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Epilepsy Surgery in Children: Innovations in Diagnosis and Treatment

David Adelson

July 19, 2021

Transcript

- Colleagues and friends, thank you for joining us for another session of the Virtual Operating Room from the Neurosurgical Atlas. Our guest today is Dr. Dave Adelson. Dear friend, he's the Diane and Bruce Halle Endowed Chair of Pediatric Neurosciences and Chief of Pediatric Neurosurgery at the Barrow Neurological Institute. He's the past President of Congress of Neurological Surgeons, as well as the board of directors of AANS. He has been truly a world or leader in epilepsy surgery and other disorders in pediatric neurosurgery. And I'm so honored today to happen with us to describe innovations and diagnosis and treatment of epilepsy surgery. David, thank you again, and we appreciate learning from you.

- Well Aaron, thank you so much for the invitation to speak again. This for me is a very particularly exciting area. Clearly from the time that I was training to now, it's allowed me an opportunity to reinvent myself because the knowledge in the area of epilepsy and epilepsy surgery, as well as the technologies that have moved forward, really have provided us a rich understanding of what's going on in the brain of children and adults with epilepsy. So, I'll move forward with my talk. I do have a disclosure. I do work occasionally as a consultant for Medtronic, but I will try not to refer to any commercial discussion during this talk. With regards to the surgical treatment of epilepsy, it's been around a long time. I mean, when we talk about neurosurgery, it dates back from the late 19th century, kind of trickled along, I think until the sort of the mid 40s and 50s, and then really was an explosion of understanding of really what epilepsy was, and where potentially origins were. But that was really mostly in the adult populations and there were good to excellent outcomes that were achieved. And now, even 30 years later, when, from when I started my training, now we're starting to see really significant advances that have come really with better understanding and better technologies. The reality is that epilepsy is the most common neurological disorder of childhood. And so, there's really a vast population of children with seizures and particularly chronic seizures in epilepsy. But I would argue that they're not really getting the best of care and that there's a lot of children who are really not being considered for surgery, even when medications and alternative treatments have failed. What I'd like for you to take away from today's talk, is really that the best outcomes from epilepsy and epilepsy surgery, come with an accurate localization of the seizure network. When we talk about innovations, those innovations have been not just in surgery, but really in the solutions to improve our diagnostic accuracy. We've also got innovations in more minimally invasive surgical approaches. And so, for that reason, now we can offer surgical options to a much greater population of patients with intractable epilepsy. And clearly some of those technologies have really been in the areas of neuromodulation, which really do give us a better opportunities for treatment that did not previously exist. So, just to highlight again, the reality is that if someone is diagnosed with a chronic seizure disorder or epilepsy, that about 50% will become seizure-free with the first drug, but then you get diminishing returns. You only have about 11% response with a second drug and down to a 4% response with a third drug. And then if you start to get into other medications, the likelihood is kind of down around a 1%. But what's really important to note, is that about a 1/3 of patients really will be unresponsive to medical therapy. And really provide an opportunity when it comes to surgical treatments for the ability to improve the outcomes for a really vast population of patients. If we look at the treatment gap for refractory epilepsy, if we think about that prevalence in the United States being about 3 million people, about a 1/3 if we use our calculation, 1 million patients have refractory epilepsy. But the reality is that only about 3000 epilepsy surgeries are being done per year with another 4,000 for neuromodulation, the vast majority of those as vagal nerve stimulators. And so you can see that a substantial number of patients are not getting adequate treatment. If we look at also the fact that about 150,000 new cases of epilepsy are diagnosed each year, and thus there are about 50,000 new intractable cases, this is a population that we are not keeping up with. And as a result, when one looks at the average duration of refractory epilepsy in patients, it can be upwards of 20 years from the time of initial diagnosis to initial treatment. So again, this is not something new. The medical treatment compared to surgery, has a long history now, showing that surgery in the right diagnosed patients, truly has a significant impact. And we can see that this study is now 20 years old from New England Journal, but there are many patients that still don't receive adequate treatment for their intractable epilepsy. And when it comes to children, we even now elevate this to a whole new level of complexity because in children we are dealing with many times, diffuse and generalized seizure types. Oftentimes, extra-temporal and cortical in nature. It's often not a small focus. And unfortunately, when we sort of come up with a definition of intractability, these children are often having numerous seizures per day, particularly with the catastrophic epilepsy, 60 to 100 seizures a day. That's not a child that can go on to normal cognition and normal development. And so for that reason, we truly have a significant population of patients that really do need our care. The goals of epilepsy intervention whether it be medical, whether it be diet, whether it be alternative treatments, is to stop the seizures. And of course, when it comes to pediatric, we wanna prevent further brain injury or the interference of normal brain function. And then further, we want to hope and our goal is for normal neuro development. Well, the best option for surgery, is those that are the best qualified. And again, qualified candidates. I should have put in quotes in this day and age, because the reality is that, we can do better for patients, even if we're not curing them. But for resective surgery where