Disease-Modifying Therapy and Cognition in Patients With Multiple Sclerosis

Ahmed Obeidat, MD, PhD; Randall Schapiro, MD, FAAN; and Jeffrey Wilken, PhD, share their opinions on the utility of disease-modifying therapies to increase cognition and brain health in patients with multiple sclerosis.

Ahmed Obeidat, MD, PhD: Talking about disease-modifying therapies [DMTs], this is a big revolution in MS [multiple sclerosis]. You’re going to tell us a bit about how these have changed over time, and we are really proud and happy with what we see now, there are a lot of options and good efficacy. Now, when disease-modifying therapy comes into play with cognition in MS, we want to hear your opinion on this, and the same for Dr Wilkens. We’ll start with you, Dr Schapiro.

Randall Schapiro, MD, FAAN: I am a believer in disease-modifying treatments. I’ve seen MS before, I’ve seen it after. I’ve been involved in lots of the research studies of most of the drugs that are available. We have now over 25 different drugs in various combinations that affect the immune system. Every single one of our disease-modifying treatments affects the immune system. That’s not the cognition system; that’s the immune system. Thus, to think that disease-modifying treatment is a treatment for cognitive problems, specifically primary cognitive problems, is probably wrong. It’s a treatment of the immune system. Now, I have been lecturing for years that if somebody has cognitive problems, we like to get them before they have the cognitive problem. Hence, it’s really important to be on a disease-modifying treatment to preserve the brain so you don’t get a cognitive problem. But to think that one disease-modifying treatment is better for cognition than another is probably faulty. However, there’s no question that there are stronger drugs among the 25 than some of the others. If I see somebody whose primary issue or major issue is a cognitive problem, I would lean toward moving toward the stronger and more modern drugs, if you will, because I’m more worried about the damage that occurs. But Betaseron [interferon beta-1b], which was the first drug that came out, if it’s working for the person, if their relapse rate is diminished, if their disease progression is not quite as bad, if their MRIs are stable, it’s as good as the alemtuzumab, or whatever it happens to be. You want the drug that works for that individual.

Ahmed Obeidat, MD, PhD: It’s more personalized, more tailored.

Randall Schapiro, MD, FAAN: You need to find the right drug for the right person at the right time.

Ahmed Obeidat, MD, PhD: I like how you mentioned the word preserve; preserve that brain. This is where we use the DMTs. Although they’re targeted toward the immune system, we are, I would say changing this immune system back or putting it back in homeostasis maybe…we’re tamping it down in a way where we’re going to preserve the brain. This is an important topic, an important kind of concept here because we’re speaking about the importance of early treatment with MS. You mentioned something about people with some signs of cognitive difficulties at the beginning. Maybe you want to put them on a high efficacy therapy right away.

Randall Schapiro, MD, FAAN: Absolutely. There are other prognostic indicators that we look at that we worry about, spasticity, we look at people who have relapses one after the other. We look at disease progression, we look at all kinds of things, age, and things that make us be more aggressive in a particular individual. But I want to add one more thing that I think is important that people don’t think about. I have a mantra; I’m old enough that I can say I have a mantra. The answer to disability is mobility. And one of the answers to cognitive problems, surprisingly, is mobility. I’ll tell you why I say that. We created a center in Minneapolis, Minnesota, for severely disabled people, it’s called a multiple sclerosis achievement center.

We had 200 people—it’s still going—who had severe disease who would come once a week for the whole day for maintenance rehabilitation: PT [physical therapy], OT [occupational therapy], speech, chaplaincy, things of that nature, maintenance rehabilitation. These are very disabled people living in the community, not in nursing homes, but they were all in wheelchairs, very disabled, all had cognitive problems of various sorts. Almost all of their caregivers would say to me that since they went to the achievement center, they got smarter. I would say, I can’t understand, we’re not giving them anything, no juice or something that’s making them smarter. Then it hit me what was going on. With severe disability, people start isolating, they don’t go out, don’t go to dinner, don’t go to movies. They don’t go to church. They stay and watch television, stay home. We were taking them and putting them in a social situation where they were asked about the Minnesota Twins and the Minnesota Vikings and how they were feeling. The brain is not a muscle, but if you don’t use, it you lose it. These people got smart. The answer to disability is mobility.

Ahmed Obeidat, MD, PhD: This is great perspective. I think to your point, it’s engaging. People are engaged mentally. They’re engaged with other people. They’re having some other activities they’re doing that are going to keep the brain functioning. We saw this also during the COVID-19 pandemic. Unfortunately, we saw a lot of isolation, where people were staying home and not interacting. That really brought up a lot.

