Seizure Diaries Episode 5 | How Brain Biomarkers Are Shaping the Future of Epilepsy Treatment

Kent Leyde  0:01  

Hi, everybody. In this episode, we’re going to be talking with Greg Worrell, who’s Professor of Neurology and Physiology and Biomedical Engineering at Mayo Clinic. Cadence and Mayo Clinic work really closely together in partnership to develop our biomarker targeted neuromodulation system, the system that we hope will ultimately bring seizure freedom to a lot of folks who are suffering from drug resistant epilepsy.

Doug Sheffield  0:25  

We discuss the unique challenges epilepsy presents for research and treatment, and we talk about how Mayo’s emphasis on research and collaboration in service of its patients has helped foster an environment of innovation.

Kent Leyde  0:38  

And we also get to dig into our own origin story as well.

Doug Sheffield  0:42  

And we’re going to jump in with some explanations and context from time to time, because Kent gets super nerdy.

Kent Leyde  0:48  

I resemble that remark, but so do you.

Doug Sheffield  0:50  

Fair.

Kent Leyde  0:51  

I’m Kent Leyde, CEO of Cadence Neuroscience.

Doug Sheffield  0:56  

And I’m Doug Sheffield, Chief Scientific Officer.

Kent Leyde  0:59  

You’re listening to Seizure Diaries, where we explore all things epilepsy and explore the latest developments in epilepsy science and therapy.

Doug Sheffield  1:05  

Together, and with expert guests, we discuss the impact of epilepsy and the work being done by Cadence Neuroscience and others, with the ultimate goal that every person lives a seizure-free life. Welcome. 

Kent Leyde  1:18  

Well, Doug, here we are again.

Doug Sheffield  1:23  

It’s amazing how time flies.

Kent Leyde  1:25  

Well, we have a guest we’re happy to introduce our podcast audience today, Dr. Greg Worrell, who we’ve known for a long time. Welcome, Greg. 

Greg Worrell  1:34  

Hello. It’s good to see you guys. 

Kent Leyde  1:35  

Good to see you. We work closely with Greg all the time and his team at Mayo, so we’re actually all pretty close here, So… So Greg, I thought we might go from the general to the specific today, maybe starting by having you help educate our audience about Mayo Clinic and what a special place it is. And then maybe talk more about the neurology and epilepsy practice in your lab, and then maybe we could shift gears and get down to the Cadence program and how that came to be at Mayo. That sound okay?

Greg Worrell  2:09  

Yeah, that sounds good. Love to do it. Mayo Clinic. I came here in 1996, I still remember arriving. I came here because of interested in neurology. I knew that I would be doing what I’m doing today in the future, but I knew what is foundational for that is a deep clinical expertise. And I looked across the country, and I really liked this place. My wife’s from South Carolina. She liked it less. She was like, yeah… 

Kent Leyde  2:42  

What time of year did you visit?

Greg Worrell  2:43  

That was actually January. 

Kent Leyde  2:45  

Yikes.

Greg Worrell  2:46  

But, but I said, you know, this is four short years. After that, I’ll always be Mayo trained. We’ll go wherever. So… 

Kent Leyde  2:55  

1996.

Greg Worrell  2:56  

Yeah. But it really is a special place. And I came here and I loved it. Loved the ethos that it’s really geared around the patient. There’s some deep science and technology, but still, I think Mayo’s got it right. That’s all in the pursuit of the patient. So if you can do foundational work, yeah, that’s fantastic. Make sure it’s actually going to affect patients. I thought that was an amazing approach. I stayed for four years, which later became almost 30 years now, and I grew up a technology guy. You know, I like gadgets, widgets, math, science, and I saw the opportunity here, and in particular in epilepsy, to really bring that to bear, to hopefully do something impactful for patients.

Doug Sheffield  3:47  

Can you share a little bit more about that journey? You had a very different path that I think has prepared you really, really well for what you’re doing today, and I think our listeners would love to hear that story.

Greg Worrell  3:59  

Now I tell that story to upcoming residents, fellows, graduate students, medical students, as the path that takes the absolute longest to actually get to where you want to go. I was in pre med for two weeks as a undergraduate when I came in, but I just really discovered — I think it was largely in physics and engineering and science — wow, what you can actually describe and understand in natural phenomena. This is just amazing. 

Greg Worrell  4:34

College really just opened a whole new spectrum of that. So I ended up in physics, like just an amazing history of that science and what you can do and what you can understand. That really just kept me enthused and excited. But I wanted to get out and make things and do things, so I took a first job was at General Dynamics, an aircraft company doing low observable radar cross section, which was totally cool. Loved it. Lot of fun. 

