Post-Traumatic Epilepsy Associated with Long-Term Dementia Risk

Article published by News Medical Life Science

In a recent study, using data from the atherosclerosis risk in communities (ARIC) study, researchers assessed the associations between post-traumatic epilepsy (PTE) and the risk of dementia. PTE is the occurrence of unprovoked seizures more than a week after a traumatic brain injury (TBI), and it accounts for up to 20% of acquired epilepsies. Research suggests that PTE is associated with poor short-term psychosocial, cognitive, and functional outcomes; however, less is known about the long-term impact of PTE. Moreover, epilepsy and TBI are independently associated with the risk of dementia. The ARIC study enrolled people aged 45–64 and participants completed in-person visits and follow-up telephone calls. The researchers found that PTE was associated with a three-fold increased risk of dementia in models that accounted for the competing risks of death individually and with stroke. Younger participants consistently showed stronger associations between PTE and dementia risk than older subjects. Dementia risk was significantly higher with PTE than with epilepsy/seizure or head injury alone. These results highlight the significance of prevention of head injuries and PTE following these injuries.

2-Photon Imaging of Fluorescent Proteins in Living Swine

Abstract found on PubMed

Featuring the work of CURE Epilepsy’s PTE Initiative Massachusetts General Team

A common point of failure in translation of preclinical neurological research to successful clinical trials comes in the giant leap from rodent models to humans. Non-human primates are phylogenetically close to humans, but cost and ethical considerations prohibit their widespread usage in preclinical trials. Swine have large, gyrencencephalic brains, which are biofidelic to human brains. Their classification as livestock makes them a readily accessible model organism. However, their size has precluded experiments involving intravital imaging with cellular resolution. Here, we present a suite of techniques and tools for in vivo imaging of porcine brains with subcellular resolution. Specifically, we describe surgical techniques for implanting a synthetic, flexible, transparent dural window for chronic optical access to the neocortex. We detail optimized parameters and methods for injecting adeno-associated virus vectors through the cranial imaging window to express fluorescent proteins. We introduce a large-animal 2-photon microscope that was constructed with off-the shelf components, has a gantry design capable of accommodating animals > 80 kg, and is equipped with a high-speed digitizer for digital fluorescence lifetime imaging. Finally, we delineate strategies developed to mitigate the substantial motion artifact that complicates high resolution imaging in large animals, including heartbeat-triggered high-speed image stack acquisition. The effectiveness of this approach is demonstrated in sample images acquired from pigs transduced with the chloride-sensitive fluorescent protein SuperClomeleon.

The Common Pathways of Epileptogenesis in Patients With Epilepsy Post-Brain Injury: Findings From a Systematic Review and Meta-Analysis

Abstract found on PubMed

Background and objective: Epilepsy may result from various brain injuries, including stroke (ischemic and hemorrhagic), traumatic brain injury, and infections. Identifying shared common biological pathways and biomarkers of the epileptogenic process initiated by the different injuries may lead to novel targets for preventing the development of epilepsy. We systematically reviewed biofluid biomarkers to test their association with the risk of post-brain injury epilepsy.

Methods: We searched articles until January 25, 2022, in MEDLINE, Embase, PsycINFO, Web of Science, and Cochrane. The primary outcome was the difference in mean biomarker levels in patients with and without post-brain injury epilepsy. We used the modified quality score on prognostic studies for risk of bias assessment. We calculated each biomarker’s pooled standardized mean difference (SMD) and 95% confidence intervals (CI). Molecular interaction network and enrichment analyses were conducted in Cytoscape. (PROSPERO CRD42021297110) RESULTS: We included 22 studies with 1499 cases with post-brain injury epilepsy and 7929 controls without post-brain injury epilepsy. Forty-five biomarkers in blood or cerebrospinal fluid (CSF) were investigated with samples collected at disparate time points. Of 22 studies, 21 had a moderate-to-high risk of bias. Most biomarkers (28/45) were investigated in single studies; only nine provided validation data, and studies used variable definitions for early and late-onset seizures. A meta-analysis was possible for 19 biomarkers. Blood glucose levels in four studies were significantly higher in patients with post-stroke epilepsy (PSE) than without PSE (SMD 0.44; CI 0.19 to 0.69). From individual studies, 15 biomarkers in blood and seven in CSF were significantly associated with post-brain injury epilepsy. Enrichment analysis identified that the significant biomarkers (IL6, IL1?) were predominantly inflammation related.

