News Topics: SUDEP

Clinical Risk Factors in SUDEP: A Nationwide Population-Based Case-Control Study

In this nationwide case-control study performed in Sweden, researchers tested the hypothesis that specific clinical characteristics are correlated with a heightened risk of sudden unexpected death in epilepsy (SUDEP).

Using medical records and the National Patient Register, they obtained data from 255 SUDEP cases (definite and probable) and 1,148 matched controls. A 27-fold increased risk was observed in correlation to experiencing generalized tonic-clonic seizures (GTCS) during the preceding year, whereas there was no excess risk in those with exclusively non-GTCS seizures.

A 15-fold risk was observed in correlation with the presence of nocturnal GTCS during the last year of observation. A 5-fold increased risk of SUDEP was observed in correlation with living alone and as per interaction analysis, the combination of not sharing a bedroom and having GTCS conferred an OR (odds ratio) of 67.10, with AP (attributable proportion due to interaction) estimated at 0.69. Excess risk of SUDEP was observed in correlation with a previous diagnosis of substance abuse or alcohol dependence among comorbid diseases. Results suggest that among patients who have GTCS and live alone, 69% of SUDEP cases could be averted if the patients were not unattended at night or were free from GTCS.

News from American Epilepsy Society Meeting 2019

Sepsis Linked to Elevated Risk for New-Onset Epilepsy in Young Individuals

Patients with sepsis, particularly younger patients and those with chronic kidney disease, may be at an elevated risk for new-onset epilepsy, according to research presented at the 2019 American Epilepsy Society Annual Meeting, held December 6-10, 2019, in Baltimore, Maryland.

Researchers conducted a population-based, retrospective, matched-cohort study to estimate the risk for new-onset epilepsy among patients hospitalized in the intensive care unit (ICU) for sepsis treatment. Researchers collected data from the patients in the Discharge Abstract Database between 2010 and 2015.

“These findings indicate that sepsis may be an unrecognized epilepsy risk factor,” the researchers concluded. “Possible mechanisms include damage to the blood-brain barrier as a result of renal dysfunction, persisting inflammation after the acute episode, and increased risk of cardiovascular events following sepsis.”

Learn more

Variable Long-Term Cognitive Changes in Pediatric Epilepsy

Children with pediatric epilepsy who undergo surgery may experience changes in verbal and nonverbal IQ, particularly when associated with abnormal electroencephalogram (EEG), according to research presented at the 2019 American Epilepsy Society Annual Meeting.

Researchers sought to assess the long-term, postsurgery cognitive outcomes of patients with pediatric epilepsy. Investigators assessed 24 participants, all of whom had pharmacoresistant epilepsy. Participants underwent a neuropsychological evaluation that included intellectual functioning assessments (overall IQ, verbal IQ, and nonverbal IQ), as well as an evaluation of postsurgical seizure status.

Learn more

Teenagers With Epilepsy Frequently Post Online Messages Related to Suicide

Using artificial tools to collect and analyze conversations and comments about epilepsy posted online, researchers revealed that 7.8% of all posts by teenagers with epilepsy were related to suicide, compared with 3.2% of adult posts, according to study results presented at the American Epilepsy Society 2019 Annual Meeting.

Previous studies have reported that roughly 30%-50% of patients with epilepsy may suffer from depression and the incidence of suicide in this population was found to be approximately 12%, which is 22% higher than the general population.2 The goal of the current study was to assess the major motivations for suicide thoughts among teenagers and adults with epilepsy, using artificial tools to analyze online conversations.

Learn more

Apnea and Arrhythmia Associated With Increased Mortality Among Patients With Epilepsy

Cardiac arrhythmias with or without apnea among patients with epilepsy are associated with increased mortality risk.  This risk may play an important role in cases of sudden unexpected death in epilepsy (SUDEP), according to study results presents at the American Epilepsy Society 2019 Annual Meeting.

Previous studies have reported that cardiac arrhythmias and apnea may play a significant part in cases of SUDEP, the second most common cause potential life-years lost in patients with epilepsy. The incidence rate of SUDEP is 1.16 cases per 1000 patients, but may be higher in those with intractable epilepsy.

Learn more

CURE Discovery: Novel Strategies to Understand SUDEP Risk and Ways to Prevent It

Key Takeaways

  • This CURE-funded study aims to develop biomarkers to assess the risk of Sudden Unexpected Death in Epilepsy (SUDEP) and therapies to prevent it.
  • By studying breathing and heart abnormalities in a mouse model of SUDEP, the researchers are trying to understand if there are specific patterns which can be detected early and used as a marker to predict risk of SUDEP.
  • Studies show that administering a drug to block a protein in the brain called orexin improved breathing and heart rate in the mouse models and potentially increased their longevity.

