The Blood-Brain Barrier and Epilepsy! - Dr. Claire Behan, Trinity College Dublin, & Dr. Chris Greene, RCSI, Ireland
This chat delves into the intricate relationship between the blood-brain barrier and epilepsy - particularly temporal lobe epilepsy! Claire, Chris, and Torie highlight the dysfunction of the blood-brain barrier in people with an epilepsy, the role of imaging techniques in assessing this dysfunction, and the outcomes of surgical interventions. Excitingly, Claire and Chris also explore future research directions aimed at targeting the blood-brain barrier to improve treatment outcomes!
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Episode Highlights
The blood-brain barrier’s role in temporal lobe epilepsy.
How imaging reveals dysfunction & guides treatment.
Future directions in targeting the barrier to improve outcomes.
About Dr. Claire Behan
As a Lecturer and Program Director in Neurology Nursing Dr. Claire Behan's PhD focused on researching biomarkers for seizures and epilepsy (funded by FutureNeuro). Claire is passionate about advancing clinical knowledge and improving outcomes in neurological care. With a background as an Advanced Nurse Practitioner and Nurse Prescriber, she brings hands-on experience from acute clinical settings and a strong foundation in evidence-based practice.
Full profile: claire-behan
About Dr. Chris Greene
Chris is a Lecturer and Principal Investigator in RCSI and FutureNeuro Research Centre and has been working in the blood-brain barrier space for about 12 years now. He did his undergraduate degree in Genetics & Cell Biology in Dublin City University and then PhD in Genetics in Trinity College Dublin. His research has revolved around how the blood vessels in our brains change in response to disease, whether these changes contribute to the disease itself, if we can measure these changes as biomarkers of disease and if we can fix the damaged blood vessels to prevent disease.
Full profile: chris-greene
Organisations mentioned
Topics & terms mentioned
Blood-brain barrier
Temporal Lobe EpilepsyEpilepsy Surgery
Anti-Seizure Medications (ASMs)
Gadolinium
Brain Endothelial Cells (BECs)
P-glycoprotein (P-gp)
Multidrug transporters.
Albumin
Astrocytes
Glutamate
Potassium
GLUT1 Deficiency Syndrome
Ketogenic diet
Protein claudin-5
Paper references
“Restoration of blood brain barrier integrity post neurosurgical resection in drug resistant epilepsy” https://www.sciencedirect.com/science/article/pii/S1525505025001647, C. Behan, C. Greene, C. Doherty, et al., Epilepsy & Behavior, Apr 2025, DOI: 10.1016/j.yebeh.2025.110425
“Microvascular stabilization via blood-brain barrier regulation prevents seizure activity” https://www.nature.com/articles/s41467-022-29657-y Greene, C., Hanley, N., Reschke, C.R. et al. Microvascular stabilization via blood-brain barrier regulation prevents seizure activity. Nat Commun 13, 2003 (2022).
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Trailer
00:00 Chris Greene
"So one of the questions that I'm always interested in is like 'What exactly is leaking out of the blood and into the brain that can promote seizures?'. And so there's, you know, it's such an obvious question, but there are so many different proteins in our blood that just should never be near neural tissue because it can cause hyperexcitability."
Intro
00:16 Torie Robinson
Welcome to Epilepsy Sparks Insights! I’m your host, Torie Robinson, and here we talk with specialist clinicians and researchers to spark improved understandings of the epilepsies worldwide. If you’re new here, please subscribe so you don’t miss future conversations — and let’s get into today’s episode. Today, I’m joined by Dr. Claire Behan from Trinity College Dublin and Dr. Chris Greene from RCSI, who are here to share their fascinating research into the blood–brain barrier and epilepsy — including how surgery may not only stop seizures, but also help the brain repair itself!
Why Study the Blood-Brain Barrier?
00:46 Torie Robinson
Now, why did you start your research into blood-brain barrier research when it comes to epilepsy? And what is the blood-brain barrier (BBB)?!
