CURE Epilepsy Discovery: Epilepsy Surgery May Be Beneficial in Reducing SUDEP

Key Points:

  • To understand how epilepsy surgery can affect the risk of SUDEP, CURE Epilepsy-grantee Dr. Lisa Bateman and her collaborator, Dr. Catherine Schevon, analyzed rates and causes of mortality in people who had epilepsy surgery versus those who hadn’t.
  • Their analysis suggests that for those who have had epilepsy surgery, there was a reduction in the occurrence of death, and significantly fewer deaths from SUDEP.
  • The reduction in the occurrence of SUDEP for those who have had surgery appeared to be most significant in the first 10 years post-surgery.

Deep Dive:

Frequent, uncontrolled seizures, particularly generalized tonic-clonic seizures (GTCS), are a risk factor for Sudden Unexpected Death in Epilepsy or SUDEP[1]. Epilepsy surgery can be an option to control or eliminate seizures in people with drug-resistant seizures. In addition to helping achieve seizure control, epilepsy surgery is also thought to reduce the risk of SUDEP, however, the evidence for this is limited. A strong understanding of how epilepsy surgery can affect SUDEP occurrence is important as it can help guide treatment decisions.

Dr. Lisa Bateman, Cedars Sinai Medical CenterCURE Epilepsy-grantee, Dr. Lisa Bateman and her collaborator, Dr. Catherine Schevon recently published results from their study comparing the number and causes of death, including SUDEP, in people who had epilepsy surgery versus those who did not undergo surgery[2].

For their study, which was generously funded by the Henry Lapham Memorial Award, the team analyzed mortality in 590 patients who had undergone epilepsy surgery between 1977 and 2014. Deaths in this surgical group were compared to those in a group of 122 people with drug-resistant epilepsy who did not have epilepsy surgery because they were either not considered suitable candidates or refused surgery.

The team found that number of deaths was significantly reduced in the surgical group versus the non-surgical group, and SUDEP was the main cause of death in both groups. Additional causes included tumors, suicide, accidental death, status epilepticus and other conditions.

Dr. Catherine Schevon, Columbia UniversityUpon further analysis, the researchers discovered that the surgical group had a statistically significant lower rate of SUDEP (1.9 per 1000 patient-years* in the surgical group versus 4.6 per 1000 patient-years in the non-surgical group), as well as a delay in the occurrence of SUDEP relative to the non-surgical group. In the surgical group, on average, SUDEP occurred 10.1 years after surgery, but in the non-surgical group it occurred an average of 5.9 years after the surgery was discussed, but not performed.

The team also found that there was a reduction in SUDEP occurrence in the first 10 years after surgery, however, this benefit appeared to lessen after this time- period. While a larger study is needed to confirm it, this finding suggests that long-term follow up of epilepsy surgery patients is important even if they are seizure-free after surgery.

This CURE Epilepsy-funded study provides evidence for the beneficial effects of epilepsy surgery in reducing overall mortality including SUDEP. A larger study will be helpful in determining how long the benefit can last and whether there are any factors that can predict who might be at greater risk for SUDEP post-surgery.

*Patient-years is a statistical term used to account for the total time all subjects spend in a study and is a more accurate measure of the rate at which an event, in this case SUDEP, occurs in the study population.

Dr. Lisa Bateman is the Director of Surgical Epilepsy Programs at Cedar Sinai Medical Center. Dr. Catherine Schevon is an Associate Professor of Neurology at Columbia University. 

Literature Cited

[1] Harden C., Tomson T., et. al. Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2017 Apr 25;88(17):1674-1680.

[2] Casadei C.H., Carson K.W., et. al. All-cause mortality and SUDEP in a surgical epilepsy population. Epilepsy & Behavior 2020 Jul;108:107093


Your support makes this research possible. Our researchers’ important work continues through the current public health crisis and beyond thanks to generous donors who, like us, envision a world without epilepsy.

The Path to a Cure: Improving Genetic-Based Outcomes

Dr. Heather Mefford is a current CURE Grantee who is as dedicated to driving science toward cures for epilepsy as she is to treating people in her clinical practice. As Associate Professor of Pediatrics at the University of Washington and attending physician at Seattle Children’s Hospital, Dr. Mefford is making an impact both in and out of the laboratory.

