Heart health and SUDEP in people with epilepsy: Dr. Katia Lin and Dr. Guilherme Fialho

Sharp Waves spoke with a neurologist and a cardiologist who are part of a team researching the interactions among seizures, heart function, heart health, and SUDEP. Learn more about their research.

Selected publications from Drs. Lin & Fialho and colleagues:


Determining factors of electrocardiographic abnormalities in patients with epilepsy: A case-control study (2017, Epilepsy Research)

Maximal/exhaustive treadmill test features in patients with temporal lobe epilepsy: Search for sudden unexpected death biomarkers (2017, Epilepsy Research)

Echocardiographic risk markers of sudden death in patients with temporal lobe epilepsy (2018, Epilepsy Research)

Increased cardiac stiffness is associated with autonomic dysfunction in patients with temporal lobe epilepsy (2018, Epilepsia)

Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.

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The International League Against Epilepsy is the world's preeminent association of health professionals and scientists, working toward a world where no person's life is limited by epilepsy. Visit us on Facebook, X (Twitter), Instagram, and LinkedIn.

Transcript

[00:00:00] Dr. Katia Lin: My name is Katia Lin. I work here at the Federal University of Santa Catarina in Florianópolis. It's a small island in the southern part of Brazil, and I work as professor of the post-graduation program in medical science.

As an epileptologist. studying patients with epilepsy here, we were thinking about some multidisciplinary studies that we could do in partnership with Guilherme Fialho as a cardiologist, who was interested in a PhD. So since I'm a neurologist and he's a cardiologist we thought the easiest way to start would be by performing an ECG, electrocardiography, in these patients. 

[00:01:00] Dr. Guilherme Fialho: Thank you, Katia. Thank you, Nancy, for having us here today. It's a real pleasure to speak to you. My name is Guilherme Fialho. I'm a cardiologist, also an echocardiographer. And I work at the University Hospital of the University of Santa Catarina, the same place as Katia, in Florianópolis. And I was looking for a PhD, as Katia mentioned, and when I started to talk to Katia, and she introduced me to some concepts in epilepsy, I was fascinated about SUDEP. When I read about SUDEP, I said, “What's going on here? Why are these young patients without any known cardiac disease, why do they die suddenly? There's something wrong with this. This should not be happening.” 

And so in cardiology, we have some issues like this as well. We know that sometimes the first manifestation of myocardial ischemia is death. So it's very frustrating for us when we have an apparently low risk individual who dies suddenly. So that caught my attention and I said to Katia, “Maybe we could use some of the things that we do with our patients in cardiology and try to look a little bit closer in these individuals with epilepsy to see if we can try to figure it out what's going on.”

My first idea was using echo(cardiography), but we didn't have the tools, the echo equipment. This was almost 10 years ago. And so we went to the treadmill test and we found some interesting things. So we do did some studies with ECG and then treadmill tests. And then we went to the echo. And now I'm a voluntary professor in the postgraduate program in the university and we have a full line of research where we have some students working on this same topic. So we can advance a little bit more in our knowledge of this epileptic heart concept. 

[00:03:13] Nancy Volkers: Thank you. So when you started looking at people with epilepsy, you said about 10 years ago, you were doing ECG and treadmill tests. Can you talk about some of the first results that you found that maybe you didn't expect to find?

[00:03:32] Dr. Guilhermo Fialho: Those first papers that we published with a colleague in Brazil were about ECG and we found some interesting aspects of P wave duration or PR interval duration, and QT interval as well. So, some markers that could point to an increased cardiovascular risk. We had a very young cohort, so we're not looking for hard outcomes, but only the ECG parameters and the treadmill test was very interesting because in the beginning we were kind of afraid. Are these patients going to be able to do an exhaustive treadmill test as we do in the individuals without epilepsy? 

We found some interesting things. Their peak heart rate during exercise was lower than a comparable cohort with individuals without epilepsy that were matched by age, sex and body mass index. Their exercise time was lower. And they had something that we call chronotropic incompetence, a marker of autonomic dysfunction. 