00:55 Chris Greene
This is a question that honestly goes back over 100 years. The blood-brain barrier is like, you know, your airport security. It's important for controlling what can go in and out of an airport, but in this case, it's important for controlling what moves in and out of the brain. Some people that have their correct passport and their boarding pass can move in, and then they go through security screening to make sure there's nothing dangerous in their bag, and that's exactly what the blood-brain barrier does. It controls what moves in and out of the brain. And so it's formed by the blood vessels in our brains, and we were interested in studying it in the context of epilepsy because it's been shown to be dysfunctional across many different neurological disorders. And so, back in the 1960s to the 1970s, when clinicians were trying to devise experiments that transiently open up this barrier so that we could get more drugs into the brain to treat brain cancer, for example, they saw that when you briefly opened it up, it could actually cause seizures in these patients. So, back in the 60s or 70s, we had the clinical studies and the clinical validation already that just by opening this blood-brain barrier we could actually cause seizures in people and so, that's why we were interested in studying “Well, what exactly is happening to this barrier, what is changing that's causing these seizures and causing these hyper excitability within the brain”.
This study: Restoration of blood brain barrier integrity post neurosurgical resection in drug resistant epilepsy
02:06 Torie Robinson
So, tell us, Claire, what did your research involve? What did you focus on?
02:11 Claire Behan
So, we recruited patients who had temporal lobe epilepsy, and we wanted to identify those who we felt would have a dysfunctional blood-brain barrier. So these were patients who were epilepsy surgery candidates. In particular, they had a temporal lobe epilepsy and they were going for epilepsy surgery. And often these are patients who have tried multiple anti-seizure medications, and they're really at the end of the road when it comes to options for improving their seizure frequency and improving, generally, their quality of life. So we recruited these patients, seven in total - so a small study, but it really allows us to give some proof of concept to the idea - and the patients needed to have imaging done before their surgery, and then imaging done afterwards, and the idea being that we were going to be able to compare their pre and post-imaging in order to make some observations about that.
03:13 Torie Robinson
And what type of imaging was this?
MRI Imagnig using dyes: Dynamic Contrast-Enhanced (DCE) MRI
03:15 Chris Greene
So we use what's called DCE imaging; it's Dynamic Contrast-Enhanced MRI. And so, to understand this, we need to understand exactly what the blood-brain barrier is. So, look, back in the end of the 19th century, there was this bateriologist by the name of Paul Ehrlich who was designing some dyes that could tell him how much oxygen was being consumed by different organs throughout the body. He injected one of these dyes, and he saw that it lit up everywhere in the body except for the brain. And so, this indicated that there's potentially some sort of… you know, at first he thought that was just that the dye didn’t have any activity within the brain. One of his students (Edwin Goldmann), then, a few years later, actually reversed the experiment and injected it directly into the brain. And this is where he saw that it lit up the brain then, as well as the spinal cord, but it didn't light up anywhere else in the body! So there's some sort of compartmentalisation. And that's exactly how we do our imaging approaches: we can inject a dye, in this case, a contrast agent called gadolinium, we can look at sequential MRI scans (so images of the brain before and after we inject this), and then we can quantify where and to what extent this dye is going across the blood-brain barrier! Because in a healthy person that has an intact blood-brain barrier, it's going to stay within the vessels. And so, in a dysfunctional case like in a person with drug-resistant epilepsy who has recurrent seizures, there's going to be hot spots within the brain where we can see this leaking out and into the brain tissue, and that's exactly what we can quantify.
The BBB and ASM drug-absorption
04:40 Torie Robinson
Okay, just on the side, in theory, if you've got a bit of a stuffed-up blood-brain barrier, could that not make absorption of anti-seizure medications even better?
04:49 Chris Greene
This, yeah, that's a very important point. So… and it’s harked back to what exactly is going on with these blood vessels that may be actually contributing to the development of epilepsy. And so, what is happening is that they're essentially undergoing an identity crisis!
05:05 Torie Robinson
Ha!
05:05 Chris Greene
They don't have the normal properties that these blood vessels in the brain should have. And so one of the key properties is their ability to transport molecules from the blood and into the brain. But, because of these unique properties, at present, of the 7,000 drugs that are available, over 95% of them can't actually cross the blood-brain barrier. And so, lots of the anti-seizure medications that are available are substrates for a certain receptor that's present on these brain endothelial cells called P-glycoprotein. So these are multi-drug transporters. And so, when an anti-seizure medication goes into one of these cells, it's immediately pumped back out. And so, what we're seeing from animal research is that these receptors get hugely upregulated in cases of drug-resistant epilepsy, in these blood vessels. So, they're dysfunctional because they're expressing too much of these, but they're leaky, and it's almost like a non-specific leakiness where you have proteins that are normally in the blood can seep in through the endothelial cells, but at the same time, you're getting much more and much greater expression of these drug metabolising enzymes and transporters. So that's also one of the reasons that we suspect that anti-seizure medications are inadequate in as many as 30% of people with these, with temporal lobe epilepsy.
