Are Blood-Brain Barrier Leaks Causing Epilepsies?! - Prof. Colin Doherty, St James’s Hospital, Ireland
Could inflammation and the blood-brain barrier help explain why some seizures remain uncontrolled? Prof. Colin Doherty shares emerging research into immune activity in epilepsy, how steroids may temporarily improve seizure control, and why future immunotherapies could help some people whose seizures do not respond to current treatments. Watch/listen here 👇!
Episode Highlights
We need precision therapy for autoimmune epilepsies
The blood-brain barrier may play a huge role in immune epilepsies
Steroids can prevent seizures in some
About Colin Doherty
Colin is a consultant neurologist and director of the epilepsy service at St James's Hospital. He served as the national clinical lead for the Epilepsy Care Programme in Ireland for nine years, with a charge to develop epilepsy services nationally to improve quality of care and access for patients. His areas of focus are population health, health services research, care delivery, and e-health, and women’s health in epilepsy. He is also the Ellen Mayston Bates Professor of Epileptology at Trinity College Dublin.
Full profile: Colin-Doherty
Topics mentioned
autoimmune epilepsy
blood-brain barrier
immunotherapy
immunology
immuno-oncology
inflammation
leaky brain
precision medicine
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Trailer
00:00 Colin Doherty
The immunologists have been telling this for years. They've been telling us “Hey, listen, it's all human disease is all about inflammation!”, and we haven't listened to them. Now I'm listening!
Intro
00:07 Torie Robinson
So, last week Prof. Colin Doherty told us about his challenge of the idea that epilepsy is just an “electrical disorder”. So now, we’re going to continue with some really cool stuff, exciting stuff (as science is!); what if we’ve just been looking down the wrong alley for a solution for people with refractory epilepsy or uncontrolled seizures? Because what if a huge part of it all is about our immune systems? Let’s jump in.
Precision therapy for autoimmune diseases
00:31 Colin Doherty
For people with autoimmune diseases, there has been a range of new biological therapies. So, people [who] get psoriasis and eczema and rheumatoid arthritis no longer have to worry about the long-term effects of steroids. If you did a study, a placebo controlled study of steroids and epilepsy; okay, maybe you'd find a positive result, but you wouldn't have anybody saying “Well, let's just let's just treat people with steroids.”, you know, because so many bad effects. But I think it's already opening up this idea of precision therapy. Let's find out what particular immune responses is happening in epilepsy. We know it's definitely there. Forget about the autoimmune encephalitis stuff, right, this is in chronic, regular, everyday epilepsy! There is an immune-crosstalk going on. And one of the things that… one of my hypotheses is, and maybe the reason that we're losing people after a month is because there's a also a physical effect on this other area of interest; it's called the blood-brain barrier,
01:27 Torie Robinson
Mm-hmm.
Hypothesis: could steroids prevent seizures through mending the leakage of the Blood-Brain Barrier?
01:27 Colin Doherty
…and I'll just briefly do two words on that. So, the blood-brain barrier is this unique covering of the blood vessels in the brain. Nowhere else, your coronary arteries, your liver vascular system, nobody else has this, it's only in the brain, and it evolved in a human to protect the brain from the poisons in the in the environment. So, when you eat the wrong food, you get sick as a dog because your stomach absorbs it, but your brain is protected from it. And so, it only lets in molecules of a certain size. What we know that epilepsy does - and this is… there's a range of diseases that do this - the other area I'm interested in is brain concussion, causes leakiness of the blood-brain barrier. So, the brain barrier leaks, big immune cells that shouldn't be in the brain are suddenly in the brain, there are activating agents, cytokines and stuff that get into the brain and activate the brain's immune system itself, which is which is the microglia, which are essentially macrophages in the brain. So suddenly there's this massive kind of immune response going on, caused by the brain leaking. We know that steroids have a physical effect in the barrier, they close the barrier temporarily. So, you can actually close the blood-brain barrier very effectively, just give big dose of steroids. And so that's why I think we're getting an initial good response lasting a month, because we're closing the barrier. And then once we stop the steroids, the barrier starts to open again. And that's why we're losing some people to back to seizures.
02:52 Torie Robinson
How interesting.