Discussion: We cannot yet recommend using the reported biomarkers for designing anti-epileptogenesis trials or use in the clinical setting because of methodological heterogeneity, bias in the included studies, and insufficient validation studies. Even though our analyses indicate the plausible role of inflammation in epileptogenesis, this is likely not the only mechanism. For example, an individual’s genetic susceptibilities might contribute to his risk of epileptogenesis after brain injury. Rigorously designed biomarker studies with methods acceptable to the regulatory bodies should be conducted.

Epilepsy Research News: August 2023

This issue of Epilepsy Research News includes summaries of articles on:

 

Brain Changes Associated with the Development of Post-Traumatic Epilepsy (PTE)

Research from the CURE Epilepsy PTE Initiative team at Virginia Tech has identified several changes in the brain that are associated with the development of PTE after a traumatic brain injury (TBI). The team examined changes in brain activity, cellular changes, and changes in the number of neurons in the brain after the development of PTE. The team found significant cellular and molecular changes in the dentate gyrus of the hippocampus, an area of the brain that has been implicated in seizure development. For example, the team found significant loss of neurons that inhibit brain activity, which may be important because seizures involve too much brain excitation, as well as changes in the structure of astroglia, which are cells that help regulate the transmission of signals between neurons in the brain. These findings suggest that changes in the dentate gyrus may contribute to the development of PTE following TBI.

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A New Brain Circuit Important in Epilepsy

Researchers have traced brain lesions (for example those caused by stroke, trauma, and tumors) that are associated with epilepsy to a shared brain circuit, indicating a unique role that deep brain circuits play in the origin and clinical management of epilepsy. The researchers found that lesions associated with epilepsy were connected to a common brain network located deep within the brain in regions called the basal ganglia and cerebellum. The researchers also examined a group of 30 individuals with drug-resistant epilepsy who underwent deep brain stimulation (DBS) to treat seizures and found that the individuals did better if the DBS site was connected to the same brain network implicated for epilepsy caused by brain lesions. The authors conclude that a lesion-related epilepsy network map could help identify patients at risk of epilepsy after a brain lesion and guide brain stimulation therapies.

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MicroRNA as a Target to Treat Epilepsy

A recent study featuring the work of former CURE Epilepsy grantee Dr. David Henshall and colleagues investigated the role of the brain molecule micro-ribonucleic acid (miRNA) miR-335-5p as a potential therapeutic target for epilepsy. miRNAs can control levels of voltage-gated sodium channels, which are important in neuronal excitability, making them an attractive target of new treatments. Additionally, voltage-gated sodium channel function is decreased in some forms of epilepsy, like Dravet syndrome. The researchers found that miR-335-5p regulates voltage-gated sodium channels’ levels and neuronal excitability, supporting a role in epilepsy. The researchers concluded that targeting miR-335-5p could potentially lead to new treatments for epilepsy through its ability to influence voltage-gated sodium channels and neuronal excitability.

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Fetal Exposure to Antiseizure Medications and Long-Term Neurodevelopment in Children

A new study found that young children who were exposed to commonly prescribed antiseizure medications in utero do not score worse on several long-term neurodevelopmental outcomes (at age three) than children who were not exposed. This study recruited women who were treated for epilepsy at 20 medical centers across the United States and followed them and their babies over the course of pregnancy and several years postpartum. To assess the effects of fetal exposure to medications, children were tested for their vocabulary and verbal comprehension skills at the age of three. Children of women with epilepsy were as good at verbally describing simple objects and pictures as children of women without epilepsy, and their ability to understand language was also comparable. The researchers did find that a high dosage of levetiracetam (Keppra®) in the third trimester of pregnancy was correlated with certain negative neurodevelopmental effects in children and recommend especially careful monitoring of blood levels of this drug and thoughtful dosing strategies.

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Atypical Neurogenesis, Astrogliosis, and Excessive Hilar Interneuron Loss Are Associated with the Development of Post-Traumatic Epilepsy

Featuring the work of CURE Epilepsy PTE Initiative’s Virginia Tech Team

 

Abstract found on MDPI

 

