety, RealTalkMS Privacy Policy

Living with MS can make everyday run-of-the-mill tasks like bathing, cooking, and driving more challenging than they have to be. The National MS Society's Associate Vice President of Research, Dr. Kathy Zackowski, joins me with a whole list of simple adjustments and easy modifications that you can make that will make the things you do every day easier. Get ready to take some notes! A lot of you have reached out to me, sharing your thoughts about Selma Blair competing on Dancing with the Stars. Collectively, your opinions illustrate the vast diversity of opinion regarding Selma's latest adventure. In this week's episode, I'm sharing some of my thoughts. I've always said that MS doesn't affect individuals -- it affects families. This week, we're talking about a study that focused on anxiety, depression, and stress communication between people living with MS and their partners.  We'll also tell you about a study that makes the case for using artificial intelligence to accurately predict EDSS scores for people living with MS. And we'll tell you about a drug that's been studied in clinical trials for cancer that may also show promise as a remyelination therapy. We have a lot to talk about! Are you ready for RealTalk MS??! This Week: Selma Blair on DWTS, I'm back from the 2022 Caregiving Research Conference, and simple adjustments & minor modifications that can make life with MS easier  :22 Researchers analyzed anxiety, depression, and stress communication in couples affected by MS  3:28 Can artificial intelligence predict an individual's EDSS score as accurately as their neurologist?   7:37 Repurposing a drug that's been studied in clinical trials for cancer may be a step forward in remyelination for people living with MS  12:27 Dr. Kathy Zackowski returns to the podcast with a boatload of simple adjustments and minor modifications that can make managing your everyday tasks a lot easier   15:38 Share this episode  36:55 Download the RealTalk MS app for your iOS or Android device   37:16 SHARE THIS EPISODE OF REALTALK MS Just copy this link & paste it into your text or email: https://realtalkms.com/266 ADD YOUR VOICE TO THE CONVERSATION I've always thought about the RealTalk MS podcast as a conversation. And this is your opportunity to join the conversation by sharing your feedback, questions, and suggestions for topics that we can discuss in future podcast episodes. Please shoot me an email or call the RealTalk MS Listener Hotline and share your thoughts! Email: jon@realtalkms.com Phone: (310) 526-2283 And don't forget to join us in the RealTalk MS Facebook group! LINKS If your podcast app doesn't allow you to click on these links, you'll find them in the show notes in the RealTalk MS app or at www.RealTalkMS.com National MS Society COVID-19 Vaccine Guidance for People Living with MS https://www.nationalmssociety.org/coronavirus-covid-19-information/multiple-sclerosis-and-coronavirus/covid-19-vaccine-guidance STUDY: Psychosocial Impact of Multiple Sclerosis on Couples: Relationship Between Anxiety, Depression, and Stress Communication of Both Partners https://journals.sagepub.com/doi/10.1177/21501319221119142 STUDY: Validation of a Machine-Learning Approach to Estimate Expanded Disability Status Scale Scores for Multiple Sclerosis  https://journals.sagepub.com/doi/10.1177/20552173221108635 STUDY: Inhibition of Chk2 Promotes Neuroprotection, Axon Regeneration, and Functional Recovery After CNS Injury https://science.org/doi/10.1126/sciadv.abq2611 Join the RealTalk MS Facebook Group https://facebook.com/groups/realtalkms Download the RealTalk MS App for iOS Devices https://itunes.apple.com/us/app/realtalk-ms/id1436917200 Download the RealTalk MS App for Android Deviceshttps://play.google.com/store/apps/details?id=tv.wizzard.android.realtalk Give RealTalk MS a rating and review http://www.realtalkms.com/review Follow RealTalk MS on Twitter, @RealTalkMS_jon, and subscribe to our newsletter at our website, RealTalkMS.com. RealTalk MS Episode 266 Guest: Dr. Kathy Zackowski Tags: MS, MultipleSclerosis, MSResearch, MSSociety, RealTalkMS Privacy Policy

Welcome to Living Well with MS Coffee Break #32, where we are pleased to welcome Regina Beach as our guest!   Our Coffee Break series is your chance to get to know members of our diverse OMS community. In each episode, you'll join Geoff Allix for an intimate chat with a different member of our global community. Our guests will share their personal stories and talk about their challenges and victories, large and small. We hope you find common cause and a source of inspiration from the stories of these very special people.   As always, your comments and suggestions are always welcome by emailing podcast@overcomingms.org. Regina is a very special guest for many reasons, including being an American living in the UK, and being an OMSer who works for the charity as its Trusts and Community Fundraising Manager. We hope you enjoy this episode's conversation with Regina, coming to you straight from the UK.   Regina's Bio:   Regina Beach is an American living in the Welsh Valleys with her British husband. She was diagnosed with RRMS in April 2021 and adopted the Overcoming MS program shortly thereafter. She is a yoga teacher and writer who regularly leads workshops and publishes poetry and essays.  She enjoys cooking and is writing an oil-free vegan cookbook with her husband. She also works part time as the Trusts and Community Fundraising Manager for Overcoming MS. Prior to diagnosis she was an avid long-distance cycler. Her goal is to feel strong enough and balanced enough to get back in the saddle.     Questions:   Regina, welcome to Living Well with MS Coffee Break. We're so pleased to have you on our program. The purpose of this series is to better get to know some of the diverse members of our community from around the world, and today you're in the hot seat. Can you tell us a little about your day-to-day life? When were you diagnosed with MS? Can you provide some context on that? When were you diagnosed and how did you initially deal with it? At which point did you come across the OMS program? How was that experience for you? Why did you decide to start following it? I understand that you're rated as having significant disability on the EDSS scale. Has the OMS Program helped alleviate this, or had no effect? What are your thoughts on people with MS choosing other types of diets or lifestyle protocols that are not OMS? Let's shift gears a little bit and talk about your professional life. You used to be a schoolteacher in the US, but now you live in the UK with your British husband, and you actually work part-time for OMS as its Trusts and Community Fundraising Manager. How did that transition come about? OMS is celebrating its 10th birthday this year, and there are some special events in the wings. I understand you're involved in some of these, such as OMS Birthday Trivia in June, and the Big Picnic in July. Can you tell us a little about what to expect? Since you work in fundraising, what advice would you give to people in our community who want to get involved in this domain to help the charity? My next question straddles the personal and professional realm: you're a devout yoga and meditation practitioner, and you also teach it. Can you tell us how that's helped you, and share some tips on how others can get into the groove of a daily mindfulness practice? Regina, thank you so much for being on Living Well with MS Coffee Break and allowing our community to get to know one of its own a little better. One last question before you go, and it's a bit of a tradition in that we ask it of all our Coffee Break guests. If you tap into your experience with MS generally and OMS specifically for a nugget of wisdom that would help people ease into and better adopt the OMS program, what would that advice be?   Three Interesting Facts About Regina (in her own words):   I'm a yoga teacher and have changed my practice to be gentler and exploratory. I used to teach hot 26+2 (Bikram style).  I used to be a public-school teacher in Chicago where I taught secondary art and design. I have significant disability, with my neurologist most recently rating my EDSS at 6.5. I have incomplete remission, so my symptoms are always with me.     Regina's Links:   Check out Regina on Instagram, all about her adventures with whole food plant-based eating. Read Regina's newsletter, all about creativity through movement, art, and whole food plant-based cooking. Have a peek at Regina's website.   Coming up on our next episode:   On the next episode of Living Well with MS, premiering June 15, 2022, meet Shari Short – MS patient advocate, professional in healthcare communications, and naturally, a standup comedian – and learn from her experience with MS how laughter can be a powerful medicine in itself.   Don't miss out:   Subscribe to this podcast and never miss an episode. You can catch any episode of Living Well with MS here or on your favorite podcast listening app. For your convenience, a full episode transcript is also available on all platforms within 72 hours of each episode's premiere. If you like our program, don't be shy and leave a review on Apple Podcasts or wherever you tune into the show. And feel free to share your comments and suggestions for future guests and episode topics by emailing podcast@overcomingms.org.   S4E52b Transcript Coffee Break #32 with Regina Beach   Geoff Allix (00:00): Welcome to Living Well With MS Coffee Break, a part of the Living Well with MS podcast family from Overcoming MS, the world's leading Multiple Sclerosis healthy lifestyle charity, celebrating its 10th year of serving the MS community. I'm your host, Geoff Allix.   Today, you'll meet someone living with MS from our diverse and global Overcoming MS community. Our Coffee Break series invites you into the lives of each guest. They share their personal MS journeys, and speak openly about their challenges and victories, large and small. We hope you find some common cause and a source of inspiration from the stories of these very special people.   You can check out our show notes for more information and useful links. You can find these on our website at www.overcomingms.org/podcast. If you enjoy the show, please spread the word about us on your social media channels or leave a review wherever you tune into our podcast. Finally, don't forget to subscribe to Living Well with MS on your favorite podcast platform, so you never miss an episode. So, get your favorite beverage ready, and let's meet today's guest on Living Well with MS Coffee Break.   Welcome to Living Well with MS Coffee Break #32, where we are pleased to welcome Regina Beach as our guest. Regina is an American living in the Welsh Valleys with her British husband. She was diagnosed with Relapse-Remitting MS in April 2021 and adopted the Overcoming MS program shortly thereafter. She's a yoga teacher and writer who regularly leads workshops and publishes poetry and essays. She enjoys cooking and is writing an oil-free vegan cookbook with her husband. She also works part-time as the Trusts and Community Fundraising Manager for Overcoming MS. Prior to diagnosis, she was an avid long-distance cycler. Her goal is to feel strong enough and balanced enough to get back in the saddle.   Regina, welcome to Living Well with MS Coffee Break. We're very glad to have you on our program. So the purpose of this series is to get a better understanding of the members of our community from around the world, and today you are in the hot seat. So, could you tell us a bit about your day-to-day life?   Regina Beach (02:12): Sure. Thanks, Geoff, for having me. I am American, but I do live in the UK. So, my day-to-day life takes place in South Wales where I am a writer, a yoga teacher, and I also work part-time for Overcoming MS as the Trusts and Community Fundraising Manager, which means I help people who want to do a charity bike ride, or a race, or if they want to sell something, or raise funds for OMS. I help in whatever way, sending out swag, helping promote and advertise, and working with some really cool OMSers doing amazing things.   In terms of my day-to-day, I was diagnosed with Relapsing-Remitting MS in April of 2021, so not that long ago, and so I am still in the middle of figuring out what works best for me and how to fully embrace the OMS lifestyle. I jumped in right away about a month after diagnosis, I found the website, devoured it, and soon after got the book, read it, joined the Facebook group. I really feel like this is the pathway back to health, or to living as well as I possibly can, for me.   Geoff Allix (03:40): So how was it being diagnosed mid-COVID pandemic? I'm guessing that's made a difference.   Regina Beach (03:50): Yeah, absolutely, because I really put off getting the tingles in my feet checked out for a long time. I wasn't really in pain; I wasn't really having mobility issues. I was just having lots of numbness in my feet. And since I had been extra active in 2019, I did miles of swimming, biking, and running, I thought I was just experiencing some overuse residual something. And I really put it off and put it off, and it wasn't until my acupuncturist was like, "Your cold tingly feet, really, I haven't been able to do anything about this. I really think you should go to your GP and get some blood work done." And I'm really glad that she said that because I think, especially for people who like to tough it out or who are used to doing physical things and maybe having their body have adjust to stuff, I really wasn't thinking that I had something neurologically wrong with me.   And so then, obviously it took a little bit of time to check, I didn't have low B12, I didn't have low iron. My GP thought maybe I had a pinched nerve and just ordered a cervical MRI, and then eventually a full MRI. And then I ended up in the hospital for a week because I was having, I guess, a big relapse where I really had some terrible symptoms, and was losing mobility, and ended up with the diagnosis about a year after I really first started having those tingles. So, I do feel like I'm getting good care now, but I feel like the road to finding that diagnosis and really finding my way was definitely prolonged because of the pandemic.   Geoff Allix (05:38): And I think MS is a difficult one anyway, because it's not like we have a key symptom. Most things you can say, "Yeah, that's likely to be that because you've got this key symptom." We're like, "Well, actually it could be anything." Your nerves do everything in your body, and we've got a problem with our nerves, so it could be, people have got eye problems, walking problems, bladder problems, temperature problems, pins and needles problems, and they're all MS. So yeah, it is really difficult.   Regina Beach (06:07): Yeah, exactly, and you don't necessarily think of, "Oh, I need to pee all the time," as being connected to this idea that the grip in my left hand is not as strong as it used to be. You don't make that connection naturally, I think, because MS symptoms can run the gamut.   Geoff Allix (06:25): So, when did you come across OMS? How did you find out about OMS? And how did that go for you?   Regina Beach (06:33): My whole life, I have said, "If I ever get really sick," kind of jokingly, "I'm just going to become a monk and be a vegan and live in the woods." And so obviously, one of the first things I Googled was, what's the best diet for MS, because I understand that what we put into our body is the molecules that we become. And so I thought, okay, someone has got to have been doing research on this, and so I came across Swank, and then came across Jelinek, and then the evidence was just so compelling to me. I spent a month researching recipes, getting rid of stuff in the fridge, overhauling things.   My husband's been really wonderful and has changed his diet too, so we cook together. We're writing down our recipes and compiling a cookbook. We have an Instagram where we post recipes. It's been really fun, and it's been a huge change because I used to really love cheese and dairy, and my husband used to be big into smoking meats and grilling meats, and so we've just done a 180 with our meals, and it's really helpful to have somebody to co-plan with and cook with.   Like last night, we had some smoked fish and veg, and it's actually really amazing what you can do, cooking without oil, that I had no idea was possible. So I'm actually really happy that we found this. He's a triathlete and has found a lot of benefits from the diet portion of Overcoming MS as well, and I've always been a meditator of sorts, but now I feel like it's really key, and I definitely carve out the time more than I used to for that component.   And yeah, I do take a DMT, and I'm hopeful that with everything together, I'll get some more mobility back because I walk currently with two sticks, and I'm really hoping to one day be able to walk without a mobility aid.   Geoff Allix (08:42): Yeah. That was the next thing I was going to ask actually, so you are listed as having significant disability on the EDSS scale. So what's two sticks? That's somewhere up like four and a half, five, or something on the scale?   Regina Beach (08:55): Yeah, so I don't leave the house without at least one stick and it really just depends on how my balance is feeling that day. And sometimes, if we're at a museum or if I'm out and about in a big public arena, I've used a wheelchair before, just because walking long distances is really tough for me. And that was really heartbreaking because it was something that, hiking and long-distance trekking are things that have been a really important part of my life up to this point. I did the Camino de Santiago, and I've done a lot of long-distance cycle trips across Europe and Asia and North America, and I feel really lucky that I was able to do those things. But yeah, so being in this new body of mine that doesn't function the same way, and is really slow, and I have foot drop on the left side, and it's really a big adjustment, and I don't think I'm totally there. I dream of running sometimes, or I dream that I can walk.   Geoff Allix (10:08): Literally in your dreams?   Regina Beach (10:09): Literally in my dreams.   Geoff Allix (10:10): I have that as well. Some people say, "Does that make you sad because you've lost it?" And it's actually no, when you half wake up and you're just coming out of a dream, if I'm getting back to sleep, I'm just like, "I'd love to get back into that dream again," the one where I'm running around.   Regina Beach (10:25): Yes.   Geoff Allix (10:26): Because it's like memories of what used to be, and very similar stuff I used to do, like do a lot of mountain walking and hiking and cycling and stuff. The things now that I think would be an amazing achievement, whereas before it would be climbing Mont Blanc or something, now it's like, something less daunting. I mean, if I can do something like Snowden, or something that's not a hard mountain, that would be such an achievement for me. I mean, I don't know if it's achievable because I'm not really, I'm similar to you, I always take a stick when I go out, but I'm not ruling out that I can get a bit better.   Regina Beach (11:04): That's how I feel.   Geoff Allix (11:06): There are people I've come across, who like me, think those aids, they're not disabling, they're enabling. So, using mobility aids, and certainly, yeah, so I've got an E-Trike that I use partly also as a mobility scooter sometimes because I can just put it a walk mode and just trundle along. Because I just, yeah, the distance is the problem really, whereas I'd love to go on a city break where I just wander around all day. But now I-   Regina Beach (11:39): I love that, yes, where you're just walking miles and miles and seeing all the things, and now you have to be a little more deliberate about where you're going to go, how long is it going to take, and where can you take a rest? But it doesn't mean you can't do it. So I was really nervous to take my first international trip since having mobility issues, but my husband and I went to Egypt over Christmas and New Year's, and it was amazing how much we were able to do and how accommodating people are when you just explain the situation, and how much people want to help and make things as easy as possible. So, we did a snorkeling trip and everyone on the boat was super helpful because that is, as someone who has balance issues, it's a nightmare to walk around on a boat.   Geoff Allix (12:27): Yeah. Well I've been scuba diving twice since I've had MS.   Regina Beach (12:27): Nice.   Geoff Allix (12:33): Yeah, I've been scuba diving in Costa Rica and in Thailand, because I used to scuba dive a lot, but actually I thought, well, why not? Because there's not a balance issue.   Regina Beach (12:33): Yeah. Once you're in the water, it's great.   Geoff Allix (12:44): Yeah. And actually when you're scuba diving, you don't really, really, it's not a lot of exertion, because otherwise you use up all your air basically. So you are trying to do everything in a very gentle motion, so I still have the skills, and yeah, the problem is getting on and off the boat. On the boat, because it's moving around, there's loads of stuff to hold onto because everyone's got to hold onto stuff, so actually it wasn't that bad. So yeah, I could do that, and that was really cool.   Regina Beach (13:11): Yeah, and it is just about finding what you can do and leaning into what you can do, and making new goals, like you said. There's a little lake, we live right near the Cwmcarn Forest Drive, and one of my goals is to make it around that whole little lake without taking a break. And that is a very small goal compared to maybe what I used to be doing, but that's fine, that's where I'm at right now, and I'd rather be getting out there and trying for that. And also I just really appreciate my good days because, obviously, I used to take walking and running for granted, and now I'm like, "Oh, I feel great today. I'm definitely going to go out for a walk or for a little hike." So there's the small joys.   Geoff Allix (13:58): Yeah. And the next question is, what are your thoughts on people with MS choosing other types of diets or lifestyle alternative to OMS?   Regina Beach (14:11): Yeah, so this is really interesting. Since being diagnosed and disclosing my diagnosis, I've had a lot of people say, "Oh I have MS too," or "I have another autoimmune condition," which I think is really interesting, how much you don't know about your acquaintances. I feel like disclosing brought me really close to some people who I had no idea also had things that they were dealing with. But I also think that it's a really personal decision about how you're going to self-manage your condition, and so I've definitely had to be firm, but kind, in my approach saying, "I'm sticking with OMS. This is what I want to do. If you want to do paleo, you want to do another diet, that's fine."   I think it really comes down to how you feel and what you can stick with. And so anybody who is managing through lifestyle, I think deserves big kudos. Anyone who's making these big changes in their lives, whether it's adding exercise or mindfulness, or taking supplements, or whatever it is. I think we're not really at odds with most of the other diets, they are mostly whole food based, they are mostly much healthier than the standard Western diet, and I think that you want to be encouraging, this idea that we have autonomy to make changes that aren't just dictated from a neurologist or a GP, that we can do something for ourselves.   Geoff Allix (15:46): Yeah, and I've spoken to people on different protocols, Mathew Embry, Best Bet Diet, talked to him, and the commonality is greater than the differences.   Regina Beach (16:00): Much more.   Geoff Allix (16:01): And with the Wahls protocol similarly, basically they're all non-dairy, they're all low saturated fat, they're all whole food based. Now it may be that you have organic grass fed, lean meat occasionally on the Best Bet Diet. It may be that you have, gluten is okay on OMS, which is not on others. So there's little bits on the edges, but the core bits are really the same, low saturated fat, whole food diet with no dairy, is basically common across all of them. And I think-   Regina Beach (16:39): Yeah, and even Swank had low fat meat after year one on his original diet, which the OMS diet is built on, so there is so much that is in that same vein.   Geoff Allix (16:53): Yeah. I think some people, as well, because there's a lot of stuff with fasting now as well, and I think there's a lot of interest in fasting. And the paleo diet, if you cut out all your carbs, then you put your body into a fasting state, but when you talk to the neurologist about this, when you are proposing this, they're saying, "Oh yeah, we're not actually encouraging you to just go on an Atkins diet because that would put you into a fasting state, but that's not actually healthy. What you want to be doing is going to fasting state by reducing the time window you eat, or not eating for a day, a week," these different ways of doing it, and then eating a healthy lifestyle. So there's sort of like-   Regina Beach (17:35): Yes, and not just putting yourself into ketosis for the sake of it by not consuming carbs, which are really in everything, and as long as you're eating whole grains, is very, very healthy. That's what so many cultures and indigenous people's whole diets are based on, potatoes, or rice, or other grains. And I think cutting them out is, like you're saying, it's not healthy for the long haul.   Geoff Allix (18:06): So, to change a little bit and talk about your professional life, you were a schoolteacher in the US, moved to the UK and live with your British husband, and now work part-time for OMS as the Trusts and Community Fundraising Manager, as you mentioned. So how did that transition come about?   Regina Beach (18:27): Oh my gosh, I feel that life in Chicago, when I was teaching in public schools there, is a lifetime ago. I was really burnt out, it's a really tough job. I really give a lot of praise to all of the schoolteachers out there, especially in these strange times. But I was really at a point in my career where I was turning into the type of teacher I didn't want to be and needed to pivot, and so I decided to take a year to do a Fulbright Fellowship in Laos in Southeast Asia, and that was my last full year of teaching. I taught teacher candidates there, and that's actually where I met my now husband, who was on a motorcycle adventure through Southeast Asia, and came back to visit me a couple times.   And so, through that process, I was really thinking, okay, what is it that I really like? What is it that I really want to do? I did yoga teacher training. I became a lot more interested in mindfulness and moving meditation, and pivoted back to my first love, which was writing. I studied journalism in university, and really decided, okay, I want to pursue writing. And so some of my work with Overcoming MS is grant writing, and blog writing, and press releases, and I also write essays and poetry in my own time. And so, I'm just trying to carve out a life that's more reflective of my values and what I really enjoy and what I want to spend my time doing. And I was kind of already in that mode when I was diagnosed, but since diagnosis, it's been even more acute that, the time I have, I want to spend it focusing on the things that I really enjoy, and the things where I feel like I can make a big difference.   Geoff Allix (20:31): So OMS is celebrating its 10th birthday this year, and you've got some special events upcoming, there's various OMS birthday trivia, OMS big picnics, and other events. So could you tell us a bit about the events upcoming?   Regina Beach (20:45): Yeah, so we're really excited to celebrate a decade of the charity promoting the OMS program for people worldwide. And so, yes, the big picnic is a great way to get family, friends, your OMS Circle, involved in some outdoor fun, a barbecue, maybe, bringing OMS compliant foods, teaching people about what the diet pillar is about and why, and possibly even doing some fundraising for the charity. And we are going to do a big birthday quiz on Zoom this year, so that will be really fun, having people answer questions both about the program and also just fun trivia stuff.   And so, this year is really important because 10 years ago, Linda Bloom decided that the OMS program needed a cheerleader. I feel the organization is a mouthpiece to help deliver the content and help people who have MS understand that there are thousands of us who are living better because we're self-managing through the program. So, yeah, if you would like to get involved, email fundraising@overcomingms.org. We're really excited to celebrate. We're celebrating the launch of the new brand, we're celebrating what we're moving towards in the future, and hopefully it will be another 10 years of growth and expansion, and yeah, great food and great fun.   Geoff Allix (22:28): So my next question straddles personal and professional, so you're a devout yoga and meditation practitioner, which you also teach, so could you tell us a bit about how that's helped you? How that yoga and meditation side of things has helped you, and share some tips to others about how they could get into a daily meditation practice?   Regina Beach (22:50): Yeah, for sure, so I used to teach a very yang, very physical style of yoga, the 26+2 Bikram series, which is done in a 40-degree Celsius hot room, which I can't do anymore because heat really exacerbates my symptoms, and a lot of the standing series involves so much balance that it is just out of reach for me right now. So I really have had to adjust my practice and my teaching from this really intense [inaudible 00:23:24] to a much gentler, more yin, more long hold, more floor-based yoga.   And so that was really tough for me at first, because obviously this is something I've been doing, I took my first yoga class when I was in university, I was 18 years old, it's been with me for a long time. I'm trying to see it as, I have all of these years of experience, but now I have a beginner's body where I can't necessarily do all of the things that I used to do, and I'm now reteaching myself.   And so, coming at it from that perspective, I feel has been really helpful because it's just being curious about, what can I do today? Being curious about, how does my body feel today? And leaning into that, and saying, "Okay, this is how I feel. This is what I can do. This is how much I can do." And just letting the rest go, and that's where the mindfulness and meditation come in because we cannot force ourselves to do something that we're not able to, and that doesn't necessarily have to lead to frustration. I think that piece is so crucial, when you are able to accept where you are at today, then everything just floats a little better and we're a little more at ease.   I think you can do meditation no matter what you're doing, whether you're doing yoga, whether you're just sitting mindfully, whether you're drinking tea mindfully, whether you're just taking a nice walk and observing the birds and the trees. I think all of that is just, what can I do? Where am I now? How am I feeling in my body? All of that is mindfulness.   And I'm just appreciating where I'm at, and what I can do, and moving towards little goals to improve my balance, to improve my flexibility, and not necessarily treating my old body as the goal, because I might not be able to do all of those yoga asanas in the future, and that's fine, that doesn't mean I can't deepen my practice. And for a while I was thinking, well, does this make me a terrible yoga teacher if I can't do all of these poses? And I've come to the realization that people don't actually care if their yoga teacher can do fancy arm balances, what they care about is if their yoga teacher can meet them where they're at, and help them find comfort and ease, and a little bit of stretch and relaxation in their own body. And so that's also been just a new version of my yoga practice and my yoga teaching.   Geoff Allix (26:03): Yeah. I mean, Usain Bolt's coach is not a world record runner, so you can teach without being at that level, can't you?   Regina Beach (26:13): Exactly.   Geoff Allix (26:14): So, thank you so much for joining us on the Living Well with MS Coffee Break, and allowing the community to get to know you a bit better. So there's one last question that we have that we tend to always ask people, which is, if you could tap into your experience with MS generally, and OMS specifically, for a nugget of wisdom to help people, particularly if they're new to the OMS program, what would that be?   Regina Beach (26:39): I think, really planning out who you'll tell, and how, and what you need from those people you tell is really important because, for as strong as we all are, you need a community behind you. So whether you're going to lean on your OMS Circle, or your family, or your friends, I think having a plan and knowing how you're going to react when someone doubts that what you're doing is helpful. Because I think as a newly diagnosed person, it can be really crushing to hear someone say, "Oh, there's no proof for that," or "Why are you doing that? That's pseudoscience," or whatever the negative, we always remember the negative more than the positive. And so building a community of trusted people, of people who are supporting what you're doing, and having ways to deflect any naysayers, would just go a long way because the mental health aspect of having MS is no joke and it takes a village to keep people moving forward and living well, and taking care of all of these different components of the lifestyle.   But we can do it, and we can do it together, and I think things like the podcast, and the OMS Circles, and all of the wonderful OMSers really do support one another. I think that's the best part of this program, is the community.   Geoff Allix (28:03): Thank you. And thank you very much for joining us, Regina Beach, and thank you for all your work that you do with OMS as well.   Regina Beach (28:11): Thanks, Geoff, it was great to talk to you today.   Geoff Allix (28:13): Thank you for listening to this episode of Living Well with MS Coffee Break. Please check out this episode's show notes at www.overcomingms.org/podcast. You'll find all sorts of useful links and bonus information there.   Do you have questions about this episode, or do you or someone you know want to be featured in a future Coffee Break episode? Then email us at podcast@overcomingms.org. We'd love to hear from you. You can also subscribe to the show on your favorite podcast platform, so you never miss an episode. Living Well with MS Coffee Break is kindly supported by a grant from the Happy Charitable Trust. If you'd to support the Overcoming MS charity and help keep our podcast advertising free, you can donate online at www.overcomingms.org/donate.   To learn more about Overcoming MS and its array of free content and programs, including webinars, recipes, exercise guides, OMS Circles, our global network of community support groups, and more, please visit our website at www.overcomingms.org. While you are there, don't forget to register for our monthly e-Newsletter so you can stay informed about the podcast and other news and updates from Overcoming MS. Thanks again for tuning in and see you next time.   The Living Well with MS family of podcasts is for private non-commercial use and exists to educate and inspire our community of listeners. We do not offer medical advice. For medical advice, please contact your doctor or other licensed healthcare professional. Our guests are carefully selected, but all opinions expressed are solely their own and do not necessarily reflect the views or opinions of the Overcoming MS charity, its affiliates, or staff.  

Welcome to Living Well with MS Coffee Break #31, where we are pleased to welcome Nigel Bartram as our guest!   Our Coffee Break series is your chance to get to know members of our diverse OMS community. In each episode, you'll join Geoff Allix for an intimate chat with a different member of our global community. Our guests will share their personal stories and talk about their challenges and victories, large and small. We hope you find common cause and a source of inspiration from the stories of these very special people. As always, your comments and suggestions are always welcome by emailing podcast@overcomingms.org.   Nigel is a special member of our community – a retired marketing professional who has fused his writing talents and penchant for humor to share his experiences with MS from a very unusual and humorous perspective. We'll dive more into that shortly, plus we have a very special surprise for you, so stay tuned. We hope you enjoy this episode's conversation with Nigel, coming to you straight from Paris, France.   Nigel's Bio (in his own words):   I was born in London but moved around the UK as a child. After a 1st degree in History and then an MBA, my career landed mostly in marketing in the financial sector. In my last job in the UK, as Sales & Marketing Director of a retail stockbroker, following spectacular growth from start-up, I helped lead the company through a heavily oversubscribed IPO onto the London Stock Exchange.    Aged 43 I upped sticks to follow Caroline, my wife, in what was planned to be a temporary career move for her to France, along with our two young children, and my rubbish French. I became a house husband, looking after the kids, improving my ‘null' French, and helping build a house in our Paris suburb (with stunning views towards the city. Temporary morphed into permanent. A joyful adventure, imbibing the beauty of our surrounds and French gastronomy became altogether more serious. Settling in France permanently meant I had to find a job. I retrained as a teacher of English, set up a language school, and taught part-time as a university Associate Professor.      All that was a breeze compared to a body which inexplicably started to go haywire. Overnight, out of nowhere, I lost 90% of the hearing in one ear (which happily came back of its own accord, more or less). In my long-gone student holidays, I worked as a tree surgeon, so heights held no fear for me. So how come I found myself sick with panic driving very slowly along the magnificent Gorge du Verdun with Caroline and the kids on board in 2003? I was petrified by the sheer drop into the ravine, something I'd have relished the challenge of scaling up in yesteryear. I suffered in silence of course.   I wasn't diagnosed with MS for another six years, time enough for my ‘flappy foot' and drunken sailor swagger to become my trademark walk. Bit by bit, bucket loads of other symptoms intruded into my daily life. Time enough also for MS to land me in plenty of challenging situations, some of which, even though they may have been difficult at the time, were clearly comic book stuff.   The idea of the book crystalised a few years later when I was on an OMS retreat. To my great surprise and delight, I realised that MS hadn't robbed any of us MS suffers of our senses of humour. Indeed, it had given us a rich new vein of experiences to mine and chortle over, so important when up to half of people with MS experience depression at some point.   The deal was sealed when the retreat facilitators, Dr Keryn Taylor and Dr Craig Hassed, a world-renowned expert on mindfulness, warmly embraced the idea of such a book for the morale boost it would bring to people with MS, and those close to them, by presenting an altogether lighter side of the condition. Off I went to write down a few of my own stories and harvest those of other people with MS. What a job the latter proved to be!   Questions:   Nigel, welcome to Living Well with MS Coffee Break. We're so pleased to have you on our program. The purpose of this series is to better get to know some of the diverse members of our community from around the world, and today you're in the hot seat. Can you tell us a little about your day-to-day life? When were you diagnosed with MS? Can you provide some context on that? When were you diagnosed and how did you initially deal with it? At which point did you come across the OMS program? How was that experience for you? Why did you decide to start following it? You mention in one of the 3 key things to know about you, which can be found in the show notes, that OMS may have saved your life. That's powerful. Can you speak a bit about that? Let's shift gears a little bit and talk about a very exciting project you've just completed and are about to launch. You've written a book called ‘MS A Funny Thing', which is an illustrated collection of humorous essays you've written through the years about your experience with MS. Can you tell us a bit about it? How has humor helped you deal with the challenges of MS? Another special thing about this book is that you've dedicated all the proceeds to several nominated MS charities. What compelled you to model the project this way? This book is illustrated, and I understand there is an interesting backstory to how you came to collaborate with the illustrator. Can you share a little about that? Since we have whet everyone's appetite about this book, we have a very special treat for you. Nigel is going to read one of his essays from the book! This is very exciting, Nigel. It's the first author reading on this podcast. Please take it away and perhaps share its title and a little context on the piece you're going to read for the next few minutes. Wow, that was fantastic. Thanks so much, Nigel. How can people get their hands on your book? Before we ask Nigel one final question, I want to remind our listeners that May is Mindfulness and Meditation month at OMS. To mark that, tune into a special webinar on May 17, featuring a live meditation session with Phil Startin. If you're listening to this episode after May 17, don't worry, you can view a replay of this or any of our webinars at any time. Details on registering for this free webinar, as well as a link to replays of past webinars, can be found in our show notes. And check out the OMS social channels for daily mindfulness tips that you can incorporate into your day. Nigel, thank you so much for being on Living Well with MS Coffee Break and allowing our community to get to know one of its own a little better. One last question before you go, and it's a bit of a tradition in that we ask it of all our Coffee Break guests. If you tap into your experience with MS generally and OMS specifically for a nugget of wisdom that would help people ease into and better adopt the OMS program, what would that advice be?   Praise for Nigel's Book:   “There are three things I'd like to say about Nigel's book. First, in medicine, we now understand that laughter is good medicine. This book is decidedly good for you! Second, all proceeds go to worthy MS charities. Win-win! Third… now what was that third thing? I need to take Nigel's sage advice and stop nominating how many points I am about to make, don't I?”   Professor George Jelinek MD, Honorary Professor, Melbourne School of Population and Global Health and Founder of Overcoming Multiple Sclerosis   Three Interesting Facts About Nigel (in his own words):   I'm physically pretty handicapped, with an EDSS of 7, but still live a fulfilled life. I haven't given up hope of getting some lost physical function back and am working hard to do that and making some early progress. I'm certain but can't prove that the OMS regime saved my life, getting me through a flirtation with the grim reaper three years ago. Until fairly recently, we who've continued deteriorate physically despite following the programme religiously, have been a real OMS Cinderella, as though somehow, we're an aberration and should be ignored. This view is shared by quite a lot of my OMS friends who have similarly failed to experience any recovery. We nonetheless continue to adhere to the programme believing it to be a force for good even if it doesn't do what it says on the tin for us.   Nigel's Links:   Nigel's book MS A Funny Thing is officially released on May 30 (World MS Day), but you can purchase early here Check out the blogs Nigel has written on the Overcoming MS website Check out Nigel's website, where you can get a taste of his writings Register here for the OMS meditation webinar with live meditation session, taking place on May 17; if you've missed the live webinar, catch the replay here   Coming up on our next episode:   On the next episode of Living Well with MS, premiering May 25, 2022, meet Arlene Faulk, Tai Chi instructor, storyteller, and author of the new book, Walking on Pins and Needles: A Memoir of Chronic Resilience in the Face of Multiple Sclerosis. Learn how Arlene deploys the ancient practice of Tai Chi to help manage chronic pain associated with MS.   Don't miss out:   Subscribe to this podcast and never miss an episode. You can catch any episode of Living Well with MS here or on your favorite podcast listening app. For your convenience, a full episode transcript is also available on all platforms within 72 hours of each episode's premiere. If you like our program, don't be shy and leave a review on Apple Podcasts or wherever you tune into the show. And feel free to share your comments and suggestions for future guests and episode topics by emailing podcast@overcomingms.org.   S4E51c Transcript Coffee Break #31 with Nigel Bartram   Geoff Allix (00:01): Welcome to Living Well with MS Coffee Break, a part of the Living Well with MS podcast family from Overcoming MS, the world's leading multiple sclerosis healthy lifestyle charity, celebrating its 10th year of serving the MS community. I'm your host, Geoff Allix. Today, you'll meet someone living with MS from our diverse and global Overcoming MS community. Our Coffee Break series invites you into the lives of each guest. They share their personal MS journeys and speak openly about their challenges and victories, large and small. We hope you find some common cause and a source of inspiration from the stories of these very special people. You can check out our show notes for more information and useful links. You can find these on our website at www.overcomingms.org/podcast.   If you enjoy the show, please spread the word about us on your social media channels or leave a review wherever you tune in to our podcast. Finally, don't forget to subscribe to Living Well with MS on your favorite podcast platform so you never miss an episode. So get your favorite beverage ready, and let's meet today's guest on Living Well with MS Coffee Break.   Welcome to Living Well with MS Coffee Break #31, where we're pleased to welcome Nigel Bartram as our guest. Our Coffee Break series is your chance to get to know members of our diverse OMS community. In each episode, you'll join me for an intimate chat with a different member of our global community. Our guests will share their personal stories and talk about their challenges and victories, large and small. We hope you find common cause and a source of inspiration from the stories of these very special people. As always, your comments and suggestions are welcome by emailing podcast@overcomingms.org. That's podcast@overcomingms.org.   Nigel is a special member of our community, a retired marketing professional who has fused his writing talents and penchant for humor to share his experiences with MS from a very unusual and humorous perspective. We'll dive more into that shortly; plus, we have a very special surprise for you, so stay tuned. We hope you enjoy this episode's conversation with Nigel, coming to you straight from Paris, France.   So Nigel, welcome to Living Well with MS Coffee Break. We're very pleased to have you on the program, and the purpose of this series is to get to know a bit better the diverse members of our community from around the world, and today you're joining us from Paris, France. So could you tell us a little bit about your day-to-day life?   Nigel Bartram (02:27): Yeah, thanks very much for having me. It's a great pleasure. First of all, a little correction. It's not your fault, but we actually don't live in the center of Paris, or actually in Paris itself, but in a very leafy suburb, with a forest on one side and the river Seine, you can see the barges going past from our bed in the morning, we're about 20 kilometers outside the center of Paris.   Geoff Allix (02:51): That actually makes it sound more idyllic than living in Paris now.   Nigel Bartram (02:55): Well, it is. And I think in common with what's happened in the UK and many countries post-COVID, people are beating a path out of big towns and cities to go to places where there are spaces which during confinement, as they called it here, are a bit more pleasurable than being cooped up in a rabbit hutch, which is many people's place in Paris.   But yeah, so my everyday life, it's I think largely unexciting. I'm fairly handicapped, so I don't get around very much, but I spend quite a lot of time writing on my computer and doing blogs for OMS and for other MS charities, and it's one of the reasons I had time to create the book. One of the great delights of living here is the gastronomy, which is a reason why we stayed and not went back. So lots of delicious meals, all conforming to the OMS guidelines, or as we called it on my retreat, legal food. And incidentally it's easier, I think, in the UK to eat out than it is here. People, with the exception where they get to know you very well, look incomprehensibly at you when you say, "Well, I can't have this, I can't have that, can't have that," and the rest of it. So they give you a plate of mushy green beans or something quite often. I exaggerate, but anyway.   Geoff Allix (04:34): No, I've been to France a number of times since following OMS diet, and I would say it's one of the more challenging places I've been to. We did eat a fair amount of pizza, because anywhere that does freshly made pizza, it's fine. Have pizza without cheese. But yes-   Nigel Bartram (04:56): I think that one of the saving graces actually is fish, because the French eat far, far more fish and seafood than in places in the UK. So even in a brasserie, you'll find fish on the menu, and they'll deign to not fry it or whatever, then you're okay.   Geoff Allix (05:19): And so when were you diagnosed with MS, and could you tell us a bit about that diagnosis and how that went?   Nigel Bartram (05:23): Yeah, I was diagnosed in 2009, but the first symptoms started appearing in 2003. And the reason for the delay was, I guess, twofold in the diagnosis. Firstly, that my GP, while I wouldn't expect him to have been able to diagnose MS, really ignored things that were happening to me, and just sent me for more and more physio, which of course did nothing at all. At the time, one of the big symptoms was what I call the floppy foot, drop foot. And so that was one cause of the delay. The other was that courtesy of SNCF, the French train company, I had a big accident so I was laid up for over a year and ended up suing the rail company. So that totally disrupted life, including getting on the trail of whatever it was that was causing the problem.   So I was diagnosed in 2009, as I said. Immediately after diagnosis, I had to go back to the UK for a week and left my wife, and the neurologist sent the results through. And in French, MS or multiple sclerosis is called sclérose en plaques, SEP they call it, for MS. And my wife is really, really bilingual, but you can only ever be totally bilingual, or you can only be bilingual to the extent you've lived in the two languages through the same life experiences. So of course, she's never had any cause to know what SEP or MS in French was, so she immediately Googled and was appalled to find out what it was that was wrong with me.   And I think it's a fairly common phenomenon that it's often tougher for the partner, for the wife or for whoever it is that's the bystander in this, than it is for the person themselves. Because I mean, we're helpless to some degree, although if you haven't got primary progressive MS then there are meds now available. They just haven't the faintest clue. And for me, it was actually a welcome relief, because I'd had this bag full of things happening over the preceding six years and I now had an explanation for it. That wasn't good news, obviously, but at least I had some rationale to explain what had been happening to me.   Geoff Allix (08:12): That's true. And for me personally it was like, I haven't got a tumor in my brain, or something. You start thinking, "What else could it be? It's something going on neurologically." And so it could have been worse, there is that.   Nigel Bartram (08:28): Yeah. Well, I think your imagination is better than mine. I didn't even think... What on Earth is causing the incontinence, whatever's causing my foot to drop and me trip up everywhere.   Geoff Allix (08:43): And when did you come across OMS, and how did that go?   Nigel Bartram (08:49): Yes, I came across OMS courtesy of... I don't know if you know the magazine New Pathways.   Geoff Allix (08:54): Mm-hmm.   Nigel Bartram (08:57): I can't remember how this happened, but anyway, I was in contact with the editor of New Pathways, and he told me about an event which was taking place in Brighton, where [inaudible 00:09:11] and Craig Hassed was there as well and was giving a conference in the Amex center there. So I went along, that was in 2014, and I absolutely bought what I was hearing.   And I was nowhere near on the OMS program, but I found over the course of the preceding years that I probably did the shopping most of all, more than my wife. And I found I'd gone off red meat almost totally. And so the family are complaining, "Why are you giving us all this chicken?" None of them liked fish, so I didn't stick my neck out that far, but the things my body was telling me that it no longer wanted. So actually the food side of it really didn't give me a big, big problem, because I was mentally and physiologically unconsciously heading that way in any case. So that's how I came across OMS, and then the following year I was lucky enough to go on a retreat, a weeklong retreat in Ammerdown. So that's my OMS story.   Geoff Allix (10:25): And you mentioned in one of the three things to know about you in the show notes that OMS may have saved your life. So that's quite a powerful statement, so could you tell us about that?   Nigel Bartram (10:43): Well, a powerful statement made by a non-medic, non-scientist. You have to take it with the caveat. Yeah, it was coming up on three years ago, I was admitted into A&E; well, twice actually, so they bundled me out the door at two o'clock in the morning the first time. And it turned out to be pancreatitis, which is probably caused by a gallstone escaping the gallbladder. I got septicemia, and I got a couple of other things. So I was six weeks in intensive care. And it's my honest belief, but I say it's an untestable thing to say, but that my body wouldn't have been strong to withstand all that.   The surgeon who subsequently took out my gallbladder to avoid any repetition with gall stones, he said... Because I was questioning whether, because it was the first time anything like this ever happened, whether it was necessary. And he said, "Well, about 50% of people who get pancreatitis like you die. So you're lucky to have escaped that. And then you had septicemia on top of it." And so that's my belief that it was some inner strength that really got me through it. It was very challenging to keep to the diet, to keep to the food regime in hospital, with hospital food. [inaudible 00:12:30].   Geoff Allix (12:30): Yes. I've had some infusions, and I found that staying in hospitals can be somewhat problematic, but yeah. Thankfully not for as long as you, so I could manage it for a few days, things being brought-   Nigel Bartram (12:45): They allowed my wife to come in with meals stuck in the fridge for a couple of days' worth. So a mixture of starvation and brought in meals got me through it.   Geoff Allix (12:59): So you've touched on your book, so if we could change a little bit and talk about this, so it's a hugely exciting project you just completed, about to launch. And the book is called MS A Funny Thing, which is an illustrated collection of humorous essays that you've written through the years about your experience with MS. So could you tell us a bit about the book?   Nigel Bartram (13:20): Yeah. Sorry, just to slightly correct what you said. Well, first of all, the full title is MS A Funny Thing (well sometimes!), not always. And secondly, that I mean, I've got two or three stories in there, but I didn't want a book about my experiences. I want a book about lots of people with MS experience, and therefore it's a collection of the stories and a couple of poems by people that I've garnered over the years. So yeah, it's an illustrated book, each story or poem is illustrated by a funny drawing or painting done by professional artists.   The genesis actually came about on the OMS retreat because I was really surprised, agreeably so, by the real positivity that I found amongst my fellow retreatees. I don't know what I was really expecting, but plenty of laughter, lots of bonhomie, and so on and so forth. And so I thought, well, this is good. People with a sentence of MS don't necessarily throw away their humorous side at all. And the two facilitators, one's Dr. Craig Hassed, the mindfulness guru, and Dr. Keren Taylor, who's a consultant psychiatrist and works under the OMS umbrella. I bounced the idea off them of a book exactly as it's turned out and asked them what they thought. And they thought it was a very, very good idea. So I floated it to the group, who all liked it as well. So I was then able to tap a few members in the group for stories. And that was really the start of it.   Geoff Allix (15:29): And has humor helped you deal with some of the challenges of MS?   Nigel Bartram (15:35): I guess so. I never really thought about it in those terms, because looking for the funny side of things, and not in a desperate search, but through difficulty, often in retrospect, you do find something to laugh about, something that wouldn't have happened to somebody else if they'd been able bodied or not been in that particular situation because of the MS symptoms causing that. And through the book, being able to talk to other people about their experiences and helping them write up in some cases their experiences, and they're genuinely funny.   Geoff Allix (16:26): And another special thing about the book is that you've dedicated all the proceeds to several nominated MS charities. So what compelled you to make that decision? Why did you decide to model the project this way?   Nigel Bartram (16:42): Because I don't need the money. We don't need the money, particularly. I thought that... Choosing the charities, that they have given me a lot. So it's a way of paying that back, hopefully with dividends. So it was pretty much a no brainer to do it for those two reasons.   Geoff Allix (17:10): And I've heard that there's an interesting backstory with how you came to work with the illustrator for the book, so could you tell us a little bit about that?   Nigel Bartram (17:22): Yes. The idea for having illustrations came from a friend in London, and at the time one of her brothers was doing an art course, and I said, "Yeah, it's a great idea, but where do I find somebody to do the illustrations?" And as I said, her brother was doing an art course at the time, so she said, "Well, I'll get my brother to post something on the notice board," which he did, and there were a couple of responses, one of which turned out to be the person that did probably about the first 12, 15 illustrations, was an Italian student studying in London at the time.   And who she termed her favorite auntie; it wasn't actually an aunt, a blood relation, but her favorite family friend; had MS and quite severely disabled. And so it obviously chimed with her as a cause. But I think what also within that struck a chord was that despite I did have a Zoom with her so-called auntie one occasion, who was in a wheelchair, unable to use a mouse so using eye movement to control the cursor, but was nonetheless chirpy. And I think that that probably resonated a lot with the illustrator. And so for a pittance, she did the illustrations, and exercised a lot of patience in dealing with somebody who is completely unartistic, and on a good day can do a half sensible brief and on a bad day nobody can understand what I'm thinking about.   Geoff Allix (19:12): And since we've whet everyone's appetite about the book, we have a special treat for our listeners, and Nigel's going to read one of his essays from the book. So it's the first author reading we've had on the podcast, so please take it away. And could you share the title and a little context on the piece that you're going to read for the next few minutes?   Nigel Bartram (19:34): Yeah. Well, this isn't one of my stories, because I wouldn't lay claim to having the best stories in the book at all. This is one I selected it because it's quite punchy and not too long. So I thought I didn't want to send your listeners off to sleep, but if I did, with a smile on their face perhaps. But anyway, so the title of this, it's by somebody called Ian Daly, and the title is MS, Walking Sticks, Waterboarding, and Much More.   Multiple sclerosis is an insidious disease. The changes that it brings about can seriously affect your life, without you immediately realizing. For me, the first and possibly hardest change to come to terms with was needing assistance to be able to get around. For context, I was a reasonably fit 50-year-old man who would walk approximately five miles a day. I loved to walk. I've always tried to preserve some sense of humor when dealing with MS and its sackful of issues. I probably laugh at things that I shouldn't, say things that cause friends to look at me, and I suspect silently tut. Consultants and nurses roll their eyes, but I usually get a laugh, and that's what matters. It's my chronic illness, and I'll take whatever pleasure I can from it.   Anyhow, jump ahead a couple of years, and I'd started to find walking difficult and falls were becoming more frequent. My legs had stiffened up; controlling them was becoming ever more wearisome. The usual test, two consultants plus an MRI, and I'm awarded a title of MAM with PPMS, middle aged man with primary progressive MS. Hooray! I remain disappointed that there isn't a badge, some form of certificate, and media recognition. With legs that were always tired, I elected to use a stick to help keep mobile and hopefully more stable. Rather than burden the NHS in innumerable physiotherapist and occupational therapists, who I suspected have better things to do, I ordered an adjustable stick through the internet. It arrived and it was reasonably successful in enabling me to walk short distances.   Accepting I was now MAM with PPMS who needed a stick was slightly harder to come to terms with. I needed to shake off this pride thing. It seems this is a common experience and is the subject of many "do whatever you need to do to get by and stay strong" articles over the internet. Due to a rapidly wasting left leg, I soon became MAM with PPMS who needs two sticks. Isn't life grand? Walking short distances was now possible, although my mean-minded MS probably reasoned that I was getting around too well with my two sticks; with cushioned hand grips, no less; elected to introduce severe vertigo for good measure. So I now find I'm walking with two sticks across the deck of a ship during high seas wearing roller skates. Superb.   Incidentally, I was once visiting a doctor with my two sticks and severe vertigo for a series of blood tests. I was discussing weight gain with the nurse, and the fact it's hard to exercise when you have two sticks, weak legs, and vertigo, as you do when someone is sucking bucket loads of blood out of your arm. "Have you tried a treadmill?" says the nurse. Fortunately, she finished extracting blood and was concentrating on filling buckets and applying the useless cotton wool bandage to each of my shoulders, so didn't see my wide-eyed stare, and although I do say myself, magnificent eye roll, combined with my mutter of "Jesus" under my breath. Some people have very little idea of how lucky they are not to go home without having been hit by an office chair.   So MAM with PPMS who needs two sticks now has a further issue: stairs. I've come to detest stairs. They have the ability to hurt my knee in a uniquely painful manner. I attempt to minimize this by using my arms on the banisters to take some of my weight. This only really works on the way down. On the way up, it's a matter of hauling myself along while trying to lessen the weight on my leg and the searing pain in my knee joint which it causes. I can't use my sticks, as I need to hold onto something. Remember the vertigo? I suppose I could try a treadmill. "You need a stair lift." "What is it I now need?" "A stair lift." So MAM with PPMS who needs two sticks becomes MAM with PPMS who needs two sticks and a stair lift. Excellent. To be fair, I rate the stair lift as one of the best inventions of mankind. Okay, there's the wheel, the car, sliced bread, gin, and the internet, but really, I can now get up and down stairs. It does however come with a few tiny issues. Issue one. The stair lifts are generally designed for the elderly and even more infirm than I; their operation reflects this. Incidentally, I have nothing against the elderly. Some of my oldest friends are elderly, and I hope to survive to join their ranks one day, PPMS permitting. Anyway, I press a button and go upstairs. Pause to count grains of sand. Nothing happens for what I'm told is five seconds. It seems infinitely longer. Nothing apart from a very loud screech from the unit, no doubt to warn any other parking elderly person in the vicinity that something's about to happen and that they should dive for cover. The screech is loud enough to hurt my ears. Dogs run down our road to get away from the sound, whilst bats, no doubt attracted by the high frequency, try to get in the window. Being of a practical nature, I've removed the cover, voided the warranty, and unceremoniously jammed an ear plug into the speaker. It dulled the screech a bit, but I can still hear it, as I suspect all the dogs in the neighborhood can.   Issue two. After a five second delay and the eardrums have perforated, we're moving. As far as I can detect, there are three speeds: very slow, slow, and a bit slow, like my walking these days. When the engineer came to fit and program the unit, I was watching it as it made its leisurely way up and down the stairs, configuring the motor all the climb and corners. "Can you make it go a bit quicker?" "No. Sorry. That's it." I'm in no position to argue. Without it I'm confined to one floor. Admittedly, it'd be one of my choosing.   Third issue. Speaking to the company which makes the stair lift. Again, don't get me wrong, I know they have a specific demographic they target for sale, and that's grand. What they do not appear to acknowledge is that everyone who needs a stair lift is stone deaf and has a man with a red flag to walk in front of their car. Indeed, I have the hearing of a bat, and until recently owned an extremely large and very fast motorcycle. That was another casualty of the MS progression. Anyway, I digress. An example will be the call to let me know when the engineer was arriving to install the lift. "Hello? Is that Mr. Daly?" The lady speaking clearly and louder than I would generally have expected. "It is," I find myself shouting a little, as if trying to join in. "Mr. Daly, we're arranging for our engineer, Adam," not his real name, "to attend tomorrow. Would you prefer AM or a PM visit?" "AM, please." "Great. Would 11 o'clock be a good time? That should give you plenty of times to get washed and dressed and have your breakfast." "Er, okay. That'll be fine."   I'm not used to this level of interest or consideration. Like most people, I normally have to endure the "We're unable to give you a time. AM or PM is best I can do." Appointment fixed; I wonder if I have time to nip out to get the engineer a gift. Nothing extravagant, you understand, just a token. "When Adam arrives, he'll show you his identification badge. If you're not completely happy, please give us a ring to confirm his ID is genuine. He won't mind waiting." "If I'm not happy, I'll bounce Adam down the drive." "I beg your pardon?" "Nothing. 11 o'clock tomorrow then. Yep." You see, everyone must be elderly if they have a stair lift. I've done the thing where you ask for a note that you put on your account, you know the sort of thing, "Please do not treat Ian as an elderly gentleman. He's not elderly, neither is he a gentleman." This makes not a blind bit of difference. It is extremely annoying, until there's a problem or you need something.   About a year ago, I was cruising up to the first floor, coffee in one hand, motorcycle helmet on in order to deaden the sound, and my finger on the requisite button. I arrived upstairs, where I spent some time playing with the internet and drinking coffee. On attempting my return journey, nothing. The whole thing was dead as a dodo. So I telephoned the company to advise them of my dilemma. "I'm trapped outside." I thought I'd go straight for the dramatic introduction, as it would raise a level of medium to high panic.   An entirely reasonable and professional sounding lady began slowly to talk me through a list of resolutions that must have previously worked. Not today though. "Are you able to get downstairs, Ian?" "Of course," my sarcasm nerve had now kicked in, "that's why we spent four and a half grand on a stair lift." "I beg your pardon?" "Nothing. Just thinking out loud. Not really, I'm pretty stuck here." "Okay. Then there's something we can try." The fix turned out to be opening the footrest and then slamming it closed. "As hard as you can." "Really?" "Yes, really." This I did. Everything lit up like a Christmas tree and the warning bleep felt compelled to join in. All sorted. Well, almost. Adam, not his real name, turned up the next day to replace the main circuit board, and at a prearranged time.   After a lot of inane rambling, my message here is if there's something, anything, which can make your life a little easier, then for the love of God, go for it. Walking stick, crutches, stair lift, car adaptations, grab rails, false limbs, parachutes; they're all there to enable you to, or at least some semblance of you. Use them. Walk or shuffle to the park. Point at pigeons with your stick. Make sarcastic comments to call center staff. The possibilities are endless. Life with MS is hard enough.   I was showering the other morning and dropped the soap, such a trivial thing for a non-MAM with PPMS. It's only a small shower cubicle, so I bent double to pick up the soap, slipped, and became wedged in the corner, and to all intents and purposes upside down. It was like being waterboarded. If it wasn't for the grab rail, I'd probably have drowned. How my partner and I laughed. Ian Daly, a middle-aged man with PPMS, who needs two sticks and a stair lift, and a non-slip mat in the shower, and grab rails in the said shower, plus a grab rail to [inaudible 00:32:39] and a stool for the shower.   Geoff Allix (32:43): Thank you very much for that. That was fantastic. So now that you've whet our appetite with that, how can people get hold of the book?   Nigel Bartram (32:54): Right, it'll be sold on Amazon in print form and also as an eBook. It's due come out on the 30th of May, which is World MS Day. I believe we chose the date in order hopefully to get a higher profile for it. So it'll be coming out shortly after, I think this podcast is released, won't it?   Geoff Allix (33:23): Yeah. Yeah. This is coming out May. So you mentioned at the end of May is World MS Day, and also I want to remind our listeners that May is Mindfulness and Meditation Month at OMS. And to mark that, you can tune into a special webinar on May the 17th featuring a live meditation session with Phil Startin. And if you're listening to this episode after May 17th, don't worry, you can view a replay of this or any webinars at any time. And details of registering for the free webinar as well as a link to replays of past webinars can be found in the show notes for this episode. And check out the OMS social channels for daily mindfulness tips that you can incorporate into your day. So Nigel, thank you so much for being our guest on Living Well with MS Coffee Break.   Nigel Bartram (33:23): Could I just interrupt you a second?   Geoff Allix (33:23): Yep, sorry.   Nigel Bartram (34:16): Your plug was instantly longer than mine.   Geoff Allix (34:16): I know.   Nigel Bartram (34:19): I must just add that just if you go onto Amazon and Google, put the search MS A Funny Thing, there won't be anything like it, so you don't need to remember the full title of the book.   Geoff Allix (34:35): And we will have links in the show notes as well actually, so you'd be able to get to the book no problem.   Nigel Bartram (34:35): Okay. Fantastic.   Geoff Allix (34:41): So one final thing that we normally ask our guests, which is a bit of a tradition that we have, which is that if you tap into your experience with MS generally and OMS specifically for a nugget of wisdom that could help people, particularly new people, adopt the OMS program, what would that advice be?   Nigel Bartram (35:04): One particular aspect or just one thing-   Geoff Allix (35:06): No, just anything that you think could help people who are maybe newly diagnosed or maybe new to the OMS program.   Nigel Bartram (35:16): I think I'd say two things, if I may.   Geoff Allix (35:18): Yeah.   Nigel Bartram (35:19): One is that although some people may find the diet difficult to come to terms with, there are so many great recipes that you can get through OMS. You won't be depriving yourself of an enjoyable gastronomy at all. And it is so utterly healthy that whether you had MS or not, it's such a good thing to do. The second thing I would say, and obviously I don't mean to plug your plug, but mindfulness is a real, real blessing because there are tough times. And being able to, I was going to use the word retreat, perhaps that's not the best verb to use; but anyway, to find a place to go to when you're in difficulty which you can emerge from tranquil and at ease with the world, having cured nothing other than maybe anxiety or stress, which is important in its own right, I'd highly recommend that.   Geoff Allix (36:29): With that, thank you very much for joining us, Nigel Bartram.   Nigel Bartram (36:34): A great, great pleasure. And do buy the book. And it comes complete with a testimonial from George Jelinek. Can I just read out what he says?   Geoff Allix (36:43): Absolutely. Yeah.   Nigel Bartram (36:45): Because he's got a bit of a teaser in there. "There are three things I like to say about Nigel's book. First, in medicine, we now understand that laughter is good medicine. This book is decidedly good for you. Secondly, all proceeds go to worthy MS charities. Win-win. Third, now, what was it, that third thing? I need to take Nigel's sage advice and stop nominating how many points I'm about to make, don't I?" In order to unpack and understand that last comment of George's, you'll need to buy the book and read the preface.   Geoff Allix (37:27): Okay. With that, thank you very much. And I would encourage everyone, search out the book on Amazon. Actually, I should say that you can do this thing called Smile at Amazon and you can nominate a charity. So not only does the money go to charity from the book, but actually everything that you buy from Amazon, you can nominate a charity, and OMS is one of the charities you can nominate, and a small amount of any shopping at Amazon would actually go to charity.   Nigel Bartram (37:55): So it's a win-win-win-win.   Geoff Allix (37:55): Thank you for listening to this episode of Living Well with MS Coffee Break. Please check out this episode's show notes at www.overcomingms.org/podcast. You'll find all sorts of useful links and bonus information there. Do you have questions about this episode, or do you or someone you know want to be featured in a future Coffee Break episode? Then email us at podcast@overcomingms.org. We'd love to hear from you. You can also subscribe to the show on your favorite podcast platform so you never miss an episode. Living Well with MS Coffee Break is kindly supported by a grant from the Happy Charitable Trust. If you'd like to support the Overcoming MS charity and help keep our podcast advertising free, you can donate online at www.overcomingms.org/donate.   To learn more about Overcoming MS and its array of free content and programs, including webinars, recipes, exercise guides, OMS Circles, our global network of community support groups, and more, please visit our website at www.overcomingms.org. While you're there, don't forget to register for our monthly e-newsletter, so you can stay informed about the podcast and other news and updates from Overcoming MS. Thanks again for tuning in, and see you next time.   The Living Well with MS family of podcasts is for private, non-commercial use, and exists to educate and inspire our community of listeners. We do not offer medical advice. For medical advice, please contact your doctor or other licensed healthcare professional. Our guests are carefully selected, but all opinions they express are solely their own and do not necessarily reflect the views or opinions of the Overcoming MS charity, its affiliates, or staff.  