02:52 Colin Doherty
So that's my hypothesis. So, you know, the it's a complex hypothesis. It's the steroids are going in, they're dampening the immune response, they're also closing the blood-brain barrier. That that's allowing, by the way, allowing the drugs now to get to their target - because, you know, the drugs are also leaking out in a leaky barrier, not getting to the place they need to be, so now you're closing the barrier, it allows the drug to get to its target. and that's why the seizures stop (in my view). And in… and some people, because the drug has got to its target, they're the people getting a prolonged response. But in about two-thirds of those, once the steroid goes away, the barrier starts to leak again and they start to have seizures again. So that's a very complex picture, but I think it needs to be studied in detail. And I think we then we need to find out what are the key elements of the immune system that are responsible for that leakage and target that, not give everybody steroids. That's not the answer, because it's it would cause as much morbidity as benefit, I think.
Neurologists and researchers need to think about autoimmune
03:53 Torie Robinson
So, what are the next steps for doing this research then? Are we looking at funding? Are we looking at getting more people interested? Because also I can imagine some neurologists and clinicians are going to be, well “This isn't a very sexy idea.” or “This goes against, potentially, what we already think.”, or, you know, things along those lines.
04:11 Colin Doherty
I think that's true. I think I think that's true. But I would appeal to every neurologist out there who sits in clinics like I do, with patients who have highly refractory epilepsy. And you know these people, Torie, you've spoken to them, you have had your own issues with chronic epilepsy. And like you're sitting there from and we say, well we're you know, we've been mining this electrical theory and it has come up with great things. There's no question. Like some of the drugs that we have now that that have transformed people's lives came through that hypothesis. But we need to move, we need to start thinking more creatively now about the other things. And I would say this is not a new idea. This is an old idea: let's go and revisit the old ideas and the old idea is epilepsy causes brain injury and a response to injury is the immune response and why don't we start thinking about that so yeah so look we would like to do more..
Blood-brain barrier, steroids and genetics - current study
04:57 Colin Doherty
We're in the middle of a study at the moment where so the blood-brain barrier theory has come that that hypothesis has arrived slightly separately but we're actually doing two different studies at the moment one is that we're giving people we're doing a an MRI, looking at the blood-brain barrier, we're giving them high dose steroids and we're looking at the effect on the barrier after it. And then the second study, which I really like, and one of my PhD students, Isabel Hunt, is doing is we're looking at the blood-brain barrier in patients with highly refractory epilepsy, and then when a clinician makes a clinical decision to change the treatment, once they change it, we will redo the look of the barrier again. So we're we're looking at this and all the while, even though it's an imaging based study, we're also measuring all these different immune cells that are leaking to and from the barrier into the parenchyma of the brain, in the hope to build a picture of what precision therapy should we be targeting in the immune system. So, it's it's exciting, it's it's a it's it's a big project, it's got a lot of legs, we need international partners. Need to do much more than just small studies that we can do because these are expensive, like we're doing imaging pre and post-treatment, and they're expensive treatment studies, and all the what's called transcriptomics now, which is this idea of looking at the at the all the serological markers, the RNA associated with differentially expressed genes. So, in other words, you know, there are genetic elements in the cell which generate the immune response. Most of these genes may be on and off, just looking at the genes is no longer good enough. So now we look at the genes that are actually active by looking at what's called their transcriptome. And that's a huge area. And we can measure thousands of these things. And we're collaborating with collaborators in Hiroshima in Japan on massive machines that they have, and they're they've got mathematicians looking at this. And that's really expensive. So, there's a lot of work to be done, but I think it's just a it's a in a sense, I'm sort of embarrassed that we haven't done this already. I'm embarrassed on behalf of the of the profession of epileptology - that we have not done this already, you know?
History: why haven’t we done this research already?
07:01 Torie Robinson
Well, for sure, I can very much understand that. And also, I imagine some about half our listeners are people with epilepsy or family members. And I imagine there's a little bit of frustration out there as well. Like, why has this not been looked at? Is it because it's not a sexy topic or are there other factors?