Background: Traumatic brain injury (TBI) remains a significant risk factor for post-traumatic epilepsy (PTE). The pathophysiological mechanisms underlying the injury-induced epileptogenesis are under investigation. The dentate gyrus—a structure that is highly susceptible to injury—has been implicated in the evolution of seizure development. Methods: Utilizing the murine unilateral focal control cortical impact (CCI) injury, we evaluated seizure onset using 24/7 EEG video analysis at 2–4 months post-injury. Cellular changes in the dentate gyrus and hilus of the hippocampus were quantified by unbiased stereology and Imaris image analysis to evaluate Prox1-positive cell migration, astrocyte branching, and morphology, as well as neuronal loss at four months post-injury. Isolation of region-specific astrocytes and RNA-Seq were performed to determine differential gene expression in animals that developed post-traumatic epilepsy (PTE+) vs. those animals that did not (PTE-), which may be associated with epileptogenesis. Results: CCI injury resulted in 37% PTE incidence, which increased with injury severity and hippocampal damage. Histological assessments uncovered a significant loss of hilar interneurons that coincided with aberrant migration of Prox1-positive granule cells and reduced astroglial branching in PTE+ compared to PTE- mice. We uniquely identified Cst3 as a PTE+-specific gene signature in astrocytes across all brain regions, which showed increased astroglial expression in the PTE+ hilus. Conclusions: These findings suggest that epileptogenesis may emerge following TBI due to distinct aberrant cellular remodeling events and key molecular changes in the dentate gyrus of the hippocampus.

CURE Epilepsy Discovery: CURE Epilepsy Grantee Makes Strides in the Understanding of Acquired Epilepsies by Investigating Inflammation in the Brain

Key Points

  • In acquired epilepsies, seizures occur as a result of a physical injury, stroke, infection, brain tumor, and various neurological diseases.
  • One way that scientists study acquired epilepsies in the lab is by using an experimental model called the “status epilepticus” (SE) model.
  • In people, SE is a medical emergency characterized by unrelenting generalized seizures lasting more than five minutes and that can be associated with negative cognitive impacts, an eventual epilepsy diagnosis, and even death.
  • One of the hallmarks of SE is inflammation in the brain that manifests in a variety of ways. The invasion of inflammatory cells called monocytes from the blood into the brain is one facet of the inflammatory cascade.
  • Nicholas H. Varvel at the Emory University School of Medicine received a CURE Epilepsy Award in 2019 to examine whether reducing the invasion of monocytes into the brain could be a therapeutic strategy for SE and potentially other acquired epilepsies.
  • Dr. Varvel’s team found that using a drug to reduce the invasion of monocytes from the blood into the brain minimized the harmful effects of SE, such as a loss in functional impairment and inflammation.
  • Dr. Varvel’s work provides yet another clue to our understanding of acquired epilepsies; with more experiments and evidence, drugs that block monocyte invasion could become a therapy for the prevention and cure of acquired epilepsies.

 

Deep Dive  

“Acquired” epilepsies are those where seizures occur as a result of a physical injury, infection, stroke, brain tumor and other insults to the brain.[1] In past Discovery articles, we shared the work of CURE Epilepsy grantees who are researching in the field of acquired epilepsies, specifically post-traumatic epilepsies (PTE) as part of the PTE Initiative,[2] and understanding neuroinflammation as it relates to epileptogenesis, the process by which the brain starts generating seizures after a brain injury or insult. This month’s Discovery focuses on another cause of epilepsy called “status epilepticus” (SE). Status epilepticus is a medical emergency and is characterized by unrelenting, generalized seizures lasting more than five minutes that have the potential to cause serious and lasting impacts. Indeed, more than 40% of individuals that survive SE go on to develop epilepsy within 10 years of the SE episode.[3]

Status epilepticus can have many deleterious effects on the brain. Hardening (also called “sclerosis”) of a part of the brain called the hippocampus can take place.[4, 5] Additionally, the blood-brain barrier (BBB) – a part of the vasculature of the brain that protects the brain from harmful substances – may erode, letting in molecules that cause inflammation.[6] In acquired epilepsies, certain inflammatory substances known as “cytokines” and “chemokines” may be activated. Additionally, there can be the invasion of inflammatory cells called monocytes from the blood into the brain.[7] Studies in animal models suggest that reducing inflammation can relieve the negative impacts of SE, namely neuronal damage, erosion of the BBB, and behavioral deficits.[8-10]

Dr. Nicholas H. Varvel at the Emory University School of Medicine received a CURE Epilepsy Award in 2019 to investigate if stopping the invasion of monocytes into the brain could be a therapeutic target for SE and potentially other acquired epilepsies. Researchers have shown that monocytes can invade the brain from blood in other neurological conditions, and this formed the basis of Dr. Varvel’s rationale.[11, 12]