Severe Pediatric Epilepsy is Often Genetic

Dr. Heather Mefford, 2019 CURE Epilepsy Grantee

As a physician who cares for pediatric patients living with severe epilepsy syndromes, Dr. Mefford has firsthand knowledge of the devastating impacts of seizures in children. These treatment-resistant epilepsy syndromes are usually caused by a genetic mutation and knowing what that mutation is can potentially inform the treatment plan. As such, genetic testing is a critical part of the epilepsy diagnosis and care process. Dr. Mefford describes what genetic testing involves and what kinds of tests are available in an episode of our Seizing Life® podcast. Watch or listen to learn more.

The DNA of Dr. Mefford’s Genetic Research
When not seeing patients, Dr. Mefford heads a research laboratory at the University of Washington. Over the last 10 years, Dr. Mefford’s team has identified many new epilepsy-related genes and mutations. Dr. Mefford’s lab is currently investigating a type of genetic change that does not alter the sequence of the gene itself but instead affects how the gene functions. This field of research, known as epigenetics, is relatively new and now, excitingly, is being applied to epilepsy. For her CURE-funded project, Dr. Mefford is studying a type of epigenetic change called methylation, in people with severe early-onset, treatment-resistant seizure disorders known as developmental and epileptic encephalopathies (DEE). Despite advanced genetic testing, more than 50% of people with DEE still do not have a genetic diagnosis and work like Dr. Mefford’s could ultimately improve the prognosis for children with these epilepsies.

Leading the Next Generation
To support the future of research, Dr. Mefford has helped launch the careers of the next generation of epilepsy scientists. One of her former trainees, Dr. Gemma Carvill, is also making a big impact on the field of epilepsy research. Dr. Carvill was awarded a CURE grant early in her career and now leads her own independent research program at Northwestern University in Chicago, where she also investigates the underlying genetic and epigenetic mechanisms of epilepsy.


Your support makes this research possible. Our researchers’ important work continues through the current public health crisis and beyond thanks to generous donors who, like us, envision a world without epilepsy.

Female psychologist working with boy who has autism and epilepsy.

CURE Discovery: The Connection Between Stress, Autism, and Epilepsy

Key Points:

  • CURE grantee Dr. Daniel Barth and his team worked to determine if autism and epilepsy, which frequently occur together, share common causes and thus can be treated similarly.
  • The team tested if preventing brain inflammation late in pregnancy and the early days of life can treat both conditions in a rat model of epilepsy with autistic-like behaviors, which they had created in a previous study [1].
  • Unexpectedly, they found that the treatment relieved the autistic-like symptoms but had virtually no effect on the development of epilepsy. This surprising result suggests that the two disorders may have distinct underlying causes and should be treated differently.

Deep Dive:

Over 30% of people with epilepsy are also impacted by autism-spectrum disorders (ASD) [2], but the links between these two conditions are not well understood. However, we do know that the two disorders can share the same genetic causes and that they are also associated with common environmental risk factors. With the help of a CURE grant, Dr. Daniel Barth and his team at the University of Colorado worked to understand how two environmental factors might impact the chance of developing epilepsy and ASD. Specifically, they looked at stress late in pregnancy and in the early days of life and exposure to terbutaline, an asthma drug occasionally used to prevent preterm labor. Dr. Barth and his team had previously combined stress and terbutaline to develop a rat model of epilepsy with ASD-like behaviors called the “ST” model [1].

With this model, the researchers set out to tease apart the biology underlying epilepsy and ASD. While both conditions are adversely affected by chronic prenatal stress [3,4], the process by which this stress may influence the development of epilepsy and ASD may not be the same. Indeed, stress is a complex phenomenon that can induce inflammation and increase levels of stress hormones. Because stress [5] and terbutaline [6] are known to independently cause brain inflammation, Dr. Barth and his team first examined the possible benefit of a unique anti-inflammatory treatment [7] to prevent epilepsy and ASD. Notably, Dr. Barth’s study was the first to evaluate use of this treatment to prevent stress-induced inflammation early in development, when the growth of a rat’s brain is rapid but also extremely vulnerable to environmental risk factors.

