Multiple Sclerosis in Older Adults

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

Disease-modifying therapies for multiple sclerosis have significantly improved quality of life and longevity for patients resulting in a growing population of older adults living with multiple sclerosis. As a result, there is an increasing need for providers to consider how age and disease duration impact multiple sclerosis progression and treatment.

In this episode of Neuro Pathways, we're discussing the management of older adults with multiple sclerosis and why current treatment paradigms may need to evolve. I'm your host, Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. And joining me for today's conversation is Dr. Le Hua. Dr. Hua is director of the Multiple Sclerosis Program and the Eric and Sheila Samson chair for MS Research at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, Nevada. Le, welcome to Neuro Pathways.

Le Hua, MD:

Thank you for having me here.

Glen Stevens, DO, PhD:

So tell us a little bit about yourself, how you found your way to Cleveland Clinic, specifically Vegas, a little bit about your background for our listeners.

Le Hua, MD:

So I have been in Las Vegas for almost 10 years. It'll be 10 years this summer with the Cleveland Clinic. And I am originally from Arizona. And when I was done with my training, I thought I would end up back in Arizona. And unfortunately at that time there wasn't a MS specialty position open in that area, but there was an opportunity here at the Cleveland Clinic in Las Vegas. And once I came on site, it was the most perfect job that was presented to me. So I snatched up that opportunity and haven't looked back since.

Glen Stevens, DO, PhD:

Great. Well we're glad to have you. So some of the listeners will know, my mother had multiple sclerosis, so I saw it firsthand. It was actually what drew me to neurology as a specialty and I thought I was going to do MS, but I ended up doing neuro-oncology. Of course when I started back in the older days, we could give patients steroids or we could give them steroids or we could give them steroids.

So there really wasn't a whole lot that we could give. It's really sort of mind-blowing how many options there are today. But really the '90s were an evolution of the disease modifying therapies and I think we're all happy about that. But with that comes other problems. So MS in older adults is, I guess in some ways a relatively newer phenomena as patients are living longer and hopefully with a better quality of life. But give us a brief overview of what we know so far about MS patients and how it progresses in older patients compared to younger patients.

Le Hua, MD:

So you're absolutely right in MS has been a disease that we've known about for centuries, but we haven't really been able to do very much to change the natural history of the disease until recently. So our first disease modifying therapy was approved in 1993. That is an interferon, trade name is beta serum, which is the first therapy for MS. And since then we've had several other therapies approved.

But it was a very slow start and the explosion of therapies didn't actually happen probably until the last 10 years. So the first 20 years or so, there was only four or five therapies. And within the last 10 years there has been significant acceleration of our understanding of the disease, significant improvement in drug development. So in the last 10 years we've had over 15 drug therapies being approved. And to date, there's over 20 different therapies now available to those with MS.

With our first therapies that were approved, they were what we would consider nowadays as low efficacy therapies. So they will work for some people, but they don't work for everybody. And there are going to be those who break through and need stronger therapy. Therefore, we develop stronger medications and those who don't do well in the initial therapies, we'll put them on stronger medications.

And again, the stronger medications work for a certain number of patients, but not everybody. And now we have what we consider high efficacy therapy, which does a remarkable job in completely stopping any and inflammatory disease activity. With our stronger medications or our more efficacious medications, those medications unfortunately will have more side effects and more safety concerns. So with the evolution of our drugs that are stronger and better at controlling the disease, there's always side effects and safety concerns that we have to take into account when we're managing our patients who have MS.

Now, the reason why I kind of went through that brief history lesson is within that with our first therapies that have been approved for MS, right from 1993, we're now seeing patients who have been on therapy for over 20 or 30 years. And there was no way that we would've had that before the therapies were approved. That means our patients are coming to us in their 50s and 60s and they've been treated for a long time of their life.

Our medications target the immune system and bring it back into balance. So with MS, the disease is an overactive immune system as a very simplistic way of viewing it where your immune system is hyperactive and causing, the dysregulation is causing inflammatory attacks on the brain and spinal cord. So our therapies bring the immune system back into balance to reduce those immune attacks. Well, unrelated to MS, if we just talk about people as they get older, we know that there's a phenomenon called immunosenescence.

