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Newswise — Studies suggest that compared with the general population, people with chronic epilepsy have three times the risk of sudden cardiac death. Several researchers, including Dr. Trudy Pang and Dr. Richard Verrier, have introduced the concept of the "epileptic heart" as "a heart and coronary vasculature damaged by chronic epilepsy as a result of repeated surges in catecholamines and hypoxemia, leading to electrical and mechanical dysfunction."  talks with Drs. Pang and Verrier about research in this area and its implications for epilepsy treatment.

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

Podcast Transcript

[00:00:00] Dr. Ravat: Hello everyone. I'm Parthvi Ravat. I'm a neurologist from Australia. In today's episode, we discuss an interesting concept that potentially has significant public health implications and might change treatment strategies.

We welcome Dr. Verrier, who has investigated sudden cardiac death for over 30 years. While on the Harvard Medical School Faculty of Medicine, where he is currently a corresponding member during the past 10 years, he has focused his attention on cardiac effects of epilepsy in close collaboration with Professor Stephen Schachter, a pioneer in vagus nerve stimulation therapy and the past president of American Epilepsy Society.

We also would like to welcome Dr. Trudy Pang, who is an assistant professor of neurology at Harvard Medical School, director of the EEG Lab, Clinical Neurophysiology and Epilepsy Fellowship Programs at Beth Israel Deaconess Medical Center, Harvard Medical School. She’s also the director of the Comprehensive Women's Health in Epilepsy Program. Dr. Pang specializes in the clinical investigation and treatment of epilepsy, women's health issues in epilepsy, and cardiac comorbidities and complications of chronic epilepsy. Together with Dr. Sachter and Dr. Verrier, they have shed new light on the cardiac effects of acute seizures and chronic epilepsy and their potential impact on the risk of premature death in epilepsy.

We are very happy to have you on the show. Doctors, what led you to explore the relationship between epilepsy and cardiac dysfunction?

[00:01:34] Dr. Verrier: Thank you, Dr. Ravat, for this question and the opportunity to speak to this important topic. As you indicated, our lab has been focused on the problem of sudden cardiac death for more than three decades, and there are commonalities between the sudden death problem and SUDEP in epilepsy in as much as the mode of death is often unexpected and premature.

So Dr. Schachter thought perhaps it would be useful to share what we've learned in terms of the pathophysiology of sudden death in general and the tools that we use to identify inherent risk. And to our surprise, as we studied this question, we found, as we'll talk about further, that the level of cardiac electrical disability in patients with drug resistant epilepsy is quite high, suggesting that they are at risk for arrhythmic death,

[00:02:35] Dr. Ravat: So what is the pathophysiology for the underlying concept of epileptic heart as proposed in your research? And how do you define this entire concept or syndrome?

[00:02:46] Dr. Verrier: Our view is that with chronic epilepsy, there are repeated episodes during seizure of hypoxemia and myocardial ischemia, which can result in damage to the heart. Furthermore, the levels achieved in terms of catecholamines are quite high, to the level that they may be toxic to the heart, and this situation may be compounded by certain anti-epileptic medications that block sodium channels, which is known to be arrhythmogenic and can alter lipids, cause hyperlipidemia.

So in one pathway, the catecholamines can actually stun the heart. And when you measure ejection fraction, it can be reduced from a normal of 60 percent, between which the blood is ejected with each beat, down to 40 percent. In intensive care units, the stunning of the heart has been documented in many conditions.

So what we have, in a sense, is a case of a neurogenic cardiomyopathy. This may be part of the phenotype that's observed with chronic epilepsy. The other important line of evidence is based on autopsy, when the heart structure, histological studies have been conducted, and the structure is changed. There's more interstitial fibrosis, contraction band changes, and the myocytes are altered. Interestingly, not only at autopsy, but during echocardiography the myocardial stiffness of the heart has been shown by Dr. Fialio to increase. So the heart is less elastic. And so in patients who undergo echo, this can be detected.

And the third pathway, which is quite concerning, is accelerated atherosclerosis.