The team monitored seizure activity and ASD-like behaviors, the latter of which were assessed with procedures designed to mimic the human symptoms of repetitive behavior, anxiety, and poor social interactions, in the rats during the first few months of life. Among rat pups that received the anti-inflammatory treatment, there was an increase in the density of the brain’s immune cells and in the levels of a specific protein known as IL-10, both of which reflect an anti-inflammatory response. In contrast to the strong anti-inflammatory response, however, the pups did not have a significant hormonal response, which was reflected in practically no change in the levels of two stress hormones. As predicted, blocking the inflammatory response prevented the development of ASD-like behaviors but, unexpectedly, it did nothing to prevent the onset of epilepsy [8].

Despite this unanticipated result, Dr. Barth’s work is still extremely valuable. In addition to providing a promising treatment for environmentally induced ASD, the findings show that the factors that cause ASD and epilepsy, disorders which are often thought to share the same underlying pathology, can be separated. These findings have also helped Dr. Barth and his team formulate alternative ideas about the development of epilepsy in their ST model. Indeed, as a result of critical CURE funding, they are starting to explore hormonal influences on epilepsy in their model.

Literature Cited

  1. Bercum, F.M. et al. Maternal stress combined with terbutaline leads to comorbid autistic-like behavior and epilepsy in a rat model. J. Neurosci. 2015; 35(48): 15894-15902.
  2. Spence, S. and Schneider, M. The role of epilepsy and epileptiform EEGs in autism spectrum disorders. Pediatr. Res. 2009; 65(6): 599-606.
  3. Beversdorf, D.Q. et al. Prenatal stress, maternal immune dysregulation, and their association with autism spectrum disorders. Curr. Psychiatry Rep. 2018; 20(9): 76.
  4. Van Campen, J.S. et al. Early life stress in epilepsy: a seizure precipitant and risk factor for epileptogenesis. Epilepsy Behav. 2014; 38: 160-171.
  5. Calcia, M.A. et al. Stress and neuroinflammation: a systematic review of the effects of stress on microglia and the implications for mental illness. Psychopharmacology 2016; 233: 1637-1650.
  6. Zerrate, M.C. et al. Neuroinflammation and beghavioral abnormalities after neonatal terbutaline treatment in rats: implications for autism. J. Pharmacol. Exp. Ther. 2007; 322(1): 16-22.
  7. Reber, S.O. et al. Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice. Proc. Natl. Acad. Sci USA 2016; 113(22): E3130-E3139.
  8. Smith, Z.Z. et al. Effects of immunization with heat-killed Mycobacterium vaccae on autism disorder-like behavior and epileptogenesis in a rat model of comorbid autism and epilepsy. Brain Behav. Immun. 2020; 88: 763-780.

 


Your support makes this research possible. Our researchers’ important work continues through the current public health crisis and beyond thanks to generous donors who, like us, envision a world without epilepsy.

CURE Discovery: Temporal Lobe Epilepsy and Memory Impairment

Key Points

Picture of the researcher

  • CURE Taking Flight grantee, Dr. Tristan Shuman and his team, in collaboration with two other research groups, used a mouse model of temporal lobe epilepsy (TLE) to examine how chronic epilepsy leads to cognitive and memory deficits.
  • The team developed innovative research tools, including a wireless miniature microscope that can “see” into the brain and analyze the exact firing patterns brain cells use to communicate with each other.
  • The team found that disrupting these firing patterns plays an important role in the development of memory deficits. Restoring these firing patterns may someday provide relief from the memory deficits and cognitive delays that accompany TLE.

Deep Dive

Temporal lobe epilepsy (TLE), which occurs in the temporal lobe of the brain, is the most common type of focal epilepsy.1,2 Unfortunately, people with TLE also often experience disabling cognitive and memory impairments.1 With support from a CURE Taking Flight award, Dr. Tristan Shuman and his team may have discovered a possible cause for these debilitating symptoms. His team at the Icahn School of Medicine at Mount Sinai in New York collaborated with Dr. Peyman Golshani’s laboratory at the University of California, Los Angeles. Together, they examined how two small areas of the brain that play key roles in memory and learning share information between each other to explore possible origins of the cognitive and memory deficits that develop in people with chronic epilepsy.