Elisa Ascherl beantwortet Fragen rund um die Emendia App für MS-Patienten, die zum besseren Verstehen und Verfolgen der MS eingesetzt wird.   Hier geht es zum Blogbeitrag: https://ms-perspektive.de/interview-zur-emendia-app-fuer-ms-patienten In Folge 137 begrüße ich Elisa Ascherl, die mir alle Fragen zur App Emendia MS beantworten wird. Der Beitrag ist Teil der Themenwoche zu digitalen Unterstützungsangeboten für MS-Patienten. Du erfährst, wie die Idee entstand mithilfe einer App die Behandlung zu verbessern, wer alles daran mitgearbeitet hat und was bereits alles möglich ist. Natürlich geht es auch um den Datenschutz und wie Emendia MS konkret im Alltag eingesetzt wird.   Inhaltsverzeichnis Vorstellung Emendia MS – App zum besseren Verstehen und Verfolgen der MS Emendia MS im Einsatz Abschluss Vorstellung Ich grüße dich aus Nürnberg, im schönen Franken – aus meinem, spätestens seit Beginn der Coronapandemie, sehr lieb gewonnenen Home-Office. Seit 2020 arbeite ich bei der NeuroSys und bin seitdem für die Entwicklung von Emendia MS mitverantwortlich. Schon vor meinem Studium im Bereich Gesundheitsmanagement und Wirtschaftspsychologie begeisterte mich die Vernetzung von tollen Möglichkeiten und Angeboten, um eine bestmögliche Gesundheitsversorgung zu gewährleisten. Dazu gehören für mich auch die Selbstverantwortung und die Selbstwirksamkeit als Betroffener einer Erkrankung. Diese als Teil des Lebens anerkennen zu können, aber gleichzeitig auf Augenhöhe mit medizinischem Fachpersonal sprechen zu können. Als Jugendliche bin ich selbst in Kontakt mit einer chronischen Erkrankung gekommen – der Skoliose, einer leichte Rückenerkrankung. Ich musste eine Orthese tragen. Schade war, dass viele Menschen eher mitleidig mit mir gesprochen und bei Fragen oft dieses Thema fokussiert haben. Ich hörte immer, was nicht mehr geht – Sport, Medizin studieren. Anstatt Hilfe zu bekommen. Erst durch eine Kur und der dadurch angebotenen Konfrontation mit der Erkrankung, durch das Erkennen der Selbstwirksamkeit wurde mir ganz persönlich geholfen, auch auf psychischer Ebene. Ich habe dadurch die „Grenzen“ und Partner erkannt. Genau diese Möglichkeiten und Potenziale, die wir bei vielen anderen Erkrankungen auch haben – die Betroffenen als Teil des Heilungs-/Therapieerfolgs anzuerkennen, treiben mich jeden Tag an. Digitalisierung kann dabei helfen, verschiedene Welten zusammen zu bringen und Kilometer zu überwinden. Ich selbst bin in Thüringen in einer ländlichen Region aufgewachsen, die Fahrten zu Kontrollterminen waren echt nervig. Da hätte ich mir nicht selten Telemedizin oder andere Möglichkeiten gewünscht, vermutlich meine Eltern noch mehr, denn diese mussten damals immer Taxi spielen. Noch ein bisschen was zu meinen Hobbys. Ich liebe das Lesen, gute, tiefgründige Gespräche und das Gärtnern – gerade wächst neben mir die erste Frühzucht für die diesjährige Saison. Außerdem liebe ich Reisen, meine Familie und Freunde und ich „arbeite“ gerne. Emendia MS – App zum besseren Verstehen und Verfolgen der MS Wie würdest Du Emendia MS in Kurzform beschreiben? Emendia ist ein alltäglicher, digitaler Begleiter im Rahmen der MS-Therapie. Ein digitale/r Partner/Partnerin. Was war die Motivation zum Entwickeln von Emendia MS? Emendia MS hat eine „Vorgeschichte“ durch ein weiteres Produkt von uns „PatientConcept“. Entstanden ist aber alles aus einer Motivation: Die Versorgung von Patientinnen zu verbessern, initial vor allem durch eine verbesserte Arzt-Patienten-Kommunikation. Ausgedacht hat sich das nicht irgendwer, sondern einer unser Mitgründer und langjähriger MS-Spezialist Dr. Michael Lang. Dr. Lang leitete damals selbst eine MS-Schwerpunktpraxis in Ulm und sah die Probleme aus der Praxis und wollte eine Lösung. Welche Probleme sah er?: MS ist eine chronische Erkrankung, doch die Patienten konnten nur bis zu 4-mal pro Jahr zur Konsultation vorgestellt werden. Als Arzt erhielt er nur eine punktuelle Bewertung des aktuellen Zustands seiner Patienten. Auch konnten sich die Patienten nur schlecht daran erinnern, wann es ihnen wirklich besser und wann schlechter ging. Das geht uns ja selbst schon fast so – man braucht sich ja nur mal fragen, wie man letzten Dienstag geschlafen hat. Wer kann sich noch erinnern? Es fehlte somit an Wissen oder auch Daten, aus dem Alltag der Patienten. Und das ist in der MS-Therapie sehr wichtig, denn die Anpassung der Medikationen erfolgt u.a. auf Basis der Rückmeldungen der Patienten. Umso bessere Verlaufsdaten zur Verfügung stehen, umso besser kann auch ggf. die Anpassung erfolgen. Die sogenannte Therapietreue der Medikamente ließ nach, denn waren die Beschwerden weniger, wurden die Medikamente nicht mehr genommen, obwohl die Entzündungsherde nicht einfach verschwinden, wenn keine Beschwerden vorhanden sind. (Auch niederschwellige Kontakte, das Gefühl mit dem Zentrum zu kommunizieren schafft eine höhere Therapietreue.) Gleichzeitig gibt es wichtige medizinische Tests, die in der Praxis vor Ort viel Zeit dauern. Um die Sprechzeit mit den Patienten so effektiv wie möglich zu gestalten, empfahl es sich, Tests bereits zu Hause durchführen zu lassen. Ein paar davon können digitalisiert werden. Wir haben mit dem MFIS und dem EDSS angefangen, dass Patienten diesen zu Hause oder vor dem Arztbesuch ausfüllen können. Wichtig ist, wir verwenden diese nicht als einmaligen Wert oder zur alleinigen Diagnose, vielmehr ist ein Verlauf der Werte über eine längere Zeit pro Patient wichtig. Es entstand, mit einem Team aus IT-Experten, unter der Leitung von Martin Mayr, das erste Produkt PatientConcept. PatientConcept besteht aus einer App für Patienten und einem Portal für Ärzte. Eines der ersten Anwendungsgebiete war MS. Dieser Weg begann 2015 – also in der Steinzeit von Digital Health. Während der vergangenen Jahre haben sich die Ansprüche geändert und wir wollten mehr den Patienten in den Fokus rücken, auch ermöglichte das Digitale-Versorgung-Gesetz (DVG) eine neue Perspektive. So ist Emendia MS, mit Fokus auf MS entstanden. Jedoch bleiben wir auch hier unserer Philosophie treu: Zu einer optimalen Versorgung von chronischen Erkrankungen gehört die Kommunikation mit dem betreuenden medizinischen Fachpersonal. Also bieten wir zur App auch weiterhin ein Portal für medizinisches Fachpersonal an. Die Motivation ist also seit Beginn unserer Arbeit, die Lebensqualität von Menschen mit MS zu steigern, indem die MS-Versorgung durch digitale Tools verbessert wird. Wer war alles an der Entwicklung beteiligt (Neurologen, Patienten, …)? Mehrere Neurologen

Die Themenwoche "Digitale Unterstützungsangebote für MS-Patienten" beginnt mit einer Einführung warum diese Angebote nötig und hilfreich sind. Die Diagnose Multiple Sklerose bedeutet momentan, dass man die Krankheit ein Leben lang behält. Zum Glück verbessert sich die Prognose stetig, da immer mehr Behandlungsmöglichkeiten zur Verfügung stehen. Dazu zählen auch die vielfältigen digitalen Unterstützungsangebote. Folge #135 bildet den Auftakt zu einer Themenwoche. Ich möchte Dir einige Beispiele vorstellen, die es für Betroffene und ihre behandelnden Ärzte gibt und welche Vorteile damit einhergehen können. Dabei habe ich mich auf eine Auswahl beschränkt. Das Angebot wächst stetig und es reicht von kleinen allgemeinen Lösungen bis hin zu spezifischen Anwendungen für ein Symptom der MS. Inhaltsverzeichnis Überblick zu drei digitalen Angeboten für MS-Patienten Wieso digital? Welche Gemeinsamkeiten haben die digitalen MS-Angebote? Wie sieht es mit dem Datenschutz aus? elevida – Online-Angebot zur Verringerung der Fatigue bei MS Emendia MS – App zum besseren Verstehen und Verfolgen der MS KONECTOM – App zum Überwachen und Messen der MS als Teilstudie, um die Krankheit besser zu verstehen und zu behandeln MS-Kaffeeklatsch zu digitalen Unterstützungsangeboten Abschluss Überblick zu drei digitalen Angeboten für MS-Patienten Ich gebe Dir einen Einblick, was digitale Gesundheitsanwendungen, kurz DiGAs, sind und wie man diesen Status erhält. Du erfährst, welche DiGA bereits zur Behandlung der Fatigue zugelassen ist, welche App die Bewerbung als DiGA vorbereitet, und welche App gerade in einer Teilstudie für eine verbesserte Behandlung von MS-Patienten getestet wird. Natürlich geht es auch um Datenschutz und den Mehrwert digitaler Anwendungen aus Patientensicht. Wieso digital? Bei einer chronischen Erkrankung wie Multipler Sklerose fallen im Laufe der Jahre und Jahrzehnte riesige Mengen an Daten pro Patient an. Und diese Daten enthalten Informationen, die wenn sie zu Tausenden anonymisiert ausgewertet werden zu einer verbesserten Behandlung beitragen können. Das wäre auf Papier ein nicht zu bewältigender Aufwand. Digital hingegen kann man nach Anhaltspunkten suchen, sowohl jetzt, als auch zu einem späteren Zeitpunkt, falls sich neue Fragestellungen und Theorien ergeben haben, die überprüft werden sollen. Wie stehen bestimmte Symptome, die Du regelmäßig vermerkt hast, in Zusammenhang mit dem Verlauf Deiner Erkrankung? Was kann man davon im MRT sehen oder auch nicht? Wie beeinflusst ein neues Medikament Dein Allgemeinbefinden? Wie wirkt sich die Ergotherapie auf Deine Feinmotorik aus? Viele Fragen, die digital deutlich einfacher überprüft werden können. Ob es immer ein aussagekräftiges Ergebnis gibt, ist eine andere Sache. Aber auch für Dich kann es interessant sein, wenn Du über einen längeren Zeitraum Deine Fähigkeiten beobachten kannst, weil Du sie regelmäßig überprüfst. Und gerade kognitive Tests fallen Dir möglicherweise im privaten Umfeld viel leichter und Du erzielst bessere Ergebnisse. Wer weiß? Die zugelassene DiGA zur Fatigue ermöglicht Dir, komplett individuelle Wege zu gehen. Denn Fatigue ist nicht gleich Fatigue. Die Ursachen sind ebenso wie die MS sehr vielfältig. Und was dem einen hilft, muss Dir nicht helfen. Aber in einem digitalen Programm ist es kein Problem, mittels Fragen Deine individuelle Problematik zu erfassen und darauf passende Lösungen anzubieten. Welche Gemeinsamkeiten haben die digitalen MS-Angebote? Eine Gemeinsamkeit haben alle drei vorgestellten Lösungen. Sie sollen das Leben mit Multipler Sklerose verbessern. Doch was heißt das? Bei einer chronischen Erkrankung wie der MS, die ohne ein Eingreifen zu einer stetigen Verschlechterung führt, geht es darum den Verlauf zu verlangsamen, am besten zu stoppen. Da MS multifaktorisch ausgelöst wird und auch der Verlauf von mehreren Faktoren abhängt, gibt es jede Menge Möglichkeiten, darauf Einfluss zu nehmen. Das beste Ergebnis kann nur gemeinsam erreicht werden, sprich wenn ein Neurologe, spezialisiert auf MS und auf dem neuesten Wissensstand, und ein Patient mit guter Kenntnis über seine Erkrankung zusammenarbeiten. In der Fläche kann es aber nicht nur MS-Spezialisten bei den Neurologen geben. Deshalb sind digitale Unterstützungen eine Möglichkeit einem Neurologen, der viele Erkrankungen behandelt dabei zu helfen auf dem neuesten Stand zu bleiben und die bestmöglichen Entscheidungen zu treffen. Da viel Krankheitsaktivität im Verborgenen stattfindet und gerade zu Beginn der MS kaum sichtbar oder spürbar ist, helfen häufig durchgeführte Tests dabei, diese verborgene Aktivität zu erfassen. Je besser der Ist-Stand dokumentiert wird und die Veränderungen über die Zeit, desto spezifischer können therapeutische Maßnahmen eingeleitet werden. Dazu zählen sowohl die verlaufsmodifizierende Therapie als auch begleitende Maßnahmen wie Physiotherapie, Ergotherapie, Psychotherapie, eine Ernährungsumstellung, Sport und andere. Wie sieht es mit dem Datenschutz aus? Datenschutz ist ein wichtiges Thema und ich persönlich überlege mir sehr genau, wo und wem ich meine Daten anvertraue. Aber Fakt ist, dass intelligent ausgewertete anonymisierte Daten, Forscher und Ärzte in die Lage versetzen Zusammenhänge zu erkennen, die zu einer besseren Behandlung führen oder vor Behandlungsfehlern schützen. Und wenn an einer Stelle alle Medikamente notiert werden, die ein Patient einnimmt, dann kann ein intelligentes Programm, das gut mit Daten gefüttert ist, aufzeigen, wo es Probleme geben kann, weil sich die Wirkung von Medikamenten aufhebt oder zum Gesundheitsrisiko wird. Selbstverständlich unterliegen alle drei vorgestellten Lösungen sehr strengen Auflagen zum Datenschutz. Bei einer normalen Gesundheitsapp muss nur die DSGVO beachtet werden, also die Datenschutzgrundverordnung. Bei den digitalen Gesundheitsanwendungen, den DiGAs werden hingegen die strikten Vorgaben des Bundesinstituts für Arzneimittel und Medizinprodukte umgesetzt. Auch das andere hier vorgestellte Angebot unterliegt hohen Datenschutzvorgaben, damit die Patientendaten zu jedem Zeitpunkt bestens geschützt sind und nur an den vorgesehenen Stellen entschlüsselt werden können, damit Ärzte und Forscher ihrer Arbeit nachgehen können. elevida – Online-Angebot zur Verringerung der Fatigue bei MS Gerade unsichtbare Symptome wie die Fatigue können das Leben in allen Bereichen stark in Mitleidenschaft ziehen. Doch es gibt erprobte Verhaltensweisen, die die Auswirkungen der Fatigue verringern können. Oft fällt das Neinsagen schwer, werden zu wenig Pausen genommen oder lieber auf Schonen gesetzt, statt auf körperliche Aktivität, was besser wäre. Die digitale Gesundheitsanwendung, kurz DiGA, namens elevida widmet sich erfolgreich diesem Symptom. Sie ist die erste zugelassene DiGA speziell für MS-Patienten und wurde von Ärzten und Psychotherapeuten gemeinsam entwickelt. Das Online-Angebot hilft dem Patienten individuell, basierend auf einem Dialog, Lösungen für seine spezifische Problematik mit der Fatigue zu finden. Der Patient erhält unter anderem Tipps zur richtigen Balance von Aktivität und Erholung, lernt gesunde Gedanken- und Verhaltensmuster kennen, und wie er die Unterstützung von Freunden, Familie und Kollegen nutzen kann. Am Ende geht es noch darum, die Veränderungen dauerhaft umzusetzen. Das läuft alles über eine Online-Plattform ab. Zusätzlich erhält man SMS-Nachrichten mit kleinen Impulsen, wie dem Hinweis, dass ich nicht alles allein bewältigen muss, sondern auch Freunde und Familie fragen kann. Näheres erfährst Du in Folge 136.   Emendia MS – App zum besseren Verstehen und Verfolgen der MS Multiple Sklerose zeichnet sich durch eine Vielzahl an sichtbaren und unsichtbaren Symptomen aus, die von körperlichen Einschränkungen über Schmerzen bis hin zu Konzentrationsschwierigkeiten reichen können. Mit der App kannst Du Symptome täglich erfassen und dadurch selber sehen, wie sie sich entwickeln. Ergänzend kannst du über medizinische Abfragen regelmäßig eine Selbsteinschätzung deiner allgemeinen Beeinträchtigung (EDSS) oder auch Fatigue (MFIS) durchführen. Die vier integrierten Tests messen Deine Feinmotorik, kognitiven Fähigkeiten und Deinen Gleichgewichtssinn beim Gehen gemeinsam mit der Geschwindigkeit. Außerdem kannst Du Dich an die Einnahme Deiner Medikamente erinnern lassen und einen neuen Schub eintragen. Die erfassten Daten kannst Du mit Deinem Neurologen teilen, der sie dann innerhalb eines Portals anschauen kann oder Du besprichst sie beim nächsten Besuch. Beides kann Deine Behandlung verbessern da so bereits kleinere Veränderungen erfasst werden. Zusätzlich bietet Dir die App Artikel zu verschiedenen Aspekten der MS an. So kannst Du nach und nach zu einem Experten Deiner Erkrankung werden und bewusst Entscheidungen treffen, die einen positiven Einfluss auf die MS haben. Mehr Einblick erhältst Du in Folge 137.   KONECTOM – App zum Überwachen und Messen der MS als Teilstudie, um die Krankheit besser zu verstehen und zu behandeln Für Wissenschaftler und behandelnde Neurologen ist es enorm wichtig, die Multiple Sklerose bis ins kleinste Detail zu verstehen. Wie viel Untersuchungen sind nötig? Welche Tests der Feinmotorik, kognitiven Fähigkeiten, des Gleichgewichtssinns und der Gehstrecke machen Sinn? Halten Patienten die wöchentlichen oder gar täglichen Tests über einen längeren Zeitraum durch? Und wie stehen die Testergebnisse mit den Untersuchungen vor Ort in den MS-Zentren in Zusammenhang? Viele Fragen, auf die die Teilstudie aus dem MS-PATH Programm Antworten liefern soll. Generell kommt jeder MS-Patient in Frage, der bereits an einem der fünf MS-Zentren an der MS-PATH Studie teilnimmt. Neben dem Beitrag zum wissenschaftlichen Fortschritt kannst Du als Teilnehmer besser Deinen MS-Verlauf verfolgen und hast gleich noch einen kleinen Trainingseffekt dabei. Zukünftig soll die App um weitere Funktionen ergänzt werden, wie die Erfassung von passiven Mobilitätsdaten und Aktivitäten, die Google Fit bzw. Apple Heath aufzeichnen. Natürlich nur mit Deiner Zustimmung. Neugierig geworden, dann hör Dir die Folge 138 an.   MS-Kaffeeklatsch zu digitalen Unterstützungsangeboten Gemeinsam mit Nadine und Martin werden wir zu dritt über unsere Erfahrungen, Wünsche und Gedanken rund um das Thema der digitalen Angebote aus Sicht von MS-Patienten sprechen. Folge 139 stellt somit den Abschluss der Themenwoche dar. Wir beleuchten nochmals die verschiedenen Perspektiven auf das Thema digitale Unterstützungsangebote, wie gewohnt in lockerer Atmosphäre . Dabei variieren unsere Erfahrungen mit den digitalen Angeboten, was ganz gut den Kenntnisstand innerhalb der MS-Community widerspiegelt. Abschluss Das war es zunächst zum Einstieg und Überblick über die kommenden Folgen. Es ist das erste Mal, das ich so eine Themenwoche durchführe und ich bin schon sehr gespannt auf Deine Meinung dazu. Was findest Du gut? Was interessiert Dich weniger? Wozu würdest Du Dir eine weitere Themenwoche wünschen? Lass es mich wissen. Und zum Schluss noch die Antwort auf eine Frage, die ich meinen Gästen sonst immer stelle: Ich wünsche mir, dass die Behandlung und Prognose für uns MS-Patienten weiter verbessert werden kann dank der digitalen Unterstützungsangebote und das ohne zusätzlich das Gesundheitssystem zu belasten. Mehr Daten, die zu mehr Erkenntnissen führen. Eine bessere und individuell passgenaue Behandlungen, damit das Leben mit MS vor allem ein Anlass zu einer bewussten und gesunden Lebensweise ist und Zukunftsängste beim Erhalten der Diagnose bald der Vergangenheit angehören.   Ich wünsche Dir bestmögliche Gesundheit, Nele Mehr Informationen rund um das Thema MS erhältst du in meinem kostenlosen MS-Letter. Hier findest Du eine Übersicht über alle bisherigen Podcastfolgen.

Micha Breakstone is the CEO and Co-Founder of NeuraLight and points out the lack of objective and sensitive evaluation measures available to diagnose neurological diseases like multiple sclerosis, Alzheimer's, and Parkinson's.  Currently, evaluations using short questionnaires, visual observations, and self-reported behavior are further influenced by biases of the physician. NeuraLight is developing an approach that focuses on using images of the eye to produce objective, repeatable measures of disease progression. Micha elaborates, "We look at over 100 parameters at once, and we capture these by standard videos or anything from a webcam to a mobile phone. And we've developed a quite unique technology that marries, on the one hand, a kind of standard machine learning. But on the other hand, something that is entirely unique to us which is signal processing. So the ability to basically bring technologies that are available for satellites, in super-resolution, bring them down to earth into mobile phones in order to take these standard videos and extract parameters at a super-resolution or a sub-pixel resolution from standard video." "There are actually over 700 papers that were published in the last 20 years or so showing that oculometrics, namely, micro measurements of the eyes, are extremely good as a proxy both for currently used endpoints like UPDRS and EDSS that I mentioned earlier. But also in phenotyping patients, looking at the difference between secondary progressive MS and repeating, remitting MS or the subtypes, four or five subtypes of Alzheimer's, just being able to look at those oculometrics or ocular measures, being able to identify the subtype of the disease is a great proxy for the standard scale." @NeuraLight #NeuraLight #AI #Oculometric #OcularMeasures #NeurologicalDiseases #NeurodegenerativeDisease #Parkinsons #MS #MultipleSclerosis #Alzheimers #Dementia #ClinicalTrials #NeurologicalEvaluation NeuraLight.ai Download the transcript here

Micha Breakstone is the CEO and Co-Founder of NeuraLight and points out the lack of objective and sensitive evaluation measures available to diagnose neurological diseases like multiple sclerosis, Alzheimer's, and Parkinson's.  Currently, evaluations using short questionnaires, visual observations, and self-reported behavior are further influenced by biases of the physician. NeuraLight is developing an approach that focuses on using images of the eye to produce objective, repeatable measures of disease progression. Micha elaborates, "We look at over 100 parameters at once, and we capture these by standard videos or anything from a webcam to a mobile phone. And we've developed a quite unique technology that marries, on the one hand, a kind of standard machine learning. But on the other hand, something that is entirely unique to us which is signal processing. So the ability to basically bring technologies that are available for satellites, in super-resolution, bring them down to earth into mobile phones in order to take these standard videos and extract parameters at a super-resolution or a sub-pixel resolution from standard video." "There are actually over 700 papers that were published in the last 20 years or so showing that oculometrics, namely, micro measurements of the eyes, are extremely good as a proxy both for currently used endpoints like UPDRS and EDSS that I mentioned earlier. But also in phenotyping patients, looking at the difference between secondary progressive MS and repeating, remitting MS or the subtypes, four or five subtypes of Alzheimer's, just being able to look at those oculometrics or ocular measures, being able to identify the subtype of the disease is a great proxy for the standard scale." @NeuraLight #NeuraLight #AI #Oculometric #OcularMeasures #NeurologicalDiseases #NeurodegenerativeDisease #Parkinsons #MS #MultipleSclerosis #Alzheimers #Dementia #ClinicalTrials #NeurologicalEvaluation NeuraLight.ai Listen to the podcast here