Greg Worrell  5:08

But yeah, after five years, I got this somewhat crazy idea that I was going to go to medical school and apply technology to medicine. You know, reading Scientific American, hey, MRI machines. Look at those pictures of the brain. I could do that. Yeah. 

Kent Leyde  5:23  

That’s a very physics-oriented instrument, right? It’s all about the physics. So there’s a natural bridge there.

Greg Worrell  5:31  

Yeah, and I still say to this day in epilepsy, of course, drugs are very important, but if you ask for drug-resistant epilepsy, let’s say, what’s the most most important discovery application? It’s imaging.

Kent Leyde  5:46  

Right.

Greg Worrell  5:47  

So, MRI imaging, I mean, it just, I mean, it changed all of neurology, but it’s very impactful for epilepsy. So I went to medical school, kind of a funny I thought, well, it’s only four years, I can stand on my head for four years. That’s all it takes. I didn’t even understand that you have to do residency then fellowship, but probably best I didn’t know that. So anyways, I went to University of Texas in Galveston, got great medical training, then residency and fellowship. Did a year at UPenn. That was a lot of fun with a colleague of all of Doug and Kent and I, Brian Litt and Mark Dichter. Was a fantastic year. 

Kent Leyde  6:26  

Fantastic team. Yeah. 

Greg Worrell  6:27  

Working on a really hot topic at that time, early 2000s: seizure forecasting, seizure prediction, you know. 

Kent Leyde  6:36  

Yeah. 

Greg Worrell  6:37  

So.

Kent Leyde  6:37  

Yeah. 

Greg Worrell  6:38  

So early 2000s there was this company that was very interested in building that technology.

Kent Leyde  6:45  

Yeah, then your lab was one of the first places we were in touch with. 

Doug Sheffield  6:49  

And that was a great experience for us. And we’ll get back to that in a little bit. But I think one other thing about Mayo that I find unique. I’ve worked with lots of different universities, lots of big names, but the ability at Mayo to carve out time as a clinician to explore clinical research questions, matters, etc. Tell us a little bit about that environment that allowed you, and then, you know, others to, I would say, politely, maybe stumble into biomarker targeted simulation, but just how, how critical that is for medical advances.

Kent Leyde  7:26  

And that’s kind of a very deep cultural theme at Mayo, right?

Greg Worrell  7:30  

Yeah, you definitely need the team. You need the infrastructure, the opportunity. We started small. Well, I was very interested in electrophysiology. Still am. And the unique opportunity as I saw at that time for us was the fact that we were implanting patients with depth electrodes. We could do micro wires to record units. Local fields on the surface of the brain. 

Greg Worrell  7:57

So that was a unique opportunity that was, was just there that I could just do. But at that time, I didn’t have an animal lab, so it was, you know, all built around this direct human recording, which I think is still very important for the lab. But that was really where we started. And then over over time, you know, we’ve grown, so we’re probably about 15 people now, and really span from doing cellular neurophysiology, electrophysiology to large animals, which was, I think, important for NeuroVista and Cadence. Probably closest working together that Doug and I had around the dogs with epilepsy. So it’s over time expanded, and we’ve had really good people. 

Greg Worrell  8:45

You know, my first primary collaborator here was Matt Stead. He made this really seminal observation that if there are ongoing seizures in a human, and you can find some parameters to actually stop the seizures or prevent them from occurring. So and that all happened at the bedside. Again, that’s we really had a pretty deep infrastructure for bedside recordings before we had all of the small and large animal two-photon image, you know, some of the fancy stuff that we have now. It was really focused around these bedside recordings.

[MUSIC]

Kent Leyde  9:23  

Okay, this is Kent cutting in again. Fair warning, the conversation gets pretty nerdy here. So let’s give a little background before we wade in, and please bear with us, because we’re talking about a pretty huge leap in the development of the therapy, and it’s really interesting stuff, I think. 

Doug Sheffield  9:40  

So first, let’s talk about that seminal observation. Basically, Matt Stead realized that if a human is having seizures, and you can figure out how and where to apply stimulation to the brain, you might be able to stop the seizures or even prevent them from occurring. 

Kent Leyde  9:58  

And, you know, real challenge of epilepsy is that normally, we can’t see what’s happening in the brain during a seizure, or even when a patient is between seizures, the so-called interictal period. And we can’t see what our therapy or our stimulation how it’s affecting the brain. And often, patients have little or no warning to when the next seizure is coming, so we need to be ready to measure the brain normally, but also measure it when it’s acting abnormally, and then measure the effects of the stimulation on the brain. And previously, we didn’t have the technology to do that. Seizures are random events. You can’t set up a repeatable experiment. You know, the key to solving a problem is, first is to really understand root cause and be able to repeat the problem so you can try things.