Meaning as we get older, our immune system also ages. And with the immune system aging, the ability to fight off infections, do cancer surveillance or just kind of manage repair is not as great as when we are young. Hence, we recommend that those who are over 60 get their flu vaccines annually. We recommend that they get their pneumonia vaccines. There's a shingles vaccine recommendations and all those happen with that chronological age marker of arbitrary 50s to 60s.

Well, our patients with MS also get older and as they get older, their immune system also undergoes immunosenescence. So if we're talking about therapies that target the immune system, bringing it back into balance as they get older, the question becomes do we really need to be attacking their immune system or would they benefit from having just that underlying immune presence to fight off normal infections and normal things?

And that's that balance that we're seeing because our therapies have been out for so long. Now with our patients as they get older, the natural history of the disease is that there's just less inflammation as people get older. So there's less relapses, there's less MRI activity, and we know that that occurs in the absence of disease modifying therapy. So people who are in their 20s to 40s have the highest rates of MRI activity as well as clinical relapses.

When they get into their 40s and 50s, the rate of relapses and the rate of MRI changes significantly drops and then it drops again in their 50s and 60s. And by the time they're in their 60s, we don't really see inflammatory disease activity. We don't see MRI new lesions. So the question really becomes do we really need to be treating somebody when their natural disease has changed with a therapy that targets the immune system when that's really not the underlying process that's actually occurring anymore.

And again, with the revolution of medications, it's been fantastic, people are getting older, they are surviving with less disability, they're doing better. And what we don't want to do is inadvertently keep someone on a medication when they really no longer need it, right? Because that's not really the goal, especially as they get older. And then now we're balancing are we treating a disease the same way when it's no longer inflammatory, but putting them at higher risk for things such as infections.

And so that's the balance that we're dealing with now and our understanding of how do we take care of this phenomenon. And we don't have great answers, but we're starting to learn more about how to treat older patients. And that of course is my area of interest in and active research. One of the first studies that we did was the question is, do older patients really need medications anymore?

So we took an arbitrary marker of age and we just picked age 60 out of convenience more than real biological, an individual biological marker to prove that you're old. But we just arbitrarily chose 60 as the age because it's an easy way to measure as a group separating who's older and who's younger. And when we looked at patients who were 60, we compared those who stopped medications versus those who stayed on medications.

And my hypothesis was that we wouldn't really see a difference between those who stayed on medications versus those who didn't because of what I had already mentioned, that relapses decrease, that the inflammation's gone, but the risk of infection increases. And we were able to show that with their study that stopping medications actually didn't seem to affect outcome, that we could successfully stop medications in older patients.

And that was kind of a nice way to prove that within our studies. Now, of your audience who understands that with any research, there's always observational studies, which is what we do, which is the study that I'd mentioned versus the gold standard, which is a randomized controlled trial, within that, taking out that inherent bias of I'm only stopping medications because I think you'll do better, but I'm going to keep the person who I'm more worried about on medication.

We want to eliminate that bias and say, okay, if we randomly assign someone to staying on medications versus stopping medications, is there a difference? So a large randomized clinical trial for patients with MS evaluated exactly that. So it was called the Disco MS trial. It is a large discontinuation study. Their age group was 55, so that was their arbitrary age that was picked. And the study is a complicated trial design, but it was evaluating non-inferiority, meaning, was stopping medications was not any inferior than continuing medications.

Unfortunately the results of the study was not absolutely conclusive one way or the other. But it does seem to look like we are able to stop medications without any really adverse effect on our patient and their outcomes if we were to discontinue medication.

Glen Stevens, DO, PhD:

Well, there's a lot of information to unpack there, but I'll go through a couple of things. One is 60 is way in my rear view mirror. So I was suggesting that maybe 90 was old, but we'll leave it at 60 for now. In terms of the Disco study, what what's going on in the real world? I mean, what are people in the community doing? Are they stopping people at 50? Are they waiting if they haven't seen a contrasting enhancing lesion in a period of time? What's the real world experience? What are physicians doing with patients or are they just say it's easiest just to leave it as it is and until you have a side effect or problem that's caused you to go off, we're just continuing on the medication?

Le Hua, MD:

So the idea of discontinuing medication is actually really new. For years in MS, we haven't had treatment. We haven't had therapy, so no one really thought about stopping therapy. We really are really focused on just putting patients on medication.