07:18 Colin Doherty
I'm not a conspiracy theorist by any means, but I also understand that there are sometimes, you know, commercial and other things which drive research in a particular direction. But I actually just think it's the way we're all trained. Like I'm as guilty as the next person. Like I'm gonna do this for thirty years and I'm only doing this now. Like you know, we were trained to think about it as an electrical disease. Our our forefathers, our heroes of epileptology, going back to the Queen Square in the in the in the nineteenth century, were telling us it's about electricity, you know? And then, you know, we all train that way and we think about it. And I did my fellowship in in the United States and it was all about electrical waves and you know and electricity is clearly part of it. But there's something else there that that was, you know, hiding in plain sight. And look, our colleagues in the lab have been telling us, listen, this is important. You need to be taking this seriously. And we're going “Don't bother us with that. We're you know, we're mining this electrical hypothesis.”.
08:13 Torie Robinson
Oooo.
Immunologists: work with us!
08:13 Colin Doherty
And there's still work to be done in the electrical hypothesis and still some new drugs coming which have an effect on dampening electrical responses and they will be valuable and I wouldn't turn that off, but we need to have a have a have a decision to go down this route and bring new people in, immunologists and stuff, bring them into the that's what I was hoping to do with this editorial. Like not I mean yes, to speak to my colleagues a little bit, you know, but actually say to immunology guys “Come on in, you know, let's make this a thing now.”, you know?
08:42 Torie Robinson
Well, if we've got, I mean, it depends what paper or source you get, but between 50 and 75 million people with an epilepsy around the world, take 30% of those who, you know, could benefit from this. Hello. That's a lot of people, right?
08:56 Colin Doherty
That's a lot of people, you know?! And even the 10% with the sustained response. I can tell you that to most epileptologists, and if you're a patient who's been through every single drug and has been told “Listen, there's very little else we can do.”, and you've tried the ketogenic diet and you've had a surgical evaluation and you've either had surgery, it hasn't worked, or you've been told surgery won't work, and you've had a VNS in, and all that's been done. And when somebody goes “Well there's nothing else to do really.” and I'm saying “No, no, let's you know, I wouldn't I just don't agree with that, you know. I think we need to look at this.”. And it's not gonna work for everybody. It's not gonna work for everybody, and that's important. but as you say, 30% is a big number.
09:35 Torie Robinson
The immunology is, but I think through COVID (t's virology), it became more widely known of. And I think if we can bring that sort of awareness and knowledge into the epilepsy, that would be quite exciting.
Comparison: cancer and immunology
09:48 Colin Doherty
Yeah, I'm… one of the thoughts I have actually, is a little around what's happened in cancer. You know, cancer has become an immunological disease essentially, you know? I mean, you know, there are now… diseases of cancer which are being cured by either externally bringing in an immune therapy or by stimulating the body's own immune system. Like, you know, the… I don't know if you know about these PD-1 inhibitors, so in cancer of the lung, right? One of the problems with cancer of the lung is that the cancer grows, you know, with sunglasses on. It pretends it's normal tissue and the immune system is asleep around it.
10:27 Torie Robinson
Ohhh.
10:27 Colin Doherty
And that's because it exit it excretes this thing which keeps the immune system sleepy, right? So, what you do is if you give them this PD-1 inhibitor, then it suddenly the immune system wakes up and recognises the lung cancer as a as a foreign body and attacks it. And that's 25% of people now are surviving long-term with lung cancer. That's unbelievable!
10:47 Torie Robinson
That is so cool!
10:49 Colin Doherty
We actually have a fully funded chair in what's called immuno-oncology. You know, and a guy called Patrick Forde who's come from Johns Hopkins and he's the guy who's done those seminal work that's been published in the New England Journal on curing lung cancer. So I think, you know, if cancer is moving into the immune system, you know, we're not we shouldn't be far behind, right? and obviously other I mean, you know, MS has always been an inflammatory, you know, autoimmune disease. Neurodegeneration has always flirted with the immuno hypothesis as well, it hasn't really delivered. You know, there are some new treatments now. Aducanumab is out there for Alzheimer's disease. It's.. I don't think that's the real future. But again, it's ploughing an immunotherapy line. Of course, the immunologists have been telling this for years. They've been telling us “Hey, listen, it's all human disease is all about inflammation!”, and we haven't listened to them. Now I'm listening!