Willkommen zu Folge 110 vom MS-Perspektive-Podcast. Ich habe heute Dr. Katja Akgün zu Gast und wir unterhalten uns über die Neuroimmunologie und ihre Bedeutung für die Behandlung von Menschen mit Multipler Sklerose. Vorstellung Dr. Akgün ist Fachärztin für Neurologie, Leiterin des Infusionszentrums am Zentrum für klinische Neurowissenschaften und Leiterin des neuroimmunologischen Labors am Universitätsklinikum Dresden. Sie arbeitet eng mit dem MS-Zentrum Dresden zusammen, da das Infusionszentrum ein Teil davon ist. Einmal hat sie bei mir vertretungsweise das Arztgespräch gemacht. Dabei habe ich sie gleich angesprochen, ob sie als Interviewgast vorbeikommen will und sie hat direkt zugestimmt. Heute gibt uns Dr. Akgün einen kleinen Einblick in das Thema Neuroimmunologie. Denn die Neuroimmunologie spielt eine wesentliche Rolle bei Multipler Sklerose. Zur Neuroimmunologie hatte ich auch schon Professor Harms zu Gast, der erklärt hat, welche Forschungsfelder die Berliner Charité genauer untersucht. Höre gerne in die Folge rein, wenn es dich interessiert. Worum geht es in der Folge? Mit Dr. Akgün spreche ich  darüber: Woran in Dresden geforscht wird? Was das für MS-Patienten bedeutet? Welche Studien im Gange sind? Und welche Verbesserungen sich daraus für Menschen mit MS ergeben? Es wird eine ganz spannende Folge, bei der ich dir viel Spaß wünsche. Transkript des Interviews mit Dr. med. Katja Akgün Nele: Hallo Frau Dr. Akgün, schön, dass Sie da sind, ich freue mich riesig. Erstmal ein ganz liebes „hallo“ nach Dresden. Dr. med. Katja Akgün (Dr. Akgün): Ja, hallo, vielen Dank, liebe Grüße zurück. Schön, dass das heute klappt. Nele: Sie sind viel beschäftigt, insofern ganz großes Dankeschön, das sie sich die Zeit genommen haben. Bevor wir beginnen, sagen sie bitte nochmal ganz kurz etwas was zu sich, wer sie sind, damit die Hörerinnen und Hörer eine gkleine Idee haben, wen ich heute interviewe. Vorstellung und berufliche Stationen Dr. Akgün: Ich bin Katja Akgün, gehöre zum Dresdner Team von Professor Tjalf Ziemssen. Wir arbeiten beide eng zusammen. Ich bin groß geworden in dem Team und habe dort den Bereich kennengelernt und die Liebe zum wissenschaftlichen Aspekt bezüglich der Multiplen Sklerose gefunden. Ich habe hier in Dresden studiert, komme zwar nicht direkt hier aus der Region, sondern ein bisschen mehr nördlich aus der Oberlausitz. Aber ich bin sozusagen gar nicht weit weggezogen, sondern in Dresden gelandet. Habe hier studiert und damals meine Doktorarbeit bei Professor Tjalf Ziemssen gemacht. So bin ich in das Team gekommen. Initial , wollte ich gar nicht Neurologie machen, es hat mich aber so gefangen und bis heute nicht mehr losgelassen. Deshalb habe ich recht schnell meinen Schwerpunkt in der MS und in der Neuroimmunologie gefunden. Ich lebe hier mit meinem Mann und meiner Tochter. Mein Mann kommt eigentlich aus Gießen, das ist eine „Ost-West-Liebe“ bei uns, aber sind hier fest verankert und das passt alles ganz gut. Persönliche Motivation für den Beruf Nele: War das spannende Thema bei Professor Ziemssen der ausschlaggebende Punkt oder was war Ihre Motivation, dass sie letztendlich doch in die Neurologie reingerutscht sind? Gab es einen ganz speziellen Auslöser? Dr. Akgün: Naja, es war initial so, ich hatte damals im Studium immer ganz kurze Berührungspunkte mit den Fächern. Die Neurologie kommt im Medizinstudium relativ spät dran. Ich wollte damals eine Doktorarbeit machen und wissenschaftlich arbeiten, also richtig im Labor. Das wusste ich. Ich habe gesagt „wenn ich schon eine Doktorarbeit mache, dann richtig. Da will ich eine Pipette in der Hand halten und mit Zellkultur arbeiten und alles, was das Herz begehrt in der experimentellen Wissenschaft“. Einstieg ins Team vom MS-Zentrum Dresden Dann habe ich erstmal querbeet geschaut und Herr Ziemssen war damals noch ein junger Assistenzarzt, der gerade nach Dresden gekommen war und sein Labor aufgebaut hat. Er hat Leute gesucht, die das mit ihm machen wollen und so bin ich in das Team gerutscht und habe auch erstmal primär immunologisch gearbeitet und das ging dann letztendlich immer weiter. Das waren interessante Projekte. Begonnen hat es mit meiner Doktorarbeit, dabei habe ich bereits gemerkt „mit einer Doktorarbeit ist das Feld bei Weitem nicht abgedeckt“ und dann führte letztlich eins zum anderen. Ich habe mich zwar schon immer sehr für die Immunologie interessiert, also auch andere Autoimmunerkrankungen wie Rheumatologie, Dermatologie. Solche Fächer kamen prinzipiell auch in Frage, aber mir hat mal jemand gesagt „mach das, wo dein Herz hängt und wo du glaubst, dass dich das dein Leben lang begeistern kann. Immerhin musst du es dein Leben lang machen als Job“, und da habe ich gesagt „wenn ich ehrlich bin, ist es die Neurologie mit der Neuroimmunologie“. Herr Ziemssen hat mir zudem eine super Option in seinem Team angeboten. Da wäre ich schön dumm gewesen, wenn ich eine Kehrtwende gemacht hätte. Nele: Sehr gut, begeisterte Leute, das brauchen wir. Dann macht das Forschen ihnen mehr Spaß und sie finden auch mehr heraus. Womit beschäftigt sich die Neuroimmunologie im Allgemeinen und spezifisch auf die MS bezogen? Dr. Akgün: Neuroimmunologie ist ja eigentlich ein sehr großes Thema. Letztendlich geht es ja um autoimmune Phänomene bei neurologischen Erkrankungen. Die Multiple Sklerose ist da einfach so sehr im Fokus, weil sie die Erkrankung ist, wo wir den größten Patientenstamm haben. Es gibt aber viele neuroimmunologische Erkrankungen, beispielsweise das Guillain-Barré-Syndrom. Auch die Myasthenie ist letztendlich eine autoimmun vermittelte neurologische Erkrankung. Wir bei uns im Zentrum im Dresden fokussieren uns viel auf die chronisch-entzündlich Erkrankungen des zentralen Nervensystems und da ist die Multiple Sklerose eine der größten Vertreter. Die Neuroimmunologie beschäftigt sich dann natürlich mit ganz unterschiedlichen Facetten dieser Krankheitsbilder, hinterfragt also „was ist die Pathogenese? Wie entsteht diese Erkrankung? Wie wirken Medikamente? Wie müssen vielleicht Medikamente wirken, um gezielter diese Erkrankungen therapieren zu können?“. Aber eben auch Thema Biomarker-Monitoring, das in den letzten Jahren sehr in den Fokus geraten ist. Das sind Felder, die vom neuroimmunologischen Bereich abgedeckt werden und eigentlich das klinische Setting unterstützen sollen. Was haben sie in den letzten Jahren Neues über die Entstehung der Multiplen Sklerose herausgefunden? Dr. Akgün: Man muss klar sagen, dass wir das nicht alleine machen. Das ist Teamarbeit und da geht der Trend in den letzten Jahren deutlich hin. Ich bin jetzt ungefähr zehn Jahre in der Klinik. In der Zeit gab es schon einen immensen Wandel, dass man nicht mehr alleine in seinem Labor steht, sondern ein Team vor Ort hat, aber auch kooperiert mit anderen Laboren, weil jeder seine Expertise hat und wir heute schon feststellen, dass das so komplex ist und es auf so viele neue Messtechniken ankommt, dass wir zusammenarbeiten müssen. Den Wirkmechanismen der MS auf der Spur Es ist ja bekannt und oft diskutiert, dass die MS eine T-Zellen-mediierte Erkrankung ist, also die T-Zellen eine ganz wichtige Rolle spielen. Auch die B-Zellen sind gerade in den letzten Jahren sehr in den Fokus gerückt. Man hat das früher hinten angestellt und diese Erkenntnis, dass die T- und B-Zellen da sehr viel mehr interagieren miteinander und beide Funktionen und Schlüsselfunktionen haben, das sind Erkenntnisse aus den letzten Jahren. Andere Faktoren aber auch und das ist ein Schwerpunkt gewesen, den wir bei uns im Labor maßgeblich mit begleitet haben, ist der Aspekt, dass gerade T- und B-Zellen erstmal einen Auftrag kriegen müssen, bevor sie überhaupt aktiv werden und z. B. eine autoimmune Reaktion generieren können, also eine Reaktion gegen den eigenen Körper. Das machen nämlich sogenannte antigenpräsentierende Zellen oder dendritische Zellen und man weiß heute, dass wenn man die z. B. gezielt programmiert oder auch programmieren kann, man folglich eine T-Zell-Antwort verändert. Man vermutet zum einen, dass diese antigenpräsentierenden Zellen eine maßgebliche Rolle in der Entstehung der MS spielen und das konnten wir in unserem Labor mit verschiedenen Projekten und Messungen und Gewebeuntersuchungen nachweisen. Neue Behandlungsansätze Und es gibt jetzt – diese Ansätze kommen primär aus der Onkologie – schon die Idee, dass man die vorgeschalteten Zellen gezielt programmiert und verändert, um dann T- und B-Zellen – man sagt auch antigenspezifisch – also wirklich ganz selektiv positiv beeinflussen zu können. Der Vorteil dabei ist, dass man andere Funktionen des Immunsystems unbeeinflusst lässt und damit komplett erhält. Somit bleibt die Immunkompetenz weiterhin erhalten, was bisher manchmal ein Problem von immunsupprimierenden Therapien ist. Nele: Und sicherlich dadurch auch weniger Nebenwirkungen erzeugt, oder? Je spezifischer man wird, desto weniger Nebenwirkungen treten auf. Dr. Akgün: Exakt. Genau das ist das Ziel. Nele: Okay und da schauen sie, wie sie die Zellen sozusagen umprogrammieren. Die sind falsch programmiert und sie schauen, wie sie denen charmant vermitteln können, sich für die Person mit MS günstiger zu verhalten. Dr. Akgün: Sie haben es ganz schön gesagt, dieses charmante Vermitteln ist ja das, was bedeutet, dass es weniger Kollateralschäden gibt im Organismus und das wiederum bedeutet weniger Nebenwirkungen. Daher ist der charmante Weg das, was wir uns wünschen. Nele: Sehr gut. Jetzt haben sie auch gesagt, sie führen z. B. Studien zur Wirksamkeit von Therapien bei MS durch und dass sie dafür Biomarker nutzen. Ich glaube nicht jeder weiß genau, was Biomarker sind. Könnten sie das bitte einmal kurz und simpel erklären. Was sind Biomarker? Dr. Akgün: Auch das ist wieder ein sehr großer Begriff. Ich glaube was viele sich nicht immer so vor Augen führen, ist, dass ja alles, was sie als Patient an Untersuchungen erfahren in der Routinevorstellung beim Neurologen, Biomarker sind, die erhoben werden. Ein Biomarker ist eigentlich nur ein Messwert, der uns einen Zustand gibt über eine Erkrankung. Im besten Fall ist dieser Messwert sehr spezifisch, also selektiv für die Erkrankung und ich kann ihn bei wiederholten Messungen immer wieder gleich detektieren. Biomarker können ein Abbild sein für Reaktion, ein Ansprechen z. B. auf eine Therapie oder ein Indiz für eine Verschlechterung oder Verbesserung einer Erkrankung und somit ist es ein sehr großes Feld. Es gibt viele klinische Biomarker, da wären z. B. die neurologische Untersuchung –  der EDSS. Dann haben wir das MRT, auch das ist ein Biomarker, wenn man es so will, aber das Feld wird aktuell in den Studien sehr erweitert, weil diese Laborbiomarker, also die kleinste Funktion in dem großen Ganzen in den Fokus rücken und diese klinischen Marker immens unterstützen können. Wie viele interessante Biomarker aus dem Bereich der Neuroimmunologie haben Sie gefunden und wie gut geben diese Aufschluss darüber, ob eine Therapie wirkt oder vielleicht sogar in welcher Sensitivität? Dr. Akgün: Man muss sagen, wenn man sich traut in die Literatur der Neuroimmunologie und Biomarker zu gehen, wird man immens viele Sachen finden. Die Grundlagenwissenschaft spuckt immer wieder total spannende Parameter aus und das ist totaler Wahnsinn, was man da messen kann. Das ist auch ein bisschen die Intention, die wir haben mit unseren Studien. Sinnvoll ist es immer dann, wenn es am Ende beim Patienten landet. Wenn es hochrangig in einem Journal publiziert ist und dann steht es da auf weißem Papier, ist dem Patienten noch nicht geholfen. Deshalb wollen wir die Parameter heraus selektieren und die Techniken so gut zu verfeinern, dass es einfach messbar wird, effizient und kostengünstig ist und einen direkten Bezug zur Erkrankung hat. Wenn man das mal herunterbricht, bleibt aktuell gar nicht mehr so viel übrig. Etablierte Biomarker der Neuroimmunologie bei MS Was wir schon relativ regelmäßig nutzen, wenn MS-Patienten eine Immuntherapie bekommen, ist der Immunstatus. Man kann z. B. ein Blutbild machen, auch das wäre schon ein Biomarker. Aber man kann an dem Punkt noch sehr viel weiter in die kleinen Gruppen der Immunzellen gehen und diese Differenzierung zeigt uns bei verschiedenen Erkrankungen sehr gut auf, ob eine Therapie genommen wird oder nicht und auch wie intensiv der Effekt letztendlich in dem Immunsystem ist. Das funktioniert zum Beispiel für Natalizumab oder beim Fingolimod. Diese Typen von Biomarkern, setzen sich relativ gut durch und gehen in die Routine über. An der Schwelle zur Routine Demgegenüber gibt es aber andere Parameter wie bspw. Zytokinmessungen oder besonders aktuell die Neurofilamente, die an der Schwelle stehen zur Routine. Da wissen wir, das macht sehr viel Sinn. Die Krankenkassen interessieren sich dafür noch nicht wirklich, weil es natürlich immer Geld kostet, aber viele Patienten sind in immunologischen Studien oder man kann es auch auf Igelleistungen oder individuelle Abstimmungen machen und da wird es auch schon herangezogen. Nele: Jetzt muss ich nochmal ganz kurz rückfragen. Das klang gerade so, als ob sie bei manchen Medikamenten sehen können, ob der Patient, der die Therapie nehmen soll, diese überhaupt nimmt, oder? Denn „Therapietreue“ ist ja ein wichtiger Punkt. Ich habe das Thema zwar noch nicht individuell im Podcast angesprochen, will aber noch eine Folge dazu machen. Denn natürlich ist es hilfreich, zu wissen, ob der Patient sein Medikament nimmt oder nicht. Ansonsten denkt man „der Wirkstoff wirkt nicht, aber es liegt nicht am Wirkstoff, sondern daran, dass der Patient das Medikament nicht nimmt“. Ist das korrekt zusammengefasst? Dr. Akgün: Genau. Es gibt solche Möglichkeiten das zu monitoren. Nicht für alle Therapien so einfach, aber für bestimmte Präparate schon. Nele: Das ist ja gut für die allgemeine Aussage zur Wirksamkeit von Medikamenten. Dr. Akgün: Genau, was sie gerade angesprochen haben. Gerade wenn eben doch eine Krankheitsaktivität da ist. Da sollte im Arzt-Patienten-Vertrauen, unter vier Augen, ehrlich zugegeben werden, ob man das Medikament nimmt oder nicht, weil am Ende macht der Patient die Therapie nicht für mich als Arzt, sondern für sich und da muss man die Karten auf den Tisch legen. Aber prinzipiell kann man so etwas durch solche Biomarker differenzieren. Wie bestimmen sie die Biomarker und was verraten ihnen die Ergebnisse? Dr. Akgün: Das ist sehr vielfältig. Der Klassiker ist das Blut, obwohl man sagen muss, das ist eine relativ einfach zu erhebende Substanz. Sie ist in gewissen Mengen verfügbar und es macht keine zusätzlichen Umstände „ein Röhrchen mehr abzunehmen“, wenn die Patienten ein Routinemonitoring kriegen wo Leberwerte, Nierenwerte, etc. überprüft werden. Das gehört ja häufig zum Standardsetting mit dazu. Und die neuen Biomarker ergänzen dabei die Diagnostik. Es ist einfach ein sehr gutes Spiel, denn im Blut ist es ein Kompartment, was auch ein Immunkompartment ist, insofern dort zirkulierende Immunzellen abgebildet werden, die ja auf Wanderschaft sind und im besten Fall schon zeigen, was im restlichen Organismus ist, also ein Spiegel ist. Alternativen zum Liquor? Was natürlich trotzdem noch intensiv verwendet wird, ist der Liquor, also das Nervenwasser. Gerade bei der Multiplen Sklerose spielt das in der Erstdiagnostik eine sehr, sehr wichtige Rolle und man würde sicherlich noch häufiger Liquor entnehmen. Es ist eine exzellente Substanz, um eine sehr gute Aussage zu treffen, was zerebral, also im Zentralnervensystem, vor sich geht. Aber das ist natürlich eine Maßnahme, die man sich jetzt nicht alle drei Monate gönnen möchte und daher muss man andere Möglichkeiten finden und diskutieren, wie man möglicherweise schon eine Aussage treffen kann, wie die Konstellation im Nervenwasser ist, aber weniger invasiv und weniger kompliziert zu entnehmen ist. Das Potenzial von Bioproben wie Urin und Stuhl Andere Parameter sind momentan auch viel in Diskussion oder andere Substanzen oder Bioproben. Urin ist relativ einfach zu gewinnen und hat viele Analyten, die eine gute Aussagekraft haben. Das ist auch sehr im Fokus im Moment, wie man das weiter nutzen und verwenden kann. Stuhlproben, das klingt jetzt etwas eigenartig, aber das ist ja auch hier schon im Podcast in Diskussion gewesen. Da Ernährung und Immunsystem eng zusammenhängen, wird sich vielleicht auch in Zukunft einiges tun, und man wird herausfinden, ob man darüber eine Aussage treffen kann hinsichtlich Biomarkern in solchen Proben. Das sind ein bisschen die Klassiker. Alles andere ist schon sehr speziell. Man kann natürlich auch Hirnbiopsien machen und solche Aspekte. Das ist aber sehr individuell. Da muss man sehr komplizierte Fragestellungen haben. Das gehört nicht zu unserem Routinegeschäft. Nele: Ja, das klingt auch nicht so schön. Ich gebe, glaube ich lieber Urin und Blut ab. Und Lumbalpunktion ist etwas, worum sich die meisten MS-Patienten nicht so reißen. Dr. Akgün: Richtig. Nele: Jetzt haben sie bereits angesprochen, dass es verschiedene experimentelle Verfahren und Methoden gibt, die sie nutzen. Wenn es dich, liebe Lesering, lieber Leser interessiert, schau gern auf der Webseite nach, dort sind alle gelistet. Man findet dort unter anderem Zellkultur, verschiedene Analysen und Zellsortierung. Wie komplex sind die Untersuchungsverfahren und -methoden? Braucht man spezielle Geräte dafür? Eine hohe Rechenleistung? Gut ausgebildete Fachkräfte? Viel Zeit oder alles in Kombination? Dr. Akgün: Alles in Kombination trifft es ganz gut. Wir haben verschiedene Projekte oder auch Analysestufen im Labor, die zu unserem Forschungsauftrag gehören. Grundlagenforschung Manchmal sind die Analysetechniken noch sehr basal. Alles wird mit der Hand zusammenpipettiert, Zellen unter dem Mikroskop einzeln ausgezählt. Das ist die Essay-Entwicklung, die ersten Schritte. In dem Stadium wird viel probiert. „Wie muss ich die Konzentration zusammenstellen?“, etc. Da wird z. B. auch viel über Zellkultur gemacht. Das ist aber eine gute Möglichkeit, um sich an Biomarkermessungen heranzutasten. Vollautomatisierte Verfahren Dann gibt es bei uns auch im Labor vollautomatisierte Geräte. Dafür nehme ich die Probe des Patienten. Die wird auf das Gerät gestellt und nach vier Stunden gehe ich wieder ans Gerät und habe einen Messwert, eine Ausgabe mit einem Referenzbereich und das sind schon die Analyten, die sehr an diesem Routinesetting sind. Analysen im Zwischenstadium Außerdem haben wir viele Projekte, die sich genau in der Mitte befinden. Meist läuft das über eine unserer vielen Kooperationen. Ich denke da gerade an die Zellmechanik. Das ist eine Messtechnik, die zellmechanische Eigenschaften von Immunzellen beurteilen kann und die wir in Kooperation versuchen zu hinterfragen „wie nützt uns diese Messtechnik speziell bei unseren MS-Patienten, als Diagnosemöglichkeit oder als Therapiemonitoring?“ Da haben wir schon viel Erfahrung und das sind auch Prozedere, die automatisierter werden. Deshalb muss man ein bisschen differenzieren, was wir für ein Labor sind, weil es ja viele Arten von Laboren gibt. Diese Routinelabore, wo ich meine Serumprobe hinschicke und meine Leberenzyme und Nierenenzyme erhalte, sind vollautomatisiert. Das ist hoch qualitätsmangementgeprüft. So etwas sind wir nicht primär, sondern wir die Stufe davor, die an der Entwicklung beteiligt ist, um irgendwann Essays genau in dieses Routinesetting zu führen, und das ist notwendig, damit es irgendwann kosteneffektiv wird. Wenn Sie jemanden haben, der gut ausgebildet ist, dann aufwändige Geräte, die komplex auch in der Bedienung sind, das braucht Zeit, das braucht Equipment. Das ist teuer und für den Durchsatz, der ja heute auch Medizin bedeutet, eben noch nicht geeignet, aber wo die Reise hingeht für solche Biomarker. Zusammenfassung Biomarker Entwicklung Nele: Okay, also sie übersetzen quasi Forschung, schauen sich das ganz von Beginn an und skalieren es größer „inwieweit ist das machbar?“. Auf dem Weg fliegen ein paar Kandidaten raus, aber die übriggebliebenen werden irgendwann zur Routineuntersuchung. Uns diese finalen Biomarker kann ich dann bei einem normalen niedergelassenen Arzt erheben, der nicht an der Uniklinik sein muss. Dieser Arzt schickt meine Bioproben in ein Labor, wo sie analysiert werden und erhält eine gute Aussagekraft über meine Krankheit oder Aktivität der MS, oder? Dr. Akgün: Korrekt, ganz genau. Nele: Super. Jetzt würde mich noch das Thema Neurofilament-Leichtketten-Analyse interessieren, weil ich gelesen habe, dass es eine schöne Möglichkeit wäre, dass man irgendwann in Zukunft dann keine Lumbalpunktion mehr braucht. Erklären sie bitte die Neurofilament-Leichtketten Analyse genauer? Wo nehmen sie die Proben dafür? Dr. Akgün: Also wir n unserem Labor, aber auch in Dresden an sich, und diese Meinung teilen viele andere Kollegen weltweit, die sich mit diesem Parameter beschäftigen, sind der Meinung, dass das ein sehr sinnvolles Add-on ist im Monitoring der Patienten. Neurofilamente gehören zum Zytoskelett von Neuronen, die wir im Gehirn und im Rückenmark finden. Wenn diese Neuronen zerstört werden, werden die zytoskelettalen Produkte, also Neurofilamente, freigesetzt. Den Prozess kennt man schon viele Jahre. Man kann das z. B. im Liquor sehr gut messen, weil Patienten eben mit einer neuronalen Zerstörung sehr hohe Werte an diesen freigesetzten Neurofilamenten im Liquor haben. Das weiß man, das hat man auch oft schon diagnostisch gewählt, aber wie sie eben richtig gesagt haben, ist das ein Marker, der sich nicht dafür eignet, regelmäßig erhoben zu werden. Die Entnahme von Nervenwasser ist eine schwierige Konstellation. Neurofilamente zeigen an, wie aktiv die MS ist Bei der MS spielt es deshalb so eine interessante Rolle, weil wir heute wissen, dass dieser Schaden, der über die Neurofilamente angezeigt wird, ein Indiz dafür ist, wie aktiv die Erkrankung gerade ist. Wir können ja die Schübe mit dem Patienten differenzieren, diskutieren, ob da ein klinischer Schub da ist. Wir machen das MRT als Unterstützung, ob neue Läsionen aufgetreten sind, aber wir wissen, dass das seine Detektionsgrenze hat. Und wenn eben noch ein Minischaden da ist, den der Patient nicht einmal merkt, den das MRT auch nicht misst, dann können uns sehr wahrscheinlich die Neurofilamente an dem Punkt unterstützen und anzeigen z. B. „funktioniert die Therapie gut oder sogar richtig gut?“ Und das wollen wir ja eigentlich wissen. Was ist der ELISA? Wie funktioniert er? Die Neurofilamente sind deshalb jetzt wieder in den Fokus gerückt, weil es neue Techniken gibt, die minimalste Mengen an diesen Neurofilamenten messen können und das hat dazu geführt, dass man festgestellt hat „die Dinger sind ja auch im Blut vorhanden“. Die Konzentration ist zwar sehr, sehr viel geringer als im Nervenwasser, aber das korreliert eng. Ich muss sie halt dort nur messen können. Dafür hat man eine Technik genommen, den ELISA, den man auch im Nervenwasser anwendet. Man hat sozusagen Beats verwendet. Beats sind kleine Kügelchen, ähnlich Magnetkugeln – die haben an der Oberfläche einen Antikörper und dieser Antikörper kann das Neurofilament binden. Man kann dann dieses gebundene Neurofilament über Gegenfärbung und Fluoreszenzsignale sichtbar machen, das ist der ELISA. Das Problem beim ELISA ist aber oft, dass das Signal zu schwach ist. Diese Einzelbeats, also das Binden auf diese einzelnen Magnetkügelchen erlaubt, dass die Magnetkügelchen in einem Schritt vor der Messung aufgetrennt werden und das Gerät jedes einzelne Magnetkügelchen abscannt, ob es da ein kleines, gebundenes, gefärbtes Protein, also Neurofilament-Protein findet. Dadurch können sogar einzelne Proteine nachgewiesen werden. Einfach nur die Differenzierung einer seit Jahren etablierten Analysetechnik auf einzelne Magnetbeats, die dann selektiv abgearbeitet werden, erlaubt diese Messgrenze so immens sensitiv zu machen und man kann sozusagen einzelne Sandkörner in zehn Schwimmbecken nachweisen, so genau ist diese Technik. Das ist schon sehr fortgeschritten, sehr automatisiert und auch Durchsatzmedizin. Sprich, man kann viele Proben in kurzer Zeit damit analysieren und daher gibt es hier schon sehr viele, sehr gute Untersuchungen und wir wissen, dass das Neurofilament ein sehr guter Marker ist, um Krankheitsstabilität vs. -aktivität zu differenzieren. Potenziale der Neurofilament-Messung Da rückt dann natürlich in den Fokus, dass man sagt „Mensch, kann ich das nicht nutzen, um mir das Nervenwasser zu sparen und möglicherweise auch MRT?“, obwohl man vorsichtig sagen muss, dass das MRT uns natürlich noch ein bisschen mehr Auskunft gibt. Aber um mal eine Idee aufzuzeigen, wenn ich alle drei Monate zum Neurologen komme, meine Beschwerden berichte, könnte ich bei diesem Besuch meinen Neurofilamentwert mit untersuchen, genauso wie ich den neurologischen Status ermittle. Dann wüsste ich, die aktuelle Behandlung „passt oder passt halt nicht?“. Das ist etwas sehr Neues und sehr Spannendes, wo wir hoffen, dass wir das Patienten in der Zukunft sehr viel häufiger in der Routine anbieten können. Nele: Super. Denn viele MS-Patienten haben Angst vor der Lumbalpunktion. Und beim MRT ist es ähnlich, da brauchen manche Betroffene extra Beruhigungsmedikamente, für die Untersuchung. Und wenn diese Menschen vielleicht nur ins MRT müssen, wenn man sieht „hier gibt es eine stärkere Aktivität“, das wäre für viele eine große Erleichterung. Ich stelle mir das jetzt so vor, finde ich nur ein Korn im großen Wasserbecken, ist alles okay, aber wenn da ein kleines Häufchen Sand ist, bedeutet das leider viel Aktivität und dann muss etwas passieren in irgendeiner Art und Weise. Dr. Akgün: Ganz genau. Nele: Okay, super. Aber das finde ich ganz toll, schöne Sache. Blitzlichtrunde 1. Vervollständigen Sie den Satz: Für mich ist die Multiple Sklerose…? Dr. Akgün: …eine Erkrankung, die aktuell sehr im Fokus der Gesellschaft steht. Das finde ich super, weil es eine Erkrankung ist, die in den Fokus muss. Sie braucht eine extrem große Lobby und Leute, die fordern und wollen und Verbesserungen wollen für die Patienten, damit wir unsere Sache einfach auch besser machen, die, die in der Wissenschaft sind und die, die in der Versorgung sind. Nele: Ja, das ist auf jeden Fall auch meine Wahrnehmung. Da passiert gerade unglaublich viel und zum Glück auch im chronischen Bereich, der in den zurückliegenden Jahren nicht so im Fokus war und in den ja doch viele – zumindest von den älteren Patienten – rutschen bzw. gerutscht sind. Welche Internetseite können Sie zum Thema MS empfehlen? Dr. Akgün: Natürlich unsere Website. Ich glaube halt, dass der Dschungel der Websites oder wo man sich Inhalte runternehmen kann, groß ist. Es ist für Patienten manchmal schwierig zu differenzieren „welchen Informationen kann ich trauen und welche sind für mich als der Typ, der ich bin, wichtig und richtig?“. Wir machen daher die Patientenpodcasts und wollen aufklären. Auf der Webseite findet man den entsprechenden Link. Das ist das, was ich empfehlen kann, und ich finde solche Plattformen einfach toll, wie sie es jetzt haben, weil das echt ist, das ist real und da kann man sich austauschen und das sind verlässliche Informationen und das ist das, was die Patienten brauchen. Nele: Genau, wissenschaftlich fundiert. Ich kann den Patientenpodcast vom MS-Zentrum Dresden auch nur weiterempfehlen. In einer Folge lernt man auch ihr neuroimmunologisches Labor genauer kennen. Dr. Akgün: Also das, was ich gerade gesagt habe, haben wir in dem Patientenpodcast vom Labor mal ein bisschen visualisiert, weil man muss da drin sein. Wir machen das jeden Tag. Deshalb wissen wir, wovon wir reden, aber es ist auch für ärztliche Kollegen oft sehr abstrakt und das war  die Idee in dem Podcast, dem Patienten das mal ein bisschen zu zeigen. Da kann man sich das auch nochmal genauer anschauen, wie das wirklich aussieht und was wir da machen. Das war die Idee von diesem Podcast. Nele: Die Folge muss ich mir in den nächsten Tagen unbedingt noch anschauen. Als Letztes habe ich den Schlafpodcast gesehen, der war auch ganz toll. Für dich da draußen, unbedingt einschalten. Man muss dafür nicht Patient am MS-Zentrum in Dresden sein. Solange du der deutschen Sprache mächtig bist, ist das eine sehr interessante Informationsquelle. Und die Folgen machen Spaß. Welchen Durchbruch wünschen sie sich für die Forschung und Behandlung der MS in den kommenden fünf Jahren? Dr. Akgün: Naja, was ich schon hoffe und da bin ich auch relativ optimistisch, ist, dass sich die individuelle Therapie durchsetzt. Davon bin ich ein Verfechter. Wir reden immer davon, dass MS die Erkrankung mit den tausend Gesichtern ist, was ja impliziert, dass die Patienten alle unterschiedlich sind. Und jeder, der reinkommt, ist unterschiedlich. Das ist er als Mensch und das ist seine Erkrankung auch. Und meine Hoffnung, und daher arbeiten wir auch so kräftig an solchen Sachen, ist, dass Biomarker dabei helfen können zu differenzieren „wen habe ich da vor mir? Was braucht er für eine Therapie? Warum wirkt die Therapie? Warum ist die andere vielleicht nicht so optimal für den Patienten und wie sieht das individuelle Monitoring aus?“. Also dass wir individueller werden, personalisierter und dafür brauchen wir ein paar mehr Werkzeuge, als wir sie heute haben. Aber da tut sich Gott sei Dank sehr, sehr viel. Nele Handwerker: Darauf freue ich mich auch. Das finde ich ganz spannend, was sich da gerade alles regt. An dich da draußen nochmal der Aufruf Wenn du gefragt wirst, an einer Studie teilzunehmen, bitte, bitte mach das. Nur so können Experten, wie Frau Dr. Akgün und alle anderen Forscherinnen und Forscher und Neurologen, uns zunehmend besser helfen. Ich nehme immer an allen Studien teil, lasse mir den Sinn und vorab immer von meinem behandelnden Neurologe, Professor Ziemssen, erklären. Und er erklärt die Studien auch immer super, sodass ich gerne teilnehme, da, wo ich helfen kann. Ich habe zum Glück die MS nicht so schlimm, insofern bin ich nicht für alles qualifiziert, aber ich finde Studien immer sinnvoll und wichtig. Natürlich werden dadurch auch Sackgassen herausgefunden, ganz klar, nicht alles führt zum Erfolg, aber so ist Forschung. Verabschiedung Möchten Sie den Hörerinnen und Hörern noch etwas mit auf dem Weg geben? Dr. Akgün: Ich mache ja auch Sprechstunden, und habe dabei viele Patienten kennengelernt und ich glaube, am Ende ist es wichtig, dass man merkt, und lernt und für sich interpretiert, wer man ist und wo man mit seiner Erkrankung hin will. Wir sind Experten und ich bin ein Verfechter der Schulmedizin, aber am Ende sind das alles Beratungen. Man will den Patienten etwas an die Hand geben, aber man muss sich selbst treu bleiben und ich glaube, das ist das Wichtige. Und dass man objektiven Empfehlungen erstmal zuhört. Was man daraus für sich selber mitnimmt, und dann entscheidet liegt in eigenen Ermessen. So muss man durch das Leben gehen, mit oder ohne Erkrankung. Wie kann man am besten über die Forschung und Ergebnisse des neuroimmunologischen Labors an der Uniklinik Dresden informiert bleiben? Dr. Akgün: Auf der Website vom Zentrum für klinische Neurowissenschaften sind wir als Labor mit verlinkt. Wir werden das jetzt auch etwas aktueller halten. Das ist sozusagen ein Ziel, damit wir das für die Patienten sichtbarer machen, sonst ist es ja immer sehr im Forschungssetting. Wenn man sich da nicht bewegt, bekommt man es sonst nicht mit. Das zum einen und über Podcasts bzw. Patientenveranstaltungen – und das wäre über den Newsletter. Dort geben wir unsere Updates heraus. So wollen wir für die Patienten verständlich vermitteln „was ist jetzt neu? Was ist für mich als Patient relevant von diesen eher wissenschaftlich angehauchten Sachen?“ Und das in regelmäßigen Abständen. Nele: Ein ganz herzliches Dankeschön, Dr. Akgün! Weiter ganz viel Erfolg für sie, ihr Team und natürlich auch die ganzen Teams weltweit, die am Thema Neuroimmunologie arbeiten. Das ist ja auch etwas Schönes, zusammen findet man mehr raus. Dann ihnen eine gute Zeit und viele Grüße nach Dresden. Dr. Akgün: Lieben Dank, Grüße zurück. Bis bald. Tschüss. Nachwort Wie gesagt, mich plagt die MS zum Glück nicht so sehr, toi, toi, toi und mein Medikament wirkt von Anfang an, aber vielleicht ist es bei dir anders, du hast schon mehrere Therapien durch und es wäre ja total schön, wenn man in Zukunft wirklich von Anfang an sehen kann „du bist Typ X“ und man kann dir mit der „Therapie Beta“, helfen. Die wird bei dir anschlagen und zum Erfolg führen und man kann das auch messen, wie gut sie zum Erfolg führt und was man noch anderes machen muss, damit man die MS wirklich so zeitig wie möglich, so gut wie es geht aufhalten, am besten auf Pause-Modus setzen kann und das bis zum Lebensende. Das wäre doch das Schönste. Und vielleicht gehörst du da draußen auch zu den Menschen, die Angst vor MRT-Untersuchungen haben. Dann wäre es natürlich wunderbar, da nur rein zu müssen, wenn es nötig ist. Mich stört das nicht. Ich hatte das nur einmal, da war ich gerade in einer ängstlichen Phase. Ansonsten bin ich psychisch gut gewappnet und gehe ohne Probleme ins MRT. Es ist halt laut, aber ansonsten stört es mich nicht. Da ist ganz viel Tolles im Fluss und nochmal zur Wiederholung die Aufforderung: Wenn es Studien gibt, die dir nicht weh tun, beim Blutabnehmen ist es vielleicht ein kurzer Piks, aber im übertragenen Sinne, dann nimm bitte daran teil. Das hilft dir selber und uns allen. Studien sind sehr wichtig, sie ermöglichen neue Erkenntnisse. Ankündigung Folge 111 Beim nächsten Mal, interviewe ich MS-Patientin Melanie, die bei Instagram auch als @melsworldinpictures“ zu finden ist. Sie wird mir Rede und Antwort stehen zu ihrem Leben mit MS. Bei Melanie spielt die Psyche ein ganz großes Thema, und wirkt sich stark auf ihre MS aus. Ein spannendes Interview mit einer ganz tollen Frau. Einschalten lohnt sich. ++++++++++++++++++++ In diesem Sinne wünsche ich dir alles Gute und komm gesund durch die Erkältungszeit. Tschüss, Nele Mehr Informationen rund um das Thema MS erhältst du in meinem kostenlosen MS-Letter.

Heute begrüße ich Johanna alias @multiple_sichtweisen zum Interview. Sie lässt uns an ihren Erfahrungen mit der Stammzelltherapie teilhaben – wie sie ihre Entscheidung getroffen hat, das ganze Prozedere ablief und wie es nun weitergeht. Vorstellung Johanna ist 34 Jahre alt, frisch verheiratet und lebt in der Schweiz. Ursprünglich stammt sie aus Franken, hat eine Ausbildung in der Gastronomie absolviert und arbeitet mittlerweile in einem Bürojob in Deutschland. MS Verlauf und Stammzelltherapie Wann hast du die Diagnose MS erhalten und welches Symptom stand am Anfang? Ende 2011 habe ich beim Auto fahren den Gegenverkehr nicht mehr erkannt und konnte nicht mehr weiterfahren. Zuerst bin ich zum Augenarzt, aber dieser schickte mich in die Neurologie, weil er nichts finden konnte. In der Uniklinik in Würzburg wurden dann Nervenwasser entnommen und verschiedene Test gemacht und es kam der Verdacht der MS auf. Nach dem ersten MRT Anfang 2012 wurde der Verdacht bestätigt. Also es fing, wie bei einigen Patienten mit einer Sehnerventzündung an. Wie hast du die Diagnose aufgefasst? Ehrlicherweise wusste ich nicht, was MS genau bedeutet und das fatale war dann, dass ich alles gegoogelt hab. Über Google erfährt man fast nur die schlimmsten Geschichten und deswegen war es für mich sehr emotional und ich machte mir viel Gedanken über die Zukunft. Welche Verlaufsform und Aktivität der MS hast du? Ich habe die schubförmige MS. Vor der Therapie stand in Abklärung, ob ich am Anfang einer sekundären progredienten MS stehe, da sich meine Gehbehinderung konstant verschlechterte. Hast du eine verlaufsmodifizierende Therapie oder sogar mehrere ausprobiert? Ja, ich hab einige Therapien von Tablette über Spritze ausprobiert. Wie entstand die Idee der Stammzellentherapie als Behandlung bei dir? Da sich meine Gehbehinderung immer mehr verschlechterte und ich meinen Hobbys nicht mehr nachgehen konnte. Ich hatte das Gefühl, mein Leben nicht mehr so weiterführen zu können wie bisher. Deshalb waren mein Mann und ich auf der Suche nach Alternativen und Dave ist auf der Suche auf diese Chance gestoßen. Wie lange hast du für die Entscheidung gebraucht die Stammzelltherapie durchzuführen und was hast du dabei gegeneinander abgewogen? Da ich öfters in ein Loch gefallen bin und ich keine Kraft mehr hatte, war die Entscheidung recht schnell getroffen. Im Unispital Zürich wird die Transplantation durchgeführt und über die Webseite konnte ich mich ein wenig einlesen. Als ich das Kontaktformular gesehen habe, habe ich es spontan ausgefüllt und abgewartet was passiert. Ich hatte so die Hoffnung, dass ich mein altes Leben wieder ein Stück zurückholen kann. Ich wollte wieder mobiler sein und ich wollte für meinen Mann kein Pflegefall werden. Hast Du Dir eine Zweitmeinung eingeholt? Nein. Ich habe die Therapie lediglich mit meinem Mann durchgesprochen und er meinte, dass er mich in allem unterstützt, was mir Hoffnung schenkt. Er kann es selbst nicht nachempfinden, aber erlebt mich auch, wenn es mir nicht gut geht. Deswegen kann er es am besten Nachempfinden, wieso ich mich für diese Therapie entschieden habe. Bevor ich das ok für die Therapie bekommen habe, wurde ich auf Herz und Niere getestet und mein „Fall“ wurde im Neuro-Board vom Unispital Zürich mit verschiedenen Ärzten besprochen. Das heißt, ich habe den Ärzten vertraut und mir gedacht, wenn sie Bedenken hätten, würden sie es nicht machen. Alle Patienten werden unter die Lupe genommen und es wird mit Fachärzten genau besprochen. Als sie mir mitteilten, dass ich in Frage komme, habe ich gleich zugesagt. Wie musstest du dich auf die Stammzellentherapie vorbereiten? Was galt es vorab zu organisieren? Vom Spital bekommt man Infomaterial über die Therapie und mögliche Nebenwirkungen. Zudem erhielt ich Empfehlungen, was ich vorab zum Vorbeugen kaufen kann. Ich habe zum Beispiel weiche Zahnbürsten, pH-neutrales Shampoo, Bodylotion und Mundziehöl gegen Mundschleimhautentzündung gekauft. Nach der Therapie bekam ich einen genauen Essensplan, an den ich mich halten muss, um Infektionen zu umgehen. Die Speisen sind all gut verträglich für meinen geschwächten Körper. Wie lange hat die eigentliche Behandlung gedauert und wie lief sie ab? Angefangen hat es mit zwei Mobilisierungschemos. Danach musste ich mich noch bzw. mein Mann mich 7 Tage daheim selbst spritzen, damit mehr Stammzellen produziert werden. Die Stammzellen gehen ins Knochenmark über und können dann entnommen werden. Als genug Stammzellen vorhanden waren, wurden sie über eine Apherese entnommen und dann eingefroren. Nach Entnahme der Stammzellen hätte man normalerweise gewartet, bis ich mich wieder erholt habe. Also 2-3 Wochen später wäre es weitergegangen. Bei mir kam aber Corona dazwischen. Sie mussten garantieren, dass ich einen Platz auf der Intensivstation bekommen könnte. Aber dank Corona wurden keine Therapien mehr bei nicht lebensbedrohlichen Krankheiten durchgeführt. Ich war also nach den ersten beiden Chemos wieder auf Arbeit und wusste nicht, wann es endlich weitergeht. Anfang Februar habe ich dann die Info erhalten, dass es jetzt weitergehen kann. Da die Stammzellen eingefroren waren, konnten wir weitermachen, wo wir aufgehört hatten. Ich habe einen zentralen Venenkatheter am Schlüsselbein bekommen. So konnten alle Chemos und Medikamente gegen Übelkeit, Schmerzen etc. über einen Zugang laufen und ich musste nicht jeden Tag gespritzt werden. Ich habe dann an fünf aufeinanderfolgenden Tagen fünf weitere Chemos bekommen. Nach den fünf Chemos und einem Tag Pause habe ich meine Stammzellen wieder transplantiert bekommen und am nächsten Tag noch eine Infusion mit Antikörpern bekommen. Damit waren dann wirklich alle Leukozyten (weiße Blutkörper) aus allen Zellen und aus dem Immunsystem vernichtet und mein Immunsystem konnte wieder neu aufgebaut werden. Die Therapie an sich dauerte nur eine Woche, aber ich musste solange im Spital bleiben, bis die Aplasie Phase vorbei war, also die Phase, in der das Blutbild stark eingeschränkt ist und ich infektionsanfällig war. Die Ärzte sagen, dass man ca. 4 Wochen im Spital bleiben muss. Ich habe alles sehr gut vertragen und konnte schon nach 2,5 Wochen wieder nach Hause. Wie war das Zimmer ausgestattet und konntest du Besuch empfangen? Das Zimmer war riesig groß, mit Blick auf dem Zürchersee, Leisten zum Aufhängen von Bildern und Postkarten. Es hatte sogar einen Stepper, den man benutzen kann, wenn man die Kraft hat.  Ich habe mir also mein Zimmer mit vielen Bildern und Fotobüchern für positive Erinnerungen heimelig gestaltet. So machte ich mir den Aufenthalt so gemütlich wie möglich. Mein Zimmer hatte große Fenster, die allerdings nicht geöffnet werden konnten, da sonst Bakterien reinfliegen können. Ich bekam also nur durch eine Lüftung frische Luft und musste den Spital-Schlafanzug ganztags anziehen, der täglich gewechselt wurde, damit alles steril ist. Während des Aufenthaltes kam regelmäßig ein Physiotherapeut vorbei und hat mit mir Übungen gemacht. Darüber hinaus besuchten mich regelmäßig Ernährungsberaterin, Psychologe, Seelsorger und der behandelnde Neurologe. Also ich war wirklich gut aufgehoben und fühlte mich echt wohl, so wohl, wie man sich für so eine Therapie fühlen kann. Durch Corona war der externe Besuch stark eingeschränkt, aber mein Mann durfte mich jeden Tag besuchen. Aus Schutz gegen Bakterien musste er zwar einen speziellen Anzug anziehen, Maske tragen und kam nur durch eine Schleuse zu mir, aber da war die Sicherheit auch wichtiger und es war ok. Welche Maßnahmen kamen nach der eigentlichen Stammzellentherapie? Drei Monate nach der Therapie, hat mich die Neurologie automatisch zur Reha angemeldet. Sie warten immer ein paar Wochen, bis die Patienten wieder ein wenig zu Kräften gekommen sind, weil Reha sonst nicht so effektiv ist. In der Schweiz wird Reha von der Krankenkasse bezahlt und läuft nicht, wie in Deutschland über die Rentenversicherung. Sie haben eine Kostengutsprache erstellt und es wurde für drei Wochen genehmigt. Da mir der Aufenthalt sehr guttat, habe ich sogar um eine Woche verlängert. Auf Reha hatte ich Physio-, Ergo- und Wassertherapie, Logopädie, medizinische Massage und bei Bedarf psychologische Unterstützung. Also ein Rundum-Sorglos-Paket. Da mein Immunsystem komplett resettet wurde, habe ich auch einen Impfplan bekommen, da keine Impfung mehr vorhanden ist und ich den ganzen Schutz neu benötige. Drei Monate nach der Therapie konnte ich mit den ersten Impfungen anfangen. Auch die Kinderkrankheiten Masern, Mumps, Röteln muss ich nachholen. Da das ein Lebendimpfstoff ist, kann ich diese allerdings erst nach 2 Jahren nachholen. Wie fühlst Du Dich jetzt? Und wie geht es in Bezug auf die MS weiter? Ich fühle mich gut. Ich merke, dass ich noch nicht voll bei Kräften bin und langsam machen muss, aber ich habe die Therapie nicht bereut. Ich kann zwar noch nicht weit laufen, aber ich bewege mich wesentlich sicherer und hab es geschafft innerhalb eines halben Jahres von EDSS 4,0 auf 3,0 zu kommen. Die Therapie war nie darauf ausgelegt, dass es zu Besserung kommt, sondern hauptsächlich, dass die MS gestoppt wird, aber ich hoffe dennoch, dass das Laufen besser wird. Ich habe bezüglich meiner Gehbehinderung noch einige Therapien wie Osteopathie, Hippotherapie, Physiotherapie. Ich muss noch geduldig sein, aber bin überzeugt, dass ich auf einem guten Weg bin. Wer hat die Kosten für die Stammzelltherapie getragen? In der Schweiz läuft die Therapie aktuell bis 2024 über eine Registerstudie und wird von der Schweizer Krankenkasse gezahlt. Die Ergebnisse der Studie entscheiden dann, ob die Transplantation in den Krankenkassenkatalog übernommen wird und von ihr bezahlt werden muss. Was war dein tiefster Punkt mit der MS und wie hast du dich wieder empor gekämpft? Ich war immer sportlich – Inliner fahren, Joggen, Zumba, Volleyball… Vor ca. 4 Jahren hat meine Gehbehinderung angefangen und ich konnte das linke Bein nicht mehr heben und konnte nur noch kleinere Strecken laufen. Ich war auf Gehhilfen angewiesen. Angefangen mit einem Gehstock bis zum Rollator. Meine Hobbys und mein gelernter Beruf (Hotelfachfrau) wurden mir genommen und ich hatte das Gefühl mir komplett ein neues Leben aufbauen zu müssen. Es fällt mir immer noch schwer, Hilfe anzunehmen, aber ich lerne, dass es ok ist und ich froh sein kann, dass es heutzutage verschiedene Möglichkeiten wie E-Bike etc. gibt. Haben sich bestehende Symptome verbessert, seit der Stammzelltherapie? Wie bereits erwähnt, hat sich mein EDSS verbessert, ich muss zwar regelmäßig Pausen einlegen, aber habe das Gefühl fitter zu sein und Schmerztabletten hab ich gesenkt von 3-4/Tag auf 2-3/ Monat und mein Sichtbild war vorher immer schwammig und das ist jetzt auch stabil. Was rätst du anderen MS-Patienten, die über diese Form der Therapie nachdenken? Sobald man verschiedene Therapien bereits ausprobiert hat und es konstant schlechter wird, würde ich die Möglichkeit der Therapie abklären und mich beim Neurologen erkundigen, damit man rechtzeitig den Weg einschlägt. Was machst du, wenn du Symptome der MS verspürst? Bei mir habe ich gemerkt, dass Schlaf sehr hilft und ich versuche mit meiner Atmung meinen Fokus auf mich zu legen und ich Ruhe benötige. Bei Schwindel hilft mir immer ein Kühlpad im Nacken. Gibt es einen großen unerfüllten Wunsch? Aktuell wünsche ich mir, dass mein Mann und ich 2022 endlich ohne Angst und Maske unsere freie Trauung nachholen können. Wir haben vor Corona am 20.2.2020 standesamtlich geheiratet und mussten die Feier schon 2x wegen Corona und der Therapie verschieben. Unseren ersten Hochzeitstag verbrachten wir im Spital und ich freue mich schon riesig darauf, die Feier unbeschwert nachholen zu können. Blitzlicht-Runde Was war der beste Ratschlag, den du jemals erhalten hast? Als Ratschlag kann ich sagen, dass man viele Situationen im Krankheitsverlauf zusammen besser bewältigen kann. Wer alleine bleibt, vergräbt sich immer tiefer. Nichts runterschlucken, auch wenn man es zum hundertsten Mal erzählt. Es ist sehr wichtig, dass man darüber spricht, sonst kann man die Krankheit nicht verarbeiten, geschweige denn akzeptieren. Also es ist allgemein wichtig, Hilfe anzunehmen, und sich nicht schuldig fühlen. Wie lautet dein aktuelles Lebensmotto? Hinfallen, aufstehen, Krone richten, weitergehen…und never give up. Vervollständige den Satz: „Für mich ist die Multiple Sklerose… “ …Fluch und Segen zugleich. Ich musste mein Leben in vielen Dingen ändern/anpassen. Ich würde gerne wieder unbeschwert Städte besichtigen oder in die Berge wandern gehen, aber leider geht das nicht mehr. Die MS zwingt mich also, mein Leben neu aufzubauen, was mir noch verdammt schwerfällt, aber gleichzeitig habe ich auch gelernt, ein wenig egoistischer zu sein, und mehr auf mich selbst zu achten. Ich muss nicht mehr überall dabei sein und mach nicht mehr alles auf einmal, sondern konzentriere mich auf mich und muss es nicht mehr jedem Recht machen. Welche Internet-Seite kannst du zum Thema MS empfehlen? DMSG finde ich eine sehr gute Gesellschaft und auch „trotz MS“ ist eine sehr gute Kampagne, bei der man viele Antworten und Hilfe bekommt. Welches Buch oder Hörbuch, das du kürzlich gelesen hast, kannst du uns empfehlen und worum geht es darin? Das Café am Rande der Welt und Wiedersehen im Café am Rande der Welt. Es geht um den Sinn des Lebens und zeigt neue Sichtweisen des Lebens auf. Regt zum Nachdenken an und ist eine leichte Lektüre. Hast du einen Tipp, den du deinem jüngeren Ich geben würdest, für den Zeitpunkt der Diagnose? Nicht googeln. Da erfährt man nur die schlimmsten Dinge. Und frühzeitig mit starken Medikamenten anfangen, damit man von Anfang an gut aufgestellt ist und präventiv gegen Beeinträchtigungen arbeitet. Möchtest du den Hörerinnen und Hörern noch etwas mit auf dem Weg geben? Denk dran, dass du die wichtigste Person bist, und gib gut auf dich acht. Wo findet man dich im Internet? Auf Instagram unter @multiple_sichtweisen. ++++++++++++++++++++ Vielen Dank an Johanna für das geführte Interview und die gewährten Einblicke. Bestmögliche Gesundheit wünscht dir, Nele Mehr Informationen rund um das Thema MS erhältst du in meinem kostenlosen Newsletter. Hier findest du eine Übersicht zu allen bisher veröffentlichten Podcastfolgen.