Glen Stevens, DO, PhD:

It's a fantastic idea.

Le Hua, MD:

Yeah, so the idea of discontinuation is new. And again, what we want to always balance is risk to benefits. So if the medication's beneficial, we should continue it. If the situation changes where the medication is less beneficial, but the risk increases, we should always stop the medication. Where we're trying to move the field is a better understanding of better prediction of what that risk and benefit ratio is.

And without clear cuts data proving one way or the other, it then just becomes that art of medicine where we're dealing real world, when we don't have all the evidence that clearly shows a better way to guide our decision making, then we're going to have to look at the person in front of us. So in the real world experience, it's varied. It's exactly what you had mentioned. Some people are stopping it as they get older. Some are really just waiting for that adverse effect where it's proven in the patient in front of us that risk outweighs the benefit and therefore will stop medication.

Glen Stevens, DO, PhD:

But I'm sure there's a lot of patient fatigue, they're tired of the constant infusions or injections if they're getting those, the blood draws. Memory starts to fade years out of the disorder if you've been stable for a period of time, right?

Le Hua, MD:

Yeah, no, absolutely. So in my practice, if we kind of get back to what I do, I won't take patients off medications proactively if they're stable and doing well. But if they're over 60 and as I'm discussing with patients what their symptoms are, what's going on, what their issues are, if they mention difficulty with injections, if they mention fatigue, if they mention side effects that's bothering them, if they're on our oral therapies and I'm noticing that their blood pressure's being more difficult to control, well, all of our medications can affect those things.

So depending on what they're on and what they're mentioning to me, if I have them in front of me, they're having intolerability or adverse effects, negative side effects and safety concerns on my medications, and then I'll look back and say, well, you actually haven't had a relapse for five or 10 years. The last MRIs that I've looked at haven't shown any change. I think this might be an opportunity for us to stop medications on you. And then we would stop the medications, see how they do. Get an MRI at six months after stopping medications to ensure that their disease is stable.

And then continue surveillance after stopping medications again to prove to us that this patient's doing okay off of the medication. Most of the patients will actually do okay off of it. Our studies show that about 10% will need to resume medication. So that's why we continue to follow them. And if we stop them and there is an MRI change early, we can resume medication. Lots of times the conversation is actually initiated by the patient.

So before I even get a chance to bring it up, patients will mention how long do I need to continue this medication? Will I ever be able to stop the medication? Sometimes my younger patients will ask that, and of course then you have someone in their 40s who ask to stop medications, I'll say, no, we will need to keep you on it for longer. But if they're over that age and they're stable and they're willing to see how they do off of medications, then we can certainly do a trial off medication to see how they're doing.

Glen Stevens, DO, PhD:

Well, it's interesting, I'm a neuro-oncologist and look after brain cancer and our standard treatment is we give them radiation and chemo and then we give them chemo for six months and then we stop it. And there are many that give the argument that it's non-curable and why would we ever stop the chemotherapy? But of course we're giving drugs that can affect the bone marrow and cause other problems.

But we're very nervous about it, but we do it all the time. These are big questions that the kind of work that you're doing will provide answers for us. So that's great. Take us through some of the other issues regarding specifically your older population and versus your younger population of MS patients.

Le Hua, MD:

I think it's a great comparison that you had mentioned earlier to oncology. The other field that we compare to is rheumatology where we really do with oncology more of that induction and then maintenance treatment. With rheumatology again, really getting the disease under control and then you might not need something as strong. One of the newer areas that we're exploring is something called deescalation.

So again, starting with really our stronger medications, our hardest hitting medications early on when patients are better able to withstand the adverse effects, that concern for infections isn't really there in a younger person, some of the side effects are better able to handle and that person, we might want to hit them really hard early on. And then after a period of time, maybe step down to a medication that's not as strong but can actually do more of a maintenance and then after a certain threshold then really kind of come off of medication.

So we're learning a lot from our colleagues in oncology as well as rheumatology on what to do. The questions in MS is exactly is even if we were to start that, how long do you actually have to be on that initial medication? And we don't have the information available yet. We're hoping that different biomarkers will help us understand if a person is a treatment responder much sooner than if we did MRIs or waiting for that clinical relapse.

