CURE Initiative: Defending Against Post-Traumatic Epilepsy

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

CURE Discovery: Understanding and Treating NMDA Receptor-Associated Epilepsy

Key Takeaways:

  • Researchers are studying whether off-label treatment with certain FDA-approved drugs can improve seizure control for individuals whose epilepsy is caused by over-activation of NMDA-R.
  • The CURE-funded team is researching previously unstudied mutations in GRIN genes and using this information to determine who might benefit from off-label treatment with NMDA-R blockers.
  • Interested families with a genetic diagnosis of a GRIN mutation and epilepsy can enroll in this important study. Contact Jenifer Sargent at Jenifer.Sargent@childrenscolorado.org for more information.

Deep Dive:

Dr. Stephen Traynelis

Can off-label use of certain FDA-approved drugs which reduce NMDA-R function

improve seizure control in patients with epilepsy caused by over-activation of NMDA-R? That is the question a CURE-funded study by Dr. Stephen Traynelis at Emory University and his team aims to answer.

Dr. Traynelis and his collaborators, Drs. Sooky Koh, Ann Poduri, and Tim Benke, will assess if epilepsy caused by over-activation of a protein in the brain, called the N-methyl-D-aspartate receptor (NMDA-R), can be improved when patients with GRIN mutations are treated off-label by their clinicians with certain FDA-approved NMDA-R blockers. They also hope to determine if treatment with these drugs has any positive effects on developmental progress in addition to improved seizure control.

NMDA-R is an essential component of electrical signaling in the brain and is made from proteins encoded by the GRIN family of genes.1 Because GRIN genes provide the blueprint for NMDA-R, mutations in these genes can impact how the NMDA-R works. Not all of these mutations cause over-activation of the NMDA-R, so in the first part of this project, the researchers are investigating each human GRIN mutation that has not been studied before by re-creating them in the laboratory and evaluating how they affect NMDA-R activity. This information will then be used to determine who might benefit from off-label treatment with drugs that reduce NMDA-R function.

People with GRIN variants that data suggest produce a strong over-activation of the NMDA-R might be candidates for treatment by their physician with NMDA-R blockers. Those with GRIN variants that reduce activity of the NMDA-R or produce complex actions which are difficult to clearly categorize would not be expected to benefit from treatment.

The investigators have created a registry where families affected by GRIN mutations can sign up to participate. The registry collects medical history data and records that are stored without any identifying information to protect the privacy of each participant. Following analysis of a patient’s mutation status, a report is shared with their clinician who will judge whether it is in the patient’s best interest to be considered for off-label treatment. Treatment could then be offered to the family and is based on treatment guidelines Dr. Traynelis and his collaborators have developed.

The team will follow up with a retrospective analysis of treatment efficacy. That is, the investigators will go back and analyze medical records, EEG data, seizure history, and other relevant data for people who received off-label treatment from their physicians to understand how well the treatment worked. This data will also allow an assessment of whether particular GRIN mutations may benefit more from the treatment than others.

This study is expected to provide data for a clinical trial that could lead to new therapies for these difficult to treat epilepsies. In a previously published study, the investigators treated a child with early-onset epileptic encephalopathy associated with a mutation in GRIN2A with the drug memantine and found a substantial reduction in his seizure burden after treatment for a year.2 Additional studies provided more mixed results, creating a need to better understand the utility of this approach.

The team is looking to enroll additional families in this important study. If you or anyone you know with a genetic diagnosis of a GRIN mutation and epilepsy are interested in participating, please contact Jenifer Sargent at Jenifer.Sargent@childrenscolorado.org to learn more about the study.

1 Hansen KB, Feng Y et. al., J Gen Physiol. 2018 Aug 6; 150(8): 1081–1105
2 Pierson TM, Yuan H et. al., Ann Clin Transl Neurol. 2014 Mar 1;1(3):190-198

CURE Discovery: A Potential Link Between Gut Bacteria and Epilepsy

Key Points

  • Dr. Tore Eid’s CURE-funded research aims to understand how gut bacteria can impact seizure development, inflammation, and neurodegeneration.
  • The team found increased levels of certain amino acids, potentially made by gut bacteria, in the epileptic brain regions of individuals with focal epilepsies.
  • Short-term treatment with these amino acids reduced spontaneous seizures in a rat model of epilepsy, while a long-term treatment worsened seizure frequency.
  • Dr. Eid’s studies have the potential to develop epilepsy treatments such as dietary interventions and other safe manipulations of gut bacteria.
Deep Dive