Some studies show that plant based diet show no significant changes in MRI scans, EDSS, or mobility. However, the Fatigue scores improved significantly. Participants showed good compliance, and were able to lose weight, reduce cholesterol levels and improved quality of life. Learn more about Plant based nutrition from Dr. Dr. Gemma Newman, specialised in Holistic health, Plant based nutrition & Lifestyle medicine. Listen to 10 minutes for MS Podcast by @multiplesclerosis.awareness and get educated about MS. --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app Support this podcast: https://anchor.fm/10minutesforms/support

Ich spreche mit Anne Geßner vom MS-Zentrum Dresden über Physiotherapie bei MS und warum sie eine wichtige Säule im Alltag von Patienten sein kann. Foto Anne Geßner Zusammenfassung der wichtigsten Aussagen: Bei der neurologischen Untersuchung überprüft man 8 Funktionssysteme und ermittelt am Ende den EDSS-Wert. Die Untersuchung trägt zur sicheren Diagnosestellung bei und hilft den Verlauf mit Verschlechterungen unter/nach einem Schub und Verbesserungen im Anschluss dank wirksamer Therapie zu ermitteln, sowie die Wirksamkeit von verlaufsmodifizierenden Medikamenten zu ermitteln. Typische Symptome wie Gleichgewichtsstörungen, Kraftdefizite, Spastiken, Koordinationsstörungen und Einschränkungen der Gehfähigkeit können durch Physiotherapie behandelt werden. Dabei sollte die Therapie für jeden Patienten individuell und gezielt angepasst werden. Ganz wichtig für physiotherapeutische Behandlungen: Es sollte auf jeden Fall »KG ZNS« verordnet werden! Behandlungszeit beträgt hier 30 min, statt normalerweise 20 min. Konzept beruht auf neurophysiologischer Basis. Ausgewählte Therapeuten, die diese Verordnung durchführen dürfen, habe eine spezielle Weiterbildung gemacht und sind spezialisiert. Spezielle Defizite können mit dem passenden Konzept behandelt werden und diese Defizite dann auch im Alltag kompensiert werden. Alle Fragen und Antworten findest du auf meinem Blog zum nachlesen: www.ms-perspektive.de/blog Falls du selber frisch die Diagnose MS erhalten hast, dann gibt dir mein Erfahrungsbericht "Multiple Sklerose? Keine Angst! Ein 15-jähriger Erfahrungsbericht" Zuversicht und versorgt dich mit vielen interessanten Informationen. Du kannst das Taschenbuch überall im Handel bestellen oder dir das E-Book holen, z.B. auf amazon. Mehr Informationen rund um das Thema MS erhältst du in meinem kostenlosen Newsletter.

Loren Sands-Ramshaw: https://lorensr.me/The GraphQL Guide (coming soon): https://graphql.guide/TranscriptLoren Sands-Ramshaw: [00:00:00] So welcome Shawn to the GraphQL Guide interview with Shawn Swyx Wang. Is that swyx: [00:00:04] it? I pronounce that, right. It's it's my Chinese and English initials. And it's just a branding that I'm leaned into because it's unique. Yeah. I think it's great. Loren Sands-Ramshaw: [00:00:11] Yeah, definitely unique. So for those of our readers who don't yet know you, swyx: [00:00:15] Who are you, what do you do?Cool. I'm Shawn. I guess I work on developer experience at Temporal. I should be more assertive. I am head of developer experience at Temporal.io. It's a Small startup that does microservices orchestration, which is a very, very fancy name that basically runs an open-source framework spun out of Uber that we can go into more details, but really, I've done.I sort of migrated from finances, which is my first career. Then I went into Front end. So I did a JavaScript bootcamp then went into front end D started doing some speaking and writing in 2017 and got noticed by Netlify. And that's how I got into developer education, which is what we're here to talk about, I guess, and then started getting into graph QR because it was all tied into the react world.At the time. You could not ignore graph QL and Gatsby and Apollo and all the other ecosystem in, in, in place. I did. Then I then went to AWS to do the same job, essentially where they have amplify an app sync apps think is AWS has graph QL gateway as a service, which we can talk about. And I recently left to join Temporal.Loren Sands-Ramshaw: [00:01:18] Going back to when you were getting noticed you were like writing blogs and doing talks and getting out a spot Netlify how did you decide to get into developer education? swyx: [00:01:25] I didn't, there wasn't actually a decision. It was just like, let's just try this. And see what happens. So that the context was that the boot, the first job I got out of bootcamp was at Two Sigma, which is a well-known Quant hedge fund in New York.The problem was that I was in a, I didn't know it, but I got into a bad part of Two Sigma where they were severely underusing their engineers to the point where four days out of five, we were not doing anything like specifically not standing on our desk. Cause we had stand up desks. And.Explicitly given to have the okay. To do whatever we wanted, whatever because we just didn't have work. And that was, it's a, it's an enviable position, right. For for a lot of people like, Oh yeah. Paid around and do whatever you want. That's that sounds like a great job, but I don't think it's a very good job for a junior.Like someone just starting out. Right. You're not going to grow up very much. So it's like frustration. Really that I was like, okay, I'm not getting any learning at work. My, my team lead was like not doing his job. So I just started blogging and, making my own mentors, like, externally New York city has a pretty vibrant meetup scene.So I just, started doing my own talks, even though I didn't feel like an expert. And then I started doing blogging and I think the first one that really picked up for me was. When react announced that it was working on async react like concurrent mode as it is known today, but back then it was async react.So it was announced at a conference in JS conf on March in March, 2018. And I remember that night because it was a big shock to the react ecosystem and it was like a sweeping change. They touching every single part of react. So I just stayed up all night to write a walkthrough of the talk, the demo, and just really like went through everything at it.And that was the first blog post that. We've got really some notice for me and that really still bald since then. And since then I've kind of enveloped everything into this principle I've learned in public. Like when you find something interesting write it up in your own words and share it with people.And at least the people involved in working on the thing will probably read it. And if you're saving some work and if you have some unique perspective than other people will find it helpful as well. Loren Sands-Ramshaw: [00:03:26] Was there a moment where you were like, I'm going to write my own blog posts instead of reading other people's.swyx: [00:03:32] I've been doing it, unsuccessfully for like the two years prior. So there was no one single moment. It was just like focusing it on something that people actually cared about. It turns out that, you want to write things that people want to read. And that's that was a pretty big insight for me.It's not, it didn't seem like that big of an insight until you look at it. The vast quantities of developer blogs out there. And a lot of them are sort of very inward facing. They don't really answer the question of why should you care? And so I, I definitely had my mentality changed around like, okay.Like it has to be an intersection of things you're very interested in and things that other people are interested in and you can't just have one or two. Loren Sands-Ramshaw: [00:04:07] Speaking of things that people are interested to read, you have a great book on the coding careers. That's called the coding career handbook.One of your first. Customers really like the parts of it that I read. What was that like coming with the idea of the book and writing it and swyx: [00:04:20] publishing it. So there's a fun story for the reason the name is so awkward. I still don't like the name, but I just had to go with it because I didn't have anything of anything else.The reason was the original name was cracking the coding career because there was a successful technical interviews book called cracking the coding interview. And the whole point was that it w I wanted it to be apparent in the title that once you're done with the interview, once you landed the job.There's a huge gaping hole of what's next. And this th this book is targeted at the what's next. Unfortunately, Gail McDonald, the author cracking Cody career actually got in touch with me and mentioned lawyers. So I had to change the name before lunch. So, by the time, like I already had my Twitter handle up and all that, and I was just like, all right, I'll just stick with this thing.But it is an acronym. Yeah the. Point I think is that people, I think my most successful writing, like it or not has been my non-technical writing which the learning public essay has reached, hundreds of thousands of people. And I constantly get shout outs every single day about people starting to own journeys.And it's something that I really. Believe it, even though I hate, I'm not like the Tony Robbins type, I don't want to be like a lifetime life coach or anything. I just think that this worked for me and it will work for a lot more other people. So I was like, okay. I just, I should probably just write down some more advice on, on, on what I think that people need, because.I think what really crystallized it for me was when you look at career ladder. So I did a study of every public career ladder out there. So career ladders are these things where it's like, all right you're junior, you're expected have these qualities or senior, you expected these qualities, staff, principal, whatever.And and everyone has some version of these in some companies are actually brave enough to publish them. And so if you just study all of them and you realize something really interesting, which is that when you look at the way that people are promoted and graded about 75% of the grading criteria is non-technical.Seventy-five right. It's like, all right, you can call it. Great. But what about your communication? What about your business impact your mentorship and all that, which is like surprisingly not the type of thing that you learn in college or bootcamp. And no one tells you to do it, but suddenly it's 75% of your evaluation, like, well, okay.And I think that just reflects the reality that we are less coders and more code enabled humans and we can code, but we're humans first. And so we need to apply all these sort of soft skills. I hate the word soft skills, but that's the common commonly accepted terms. So I use it Two two, we need to teach each other, lessons from these things.I am not saying I'm the world's foremost expert at them. I have things to work on myself and it's a very difficult thing to, to come on and say like, I have something worthwhile for you, even though I'm imperfect. But I don't base my advice on myself. I also base my advice on.Hundreds of other people that I've interviewed and collect collected the book has like 1400 references to people smarter and wiser and more accomplished than I have. And that, that's just what research does for you. And hopefully you can decide yourself which of these ideas you agree with and which are not.And that's all I ask really, I think it's really hard to write a soft skills book. Because your sort of character has to be impeccable. Like the moment you're like, Oh, I had a bad interaction with this person. Therefore, the entire book is wrong. Like, I'm sure, if you want to take that view that's fine for you.But I view ideas as sort of independent, you can sort of pick and choose. And if this book, has 40 chapters and three of them make sense for you then that, that would be a good investment of time for me. Loren Sands-Ramshaw: [00:07:39] I liked it like the field of life coaches and career coaches and therapy and stuff.And I really appreciate the knowledge that you've put into the world with that book. So thank you swyx: [00:07:49] for writing. Well, yeah. Thanks for asking about it. It's kind of, it's still awkward that you can hear me like being very hesitant about like, talking about this thing, but people like it.I think that, everyone wants to hire seniors. That's the truth. There's a huge glut of bootcamps producing juniors. There's lots of people self-teaching. And then from junior to senior, somehow you magically, hope to. Find something that works. And then once you're seeing her every once a hi, everyone wants to hire you.So I guess if I had to narrow it down, like I need to make it. Easier for people to up-level whether or not they can use the book as a guide or they can join the discord that I have and interact with me directly and ask me questions and all that. These are all passed into upscaling, more people from junior to senior.And I think people don't do it. It's just, it's a very awkward thing to do. But that's an interesting challenge. I really Loren Sands-Ramshaw: [00:08:37] liked the boot camps. There were like nine months. You can go really deep. It'd be cool if I was like a graduate school version of boot camp. So you go to the bootcamp one, and then later on you go to the boot camp two.swyx: [00:08:46] Oh, there is a Recurse center, which is the self guided one in New York. Yeah. A lot of pretty famous people have come out of the recur center because they do it's essentially like graduate school. Like you propose your topic and then you sit in a room with a bunch of other people who are very self motivated as well.And you produce something to impress each other and the kind of people that actually self-select to go there are very intellectually curious themselves. So they work on pretty cool stuff. And it turns out that once they graduate, they will actually go on to do some pretty interesting things as well.So, that's a comparison, but like the thing is that doesn't scale. Like they, they admit like maybe a few dozen people there's tens of thousands who will never do it. Loren Sands-Ramshaw: [00:09:23] Also. There are a couple more ideas in that area that I have where like, Having it be more of a norm for companies of like even medium size to have like a junior teaching mentorship program.swyx: [00:09:37] Yeah. Yup. More apprenticeships, especially for people from non-traditional backgrounds. I find, I see so many companies that have, Campus recruiting for colleges. But actually, what about everyone else? So, yeah. And then in the mentorships, it, th the thing is like, it's perceived to be a cost.And we need to turn that around and turn the tenant equation around and say like, actually you're getting. To upskill talent, there's that cheap, that becomes very valuable once you put, once you invested in them. And I think some companies are getting into this mindset. So Stripe is having direct integration with the university of Waterloo.And I think shop, sorry. Stripe is integrating with the university of Limerick, I think in Ireland. And Shopify is. Has a has a degree offering with the university of Waterloo. And it's just amazing to see all these innovations, but they're just sort of piecemeal. And then, they'll improve a few dozen people, a few hundred people at a time, but it's a slow process for sure.Loren Sands-Ramshaw: [00:10:28] I would think of it makes sense for there to be like a lower part of the market where like, like the, maybe under the entry-level for expected junior does, there's like a gap where people can do like. Traditional apprenticeships where it's more of a stipend or like an internship kind of thing where you're not being paid like a normal dead salary, but you are learning a lot.Yeah. And maybe like that would be low enough that it would be profiled. swyx: [00:10:52] They are doing that at they are doing that at Lambda school, which is the online bootcamp. The problem is Whenever you talk about paying people perhaps less than an average developer salary the, there people online who get very angry about that.And I, it's not my place to say. Who's right and who's wrong. I defend the right of consenting adults to agree to whatever contract they want, even though, some, some of them may be exploitative in retrospect, but we have to let people make mistakes. And we have to let people experiment with new forms because all we know is the current system.Doesn't work well in, in some way we need to try new ideas. We need to make it safe to try new ideas. And and so Atlanta school was really trying. And I think what they have right now is they'll guarantee you they'll give you a student for a month.And they'll pay the full month of it. So it's totally cost free to you, except that you have to give them, stuff to do. And I think that's a really beautiful experiment. So I don't know, some people get angry about that. I'm like, you're, you don't know what it's like to be a bootcamp student.I would've killed for that. When I was a BlueCat student, Loren Sands-Ramshaw: [00:11:51] I have friends who haven't found a job after boot camp. So, hope that swyx: [00:11:56] system works fine. Yeah. Nothing is better than sort of just getting into a real work scenario and like, stop jumping on the artificial hoops with like in video binary or whatever.And just get into the real work. And after three months, six months, nine months, you're a dev. And. You know that w yeah. Every, everything else is just gate keeping. So whatever. Loren Sands-Ramshaw: [00:12:14] So you think of algorithm, coding interviews? I had an interview with Toptal, and I didn't know they were going to do data structures and algorithms.So I didn't study and like, I haven't studied it in over 10 years. And I got an a in my courses at Dartmouth, so like I knew it at one point. swyx: [00:12:30] But I totally did you burn, did they give you a grade? Did they give you a number? Like how bad? I know they just like stop Loren Sands-Ramshaw: [00:12:35] asking your questions. swyx: [00:12:36] Yeah.Yeah, yeah. So tail, the reason that'd be so stringent is the marketing, right? They're like we, they have to have a rejection rate to, to show off. Because that's part of the marketing appeal. I totally get it from their angle, but then also, like you don't need them. So, whatever.Loren Sands-Ramshaw: [00:12:49] What are your thoughts around different education mediums? Like how did you decide to do a book versus a video course? And do you have any plans for doing books or courses or. swyx: [00:12:59] Inefficient. That's an interesting question. The reason I did a book was because the MVP of a book is a blog post, and I already done like three, four years of blogging prior, and people already knew me from my blogging.So it was very natural progression. So I didn't really question it. I also know that I take a lot more time to do video than I do writing or, yeah. No, let's just put it, let's put it the other way. Like, I don't think I'm ever on the world's most natural speaker. I have a lot of false starts.I've thought I'm sinners and I'm still working on it as you can probably tell. But yeah. And so when it comes to writing, it's SEO, searchable, it's you can edit it anytime and reformat things, and it's not it's super cheap. You can add hyperlinks, which I love dropping references.Right? Like when I. Have references in a podcast or a talk. I can't drop a hyperlink in my mouth and you can click on it and it just leads you right to the source. I really liked that. And it annoys me when podcasts say, like, we'll put it in the show notes on any deal. They don't it's really super annoying anyway.So writing solves all of that. It's it's perfect. Medium. It's very scalable. In fact, I have a whole chapter on why writing is great. Everyone, every developer should write. So yeah, I mean, no, no contest on mediums. That's it. One of the downsides of writing is that the moment you call anything, a book, what's the normal price of a book it's nine to nine to $59 or something like that.Like you can go to maybe 99 or whatever, actually, I don't know how much theYeah, got it. Yeah, there's a range. Right. And it's basically constrained by the format rather than the value of the knowledge contained in the book. So if my book happens to. Yeah. Increase your the slope of your career by $10,000 a year. The Mexican charge is 59, which is what I charge that's absurd.Right. And other formats, like video courses, that's automatically like 200 to $300. Irrespective of like the actual value of the delivers to you. And so that's a really bizarre way to do things. So that, that was one, that's one argument for why you might want to do other formats.So apart from this book, I actually considered doing a reactant types, of course, because my other one of my other side gigs is that I run the react and TypeScript cheat sheet, which is. The de facto community docs for react and TypeScript. And it's a, it's a much bigger deal now with them back when I started.So I teach, a thousand people a day react to TypeScript and it's been a completely volunteer behavior volunteer activity. And if I, sold 1% of those on a video course, I probably make a living.It's something that I thought about. Th the only reason I don't do it is because I don't want to be a teacher. I don't think I'm a, I've a very ever temperament to be a good teacher. I don't think I have the patients. I want to do other things with my life apart from teaching.So I think I'll just leave it to someone else, or maybe collaborate with someone. Loren Sands-Ramshaw: [00:15:44] Let's move to the backfield topic. What is your swyx: [00:15:47] take on evacuation? Greatest thing since sliced bread. Is that what I'm supposed to say? So I had a talk about this Hawaii where like kinda compared it to like, I hate I wish that people would start comparing graph QL to risk.Like we have to, because that's kind of what we. What the paradigms are and how people mentally place them. But rest doesn't go away at Graco has a protocol over rest. And so it was like, it's, it's not either, or it's like one and the other. That's it. My sort of galaxy brief summary of graph you all is that instead of creating a dozen different end points that are all kind of dumb you create one smart end point and then you have contracts that can specify whatever that end point does sort of on, on request.And I think that's a really simplified take, but it really. You were there at Apollo day. And I think the Apollo folks have a really good present explanation of this. It really starts to come into its own when you start having multiple devices to support. So you have mobile and desktop and web Sr and, and Sorry.Well, mobile native and desktop and mobile web and on whatever other devices that you may have, these are all have the different data requirements. And there's a combinatorial explosion. They have all these lines crossing over from different services, into different devices that you could simplify by just having one single sort of smart endpoint.And everyone connects to that one smart end point. It speaks to the right contract and that smart endpoint has. The means to resolve all the data from each individual data source then that's essentially graph QL. Like you could do this in a bunch of different other ways as well. And there have been many, many other attempts like graph QL is, is, it's not new.They're there. And I think the creators of graph you all are pretty upfront about like the inspirations that led to. Craft you are like all data, which I never really tried any of these. So outside, I don't have much sympathy. All we know is that graph QL is successful. Now it has the network effects now, and therefore it's a much better bet than the other formats.Which is an argument by like it's success, it's popular. Therefore it should be more popular like that kind of argument, but it's true. There's some amount of validity to betting on things because the ecosystem is better. And so, so that's really smart.I have another take, which kind of combines into one of the questions that we prepped for is what I dislike about it. So, I think that it's very, very easy for front end developers to wax poetic about graph QR, because it makes their lives a lot easier. And the people that we kind of leave behind, or we sort of punt all the tough questions too, are the backend developers for whom It turns out it's not true.It's not always true, but net, it turns out that it's more work for them, whatever it is from like, figuring out how to do off figuring out how to do like rate limiting or like query complexity, limit limitations and like, Inserting all the validation steps or like joining schema is, and the federating them, these are all the tough work that was maybe sometimes shift done on the client side has all been shifted onto the backend.That's really unfortunate for graphical adoption. Like the main bottleneck of graphical adoption is backend. That's it there. And I wish we would stop. Okay. I wish front end developers would stop selling graph QL based on how easy it makes their lives, because it's totally unsympathetic to graph to back in people back.And people are just like, you guys are not thinking about the security risks. They're not thinking they're not talking to them in terms that they are thinking about. And I wish that more evangelism, more graphical individualism was more sympathetic to the backend perspective. Loren Sands-Ramshaw: [00:19:08] What are your personal swyx: [00:19:10] favorite parts?Oh, graphical. I, this is the common answer, right? Like it's I feel like graphical is kind of like the common ground of all of them. Cause like, you can, it's a raffle or it's a postman or whatever it is. It's the common tool and it's so good and actually got a lot better. We graphical Explorer sorry, graphical Explorer.And that's the little side tab that the added and I think, their plans were a graphic for 2.0 in graphical. And it. It's just such a introspective tool that has embedded documentation in it. Like, it's just, it's everything you want out of a documentation tool and of API documentation that  rest never really got to, like the best you got.It was open API and even that's kind of like a sprawl and it doesn't have embedded like try this, it, it does, but like it, it's just not as smooth as graphical. So yeah not really galaxy brain take here. But I think, yeah once you make experimentation and modification a lot easier than you, you move the pace of development faster, at least on the front end.So, I definitely like that a lot. The errors kind of bother me a little bit with, areas being 200. Okay. That's a common sort of gripe among people who don't like graph QL, but you'd learn to deal with it. You just, yeah. Loren Sands-Ramshaw: [00:20:16] Any advice for swyx: [00:20:16] people learning Graco?Nice. We're learning people that are in graph. Y'all I think the thing that you do in the book where like you explain the validation and set it, set things up from scratch you should do that. You should go through the exercise. Actually even set up a server using just pure graph LGS without all the fanciness that maybe Apollo server does for you.And just, yeah. Fundamentally understand like, or, so like, I guess the advice would be like stripped down the tooling as much as possible and build your way back up instead of just starting at the tooling and never going down the stack a little bit. So, did you know that you can query Aggreko end points just with fetch?Do you know how to do that? If so then great. Then what's the next step after fetch? What does caching actually do for you? So on and so forth, like these are all this, these are the steps that you knew you need to sort of work through to, to build up to a complete understanding of graph you are so that when things go wrong, you know how to fix it.And that's one thing which I really encourage because graphene is a complex system. It's client side is service side and there's like, This complex chain of events that go through it. And sometimes the errors can be a bit too loose. If you don't really know what's going on under the hood.Loren Sands-Ramshaw: [00:21:19] Yeah. I don't a friend who I was a junior dev working at a company that like had a Apollo in place and like their view of craft kill was if I add this like fragment or this query to this component, then. I'm going to get the data. And so they don't have the understanding of like what's happening, how it's all getting collected, where the cash is doing.Which is definitely helpful. When things go wrong. swyx: [00:21:47] Yeah. Yeah. Loren Sands-Ramshaw: [00:21:48] What are your, yeah. So you had a chance to read parts of the guide. Thank you so much for being here. I really valued your feedback. What swyx: [00:21:55] were your favorite parts of the book? So I noticed that you do something unique, which I don't see a lot in a lot of other books, which is every code sample has like a good tag.Is that what you do? And you can just view the defer or go straight to the, get, get tag from that sample. And I actually really liked that. Sorry. So this is really tiny detail, but then like, I appreciate that. Cause I read a bunch of other books as well. Like I got another, a book here.And on top of this monitor that I'm looking at you on, I have a bunch of other techniques as well. I really enjoy reading technical books as a way to level up. And so like when you can actually follow through on the code and download it and run it yourself, that's a really nice detail.Overall, like, I think it's, I think it's a very comprehensive, like 500 something pages, which is huge guide, and it's the kind of detail that you would take months to really pick up on. And, you get it within a Yeah. Within a few days of just reading this book.And so I just really appreciate it, like all the research and all the piecing together of things. Obviously you had to make some tough choices, like, picking on picking Apollo. But I don't think these are controversial at all. These are just like, the industry standard things that, that you would at least expect people to be familiar with.Even if they go with the alternative. And then going into like each individual client and framework, I don't use react native sorry, I don't use Vue or react native, or I think you have some other native iOS, even that you went into there. I don't use any of those platforms. I'm just a web person.But I know that, when the time comes, I can just pick it up and start there. So that's a really good perspective as well as like the broader ecosystem, right? Like, Apollo Federation, which is like a fair, fairly new thing. And then talking a little bit about history as well, which I think is one of the most significant graph your companies out there.So, so yeah, it really like combines, condenses a lot of research that's done by you and John Resig and that's pretty well, this very much worth the sticker price. Loren Sands-Ramshaw: [00:23:36] Thank you. So the tags is particularly difficult because I have a tag for each section of each coding chapter.And those are chapters six through 11, and then for each version of the book has a different tag of version. So it's like the react chapter is maybe 40, 40 tags with each, with a version number. And then each time I changed the code for the next version of the book, I can make another 40 tags. It's a big process.Yeah. swyx: [00:24:05] I was thinking about, is react the best pear to graft you all like, does it, is it an accident of history that it just happened to also come out of Facebook? That's. Which is why we use it together. I always wonder that because, we act it's very weird with its effects and all that.It's kinda clunky to, to use. So you basically have to use a third party library, like, or goal, or Apollo client to wire to that. I don't, I'm not sure how I feel about that. Like I was just like, Ugh. Anyway, we can talk the frame, talk about frameworks in a day, but yeah, I appreciate it that all the guys are in there and you took pains to, to cover other devices.Like, like I said, like, one of the main benefits of adopting graph is that you can support multiple devices, multiple frameworks in paradigms pretty easily. Okay. Loren Sands-Ramshaw: [00:24:47] Any visions swyx: [00:24:48] for the future of death off? OhLoren Sands-Ramshaw: [00:24:51] well just probably like, having the backend story be. More developed. I think it was both pitching them and then swyx: [00:24:56] also the software supporting them. I have a pretty good coverage of this in the book where you talk about differ and idea, the two directors, which I never remember stream yes.Street. So like all these spec level things are very important because once it's in the spec then multiple, different parties can implement them. And we because right now everyone's kind of haphazardly kind of. Hacking their way around it if they need it. And once it's standardized we can really build some rails around it to make it a lot more reasonable and, things like the, for like, they need to be in there just cause once your graph gets big, like you, you need to, query things at different paces and have them all in one quick one single query. Yeah. So, so more standardization of stuff. Like I even, I don't know. I don't know how you feel about this, actually. I should ask you a do, but I think that graphic, I wish that graph y'all had a date time. Standard type. Loren Sands-Ramshaw: [00:25:41] Definitely. I think it's a, swyx: [00:25:43] some stage in the spec. Okay. Super annoying. It doesn't happen.Yeah, so, I think Lee Byron has had arguments for why did kept it out. And definitely simpler is better for the initial success of graph. You would prefer would not be where it is today. If it had done all the things it had to really, really scope down and just solve a specific problem for Facebook and the early adopters.Then it got big and then people want more out of it. This is the natural way of things is how it always goes. That's it. It's super annoying to work with the time in in graph QL and everyone has their own really weird spec. And we should probably standardize on that. I think relay seems to, relay seem kind of dead for a while.And then it had a little bit of resurgence and people really like the the cursor format which which I think you briefly touch on as well. There's, there seems to be some amount of need for standardization of like, the way we do pagination, the way we do a bunch of things like even authorization as well.I don't think it's really it's too. Left to influence that it's too hand-wavy. And so, yeah, which is, which kind of goes back to the solving backend developers, pain points, like having best practices that are sort of, well defended and in production at well-known companies that really gives a lot of assurance to the rest of us who are just trying to figure this out and trying to evaluate like, Oh, Hey, I have this thing that has worked for 15 years.That's that happens to be rested. I can ship faster with that, or I can deal with this cutting-edge thing, which like I might make a critical mistake on. Sorry, my cat and my Comey. Exactly. So, nine times out of 10, the, I was going to say no, because it's just like, are you a dev just trying to play it a new toy or are you trying to ship, do you know how to ship things, which I've always worked in, nothing's broken about it.So you really need to pave the path, which is something that obviously I do for a living, but Graffio has a lot of smart people working on that. Yeah. Did I answer the question about the future?Well, Federation used to be a big sticking point and then they actually, came out with it. So I think it's less of a talking point now. And hopefully I, I haven't used it in any sort of work setting, so I don't know how actually people feel about it. All I know is that it was there were multiple competing solutions and now there's an official one.Loren Sands-Ramshaw: [00:27:48] So, I guess the last thing on graphica was app sync. I'm curious. But what kind of companies you see you saw using it? I guess I quick over here for people. swyx: [00:27:57] Okay. Absolutely. So graph yall tends to end up as a gateway meaning that it starts to wrap around other rest API starts to wrap around your other data services.And then you start to that's as natural. In my view, state of where it should lie in your stack and then your front end sort of starts to query against the graphical gateway rather than your rest or API gateway. In Amazon's terminology, it is literally called API gateway, the most unimaginative name possible.So, the graphical version of that is called app sync. Not graphically I'll get waived for whatever reason. And it really does essentially the same thing. You can define resolvers and resolve against data sources, whether the rest or a third party, or even then I can include a dynamo DB database, which there's a specialized schema for that.We can, which is really intuitive to set up. And I, I think so, people are using that Amazon music, 30 million monthly active users, it's is based on that think there, there are some clients, I, big sort of consumer brand clients. And then there are a bunch of smaller smaller of a well-known names.Like, orange theory is another one that, which we talk about a lot which is a gym that converted to like an online fitness training company during COVID that has like, that does like 2 million, monthly subscribers a month or something like that. And. And yeah, I it's used in production by the kind of companies that use AWS and they may not necessarily be, well-known names to developers, but they are successful businesses in an off their own.Right. We also have a bunch of non-profits, which I really enjoy because it helped them get to market quicker. I feel like I, I still am still performing my role as AWS spokesperson here, but like, it really, I really enjoyed this cause like during COVID, a lot of people had to go online and a lot of nonprofits actually built out their apps using app sync and they got to market in like three weeks and, started serving people.Like some of them were like homeless shelters. Some of them were like sort of critical medical care facilities and and. When you see the pace of development solve by, by, by this, by the service like you, you can get naturally very excited by them. And sorry. So let me get to the point.The point is that you want a service, a graph, your service and either someone at your company is going to build it and it's going to be. Weird and funky and kind of, custom to your company or it's sort of, specked out and developed and scaled by someone like AWS or her Sera or Apollo, w whoever else does the graphic as a gateway service?Because I, it could, because I just said like the backend stuff is the hard part. So when on, let someone else do that for you, that's the SME pitch. So yeah. Sorry. I feel really weirdly passionate about this just cause like it's a really fascinating investment. It'll be, this is the only big cloud to invest in graph you off.As you're in Google and awareness on this and now Facebook is in the cloud. So, so, I feel like it, it has, maybe it doesn't get enough credit for like the amount that is really investing in making graphical a thing and making graphical easier for people to, to put it into production. I would say it's not the easiest thing in the world because it still has to encounter a lot of AWS hurdles, like, how do you deal with IAM policies and billing and all that which has its own sort of nightmares and EWS.Nothing's perfect, but it's a trusted brand and it serves people who are familiar with AWS. It serves them well enough. Oh. One example. I think I really liked was a Yan tweet on Twitter. I don't know if you, if if you come across him he's actually done a bunch of tests and actually helped to help a bunch of clients build with ASIC.And one of the interesting things is that graph Jaan natively has his subscription sort of. Paradigm association method, method which you can implement it with like long polling, whatever. But yeah, the high thing was serverless has been using has been developing serverless, which with WebSockets like having the scalability, serverless with the persistent connections or web sockets absent has this built in.And so it's much easier to to develop sort of live apps, w. With the live reaction functionality that that website has give you with seeing them without, and to go pure serverless with API gateway. I'm sorry, I'm throwing a lot of jargon at you, but if you're in the AWS ecosystem, you know what that means?Loren Sands-Ramshaw: [00:31:42] No, I've. I've used it on one or two. What did they call it? Consulting gigs. And I swyx: [00:31:48] remember not understanding the UI Loren Sands-Ramshaw: [00:31:51] very well, like you're not feeling intuitively, but then being able to do most with like CloudFormation via the amplify CLI. swyx: [00:31:58] So I liked that.Yeah, that's a that's the common starting point which is like, if you just have a pretty common use case, I definitely recommend using a CLI then the more. Custom you get I would recommend checking out co CDK, the CAGR development kit where you can programmatically create confirmation resources to attach onto your API gateway.And that's the migration path. You start with the CLI started out, building something simple, a proof of concept get familiar with the graphical schema definition, language that maps onto your resources. Like. And that's ultimately what you want. Right? You want your, the graphical, SDL SDL that you write to to do as much work for you.So that means provisioning infrastructure in the backend and doing Kojin and the front end. Right. That's what, that's the ultimate dream of like do one thing, one source of truth. And it flows both ways. Right. And that's what I think, is. Building towards I'd definitely say it's not perfect.Like, like exactly AWS will never win any awards, but the bar is very low for AWS. Like, all you have to do is to be in better than existing services that AWS has is not trying to win the world's best API for, compared to all the other startups out there. It just has to serve existing AWS customers.Very well. So, so yeah that's kind of my perspective on that. Like, and like the core gen goes all the way down to the front end. So, EDSS has this sorry. Amplify has this idea of the data stores, which is on-device cache of your remote data, which is powered by your graph, your schema.I remember Loren Sands-Ramshaw: [00:33:16] When Twitter figured out that JB amplify a client was based on a public client, but also had a lots of added things like offline. swyx: [00:33:25] Data. Yeah. And th this kind of thing is only possible with strong typing, right? Like w which is essentially what graph provides for you, strong typing of your backend schema.And so once you have that, you can produce a front end replica of that, and then it works offline which is the kind of thing that you basically only possible by vertical integration. And if you don't, if you piece things together yourself, then you're on the hook for building all of that.Which is pretty rough. So like, I just think it's amazing that they want an investment that's going into this. I feel like it's really rough to make easy and get right, because the surface area is massive, but but I think that the vision is correct. I think the vision of like, let's make this graph, Gail schema do everything.Drive make it the source of truth and drive the whole app. And when you do migrations it's very easy to see what to regenerate the clients regenerate the backend infrastructure. That's the way you want to do things. Because if everything's disconnected, then you're essentially doing a lot of things twice.Like, you change the schema. All right. Then you write the resolver then. Alright. Provision the infrastructure, the backend. These can all be done in one step. If you had tight integration any Loren Sands-Ramshaw: [00:34:25] final message you'd like to give to the readers in the graph? Yoga. swyx: [00:34:28] Enjoy the book and ask the authors for coverage of relay.Cause I feel like there's a lot and no fault to you. Like I think graphic equals ecosystem is big enough and you already did a fantastic job of covering all of these things. I just feel like, Apollo is one perspective on what graft Cal could be. And there are very, very smart people that I really, really respect that love relay and I don't know anything about it and I wish I could read more about it.Loren Sands-Ramshaw: [00:34:51] I planned on adding at least a little bit about relay pursuant to your feedback. So thank you for that. And thank you for joining us today, Shawn.swyx: [00:34:58] Yep. Likewise.

FDA 批准抗补体蛋白C5的单克隆抗体治疗视神经脊髓炎Lancet 2020年关于痴呆的预防、干预和护理的报告Nature Medicine 阿尔茨海默病的血液学监测视神经脊髓炎谱系疾病（Neuromyelitis Optica Spectrum Disorder，NMOSD）是中枢神经系统炎症性疾病，特征为严重脱髓鞘和轴突损伤，主要累及视神经和脊髓，但也可以累及脑和脑干。女性发病率可高达男性的10倍，中位发病年龄为32-41岁。典型症状包括：双侧同时或短时间内相继出现的视神经炎（可致视力丧失）、横贯性脊髓炎（可致肢体无力和膀胱功能障碍）、以及最后区综合征（顽固性呃逆或恶心呕吐）。对于视神经脊髓炎急性发作或复发的患者，可使用大剂量激素冲击治疗或血浆置换。因为视神经脊髓炎的自然病程是反复发作、逐步恶化、最终致残，所以患者需尽快开始长期免疫治疗，降低复发风险。可选用的药物包括：硫唑嘌呤、利妥昔单抗、吗替麦考酚酯等。依库珠单抗（eculizumab）依库珠单抗（eculizumab），抗补体蛋白C5单克隆抗体，2019年6月被批准用于治疗水通道蛋白阳性的NMOSD。《PREVENT研究：依库珠单抗治疗水通道蛋白4阳性的、视神经脊髓炎谱系障碍的临床研究》New England Journal of Medicine，2019年8月 (1)这项随机、双盲、对照试验中，143名、水通道蛋白4阳性的、视神经脊髓炎患者，被随机分配接受是静脉依库珠单抗组或安慰剂组。研究过程中，允许患者继续使用稳定剂量免疫抑制治疗。入组前，患者24个月的平均年化复发率为1.99次，76%的患者在试验期间继续接受先前的免疫抑制治疗。随访期间，依库珠单抗组和安慰剂组中，复发的比例分别为3%和43%（P < 0.001）；年复发率分别为0.02和0.35（P < 0.001）；扩大致残状况量表（EDSS）评分的平均变化分别降低了0.18和增加了0.12。依库珠单抗组上呼吸道感染和头痛更常见，有1例患者死于脓胸。结论：在水通道蛋白4阳性的、视神经脊髓炎患者中，依库珠单抗可以显著降低疾病复发率，两组间在残疾进展指标上无显著差异。阿尔茨海默病的预防和治疗阿尔茨海默病（Alzeimer's Disease，AD）的预防包括：（1）生活方式和活动，如身体锻炼、认知训练、教育和认知储备；（2）纠正血管性危险因素，如降压；（3）饮食改变仍有争议，如ω-3脂肪酸、维生素、他汀、地中海饮食。AD的药物治疗包括：（1）胆碱酯酶抑制剂，如多奈哌齐、卡巴拉汀、加兰他敏；（2）NMDA受体拮抗剂，如美金刚；（3）单胺氧化酶抑制剂：司来吉兰；抗氧化剂，如维生素E，仍有争议。非药物治疗：（1）照顾行为障碍的患者；（2）营养支持；（3）认知康复；（4）锻炼计划；（5）技能训练；（6）控制危险因素。《Rush研究：早期生活认知丰富与AD病理改变和认知衰退的关系》JAMA Neurology，2020年10月 (2)早期认知丰富的指标与较慢的认知衰退和晚年痴呆症的减少有关，该研究的目的是探讨早期认知丰富与AD的关系。对参与者进行了平均7.0年的随访，每年进行认知和临床评估。22年间，共有2044名参与者参与，其中1018人死亡，813人的尸检数据。四个早期认知丰富的指标，包括早期社会经济地位、12岁时认知资源的可用性、参与认知刺激活动的频率和早期外语教学。最终纳入分析的813名参与者，死亡时的平均年龄90.1岁，69%为女性。校正年龄、性别和教育水平后的线性回归模型中，较高的早期认知丰富水平与较低的总体AD病理评分相关（P = 0. 01）；较高的早期认知丰富水平与认知下降缓慢相关。通过AD病理改变的间接影响，占早期认知丰富与老年认知能力下降率相关性的20%，80%为直接相关性。结论：早期认知丰富与更好的晚年认知健康有关，部分与AD的病理改变较少有关。《AD队列研究：重复消极性思维与淀粉样蛋白、tau蛋白和认知能力下降有关》Alzheimers & Dementia，2020年7月 (3)重复消极性思维也称为认知固着，主要包括对过往发生的事情的持续反思，重点是产生情绪的思维模式。通常认为重复性消极思维通过多种心理因素增加AD的风险；目前认知债务假说提出重复性消极思维本身就会增加老年痴呆的风险。研究中把重复性消极思维和焦虑症、抑郁症相比较。参与者中292名老年人来自（他们在55岁以上，且父母之一或至少两个兄弟姐妹有AD）。研究通过问卷调查和PET扫描等手段发现，重复性消极性思维与认知能力下降、短期及长期记忆能力下降有显著相关，而且与脑内淀粉样蛋白和Tau蛋白沉积相关。调整了潜在的混杂因素后，关系仍然存在。结论：重复消极性思维与AD早期认知功能下降，以及神经影像学生物标记物相关，未来需探讨改善消极思维是否有预防作用。《健康退休研究：美国中老年人中少量或中度饮酒与认知功能的关系》JAMA Network Open，2020年6月 (4)适量饮酒与认知功能衰退之间有关吗？这一项前瞻性队列研究，从1996年到2008年，共有19887名参与者接受了认知功能测试，他们至少参加了3次两年一次的调查，平均年龄61.8岁，研究随访9.1年。研究评估了参与者的心理状态、单词回忆和词汇量等认知领域的变化轨迹和年变化率，以及总分。根据认知功能的轨迹测量和整个研究期间持续的表现，参与者被分为低认知水平和高认知水平两组。少量或适量饮酒（女性每周饮酒少于8杯，男性每周饮酒少于15杯）与持续的高认知功能轨迹和较低的认知衰退率显著相关。与从不饮酒的人相比，少量到中度饮酒的人中与心理状态、单词记忆、词汇量相关的认知评分更高，各领域的认知能力的下降率更低。而且这种关联在白人参与者中似乎比黑人参与者更强。另外，饮酒剂量与所有参与者的所有认知功能区域呈U形关系，最佳剂量为每周10到14杯。结论：目前中老年人中少量或中度饮酒可能与更好的整体认知功能有关，有必要对其机制进行研究。《REWIND研究：杜拉鲁肽对2型糖尿病认知功能的影响》Lancet Neurology，2020年7月 (5)杜拉鲁肽是一种胰高血糖素样肽-1 (GLP-1)受体激动剂，2014年上市，一周一次皮下注射用于治疗2型糖尿病。该项研究旨在研究杜拉鲁肽与认知障碍之间的关系，这是一项随机、双盲、安慰剂对照试验，参与者年龄>50岁、糖化血红蛋白>9.5%、体重指数>23 kg/m2，共9901人参加，中位随访5.4年。研究使用蒙特利尔认知评估（MoCA）和数字符号替代测试（DSST）评估认知功能。在对个体标准化基线评分进行事后调整后，杜拉鲁肽治疗组患者相比安慰剂，实质性认知障碍的风险降低了14% （p = 0·0018）。结论：长期使用杜拉鲁肽可能减少2型糖尿病患者的认知障碍。《2020年关于痴呆的预防、干预和护理的报告》Lancet，2020年8月 (6)报告认为调节整个生命历程中的12种危险因素或能延缓或预防40%的痴呆病例发生。该报告已经在AD协会国际会议（AAIC 2020）上进行了报告。为了降低罹患痴呆的风险，作者向政策制定者和个人提出了9项积极建议：（1）从40岁左右的中年开始，将收缩压维持在130mmHg及以下；（2）鼓励听力受损者使用助听器，并通过避免强噪声来减轻听力损失；（3）停止吸烟并支持身边人戒烟；（4）为所有儿童提供初等和中等教育；（5）减少中年时期的肥胖；（6）减少糖尿病；（7）减少抑郁症；（8）在中年时期甚至老年时期尽量保持积极的运动和体力劳动；（9）保持社交活动；作者估计，这9种危险因素与35%的痴呆病例发生相关，而在中国40%的病例归因于这些因素；这份报告还把预防建议从9种增加到了12种；（10）减少对于空气污染和二手烟的暴露；（11）防止头部损伤（特别是从事高风险行业和运输行业的人群）；（12）防止酒精滥用并将每周饮酒量摄入量限制在21单位以内。癫痫癫痫是指间隔24小时以上出现2次或2次以上无诱因的癫痫发作的综合征。首次非诱发性癫痫发作的成人中，约1/3将在未来5年内复发。根据电活动的起源分布在大脑的一个局灶区域或同时涉及整个皮质，癫痫可以进一步分为局灶性发作或全面性发作。癫痫的病因可分为遗传性、结构性、代谢性、免疫性、感染性等。大多数癫痫在发作2分钟内自行终止。癫痫的治疗有三个目的：控制癫痫发作、避免治疗副作用和恢复维持生活质量。抗癫痫药分为：（1）影响钙电流的药物，如乙琥胺、加巴喷丁、普瑞巴林和拉考沙胺；（2）影响钠电流的药物，如苯妥英、卡马西平、奥卡西平、艾司利卡西平、卢非酰胺、丙戊酸；（3）同时影响钠通道和钙通道的药物，如唑尼沙胺；（4）影响γ-氨基丁酸（GABA）活性的药物，如苯二氮卓类（氯巴占、氯硝西泮、氯拉卓酸、地西泮和劳拉西泮）、苯巴比妥、扑米酮、噻加宾、氨己烯酸；（5）影响谷氨酸受体的药物，如吡仑帕奈、非尔氨酯和托吡酯；（6）调节突触传递的药物，如左乙拉西坦和布瓦西坦；（7）其他药物，如大麻二酚、拉莫三嗪。耐药性局灶性癫痫可考虑手术治疗：内侧颞叶硬化继发的内侧颞叶癫痫是最常见的可手术治疗的癫痫综合征。最常用的手术操作是前颞叶切除术，一并切除颞极、海马和部分杏仁核。《回顾性队列研究：根据组织病理学诊断癫痫手术后癫痫发作的结果和抗癫痫药物的使用》Lancet Neurology，2020年9月 (7)手术是广泛接受的治疗方案耐药性局灶性癫痫，研究的目的是分析组织病理学和癫痫发作的结果以及癫痫手术后5年的药物自由之间的联系，以改善术前的决策和咨询。这项回顾性、多中心、纵向、队列研究中，纳入欧洲18国37个中心9147例、行癫痫手术的患者。其中，89·5%的患者有至少2年癫痫病史，61·0%的患者有5年的癫痫病史。神经上皮肿瘤、血管畸形和海马硬化引起的轻度癫痫发作患者手术效果最好，术后2年分别有77.5%、74·0%和71·5%的患者没有癫痫复发。局灶性皮质发育不良I型、皮质畸形发育、无病理损伤的患者手术效果最差，术后2年分别有50·0%、52·3%和53.5%的患者没有癫痫复发。术后第一年，Engel1类患者不再服药的比例为0-14%；术后第五年，增加到14-51%。儿童术后不再服药的比例较高；颞叶手术效果较好；癫痫持续时间越长，手术效果越差。结论：组织病理学诊断，手术年龄和癫痫持续时间是癫痫手术结果的重要预后因素。《多中心随机临床试验：意识改变且近期无癫痫发作的危重症成人连续与常规脑电图》JAMA Neurology，2020年10月 (8)在意识改变的危重病人中，连续脑电图（cEEG）可以提高了对癫痫发作的检测，研究的目的是探讨cEEG与常规脑电图（rEEG）是否具有降低死亡率的作用。研究实际招募了Glasgow评分≤11分、反应性完全评分≤12分、近期无癫痫发作的危重症患者。不论是否有基础脑部疾病，被随机分为30~48小时的cEEG和2个20分钟的rEEG。6个月时，cEEG组和rEEG组患者死亡率没有统计学差异（P = 0.85)，多个亚组间的探索性比较后，结果仍没有差异。cEEG与癫痫检出率增加相关（P = 0.004），cEEG也和更频繁的抗癫痫治疗相关（P = 0. 01)。结论：在意识受损且近期无癫痫发作的危重成人患者中，cEEG可提高癫痫发作的检出率，改善抗癫痫治疗，但不改善预后。《ESETT研究：左乙拉西坦、福苯妥英和丙戊酸钠对癫痫持续状态的疗效》Lancet，2020年4月 (9)研究的目的是比较左乙拉西坦、福苯妥英和丙戊酸钠在不同年龄患者中的、癫痫持续状态的有效性和安全性。这项多中心、双盲、疗效适应性、随机对照试验中，招募了≥2岁的、苯二氮卓难治性的、持续性或复发性癫痫患者。根据年龄分组（65岁51人）后，被随机分配到左乙拉西坦、福苯妥英、丙戊酸盐组。在儿童、成人和老年人中，左乙拉西坦组治疗成功率分别为52%、44%和37%；福苯妥因治疗的成功率分别为49%、46%和35%；丙戊酸钠治疗成功率分别为52%、46%和47%。各年龄组药物在疗效或主要安全性方面均无差异。结论：癫痫持续状态的儿童、成人和老年人，对左乙拉西坦、福苯妥英和丙戊酸钠的反应相似，约半数患者的治疗成功。对于苯二氮卓难治性癫痫持续状态，这三种药物中的任何一种都可以被认为是潜在的首选二线药物。阿尔茨海默病（AD）的血液检测多年来，AD的诊断的金标准是尸检中的脑内淀粉样斑块和tau蛋白缠结。淀粉样蛋白和tau蛋白在脑脊液和PET中的生物学标志物已经能够很准确的用于诊断AD，但使用起来仍有局限性。《血磷酸化-tau181蛋白用于AD和额颞叶痴呆的诊断》Nature Medicine，2020年3月 (10)目前认为磷酸化-tau181蛋白有望成为高度特异性的生物标志物，用于AD。加州大学旧金山分校的研究人员检测了血磷酸化-tau181蛋白在临床诊断的、或尸检证实的，AD和额颞叶痴呆患者中的浓度。研究发现AD患者血浆磷酸化-tau181蛋白的浓度较比对照组升高3.5倍，而且可以用于与额颞叶痴呆进行鉴别诊断。在不考虑临床症状的情况下，血磷酸化-tau181蛋白与PET检测β-淀粉样蛋白、皮质tau蛋白沉积相关性很好。结论：血磷酸化-tau181蛋白有望用于ADtau蛋白相关病理的筛查。《血磷酸化-tau181蛋白用于AD的诊断》Lancet Neurology，2020年5月(11)研究旨在评估血液中磷酸化-tau181蛋白用于AD的诊断的价值。研究在四个前瞻性队列中开展，研究对象包括老年痴呆症患者和年龄匹配的对照组。研究发现血磷酸化-tau181蛋白最低的人群包括：β-淀粉样蛋白阴性的认知正常的年轻人和认知正常的老年人。血磷酸化-tau181蛋白最高的人群包括：β-淀粉样蛋白阳性的认知障碍人群和已诊断为AD患者。磷酸化-tau181蛋白能用于区别AD引起的痴呆和其他疾病神经退行性病变引起的痴呆：比如额颞叶痴呆、血管性痴呆、进行性核上性麻痹、皮质基底节综合征、帕金森病或多发性硬化（准确性可以达到81-99%）。同时，血磷酸化-tau181蛋白与PET脑内tau蛋白和和淀粉样蛋白的检测相关性在76-93%；与1年认知能力下降（p=0·0015）和海马萎缩（p=0·015）相关。在人群筛查中，血磷酸化-tau181蛋白可以用于区分青壮年和无认知障碍的老年人，但无法区分轻度认知功能障碍的人群。结论：血磷酸化-tau181蛋白可以预测脑内tau蛋白和淀粉样蛋白的病理变化，与其他神经退行性疾病区分，有望成为筛查、诊断AD的测试。《血磷酸化-tau217蛋白鉴别AD和其他神经退行性疾病的准确性》JAMA，2020年8月 (12)根据这项新的研究发现tau蛋白之一的磷酸化tau217蛋白（p-tau217）的测量可以提供敏感而准确的的淀粉样斑块和tau蛋白缠结的信息，并与阿尔茨海默氏症的诊断相对应。研究对3个队列研究的参与者均进行分别研究（亚利桑那州的神经病理学组群、瑞典BioFINDER-2队列和哥伦比亚常染色体显性AD亲属），主要目的是研究血浆P-tau217对临床或神经病理诊断的AD的鉴别准确性，以及这个检查结果与tau病理相关性。在这3个队列，共1402名参与者中，血磷酸化-tau217蛋白可以用于鉴别阿尔茨海默症和其他神经退行性疾病，其准确性可达到89-98%，明显高于其他血浆和MRI的生物标志物，与基于脑脊液或基于PET的测量结果没有显著差异。在对于有早发AD家族史的的患者中，600名参与者有60%携带PSEN1基因突变，不携带基因突变的参与者的磷酸化tau217蛋白浓度为1.9pg/ml，携带基因突变但认知功能正常的参与者升高至4.5pg/ml，携带基因突变同时出现认知功能障碍的参与者高达16.8pg/ml；而且，携带基因突变的参与者25岁时就会出现磷酸化tau-217蛋白显著升高，比出现症状早了20年。结论：这一项大型国际研究发现的新型血液测试最早可以在认知障碍发病前20年预测阿尔茨海默氏症。 参考文献1.Pittock SJ, Berthele A, Fujihara K, Kim HJ, Levy M, Palace J, et al. Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019;381(7):614-25.2.Oveisgharan S, Wilson RS, Yu L, Schneider JA, Bennett DA. Association of Early-Life Cognitive Enrichment With Alzheimer Disease Pathological Changes and Cognitive Decline. JAMA Neurol. 2020.3.Marchant NL, Lovland LR, Jones R, Pichet Binette A, Gonneaud J, Arenaza-Urquijo EM, et al. Repetitive negative thinking is associated with amyloid, tau, and cognitive decline. Alzheimers Dement. 2020;16(7):1054-64.4.Zhang R, Shen L, Miles T, Shen Y, Cordero J, Qi Y, et al. Association of Low to Moderate Alcohol Drinking With Cognitive Functions From Middle to Older Age Among US Adults. JAMA Netw Open. 2020;3(6):e207922-e.5.Cukierman-Yaffe T, Gerstein HC, Colhoun HM, Diaz R, García-Pérez LE, Lakshmanan M, et al. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. Lancet Neurol. 2020;19(7):582-90.6.Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet. 2020;396(10248):413-46.7.Lamberink HJ, Otte WM, Blümcke I, Braun KPJ, Aichholzer M, Amorim I, et al. Seizure outcome and use of antiepileptic drugs after epilepsy surgery according to histopathological diagnosis: a retrospective multicentre cohort study. The Lancet Neurology. 2020;19(9):748-57.8.Rossetti AO, Schindler K, Sutter R, Ruegg S, Zubler F, Novy J, et al. Continuous vs Routine Electroencephalogram in Critically Ill Adults With Altered Consciousness and No Recent Seizure: A Multicenter Randomized Clinical Trial. JAMA Neurol. 2020.9.Chamberlain JM, Kapur J, Shinnar S, Elm J, Holsti M, Babcock L, et al. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial. The Lancet. 2020;395(10231):1217-24.10.Thijssen EH, La Joie R, Wolf A, Strom A, Wang P, Iaccarino L, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nature Medicine. 2020;26(3):387-97.11.Karikari TK, Pascoal TA, Ashton NJ, Janelidze S, Benedet AL, Rodriguez JL, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020;19(5):422-33.12.Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, et al. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020.

