Our presentation today is brought to us by Doctor Roxanne Simmons. Doctor Simmons is a child neurologist here at Children's Oakland and a specialist in pediatric epilepsy. She went to medical school at the University of Texas Houston and completed her child neurology residency in pediatric epilepsy fellowship at U CS F Mission Bay. She joined our faculty on the Oakland side in 2021 and we are so grateful to have her clinical expertise as well as her time today. And with that, I will hand it off to Doctor Simmons. Thanks so much Sarah for that kind introduction and thank you for the opportunity to let me give this talk today. Um So I'm giving a talk today on treatment of medication resistant epilepsy and this isn't intended to be a spooky talk even though it's being given on Halloween. Um But my goal is to really introduce, introduce everyone. It's participating. Now with a general overview of what are some new treatments that we have to offer our patients who have very difficult to control epilepsy. Just briefly, I have no disclosures relevant to this talk and in terms of our objectives here today. Well, first of all, just identify, you know, what is medication resistant epilepsy. Then we'll move on to differentiate between the surgical options and devices for treatment of medication resistant epilepsy. And last, I'm going to describe several medications with new mechanisms of action and diet for treatment and medication resistant epilepsy. So, first of all, let's just define what we're talking about, what is medication resistant epilepsy. Those consensus paper um came out that the way that we now define epilepsy. Um Basically saying it's a disease of the brain that's defined by any of these conditions. So at least two unprovoked seizures that are happening at least a day apart, um or one unprovoked seizure with the probability of having another seizure that's greater than 60%. And what does that mean? That kind of just gives us epileptologists some leeway to say that well, if the patients had one unprovoked seizure, but they have, for example, abnormal eg background or an abnormal MRI that demonstrates something that suggests a higher risk of epilepsy like prior brain injury, heterotopia, focal focal cortical dysplasia. These are things that can allow us to give that diagnosis to a patient who's just presenting with their first seizure. So if that's epilepsy, then what is medication resistant epilepsy? So this is also known as medication refractor, epilepsy, drug resistant epilepsy, you'll see various terms used to describe the same condition. But medication resistant epilepsy is when someone has failed at least two or more anti seizure medications. And assuming these patients are taking adequate dosages for the correct seizure type. For example, they're not uh you know, treating a uh vocal epilepsy with an incorrect medication or vice versa if it's something else and that the medication is not discontinued due to side effects and that it's used in adequate dosage. I'm just highlighting here on the right that I'll speak about this in, in a moment. But you know, one in three people um with epilepsy can't control their seizures just with medication. So this slide is a graph depicting all the development of new anti seizure medications over the years. You can see there's a really, really steep uptick that happens around 1990 where just tons of new anti seizure medications are being introduced to the market. And, and actually this is now an outdated slide there even more beyond this. You can see that really, um stark increase. And I remember learning this as a fellow and it still just surprises me today. But despite all of those new medications, still, one third of our population remains uncontrolled, meaning that you still have, we still haven't moved um the dial at all and treating medication with an epilepsy. Despite all of these new advances in medications, I would say what we have done a better job at is developing medications that come in different formulations. For example, like Sprinkle formulations for Children or there are even some 3d printed versions of certain medications that can be, um, dissolved on the time. And so, while we've made new formulations and much more tolerable side effects, overall, the efficacy really hasn't changed much. Um, which to me is still shocking when I see this. Now, they've told you that, um, you know, epilepsy is a, a disorder where someone has either two or more unprovoked seizures or one unprovoked seizure. And what we call a greater than a 60% chance of having another seizure. And the medication resistant epilepsy is someone who has failed more than two or more anti seizure medications. And like I've showed you too that that number in terms of medication resistant epilepsy patients really hasn't changed throughout the past decades. Um Let's switch gears and talk about different treatments for this condition specifically between surgical options and devices for treatment of medication resistant epilepsy. And so, as part of my role over here at Children's Oakland Hospital, um I am tasked with developing epilepsy surgical program here. And so what is epilepsy surgery for patients who have medication resistant epilepsy that can constitute a bunch of different things. But the way that I tend to break it down is either um resection, um hemi forot hemispherectomy, um corpus callicott or laser ablation. I'll go through each of those individual features to give you some more details about that. So, receptive surgery is when we, let's say, for example, we've identified um uh a focal area in someone's brain where we think the seizures emanating from and they've proven to become medication resistant. We have a good idea that we can actually remove the area that we're interested in, that we think is causing epilepsy. What we can do is what's called receptive surgery. So for example, taking out the temporal lobe, we might have heard of like a medial temporal lobectomy is a really common procedure. It's done more often in, in adults. Um And the way that we do that is we use something called um interoperate monitoring with electric cortic gray, which is abbreviated ECO G. And what we do is actually in the or with our neurosurgery colleagues, we will um look at the subdural grids which are placed directly on the cortex and record directly from the cortex itself. And this can be really helpful for finding margins of resection, for example. So for a patient where they and this is actually a case that we did um a couple of months ago. So you can see this patient has and the left temporal lobe is little bubbly looking structure which um was a low grade glioma. This patient actually had um interoperate guided um electrocorticography where we helped to delineate and define the margins around that lesion. Because oftentimes you'll find that um while part of the lesion itself is visible in MRI there might be adjacent regions that are not visible and the real way to help delineate that can be by using this to detect, are there, you know, abnormal spikes that we're seeing inter operatively that's surrounding that lesion itself. Um And there's been some literature that looks into the effectiveness of E COG and the thought is that it may help with seizure freedom outcomes. For example, if you do eco E cog effectively and you find that oh actually, this this lesion is extending more posteriorly and I need to res respect a little bit more um that can help overall with the seizure freedom outcomes for these patients, the more dramatic example. But something that we use nonetheless. So with hemisphere atomy or hemispherectomy, what we're doing with this procedure is basically removing um or disconnecting