Doug Sheffield  10:51  

Greg’s lab was fortunate and had in their lab a neurologist, Matt Stead, who had a background in movement disorders. Movement disorders are something that occur continuously, like a continuous tremor. So you have a signal that you can assess the effect of neuromodulation in modifying or stopping that tremor.

Kent Leyde  11:12  

So we have this really unique opportunity. You’ve got people who have got a lot of experience with neuromodulation and epilepsy. You’ve got a patient with a very unique situation in that they’re having seizure activity that can be used as a basis for learning. And then you’ve got Mayo Clinic. And as it turned out, some light bulbs came on, some really important light bulbs, some real insights were made. And this was really kind of the that spark of inspiration and that that’s where Cadence comes from. 

[MUSIC]

Kent Leyde  11:47

We should take a moment and drill down on this one, because we’re really close to the origin story of of Cadence here. A lot of our audience is going to know this, but you know, there’s not a lot of great options for patients if they don’t get seizure control with medications, and then you start looking for other options. And even 10 years ago, there were fewer options than there are today. And it’s improving. And you know, at Cadence, we hope to really improve things a lot further. But from my perspective, it seems like, it was this ability to do what’s right for the patient, be kind of stubborn, try some things, and when the right opportunity presented itself, you guys were able to turn that into some really important discoveries. Maybe you could tell us a little bit about how that all occurred.

Greg Worrell  12:33  

Yeah, I think you know, it’s really a confluence of a number of things. One, we had the infrastructure to do it. Again, talking about these temporary implants in humans were at the bedside. I mean, more and more people do that these days, but there’s still a lot to be learned. But so we had that, that infrastructure, and there were a few other little things that Matt had actually done a fellowship in movement disorders.

Kent Leyde  12:59  

Yeah, he has a stimulation background as well, right? 

Greg Worrell  13:02  

Matt had that paradigm of brain mapping, stimulation mapping, and Parkinson’s disease. You’ve got the biomarker, the physiology, the phenomena right in front of you, the hands tremoring, and you dial in the therapy until, or you move the electrode until the therapy stops the tremors. And so that first patient had persistent, ongoing focal seizures, and with that, he’d occasionally have some leg or arm jerking, but largely it was loss of function because of just continuous electrographic activity. 

Greg Worrell  13:43

He couldn’t walk, and so we had electrodes tiling the brain like we used to, you know, there’s subdural grids on the surface of the brain recording really nice seizures. It was part of the evaluation for resective epilepsy surgery. The hope was we could localize the where the seizures were coming from and safely remove that. We localized where the seizures were coming from, but there was no way you were going to remove it. It was primary motor cortex. 

Kent Leyde  14:12  

So he would have been paralyzed. 

Greg Worrell  14:15  

He would have lost the yeah, lost the use of the arm there. And so while that patient was implanted with the temporary electrodes was an opportunity to explore. It was lots of hours over multiple days, and really remarkable phenomena. The guy so having so many seizures, his leg wouldn’t work. He couldn’t, he couldn’t walk, to being stimulated and actually able to regain function. So there’s a whole ‘nother story in there for the future, not only keeping seizures from happening, but the idea of with modulation, maybe you can even regain functions that you’ve lost. And so with that observation, just, I think we thought more and more deeply about it, pursued the opportunities that we had to test patients. And that’s thankfully, a pretty rare, rare condition.

Kent Leyde  15:10  

Yeah, so that, I mean that which was the key, right? I mean normally, normally, when you solve a problem, step one is you try to get the problem to repeat.

Greg Worrell  15:18  

Yeah.

Kent Leyde  15:19  

And then you can try different things to see if you can figure out what the problem is, and once you understand it, what can I do about it? But with epilepsy, we can’t make seizures in a natural way anyways, repeat when we want them to, and so to have a essentially a patient who happened to be instrumented, and you could also stimulate them and they were having seizure activity, so you had a repeatable experimental setup. You could actually learn, learn from that. And that’s a really rare opportunity. That probably didn’t jump out at you all at once, that you had this ideal learning situation. Did it or did, when did the lights come on?

Greg Worrell  15:59  

I can think of two times with with Matt, working with Matt, where we are like, yeah, that’s important.

Kent Leyde  16:06  

Those moments of inspiration and clarity, right, where you go, wow, this is the part. I mean that I think, I think that’s a real key, too, to the again, the Mayo setup of by putting yourself in the game, by having a research mentality, you pay attention to these things, and when these moments of inspiration happen, it’s, it’s not just a oddball thing that you forget about. It’s like, okay, I can do something with this. This is really interesting. I’m ready. I’m prepared to, you know, move forward. 

