This Treatment Talk will discuss the diagnosis, treatment, and prognosis of childhood absence epilepsy. The talk features Dr. Juliet Knowles, Assistant Professor in Neurology at Stanford University and a physician-scientist who provides clinical care for children with epilepsy and leads a lab team conducting basic, translational and clinical research on pediatric epilepsy. She will be joined by Francine Ang, a patient of Dr. Knowles who has been diagnosed with childhood absence epilepsy. Viewers will learn about absence epilepsy, including how it is diagnosed, current treatments available for childhood absence epilepsy, the prognosis for those diagnosed with childhood absence epilepsy, and some of the current research that is occurring in the field.
This video was sponsored by UCB Biosciences, Inc. and was produced by CURE Epilepsy in an effort to raise awareness of absence seizures.
UCB’s EXPAND study is one clinical trial currently available for childhood and juvenile absence epilepsy. If you are interested in learning more, visit www.expandstudy.com/cure
This talk is supported by an independent educational grant from UCB, Inc. CURE Epilepsy is solely responsible for the selection of the presenters and moderators. The opinions and recommendations expressed are those of the presenters and do not necessarily reflect the opinions, recommendations, or endorsements of CURE Epilepsy.
Epilepsy with eyelid myoclonia (EEM), formerly known as Jeavons syndrome, is a type of rare absence epilepsy characterized by a brief but intense and repeated jerking of the eyelids. Seizures can be triggered by bright and/or flickering lights and can be associated with abnormal EEG patterns.
EEM most often starts in children aged between 6 and 8 years and is more prevalent in girls than boys.
In this webinar, attendees learn how to recognize the clinical features of EEM, as well as how to differentiate it from other epilepsy syndromes. The webinar also reviews the consensus first-line treatments for EEM.
Kelsey M. Smith, MD is an Assistant Professor of Neurology and epileptologist at Mayo Clinic in Rochester, MN. Her clinical and research interests include genetic generalized epilepsy syndromes including EEM, autoimmune-associated seizure disorders, and women with epilepsy. She is the first author of multiple publications that address the diagnosis and treatment of EEM.
Q&A with Dr. Kelsey M. Smith
We’ve talked about the difficulty of controlling seizures in this epilepsy syndrome. Since it is hard to treat, what level of control should be expected and how do we know when to consider a new or an additional treatment or medication?
I think that that’s a great question and it’s a question that I think should be very individualized and depends on the patient itself. So it depends on what a patient’s goals are. If the patient really wants to be driving, then we need to try to escalate therapy to the point where the patient isn’t losing awareness where that could be safe and also a risk-benefit ratio of trying a new anti-seizure medication. And so, I try and just have a discussion with my patient to see and for us to agree on that difficult question.
Does the VNS or DBS work for this syndrome?
So there’s limited data out there. In our series, we did have some patients who had VNS implanted from our 30 patients we published in 2018. I have personally seen some patients who’ve had some nice response to vagus nerve stimulation, but I would just say we don’t have enough knowledge. Deep brain stimulation as well, there’s even less knowledge on. There’s actually one case report of responsive neurostimulation to the thalamus, which is similar to deep brain stimulation. Deep brain stimulation is advancing in areas of generalized epilepsy, but there’s just not as much experience in generalized epilepsy. So that also includes epilepsy with eyelid myoclonia. It’s definitely an area of research and we should know more in the coming years.
It’s perplexing about lamotrigine. In your talk, you talk about lamotrigine works and can be prescribed, but sodium channels as a rule are not prescribed. So can you explain that dichotomy since?
I’ll try. And this is not just for epilepsy with eyelid myoclonia where there’s this dichotomy. So we know that lamotrigine works for some generalized epilepsy syndromes. We use it in multiple generalized epilepsy syndromes. It can make myoclonic seizures worse. There’s some good data for that. And there’s some debate about the eyelid myoclonia being just myoclonus of the eyes. But also, we know works usually well for the generalized tonic-clonic seizures and these generalized epilepsy syndromes. And that’s probably due to other properties than just the sodium channel blocking properties. And so, I think it’s a bit of a balance. If a patient has a lot of extremity myoclonus, that’s something to consider when starting the lamotrigine. But still typically, it’s one of our go-to medicines for generalized epilepsies despite its sodium channel, part of its action being at the sodium channel.
Have combinations of medications been trialed for effectiveness against DEM? This person has seen some better control during medication transitions when there may be multiple meds on board. Is there any evidence for that? ?
There’s no great evidence for that to, most of the studies looking at epilepsy with eyelid myoclonia are retrospective studies. And it can be hard when you look at some of that data for the confounding factors of multiple medications. It wouldn’t surprise me if there is sometimes a combination that works better balancing the eyelid myoclonia and things like that. But we just don’t have enough data to say, I would say. There’s a couple of retrospective series that puts some of the combinations together, but that data is limited and half interpreted.
So, there are some new medications available now. Is there any knowledge about how well Xcopri might work?
There was a series published actually out of Mayo by one of our fellows, Shruti Agashe, looking at Xcopri or cenobamate in generalized epilepsies. And I believe there was one patient with epilepsy with eyelid myoclonia in that. So obviously very limited data. There are studies that are hoping, my understanding is to study cenobamate or Xcopri in generalized epilepsies, and we don’t have the results from those in general. So I just don’t think we have enough knowledge at this time.
The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified healthcare professionals who are familiar with individual medical conditions and needs. CURE Epilepsy strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified healthcare professionals who are familiar with the individual’s specific health situation.
Stem cells, the cells in the body that provide the blueprint for the creation of all other specialized cells (e.g., nerve, cardiac, blood cells, etc.), have generated significant interest in the research community over the past decade. Stem cells can help regenerate or repair tissues in individuals that have been affected by certain disorders and are being assessed for the ability to reduce seizures in people with epilepsy.
This webinar will discuss a pioneering neural cell therapy approach that could provide a novel treatment for drug-resistant focal epilepsy. Viewers will learn about the promising new data supporting this approach which will be presented by Dr. Robert Beach from the State University of New York (SUNY) Upstate Medical University.
About the Speaker:
Dr. Robert Beach, MD, PhD, is an Associate Professor of Neurology and Director of the Epilepsy Program at SUNY Upstate Medical University. His clinical interests include epilepsy, epilepsy surgery, anti-seizure therapies including medical, surgical, and experimental approaches, and differential diagnosis of seizures.
Q&A with Dr. Robert Beach, MD, PhD
Will this approach only be useful for epilepsy located in the temporal lobe or any drug-resistant epilepsy? Where do you see this going?