CURE grantee, Dr. Tore Eid, and his team at Yale University, are conducting exciting research to understand how gut bacteria can influence the development and manifestation of seizures. This impactful work, funded by the Heldman-Kirshner family grant in honor of Alex Heldman, could lead to simpler and safer treatments for epilepsy.

ffb08cad-f59b-4586-b913-140d701d2c1f.pngOver 500 different types of bacteria live in our gut alone.1 This dense collection of bacteria, called gut microbiota, helps us digest food, provides important nutrients, builds immunity, and protects us from harmful pathogens. Disruptions to the gut microbiota play a role in many diseases including irritable bowel disease, colitis, and diabetes. There is also evidence that gut microbiota problems are linked to anxiety, depression, and autism spectrum disorders.2 How and whether these bacteria influence epilepsy development and progression is not very well studied. There is some evidence that the ketogenic diet, which is effective in reducing seizure frequency in a number of different epilepsies, may work by modifying the gut microbiota.3

To better understand the role gut bacteria may play in epilepsy, Dr. Eid and his team analyzed brain fluid samples from people with focal epilepsy. They found that epileptic brain regions had increased levels of certain amino acids called branched chain amino acids, which can be made by gut bacteria. Levels of some of these branched amino acids increased in the brain three hours before a spontaneous seizure occurred, while levels of other branched amino acids increased an hour before. This may indicate that there is a “fine-tuning” of these amino acids happening within the body which potentially impacts seizure occurrence.

Next, the team fed these branched chain amino acids to a rat model of epilepsy they developed. A short-term treatment decreased spontaneous seizures while a long-term treatment worsened seizure frequency and caused neuronal loss in an area of the brain called the hippocampus.4 These results provide evidence that molecules derived from gut bacteria can impact brain chemistry and seizure development.

The team is also interested in understanding how bacteria living in the gut can influence epilepsy development and progression in the brain, focusing on a large nerve called the vagus nerve. This nerve allows the brain and the gut to directly communicate with each other. Dr. Eid’s team has developed techniques to selectively stimulate or suppress signaling only through the afferent vagus nerve, which transmits messages from the gut to the brain, without affecting the efferent nerve, which transmits messages from the brain to the gut and other organs.

In future studies, Dr. Eid and his team will perform careful manipulations of gut bacteria in a rat model of epilepsy by feeding the animals specific types of bacteria. The types of bacteria the team plans to use make molecules which can influence brain chemistry and thus potentially affect seizures. The team will study the effect of this treatment along with afferent vagal nerve stimulation/suppression on seizure development, brain inflammation, and neuronal loss in the rats.

These studies have the potential to impact epilepsy treatment through safe manipulations of gut bacteria through, for example, dietary interventions, probiotics, or antibiotics.

1 Eckburg PB et.al. Diversity of the human intestinal microbial flora, Science. 2005 Jun 10;308(5728):1635-8
2 E.Y. Hsiao et.al Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders, Cell. 155 (2013) 1451-1463
3 Olson CA, Vuong HE et. al. The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet, Cell. 2018 Jun 14;173(7):1728-1741.e13. doi: 10.1016/j.cell.2018.04.027
4 Gruenbaum SE, Dhaher R et. al., Effects of Branched-Chain Amino Acid Supplementation on Spontaneous Seizures and Neuronal Viability in a Model of Mesial Temporal Lobe Epilepsy, J Neurosurg Anesthesiol. 2019 Apr;31(2):247-256

CURE Discovery: New Genetic Models of Epileptic Encephalopathies Deepen Our Understanding

This research is generously supported by a grant from Jen Scott and Pierre-Gilles Henry, PhD, in honor of Felix Henry.

Key Points

  • CURE grantee Dr. Mingshan Xue created mice modeling the features of STXBP1-related epileptic encephalopathy (EE) to explore why not having enough STXBP1 activity can cause epilepsy.
  • The team found that inhibitory brain signaling was diminished in the models, causing excessive neuronal excitation, seizures, and other neurological features seen in humans with EE.
  • The long-term goal of the team’s project is to understand the mechanisms that cause EEs and use this knowledge to develop new therapies.

Deep Dive

Reduced activity of a gene called STXBP1 is one of the most common causes of epileptic encephalopathy (EE),1a group of severe pediatric epilepsies which includes Ohtahara Syndrome, West Syndrome, and Dravet Syndrome. Patients with EE often have aggressive, treatment-resistant seizures, developmental delays, behavioral deficits, and intellectual disability among other clinical features. There is an urgent need to better understand these syndromes and develop new therapies for them.