an entire hemisphere. And so really the main indication that I think about for this type of surgery would be for Rasmussen's encephalitis or Rasmussen syndrome. And this is where patients um have a very, very rare autoimmune condition where they basically have um progressive atrophy and deterioration of one hemisphere. And really the only cure for that is actually removing the affected hemisphere before it spreads contralateral to the other hemisphere. Um So this is actually an example of a child who had a hemisect toy. So had that brain that actually that brain tissue removed. But hemisphere toy now is being used more commonly, that's basically where they disconnect the hemisphere, but leave it inside the skull. And so while it's not connected to the other parts of the brain tissue. Um It's still physically there and that can actually reduce some of the rates of um complications from this procedure, which might be um bleeding or uh hydrocephalus is the main way to think about. And you might say like, wow, that looks really extreme. And um this is actually an example of a seven year old girl who had a hemispherectomy at age three years for Rasmus syndrome, um had intractable epilepsy and had um had already really progressed to rights sided hemiplegia and had really severe aggression of language skills. Um And while this was her dominant hemisphere that was removed, um basically, this child was still uh fully bilingual and multiple languages and her hemiplegia had partially recovered and was only really noticeable for some slight spasticity of her left arm and leg. Um So one example about how when this procedure is done specifically before age five years, Children can have really astounding outcomes. So while this procedure would be pretty devastating to an adolescent or an adult, um we found that when you remove half a hemisphere before the age of five years, the brain actually does a pretty decent job of rewiring a lot of those connections. So in these cases of of Remus syndrome, it's good to identify them early and actually move forward with this um hemisphere hemi to help with the outcomes. So moving on to Corpus callis soom another type of another form of disconnection. Um oops to um so Corpus Callan, I tend to think of it more as a palliative form of treatment. Um it seems main indication would be for drop seizures and what is a drop seizure? So any sort of seizure type that makes someone fall? So that could be a tonic seizure. So, loss of tone or tonic seizures or someone stiffens and then falls could be my iconic seizures. They have a jerk and then fall. Or of course, we think about it in spasms specifically and um infantile spasms too. Um The outcomes in terms of Corpus Callas soy were about a 90% reduction in drop attacks for a total corpus callicott versus 50% reduction for a partial calci, which is about just two thirds of it. And what a corpus cal soy actually does is the neurosurgeon in there. And they um basically sever these fibers that are connecting both hemispheres. Um They used to do this, you know, physically basically with a scalpel, but now they've actually had newer techniques where they can do this with lasers too. So developing some techniques that are potentially less invasive and again, complications with doing this is you can get what's called disconnection syndrome. So kind of when the left hemisphere isn't communicating well with the right hemisphere and that could lead to some funny situations. Um And then of course, we always think about surgical complications like hydrocephalus or infection or risk factors too. Um You won't see us to use the corpus scouts on you so much but more so is reserved for those really risk factory populations like Children who have might have heard the term le Lenox Gusteau syndrome, but really, really horrible lifelong epilepsy, it's been difficult to control. Um or in the case of very rare fracture, infantile spasms, it's been used to, there was some success. So next, I'll move on to another potentially less invasive type of epilepsy surgery known as laser ablation. Um It's also known as laser laser interstitial thermal therapy, which is how it's abbreviated um patients like it and we like it too because it's mentally invasive. It doesn't require craniotomy. So we're not actually opening up of the skull to access the brain tissue and it can be really helpful in treating those small well defined regions. So the classic example might be um mesiotemporal sclerosis, which is, you know, commonly seen in usually in older Children and adults. Um It can be very effective since we're just a blading that one small area. Um It's also been used in terms of treating cat o sorry, somebody just keeps like out there, we go, stay there. Um Also been helpful for treating cavernous malformations too. So you think about those little bundles of blood vessels that are located on the vortex could be helpful for that. Um They've used it for small tumors. So small, low growing tumors, low grade tumors. And then now it's being used maybe for tumors from tubs, uh tubers in patients with tuber sclerosis complex. If you think about those patients, they might have, you know, dozens of, of tubers that may not all be um epileptogenic or causing issues, but the laser ablation can help to potentially remove some of those more uh aggressive tubers that are causing issues. So now that we discussed some of the different surgical options for epilepsy and we want to talk about devices which I know I'm pretty interested in this and a lot of other people are interested too. But um as I mentioned before, as you've kind of seen that explosion in new um medicines over the past few decades, you've also probably counted a lot more devices. So not only for epilepsy, but you've probably seen these for migraine treatment, headache, other sort of things. Um But I really wanted to take time to highlight here the devices that we're using specifically for epilepsy patients, some which have been around for a long time and some that are newer. Um So I'll start with that, but we'll go over VN SRN SD BS and some wearable seizure detection devices. So first, I'll start with VNS which stands for vagus nerve stimulation. This is a device that's been around for gosh, a few decades. Now, I think it came out initially in the eighties actually. Um and it is an implanted device that delivers stimulation of the vagus nerve and really has three kind of I call it like more of like a dumb device. There are three modes where um uh just a preventative mode where it's kind of always stimulated in the background and auto mode where it transiently goes up and then a magnet swipe which can also activate that, that transit increase in settings. And like most of these devices, we found that it really takes time to see the effect of them. So in terms of outcomes, um about the number that I always give that was shown by data is that there's a 50% reduction seizure burden around one year. And then there can be up to a 70% reduction seizure burden of five years for patients who continue to use this device. And that being said, we're of course, using these devices specifically BNS two and some of the more refractory population patients. Again, those patients with Lenox Gusteau syndrome with multiple seizure types who are um pretty impaired or pretty have a have a fairly low neurologic baseline sometimes. Um And so it can be harder to assess the efficacy of these most of some of those cases. Um I like Venus because you said it, it's there and it's kind of as functioning and working in the background. It's not a medication that someone has to remember to take every day. So for example, for patients who really struggle with medication