CURE Epilepsy Discovery: When Does a Seizure Lead to SUDEP?

Key Points:

  • CURE Epilepsy Taking Flight grantee Dr. Ian Wenker and colleagues used mouse models to determine the series of biological events underlying sudden expected death from epilepsy (SUDEP).
  • Analysis of electrical activity from the brain and heart, along with breathing, revealed that the main cause of death was apnea (breathing cessation), which originated during the tonic phase of a seizure, the stage during which muscles stiffen.
  • Restoration of breathing, either naturally or artificially, soon after the seizure had ended increased the rate of survival, thereby preventing SUDEP.
  • The clinical relevance of these data was reflected in an epilepsy patient whose breathing disruptions were similar to those observed in the mice.

Deep Dive:

SUDEP is a devastating outcome for some people with epilepsy, and the most common cause of death among people with treatment-resistant epilepsy [1]. Despite significant research into the cause of SUDEP [2], including an implication of cardiorespiratory dysfunction [1,3], the precise series of biological events ultimately leading to death is not clear.

With the help of a CURE Epilepsy Taking Flight Award, Dr. Ian Wenker and colleagues, working in the laboratory of Dr. Manoj Patel at the University of Virginia School of Medicine, sought to better understand these events. Specifically, they sought to determine the order in which physiological processes occur, the circumstances that lead to death, and what could be done during the seizure to prevent death [4]. The researchers used mouse models of epilepsy wherein seizures were induced either genetically or chemically. They measured breathing and monitored electrical activity from the brain and heart for both fatal and nonfatal seizures.

Dr. Wenker and colleagues found that during the tonic phase of a seizure, the phase in which muscles, including the primary breathing muscle known as the diaphragm, become rigid, breathing disruptions (apnea) were common. However, death only occurred if breathing did not promptly restart after the seizure. This conclusion was then tested by mechanically ventilating those mice whose breathing had not fully recovered after the seizure, and they survived.

To extend these exciting findings from mice to people with epilepsy, the researchers examined the corresponding data from a patient with a harmful genetic mutation similar to that in the mutant mice. The breathing patterns, frequency, and disruptions in this individual were comparable to those from seizure-susceptible mice, suggesting that treating any breathing disruptions in patients post-seizure may prevent SUDEP. Dr. Wenker plans to build on these data and hopes to contribute to the development of a protocol that may one day eliminate SUDEP completely.


Literature Cited

  1. Ryvlin, P. et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 2013; 12(10): 966-977.
  2. Jones, L.A. & Thomas, R.H. Sudden death in epilepsy: Insights from the last 25 years. Seizure 2017; 44: 232-236.
  3. Stewart, M. et al. Causes and effects contributing to sudden death in epilepsy and the rationale for prevention and intervention. Front. Neurol. 2020; 11: 765.
  4. Wenker, I.C. et al. Postictal death is associated with tonic phase apnea in a mouse model of sudden expected death in epilepsy. Ann. Neurol. 2021; 89: 1023-1035.
a red pencil draws the outline of a human head over a graphic of neurons

CURE Epilepsy’s Impact: Investing in Early-Stage Research Leads to Critical Advancements

Key Points:

  • Nearly 20 years ago, Peter Carlen, MD received a one-year grant from CURE Epilepsy that served as a catalyst for his research into seizure detection and electrical neurostimulation. One of the companies Dr. Carlen established continues the work in seizure detection and is currently building on his lab’s recent identification of a biomarker for sudden unexpected death in epilepsy (SUDEP).
  • For more than 20 years, through investing in paradigm-shifting ideas, CURE Epilepsy has enabled scientists to discover insights essential for advancing the understanding of epilepsy and moving us closer to a cure.

Deep Dive:

Dr. Carlen began his career as a general neurologist at the University of Toronto. He founded the Epilepsy Program at the Toronto Western Hospital 25 years ago and is now one of its staff epileptologists. With his 2002 funding from CURE Epilepsy, he collaborated with mathematician and engineer Dr. Berj Bardakjian and a student with a background in physics, Dr. Houman Khosravani, to investigate the promise of computation and engineering techniques to understand epileptic networks and to ultimately develop the ability to disrupt them.