Well, if it is successful in this well-studied area of the brain, it will probably be useful in other focal epilepsies. As long as you can localize the seizures and target them with the cells, it has the potential to be beneficial. We’re starting with the best studied and most frequently treated surgically part of the brain as a starting point because it’s far and away the best understood and the most likely to provide us with realistic estimates as how it might work elsewhere.
Do you think it will eventually help people with Lennox-Gastaut syndrome or genetic disorders?Question?
Well, most genetic disorders are not focal. Some of them, like tuberous sclerosis for example, have multiple foci, and it might be useful in that sort of setting because it’s very hard to necessarily know which is the active focus. If you’re not damaging the area as you would with surgery or something, you may be able to treat more than one focus. But many of the genetic disorders are too diffuse and not well-localized enough to likely benefit from this kind of stem cell implant.
Can stem cell therapy be used in a patient who has a deep brain stimulator?
Well, not at this point, but it could be, theoretically. Deep brain stimulation is often used for less well-localized epilepsies, and some of those probably do not have a focal area that could be treated. Some of them have multiple focal areas of which you’ve … concurrently with the responsive neurostimulator or RNS, treat two of them, but not multiple ones. This could potentially have the ability to treat these area parts epilepsies where there are more than two foci or two focus that aren’t easily addressed by the RNS.
Are the cells manipulated in any way? Are they grown to increase their number
or cultured in any way? Selected in any specific ways?
Yes, all of the above. They are put into culture and they’re differentiated using a variety of growth factors and other things that influence distill differentiation. Then they’re tested to be these inhibitory GABAergic neurons, and then they’re expanded and tested for purity, and then they’re frozen in small amounts to be used in a particular implantation, and that you have multiple samples of the cells that can be used over a longer period of time with the frozen cells.
This isn’t actually coming from the person who’s having the surgery, but these are cells that were generated some time ago?
Yes. I don’t know exactly when they were generated, but they were generated from stem cells that have been obtained from, not from an embryo or not from a fetus, I should say. I don’t know exactly where they’re obtained from. Theoretically, you might be able to generate stem cells from the individual, which would have immense advantages in terms of not needing the immune suppression. That is one of the more complicated parts of this kind of approach, and I think that that’s potentially doable. It may be that cord stem cells may be more versatile and require less immune suppression. These are things that I don’t have a lot of information on, but are potential.
So, this person has a daughter with epilepsy, but an SCN1A mutation. They have stem cells saved from birth via the cord stem cell banking, and they’ve saved it from both of their children. Do you think this type of stem cell can come in handy for treating epilepsy?
That’s a very good question. I think there probably is a potential for those stem cells for this person, but I don’t think it’s going to be necessarily this kind of stem cells delivered focally, and it may not be primarily GABAergic neurons. It may be something that might introduce a different or correction of a different deficit that would be seen in SCN1A. But at this point, I really don’t know exactly how that would work.
How long does it take to see improvement, for example, a reduction in seizures after cell implantation?
Well, we don’t know. We were pretty surprised that this person did as well as he did in terms of seizures. So, the hypothesis that we are operating under is that the benefit of the cells would come mostly after they integrated with the other cells, and form new connections and new networks, which would take time. The plan was to assess this over a year, basically, be looking at six months, but expecting to find some realistic estimate over a year. This is, being the first patient, I think it’s premature to say that this is going to be a characteristic of everybody getting these cells, but it’s very encouraging.
If somebody has a VNS and can’t have an MRI, is it still possible to be assessed for this?
Well, a person with a VNS, as long as they don’t have it slipped way down below their chest or in the lower part of their chest, can have an MRI. There’s a, you require certain things in the MRI to be able to get, in the scanner, be able to get an MRI in somebody who has a VNS. There’s an absolute area of exclusion where if it exists, you can’t do it. But for the most part, they are coils that are used that go around the head and localize the flow of the changes of magnetic fields that keep it from interfering and keep it from damage the VNS. The VNS has to be turned off during the MRI. One obvious reason is if somebody has their magnet on and they go through the MRI, they’re going to be exposed to rapidly fluctuating magnetic fields, which will trigger it on and off multiple times, which would be intolerable very quickly. But most people with a VNS can get an MRI. If they have a focal abnormality that is likely to be the source of their seizures, or a couple maybe in the future, they may be candidates, but for now we’re looking at one focus.
So, back to the GABAergic interneurons, will they only work in the hippocampus or could they work in other areas?
Well, these are neurons that come from an area of the brain that spreads out throughout the cortex. The cells are formed in the median ganglia eminence, and then they migrate to various parts of the cortex. The reason it’s being tested in the hippocampus is because it’s a well-studied model, and we know that there’s GABAergic cell loss. They should potentially work in many other areas if there is a loss of GABAergic input and they can be replaced, which if there’s a loss of GABAergic cell loss, and it’s an area that can be, well almost in the area can be accessed using stereotactic implantation. So, probably, as long as there’s a focal area that can be identified as a seizure source, and there’s a good reason to think there’s GABAregic cell loss, it does have potential again, in the future.
How long do you think it will take to get a good readout from this clinical trial and know what the next steps will be? We’re getting a lot of questions about the future of this and where it could be used, but clearly, we’ve got to complete this trial first. Talk about this trial and how long it might go.
The way the trial’s set up now is the first two patients had to be separated by I think, three months. So, second patient was implanted about three months ago, who I don’t know much about their seizure effects or side effects. But I note, they’ve had no major side effects, and the cells were implanted a very similar way as to what I demonstrated with our patient in approximately on, well, actually as of now, there’s been several things that the Data Safety Monitoring Board has allowed us to do that’s going to facilitate getting patients in faster. One of them is to open it up for additional studies in this preliminary group of patients who are really getting a low dose, and there’ll be five people in that initial cohort that should probably be all implanted within the next six months, I would hope. Approximately a year after those five people go through, we should have some idea as to whether this effect on epilepsy is real, and whether there are side effects that we haven’t yet seen that are going to be an issue.
We also may have an idea, because they’ve opened it up now, so we can do non-dominant hemisphere patients, I’m sorry, dominant hemisphere patients as well as the non-dominant hemisphere patients. We may get an idea as to whether the most important benefit for this, it may be realized, and that is if you’re treating the dominant hemisphere temporal lobe epilepsy, in somebody who has relatively normal verbal memory and function, you’re going to get a decrement on surgery, because you’re going to be taking out areas important for that. But it is very possible, and it’s been shown with the less you take out, the more likely you are to have less effect on memory and language function. It’s very likely that with this kind of approach that you’ll have even less effect, or we hope that there’s even less effect on the language and verbal memory, and that we might have some information on that within the next year. I’m not really sure.