When carotid arteries have been imaged by echo, intimal thickening has been observed, which again can be worsened by enzyme-inducing anti-epileptic medication. These different pathways converge to confer cardiac electro instability and susceptibility to both atrial and ventricular arrhythmias.

In terms of definition, our formal definition for the epileptic heart is a heart and coronary vasculature that is damaged by catecholamines and hypoxemia, leading both to electrical and mechanical dysfunction.

The other salient aspect is the age-accelerated atherosclerotic condition in patients with chronic epilepsy. It increases the rate of aging of the heart in circulation by some in the range of 10 to 20 years. So a patient who is 40 years old who has chronic epilepsy, their heart in may be that of an over 50-year-old. So these are fundamental changes that we observe, have observed.

[00:05:58] Dr. Ravat: Thank you for simplifying that concept so well. So we now come to SUDEP, which stands for sudden Unexpected Death in Epilepsy. What are the factors affecting SUDEP and is cardiac risk dysfunction a part of that risk factor profile?

[00:06:14] Dr. Pang: Thank you, Parthvi, for that great question. So, you know, we have a landmark study through the MORTEMUS study that really helped us to understand the mechanisms that could be involved in SUDEP. And there are a number of studies out there that have looked at potential risk factors. And of course, the ones that stand out, as we know, are uncontrolled seizures, especially generalized tonic-clonic seizures. And patients are often found in the morning, presuming that something had occurred at night, and patients are found in the prone position. So these are all you know, time and time again found to be consistent risk factors.

The MORTEMUS study, through studies in the EMU [epilepsy monitoring unit], helped us to understand that SUDEP as currently defined is a postictal phenomenon, meaning that patients had a generalized seizure and then in the aftermath then they go into respiratory failure and then this leads into the terminal event resulting from cardiac asystole.

And then, of course, to meet really the SUDEP criteria, often patients who are not in the EMU would require an autopsy to exclude other potential causes. So, by definition, this SUDEP entity excludes patients with any kind of heart disease that the pathologist may identify. And this is really in contrast to patients with sudden cardiac death, because that's really a result of heart disease.

Patients may have coronary artery disease. They tend to be males in the slightly older population age group. And we typically find that patients are particularly at risk for lethal cardiac arrhythmias like ventricular tachycardia that could then develop into ventricular fibrillation.

So that is the root cause, and that's how we try to conceptualize. And of course, patients with sudden cardiac death have other exclusions of potential seizure as a potential cause. So by definition, they don't have much overlap. And when you look at the age group, the sudden cardiac death group tends to be slightly older, you know, 40 to 75. And then patients in the SUDEP group tend to be younger, 20 to 40. So that's sort of how we think about the different mechanisms that are underlying these, but currently, I think we think of these as potentially different physiologic etiologies underlying them, but there could be some overlap as well.

When we look at the rates of SUDEP, it's typically estimated to be around 3,600 cases per year according to the [U.S. Centers for Disease Control and Prevention]. But when we look at cases through prospective population studies, we understand that patients with sudden cardiac death actually are four times higher in the annual incidences compared to SUDEP. So the risk for both entities actually increases with time. That's a function of the natural history of disease and the development of risk factors over time. Our particular interest, we are highlighting the rates of sudden cardiac deaths, which have previously been underappreciated.

And we'd like to draw the attention of both physicians and patients to the risk of sudden cardiac death.

[00:09:45] Dr. Ravat: Would you like to share any patient stories or case studies highlighting the significance of epileptic heart in clinical practice?

[00:09:54] Dr. Pang: Yes. So we think of the epileptic heart as a condition that develops over time in patients with continued seizures that are poorly controlled, and even sometimes in patients who had seizures that were poorly controlled at one time and then maybe became better controlled. These patients have suffered, as Dr. Verrier pointed out, cytotoxic effects of the sympathetic storm that then resulted in scarring and altered pathways for polarization and conduction, and these patients have developed a milieu that puts them at increased risk for cardiac arrhythmia. Whether that occurs in the context of a seizure or at other times when there is increase in sympathetic stimulation, both conditions may predispose these patients to cardiac arrhythmia.