we're trying to obtain a cure, the reality is that, the definition is that patients that have been drug resistant, medically refractory, where they've failed two or three medications, has been around now for over 10 years and truly provides us a framework for making decisions for these patients. Clearly the seizure type, the lateralization of localization of the seizures, and particularly, if we can identify a pathologic substrate, then those are likely gonna be the best outcomes, whether indeed it's for resective surgery or for neuromodulation. The reality is also that while being able to visualize an anatomical abnormality, epilepsy is a functional problem. And thus, we need to better be able to diagnose and understand where the epileptic focus is, and where is the epileptogenic zone. And that's really where we've seen market insignificant improvements in our technologies and our understanding. There's now new areas of research, as well as clinical application to start to look at improved source localization. Our anatomic imaging has improved. Many of you have experienced. I was at training in the early MR era and we, you can see that our sequences have gotten better. We also now have DTI which shows tractography and an ability to see where potential safe avenues for treatment arise. Our functional imaging has markedly improved. Again, epilepsy is a functional abnormality. So, the use of SPECT or PET have been around for a number of years, but now with changes in sequences, we can, we've improved things with resting state functional MRI and MEG, which really do provide a very rich understanding of where the seizure foci may be arising. And then now with cortical mapping and transcranial magnetic stimulation, there's many opportunities for us to be able to not just localize where the seizures are, but again, as mentioned, what would be a safe corridors or opportunities for minimally invasive approaches. So, I'm just gonna first go through the neuroimaging. Again, basic MRI doesn't really look particularly concerning or abnormal on this MRI, but with a T2 sequence here, you can see an insular abnormality. And then obviously when one starts to look at different projections, we can now start to localize, lateralize where the abnormalities lie and then start to look at how might we target diagnosis and therapy to this particular region. As well, we can now start to look at cortical thickness. And so, identify where there are potentially cortical dysplasias, again, looking at cortical thickness relative to normative data for age matched, gender matched controls. And so, here's a patient with overlay of their surface electrodes in an area where there was indeed some increased cortical thickness. And then again, also looking at where is the motor strip in these patients. And so, now you can do a much more targeted understanding of identifying the seizure network and what might be a safe avenue for a surgical treatment. Again, using DTI to identify corridors, this information really provides a rich understanding of what's going on in these patients. Again, to reiterate, epilepsy is a functional disease. There are many opportunities for functional imaging. And again, these are the things that I think have become really quite innovative over the last number of years. PET has been around since my day of training. And so, being able to identify an area of hypometabolism, is really fairly straightforward and well-established. But clearly, areas of hypometabolism are not the end all. And we need to consider that there may be other opportunities for different light guns to be able to identify different areas of the seizure network. In addition, now with advanced imaging, we can start to overlay multiple types of images, one over the other. So, here we can overlay the functional imaging on top of the anatomical imaging. Again, this is an opportunity for us to start to think about surgical planning, whether it be diagnosis or treatment. SPECT again, has been around for a number of years and then the intermix between interictal and ictal SPECT. And then now you add a subtraction image. One can appreciate the significant differences and so blood flow in this area. And then now, if you marry that on top of the MRI, you have a very targeted area of potential diagnosis and treatment. With regards to other types of functional imaging, with regards to eloquent areas of the brain, this is my era functional mapping with Wada testing. So, one is injecting Amytal, putting the brain to sleep and doing testing in a very primitive way. Clearly, with the advent of functional MRI, we have now have for a number of years, test-based functional MRI. But functional MRI requires a co-operative patient who can tolerate being in the magnet, who can follow commands and stay still. That is unfortunately difficult to impossible in most children, and particularly those that have other behavioral or cognitive problems. Those patients do not and cannot really undergo a test-based type of functional MRI. The images are wonderful, and we can appreciate in the test-based MRI where normal motor functions are, and again, provide a map for us to consider for surgical intervention. But now with the advent of resting state functional MRI, using cerebral blood flow and BOLD signal sequences, we can start to understand where there are normal networks, as well as abnormal networks. And then we can see how they overlap and where it might be opportunities for treatment in some of these children. Excuse me. These are the normative data that you would see with a resting states and knowing where normal functional networks are. We can identify now language networks. This patient is showing a left language dominance, but still some language on the right side in this particular patient. But then we can also look at the abnormal functional networks. So, we can see here, left temporal lobe abnormality. On the resting state, this was correlated to the EEG and again, showed very much of a hippocampal targeted area of abnormality in this child's concordant data for EEG in a resting state, excuse me, resting state functional MRI. Resting state can also be used to see the seizure network relative to a tumor. Here was a patient, a different patient with a left temporal tumor. And so, we were trying to come up with a strategy to try to preserve the dominant hippocampus, but one can see and appreciate the location of the epileptogenic zone relative to the tumor. And