compliance, it could be a better option for that um it does have potential side effects. But in general, I would say there are a lot less than taking oral medication. So some potential side effects you might see from VNS could be dysphonia, which is a change in the voice quality. You can see dyspnea, which is difficulty breathing, coughing, or sometimes patients can have a little bit of oropharyngeal pain or pain at the stimulation site. Um But overall, we tend to be able to mitigate those side effects with adjusting the settings. And basically, we're implanting this device. I'll show this picture here. Um The way that the neur our neurosurgical colleagues do it is there is um a very small battery pack that's implanted in the left chest underneath the skin. So really you could palpate it but you can't really see externally and then a wire is run from that all the way up to the vagus nerve and a wire is basically wrapped around the vs nerd and providing this constant source of of stimulation. Um That for whatever reason, again, we don't know the exact mechanism, but we know that it can't work, can reduce the frequency of seizures. I tend to think of VNS too as more of a palliative treatment as well. So for patients who have, for example, like I talked about a really discreet focal lesion where we think they might benefit from receptive surgery. Um VNS, it wouldn't be the best option necessarily for that, but it can be for someone who, for example, has a really bad genetic generalized epilepsy um or has multiple seizure types and doesn't have a clear uh focal leisure lesion that would respond to resection. Um So that's when I think about VNS now move on to responsive neural stimulation, which is abbreviated RNS. So this is developed maybe about 1015 years ago at this point, it's a much smarter, more savvy device in the VNS. Um It is an implanted intracranial device. So, whereas VNS was um technically, it's a, it's a surgery, it's done by neurosurgeons, but it's not an intracranial surgery, which is why it's pretty easy. It's just that small incision in the neck and then in the upper left chest. Um RNS is actually an intracranial device. So it does require a craniotomy part of the skull has to be removed. Kind of like we were saying initially with that um uh the techniques that we use for either um lesion toy or or eco guided studies, we have to remove part of the skull to actually put um electrodes directly on the cortex itself. But we like this because it's a a smart device that both detects and responds that it uses a closed feedback loop. Um And again, it tends to work over time too, but tends to work better than Venus over time. So for a study that was done, the median reduction and seizure frequency after nine years was 75%. And then they even found that within the study, there was a super group of responders, about 30% that had a 90% reduction in seizure frequency. And this is really based on the technique that's used for this. So RN si say is again a smart device that requires a lot more input and um a lot, a lot more input and guidance from the epileptologist who's using it to be effective. And with this picture here, I just wanted to highlight what it looks like. So um our neurosurgeons help by carving out a portion of the skull itself and putting the battery pack in there. So it's laying internally to the skull, it's flushed there. So you actually don't see anything externally. And then what we do is, for example, patients that have um a type of focal onset seizures, what we can do is actually place either 21 by four strips. So here's an example here of a strip that has four electrodes or uh the equivalent to that two would be what's called a depth electrode. So similar thing, but this can actually be inserted um in deeper portions within the cortex itself. So with this RNS device, you're allowed um two of those one by four either strips or depth electrodes. And if you can think about it can be really, really helpful for those patients that have a small discrete lesion. Um but it's not so helpful for someone who has, for example, a really broad area of cortical dysplasia or has multiple areas. Um I'm sure that will change in the future as our technology advances and we're actually doing some things where some people are actually using implanting two RNS devices. So if someone has, let's say bilateral pathology, that's small, that's not covered well enough by just one of these devices with two of those strips, they can actually do two on each side. And one of the classic examples that's used more commonly in adults because we see it more often there would be for um bilateral mesiotemporal sclerosis. So, you know, obviously, you can't take out both hippocampi for a patient who has that, that would lead to, you know, permanent um amnesia. And so with these patients in particular, especially if we're not sure where um where the burden of their seizures are coming from RNS is being really helpful to understand what the long term um implantation looks like. So um it should have gone back to at the very beginning when I was talking about electrocorticography and recording from the scalp itself. So oftentimes what we do for patients who were actually undergoing a surgical work up, we might have um uh uh those electrodes implanted on the cortex itself. And the patients in the IC U has a skull, uh skull flat place back on, but we actually record their seizures for an extended period of time. And that can be helpful again for patients that have really occult seizures that are start starting in a deep location or might maybe have really infrequent seizures. Um And with the RNS, we're finding that we're actually getting very, very long term recordings just like that um electrocorticography that we use in the or, but we're getting over the course of months to years and this can be really helpful again for patients who might have bilateral pathology, but you're not sure what percentage is arising from the left side or the right side. Um So what people are doing, which I think is really interesting and I think probably very helpful for outcomes overall in terms of um reducing morbidity. Um they're using RNS long term. And for example, I'll give the case again of someone who has bilateral meal sclerosis, you could say, well, you know, I suspect that, you know, 80% is coming from the left and, you know, 20% coming from the right. But let me implant both sides with, with RNS here and we're gonna monitor for a year and see what the actual percentage is and maybe find out that it's actually 98% from the left side and 2% from the right side. And that's with chronic recordings again over a long period of time, which could help guide the epileptologist think about, you know, well, actually let me, let me actually go back and respect the left side. So people will do that where they might have artists implanted for a long period of time and gather better information and then ultimately make a decision to go back and resect that portion too. Um And I'll just add here too that it's really, really dependent on how that Plato is using it to acquires a lot more nuance. And, um I did unfortunately include any of the recording, the raw recordings that we get from RNS. And here too. But uh with those patterns, we really think about how we can change the settings on the RNS both to detect and stimulate seizures. So you can either reduce or increase the sensitivity threshold, you can change the amount that it's fine. And with this battery pack too, you know, it does depend on how often it's going off and eventually does usually require replacement if it's been in place for a few years. Um But I like this device because again, it's