Deep Dive

This grant was supported generously by the Cameron Benninghoven Award.

Dr. Kristina SimeoneThe ability to predict and prevent SUDEP is a vital need for the epilepsy community, and a recent discovery by CURE Grantee Dr. Kristina Simeone and co-investigators Dr. Peter Abel and Dr. Timothy Simeone at Creighton University could lead to strategies that can help do so. The team is studying specific changes in cardiac and respiratory function health that can lead to SUDEP in hopes of developing biomarkers to predict SUDEP risk and treatments to prevent it.

The researchers are conducting experiments in a mouse model called Kv1.1 KO, which lacks part of the potassium channel, an important component of electrical signaling in the brain. These mice develop spontaneous seizures which progressively become more severe until the mice reach a specific age and are impacted by SUDEP.1

A 2013 study of SUDEP in humans noted a pattern of rapid breathing followed by apnea and bradycardia (slow heart rate) which eventually led to SUDEP.2 In their studies with the Kv1.1 KO mice, Dr. Simeone and her team similarly found that these mice had chronic periods of hypoxia (low oxygen), experienced apnea caused by periods of rapid breathing, and had periods of bradycardia. They found that these breathing and heart problems were more likely to occur as the mice approached SUDEP age. The researchers are interested in understanding whether this abnormal pattern of breathing and bradycardia can be detected early and used as a novel marker to predict SUDEP risk.

Cameron BenninghovenThe researchers also gathered evidence suggesting that a protein in the brain called orexin, which is known to regulate breathing and heart rate, may be a central player in causing SUDEP. They previously found that blocking orexin’s actions can improve sleep and reduce seizures in the Kv1.1 KO mice model.3 The team treated mice with a drug which blocks orexin’s actions and found that it beneficially increased heart rate in mice with bradycardia, and improved abnormal breathing patterns. The team also found that treating mice at high risk for SUDEP daily with the drug may increase their lifespan.

Dr. Simeone and her co-investigators are interested in using these important new discoveries to develop monitoring strategies for estimating SUDEP risk and eventually developing therapies to prevent SUDEP.

1 Simeone KA, Matthews SA, Rho JM, et al. Ketogenic Diet increases longevity in a model of Sudden Unexpected Death in Epilepsy, the Kv1.1KO mice. Epilepsia. 2016;57:178–82
2 Ryvlin P, Nashef L et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 2013 Oct;12(10):966-77
3 Roundtree HM, Simeone TA et al. Orexin Receptor Antagonism Improves Sleep and Reduces Seizures in Kcna1-null Mice. Sleep. 2016 Feb 1;39(2):357-68

Nationwide, Icelandic Population-Based Study Confirms SUDEP Incidence Found in Previous Studies

Objective: The incidence of sudden unexpected death in epilepsy (SUDEP) varies between studies. This study determined the incidence of SUDEP in the entire Icelandic population during a 20-year period.

Methods: All individuals in Iceland with epilepsy who died unexpectedly from January 1, 1991 through December 31, 2010 were included. Case ascertainment was based on autopsies, reimbursement for antiepileptic drugs, death certificates, information from neurologists, and medical records. The incidence of SUDEP was calculated according to the total number of residents in Iceland during the study period and an estimated epilepsy population of Iceland.

Results: The research team identified 37 individuals (26 men, 11 women) with definite SUDEP (n = 29), definite SUDEP plus (n = 4), and probable SUDEP (n = 4). Incidence of SUDEP was 0.6 per 100 000 person-years for the general population, and higher among men. The estimated incidence of SUDEP in the epilepsy population was 1.3 per 1000 person-years. SUDEP accounted for 0.1% of all deaths in Iceland during the study period.

Significance: SUDEP is an important cause of death in working-age people. This study provides the incidence of SUDEP in an unselected population of an entire country. The SUDEP incidence in the epilepsy population is comparable to that of previous studies.

Why Do Some People Stop Breathing After Seizures?

Could a chemical produced by the brain that regulates mood, sleep and breathing also be protective in people with epilepsy? New research has found that higher levels of serotonin in the blood after a seizure are linked to a lower incidence of seizure-related breathing problems called apneas, when a person temporarily stops breathing. The study is published in the September 4, 2019, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Serotonin, a hormone that transmits signals between nerve cells in the brain, is known to regulate breathing and waking from sleep, but what is unknown is how it may influence breathing before, during and after seizures,” said study author Samden D. Lhatoo, MD, FRCP, of McGovern Medical School at University of Texas Health Science Center in Houston, Texas, who conducted the research at Case Western Reserve University in Cleveland, Ohio. “Our findings show that higher levels of serotonin after a seizure are associated with less breathing dysfunction, and while we cannot make any links between serotonin levels and a risk of sudden unexplained death in epilepsy (SUDEP), our research may provide some important clues, since SUDEP has been linked in previous research to profound breathing dysfunction after generalized convulsive seizures.”