The work facilitated by his CURE Epilepsy-funded grant has contributed substantially to prediction and treatment of epilepsy. The researchers first published a paper documenting arrest of seizure activity with brief, low frequency electrical pulses delivered to brain tissue [1] and later published two additional papers on electrical neurostimulation [2,3]. Since these initial studies, Carlen’s lab has progressed to more advanced testing paradigms with modified parameters to make the pulses more akin to what actually happens in the brain. Significantly, this newer protocol appears to result in better seizure control than the more traditional pattern of repetitive square pulses.

Perhaps some of the most frightening and challenging aspects of epilepsy are seizure unpredictability and the potential for SUDEP; thus, seizure and SUDEP forecasting remain priorities in epilepsy research. Dr. Carlen’s current research also focuses on the brainstem, a small area at the base of the brain located just above the spinal cord, that regulates functions such as breathing and heart rate. Hypothesizing that SUDEP reflects disturbances in the brainstem, Carlen’s lab measured the electrical activity from this brain region in rats and discovered that seizures originating here led to cardiorespiratory arrest and death [4,5], important findings that continue to influence the field.

Since the initial research supported by their 2002 CURE Epilepsy grant, Carlen and Bardakjian have continued to collaborate, recently making a breakthrough that could reduce overall morbidity and mortality in epilepsy: they have developed a seizure alarm and identified SUDEP biomarkers in the unique electrical patterns of the electroencephalogram (EEG) [6]. They have since founded a company called Neurometrics Technologies to develop this technology further, with the goal of combining a wireless headset with complex computer algorithms capable of analyzing a patient’s EEG patterns to predict seizures and detect SUDEP biomarkers.

Carlen finds serving as the bridge between his patients in the clinic and the basic research in his lab especially rewarding. As an epileptologist, he witnesses firsthand the intense suffering endured by people with epilepsy and, as a scientist, he is in a unique position to develop more effective treatments with little to no side effects, a true cure.

CURE Epilepsy is proud to have played a role in advancing research by Dr. Peter Carlen and his colleagues, building hope for prevention and cures, and ultimately, a world without epilepsy.


Literature Cited
[1] Khosravani, H., Carlen, P.L., & Velazquez, J.L.P. The control of seizure-like activity in the rat hippocampal slice. Biophys. J. 2003; 84: 687-695.
[2] Chiu, A.W.L., Jahromi, S.S., Khosravani, H., Carlen, P.L. & Bardakjian, B.L. The effects of high-frequency oscillations in hippocampal electrical activities on the classification of epileptiform events using artificial neural networks. J. Neural Eng. 2005; 3(1): 9-20.
[3] Khosravani, H., Pinnegar, C.R., Mitchell, J.R., Bardakjian, B.L., Federico, P., & Carlen, P.L. Increased high-frequency oscillations precede in vitro low-Mg2+ seizures. Epilepsia 2005; 46(8): 1188-1197.
[4] Salam, M.T., Montandon, G., Genov, R, Devinsky, O., Del Campo, M., & Carlen, P.L. Mortality with brainstem seizures from focal 4-aminopyridine-induced hippocampal seizures. Epilepsia 2017; 58(9): 1637-1644.
[5] Lertwittayanon, W., Devinsky, O., & Carlen, P.L. Cardiorespiratory depression from brainstem seizure activity in freely moving rats. Neurobiol. Dis. 2020; 134: 104628.
[6] Grigorovsky, V. et al. Delta-gamma phase-amplitude coupling as a biomarker of postictal generalized EEG suppression. Brain Commun. 2020; 2(2): fcaa182.

