Advancements in Neuromodulation for the Treatment of Epilepsy

Podcast Transcript

Dr. Alex Rae-Grant: Neuro Pathways, a Cleveland Clinic podcast for medical professionals exploring the latest research discoveries and clinical advances in the fields of neurology and neurosurgery. Welcome to another episode of Neuro Pathways. I'm your host, Alex Rae-Grant, neurologist in Cleveland Clinics Neurological Institute. In an effort to explore the latest advances in neurological practice today we're talking about developments in neuromodulation for the treatment of epilepsy. I'm very pleased to have Dr. Dileep Nair join us for today's conversation. Dr. Nair is section head of adult epilepsy in the epilepsy center in Cleveland Clinic's Neurological Institute. Dileep, welcome to Neuro Pathways.

Dr. Dileep Nair: Oh, thank you Alex. This is a fantastic opportunity to talk about something exciting in the field of epilepsy, neuromodulation, even though it sounds new, we've had neuromodulatory therapies around for a while in epilepsy. The first neuromodulatory device was the vagus nerve stimulator. And then following that we had a approval for responsive neural stimulation. And I think today we're going to be talking about deep brain stimulation for epilepsy.

Dr. Alex Rae-Grant: It's quite an evolution, isn't it?

Dr. Dileep Nair: It sure is. It sure is. And it's actually an interesting avenue of therapy, very different from what we traditionally are used to in epilepsy.

Dr. Alex Rae-Grant: Let's go back a little first though. Let me have you tell the audience a bit about yourself.

Dr. Dileep Nair: I'm sure.

Dr. Alex Rae-Grant: Know your background.

Dr. Dileep Nair: Yeah, I know. So I started my practice in epilepsy in 2000. I trained here at the Cleveland Clinic, both as a resident fellow. Been a very active here in the clinic at some ways to best treat our patients who have very difficult to control epilepsy, those of which we call medically refractory epilepsy. So I deal with patients who come in from various different parts of the world and we're very lucky to have a very large group here and great experience in both diagnosis and therapy. And I also do a lot of clinical neurophysiology both in the operating room, as well as in the extra operative area where we do mapping various different brain networks involved in epilepsy as a part of the surgical evaluation for epilepsy surgery.

Dr. Alex Rae-Grant: So maybe let's go back and sort of talked a bit about how we define medically intractable epilepsy and what kind of population that affects.

Dr. Dileep Nair: In the current state of affairs the definition really is if you failed two appropriately chosen and taken anti-seizure medication. So those are very specific words and in fact the first part is appropriately chosen. And what that means is that you've been tried on a seizure medication that must have been appropriate for the type of epilepsy that you have had. And so there are various different anti-seizure medications. Numerous actually, we've really had an explosion of seizure medications come around in the mid-nineties and then again more recently. And so amongst them there are some that are very selective and there are others that are more broad spectrum, I'd say. And so appropriately chosen means that the medication that was given to the patient was appropriate for the epilepsy type that they had. And then there's also appropriately taken, which means that the patients should have taken the medication and sometimes it's hard to remember and some people have compliance issues, remembering to take the medication. There also is a dose issue too.

So was the dose that was prescribed appropriate for the likelihood of that being successful? And that's a very nuanced question. It can vary from patient to patient what that appropriate doses. And then finally there's a time interval too. So you've must have tried the medication for appropriate amount of time and that's kind of dependent upon what their baseline seizure frequency was to assess the efficacy, the effectiveness of the drug. So if you have a seizure frequency of once every day versus once every six months, you clearly understand that there is a period of time that's very different between those two patients to see whether that particular medication was successful or not. So there needs to be a certain amount of time, but once you failed then too, appropriately chosen anti-seizure medications and you failed, meaning your seizures have occurred, then that's really definition of what we consider now medically refractory.

And the reason for that is that the likelihood that further anti-seizure medications will substantially reduce their seizures are down to nil or down to as close to zero is very low. Probably in the realm of somewhere between five or 10% chance in the long-term. So that's the real conundrum of all of this is that, you know, in order to be effective in treating patients, you need to reduce their seizures down to no morbid seizure so that the seizures are not affecting their awareness, for instance, so that they would be impaired or if they're having convulsive seizures that they result in injury. So it's a matter of trying to determine, have we reduced the seizures down to that appropriate amount where they're able to function on a day to day.