FDA 批准抗补体蛋白C5的单克隆抗体治疗视神经脊髓炎Lancet 2020年关于痴呆的预防、干预和护理的报告Nature Medicine 阿尔茨海默病的血液学监测视神经脊髓炎谱系疾病（Neuromyelitis Optica Spectrum Disorder，NMOSD）是中枢神经系统炎症性疾病，特征为严重脱髓鞘和轴突损伤，主要累及视神经和脊髓，但也可以累及脑和脑干。女性发病率可高达男性的10倍，中位发病年龄为32-41岁。典型症状包括：双侧同时或短时间内相继出现的视神经炎（可致视力丧失）、横贯性脊髓炎（可致肢体无力和膀胱功能障碍）、以及最后区综合征（顽固性呃逆或恶心呕吐）。对于视神经脊髓炎急性发作或复发的患者，可使用大剂量激素冲击治疗或血浆置换。因为视神经脊髓炎的自然病程是反复发作、逐步恶化、最终致残，所以患者需尽快开始长期免疫治疗，降低复发风险。可选用的药物包括：硫唑嘌呤、利妥昔单抗、吗替麦考酚酯等。依库珠单抗（eculizumab）依库珠单抗（eculizumab），抗补体蛋白C5单克隆抗体，2019年6月被批准用于治疗水通道蛋白阳性的NMOSD。《PREVENT研究：依库珠单抗治疗水通道蛋白4阳性的、视神经脊髓炎谱系障碍的临床研究》New England Journal of Medicine，2019年8月 (1)这项随机、双盲、对照试验中，143名、水通道蛋白4阳性的、视神经脊髓炎患者，被随机分配接受是静脉依库珠单抗组或安慰剂组。研究过程中，允许患者继续使用稳定剂量免疫抑制治疗。入组前，患者24个月的平均年化复发率为1.99次，76%的患者在试验期间继续接受先前的免疫抑制治疗。随访期间，依库珠单抗组和安慰剂组中，复发的比例分别为3%和43%（P < 0.001）；年复发率分别为0.02和0.35（P < 0.001）；扩大致残状况量表（EDSS）评分的平均变化分别降低了0.18和增加了0.12。依库珠单抗组上呼吸道感染和头痛更常见，有1例患者死于脓胸。结论：在水通道蛋白4阳性的、视神经脊髓炎患者中，依库珠单抗可以显著降低疾病复发率，两组间在残疾进展指标上无显著差异。阿尔茨海默病的预防和治疗阿尔茨海默病（Alzeimer's Disease，AD）的预防包括：（1）生活方式和活动，如身体锻炼、认知训练、教育和认知储备；（2）纠正血管性危险因素，如降压；（3）饮食改变仍有争议，如ω-3脂肪酸、维生素、他汀、地中海饮食。AD的药物治疗包括：（1）胆碱酯酶抑制剂，如多奈哌齐、卡巴拉汀、加兰他敏；（2）NMDA受体拮抗剂，如美金刚；（3）单胺氧化酶抑制剂：司来吉兰；抗氧化剂，如维生素E，仍有争议。非药物治疗：（1）照顾行为障碍的患者；（2）营养支持；（3）认知康复；（4）锻炼计划；（5）技能训练；（6）控制危险因素。《Rush研究：早期生活认知丰富与AD病理改变和认知衰退的关系》JAMA Neurology，2020年10月 (2)早期认知丰富的指标与较慢的认知衰退和晚年痴呆症的减少有关，该研究的目的是探讨早期认知丰富与AD的关系。对参与者进行了平均7.0年的随访，每年进行认知和临床评估。22年间，共有2044名参与者参与，其中1018人死亡，813人的尸检数据。四个早期认知丰富的指标，包括早期社会经济地位、12岁时认知资源的可用性、参与认知刺激活动的频率和早期外语教学。最终纳入分析的813名参与者，死亡时的平均年龄90.1岁，69%为女性。校正年龄、性别和教育水平后的线性回归模型中，较高的早期认知丰富水平与较低的总体AD病理评分相关（P = 0. 01）；较高的早期认知丰富水平与认知下降缓慢相关。通过AD病理改变的间接影响，占早期认知丰富与老年认知能力下降率相关性的20%，80%为直接相关性。结论：早期认知丰富与更好的晚年认知健康有关，部分与AD的病理改变较少有关。《AD队列研究：重复消极性思维与淀粉样蛋白、tau蛋白和认知能力下降有关》Alzheimers & Dementia，2020年7月 (3)重复消极性思维也称为认知固着，主要包括对过往发生的事情的持续反思，重点是产生情绪的思维模式。通常认为重复性消极思维通过多种心理因素增加AD的风险；目前认知债务假说提出重复性消极思维本身就会增加老年痴呆的风险。研究中把重复性消极思维和焦虑症、抑郁症相比较。参与者中292名老年人来自（他们在55岁以上，且父母之一或至少两个兄弟姐妹有AD）。研究通过问卷调查和PET扫描等手段发现，重复性消极性思维与认知能力下降、短期及长期记忆能力下降有显著相关，而且与脑内淀粉样蛋白和Tau蛋白沉积相关。调整了潜在的混杂因素后，关系仍然存在。结论：重复消极性思维与AD早期认知功能下降，以及神经影像学生物标记物相关，未来需探讨改善消极思维是否有预防作用。《健康退休研究：美国中老年人中少量或中度饮酒与认知功能的关系》JAMA Network Open，2020年6月 (4)适量饮酒与认知功能衰退之间有关吗？这一项前瞻性队列研究，从1996年到2008年，共有19887名参与者接受了认知功能测试，他们至少参加了3次两年一次的调查，平均年龄61.8岁，研究随访9.1年。研究评估了参与者的心理状态、单词回忆和词汇量等认知领域的变化轨迹和年变化率，以及总分。根据认知功能的轨迹测量和整个研究期间持续的表现，参与者被分为低认知水平和高认知水平两组。少量或适量饮酒（女性每周饮酒少于8杯，男性每周饮酒少于15杯）与持续的高认知功能轨迹和较低的认知衰退率显著相关。与从不饮酒的人相比，少量到中度饮酒的人中与心理状态、单词记忆、词汇量相关的认知评分更高，各领域的认知能力的下降率更低。而且这种关联在白人参与者中似乎比黑人参与者更强。另外，饮酒剂量与所有参与者的所有认知功能区域呈U形关系，最佳剂量为每周10到14杯。结论：目前中老年人中少量或中度饮酒可能与更好的整体认知功能有关，有必要对其机制进行研究。《REWIND研究：杜拉鲁肽对2型糖尿病认知功能的影响》Lancet Neurology，2020年7月 (5)杜拉鲁肽是一种胰高血糖素样肽-1 (GLP-1)受体激动剂，2014年上市，一周一次皮下注射用于治疗2型糖尿病。该项研究旨在研究杜拉鲁肽与认知障碍之间的关系，这是一项随机、双盲、安慰剂对照试验，参与者年龄>50岁、糖化血红蛋白>9.5%、体重指数>23 kg/m2，共9901人参加，中位随访5.4年。研究使用蒙特利尔认知评估（MoCA）和数字符号替代测试（DSST）评估认知功能。在对个体标准化基线评分进行事后调整后，杜拉鲁肽治疗组患者相比安慰剂，实质性认知障碍的风险降低了14% （p = 0·0018）。结论：长期使用杜拉鲁肽可能减少2型糖尿病患者的认知障碍。《2020年关于痴呆的预防、干预和护理的报告》Lancet，2020年8月 (6)报告认为调节整个生命历程中的12种危险因素或能延缓或预防40%的痴呆病例发生。该报告已经在AD协会国际会议（AAIC 2020）上进行了报告。为了降低罹患痴呆的风险，作者向政策制定者和个人提出了9项积极建议：（1）从40岁左右的中年开始，将收缩压维持在130mmHg及以下；（2）鼓励听力受损者使用助听器，并通过避免强噪声来减轻听力损失；（3）停止吸烟并支持身边人戒烟；（4）为所有儿童提供初等和中等教育；（5）减少中年时期的肥胖；（6）减少糖尿病；（7）减少抑郁症；（8）在中年时期甚至老年时期尽量保持积极的运动和体力劳动；（9）保持社交活动；作者估计，这9种危险因素与35%的痴呆病例发生相关，而在中国40%的病例归因于这些因素；这份报告还把预防建议从9种增加到了12种；（10）减少对于空气污染和二手烟的暴露；（11）防止头部损伤（特别是从事高风险行业和运输行业的人群）；（12）防止酒精滥用并将每周饮酒量摄入量限制在21单位以内。癫痫癫痫是指间隔24小时以上出现2次或2次以上无诱因的癫痫发作的综合征。首次非诱发性癫痫发作的成人中，约1/3将在未来5年内复发。根据电活动的起源分布在大脑的一个局灶区域或同时涉及整个皮质，癫痫可以进一步分为局灶性发作或全面性发作。癫痫的病因可分为遗传性、结构性、代谢性、免疫性、感染性等。大多数癫痫在发作2分钟内自行终止。癫痫的治疗有三个目的：控制癫痫发作、避免治疗副作用和恢复维持生活质量。抗癫痫药分为：（1）影响钙电流的药物，如乙琥胺、加巴喷丁、普瑞巴林和拉考沙胺；（2）影响钠电流的药物，如苯妥英、卡马西平、奥卡西平、艾司利卡西平、卢非酰胺、丙戊酸；（3）同时影响钠通道和钙通道的药物，如唑尼沙胺；（4）影响γ-氨基丁酸（GABA）活性的药物，如苯二氮卓类（氯巴占、氯硝西泮、氯拉卓酸、地西泮和劳拉西泮）、苯巴比妥、扑米酮、噻加宾、氨己烯酸；（5）影响谷氨酸受体的药物，如吡仑帕奈、非尔氨酯和托吡酯；（6）调节突触传递的药物，如左乙拉西坦和布瓦西坦；（7）其他药物，如大麻二酚、拉莫三嗪。耐药性局灶性癫痫可考虑手术治疗：内侧颞叶硬化继发的内侧颞叶癫痫是最常见的可手术治疗的癫痫综合征。最常用的手术操作是前颞叶切除术，一并切除颞极、海马和部分杏仁核。《回顾性队列研究：根据组织病理学诊断癫痫手术后癫痫发作的结果和抗癫痫药物的使用》Lancet Neurology，2020年9月 (7)手术是广泛接受的治疗方案耐药性局灶性癫痫，研究的目的是分析组织病理学和癫痫发作的结果以及癫痫手术后5年的药物自由之间的联系，以改善术前的决策和咨询。这项回顾性、多中心、纵向、队列研究中，纳入欧洲18国37个中心9147例、行癫痫手术的患者。其中，89·5%的患者有至少2年癫痫病史，61·0%的患者有5年的癫痫病史。神经上皮肿瘤、血管畸形和海马硬化引起的轻度癫痫发作患者手术效果最好，术后2年分别有77.5%、74·0%和71·5%的患者没有癫痫复发。局灶性皮质发育不良I型、皮质畸形发育、无病理损伤的患者手术效果最差，术后2年分别有50·0%、52·3%和53.5%的患者没有癫痫复发。术后第一年，Engel1类患者不再服药的比例为0-14%；术后第五年，增加到14-51%。儿童术后不再服药的比例较高；颞叶手术效果较好；癫痫持续时间越长，手术效果越差。结论：组织病理学诊断，手术年龄和癫痫持续时间是癫痫手术结果的重要预后因素。《多中心随机临床试验：意识改变且近期无癫痫发作的危重症成人连续与常规脑电图》JAMA Neurology，2020年10月 (8)在意识改变的危重病人中，连续脑电图（cEEG）可以提高了对癫痫发作的检测，研究的目的是探讨cEEG与常规脑电图（rEEG）是否具有降低死亡率的作用。研究实际招募了Glasgow评分≤11分、反应性完全评分≤12分、近期无癫痫发作的危重症患者。不论是否有基础脑部疾病，被随机分为30~48小时的cEEG和2个20分钟的rEEG。6个月时，cEEG组和rEEG组患者死亡率没有统计学差异（P = 0.85)，多个亚组间的探索性比较后，结果仍没有差异。cEEG与癫痫检出率增加相关（P = 0.004），cEEG也和更频繁的抗癫痫治疗相关（P = 0. 01)。结论：在意识受损且近期无癫痫发作的危重成人患者中，cEEG可提高癫痫发作的检出率，改善抗癫痫治疗，但不改善预后。《ESETT研究：左乙拉西坦、福苯妥英和丙戊酸钠对癫痫持续状态的疗效》Lancet，2020年4月 (9)研究的目的是比较左乙拉西坦、福苯妥英和丙戊酸钠在不同年龄患者中的、癫痫持续状态的有效性和安全性。这项多中心、双盲、疗效适应性、随机对照试验中，招募了≥2岁的、苯二氮卓难治性的、持续性或复发性癫痫患者。根据年龄分组（65岁51人）后，被随机分配到左乙拉西坦、福苯妥英、丙戊酸盐组。在儿童、成人和老年人中，左乙拉西坦组治疗成功率分别为52%、44%和37%；福苯妥因治疗的成功率分别为49%、46%和35%；丙戊酸钠治疗成功率分别为52%、46%和47%。各年龄组药物在疗效或主要安全性方面均无差异。结论：癫痫持续状态的儿童、成人和老年人，对左乙拉西坦、福苯妥英和丙戊酸钠的反应相似，约半数患者的治疗成功。对于苯二氮卓难治性癫痫持续状态，这三种药物中的任何一种都可以被认为是潜在的首选二线药物。阿尔茨海默病（AD）的血液检测多年来，AD的诊断的金标准是尸检中的脑内淀粉样斑块和tau蛋白缠结。淀粉样蛋白和tau蛋白在脑脊液和PET中的生物学标志物已经能够很准确的用于诊断AD，但使用起来仍有局限性。《血磷酸化-tau181蛋白用于AD和额颞叶痴呆的诊断》Nature Medicine，2020年3月 (10)目前认为磷酸化-tau181蛋白有望成为高度特异性的生物标志物，用于AD。加州大学旧金山分校的研究人员检测了血磷酸化-tau181蛋白在临床诊断的、或尸检证实的，AD和额颞叶痴呆患者中的浓度。研究发现AD患者血浆磷酸化-tau181蛋白的浓度较比对照组升高3.5倍，而且可以用于与额颞叶痴呆进行鉴别诊断。在不考虑临床症状的情况下，血磷酸化-tau181蛋白与PET检测β-淀粉样蛋白、皮质tau蛋白沉积相关性很好。结论：血磷酸化-tau181蛋白有望用于ADtau蛋白相关病理的筛查。《血磷酸化-tau181蛋白用于AD的诊断》Lancet Neurology，2020年5月(11)研究旨在评估血液中磷酸化-tau181蛋白用于AD的诊断的价值。研究在四个前瞻性队列中开展，研究对象包括老年痴呆症患者和年龄匹配的对照组。研究发现血磷酸化-tau181蛋白最低的人群包括：β-淀粉样蛋白阴性的认知正常的年轻人和认知正常的老年人。血磷酸化-tau181蛋白最高的人群包括：β-淀粉样蛋白阳性的认知障碍人群和已诊断为AD患者。磷酸化-tau181蛋白能用于区别AD引起的痴呆和其他疾病神经退行性病变引起的痴呆：比如额颞叶痴呆、血管性痴呆、进行性核上性麻痹、皮质基底节综合征、帕金森病或多发性硬化（准确性可以达到81-99%）。同时，血磷酸化-tau181蛋白与PET脑内tau蛋白和和淀粉样蛋白的检测相关性在76-93%；与1年认知能力下降（p=0·0015）和海马萎缩（p=0·015）相关。在人群筛查中，血磷酸化-tau181蛋白可以用于区分青壮年和无认知障碍的老年人，但无法区分轻度认知功能障碍的人群。结论：血磷酸化-tau181蛋白可以预测脑内tau蛋白和淀粉样蛋白的病理变化，与其他神经退行性疾病区分，有望成为筛查、诊断AD的测试。《血磷酸化-tau217蛋白鉴别AD和其他神经退行性疾病的准确性》JAMA，2020年8月 (12)根据这项新的研究发现tau蛋白之一的磷酸化tau217蛋白（p-tau217）的测量可以提供敏感而准确的的淀粉样斑块和tau蛋白缠结的信息，并与阿尔茨海默氏症的诊断相对应。研究对3个队列研究的参与者均进行分别研究（亚利桑那州的神经病理学组群、瑞典BioFINDER-2队列和哥伦比亚常染色体显性AD亲属），主要目的是研究血浆P-tau217对临床或神经病理诊断的AD的鉴别准确性，以及这个检查结果与tau病理相关性。在这3个队列，共1402名参与者中，血磷酸化-tau217蛋白可以用于鉴别阿尔茨海默症和其他神经退行性疾病，其准确性可达到89-98%，明显高于其他血浆和MRI的生物标志物，与基于脑脊液或基于PET的测量结果没有显著差异。在对于有早发AD家族史的的患者中，600名参与者有60%携带PSEN1基因突变，不携带基因突变的参与者的磷酸化tau217蛋白浓度为1.9pg/ml，携带基因突变但认知功能正常的参与者升高至4.5pg/ml，携带基因突变同时出现认知功能障碍的参与者高达16.8pg/ml；而且，携带基因突变的参与者25岁时就会出现磷酸化tau-217蛋白显著升高，比出现症状早了20年。结论：这一项大型国际研究发现的新型血液测试最早可以在认知障碍发病前20年预测阿尔茨海默氏症。 参考文献1.Pittock SJ, Berthele A, Fujihara K, Kim HJ, Levy M, Palace J, et al. Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019;381(7):614-25.2.Oveisgharan S, Wilson RS, Yu L, Schneider JA, Bennett DA. Association of Early-Life Cognitive Enrichment With Alzheimer Disease Pathological Changes and Cognitive Decline. JAMA Neurol. 2020.3.Marchant NL, Lovland LR, Jones R, Pichet Binette A, Gonneaud J, Arenaza-Urquijo EM, et al. Repetitive negative thinking is associated with amyloid, tau, and cognitive decline. Alzheimers Dement. 2020;16(7):1054-64.4.Zhang R, Shen L, Miles T, Shen Y, Cordero J, Qi Y, et al. Association of Low to Moderate Alcohol Drinking With Cognitive Functions From Middle to Older Age Among US Adults. JAMA Netw Open. 2020;3(6):e207922-e.5.Cukierman-Yaffe T, Gerstein HC, Colhoun HM, Diaz R, García-Pérez LE, Lakshmanan M, et al. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial. Lancet Neurol. 2020;19(7):582-90.6.Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. The Lancet. 2020;396(10248):413-46.7.Lamberink HJ, Otte WM, Blümcke I, Braun KPJ, Aichholzer M, Amorim I, et al. Seizure outcome and use of antiepileptic drugs after epilepsy surgery according to histopathological diagnosis: a retrospective multicentre cohort study. The Lancet Neurology. 2020;19(9):748-57.8.Rossetti AO, Schindler K, Sutter R, Ruegg S, Zubler F, Novy J, et al. Continuous vs Routine Electroencephalogram in Critically Ill Adults With Altered Consciousness and No Recent Seizure: A Multicenter Randomized Clinical Trial. JAMA Neurol. 2020.9.Chamberlain JM, Kapur J, Shinnar S, Elm J, Holsti M, Babcock L, et al. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial. The Lancet. 2020;395(10231):1217-24.10.Thijssen EH, La Joie R, Wolf A, Strom A, Wang P, Iaccarino L, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nature Medicine. 2020;26(3):387-97.11.Karikari TK, Pascoal TA, Ashton NJ, Janelidze S, Benedet AL, Rodriguez JL, et al. Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts. Lancet Neurol. 2020;19(5):422-33.12.Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, et al. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020.

Diese Folge widme ich dem EDSS-Wert (Expanded Disability Status Scale), den Status der Einschränkungen der funktionellen Systeme. Damit können Neurologen beurteilen, wie stark die MS das Leben einer Person beeinträchtigt oder auch nicht.  EDSS ganz exakt Wenn du genau nachlesen willst, empfehle ich dir die folgenden beiden Seiten auf Neurologienetzwerk.de: Funktionelle Systeme zur Errechnung des EDSS EDSS - Übersicht der Stufen von 0.0 bis 10.0 In der Podcastfolge und dem dazugehörigen Blogbeitrag auf www.ms-perspektive.de habe ich versucht, das Ganze vereinfacht darzustellen. Folgende Punkte werden im Beitrag besprochen: Einblicke in die EDSS Bewertung (inklusive Beispielen für alle acht Funktionsbereiche) Pyramidenbahn Kleinhirn Hirnstamm Sensorium Blasen- und Mastdarmfunktionen Sehfunktionen Zerebrale Funktionen Gehfähigkeit Auswertung der EDSS Viel Spaß beim Hören und bestmögliche Gesundheit wünscht dir, Nele PS: Du kannst dich auch für meinen kostenlosen Newsletter anmelden, um mehr Infos und positive Impulse rund um die Multiple Sklerose zu erhalten. ---------- Im MS Perspektive Podcast stelle ich dir meine Sichtweise auf die Multiple Sklerose vor und wie du das beste aus der Diagnose machen kannst. Denn ein schönes und erfülltes Leben ist auch mit einer chronischen Autoimmunerkrankung wie Multipler Sklerose möglich. Hier findest du Informationen und Strategien, wie du aktiv Einfluss nehmen kannst. Ich will dir Mut machen und zeigen, was du alles selbst in der Hand hast. Dazu veröffentliche ich Solobeiträge mit meinen Erfahrungen zur Basistherapie, zur Ernährung, zum Reisen, Arbeiten und der Familienplanung. Außerdem interviewe ich Experten zu verschiedensten Themen rund um ein Leben mit MS. Und einige Folgen dienen der puren Entspannung, die in jedem Leben einen wichtigen Platz einnehmen sollte.

Last week, the National MS Society and RealTalk MS announced a new partnership. And we're definitely talking about it!     My guest is Dr. Soha Saleh, a research scientist at Kessler Foundation's Center for Mobility and Rehabilitation Engineering Research, and we're talking about her innovative research in understanding how MS impacts dual-tasking -- something that all of us do, all day long.   We'll tell you about the newly announced Weill Neurohub, and why that's such promising news for people affected by MS.   We're also talking about the price of Vumerity, the new oral disease-modifying therapy, and suggesting some of the things to keep in mind as we consider steps to ensure that everyone living with MS has access to affordable prescription medications.   And we'll tell you about the alternative to EDSS that's been proposed by the Multiple Sclerosis Outcome Assessments Consortium.   We have a lot to talk about! Are you ready for RealTalk MS??! ___________   A BIG Announcement About RealTalk MS!   1:19 Introducing the Weill Neurohub  3:36 The Price of Vumerity    5:47 An Alternative to EDSS Has Been Proposed   9:58 My Interview with Dr. Soha Saleh  13:49 How to Subscribe to RealTalk MS, Download the RealTalk MS App, or Listen with Alexa  29:31 ___________ SHARE THIS EPISODE OF REALTALK MS Just copy this link & paste it into your text or email:  https://realtalkms.com/116 ___________ ADD YOUR VOICE TO THE CONVERSATION I've always thought about the RealTalk MS podcast as a conversation. And this is your opportunity to join the conversation by sharing your feedback, questions, and suggestions for topics that we can discuss in future podcast episodes. Please shoot me an email or call the RealTalk MS Listener Hotline and share your thoughts! Email: jon@realtalkms.comPhone: (310) 526-2283 ___________ LINKS If your podcast app doesn't allow you to click on these links, you'll find them in the show notes in the RealTalk MS app or at www.RealTalkMS.com Give RealTalk MS a Rating & Review  The National MS Society & RealTalk MS Announce a Partnership The Weill Neurohub Evaluation of Multiple Sclerosis Disability Outcome Measures Using Pooled Clinical Trial Data The Kessler Foundation Center for Mobility and Rehabilitation Engineering Research Give RealTalk MS a Rating & Review  Download the RealTalk MS App for iOS Download the RealTalk MS App for Android ___________ Follow RealTalk MS on Twitter, @RealTalkMS_jon, and subscribe to our newsletter at our website, RealTalkMS.com. RealTalk MS Episode 116 Hosted By: Jon Strum Guests: Dr. Soha Saleh Tags: MS, MultipleSclerosis, MSResearch, MSSociety, KesslerFdn, RealTalkMS Privacy Policy

In this episode of The MS Gym Podcast, the host becomes the guest, when comedic actor and MSr, Damian Washington, interviews Brooke Slick about HSCT (hematopoietic stem cell transplant) for MS. Brooke, a 6+ year veteran of the treatment, explains what HSCT is, how it works, who it's for, where you can get it done and why it's currently considered your best chance at halting your disease progression. In addition to this podcast episode, starting next week, you will be able to hear portions of this interview on Damian Washington's weekly YouTube vlog (link below) where he chronicles his journey with MS and Ocrevus as  well as discusses a plethora of MS lifestyle topics. It's important to note that although HSCT has continued to gain exposure recently, the MS Gym was way ahead of the game when over 2 years ago, Coach Trevor Wicken designed a 30-day "Rebuild" program that's designed specifically for HSCT veterans and available in the membership. EPISODE NOTES: - What is HSCT? - The logistics of HSCT - The role stem cells play in HSCT? - The two types of HSCT protocols - It's all about the chemotherapy - Safety precautions after HSCT - Symptomatic improvements - Criteria for acceptance - What is EDSS and why it matters? - DMDs slow disease progression. HSCT halts disease progression. - How long should you wait to get HSCT? - Recovery & expectations - Statistics/success rates - Does insurance cover it? - The cost - Mortality rates - The best online resources for HSCT information Damian Washington's Weekly Vlog on Multiple Sclerosis: https://www.youtube.com/user/DigitalRidiculous Brooke Slick - https://brookeslick.com/ The MS Gym - http//www.themsgym.com/ HSCT Resources: General HSCT Facebook Group https://www.facebook.com/groups/hsctworldwide/ Russia HSCT Facebook Group https://www.facebook.com/groups/404629779644453/ Mexico HSCT Facebook Group https://www.facebook.com/groups/mexicohsct/

If someone is being treated for MS, their neurologist is using the Expanded Disability Status Score, or EDSS, to indicate their level of disability. What if there were a better, easier, and more accurate way to measure mobility and evaluate disability?      My guest today is Dr. Valerie Block, a Postdoctoral Fellow in the Department of Neurology at University of California San Francisco.  As a physical therapist, Dr. Block is focused on MS rehabilitation. And we're talking about a just-published study that demonstrates that the way neurologists measure disability may not be providing a complete and accurate picture...and there may be a much better way to get that done.   We're also talking about a new effort to eliminate the Affordable Care Act and strip away all of its protections for people living with MS and every other chronic illness -- and how the National MS Society and 25 other national patient organizations are fighting back by supporting new legislation designed to strengthen the ACA.    We'll tell you about the TWO!!! MS prescription medications that just received FDA approval, and we'll even tell you about yet another MS prescription medication that's now awaiting FDA approval.   We have a lot to talk about! Are you ready for RealTalk MS?!   ___________ RealTalk MS Reaches a Milestone  :26 Join the RealTalk MS Conversation  :48 Living with MS? Your Access to Healthcare is Under Attack ...Again!  2:53 Mavenclad Receives FDA Approval for Treating Relapsing-Remitting and Active Secondary Progressive MS  11:37 Siponimod Receives FDA Approval for Treating Relapsing-Remitting and Active Secondary Progressive MS 15:01 Celgene Submits Application for FDA Approval of Ozanimod for Treating Relapsing-Remitting MS  16:41 My Interview with Dr. Valerie Block  19:16 Download the Free RealTalk MS App  34:04 ___________ ADD YOUR VOICE TO THE CONVERSATION I've always thought about the RealTalk MS podcast as a conversation. And this is your opportunity to join the conversation by sharing your feedback, questions, and suggestions for topics that we can discuss in future podcast episodes. Please shoot me an email or call the RealTalk MS Listener Hotline and share your thoughts! Email: jonstrum@RealTalkMS.comPhone: (310) 526-2283 ___________ LINKS If your podcast app doesn't allow you to click on these links, you'll find them in the show notes in the RealTalk MS app or at www.RealTalkMS.com Download the RealTalk MS App for iOS Download the RealTalk MS App for Android Give RealTalk MS a Rating & Review 26 Patient Groups Support Bill to Stabilize and Strengthen the Affordable Care Act   FDA Approves New Oral Treatment for Multiple Sclerosis   FDA Approves New Oral Drug to Treat Multiple Sclerosis ___________ Follow RealTalk MS on Twitter, @RealTalkMS_jon, and subscribe to our newsletter at our website, RealTalkMS.com. RealTalk MS Episode 84 Hosted By: Jon Strum Guest: Dr. Valerie Block Tags: MS, MultipleSclerosis, MSResearch, ProgressiveMS, Mavenclad, EMDSerono, Siponimod, Novartis, Celgene, RealTalkMS

Two interesting stories. The first comes from Jesse M. who, on purpose, tells and obnoxiously long story about an encounter in a Vegas bathroom. Ken, on the other hand, starts thinking about his regrets and the mistakes he's made and ends up owning his mistakes because they lead him to where he is today.

Regret was the theme and Jonathan talks about his lack of regret and Alex tells a story of paint a grumpy old man's house. Turns out that the old man had a reason to be grumpy.

[intro music]   Host – Dan Keller Hello, and welcome to Episode Ninety-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller.   Today's interview features a conversation with Dr. Shiv Saidha, an associate professor of neurology in the Division of Neuroimmunology and Neuro-infectious Diseases at Johns Hopkins University in Baltimore, Maryland. His work has focused on the retina in MS, using the technique of optical coherence tomography, or OCT, to follow the disease, assess and monitor therapeutic strategies, and to better understand the pathobiology of MS. I asked him why the retina is of interest in MS and about the utility of OCT.   Interviewee – Shiv Saidha OCT is the optical analogue of ultrasound B mode imaging. And it's a noninvasive technique that has a lot of utility in quantifying the ultrastructure of various tissues, including the retina. We have a lot of interest in being able to quantify retinal structures specifically in multiple sclerosis because optic nerve pathology, which basically refers to affliction of the optic nerve as part of the MS disease process, is virtually ubiquitous. At the time of postmortem examination of MS patients, 94 to 99% of MS patients are found to have demyelinating plaques within their optic nerves.   So the premise is that demyelination within the optic nerve results in retrograde degeneration of the constituent fibers or axons within the optic nerve. And since those axons or fibers are derived from the retinal nerve fiber layer, which is the innermost layer of the retina, this layer is felt to thin out as part of the MS disease process. Additionally, the neurons – referred to as ganglion cell neurons located in the ganglion cell layer immediately below the retinal nerve fiber layer from which retinal nerve fiber layer axons are derived – are also thought to drop out as part of the MS disease process.   We traditionally conceptualize optic nerve pathology in MS as being an acute phenomenon, namely acute optic neuritis, which does occur in up to, you know, 20 to 70% of MS patients; and in 20 to 25% of cases of MS is the initial hallmark clinical manifestation of the disease process. But beyond acute optic neuritis, there is subclinical optic nerve pathology, which we refer to as subclinical optic neuropathy ongoing within the optic nerves of MS patients.   And so, if we had a technique or an ability to accurately quantify the effects of optic nerve pathology or optic neuropathy – in other words, if we had a way to quantify retinal nerve fiber layer thickness and thickness of ganglion cell…the layer within which ganglion cell neurons are located in the retina – that would provide a substrate or insight into the state or integrity of the optic nerve. And so, optical coherence tomography is a technique which allows us to do this. It allows us to measure thickness of the retinal nerve fiber layer not just around the optic disk which we refer to as the peripapillary retinal nerve fiber layer but also in the macular region.   And with the advent of novel segmentation techniques in OCT – many of which are now commercially available – we now are also afforded the capability of quantifying thickness of other discrete retinal layers such as the combined thickness of the ganglion cell layer and inner plexiform layer, which many of us refer to as GCIP or some also refer to it as GCIPL. Conventionally, peripapillary retinal nerve fiber layer thickness – at least in cross-sectional studies – was found to be associated with high and low contrast visual function, as might be expected since the retina subserves vision as a function.   But interestingly, early studies even found that thickness of the peripapillary retinal nerve fiber layer was associated with disability scores as determined by Expanded Disability Status Scale scores or EDSS scores in MS patients, as well as whole brain volume in MS patients, implying that these metrics derived from OCT somehow provide a window or insight into the global MS disease process. With time, we started to realize that the GCIP thickness might actually be an even more powerful measure of the state of integrity of the optic nerve.   GCIP thickness seems to be more reproducible than that of the retinal nerve fiber layer. It has a intraclass correlation coefficient of about 0.99 with a very tight confidence interval. It has superior structure function correlations with EDSS scores, brain volumes, as well as high and low contrast visual function, as compared to retinal nerve fiber layer thickness. This is really a very interesting and important point about, you know, the potential utility of OCT. Because with this thickness of the GCIP, what we were really getting is a very good estimate of neuronal integrity.   And, one of the factors that has been limited in terms of MRI – or magnetic resonance imaging – is the ability to really accurately and reproducibly quantify collections of axons and neurons. Now in terms of MRI, we often think that the white matter is a very good reflection of axonal integrity, and that gray matter is a good reflection of neuronal integrity. This is not necessarily the case, however. In terms of the white matter, quite a lot of inflammation obviously occurs within the white matter in MS brains. And when that inflammation occurs, white matter volume increases. And then, as that inflammation subsides, the white matter volume drops.   And then, as the next wave of inflammation comes in, again, there's swelling and the white matter volume goes up. And as it resolves, the white matter volume comes down. And so there's this waxing and waning in terms of white matter volume which limits the utility of white matter volume. And in fact, it's for that particular reason that many researchers have found that when you track MS patients over time that the bulk of change is actually seen within the gray matter.   In terms of the gray matter, there is a lot of axons present within the gray matter. And so, gray matter volume is not just a pure measure of neuronal integrity. And the other thing is that the axons within the gray matter are predominantly myelinated similar to within the white matter. And so these brain substructure volumetrics are confounded by myelin too. The retina is an unmyelinated central nervous system structure. And so the measurements that we derive with OCT are not confounded by myelin. And secondly, GCIP thickness does not seem to increase during inflammation of the optic nerve.   There's been a number of studies showing that during acute optic neuritis peripapillary retinal nerve fiber layer thickness increases. There's a number of reasons for that: there's inflammation within the optic nerve, and so there's edema. And so we think that some of that edema may track down to the retinal nerve fiber layer. And there may also be some impaired axonal transport resulting in congested axons within the retinal nerve fiber layer. In addition to that, the retinal nerve fiber layer also contains the bulk of glial cells. And by that, I was mainly referring to astroglia. Now microglia are thought to be present throughout the retina, but there's really no astroglial confound of GCIP thickness as well.   During acute inflammation in the optic nerve, GCIP thickness was not found to increase. And so if you take a patient, as an example, with an acute optic neuritis now, and then you repeat the OCT scan six months later, the GCIP thickness at six months subtracted from that at baseline is felt to be a fairly accurate reflection of net neurodegeneration in terms of net loss of ganglion cell neurons. That absence of edematous or inflammatory or swelling related confound of GCIP thickness yields yet another advantage for this particular measure.   Interviewer – Dan Keller How does the time course of changes in the GCIP correlate with brain MRI? Can it be predictive or are they in lockstep or how do they relate?   Dr. Saidha Yeah, so that's a great question. I think one of the things with OCT research has been that the bulk of research to date has been cross-sectional. And so it has really been one of those key things on our mind is does the way that the GCIP atrophies or thins really mirror what's happening in the brain? In other words, are they locked in together? Are the rates of GCIP atrophy and brain atrophy actually associated with one another, or are they a little disconnected?   So in a recent study, which we published in Annals in Neurology, we tracked a little over 100 MS patients for roughly a four-year period, and we did annual MRI scans with a 3-Tesla scanner, and we did six monthly OCT scans. And very importantly and interestingly, we found that the rate of GCIP atrophy was highly correlated with the rate of brain atrophy and a particular rate of gray matter atrophy. Of course, that's a little bit to be expected partly on the basis of what I said earlier that white matter atrophy in itself is not as well detected as gray matter atrophy.   And then when you look by subtypes of MS – meaning, you know, relapsing MS versus progressive MS – we found that the rate of atrophy was even better or more highly correlated in terms of its association with brain atrophy rate. In fact, it appeared that the rate of retinal atrophy could predict 80% of variance in rate of brain atrophy, which is fascinating because it really does imply that what we're seeing within the retina of MS patients is a reflection of global central nervous system pathology.   And the pathobiological changes that we can detect and monitor with OCT appear to very nicely reflect what's happening within the brain. And that this cheap, noninvasive, easily tolerated, easily repeatable technique that's painless can provide so much insight into this disease process is really quite fascinating and really phenomenal when you consider the increasing and growing need for an ability to measure and monitor neurodegeneration in this disease process. We traditionally conceptualize MS as being an inflammatory demyelinating disorder of the central nervous system, and absolutely there's inflammation that occurs as part of the disease process. And when acute inflammation occurs, there's some immediate damage to axons on the form of axonal transection. And then when axons do not have enough myelin around them or are devoid of myelin over sustained periods of time, that normal protective environment for axons is not present, and so we feel that those axons slowly neurodegenerate.   The advent of putatively neuroprotective and putatively remyelinating therapies now more than ever increases our need for an ability to be able to track neurodegeneration. And in fact, it is neurodegeneration that is the principal substrate of disability in MS. And while the inflammation may be at the root cause of this neurodegeneration, the disability that patients have is better associated with the amount of neurodegeneration that's present. So, it's possible – and we postulate – that OCT could be a very useful outcome measure in terms of assessing therapies which are putatively neuroprotective and/or even neurorestorative or remyelinating.   MSDF Do you think that there is a common process going on more centrally and in the retina causing the changes in both? Or is it possible that there is more central degeneration, which then is transmitted peripherally causing problems in the retina?   Dr. Saidha So that's a great question. We think that the bulk of the retinal changes that we're observing are related to pathology within the optic nerve. And because optic nerve pathology is basically ubiquitous as part of the disease process, we think that the changes that we're seeing within the retina are really just a reflection of what's happening throughout the central nervous system.   Now, you do raise a very important point though. Although we think that the bulk of the change that we're seeing within the retina is related to pathology within the optic nerves, that does not exclude the possibility that some of the changes that we're seeing – in terms of thinning of the retinal nerve fiber layer and GCIP, in particular – are actually related to transsynaptic degeneration. Meaning that if you have a distant lesion or distant pathology that as an axon dies that the next neuron and axon, as part of a sequential chain, is not affected. And that's something that we're actively studying at the moment to try to better understand the effects of transsynaptic degeneration on retinal measures. There is some data to suggest that there is transsynaptic effects on retinal measures, but my own view is that longitudinal studies to definitively establish this are currently lacking.   MSDF Do you have to watch out for a history of optic neuritis when you look at the OCTs? Does that affect what you're finding?   Dr. Saidha I think it does. So, if we are kind of going to say that what we're seeing in the retina is a general reflection of what's happening in the brain, we have to at least consider the possibility that a severe inflammatory event with disproportionate local retinal tissue injury might have an affect on the global relationships between OCT derived measures and brain measures. So, when we look at the relationships between rates of GCIP atrophy and rates of brain atrophy, we find that in eyes with a history of optic neuritis that that relationship is not as strong. And we think that that may be the case because immediately following optic neuritis there's an excessive amount of local tissue injury. And that local tissue injury that results in excessive loss of retinal nerve fiber layer and GCIP tissue somehow masks the global information that we're deriving from OCT.   But then what's interesting is that although a history of optic neuritis seems to be relevant at least in the relapsing-remitting subtype it seems to be less relevant in secondary progressive MS. Part of our hypothesis for this – although it needs to be better elucidated and studied – is that brain atrophy continues on following the optic neuritis, and let's just say it carries on, as an example, at the same rate that it did beforehand. Well eventually, the rate of retinal atrophy, although there was initial disproportionate surge in neurodegeneration within the retina, there will be some ongoing neurodegeneration occurring too. And eventually the two rates will become realigned again in the future.   Kind of to get at that point we also looked at rather than just history of optic neuritis we looked at whether baseline GCIP thickness might have an impact on rate of GCIP atrophy to kind of expand a little bit upon that hypothesis. And indeed, what we found was that rate of GCIP thickness at baseline is highly associated with rate of GCIP atrophy. In kind of simplistic terms the way I conceptualize this is that the more retinal tissue that's available the faster the potential rate of retinal atrophy is. And if there's less retinal tissue available, then there's maybe less potential for that rate to be as fast. If the rate was to remain steady the entire time from the day that the disease first begins – and I think this also applies to the brain too – it wouldn't be very long before there's no tissue left.   MSDF You had alluded to looking at new potential therapies using OCT as an outcome. Does that also mean that it may have utility in looking at current disease-modifying therapies and being able to compare them?   Dr. Saidha So that's an excellent question. In fact, that's actually currently no data available that I'm aware of that has assessed the effect of currently available disease-modifying therapies on rates of GCIP or retinal nerve fiber layer thickness atrophy. And I think that's something that a lot of academics and people who do research utilizing the visual system and a particular OCT would be interested in seeing. We have such data – and such data is routinely collected in terms of effects of disease-modifying therapies – on brain volume, and this is something that's now fairly standard to be collected as part of clinical trials. It may be useful to know whether currently available disease-modifying therapies have differential effects on rates of retinal atrophy. Which would imply that maybe in addition to having a role as an outcome measure in trials of putative neuroprotectants, as well as neurorestorative agents, that maybe OCT might actually also have a role in studies of potentially anti-inflammatory treatments or treatments which modulate or suppress the immune system, as do most currently available licensed disease-modifying therapies.   MSDF Very good. I appreciate it.   Dr. Saidha Thank you very much.   [transition music]   MSDF Thank you for listening to Episode Ninety-two 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. Msdiscovery.org is part of the nonprofit Accelerated Cure Project 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.   [outro music]   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.  