Greg Worrell  16:36  

Yeah. The prepared mind.

Kent Leyde  16:38  

Yes. Chance favors the prepared mind. Yeah, exactly. 

[MUSIC]

Kent Leyde  16:43

A real challenge in treating epilepsy with a neuromodulation device or with any therapy for that matter, is that the brain is a big place. Where in the brain should I stimulate? How should I stimulate? What parameters should I stimulate? With epilepsy, we don’t enjoy any method that gives us quick feedback to guide that personalization.

Doug Sheffield  17:05  

The advantage of neuromodulation for treating Parkinson’s is that you have a tremor that you can dial in the correct neuromodulation to stop that tremor. Greg and his lab were looking at what is that persistent marker in epilepsy, that we could do the same thing? And it turns out that it’s the abnormal, interictal EEG that’s persistent, and they use that similar to Parkinson’s. 

[MUSIC]

Doug Sheffield  17:34

I want to go back to that Parkinson’s background that you said Matt brought here. And one of the things that when we’re explaining biomarker targeted stimulation, sort of liken it to the tremor that Parkinson’s patients have when as you dial in, you know, optimal location of leads and parameters. And can you just share a little bit that, again, for the listeners of you know why we use the Parkinson’s paradigm to explain this individual?

Greg Worrell  18:02  

Yeah, I think one of the fundamental challenges in epilepsy is that there are these seemingly random paroxysmal events that happen. They generally don’t leave any signature behind after they’re over. So if you can imagine, if you have, I don’t know, like brain tumors, you give a therapy, you do serial MRIs, and you track the shrinkage, hopefully, of that tumor. 

Greg Worrell  18:29

So all these diseases have chronic biomarkers that you can track and assess the effectiveness on your therapy. And epilepsy is, I think, fundamentally challenging in that way. With epilepsy, you know, you don’t have a true, you don’t have a persistent tremor to that you can dial a therapy into. You don’t have a way of determining whether the stimulation you’re giving is working until it fails, until you have another seizure. And, I mean, that’s the paradigm we have, you know, in current epilepsy, but that’s not a good paradigm. 

Greg Worrell  19:08

So you really need a biomarker that you can track that is a good surrogate for the tendency to have seizures. So after that index case of biomarker targeted therapy that Matt delivered for a patient was just having a focal, continuous seizure with leg and hand dysfunction. You know, where do you go from there? Because, again, that’s a rare entity. So if you’re going to deliver your therapy, what are you going to track? Obviously, it’s a whole spectrum of engineering challenges for tracking changes, and we’ve always had a deep interest in electrophysiology. 

Greg Worrell  19:49 

One of the fundamental primary markers, biomarkers of epilepsy is the electrophysiology. When the brain’s not having seizures, you still see abnormalities. Electrophysiologic abnormalities. So the idea, could you use those electrophysiologic markers as a surrogate? What you really want to treat are seizures, right? But you don’t want to wait months and months and all the challenges of collecting them and patients’ difficulties with reporting and stuff. But so could you use those electrophysiologic biomarkers as a surrogate for seizures. 

Greg Worrell  20:23

And there’s a couple of steps there. One, is there an association with, let’s just call it irritable brain activity, or interictal spikes, interictal meaning it’s the time in between seizures. All people with brain that generates seizures also creates these interictal spikes, are those directly correlated with seizures? Does suppression of those markers portend suppression of seizures? So lots of lots of questions there, but that was the direction, and there were a number of engineering challenges. It just so happened we knew some really good engineers that might be interested in this problem.

Kent Leyde  21:04  

We were just passing by. 

Greg Worrell  21:08  

Because when you’re stimulating, if you’re stimulating with high frequency stimulation, which is one of the primary, if, I guess, really the primary way to stimulate the brain, say, you know, over over 120 hertz or so, it totally obscures the electrophysiology. So if you’re trying to use these very low signal, fairly low signal to noise resolution recordings as a biomarker to see if, when you stimulate, you suppress those, well, if you can’t see that biomarker through your stimulation, you know, that’s a challenge. You asked me one question, Doug, and I’ve, I’ve gone on a bit of a tangent here, but….

Doug Sheffield  21:48  

This is great. This is great. Kent always uses a quote. What’s your quote? I love it. If you can’t measure it, you can’t what?