Drugs and food - too much vs too little
06:20 Torie Robinson
You're making me think of food, like how you can eat too much, and you can eat too little. You've got to have just the right amount to not be unwell (to a degree). And I guess that's kind of similar in terms of what is allowed through the blood-brain barrier. You can have too much of one thing, one molecule: you can have too little of it.
06:37 Chris Greene
Food is the perfect example because we don't produce energy in the brain; we get all of our energy from what we eat. So if you think about having a sandwich at lunch 25% of the energy of that in the form of glucose has to go to the brain because it's such a hungry organ; it consumes so much glucose. But it can't just move into the brain - if it done that it would be catastrophic. There would be way too much activity, and it would be horrendous seizures, and it would just be catastrophic for the homeostasis (for how our brains function). So instead, we have specific transporters for glucose. So it's one called the GLUT1 transporter, and you'll probably know from people that have GLUT1 Deficiency Syndrome; they can't get enough glucose into their brain because they have a deficiency in this transporter, and what do they get? They have seizures and epilepsy.
07:20 Torie Robinson
Gosh, we are such sensitive animals, primates, aren't we?
07:25 Chris Greene
But at the same time, it shows how adaptable we are because if we switch to an alternative energy source in the case of people with GLUT1 Deficiency Syndrome, like a ketogenic diet, we can have an alternative fuel source that can get into the brain. And it's very beneficial for those patients as well.
Epilepsy Surgery and the Blood-Brain Barrier - discoveries!
07:40 Torie Robinson
Tell us about how surgery helps with all of this, though. So, say you've got a bit of a stuffed-up BBB. What difference does epilepsy surgery make to that?
07:49 Claire Behan
The patients in our study (who had their epilepsy surgery and they had their temporal lobectomy), five of those patients became seizure-free. And so we are assuming that we've removed the epileptogenic part of the brain…
08:06 Torie Robinson
What happened to the other two? Do you know? Or they partially reduced seizures or just...
08:10 Claire Behan
They continued to have seizures. One of them is listed for a secondary follow-up procedure, and the other one continued. The other one had that kind of… sometimes that you observe this “honeymoon period”...
08:24 Torie Robinson
Mm.
08:24 Claire Behan
…where their seizures reduce, and then they restart again. And in those two patients, their blood-brain barrier; when we scanned them after the procedure, they continued to have a dysfunctional blood-brain barrier. So in the five patients who had their seizures resolved, their blood-brain barrier looked good, looked nice and healthy, and restored, so essentially “healed”. But in our two patients who continued to have seizures, we didn't observe that. They still had that dysregulation or poor blood-brain barrier, leaky blood-brain barrier ([there are] lots of ways that we describe this!). Which was very interesting.
09:06 Chris Greene
It's important in this particular group of patients. They were all having different types of seizures. So the type of seizure is going to influence the surgical outcome as well…the number of seizures that they're having as well. Because what we're seeing when we look at these pre-surgery scans is that there is a huge variability in the degree of the dysfunction of this barrier. And so for an individual that's having a focal to bilateral generalised seizure, it's going to encompass their whole brain and not just their temporal lobe. So that begs the question: “How can a surgical removal of a very specific brain region ultimately affect distant regions of our brain as well?”. And I'm kind of just spitballing ideas here(!), but, you know, it points to the idea that the blood vessels in our brain retain an inherent plasticity. They are injured, but they can resolve from this injury. They can recover their normal natural functions. And I expect that this is what we're seeing in this particular case. And so for individuals that have recurrent seizures - whether it's a case of it was a failure of surgery - we don't know, maybe we didn't get the entire epileptogenic zone, or maybe there's a continuing dysfunction of the blood vessels that's driving… having a seizure-promoting effect that's sustaining their epilepsy. And we're seeing this when we go back to our animal models.
What is leaking out of the blood and into the brain that can promote seizures?
