AES 2022 | Studying epileptogenesis in post-traumatic epilepsy
Ramon Diaz-Arrastia, MD, PhD, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, shares an overview of our understanding of post-traumatic epilepsy (PTE) and the epileptogenic processes that occur after brain trauma. Many types of insult have been noted as a cause of epilepsy and brain trauma is one such cause, estimated to underly as many as 5% of all epilepsy cases. PTE is an attractive model in which to study epileptogenesis, as the inciting event is known and there is short latency period between traumatic brain injury occurrence and PTE onset. However, much remains unknown about the mechanisms underlying PTE and no pharmacological agents can successfully prevent its onset. Prof. Diaz-Arrastia highlights the heterogeneity in PTE development that has been identified in recent studies. While a focal injury leading to scarring is a well-studied cause of PTE, at least half of patients show no focal injury and instead show damage due to diffuse mechanisms. The research community are looking into overlapping features between these two types that could be targeted with therapy. This interview took place at the American Epilepsy Society (AES) Annual Meeting 2022 in Nashville, TN.
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Transcript (edited for clarity)
Obviously, epilepsy can result from many, many different causes. Anything that damages the brain, be it a stroke, an infection, a developmental anomaly can result in epilepsy. But one of the ones that is very recognized to do that is brain trauma. And I think the estimates are that approximately 5% of all epilepsy is due to brain trauma. And that could be a bit of an underestimate, actually. But this has been known for a long time, and I think there’s been a lot of interest in using post-traumatic epilepsy as a model of epileptogenesis...
Obviously, epilepsy can result from many, many different causes. Anything that damages the brain, be it a stroke, an infection, a developmental anomaly can result in epilepsy. But one of the ones that is very recognized to do that is brain trauma. And I think the estimates are that approximately 5% of all epilepsy is due to brain trauma. And that could be a bit of an underestimate, actually. But this has been known for a long time, and I think there’s been a lot of interest in using post-traumatic epilepsy as a model of epileptogenesis.
So one of the problems that we have in developing anti-epileptogenic therapies is that most of the time, we don’t know when the initial inciting event that led to epileptogenesis started. I mean, for people who develop epilepsy from a developmental problem, et cetera, we don’t really know when the initial inciting event happened. Therefore, we wouldn’t really know when to start therapies for that. Whereas with brain trauma, and with some other conditions, I think we know pretty clearly when the insult occurred that eventually led to an epileptogenic circuit.
And there have been attempts really going back many decades to use anti-epileptic drugs, and potentially other kinds of treatments to block the epileptogenic process. And frankly, those have all been unsuccessful. There’s been some success in animal models, but certainly anything in clinical trials, that has all failed. So really, the motivation for really my research program, and then I’ve been working on this for a long time now, is try to understand on a granular level, on a detailed granular level, what is the epileptogenic process after brain trauma? Meaning, looking at things like what are the biomarkers that are telling you something about the epileptogenic process? What are the imaging features that can tell you something about the epileptogenic process, potentially, what are the genetic features that tell you something about the epileptogenic process? And that’s the kind of information that really we’re going to need if we’re ever going to be successful in testing and ultimately developing anti epileptogenic therapies.
I think one thing that we’ve discovered over the last several decades, and this is work from my lab as well as from many others, is that post traumatic epilepsy actually is fairly heterogeneous. And a traumatic brain injury in itself is fairly heterogeneous. So we should not be surprised that the epileptogenic process after brain trauma is also heterogeneous. So many people who develop epilepsy after having had a traumatic brain injury, that’s a consequence of them having had a focal injury, meaning a contusion, or a bruise in the surface of the brain that over time, as it scars up, and there is some plasticity around the edges of the scar, that ends up with an epileptogenic circuit.
So that is actually the most easily understood model. And historically, that’s the model that has received the most attention, and that clearly does happen. However, one of the things that we’ve discovered is that at least half of people who develop post-traumatic epilepsy do not have any focal contusions or any focal scarring in the brain. And the injury in those cases are due to diffuse mechanisms, which are also very well understood to occur after traumatic brain injury. And these diffuse mechanisms are things such as axonal shearing, or axonal stretching, they can also include blood-brain barrier disruption, or other disruptions of the microvasculature, or neuroinflammation, which can be more diffuse.
And that actually is actually pretty significant as well, and it’s not something that has been as widely studied in animal models in the past. And that’s a common mechanism. So obviously, you would believe, you would hope and believe that at some level, at some fundamental molecular or cellular level, there going to be similarities between epileptogenesis after a focal brain injury, compared to epileptogenesis after a diffuse brain injury. And I think that’s kind of where we are right now, trying to identify what features of either imaging, or biomarkers, et cetera, would point to potentially some of those similarities, which are things that could be targeted for therapies.
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