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Neurology

Deaths shrouded in mystery

Groups in Brazil and abroad work to identify causes behind sudden unexpected death in people with epilepsy

Person on a gurney suffering an epileptic seizure; drawing attributed to Jean Jouvenet (1644-1717)

attributed to Jean Jouvenet/Wikipedia Person on a gurney suffering an epileptic seizure; drawing attributed to Jean Jouvenet (1644-1717)attributed to Jean Jouvenet/Wikipedia

Neurophysiologist Fulvio Scorza, coordinator of the Sudden Death in Epilepsy Research Laboratory at the Federal University of São Paulo (Unifesp), is interested in identifying the molecular changes that epileptic seizures may trigger in the hearts of rats. In the coming months, his team will conduct a long process of brain sensitization on 40 animals, prompting the rodents to develop epilepsy, also known as seizure disorder. The study is expected to help with research that Scorza has been conducting for almost 15 years on the cause of epilepsy-related death, especially Sudden Unexpected Death in Epilepsy, or SUDEP, a problem that physicians only rarely mention during office visits with patients and their families. It is suspected that the brain’s abnormal electrical activity during seizures may lead to heart problems and even cause the organ to stop working.

Scorza hopes to find some molecules in the hearts of these animals that are produced at altered levels and serve as signals of heart damage brought on by the seizure disorder. If he identifies them – other research has indicated that this is possible – and succeeds in quantifying them through a simple blood test, he will finally be near a cardiac risk marker specific to epilepsy. This tool, which various international groups have been pursuing recently, may help identify those individuals with epilepsy who have a greater likelihood of suffering cardiac arrest during a seizure. “If we can identify these patients, we can advise them to undergo more rigorous cardiology follow-up or, if appropriate, inform the neurologist that their medication needs to be changed to control their seizures,” says the researcher.

International research shows that SUDEP accounts for around 8% to 17% of deaths among people with epilepsy. What is most surprising and intriguing, however, is that its victims are generally under the age of 40 and have no health issues other than epilepsy.

Some estimates suggest that an average of one in 1,000 people with epilepsy suffers sudden death. If these data hold for Brazil, where roughly two million people have active epilepsy – or 1% of the population – the projection would be for 2,000 cases of SUDEP each year. Experts suspect that cardiac arrest is the immediate cause of a relatively large portion of these deaths. “I calculate that sudden death is attributable to cardiac arrhythmias and subsequent cardiac arrest in one-third of the cases,” says Brazilian neurologist Josemir Sander, one of the world’s leading researchers of SUDEP. For 33 years, Sander has lived in England, where he is a professor at University College London (UCL); he has published over 600 scientific papers, nearly 10% of which are related to SUDEP.

Sander’s interest in the topic was sparked by a random incident in 1993, when he was working as a medical resident at the UCL teaching hospital. While out for a stroll, he bumped into the brother of a patient who had not shown up for recent appointments. Sander asked the fellow about his brother’s health and was surprised to learn that he had died unexpectedly. The news left him stunned. “I rushed to the hospital and started looking up the names of patients who had missed their latest appointments,” says Sander.

He identified around 30 people who were no longer coming to the hospital and he wrote a letter to each patient’s family doctor. His discovery that most of them were dead changed how he viewed epilepsy. A good share of neurologists have always felt that the disorder was not a very serious health issue. Many still feel that way, but not Sander – or Scorza. “If not treated appropriately, epilepsy can kill,” emphasizes Unifesp neurophysiologist Scorza, one of the few researchers investigating SUDEP in Brazil.

There are an estimated 50 million people with epilepsy worldwide, roughly 80% of whom live in developing nations. Research conducted in the 1990s and early 2000s suggests that the frequency of SUDEP can vary greatly, depending on the seriousness of the epilepsy. The lowest figures, drawn from less rigorous surveys, indicate that one to four out of every 10,000 people with epilepsy may die suddenly each year. But more accepted statistics suggest that the figure may be up to 10 times higher, with one to two deaths per 1,000 each year. This rate may reach one in every 100 in the case of people with hard-to-control epilepsy and frequent seizures, who are candidates for surgical removal of the area of the brain that sets off electrical storms in that organ.

In the 1990s, Sander and his collaborators at UCL began following different groups of patients, some of whom are still being followed, and surveyed information on hundreds of people with epilepsy who had died. They also established collaborative efforts with researchers in Europe, Africa, and Asia in order to ascertain how common SUDEP is. Over the course of this research, Sander and his team detected important patterns that helped characterize this form of death.

One of their earliest findings, which was recently confirmed, is that most sudden deaths occur at night, generally during sleep. The person who dies is almost always alone and is found with lesions suggestive of a recent episode, such as bite marks on the tongue. This discovery has prompted physicians to make a general recommendation: anyone who has epilepsy, especially when it is not controlled by drugs, should sleep in the company of an adult whenever possible. “If someone is nearby, he can keep the person from suffocating if he has a seizure while sleeping on his stomach. It’s also possible that if the accompanying person simply touches the patient, it may be enough for him to come around and go back to breathing after the seizure,” says Sander.

recording of epileptic seizure (top), showing reduced brain activity

recording of epileptic seizure, showing reduced brain activity

Electrical Storm
The range and duration of seizures varies greatly. Some last seconds and go almost unnoticed because they cause only mild trembling or a slight movement of the head, while others can last for minutes and trigger fainting and violent muscle spasms. The most serious are generalized tonic-clonic seizures. They begin with the abnormal functioning of a group of highly excitable neurons that sparks the synchronized firing of electrical signals, producing a wave of activation that sweeps through the brain. This electrical storm is accompanied by a discharge of chemical compounds that floods the body. Various hormones are released, heart rate may jump from 60 to 180 beats per minute, and systolic blood pressure may climb from 120 to 210.