And so there are reported cases of seizure induced malignant cardiac arrhythmia where a patient goes into a ventricular tachycardia.

And there's a reported case of a patient who was undergoing EEG monitoring and was fortunate enough to be in the most monitored setting such that during ventricular tachycardia, there was a counter shock delivered and the patient was fortunate enough to survive. You can imagine that the majority of our patients who may have the substrate for epileptic heart may not be under continuous monitoring or close monitoring, and if and if the countershock or intervention is not delivered in time, these are the patients who are then susceptible to the unfortunate effects of untreated ventricular tachycardia, ventricular fibrillation and sudden cardiac death.

[00:11:45] Dr. Ravat: In your paper, you found ECG changes in people with epilepsy, specifically T wave alternans. What is the yield of a routine 12-lead ECG for T wave alternans?

[00:11:57] Dr. Verrier: The EKG, probably standard EKG, is extremely valuable. There are routine measures in the EKG that can provide important insight. First of all, the P wave. As it turns out, up to 10 percent of patients with epilepsy are prone to atrial fibrillation. So any irregularities in the P wave, such as duration or morphology, is worth inspecting in the 12-lead EKG.

Also any signs of ST segment changes are noteworthy. Up to 40 percent of seizures have been associated with change in ST segment. Also extremely important is the presence of Q waves. Because they may reveal a prior silent myocardial infarction. And the fact that there's a nearly five-fold increase in [myocardial infarction] in patients with chronic epilepsy, so inspecting the electrocardiogram for Q waves is quite important.

And finally, the QT interval, which is also a routine measure in EKG. Approximately a third of patients with drug-resistant epilepsy have prolongation in the QT interval. So this reflects an increased susceptibility to ventricular arrhythmias, which could also be worsened by certain medications. So beyond the standard EKG, we've developed a measure, which Dr. Revat has mentioned, is called microvolt T wave alternans. Fundamentally, it's a beat-to-beat fluctuation in the ST, T wave of the electrocardiogram. If for example, one inspects an individual at risk for sudden death, we can see that the morphology of the T wave may alternate in an A and B form where, for example, in the A form, there may be a relatively flat sloping first half T wave and then followed in the next beat by a steep pattern.

So this flat, steep pattern, it can repeat itself. And when you superimpose the electrocardiogram, you can see that the A form and the B form are separated. The greater that separation, the greater the risk for sudden death. And this alternating A and B is what we refer to as microvolt alternans. And that's available on commercial equipment.

So for those interested in using this parameter, it has been FDA cleared and can be assessed quantitatively using commercial equipment. And what we have found, in fact, is a ladder of risk in patients with stable disease, coronary disease, the alternans is relatively low, below the cut point of 47 microvolts. But then with cardiomyopathies, myocardial infarction, the, especially those who experienced life-threatening arrhythmias, the alternans exceeds the 47 microvolt level. What was a surprise to us nearly 10 years ago, we found that patients with drug-resistant epilepsy that the alternans level was in excess of 60 microvolts, well beyond the cut point for risk for life-threatening arrhythmias.

This was a significant revelation. And one can exploit this even further with new technology involving an ambulatory patch monitor, which is a simple patch can be placed over the chest. It can be, it's wireless, can record 1 or 3 channels, and you can measure alternans during the daily course of activity.

And in one of our articles, we found a patient who, after four days of monitoring, well past what would be detected with standard Holter monitors, that during the course of monitoring there was a surge in alternans that culminated in ventricular tachycardia. So this epilepsy patient was then referred to a cardiologist and was found to have undisclosed coronary disease. And it was important because she was at risk for a lethal rhythmic event that would require defibrillation. So that's how we can apply 12-lead EKG and patch monitoring to have a more complete picture of the electrical functioning of the heart in patients with drug resistant epilepsy.

[00:16:42] Dr. Ravat: Are there any markers on 2D echocardiography specific to epilepsy?