Full Transcript: [intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-five of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Many MS patients will require a change of drug therapy over the course of their disease, possibly because of relapse or tolerability. At last fall's ECTRIMS conference in Barcelona, I spoke with Eva Havrdová MD PhD, professor of neurology and head of the MS Center at Charles University in Prague, Czech Republic, about when and how to change therapy. I first asked her how she detects a need to change therapy because of a suboptimal response. Interviewee – Eva Havrdová It's very difficult to find the right solution for each patient, but as to our opinion, the best thing is to really start early treatment and monitor closely the patient. It means that you look not only at relapses or progression. It's too late. We also look at MRI after six months after starting treatment. And I think it is now quite proven that, if the patient has either relapse or new MRI activity, the response in the first year is suboptimal and the treatment should be already changed. Interviewer – Dan Keller So you have a very high suspicion? Dr. Havrdová Yes, definitely very high suspicion. And you can add some quality of life measures. You can add cognitive measures. You can ask the patient, what’s the level of fatigue. And of course, all this together brings you to the solution to change the treatment. MSDF Do you generally find that you will pick something sooner on MRI then by patient report? Dr. Havrdová Yes, of course, because the events on MRI occur 10 times more frequently. But on the other hand, as to regulations for reimbursement, I cannot change the treatment just based on MRI in our country. So definitely in the future, this will be an option. But we need more data to prove to the sick fund that it's really worth doing it because if you do these changes and find optimal treatment for patients early, then the patient stays at work, and of course, the cost effectiveness of the drugs increases. MSDF I suppose that depends on having a unified system, which is not built into silos. You know, when you get one payer here and one payer there; they don't care what's coming out of the other guy's pocket. Dr. Havrdová Yeah, yeah, of course. It's very difficult; and therefore, I think we need guidelines. And one of the ECTRIMS activities is to start working on some guidelines, and I hope next year we will have it. MSDF So what do you do when you find something that would raise your suspicion or prompt you to do something different? Dr. Havrdová We monitor the patient even more closely, in three-month intervals. And very often we see that the patient develops a relapse after some MRI activity occurs. So we can change the treatment. MSDF Do you often escalate the present drug? Or switch drugs immediately? Dr. Havrdová We have to start with injectables in our country, not with oral drugs, which is the mainstream now in other countries. And we hope we will also push our authorities to this strand because patients, of course, want orals. On the other hand, the safety of injectables is well-proven for more than 20 years. So for those especially who want to get pregnant, the safety is number one. And we try to switch as early as possible, because if another relapse comes, the relapse may be disabling, and we are just losing time in the brain of the patient. And as you know, here at ECTRIMS, the one day before, the health of brain was promoted in MS. And we would like to stick to this idea. MSDF So it sounds like you change drugs, not escalate the present drug? Dr. Havrdová The escalation means the change as well. So we try not to switch within the first line, but we want to see more effect. Just because of intolerability or some known adherence of patient on injectables, we can switch within the line if there is no activity of the disease itself. Or if there are neutralizing antibodies on interferon, we can switch to Copaxone. But on the other hand, it was now published, based on data in MS base, which is a big registry of real world data, that it's really worth escalating to the higher efficacy drugs because you can reach much better effect. MSDF Over the years, do most patients require some change? Dr. Havrdová Most of them do, though there are patients who are completely stable and not developing higher EDSS steps on injectables, but it's less than 25% of them. MSDF Is there any way to generalize and say what the time course is? Or is it so variable? Dr. Havrdová No, it's very variable. And we do not know if it is based just on genes or on environment or lifestyle changes the patient is willing to undertake. We do not know yet. MSDF So I don't know if you can generalize because each country is different, but do you have some scheme or algorithm in mind about how you would escalate therapy? Dr. Havrdová The problem is if the patient is not responding to the second line or higher efficacy therapy, because we then have to switch within that line. And we do not know if he doesn't respond to anything we have. We do not know what to do. So we cannot switch or jump from one treatment to the other after six months of treatment, because you have to allow the treatment to have an effect. So at least six or nine months is okay. If the patient is not responding, then you can jump to other treatment. But hopefully the patient will respond to the third or fourth treatment, because it's not without limitations. MSDF Is combination therapy every indicated? Dr. Havrdová Not yet. I have thought many years ago that neurologists are just reluctant to use combination therapies, but now there were some trials, and it's not showing that effect. So it's not like in oncology. Though the principle is so clear, that you can combine drugs with various mechanisms of action decrease, some side effects, and increase the efficacy. Oncologists do that. We don't have drugs in the multiple sclerosis with this potential yet. MSDF Right. In hypertension they've just assumed they're always going to have two or three drugs, and same thing now with diabetes and things like that. But I guess this would be a big conceptual breakthrough for neurologists? Dr. Havrdová Yeah, and doesn't seem to be today's issue. MSDF What has been tried in combination? Dr. Havrdová The first combination which was tried was natalizumab and interferon. And it seems that it didn't work. And then, of course, it was also a small trial, natalizumab plus glatiramer acetate, and nothing just to safety was, of course, seen that. And some others, but nothing really. MSDF When there's an acute exacerbation, do you overlap steroids with the ongoing drug? Dr. Havrdová Yes, of course. Yes. It was proven that it's safe, and it's okay. MSDF So there is a combination, but short-term? Dr. Havrdová Yeah, it's a short-term combination. And definitely it helps because all the underlying immunomodulating drugs do not work against the acute relapse. MSDF What have we missed or is important to add on the topic? Dr. Havrdová I think that neurologists have to be aware, and of course, pharmacovigilent. You have to know the mechanism of action of the drug; you have to know the adverse events possible and how to prevent them—how to monitor the patient to be safe. [transition music] MSDF Thank you for listening to Episode Eighty-five 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 Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project 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. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.  

[intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. People with MS take disease modifying therapies, or DMTs, for years. But is it possible to stop the drugs at some point or at least take a drug holiday? I spoke last fall at the ECTRIMS meeting in Barcelona with Dr. Ilya Kister, an assistant professor in the MS Care Center at the New York University School of Medicine. He has looked at various studies and registries that shed light on the question, and he discusses the utility and limitations of using observational data from big data sets. Interviewer – Dan Keller People know a lot about starting DMTs, but not about stopping. And, I take it, there's not much been looked at yet in terms of could you stop and what happens. Interviewee – Ilya Kister Yes, that’s a question that patients often ask, and clinicians certainly wonder about. Is it safe to stop the drug? When is it safe to stop it? And all the literature that I’ve seen on stopping the DMTs has basically analyzed the reasons for stopping them. The reasons for non-adherence—why did patient not want to continue—but there is very little data on actually what happened in terms of disease course. It’s just an observational study, you know. Do those patients continue to have relapses? Do they have more relapses or less? The only exception is natalizumab, where we have, you know, more than a dozen—probably two dozen—articles looking at what happens when you stop the drug. But that’s a little kind of almost an exceptional circumstance. There is a question of disease rebound and such. With the other drugs, very little to no data. So, so one wonders whether it’s an okay thing to do. MSDF What are the pros versus cons of stopping? Dr. Kister I think you can make almost equally appealing arguments on both sides. The arguments to continue the drugs, the main ones, are that relapses are unpredictable, and even though they’re less common as people age, we do see patients in practice, even in their 60s, who have relapses. And there was a recent study that showed that about 30% of secondary progressive MS patients have relapses. So, presumably, the drugs which work to decrease the risk of relapse would be helpful to reduce the risk of relapse even in those circumstances as well. But that’s not entirely clear, because they were never shown to be beneficial, truly, in the secondary progressive patients or in the older patients, because older patients are, by and large, excluded from all the studies. So we really don’t have any high-level data on these subpopulations. So the reasons to continue would be to try to prevent relapses, even in older patients. And the reasons to stop would be that the relapses are kind of few and far between. It may be not worth the hassle, and maybe the disadvantages of continuing in DMT long-term outweigh the theoretical risk of decreasing relapse rates. So it’s in a clinical equipoise situation, as far as I am concerned. MSDF How have you looked at this issue? Dr. Kister This is just kind of our individual practice, and many people may agree or not agree with it. This is not really based on our studies, but generally speaking, patients after age 60 who haven’t had relapses or MRI activity for at least five years, I do have a discussion with them and kind of feel them out whether they’re interested in stopping or not. And the reactions vary widely. You know, some people are very attached to their drug. They feel like it’s helping them and protecting them and has done good for them, and they don’t even want to think about stopping. And some people are very tired from being treated for many years. They don’t necessarily see the advantages of it, and they’re very willing to consider stopping and take you up on the offer. They just need a blessing to do this, because the doctor says to stop. You know, there are people in between who are kind of vacillating and not sure. But this is a population that I would consider stopping the drug. But now, about two weeks ago, we received the news that we have funding for study, wherein we’ll randomize patients. Some will continue on whatever drug they were on, and some will stop. And then this way we’ll actually collect, in a more rigorous fashion, the data of actually what happens to those patients. And that’s a study where the primary investigator is Dr. John Corboy from the University of Colorado in Denver. And there are six sites across the states that were approved for this, and where NYU is one of the six sites, and maybe a few more sites will be added. So this is our best hope, I think, to conduct, not a randomized clinical trial of starting a drug, but a randomized clinical trial of stopping a drug, which has been done in other fields, most important in oncology, a little bit in psychology, but not in neurology or in MS, as far as I know. MSDF But short of that, you've done a database study and looked at people who have stopped? Dr. Kister Yes, though that was a study that was just presented at this ECTRIMS meeting. And there we used a very large international registry called the MS Base, which has over 30,000 patients enrolled in it, so, and dozens of countries. And it's open to any investigator in the world who is interested, and he can contribute patient data. Obviously, it's patient consent, and many patients are interested in contributing their data to the registry. So because the registry is so large, we were able to include for this study almost 500 patients who met our criteria, which were fairly rigorous. We required that patients be on some drug for three years; have no relapses for at least five years, because we want to exclude active patients; and be followed for at least three years. Three years is more than most clinical trials, which are one to two years. But we really wanted to see what happened to them this time. And we excluded people who went from one DMT to another within three months. So this was the crux of this study. We looked at this—485 patients to be exact—and we followed them. And the minimum was three years, but the median was almost five years. And we found that in this population during this followup of almost five years, 36% of patients had at least one relapse. And 31% of patients had a confirmed disability progression, meaning three months apart they had a worsening of EDSS. And almost half of the patients have restarted a DMT, but not right after stopping, but two years or more after. That was the average time to restart. So that was the main kind of result. So when you talk to the patient, you try to kind of lay out the data for them, you know, this is the numbers you can use, I think. Even though somebody hasn't had relapses for five years or more, they still are at risk of relapses. And what we found was a predictor of relapses was age and EDSS. The younger patient and less disabled patients who we think are typically probably more in the relapsing phase, rather than in the secondary progressive phase, were more at risk for relapses. So for younger patients, I would be much more wary of stopping the drug, even if they have been relapse-free for years, than in an older patient. So that's one result of the study. But there was a second component of this study which was interesting, I thought, wherein we compared the people who stopped the drug with the people who continued on the drug, and we matched them. There is a technique called propensity score matching. So we matched the people who stopped and the people who stayed. And the two groups were almost identical. All the parameters, like age, disability, how long they've been on the drugs, proportion of times they've been on the drug, their gender—very, very similar according to most of the variables. And we followed them through time, and the mean followup for both groups was about five years. And we found, a little bit counterintuitively, that people who stopped the drugs did not have any more relapses than people who did not stop the drug. If you think that the drugs are protective, you will expect some effect; we didn't see any effect whatsoever. There was absolutely no effect. But interestingly enough, the people who stayed on the drug tended to progress, to show confirmed disability progression, a little less. They were at less risk of disability progression, about 40% compared to people who stopped. So it's a little hard to interpret this data. It may be that the drugs actually have some cumulative effect and maybe continue, and that does delay disability progression. That would be a very favorable interpretation as far as clinicians are concerned and the rational to continue. But it may be that people who stayed on the drug were really in some what we call unmeasured confounders. They had some reasons why they stayed, and they are not really entirely comparable to the people who stopped. Maybe they were a little more, for whatever reasons, considered to be more active by the clinician, and that's why they kept them on the drugs. So maybe there're intrinsically different groups with intrinsically different disability progression, and that is the reason for the finding. So this is where we stand right now, and this goes to show kind of the utility and the limitations of using observational data sets. The utility is that we're able to basically run that kind of a pseudo-trial, if you will, comparing the stoppers and stayers, and run it for many years. We actually have data six, seven years after stopping the drug, which is almost not possible with randomized clinical trials. And we're able to use this data. In fact, to power the clinical trial that I talked about earlier, because we can predict how many people are expected to have relapses at this age and such. And the limitation that there are known unmeasured confounders, and that there're biases in who continues to be observed and who is not, and we cannot control for that without randomization. MSDF Now, from your study, it looked like people who had been off of a DMT for more than two years had a higher relapse rate. Is there any possibility of having a drug holiday? Or, when someone comes off drug, a silent insult happens that you only see later, so you really have to not give them a holiday? Dr. Kister Well, it's a hard question to answer. They had a higher risk of disability progression, not relapses in this study. The curves begin to diverge after about two years. It was more of a long-term effect. So, you know, one wonders. But the counter argument to what you are describing is maybe there's a cumulative effect, that you really have to stay on the drug for long periods of time in order to see. And if you stop and have a holiday, you kind of wash out that possibility. So the answer is, we really don't know whether it's okay or not to give holidays. It's definitely not okay in actively relapsing patients, especially if they're on strong drugs like natalizumab or even Gilenya or even interferon. That's pretty clear. So but as far as the patients who hadn't had relapses for a long period of time, we don't know. It remains to be seen. MSDF Is there a continuing effect of any drugs, such as monoclonals, like alemtuzumab, where you might get a tail effect even after stopping it, which would essentially be your accumulative effect? Dr. Kister I think that is, you know, a very important point that we talked about stopping the drugs, but we really have to specify which drug we're stopping. Because drugs like alemtuzumab have been shown to have an effect that lasts for four years or more. And I think at this conference they will show data for even longer term effect of alemtuzumab. I've seen some posters to that effect. So those drugs have an effect on the immune system that persists. Some chemo treatments as well, you know, a stem-cell transfer. It's not something you do every year; it's something you've done once, and you see the effect that lasts for a long period of time. So I think a lot depends on the mechanisms of the drug, you know, how long they're expected to affect the immune system for. Something like natalizumab that washes out within three months or so, and you don't really see, you know, effect on the receptor level than you'll be after about three or four months. We don't really…you wouldn't expect it to work beyond that time, and it really doesn't. It only lasts that long. And other drugs, there is a sustained loss of T cells and B cells for a long period of time, and perhaps that's why there's a clinical effect that lasts for many years. MSDF Have we missed anything? Or is there anything important or interesting to add on the topic? Dr. Kister I think your interest was in observational data sets, and I think MS Base registry and others, like NARCOMS registry, they show the power of, kind of all of the people power. It's not the big pharma who is collecting the data, which is very important and has a big role, obviously. It's actual clinicians and actual patients who volunteer their data. And I think patients should be gratified to see that their data is used to actually come up with some insight as to advantage them, come back to the patients and answer some of the questions they had. So I think those databases are very important. MSDF I appreciate it. Thank you. Dr. Kister Thank you very much. [transition music] MSDF Thank you for listening to Episode Eighty-four 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 Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project 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. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. For years, MS researchers have been looking for a measure of MS progression and disability that would be meaningful to clinicians, clinical researchers, patients, and the regulatory agencies that approve new drugs, such as the Food and Drug Administration. To this end, people have looked to composite endpoints that are sensitive to small changes in patient condition and comparable across studies. At the ECTRIMS conference last fall in Barcelona, I met with Dr. Jerry Wolinsky, professor of neurology and director of the MS Research Group at the University of Texas Health Science Center at Houston, who leads us along the path to develop a useful measure incorporating composite endpoints. Interviewer – Dan Keller In terms of assessing progression and disability in MS, is there some advantage to having composite endpoints as opposed to the standard tests we’ve looked at? Interviewee – Jerry Wolinsky There are several different ways to think about composite endpoints. So one of the things that was introduced almost several decades ago was MSFC functional composite. So this was using three different ways of looking at different components of disability in patients with MS. One was a test of cognition. One was a test of fine motor skills in the upper extremities. And one was a test of walking abilities/walking speed. That particular composite looked very attractive. There was a fair amount of theoretical and practical work behind instituting the composite, and it was used in a number of trials. And it was based on some very important, I think, kind of statistical analysis. So what it allowed one to do was to take patients either in a given study or across studies and try to normalize the data that you would get from those patients into something called a z-score, which is a way of ranking and evaluating how far across the group of patients people were scattered. And then one could conceptually add up the z-scores and have a composite number, and a single number that you could use to analyze trial data. It seemed to be rather sensitive, and it seemed to work well. But the z-score is very dimensionless, and it makes little sense to the practicing clinician, or certainly to patients, to know that you’re minus-two or minus-five or plus-two, and that maybe this has moved by two-hundredths of a point from the time you started in the study until you got to the end of the study. So, highly sensitive, seemed very reproducible, maybe even a way to look across studies at different results, but neither patients or physicians and, most importantly, the FDA thought that this would be useful in day-to-day practice. So, while we’ve tested that kind of approach in multiple studies, it just hasn’t worked. But it did set up the notion that we could get a little bit more quantitative in things that could be useful on a daily basis, even using some of the same components of that MSFC. So instead of thinking about how fast could one person walk compared to another, we said, how fast can a person walk using a timed walk of a fixed distance and at one point in time? And then say how much change over an interval of time would represent something that was likely to be reproducible and, more importantly, likely to be correlated with some measure of quality of life that also was deteriorating? So then we got to the notion–and this was really best utilized thus far in the trials of 4-aminopyridine in terms of registration studies there–to say could you show a 20% improvement or more in this timed walk over an interval of time? And in that study, a certain number of patients were able to show it, and there was also some correlative data done to show that that amount of improvement correlated with things which were meaningful to the individual. And so I think that helped facilitate getting that drug through the registration process with the FDA. One of the things that my colleagues and I did in looking at one of the trials in progressive disease, specifically the trial of rituximab in primary progressive MS, where we had the data that goes into the MSFC, because it had been collected in the study, was to try to develop a number of different composites. And actually, when you think about it, the main score that we use to rate studies is the EDSS score, and it itself is a composite. It takes into account graded changes in fine motor skills in what we would call the cerebellar system, in the pyramidal system, in the sensory systems, and cognitive systems. It’s just that the boundaries in moving in these individual functional scales are a little bit more subjective in terms of going from a zero to a one, two, or three. And then the scale itself is rather complicated in terms of how it put together to come to the final score, the extended disability status score. But it’s very well accepted by neurologists, and it’s accepted by the regulatory authorities as the standard. So we took our standard changes on EDSS, which in this particular study had not shown efficacy across the group as a whole. So we looked at that in the placebo arm, and didn’t contaminate that with the treated arm, to say what was the rate of change on the EDSS alone? But then we also said, what about a 20% change over baseline that had occurred in an individual patient over intervals of testing and not just one that occurred at a particular setting compared to baseline, but one that continued to be seen at the next 3 months and the next 3 months. So it looked like it was a sustained change in the same way that we use EDSS now in trials to talk about sustained or accumulated permanent disability, at least over some interval of time. So we said, okay, we can construct a progression curve based on that. And then we said, what does that look like? And said, well, this has some dimensions to it that are interesting. And we did the same thing with the Timed 25-Foot Walk, and we didn’t fool around with the PASAT [Paced Auditory Serial Addition Test] the cognitive measure because nobody likes it. Patients don’t appreciate it, and it’s a rather prolonged and not a simple test to use. And this is one that probably could be easily changed out with other cognitive tests that are probably as reliable and easier to complete. And we looked at how did patients progress using that change in the timed walk and said, well, that’s interesting too. And then we went into the group as a whole and said, okay, how many patients changed on the EDSS over three months, confirmed? How many over six months, confirmed? How many did this on the Timed 25-Foot Walk? Did it cross the 20% threshold? How many did this on the 9-Hole Peg Test and, again, crossing the 20% threshold? And who were these patients, more importantly? So then we could develop series of Venn diagrams–if you will, circles–that showed who did it on just one test, who did it on all tests, who did it on two tests? And looked to see could we get a larger and larger proportion of the population that were showing progression? And the answer is: We could. And for some tests, the incremental change was small, and for other tests the incremental change was relatively large. But when we looked at the results of the study, then, using different kinds of composites, you fail just on EDSS; you fail on EDSS, or you fail on Timed 25-Foot Walk; you fail on Timed 25-Foot Walk or 9-Hole Peg Test—we don’t care about EDSS in that one—you fail on all three. We could see that we could increase the sensitivity, that is, the number of people who were showing progression, using these kinds of composites, and hoped, therefore, that we could increase the sensitivity to drug effect. So then we did the next step, which was to take both the placebo arm and the treated arms and say, okay, how did the curves change? So the overall curve showed no statistical benefit with the EDSS, until you went to subgroup analysis. And that was reported in the original paper. But when we modeled this, of course, the overall didn’t show the statistical effect. That’s where we were starting from. When we added in the Timed 25-Foot Walk, it looked like there was a better split. In fact, the effect size for the treatment improved. And this was not across subgroups, but across the entire population. Interestingly enough, we probably got the biggest punch by throwing out the EDSS and just using the 9-Hole Peg Test and the Timed 25-Foot Walk. That has some advantages, because they can be done by anyone. In fact, they probably could be done remotely, or we probably could convert it to how many steps a day did you take and have your watch feed the message to us over the course of a day. There are a number of interesting different approaches that can be taken to this kind of concept, and some of these are being pursued by a collaborative group spearheaded through the NIH, as well as a private consortium, looking at newer ways to measure progression. The good news is, I’m sure we’ll find things that are more sensitive. The good news is, I’m sure we’ll find things that are easier to apply. Another part of the good news is that the additional work increasingly is carried out with some representatives from the regulatory authorities to give us a feeling for what they really want to see. And what they would like to see is not just that we have composites that are sensitive and reproducible, but each of those composites that, before using them, has been shown to have some relevance for what patients complain of and what patients are looking for. So that’s the good news. The bad news is we have to not only develop them, validate them, show that they work, we’ll probably have to constantly be comparing them back, in our future trials, to the standard, until we get our first drug that really works in these new, validated approaches that are being taken. MSDF Do you think that different drugs will show you different effects on different parameters within the composite score, or do things pretty much move in synchrony? Dr. Wolinsky You know, because multiple sclerosis is such a heterogeneous disease—heterogeneous in many ways, but the simplest one to think about is the lesions don’t exactly form in a way that suits us as trialists. So, many of the lesions are silent for whatever it is we’re trying to test, no matter how carefully we test for them except maybe with really high resolution MRI. So it depends where in the real estate the lesion has hit. So it’s easy to imagine that a relatively small lesion in the cerebellum particularly well-situated could cause some slowing of the ability to do the 9-Hole Peg Test, and yet it might take a very large lesion in the frontal lobe to do the same effect in that system. In the same way, it may take just a small lesion in a pyramidal pathway, either in the spinal cord or in the internal capsule, to cause a significant change in the 25-Foot Walk and do nothing in the 9-Hole Peg Test. So, conceptually, we want to be able separately test—or relatively separately; the brain is fairly interconnected—separately test as many systems as we can and build upon them. Usually with these composites, you don’t lose too much by adding composites, as long as they’re truly independent of each other. As they become more interdependent, then the more you add, you may lose some of your ability to find small changes statistically. They’ll cancel out. MSDF Even though these are composites, you’re still interested in the separate parameters? I mean, it looks like one parameter could offset another, and your composite score could be neutral, even though you have larger changes in the separate parameters. Dr. Wolinsky What you’re trying to do, if you’re setting up your composites correctly, is not to have them cancel. And with the z-score we talked about before, it can cancel. With a composite, where you’re expecting each of the scales to be moving in a particular ordinal fashion that is going from better to worse, you don’t care where the worst comes from, if you’re saying we’ll take worse in any system. Where it gets tricky is, once you get good at that, then you might want to say, well, you get two points for getting worse in the walking system, because that’s more correlated with whether or not someone’s employable than it is if it’s in, let’s say, bladder measures, which we don’t have quantitatively—well, we do, but they’re just harder to apply—or perhaps on using other visual pathway measures that have yet to be introduced into the composites very well. [transition music] MSDF Thank you for listening to Episode Eighty-three 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 Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project 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. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music] Host – Dan Keller Hello, and welcome to Episode Eight-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Depression affects as many as 50 percent of people with MS during their lifetimes. But according to Dr. Adam Kaplin, a psychiatrist in the Johns Hopkins MS Center in Baltimore, it is treatable to a large extent, and with good results. Dr. Kaplin studies the immune basis of depression and cognitive impairment, specifically in MS and central nervous system-related autoimmune diseases. We met in Baltimore. Interviewer – Dan Keller Let’s talk about depression in multiple sclerosis. Is it a reaction to someone having a chronic disease, or is there something more going on because of the disease? Interviewee – Adam Kaplin It’s a great question, and what I will tell you is one of my patients says to me that you’re either stressed, or you’re dead. We all have stress going on, and it’s always possible to look at something in our life and say, ah, that’s what caused the trouble. But we know now, in multiple sclerosis, the depression is due primarily and dramatically significantly to the inflammation going on in the brain that causes all of the symptoms that you see in MS, such as cognitive impairment, or weakness/numbness/tingling, autonomic nervous system dysfunction; all of those are effects of the MS on the CNS. And in the case of depression, it is similar. It’s not a character flaw. It’s not a personal weakness. And just to, you know, clarify, one of the best pieces of evidence we have for that is, number 1, that people who are depressed with MS, it does not correlate with their EDSS scores. It doesn’t correlate with their level of disabilities. So if it was you know, gee, it’s just a matter of stress, then those people who are in wheel chairs or on ventilators should be depressed, and those people who are upright and walking around shouldn’t. But in fact, I think the key element is that this is one of the, as they often say, silent symptoms of MS. It occurs to 50% of patients across their lifetime. And it is important you know for people to understand that this is not something that people aren’t rising to the occasion, or those kinds of things. MSDF Is depression accompanying MS more prevalent than in the general population, and how serious is it? Dr. Kaplin You know people often ask why, as a neuropsychiatrist, why study MS? And I say, you know, why did Willie Sutton rob banks? That’s where the money is. MS has the highest rate of clinical depression of any medical neurological or surgical disease. Again, 50% of people, following the diagnosis of MS, will have a clinical depression. We can talk about what that is. And it turns out that that’s in any clinic you go into – neurology clinic – that’s one in four patients. If you go out to the waiting room, one in four patients will be suffering from a clinical depression. MSDF How serious a problem is it? What aspects of life does it affect? Does it affect everything, and how serious is it? Dr. Kaplin I think what is often misunderstood about the depression in MS is, I would argue, that it has the highest morbidity and mortality of any of the symptoms of MS, in the sense that it is the third leading cause of death in the largest study that looked at, across the lifespan, what causes death in people with MS, [found] a study out of Canada, where it’s more prevalent because of the higher elevation and the lower vitamin D levels, probably. And it is absolutely the case that seven-and-a-half times the rate – the suicide rate in MS – to the general population. And in fact, in the studies that were done, 30% of people with multiple sclerosis will have thoughts of suicide at some point during their life. Ten percent – fully 10% will attempt suicide. And that lethality is profound. But if it doesn’t kill you, it is important to understand that it has significant, significant morbidity associated with it. Just to begin with, the number one correlate of quality of life of patients—more important than their pain, or more important than their cognitive impairment, or weakness, or other symptoms—the number one correlate of the quality of life of the patient is their depression or whether they are depressed or not. And it’s similarly the number one quality of life of the care givers—not whether they have to push them around in a wheelchair, it is whether their loved one is suffering from a clinical depression. So it has significant morbidity and mortality associated with it. MSDF Are there aspects of serious depression in MS that are very characteristic? Any different from other severe depression? Or can it be recognized in the same way with the same diagnostic criteria? Dr. Kaplin There actually are some specifics to MS, although that hasn’t been well-published. I can be clear about things that are well-supported by the literature, and then those that are my clinical experiences. What I can tell you is that the way we diagnose depression in MS is the same way we diagnose depression in people without MS, which is you have to have 5 of 9 symptoms greater than two weeks, one of which must be either decreased mood or decreased interest. And we remember it by SIG-EM-CAPS, the nine symptoms. Trouble with sleep, where people are often having early morning awakenings or hypersomnia where they just sleep all day. Loss of interest, people’s get up and go has gotten up and gone. Feelings of guilt or worthlessness – and that’s a big problem, because patients who are depressed as a result of that often won’t seek help. You have to ask about it. They won’t volunteer it. And loss of energy or fatigue; low mood – that’s the sadness part; concentration problem; appetite changes, either increased or decreased weight; and psychomotor retardation, they’re not their normal bubbly self; and thoughts of death or suicide. With MS, what I will tell you, I find that patients with MS often, rather than sadness, have very frequently irritability. That tends to be more common. And sleep is usually decreased, not increased, so I see very frequently increased early morning awakening and those kinds of things. One pearl, though, to keep in mind is – or two pearls – if you’re trying to make the diagnosis of depression in somebody with MS, the first thing to do, because there are overlapped symptoms like fatigue, like concentration problems between depression and MS, so there is frequently, in up to 80% of people, will have diurnal variations in their moods; so usually worst in the morning and better at night. Sometimes it’s reversed, but you know that person has the same life circumstance, the same disease circumstance in the evening that they did in the morning, but their mood has changed dramatically, often, with MS with these cyclical changes. And that’s a good indication that it’s not demoralization; it’s depression. The other thing is ask the loved one. Get an outside informant, because nobody gets the brunt of it quite like the family. And they know that person, and if the family member says the one thing I hear so often, this is not the person I married, then you’re pretty much on the right track if you’re thinking about depression. MSDF How amenable to treatment is depression in MS? Dr. Kaplin I think that that is probably one of the key aspects is to understand that it is very treatable. So my expectation when patients come to me and I diagnose them with depression is that I will get them a hundred percent well with respect to those SIG-EM-CAPS symptoms, back to their baseline. And it’s very hard to get patients a hundred percent well from their gait problems; a hundred percent well from their cognitive problems. And, again, what I tell people is, look, I can’t tell you whether your cognitive impairment is due to the depression or due to the MS, or maybe it’s 10% depression/90% MS or 90% depression/10% MS. But I can promise you this: treating the depression, the depression is much more amenable to treatment. We don’t have good treatments for cognitive impairment in MS to reverse the cognitive impairment, but boy, we can reverse it if it’s a symptom of depression. What’s really exciting now is that we are now understanding more and more that many of the treatments you use for depression end up being good nerve tonics. So, there was a double-blind placebo-controlled study of fluoxetine demonstrating that, in patients who weren’t depressed with MS, they had fewer gadolinium-enhancing lesions over 24 weeks. And then there was the FLAME study in a related kind of way looking at fluoxetine as a way of significantly enhancing the recovery of hemiplegic stroke patients. So it turns out that I wasn’t so misguided in thinking that studying the immune basis of depression would be important, because as it turns out, our treatments actually do have an effect on the nervous system and the immune system for general types of depression as well. MSDF That sort of covers the SSRI class. What about tricyclic antidepressants? What about SNRIs? Do those fit in? Dr. Kaplin Yes, so absolutely. So the topic of how to choose and select the right treatment for patients with MS is … we could spend an hour and just sort of get only the highlights done there. But generally there’re sort of two strategies. One is to use a medication that has the fewest side effects, so that you won’t have drug-drug interactions with the patient if they’re on a numerous medicines for other concerns—their other symptoms and syndromes—that the antidepressant won’t interfere with it. And so along those lines, escitalopram and sertraline have the fewest drug-drug interactions. You essentially don’t need to look up drug-drug interactions if your patient is on one of those two medicines. The other approach is to say let’s choose a medicine that will have favorability with respect to the side effects, will be beneficial for the problems that the patient has. So a classic example is duloxetine is FDA-approved, not just for depression, not just for anxiety, but also for neuropathic and musculoskeletal pain. So here you’re talking about one treatment that will help you with the fact that your patient, their depression will get better; their neuropathic pain will get better if they have migraines—which are often a comorbidity—that will also benefit the neuropathic pain from that as well. And you know you will get two birds with one stone, as it were. And then the tricyclics, as you had asked about, we’ve had a lot of experience with them. They also will benefit in terms of the urinary incontinence problem. They are strongly anticholinergic, and so you can also benefit in terms of preventing the urinary/bowel problems. So really Cymbalta as just sort of son-of-tricyclics, has some fewer side effects, but doesn’t, therefore, cover some of the things that the tricyclics will. MSDF As you alluded to earlier, the depression in MS may largely be a result of immune processes going on—inflammation, cytokines, things like that. So how well do the disease-modifying therapies of MS attack the depression? Dr. Kaplin You know you mentioned cytokines. So that is another way that we know that this is due to the inflammation—the depression in MS—and not just other things, because for instance, interferon-alpha used to treat patients with hepatitis C will cause depression in upwards of 20 to 25% of people who take it, not when they first start it, but within you know a week to two weeks after starting it, you know, then up to eight weeks. So that’s just one cytokine, and in MS, all of the cytokines get activated. And similarly, interferon-beta that’s used, or Copaxone, you know, the ABCR drugs that we’ve used to try to—you know, with great effect since 1993—to slow the exacerbations down in MS; they don’t stop the inflammation, they just alter it. And so not surprisingly, they do not have antidepressant properties. But when you look at something like Tysabri, we actually have not published this yet. We did present it at a MS conference but working in collaboration with Biogen. We are going to publish shortly data that shows that, in a double-blind placebo-controlled study of adding natalizumab to Avonex, or adding placebo to Avonex, those patients who were depressed to begin with show a dramatic and statistically significantly decrease in their depression as a result of the natalizumab. So natalizumab is actually quite a good antidepressant—we have data for it—because that really does shut the inflammation down in the brain, and since that’s causing the depression in MS, that’s what benefits them. MSDF Just to clarify, natalizumab is a good antidepressant in MS. Dr. Kaplin Exactly right. That’s exactly right. Although, you know, it’s good that you clarified that. What’s interesting is that now that people are beginning to appreciate the role of the immune system in idiopathic depression, people are beginning to say, hmm, maybe we should be looking at these anti-inflammatories and seeing if the anti-inflammatories benefit patients with depression. Now, nobody has tried natalizumab, but TNF-alpha inhibitors have actually been tried. There was a study out of Emory looking at using TNF-alpha inhibitors for refractory depression. And I think coming down the road there will be more and more studies that begin to show the role of anti-inflammatories for not all, but some people with refractory depression. MSDF Yes, I’ve seen some studies on anti-inflammatories—traditional ones, NSAIDS sort of things—presented a German study at a neurology conference. Didn’t do too much. Dr. Kaplin Yes. What I can tell you is that not all NSAIDs are created equal. Celecoxib actually now has five studies that are placebo-controlled that have shown its benefit for depression or bipolar disorder. And so when added to antidepressant by itself: No. But when added to fluoxetine or—I can’t remember what other; it might have been sertraline—it clearly had a statistically significant improvement in the depression response, celecoxib. But not all NSAIDs are created the same. MSDF What about non-drug therapies, cognitive behavioral therapy, even just physical activity? And, if someone’s depressed, isn’t it hard to get them up and do physical activity? Dr. Kaplin Well, I’m so glad brought that up, because I’d be remiss to forget that. So all of the data says, look, therapies like cognitive behavioral therapy are effective for mild and moderate depression. Antidepressants are effective as well. The data shows that the antidepressants work quicker, but that the combination of antidepressants and psychotherapy is much better than either one alone. So that’s a crucial issue. And to make sense of what has happened—and often when people are depressed, they’ve been depressed, and that’s caused damage to their professional life and personal life, and having someone help them sort of, depending how long the depression’s been going on, sort of talk them through, coach them through, how to get back up and going. However, in severe depression, you can talk till the cows come home. If your patient is so depressed that basically they have this tunnel vision, and all of the options that are in front of them, the kind of mental flexibility that you need for CBT to work, for instance, it will not work if you patient is really severely depressed. You have to get them started with the antidepressant, which really then serves as a catalyst for the psychotherapy to kick in. And then the aspect of exercise, you can’t really pick a topic related to MS where the answer isn’t exercise. Cognitive impairment, absolutely exercise is beneficial. Depression, exercise is beneficial. It stimulates growth hormones that have positive neurological effects on the CNS, as well as on the peripheral nervous system and body. What I tell people, again, is that if your patient is severely depressed, they’re not going just go back out and start running. So you’ve got to begin to have a plan where you say, look, we’re going to begin this medicine. As you start to be able to have the ability to you know maybe push yourself more than you might usually and just sort of walk down the block, and then you know walk for a mile and then start jogging for a mile and sort of build up to it, that’s very beneficial. MSDF Are there barriers to recognizing and/or treating depression both on the patient’s side and on the physician’s side? Dr. Kaplin The big barrier on the physician’s side is, you know, don’t ask, don’t tell. So if you don’t think of depression, or worse, if the neurologist says, well, I went into neurology not psychiatry, you know, this whole depression thing, that’s not my bailiwick, that’s not my responsibility, you’re missing the fact that this is —first of all, this is very rewarding. There’s nothing else that you could treat that gets a patient from being non-functional, sitting at home, not taking care of the family, not working, in a bed to fully functional, taking care of the family, back at work, like treating the depression can. But also it is. It affects all aspects. It affects the patient’s compliance with all your other medicines. It affects their ability to exercise, etc., etc. So, you know, you’ve got to think of it. And then you have to know something about treating it. One of the big problems with neurologists when they treat depression is that they don’t appreciate the fact that the goal is to get that patient a hundred percent well, because you sort of have this sigma curve where, if you get them 50% well, they’re still in that sort of steep portion of the curve where something comes along—an MS attack or you even a viral infection—and they will slip right down that curve. Whereas, if you can push them way out into the hundred percent well, that’s great. Now you can’t always do it with one medicine. You take the dose as high as the patient can tolerate, where the side effects don’t become worse than the depression you’re trying to treat. But then you might need to add another medicine, an augmenting agent or something, so you’ve got to make sure you recognize it and treat it. And then, what I always tell my colleagues—and my colleagues at Hopkins are wonderful; they do appreciate you know you’re treating the whole patient, not just you know their reflex arcs and that kind of stuff—and what they are very good at is, if the patient is depressed and suicidal, that is the psychiatric equivalent of a heart attack. So then they will get in touch with me and we’ll work together. So if you’ve got someone who’s suicidal, you really want to get in touch. Unless you have the utmost experience and confidence in treating the worst cases of depression, you probably want to get a psychiatrist involved, or mental health professional involved, to help coordinate the care for someone like them. MSDF Very good! I appreciate it. [transition music] MSDF Thank you for listening to Episode Eighty-two 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 Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project 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. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

Transcript: [intro music] Host — Dan Keller Hello, and welcome to Episode Seventy-two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Today's interview features Nathaniel Lizak, a young Australian investigator from the University of Melbourne who gave the first talk at the recent meeting in New Orleans of the Americas Committee for Treatment and Research in Multiple Sclerosis, or ACTRIMS. Mr. Lizak discusses new findings showing that moderately advanced and advanced multiple sclerosis are more unpredictable than anyone knew, but worsening disability may be slowed by highly effective therapies. But first, let’s look at new content on Msdiscovery.org. Our latest data visualization shows statistical snapshots of MS worldwide. Survey data from the MS International Federation show that, as of 2013, the estimated number of people in the world with MS increased to 2.3 million, or about 33 people with MS for every 100,000 people. But MS rates and access to care vary widely from country to country, as you can see from the data visualization. In a new job posting, the Stanford-affiliated Santa Clara Valley Medical Center Department of Neurology seeks a general neurologist. Subspecialty training in MS, movement disorders, or vascular neurology is preferred. You can post your job at MSDF at no charge to reach researchers and clinicians specializing in MS and related demyelinating disorders. [transition music] And now to our interview. Australian medical student, Nathaniel Lizak, and his academic mentors took a second look at how disease progresses in people with moderate and advanced MS and what can be done about it. Researchers are looking for better measures of disability, but the most common one is the Expanded Disability Status Scale or EDSS for short. Lizak and colleagues looked at worsening disease from several starting points, using an international registry known as MSBase that tracks medical record data on nearly 38,000 people with MS. They divided people in three epochs ranging from EDSS 3.0 (where people are moderately disabled but are fully ambulatory) to EDSS 6.0 and higher (where people need assistance to walk short distances). An older study suggested a steady worsening of disease after EDSS 3.0, which Lizak and co-workers questioned. Executive editor, Carol Cruzan Morton, spoke with him about their findings. Interviewer – Carol Cruzan Morton We are here at the ACTRIMS meeting in New Orleans, and you opened the conference with a really interesting paper. I wanted you to explain a little bit about what you were asking and why. What area of MS, what questions you are addressing? Interviewee – Nathaniel Lizak So we did this work under the MSBase group, which is an MS-based cohorts; it is an international really large study that has data from over 30,000 patients worldwide. We have access to all of their data, and we really thank our contributors throughout the world who have provided this. We decided – because we have so much power with so many numbers and so much data from patients – to look at the latest stages of multiple sclerosis which, so far, haven't really been that well explored. There have been three studies in the past which looked at disability and how it progresses in what they have called the moderately advanced stage of multiple sclerosis. So yeah, we looked at disability accumulation in the later stage of multiple sclerosis moderately advanced, which is defined before as between the EDSS steps of 3.0 or 4.0 and 6.0, and we wanted to look at what predicts how the disability accumulates, because a lot of the previous studies didn't really suggest anything really changes disability. There is this notion amongst doctors that once it hits these thresholds the trajectory is set, and there is nothing you can do to help patients. We didn't believe that. We were hoping there was something you can still do for patients, even once they have already accumulated substantial amounts of disability. We set this up to look at just how much variability there is in these later stages of disease and what we can do to take it from going really fast to going really slow, to preventing patients from getting even worse. We used our cohorts, ran lots of statistics, and we found some very interesting results. The first is that this late stage of disease is quite independent from what happens before. How many relapses people have early in the disease, how fast they got to the early disability landmarks, how fast they accumulated disability, if they were on therapy in the past—all of those things don't really seem to impact what happens later on in the disease. That is what we call the amnesic disease phenomenon. That is something that has already been explored in the past. We kind of confirmed that and saw that, that happens at lots of stages in multiple sclerosis. What is more interesting, though, is that we still found that patients have a lot of variability in what happens to them, even after they have accumulated substantial disability. So in technical terms, after EDSS 3.0, 4.0, and 6.0, there is still a lot of variability in what happens to patients after they have reached these steps, after they have already obtained disability. That suggestion that after the threshold the disease is set doesn't seem to be at all the case. That is all we observed in our patients. We had over 3,400 patients— we had 3,415 patients exactly. So it is quite I think, generalizable, our results. There is a lot of variation in what will happen at these later stages of disease. MSDF You can't predict what happens next. And it is different. Mr. Lizak It is different for everyone. It is independent of what happened before, and almost nothing predicts what is going to happen next. The only things that we found which did predict such as how does disability progress in these later stages, the first one was how many relapses they are having now. Not before, not early in the disease, but how many relapses are they now having per year at these later stages? We found that more relapses later in the disease still contribute to disability. That wasn't something that the other studies had actually shown, and I think that is to do with their methodology more than anything else. I think we are confirming that relapses are still important, inflammation is still important, we still need to treat it, no matter how far along the disability line the patients are. The relapse is still a problem. A more exciting thing that we found was that the immunomodulatory medications that the disease modifying therapies, the higher efficacies ones, the new medications, the longer patients are on those in the later stages of disease—so again, after those landmarks, after EDSS 3.0, 4.0, and 6.0—he longer patients are on those after they have gone into that disability the lower their likelihood of progressing even further to EDSS 6.0 and 6.5, which is mobility issues needing unilateral assistance or a walking stick, EDSS 6.0 or bilateral walking assistance EDSS 6.5. So those are pretty, obviously, important to patients in being able to move around without needing any aid. We found that we can prevent patients from getting to these later disability stages with longer time on disease therapies later on in the disease. So the conclusion we got from this is patients should continue being treated later in multiple sclerosis. Of course, it's always a risk/benefit calculation. You always need to take the side effects into consideration and look at the patient that you are seeing. It is not a blanket rule, but there are countries in the world where it's by policy you can't give therapies later on in disease after EDSS 4.0. New Zealand is one example. In other places in the world, it is just practice to stop giving treatments later in multiple sclerosis, and we are suggesting no there still is a benefit and you should be weighing that up when considering whether or not to continue patients on therapy, whether to start them on stronger therapies. There is evidence that we can still slow down how the disability will accumulate. That was our main message. We were a bit surprised to find out it was not what we were expecting, but we are very happy that we found such results. MSDF In your study, what drugs were categories as the high efficacy? Mr. Lizak I don't remember exactly every single drug, but we just put into two groups. The low efficacy being primarily the initial very first-line drugs, so interferon, glatiramer acetate, and teriflunomide; everything else categorizes as high-efficacy therapy, so natalizumab, fingolimod, alemtuzumab, dimethyl fumarate, cladribine, mitoxantrone, I might be missing a few. By no means are we saying that one therapy is better than another. We're just looking at the class effect of the really strong medications. We don't yet have the power to say this is the best medication after EDSS 6.0, this is the best medication after EDSS 4.0, or don't go on that one. We're just trying to say that the stronger perhaps second-line therapies often used second-line do have a better effect in this later period of disease, and doctors should be considering that when deciding what treatments their patients should go on, and patients should obviously be made aware of that as well. MSDF The idea that things that happen before don't affect the later stages seems on the surface to be at odds with the idea that progressive disease starts early, like treat early. Mr. Lizak …to try to treat disease as early as possible. I don't think it is at odds. There's been a lot of work, so far, to say that the earlier you treat your patients the better. We agree with all of that. We are not saying treating later is any better. Probably believe that treating earlier is better, but what we are saying is: a) continue treating, and don't stop treating. I completely agree that all of the patients that we found that after EDSS 3.0, 4.0, and 6.0 improved with more therapy after those landmarks, still probably did better earlier on in their phase of disease with therapy then. But I guess what we saw is the therapy they had earlier in disease won't make an impact now. You need to continue treating these patients for them to have an improvement. We still absolutely encourage the earlier treatment, the better. That evidence is beyond doubt in multiple sclerosis. We are definitely not challenging that. We completely agree with that. Our evidence just goes and takes it one step further of, the earlier the better, but it is not too late. MSDF Now you are doing this study in the context of a clinical practice. How has that changed – or has it changed – how people with MS are treated in the decision making? Mr. Lizak The thing is, first of all, I am a medical student, so I don't make any of the decisions. Secondly, where we are based in Melbourne, Australia, there is already a tendency to treat patients later on in disease. Obviously we haven't published the results yet, so we haven't seen how much of an affect it will have worldwide. Perhaps now we will begin to start changing things. But in Australia where nothing was studied, no one was surprised to find that this was the case. All the doctors there already treat their patients later on in the disease. So it just confirmed that what they are doing is correct. No one has yet drastically changed how they are treating patients. We hope though that, say countries like New Zealand whereby policy after a certain EDSS score, after EDSS 4.0, after moderate disability has been accumulated, you can't put patients on disease-modifying therapy anymore—we hope that is where we will have the biggest impact. MDSF When you gave your talk, you talked about the earlier study. There wasn’t an appreciation for the variability. How did you come to ask that question in the first place? Mr. Lizak I have to give credit to my supervisor, as well as the whole MS based team that was behind this study, and obviously they conceptualized it a lot more than I: Dr. Thomas Kalincik and Helmut Butzkueven, in particular. But a lot of doctors, particularly our team, are not happy with that graph. Which it looks like everyone after EDSS 3.0 has the same trajectory. We looked at this, and we thought we wanted to do a study to prove this wrong. We didn't know exactly what we were going to find. We actually proved that what they first suggested of disease being independent to be quite correct. But they just missed the variance in the second half. It is independent, but it is still really variable. We looked at the graphs carefully, and we looked at the study carefully, and we made the note of they only have a mean value on that top half, they don't show how much variability there may or may not be in disease. We got confused. We said it is unlikely that patients have no variability at all after EDSS 3.0, and we decided not only are we going to look at what predicts the later disease, but we need to know just how variable is this disease this late, and we found that it is extremely variable. After EDSS 6.0, patients might go straight through to worse disability, and many will improve, and many will stay stable for many years. We were just unhappy with the message that the graph gave. Then we tried to scrutinize exactly where can we change this message, where can we improve this. MDSF That’s great. What questions are your colleagues asking you here about the study? Mr. Lizak I have had a lot of questions about this study, some more helpful than others. A lot of people have asked how will this change management? And I think we have just spoken a little bit about that. I am asked, as well, how do you tell patients that we can no longer predict their disease? We used to think that we could and now we just outright can't predict their disease and that is something that is going to be difficult to tell the patients. I think you need to frame it differently. It is not we can't predict how your disease is going to go, it is, we have hope for making it better. You might have been doing not so well up until now, but we still have hope to continue fighting. We haven't given up yet. And I think that is what we need to be framing it as. That is one of the questions I have gotten the most. A lot of people have asked about why we chose certain therapies, and there is very little evidence about which therapy is high and which therapy is low. We just used the available studies as well as the clinical experience and just compared how much they reduced relapse rates and so on. It was partly based on intuition and observation. It could be the case that some therapies should have been classified differently to what we did, but it is very hard to tell at this stage. Even then, even looking at the list, you should be mindful that a therapy that we classified as high efficacy might have actually been bringing that group down. And maybe should have been a low efficacy therapy, and maybe a low efficacy therapy was the only one working in that group, and it should have been in the high efficacy group. So obviously, be very careful when you look at that. At that strata, it is not meant to be telling anyone I should be on that drug or I shouldn't be on that drug. It is just meant to be saying that strong medications are better in this stage, but the decision of the medication should be a decision made entirely by the patient and their doctor, and it should only be used to influence and it shouldn't be taken any more than that. MDSF Is rituximab in your …. I was going to say before a B cell therapy. Mr. Lizak I don't think we have many patients on rituximab, but we would have had quite a few. Yes, because it was used quite extensively. MDSF Thanks. Is there anything else that I haven't asked or that you wanted to add? Mr. Lizak Rituximab wasn't the high efficacy group. I should mention that. Yes. Thank you for the fantastic opportunity to showcase the work we have been doing. I obviously have to give credit to everyone at MSBase who conceptualized and gave patients the study. We couldn't have done it without the help of our collaborators worldwide. [transition music] MSDF Thank you for listening to Episode Seventy-two 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 Carol Cruzan Morton. The data visualization was developed by Jean Mercier of Khawai Data Visualization at Khawai.com. Msdiscovery.org is part of the nonprofit Accelerated Cure Project 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. [outro music]   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.      