HippocampusThe temporal lobe of the brain contains a region called the hippocampus which plays a vital role in regulating learning, memory, and spatial navigation.3 Dr. Shuman and his team focused on two subregions of the hippocampus important in spatial navigation: the dentate gyrus (DG) and the CA1. Spatial information from other areas in the brain enters through the DG and leaves through the CA1.3 Dr. Shuman aimed to understand if disrupting this input/output circuit contributed to the cognitive and memory deficits observed in mice with TLE.

To study the interactions between the neurons in the DG and CA1, Dr. Shuman and colleagues first developed novel tools which enabled them to make their initial findings. They determined that in mice with chronic epilepsy, electrical impulses moving between neurons in the DG and CA1 were disrupted, indicating that these two regions were not able to process spatial information.

Hippocampus

The researchers then examined how each individual neuron fired as the mice ran along a track. To accomplish this, the mice were fitted with a wireless, mouse-sized mini microscope, created by Dr. Shuman and his collaborators, that can “see” into the brain and record the activity of hundreds of neurons. They discovered that in the brains of mice with epilepsy, the number of place cells, a specific type of CA1 neuron that gathers and relays information about the position of objects in space, was reduced when compared to normal mice. In normal mice, these place cells were stable and active in the same location every day that the animals ran on the track. However, in the mice with TLE, the place cells changed their firing patterns every few minutes, indicating that the mice could not remember their location.

To further his research, Dr. Shuman collaborated with Dr. Panayiota Poirazi at the Foundation for Research and Technology Hellas in Greece to confirm his findings using a computer model. Using this approach, the team confirmed that by changing the timing of electrical inputs into the hippocampus, they could disrupt processing of spatial information.

Understanding how individual neuronal circuits are disturbed in epilepsy is a first step in creating future therapies to target disrupted firing patterns in people with epilepsy. By continuing to explore this promising avenue of research, scientists may one day be able to design therapeutic interventions that restore neuronal firing patterns, reducing seizures and improving cognitive function for people with chronic epilepsy.

Literature Cited

1Bell, B. et al. The neurobiology of cognitive disorders in temporal lobe epilepsy. Nat. Rev. Neurol. 2011; 7(3): 154-164.
2 Téllez-Zenteno, J.F. & Hernández-Ronquillo, L. A review of the epidemiology of temporal lobe epilepsy. Epilepsy Res. Treat. 2012; 2012: 630853.
3 Saniya, K. et al. Neuroanatomical changes in brain structures related to cognition in epilepsy: an update. J. Nat. Sci. Biol. Med. 2017; 8(2): 139-143.

The Path to a Cure: An Update on Genetic Research

Dr. Gemma Carvill, a former CURE Grantee who is a leader in epilepsy genetic research, was awarded a Taking Flight Award in 2015, early in her career. This grant aims to encourage young investigators to conduct independent research and blossom in the field of epilepsy. Her intriguing study explored how genetic mutations can cause epilepsy to develop, particularly a group of severe, treatment-resistant childhood epilepsy syndromes called “epileptic encephalopathy”.

Since receiving her CURE grant, Dr. Carvill’s career has certainly “taken flight”. Today, she heads her own lab at Northwestern University in Chicago, IL, where her team continues to focus on understanding the underlying genetic and epigenetic mechanisms of epilepsy.

We had the chance to catch up with Dr. Carvill during a recently aired episode of our Seizing Life® podcast. Watch or Listen to learn more about epilepsy genetics and Dr. Carvill’s exciting research.

Watch Seizing Life

Taking Flight in Epilepsy Research

2018 DiscoveryIn 2018, Dr. Carvill partnered with Dr. Gaetan Lesca of the Lyon University Hospital in creating an international study on epilepsy genetics. Together, they identified a new cause of epilepsyde novo mutations (genetic mutations existing only in affected patients and not in their parents) in the CUX2 gene.1 CUX2 is a protein that activates (turns on) or suppresses (turns off) other genes, and specifically regulates genes involved in establishing connections between nerve cells.

