Could Immunotherapy Control Seizures? - Prof. Colin Doherty, St James’s Hospital, Ireland
Could the immune system play a bigger role in epilepsy than many of us realise? Prof. Colin Doherty explains how autoimmune epilepsies challenged the traditional view of epilepsy as purely an electrical disorder. He also discusses antibody-negative autoimmune epilepsy, early immunotherapy studies, and why some people with highly refractory epilepsy may respond to steroid treatment. Watch/listen here 👇!
Episode Highlights
The immune system could be part of why some seizures remain uncontrolled.
Early immunotherapy studies produced promising results in some highly refractory epilepsies.
Autoimmune epilepsies may require very different treatment approaches.
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
autoimmune encephalitis
antibody-negative autoimmune epilepsy
immunotherapy
steroids
inflammation
synaptic antibodies
precision medicine
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Trailer
00:00 Colin Doherty
“Work done in in Barcelona and in Philadelphia by scientists found these antibodies directed towards synaptic proteins, and suddenly we realised “Oh my god, this is an epilepsy, which is basically an immune disorder!”. And so that made us go back to all the refractory cases of epilepsy and go, “God, could this be one of those?!”
Intro
00:19 Torie Robinson
For basically forever, doctors have learnt - that epilepsy is mainly down to dodgy electrical activity in the brain. But what if that's only part of the story?! Because what about our immune systems?! Well today I'm joined by Prof. Colin Doherty, who thinks our immune systems may play a way bigger role in epilepsy than many of us realise - especially when seizures aren't controlled by medication, surgery, or other methods.
Not just an “electrical disorder”
00:44 Torie Robinson
For decades, epilepsy has mainly been understood as an “electrical disorder”. So, what made you start questioning whether that explanation was incomplete? And, how did you come across this? And why are you the only person talking about what we're going to speak about?
00:58 Colin Doherty
Right into the controversy!
01:00 Torie Robinson
Of course!
01:01 Colin Doherty
I don't think I'm I don't think I'm the only person talking about it, but I certainly, in a recent editorial I wrote for the journal Immunotherapy, I was trying to articulate why we need a more cohesive approach to this. There is lots of research in the immune system and epilepsy. It goes back decades and decades, you know, but it's never translated into a proper sort of therapeutic modality for an epilepsy. And I just find that a bit amazing because, you know, we have… and I don't think there's a political reason or a financial reason or any other reason for that, except that we have all been trained on this electrical hypothesis. Like, you know, epilepsy, you know, going back to the father of epilepsies, the famous, the great Queen's Square neurologists like Jackson; this was this was an electrical disorder and therefore we all trained in that. We all learnt about reading EEGs and the electrical discharges in the brain, and then we targeted all the all the electrical systems in the brain, the transmitters that transmitted electricity in the brain, and it was kind of electrochemical, right? So, there were chemicals at the bases of that, receptors. And look, it that has been incredibly productive, obviously, and it's given us our full armoury of drugs, right? But I'm hoping to connect with clinicians across the spectrum.
30% still don’t have seizure control
02:19 Colin Doherty
And I've been working in this field for 30 years. We still, and we talk about it all the time, we still have, what is it, 25, maybe even 30% of people who just don't respond to these approaches, right? And that's just the reality. And I don't care how good you know all the precision therapies are coming and how much more we understand about all these electrical receptors and electrochemical changes, we're still have, you know, epilepsy is still a very hard nut to crack. And it's kind of depressing to be… have been a whole career in epilepsy, 30 years, and still be dealing with that large figure of, you know “What are we doing for these people? You know?”. And, you know, most of the scientists don't have to sit in clinics and go to people “Well, yeah, we've given you all this stuff and you know, you've tried everything now.