Researchers found that serotonin levels after a seizure were higher than before a seizure in people who did not temporarily stop breathing during a seizure. For 32 people who did not temporarily stop breathing during a seizure, serotonin levels were an average of 140 nanograms per milliliter (ng/ml) higher than an average of 110 ng/ml before seizure. For 17 people who did temporarily stop breathing, their serotonin levels were not significantly higher compared to before seizure.

“Our results give new insight into a possible link between serotonin levels and breathing during and after seizure,” said Lhatoo. “This may give hope that perhaps someday new therapies could be developed that may help prevent SUDEP. However, our study was small and much more research is needed to confirm our findings in larger groups before any treatment decisions can be made. It is also important to note that excess serotonin can be harmful, so we strongly recommend against anyone trying to find ways to increase their serotonin levels in response to our study findings.”

In addition to the small study size, a limitation of the study was that the timing of blood draws was not consistent.

Possible Role of SCN4A Skeletal Muscle Mutation in the Loss of Breathing During Seizure

SCN4A gene mutations cause a number of neuromuscular phenotypes including myotonia. A subset of infants with myotonia-causing mutations experience severe life-threatening episodic laryngospasm [a spasm of the vocal cords that makes it difficult to speak or breathe] with apnea.

This research team recently identified similar SCN4A mutations in association with sudden infant death syndrome. Laryngospasm has also been proposed as a contributory mechanism to some cases of sudden unexpected death in epilepsy (SUDEP). The team reports an infant with EEG-confirmed seizures and recurrent apneas. Whole-exome sequencing identified a known pathogenic mutation in the SCN4A gene that has been reported in several unrelated families with myotonic disorder.

This study proposes that the SCN4A mutation contributed to the apneas in our case, irrespective of the underlying cause of the epilepsy. They suggest this supports the notion that laryngospasm may contribute to some cases of SUDEP, and implicates a possible shared mechanism between a proportion of sudden infant deaths and sudden unexpected deaths in epilepsy.

Epilepsy Research Findings: August 2019

The past month has been filled with interesting research discoveries, including work done by CURE Grantee Dr. William Nobis and colleagues to advance our understanding of the areas of the brain that may be important in Sudden Unexpected Death in Epilepsy (SUDEP). In the field of epilepsy genetics, a large-scale study identified new epilepsy-associated genetic variants by examining the genetic make-up of more than 17,000 people with epilepsy. There is also intriguing research news looking at why cilantro, used in traditional medicine, may work to combat seizures.

Summaries of these research discoveries are below.

Plus, get epilepsy research news all month by downloading the new CURE mobile app! Find the details here.

Research Discoveries

  • SUDEP: A study featuring the work of CURE Grantee Dr. William Nobis and colleagues suggests that an area of the brain called the amygdala plays a role in dysfunctional breathing during seizures and possibly SUDEP. Learn More
  • Epilepsy Genetics: In one of the largest studies of its kind to examine the genetic make-up of individuals with epilepsy, scientists discover rare genetic variants associated with epilepsy. Learn More
  • Herbal Treatments: A study examines how the molecular action of cilantro, which is used as a traditional anticonvulsant medication, can help combat seizures. Learn More
  • Dementia and Epilepsy: Patients with dementia who are registered in the Swedish dementia registry were found to have increased rates of epilepsy. Learn More
  • Multiple Sclerosis and Epilepsy: Patients with multiple sclerosis have a higher risk of developing seizures compared with the general population. Learn More
  • SCN8A-Related Epilepsy: A study featuring the work of CURE Grantee Dr. Gemma Carvill and colleagues identified a set of neurons in the brains of mice that have a SCN8A gene mutation similar to humans that may be critical targets for therapeutic intervention. Learn More

Introducing the CURE Epilepsy Research Mobile App for research updates in the palm of your hand! Download today. iOS | Android

SUDEP: Untangling the Causes

Article featuring the work of CURE Grantee Dr. William Nobis

Earlier this month, 20-year-old Disney star Cameron Boyce died suddenly from what was most likely sudden unexpected death in epilepsy, or SUDEP. In this rare complication from epilepsy, a patient who is otherwise healthy dies during or following a seizure, and postmortem examination reveals no structural or toxicological cause for death. Boyce’s family confirmed he had epilepsy.