Kent Leyde  21:55  

I’m not going to get it exactly right. But if you can’t measure it, you can’t improve it. Yeah, it’s the basic idea. And we’ve got a tremendous body of experience at interpreting the electrical signals that come from the brain. EEG, you know, that first started 100 years ago, or something, our problem is, is those are kind of small signals. Like, you know, if we put little electrodes on the brain, the signals, you know, maybe a 1,000th of a volt,

Greg Worrell  22:26  

Yeah.

Kent Leyde  22:26  

So it’s, it’s not real big, and the signals that we use to simulate the brain are 1000s of times larger, which makes it really hard to see what the brain is doing. So that’s been our engineering contribution, is to, is to help folks, help epileptologists, watch what the brain is doing using their normal EEG interpretation skills, watch what the brain is doing in response to stimulation and the not-so-fancy version of the idea is, well, maybe we should make the brain look more normal. Maybe that’s a good thing.

Doug Sheffield  22:59  

Maybe this is a good time, Kent, to just to visit before we get further into the Cadence story, a little bit more about the NeuroVista story, that journey that we had with Greg, where, again, I’m a believer that life prepares you for what you’re doing right now. We were actually with Greg in pre-clinical models. And, you know, looking at what are those signals that are associated with, in this case, it was the animal model having a seizure, and how that really helped prepare us for what we’re doing right now, with Cadence. 

Doug Sheffield  23:32

You know, we had to have excellent recordings of these animals and and also understand what are those interictal events that are important, right? That precede a seizure. And you were intimately involved with NeuroVista, and that research and sort of was like our dating stage with Mayo that got us to this current marriage. So maybe a little bit about that experience, you know, who would you go to and ask to help take the Mayo therapy and commercialize it? How did that NeuroVista experience guide some of your thoughts about biomarker targeted simulation?

Greg Worrell  24:07  

Patients will tell you consistently one of the most disabling facts about having seizures, if I’m going to have seizures, is I don’t know when they’re going to occur. So that we knew was disabling. You guys had that deep expertise of how to bring a technology along, how you build a device, how you test it. We had the opportunity with Doug’s background. That was an amazing program with the canines, with naturally occurring epilepsy, devices designed for humans that the dogs could accommodate. I, you know, have run with that same playbook for a long time. I often say, as do many people, that it’s about the relationships you make. You know, I maybe it doesn’t always work out like this, but it’s like I’ve been working with these guys for over 15 years, and it’s been good.

Kent Leyde  25:02  

We have brought up the importance of relationships and this community we work in a bunch of times on our podcast so far. Yeah, it’s pretty, pretty common theme, and it’s an amazing community. I really count my blessings, and really enjoy working in this in the epilepsy community, and I’m really looking forward to doing some good things for patients. You know, knock on wood, I think we’re on a good on a good track and and I’m excited about what the next year’s holds holds for us. 

[MUSIC]

Greg Worrell  25:32  

Second that.

Doug Sheffield  25:35  

You know, one of the things for me, Greg, is that regular meeting with you and your lab. And, you know, we don’t see the patient. Kent’s building a fantastic system, but you’re that link, you know, with the patient. And for those listeners to this podcast, we emphasize, I think every, every podcast, is all about the patient, and that’s, that’s our focus. And you really do, you and your group really help us keep that focus alive, and even with our our current study. You know, we are in a clinical study with Mayo right now with a really important aspect of of the Cadence therapy, and that’s looking to see what neuromodulation, how that impacts the interictal EEG for patients that are undergoing invasive monitoring and and that opportunity to learn together. That has inspired us. You know, it’s a long journey, and if Kent and I didn’t get that periodic, you know, input from the patient through Mayo, it would be much harder journey. It brings a lot of energy and enthusiasm, I think, Kent, to the whole team, right?

Kent Leyde  26:44  

Absolutely. It’s one of the best parts about what we do at a company like Cadence and medical devices in general. I can say this, having been in this field for 30 or so years now, is it’s tied to patients and tied, tied to helping, helping somebody else that needs some help. So if you can use your skills and your background and your professional time to help other people, it can be very rewarding.

Doug Sheffield  27:09  

And you’re not shy, Greg, when you share what you think how this device should, should be made, and how many channels we should have, and I think that’s excellent, too. You push us. You push us to the system that we have today, providing the voice of the patient that you’re treating, you know, from the clinician side. I’d love to hear your thoughts about how critical this interaction is between the commercial side and the clinical research, research side. I mean, can either one succeed without the other?

Greg Worrell  27:40  

It’s absolutely necessary, and obviously it has to be done in a principled way. But to create a therapy for patients and populations of patients, it’s going to take a team, and a team with a range of skill sets: clinicians, surgeons, engineers. And there, and there’s that industry piece of that, you know, that someone’s got to make the device. That’s one thing I just really loved about our trajectory, you know. And you were making me feel good when you said, Well, yeah, we’re doing this trial stimulation study, which we’ve been doing for a number of years now. Yeah, we’re still at the bedside of the patient. So I just want to point out I made a pretty good decision a long time ago, that we got to make sure that we really have that opportunity. 