pretty effective um in terms of long term use to manage focal and onset seizures. And I think it could be a really great option for patients where you're not quite sure um for someone who's multifocal which areas is causing most of the issues. So now we move on to deep brain stimulation that's abbreviated as D BS. And some of you might be familiar with this particular device used in the context of movement disorders. So actually, our movement disorder neurology colleagues have been using this device for a number of years now to help with patients who have, for example, refractory. Um Parkinson's a refractory tremor, you might have seen it in those scenarios. But more recently, um we uh as epileptologists have adopted this device to use for treatment and medication resistant epilepsy. There was actually a trial that abbreviated sane which stands for a stimulation of the anterior nucleus of the thalamus and epilepsy. And with that study, a seven year follow up period showed that there were really lasting reductions in seizure frequency and improvements in quality of life. And so, while this is still a somewhat newer device for our field, we are using it more often and just to illustrate what this device actually looks like. So it's a little bit similar to the VNS in the sense that you have this little battery pack that's here, it's placed um under the left chest that you know, you can obviously palpate, but you can't see externally. Um and then a catheter is tunneled underneath the skin. And um what our neurosurgery colleagues do is they actually um will put a stimulation raw that's going directly into the bilateral um uh deep, deep brain structure is usually the thalamus. Um it could be really, really highly technique dependent surgery. And um uh it, as you can imagine, it can be very, very difficult to parcel out the different nuclei of the thalamus individually. Um for example, for most patients who uh with this trial, in particular, we're using anterior nucleus of the thalamus that for patients who mostly had um things like meso temporal sclerosis. Um But they've actually found more recently that in um Children and adults with Lenox Gusteau syndrome where those who have a really generalized epilepsy, multifocal epilepsy that stimulating what's called the central median nucleus can also be helpful too. So you can imagine it's very, very highly technique dependent study and similar to the VNS at this point right now, at least it's not necessarily a closed loop system. So it's kind of a set it and then um there's a steady uh frequency of pulsations in the background that doesn't really change. But I think some of the um manufacturers are looking at making this similar to the RNS where it's actually closed loop system where you can actually change settings over time. As you can imagine, as epileptologists, we really focus on the cortex. So not, we don't really know what signals look like in the faline, the deep gray structures. And so um uh that is something that is, is gonna become more prominent throughout the years. And um I think could be a really good option again for our patients who don't have a focal lesion um but obviously have really difficult to control epilepsy. So now we move on to some of the seizure detection devices which your patients may or may not be asking you about. I know mine certainly asked me about this and everyone loves a fun, you know, posh new detection device. Um And so I'll start with just the seizure detection watches. And this is probably the most commonly used device that we have. Um, the main example that I can think of is through a company called Tica, which is called the Embrace Watch. And it's an FDA approved device and it uses some proprietary system that measures skin conductance, skin temperature and um motion intensity and blood volume changes. Um It it is quite expensive, you know, it requires a monthly subscription fee. I think the cost of the device itself is around $250 and the monthly subscription fee could be anywhere between 10 and $20 per month. Um But what it does is again, for patients who might have, for example, nocturnal convulsive seizures, I think it can be helpful in that specific situation for detecting the seizures. And I always like if it provides the family and the child with peace of mind. So for example, for a family where the child is cosleeping with the parents and you know, feels anxious about sleeping independently or, or doing things independently. I think it can be very helpful. And what the watch does is when ideally when someone's having a convulsive seizure, it picks up on that and it will send an alert to the parent smartphone where it was registered for the for the device and it can alert them. Um I think that being said, I, I have used in patients, I think it's great for helping with anxiety in some situations. Um To be honest though, I'm not sure how effective it is actually detecting seizures. I have more families telling me that it tends to give a lot of false positives. So for example, if a child is um scratching themselves, um or if a child, I one family tell me the kid was jumping on the trampoline and it went off. So of course, there are scenarios where if there's a change in movement that it's likely to, to trigger the seizure detection, that being said, I think it's a great option again for families that can't afford it where it provides peace of mind and allows for more um independence in terms of the patient. So now that we've gone over some of the different surgical options and devices for medication versus epilepsy, we'll shift gears. I just wanted to highlight some of the newer medications with newer mechanisms of action and also diet for treatment medication, which is an epilepsy. I'm sure you're all familiar with the ketogenic diet. You've um a lot of our residents here are so helpful when we admit patients to start the diet too. And I'm sure you all know Marian Roone, who's our ketogenic dietitian here at um Children's Hospital, Oakland is really wonderful with managing this diet for our patients. Um And so the ketogenic diet as, as most of you probably know, is a very, you know, high fat, high protein, low carbohydrate diet. And its indications are again for medication resistant epilepsy. Um but specifically for a couple of really rare genetic conditions. So, in particular, um glut one deficiency, which is where um a genetic cause where um patients actually are not able to move glucose into their brain. And so the ketogenic diet in that sense can help them use a different source of energy. And also for pyruvate D A digest complex. Another um example of um a condition where energy metabolism is lacking and where ketones from the ketogenic diet can actually help in those situations. And again, we don't know exactly the mechanism why it works. But um the theory is that ketosis or ketones itself somehow um reduce the frequency of seizures. And we've actually known this because, you know, thousands of years ago, it was described, I think in, in Roman patients who had epilepsy that they recognize that when they fasted, that would tend to temper or reduce their seizures. And so people have been inherently doing this for thousands of years where they've noticed there's something about diet and fasting in particular um that can reduce their seizures. And of course, it's not possible for to fast all the time. But I think the sense was that um people understood even, you know, thousands of years ago that um there was something about the state of fasting something that was produced that could reduce the the frequency of seizures themselves. And in terms of studies, there have been a lot of really good, you know, randomized control trials