Transcript [intro music] Host – Dan Keller Hello, and welcome to Episode Fifty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features an interview with Dr. Gavin Giovannoni who discusses the first experimental drug to show some benefit in a progressive form of multiple sclerosis in a major trial. The drug is ocrelizumab, and the trial is called ORATORIO. But first, here are some new items in the MS Discovery Forum. The ocrelizumab findings were the big news at last week’s large international MS meeting in Barcelona, Spain. Our Research Roundup highlights other breaking stories from the meeting. Stay tuned for more in the days to come. We’ll be rolling out in-depth stories on some research themes we followed at the meeting. And we will have some extra meeting-related podcasts for you in the next two weeks. Every week, MSDF lists the latest scientific papers related to MS, with links to the abstracts on PubMed. Of 138 new studies published last week, we selected three as editor’s picks. In one study, a British team found a new reason why remyelination fails in disease. When damaged axons lose their myelin sheath, as in multiple sclerosis, they strike up a conversation with immature myelin-making cells. The axons reach out with new synapses to order the cells to grow up and make new myelin. If axons can’t call for help, as also may happen in MS, the myelin-making cells cannot respond. The team made their discovery in rat brains. They also found new synapses and telltale signaling molecules in postmortem brain lesion samples from people with MS. In another paper, a Spanish group looked at other factors that may block the brain’s ability to repair itself after inflammatory damage. A pair of molecules, known as semaphorins, may block myelin-making cells from coming to the rescue of damaged axons. The findings come from human tissue samples and may hold promise as targets for future treatment. Our third editor’s pick paper looks at factors influencing the intention to exercise and the execution of exercise among people with multiple sclerosis. A Danish team did an extensive review of rehabilitation and sports medicine literature. They found that health professionals can help on both fronts. Our Drug-Development Pipeline contains 44 investigational and approved agents for MS. Last week, we added two new findings from clinical trials, we updated information from another trial, and we added 10 other pieces of information to the database. The drugs with important additions are alemtuzumab, dalfampridine, fingolimod, glatiramer acetate, idebenone, natalizumab, and teriflunomide. One update summarizes the finding that fingolimod induces the expression of neuroprotective factors by human astrocytes. [transition music] And now to our interview with Dr. Gavin Giovannoni, head of neurology at Barts and The London School of Medicine and Dentistry in the U.K. We spoke with him at the recent European Committee for Treatment and Research in MS, or ECTRIMS, meeting in Barcelona about the Brain Health report that was launched at the meeting and about the ORATORIO trial of ocrelizumab in primary progressive MS. We'll cover the Brain Health report in future podcasts with him and other authors of the report. But today, Dr. Giovannoni lays out the methodology of ORATORIO, which may explain some of the very good reduction in disease progression, observed in this trial for the first time in primary progressive MS. Interviewer – Dan Keller In the ORATORIO trial, what was the aim, and I guess what's the big outcome? Interviewee – Gavin Giovannoni Well, the ORATORIO trial is essentially a phase III trial of depleting anti-CD20 monoclonal antibody called ocrelizumab in primary-progressive MS. As you're aware, almost every trial done in primary-progressive MS has been negative. And then the motivation behind the ocrelizumab trial was based on the rituximab trial; ocrelizumab is a follow-on and rituximab is more humanized, so that should come with fewer side effects like infusion reactions and anti-drug antibodies. In that rituximab trial, there was a subgroup of the population that responded. These were people that are younger and had MRI activity. So when we designed the ocrelizumab ORATORIO trial, we tried to enrich the study for young people and people that were more active, more enhancing lesions, and we did that. So the population is younger, and the proportion of patients with gadolinium-enhancing lesions at baseline was about a quarter of them. And we also made sure that all the patients had an abnormal CSF spinal fluid. The reason for that is in the Copaxone glatiramer acetate trial, patients who didn't have an abnormal CSF behaved very differently to those with an abnormal CSF, so we wanted to make sure that we had a homogeneous population. And we made sure they had oligoclonal bands or raised IgG in the spinal fluid simply because we we're trying to target a B cell response; so those that are CSF-negative may not be responsive to a B cell therapy. Lots of features of this trial that we try to wait to make it positive, so we're really, really excited about the results, that people on ocrelizumab had an approximately 25% reduction in confirmed disease progression on EDSS compared to patients on placebo. And it was an event-driven, so the trial wasn't designed to be a fixed time point, it was designed as soon as you got enough events; it was like an adaptive trial, so it was quite cleverly designed in that regard. So it's great news. Now whether the trial was positive because ocrelizumab is a more effective therapy than the others, or because it's targeting something special like the B cell, at the moment is not known. The only way we're going to find that out is if we do another primary-progressive trial with another highly effective therapy and see what happens there. But this is fantastic news for people with progressive MS. If you follow any patient forums or blogs or whatever, the most frustrated, depressed group is the primary-progressive patients; they've been neglected for years, decades. I think that's the big news, we now will have a therapy which we can offer them. The one unknown, though, is maybe this result has been driven by a particular subgroup, and I think the regulators and the payers will want to get that data from us. Because if it is driven by a particular subgroup, they may limit the license and the payment for that particular subgroup, the responder group. And so I can't talk to that yet, because most of the subgroup and post-hoc analyses haven't been done. But potentially maybe like the rituximab trial, there will be a proportion of the patients that have characteristic features that are more responsive to the drug, and drive the trial results compared to the other group. And if that is the case, then it's still good news regardless. MSDF As it stands now, it seems like the indication would be for people with abnormal CSF, oligoclonal bands, or elevated IgG. Is there any thought that this drug may work possibly by the same mechanism even if you're not seeing abnormal CSF? Dr. Giovannoni The spinal fluid tests aren't 100% perfect, so there are people who will have false-negative results. But I've always been a big proponent of the hypothesis that the oligoclonal response in the spinal fluid is something key to this disease. We see that response in infectious diseases like neurosyphilis, measles, rubella panencephalitis, herpes; it's really a signature of its common to infectious diseases, which is why I'm still a supporter of the hypothesis that MS may be an infectious disease. You do find that in a few other autoimmune diseases, particularly the paraneoplastic plastic syndromes, that it's a signature of an intrathecal B cell response. And this drug targets B cells. One thing it doesn't target, though, it's the long-lived plasma cell, and so CD20 actually stops being expressed, even on plasmablasts, so as soon as you go from the mature B cell to plasmablast to plasma cells, you don't deplete those with anti-CD20. So we know from rituximab data that the oligoclonal bands persist, so we need longer punctures, you don't get rid of those. But until we have long-term followup, we don't know. Maybe drugs that target the plasmablast and the plasma cell will be more effective than rituximab. We don't have any of those drugs available in MS yet. There's one that's being developed, it's anti-CD19; CD19 gets expressed onto the plasmablast and some plasma cells, and there are some specific markers for plasma cells. But if you gave those to people with MS, you'd probably deplete them of their antibody-producing cells and make them a gamma globulin anemic. Then you'd have to probably then start supplementing with gamma globulin, so it gets quite complicated. But at the moment, the drug will be licensed, I think, for continuous use every 6 months; it won't be induction therapy. Some of the data would suggest you could potentially use it as induction therapy, so, you know, do 2 years and then wait and see if the disease comes back. But the way the drug's been developed at the moment is for continuous maintenance use. There are some concerns; can you continue to use it in the B cell depletion forever? And that's going to have to be answered with the open-label extension studies. MSDF Since plasma cells persist and oligoclonal bands persist, if I understood you correctly, do you think that the pathology is mediated through antibody, or this depletion of B cells is acting in a different way, that the B cells are interacting either with T cells or on their own doing something? Dr. Giovannoni I mean, there is pretty good evidence from the pathology literature that antibodies are very important in MS. So whether or not you accept it, there is pathological classifications of the top 1 to 4. And there is antibody and complement activation in MS lesions, and there is emerging evidence that so-called grey matter lesions and subpial lesions on the surface are particularly driven by antibody and complement. So I do think they are pathogenic. And so you may get rid of the focal inflammatory lesions that appear to be T cell-driven, whereas the cortical subpial lesions may be antibody-driven. So you may be getting rid of one pathology and not all the pathologies, which is why I remain a little bit skeptical still about whether or not this anti-CD20-depleting antibody will be effective in the long-term. So we may need additional treatment to target plasma cells. And what you've got to ask yourself really is what's driving those oligoclonal bands. We know they are highly selected, so they're not just there. They're oligoclonal, they've undergone selection by hypermutation, so there's some antigen driving them. They respond to something, and we just haven't been able to find out what they respond to. They are pathogenic, and if we do find the cause of MS, that will almost certainly begins to cause the disease. An analogy would be herpes encephalitis; if somebody's had a herpes infection, then you take those oligoclonal bands out and you absorb them against the antigen from herpes, you remove almost all the antibodies. So they are antigen-specific in the infectious space. We've tried for years to find out what those bands react against in MS, and we haven't found it. There's several groups still working on it, and I would encourage them to continue working it, because that may be where the action is. MSDF The ORATORIO data was only begun to be analyzed very recently. You had mentioned that you were going to be doing subgroup analyses. Are there other analyses yet to come? Dr. Giovannoni I mean, the headline results are probably in main secondary outcomes, and there's less of tertiary outcomes. We need to do subgroup analyses trying to look at brain atrophy, the time course of the progressions. I'm very interested in second progressions, because I have this theory that early progressions in progressive disease is not driven by inflammation that occurs in this epoch, it's in the past; so inflammation a year or two ago is driving progression now. And so when you design these progressive trials, a large number of people progress early. And I think it's nothing to do with the trials because it's happened before the trial. So what you then need to do is look at progressions in the future to see if they flatline or stabilize. So there's lots of luck. I think we need to play around with the data, look at the first and second confirmed progressions, incorporate the brain MRI activity as the confounder. There's lots to do, tons to do. But it's good news. The excitement about those analyses are generated because you've got a positive result. MSDF Picking up on this idea that what you see today is the result of an insult that happened sometime before, what is the time course that you see using ocrelizumab in terms of benefit; is it so rapid that it questions whether what you said is what's operating? Dr. Giovannoni Yes, it's too rapid. When you see the survival curves, they go flat very early, so this is actually saying something else which is really surprising me, which is why I think some of the activity may be driven by an anti-inflammatory, because we know that anti-inflammatory drugs have an effect quite quickly. So that's why I'm suspicious that the positive result is driven by an inflammatory core of patients, and those with the more neurodegenerative or previous inflammation are unlikely to respond. That's my worry with the drug. But let's see what their subgroup analyses show. MSDF Anything we've missed or important to add on that? Dr. Giovannoni What I want to mention to people with the disease is they shouldn't overhype expectations. The simple reason is when you've got progressive disease you've already lost reserve, so that's why you're progressing. So in early relapsing disease, you make recovery from attacks because you've got ability to recover, a reserve. And so early on you stabilize or improve, and later on you slow down progression. So I'm trying to tell people with the disease if you do go into this therapy, don't expect to improve or get better. You're much more likely to progress more slowly, which you won't notice. It's hard in an individual to say they're progressing more slowly, or you'll plateau out and stabilize. I think that must be the expectation, rather than improvement. And I think we need to manage those expectations, that people may not at a personal level find a big dramatic response in terms of their disability on the drug. MSDF But this sounds like – getting back to the discussion of the Brain Health report – where you should diagnosis and treat rather quickly. At least now if someone comes in with primary-progressive, there may be at some point something to do from the start. Dr. Giovannoni Yeah. Well, it's like with any neurodegenerative disease, the sooner you treat the more you've got to protect, and the later you treat the less you've got to protect. So this would be a call to get primary-progressive disease diagnosed as soon as possible and treat as soon as possible. And if you look at the diagnostic delay in primary-progressive disease, it's probably worse than relapsing disease. People often go years before being diagnosed. So we're going to have to sharpen up the referral pathways and the diagnostic pathways in primary-progressive disease to get that timeless brain concept across there, too. [transition music] Thank you for listening to Episode Fifty-Six 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 Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project 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 editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller. [outro music]

[intro music]   Host – Dan Keller  Hello, and welcome to Episode Forty-eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features Dr. Bruce Cree on the EPIC, CLIMB, and SUMMIT clinical trials in MS. But first here are some new items in the MS Discovery Forum.   We're very happy to report that MSDF has received three generous grants that will allow us to continue our mission: to focus attention on what is known and not yet known about MS and related conditions in a way that builds bridges among different disciplines. Genzyme has given us two grants. One will allow us to continue producing this weekly podcast for another year, and the other will allow us to develop an additional 12 monthly data visualizations. And Biogen has given us a grant for general operating support. None of these grants will interfere with our editorial freedom, and you can continue to count on MSDF to be an independent source of unbiased MS news.   A conference in Cambridge, Massachusetts several weeks ago sponsored by Orion Bionetworks outlined the progress and challenges in turning computational modeling into actionable knowledge in MS and other brain disorders. Allison Provost, who is Orion’s scientific program manager, has written a blog post describing the parts of the conference of particular interest to MS researchers. You can find her post by going to msdiscovery.org and clicking first on News and Future Directions and then on Blogs.   According to our curated list of the latest scientific articles related to MS, 50 such articles were published last week. To see the list, go to msdiscovery.org and click on Papers. We selected three of those papers as Editors’ Picks. Two of them are comprehensive review articles: one on biomarkers in MS and the other on MS immunogenetics. The third is an evidence-based consensus guideline on the use of MRI in MS diagnosis.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week we added 1 new trial, we updated information on 3 other trials, and we added 13 other pieces of information.  The drugs with important additions and changes are alemtuzumab, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, natalizumab, and rituximab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   [transition music]   Now to the interview. Dr. Bruce Cree is a neurologist at the University of California, San Francisco. MSDF Executive Editor, Bob Finn, caught up with Dr. Cree in his office at UCSF’s Mission Bay Campus shortly after a departmental seminar entitled “An EPIC CLIMB to the SUMMIT.”    Interviewer – Bob Finn Dr. Cree, welcome.   Interviewee – Bruce Cree Thank you.   MSDF Now EPIC, CLIMB, and SUMMIT are acronyms for three MS clinical studies. So first, what's EPIC, what's CLIMB, what's SUMMIT?   Dr. Cree Great question. So the EPIC study is a long-term observational study now in its 11th year at UC San Francisco. It's a a cohort study of multiple sclerosis patients who have been followed annually for the last 11 years. And this cohort initially had about 517 participants, and now – in its 11th year – we have about 91% of those patients coming back for ongoing assessments. The assessments include annual MRI scans, as well as clinical assessments and the blood draws for biomarker studies.   The CLIMB study is a similar related study that was developed independently at the Brigham and Women’s Children's Hospital in Boston under the directorship there of Howard Weiner. And it is also a long-term followup study. And now, after about seven years, that study has some 217 patients who have been retained out of the original cohort.    SUMMIT is the idea of bringing together long-term, well-curated observational cohorts from multiple sites. And the first iteration of SUMMIT will involve investigators from Basal, Amsterdam, UCSF, and Harvard who will merge together their long-term observational cohorts into a larger study. And the hope here is that we will obtain greater statistical power and be able to answer some of the more pressing questions about MS therapeutics, outcome measures, and utility of both conventional and nonconventional MRI in assisting with the diagnosis and management of patients.   MSDF So in the EPIC study, I'm struck by the fact that you've been able to retain 91% of your patients after 11 years; whereas in the CLIMB study they've lost 90% of their patients in just 7 years. How do you account for that difference?   Dr. Cree The EPIC study has had a great amount of support for long-term followup and subject retention. And we've gone to great lengths to keep our participants interested in the study and wanting to come back. And we have a terrific group of study coordinators who work day and night to maintain contact with our patients, inform them about why it's important for them to participate in the study. And we've even done outreach where we've gone to people's homes to perform evaluations in their homes where they were too ill to come in, as happens with multiple sclerosis as people develop more advanced disability. So we have very good retention as a consequence of the hard efforts made on behalf of the overall study by the coordinators and other members of the team.    MSDF Now you've used several measures of disease progression in the EPIC study, as have others in other studies. There's the EDSS, there's the MSFC, and there are several other measures. But let's talk about the EDSS first. That's probably the most commonly used measures, and it's also the one that people seem to love to hate.    Dr. Cree Yes.   MSDF Can you tell me about the EDSS and what its advantages and disadvantages are?   Dr. Cree Yeah, so the Expanded Disability Status Scale of Kurtzke is an ingenious scale that was really intended to describe where patients are at during the course of their lifespan. And it's a 10-point scale with half-point increment changes after the score of 1. And this scale has been adopted for use as the disability outcome measure in all MS clinical trials. The scale has a fair amount of inter-rater variability, which makes it challenging to administer. Because anytime you have a scale where there's a fair amount of variability it gets harder to interpret change. We did look at the EDSS systematically and looked at change over the first few years in the study and used that as a predictor for long-term disability transitions. We also looked at harder endpoints in the EDSS such as the time it takes for patients to go from no systems, disease onset, to the time where they require a cane to ambulate.    You mentioned the MSFC, the Multiple Sclerosis Functional Composite. This is a set of scales that were developed for use in multiple sclerosis that included the Timed 25-Foot Walk, which is a measurement of how fast somebody can walk 25 feet. That is clinically relevant because the speed at which somebody walks correlates quite well with the distance they can walk. So the faster you can walk 25 feet the longer you can walk. The 9-Hole Peg Test is a test of upper arm coordination and function. And the Paced Auditory Serial Addition Test is a test of cognitive function that measures specifically the tension and processing speed.    So we looked at these things, and we set up thresholds based on other clinical work that were considered to be clinically meaningful changes. So with respect to the Timed 25-Foot Walk and 9-Hole Peg Test, we were looking for a 20% worsening in function over the course of the trial. And with respect to the Paced Auditory Serial Addition Test – or PASAT – we were looking at the reliable change index for that outcome. And so these have been validated outcomes that are related to actual disability.   So we looked at all of these measures. And what we found was that when we looked at our relapsing MS patients about half of the patients experienced worsening in terms of EDSS change over 10 years. For the patients who had progressive multiple sclerosis, about 70% of them worsened. And then for these more stringent measures with respect to the MSFC components, we found lower proportions of patients with relapsing MS in secondary progressive or primary progressive disease had worsening in those outcomes, as well. So those were our endpoints for the study; they're clinical endpoints.   MSDF One of the things I noticed in your talk was that there was a great deal of overlap between the EDSS and the overall MSFC score; whereas there wasn't much overlap between the individual components of the MSFC score. What is the significance of that?   Dr. Cree Well the EDSS is itself a composite measure, and people tend to forget that. Especially earlier on in the scores that go from 0 to about 4, there you have 6 functional scale scores that contribute to the overall EDSS. That includes assessment of vision, brain stem function, motor function, sensory function, cerebellar function, bowel and bladder function, and cerebral function. And those separate functional scale scores are scored independently and then are summarized into an EDSS score between 0 and 4. After that, the EDSS score becomes really much more of an assessment of how far patients can walk until they have hit the major disability milestones of an EDSS of 6, which is walking with a cane, 6.5 a walker, 7 a wheelchair, or 8 bed bound.    MSDF So why is there a lot of overlap between EDSS and MSFC but not so much overlap between the components of MSFC?   Dr. Cree So when you look at the MSFC, you have two measures to the MSFC that are looking at motor function: the 9-Hole Peg Test and the Timed 25-Foot Walk. They can also be measures of cerebellar function. Both of things are very well measured in the EDSS by the functional scale scores for pyramidal and cerebellar function. The PASAT is not as well measured in the EDSS, although we have a cerebral functional scale score it's not a very precise measure, and there's a weakness associated with EDSS. Whereas in the MSFC, it's a very precise measurement.    When we look at the individual MSFC scores themselves, you can have patients who worsen in terms of walking, patients who worsen in terms of arm function, and patients who worsen in terms of cognitive function. And there is some degree of overlap in those three domains but not complete. And that just underscores how MS will affect different individuals differently. Some people have more ambulatory impairment, other people have more upper limb function impairment, and still other people have more cognitive impairment.   MSDF You made an interesting analogy to rheumatology in the treatment MS: the question of whether you should treat to no evidence of disease activity. I wonder if you can talk about that analogy and the NEDA, or no evidence of disease activity, goal.   Dr. Cree Sure. So in rheumatology in the 1990s, the discussion at that time had to do with how to treat rheumatoid arthritis. And this concept was advanced, which was a treat-to-target approach. The idea of using increasingly effective therapies to silence and suppress any evidence of active rheumatoid arthritis. And this strategy turned out to be extremely effective in treatment of rheumatoid arthritis. And instead of waiting for people to develop more disability, initiation of early highly effective treatments and really suppressing all joint inflammation became the current standard of therapy. And this has resulted in significant improvements in long-term disability in patients who are living with rheumatoid arthritis.    So taking that example and extending it to the field of multiple sclerosis, the idea here is that you have evidence of active multiple sclerosis on MRI scans such as gad-enhancing lesions and new T2 lesions; and evidence of relapses, which are clinical manifestation of acute inflammation; and disability progression, which is looking at the EDSS score and saying okay well if we have a combined measure that looks all of these things, and we try to suppress disease activity perhaps we're going to wind up with better outcomes. And so, this metric of no evident disease activity is defined as no evidence of relapses, no evidence of disability progression by the EDSS, and no evidence of MRI disease activity.    And it was originally developed in the context of clinical trials; specifically the pivotal trial of the natalizumab versus placebo study. And a certain proportion of patients in that study met this criteria of no evidence of disease activity. Subsequently, with more recent trials, other compounds have also been looked at and compared to their placebo or active comparator controls. And in each of these studies, you can see differences between treatments with respect to the proportion of patients with no evident disease activity.    The field of MS today is considering use of no evident disease activity as a therapeutic strategy or goal so that one would escalate therapy to the point where you see no evident disease activity. And the hypothesis here is that if you are able to effectively reach no evident disease activity that that is similar to putting patients in remission or preventing further disability from occurring. So we were very interested to find out whether there was long-term prognostic value of this marker, no evident disease activity.    And so, within the EPIC study, we looked at no evident disease activity over the first two years of the trial, and there was a proportion of our patients from this study who met those criteria: who had no change in terms of disability, no change in terms of clinical relapses, and no evidence of active multiple sclerosis by MRI scan. And we thought that that group would have a better outcome overall than the rest of the cohort. To our surprise, we found that there was no predictive value of no evident disease activity on any of the clinical markers that we looked at for 10 years.    So these patients had exactly the same risk for disability progression as patients who had evidence of active multiple sclerosis. And this was very perplexing; we just didn't really understand why that would be the case until we really started to look at the impact of treatment and use of escalation therapy in our cohort. And I think that when you look at the influence of therapeutic intervention in multiple sclerosis the effect size of therapeutic intervention is so great that other markers of biological disease activity such as new lesions wind up being minimized by the therapeutic impact. And as a consequence, things that might have been predicted based on natural history studies – such as brain volume loss, new lesions – become less apparent as having clinical meaning over a 10-year period of time because of the dominant influence of therapeutic intervention.    With respect to the no evidence disease activity, one of the questions that I think needs to be answered is do we really have the best markers for this? And if we are going to use a treat-to-target approach, are the things that are currently being looked at in no evident disease activity the right things to look at? And there is now interest in looking at other markers, as well, looking in incorporating, for example, brain volume into the no evident disease activity. And it will remain to be determined whether other ways of looking at no evident disease activity wind up performing better as a long-term predictor.   MSDF So when you're confronted with an individual patient – a new patient early in their course of disease – every neurologist is confronted the question of whether you start them with an interferon and escalate as they progress, or whether you start them with a highly active therapy. How do you make that decision, and how does the evidence from EPIC inform that decision?   Dr. Cree That's a great question, and I think this is probably one of the most provocative aspects of this long-term study. In EPIC, we used the escalation strategy where we began with so called platform therapies; drugs that are used as disease-modifying therapies that have been around for a long time, specifically the interferons and glatiramer acetate. And in the event that patients experienced relapses or had other markers of worsening such as brain volume loss, many of those patients were escalated onto what we would consider to be high-potency therapies. Drugs like natalizumab or medications that are off-label but still used in treatment of multiple sclerosis like rituximab or cyclophosphamide.    So we used this escalation strategy in this cohort. And what we found was the following. Treatment escalation was not associated with improved outcomes. In fact, treatment escalation was associated with worse outcomes in some patients. Now, why would that be the case? Well there's probably a confounder there of the indication to treat so that the patients who were getting escalation therapy are doing worse, and so they get the escalation therapy. So what we don't know from this study is if those patient hadn't gotten escalation therapy how would they have fared? We can't answer that question. That would require a randomized controlled trial.    But what this study does provide is this provocative idea that perhaps escalation therapy was really too little too late. That we were identifying a group of people who were at high risk of disability progression, but we weren't really setting things back to restore them onto a normal pathway and certainly not to prevent long-term disability. And this raises the idea that perhaps we should be utilizing these higher-potency therapies earlier. Now, that type of approach – the maximal efficacy approach – doesn't have data yet to support its use, but there are a few provocative studies that suggest that high-potency therapy might be associated with better outcomes. And we have the recent results of the cladribine study in clinically isolated syndrome where we had the best data yet for use of a broad-spectrum immune suppressant in terms of venting, time to the next clinical or radiographic event in patients who have presented with a first demyelinating event. And that study out performed all prior trials in clinically isolated syndrome so raises the question should be using an aggressive therapy right from the get-go?   And then, we have the alemtuzumab pivotal trial where alemtuzumab was compared head-to-head versus interferon beta-1a twice weekly in newly diagnosed patients. And in that study, alemtuzumab also out performed interferon beta-1a on many of the short-term markers of inflammatory disease activity. And we recently saw long-term data with alemtuzumab indicating that those patient do really quite well over a four-year period of time. So actually midterm data.    So we have a few lines of evidence to suggest that perhaps we should be using these high-potency therapies earlier. What we don't know is the relative risk-to-benefit profile. Certainly these higher-potency therapies carry greater risk to the individual subjects who are treated with these medications. And what we ultimately have to determine is whether those risks at a population level are worth the potential benefits of using a greater potency therapy early on in the course of MS.    It's my opinion that it's unlikely that the pharmaceutical industry is going to answer this question for us definitively. This type of approach to compare escalation therapy to high-potency therapy or maximal efficacy therapy from the get-go will require quite a bit of time of followup – at least five years if not longer – and will require large studies. So it seems to me unlikely to be endorsed by the pharmaceutical industry. It also seems unlikely that it's going to be sponsored by national organizations such as the National Institute for Neurological Disease and Stroke because of the extremely high costs associated with this type of clinical trial.    So that raises the question how are we going to answer this pressing unmet and unanswered question? And I think observational studies such as EPIC will be able to do this when merged together with other long-term followup cohorts. Today we have treatments that we didn't have 10 years ago, for example, fingolimod, dimethyl fumarate, alemtuzumab. These medications are currently being used in clinical practice. And I think we should be responsible for aggregating data on the patient experience with these medications, putting it into a systematized process for analysis, and aggregating this type of data across multiple centers. And that really is the goal of SUMMIT, which is going to involve pooling together our patient experience with our existing cohort, as well as new cohorts from UCSF, from Harvard, from Basal, from Amsterdam, and hopefully from many other MS centers as well. And then, with that pooled data, we'll hopefully be able to answer this question in a meaningful way.    MSDF Well, Dr. Cree, thank you very much.    Dr. Cree My pleasure.    [transition music]   MSDF Thank you for listening to Episode Forty-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 Project 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 editor@msdiscovery.org.   [outro music]      

[intro music]   Hello, and welcome to Episode Thirty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Seema Tiwari-Woodruff about estrogen in animal models of MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Last week, we reported on the results of another clinical trial for hematopoietic stem cell transplantation in relapsing-remitting MS. Compared to the “halt-MS” trial, which we reported on in January, this study used a less aggressive conditioning approach. Patients involved in the study demonstrated improvement in EDSS scores, and eighty percent of them were relapse-free at four years. The results raised important questions about how to prep MS patients for the transplant. Visit our “News and Future Directions” section to read the full story.   A recent study published in the Multiple Sclerosis Journal demonstrated a potential new way to monitor lesion repair using standard MRI techniques. Clinical trials usually look for new lesions in brain scans to monitor drug efficacy. Lead author, Daniel Reich, told MSDF it’s more important than ever to be able to visualize changes in tissue since drug development is shifting towards neuroprotection and repair.   We’re also pleased to announce that Daniel Reich is one of two new members of our Scientific Advisory Board. Dr. Reich is the director of the Translational Neuroradiology Unit in the National Institute of Neurological Disorders and Stroke, part of NIH. Our other new board member is Deborah Backus, an expert on rehabilitation who is Director of Multiple Sclerosis Research at the Shepherd Center in Atlanta, Georgia. Read their full bios in our “Who We Are” section under the “About Us” tab.   [transition music]   Now to the interview. Dr. Tiwari-Woodruff is an associate professor of biomedical sciences at the University of California, Riverside. She met with MSDF editor-in-chief, Bob Finn, to talk about her research on estrogen and multiple sclerosis.   Interviewer – Robert Finn Dr. Tiwari-Woodruff, welcome.   Interviewee – Seema Tiwari-Woodruff Thank you.   MSDF So what is the connection between estrogen and MS?   Dr. Tiwari-Woodruff It’s an interesting connection between estrogen and MS, because estrogen is actually a part of life in a way that our brains require it, our bodies require it at every moment of our life, I should say. Many years ago it was found that relapsing-remitting patients had less relapses when they were pregnant, and the causes of that was potentially estrogens – high levels of them – or progesterone or vitamin D. Many researchers went ahead and looked at those high levels of pregnancy estrogens called estriol and found that high levels of estriol were the reason why these women patients had lower levels of MS symptoms.   So eventually down the line, estrogens were parsed out of which estrogen was better. And it turns out that one type of estrogen, which is the estrogen of the alpha, is more immunomodulatory – it actually suppresses the immune response – and that is probably what makes MS symptoms better versus estrogens of the beta ligand was known not to have that much immunomodulatory effect; instead, it was actually directly neuroprotective. So estrogens of the alpha and beta both seem to have an effect on various cell types which are involved in multiple sclerosis.   MSDF So if estrogen seems to be protective in pregnant women with MS, why not just use estrogen, or an analog like estriol or estradiol, as a treatment?   Dr. Tiwari-Woodruff That’s a very good question. And, first, these therapies were thought that we were going to use those first, and a lot of clinical trials were going through with that. But what happens with high levels of estrogen is there are two things which are important to know. One is they have a feminizing effect, and the second one is they have a preponderance for causing uterine cancer or breast cancer. So you don’t want to stimulate those two types of cancer. So high levels of estrogen could be dangerous in that aspect. So that is why we don’t want to use that as potential therapy.   MSDF So you’ve done a lot of work with a specific estrogen receptor agonist called indazole chloride. First, tell me how you came upon this compound.   Dr. Tiwari-Woodruff So estrogens of the beta ligands are not just being looked at for multiple sclerosis, they were being looked at as a potential therapeutic for menopause – hot flashes included – rheumatoid arthritis, and other impairments like prostate cancer, etc. So there were quite a few chemists who were coming up with various different types of estrogen receptor beta ligands. So while I was doing my work with mouse models of MS in generic estrogen receptor beta ligand, which was the DPN – diarylpropionitrile – a study came out which was actually on indazole chloride which was developed by a chemist, John Katzenellenbogen; he’s done a lot of work on developing these molecules. And this particular compound showed that it decreased activation of astrocytes and microglia; this was published in Cell a few years back. And we met at a meeting, John Katzenellenbogen and myself – we were giving a talk at the same time in a meeting in Stockholm – and we decided to talk to each other. And he said, “Your research is very intriguing on estrogen receptor beta ligand, would you like to try this out?” And that’s how I got my hands on the indazole chloride. And we did some preliminary studies and showed good results. Then we decided to embark on a full-fledged study which was published in PNAS.   MSDF So you used indazole chloride in two different mouse models of MS, and you used it both prophylactically and in mice that are already showing symptoms. What did you find?   Dr. Tiwari-Woodruff So prophylactically when you use a compound, you are actually trying to see if you can inhibit the symptoms which are going to come up when you induce a disease, and that is all good. But when you are talking about patients who come to see the doctor, they’re always coming in with symptoms, so they already have the disease ongoing. So the second paradigm where you give the drug when the disease symptoms are already there is closer to what humans are going to be able to see. So the nice thing about indazole chloride was that, prophylactically, definitely it made the mice better, but therapeutically also; they were able to decrease the disease symptoms by nearly 50%.   MSDF What is the significance of the fact that it seems to work on two different mouse models of MS?   Dr. Tiwari-Woodruff So when you’re looking at a drug especially in a disease like multiple sclerosis which has two major components – one is inflammatory component and another one is a neurodegenerative component – if you can show that this drug is working in one way or both ways would be very useful for developing better drugs or better treatments. So what we did was when we treated the mice with indazole chloride, in one mouse model which is the experimental autoimmune encephalomyelitis which contains both the inflammatory and the neurodegenerative component, we saw a decrease in the disease symptoms. But we couldn’t tell if the indazole chloride was working in the inflammatory component or the neurodegeneration component, because it showed effect on both.   So we went to a second mouse model which is the toxic cuprizone diet model which doesn’t have a primary inflammatory component. The disease starts with oligodendrocytes, the cells which make the myelin. They die when you feed this diet to the mice, so they have massive demyelination in regions of the brain. When we gave the drug during the remyelination phase, we found that indazole chloride was able to remyelinate the axons better when the drug was present versus when it was absent. So this actually showed us that indazole chloride has two arms to it. One, it inhibits the inflammatory component and the second, it inhibits the neurodegenerative component independent of the inflammatory component.   MSDF Is it also sort of confirmatory? The EAE is not a perfect model of MS and neither is the cuprizone mouse model, but does it make you feel better that these two completely different models are showing similar effects?   Dr. Tiwari-Woodruff Absolutely, you really hit the point where… We are always looking for the best model for multiple sclerosis, but because the disease is so complex no one model can be said that it’s 100% mimicking multiple sclerosis. So for us to see that demyelination which occurs both in EAE and the cuprizone model was improved – we actually saw remyelination in both models – really gave us hope that this drug could be directly acting on oligodendrocytes which are forming the myelin, which is the cause of major mode of dysfunction in multiple sclerosis.   MSDF So does indazole chloride help these mice a little bit, or does it help them a lot?   Dr. Tiwari-Woodruff So that’s a very good question. Similar to what you might see in the patient population, in the mouse model of MS, especially in the EAE model, the disease is not consistent. So the lesions which appear in the brain of EAE animals are very diverse, unlike the cuprizone model where the demyelination is very consistent. So when you’re looking at these mice, especially in the EAE cohort, if the animal is really, really sick, you actually see the disease symptoms go down just a little bit. But if the animals were sick to the middle level, they actually showed a bigger difference, they showed better recovery. And we hypothesize that the axons which have been injured to the point of no return, if the axons have been demyelinated and injured, it doesn’t matter now when you give them therapeutic drugs, these are not going to improve. So there are certain number of axons in the brain which drop out and we don’t see recovery in those. But said that, overall we still saw a significant increase with indazole chloride treatment in both models.   MSDF Have you done histology?   Dr. Tiwari-Woodruff Yes. We’ve done histology, we’ve done electron microscopy. And we do one more thing my lab is very good at, we do electrophysiology. Because one of the things we always think is when you look at remyelination you can see myelin coming up, but is the myelin functional? If the axons can conduct faster or better, then you know that the myelin which has covered the axons is functional. So we do all three. And we also include behavioral testing. So one of the tests we included which a lot of people use is a Rota rod; it’s a motor test to show that the mice can stay on the Rota rod much longer after treatment with indazole versus just the vehicle.   MSDF Do you see any side effects?   Dr. Tiwari-Woodruff So that’s interesting. We did not see any side effects in these mice. Agreed, we treated them up to 60 days, we haven’t treated them longer than that, plus we were giving them at a 5 mg/kg/day concentration. So we didn’t see any kind of toxicity. But said that, we still need to do those studies in a thorough way before we can safely say that they had no side effects.   MSDF So what’s next in the development of indazole chloride as a potential MS treatment?   Dr. Tiwari-Woodruff So indazole chloride is a good target. And while these studies were going on last year, John Katzenellenbogen and myself, we were talking about how are we going to proceed with this because we were seeing really good results; this is even before I published the paper. And he said what would you like to do? And one of the things we said was is it possible to make better analogs of this compound which are going to be more specific, could be used in a lower concentration and may have a better therapeutic outcome?   So he came up with four analogs which he has sent to me, and we did some preliminary studies to see if they were toxic to cells in culture, because that’s the first thing you do. And they have no toxicity in cells, they actually have shown to behave well with proliferation – depreciation of the cell – and we haven’t seen more cell death or less cell death with them. So we are very excited about that. So coming next month, we are actually going to start treatment of EAE animals, and once that goes through the goal is to do toxicity studies on the two best compounds and see if we can find a company so we can have a backing on these drugs for potential human trials. It’s a couple years from now, at least – it could be even more – but we are actually moving in that direction.   MSDF Dr. David Baker in a commentary on his multiple sclerosis research blog seemed less than enthusiastic about indazole chloride. He suggested that many compounds seem to work similarly in mouse models. How do you respond to that criticism?   Dr. Tiwari-Woodruff So Dr. Baker has a very good point on saying that there could be many compounds which are good in EAE but they fizzle out and they don’t go up to clinical trial. I disagree on one point where it comes to indazole chloride, because we have precedence of estrogens showing good therapeutic indication in humans; there were clinical trials done in UCLA where they showed that there was improvement with estriol treatment. And estriol does target both ER-alpha and ER-beta – ER-beta a little more than ER-alpha – so I’m very confident that what we are seeing with estrogen receptor beta is not a fluke. And because it’s a steroid and a small molecule, it does not seem to have a lot of toxicity involved which could be somewhat which is brand new. So we’ll see. I hope Dr. Baker’s wrong and we do manage to get this drug to human patients and we see therapeutic efficacy in them.   MSDF Dr. Baker also said that a critical experiment had not yet been done. And let me quote from his blog post. He said, “The development of demyelination should be allowed to occur after this damage has abated, then punitive remyelinating drugs should be given.” How do you respond to that?   Dr. Tiwari-Woodruff Very good point made by Dr. Baker, but I have actually addressed those in the PNAS paper. We part off particularly this aspect of the disease. So the prophylactic treatment was before the disease started; that is what he’s mentioning in the blog. The second part is what is important where EAE disease was induced, and after peak disease had occurred we gave the drug, indazole chloride. At the peak disease, we actually see increased inflammation, but alongside with that we see demyelination and axon degeneration. So the damage has already started. The drug treatment after that is what caused the disease to get better. We saw increased conduction, we saw increased remyelination, and less axon damage.   Similar to that, we also did the experiment in cuprizone. The treatment paradigm was as such: We actually had nine week of demyelination ongoing in the cuprizone model, which is very chronic; it’s chronically ongoing where you have quite a bit of damage of the axons and you have acute demyelination. During the remyelination phases where we gave the drug either to one group and vehicle to the other group, what we saw was that the drug treatment, indazole chloride, actually increased remyelination and decreased axon damage. So I think Dr. Baker was trying to make a point on we haven’t done the right experiment, but I think we have done the right experiment. And further research with indazole chloride will let us know if this is a good drug or not.   MSDF Dr. Tiwari-Woodruff, is there anything you’d like to add?   Dr. Tiwari-Woodruff I would like to add one more thing. We have actually looked at indazole chloride in optic neuritis – EAE-induced optic neuritis – and we are going to be publishing a paper fairly soon showing that in optic neuritis we see less inflammation in the retina and increased remyelination in the optic nerve. So I’m very confident that it’s not just a phenomenology in one part of the brain which we picked last time – it was the corpus callosum – that we see increased remyelination and decreased damage caused by EAE with treatment of indazole chloride.   MSDF Well, thank you very much.   Dr. Tiwari-Woodruff Thank you.   [transition music]   Thank you for listening to Episode Thirty 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 editor@msdiscovery.org.    [outro music]