Kent Leyde  28:32

Yes.

Greg Worrell  28:32

I mean, we’ve spent time on the bench and time in animals, but really getting to humans as fast as you know, safely possible, has really positioned us well, and we’ve obviously learned a lot along the way.

Kent Leyde  28:47  

Yeah, no substitute for the close collaboration and the contribution that patients are able to make when they volunteer to help with research. They’re really helping move everything forward for everyone. So I had a couple of questions we wanted to work into the mix here, Greg. Can you share with us a success story of a patient, someone who pops into mind, you’ve been able to treat and improve their life?

Greg Worrell  29:11  

We did a little piece a few months ago on a patient. She’s still one of my favorite patients. I ran into her in the hospital. She was there with her child, her four-year-old child, there because her father was in the hospital. I just happened to run into her. Just an amazing story, a woman with drug-resistant epilepsy, on four drugs and wanting to start a family.

Kent Leyde  29:36  

Yeah, that’s tough. Want to explain the concerns there?

Greg Worrell  29:40  

We know that there are particular drugs that are more meaning associated with fetal malformations of development. We know some drugs are worse, but we also know the combination of drugs can be more dangerous.

Kent Leyde  29:54  

Which is really tough. When you get into combinations and now you’re in thinly mapped ground, right?

Greg Worrell  30:00  

Yeah, it’s really a lot of unknown. I mean, we know that seizures are bad, so you take that known bad and, you know, weigh that against what you can do with drugs. And again, there’s some drugs that we just largely won’t use in childbearing age women, just because of, again, the risk of the drug to cause a malformation of development in the infant. So that was her. We talked about neuromodulation, and the story that, well, current neuromodulation therapy, we’re probably not going to get you seizure free. We generally reduce seizures with current technologies. And of course, that’s why we’re on this podcast, because we’re trying to make that better, or. 

Kent Leyde  30:46  

That’s right. 

Greg Worrell  30:47  

That’s the collaboration. But currently, her treatment’s effective but rare to be seizure free. So had that long discussion with her that with neuromodulation, I think there’s a good chance that we could reduce your medication, maybe you need, you know, two drugs rather than four drugs. She had an investigational device, complicated, bilateral A and T of the thalamus, bilateral hippocampus. Really had a really great effect. 

Kent Leyde  31:18  

Is that right? 

Greg Worrell  31:18  

She went in, assumed all the risk of the, of the surgery and everything.

Kent Leyde  31:23  

And you didn’t have a biomarker that you could monitor and say, Looks like we’re making a beneficial change to your brain, let’s proceed with the therapy. You had to commit to quite a lot of hardware with your fingers crossed. 

Greg Worrell  31:23  

Yeah, yeah. And it was an enormous success. She went on to have two children. 

Kent Leyde  31:42  

Ah, fantastic. 

Greg Worrell  31:43  

One I saw that day, and it’s just done really remarkably well. So it’s stories like that that sometimes it gets tiring doing the work, but it’s definitely rewarding.

Kent Leyde  31:55  

Yeah, we have a lot of ground to cover still in this field, right? I mean a lot, but that’s awesome, huge win for that patient. We’re 100% committed to doing everything we can to create a world where we get to share more stories like that.

[MUSIC]

Greg Worrell  32:08  

Yeah. 

Doug Sheffield  32:09  

Okay, that’s such a great story. I’d like to take a second to recap what Greg told us in layperson language. 

Kent Leyde  32:18  

Absolutely. So here’s a case where a young woman has drug-resistant epilepsy and she wants to start a family, but she’s on a bunch of medications that could pose a real risk to the child, and this is a not-uncommon story. Thankfully, she had the option to go with an implanted device to help control her seizures.

Doug Sheffield  32:40  

The device worked and allowed her to reduce her medication safely. That’s really what it’s all about, right? Improving the quality of life for people with epilepsy.

[MUSIC]

Kent Leyde  32:51  

So, Greg, tell me a bit about how the patient journey, how you know the patients you see, how did they come all the way to Rochester, Minnesota, and make it to Mayo Clinic and make it to your practice? It’’s not always a simple, straightforward patient journey, is it?