CURE grantee Dr. Mingshan Xue and his colleagues at the Baylor College of Medicine created mouse models with reduced STXBP1 activity to study epilepsy associated with this genetic variant. Through extensive testing, they determined these mice accurately represented EE clinical features such as seizures, behavioral, and cognitive deficits.2

For their CURE-funded work, the team used these models to determine how not having enough STXBP1 activity could cause EE. The team previously observed high levels of neuronal excitation in the brains of mice with low STXBP1. Thus, Dr. Xue’s team hypothesized that not having enough STXBP1 must prevent inhibitory neuronal signaling, causing an imbalance between excitation and inhibition in the brain.

To test this, the team recorded the electrical activity of neurons in the model with reduced STXBP1 activity. They found that inhibitory brain signaling was indeed diminished in these mice while excitatory signaling was not affected, resulting in excessive excitation, seizures, and other neurological features of EE. Further testing revealed that mice with reduced STXBP1 activity specifically in inhibitory neurons had higher anxiety, impaired motor skills, and reduced cognitive function – all features that are seen in humans with EE.

EEs are typically hard to treat with currently available options. The team’s long-term goal is to understand the mechanisms that cause EEs and use this knowledge to develop new therapies. Since completing their CURE-funded grant, Dr. Xue and his co-investigator have received a National Institutes of Health grant, as well as an American Epilepsy Society postdoctoral fellowship to continue this important work.

Bridging the Gap Between STXBP1 Researchers and Families

We are honored to sponsor and attend the first ever STXBP1 Investigators and Family Meeting (SIFM) on June 21, 2019 and June 22, 2019 in Philadelphia. This conference is hosted by STXBP1 Foundation and the Center for Cellular and Molecular Therapeutics (CCMT).

The need for developing community and driving more research on this group of EEs is clear. The inaugural SIFM will bring together researchers and families of individuals with STXBP1 encephalopathies to foster community development and accelerate the search for a cure. This conference is designed to encourage interaction and in-depth discussions among researchers and clinicians to further research and innovation in this field.

You can find out more information about this conference here.

1 Carvill GL et.al. Nat Genet. 2013 Jul;45(7):825-30. doi: 10.1038/ng.2646
2 Wu Chen et.al., Apr 29, 2019, https://www.biorxiv.org/content/10.1101/621516v1

CURE Discovery: Safe, Quick Measurement in Epilepsy Monitoring Units (EMUs) Has Potential To Identify SUDEP Risk

When the body detects high carbon dioxide (CO2) levels in the blood, a condition known as hypercapnia, it responds by moving more air through the lungs. This increased ventilation helps remove the excess CO2. Research by CURE grantee Dr. Rup K. Sainju and his team at the University of Iowa shows that this response may be weakened in some people with drug-resistant epilepsy, which puts them at an increased risk for severe breathing abnormalities and Sudden Unexpected Death in Epilepsy (SUDEP) following a generalized convulsive seizure.

For their CURE-funded project, Dr. Sainju’s team conducted a study in adults with drug-resistant epilepsy who were admitted to the epilepsy monitoring unit (EMU) at the University of Iowa. In addition to comprehensive heart and breathing monitoring, the team measured the hypercapnic ventilatory response (HCVR) in each patient.1,2 The HCVR measurement evaluates how the body responds to increased blood CO2levels. A low HCVR indicates a poor or weakened ability to remove CO2 from the body.

Epilepsy Monitoring Unit

The study found that patients who had a low HCVR were more likely to have severe breathing abnormalities and a longer period of high, potentially dangerous CO2 levels in the blood after a generalized convulsive seizure. Long-term follow-up revealed one of the patients in the study with the third lowest HCVR passed away of SUDEP 11 months after the study.2

Importantly, this is the first time HCVR has ever been studied in patients with epilepsy. The team demonstrated that an HCVR measurement can be conducted in the EMU rapidly and safely.2 The team also reported that the HCVR measurement was well tolerated by the patients.2

Building on their work, Dr. Sainju’s team also conducted a CURE-funded pilot study to determine if the drug fluoxetine, more commonly known as Prozac, could increase HCVR and reduce seizure-related breathing abnormalities. Fluoxetine increases the availability of serotonin in the brain and there is evidence that the serotonin system increases ventilation in response to hypercapnia. Drugs similar to fluoxetine have been safely tested in mice and humans and shown to increase HCVR. The team hypothesized that giving fluoxetine to patients who have a low HCVR would improve the body’s ability to sense high CO2 levels and reduce post-seizure breathing abnormalities. The team has finished this study, which shows that patients completed it with good adherence. We are eager to see their final analysis.