so, we needed to incorporate in our surgical plan, the ability to remove this tumor, remove the seizure network, but try to preserve as much of the hippocampus as possible, for this child's long-term function. With regards to surgical options, I think that really some of the excitement has been really based on our ability to localize these different areas. And the first part that I'm going to discuss is invasive monitoring. Invasive monitoring has been around a long time. It's one of the first cases I did as a neurosurgical resident. It was a lot different then, but it did require a surgical implantation and the removal of electrodes. There were very straightforward indications. Insufficient data to lateralize or localize the seizure focus or network, a non-concordant data. So, EEG that might be showing one thing, and a functional MRI showing something else, as well as insufficient information as to the relation to eloquent cortex. Some of these things have already been obviated by our advances in imaging, but it's not 100% yet. And so, that's the reason for one's consideration for invasive monitoring. Again, in my day, and this was not one of the patients that I treated, but it was the techniques we used when I was an intern and junior resident. Pneumoencephalogram, for those of you who would remember that, angiography, and then targeting depth electrodes to the areas that we had some concern. We've come a long way in that time. Here's a child that we treated recently, whose EEG showed frontal lobe seizures, but yet had an area of abnormality here in the parietal lobe. Here is the MEG study, which seemed to be concordant with the area of anatomic abnormality, but we weren't sure, and it was in our early experience with MEG. And so for that reason, we put in a series of electrodes SEEG, both frontal and around the area of the lesion. And again, I should say that there was some possible EEG abnormality on the right. And for that reason, we targeted these areas. Well, in this particular patient, the MEG was correct. The anatomic imaging was the location of the abnormality. And then this was the very targeted, minimally invasive approach resection of this particular lesion. Now, with our advances in SEEG, we can now create 3D models and we can do a fair spread of SEEG electrodes. This allows us to better localize the seizures. We can now pull off the scalp and bone, and do a brain imaging overlay of the electrodes and the possible localization. And then, similarly with advances in EEG, and these are, this was a patient in which we looked at high frequency oscillations. Again, new diagnostic approaches. We could see and identify different electrodes, where there was indeed different areas of high-frequency oscillations. Importantly, in this patient, you can see we were seeing them in the right amygdala, but we were also seeing it on the contralateral side. So, clearly this was a patient with diffuse seizures with though fairly localized areas. So, two specific seizure foci in very targeted areas of the brain, not really the best candidate for surgical resection. So, now moving on to surgical treatments, again, taking into consideration our diagnostic studies, one can appreciate that these were the surgical treatments that I was taught as a resident. This was basically what we could do back in the 1980s. We've come a long way, but back then, for most of these type of surgeries, we could get upwards of 90% seizure freedom in very specific included patients who met criteria in order to do a very targeted approach toward surgery. Usually it was right temporal lobectomy. Occasionally we would do obviously frontal lobectomies or anatomical hemispherectomies. The goal was to improve outcome by removing or stopping the intractable seizures. Complications were relatively low, but given me very extensive and sometimes very market insignificant surgery. We were happy with those type of outcomes, but surgery has come a long way in that time. So, now we no longer do anatomical hemispherectomies. We can do more minimally invasive resections with laser ablation. Clearly we do disconnective procedures, but now we do cerebral hemispherectomies. I haven't done an anatomical hemispherectomy in probably close to 15 years. In addition, neuromodulation has come on the scene, and now there are many opportunities for neuromodulation. I don't think we're ready for prime time on transplantation right now, but I would see that as a possible neuromodulatory strategy, over the next number of years, because I think there is some exciting literature in this area, but there are now many more opportunities for surgical intervention for these patients. So, I'm gonna discuss again, because this is more on an innovations talk, really talk about the more minimally invasive approaches for treatment. Laser ablation has clearly revolutionized a lot of what we do, because of its minimal invasive approach. Now, with a three millimeter incision, we can place a laser probe into a seizure focus. We can monitor in real time as we heat up that area in the MR scan. So, we're getting real-time information as to the heating, as well as the calculated cell death maps. We have ways to create safety targets around an area so that we're not damaging the tissue beyond what we wish to, as well as the borders zones. So, including things like optic nerve chiasm or looking at different fiber tracts. So again, where has anatomical imaging really come and improved, has allowed us to see where there are functional tracks or important anatomical structures that we might want to avoid. Clearly the initial use of laser ablation was for hypothalamic hamartoma, but in this day and age, now we can clearly use it for many, many other things. And I'll show those to you now. Here's a great example. This was a 14 year old that we treated about a year and a half ago from Hawaii. She was, she had gelastic seizures since six months of age. So, 13 and a half years of seizures. Otherwise neurologically normal, but was having seizures six times per day. She came to us for evaluation and clearly her EEG was not localizing. She did have that HH and you can see it here on the anatomic imaging. But also with great imaging, we can also identify the mammillary bodies here and see its relationship to that hypothalamic hamartoma in order for us to develop our surgical strategy. In this patient, we also did a resting state functional MRI. And so you can see here, the directionality of