Greg Worrell  33:07  

It’s often not, but not so much about distance. I mean, of course, we see people from around the world, but the vast majority of patients we see come from the four states around us. Then of course, there’s a certain percentage that come internationally. But more than the distance, one of the key things that has been discussed and is established is that the duration of time that people live with their epilepsy, uncontrolled epilepsy before they come to an Epilepsy Center, 

Kent Leyde  33:44  

Right.

Greg Worrell  33:45  

Before they’re considered for what might even be a curative therapy with epilepsy surgery, or these next, currently available neuromodulation technologies. We know these work, and so it’s, it’s, it’s often disheartening to hear those stories that they’re, they’re 20 years out, you know, and no, my seizures have never been controlled. And… 

Kent Leyde  34:09  

Yeah, this is, to share with the audience, this is something that gets talked about frequently when we the community gets together for our big national meetings and so forth. For a lot of patients, there are definitive treatments, and for a lot of these drug-resistant cases. And yet, a lot of these patients don’t find their way to the Mayo Clinics of the world where they might receive those treatments. They don’t. There seems to be a kind of a break in the in the pipeline, and not all the patients make it to these centers, which is, I think, leaves us all scratching our heads a little bit. Is that referral pattern problem different for Mayo than it is for other centers?

Greg Worrell  34:50  

That’s largely a national problem, universal observation. And there’s probably many reasons for it, you know, and some of which are related to the disease. Sometimes people do do better for a period of time and then have flare ups of their seizures. So as far as how patients get here, we just like them to get here earlier.

Kent Leyde  35:13  

Yeah, well, it’s not it’s not good to keep having seizures either, right? 

Greg Worrell  35:16  

No. 

Kent Leyde  35:17  

We’re not making things easier, besides it being an awful experience with a patient, it’s better to get treatment sooner.

Greg Worrell  35:23  

That’s right. So then here, similar to many Epilepsy Centers across the country, very sophisticated imaging. One of the most important pieces is to record the patient’s seizures. We do that non-invasively, initially with scalp EEG and then subsequently, if it looks that there could be either a surgical therapy, neuromodulation therapy, they may go on to what is often termed phase two monitoring, where we’ll directly implant electrodes into the brain and capture seizures there with the goal of better understanding the network that’s generating the seizures, identifying if there’s a focal region of the brain that can either be destroyed or directly modulated. And those are big endeavors, but can be incredibly impactful for patients and for their epilepsy.

Kent Leyde  36:23  

Yeah, and all the data, this is not at all controversial, but you know, once you’ve tried two or three….

Greg Worrell  36:30  

Yeah. 

Kent Leyde  36:30  

Or four drugs, your chance of getting seizure free is is shrinking exponentially each time that number goes up and you didn’t it didn’t work. So no good sense in, in not finding your way to a Mayo Clinic or a similar kind of Epilepsy Center. 

[MUSIC]

Kent Leyde  36:50

Okay, so Greg, let’s get out our crystal balls and gaze into the future a little bit. Where do you see this field in five years? How are things going to look differently than they look today?

Greg Worrell  37:00  

Yeah, I think that’s a it’s a great question. Obviously, I’m probably biased here a little bit, but I see the trajectory that, not only Cadence but the field in general is on, that neuromodulation is already proven to be an effective therapy. You know, there are a couple of gaps. It takes too long to get that optimized therapy. We don’t get enough patients seizure free, but we already impact people’s lives, people with epilepsy. So I’m excited about that trajectory, you know, because that just started mid 2000s, you know. So it’s not, not that long.

Kent Leyde  37:38  

It’s kind of new still, yeah, I mean, it’s not about new new anymore, but it’s, there’s no doubt about it, and we’re on the board, right? We need to make it better.

Greg Worrell  37:47  

So a couple of things that I’m really excited about. One is sensing technology and the ability to capture all the data that we need. You need seizure counters. We need to know when the patients are having seizures, how many seizures they’re having. This new generation of technologies is going to make that possible. That’s been just a fundamental engineering gap. So I’m glad I’m going to live to see that one rolled over. 

Kent Leyde  38:16  

Yeah.

Greg Worrell  38:17  

I think the idea of being able to improve not only the trajectory, the time that it takes to get to optimal benefits, but to get to a higher, higher bar. And ….

Kent Leyde  38:28  

Yeah. 

Greg Worrell  38:29  

I think we’re on a good path with the technologies for that as well, the ability to target multiple nodes in an epileptic network. You know, it’s the brain’s complicated. We know that.

[MUSIC]

Kent Leyde  38:41  

Yes, and every patient’s different. 

Greg Worrell  38:44  

And every patient’s different. 

Kent Leyde  38:49  

Data collection in general has been a theme throughout your work, and when we talk about this off of it, there’s one new thing in the whole world of science, is the building in collection and analysis these large data sets using machine learning and all these fun tools that are now available to us.