In epidemiological papers the cardiovascular fitness that we measure by metabolic equivalence of task (MET) is a very strong marker of risk for not only cardiovascular death, but all cause death. Some authors, they say that the cardiovascular fitness is considered the fifth vital sign that we should look into in our patients every day. In our cohort, the individuals with epilepsy, they had a 1. 7 MET (metabolic equivalent of task) less physical fitness measure. 

So this is a very important deal.

We have huge cohort studies. One of them is from Jonathan Myers. He published in New England Journal about 15 or 20 years ago, and he had a cohort of 6,000 individuals and he found that for one less MET that the individuals were exercising, they had increased risk of death in order of 12%, something like that.

And other studies find even worse numbers: 15, 18, 20% less deaths when you exercise more. So this 1.7 less cardiovascular fitness measure was a very big deal, and it was clear that these individuals, although they apparently didn't have any cardiovascular risk factors. You put those individuals into our classic Framingham table or, other scores to study their cardiovascular risk and they would be considered low risk, but they're not low risk. 

[00:06:29] Nancy Volkers: So, you found their heart rate did not go as high as the control groups that they were matched with. And you also found they were significantly less physically fit. So could that explain why their heart rate didn't go as high? Is it because they're not as physically fit or is there some inherent difference that is preventing them from working out as hard as they could, or as hard as a control group could?

[00:07:00] Dr. Guilherme Fialho: that's a wonderful question. This same question was asked when I presented this paper. I don't know if Katia will remember this, but we have a very important cardiologist here in Brazil that works with sports cardiology, and he asked the same question. It was wonderful because we it was something for us to think about. There are some possible explanations. Those individuals were discouraged from performing exercise or to play sports.

So this is a huge thing. Maybe they don't do exercise because nobody told them, “Hey, you've got to exercise.” And another thing is autonomic disturbances, dysfunction, right? So some of them, they have a different brain circuitry and maybe they have autonomic dysfunction, and this is causing chronotropic incompetence.

So we don't know what comes first. We need trials to try to train these individuals to see how are they responding. And until we have those trials, we can't say what came first. We don't know that yet. But that was a marker of risk. 

We have to remember this. These individuals are dying from sudden death or arrhythmia, they have arrhythmia. So we have a marker of this and we have to work on this. 

[00:08:16] Nancy Volkers: Yeah, that, that makes a lot of sense. So maybe we could talk a little bit about the cardiac risk factors that people with epilepsy have.

[00:08:27] Dr. Guilherme Fialho: So, we know that there's a link with epilepsy and the heart, and I mean, this is getting more and more clear every day. Maybe it's not for everyone who has epilepsy, but we have to check some things. For example, the common risk factors, they have to be checked. I have to measure the blood pressure of my patient. I have to see if he has, or she has a high LDL cholesterol. This is important. Do they have diabetes? Do they smoke? Are they obese patients? Do they exercise? This is important as well. 

The other thing we have to remember is that some treatments for epilepsy in some individuals may cause harm. For example, we know that some kinds of anti-seizure medication, especially enzyme-inducing seizure medication, they can increase, for example, inflammatory markers or cholesterol.

So we have to be aware of this and remember that this can happen really can happen. And we have the sodium channel blockers. That's a very delicate issue for cardiologists because we have a classic trial from the 80s or 70s. I think the 80s, the CASH trial and the CAST trial. We actually had two, two big trials and in those trials, we used a sodium channel blocker to stop premature ventricular beats in post myocardial infarction individuals. And so the drug worked perfectly. We had no premature beats, but we killed more patients doing that. So that's a big issue. Maybe these drugs should not be used in individuals who have some myocardial ischemia or have heart failure, for example, so we have to check for is who's the patient in front of me? Can I use this drug in him? So this is very important issue. 

And we have to tell the patient that they should exercise. It's good for them. It's good for them. They have to exercise. So there's a lot of things that we can do before thinking about any fancy measurement or exam, you know. The clinical part is the first step. And the most important part, I think, in this initial conversation with our patient.