[intro music]   Host – Dan Keller  Hello, and welcome to Episode Seventeen of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Hans Lassmann about the usefulness of animal models for studying multiple sclerosis. But to begin, here’s a brief summary of the developments at the MS Discovery Forum at msdiscovery.org.   In the progressive stage of multiple sclerosis, some astrocytes appear to upregulate genes that intensify inflammation and neurodegeneration. Researchers think that genetic changes cause astrocytes to release a fatty molecule that beckons inflammatory monocytes from the blood into the brain. A drug, miglustat, currently used in the treatment of Gaucher’s disease, may be a good candidate to repurpose as a drug to inhibit astrocytes from initiating this destructive process.   The so-called “long life” protein, Klotho, may hold the keys to remyelination. Named after the Greek goddess responsible for “spinning the thread of life,” an abundance of Klotho leads to longer lifespans in mice. The protein has also been associated with numerous age-related conditions such as Alzheimer’s disease. Recent research noted that reduced Klotho was associated with myelin degeneration in normal, aging Rhesus monkeys. A small molecule, currently known as ‘Compound A’ can promote Klotho in the CNS of mice, enhancing remyelination in the cuprizone mouse model.   We recently released a new data visualization comparing various characteristics – such as age, gender, and EDSS scores – across 74 clinical trials. You can look at each characteristic in every trial, or compare the means of all the trials. To view, go to the “research resources” tab at msdiscovery.org and click on “data visualizations.” Then click on “RRMS and CIS – Baseline Characteristics.”   [transition music]   Now to the interview. Dr. Hans Lassmann studies the pathogenesis of inflammatory diseases at the Center for Brain Research at the Medical University of Vienna in Austria. He met with MSDF at the MS Boston meeting in September to discuss demyelinating disorders.   Interviewer – Dan Keller In terms of what we can learn from other demyelinating diseases, ones caused by infectious agents, how can this shed light on the processes and possible treatment of MS?   Interviewee – Hans Lassmann That depends, obviously, on the models which we are looking. I think there is a major difference between multiple sclerosis and these other experimental models, because the experimental models which really induce large areas of demyelination always are associated with infection of oligodendrocytes. But in multiple sclerosis, there is actually no indication that oligodendrocytes are infected. Now this has consequences that also the demyelination is different in these experimental models because it follows the death of single infected oligodendrocytes. That means that lesions have, more or less, some sort of moth-eaten edges where single oligodendrocytes are falling apart with small pieces of demyelination in between intact myelin, whereas in multiple sclerosis the demyelination is a sharply demarcated lesion which does not follow the oligodendrocyte territories. What we, however, can learn from the models is the question how the brain handles an infectious process in the white matter with respect to inflammation and the amplification mechanisms of tissue injury in the demyelinating process.    MSDF So are they similar enough that we can discern something useful from it, even though the patterns do seem to differ in some ways?   Dr. Lassmann Yes, we can. For instance, there is a major difference between the autoimmune models which we have and the virus models. The autoimmune models are predominantly mediated, or driven, by an MHC class 2 CD4-positive T cell response, whereas the virus models are predominantly driven by a CD8 T cell response. Interestingly, in multiple sclerosis, also the CD8 T cell response dominates. So we can actually learn a lot from these models on the mechanisms of CD8-mediated inflammation in the brain, and also on what are the consequences of a CD8-mediated inflammation in the brain with respect to tissue injury.    MSDF What about some of the diseases that are closely associated with MS but are distinct from it, like neuromyelitis optica and, I guess, concentric sclerosis and others, how do they shed light on things, if they do?   Dr. Lassmann I think they shed a lot of lights on that. Let’s take first neuromyelitis optica. Here we are in a very favored situation because we know it is an autoimmune disease and we know the specific target antigen, and the specific target antigen is a water channel in astrocytes. So from that we have actually learned how antibodies against these astrocytes actually induce the tissue injury, in that case, by first destroying the astrocytes themselves, and then secondarily leading to oligodendrocyte destruction and demyelination, and also some axonal loss. So that actually is a perfect model for a scenario where T cells and pathogenic antibodies play a role in disease mechanisms, and that is apparently also the case in a subset of multiple sclerosis patients, but only in a subset.    MSDF How does the glia enter into this, both as a target and maybe as a mediator or effector?   Dr. Lassmann Now, obviously, the prime target in multiple sclerosis is the oligodendrocyte and the myelin sheath, but there is obviously also pathology in other glial cells. There is an astrocytic pathology, and there is also a microglia activation and pathology in these cases. Now, the astrocytic pathology itself may also contribute to the lesion propagation because when astrocytes are also destroyed in the lesion, or primarily destroyed in the lesion, it will also secondarily lead to the oligodendrocyte loss and demyelination. This is a classical example of neuromyelitis optica.    MSDF Is that through mechanisms of macrophage activation, or debris, or mediator release, or toxic release?   Dr. Lassmann No. From the astrocyte pathology, it’s so that the astrocytes and the oligodendrocytes are connected with gap junctions, and the astrocytes play a major role in supporting the energy demand of oligodendrocytes. So if you kill out the astrocytes, the oligodendrocytes starve to death.   MSDF Now that you bring up energy, can we learn anything from mitochondrial diseases and their consequences?   Dr. Lassmann Yes, here we can learn a lot because the mitochondrial injury and damage is in the center of neurodegeneration and demyelination in multiple sclerosis. In that case, in the disease the mitochondrial injury is apparently driven and induced by oxidative injury, but that it leads in a secondary consequence also to mitochondrial gene deletion, so to deletions of mitochondrially-encoded genes. And here the mitochondrially-encoded gene deletions are also present in many mitochondrial diseases, and for that, obviously, mitochondrial diseases are perfect models to study these aspects of multiple sclerosis pathogenesis. A key issue, for instance, is the mechanisms of mitochondrial quality control. Normally, it’s so that the damaged mitochondrion is just removed from the cell in autophagosomes. But this needs very specific mechanisms of recognition. If this quality control is actually missing or disturbed, then these damaged mitochondria can expand, can clonally expand, and then you get an upward cells having more and more and more damaged mitochondria. And that’s, for instance, also a mechanism which is very prominent in mitochondrial diseases.    MSDF Is that a failure of phagosomes? Is there a defect at that level?   Dr. Lassmann No, I think it’s rather a defect in the mitochondrial proteins, because the mitochondrial proteins are expressed on the surface indicating the phagocytic system, whether they are intact or damaged. And when this process is more or less disturbed, then the phagosomes don’t recognize the damaged mitochondria anymore.    MSDF What are you doing now? What sort of paths are you pursuing in terms of these things that we’ve been discussing?    Dr. Lassmann We have in principles three major projects. The first is that we try to define more precisely what is the nature of the inflammatory response in multiple sclerosis and in to what extent this is different from what is seen in the respective experimental autoimmune models. Now, the second project deals with mechanisms of demyelination, and here the key question is there is soluble demyelinating factor in multiple sclerosis, but it’s not very clear what exactly the soluble factor is; it could be demyelinating antibodies, and that can be modeled in experimental models, like autoimmune encephalitis. But many data suggests that there must be other factors which are not immunoglobulin and not antibodies which are responsible for this demyelination. And then the third project deals with the progressive stage of multiple sclerosis, and here it’s the central pathogenic pathways, oxidative injury and mitochondrial injury. And our projects now go in the direction of what is the course of this massive oxidative damage in multiple sclerosis, how does that relate to mitochondrial injury, and what is the consequences then on the tissue with respect to energy deficiency and other things.    MSDF In progressive disease, do you see a shift towards more mitochondrial damage and oxidative damage or stress?   Dr. Lassmann We have oxidative damage already in the early stages of MS, but in the early stages of MS the oxidative injury seems to be mainly driven by the inflammatory component; that means by inflammation, activation of microglia and then the production of reactive oxygen-producing enzymes. In the progressive stage of MS, we get additional amplification factors for oxidative injury, and they are related to brain aging and related to accumulation of lesion burden. So what we get, on the one hand, an age-related increase of iron in the human brain, and iron can massively potentiate oxidative injury by a reaction which is the so-called Fenton reaction. The second thing is that you have accumulated tissue injury in multiple sclerosis with retrograde and anterograde degeneration, and that leads to progressive microglia activation, which then can actually be transformed more easily in cytotoxic microglia cells by additional proinflammatory stimuli. And the third mechanism is that the mitochondrial injury increases, and in particular the mitochondrial gene deletion and the clonal expansion of defective mitochondria expand in the progressive stage with disease duration. And mitochondria, when they are damaged, they can liberate electrons, and the electrons can actually, again, react with oxygen, producing a reactive oxygen species. And so this is a more or less self-amplifying process which then leads to enhancement of neurodegeneration and demyelination.    MSDF Is there a role for glutathione here?   Dr. Lassmann Yes. Glutathione is one of the key molecules for the oxidative injury, and obviously this is one of the players, but it’s only one.    MSDF It’s a player in the injury or in limiting injury?   Dr. Lassmann That is not entirely clear yet.   MSDF What have we missed or you think is important to discuss or add?   Dr. Lassmann There is certainly in the multiple sclerosis therapy also the tests to increase remyelination and possible regeneration in the lesions, including stem cell therapies or increasing remyelination by soluble factors by cytokines and growth factors. This is all very interesting, but the key point is that as long as the disease process is active, newly-formed myelin is destroyed relatively quickly.    MSDF It seems that there’s almost an analogy to osteoporosis where it’s a balance between formation and destruction. Is there ongoing remyelination or turnover in the healthy brain?   Dr. Lassmann Yes, there is a myelin turnover in the healthy brain, but there is also a profound attempt for remyelination in multiple sclerosis lesions. And what you see even in the early stages in very active MS lesions, you always find signs of ongoing remyelination. But, interestingly, in these early stages, really established remyelination is generally missing, and we have performed a study on that issue showing that if you have disease activity, the remyelinated areas are actually more prone to show new demyelination compared to the normal old myelin which is in there. So that suggests that this remyelination is present and all attempts are present, but this process is relatively instable as long as the disease process is active.   MSDF Is there a thought of being able to inhibit that further, or accelerate a destructive process in these remyelinated areas?   Dr. Lassmann I think this is not really specific for the remyelinated areas. If we are a [?], for instance, that disease process or the progression of the tissue damage can be stopped, for instance, with measurements making some sort of mitochondrial protection, or with certain antioxidative therapeutic strategies, then it will certainly be beneficial both for the old lesions and the newly formed lesions and the remyelinated lesions. But that’s more or less something which has to be solved before we can think of really effective remyelinating strategy.   [transition music]   Thank you for listening to Episode Seventeen 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 Project 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 editor@msdiscovery.org.   [outro music]   

[intro music]   Host – Dan Keller Hello, and welcome to Episode Twelve of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Professor Gavin Giovannoni about the potential for finding a cure for MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Monocytes and microglia are hard to tell apart and as a result, their roles are poorly understood in MS. But we recently covered a paper that demonstrated separate roles for these macrophages in EAE. Using fluorescent tags, the researchers were able to determine that monocytes were directly attacking the myelin. Meanwhile, microglia arrived to the same area of myelin attack only to be shut down. The paper has major implications for future methods in studying MS as well as for the mechanisms of the disease itself.   We published another data visualization recently, titled the “MS Galaxy.” The visualization shows 250 authors of phase 3 clinical trials in MS, and how they are connected to each other. You can explore the galaxy by visiting msdiscovery.org and visiting the data visualizations section under the “research resources” tab.   Additionally, we published a different sort of visualization. This one is an animated video that synthesizes the current understanding of MS immunopathogenesis. Often in presentations, immunologists will toss up a confusing slide covered in shapes, arrows, and acronyms. ACTRIMS’ president, Dr. Suhayl Dhib-Jalbut, has taken that slide and broken it down into its component parts. It’s a wonderfully illuminating experience to listen to him go through the slide step-by-step. MSDF worked in collaboration with Dr. Dhib-Jalbut to make the video. You can view it in the data visualizations section of our website.   [transition music]   Now to the interview. Professor Gavin Giovannoni from Queen Mary University in London is one of the world’s most prolific and most visible MS researchers and clinicians. He is also on the scientific advisory board of MSDF. I met with him at the university to discuss the potential of a cure for MS. This is part one of the interview. Next week’s podcast will feature part two, in which Professor G, as he’s known, discusses the role of Epstein-Barr virus in MS.   Interviewer – Dan Keller Professor Giovannoni, let’s talk about the possibility of cure of MS. I suppose the first question would be what would you define as a cure?   Interviewee – Gavin Giovannoni Because MS is considered to be an autoimmune disease, we should really be able to destroy the autoimmunity by replacing the immune system, or rebooting the immune system, that’s the concept. And there are certain drugs that do that. Obviously, the most aggressive would be bone marrow transplantation, this autologous bone marrow transplantation. And the other one is a recent drug we’ve been using, alemtuzumab, which is a drug that targets leukocytes and depletes them and allows the immune system to repopulate, and when repopulated comes back clearly in a different way. And hopefully those two strategies will remove the autoimmunity. And those two strategies are very effective.   A significant proportion of the people who are treated with bone marrow transplantation or alemtuzumab go into long-term remission; I’m talking about remission 10, 12, 15 years in some of these patients. And if you follow these people up, there’s no evidence of inflammatory activity, so they don’t have relapses. And you monitor their MRI scans, you don’t see any new lesions; the lesions that are there are stable, scarred lesions. And also if you monitor the end-organ brain atrophy rates are not accelerated, their brains are shrinking in the same range as in normal aging. You know, looking at it at a superficial level, we can’t find any evidence of active MS.   Now the question is are those people just in long-term remission or are they cured? And so the definition of a cure then is how long would you follow these people up and say, alright, your MS has gone away. We’ve been debating this in the field for a while. And we think a reasonable definition would be 15 years after they’ve had the treatment, and that would give us sufficient time to study a population and compare them to what we would expect to happen in a natural history study or other treatments. And it’s looking like a significant number of these people are staying in long, long-term remission. So I’m hoping that a portion of them will be cured of the disease.   MSDF Now these are autologous bone marrow transplants?   Dr. Giovannoni Yes.   MSDF So what would prevent them from re-reacting to whatever caused their problem in the first place? I can see allogeneic transplant, you would have a sort of non-susceptible population of cells.   Dr. Giovannoni Yes. I mean, we don’t really know the pathogenesis of autoimmunity in the sense where’s it driven from. I mean, there’s lots of epidemiological evidence in the MS field it probably starts in utero, actually. There’s evidence for parental origin, and migration studies, and monthly birth defect, etc., to suggest that something’s happening in utero. And there’s probably something happening in early life that imprints the autoimmune phenotype or the susceptibility to get autoimmunity. And then, obviously, there’s some trigger that occurs that happens later in life. And I would imagine that that rebooted immune system that we say the autoimmunity is gone would probably still be susceptible because you’re repopulating from a susceptible background, but maybe that trigger won’t come again.   I mean, one of the things people have got to realize is we’re not trying to say this is a cure in everybody who gets this treatment, it’ll only be a proportion of people, and those are the people who don’t reactivate. I mean, we need to learn a lesson is what’s triggering their reactivations if they’ve been in long-term remission. Is it an environmental agent, infection, or something like that? So I wish one knew where the autoimmunity is being triggered from, we don’t know.   MSDF What sort of experiments are going on now? Is this just registries, or do you have multiple strategies? It seems like you have to do very, very long-term follow-up.   Dr. Giovannoni Alemtuzumab was developed in Cambridge and they’ve been using the drug now since 1992, and they’ve got an open-label extension study that they’ve been following up, and they’ve just published a 12-year follow-up data about a month ago in the JNNP. And of that open-label study, about just over 50% of the population are stable. Then there’s obviously the clinical trial programs, and there have been relatively large phase 2 and two phase 3, and those have all gone into open-label extension and those people will be followed up indefinitely, and we’ll probably get data from that.   The bone marrow transplant, it’s a little bit more complicated because most of the development has been done by academic units, so there are registers. And there is a larger phase 3-type study happening in the US at the moment. The registers follow these patients up long-term, so we’ll see what happens. But the cohorts that have been treated early with the disease are doing extremely well. The majority of them, provided they get through the bone marrow transplant, their disease goes into remission and their brain atrophy rates after year 1 are within the normal range, no relapses at MRI, no new MRI activity. So it’s looking very promising.   The problem with bone marrow transplants, it’s quite a risky procedure. For some people it’s a risky procedure, for others it’s not, which is one of the things we find out. If you go to the community and you ask people with MS, when you say to them your chances of dying from the procedure – because in very good bone marrow transplant units now, the mortality rates are between 0.5 and 1% – a lot of people with MS will take those risks. I mean, it’s up to them, they’ve got the disease. The difficulty we have is which patients do you offer those aggressive therapies to.   MSDF Does the feasibility of bone marrow transplantation go down with age?   Dr. Giovannoni I mean, if you train in MS is that all these therapies really work early in the disease. I think the reason for that is the longer you’ve got MS, the more damage is left behind, and that primes that nervous system to degenerate. So when they’ve used bone marrow transplantation in secondary progressive disease and people have really got quite a lot of disability, the induction part of the chemotherapy – the chemotherapy itself is neurotoxic, so they tolerate the induction therapy very poorly. And although the bone marrow transplant switches off the inflammatory component of the MS, that damaged central nervous system is still there and they continue to progress. We think they may progress at a slower rate, we don’t know that, so it doesn’t really stop the secondary progressive phase of the disease when it’s been used in that, which is why most people who do bone marrow transplant now are shifting towards early MS when there’s much more to protect.   And the other issue is there’s a big theory evolving in the MS field that a part of the progressive phase of the illness is premature aging. I’m not talking about premature aging across the whole body, but premature aging within the central nervous system. We know now that any inflammatory or chronic inflammation triggers aging pathways, and that may just drive some part of the progressive component to the disease. And if that’s the case, then we’re not going to be able to modify with anti-inflammatory therapies the strategies that target aging.   MSDF Is this total bone marrow ablation as you would do in any other transplant for curative purposes in oncology, or is it something less than that?   Dr. Giovannoni Well, it depends who you speak to. I went into detail with this in terms of wanting to set up a bone marrow transplant program here about 15 years ago, and I opted out because the risks then were too high. So some people say you really need myeloablative therapy and some people say you don’t need as much as myeloablative; less, you know, these partially ablative ones. So there’s two schools of thought; some want to go for the aggressive and some go for the less aggressive. The Canadian group have used really aggressive induction therapy with myeloablative therapy, and they had, unfortunately, one death and some serious toxicity. So there again is a tradeoff between which one you go for, and I think the results will show over time.   To be honest with you, now that we’ve got alemtuzumab which is a licensed therapy, it’s going to be hard to justify using bone marrow transplant when we’ve got a less toxic monoclonal antibody available. It’s also got safety issues, but I think those safety issues are manageable with monitoring. So I think it’s going to be very hard in the current climate to justify bone marrow transplantation when you have alemtuzumab as a licensed drug.   MSDF Is chemotherapy in itself a reasonable treatment?   Dr. Giovannoni They’ve been tried in the past. I mean, the mistakes we made would say cyclophosphamide, which is an alkylating agent, is that when the trials were done we did them in an era when we didn’t know how to do MS trials. So they were done prior to MRI monitoring, they tended to be doing advanced MS, and the trials were underpowered. I think if we had to do cyclophosphamide in the modern era, we would have done the trials differently, and I’m almost certain they would be effective. We have mitoxantrone which is a chemotherapy agent; that’s got a license in quite a few countries. It’s unfortunately a topoisomerase inhibitor and it’s associated with translocations and causes leukemia. And that’s pretty common actually. The registries that have been tracking are reporting the incidence of mitoxantrone-related leukemia at about 1:150 to 1:200, and I think that itself takes that drug out of practice, to be honest with you. And it also is dose-related treatment; you can only give it for a certain number of infusions because it causes a cardiomyopathy, and it’s also linked to premature ovarian failure. There’s a lot of the issues about using that drug in clinical practice, and most centers now have stopped using mitoxantrone.   MSDF Does this lead into the idea of aborting MS so you don’t get into a progressive phase, all these strategies?   Dr. Giovannoni Yes. We all talk about secondary progressive disease. I’ve stopped using the term secondary progressive disease in isolation. I say clinically progressive disease because the progressive phase of this illness is present from the very beginning of this disease. So when people present with their very first clinical attack, a significant number then will already have had brain atrophy and cognitive impairment. And if you monitor people at every stage of the disease, there’s this progressive brain atrophy occurring. So we think the pathological substrate for progression is there from the outset.   What makes somebody transition into the progressive stage clinically is when the brain reserve runs out. So what stops the progressive phase manifesting is the fact that we’ve got reserve capacity and we compensate. And once that’s run out, people enter the clinically progressive phase of the disease. So I talk about progression being there from the outset; at some point in time you’ll present with secondary progressive MS, and I think it’s system-related.   This is one of the other concepts I’m trying to get across is that progressive disease is not just progressive disease. I mean, most people present initially with the motor system and the lower limbs or their bladder involvement, and then it gradually spreads to their arms, their cerebellar systems, etc. I call it asynchronous progressive disease, and I do this because I really want to give people with progressive MS hope that if you’ve got progression in one pathway, we may be able to treat you and prevent it from becoming clinically progressive in the other pathways.   So this is where we need to rethink our trials, because all of our outcome measures in clinical trials are based purely on lower limb function and mobility. If we wait for people to become progressive in that system, then use that system as a readout, we might miss an important therapy. So what we probably should do is say, well that system’s in the progressive phase, let’s focus on preventing the other systems from entering the progressive phase, those systems that have got reserve capacity. If we change our thinking like that, we’ve got a much greater chance of getting a drug licensed for progressive disease than we have at the moment.   MSDF Because you can choose various endpoints to look at and show that it’s having some effect somewhere?   Dr. Giovannoni Yes. The idea would be to stop or prevent people entering the progressive phase in the other systems. Once somebody’s in the clinically progressive phase in a particular neuronal system, it means that they’ve lost reserve capacity. And that reserve capacity is what predicts recovery. So somebody who is really progressing along that pathway is extremely vulnerable and probably prime to continue to progress. That’s going to be very difficult to show an effect in that pathway. And that’s what we’re doing right now. We’re saying let’s take people with progressive MS that are having walking difficulties, let’s put them in a trial and try and slow down that walking problem. And I think that’s the wrong strategy. I think we should be changing our way we do trials.   MSDF My impression has been that when someone enters the secondary progressive phase, there seems to be an acceleration. But from what you say about loss of reserve leading to progression, it sounds like it’s just the same slope but without the remissions.   Dr. Giovannoni Yes. We think the mechanisms are different though. There is some evidence what I call a therapeutic lag. This is complicated. Let me explain what a therapeutic lag is. When you’re in the progressive phase of the disease, we think the progression that’s occurring this year or next year has been primed by inflammation that’s occurred over the two years. So there’s a lag between the inflammatory component which damages those nerve fibers, and then they dive over the next few years. It probably damages them and they’re probably surviving and functioning but compromised, and that process then runs its course.   So I think what we really need to do is if we do clinical trials and switch off inflammation now, you’re not going to see an effect of an anti-inflammatory drug in the next two years, we have to look in year three, four, and five. And there is data now from extension studies supporting this. So I actually think we also need to change our trial design in progressive MS if you’re going to look at a progressing pathway; not to look in two years, we’ll be looking at year three, four, and five.   The current crop of trials are kind of doing that. What they’ve done is instead of having a fixed time point of two years, most of them are event-driven, so when they have enough events they will stop the trial. And the event-driven trials looks like they’re taking the follow-up into year three and sometimes year four. So we may get enough power to see if that works in the current crop of trials in progressive MS. But I really do think that we need to go to probably five years in progressive MS trials to get a readout that we can trust, based on our understanding of the progression of the disease.   MSDF So can you enumerate or summarize what you think trials should look like? What one would choose as endpoints, definitions, anything else that would be different from how they’re doing it today?   Dr. Giovannoni Yes. So if we’re going to continue to use the gold standard, which is EDSS, this expanded disability status goal which has a lot of psychometric problems – it’s got a flawed seeding effect, it’s not linear, it’s got a high inter-rater. . – with all those problems, we’ve still got this damn gold standard, EDSS. If we’re going to use the EDSS and we’re going to focus on mobility, then we’re going to have to do 5-year trials. And know that there’s a therapeutic lag, forget about expecting to see a result in year two and look at year three, four, and five. In addition to that, I think we need to actually then develop new outcome measures that assesses the systems that aren’t affected, like upper limb function, cognition, cerebellar, eye movements, etc., and look for differences in those systems on active treatment versus placebo. We’ve changed the question. In other words, we’re trying to prevent those systems from being damaged relative to the system that is damaged. And I think then we may get an answer. And I’m almost certain anti-inflammatory strategies that I’ve been told not to work in progressive MS will work.   MSDF If you look long enough.   Dr. Giovannoni If we look long enough or we change the way we define the outcomes. Because I do think that those other systems that aren’t progressing clinically will be more responsive in a shorter period of time; they’ve still got reserve capacity. And that reserve capacity really predicts recovery. We’ve seen this now in early MS is if somebody has got a low disability score and you treat them with a powerful anti-inflammatory, be it natalizumab or alemtuzumab, a significant number – 30 to 40% - actually improve in function. And that’s because they’ve got reserve capacity; they have the ability to recover function. I think if you can choose pathways that have got reserve capacity and you treat with anti-inflammatories, those pathways may have an ability to recover or improve, and you’ll see the difference between the treatments much earlier. It’s just an observation that needs to be taken into clinical trials.   MSDF Locking the barn door while the horse is still in.   Dr. Giovannoni Yes. This is like any other disease. There’s no point in treating a disease after you’ve missed the boat. If you speak to rheumatologists or nephrologists, it’s much better to protect the kidney and the joints before they’re damaged. The same concept needs to come into the MS field. You need to target the organ before it’s damaged, because prevention is much better than trying to promote recovery.   MSDF Very good. We appreciate it. Thank you.   [transition music]   MSDF Thank you for listening to Episode Twelve 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 Project 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 editor@msdiscovery.org.   [outro music]    

[intro music]   Host – Dan Keller  Hello, and welcome to Episode Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with neurologist, Dr. Daniel Kantor. But to begin, here's a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.   At MSDF, we publish short, medium, and long articles. The longest News Synthesis articles cover an entire area of MS research. In one recent News Synthesis, science journalist Cynthia McKelvey, provided a primer on epigenetics. Epigenetic modifications are defined as any change to gene expression that happens without altering the  DNA sequence, and they could be the key to understanding heterogeneity in MS. Though the literature on the role of epigenetics in MS is growing, the field remains in its infancy and is not very well understood by many MS researchers and clinicians.   The medium-length articles we call New Findings, and they focus on either a single study or a small group of closely related studies along with comments from experts not directly involved in the studies. An excellent example by Science journalist, Mitch Leslie, explores an iPad app that may become a more convenient alternative to the much maligned Expanded Disability Status Scale, the EDSS. The app mimics four tests in the Multiple Sclerosis Functional Composite test. In an initial study, the app was sensitive enough to discern people with MS from healthy controls. If future trials are successful, it could allow patients to test themselves at home. It could also streamline data collection making the app useful to researchers as well. Our article includes a video demonstrating the app in action.   Then there are the News Briefs—short, meaty, and easy to digest summaries of noteworthy studies. For example, we reported on a large international survey that recorded a high statistical correlation between physical activity and health-related quality of life in MS patients. Another news brief looked at a study showing that evaluating a patient’s treatment preferences may play a key role in how long he or she will stick with a disease modifying treatment. We also reported on a study that described differences in overall brain atrophy between MS patients with oligoclonal bands and those lacking them.   Now for the interview. Dr. Daniel Kantor is a neurologist based at the Neurologique Foundation in Florida who is concerned with MS patients’ access to care. Dr. Kantor met with MSDF editor, Bob Finn, to discuss this issue.   Interviewer – Bob Finn Dr. Kantor, welcome   Interviewee – Daniel Kantor Thank you.   MSDF  In a recent article in MS Focus, you wrote that there are three types of access to care. What are they?   Dr. Kantor  Access to care means many things. Sometimes people think access to care just means access to medications. But access to care actually means access to physicians, access to medications, and then access to all the other diagnostics and other types of testing.   MSDF And how would you grade the US healthcare system on each of those as it relates to MS patients on each of those factors?   Dr. Kantor 2014 has been an important year with the Affordable Care Act as well as with other federal legislation as well as state legislation that's happened. Access to care for some patients has gotten better. People who maybe couldn't get insurance have been able to get it. For a lot of people, though, their access to care has either remained the same or actually their access has come down. What I mean by that is somebody who could see the physician of their choice in the past now, in 2014, has found it increasingly difficult to have access to physicians who are familiar with their care, familiar with their disease state, and familiar with the treatments that are out there.    MSDF You mentioned the Affordable Care Act. How is that specifically affecting access to treatments, access to physicians, access to diagnostics?   Dr. Kantor The Affordable Care Act did several things. One of the things that happened in the Affordable Care Act was the creation of these exchanges or the marketplace. So in states that either ran their own marketplace or that go with the federal marketplace, there are plans that are really "stripped down" insurance plans. And that means that there's more restricted networks – meaning the patient has less choice when it comes to who to see about their disease state – and there's also sometimes more restrictive choices in terms of the medications. So you have less physicians to offer them care, maybe not physicians who specialize in multiple sclerosis, and then that physician also has less choices of what to use. So as you can imagine, those things get compounded, and a patient may have a lot less access to care than they would have had otherwise. A simple example is a patient who did not have insurance and now has insurance. So a patient who didn't have insurance before they've gained access because now they carry a plastic insurance card. But while they may have been paying a reasonable sum to a physician to see them with a cash pay, now that physician is not offered on their health insurance plan. While they may have been part of a patient assistance program with many of the pharmaceutical manufacturers, they may or may not still be eligible for those same patient assistance programs. Meaning that a drug that may have been free to them – or very low priced – may be even more expensive to them now.    MSDF At MSDF, we recently ran an article about a study; it was a survey of neurologists. And the survey was looking at a number of different things. But the neurologists were saying that their patients were happy with fingolimod but not happy with their insurance companies giving them access to fingolimod. What other sorts of issues like that are arising in MS?   Dr. Kantor I think it's a perfect example. Prior to 1993, we had no disease-modifying therapies that were FDA approved. Since 1993, we now have 10 separate branded products. That's an amazing leap forward. Not many fields in medicine have seen that kind of increase and certainly not in the world of neurology. For many patients with other neurological conditions – like Huntington’s disease, amyotrophic lateral sclerosis or Lou Gehrig’s disease, even stroke – they look at MS, and they're jealous. They have seen such an increase in the amount of research. At the same time, however, we see a decrease in the practice. We see it being harder and harder to actually practice good MS clinical care. And so, while patients may have access in some ways to medications that have even more efficacy than our traditional medications, if a patient can't get their medication or has to go through many, many insurance hoops to get there, then that's not good for them.   MSDF What's the solution?   Dr. Kantor The solution really is the neurology, physician, nurse practitioner, and physician assistant and community working alongside the patient community together and engaging our colleagues in the managed care world. Like it or not, in America, healthcare is usually paid by somebody else. Most people do not walk into a hospital or walk into a doctor's office and write the payment themselves. They are either part of an employer group – where the employer is frankly handling much of the payment – or now they're part of exchanges, or they may even be part of a federal program like Medicare or a state program like Medicaid. So the client for the doctor is not really the patient. Our patients are our patient; and we have a Hippocratic Oath; and we have a long, long time of tradition of what we do for that physician/patient relationship. But it's not really a client relationship. That might be good/that might be bad, but it's the fact. In fact, for most practicing physicians, most practicing clinicians, our client is actually the insurance company. And so that means that there's some disconnect between what a patient might think they want and even what the physician might think they want for the patient and what the patient actually gets. So what we need to do, though, is engage these managed care organizations better in terms of recognizing that things like step edits, like prior authorizations those are here to stay. Sometimes some neurologists see them as so unethical that the real prior authorization should be the doctor's prescription. The fact is that that's not the case. And it's going to be very hard to change that system (9:26) unless the person who's actually paying is the actual patient. And so recognizing that managed care organizations are there to manage their medical costs we need to work better at giving them the tools they need. We think that there's no guidelines for treatment of MS; there actually are; there are many guidelines. Each state – if you look at the major insurance company in that state – their prior authorization and utilization management criteria that is the most commonly used guideline for multiple sclerosis in that state. So while we may think, as physicians, it doesn't exist, it does exist; it's just not being written by us. These are being written by pharmacists at either pharmacy benefit management companies or pharmacists at insurance companies, and they're deciding the fate of our patients. We need to take a more proactive stance and work together at developing guidelines that can make sense and that have also "outs". What I mean by that is even if you say that we have a treatment algorithm that works for most patients there's always going to be patients who for some reason or other you don't want to put them through that algorithm. An example may be if you're going to start a medicine that has a potentially high chance for a certain side effect – and you think from past experience that that patient may have that side effect because they've been on similar medications with a similar side effect – then you may not want to put them through that algorithm. You may want to say well they haven't failed the medicine yet, they haven't had an intolerable side effect from this medicine, but they've had from a similar medication. And that becomes a big issue, for example, in the use of one of the oral medication, dimethyl fumarate – also called BG-12 or by the brand name of Tecfidera – where we do see significant GI side effects. For a lot of people, we don't; for most people they tolerate it well. But if you have a patient who has already shown you on multiple other medications for different symptoms that they have sensitive stomach, then even without a diagnosis of Crohn’s disease or celiac, you still would probably want to avoid using that medication. So that's an example where it's not a contraindication listed on the label, it's not an absolute contraindication – and it may not even be considered a relative contraindication – but in the physicians' opinion that patient would have a negative outcome because of that medication that's where they shouldn't go through that algorithm in the same way.   MSDF How successful are you at convincing insurance companies of that?   Dr. Kantor I think we're getting increasingly successful. In 2009, we started a group which was at first called the SouthEastern MS Consortium, or seMSc, sort of like the SEC in football. And then Texas A&M entered the SEC in football so we expanded to the Southern MS Consortium. And we go from Texas east and Delaware south; we take the most liberal definition of the South. Now there are members from California, Minnesota, Pennsylvania, and we're actually about to relaunch and rebrand as the Medical Partnership for MS. And the idea was that prior to this MS neurologists, as well as nurse practitioners, physician assistants, speech therapists, physical and occupational therapists, case managers, social works didn't feel like they had a voice when it came to advocacy for their patients. They felt like the existing organizations didn't always reflect what they're going through and what their patients are going through with taking a proactive stance on some difficult issues but by engaging in a collegial way with the insurance companies. Instead of taking in a stance that every medication should be available for every single patient, we've taken a more reasoned approach of while that may be in an ideal world that's not the world we live in. And so, let's look at the different utilization criteria, utilization management criteria, of the different insurance companies and work with them on a one-by-one basis. So we have constant conversations with insurers throughout this country.   MSDF  Dr. Kantor, I thank you very much.   Dr. Kantor Thank you for having me.   [transition music]   Thank you for listening to Episode Seven 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 Project 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 editor@msdiscovery.org.   [outro music]   

Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum Transcript of Episode 1 with Dr. Timothy Vollmer [intro music] Host – Dan Keller Hello, and welcome to Episode One of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s Podcast features an interview with Dr. Timothy Vollmer, who discusses strategies for maximizing brain health in people with MS. But first, here is a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org. First, oral contraceptives. According to a retrospective study published in the journal Fertility and Sterility, women with relapsing remitting MS who used combined oral contraceptives tended to have less severe disease, and they were less likely to move on to secondary progressive MS. On the other hand, this study showed no association between oral contraceptives and annualized relapse rates or EDSS scores. An intriguing set of associations, but correlation does not imply causation. Next, the blood brain barrier. A study in PLOS ONE showed that when cultured blood-brain barrier cells are treated with serum from MS patients the cells decrease their production of tight junction molecules and increase their production of cell adhesion molecules that promote cell migration. Breakdown of the blood-brain barrier is an early feature of MS, and this allows activated leukocytes to migrate into the brain. Understanding this process is important in its own right, but the study also raises questions about the safety of blood donations from people with MS. Does this study suggest that people with MS should be barred from donating blood? Let us know your opinion in the comments. Finally, we hope you’ll check out our new data visualization section, which will allow you to see MS-related data in new ways. Our first visualization is a bubble chart presenting data from 106 MS clinical trials published between 1986 and April 2014 involving 44,606 patients. You can easily sort the data by compound, by trial phase, by dose, by year, by funding, or by population. Please let us know if you discover something unexpected or particularly striking in the data. [transition music] Now, onto the interview. Dr. Timothy Vollmer is a practicing neurologist specializing in MS. He’s also professor and director of clinical research at the University of Colorado Denver. Bob Finn, our executive editor, caught up with Dr. Vollmer at the annual meeting of the American Academy of Neurology in Denver. Interviewer – Bob Finn This is Bob Finn from the MS Discovery Forum. I'm here with Dr. Timothy Vollmer of the University of Colorado Denver Rocky Mountain MS Center, who among other things is interested in how to maximize lifelong brain health in people with MS. Dr. Vollmer, welcome. Interviewee – Timothy Vollmer Thank you. MSDF Why is now a good time to ask about maximizing brain health? Dr. Vollmer Well two reasons: one is because recent research has indicated that there are both medical ways and lifestyle ways to actually improve brain health, and the the data suggests that if we do that that's going to improve people's function later in life and allow them to be the grandparents that they want to be or other things that they want to do later in life. And the second reason is is that we now have nine FDA approved therapies to alter the course of MS by inhibiting the inflammation that causes the damage in the brain. And our challenge is figuring out how to use those most effectively. MSDF So how do you measure a concept as broad as brain health? Dr. Vollmer The easiest measure is actually the size of the brain. One of the unfortunate consequences of multiple sclerosis – as is true with hypertension, cardiovascular disease, strokes, dementia, and other things – is that neurons are dying. So MS is not just a disease of myelin; it's a disease of the entire brain, and it affects neurons and cells called astrocytes and cells called oligodendrocytes that make up the bulk of what the brain is. The result of of loss of these neurons is the brain has less and less flexibility in terms of shifting function around from areas that are not working well to areas that are working well. That ability to switch, or shift function around, is something that we do automatically throughout life. Every time we bump our head and get a little bit of bruising in the brain the brain can compensate by shifting function around. This is the same issue that the NFL is dealing with with its football players and mothers are worried about with their kids in contact sports. The problem of multiple sclerosis is that most of the disease activity is actually below the radar – it's not presenting as relapses – and you don't see it unless you're doing regular MRIs, or you're doing a a more modern MRI technique called a volumetric MRI where you can actually measure the three-dimensional volume of the brain. And we do that routinely in studies, and we know that in MS the brain is shrinking at a rate of about six times faster than the normal healthy controls. That's the fundamental problem in terms of maximizing lifelong activity is we're losing brain function too fast in the early phase of the disease. MSDF So how does this concept help guide treatment? Dr. Vollmer Well it turns out that there actually are three components to a treatment plan that wants to maximize brain health over a lifetime. The first one in multiple sclerosis is obviously to try to prevent further damage to the brain by using the immunological therapies that we have in the most effective way possible. And that's a a bit challenging, but the fact is we have a lot of opportunities now that we've never had before. And this is an issue for the medical field. The second aspect is it turns out that more and more research – including that presented here at the American Academy of Neurology meeting – suggests that if you exercise and are intellectually and physically active that increases your brain reserve. It does that because as you fire neurons by doing something – learning a language, volunteering, going to church, reading, whatever – that causes the nerve cells to put out new branches called neurites. And those neurites randomly connect with other neurons in the vicinity. If you do something to activate that pathway, then you make it permanent. If you don't do something to activate that pathway, it breaks automatically within 24 to 48 hours. So you need to be active on a daily basis really to try to maximize those connections. And what you're doing you're just creating this three-dimensional network of connections between nerve cells that gives the brain the flexibility of shifting function around. And it was reported at this meeting – and it's been reported in the literature a number of times – that people who are intellectually active actually have less disability controlling for all other factors than people who are not intellectually active. And we now know that that's also true by being physically active. And again, this cuts across multiple diseases, but it's just as important in MS as it is in other ones. And then, the third factor is diet. The reason for that is not that there's a specific MS diet; there isn't. But we know that if you develop other dietary related diseases, that substantially increases your risk of disability from MS. So for example, just developing diabetes almost doubles your risk of being disabled from MS than just having MS alone. So just having high blood pressure, just being overweight or obese increases your risk of disability. So that means if we want to maximize lifelong outcomes then we prevent injury by using the drugs as effectively as we can; we get people to exercise and be intellectually active to create more connections with brain, create more cognitive and brain reserve; and we also help them develop a healthy lifestyle from a nutrition aspect, as well, to prevent them from developing other diseases that would compromise neurological health.  MSDF Well all of this sounds interesting, but it sounds completely obvious to me. What is controversial about this subject? Dr. Vollmer There are two things. One is that the medical profession is just now beginning to evolve in the direction of trying to think about global health and chronic diseases. Primary care physicians have been thinking about this for some time, in general, but in terms of applying it to chronic diseases this is a a relatively new concept, and how to do it is still a challenge. The second reason is that regulatory agencies, in other countries, and then in this country, health insurance organizations, prevent us from doing this. So for example, in early phase disease for patients who don't carry a virus called JC virus, a drug called natalizumab or a drug called fingolimod might be actually be the best drugs for them. But the insurance companies, even Medicare and Medicaid, make it very difficult for us to use them in the patients. They tend to approve the old drugs first because they perceive them as cheaper usually through sweetheart deals made by the private insurance companies or just because of concerns of cost on the part of Medicaid. And they prevent us from using more effective drugs earlier; they don't understand this concept of preserving brain volume and brain health in terms of trying to maximize lifelong outcomes. MSDF Is there any proof though that starting with fingolimod or natalizumab – starting with the "heavy hitters" – will prevent the the long, slow progression? Dr. Vollmer Yes and no. The problem is the gold standard would be a 50-year study looking at 10,000 people. That's never going to be done partly because the target is constantly moving as new therapies come into the marketplace, but also it's just not practical. However, having said that, published both in the peer reviewed literature and at the American Academy of Neurology meeting are a number of relatively large studies done at centers around the world – most not funded by drug companies – that have reported that patients on fingolimod or natalizumab are significantly better off after two years of treatment than patients using interferons or glatiramer acetate. And at this meeting, specifically they compared in an open-label way patients who were started on fingolimod versus patients started on interferons or GA or switched, and again they showed a 50% reduction in relapse rate. And in the literature for natalizumab, there have been reports since 2010 of the fact that if you're treating relapsing MS patients over two years period of time, on average, that group is improving in function. And that includes fatigue, cognition, mobility, employability. So with highly effective therapies, we do have evidence, substantial evidence, that slowing down brain volume is important, and that results in better function and often resolution of symptoms – patients actually get better on these highly effective therapies. And we've not seen that with interferons and glatiramer in most patients. MSDF As a physician, can you recommend strategies for making the argument to third party payers? Dr. Vollmer Yes. There is a lot of research data that proves that brain volume or gray matter volumes or the number of neurons that you have in your brain is the most powerful predictor of what's going to happen to you in terms of disability over your lifetime, and this is not an arguable point. However, regulators tend to look at relapse rate reduction and gadolinium-enhancing MRI lesion reduction, which are not very good at predicting long-term outcomes. So we need to reeducate health insurers and third-party payers that if you really want to optimize patients' lifelong health you need to make the investment upfront in highly effective therapies to prevent them from developing more disability. We know there are a number of studies reporting that total healthcare costs are less if you're using highly effective therapy like natalizumab or fingolimod over time than they are with interferon and and glatiramer acetate. So this has been published in many different ways; there's more than a dozen papers in the literature on this. The problem is is that any one study is relatively small, and it's easy to criticize it. But the field needs to step back and look at the overall literature. And the overall literature is consistent; we consistently demonstrate that if there's an effect the effect is in favor of using more effective therapies as early as possible in the disease course.  MSDF Aside from brain volumetrics, what are what are some other good ways of measuring brain health? Dr. Vollmer Well you can look at the number of what are called T2 lesions that are developing on the MRI; so your neurologist can look at that, and they can compare you to other patients of a similar age and try to determine are you on the good end of the spectrum or or the more worse end of the spectrum. You can look at what's called T1 black holes; it's a typical MRI measure that's always done. But T1 black holes are more correlated with worse long-term outcomes, and so if you have more T1 black holes you really should be thinking about being on a more effective therapy. And certainly, if somebody is on a therapy and they continue to have any evidence of disease activity – which means a relapse, a change in the MRI or progressive disability – they should probably be thinking about being on a more effective therapy, and they should be discussing that with their physician.  MSDF I'm a little surprised that you didn't mention any cognitive measures. Dr. Vollmer It’s only because I assume automatically that they're very important, and, in fact, most of the data on brain reserve is focused on cognitive function. However, I would argue that the same principles apply for mobility, for sensation, for vision, for creativity. And so, MS is a disease of the central nervous system, so it attacks the very core of what it is to be human. We tend to focus on the bipedal nature of human behavior, but that's not the most important thing. The most important thing is maintaining your interaction with your family, with your friends, with your profession, being able to progress and learn, etc. We can deal with mobility issues, but we don't have a way to recover cognitive function yet. MSDF Are you yourself conducting any studies in this area? Dr. Vollmer Yes. We have a number of studies; we actually have 28 clinical studies going on in MS. But two of the ones that I think are very relevant to this particular issue is we have been funded to be able to look at the changes on MRI in patients that have been on either fingolimod or natalizumab for two years or longer. And we're comparing them to age matched healthy controls. And what we're asking is is the rate of brain volume change, which all of us suffer, but is the rate of that change in those patients now similar to what it is in healthy controls versus patients who have MS? And as I said, we know that the percent change in brain volume for healthy people is about 0.1% per year; in MS it averages about 0.6% per year. So we're we're doing this study now to see the patients who are doing well – they're coming into the clinic, they're saying I'm feeling good, I feel like I'm as good or better than I was last year – is their brain now normalized in terms of its very modest loss of brain volume over time as a result of normal aging?  MSDF And you said there was a second one that that is particularly relevant. Dr. Vollmer The second one is is to take and ask patients, it's called patient reported outcomes – where we actually ask the patient about how they're doing in cognition, how they're doing with energy, how they're doing with mobility, how they're doing with sexual function, you know, the things that are important to us – and we're asking how that is changing over time on these therapies, and we're trying to correlate that back with what's happening to their brain MRI in terms of brain volume.  MSDF Dr. Vollmer, I've come to the end of my prepared questions. Is there anything else you'd like to add or any questions I didn't ask that I should have asked? Dr. Vollmer Two things. As I said, one is it's very important for patients and the healthcare profession to really begin to understand that MS is a disease of the entire central nervous system, and its impact on neurons is actually the most important aspect of this of this disease. The second one is that healthcare providers working with MS patients and MS patients and families need to advocate to the healthcare system to allow healthcare providers to use the most effective therapy that works best for that patient based on individual assessments of safety and efficacy.  MSDF Well thank you very much. Dr. Vollmer Thank you. Appreciate the interest.  [transition music] Host – Dan Keller Well that’s it for Episode One 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, Robert Finn, executive editor. MSDF is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is the 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 editor@msdiscovery.org.  [outro music]    

Background: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. Objective: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. Methods: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). Results: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome.

Multiple sclerosis (MS) is characterized by high variability between patients and, more importantly here, within an individual over time. This makes categorization and prognosis difficult. Moreover, it is unclear to what degree this intra-individual variation reflects the long-term course of irreversible disability and what is attributable to short-term processes such as relapses, to interrater variability and to measurement error. Any investigation and prediction of the medium or long term evolution of irreversible disability in individual patients is therefore confronted with the problem of systematic error in addition to random fluctuations. The approach described in this article aims to assist in detecting relapses in disease curves and in identifying the underlying disease course. To this end neurological knowledge was transformed into simple rules which were then implemented into computer algorithms for pre-editing disease curves. Based on simulations it is shown that pre-editing time series of disability measured with the Expanded Disability Status Scale (EDSS) can lead to more robust and less biased estimates for important disease characteristics, such as baseline EDSS and time to reach certain EDSS levels or sustained progression.

Background: The annual relapse rate has been commonly used as a primary efficacy endpoint in phase III multiple sclerosis (MS) clinical trials. The aim of this study was to determine the relative contribution of different possible prognostic factors available at baseline to the on-study relapse rate in MS. Methods: A total of 821 patients from the placebo arms of the Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) database were available for this analysis. The univariate relationships between on-study relapse rate and the baseline demographic, clinical, and MRI-based predictors were assessed. The multiple relationships were then examined using a Poisson regression model. Two predictor subsets were selected. Subset 1 included age at disease onset, disease duration, gender, Expanded Disability Status Scale (EDSS) at baseline, number of relapses in the last 24 months prior to baseline, and the disease course (RR and SP). Subset 2 consisted of Subset 1 plus gadolinium enhancement status in MRI. The number of patients for developing the models with no missing values was 727 for Subset 1 and 306 for Subset 2. Results:The univariate relationships show that the on-study relapse rate was higher for younger and for female patients, for RR patients than for SP patients, and for patients with positive enhancement status at entry (Wilcoxon test, p

The course of multiple sclerosis (MS) is generally difficult to predict. This is due to the great inter-individual variability with respect to symptoms and disability status. An important prognostic endpoint for MS is the expected time to sustained disease progression. Using the Expanded Disability Status Scale (EDSS) this endpoint is here defined as a rise of 1.0 or 0.5 compared to baseline EDSS (5.5) which is confirmed for at least six months. The goal of this paper was threefold. It aimed at identifying covariates which significantly influence sustained progression, determining size and form of the effect of these covariates and estimating the survival curves for given predictors. To this end a piecewise exponential model utilizing piecewise constant hazard rates and a Poisson model were devised. In order to improve and simplify these models a method for piecewise linear parameterization of non-parametric generalized additive models (GAMs) was applied. The models included fixed and random effects, the posterior distribution was estimated using Markov Chain Monte Carlo methods (MCMC) as well as a penalized likelihood approach and variables were selected using Akaikes information criterium (AIC). The models were applied to data of placebo patients from worldwide clinical trials that are pooled in the database of the Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR). Only with a pure exponential model and fixed effects, baseline EDSS and the number of relapses in the last 12 month before study entry had an effect on the hazard rate. For the piecewise exponential model with random study effects there was no effect of covariates on the hazard rate other than a slightly decreasing effect of time. This reflects the fact that unstable patients reach the event early and are therefore eliminated from the analysis (selection effect).