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New Study Suggests Larger Role of Cardiovascular Causes in SUDEP

ARTICLE IN BRIEF

A new study found that cardiovascular disease, rather than epilepsy, may cause sudden unexpected death due to epilepsy.

Cardiovascular disease, rather than epilepsy characteristics, is the main determinant of sudden cardiac arrest in epilepsy. That new finding from a team of Dutch researchers challenges the conventional way in which neurologists have generally approached the approximately 5,000 annual cases of sudden unexpected death in epilepsy (SUDEP), with a focus on how the seizure itself, or seizure-related consequences, may cause SUDEP.

The study, led by Robert J. Lamberts, MD, of Stichting Epilepsie Instellingen in Heemsteded, the Netherlands, drew data from two national Dutch registries: one comprising patients with cardiac arrest, and the other comprising outpatients with epilepsy. The study was published in the June 19 online edition of Neurology.

The multicenter group comprising both cardiologists and neurologists sought to identify risk factors in people with epilepsy by comparing three populations: cases with epilepsy and sudden cardiac arrest (SCA; n = 18); controls with SCA without epilepsy (n = 470); and controls with epilepsy without SCA (n = 54).

They found that in 15 of the 18 epilepsy/SCA cases, there were obvious cardiovascular causes in 10 patients and presumed cardiovascular causes in five. Among the 10 cases, cardiovascular causes included acute myocardial infarction, hypertrophic cardiomyopathy, incidence of transient cardiac ischemia, and drug-induced QTc prolongation. In five cases, an underlying cardiovascular cause was presumed, as the patient had recent-onset cardiac symptoms (severe recurrent chest pains less than one week before ventricular tachycardia/ventricular fibrillation [VT/VF]) or clinically relevant pre-existing heart disease. These suspicions could not be confirmed, however, as all died before hospital admission and had no postmortem investigation, the investigators noted.

Patients with epilepsy had a higher prevalence of congenital heart disease as compared with a control cohort of non-epileptic VT/VF patients (17 percent vs. 1 percent, p=0.002), and were younger when experiencing VT/VF — 57 years old versus 64 years old (p=0.023). And when compared with epilepsy controls, these patients more frequently had clinically relevant heart disease (50 percent vs. 15 percent, p=0.005) and intellectual disability (28 percent vs. 1 percent, p<0.001).

“Congenital/inherited heart disease, epilepsy and intellectual disability may result from a multiple malformation syndrome affecting the heart and brain,” the authors suggested. “Epilepsy may also be associated with an increased prevalence of acquired cardiovascular comorbidity.”

The investigators also suggested that future research consider the possibility that “a single ion channel mutation expressed both in the brain and in the heart may confer intellectual disability, a propensity for epilepsy and an innate vulnerability to cardiac arrhythmias (especially in the presence of new-onset or preexistent heart disease).”

EXPERTS COMMENT

“We have to expand the way we think about SUDEP and go beyond just focusing on the issue of seizure control,” said Lara Jehi, MD, director of the Cleveland Clinic Epilepsy Center, who co-authored, along with Stephen Schuele, MD, a commentary accompanying the study in Neurology. “We know we have to achieve seizure control to reduce the risk of sudden death, but what we learn from this article is that sudden death in patients who have epilepsy is not only related to seizure problems. These patients have a higher prevalence of cardiac problems that can put them at higher risk of sudden death from a cardiac issue. This article suggests that most cases of sudden death that happen in patients with epilepsy may in fact be due to a cardiac problem, rather than the epilepsy triggering sudden death.”

Practically speaking, what does this mean for the neurologist?

“We need to be aware that our patients who have seizures are at higher risk of having sudden death, whether it is SUDEP or not,” said Dr. Jehi. “From a practical perspective, if a patient of mine talks about ‘passing out’ events that may not necessarily be corresponding to what their seizures would look like, or if they have an epilepsy that can also involve the heart, such as genetic epilepsies or long QT syndrome, I should at least be cognizant in the setting of my clinic visits with them of problems that could be cardiac and not necessarily epilepsy-related.”

Selim Benbadis, MD, a professor of neurology and director of the comprehensive epilepsy program at the University of South Florida and Tampa General Hospital, agreed that cardiac risk factors in epilepsy are not sufficiently appreciated by neurologists.