[00:10:53] Nancy Volkers: Katia, did you have anything you wanted to add to that? 

[00:10:57] Dr. Katia Lin: Yes from the neurologist's perspective a great portion of anti-seizure medications used everywhere are sodium channel blockers. So we really should be more and more aware of that. Because we can find sodium channels not only in the brain, but also in the heart and as a neurologist, we usually think only about the brain and forget about the heart, but we have to think about it.

And we are raising awareness about that. When we do a multidisciplinary team, we think outside the box and then we can find many interesting findings that are there, but that we couldn't see by ourselves, but when we think together, put different specialties together we start to see through another perspective, and when we start research, we have more questions than answers and one answer leads to another question and so on and so on.

[00:12:11] Dr. Guilherme Fialho: It's interesting because when we speak about SUDEP for example, few colleagues in the cardiology field know about it. This is not a thing that we talk in cardiology, but we should talk about this more often because this is happening.

SUDEP is a very difficult diagnosis because we have to exclude lots of things, right? You can have trauma, you can have drowning, we have to exclude status epilepticus, toxicological causes, and anatomical causes.

So it's like you have to exclude lots of things. The problem is, for example, in cardiology, we know that one of the modes of death of sudden cardiac death is arrhythmic death. And when we go an autopsy to see what's going on in this patient, some have normal hearts, apparently normal hearts. That could happen, for example, after myocardial infarction, so we can see something in the autopsy. Okay, but maybe those patients have like a channelopathy that you can't see in the autopsy or they have very small lesions in the heart, like cardiac fibrosis, that can facilitate arrhythmia.

And we have to remember that this individual, they have a very different autonomic function, right? So not only during the seizure, but they have some differences in the brain circuitry that maybe because they have an autonomic dysfunction. So this can promote arrhythmia in these patients. So I believe that many patients that die and we say, “Oh, he died from SUDEP.” I believe that some of these patients are not really SUDEP. Probably there's sudden cardiac death, but we have to, to improve our autopsy, maybe molecular autopsy, to look for channelopathies, for example.

 The MORTEMUS study it was a very important study, and they showed us that during individuals after seizure, they had apnea and they died from hypoxia and arrhythmia after the apnea. I mean, SUDEP involves the brain, the lungs, the heart and as we start to understand a little bit more the different ways of dying, maybe some individuals that we used to call SUDEP, they will not be SUDEP. There'll be sudden cardiac death. So I think we're starting to learn and to think about this. Dr. Richard Verrier had a very important paper in 2020 where he developed the epileptic heart concept, where he had a beautiful review of the literature of sudden cardiac death. He mentioned lots of trials, the ARREST trial, the Oregon sudden death trial. And he showed us that individuals with epilepsy, they have a two- to threefold increased risk of sudden cardiac death. So they are dying from the heart. We know this. And I think SUDEP is when I don't know what to say. I mean, I couldn't find anything. So it's SUDEP. But as we start to understand and to learn a little bit more about the mechanism of sudden death, I think some of those, those patients will be categorized as sudden cardiac death.

[00:15:46] Nancy Volkers: Katia, you're nodding very vigorously. Do you want to add? 

[00:15:51] Dr. Katia Lin: Yeah, when we started to dig in this subject and we invited Guilherme to try to study this subject with us, we were interested in studying SUDEP. But as for the reasons Guilherme already mentioned, SUDEP is difficult to study because it's rare, it happens outside the hospital, at the patient's home, most of them we don't have the autopsy available.