Because of Drs. Carvill and Lesca’s collaboration, this genetic cause of epilepsy can now be targeted for the development of potential therapeutic interventions.

A “Crazy Idea” to Transform Clinical Care

Dr. CarvillDr. Carvill is continuing her important work with the help of a New Innovator Award from the National Institute of Health (NIH). In her own words, this award is granted to researchers with “a completely crazy idea that, if it pans out, could really transform clinical care for patients.” Her lab is examining if cell-free DNA (short fragments of DNA released when a cell dies and bursts open) found in plasma can be used as a biomarker of epilepsy.

A big challenge in diagnosing and treating epilepsy is that we only have one reliable biomarker; structural abnormalities in the brain. While widely used, EEG testing can fail to capture seizure data. Dr. Carvill’s work may lead to a new way to identify when patients have had seizures.

Hear more about this innovative work from Dr. Carvill on this episode of the Seizing Life® podcast and learn more about how discoveries in the lab are translated into improved patient care.

Literature Cited

1Chatron N et al. The epilepsy phenotypic spectrum associated with recurrent CUX2 variant. Ann Neurol 2018; 6

Two doctors, a man and a woman, in blue scrubs look at a brain scan.

CURE Discovery: Inhibition of an Important Brain Enzyme Attenuates the Development of Epilepsy

In his CURE-funded research, Dr. Detlev Boison and his team found that an adenosine kinase inhibitor called 5-ITU increases adenosine levels in the brain, protecting it from seizures.

Key Points

Dr. Detlev Boison

  • CURE Grantee Dr. Detlev Boison and his team discovered that short-term use of a substance called 5-ITU prevents epilepsy from developing in mouse models of acquired epilepsy.
  • 5-ITU inhibits a brain enzyme called adenosine kinase (ADK) that regulates a substance called adenosine (ADO), which, in turn, plays a critical role in preventing epilepsy following an injury to the brain.
  • Dr. Boison’s groundbreaking work supports the development of improved, more selective treatments which aim to cure underlying causes of epilepsy, rather than merely control seizures.

Deep Dive

A graphic which illustrates the relationship between adenosine and adenosine kisase.One of the most common ways of developing epilepsy is through “acquired” means, such as a severe concussion, brain infection, fever-induced seizure, or stroke. A naturally occurring substance in the brain, called adenosine (ADO), plays a protective role by decreasing excessive neuronal activity1,2 and protecting the DNA in nerve cells from changes that contribute to the development of epilepsy.3 ADO levels in the brain are regulated by an enzyme called adenosine kinase (ADK) and, unfortunately, brain injuries often trigger a series of events that elevate levels of ADK. In his CURE-funded research, Dr. Detlev Boison and his team found that an ADK inhibitor called 5-ITU increases ADO levels in the brain and protects it from seizures.

To make this discovery, the team evaluated if short-term treatment of 5-ITU following an injury to the brain could halt the development of epilepsy over the long-term.4 To do so, they used a mouse model of acquired epilepsy that reliably develops seizures two weeks after an injury. The team first had to determine the appropriate time points to administer 5-ITU following a head injury. Over a two-week period, the team monitored the progression of brain tissue damage in their mouse model, along with ADK levels and changes in EEG, analyzing samples at different days post-injury compared to controls. The team found that by the third day, ADK levels had started to increase and continued to increase over the two-week time period, accompanied by a loss of neurons in an area of the brain called the hippocampus and changes in EEG patterns by the fourteenth day post-injury.

Reasoning that 5-ITU should first be administered when ADK levels initially rise, the team gave their mouse model the substance for a limited time – for only five days starting on day 3 post-injury – and continued to monitor the mice closely. After six weeks, the team found that the 5-ITU-treated mice had little brain tissue damage, significantly decreased ADK levels, and fewer seizures compared to the control group. Importantly, these changes were sustained even after nine weeks.

Discovering that short-term inhibition of ADK leads to a long-lasting antiepileptogenic effect makes this a promising therapy, especially since it could avoid any potential toxicities and intolerable side effects from long-term use of ADK inhibitors. Such a treatment would represent a true cure for epilepsy. Dr. Boison’s groundbreaking research supports the development of improved, more selective compounds which can one day be tested in clinical trials and, hopefully, approved for clinical use.