[00:16:47] Dr. Verrier: Thank you for this excellent question. This, I believe, is one of the great tools that can be added to the armamentarium of monitoring beyond the EKG. Dr. Fialho in Brazil has shown that with routine 2D echo, you can discover, you can quantify whether there's myocardial stiffness that develops in a patient with epilepsy, due to the cardiotoxic effects of catecholamine. Also you can detect changes in the left atrium because if there's increased stiffness of the left ventricle, the left atrium has to adapt, and enlargement of the left atrium and hypertrophy can predispose to atrial fibrillation.

So you can check on two important issues. One is ventricular risks for arrhythmias and then also for atrial fibrillation. So I think this is a valuable tool that should be used increasingly in patients with chronic epilepsies.

[00:17:51] Dr. Ravat: So with the investigative armamentarium of ECG, ECHO, and lipids, how does the concept of epileptic heart influence the management and treatment of epilepsy? And as we talk about treatment, are there any preventive measures or interventions that can mitigate the risk of sudden cardiac death in epilepsy?

[00:18:12] Dr. Pang: Yes that is perhaps one of the Holy Grails of how we think about the epileptic heart. So our group would like to propose a syndromic approach to the epileptic heart, similar to how we approach the metabolic syndrome, where there are a group of features or clinical characteristics that can help us to identify whether somebody is at risk for developing it, or may have early features of it.

So, first and foremost, of course, is having a diagnosis of epilepsy, and especially if a patient is refractory to medical treatment. And beyond asking for seizure frequency, we also want to think about various cardiac risk factors. Maybe something that we haven't been routinely doing as epileptologists.

We want to look for features or clinical signs of potential cardiac injury and the risk for potential arrhythmia on EKG that Dr. Verrier just pointed out. Whether that is a 12-lead standard EKG or a multi-day ambulatory monitor, both can be quite revealing in terms of signs of previous injury or ongoing cardiac electrical instability as measured by T wave alternans.

And Dr. Verrier also mentioned the echocardiographic features of diastolic dysfunction. There's a measure called the cardiac stiffness that the cardiologist can determine.

And then, of course, next are signs of altered autonomic tone as assessed by HRV or heart rate variability. Many studies have shown that heart rate variability is altered and there's depression of vagal tone in patients with chronic seizures, and in particular, certain epilepsy syndromes like Dravet syndrome. And that seems to be a strong predictor for premature death.

And finally, the classic cardiovascular risk factors, the lipid profile, and in patients we've discovered that they are at risk for accelerated atherosclerosis if their seizures are poorly controlled.

And so when we think about this particular collection or conglomeration of clinical risk factors we hope that we can use these to help us identify patients who may be at risk for developing the epileptic heart. And if there is someone who has multiple risk factors, they may belong to the high-risk category. For those patients, we would definitely advocate for regular routine EEGs with ambulatory EKG monitoring on a case-by-case basis to identify the risk for arrhythmia, uncovered arrhythmia, as well as structural imaging, which is readily available to many of us in the healthcare centers to look for structural change, diastolic dysfunction.

And I would then go on further to say that in these patients in the highest risk category, for example, uncontrolled, generalized tonic-clonic seizures, multiple vascular risk factors, these are the patients who should be referred to our cardiology colleagues for a really detailed cardiac evaluation and nd consider risk mitigation and preventative strategies.

[00:21:34] Dr. Ravat: How does this help in evaluating and deciding treatment strategies?

[00:21:39] Dr. Pang: That's an important question, too, that we must approach in a more holistic perspective as an epileptologist. So anti-seizure medications are effective for reducing seizures, but there are certain agents that are considered deleterious to cardiovascular health with regard to two particular mechanisms that have been shown by various research groups.

Many of the agents that we use belong to the category of sodium channel blockers. And we know that these particular agents can affect the heart because of their particular mechanism. In patients who are taking high doses or perhaps combination therapy, these can be arrhythmogenic and that's been reported.

So there's a study by Bardai and colleagues that showed that patients who take sodium channel blocking agents are at risk for sudden cardiac death, higher than those who are not taking these types of anti-seizure medications. And the risk is still elevated when you control for heart failure and for epilepsy.