So we try to study indirectly what would be the risk factors for SUDEP. That's why we started looking at the heart. But then when we look at it in the literature, we saw that all these studies in SUDEP were conducted by neurologists who tried to make a neurological explanation for it. So, probably it was the inhibition due to the seizures and then the brain counteracting to an excessive inhibition that induces apnea and this was one of the conclusions of the MORTEMUS study, inducing a central apnea and then the central apnea leading to the cardiac arrest. But then when we started studying the cardiological perspective, we learned that in fact sudden cardiac death is even more common than SUDEP. And we did not have the least idea about that. I have only heard about SUDEP and not cardiac death, about sudden cardiac death, but now we see that. It makes so much sense. And how come we never thought that our epilepsy patients, of course, they have a heart, a heart that is prone to adverse events of the anti-seizure medication too, and well there are so many other things about the heart that we should study. The sudden cardiac death is probably something that we should be even more aware of than SUDEP.

[00:18:15] Nancy Volkers: Thank you. 

 Are there certain groups of people that should be considered for referral to a cardiologist or is it just. kind of watchful waiting, like Guilherme was saying, you know, check the blood pressure, check the lipids, ask them if they're exercising and all those things. Or is there a second step where you get an ECG just to see what's going on? 

[00:18:43] Dr. Guilherme Fialho: This is a very, very good question. And I don't have a complete answer to it. But I think that the clinician or the neurologist who is in contact with the patient, who has the opportunity to talk and to examine the patient, he should remember the importance of looking at those cardiac risk factors and the heart in general and the vessels. So he has to remember all those classic traditional risk factors that we mentioned already. And then I think an ECG is a very good way to have a first look in our patient because they're using medications that can alter the ECG. They can have some autonomic disturbances that maybe you have some signal in the ECG at a first glance. So I think ECG should be done in patients with epilepsy. In the last year we have been trying to write something about this with our colleagues in Boston: when should we use the ECG and maybe you have to repeat the ECG more than once, right? Especially in those individuals that have uncontrolled seizures, or they use lots of medication, different medications, or they have changes in treatment medication, for example. This is just very easy to do and it's cheap.

And then if you have any kind of doubt or if you suspect anything, if I think you should go on and maybe an echo, Holter monitoring, and maybe you have to talk with your colleague from cardiology. “Look, this patient has something that I'm not understanding. Maybe you can help me.”

So, you know, I think that the thing is like a ladder and you go step by step. But the first thing is the clinical exam and history taken from the neurologist with his patient. This is the very first thing. It's the most important thing, I think. 

[00:20:50] Dr. Katia Lin: Yeah. The ECG is easily available everywhere. And it's even part of a health checkup. So why not do it in our epilepsy patients, especially on the pharmacoresistant ones under polytherapy and having uncontrolled seizures?

[00:21:10] Nancy Volkers: In cardiology, is there a sense or an understanding that if someone comes to me with chest pain or dyspnea or any of those, and they also have epilepsy that this is like a different sort of situation than someone who doesn't have epilepsy? To a cardiologist, is a person with epilepsy, is that a special case? Or is that just sort of an extra thing that they don't think about? Do you have a sense of that at all?

[00:21:39] Dr. Guilherme Fialho: Yeah, I think I can speak very easily about this because I didn't know anything about SUDEP. This was very new to me. And when I speak to my colleagues, “Did you know, though, that epilepsy individuals, they just die suddenly? And we don't know why.” They say, really? Why? Why is that? I mean, probably some know, but the main group, we don’t. It’s just another comorbidity, but we don’t link it to the heart. So it’s important for cardiologists as well. And we're trying to, to work with our community of cardiologists to raise awareness about this as well. 

[00:22:20] Nancy Volkers: Was there anything else that either of you wanted to speak about? Anything you wanted to add, either of you? 

[00:22:27] Dr. Guilherme Fialho: I just want to thank you because I think it's a very good opportunity to increase awareness of our colleagues in this very fascinating concept. And I think we all have the same goal here. We're trying to understand why does this young individual, why do they die suddenly? Is there anything that we can do to change that? So this is a very big deal, I think. And I think this is an opportunity to spread this word and to bring more individuals into the field, curious people, because we need more trials. We need more studies on this subject. So we have to join forces. 

[00:23:09] Dr. Katia Lin: Yeah, I think, I believe Guilherme has said it all. Thank you very much.