the seizure spread in this particular child's seizure network. And so, this really told us that the seizure fibers were located from the HH going off the dorsal aspect, dorsal posterior aspect of this hypothalamic hamartoma. You can see here, we targeted that location. So again, here is the fornices. You can see the mammillary bodies and you can see our laser probe, where we targeted for this particular patient. Here's the heat maps again staying high at the dorsal aspect of the dorsal posterior aspect of this HH avoiding the fornices, avoiding the mammillary bodies. And in this patient, we were able to obtain seizure freedom. She has not had a single seizure since her surgery. Here's another patient that we treated about two years ago, 17 year old, who'd had a prolonged febrile seizure at eight months and you know where this is going. This is a patient with left mesial temporal sclerosis, and the resting state confirmed this location, all of our rest of our workup was concordant with that. And then this allowed us to show and target this particular left temporal lobe abnormality. You can see the MTS here on this patient. Here's the damage map from the laser ablation. And you can see very nice, very targeted ablation in this patient. And he's been seizure-free now since surgery. This was a patient as well as the other patient who just stayed overnight for observation. These would have been patients who would have been at least a two to four, two to five days in the hospital postoperatively for open procedures. Here's the post ablation imaging on this particular patient. Here's the left temporal lobe. And you can see the first, the DWI map here. And then also the T1 with contrast to confirm the extent of our ablation in this particular location. Laser ablation can also be used for cortical dysplasias, and you can see that here. Here was a patient with, who had multiple dysplasias, and you can see the number of targets that we were able to use and a blade in this particular patient, has also been seizure-free since surgery. Here is a patient with Lennox Gastaut and atonic seizures, really unresponsive to multiple medications, diet and neuromodulation. The family considered the VNS a loser, though I would argue a little bit that it had better control of the patient's complex partial seizures, but was really not helping when it came to the drop attacks, unfortunately, that this patient was having. This would have been our typical view of a corpus callosum. Here's the anatomy. It's beautiful. It's really, to be honest, one of my favorite surgical procedures, because it's so such a beautiful anatomical picture, you can see the ependyma. This is a nice disconnection through the callosum, leaving the ependyma intact. Unfortunately now with laser ablations, with appropriate anatomy, now we can approach this in a more minimally invasive way. In this particular patient, we used a multiple probes to ablate the different segments of the corpus callosum. And you can see here, going all the way back to the splenium, really covering and being able to get a nice disconnection here. And again, this patient has not had a single atonic seizure since surgery. And then just here is the post ablation imaging showing the extent by which we were able to do the ablations. Moving on to neuromodulation, I think that we've really had to deal with, and change our perspective that we're not gonna cure every single child with intractable epilepsy with surgery. We're not gonna be able to oftentimes identify a discrete seizure focus that we can remove or ablate. Sometimes the seizure focus, is an area of eloquent tissue. So, even if it was a small lesion or a small area, it may not be able to be removed. Sometimes there's bilateral involvement. So, if it's involving both hippocampi, we can't remove both of those. And so, in those cases, neuromodulation can be recommended. As well, the other challenge is identifying where that seizure network is and its relationship to eloquent areas. And that's again, where these innovations in diagnosis have truly come on and been a great opportunity for us to provide new offerings for surgical intervention. As I mentioned, there are multiple modalities that are now available. Again, I don't think that any one modality should be used over another. I think that clearly in this day and age of individualized, personalized epilepsy care, that indeed the best surgical intervention is those for those that have the best indications. I think we're still working on some of the indications for these different modalities, but our knowledge is rapidly expanding and as surgery becomes more and more accepted, I think you'll start to see many more of these modalities available and useful in your patient population. VNS has been around for now close to 25 years. And to me, it still astounds me that that more neurologists are not using them for their patients when they've tried 2, 3, 5 medications. It is not the end all, but clearly 50 plus percent of improved seizure outcomes in those patients is gotta be better than one to 4% to try another medication. And it still astounds me to this day when a patient will come in after four or five years of medically intractable seizures, been on five medications and a discussion of a VMS is not even been entertained. Really is because it's been around a number of years. I'm not gonna belabor it, other than to say that it should be your first line. The risk benefit for VNS is absolutely heavily weighted toward these patients in the outpatient procedure that can easily be done and helpful for these patients. Clearly, where I think things are moving, is in deep brain stimulation, as well as combinations with responsive neurostimulation. And I'm gonna talk briefly on those. We know deep brain stimulation has a longstanding history for movement disorders, Parkinson's, dystonias those kinds of things, but now we have some recent literature that supports the use in epilepsy and now FDA approval for electrodes placements into the thalamus for epilepsy control, mostly in the anterior thalamus, that's really where the focus has been for epilepsy. But again, with emerging literature, I think we're gonna start to see that other targets are possible for these patients. The RNS system as well as the DBS system, have now been around for a number of years, and these are great modalities again for the right patients. If you've got a targeted seizure network or focus, a strip-strip