Monocytes express a receptor known as CCR2, which mediates their migration from the blood to injured tissues. Previous studies done in Dr. Varvel’s lab showed that using a genetic technique to remove CCR2 prevented the invasion of monocytes into the brain. This technique also reduced inflammation as defined by neuronal damage and erosion of the BBB.[7]  Recent work from Dr. Varvel’s lab explored if using a drug to reduce CCR2 in the days after SE could provide benefits similar to the genetic method. Understanding the consequences of early inhibition of CCR2 immediately after SE might eventually lead to the development of a therapy that could target inflammation and the harmful effects that usually follow.[13]

In this study Dr. Varvel showed the specific involvement of monocytes in SE; blocking CCR2 (a receptor that is found on monocytes) through the use of an orally-administered drug was neuroprotective, as seen by fewer changes in inflammatory markers, the extent of erosion of the BBB, and most importantly, improved functional recovery. Hence, the CCR2 antagonist represents a strategy by which the immediate harmful effects of SE could potentially be reduced. More experiments are necessary to provide definitive answers, but one can envision a therapeutic intervention and future clinical trials, using a CCR2 antagonist that when administered to an individual after SE could reduce its harmful effects and potentially even prevent epilepsy.[13]

 

Literature Cited:

  1. Sirven JI. Epilepsy: A Spectrum Disorder Cold Spring Harb Perspect Med. 2015 Sep 1;5:a022848.
  2. Iyengar SS, Lubbers LS, Harte-Hargrove L, CURE Epilepsy Post-Traumatic Initiative Advisors, Investigators. A team science approach for the preclinical and clinical characterization and biomarker development for post-traumatic epilepsy Epilepsia Open.n/a.
  3. Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Risk of unprovoked seizure after acute symptomatic seizure: effect of status epilepticus Ann Neurol. 1998 Dec;44:908-912.
  4. Lewis DV, Shinnar S, Hesdorffer DC, Bagiella E, Bello JA, Chan S, et al. Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study Ann Neurol. 2014 Feb;75:178-185.
  5. Fujikawa DG, Itabashi HH, Wu A, Shinmei SS. Status epilepticus-induced neuronal loss in humans without systemic complications or epilepsy Epilepsia. 2000 Aug;41:981-991.
  6. van Vliet EA, da Costa Araújo S, Redeker S, van Schaik R, Aronica E, Gorter JA. Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy Brain. 2007 Feb;130:521-534.
  7. Varvel NH, Neher JJ, Bosch A, Wang W, Ransohoff RM, Miller RJ, et al. Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus Proc Natl Acad Sci U S A. 2016 Sep 20;113:E5665-5674.
  8. Broekaart DWM, Anink JJ, Baayen JC, Idema S, de Vries HE, Aronica E, et al. Activation of the innate immune system is evident throughout epileptogenesis and is associated with blood-brain barrier dysfunction and seizure progression Epilepsia. 2018 Oct;59:1931-1944.
  9. Jiang J, Quan Y, Ganesh T, Pouliot WA, Dudek FE, Dingledine R. Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation Proc Natl Acad Sci U S A. 2013 Feb 26;110:3591-3596.
  10. Rojas A, Amaradhi R, Banik A, Jiang C, Abreu-Melon J, Wang S, et al. A Novel Second-Generation EP2 Receptor Antagonist Reduces Neuroinflammation and Gliosis After Status Epilepticus in Rats Neurotherapeutics. 2021 Apr;18:1207-1225.
  11. Gyoneva S, Kim D, Katsumoto A, Kokiko-Cochran ON, Lamb BT, Ransohoff RM. Ccr2 deletion dissociates cavity size and tau pathology after mild traumatic brain injury Journal of Neuroinflammation. 2015 2015/12/03;12:228.
  12. Howe CL, LaFrance-Corey RG, Overlee BL, Johnson RK, Clarkson BDS, Goddery EN. Inflammatory monocytes and microglia play independent roles in inflammatory ictogenesis Journal of Neuroinflammation. 2022 2022/01/29;19:22.
  13. Alemán-Ruiz C, Wang W, Dingledine R, Varvel NH. Pharmacological inhibition of the inflammatory receptor CCR2 relieves the early deleterious consequences of status epilepticus Sci Rep. 2023 Apr 6;13:5651.

Hidden Brain Circuit Linking Lesion Locations to Epilepsy 

Article published by Neuroscience News

 

A new study by investigators from the Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, found that a common brain circuit may link different lesion locations causing epilepsy. 

In a paper published in JAMA Neurology, the researchers used a technique called lesion network mapping to identify this brain circuit with findings that point to potential targets for brain stimulation. 

