SUDEP Caused by Lack Of Air Hunger? - Brian Dlouhy, Human Brain Research Lab, University of Iowa Health Care, USA
Could the amygdala be responsible for lack of air hunger and SUDEP? Learn about the research from neurosurgeon and researcher Brian Dlouhy.
Reported by Torie Robinson | Edited and produced by Pete Allen
Podcast:
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00:00 Brian Dlouhy
“What we're excited about it is potential, hopefully leads down the path of a prevention for SUDEP. “
00:05 Torie Robinson
Fellow homo sapiens! Welcome back to Epilepsy Sparks Insights.
And our first episode, actually of 2024. We don’t mess around (!), so today we’re chatting to epilepsy neurosurgeon Dlouhy about his research into how SUDEP (Sudden Unexpected Death in Epilepsy) could be caused by a brain not feeling “air hunger” or the need to breathe following amygdala seizures. So, rather than SUDEP being potentially caused by cardiac issues, maybe it’s respiratory dysfunction?!
00:45 Brian Dlouhy
My name is Brian Dlouhy. I am a neurosurgeon and a scientist as well, a researcher. I'm currently at the University of Iowa, associate professor there. I did my medical school training at NYU, New York University School of Medicine. Then I went to University of Iowa for my residency in neurosurgery. I did a post-doctoral fellowship there in epilepsy, where I started focusing on understanding SUDEP [Sudden Unexpected Death in Epilepsy] and how the brain controls breathing. And I did a focused fellowship in paediatric neurosurgery. So I do mostly paediatric neurosurgery. And I have a clinical interest in paediatric epilepsy surgery. And then again, my research is mostly epilepsy and SUDEP.
01:25 Torie Robinson
And what led you to this sphere? SUDEP is something that often scares a lot of people. I think we should all be talking about it. But tell us what led you to that part of the epilepsies.
01:35 Brian Dlouhy
I've always been interested in research and understanding how the brain functions. The, you know, and I just kind of followed the science and the data that I was gathering. I was actually working on emotion and fear and panic and anxiety and understanding how the brain processes that and how we as humans integrate, you know, and how the, what areas of the brain then kind of control those, those perceptions that we have in those, really in those conditions, those disorders. And that led me down a path of looking at breathing control. And then I kind of combined that with human data and epilepsy. And it all just kind of, we came to this hypothesis, yeah, all kind of together kind of serendipity and this hypothesis that there may be areas in the brain that control breathing during seizures, and that's what leads to apnea during seizures and then pseudo [seizures].
02:37 Torie Robinson
So your recent paper, I believe it's the one that “Failure to breathe persists without air hunger or alarm following amygdala seizures”.
02:44 Brian Dlouhy
Yeah, that's it.
02:45 Torie Robinson
Perfect. Tell us about that, because this, I honestly, this is complete coincidence: I was talking to somebody else about SUDEP and breathing (or not breathing) at the same time. So this comes at like a really cool moment for myself. But tell us about your work and what you discovered in this.
03:00 Brian Dlouhy
The, so, um, the, we've been working on this, I would say for like - and we have, you know, this is our third kind of paper in a row on this - but probably the last decade of the last 10 years. The, um, a lot of data came out like kind of early 2010s that suggested that, you know, SUDEP was probably more respiratory, you know, dysfunction after a seizure or during a seizure, um, rather than cardiac. Um, and, but the, really the mechanisms, you know, underlying how a seizure causes loss of breathing were really unknown. And so then we started studying our epilepsy patients, right? So we studied them and we're studying my surgical patients (these are the patients that get implanted with electrodes to identify their seizure focus). And the goal there was to record their seizure activity and record their breathing at the same time they're having seizures. And at the same time that we’re going to functionally map their brain by electrically stimulating different parts of the brain to understand what their motor system is, their sensory system and their respiratory system, what controls breathing. And interestingly, we found that when seizures spread to the amygdala - or when we electrically stimulate (and it's the specific site in the amygdala, not the whole amygdala, and that's key), then patients will stop breathing. And really we had no understanding of how this kind of occurred before that. It was thought that maybe, you know, seizures somehow, you know, affected the brainstem. But really how they did that was really unknown. So the amygdala seemed to be that kind of key structure. Interestingly, you know, and over time, I thought that there'd be many other sites and we'd be able to kind of create this respiratory kind of homunculus or network in the brain, and there'd be many sites that would inhibit breathing, but we've only really found this specific area in the amygdala so far today. Now that may be other structures, but that's what we're kind of honing in on, just because it seems to be such a critical structure. It just has a potent ability to inhibit breathing in humans.
