Sudden unexplained death more frequent among people with epilepsy

Disease and treatment 6. jan 2022 4 min PhD and MD Marius Kløvgaard Written by Sybille Hildebrandt

A new retrospective population-based study in Denmark shows that people with epilepsy have a much higher risk of sudden unexplained death than the general population. The researchers hope that their discovery may help to make doctors and people with epilepsy more aware that epilepsy increases the risk of premature death and that addressing the risk factors can avoid this in many cases.

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The results of a new registry-based study published in Epilepsia show that people with epilepsy who are younger than 50 years have a 34-fold increased risk of sudden unexplained death. Marius Kløvgaard, the first author, is a doctor who recently obtained his PhD degree, defending his thesis on why people with epilepsy have an increased risk of dying prematurely.

“Our study shows that sudden unexpected death in epilepsy is a leading cause of death, and we should take this seriously,” explains Marius Kløvgaard, adding that, so far, doctors internationally have tended not to discuss this risk with people with epilepsy since the causes of these unexplained deaths were still unknown.

“A prerequisite for being able to reduce excess mortality is doctors making their patients with epilepsy aware of this and advising them on preventive measures,” he says.

Thinking outside the box

Marius Kløvgaard and colleagues combined two approaches: identifying the incidence of sudden unexpected death among people with epilepsy and comparing how often people with epilepsy and the general population die from sudden and unexplained causes. In the first approach, the researchers established a cohort of everyone in Denmark with epilepsy younger than 50 years, which they followed from 2007 to 2009. The researchers identified everyone with epilepsy by finding those who had been diagnosed with epilepsy in registries and reports and who had been prescribed various types of antiseizure medication.

The result was a cohort of 30,437 people, 700 of whom died during the 3-year study period.

The researchers reviewed all available information about the deaths recorded through death certificates, autopsy reports and the Danish Registry of Causes of Death and the health of the individuals until their death through their unique personal civil registration number, the Danish National Patient Registry and the Danish National Prescription Registry to classify and compare the causes of death. Sudden unexpected death was the second leading cause of death among everyone with epilepsy younger than 50 years. Although people with epilepsy comprise only 0.8% of the population, they accounted for nearly one fourth of all sudden unexplained deaths in the entire population during the study period.

“Measuring the incidence of sudden unexpected death in epilepsy is quite a challenge because the International Classification of Diseases lacks codes for sudden unexpected death. This precludes directly identifying the people in this group in Denmark’s registries and thus carrying out a pure, classical registry study,” explains Marius Kløvgaard, who says that only a few nationwide studies have measured these deaths.

May affect the respiratory system and the heart

The only way to find an answer is therefore to collect and analyse the different types of additional material, he says.

“The study shows that people with epilepsy generally have a high mortality rate and that sudden unexpected death is a significant cause of death for them compared with all other causes. Sudden, unexpected and unexplained deaths are frequent among people with epilepsy,” says Marius Kløvgaard.

He indicates that the study is not designed to advance researchers’ knowledge on the mechanisms behind these sudden, unexpected deaths, because other studies have done this. They show that sudden unexpected death in epilepsy is often linked to people who have generalised seizures, with the person being unconscious and having arm and leg spasms. Another condition that appears to increase the risk of sudden unexpected death is poor seizure control. The same applies to low-quality, deficient or extensive medication. And finally, among those found dead in their bed, strikingly many were lying on their stomachs. Whether this shows that lying on your stomach is dangerous or that people have turned over onto their stomach during a fatal attack is still unclear.

“The biological mechanisms behind this are unknown. However, a common hypothesis is that the electrical impulses between the brain cells not only run wild and uncontrolled, which is common among people with epilepsy, but that these impulses shut down breathing and the heart rhythm by reaching brain areas that control the respiratory system and heartbeat,” explains Marius Kløvgaard.

Improving prevention is key

Although the study does not say anything about the mechanisms of sudden unexpected death in epilepsy, he hopes that the research group’s characterisation of the different types of deaths can lead to doctors and patients becoming more aware of what it takes to prevent people with epilepsy from dying prematurely. Doctors and the public authorities, for example, have had good experience in reducing the number of drownings among people with epilepsy.

Children with epilepsy have been taught that they should not swim alone through a comprehensive campaign emphasising that this is life-threatening. The public authorities may have advised precisely that population group on how to act in situations that can be dangerous for them because of epilepsy.

“We know that a huge effort has been made in recent years to prevent epilepsy-induced drowning. And this message spread to the wider population, in which we did not find very many of those types of deaths,” says Marius Kløvgaard, who explains that the international peer-reviewers noticed the low number of deaths from drowning among people with epilepsy in Denmark during the 3-year period and thought that this was incredibly positive.

“Whether we can achieve the same effect by focusing on sudden unexpected death in epilepsy is perhaps doubtful as long as the biological mechanism remains unclear, because then providing guidelines is more difficult. But focusing on and knowing that it occurs could at least make people with epilepsy and doctors more aware. This also demonstrates the importance of treating people with epilepsy optimally and ensuring that they do not have seizures,” he says.

Linked to the heart

In addition to elucidating the incidence of sudden unexpected death in epilepsy, the study also aimed to compare sudden unexplained death among people with epilepsy versus the general population in Denmark for those younger than 50 years between 2007 and 2009. The researchers identified all people with no explanation for their sudden death according to the autopsy report. The people diagnosed with epilepsy had a 34-fold increased risk of dying suddenly from unexplained causes compared with the general population. People with epilepsy accounted for nearly one fourth of these types of deaths – despite accounting for only 0.8% of the general population.

“We are the first research group to have made these comparisons. We do not know the reason, but the epileptic seizures probably shut down the respiratory system and the heart. Determining whether this is true could be the basis for future research,” explains Marius Kløvgaard, adding:

“Investigating the incidence of arrhythmia among people with epilepsy and whether this is associated with sudden unexpected death could be interesting. In theory, some of the many cases could be explained by underlying arrhythmia, diagnosed or undiagnosed. We and other research groups are focusing on the association between epilepsy and arrhythmia, and we have begun to examine a potential association with the many sudden unexpected deaths,” concludes Marius Kløvgaard.

Sudden unexpected death in epilepsy in persons younger than 50 years: a retrospective nationwide cohort study in Denmark” has been published in Epilepsia. In 2014, the Novo Nordisk Foundation awarded a grant to Jacob Tfelt-Hansen for the project Risk Factors for Sudden Cardiac Death during Acute Myocardial Infarction (MI-RISK).

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