“We’re learning more and more about where in the brain epilepsy comes from and what brain circuits we need to modulate to treat patients with epilepsy,” said lead author Frederic Schaper, MD, PhD, an Instructor of Neurology at Harvard Medical School and scientist at the Brigham and Women’s Center for Brain Circuit Therapeutics. 

“Using a wiring diagram of the human brain, lesion network mapping allows us to look beyond the individual lesion location and map its connected brain circuit.” 

Schaper and the team studied 5 datasets of over 1,500 patients with brain lesions. Participating centers across the US and Europe included the Brigham and Women’s Hospital, Massachusetts General Hospital, Boston Children’s Hospital, Northwestern University, and University Hospitals of Turku in Finland, Maastricht in the Netherlands, and Barcelona in Spain. 

They studied a variety of brain lesions such as stroke, trauma, and tumors, which allowed them to search for common network connections associated with epilepsy across different regions and types of brain damage. 

One of the datasets included combat veterans from the Vietnam Head Injury Study, which was originally designed in the 1960s because brain damage from combat shrapnel wounds resulted in a significant increase in the occurrence of epilepsy.  

“In our studies, up to 50 percent of Vietnam combat veterans suffered at least one seizure post-injury, sometimes many years after the injury,” said co-author Jordan Grafman, Ph.D. of the Shirley Ryan AbilityLab in Chicago. “However, it has remained unclear why lesions to some locations cause epilepsy and others don’t.” 

The Brigham researchers compared the locations of brain damage in patients that developed epilepsy to patients that did not, and found that lesions associated with epilepsy were distributed throughout the brain. 

However, these same lesion locations were connected to a common brain network, suggesting the brain connections disrupted by the lesions, rather than the locations of the lesions itself, were the key. 

These findings may have clinical implications for predicting the risk of epilepsy after brain damage. 

“If we can map a lesion to the brain network we identified, we may be able to estimate how likely someone is to get epilepsy after a stroke,” Schaper said. “This is not a clinical tool yet, but we lay the groundwork for future studies investigating the use of human brain networks to predict epilepsy risk.” 

The key brain connections they identified were not on the brain’s surface but were located deep within the brain in regions called the basal ganglia and cerebellum. The authors state that for decades, these deep brain structures have shown to modulate and control seizures in animal models of epilepsy and are hypothesized to act like a brain “brake”. 

Based on these findings, the researchers analyzed outcome data of 30 patients with drug resistant epilepsy who underwent deep brain stimulation (DBS) to treat seizures. They found that patients did a lot better if the DBS site was connected to the same brain network, they identified using brain lesions. 

CURE Epilepsy Discovery: Better Understanding of Post-Traumatic Epilepsy Provides a Foundation for the Development of Novel Therapies

Key Points

  • Post-traumatic epilepsy (PTE) is an acquired epilepsy that develops as a result of a physical injury to the brain.
  • CURE Epilepsy established the PTE Initiative in 2017 and utilized a team science approach to leverage the expertise of six research teams to develop better ways to study PTE in the laboratory, identify biomarkers that may predict risk of developing PTE, and better understand the biological pathways that lead to PTE after injury.
  • The PTE Initiative has led to many scientific successes to date: PTE Initiative teams developed and characterized several different laboratory-based models of PTE, enhanced the understanding of the biological underpinnings of PTE, and identified potential risk factors and potential biomarkers for PTE.

 

Deep Dive  

Last month’s CURE Epilepsy Discovery shared that some epilepsies can be “acquired.” More specifically, in acquired epilepsy, seizures occur as a result of physical injury, infection, brain tumor, or stroke.[1] Post-traumatic epilepsy (PTE) is a type of acquired epilepsy that occurs following a traumatic injury to the brain, for example, as a result of a motor vehicle accident, a fall, a sports injury, or a combat-related injury.[2] PTE may also be accompanied by changes in learning and memory, anxiety, depression, difficulties focusing, and sleep disturbances.[3,4] The risk of PTE following a TBI depends on the type and severity of the injury. PTE caused by traumatic brain injury (TBI) comprises 5% of all epilepsies.[5] In military service members who have suffered injuries, the risk of PTE can be as high as 53%.[6] Current treatment strategies for PTE include anti-seizure medications, but these are not effective in all individuals with PTE and are associated with many side effects. At this point, it is not possible to predict who is at a higher risk for developing PTE after a TBI.