Dr. Sainju’s study suggests that HCVR is a key measurement which may be useful in predicting the risk of breathing abnormalities and SUDEP. It can be easily and rapidly performed in the EMU with minimal discomfort to people with epilepsy. Future studies will build on this work, analyzing the usefulness of HCVR as a biomarker for SUDEP. Having demonstrated the feasibility of a randomized trial of fluoxetine versus placebo to improve HCVR, the team plans to continue studying fluoxetine and other therapeutic targets.

1 Gehlbach BK et. al. Tolerability of a comprehensive cardiorespiratory monitoring protocol in an epilepsy monitoring unit. Epilepsy Behav. 2018 Aug;85:173-176.
2 Sainju R.K. et. al. Ventilatory response to CO2 in patients with epilepsy. Epilepsia. 2019 Mar;60(3):508-517.
3 Hodges MR, Richerson GB. Medullary serotonin neurons and their roles in central respiratory chemoreception. Respir Physiol Neurobiol. 2010 Oct 31;173(3):256-63.

CURE Discovery: Using Patient-Specific Cardiac Cells to Predict SUDEP Risk

CURE-funded researchers are using a novel technique to discover ways to predict patients at an increased risk of Sudden Unexpected Death in Epilepsy (SUDEP). Dr. Lori Isom, her team, and co-investigator Dr. Jack Parent at the University of Michigan are transforming skin cells from patients with developmental and epileptic encephalopathy (DEE) syndromes into induced pluripotent stem cells (iPSCs). The team then generates cardiac cells from the iPSCs which retain the patients’ exact genetic information. These unique, patient-specific cardiac cells are used as models to understand if DEE-associated genes play a role in causing heart abnormalities which may lead to SUDEP. The team also hopes to develop measurable indicators, known as biomarkers, of SUDEP risk.

Severe DEE syndromes, such as Dravet syndrome, are associated with a high incidence of SUDEP. It is estimated that up to 20% of patients with Dravet syndrome die from SUDEP.1 There is still much to be understood about the mechanisms of SUDEP and how to predict who is at risk for it.

Dravet syndrome and other DEEs are often associated with variants in genes, such as SCN1A, SCN1B, and SCN8A. These genes provide instructions to make sodium ion channels, which are very important proteins that help brain cells transmit electrical signals. The same genes are also expressed in the heart; thus, the team hypothesizes that any variants in these genes that disrupt electrical signaling in the brain would affect normal electrical function of the heart as well. In support of this hypothesis, the investigators’ previous work in mouse models of Dravet syndrome and DEEs showed that these mice exhibited irregular heartbeat, which in some cases preceded SUDEP-like events.2-4

In this CURE-funded project, the investigators expanded upon their previous work by testing their hypothesis in heart muscle cells called cardiac myocytes, generated in the laboratory from skin cells of patients with Dravet syndrome or other DEEs using iPSC technology. This Nobel Prize-winning technology involves obtaining skin or blood cells from patients and converting them to iPSCs. These are stem cells that can be converted into almost any specialized cell type in the body, such as heart, muscle, pancreatic, or neuronal cells. The cells are patient-specific, meaning they retain the unique genetic make-up of the patient they originated from, allowing investigators to study cell types which would otherwise be very difficult or impossible to obtain from a living patient.

Dr. Isom, Dr. Parent, and their colleagues previously used iPSC technology to generate heart muscle cells from four patients with variants in the SCN1A gene and found increased sodium currents and spontaneous contraction rates in these cells, suggesting cardiac electrical dysfunction.5 Cardiac abnormalities were subsequently found in the patient with the highest increase in sodium current.5 These data suggest that iPSC-cardiac cells may be useful models for identifying and developing biomarkers, such as increased sodium current, as indicators of SUDEP risk.

The investigators used the same technique to study variants in the SCN1B and SCN8A genes. The team observed that iPSC-cardiac myocytes derived from a patient with SCN1B Dravet syndrome had increased sodium currents similar to those seen in iPSC-cardiac myocytes from the patient with SCN1A Dravet syndrome, suggesting that variants in these two different genes could cause heart abnormalities through similar mechanisms. Preliminary data in iPSC-cardiac myocytes from patients with DEE caused by variants in SCN8A, suggest that these cells have altered beating rates but no change in sodium current, which is aligned with their observations in a mouse model with a variant in SCN8A.

Taken together, these results reveal mechanisms by which different epilepsy-related genes can affect heart function and SUDEP. Future research will investigate the impact of variants of a specific non-ion channel gene to see if it causes altered cardiac beating. Patient-specific iPSC cardiac myocytes are a very useful model to study SUDEP mechanisms and could be developed as diagnostic biomarkers to identify SUDEP risk in patients.