Epilepsy surgery
03:06 Colin Doherty
And then we go to surgery, obviously.”. Like, I think the more we learn, - and I have great relationships and I love all my surgical colleagues - but they would also agree that when we reach a point where we're never having to take a person's part of a person's brain out, surely that's the goal, right? The surgery, you know, nobody wants to be doing that. Even the surgeon…
03:29 Torie Robinson
Haha! Right!
03:29 Colin Doherty
…doesn't want to be doing that, right? But at the moment it's the only thing that really for definite cures people.
03:35 Torie Robinson
Well, in some cases, right? Not even in all cases!
03:37 Colin Doherty
Not even in all those cases, exactly! But you know, if somebody says “I want to be cured by this.” you can really only offer them surgery. And even then, as you say, we've still got to warn them, look, even under the best circumstances, but all the best, you've got the scar there and it's in the right area, and the EEGs is coming from there, and all that works; we all still find out, you know, six months later, actually the seizures have come back, you know.
04:00 Torie Robinson
And there can be the other effect of the surgery too, right? The impact on cognition in many cases, especially temporal lobe, right? Which is the most common. It's huge. It's not just about the impact, potentially positive impact on lack of seizures, but actually the impact on cognition. When somebody says to you “You're taking out that whole thing. You know, we've got this little scar.” but you're gonna take all of that out. Surely am I not using that bit, you know? And like the you know, the common thought is, well, you know what “Most of the functions have moved out to other areas and it's just a bit like an empty you know.” - but really? You know, people who've had surgery will tell you “No, that's not right. That's not true.
04:35 Torie Robinson
Mm-hmm!
04:35 Colin Doherty
Do you know what I mean? And they know that there's stuff missing that they, you know, proclivities and capacities and skills that they had that they no longer have. So, surgery, while albeit curative now in the best-case scenario, surely, we need to be looking…
Immunotherapy for epilepsy
04:54 Colin Doherty
And look, none of my colleagues would disagree, but they I think, certainly, maybe before I got into this area, we were always looking to the next drug that was still dealing with the same set of criteria; where we need to dampen down the electrical response, we need to target the electrochemical receptors, you know, all that sort of stuff. So, where did this suddenly think of immunotherapy? And I think there's two things that occurred to me. One is that we found this form of epilepsy, which sometimes is chronic but often very acute, which is definitely related to these synaptic antibodies. So, it's autoimmune encephalitis. And that's a fascinating condition, which I think has been around for centuries. We never really understood it and work done in in Barcelona and in Philadelphia by scientists found these antibodies directed towards synaptic proteins, and suddenly we realised “Oh my god, this is an epilepsy, which is basically an immune disorder!”. And so that made us go back to all the refractory cases of epilepsy and go, “God, could this be one of those?!”! And we looked for the antibodies, we never found them, and so then we abandoned again. Okay, so that's not autoimmune. This one is, and we know now if you treat that with immunotherapy… if you treat it with just anti-epileptics, you don't get anywhere. They become refractory, they're the worst cases of epilepsy. You have to treat it with immunotherapy, and you have to do it early. This is really important.
06:16 Torie Robinson
We've had a wonderful guest from Ireland, a neurologist, who had this type of epilepsy and needed exactly that treatment, right?
06:24 Colin Doherty
I know that neurologist, yeah, exactly. Yeah. And yeah.
06:26 Torie Robinson
Yeah, this is real life, can happen to anyone!