Dr. Alex Rae-Grant: So I guess it's safe to say the days of just carrying on, trying one medicine after the other for years have gone away and it's really appropriate treatment, but then decision to go to something else such as neurostimulation seizure surgery. Right? One of those others?

Dr. Dileep Nair: You know, that's just a really beautifully worded question because you would think that, that would be true, right? If we're at this point in time or a defining medical refractoriness in which that would amount to about roughly 30% of our patients, so the good news in all this is the vast majority of our patients do get controlled with use seizure medications. But there is a substantial number, 30% that are not. And the sad news there is that there are still patients out there to this day that don't seek appropriate care or aren't referred to the appropriate medical center, level four at epilepsy center, where there can be some other options given to the person. So each person's different and it really requires an individualized approach and that requires the skills of a neurologist who's an expert in this field to understand the patient's epilepsy type.

Understand what are the aspects of the data, what do they show, where is the epilepsy arising? It's really that thorough evaluation that's done to kind of make sure we have the diagnosis correct, make sure that the medications are all appropriate. And then finally understanding if they do have epilepsy, where is it coming from and is it a surgically amenable type of disease? Because in fact, at the end of the day, still if you are medically refractory and we find that your epilepsy's arising from a non-eloquent area of the brain for example, or an area of the brain that can be approached surgically, it's clear we have two randomized controlled trials for surgery that show benefit over continued medication therapy so that's very important. I think that's a very, very important part of the today's conversation is just to understand that.

Because in fact today, if you look at the number of epilepsy surgeries across the country, it's something like, if I remember correctly, it's something like 1500 and if you think of percentage of patients who have epilepsy, the prevalence of epilepsy across country is about 2%. So that disease reflects a very large number of patients. And so it's clear that our medically refractory epilepsy patients are being underserved. And one of the messages that we want to make sure we get out is that there are other options available. And in order to get to those options, you need to be seen and talk to your physicians about your options.

Dr. Alex Rae-Grant: So that kind of brings us back to one of those options, which would be the various forms of neuromodulation for epilepsy. We know neuromodulation therapy in epilepsy is not new, but there are new things and neuromodulation.

Dr. Dileep Nair: Right.

Dr. Alex Rae-Grant: Could you talk through the evolution of that?

Dr. Dileep Nair: Yeah, absolutely. So neuromodulations as I mentioned started with the vagus nerve stimulation. That was some approved in the 1990s. And that's what many might call, I'm going to use the word shotgun approach. And it's not a criticism, it's just a point, meaning that the target is outside the brain, it's the vagus nerve. And the idea then is that by stimulating the vagus nerve in a fashion that is called open loop, where mostly it's stimulated by, where originally, I should say the stimulation was delivered in a sequenced manner, a scheduled manner. It was typically 30 seconds off, five minutes off for an example of therapy. And it was unrelated to whether a patient was having a seizure or not. That's why it's called open loop. That therapy was, were the very first neuromodulatory therapy, the idea that you could alter the brain's physiology by applying an external electrical stimulation, which was really fascinating actually.

So if you think about how the brain works through synaptic interactions and electrical interactions of various substrates in the brain, the core of cognition, the core of the ability for us to talk, to move, all of those rely on electrical signaling. And the notion that the pathophysiology, the mechanism of disease for epilepsy, which is an abnormal synchronization of brain activity could be disrupted by applying an electrical stimulus was really kind of interesting. And it's not new though. You know, we think as soon as we've discovered something new, it's really just because we haven't looked into history long enough. In fact, way back in ancient Greece, it was clear that they were using electrical stimulation to treat all things like gout for instance. So the idea of electricity could affect disease is not a new issue, but applying it to epilepsy in a way and looking at it in studies that resulted in the first approval of a device was the vagus nerve stimulation.

Dr. Alex Rae-Grant: Dileep. Let's talk about the second type of neurostimulation, responsive neurostimulation.