CURE Epilepsy Discovery: A Novel Molecule as a Biomarker of Epilepsy

Key Points:

  • CURE Epilepsy Taking Flight Award grantee Dr. Gary Brennan and colleagues used three different, well-established rodent models of acquired epilepsy to identify biomarkers for both diagnosing active epilepsy and for predicting who might develop epilepsy after a brain injury.
  • The team found that a family of small molecules known as microRNAs (miRNAs)[1], which are important in regulating gene expression and brain activity, were altered in rodent models of acquired epilepsy.
  • Three of the five identified miRNAs were also present in blood samples taken from epilepsy patients, thereby validating their relevance to human epilepsy.
  • Administration of a molecule known as Ant-134, which has been previously shown to reduce seizure frequency in different animal models, affected the levels of three of the five miRNAs in rodent models of acquired epilepsy in the current study.
  • These preliminary data suggest that circulating miRNAs may represent biomarkers that can accurately diagnose epilepsy and predict who may develop it after a brain injury. Additional steps to validate these miRNAs as biomarkers of acquired epilepsy are needed.

Deep Dive:

Epilepsy is often “acquired” by injuries to the brain such as those resulting from a stroke, head trauma, or infection. There is currently no way of reliably predicting who will develop epilepsy following these types of injuries [2]. Thus, it would be valuable to have a stable, readily accessible substance (in the blood, for example) to assist with diagnosis, treatment, and epilepsy prediction following a head injury for people at risk. MicroRNAs (miRNAs), small molecules that have been implicated in the development of epilepsy [3], may make ideal biomarkers due to their relatively high concentrations in the blood. CURE Epilepsy Taking Flight Award grantee Dr. Brennan investigated whether miRNAs might be used as biomarkers of acquired epilepsy.

Dr. Brennan and his colleagues employed three different rodent models of acquired epilepsy to evaluate the feasibility of using miRNAs as biomarkers for the development of epilepsy [4]. The researchers first collected blood from all rodents to establish baseline levels of the different miRNAs. They subsequently sampled blood several times prior to the first seizure and also on the day of the first spontaneous seizure, which was indicative of the actual onset of epilepsy.

The researchers found that blood from rodents with epilepsy had several unique miRNAs, either newly-emerged or whose levels had changed during epileptogenesis –the process by which an initial “insult” or injury to the brain leads to seizures and epilepsy–and into the chronic epilepsy stage. Based on consistency among the three rodent models and previous associations with epilepsy, the researchers chose five of these miRNAs as a focus for the next steps of their work. Importantly, they found that three of the five miRNAs were also found in people with epilepsy.

Dr. Brennan also found that levels of three of the five miRNAs were affected by a potential new therapy for epilepsy called Ant-134. Anti-134 is a molecule that specifically targets a different miRNA (miRNA-134), distinct from the five miRNAs that were the focus of Dr. Brennan’s study. Anti-134 has been shown to reduce seizures in several different rodent models of epilepsy [5]. Dr. Brennan’s finding supports the idea that specific miRNAs may be useful for predicting the likelihood of developing an acquired epilepsy as well as potential indicators of treatment responsiveness.

These exciting data reveal a novel mechanism of epilepsy prediction, diagnosis, and treatment that may one day be studied in clinical trials to determine its ability to identify individuals who have suffered a brain injury that are likely to develop epilepsy.


Dr. Gary Brennan

Dr. Brennan performed his work while in the laboratory of Dr. David Henshall at the Royal College of Surgeons in Ireland. He collaborated with multiple colleagues, both in Dr. Henshall’s lab and from specialist labs across Europe.

Dr. Brennan has received additional support from the Science Foundation Ireland and is a funded investigator in the FutureNeuro Research Centre. His research group is based in the School of Biomolecular and Biomedical Science at University College Dublin.