It might take longer than that, but it’s going to take larger numbers to really get a good sense for how likely various things are. I think we’re definitely seeing some very promising results, but it’s very early to know.
So, we’ve got a question about eligibility, and you’ve been talking about unilateral mesial temporal lobe epilepsy in the non-dominant side, and you just shared that there’s been a loosening of restrictions to also now allow the dominant side. It sounds like that might be because of the lack of concern around changes in some function.
Well, it’s because there doesn’t appear to be any major risk showing up from what we’ve done so far. It’s the dominant hemisphere of patients who this is most likely to be the most attractive approach for, because of that potential for sparing language function or even getting improvement potentially. So, as long as somebody has unilateral at this point, unilateral left or right mesial temporal sclerosis and seizures coming from that area, and no progressive degenerative diseases, and various other minor or unusual restriction criteria, they would be a candidate for this. But it’s basically, think of it as somebody who might be a candidate for epilepsy surgery on one temporal lobe, may be a candidate for this. There are some details beyond that, but that’s a good starting point.
Are there any discussions about trying this in children? I know that’s a difficult question, I’m sure.
Yeah. I think there will be plans to do that, because temporal lobe epilepsy is fairly common in children. But I think that there are some differences in, I would guess that’s going to take a while before we have a good handle on anything that’s going to actually try that. If it’s very successful, maybe a no-brainer to go forward with children, but it’s a little unclear at this point.
Do immunosuppressants have any effect on seizures themselves?
Not that I know of. I mean, they have side effects that can be somewhat systemic, but I’m not aware that any of them are actually anti-convulsant. Now, there are drugs that reduce proliferation that are in some ways related to the immune suppressants that can affect development of some of the epilepsies that require things like tuberous sclerosis, where you get growth of cell populations as tubers or as giant cell astrocytomas, where they suppress that. But that’s not truly an immune suppressant. I’d have to look to see what data there is. I’m not aware of any, but there might be some data on that.
Here’s somebody who is asking about autoimmune epilepsy and its impact on the hippocampus. The autoimmune epilepsy appears to have shrunk or changed their hippocampus. So, is somebody like this a candidate?
So, autoimmune epilepsy should first be treated to reduce the impact of the molecule causing the autoimmune response and the autoimmune response itself. If that is unsuccessful, and there’s residual long-term epilepsy, then they may be a candidate for this, but autoimmune epilepsy is usually a monophasic course where if you can remove the inciting antigen, which might be in some cases related to a tumor or an abnormal cell growth, or if you can suppress the response adequately, you can get control of those seizures in most people. And, if they are treated quickly enough and aggressively enough, they’re likely to get enough of a benefit. So, long-term epilepsy is not likely to occur, but for some people it does, and I think those people, if it’s in the hippocampus, would be candidates. I don’t think they’d be candidates for this study because that’s probably a restriction, but because autoimmune is not really a clearly defined stimulus that ends at a given time, but I think that they would be candidates for this kind of approach.
So why do the cells have to be injected into the brain? Why couldn’t they be injected into the bloodstream?
So, there are immune therapies to which are largely for blood cells where there can be replacement or treatment directly into the blood, and there may be epilepsies which are widespread and without a focus that might benefit from some blood cell treatments in the future. But for the effect of the GABAergic cells to be beneficial without causing widespread suppression of activity, you want to be able to put them where the abnormality is, where the hyperexcitability is, and that requires injecting them into the brain. There might be some genetic cases where that would be different, but not at this point.
Are there any outwardly visible components of implanting stem cells in long term?
Outwardly visible? Well, I guess if you palpated their skull, you might find a small little burr hole in the back where the burr hole is made. If the person is on long-term immunosuppressants, there might be some side effects that could last over a longer period of time, and of course, being on immunosuppressants does increase the risk for infections, but that’s not really a marker. That’s just a risk, I’d say.
You’ve talked about long-term immunosuppressants. It’s likely that people would have to be on immunosuppressants for their lifetime or do we know?
Probably on some level for lifetime. The aggressive approach initially is much more, all of, I think he was at one point on three strong immunosuppressants, and is now on a single low dose of Tacrolimus, which is one of the more common immunosuppress use for tissue transplants, which is probably not causing significant side effects at this point. Does have the increased risk of possible infection though.
Do you see this being used for any other kinds of neurological disorders?
Yes. I don’t think the, there’s probably ones where I think GABAergic cells may be beneficial, but I do think that stem cell of particular kinds will be useful in some other diseases, perhaps even in something like Parkinson’s disease where we now do stimulation, there might be potential to use certain kinds of cell implants to benefit there, but that’s something that I really don’t know for sure, and it’s in the future for sure.
So, you’ve talked about, you mentioned these people who are being enrolled are on a low dose. So, is the anticipated that the next steps in the clinical trial will try different levels of stem cell infusion or different numbers of stem cell infusions?
Yeah, the plan was to try a higher dose with the second cohort, which would be after these five people have gotten adequate results, which would be roughly a year from now or maybe slightly more. I’m not sure if the results are particularly impressive with the low dose. That may be modified.
Would be useful for generalized genetic epilepsies, and generalized epilepsies in general?
Well, I think most of the generalized epilepsies don’t have a focus where we could inject GABAergics neurons and expect to get a benefit. There may be particular subtypes of GABAergic cells that might be useful in some of the generalized epilepsies, but that’s very theoretical, because you’d have to be able to figure out which subtype and where to inject it. Theoretically, with some of the generalized epilepsies, it might be in the internuclear or reticule thalamic nuclei, which is part of the relay for some of the so-called spike-wave epilepsy, which are often called primary generalized. But I think that’s highly theoretical at this point.
The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified healthcare professionals who are familiar with individual medical conditions and needs. CURE Epilepsy strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified healthcare professionals who are familiar with the individual’s specific health situation.
Mental health and behavioral problems are just a few of the concerns that can affect children with epilepsy and these can vary greatly from one child to the next. While some people with epilepsy experience few if any mental health issues, others may suffer debilitating problems of inattention, anxiety, or mood disorders. It is important for parents and health care professionals alike to address these concerns early in their diagnosis as this can have a big impact on the quality of life for both the patient and their support system.