Dr. Boison’s Research Continues

For more than 20 years CURE has been on an unrelenting mission to end epilepsy. We have funded more than 240 grants in 15 countries to better understand the causes of epilepsy, uncover new therapies, and cure epilepsy once and for all. Now it is time to take those research findings one step further.

We are thrilled to expand our current research approach with the CURE Catalyst award, and to name Dr. Boison the first grantee under this new mechanism. This grant funds translational research, where findings from basic research studies are “translated” into the next phase of research to prepare potential new treatments for clinical trials. You can learn about the continuation of Dr. Boison’s work here.

1 Fedele, D.E. et al. Engineering embryonic stem cell derived glia for adenosine delivery. Neurosci. Lett. 2004; 370(2-3) 160-165.
2 Guttinger, M. et al. Suppression of kindled seizures by paracrine adenosine release from stem cell-derived brain implants. Epilepsia 2005 46(8): 1162-1169.
3 Williams-Karnesky, R.L. et al. Epigenetic changes induced by adenosine augmentation therapy prevent epilpetogenesis. J. Clin. Invest. 2013; 123(8): 3552-3563
4 Sandau, U.S. et al. Transient use of a systemic adenosine kinase inhibitor attenuates epilepsy development in mice. Epilepsia 2019; 60: 615-625.


Your support makes this research possible. Our researchers’ important work continues through the current public health crisis and beyond, thanks to generous donors who, like us, envision a world without epilepsy.

CURE Initiative: Defending Against Post-Traumatic Epilepsy

A graphic which states, "CURE and the Department of Defense. From 2000-2019, over 400,000 US service members were diagnosed with a TBI."Post-traumatic epilepsy (PTE) is a seizure disorder resulting from injury to the brain. It is a devastating complication of traumatic brain injury (TBI), which can occur as a result of car accidents, sports-related injuries, or military combat. PTE can develop weeks, months, or even years after TBI, offering a window of opportunity for interventions to prevent seizures. Unfortunately, there is currently no way to predict who will develop epilepsy following TBI, and there are no therapies to prevent it.

CURE’s collaborative, multi-investigator PTE research program aims to develop better models to study PTE and discover methods to predict who is at risk as a way to intervene early and prevent PTE. With a $10 million grant from the US Department of Defense, this initiative brings together leading scientists in the field from around the world. This groundbreaking initiative, which launched in 2018, involves six primary investigators and their research teams for a total of over 60 scientists. To further encourage collaboration and scientific rigor, CURE has contracted with the Laboratory of Neuro Imaging (LONI) at the University of Southern California to create a database to house data from the teams and make it accessible for cross-comparison and analysis.

These teams are enhancing knowledge about PTE by researching what changes occur in the brain, as well as by developing robust animal models to study PTE. In addition, the researchers are investigating how different types of head injury can contribute to seizure onset and occurrence, and they are identifying potential EEG, MRI, or blood biomarkers to predict PTE in humans.

One exciting, ongoing PTE project is led by Dr. Jeffrey Loeb of the University of Illinois at Chicago. Dr. Loeb’s team project will focus on a type of bleeding commonly caused by TBI called subarachnoid hemorrhage. This kind of bleeding occurs when there is blood between the brain and the protective tissue surrounding the brain. By studying both rat models and in-patient instances of subarachnoid hemorrhage, Dr. Loeb’s data-driven approach will hopefully lead to methods or guidelines to help doctors take steps to prevent the development of epilepsy. Check out our recent interview with him to learn more.

We’ve also seen significant achievements over the course of the past two years. These includes a publication from Dr. Harald Sontheimer’s team at Virginia Tech University on a new mouse model for PTE,1 and a manuscript in preparation by Dr. Victoria Johnson’s team at the University of Pennsylvania on neuropathology in humans after TBI. The investigators have presented abstracts of their work at scientific meetings including the 2019 National Neurotrauma Society meeting in Pittsburgh, PA and the 2019 American Epilepsy Society Meeting in Baltimore, MD.