and in Children um that demonstrate that there was a mean seizure frequency that was actually um nearly 60% lower. So it's quite effective. And that's kind of the, the general standard that we use when looking at a new treatment for epilepsy is, do you know, 50% of the patients have a 50% or greater reduction in their seizures. And then with the ketogenic diet, I just one of the highlights here that um of course full ketosis, uh full ketogenic diet is um tends to be very effective. But we found that actually variations among that can still be quite effective too. And as you can imagine trying to get a, you know, five or seven year old child to adhere to ketogenic diet can be a little bit tricky. It's easier now because there are a lot of fun keto friendly foods. I'm sure you've seen lots when you've gone to the grocery stores and the different options and sort of bad diet that's been out there. Um But we're learning too that there are of course variations along the diet. So while the, the fol ketosis like a 4 to 1 ratio is the most extreme of that. Um we've been using in patients, for example, a modified Atkins diet or even a low glycaemic index diet. And while those patients may not be incomplete tosis, we found that they can still have some reduction of seizure frequency, which is really great. Um with the ketogenic diet, it does have adverse effects. So, while it doesn't have some of the typical medication interactions and some other other anti seizure medications, it can have um um adverse effects. The main things that we think about with this diet would be um nutrient deficiencies or bone density issues, which is why we monitor our patients fairly regular with blood work to check their vitamin D levels and their electrolytes and the ketogenic diet can increase the risk of developing renal stones. So for patients of mine that are already on, for example, Topamax, which has an increased risk of developing renal stones. I actually think about, for example, coming off pyramid, um when we're thinking about starting a diet, a lot of patients can experience digestive issues, either initially weight loss or constipation are the really big ones, sometimes diarrhea too. And then long term, although it's not really seen in the pediatric population, on the adult side, we worry about heart disease. So if someone's constantly using a high fat, um high protein diet, how does that affect their cardiovascular system in the long term? That being said, I think ketogenic die is a great option. Again, it uses a different mechanism than any of our other anti seizure medications. So I do use it often and I certainly think about using in patients who, um, have medication resistant epilepsy. And I would add to that in infants or a child who is g tube fed, the ketogenic diet can be even easier because it does come in basically a formula keto cal formula where you can give them to, um, to be adherent to the diet. So everyone loves asking about CBD. So this is um something I'm sure you've encountered with your patients even not being an epileptologist. And um um while uh cannabidiol which is known in the um the brand name is epi because I'm sure you've seen too uh while this has been around for a number of years. Now, patients are still asking about it. And initially, when it was first introduced to the market for epilepsy, it was used for patients with um unique syndromes called Gervais syndrome and then Lenox Gusto Syndrome. But now really, they've expanded it to any patient with epilepsy. And in terms of outcomes for a randomized control trial trial for patients with Linux cow syndrome who were taking um cannabidiol, the median reduction in monthly drop seizures was around 50%. So it's still meeting that criteria where you want to see about 50% of our patients responding with um at least a 50% reduction in their seizure frequency. And the mechanism for cannabidiol is really unknown. So, there are a lot of theories out there, we know we, we see that it works but we're not quite sure why, like most of our medications that we use in treatments. Um, one thought is that it somehow reduces neuronal hyperexcitability and, um, can work at some different excitatory synapses. Um, but the truth is we're, we're not quite sure how it works and then, you know, I just want to highlight too that while a lot of families will come asking specifically about CBD and can have a dial, it's I always try to emphasize to them that it's still a prescribed medication, it's a purified form of CBD. Um and that like any other medication, it also has some adverse effects. So a lot of people would think of as almost a homeopathic or holistic medicine. And that's not the case. Um in terms of a side effect profile, it can actually cause decreased appetite and weight loss, which I have seen it can cause of course lethargy, um which for some patients who might be very hyperactive or have behavioral issues, it can be could be helpful in that situation. Um But just like any of other drugs that does require monitoring of some labs. So you have to monitor a ST and a LT with some frequency, it can cause some liver enzyme element patients um and it can interact other medications. So the specific interaction I always think about because oftentimes we'll have patients on both these medications would be um on for cloBAZam. So um eps can actually raise the levels of on for cloBAZam, which in some situations that could be beneficial. So you're getting more, you know, bang for your buck for the medication. But for um people on that medication, you have to be aware of that interaction as well. So moving on to new posh medication. So fenfluramine, which some of you may or may not have heard of. Um this is introduced to the market uh maybe five or six years ago at this point, specifically, initially, for, again Gervais syndromes, a lot of the drug companies you'll see will target these unique um epilepsy syndromes to first introduce and use a medication for now, it's been expanded to patients who have Lenox Gusto syndrome. And um you might have heard of the, you know, cool drug Fen Fen that was back in the seventies eighties, it was a diet pill. So it was used for weight loss. Um And this drug has an interesting history because ultimately, um it was first used as a weight loss pill and then was ultimately pulled from the market due to really adverse cardiovascular side effects. So, um again, this is used in a different population that we're using now. So in adults who were mostly um obese or overweight and were taking much higher doses and they found that um over time, some of those patients developed a valvular cardiomyopathy. Um And so for that reason, fin forming was pulled initially from the market, but then was reintroduced later with a different indication for use in epilepsy. Specifically patients with vase syndrome. And it would had a here that was first introduced um actually in, in Belgium, the king there used it as it had a compassionate case used for this and used it in in um a group of patients with Gervase syndrome and found that it worked exceptionally. And these patients have been on Florine for over a decade now and have not developed any um uh valvular issues and in terms of outcomes. So this is one exception where um again, I gave you that, that chart at the beginning, it said that, you know, in terms of pushing the needle on medication with epilepsy, most medications are not doing that. There are some rare exceptions for subgroups of patients with epilepsy and this is one of them. So, so fenfluramine when used in patients with Dravet Syndrome, um nearly two thirds. So 60 70% experienced a reduction convulsive seizure frequency per month, which is really