SUDEP occurs in about 1-2 per 1,000 patients with chronic epilepsy and 3-9 per 1,000 in those with severe, refractory seizures, though its frequency is difficult to calculate. It is most common in patients 20 to 40 years old.

“SUDEP is difficult to detect; it is often unobserved when it happens and autopsy doesn’t reveal any changes,” said William Nobis, M.D., an instructor in the Department of Neurology at Vanderbilt University Medical Center. “No definitive cause has been discovered, but we believe that respiratory dysfunction leads to cardiac abnormalities and arrest.”

While the brain regions responsible for a seizure’s role in inducing respiratory depression are unclear, “we have some clues that the pathways involve the amygdala and the brainstem,” Nobis said. In a new study published in the Journal of Neurosurgery, Nobis and colleagues at Northwestern University suggest that activation of amygdalar networks is correlated with central apnea during seizures.

Sudden Death in Epilepsy and Breathing Troubles Linked to Gene Mutation

In Sudden Unexpected Death in Epilepsy (SUDEP), people stop breathing for no apparent reason. Now, a group of UConn neuroscientists have a lead as to why, they report in the journal eLife.

“People with epilepsy have a high mortality rate, but it’s mysterious,” says Dan Mulkey, a neuroscientist in UConn’s physiology and neurobiology department.

Mulkey and his colleagues, graduate students Fu-Shan Kuo and Colin Clearly, wondered if there was a genetic basis for SUDEP. Perhaps the same genetic mutation that causes the seizures also disrupts the cells in the brainstem that control breathing.

To understand how this [genetic mutation] might lead to SUDEP, Kuo wanted to test two things: first, whether the mice with the Dravet syndrome mutation show breathing problems and die prematurely of SUDEP, and second, whether the cells in the part of the mice’s brainstem that controls breathing were normal or were somehow perturbed by the mutation.

The first question was answered quickly: the mice with Dravet syndrome had bad seizures that became more severe when the mice got hot, exactly like humans with Dravet syndrome. They tended to die very young, in a manner similar to SUDEP; none lived much past three weeks.

The second question took longer to answer, but there were early clues that Kuo and Mulkey were on to something. The mice with Dravet Syndrome had disordered breathing. They tended to hypoventilate (breathe too little) for no apparent reason sometimes. Other times they would have long apneas, or pauses between breaths. And these mice didn’t breathe more in response to high carbon dioxide levels in the air, the way humans and normal mice do.

When Kuo zoomed in on the part of the brainstem that controls breathing, she saw that the inhibitory cells – the stadium bouncers of the brainstem – were definitely less active than they should have been. This led the excitatory neurons to run wild, and constantly tell the part of the brain that generates the breathing rhythm to push faster. But shouldn’t this lead to increased breathing, not stopping?

Even People with Well-Controlled Epilepsy May be at Risk for Sudden Death

Featuring the work of former CURE Grantee Dr. Elizabeth Donner

People with epilepsy have a rare risk of sudden death. A new study shows that risk may apply even to people whose epilepsy is well-controlled, which is contrary to previous, smaller studies that showed the risk was highest among those with severe, difficult-to-treat epilepsy. The new study is published in the June 19, 2019, online issue of Neurology, the medical journal of the American Academy of Neurology.

The study also found that sudden death occurred in people who had not taken their last dose of epilepsy medication, those who were sleep deprived and people who had not had a seizure in at least a year.

“Since sudden death can happen to anyone with epilepsy, doctors need to discuss this rare possibility with people with epilepsy and their families,” said study author Orrin Devinsky, MD, of NYU Langone Health in New York City and a Fellow of the American Academy of Neurology. “They need to understand the critical–and potentially life-saving–importance of taking their medications on time and not skipping their medications or taking less than their prescribed dose.”

For the study, researchers reviewed cases referred to the North American SUDEP Registry, which was established in 2011. For the 237 cases with definite or probably SUDEP, researchers collected information from family members and medical records.

The median age of those who died was 26, with ages ranging from one to 70.

In nearly all of the cases, 93 percent, no one witnessed the death. A total of 70 percent of the deaths occurred during sleep.

Only 37 percent of the people had reportedly taken their last prescribed dose of epilepsy medication. Family members said that overall 34 percent did not always follow their medication treatment, either from forgetting to take doses, taking lower doses to reduce side effects or intentionally skipping or stopping taking their medication. Eleven percent had never been prescribed medication for epilepsy.

Fifteen percent of the people had been free of seizures in the year before their death.