So I can imagine that we might have a biomarker where a patient comes in, we start them on therapy, and then we evaluate for this biomarker and the biomarker would show that their disease is under control. And then after a time period if we wanted to switch them to another medication that's less strong, ensuring that the biomarker doesn't change. And then of course once we discontinue it, can we stop the medication and again, ensure that this biomarker hasn't changed. An early candidate for what that marker would be, it would be something called serum neurofilament light chain.

It is a marker of axonal injury or neuronal injury in the brain. And whenever there's injury, we kind of see this neurofilament level become elevated. And although it's not specific to MS, it's a marker that is being explored across multiple different neurological diseases. We know that in MS itself, we do see a correlation with inflammatory disease activity and there is some suggestion that we can see if a person is responsive to disease modifying therapy based on normalization or dropping off of their neurofilament level. So that might be a strategy we'd use in the future.

We would certainly need more studies, but I think that's something that's certainly exciting. If we step back and say that's future, what we're looking at and what we're doing with research, what do I do for the person in front of me today and what other issues would I have to take in into a account? So as patients get older, they actually develop other diseases and they develop other problems that we would actually want to take care of.

And some of those problems might cause worsening of their function, but not actually be due to multiple sclerosis itself. So we would term those things pseudo-progression. So for example, if someone gets older and they develop osteoarthritis of their hip and they have trouble walking, they're achy, their pain, they're having some trouble walking, and as clinicians we don't ever think about that happening as a phenomenon of getting older, then we might just say, oh, you're worsening because of MS and then we're not actually treating the right problem because if they actually were to undergo a hip replacement, they would have significant improvements in walking. And yet instead of looking at that, we're again just treating the progression of MS.

We're thinking that their disease is worsening, when in fact, that's actually not what's actually happening. So evaluating for comorbidities, evaluating for other processes that could also lead to worsening is always critical in how we're evaluating older patients. With that, one of the most common comorbidities that's not only associated with disease progression in MS but can cause a confounding of our ability to detect changes on MRI would be a vascular disease.

So hypertension risk increases with age, diabetes risk increases with age, increasing risk of strokes and increasing risk of heart disease. And for those patients when we evaluate who's at higher risk for a worse outcome from MS, those with uncontrolled vascular disease will have a worse outcome. So controlling those vascular risks is actually critical. We know that hypertension can cause development of white matter lesions on MRI. So something that we would term small vessel disease, chronic microvascular changes depending on who's reading the MRI.

And if we're doing MRI surveillance on our patients and we see the development of a new white matter lesion, it's imperative that we do our best to differentiate. Is this new lesion due to a vascular process such as hypertension or is it due to a process such as multiple sclerosis? And location of the lesions really help us with that.

So the MS lesions are the standard peri ventricular juxtacortical peripheral in the brainstem or spinal cord, whereas vascular lesions tend to be in the vascular territories, the watershed area, so more subcortical, deep gray, so like a lacuna stroke in the basal ganglia or the thalamus or in the central pons and vascular lesions wouldn't be associated with a spinal cord change. So within that, we can use those locations and if we actually are asking your questions what their comorbidities are, we can differentiate are they worsening because of MS or they worsening from their comorbidities.

Glen Stevens, DO, PhD:

So I'm just curious, you mentioned the neurofilament. If somebody has a new plaque and let's say it's three or four neurofilament level in the blood or is there a larger inflammatory process going on that would show you changes in the blood or could you actually pick that up?

Le Hua, MD:

I don't know that we have that discrimination yet to differentiate between neurofilament light chain elevation due to MS versus another disorder, right? It's being explored across lots of neurodegenerative disorders. Neurofilament light chain also increases with age. So that's going to be a confounder that we're going to need to be able to evaluate. So I don't think neurofilament light's ready yet for that, but it's going to be something that we're going to need to be able to figure out is if it's elevated, we're probably going to need to have another marker besides neurofilament to differentiate MS versus something different. But if we just look at MS patients, we could probably differentiate are they responding to the medications or not.

Glen Stevens, DO, PhD:

So I guess you're kind of a geriatrician MS expert here, and I assume that over time as that population age is more people will have an interest in the same thing that you have an interest in. Where's the research going for the patient population as they age? What are the questions we're asking? What are we looking at other than trying to determine how long patients should stay on medication?