Immunotherapy cases
06:28 Colin Doherty
And so now when we hear a story of the emergence of this, I mean one of the last cases I dealt with; we got the story a per person had been admitted to a secondary hospital a hundred miles away. We got the therapy started in that hospital. We got them transferred because they were an ICU case. They're often very, very unwell. But we knew instinctively, even without the antibody test, we knew this was it. And then having started the immunotherapy early, she had a very good outcome. So, so this was great, right? So now we have these antibodies. And yeah, we'll go to the other epilepsies, and we'll check “Oh, no, we don't have the antibodies.”, and then someone says “Well, you know what every week, every year, there's more and more new antibodies.”. So suddenly you've got a panel of 10 or 12 antibodies for the synapses for the synaptic proteins, and you're checking those. And then “Okay, that's negative.”. And then it began to sort of emerge that okay: this does not have an antibody (that we can find!) but it's behaving very like an immunological… it's like very much like the autoimmune encephalitis. And then we treat those and in fact they get better as well. So suddenly we have got this thing called antibody negative autoimmune epilepsy. Okay? And so, okay, so that's interesting. And so that's sort of saying, well we haven't seen an antibody, but we expect somebody, some clever person's gonna find one. So that was all bubbling around in the last five years. So, so maybe seven to… five to seven years, right? So then about… around that time, I said to my colleagues, we were in St. James's and we were dealing with all these highly refractory epilepsies… by the way, people for whom surgery was not an option, got bilateral discharges, they weren't gonna have surgery, or they failed surgery, and they'd obviously been through all the medicines, and we said “Look, is there a case to be made to say (and I still had that mode of thinking) maybe there's an antibody somewhere here, you know, why don't we just give them immunotherapy?” - what we call “empirically” (that idea that you don't have the definite evidence but you're doing it because there's nothing else to do, nothing else to lose.). Talk about the dangers maybe of immune therapy in a while also, but why not try this, you know, as a last resort?
08:36 Torie Robinson
We're desperate basically, right? If you don't have any other choice, you go for it.
08:39 Colin Doherty
Exactly. We'd say “What we'll do is when we do this, we'll make sure we'll see of what characteristics they all have in common.”. Because I was sure we're gonna find a few antibodies that we hadn't suspected they had, and we're gonna do a lumbar puncture and we're gonna do serological testing and all that. Well, we did about thirty-three of these cases and we had a spectacular response in about a third of them within the first month. Right? And no antibodies in any of them.
09:05 Torie Robinson
And by spectacular, what do you mean, exactly?
09:07 Colin Doherty
I'm talking about going seizure-free initially for an extended period. Now, six months later, some of them had reverted back and we had a prolonged response in about 10% of them. 9%. So, one in ten. Now look, for people like me who deal with, you know, our clinics are full of people that we've tried everything with, that's still a very, very viable option. And there's something about that initial response of a third that we have to understand what was going on there as well. We were giving the steroids (which is the standard immunotherapy treatment), we were giving that intravenously over a 3-to-4-day period, and you just can't be doing that forever. I mean there's serious long-term problems with that. But we had an initial very, very good response in about a third of those patients. So, something the steroids were doing early was working. And then in some of them, in about a third of those, which it ended up being 10% of the total, we had a prolonged response.
10:06 Torie Robinson
And by prolonged, how long is that?
10:08 Colin Doherty
I mean as in they're seizure free still.
10:09 Torie Robinson
Like, oh my god, and how long has that been?
10:11 Colin Doherty
It's been, well, the first patient we enrolled was probably about three and a half years ago.
10:15 Torie Robinson
Goodness. But then, why, do we know why some of them six months later started having seizures again?
Needing an immunotherapy program
10:20 Colin Doherty
We don't. So, this is why I think what I'm calling for here is let's get you know, let's get a proper immunotherapy and program around this! If you want my theory and the one that I would test, I've got two theories. One is that there's a cellular immune response that we don't really understand. What I mean by that is, you know, immunological diseases are often antibody mediated, you know, B cell mediated or T cell mediated. And in the concussion work, for instance, we know that there's quite a huge amount of T cell activity. There's also this immunological agent called complement release during brain trauma. So, there's a lot of immunological stuff going on in the brains of people with epilepsy that is that is not what we call humoral. It's nothing to do with antibodies.
11:08 Torie Robinson
Okay.
11:08 Colin Doherty
And by the way, there's nearly a century of data on this! Like, there's been hundreds of animal studies looking at this, you know. And why not?! Of course! You know, like, injury in the brain of any sort, inflammation is the response. That's the natural response of the brain.