 


Literature Cited
[1] miRNA are (a relatively newly discovered form of ribonucleic acid (RNA) and) distinct from other forms of ribonucleic acids (RNA) like mRNA or tRNA that serve different biological functions.
[2] Löscher, W. The holy grail of epilepsy prevention: preclinical approaches to antiepileptogenic treatments. Neuropharmacology 2020; 167: 107605.
[3] Henshall, D.C. et al. MicroRNAs in epilepsy: pathophysiology and clinical utility. Lancet Neurol. 2016; 15(3): 1368-1376.
[4] Brennan, G.P. et al. Genome-wide microRNA profiling of plasma from three different animal models identifies biomarkers of temporal lobe epilepsy. Neurobiol. Dis. 2020; 144: 105048.
[5] Morris, G., Reschke, C.R., and Henshall, D.C. Targeting microRNA-134 for seizure control and disease modification in epilepsy. EbioMedicine 2019; 45: 646-654.

Understanding the Neurodevelopmental Origins of Focal Cortical Dysplasia (FCD)

Key Points:

  • CURE Epilepsy Taking Flight Award grantee Dr. Lakshmi Subramanian is working to uncover the underlying causes of focal cortical dysplasia (FCD), a severe childhood epilepsy syndrome characterized by developmental malformations in the part of the brain known as the cortex.
  • Dr. Subramanian found that disrupting the mTOR signaling pathway caused a series of biological changes that may explain how FCD arises.
  • Understanding these changes could help researchers identify newer, more effective, and less invasive therapeutic options than those currently available.

Deep Dive:

During development in the womb, the human brain undergoes a substantial expansion in size, particularly in the outermost part known as the cortex [1]. During this time, brain cells grow and divide rapidly, normally organizing themselves into layers. As the brain develops, an orderly arrangement of cells is created, in part, by the shape, position, and movement of outer radial glia (oRG) cells. These cells give rise to newborn nerve cells in the human brain and also form the scaffold that the immature nerve cells use to navigate to their correct location, mature, and connect normally [3]. In focal cortical dysplasia (FCD), however, brain cells fail to organize properly, leading to focal lesions and usually intractable epilepsy [2]. Surgery is often the only effective treatment option.

The mTOR pathway is known to be active in human oRG cells during development [4], but the function of this pathway in these cells is unknown. Taking Flight Award grantee Dr. Lakshmi Subramanian, while working in the laboratory of Dr. Arnold Kriegstein at University of California San Francisco, sought to determine the specific role of the mTOR pathway in the development of FCD [5].

Dr. Subramanian and colleagues first successfully established simplified models of the developing human cortex in order to manipulate mTOR signals and evaluate the resulting effects on oRG cells. They activated or blocked mTOR signals in two different human tissue-based models and found that sustained mTOR signals were required to maintain oRG cell shape and structure. Specifically, when mTOR signals were disrupted, oRG cells lost their typically elongated shape, shortened significantly, and lost their ability to “move” normally in the developing brain. As a result, the scaffold along which nerve cells migrate, mature, and connect was also disrupted, providing a mechanism for how abnormal brain organization may arise in FCD.

In future research, Dr. Subramanian hopes these human brain model systems can be used to investigate how displaced, misshapen oRG cells affect long-term changes in the brain. More information about how oRG cells use mTOR signals may help identify additional components of the pathway that can be investigated as potential therapies or diagnostics. An advanced understanding of this pathway may allow for development of less invasive approaches to treating FCD and other mTOR-mediated developmental epilepsies. These proteins could conceivably be targeted to develop new diagnostics and treatments other than invasive surgery for patients with FCD and other mTOR-mediated developmental epilepsies.


Dr. Lakshmi Subramanian

Dr. Lakshmi Subramanian is a CURE Epilepsy Taking Flight Award grantee and NARSAD Young Investigator, Neuroscience/Stem Cell Biology Research at Broad Center for Regeneration Medicine, University of California San Francisco.

