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.

Epilepsy Research Findings: June 2019

This month’s round-up of epilepsy news features an announcement about a new antiepileptic rescue medication, NAYZILAM®. This therapy is the first FDA-approved nasal treatment option for people with epilepsy who experience episodes of frequent seizure activity.

We also highlight many research advances, from the discovery of a compound found in fruit and honey which can inhibit seizures to the development of a new drug to treat Dravet syndrome. Research in the cannabidiol (CBD) space has also advanced, with the creation of a synthetic form of CBD which may be easier to purify and does not need to be cultivated from hemp plants.

In more sobering news, reports over the past month show that one-third of epilepsy cases go without appropriate treatment for up to three years following diagnosis. In addition, people with psychogenic nonepileptic seizures (PNES) as well as epileptic seizures may be at a higher risk for sudden unexpected death in epilepsy (SUDEP)during the years immediately following diagnosis with PNES.

Summaries of all highlighted studies follow below. I’ve organized the findings into three categories: Treatment Advances, Research Discoveries, and Also Notable.

Treatment Advances

FDA Approves NAYZILAM® Nasal Spray to Treat Intermittent, Stereotypic Episodes of Frequent Seizure Activity in People Living with Epilepsy in the US
Learn More

The FDA has approved a New Drug Application for UCB’s newest antiepileptic drug NAYZILAM® (midazolam) nasal spray. This therapy is a benzodiazepine indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) distinct from a patient’s usual seizure pattern in individuals with epilepsy who are 12 years of age and older.

Study Advances More Effective Laser Ablation and Standard Epilepsy Surgery 
Learn More

In the largest study of its kind to date, researchers across 11 centers analyzed data on a relatively new minimally invasive alternative surgery for epilepsy. These researchers discovered changes that could make the procedure more effective in both laser ablation and standard surgery.

Research Discoveries

Brain Network Activity can Improve in Epilepsy Patients after Surgery
Learn More

Successful epilepsy surgery can improve brain connectivity similar to patterns seen in people without epilepsy, according to a new study published in the journal Neurosurgery. The study of 15 people with temporal lobe epilepsy is the first to show improvements in brain networks after surgery compared to a group of healthy subjects.

New Drug Could Help Treat Neonatal Seizures
Learn More

A new drug that inhibits neonatal seizures in rodent models could open new avenues for epilepsy treatment in human newborns. Researchers have found that gluconate—a small organic compound found in fruit and honey—acts as an anticonvulsant, inhibiting seizures by targeting the activity of channels that control the flow of chloride ions in and out of neonatal neurons.

Research Looks to Halt Stress-Induced Seizures Following Brain Injury
Learn More

The likelihood of developing epilepsy increases significantly with a traumatic brain injury. Stress and anxiety increase that likelihood even more dramatically. Researchers have been able to demonstrate that an injured brain responds differently to stress hormones than a healthy brain. The research team showed abnormal electrical activity in the brain tied to these stress-induced seizures and, most importantly, found a way to stop this activity from occurring.

Synthetic Version of Cannabidiol (CBD) Treats Seizures in Rats
Learn More

A synthetic, non-intoxicating analogue of CBD was found to be effective for treating seizures in rats. Researchers note the synthetic CBD alternative is easier to purify than a plant extract, eliminates the need to use agricultural land for hemp cultivation, and could avoid legal complications associated with cannabis-related products.

AZD7325 Has Seizure-Protective Effect in Mouse Model of Dravet Syndrome, Study Says
Learn More

Treatment with AZD7325, a compound that stimulates an inhibitory receptor in the brain, has a seizure-protective effect in a mouse model of Dravet syndrome. This treatment significantly increased the temperature threshold animals could withstand without experiencing any seizures during a hyperthermia-induced seizure test.

Children’s Brains Reorganize after Epilepsy Surgery to Retain Visual Perception
Learn More

Children can keep their full ability to process and understand visual information after brain surgery for severe epilepsy, according to a study funded by the National Eye Institute, part of the National Institutes of Health. This new report from a study of children who underwent epilepsy surgery and suggests that the lasting effects on visual perception can be minimal, even among children who lost tissue in the brain’s visual centers.

One-Third of Epilepsy Cases Go Untreated up to 3 Years After Diagnosis
Learn More

A small yet substantial subset of patients with newly diagnosed epilepsy go without appropriate treatment approximately 3 years after diagnosis. This gap in treatment may be increasing the risk for medical events and hospitalization in these patients.

Study Suggests ‘High Risk Period’ for SUDEP for People with Psychogenic Nonepileptic Seizures in Addition to Epileptic Seizures 
Learn More

Findings of a recently published study suggest that patients with comorbid epileptic seizures (ES) and Psychogenic Nonepileptic Seizures (PNES) can die from SUDEP and that there may be a high?risk period after the diagnosis of PNES is made. The authors state such patients should be closely monitored and provided with coordinated care of both their epilepsy and psychiatric disorder(s).

Also Notable

Fralin Biomedical Research Institute Neuroscientist Awarded Grant to Study Epilepsy
Learn More

Featuring CURE Grantee Dr. Sharon Swanger

Dr. Sharon Swanger of the Fralin Biomedical Research Institute was recently awarded a $1.7 million grant through the National Institute of Neurological Disorders and Stroke to study the role of glutamate receptors in the thalamus – an area of the brain involved in seizure generation. “If we can figure out how each [receptor] subtype functions and modulate select subtypes, then maybe we can target therapies to the circuit where the disease originated while leaving healthy circuits intact,” said Dr. Swanger.