This webinar will cover:
Prevalence of mental health conditions in children and youth with epilepsy compared to the general population and peers with other chronic medical conditions
Risk factors associated with co-occurrence of epilepsy and mental health conditions
Importance and process of monitoring, evaluation, and management of mental health concurrently with epilepsy
Treatment approach using evidence-based mental health interventions
Technology support for the CURE Epilepsy Webinar Series is provided by Cisco Systems, Inc.
About the Speaker: Dr. Clemente Vega is a board-certified clinical neuropsychologist and a certified subspecialist in pediatric neuropsychology. He is employed in the Epilepsy Center at Boston Children’s Hospital with clinical and academic efforts that focus on pediatric epilepsy syndromes, neurosurgical outcomes, and cross-cultural application of neuropsychological assessment. He is also an Instructor of Psychology in the Department of Psychiatry at the Harvard Medical School. Dr. Vega also practices as a consultant in criminal and civil forensic neuropsychology, public schools, and the Boston Red Sox.
Q&A with Dr. Clemente Vega
Can you briefly explain what ODD (oppositional defiant disorder) is?
It’s essentially the difficulty following rules, and just adhering to the structure in the environment. It’s essentially a child, or adolescent who does not have problems respecting authority, does not follow rules, breaks the rules on purpose, and presents with this type of behavior for at least six months, or more. And they seem to essentially also engage in other types of less socially appropriate behaviors like lying, or deceiving others, stealing, and so on.
The studies will show that it can range the prevalence [of ODD in children with epilepsy] is anywhere between five, and 20%. It often co-occurs with other inhibitory condition, other conditions that present with difficulties with inhibition like ADHD, and it can also be a transient side effect of medication. So, sometimes medications that cause aggression for example, or cause a lot of frustration, difficulties with frustration tolerance. The way that presents in the environment is a child who just doesn’t follow rules, breaks the rules, doesn’t want to do what they’re being told to do, whether it’s at home, or at school. So, generally, studies will be as high as 20%, some as low as 5%. I think most of the meta-analysis will put it on the lower end. It’s not as common as depression, anxiety, and ADHD.
It’s really important to talk about the side effects of medication with the physician, and as you mentioned, some have negative side effects, and some have more mood supporting side effects, right??
Yes, and it’s very important for me to mention that I’m not trying to talk about the medicines in a negative light. I think it’s important to keep in mind that the medicine’s goal is to try to control the seizures as best as possible, and having more seizures is going to have a worse long-term effect on mood, anxiety, ADHD, and academic performance if they’re experiencing some cognitive side effects related to the medicine. So, the side effects of the meds sometimes are present, but they are less to a degree compared to how those same symptoms may present when the seizures are happening more often. There is a tipping point where the severity of the side effects, and the benefits therapeutically of the medicine from a seizure control perspective may not make sense for that particular individual. So, trying other type of meds may be a better option.
This is often seen for example in a medicine like Keppra, which does great, in terms of controlling seizures in a ton of in to ton of patients that have both generalized, and focal seizures but can present with side effects of irritability, negative mood, and some aggressive behavior. So, maybe that is [inaudible 00:35:57] Some people only have that in the beginning, or the first few weeks of the medicine. Some people actually get… They don’t go away. So, that’s something I like to mention. I also think it’s important for all of us when we are starting medicine to get a general sense of behavioral presentation in the weeks, to a month leading up to the beginning of the med, and the first four to six weeks after starting the meds, and then the next couple of months after. Because it all kind of blends together the frequency, and severity of behavioral side effects of meds, or cognitive side effects of meds with the difficulties that were there before the med was introduced, because they’re just part of the epilepsy.
They’re having a lot of seizures, or the disruption in sleep, or some of the other changes that are associated with the medical condition that may be there with, or without that particular medicine. So, having a, I’m not necessarily promoting journaling on a daily basis, but maybe on a week to week sitting down, and trying to get a sense of the presence of some of these mental health symptoms such as anxiety, depression, irritability, difficulties with attention, and problems in school. So, we can track little bit before meds in the beginning of the meds, and after the person has reached the therapeutic level of the meds maybe four to six weeks afterwards.
Are there any genetic epilepsies more at risk for psychosis?
I’m not familiar with any particular genetic conditions increasing the risk for psychosis. I can say, generally speaking, in the psychology world, we understand that psychosis is found more in populations that have neurocognitive impairment for example, and also in populations that have a family history. So, perhaps not necessarily, maybe it’s there, and I’m just not familiar with it in terms of genetic conditions increasing the risk of psychosis. But we do know that genetic conditions also increase the risk of neurocognitive impairment compared to epilepsies that have a different type of etiology. And it may just be the multiple factors that are associated with the genetic epilepsies that increase the risk of psychosis if it’s something that the person asking the question has been finding, or is familiar with, or something that makes sense to them. But to date, I haven’t come across any literature that has presented that as a risk factor.
A viewer has heard that stimulants are not as effective with SCN 1A epilepsy. Would that be true? Do you know?
So, I don’t know about SCN1A, and stimulants specifically, but I do know that stimulants tend to be less well tolerated in some populations with epilepsy. SCN1A is a condition that usually comes with a lot of other situations. They tend to have a lot of medicine, because the seizures are hard to control, and in my experience a lot of my patients that have neurological conditions, whether it’s epilepsy, or something else, have a higher risk of having side effects of any medicine that they are taking. So, stimulants are known to have side effects, and the population may just be much more at risk of having side effects. The problem with stimulants sometimes it’s not that they don’t help the cognitive aspect of the person, it’s not that they’re not helping attention, it’s that we can’t reach the therapeutic dose without having significant side effects such as irritability, depression, and difficulty sleeping, and appetite.
I also have worked with folks that spend a lot of their research career with populations that have autism, which is known to occur more frequently in genetic epilepsies that have SCN1A mutations, and their practice tends to be used more non-stimulant medication before stimulant medications like Stratera for example, because it’s much better tolerated, and they can reach therapeutic levels compared to what type of efficacy they can have with the stimulant meds. But I haven’t come across specifically research with SCN1A, but it would make sense to me if somebody publishes that, why that would be a problem.
Are there ways for parents to screen for mental health, and needs in younger children like toddler, pre preschool-aged children?
That’s a challenge for an anybody, even parents that don’t have children with… Whose children do not have epilepsy. It’s most of the studies that look at general populations age when depression, and anxiety begins to actually present, when certain states have looked at this for example, and they estimate that anxiety, and depression really begin to emerge more between the ages of eight, and nine years old. So, ADHD presents more often between the ages of five, and six, but we hesitate to diagnose, or to talk about someone who’s presenting very sad as being depressed when they are young like a toddler, or even a preschool-aged kid, or kindergarten age kid. Similarly, we are very hesitant to start thinking about ADHD in a toddler, or someone who’s even three, or four years old, because in my experience most toddlers have a lot of difficulties paying attention, and they have a lot of hyperactivity.