11:42 Torie Robinson
Well, I'm sure diseases aren't… usually aren't all about one thing…
11:46 Colin Doherty
I know, you're right!
11:46 Torie Robinson
…right?! But to leave one potential cause out is just nuts, isn't it? And just think of the suffering and literal deaths of people that could potentially be prevented if we look at immunotherapy. So, for anyone listening, whether it's a clinician, researcher or somebody with an epilepsy, what would you say? What do we need to do?
Clinicians and scientists: work with us!
12:08 Colin Doherty
We need to get the immunologists, the people who live in this world interested in this and they need to be asking you know for serum samples and samples of spinal fluid and start to analyse, you know, the different components of the immune system in the different forms of epilepsy. That's the that's the first thing. The vascular biology people like Matt and his group in in and Chris Greene now in RCSI and Claire Behan who's there, you know we've all cut our teeth on this theory about the blood-brain barrier and epilepsy. Claire actually published that series of cases of surgery, seven people who had terrible blood-brain barrier dysfunction then had surgery and the barrier then it improved itself.
12:50 Torie Robinson
Mmm.
12:50 Colin Doherty
So, there's a bit of work to be done on the blood-brain barrier people. So, it's kind of bringing all these people together and then we need to do some clinical trials. I mean clinical trials, this, as you know, this big gap between the look why hasn't there been a proper study of steroids and epilepsy? And that gap… you know, when we come up with the hypothesis because it costs so much to do clinical trials and… but I think there are funding agencies now that are open to this idea of investigator led studies and we need to get people into clinical trials and start really understanding this better. And then, like, so, in my envisagements for the future, in the next 5 to 10 years, there will be a number of precision therapies purely immune-based for people with epilepsy. We will be able to stratify people into the people who will respond to immunotherapy and they will not get antiepileptic drugs. They will not be on antiepileptic drugs. They will get treated with an immune therapy. They may need to have it intermittently, but imagine that. That’s an interesting future isn’t it?!
People with an epilepsy and carers: work with us!
13:51 Torie Robinson
Exciting, think is the word, rather than just interesting. Exciting. And for people who have an epilepsy, specifically refractory epilepsy, what can they do to support this work, this research? I mean, do we jump on the government or…
14:07 Colin Doherty
Well I think I think the more what I what I would like is that when people go in to see their doctor - and it really has to be in in a tertiary epilepsy centre - I don't think people in their… in like their GPs and stuff can be expected to prescribe people immunotherapy, do you know what I mean?
14:23 Torie Robinson
Haha.
14:24 Colin Doherty
But if they're if they're attending a tertiary or a quaternary specialist epilepsy centre, I think they need to ask their doctor when they're having that conversation, as many people have had, “Well, we've kinda done everything we can.”, you know, that's a kinda hard conversation to have. And, you know, even the most optimistic thing is “We're gonna revisit some of these drugs that you tried before and in different combinations…” and when somebody says “Well, actually, can I not try this immunotherapy? You know, you know, like what else have I got to lose? I know there's still a lot more to learn about it, but you know what I mean? Is there is there something to be said for giving immunotherapy?”. And I think that will get a lot of my colleagues on the same page. They'll be coming to our publications and going “Oh yeah, this is interesting.”. I know if it was my family, or if it was me, and again, setting aside all the problems that steroids would have, if I had tried everything and epilepsy was defining my life now, I'd be going, I'd be asking for intravenous steroids. And I would take all the, you know, all the caveats about the safety issues, and sign whatever I needed to sign, but I would be taking it.
Closing thoughts and thanks
15:27 Torie Robinson
Ok. This has left me with way more questions than answers - in a good way! Thank you to Colin for making us - well, myself anyway (!) - truly excited about what future research may discover. Because, imagine: if science discovers more about autoimmune epilepsies that could lead to reducing 30% of people for whom drugs do not control their seizures. And what if it could lead to something preventing the removal of brain tissue in some. What if it made life feel more worth living for those affected in this way? And of course, there is like a nuts, crazy amount of work to do - requiring an equality nuts amount of funding, but keep your eyes on Colin for developments. And a huge thank you to him for being with us on the podcast. See you next time.