Many issues make PTE a challenging epilepsy to study in laboratories and clinical settings. One of these issues is the process of epileptogenesis, which is the time between the injury and when the brain starts generating seizures and can span days to months or years. Epileptogenesis could provide a unique window of opportunity for intervention, but at present, we do not know enough about this process to develop therapies to halt it in its tracks. Therefore, in order to develop effective treatment strategies to prevent PTE, we need to understand the changes taking place in the brain after TBI and before the development of PTE. Additionally, a PTE biomarker (a biological factor that can be measured through genomic analysis, in blood, or via brain activity that can indicate the potential of developing of PTE) would be especially helpful. Addressing these needs may be best approached in a cohesive effort within the scientific community in order to find effective preventive strategies and treatments for all individuals at risk of this type of epilepsy.

One way of bringing researchers together in an intentional way is through a “team science” approach. Team science is a collaborative effort where different researchers with a breadth of skills come together to solve a single issue, taking advantage of diversity of scientific background, knowledge and expertise.[7] CURE Epilepsy has a track record of funding team science initiatives, such as the Infantile Spasms (IS) Initiative, which brought together eight different research teams across the US  with an array of expertise to advance the understanding of IS and potential treatments. Team science initiatives provide a unique opportunity for transparent and real-time collaboration.[8]

With learnings from the IS Initiative, CURE Epilepsy developed the PTE Initiative with a $10 million grant from the Department of Defense. The main objectives of the PTE Initiative were to improve how PTE is studied in the laboratory and identify biomarkers and risk factors that could help predict who will develop PTE after TBI. The PTE Initiative consisted of six global teams examining various facets of PTE, coming together to collaborate and accelerate discoveries. CURE Epilepsy also convened an External Advisory Committee comprised of thought leaders in the field of PTE to advise the teams on scientific challenges and provide logistical oversight and guidance. CURE Epilepsy led quarterly meetings to share advancements, discuss challenges, and transfer information that helped accelerate learning, especially for early career researchers. In multiple instances, research teams using similar models were able to compare and contrast their methods and data. In another example, an outside group with expertise in machine learning and artificial intelligence joined the EEG focus group and presented ideas to refine EEG analysis. One investigator shared, “Thanks to CURE Epilepsy support we were able to speed up our studies, but especially we could join a very active consortium aimed at discussing hypotheses, sharing data and cross-validating results across preclinical models and patients.”

More information about the specific projects and their impact can be found below:

Dr. Victoria Johnson at The University of Pennsylvania: Using an animal model that mimics certain features of human TBI, Dr. Johnson’s team looked separately at changes in the blood brain barrier (a  layer of cells that protects the brain by blocking most substances from passing from the body’s circulating blood supply into the brain), changes in different brain cells including support cells called glia, and changes in brain activity following TBI. The team also conducted parallel analyses of changes in the blood brain barrier and brain cells in postmortem human tissue from people who sustained a TBI, some of whom developed PTE. Preliminary results from her work also suggest the activation of a specific pathway known as mammalian target of rapamycin (mTOR) following TBI in humans.[9] More about Dr. Johnson’s work can be found here.

 

Dr. Kevin Staley at Massachusetts General Hospital: To better understand why certain individuals develop PTE, Dr. Staley’s team focused on the ways that changes to the extracellular matrix, a network of molecules and proteins that provides support to brain cells, might contribute to the development of PTE following TBI. The team hypothesized that alterations in the extracellular matrix might cause an imbalance between excitatory and inhibitory neurotransmitters and that this imbalance may ultimately lead to seizures. The team found hallmarks of increased excitation in animal models around the time of convulsions.[10] More about Dr. Staley’s work can be found here.

 

Dr. Jeffrey Loeb at The University of Illinois at Chicago: Dr. Loeb’s team studied a condition called subarachnoid hemorrhage, which occurs when there is bleeding in the space between the brain and the tissues that surround the brain and may contribute to the development of PTE.[11] Dr. Loeb’s team employed techniques such as EEG and magnetic resonance imaging to examine subarachnoid hemorrhage in a laboratory model and in humans with a goal of eventually developing therapies for PTE. More about Dr. Loeb’s work can be found here.

 

Dr. Michelle Olson and Dr. Harald Sontheimer at Virginia Polytechnic Institute and State University: This team looked closely at abnormal changes in a certain kind of glial support cell in the brain called an astrocyte. The team set out to develop a novel, more accurate animal model of PTE, and also examine various changes in astrocytes at the cellular, molecular, and functional levels in animals that develop PTE after TBI versus those that do not. More about this team’s work can be found here.