Dr. Dileep Nair: So responsive neural stimulation was the next step in the evolution of neuromodulation. And this device took on a little bit of a different approach. The notion there was to first understand the target of where this epilepsy was arising, the seizure onset zones, and these electrodes then would be placed in those or close to those targets. So unlike vagus nerve stimulation, which the electrodes are completely outside the brain, the response of neuro stimulation device housed the stimulator completely within the cranial vault. So first of all, the device itself is seated in the cranium. So a full thickness craniotomy is performed and a tray is inserted on which the device is seated and it's flush with the skull. And two electrodes, either a depth or a subdural strip or a combination of those two are connected to the device and these electrodes are placed near the location or locations. This device is approved for one or two seizure FOA site.

So one of the phenomenal things about this device is that it can continuously sense and record what it's sensing in the sense that it can tell when a detection has occurred, which means a time in which the seizure is thought to be seen. And that's all programmed by the provider. So those patterns are detected and stored in terms saying our detection was given at this moment. And as stimulation is also delivered, and this is performed over many, many years in a very naturalistic setting. The patients are on their seizure medications, they go about their daily life and seizures are being detected and stimulated with very brief pulses. And so that's responsive neurostimulation, and then that was different than the vagus nerve, it's closing the loop. It's sensing and stimulating only the times where a seizure focus is fought to being generated. I should say that the more recent versions of the vagus nerve stimulator do record heart rate. So in a sense they have an ability to have a closed loop feature. So when heart rate detections are seen are a tachycardia is seen, it presumes that there is a seizure going on and extra stimulation's are given during that time. But really a real sort of detection and stimulation therapy is really the response of neurostimulation that we had approved in 2013.

Alex Rae-Grant: So just recently, deep brain stimulation was approved for epilepsy. Can you talk about that.

Dr. Dileep Nair: Yeah. You know, it's interesting. The deep brain stimulation trials began in 2003, the first implant was some time around there and the SANTE trial, which is the trial that looked at the stimulation of the anterior nucleus for treatment of epilepsy was published in 2010, and it took eight years before the device got approved. And between that time, the device was available in Europe and was available in Canada and Australia. And eventually you're writing, it just recently got approved last year, April of 2018 and then made available to us December. So we're very excited to have this third neuromodulatory therapy now. This is very different than both types of therapies we've already talked about.

Unlike the responsive neurostimulation, this is open loop, very similar to the vagus nerve stimulator, but unlike the vagus nerve stimulator and responsive neurostimulation, there's a single target that's in the brain and that is the anterior nucleus of the Thalamus, which is the Thalamus is a very large, relatively large structure deep in the brain and it has many sub nuclei of which the anterior nucleus is one of the sub nucleus. Now you may ask me why the anterior nucleus of the Thalamus of all places, right?

Dr. Alex Rae-Grant: Why is that?

Dr. Dileep Nair: So the reason for that target was because it is a part of a circuit called the Papez circuit. And the Papez circuit was well established in neuro-cognition as the memory circuit, the cognitive circuit, the emotional circuit, but also the limbic circuit for epilepsy. And so it was originally proposed that the entire nucleus of Thalamus would be an interesting structure to target for stimulation for limbic epilepsy. And so that was kind of the purpose for using that target. Since that time, there've been various other types of epilepsies other than just limbic epilepsies that have been studied for this particular type of stimulation.

Dr. Alex Rae-Grant: So it sounds like we've got all sorts of ways to approach some medically refractory epilepsy patient. How do you guys figure out what to do now?

Dr. Dileep Nair: That goes back to the point that it has with a lot of medicine. It's really being personalized to the patient, so you can talk about them in forms of types of epilepsies, various different groups. But really it's important to understand that person is an individual and there are a lot of different unique aspects to a patient and a lot of different issues that we have to address that come into play. So we think about it in a variety of different ways. It's complicated. That's how I wanted to make that big sort of introduction to say it's all complicated. You got to be, it's, you know, I have to train for that. That's an easy way to come out of that. But if we wanted to think about this in kind of a very sort of, the forest view of this problem, the first aspect is first to define that a patient has medically refractory epilepsy. That begins with a video of EEG evaluation, it begins with an MRI scan. And from there we begin to ask various questions, what type of epilepsy is this, where is it coming from?