 


Literature Cited
[1] Hatten, M.E. Central nervous system neuronal migration. Annu. Rev. Neurosci. 1999; 22: 511-539.
[2] Iffland, P.H. and Crino, P.B. Focal cortical dysplasia: gene mutations, cell signaling, and therapeutic implications. Annu. Rev. Pathol. 2017; 12: 547-571.
[3] Ostrem, B., Di Lullo, E., and Kriegstein, A.R. oRGs and mitotic somal translocation – a role in development and disease. Curr. Opin. Neurobiol. 2017; 42: 61-67.
[4] Pollen, A.A., Bhaduri, A., Andrews, M. et al. Establishing cerebral organoids as models of human-specific brain evolution. Cell 2019; 176(4): 743-756.
[5] Andrews, M.G., Subramanian, K., and Kriegstein, A.R. mTOR signaling regulates the morphology and migration of outer radial glia in developing human cortex. eLife 2020; 9: e58737.

Screening of Genetically Diverse Mice Identifies Novel Rodent Models of Diverse Epilepsy Outcomes

Funded by the generosity of families who have experienced a loss due to SUDEP.

Key Points:

  • CURE Epilepsy Taking Flight Award grantee Dr. Bin Gu and colleagues used genetically diverse mouse strains to identify those that vary in seizure susceptibility, seizure spread, seizure development, and sudden unexpected death in epilepsy (SUDEP).
  • Initial screening of these mice identified four different genetic strains that suddenly and unpredictably died after inducing a single seizure, suggesting these mice may represent novel models for studying SUDEP.
  • Further genetic characterization of these four mouse strains should provide valuable insights into the underlying genetic risk factors for SUDEP.

Deep Dive:

Dr. Bin Gu, PhD

Dr. Bin Gu, PhD

SUDEP is the sudden, unexpected death of someone with epilepsy who otherwise appears healthy. To facilitate an understanding of the complex genetic basis of SUDEP, studies need to use genetically diverse mouse populations [1,2], such as the “Collaborative Cross” [3,4], which can help identify different genetic risk factors that control SUDEP susceptibility.

With the help of a CURE Epilepsy Taking Flight Award, Dr. Bin Gu and his colleagues in the laboratories of Drs. Ben Philpot and Fernando Pardo-Manuel de Villena at the University of North Carolina at Chapel Hill used Collaborative Cross mice to identify mouse strains that were more likely to have seizures, were more prone to having subsequent seizures, were more susceptible to having their seizures spread throughout the brain and were especially vulnerable to SUDEP [5].

The researchers screened mice from this population to identify candidate genes and genetic variants linked to many key symptoms of epilepsy. For example, within this population of mice, when Dr. Gu induced epilepsy, he observed that some mouse strains were resistant to developing epilepsy, whereas others were more susceptible. Identifying the genetics of the resistant strains is important for understanding the mechanisms underlying seizures and developing new ways of stopping seizures before full-blown epilepsy develops.

Among the groups of mice that Dr. Gu studied, four strains of mice died suddenly after a single seizure that was not fatal in “normal” mice. Although the precise cause of sudden death in these mice is currently unknown, the specific strains may eventually provide important clues to the causes of SUDEP in humans.

Dr. Gu’s upcoming research will focus on characterizing these “pro-SUDEP” strains, identifying those genes that control SUDEP susceptibility and resistance and studying the biological causes, including cardiac and respiratory events, that can provoke SUDEP. Such an understanding will hopefully lead to effective strategies to prevent SUDEP.

By providing Dr. Gu with critical initial funding for his research through a Taking Flight Award, CURE Epilepsy has also helped advance Dr. Gu’s career. He will soon establish his own independent lab as an Assistant Professor of Neuroscience at Ohio State University, where he will continue to pursue his passion for epilepsy research.

Dr. Bin Gu is a postdoctoral fellow at the University of North Carolina at Chapel Hill.