Tool Helps GPs Predict Risk of Seizures in Pregnancy
Learn More

Doctors, midwives, and others can use a new risk calculator to identify those pregnant women at high-risk of seizures and to plan early referral for specialist input. The specialist could determine the need for close monitoring in pregnancy, labor, and after birth, and assess antiepileptic drug management, according to new research in PLOS Medicine. The study authors added that the model’s performance is unlikely to vary with the antiepilepsy drug dose management strategy – and that it could save maternal and infant lives.

Development of Epilepsy Prediction Device to Improve Independence for People with Epilepsy
Learn More

The University of Sydney’s Faculty of Engineering and Information Technologies is developing a system, NeuroSyd, which aims at real-time monitoring and processing of brain-signals while driving in a group of people living with epilepsy. NeuroSyd will be developed to deliver an early warning of the likelihood of an epileptic seizure.

Pfizer’s Lyrica at Doses 5mg and 10mg Fails Phase 3 Trial in Epilepsy
Learn More

Pfizer’s Lyrica has failed to meet its primary endpoint in a phase 3 trial in primary generalized tonic-clonic (PGTC) seizures. The study evaluated two doses of the drug – 5 mg and 10 mg – over a period of 12 weeks. Treatment with the drug did not result in a statistically significant reduction in seizure frequency versus placebo. Another phase 3 trial in May 2018 was successful, showing that a 14 mg dose of Lyrica resulted in a statistically significant reduction in seizure frequency versus placebo.

Study Suggests ‘High Risk Period’ for SUDEP for People with Psychogenic Nonepileptic Seizures in Addition to Epileptic Seizures

Background: This study reports 13 SUDEP cases in the North American SUDEP Registry with both psychogenic nonepileptic (PNES) and epileptic (ES) seizures among a consecutive series of 231 cases (excluding epileptic encephalopathies).

Results: On average, cases of PNES+ES died at a younger age (23 ± 11 years) than the ES-only cohort (30 ± 14 years), and died an average of 3 years after PNES diagnosis. The research team found no statistically significant confounding cardiac, respiratory, or psychiatric comorbidities and equal rates of anti-seizure medication adherence, although there was a trend for higher rates of psychiatric disorders in the PNES group.

Significance: Researchers state these findings confirm that patients with comorbid epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) can die from SUDEP and that there may be a high-risk period after the diagnosis of PNES is made in patents with comorbid ES. Such patients should be closely monitored and provided with coordinated care of both their epilepsy and psychiatric disorder(s).

Study Explores Way to Automate Detection of Sudden Unexpected Death in Epilepsy Risk Factors in Electronic Medical Records

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is an important cause of mortality in epilepsy. However, there is a gap in how often providers counsel patients about SUDEP. One potential solution is to electronically prompt clinicians to provide counseling via automated detection of risk factors in electronic medical records (EMRs). This study evaluated (1) the feasibility and generalizability of using regular expressions to identify risk factors in EMRs and (2) barriers to generalizability.

METHODS: Data included physician notes for 3000 patients from one medical center (home) and 1000 from five additional centers (away). Through chart review, the researchers identified three SUDEP risk factors: (1) generalized tonic-clonic seizures, (2) refractory epilepsy, and (3) epilepsy surgery candidacy. Regular expressions of risk factors were manually created with home training data, and performance was evaluated with home test and away test data. Performance was evaluated by sensitivity, positive predictive value, and F-measure. Generalizability was defined as an absolute decrease in performance by <0.10 for away versus home test data. To evaluate underlying barriers to generalizability, the team identified causes of errors seen more often in away data than home data. To demonstrate how small revisions can improve generalizability, researchers removed three “boilerplate” standard text phrases from away notes and repeated performance.

RESULTS: Researchers observed high performance in home test data (F-measure range = 0.86-0.90), and low to high performance in away test data (F-measure range = 0.53-0.81). After removing three boilerplate phrases, away performance improved (F-measure range = 0.79-0.89) and generalizability was achieved for nearly all measures. The only significant barrier to generalizability was use of boilerplate phrases, causing 104 of 171 errors (61%) in away data.

SIGNIFICANCE: Regular expressions are a feasible and probably a generalizable method to identify variables related to SUDEP risk. This study’s methods may be implemented to create large patient cohorts for research and to generate electronic prompts for SUDEP counseling.

SUDEP Action Win BMJ Award for Life-Saving Epilepsy Tools

SUDEP Action claimed Education Team of the Year at the British Medical Journal (BMJ) Awards 2019.

Judges commented that the ‘outstanding winner’ of the category were two free lifesaving epilepsy safety tools; the digital app EpSMon for people with epilepsy, and the clinician tool, the SUDEP and Seizure Safety Checklist.

The charity is working on bringing the lifesaving solutions, which it says transforms epilepsy patient safety, to wider Oxfordshire and across the UK.

Sammy Ashby, SUDEP Action Deputy CEO and manager ofthe projects, said: “We’re delighted that these projects have been recognized by this award; many people with epilepsy and their clinicians are not well supported to reduce their risks, yet these simple conversations and checks have the potential to save many lives each year.”