1 Cooper MS et al. Mortality in Dravet Syndrome. Epilepsy Res. 2016 Dec; 128:43-47.
2 Auerbach DS et al. Altered Cardiac Electrophysiology and SUDEP in a Model of Dravet Syndrome. PLoS One. 2013;8(10).
3 Lopez-Santiago LF et al. Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals. J Mol Cell Cardiol. 2007;43(5):636-47.
4 Frasier CR et al. Cardiac arrhythmia in a mouse model of SCN8A Epileptic Encephalopathy. Proc Natl Acad Sci U S A. 2016; in press.
5 Frasier CR et al. Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient Derived Cardiac Myocytes. Stem Cell Reports. 2018 Sep 11;11(3):626-634.

CURE Discovery: Potential Genetic Link Between Epilepsy and Sudden Unexpected Death in Children

This grant is generously supported by the Isaiah Stone Foundation.

A potential link between epilepsy- and SUDEP-associated SCN1A gene variants and Sudden Infant Death Syndrome (SIDS) has been discovered by CURE Grantee Dr. Annapurna Poduri of Boston Children’s Hospital.1 Her work, generously supported by the Isaiah Stone Foundation, may provide insight into SIDS and support genetic evaluation focused on epilepsy genes in SIDS. In Dr. Poduri’s analysis of 10 infants who died of SIDS, two children were found to have disease-associated variants in the SCN1A gene. Despite finding variants in an epilepsy-related gene and hippocampal lesions that are commonly associated with temporal lobe epilepsy, these children had no history of seizures or epilepsy.

SIDS occurs when a seemingly healthy baby dies suddenly. The sudden death of a child is a tragic occurrence and even more distressing when there is no known cause. There are several categories of this type of death: SIDS if the child is less than one year old; Sudden Unexplained Death in Childhood (SUDC) if the child is greater than one year old; and Sudden Unexpected Death in Epilepsy (SUDEP) if the child has epilepsy.

These types of childhood death are traditionally thought of as separate entities and the causes behind them are largely unknown. However, by finding a link between SIDS and SCN1A mutations,2,3 Dr. Poduri and her colleagues have deepened our understanding of the potential genetic factors behind sudden death in children. This research also suggests epilepsy genes may be more widely important in cases of sudden death in children than originally thought.

In fact, as an integral part of her CURE-funded work, Dr. Poduri and her colleagues in Robert’s Program on Sudden Death in Childhood set out to understand the genetic basis of these sudden childhood deaths, with the hypothesis that there may be a common mechanism between some cases of SIDS, SUDC, SUDEP, and epilepsy. This hypothesis is based on neuropathological abnormalities seen in the hippocampal region of approximately 40% of cases with SIDS and SUDC.4

Although typically considered rare, more children die each year from Sudden Unexplained Death in Pediatrics (SUDP), a category that includes SIDS and SUDC, than from childhood cancer or heart disease.5 Understanding the reasons behind these types of death is important in understanding how to prevent them.

Besides finding variants in the SCN1A gene in two children who died of SIDS, Dr. Poduri and her colleagues also found variants in the epilepsy-related SCN1B gene in two siblings who died suddenly and unexpectedly.6 These important findings identify additional epilepsy-related genes which may underlie some cases of sudden death in children, supporting the team’s idea that there are shared mechanisms between SIDS, SUDC, and epilepsy.

In the future, Dr. Poduri and her colleagues plan to continue their analysis of potential epilepsy-associated genetic variants, which may contribute to sudden childhood death, to better understand causes of these devastating occurrences. They are hopeful their findings will apply to children with and without epilepsy who may be at risk for sudden death. Their overall goal is to identify not only genetic risk factors for SIDS and SUDC, but also other means of identifying children at risk for sudden death. This work could lay the foundation for strategies which can be systematically implemented to prevent these deaths from occurring.

1 Brownstein CA et al. SCN1A variants associated with sudden infant death syndrome. Epilepsia 2018; 59(4):e56-e62.
2 Escayg A and Golding AL. Sodium channel SCN1A and epilepsy: mutations and mechanisms. Epilepsia 2010; 51(9):1650-1658.
3 Goldman AM. Mechanisms of sudden unexpected death in epilepsy. Curr Opin Neurol 2015; 28(2):166-174.
4 Kinney HC, Poduri A et al. Hippocampal formation maldevelopment and sudden unexpected death across the pediatric age spectrum. J Neuropathol Exp Neurol 2016. 75(10):981-997.
6 Poduri, unpublished.