“That said, we should really distinguish between the ‘run-of-the-mill’ epilepsy patient seen by a neurologist, who is doing well, with seizures that are essentially controlled, and the difficult patients with poorly controlled, convulsive seizures like generalized tonic-clonic and young adults with nocturnal seizures,” he said. “Those are the patients for whom SUDEP is a great risk factor, and they should alert us to doing a full cardiac workup and referring them to a cardiologist for a comprehensive evaluation.”

Should a cardiac referral for these types of patients be standard of care? “It certainly should be strongly considered,” Dr. Benbadis said. “We need to know more about these patients who are particularly at risk. At most epilepsy centers, at least once or twice a year we have a patient who dies unexpectedly, and far from enough is known.”

The research team also found that the use of automated external defibrillators (AEDs) that block sodium ion channels was associated with an increased risk of sudden cardiac death in people with and without epilepsy. The study wasn't powered to confirm the finding, but the authors note that until future studies replicate the association between sodium channel-blocking AEDs and cardiac arrhythmias, “prudence and careful monitoring of presence of additional sodium channel blocking factors (such as cardiac ischemia or heart failure) is warranted when treating people with epilepsy with these AEDs.”

“The challenge is that events of sudden death in our patients with epilepsy are very rare,” said Dr. Jehi. “Documented cases of SUDEP have for the most part started with a seizure followed by brain activity suppression — post-ictal suppression — and/or a cardiac arrhythmia. But those are individual cases. We need larger epidemiological studies that look equally carefully at the seizures and at the heart.”

Dr. Jehi praised the study, but noted that it has limitations and suggested the need for further research. “It uses two distinct, large, population-based databases that were not really designed to address the question at hand. This introduces the potential for ascertainment bias,” she said.

In her Neurology commentary, she underscored the difficulty of teasing out the difference between the inclusive definition of sudden cardiac arrest and the more exclusive definition of SUDEP. These “likely neglect a mechanism of sudden death requiring the co-existence of cardiac disease and recurrent seizures, supporting the concept of ‘SUDEP Plus,’” she wrote.

Managing the risk of SUDEP is primarily the responsibility of the epileptologist, said Dr. Jehi, but they should partner more frequently with cardiologists. “This study is really a step in the right direction, particularly because of the multidisciplinary approach. We don't generally talk about cardiac health as a comorbidity in epilepsy, but this article suggests we should.”

EXPERTS: ON CARDIOVASCULAR CAUSES FOR SUDEP

Figure

DR. LARA JEHI: “We know we have to achieve seizure control to reduce the risk of sudden death, but what we learn from this article is that sudden death in patients who have epilepsy is not only related to seizure problems. These patients have a higher prevalence of cardiac problems that can put them at higher risk of sudden death from a cardiac issue. This article suggests that most cases of sudden death that happen in patients with epilepsy may in fact be due to a cardiac problem, rather than the epilepsy triggering sudden death.”

Figure

DR. SELIM BENBADIS: “We should really distinguish between the ‘run-of-the-mill’ epilepsy patient seen by a neurologist, who is doing well, with seizures that are essentially controlled, and the difficult patients with poorly controlled, convulsive seizures like generalized tonic-clonic and young adults with nocturnal seizures. Those are the patients for whom SUDEP is a great risk factor, and they should alert us to doing a full cardiac workup and referring them to a cardiologist for a comprehensive evaluation.”

LINK UP FOR MORE INFORMATION:

•. Lamberts RJ, Blom MT, Wassenaar M, et al. Sudden cardiac arrest in people with epilepsy in the community and risk factors http://www.neurology.org/content/early/2015/06/19/WNL.0000000000001755.abstract. Neurology 2015: Epub 2015 June 19.
    •. Jehi L, Schuele S. Sudden death in epilepsy: Where is the “heart” of the problem http://www.neurology.org/content/early/2015/06/19/WNL.0000000000001768.short. Neurology 2015; Epub 2015 June 19.
      •. Neurology archive on SUDEP: http://bit.ly/SUDEP-neurology
        •. Neurology Today archive on SUDEP: http://bit.ly/NT-SUDEP