stimulation or a strip-depth stimulation using RNS can be an effective means. For more diffuse type of epilepsy, a deep brain or thalamic modality may be your modality of choice. Or you could potentially do a combination. Again as mentioned, there are many opportunities now for targeted areas and there's emerging literature about how to best identify which patients would identify, respond best to different therapies. So again, anterior nucleus for limbic system and hippocampus, centromedian nucleus for more frontal and cortical regions, and then pulvinar for more posterior regions of a potentially epileptic foci. So, there's now emerging literature. Again, the numbers are not large and I'm not espousing this, but for these patients who have no other options, we need to start to look at better opportunities for a potential treatment. So again, placement of electrodes based on a location of their seizures. And you can see now the number of patients being implanted is growing in these areas. There's now a fair amount of experience, particularly with centromedian nucleus placements for these patients. And you can see here that targeted pictures on this particular paper. I wanted to highlight one of our patients, a 15 year old, seizure onset at 10 years of age, following auto-immune encephalitis. This is a patient that you would expect fairly diffuse type of epilepsy. You can see the vast amount of diagnostic evaluation, but in particular, the reality was, is that this was a patient who had most likely bi-lateral involvement. Resting state also showed a bilateral involvement, but maybe targeted areas, not really clear where this patient's seizures might be arising. These were the EEG electrodes that I showed earlier with regards to this patient. Here were the HFOs. So again, marrying the diagnostic and localization, we found two targets, right amygdala, and then fairly diffuse on the left side. And so, for that reason, excuse me, this is just a reiteration of the different HFOs that we saw in this particular patient. But then we did a hybrid strategy in this patient. We placed a left centromedian nucleus, depth electrode, we placed a right amygdala electrode, and then married this to the RNs system. And so again, for this patient, a very targeted approach based on our findings of our diagnostic studies. So, clearly, when one talks about trying to improve these type of targeted approaches, I think that neuro-robotics are an exciting future for neurosurgery and just to touch on these, I think there are some, a number of different opportunities for the use of neurosurgical robotics. I think they're still in their infancy stage. And so, I think for specific patients for targeted reasons, clearly the robot is a very useful tool. This was our decision making when it came to getting a surgical robot at Phoenix Children's Hospital and our Institute. These were the kinds of questions that I would suggest that you explore when it comes to making your decisions. We defined our needs with regards to accuracy and efficiency. We had some sort of technical needs and was the robot capable of doing that? Was it able to integrate with our already existing image guidance system, which was part of the reason for our decision-making? Did it work into our present workflow? Again, these were our decisions based on what we had going on. And then as well, the consideration of value and cost and a potential future growth. This was just, as our surgical robot, we use the Stealth Autoguide. You can see it's used here in the operating room. We did start this when it came out. We were actually first to use in the United States in January of 2020. We've expanded its use. We use it for SEEG and for laser ablation. We've done biopsies, combination treatments. It has helped us in our workflow. Accuracy, one has to be careful. It's wonderful if the target is within five centimeters, but if you need some millimeter accuracy, for example, the centromedian nucleus in a deep target, I have not found that it provides that type of accuracy. And so, we still use frame based localization and placement for electrodes deep into fell onto thalamic targets. We also use a frame for small hypothalamic hamartomas where we have a very limited corridor for accuracy. Here was just the example. This was a patient where we used the robot for laser ablation for that patient from Hawaii that I mentioned earlier, but you can see that there was a little bit of error compared to our original plan. So, this was our plan. This was the slight error. With the targeting, we did not take the patient back to a replant because we still felt we could obtain that ablation safely away from the fornix and the mammillary bodies. And so, we did not take this patient back. If you needed that kind of accuracy, or if the probe were a bit further posterior, that would have been a patient we needed to take back using if we were to abuse the robot. So in summary, I'd like to say that intractable epilepsy clearly impacts mortality, morbidity and quality of life. This is a well-known fact and I don't need to reiterate it for this audience. We also know without a doubt, that outcomes from surgery are much better as compared to continued failed medical therapy. The percentages are clearly there. And with our improvements in diagnosis, our improvements in our more minimally invasive surgeries, there is no question that we can improve the outcomes for these children and for adults with medically intractable epilepsy. I do see that future advancements will be in our improvements in seizure localization and network identification, especially with regards to where they sit in regards to eloquent areas of tissue. This will expand our ability to do surgery, and then clearly with our advances in more minimally invasive approaches for surgery for more targeted approaches for surgery, and for improved accuracy and efficiencies using neurosurgical robots. I think that there are many, many, many more opportunities for patients that existed when I started training. And then now, clearly in this present day and age, I also like to give a plug for these advancements, helping me stay young. I've had to retrain in the use of a new technologies almost on a yearly basis. And so, having to relearn things and move from there, has been exciting. Again, I couldn't do it without a really dedicated, comprehensive team. And with that, I thank you for your attention and the opportunity to be with you here today.