So, it’s very challenging to differentiate what is a clinical mental health condition versus just kind of normal brain in that young age. That being said, I will always recommend the parents of any age, of kids with any age to just monitoring change in their behavior over a course of on a week to week basis. Any of our kids can be a little bit more irritable, a little bit more sad, or a little bit more anxious, or different in their behavior presentation from one day to another. Kids are very sensitive to changes in their schedule, in their sleep patterns, in their nutrition, and we may just be seeing a transient change in behavior as a result of some of these environmental variables. But if we start measuring on a week to week, a change that seems to be a little bit more there between one week, or another week, and really notice a change that we can compare to what was going on the month before, or the month before that, that’s how we can start really identifying the potential presence of anxiety, depression, or sadness in children that are younger like toddlers, and kindergarten.
The studies also say, also show us that anxiety, and depression may present very differently at that young age compared to how it presents in middle childhood, or even as we get into adolescents, and in adulthood, they tend to, for example, in anxiety tends to present more as mutism, or social isolation when they’re really young. If they’re in school, they stop playing, they stop talking, they stop interacting with others. Mood changes may present much more as irritability, and crying, but not necessarily verbalizing that they’re feeling a particular way. And also changes in their kind of basic physiological activity like changes in sleep patterns, changes in appetite. Those may also be more signs to be on the lookout for with younger kids that are three, four when we are trying to make sure that the anxiety, or mood are not being affected by whatever is happening, whether it’s a condition, or changes in their treatment.
For absence seizures, would mental health issues lessen if the child were to grow out of these types of seizures?
Unfortunately, the answer to that depends on that particular person. So, there is evidence that the curing the seizure, or outgrowing the syndrome does not always predict the resolution of a mental health condition. And they’ve done these kinds of studies in Canada where they look at folks that have these pediatric conditions, and trying to predict based on seizure control, or seizure severity whether the mental health condition will be benefited, or they outgrow it. And what they found is that there’s very little way, there’s no way to actually predict it. Some people get better, and some people don’t. And we are still trying to figure out what may be some variables that can differentiate that. Is it the family history, that maybe predisposes some folks to have depression, or ADHD regardless of the presence of absence epilepsy? Is it environmental factors, or something else?
So, I would say that there is a subset of children, and youth with epilepsy that experience these mental health conditions as a consequence of their epilepsy that the effects that it has on their academics, or their quality of life is impacting them to the extent that it is increasing their anxiety, and their feelings of sadness, and depression, and honestly as a human being that makes perfect sense to me. Oftentimes, I think my patients are so resilient, and so strong because they don’t present with the degree of anxiety, and depression, and other symptoms that I think would be a total normal response to having to deal with a medical condition like this.
And folks that are having this sort of direct response to the changes that they experience as a result of the condition, we would expect a lot of improvement as they outgrow the condition like absence epilepsy, and whatever contribution may be there with the meds to their mental health that won’t be there anymore if they’re [inaudible 00:47:32] not taking meds. But there might still be an underlying biological process that is really contributing to their mental health that will be present, whether the seizures are still there, or not as they transition into adolescents, and adulthood.
Are there any books that you would recommend for mental health, ADHD, epilepsy on how parents can do CBT (cognitive behavioral therapy)? What we know it’s that while this seems to be an available treatment for adults, in some areas it’s really hard to actually get access to a psychologist for children. So, are there programs that you would recommend, or books to support people in areas of our country where there don’t have easy access to specialists who know how to do CBT?
Yeah, so for ADHD first, there are a few books that were written for parents that I always find very helpful, and I recommend often. Maybe not for ADHD primarily, but for the symptoms of ADHD, which are frequently just executive dysfunction problems, just getting their task organized, planning, and problem solving. And there’s a book that is called Smart but Scattered, there’s version for younger children. There’s a version for adolescents, and there are a version for young adults. Again, the book is called Smart but Scattered, and it was written by neuropsychologists who do a lot of work in ADHD, and it’s essentially a parent guide. There are books on mindfulness, and on behavioral therapy that may also be available. There’s a lot of these, I don’t think I recommend one over the other. I would say a few things. Hopefully, now, as we are transitioning to more telemedicine availability, then people can have more access to mental health services compared to where we were before telemedicine became so normal.
So, that may increase access a bit. The other thing is that the providers who don’t specialize in kids may be okay under certain circumstances. It’s really hard to find someone who is a specialist in mental health that matches all of the needs of one particular patient that I work with who knows epilepsy well, and also knows anxiety, and also knows anxiety in this particular [inaudible 00:50:38] adolescent female that’s 15 as an example. So, I tend to create a bit of a decision trait, because of the treatment that I’m referring for is the mental health condition, an anxiety specialist with good training is able to translate their work into epilepsy if they don’t have a lot of work with children, and youth that have epilepsy, and may be able to adjust what they do. Someone with experience with adolescent may be able to work with a high functioning 10, or 11 year old, for example.
When it’s younger kids, CBT may not actually be as helpful. It may be more helpful to do parent type of therapy that may be more accessible in the community, or something that can be managed with a multidisciplinary team like the school, and counselors along with the parents, and some of the physician providers. I can probably go back into my library, and look for some of these CBT specific books that may be very helpful, and answer that question more specifically, but I can’t think of a specific book off the top of my mind for that one.
We’ve talked a little bit about Keppra, and its impact on mood. One question we have here is about phenobarbital. Do you know if it changes aggression, or mental health has an impact?
Well, I know that phenobarbital has cognitive effects, and it’s associated with slowing processing speed, difficulties concentrating, and can cause fatigue. These can certainly have an effect on mood. As I mentioned earlier, if we are fatigued at any point, or for any reason, we’re going to have more difficulty modulating our feelings, and our emotions, and maybe more anxious if we have cognitive effects, and have difficulty keeping up with what is expected of us on a regular basis, that’s going to make us more anxious, and it’s going to impact our mood as well. I’m not familiar with a lot of studies looking at higher rates of depression, or irritability in patients that are prescribed phenobarbital.
We tend to see more of a cognitive effective profile in that particular medication as opposed to more of a mood, or anxiety profile in that medication. But I think it’s important to always keep in mind that anybody can have any kind of side effects with these medicines, because our brains are so different that we know of some side effects that may present more often than not, but that doesn’t negate the potential of other side effects, or any side effects being there with any medication.