Le Hua, MD:

What I mentioned earlier is that we want to discontinue therapy that might be immunomodulatory because if that's not the underlying process that's occurring causing patients to worsen, we don't really want to be treating with the therapy that's targeting the wrong process. We know that our patients with MS undergo neuro-degeneration and they have loss of axonal integrity. They have chronic smoldering inflammation within their brain, something we term inflammaging.

We know that there's decreased energy use, decreased ability to utilize mitochondria, decreased ability to remyelinate. The macrophages don't clear debris as well. So there's lots of other processes happening in the brain. And what we really want to study in our older patients is what is the underlying biological process that's causing worsening that might be a better treatment target? So rather than treating the immune system, we want to develop therapies that help with neuro protection and we want to develop therapies that might help with regeneration or restoration of function.

So I think that's going to be what's key in the research as we're studying not only young patients and how to stop relapses from occurring, but how do we really stop progression and how do we help our patients who are undergoing different aspects of their disease, different processes, and actually targeting correct therapy. Within that one of our barriers that I'd mentioned that might not have been emphasized is that chronological age is just kind of a convenient marker.

So we arbitrarily will pick 60 or 70 or 90 or 55 or whatever have you, but that doesn't give us individualization. So you can take two 60 year olds and underlying biological age might be different. So the age of their immune system might be different. The age of their neurons are different, and until we can really clarify what their biological age is, that's separate from chronological age, we might not be targeting the right process and the right person. So our understanding has also improved biomarkers to really not only measure progression in MS, to not only measure response to treatment, but if there's a better way we can identify someone's actual biological age separated from their chronological age.

Glen Stevens, DO, PhD:

So unfortunately cancer's quite frequent and there's been a real explosion of medications to try to allow the immune system to target tumor better, which would suggest that we're upregulating the immune system. Surely there's got to be overlap of MS patients that develop cancer that someone wants to put them on a checkpoint inhibitor. Any anecdotal evidence, have you read anything about this? Are you seeing it? Have you not had exposure to it? Does it worsen the MS or not? I have treated a few patients with MS, I've not seen an issue, but curious if you've seen this.

Le Hua, MD:

So the data behind checkpoint inhibitors is a little confusing. There was suggestion early on that in people with MS who are exposed to checkpoint inhibitors, it will actually cause worsening demyelination the same way that we had understood TNF alpha inhibitors to cause worsening demyelination in people with MS in the past. So early studies have shown that checkpoint inhibitors can worsen underlying demyelinating disease.

There are newer reports that challenge that and don't see that association in any causal relationship. So I think that data is still uncertain. What's reassuring is that if someone stays on disease modifying therapy and then they're exposed to a checkpoint inhibitor, the protection from their disease modifying therapy for MS will still counter whatever potential worsening of demyelinating disease that we would see from checkpoint inhibitors.

Glen Stevens, DO, PhD:

Any final takeaway points for our audience that we didn't cover you think is important?

Le Hua, MD:

I think that really evaluating our older patients, questioning the treatment paradigm, I don't want anyone to then be started on medications and be told they need to stay it on the rest of their lives, but really looking at our patients on a deeper level so that we're not just discontinuing therapy arbitrarily, but we're actually discontinuing therapy because it's not appropriate for our patients. And really developing therapies that would be more appropriate to treat their underlying biology and the correct processes at the time will do wonders for our field.

And then again, paying attention to comorbidities or other processes that can lead to worsening our patients that have nothing to do with MS so that we are offering treatments that actually can improve quality of life that really don't have to do with our medications or the MS itself.

Glen Stevens, DO, PhD:

Well, I really enjoyed the conversation. As mentioned, my mother sadly passed away from MS. Really no treatments were available at the time. And to sit here and have a discussion with you about should we stop treatment because patients are doing okay, is just unbelievable in a fairly short period of time. So I'm so impressed with what has gone on in the MS literature over time and really applaud your efforts and the efforts of your group and just implore you to continue the fantastic work that you're doing. Appreciate it.

Le Hua, MD:

Yeah, no, thank you. MS is a super interesting field of growth and understanding and it's been fantastic and such a privilege to be able to be part of it.

Conclusion: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.