People often lose consciousness during this type of seizure. Excited neurons make the muscles spasm intensely and then remain rigid for some seconds; this is the tonic phase. As the electrical charges abate, the clonic phase then begins, with the muscles relaxing and contracting in rapid succession, causing the body to jerk. “This is a frightening phase, which generally lasts one to two minutes,” says neurologist Elza Yacubian, professor at Unifesp and epilepsy specialist.

Physicians believe that in order to prevent death, the brain reacts to the excessive activation by releasing neurotransmitters to calm the neurons. If this reaction is too strong, however, it can turn off the areas of the brain that coordinate heartbeat and respiration, leading to death from cardiac or respiratory arrest or both.

Six years ago, Sander was on a team that undertook a combined analysis of the results from four major studies that had compared the characteristics of SUDEP victims with those of individuals with epilepsy who were still alive. When they compared the signs presented by 289 people who died suddenly with those presented by the 958 who had survived, the researchers found important differences.

One of the factors that most boosted the risk of death was the number of seizures per year. Suffering one to two generalized tonic-clonic seizures tripled the risk of sudden death, according to the study, which was published in the journal Epilepsy in 2011. But the likelihood of sudden death was eight times higher among those who had three to 12 seizures per year than among those who stayed seizure free. The risk of death was 10 times greater for those who suffered more than 13 seizures.

Two other factors also influenced the risk of death: early onset of epilepsy and the number of medications used to stave off seizures, which is an indirect indicator of the seriousness of the problem. Generally speaking, the more serious the epilepsy, the more types of medications must be combined to control the problem, although there is an unconfirmed suspicion that certain drugs can increase the risk of death. The study also showed that the risk of death rose further if the individual continued to have seizures despite medication.

Surveys investigating cases of sudden cardiac arrest in the absence of previous heart disease have suggested that the problem is as much as 20 times more common among people with epilepsy than among those without this neurological disorder. More recently, the team of French neurologist Philippe Ryvlin found that interrupted cardiac activity was generally preceded by respiratory arrest.

Ryvlin is a researcher at Lyon Neuroscience Research Center in France and the CHUV Lausanne University Hospital in Lausanne, Switzerland. He coordinates the MORTEMUS project, which follows people in five countries who have epilepsy that is refractory to treatment. In an effort to discover the mechanisms that precipitate these deaths, he and his teammates collected information on 29 cases of cardiorespiratory arrest and 16 cases of SUDEP that occurred following an epileptic seizure. The analysis found that shortly after a seizure, respiration accelerated and sometimes paused temporarily before ceasing definitively, according to the preliminary findings of the study, presented in the journal Lancet Neurology in 2013.

In this image from the 14th century, a physician performs trepanation, a surgical procedure then used to treat epilepsy

Reproduction from Guido da Vigevano, Anathomia (1345) In this image from the 14th century, a physician performs trepanation, a surgical procedure then used to treat epilepsyReproduction from Guido da Vigevano, Anathomia (1345)

Almost standing still
In 2013, neurologist Veriano Alexandre, attending physician at the University of São Paulo’s Ribeirão Preto School of Medicine Hospital das Clínicas, a teaching hospital, spent a year in Lyon, France, working with Ryvlin’s team on another project. While there, he analyzed EEG data from 69 individuals in France who had uncontrolled epilepsy and found that in some cases the electrical activity in the brain dropped off sharply after a seizure, as if the organ had stopped working. He also saw that this decrease in activity could be averted if the patient received oxygen-rich air shortly after the episode. It is unknown whether this problem increases the risk of SUDEP, but the researchers recommend that oxygen be administered during and before seizures whenever possible.

Sander says that he has given up searching for a single cause for cardiac and respiratory arrests related to epilepsy. “It is becoming clear that SUDEP is a multifactor problem,” he explains.

Until more is learned about the issue, physicians are unanimous in their recommendations. The most important thing, they say, is to undergo suitable treatment to prevent seizures; drugs can effectively control epilepsy in 70% of the cases. They also advise sufferers to maintain healthy habits, such as sleeping regular hours, exercising, and avoiding too much stress, which can give rise to seizures. In research with laboratory animals, Scorza, from Unifesp, found evidence that the consumption of supplements rich in Omega-3 fatty acids has a protective effect on the brain and heart.

Project
The impact of seizure frequency on the heart and heart rate variability (nº 2015/19279-0); Grant Mechanism Regular Research Grant; Principal Investigator Fulvio Alexandre Scorza (Unifesp); Investment R$ 77,883.90.

Scientific articles
HERSDORFFER, D. C.; et al. Combined analysis of risk factors for SUDEP. Epilepsy. January 28, 2011.
RYVLIN, P. et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (Mortemus): A retrospective study. Lancet Neurology. October 2013.
ALEXANDRE, V. et al. Risk factors of postictal generalized EEG suppression in generalized convulsive seizures. Neurology. September 2015.
BORGES, M. A. et al. Urban prevalence of epilepsy: Populational study in São José do Rio Preto, a medium-sized city in Brazil. Arquivos de Neuropsiquiatria. V. 62, No. 2-A, pp. 199-205. 2004.