Greg Worrell  39:10  

Yeah. So with that data, we’ll be able to track the patient’s number of seizures, so we’ll quantify that primary outcome. We’re going to have that the idea of individualized therapies, with those ability to target multiple nodes in a network that can be individualized. The idea of optimizing therapy, not only based on seizures, but on biomarkers, so that we can get to the most effective therapy as quickly as possible. So it doesn’t take a, you know, six months or a year to get that optimal parameter set. You know, the idea of getting the data off, off the implant, onto a handheld, up into the cloud. This is, this is just like standard commercial electronic stuff.

Kent Leyde  39:58  

Yeah. Why aren’t we doing this?  

Greg Worrell  40:00  

I really think this is, this is going to have a big impact. So you’re no longer computing on the little device that is very limited. You know, you’re moving at the speed of commercial electronics, how fast the iPhone or Android phone, or whatever. 

Kent Leyde  40:17  

Moore’s law.

Greg Worrell  40:18  

Yeah. And then scaling with how the cloud is scaling. So connecting patients to the devices and to the cloud through the devices, that’s going to be huge. And then, I think the other thing that we’ll see, and we’ve known this for a long time, of course, epilepsy, it’s not just about the seizures. I said we’d be able to track those, we will. But then we can begin to target also the comorbidities of epilepsy, because these are diseases of brain networks. 

Kent Leyde  40:48  

Yeah. 

Greg Worrell  40:48  

So not only can we use neuromodulation, stimulation therapy to modulate epileptogenic brain, we can also modulate circuits that are producing depression, producing anxiety, disrupting memory, disrupting sleep. So I’m just super excited about being able to be on this next five to, oh, come on, it’s going to be a 10-year, five-to-10-year journey.

Kent Leyde  41:19  

It does take. It takes longer than any of us would like it to. By the way, we’re five years down this road. So ….

Greg Worrell  41:24  

Yeah, there you go. 

Kent Leyde  41:25  

Yeah, we’re getting some some water behind us.

Doug Sheffield  41:28  

It’s the long and winding road. 

Greg Worrell  41:30  

Yeah.

Doug Sheffield  41:30  

Right. 

Kent Leyde  41:30  

Yeah. 

Doug Sheffield  41:31  

I know. When we we first met the three of us, we talked about the crawl, walk, run, and this is a journey. 

Greg Worrell  41:37  

Yeah. 

Doug Sheffield  41:37  

And we wanted to build tools that will guide the journey. The way I look at it is, based on the work that Mayo has done, where, you know, the next step makes a lot of sense, but I think the steps going on from that are going to be informed as as we move forward together. I think it’s going to be, well, let’s try this, and let’s do that, and it’s going to be based on all this rich database that we’re pulling together between Mayo and all the other sites and and where, where that’s going to lead we don’t really know yet.

Kent Leyde  42:09  

Now, kind of fun to think of what some of these new instrumentation approaches, where they where they could take us. That be really, really fun to see that drive some new discoveries.

Doug Sheffield  42:19  

And I think that helps keep us humble on the journey too. You know, that, which I’m always a big believer of bringing humility, and let’s base our decisions on what we’re learning. And I think that’s characterized the relationship with Mayo right now. You know, you we’re guided by what we learn, and that’s that whole crawl, walk, run. It’s good that we’re all on the same page with that. 

Greg Worrell  42:41  

Yeah, it’s been a lot of fun. 

Doug Sheffield  42:43  

I’m with you for that anti-aging breakthrough too. It’ll help us. You’re working on that too, Greg?

Greg Worrell  42:50  

Yeah. Neuromodulation for aging, that’s that’s probably going to happen too. 

[MUSIC]

Kent Leyde  42:54  

Well, Greg, thanks again for joining us on this podcast. We talk all the time, but it’s fun to be able to share some of the kind of conversations we get to have with our audience.

Greg Worrell  43:06  

No, it’s been, it’s been a lot of fun. Thanks for, thanks for having me. 

Doug Sheffield  43:10  

Sounds like a wrap to me.

Kent Leyde  43:13  

Thanks so much for joining us for Seizure Diaries. 

Doug Sheffield  43:16  

We hope you find these conversations helpful. If you do, we hope you’ll consider sharing our podcast with others.

Kent Leyde  43:23  

Everybody says it, but it really does help others to discover the show when you rate, review, and share. You can find Seizure Diaries wherever you listen to podcasts. 

Doug Sheffield  43:32  

We’ll see you next time. 

Kent Leyde  43:34  

You’re getting better at this.

Doug Sheffield  43:35  

You say that every time.