spectacular because that's much higher than our typical standards. Um and the way that works is not completely understood, but we know that it acts as an amphetamine derivative. So it's a symptom mimetic stimulant and it also um works on uh selective serotonin um receptors as well and it stimulates also five HT receptor subtypes. And so because of the side effects, like I mentioned. So common side effects you might expect from, from florine would be um appetite reduction or weight loss, which actually, I do see quite a bit in our patients. And so in those scenarios might have to try reducing the dose a little bit or I've actually used appetite stimulants with some success and I've been able to continue using flamin in those cases. Um All these patients who are on femine um have to be enrolled in a, a REMS monitoring program where they have to get a uh echocardiogram basically every six months to monitor for any disturbances or changes in the structure that are specific, specific, specifically that valvular um cardiomyopathy that can be seen. But luckily, um while this has been approved for, for Gervase syndrome, we have yet to find that any patients who have been taking florine, which is good news moving on to another drug. This is probably the newest of the drugs that that I'm talking about here is a drug called Sonobo Made is the brand name or X Corp or sorry. Survey is a generic name and X corporate is a brand name. Um This is a newer drug that was introduced a few years ago and its indications are mainly for focal epilepsy. Um Well, so far it's only been technically approved in adults. We have been using it in Children, specifically, more of the adolescent, older Children. Um And this drug is, it's taken once a day So it's a long acting formulation which, which I like. Um and in terms of outcomes and randomized controlled trials for uncontrolled focal epilepsy. Um they saw a responder rate of about 64%. So again, 50% or more reduction in baseline seizure frequency. This is using a high dose of 400 mg daily. And the mechanism is different than some of our other anti-seizure me uh anti seizure medications. So it is a sodium channel acting medication that acts at both inhibiting fast and slow in activation sodium channels. And then in addition to sodium channel activity, it's a positive allosteric modulator gabba channels. So it has that gab effect plus the sodium channel effect, which tends to work well really well for some patients. Um in terms of side effects, it's similar to some of the other sodium channel medications where at higher doses, it could make someone feel a little bit more dizzy, a little bit more tired. Um The most uh the most common side effects that we see with this could be could be those sort of things. Um And then similar to lamoTRIgine you might see here that with this image, it's a image of X Corp we using a blister pack. Um you have to increase it really, really slowly. And the thought behind that is because similar to LamISIL in in um a trial, it was noted that that several patients developed a sort of drug rash to it And so the reason for the really slow increase is to monitor closely for any development of drug rash. I haven't experienced that yet thankfully, but um something to be aware of and then Sonova kind of like cannabidiol or Bidya can actually increase on levels as well. And so it's important to keep in mind those drug drug interactions. So oftentimes, the biggest challenge I've had is we've been using in these, our patients who are very medication refractor on multiple medicines. And then introducing it to someone who's already on, on fee can cause them to feel over sedated or tired. And they can attribute that to the Sonoma when actually it's just increasing on fee levels in patients who are on that. So we usually have to do some sort of um simultaneous dose reduction of on fee. And then while I've gone over those new drugs, I just wanted to highlight, um, wrapping up towards the end of this talk, um health disparities. So, of course, um, with our population here at Children's Oakland and 90% of my patients are, are Medic Medicaid. Um, only 10% are private care and this particular study looked at and, and Children with medication was an epilepsy. Um, patients who were younger of minority race or ethnicity, ethnicity and had Medicaid insurance were more often treated medically than surgery. And so I've just spent the last, you know, 40 ish minutes or so, talk to you about how um, medications just aren't sufficient for treating medication. This is an epilepsy that we are still really struggling to move the needle on. That one third of the population that patients who have epilepsy that um have incurable epilepsy. And, um, you know, why aren't we offering the same sort of treatments to our patient population here? And so I, I'd love for you to think about that next time. Um, and that's again, part of my motivation for building the epilepsy surgery program over here as well as to offer our patients the same sort of effective treatments that we can for their epilepsy. And with that, I think we're on time, we can move on to the practice questions. I think Sarah, you're going to read the questions or let me know if you'd like me to do that instead sounds good. These are practice questions that you have for our audience or you are ready for the Q and A? Oh I can do either of them. Why don't we go through the, the practice questions and then we can do Q and A afterwards? Ok. OK. After how many failed anti seizure medications is a patient with epilepsy considered medication resistant? You want me to answer? Am I supposed to be looking in the Q and A box for answers? It's a little hard for folks to um chat answers. Uh participants, you can chat into the Q and A your responses rather than the chat function. Ok. I'm seeing some coming into the Q and A box now. So it's working the couple of twos and threes. So it's on the right track. So the answer is actually after two medications. So once someone has, um, failed two anti seizure medications at adequate dosages and not because of side effects in particular, they're considered medication resistant. Question. Two, what fraction of patients with epilepsy are medication resistant? I feel like I have some background music here with people answering questions. This is great though to cement the knowledge. OK. So I'm seeing a lot of CS and one third, if there's one thing that I've hammered into throughout this talk is that uh despite all of our advances, one third of our population epilepsy is medication assistant seems like everyone got that. So for question three, which device uses pattern detection to stimulate seizure, FF and abor seizures going back to our devices and just to define them too. VNS stands for vagus nerve stimulation. RNS for responsive neural stimulation, devious for deep brain stimulation. See some B, some RNS one dvs. So there's actually RNS for this. So R NSA responsive neural stimulation is that smarter device, we can actually train it over time by changing the detection settings and the stimulation settings. Um to both detect seizures more eloquently and to stimulate abo those seizures. And again, this could change in the future with D BS. But right now VNS and D BS are typically open loop systems that, that don't really react as well. Question four, which of the following is a potential side effect of the ketogenic diet. Can't disappoint Marianne with this. She's counting on you. OK. I'm seeing a lot of ease. I think he is a consensus there. That's right. So renal calculi are one of the potential side effects of the ketogenic diet. But conversing more often causes weight loss and weight gain, um can be used again to