 

Dr. Kevin Wang (formerly at the University of Florida and now at Morehouse School of Medicine): Dr. Wang’s team, working with collaborators at Mario Negri Institute for Pharmacological Research, studied changes in proteins, metabolites and microRNA (a specific kind of genetic material) following TBI in preclinical and clinical samples that may contribute to the development of or predict PTE. Preliminary results from Dr. Wang’s team show changes in specific biological pathways that coincide with epileptogenesis. More about Dr. Wang’s work can be found here.

 

Dr. Pavel Klein at Mid-Atlantic Epilepsy and Sleep Center: Dr. Klein worked with ten clinical research teams in the US and Europe to characterize people who were considered “high-risk” for PTE following severe TBI. As a part of this characterization, the research teams collected blood samples with a goal of identifying biomarkers in collaboration with Dr. Wang and other researchers that may help predict risk of developing PTE. More about Dr. Klein’s work can be found here.

 

Conclusion

CURE Epilepsy’s PTE Initiative has progressed our understanding of epileptogenesis after a TBI, developed animal models to better predict who is at risk for PTE, and moved the community closer to identifying biomarkers for PTE. Research findings are now being advanced through CURE Epilepsy’s newest team science initiative, the PTE Astrocyte Biomarker Initiative. Stay tuned for more details on this exciting new project!

 

Literature Cited:

  1. Epilepsy. Available at: https://www.who.int/en/news-room/fact-sheets/detail/epilepsy. Accessed May 2.
  2. Pitkänen A BT. Head Trauma and Epilepsy. In: Noebels JL AM, Rogawski MA, et al. , editor. Jasper’s Basic Mechanisms of the Epilepsies [Internet]. 4th edition ed. Bethesda (MD): National Center for Biotechnology Information (US); 2012.
  3. Golub VM, Reddy DS. Post-Traumatic Epilepsy and Comorbidities: Advanced Models, Molecular Mechanisms, Biomarkers, and Novel Therapeutic Interventions Pharmacol Rev. 2022 Apr;74:387-438.
  4. Hammond FM, Corrigan JD, Ketchum JM, Malec JF, Dams-O?Connor K, Hart T, et al. Prevalence of Medical and Psychiatric Comorbidities Following Traumatic Brain Injury J Head Trauma Rehabil. 2019 Jul/Aug;34:E1-e10.
  5. Verellen RM, Cavazos JE. Post-traumatic epilepsy: an overview. Therapy. 2010;7:527-531.
  6. Ding K GP, Diaz-Arrastia R. . Epilepsy after Traumatic Brain Injury. In: Laskowitz D GG, editor. Translational Research in Traumatic Brain Injury. Boca Raton (FL): CRC Press/Taylor and Francis Group; 2016.
  7. What is team science? . Available at: https://cancercontrol.cancer.gov/brp/research/team-science-toolkit/what-is-team-science#:~:text=Team%20science%20is%20a%20collaborative,oftentimes%20trained%20in%20different%20fields. Accessed June 6.
  8. Lubbers L, Iyengar SS. A team science approach to discover novel targets for infantile spasms (IS) Epilepsia Open. 2021 Mar;6:49-61.
  9. Iyengar SS, Lubbers LS, Harte-Hargrove L, CURE Epilepsy Post-Traumatic Initiative Advisors, Investigators. A team science approach for the preclinical and clinical characterization and biomarker development for post-traumatic epilepsy Epilepsia Open.n/a.
  10. Lillis KP BB, Martinez-Ramirez L, Normoyle K, Staley K. Intraneuronal and extracellular chloride changes following TBI in a porcine model of post-traumatic epilepsy.  American Epilepsy Society Chicago, USA2021.
  11. Kanner AM. Subarachnoid Hemorrhage as a Cause of Epilepsy Epilepsy Curr. 2003 May;3:101-102.

Epilepsy Research News: June 2023

This issue of Epilepsy Research News includes summaries of articles on:

 

CURE Epilepsy’s Team Science Post-Traumatic Epilepsy (PTE) Initiative: Approach and Advances

CURE Epilepsy’s PTE Initiative united six preclinical and clinical research teams to form a consortium focused on improving ways to study PTE in a laboratory setting, understanding changes in the brain that occur after a traumatic brain injury (TBI) that lead to PTE, and uncovering risk factors associated with the development of PTE. PTE is a debilitating type of epilepsy that can develop in the months or even years following a TBI. Currently, there is no way to predict who will develop PTE or any way to prevent it. A recently published paper from the PTE Initiative describes scientific advances from CURE Epilepsy’s PTE Initiative, as well as its methods, implementation, and emphasis on team science and collaboration. Work on the PTE Initiative is ongoing, with the ultimate goal of understanding who is at risk for PTE, and laying the groundwork for the development of ways to prevent it from occurring. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Psychological Health and Traumatic Brain Injury Research Program under Award No. W81XWH-15-2-0069.

