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.

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.