11:24 Torie Robinson
Yeah!
11:24 Colin Doherty
And in in a sophisticated animal like a human, there are both humoral and cellular responses, there are… the whole immune system comes with all the different aspects of its cells and antibodies respond. And all we've been doing in the clinic is being worried about the antibody response! And I said, Well look, a hundred years of data saying that there's a cellular response and then we looked at say “Well, god, we did this steroid treatment, I mean surely somebody else did this?!” and we looked at the literature, we published it with a medical student at the time, published a review of all the work in the use of steroids in epilepsy, and we found only 4 studies! Four! Which is kind of incredible given the amount of work in the lab.
12:08 Torie Robinson
That's nuts, nuts, right?
Steroids and profit
12:10 Colin Doherty
And by the way, the quality of those was so poor because they were giving steroids along with some other agents, and you couldn't tell… there wasn't re wasn't really a good study of steroids in epilepsy. Not single one! Now look, there could be a commercial issue there, Torie, to be kind of controversial, right?
12:27 Torie Robinson
Mmm.
12:28 Colin Doherty
So, steroids of course were discovered, I think, in the 1940s and they began to be used in the 1950s clinically, and so there's no patent on those. There's no money to be made on given people high dose of steroids, right? So, there's very little interest from a pharma company in running a study. Now, there could have been a what we call an investigator led study, like someone like me…
12:45 Torie Robinson
Mmm.
12:45 Colin Doherty
..could run a study. That study, a placebo control study, needs to be done, I think, in my view. That's the first thing. So why don't we just do that? The reason I don't think we should rush into that is because I think that there are significant issues about steroids in terms of their safety profile, which would mean even if you found a placebo-controlled, you know, a response at a proper control trial, you'd still find it very hard for people worldwide to consider using steroids long term.
Impacts of steroids - safety
13:16 Torie Robinson
For people who aren't familiar with steroids, could you just give us an overview of what the impacts of them can be?
13:21 Colin Doherty
So, steroids are, first of all, a naturally occurring hormone in the human body, and you have a very small amount of steroid always in your body, and the steroids are responsible for your stress immune response. They're the things which help when you, you know, go over on your ankle and your your ankle swells up, when you develop a cough, and a bit of a respiratory tract infection, your steroids are helping you respond to that by modulating the immune system. If you really want to dampen it down, if you want to turn it off temporarily, you can give large doses of steroids. And they're a very, very… it's like a blunderbus, it's like a, you know, a shotgun. There's no precision, it just shuts down the immune system, particularly the T cell mediated, the cellular immune response is particularly turned down. And so, what happens then, obviously you're susceptible to other things that are going on that you need your immune response for is now off, so suddenly you're now an immune compromised patient. And these were the patients we worried about who were in during COVID (if you had been on steroids for whatever reason). And then people who are on long term steroids, there's various very significant metabolic effects. People put on weight, they have… their blood pressure goes up, their blood sugar maintenance goes off the rails, you can turn person into a diabetic temporarily with steroids, you can thin their skin, they have easy bruising, their gums start to fall apart, so there's a… and hair starts to fall out. I mean, people in long-term steroids will tell you they're awful.
Closing thoughts & thanks
14:55 Torie Robinson
So, for decades we’ve been thinking about epilepsy, generally, primarily, as an electrical disorder. Like, zaps of electricity are the problem. But really? It is not that simple. And we know this! And the whole immune system faffing about with our brains - it’s wild - but fascinating! We’ve got part 2 with Colin next week - where he’s going to go into his early research findings, the blood brain barrier (which we have an episode on - link below!), and what we need to do (us lot, you and I, we(!)) what we need to do to get things moving on the research front to help those who’s epilepsy may be about their immune systems! Thank you so much to Colin for today and for having us really think outside of the regular epilepsy box! See you next week for part 2!