- Thank you so much David, really a spectacular tour of the evolution of epilepsy surgery, specially in children to date. I really liked your last slide of this. All of them are great. Specifically the last one, you discussed the issue of the seizure network, and I think that's something so much unrecognized and such an important role that you will make, it will play especially in the future because seizures the way we locate it as a focal point in the brain, is most likely, extremely simplified.

- I agree. Not only simplified, but a really dated perspective. So even with MTS patients that have generalized or complex partial seizures, are not existing because of a single focus. And that's the reason for in my mind, the failures of these patients, is that the focus has become a fairly extensive network, often now starting to recruit other areas from the brain.

- Very well said. The challenge with understanding network, is we have to understand the connectivity of the brain a lot more, and that's been essentially the frontier of medicine for the next century. In other words, for us to understand brain better, is gonna be through understanding to treat epilepsy. And therefore, epilepsy is such an extremely important part of neurosurgery because through it, we'll understand how the brain in fact works. And so, I'm really looking forward to seeing the next generation of neurosurgeons focusing so much more on epilepsy surgery, because that's where we're gonna understand really the next frontier in neurosurgery and how the brain functions. How does thalamus, for example, coordinate all of these activities? I think so much of treatment of epilepsy surgery will rely on thalamus and how it's synchronizing networks within the brain. Don't you agree that thalamus could have really the solution to many of the problems we're facing in epilepsy surgery?