And if it's generalized, if it's a genetic epilepsy, there really, it becomes more of a smaller, a group of options available if it's genetic. Generalized, unfortunately and there are some people who are thinking about various roles of neuromodulation but vagus nerve stimulation is maybe still an option there. But there are people who are thinking about very specific various targets that have not yet been approved, I should say, for that genetic generalized group. And same goes for the multifocal, sort of symptomatic generalized in the old term. There not a lot of neuromodulatory options yet available. So we have to think about then, that we've made the diagnosis of epilepsy, that is medically refractory and then it's not one of these various subtypes, it's a focal epilepsy. Then the question becomes is there an MRI lesion and does the MRI lesion correspond nicely to all the other data that we have including history, very importantly, but all the sophisticated tests also involve, are involved there in that discussion.

And these data sets are all collated for that particular patient. And we ask the question, are we confident about where the epilepsy is? Is there risks to undergoing surgery or not? And that specific question is there overlap of eloquent function? And if there is, how can we resolve that? Is there a way to resolve that. If there is no MRI lesion, what other testing do we need to do? Do we need to put electrodes in the brain? Do we need to do other special studies like magnetoencephalography (MEG), ictal SPECT? PET scans are almost uniformly performed, but do we need to do other advanced image processing techniques that we have here at the clinic? 7T, voxel-based morphometry, etc. The point is that the discussion is held at a very personal level and we have a committee. It's not just me, you know, if it's my patient, it's not me, it's me plus all of the other epileptologists all in their inner group. We have a numerous number of epileptologists, always astounds me how many people we have in our group.

We have, I think 12, I want to say people who just see adult epilepsy, we have five who are pediatrics. And the nice thing about patient management conferences is that we all sit together in the same room along with the surgeon, along with the imaging person and we address these points. And if surgery is an option in a sense that it's safe and these patients are willing to pursue that, it is still the first option being given to the patient. There are some patients though that surgery is not an option. Either there's an overlap or there's more than one location. We don't know where the location is. And we have to think about other options. You need to do something for these patients. We can't just give up. And so neuromodulation comes up in those periods of time.

But one thing I want to make sure I talk about is the effect of neuromodulation. It's not something that is immediate. The expectation is that we don't start the stimulation of any of these types actually and that it works immediately. It takes years sometimes, it takes years to develop a benefit. And so there's a little bit of an expectation walking in that, that's what we're going to be looking for and that's what we're going to strive for. I think one of the leading questions in the neuromodulatory field is how can we speed up this efficacy? You know, unlike surgery where it works like that right after the surgery is over, you pretty much know whether you're successful or not. That doesn't happen with neuromodulatory therapy. And so, you know, unfortunately there's about 30, 50 to 34 center patients who even after epilepsy surgery are still having seizures. And so it's nice to know that these options are available even in those situations.

Dr. Alex Rae-Grant: So it sounds like it's pretty exciting time with lots of potential, but very individualized at the individual patient level.

Dr. Dileep Nair: I think you hit it on the head. It is exciting. I tell my residents and fellows to be an epileptologist today, you have to have a lot of different hats. You have to be a good clinician. You have to be a good clinical neuro-physiologist. You have to be a good anatomist. You have to know pathways, you have to know networks. And it is exciting. And so you can't do everything. You need a team and in our group we have biomedical engineers who are embedded with us. We have nurse practitioners who are extraordinarily important in the care of our patients. And the benefit of having an epilepsy center like ours, and there are others out there, is that you have a team of people all caring about the patient, the patient in terms of their disease, understanding them as best as we can, addressing their needs, both from a seizure standpoint, but also understanding there's other aspects to their life than just epilepsy and having, trying our hardest to address those two.

Dr. Alex Rae-Grant: Well, it sounds like a good place for us to finish our conversation loop. Thank you so much for joining us.

Dr. Dileep Nair: Thank you, Alex.

Dr. Alex Rae-Grant: This concludes this episode of our Neuro Pathways podcast. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast. Subscribe to the Neuro Pathways podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you get your podcasts. Don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website, consultqd.clevelandclinic.org/neuro, or follow us on Twitter at CleClinicMD. All one word. That's at C-L-E Clinic M-D on Twitter. Thank you for listening. Please join us again soon.