Jeffrey Wilken, PhD: The pandemic was terrible for cognitive issues in every disease condition, especially MS. People come in and they tell me this. I don’t even have to ask them. They’ll be like, “I know that I got worse because I was asleep when I was in my house all the time.” If I can go back to the question you had before about the DMTs, one thing that we have a problem with is the research. Probably one of the best studies ever done on MS and cognitive issues with a disease-modifying treatment was one of the first ever done. It was done with Avonex [interferon beta-1a] by Jill Fischer, PhD, way back when. I understand that study was driven by external forces to include not only control groups, but also a really nice neuropsychological battery. It showed some very positive effects for a drug that isn’t supposed to be all that strong nowadays, but some good positive effects. That was probably a couple of years after I got into working with MS. That was early 2000s, I believe that study was maybe 2000. I started in MS in about 1997, 1998. I don’t know that I’ve seen many decent studies. I see studies that talk about cognition, but they’re not really doing what they need to be doing.

But one of the things I also see is they are all funded by pharmaceutical companies, which I’m not bashing that, because I actually think some very good research has been done by pharmaceutical companies. The one problem is that then there are internal pressures about whether there can be a control group, what type of control group it needs to be. And I’ve battled with many of the companies. If they were sitting here right now, they’d be like, “No, we’ve heard this from you before.” But there needs to be control groups. And there typically are not control groups, and they tend to be these 1-arm studies. They’re not necessarily looking at all the things they need to look at. Hence, we do not see great studies yet on the DMTs. Any of us in cognition continue to work with them on trying to develop some nice studies. It has not been easy. I agree with Dr Schapiro, you’ve got to look at the whole person. I also agree that what the real issue is, if that person’s DMT is helping them in all these other ways, if it is helping with the atrophy, helping with lesions, relapses, all these things, why wouldn’t it be helping with cognition? Why wouldn’t it be….

Randall Schapiro, MD, FAAN: Well, it would preserve cognition. It’s not going to make cognition.

Jeffrey Wilken, PhD: Not getting better. Although there are people out there who want to talk about it.

Randall Schapiro, MD, FAAN: They will say that, but it doesn’t make any sense.

Jeffrey Wilken, PhD: It doesn’t make sense to make it better, because unless we find out that one of these drugs is actually repairing, literally repairing….

Randall Schapiro, MD, FAAN: How do you make it better? Well, maybe there are drugs that can do that. If you treat the symptoms of fatigue, for example, if you treat the symptoms of depression.

Jeffrey Wilken, PhD: People do not understand how important that is.

Randall Schapiro, MD, FAAN: …a drug that allows nerves to conduct better, potentially. These things need to be studied in some detail and be approved by the FDA in order for it to work for cognition specifically. But that makes some sense as opposed to the immune system itself.

Jeffrey Wilken, PhD: When people come into my office, a lot of times they’re sent in, and the question is cognitive impairment or not. And that’s never really the whole question. The whole question is, if there is cognitive impairment, what’s causing it? If it’s MS that’s causing it, that’s fine. But there are so many things that can be done to improve it. Improve it, but not to back to baseline. But this person’s having X, Y, and Z symptoms, and you treat this major depression that they’ve got, and you then go ahead and help them with their fatigue.

Randall Schapiro, MD, FAAN: And their isolation, etc.

Ahmed Obeidat, MD, PhD: Those confounders.

Jeffrey Wilken, PhD: Confounders, and people do not realize the value of exercise. This is something that is starting to become known. Of course, I always send my patient back to the doctor to say, “Help develop an exercise program that’s right for this person.” A person wheeling into my office may say, “How am I going to exercise? You see I’m in a wheelchair. Why are you telling me this?” I say, “No, you don’t need to get out of your wheelchair necessarily. There things you can do.”

Randall Schapiro, MD, FAAN: Let me put a pitch in now for an organization that I helped found, and I’m very much involved with, called Can Do Multiple Sclerosis. It’s organization that was founded by Olympic skier Jimmie Heuga, with the idea that exercise and appropriate lifestyle changes can make your MS better. They can learn how to exercise. They put on programs that are free around the country, and by video and in person. It’s Can Do Multiple Sclerosis, if you want to learn how to exercise.

Jeffrey Wilken, PhD: You just have to change how you’re doing it. It’s not easy and it’s exhausting, and it’s going to make people tired. But in the long run, they’ve shown that with dementia as well, people walking a mile a day, just a mile, and it’s a lot to some, not that much to others. It actually has some positive outcomes with respect to things.

Randall Schapiro, MD, FAAN: The answer to disability is mobility.

Ahmed Obeidat, MD, PhD: To this point, even in the Milwaukee, Wisconsin, area, we have a place called MS Just Keep Moving. A group of people come together, it has a gym, and they have a lot of online activities and things. This is key.

Randall Schapiro, MD, FAAN: For those who can’t walk, and when I say mobility, I mean in a chair or whatever, stay mobile. I don’t care how it is. You stay mobile.

Ahmed Obeidat, MD, PhD: Stay mobile, and stay engaged.

Transcript Edited for Clarity

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