So we've done this in adults. We did this in even a person without epilepsy. So this function of the amygdala is probably in all of us. And we all have this, the amygdala in all of us probably inhibits breathing in for different purposes, physiological purposes. But seizures hijacked that area then to cause apnea during seizures. And so we did that in adults, we did that in kids, again, patients without epilepsy. We've all seen, found the same effect. We've done this now as young as two years of age in different, even different epileptic syndromes: tuberous sclerosis, all different types of epilepsy, and temporal epilepsy, frontal lobe epilepsy, generalised epilepsy, and so forth.
Our latest paper and what was so novel about it and what we're excited about it is potential, hopefully [it] leads down the path of a prevention for SUDEP in patients with intractable epilepsy is this finding that in some patients, when seizures spread to the amygdala they not only have apnea during a seizure but that apnea then persists even after the seizure ends. And it can persist for even up to 15 minutes in what we saw in some patients. We'll have intermittent breaths but in between these breaths might be 20 seconds of apnea, right. And in the patients that we studied, right, there are 5 out of 20 that we found this effect. The, you know, there'll be this apnea that almost gets longer and longer and longer after the seizure. And then in these patients, then they're able to recover. And you can see this kind of slow recovery where, you know, they start breathing a little bit more and a little bit more regular, and then finally they just, they, they take off and then become regular again. And it varied kind of on the timing in different patients.
Interestingly, we could also stimulate the amygdala and even a smaller site in the amygdala and find a similar effect in 5 of the 20 patients where when we’d stimulate, they'd cause apnea, but then the apnea then would persist even longer after the stimulation ended. So, that was helpful because it really kind of pinpointed this amygdala site and we can map it. And we find what kind of what nuclei are in this, in the human amygdala that are involved in this circuit.
And interestingly, in all of these patients that we study, they're not aware that they've stopped breathing. And we think that's part of this really kind of critical, you know, part of the critical mechanism underlying SUDEP - is that not only do seizures spread to the amygdala and cause loss of breathing or apnea, but it also inhibits….that amygdala structure is inhibiting that air hunger that you would typically have with such loss of breathing, right? Most people, you know, if you hold your breath for even just a couple of seconds, you're aware of it. These patients, they're completely unaware of it. So it's that kind of, they're not, you know, when SUDEP is that thing where people, you know, they die alone in bed - it's that scary phenomena of just, there's no alarm bells that go off, right? No one's alerted, everyone's like, well “Geez, how did this happen?”, you know, you know, there's no… “We didn't know!”. I mean, no one, you know, there was no cry for help, right? And that's because those alarm bells aren't going off in the individual. And so we think it's like this two-hit hypothesis, that's what we have: this two-hit hypothesis that occurs that ultimately then leads to SUDEP.
So hopefully, you know, we've been able to kind of map this circuit to the brainstem using the unique tools like imaging and MRI scanner while we stimulate the brain, electrically stimulate the amygdala. And so we can find the circuit. We've been able to kind of tease out mechanistically what areas the brainstem we think are affected and that are controlled breathing by studying patients in the operating room as well. And we find that there's this site - well that site in the amygdala also can inhibit breathing - but also appears to inhibit like this chemosensory function that controls breathing as well. So we think that it's inhibiting like multiple pathways in breathing control as well as our ability to sense breathing. So it's also inhibiting kind of the interoception; our internal sensation and integration of breathing signals up to the brain and tells us “Hey, look, we're not breathing normally or we're not breathing at all, do something different”.
So we think that these patients that have this kind of more persistent loss of breathing and that persistent kind of loss of the air hunger are the ones that are probably higher risk of SUDEP.
09:31 Torie Robinson
And do we know why these people might have less of that hunger? Could it be a genetic thing or what? Do you know?
09:38 Brian Dlouhy
So that's the question. Why do some patients, I guess in general - because only 5 of the 20, right? Everyone, everyone has this apnea when we simulate the amygdala. Everyone has apnea when seizures go to the amygdala. Why is it that in some patients it persists, right? It puts them at a higher risk. And we think that this is some kind of, you know, epileptogenesis, repeated seizures that are changing the networks in the amygdala, and that circuit from the amygdala to the brainstem that plays a role in that inhibition of breathing - as well as the other circuits that go to other parts of the brain, like the insula, which are involved in air hunger. So we think that these patients probably, they may have a genetic risk factor for this as well. They, and maybe the types of seizures they've had, and that also may play a role, right?