This collaborative, team-science approach has the potential to develop innovative ways to study PTE, build understanding of the neural mechanisms behind PTE, and ultimately help us understand who is at the greatest risk. This research can pave the way for the development of therapies to prevent and/or treat PTE, having a positive impact on the lives of all affected by TBI and PTE.

1 Shandra O., Robel S. Inducing Post-Traumatic Epilepsy in a Mouse Model of Repetitive Diffuse Traumatic Brain Injury. J Vis Exp. 2020 Feb 10;(156)

Learn More about PTE

Mike and Kim Adamle smiling as they are being interviewed for an episode of Seizing Life, a CURE podcast

Podcast: Former football star and broadcaster Mike Adamle discusses developing and managing PTE resulting from sports injuries.

Watch or Listen Now

Woman sitting at a laptop participating in a CURE webinar.

Webinar: Watch a free webinar on what triggers seizures in people who sustain traumatic brain injury.

Watch Now

Dr. Graffman being interviewed by Kelly Cervantes, CURE Board Member and Seizing Life podcast host.

Podcast: Explore the relationship between TBI and PTE, particularly in Vietnam veterans, in this Seizing Life podcast episode.

Watch or Listen Now

Woman standing in a research lab wearing a white coat with her back to the camera.

CURE Discovery: Discover the results of an innovative CURE-funded study aiming to find a way to prevent PTE.

Learn More

Doctor wearing a white coat typing at a computer

CURE Discovery: Two Major SUDEP Risk Factors Identified in Nationwide Swedish Study

This grant was generously supported by the Leisher Family Award.

Key Takeaways:

  • Dr. Torbjörn Tomson’s study confirms previous research suggesting that generalized tonic-clonic seizures (GTCS) are a significant risk factor for Sudden Unexpected Death in Epilepsy (SUDEP)
  • The study found that for people with GTCS, living and sleeping alone are also significant SUDEP risk factors
  • The research suggests that treatments to reduce the occurrence of GTCS or to convert GTCS to non-GTCS would be useful in reducing SUDEP risk

Deep Dive:

Dr. TomsonDr. Torbjörn Tomson at the Karolinska Institute in Sweden, whose 2010 CURE-funded study was supported generously by the Leisher Family Award, recently published his findings from a large, nationwide study on factors associated with increased risk of SUDEP.1

For this study, Dr. Tomson and his team analyzed medical records for 255 people who passed away due to SUDEP between July 1, 2006 and December 31, 2011. These SUDEP cases were classified as either “definite SUDEP” or “probable SUDEP”2 based on available information. To build a strong understanding of SUDEP risk factors, the investigators compared each case of SUDEP to the medical records for 5 people with epilepsy of the same sex who were alive at the case’s time of death. These individuals served as controls against which to compare factors that might contribute to SUDEP risk. For SUDEP cases and controls, the team used medical records to collect information on age, sex, epilepsy type, and occurrence of seizures, as well as lifestyle information on whether the individuals lived alone or with someone and if they shared a bedroom. The team performed analyses to understand how each of these factors contributed to SUDEP risk.

The analyses of these data found that the presence and frequency of GTCS was the most important risk factor for SUDEP. A history of GTCS was associated with a ten-fold greater risk of SUDEP. Of those with this increased risk, patients who had 4-10 GTCS in the year preceding SUDEP had a 32-fold increase in SUDEP risk. Dr. Tomson’s team also found that the presence of nocturnal GTCS in the year preceding SUDEP was associated with a 15-fold increased risk of SUDEP. Further, this study found that there was no increased risk of SUDEP in people with only non-GTCS, suggesting that treatments to convert GTCS to non-GTCS could reduce SUDEP risk.

Importantly, the team observed a substantial increase in SUDEP risk for individuals with GTCS who lived alone and those who live with other people but don’t share a bedroom. The combination of sleeping alone and having at least one GTCS in the preceding year resulted in a 67-fold increased risk for SUDEP compared to not having GTCS and sharing a bedroom. This data confirms previous research suggesting that unattended GTCS are the most significant risk factor in SUDEP.3

This important study identifies GTCS and sleeping alone as significant risk factors for SUDEP. In addition, Dr. Tomson’s work makes the case for improved seizure monitoring devices to alert caregivers of night-time seizures and for people with GTCS to share a room with someone when sleeping whenever possible. The research further suggests that treatments to reduce occurrence of GTCS would be useful in reducing SUDEP risk.