A question about cognitive behavioral therapy (CBT), and would it be recommended when adolescents also have cognitive regression?
So, I guess that may depend on the degree of regression, but if the question is related to an adolescent that may have some pretty significant cognitive difficulties, or maybe not to the degree of an intellectual disability, but certainly having a lot of difficulty keeping up with the expectation academically, or otherwise in their day-to-day. So, they’re certainly not functioning at the level of their age, and maybe a few years behind. CBT may be much more challenging, or ineffective in someone who they can’t process the information at a cognitive level, and it’s a lot more reflective, or maybe is more immature in their behavioral presentation. So, behavioral therapy that is less cognitive, but more based on reinforcements, rewards for behavior, and designing more of a behavioral treatment plan that is similar to what we would do for someone who’s younger, like a eight year old, nine year old, 10 year old, that may be much more effective for treatments compared to cognitive behavioral therapy.
If it’s an adolescent with cognitive aggression that is presenting with more of the anxiety depression, there are other treatment options that may be better, like DBT (dialectical behavioral therapy) has been shown to be effective in adolescents for treatment of depression, and anxiety, and it’s a lot more on the here, and now type of behavior management as opposed to changing our cognitive thinking, or our patterns of negative thinking over the course of six months. That may be very challenging. Someone to make the slow gains if they have cognitive progression, and they may just need more of a here, and now type of approach for management like DBT can present, or other forms of behavioral therapy.
This Treatment Talk, a social-media broadcast that will be released on CURE Epilepsy’s YouTube channel, will discuss focal epilepsy and the most recent treatments to help patients achieve medical remission. The talk features Dr. Michael Smith, Senior Attending Neurologist and Director of the Rush Epilepsy Center in Chicago, and Sarah Carlson, a patient of Dr. Smith’s who battled epilepsy and its corresponding stigma for many years before achieving seizure freedom. Viewers will learn about focal epilepsy, how a new treatment (cenobamate) can offer patients the hope of medical remission, and the benefits and risks identified in recent clinical trials of cenobamate.
This talk is supported by an independent educational grant from SK Life Science.
CURE Epilepsy is solely responsible for the selection of the presenters and moderators. The opinions and recommendations expressed are those of the presenters and do not necessarily reflect the opinions, recommendations, or endorsements of CURE Epilepsy.
Medicinal cannabis has been of interest to the epilepsy community with greater interest fueled in 2018 by the FDA approval of a cannabidiol (CBD) extract called Epidiolex®. In fact, the marijuana or cannabis plant contains over 100 different substances, two of which specifically, CBD and tetrahydrocannabinol (THC), have been widely studied to understand their effects on the brain.
THC is the major chemical compound found in marijuana that creates a psychoactive effect when it binds to receptors in the brain. CBD binds to a different set of receptors and is not psychoactive. Epidiolex® is a purified, plant-based CBD extract used to treat seizures associated with rare genetic epilepsies. Because of its effectiveness, there is great interest in further understanding how CBD acts in the brain and also if other cannabinoids might be useful in the treatment of seizures.
In contrast, marijuana products sold in dispensaries and online are not approved or regulated by the FDA. They can vary significantly in quality, dosage, safety, and effectiveness. In some cases, commercial, nonprescription cannabis products are thought to increase seizures.
This webinar will review the basics of cannabis biology and the differences between cannabis strains. It will also explain the medical uses of medical marijuana and the recent approval of CBD to treat specific types of epilepsy.
This webinar is generously supported with funding from Jazz Pharmaceuticals.
About the Speaker:
Dr. Eric Marsh is an Associate Professor of Neurology at the University of Pennsylvania Perelman School of Medicine and the Children’s Hospital of Philadelphia (CHOP). He is the Clinical Director of the Penn Orphan Disease Center, and Director of the CHOP Rett and Related disorders clinic.
Dr. Marsh’s clinical interests include developmental and epileptic encephalopathies (DEE), neurodevelopmental disabilities, and cortical malformations. His research interests have focused on the role of intraneuronal development and altered excitability on epilepsy, analyzing intracranial EEG recordings to better localize the epileptic zone and network, and performing natural history and biomarker studies. In addition, he has studied the role of mutations in specific genes related to epilepsy such as ARX and CDKL5. Dr. Marsh has been involved in a number of clinical trials for children with the DEEs, including Dravet, Lennox Gastaut and Rett syndromes.
Q&A with Dr. Eric Marsh
Has CBD been found to affect the metabolism of benzos other than
Onfi?
So yes it does. Onfi is a unique benzodiazepine, in that its structure is different. So most benzodiazepines, the side chains off the benzo ring, which is why it’s called a benzodiazepine, are on the first and sixth carbon. Onfi, it’s the first and fifth carbon, so it’s a unique benzodiazepine. That’s the name Onfi, one five. It’s off of the first and fifth carbon, so it’s a unique benzodiazepine. But all benzodiazepine are affected, though Onfi more so than the rest.
Would CBD or Epidiolex be considered a treatment for epilepsy or autism in megalencephalic leukoencephalopathy (MLC)?
So there’s kind of two ways to answer that. So our expanded access program included a lot of different rare genetic disorders, and the effect was the same across the board. I think everyone now believes that Epidiolex, or purified CBD, is a good broad-spectrum anti-seizure medication, and that, for any different cause of epilepsy, it should potentially have some effect. As the data showed, it’s not a cure for most, it just reduces seizures. And you would expect the same for whether MLC is the cause of the person’s epilepsy or anything else.
The second way to answer is that too, for the FDA-approved Epidiolex, there are indications that are required, including Lennox-Gastaut syndrome, Dravet, and TSC. So for MLC, the question would be, does the child have the electrical clinical pattern consistent with LGS, in which case, they could have LGS due to their MLC, in which case they’d actually be allowed to be prescribed the FDA approved Epidiolex. If they don’t, then your doctor would have to prescribe it off label, and that’s a discussion to have with your doctor.
And then same thing with the behavior, as I said, there might be positive responses in behavior. I think you just have to be very critical if you try to treat an individual with this. If you don’t see anything, then like any drug, stop it. Don’t continue it just because you want it to work, but really be critical of whether you think it’s working or not
Can oils from dispensaries be tested, to understand what they correct amounts are from using a third-party tester?