treat things like uh type two diabetes and and doesn't cause anything related to liver function. So, no hepatic sister jaundice. Excellent. Last question, true or false. RNS is contraindicated with MRI use. We get calls from community physicians about this all the time. So next time I get a call, they'll know the answer. I see some false in there too. And it's right. So RNS is MRI conditional not contraindicated kind of like VNS. We actually have to put it in an MRI safe mode. Um The main thing to worry about with any implanted device that's intracranial would be if it heats up or shifts in terms of when the patients receiving the MRI. But um RNS is, is safe for MRI when it's put in the correct mode. So does not, does not prevent a patient from receiving an MRI. Excellent. And then moving on have my references listed here which I'm happy to share later. Then maybe we can move on to the Q and A part. That would be great. Yes, thank you. That was so cool and interesting. I think we, you know, see a lot of these kiddos that are on a lot of medications and have tried and failed various things and it's exciting to think that there may be kind of hope on the horizon and creative ways to, to target their seizures. Yes. Absolutely. It's a fun field to be in right now. Yeah. Can you give us a couple specifics of what might be coming to the Oakland side soon or what you're hoping for for this campus? Yeah. So in terms of our epilepsy surgical program, um we obviously have Doctor Curtis Auguste is our wonderful neurosurgeon that works both on the East Bay and West Bay. So he's already here and functioning and we're actually, you know, doing some of those E COG studies now and we have capabilities of doing um uh certain types of, of longer intracranial monitoring too. Um Really the only thing that we, that we won't be able to do at this side of the campus would be um D BS, which is deep brain stimulation or laser ablation therapy, just because those require um a different uh different sets of tools and skills. And um uh those can still certainly be done. But I'm actually referring my patients to have the procedure done physically at the West Bay location. But basically, our goal is for anything else that, you know, can and should be done over here. Um And obviously, as you guys know, we have a, a different patient population that might need assistance with various things. And um we're, we're excited to be offering that to them. Yeah, that's super exciting and is insurance covering these is Medica covering these procedures. That's a great question. So from my experience, Medica has actually been better than some of the private insurance um where we can run into issues might be, for example, if we want to use RNS patients. So technically, it's FDA proof for adults or I forget the exact age of 17 and up. But um we have the in patients, I know that other institutions have even implanted RNS as young as like five or six years, which um I think the real limitation and that is um physically with the battery pack for RNS. Um the skull has to be a certain degree of thickness to be able to implant it. And so obviously, for someone who's still got a thin skull or two or three years old, it's not the right option for that. Um But it, it is being used in Children and from, I haven't implanted one yet personally myself. But from my experience of colleagues, it can be done, it just might require a little bit more work on our end. And again, we're taking really difficult to control epilepsy patients. And so usually in those scenarios, insurance is uh much more forgiving for the, you know, that you said the raw data that comes out of the RNS monitoring. Does that, is that something that you the epileptologist interpret it or does it go back to the company? Does it look like it's um it's left to the log? So there have been a lot of studies ongoing. We're looking at some of that raw data um but it's basically fed back to the log and of course, we can use the assistance of um uh rep reps from that company to help us interpret the data and how to change the settings. But that's why I think it's a much more savvy smart device that's very dependent on how the Epito is using it. Um I didn't mention it here too but there have been even sometimes where people have used like stimulating across the two, the two strips themselves as post to direct. So a lot more um fancy techniques that, that I myself, I'm not so well versed at this moment, but uh I, I like that as an option. Yeah, that's super cool. Um We had one question about the watches, the seizure detect detection devices and whether insurance is covering those and wondering if you've seen them used as kids are either going off to college or transitioning to like adult care centers in their parents' homes. Yeah, it's a great question. So um it has been covered a portion by some insurances, I would say it's not usually the complete amount, it's usually just covering, helping to cover a portion of the upfront cost of the device itself. So the device cost $250 they might cover half of that. Um, that thinks that they don't cover the monthly subscription fee. And so that can be um, not an insignificant cost of someone paying, you know, 20 bucks a month for that. Um I think it can be really helpful for patients who are changing their environment and going away from a typical setting. So I haven't specifically used it for patients that are going off to college, but I think it could be helpful in those situations, especially if there's a lot of parental anxiety surrounding that. Um And the way it functions is it's connected to Bluetooth and it's really um only alerts a device within a certain range. I forget the exact range of it. And so, um I can't, you know, alert a parent who's in a different city, but if there's someone who's in the same building roommate, it could be used in that situation. Interesting. You feel like it's something an Apple watch might someday be interesting. I was thinking that I guess maybe they don't have any, they don't have any incentive to make it or not. So, so many other devices out there. But um I wouldn't be surprised if Apple tries to come out with something. Um, I was wondering how did they discover that famine works for seizures and in particular for Rebe. Yeah. I actually, you know, I wrote a paper on this a couple of years ago and I forget exactly how it was first discovered. But I, again, from what I remember it was first used in Belgium, like with compassionate care um for a population who had this Gervais syndrome and was medication resistant. Um I don't actually remember the, how they figured out that Florine might work for Gervais syndrome. Um Super interesting. I'm glad they did. Yeah. And so like a lot of other drugs, they tend to be repurposed over time. So, you know, bringing back an old drug that has um totally different indication, right? Um We had another question that is, you know, for our chronic seizure patients who, you know, we often see that they've trialed many medications in the past. Um, and are medication resistant, is the, the, the intent of multiple trials sort of that? We think the next drug might work better or is there sort of a wearing off effect? Like a medication works for a little while and then stops working. Is that? Yeah, we definitely see that there's um, a lot of families might describe like a honeymoon period where we introduce new medication. They respond really robustly for a few weeks or a couple of months and then they eventually seems like it wears off again. So I don't, we don't fully understand the mechanism behind that, but we certainly see it and we have families tell us that um the intent of trying different medications