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Genetic Mutations Contributing to Adult Epilepsy

A recent study sheds new light on the role of changes in DNA known as somatic mutations in patients who develop mesial temporal lobe epilepsy (MTLE). Unlike inherited DNA mutations, which are passed down from a person’s parents, somatic mutations occur after a person is conceived. To examine the role of somatic mutations, researchers analyzed DNA from brain tissue samples collected from 105 patients with drug-resistant MTLE as well as 30 people who did not have epilepsy. The team pinpointed 11 somatic mutations that were enriched in the hippocampus (the region of the brain where seizures typically originate in MTLE) of 11 patients with drug-resistant MTLE. All but one of the 11 mutations were connected to a specific genetic pathway known as the RAS/MAPK pathway. The researchers noted that certain anti-cancer drugs target this pathway, opening a new avenue of therapeutic possibilities for MTLE patients that are resistant to antiseizure medications. In addition to suggesting a potential path to treatment, the findings could also be used to help inform treatment decisions for patients who harbor these somatic mutations.

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Improving Seizure Freedom After Epilepsy Surgery

A network of connections in the brain could be the key to improving frontal lobe epilepsy surgery, according to new research. This research suggests that disconnecting certain pathways in the frontal lobe could lead to longer-lasting seizure freedom after brain surgery. These pathways link the frontal lobe to brain structures deep in the brain, including areas called the thalamus and striatum. The researchers analyzed the cases of 47 people who underwent surgery for drug-resistant frontal lobe epilepsy and found that disconnection of these pathways was associated with seizure freedom after three and five years. The research found that this surgery also did not have negative effects on language or executive functions like planning, self-control, and focus. However, other functions, such as mood and emotions, still need to be studied. These findings provide hope that disconnection could lead to improved outcomes and long-term seizure freedom in people with frontal lobe epilepsy.

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Predictors of Epilepsy in Children with Complex Febrile Seizures

Four predictors of future epilepsy in children with complex febrile seizures (CFS) have been identified in a recently published study. These include experiencing more than three febrile seizures in 24 hours, a certain type of brain activity seen on a post-CFS electroencephalogram (EEG), a family history of seizures not associated with fever, and CFS onset at age three or later. The researchers retrospectively examined 621 children and found that having all four risk factors raised the risk of developing epilepsy to over 75%. The researchers noted that early identification of children who will develop epilepsy after a CFS is essential to future management and counseling for parents and caregivers.

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A Team Science Approach for the Preclinical and Clinical Characterization and Biomarker Development for Post-Traumatic Epilepsy

A Report of CURE Epilepsy’s Post-Traumatic Epilepsy Initiative

Abstract found on Wiley Online Library

Objective: Post-traumatic epilepsy (PTE) is an acquired epilepsy that develops in the months or years following a traumatic brain injury (TBI) and can lead to substantial personal, financial, and societal burden. To date, PTE is rarely curable; current treatments are partially effective and often accompanied by adverse side effects. While research on PTE has expanded significantly in the last several years, there remain numerous challenges to identifying effective prevention and treatment strategies. In this paper, we describe advances from the CURE Epilepsy PTE Initiative, including its implementation and the emphasis on team science.

Methods: The CURE Epilepsy PTE Initiative funded six research teams to link preclinical and clinical studies to engage in the validation of experimental models, characterization of pathophysiology and biological pathways, and identification of risk factors associated with PTE. Three teams had projects with both a preclinical and a clinical component; these teams focused on: targeting the epileptogenic effects of subarachnoid blood, exploring the neuropathological mechanisms of epileptogenesis, and defining the role of extracellular matrix injury. Two teams undertook entirely preclinical projects: exploring the role of vascular injury, gliosis, and neurogenesis as drivers for PTE, and identifying genetic, proteomic, metabolomic, and microRNA biosignatures to improve the prediction of PTE. One team’s project was entirely clinical and investigated genetic and protein biomarkers to improve the prediction of PTE.

Results: In addition to scientific discoveries including characterization of a variety of animal models and progress towards the understanding of biological underpinnings and biomarkers for PTE, significant programmatic and personnel-related processes were incorporated, including standardized, rigorous policies and procedures to ensure quality and accountability between and within groups.

Significance: We propose CURE Epilepsy’s team science approach as an effective way to bring together a diverse set of investigators to explore biological mechanisms that may lead to cures for the epilepsies.