Yeah, so absolutely. There are labs around the country that will test. I don’t know what the cost is, so I don’t know if it’s prohibitive to have something tested. Which also brings up the other issue with dispensaries, which I didn’t mention, because that study didn’t go over it, is batch to batch variability. So if you test it at one time, you might say, oh look, it actually is exactly what it says, but the next time they produce that batch, will they have the same accuracy of what they say is in the product is now in the product?
So you could get to a third party tester to test, but that will just give you reassurance for that batch of the product you have. For the next batch, you’d have to do it again. So I think, to some degree, when you go to a dispensary, you have to have a conversation with them, get as much reassurance from them that they’re doing it in a rigorous way, the way they grow, and the way they extract, and the way they produce. And then, just know that if you see a difference from time to time that it could happen. And if seizures are in good control, and seizures stop being under good control, it could be because the product has changed.
Is there a shelf life for these products in oil? How long can you keep them?
Yeah, so there is. Cannabinoids are actually light-sensitive compounds. So that’s why the bottle that it comes in, like Epidiolex comes in, is a brown bottle, in order to filter out light getting into it. And you should store any dispensary or FDA-approved cannabidiol in a cabinet out of the light, because light will make the product degrade rapidly. In the dark, in a cool environment, its shelf life is fairly stable. I don’t want to give you numbers, because I don’t actually, don’t quote me on a number, but it is fairly stable if it’s kept in the dark and cool. But I’m not going to give a number, because I don’t remember offhand what the stability is
What is the dosage of CBD in Epidiolex?
Epidiolex is 100 milligrams of CBD per ml. And the FDA recommended starting dose is five milligrams per kilogram per day, divided in two doses. And there actually is no max dose. So it’s based by weight. There’s no max dose in reality. The FDA label might have one, so I don’t remember if the FDA label has a max dose of like 1000 milligrams a day. Most of my patients are little kids, so we don’t get to that, they’re all small, so that’s not an issue. It’s all weight-based dose for me.
So is cannabidiol only used as a treatment for tonic, clonic, and atonic seizures? Are there other seizure types that might be, it might be useful for?
So for the studies, motor seizures, whether tonic, clonic, or atonic, were the primary endpoint, and that’s where we saw the greatest effect. In my own personal practice, I’ve had families who have LGS with multiple different seizure types, see response to a variety of the different seizure types, including myoclonic seizures, absence seizures, and focal seizures. Though it seems to be greatest for the kind of generalized tonic, clinic, bigger seizures.
Would using THC recreationally affect the effectiveness of clobazam or lamotrigine in generalized epilepsy?
So yeah, THC also alters the metabolism of some of the CYP enzymes, and I don’t remember the direction to which it does, but it does. So medical marijuana, taking a whole product recreationally, is going to potentially alter the metabolism of some of your medications, particularly in that case, clobazam. Less so lamotrigine, but I’d have to look up what the metabolism of lamotrigine is, to say for sure.
Have the individual terpenes been studied for their potential therapeutic effects on epilepsy?
Not that I’m aware of. So I know that GW/Jazz is really interested in exploring other aspects of the cannabinoids and terpenes for their role. But I’m not aware of any information that they’ve published to this end. And there are mouse basic science studies looking at some terpenes and other cannabinoids, but nothing human that I’m aware of.
Are there substantial side effects, such as liver or kidney damage, with use of CBD?
So far, the answer is no. That it is, in all the studies, there was no effect on kidney function. The liver questions a good question. So what was found in the studies, was that there was a increase in liver enzymes in a group of the patients. None of the patients got to the point where there was any issue of liver damage, but there was suggestion that the liver was being irritated. Because an elevation of the ALT and AST, the enzymes we used to measure kind of liver function, and they all went back to normal when you stopped the cannabidiol. So we don’t think there’s any long-term effect, but again, the medication’s only been approved now for six, seven years. So I think, long-term we’ll learn more about that, as people follow patients who are on cannabidiol for longer and longer periods of time.
This person says that their son is on Epidiolex, and it causes high anxiety. Is there anything else that might explain this, or might not cause the high anxiety? Is there anything that could be done?
Yeah. That’s a good question, and I would need a lot more information to really answer that question. As the Epidiolex could be interacting with other drugs, it’s possible by the alteration of the metabolism of another drug is bringing out his anxiety. So it could be related, but indirectly related. And in my experience, I’ve had families report that when they started Epidiolex, that it improved anxiety. But I also have some families who’ve reported that they think their kid’s more anxious, or their behavior has gotten worse on Epidiolex. So I think there’s a lot of variability there.
And one of the things I didn’t mention is that, these cannabinoids are actually, they don’t get absorbed very well via the gut, and so, they’re the metabolism and the individual’s ability to absorb and process these are going to be very variable. So some of the differences we might be seeing in this might be due not to how the drug works in their brain, but also, how the drug even gets into the body. So differences you see, something like that, could potentially be what we call pharmacokinetic, or pharmacodynamic properties, and not actual brainderived properties. But that said, we do, there’s a lot more we need to learn about these things
In the graph that you showed, there where a majority of people showed a reduction in seizure activity, but some actually saw an increase in seizure activity. I’m wondering if you can comment on that, and the variability there?
Yeah. So there’s two aspects of that. So one is that, we know that individuals who have epilepsy, and particularly epilepsy that has not responded to many medications, their seizures often fluctuate, and that they go up and down. And there’s some really nice data from people who’ve had RNSs implanted in them, where they’ve been able to follow count, people’s seizure counts for months on end, that we see these oscillations in people’s seizures. So one possibility for that increase, is that they started the trial at the low point, and they, as the trial went on, they just were in their normal up oscillation, and the medication had no effect, neither good nor bad, but it just looks like it went up, because they happened to be on an up oscillation.
The other potential possibility is that, yeah, for whether it’s a metabolism issue or a brain issue, that it actually altered the brain dynamics in such a way that it made someone’s seizures worse. So again, there’s still a lot we need to learn about that group who did really well. Who are they? Why are they? And can we figure those people out? So we know, hey, you’re their best people to put on Epidiolex. That would be something that would be great to be able to do. And unfortunately, we don’t have that type of data.
Can you take Epidiolex at the same time as Depakote or other seizure drugs, or should you be separating them in time?
Yeah. So you can take them at the same time. What’s important for Epidiolex is, because of the absorption issues that I just mentioned, is that you try to do it always at the same time, or approximately the same time, particularly around meals. So you don’t want to give it one time with food, and the next time without it, because it’s going to be absorbed differently. So always give it with food, or always give it without food, so that you’re just consistent. So that’s the best advice for when you give it, is trying to give it as consistently as possible, so that you know its effect, and that you’re not getting variable amounts based upon how it’s being absorbed.