And then the second part of this story is that the older generation of drugs, many of them belong to the category of enzyme inducers. And the studies by Dr. Mintzer and colleagues showed that the enzyme inducers can wreak havoc on lipid profiles, either by increasing LDL and total cholesterols overall, or by actually making lipid-lowering medications less effective.

So when we're considering which anti-seizure medications to use, we have to use a more tailored strategy and choose agents more judiciously. For patients perhaps in the older age group I mentioned with other cardiovascular risk factors or a known heart disease, we may want to consider avoiding high-dose recombination sodium channel blocker therapies, and also to avoid particularly the use of enzyme-inducing agents.

And this is particularly important for patients who are already known to have hyperlipidemia. If for certain reasons we can't particularly avoid these agents, then we need to be vigilant for monitoring. So checking the lipid profiles regularly and when possible, we should substitute more appropriate agents as to not to aggravate these risk factors.

[00:24:21] Dr. Ravat: What are the potential implications of your research for public health policies or guidelines related to epilepsy care?

[00:24:30] Dr. Pang: Good question. I would say that as epileptologists we have been practicing mainly focused on seizure frequency and seizure control, but now I would say that we need to be more comprehensive and treating the patient as a whole and not segregate the neuro aspects with the cardiac aspects of a patient's health.

So this is to say that we need to recognize this really, really important brain-heart connection and how our treatments may affect both systems. That includes following the patient's cardiovascular status regularly and assessing their response to seizure treatment and understanding how these treatments may interact with one another.

And now that we understand there are particular markers on the EKG, on the ambulatory monitors, we can then think about how we integrate the use of these monitoring tools in everyday care and identify patients who may be at risk for heart disease or accelerated atherosclerosis, so that we can address the patient's health status, both in terms of long-term neurologic outcomes and in cardiac outcomes.

[00:25:48] Dr. Ravat: So now coming to a very pertinent question. If a neurologist or a young researcher wants to study this area, what would be your guidance for designing a clinical trial or a study and what are the most pressing unanswered questions or areas for future investigation in this field?

[00:26:08] Dr. Pang: So I would say that we're still in the early phases of understanding the epileptic heart.

A lot of work still needs to be done to help us to understand how quickly the condition develops. What are the epilepsy characteristics that are closely associated and contribute to the development in this condition? And with some of those questions answered, then we can start thinking about at what point should we start to consider instituting preventative strategies and treatment options.

How do we balance the sympathetic versus parasympathetic, tone in patients, especially in patients with Dravet syndrome. And then we can think about designing studies to test the effectiveness of these potentially cardioprotective and interventional strategies.

I'll let Dr. Verrier talk more about some of these potential preventative and treatment strategies.

[00:26:36] Dr. Verrier: One point that I would like to add is that one way to accelerate our progress is the archival data which has been accumulated at multiple institutions. There are tremendous databases, and if the electrocardiograms are stored, then one can use these metrics that we've discussed to determine, to generate hypotheses for prospective studies.

While we've been discussing older adults or older individuals, there may be conditions, pediatric conditions, such as Dravet syndrome, where we need to understand either autonomic abnormalities in these young individuals or changes in their channelopathies, for example, that increase risk for arrhythmic events.

So those are areas where we need to focus. I would also emphasize that one of the very important areas is to try to apply the tools that we've developed to evaluate the effects of anti-seizure medications. There's evidence that, for example, sodium channel blockers can increase risk for sudden death from Bardai's study, but can we actually measure using noninvasive EKG measures to see whether or not we can detect inherent risk using our tools related to anti-seizure medications? If we can continuously evaluate instability of therapy, that would be a major step forward.

[00:28:21] Dr. Ravat: Wonderful. Thank you so much for this very interesting discussion about this topic. It was a great pleasure talking to you guys.

[00:28:27] Dr. Pang: Thank you so much for the opportunity to speak to you about a topic that is I would say previously underappreciated, but much more attention is being drawn to it.

And I hope this really helps to improve our understanding and move the field forward so that we can really improve the overall treatment and outcomes of patients with chronic seizures and epilepsy.

[00:28:52] Dr. Verrier: And we welcome any questions from the listeners where we might be able to address their particular concerns or queries.

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