1 Sveinsson O, Andersson T, Mattsson P, Carlsson S, Tomson T, Clinical risk factors in SUDEP: A nationwide population-based case-control studyNeurology. 2020 Jan 28;94(4):e419-e429
2 SUDEP was defined as “definite” or “probable” based on previously developed criteria. When these criteria were met with a sufficient description of the circumstances of death and a postmortem report was available, SUDEP was classified as “definite”. When criteria were met but a postmortem report was not available, SUDEP was classified as “probable”. A third category of “possible” SUDEP included cases where SUDEP could not be ruled out but did not have sufficient evidence or a postmortem report. Possible SUDEP was not included in this study.
3 Devinsky O, Hesdorffer DC, Thurman DJ, Lhatoo S, Richerson G Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention, Lancet Neurol. 2016 Sep;15(10):1075-88

CURE Discovery: Predicting Focal Epilepsy’s Path through the Brain

Key Takeaways

Dr. Jennifer Gelinas

  • In a study funded in part by CURE, Dr. Jennifer Gelinas aimed to understand how focal epilepsy resulting in partial seizures can progress to different parts of the brain over time.
  • She discovered that abnormal electrical activity between seizures can affect regions of the brain outside of a person’s epileptic network (regions of the brain involved in creating and spreading seizures).
  • Examining these interactions may provide opportunities to predict how focal epilepsy might progress in individuals.

Deep Dive

Focal epilepsy is often a progressive and unpredictable disease because focal seizures can evolve into new, individual-specific seizure types over time, making treatment challenging.

Interictal discharge

Some people with focal epilepsy experience seizures that get worse with time, while other individuals have a more stable course. CURE grantee, Dr. Jennifer Gelinas at Columbia University, hopes to understand how and why this variability happens. The aim of her CURE-funded work is to find ways to predict how focal epilepsy will progress to other regions of the brain so that doctors can treat patients more effectively.

Dr. Gelinas previously reported that, in a rat model of temporal lobe epilepsy, interictal epileptiform discharges (IEDs) can trigger neural activity in distant brain regions.1 IEDs are a type of abnormal electrical activity that occurs between seizures. Now in her recently published study,2 funded partly by CURE, Dr. Gelinas sought to understand how IEDs can affect the progression of focal epilepsy over time in people.

For this study, Dr. Gelinas and her team analyzed intracranial EEG (iEEG) recordings from 10 people with focal epilepsy who were undergoing clinical evaluation for epilepsy surgery. For each person, the team first identified brain regions where IEDs could be detected. They then located brain regions which had abnormal neural activity in response to IEDs. Although the patterns of neural activity coupled with IEDs were specific to each person, in each case they were located in distant brain regions outside the patient’s epileptic network. Moreover, distant brain regions where neural activity coupled with IEDs was detected had different characteristics compared to regions that were not affected by IEDs. The researchers also found that affected regions could be identified even in the absence of detectable IEDs.

This important study suggests that abnormal electrical activity (such as IEDs) in one part of the brain can disrupt normal neural activity in distant parts of the brain and may be an indicator of where the epileptic network will spread. Detection and manipulation of these patterns may present opportunities for diagnosis and therapies to prevent the spread of the network to other brain regions.

Dr. Gelinas was awarded a $100,000 Taking Flight grant by CURE in 2018. This grant seeks to promote the careers of young epilepsy investigators to allow them to develop a research focus independent of their mentor.

1 Gelinas J.N., Khodagholy D. et. al., Interictal epileptiform discharges induce hippocampal-cortical coupling in temporal lobe epilepsy. Nat Med. 2016 Jun;22(6):641-8. 2016;57:178–82
2 Dahal P., Ghani N., et. al. Interictal epileptiform discharges shape large-scale intercortical communication. Brain. 2019 Nov 1;142(11):3502-3513

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