- Yes, absolutely. Actually, what I would argue is that, I really started off as an epilepsy surgeon. I wasn't really doing movement disorders because one of my other partners was very much into spasticity and those kinds of things. But really, epilepsy surgery and movement disorders and other functional abnormalities, really now have started to become so exciting. So, I don't consider myself just an epilepsy surgeon anymore. And what we're now starting to see very exciting, is the impact that neuromodulation has on other functions of the brain. So, we now are seeing much more literature that for example, vagal nerve stimulation improves neuroplasticity. And so, we actually see improvements in functional networks, normal functional networks in the hippocampus in patients where they had previously had significant memory issues and other things. So, because the brain is still plastic, even as I said, you can teach an old dog new tricks, the brain is able to still make new connections and create new connectivity. And so, I think it's not just the localization or diagnosis of the seizure focus or network, but what is the impact of other diseases and disorders on the brain's function? And so, we're now getting better at understanding exactly what you were pointing out, is what are these networks? What's a normal network for memory, for language, for motor, and where is the processing, and where are we starting to see defects? So, somebody who's having memory difficulties, is it truly just the hippocampus memory advised fantasies, et cetera, or is it a much more complex network that maybe we do and could modulate to a different extent to improve memory function for those with dementia? And so, in epilepsy patients who we see declines in their cognitive function, what's the etiology of that decline and where and how is it being impacted? And can we then also see that if we put in a neuromodulation device, do we start to see improvement? So, does those diagnostic opportunities become biomarkers of showing that our treatments are truly making a positive impact?

- Very well said. We barely understand why one side of the brain controls the contralateral side and not the same side. This is how far behind we are. This is how little we know now why there is a contralateral mapping on the cortex of controlling limbs. If we still don't understand that, which we don't, there's many theories obviously, it tells you how little we know about real neurosurgery and real functions of the brain. So, therefore for future of neurosurgery, is extremely bright in functional neurosurgery, and really understanding the really truly the "Seat of the Soul". So, I wanna thank you David. I wanna really congratulate you for huge legacy you've had, immense reinventing throughout your career. You have done that all of us need to do in neurosurgery and any work we do. Always have to reinvent yourself. If we don't reinvent ourselves, we lose. There's nothing more true that if you don't adapt, relearn, reinvent yourself, you will fail. And that's, it was something Steve Jobs always used to say. And I think it's so true in our professions as well. So, with that in mind, I wanna thank you. Thank you, thank you for being with us and look forward to having you again in the future David.

- Thank you Aaron. I Really appreciate your invitation.

- You're welcome.

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