Literature Cited
[1] Saul, M.C. et al. High-diversity mouse populations for complex traits. Trends Genet. 2019; 35(7): 501-514.
[2] Bogue, M.A. et al Collaborative cross and diversity outbred data resources in the mouse phenome database. Mamm. Genome 2015; 26(9-10): 511-520.
[3] Churchill, G.A. et al. Complex Trait Consortium. The collaborative cross, a community resource for the genetic analysis of complex traits. Nature Genetics 2004; 36(11): 1133-1137.
[4] Srivastava, A. et al. Genomes of the mouse collaborative cross. Genetics 2017; 206(2): 537-556.
[5] Gu, B. et al. Collaborative cross mice reveal extreme epilepsy phenotypes and genetic loci for seizure susceptibility. Epilepsia 2020; 61(9): 2010-2021.

A blond woman cradles her infant in her arms, trying to soothe them.

CURE Epilepsy Infantile Spasms Initiative: Using Team Science to Discover Novel Targets

Key Points:

  • Infantile spasms (IS) is a rare debilitating pediatric epilepsy syndrome marked by distinct observable symptoms.
  • CURE Epilepsy directed its unique resources to establish a team science-based initiative to support research into this devastating disorder.
  • The IS Initiative has successfully accelerated advancements in IS research and underscored the advantages of working as part of such a formal collaboration.

Deep Dive:

Dr. John Swann, Ph.D

Infantile spasms is a rare, devastating epilepsy disorder that generally begins within the first year of life. The condition is typified by seizures with sudden jerking motions or head bobs and often, though not always, an atypical EEG marked by a chaotic pattern of brain waves (hypsarrhythmia). The seizures are accompanied by significant developmental delays and cognitive and physical deterioration. Current standardized treatments include a hormone (ACTH, prednisone) or the antiseizure medication vigabatrin. Unfortunately, only 50% of children suffering from IS respond to these treatments, and there remains no reliable way of predicting who will respond favorably.

Launched in 2013, CURE Epilepsy’s IS Initiative was an innovative interdisciplinary program designed to advance findings that could lead to better treatments for IS. It brought together eight research groups from different institutions who functioned as a united team, collaborating and sharing data to accelerate understanding of IS in an effective and efficient fashion. Collectively, the investigators studied the basic biology underlying IS, searched for biomarkers as well as novel drug targets, and developed improved treatments. The availability of several widely accepted rodent models of IS allowed for cross-testing of promising targets and therapeutic interventions. The initiative generated 19 publications to date, 7 additional manuscripts in preparation, 3 federal grants from the National Institutes of Health (NIH), and even a patent, published in October 2018.

One exciting project was led by John Swann at the Baylor College of Medicine. Building on previous findings, Dr. Swann’s team focused its efforts on discovering novel drug targets and devising better treatment strategies to arrest the spasms as well as the associated developmental delay. The team was able to show that treatment with (1-3) IGF-1, a derivative of the growth hormone insulin-like growth factor 1 (IGF-1), diminished the spasms and irregular brain wave pattern in an animal model. Importantly, adding this compound to vigabatrin, one of the standard IS treatments, reduced the dose of vigabatrin required for the complete elimination of the spasms, thereby decreasing the risk of serious side effects, the most serious of which is irreversible loss of peripheral vision. These data allowed the Swann lab to patent the novel combination treatment and to obtain two NIH grants. One, worth a total of ~$350,000 over 5 years, aims to investigate the molecular basis for the combination therapy. The second grant seeks to establish a specific IS rodent model for identifying more effective, less toxic therapies.

In addition to the more concrete evidence of increased knowledge of IS reflected in the publications, federal grants, and patents, the CURE Epilepsy IS initiative yielded numerous intangible benefits. The most significant of these was the active collaboration among teams that might otherwise have been competing. Such interactions facilitated rapid dissemination of results among teams, cross-fertilization of ideas between basic scientists and clinicians, and mentoring of junior investigators. All these factors served to accelerate basic research that will hopefully benefit patients and their families who suffer from IS. Learnings also indicated the need for a dedicated project manager and more transparent real-time communications with the investigators. CURE Epilepsy has applied these valuable insights to its ongoing Post-Traumatic Epilepsy Initiative, funded by the US Department of Defense.

You can read more about our work and the full paper here.


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 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 MeffordAs 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.

 


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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.