10:25 Chris Greene
So, one of the questions that I'm always interested in is like “What exactly is leaking out of the blood and into the brain that can promote seizures?”
10:32 Torie Robinson
Yeah!
10:33 Chris Greene
And so there's, you know, it's such an obvious question, but there are so many different proteins in our blood that just should never be near neural tissue because it can cause hyperexcitability. And there's been lots of studies actually done from resected tissue from patients that have underwent these surgeries, and then they've screened these tissue samples to see, okay, what was normally in the blood and seeping out. And there's a tonne of different proteins, but one of them in particular that's really interesting is albumin. It's our most abundant protein in our entire blood. But when it seeps out of blood into our brain, it can be taken up by these other cells called astrocytes. Now they're really important for providing structural support to our blood vessels, but they're like hoovers. They mop up extracellular glutamate and potassium, and they maintain buffering. Too much glutamate, the major excitatory neurotransmitter in the brain, what's going to happen? It's going to cause hyperexcitability, and it's going to prime an environment where seizures are likely to recur. And so one of these proteins, albumin, can be taken up by these astrocytes, and it completely changes their function so they can no longer hoover up all this excess potassium and glutamate, and so it's priming this environment, and it's also causing dysfunction of the blood-brain barrier at the same time.
11:45 Torie Robinson
Outrageously complex. And so what are the next stages when it comes to the results we have from this study? Because it looks, the results look very, very interesting, but what do we do next?
Do changes in blood-brain barrier function contribute to disease? Can we actually target these blood vessels?
11:59 Chris Greene
For me, in my line of research, it's like we're always interested in asking questions like: “Do changes in blood-brain barrier function contribute to disease?”. It's well established now that this is the case. “Can we measure changes in blood-brain barrier integrity as a prognostic marker for disease and for recurrence?”
12:18 Torie Robinson
Mm-hm.
12:18 Chris Greene
And I think that's where we need to go now, with much larger clinical studies to see if we can look at patterns of blood-brain barrier disruption on these scans to ultimately predict the likelihood of someone having a successful surgery outcome or as long-term biomarkers for understanding their treatment journey as well. But then, finally, “Can we actually target these blood vessels? You know, can we design some innovative therapies that can stabilize their integrity?”. And this is actually something that we've already done in animal models. Back in 2022, we published a paper where we showed that there was one particular protein, one of these tight junction proteins, that actually seals the cells together in these blood vessels.
12:58 Torie Robinson
Wow!
12:59 Chris Greene
And so, it's called claudin-5. And so we went back to our genetic tools and we depleted it in the blood-brain barrier cells (so in our endothelial cells in mice), and when we remove it, what do we think happens? The mice develop spontaneous recurrent seizures because they had an open blood-brain barrier! So this is our kind of, you know, our proof of principle that you can remove just one component of the barrier, you can cause epilepsy in mice, and so what happens when we restored it? The seizures went away. And so we're now kind of at a stage where we can test in our preclinical animal models. Okay, are there any specific barrier-restoring therapies that we can potentially trial that could be disease-modifying an epilepsy?
13:40 Torie Robinson
Or I would say, rather than treating the issue, perhaps identifying when the issue may be likely to occur so that people don't actually end up having seizures.
The future: precision therapy and pre-seizure identification
13:51 Claire Behan
In the clinic, this is really exciting. And I think, you know, that part of the prognostic piece, when you're having that conversation with someone about surgery, it's a big deal. There's lots to consider. To be able to give a little bit more certainty “Well, you have this type of blood-brain barrier, so you are more likely to have a successful surgery”, versus “Maybe this isn't the right route. Maybe we need to consider other options.”. So that part is very exciting! And yeah, potentially being able to identify a particular blood-brain barrier pre-seizure, you know, that early, that would kind of revolutionise what we do and have very different outcomes for patients!
14:39 Torie Robinson
That'd be amazing!
14:40 Claire Behan
And precision therapy, you know, wow, this is…we're not gonna just dampen down everything that's happening with these medications - that potentially have lots of side effects - and instead we're going to look specifically at you and what we can do to target your issue individually.
Conclusion
15:03 Torie Robinson
Thank you so much, Claire and Chris, for shedding light on how the blood–brain barrier is involved in epilepsy, and how further research could help guide future treatments and surgical decisions. And thank you for watching Epilepsy Sparks Insights!
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