So some genetic components, there's this other component where probably repeated seizures also has a role in changing this network and the structure in the amygdala, but that network to the brain and we think it's kind of critical.
10:42 Torie Robinson
Does this kind of mean that perhaps if … the longer a person has refractory epilepsy, potentially, the higher their risk of SUDEP may be?
10:49 Brian Dlouhy
The data would bear that out too in the literature. And we see that, right? So it's intractable epilepsy patients. And you will see this occasionally, you know, first-time seizure or even like, we haven't had a seizure in a long time, and they have that. So there may be some other, you know, components to it that we don't understand just yet, but some genetic components.
And there's definitely an environmental component, right? You know, when patients are in bed invariably, right? That it's at, you know, at nighttime, right, in bed, and they're found face down prone in bed.
So there's other environmental components as well. People aren't dying from SUDEP, right, out in public, for example, right? The thought there, obviously, someone has a seizure in public, they get help, right, and that's witnessed. And so that's the key there.
But alone in bed, the person is by themselves, so then there’s, they have no alarm going off, that their breathing has changed. And there may be other, other roles of the sleep that makes breathing more dependent on different mechanisms that are really inhibited from that seizure.
11:48 Torie Robinson
So what are next steps in your research? You have collated this excellent information, all this data, and come to these conclusions, but what are your next steps?
11:58 Brian Dlouhy
We, um, want to better understand the circuit as well from the amygdala to the brainstem. We also want to really kind of test the hypothesis that this amygdala, that the amygdala right is really critical, um, for this pathway, and for, for SUDEP. Um, and so, you know, doing things like ablation in the amygdala and then TET, and then seeing if that affects, um, breathing after a seizure, and see if it stops that seizure-induced apnea or the persistent apnea after seizure ends. And so that's one area that we're exploring and we're very excited about.
One other thing is that, you know, we're interested in looking at, using this as a biomarker too, we wanna develop a platform where we can use different tools, investigations, whether it's respiratory measures just at the bedside or an outpatient clinical setting, as well as imaging tools like MRI or functional imaging, as well as then possible mapping of the brain to create a risk profile, as well as then the clinical demographics of patients, combine all that together to, you know, identify patients that are high risk, right? So we can create this risk profile for patients to say “This patient seems to be at high risk.”, you know, so everyone who has epilepsy could undergo this, right? And they could put them into this kind of clinical, kind of profile. I think, you know, no one, everyone's… if you have epilepsy, if you have intractable epilepsy, you're afraid of SUDEP. I think rightfully so, right? And it's… and trying to alleviate some of that concern; it would be very helpful. And then also, you know, by saying “Hey, you're lower risk”, you know, you're less concerned. I think that would help people, number one.
I think identifying patients at high risk, then would say “Hey, look, you're high risk, you know, hey, you know, we are trying to develop some preventative strategies, I think, therapeutically to prevent SUDEP in patients.” And, you know, I think those are the things that we're thinking of, and could those patients then enroll maybe in a clinical trial or something that we're interested in doing in the future. And by identifying the high-risk patients, then we identified that patient population that may consider something like that.
14:12 Torie Robinson
Thank you to Brian for researching SUDEP causes and helping so many of us with epilepsy to have hope for the future when it comes to further minimising SUDEP risk. Again, if you haven’t already, don’t forget to like, comment, and subscribe, and see you next time!
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Brian Dlouhy is an Associate Professor of Neurosurgery and Associate Professor of Pediatrics at the University of Iowa Health Care in the USA.
Brian’s basic science and translational research lab focuses on understanding the mechanisms of Sudden Unexpected Death in Epilepsy (SUDEP). He uses animal models and studies children and adults with epilepsy to identify the neural networks in the brain that influence breathing and to better understand how breathing is inhibited during seizures.
In the pediatric human brain research lab, the group studies normal brain function (speech, language, hearing, emotion) and brain physiology of children with epilepsy. This research will allow a better understanding of how the child's brain is organised, how brain function develops in humans, and give better insight into treating children with epilepsy. Brian also has a clinical interest and research interest in understanding the pathophysiology, genetics, and proper treatment strategies for Chiari disorders and disorders of the craniovertebral junction (CVJ).
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