might be really, I think about scientific profile and um dependent on the type of epilepsy. So, you know, for a, a focal epilepsy, you'll focus on using a narrow spectrum agent versus, you know, generalized epilepsy was a broad agent. Um And that may always, may not always be clear initially when you're first um diagnosing epilepsy. So you might use something of mine. Oh, it was actually a different type of epilepsy. Let me switch this. Um But really, we're switching medications if something is either failing due to inefficacy or it's failing due to side effect profile. And again, I always tell families like I'll let you know one of the most common side effects, but that being said every person reacts to medications differently. And so I've had some families tell me things that, you know, are not even described with medication side effects which, you know, who knows? It's actually the medication itself versus the um the situation of, you know, relevant new diagnosis of epilepsy. And so those are things that we, that we encounter often. Yeah, super interesting. Um We had a couple questions about the keto diet. Yeah. Um First of all, do you, I know this, that you're a pediatric epileptologist, but do you, do your adult colleagues end up having to take off a fair number of patients off of the keto diet because of the metabolic side effects. Yeah, that's a great question. I've often wondered about that and, and to be honest, um, our adult colleagues, at least at U CS F, they don't have a dedicated ketogenic dietician in their clinic. And so I think in those situations, a lot of it's left to the, you know, the families themselves to continue the diet or their, um their new adult epileptologist to continue that. Um That being said, I don't know, I've actually transitioned many patients at this point who have been on the ketogenic diet, but I'm sure it's bound to happen um in those scenarios. So, technically, with the ketogenic diet, we focus on using it for at least two years and then if epilepsy is improving for whatever reason, trying to come off of that. Um That being said, realistically, I find myself using it in those patients who are very medication refractory and um you know, are not, are not um outgrowing or changing their epileptic significantly. Um And in those cases, we might think of it just as another medication where you have to try a different one to sort of replace it over time, they counter issues like bone density. Um I have had patients for example, who have experienced fractures on the diet. And that's again, for our patients who are nonweightbearing at baseline already have very fragile bones. Um And in those cases I think about being very careful or even coming off the diet in some instances. Interesting. And are there any hypotheses about why the the presence of ketosis? I know you mentioned the one specific diagnosis where they, they can't transport the glucose into the brain. But for the other types of epilepsy, why is it that this works? Yeah, I think I'd say we don't, we don't actually know um even people have tried doing additional studies. So, you know, maybe if someone can't actually produce their own ketones, can we give them like those ketone esters to see if that helps with seizures? And um doesn't seem to be as effective if you use those, you know, ketone like trying to supplement ketones to the body doesn't seem to be as effective. So there's some complicated pathway that's going on that we don't understand. Interesting. Ok. Um Are there any medications or procedures that are coming that, that you're excited about that aren't like that you haven't discussed today? But that are on the horizon that people have been whispering about? Yeah. So you'll see a lot more um advancement in terms of uh again, using for really niche types of epilepsy like gervais syndrome is the one that I gave the example of it was used for florine and um initially for uh cannabidiol. But what we're coming across too is that um people are now starting to shift and focus and think about how can they actually fix the underlying problem for, for example, someone who has a genetic epilepsy. Um And so you'll see there have been gene therapy trials done, for example, for Dr Syndrome or for other genetic mutations. Again, that's a very small subset of our patient population. But I think nonetheless could be, you know, really impactful, able to cure some of the epilepsy. Um So I'm excited to see some more of those drug developments for gene therapy and actually fixing the underlying problem as opposed to just, you know, throwing a medication and hoping that that, that, you know, works for that particular receptor subtype. Um And of course, some advanced advancement in new devices too. So, like I said, DVS may be used not as a um an open loop system as a closed loop system. So how can we, you know, respond to some of the patterns and tracing we're seeing when we're monitoring from the, the thalamus? And how can we stimulate that? I think would be really interesting and is way above my head right now. But um sounds pretty cool if that does happen. Yeah, it's super cool to think about all these people thinking about how to come at this from different ways. Yeah. Um I think that's most of the questions that we have from our participants. Is there anything, you know, we have a lot of community pediatricians on this call? Is there anything you wish that they would know in in our last few minutes with you about treatment resistant epilepsy or things that would help referrals to you. Yeah. So I would just um emphasize that anytime you have questions about, you know, is, does this patient actually have epilepsy? Do they have medication versus epilepsy? Again, it can get kind of tricky for someone who has, for example, non epileptic seizures. You may not be aware of that and really the best way to answer that question is doing a video admission. So if you have patients, you you think could have epilepsy or patients who um you question if they're well controlled or not. We really um welcome any sort of referrals to our clinic. So I provided there my personal email and then also our Oakland Neurology Clinic number too. And um you know, please feel free to reach out for any questions and always happy to help see um patients in the community too. And then you oh go ahead. I would just add to I have some pictures, some cute pictures on the bottom. That's my my dog ev who's there. She's a lot bigger now and then a picture of our, our chickens. I was gonna be the crazy chicken lady for Halloween, but I really slacked on my outfit and didn't get it together in time. But um I just wanted to highlight here. This is a, this is chicken named snacks. The one with the kind of brown and black coloring and she actually had seizures and so poor snacks actually packed passed away recently. But um she had seizures as a chicken. And it's always good to try to um not normalize it, but to tell patients that they're not, you know, help them feel not so isolated. So I always try to connect my patients with support groups. Um The Epilepsy Foundation in Northern California is a really great resource to where they actually have. Um I think virtual and in person support groups for adolescents and adults too. And so I think it's good to emphasize the patients that they're not the only ones out there with this condition and um connect them with other, other people have this as well and let them know that chickens can have seizures too. I'm so sorry for poor snacks but snacks. Well, thank you again, Doctor Simmons. It was such a pleasure to have you here and, and learn from you today. Thank you for having me and thanks uh thank you to the audience for listening.