Rare diseases are generally defined as those diseases that affect fewer than 200,000 people in the United States1. However, there are many diseases that are caused by genetic mutations that only impact a handful of individuals worldwide. In these cases, the small number of patients present a variety of challenges to identifying and developing effective treatment options including a long diagnostic journey, often with misdiagnosis and the high cost of clinical trial development.
This webinar will highlight the work of the n-Lorem Foundation. The n-Lorem Foundation is focused on creating free, individual treatments for people with what are termed nano-rare diseases, caused by genetic mutations that affect 30 patients or fewer in the world. 40% of n-Lorem Foundation patients suffer from epilepsy, and these individuals may benefit from more individualized genetic treatments that meet the unique needs of each person. This webinar will discuss the use of individualized antisense oligonucleotide (ASO) treatments for patients with nano-rare epilepsies. ASOs are short strands of modified deoxyribonucleic acids (DNA) that can be developed rapidly and inexpensively and can specifically target and potentially halt the development of the disease-causing proteins, thus attempting to change the course of the disease.
About the Speaker:
Sarah Glass, Ph.D. is the Chief Operating Officer at the n-Lorem Foundation, where she leads the implementation of the foundation’s mission to discover, develop, and provide personalized experimental medicines for patients with diseases caused by genetic mutations affecting fewer than 30 individuals worldwide. Sarah is passionate about forging partnerships to increase our collective ability to help and provide hope for people in need. She combines her professional experience as a geneticist, drug developer and clinical trialist with the urgency she has felt as the parent of a nano-rare child.
Q&A with Dr. Sarah Glass
Can you speak to families that have a diagnosis of L G S or Jevens or infantile spasms? How do they think about this technology? Is it right for them or not yet?
Honestly, it is very specific to every single mutation and I think that’s the unfortunate reality. And as much as that doesn’t help broadly speaking, and I think that’s what we’re really finding, especially in some of these cross patient groups, is like how can we actually give you a much more informative answer than that? What we have started to put in place is almost even a, we started pre-submission type of assessment, if you will, is almost even just like a triaging because we do have a lot of questions like that. So for my patient community, we have this type of mutation or this type of mutation or we have here these two which are affecting three people or five people, and what do we do? Should we find a physician? Should we submit an application? And so I think that’s the best that I can offer is that I think what we found is typically, first of all, the prevalence of the mutations is very important, obviously.
The functional consequence of the mutation. If we understand the functional consequence and if there is a realistic ability to affect the consequence of that mutation. So ultimately, for example, null mutations, ASOs aren’t able to help, those are typically going to move into the gene therapy space to some extent. We do know a hundred percent for as far as the organ system, obviously these are all C N S, but I think we get those questions a lot as, so if we want to target the muscle or if we want to target lung and things like that, those are also areas that we cannot target. So I think part of it is understanding what ASOs cannot target. So some of that also is really focused on the mutation but focused a little bit broader than that. And so I think that would be my suggestion is really in thinking about those questions is to say, the first question is what does the mutational spectrum look like for each of those areas that you mentioned, those patient groups and to say, okay, do we have some functional consequences that are well understood? Are the prevalences in these regions that would apply here? And all this is really driven by what these F D A guidance documents provide. They’re very specific, actually, refreshingly specific on the type of patients that actually qualify for these because this is a different drug discovery and development path than a commercial program. So it’s a much abbreviated path. And that’s very important for all of the patient communities to know is that these go specifically from a single G L P animal talk study right into the patient. Whereas in traditional clinical trials you go multiple animal talks, phase 1, 2, 3, et cetera. And so that’s why the F D A is very specific on what are the characteristics of patients that are actually suitable for this path. And some of those characteristics are in the genetics, it’s in the clinical manifestations, it’s in what is the other treatment landscape.
So that’s another element as well, is really just do we have a sense of, well, there are all these other treatments that are already really targeting these patient populations. So this is really focused on patients who just really and truly don’t have any other options.
How does that work get funded and if it’s not done by n-Lorem, how does that research get accomplished so that it can perhaps inform you?
It’s really variable honestly. And I think the most interesting, it’s actually fascinating, sometimes you will find a mutation that will have evidence for having gained a function consequence in some circumstances and loss in others. And some you might not necessarily very clearly be able to understand it and it could just require a little bit more research in a particular lab. Most of the research that’s happening is back into the lab of the submitting physician for the most part. So that’s only helpful, however, if one, a patient is connected with the physician who is also a lead researcher in that particular gene. And so I think what we’re working to do, and we have a couple of potential partnerships where there could enable almost a proof of concept lab to some extent, where you say, okay, this could be amenable if we have X, Y, Z data that will then get us over the ability to make that decision as far as do we have an ASO strategy or not?
And so that’s very much something that we’re working on now is to have a more centralized location. So as with a lot of rare diseases is how are we looking across diseases? So instead of saying we’re focusing on the gene, if we’re saying, well, here’s a type of study, here’s a type of experiment that is often missing, if we could only have this capability to do this for many different genes or for different patients in a more centralized type of location, I think that’s what we’re aiming to do in the future as well. That research piece is so important.
What are some of the reasons for declining an application for an ASO? And you’ve talked about some of those, but can you fill in any other information? Why would you decline an application?
Yeah, so the primary reason to decline is really around the mutation itself and the consequence of the mutation. So again, whether it’s ultimately a functional consequence that we can’t, so if it’s a null mutation, we still continue to have some of those. It also depends on the gene itself. So for example, if we’re looking at trying to upregulate, well, upregulation is not the same across the board. That’s going to be driven by specific characteristics of that particular gene itself. And so then it comes down to, well this particular gene has these different characteristics. So again, most of the decline is really related to the clinical or to the genetic, to the genotype. And so really trying to, from a technical perspective, address whether we feel at all antisense technology can help. Now there are a small, I think proportion as well where the physicians or the patients will ultimately be presented in a way that it isn’t entirely clear.
Well, the gene is the causative gene, so that we do have a handful of patients that will have maybe two mutations or more. And ultimately these are really driven towards having single mutations in a causative gene with that being very apparent. We have a number that will then creep above the 10 bus 20, 30, 40, 50 patient range. And so I think we’re not there where right now we’re really stricken directly to the guidance. I think eventually over time, one could envision that there could be a path even for if it’s an experimental ASO for almost like an intermediate population, if you will, that doesn’t exist at this stage. So that’s another reason as well. Let me think. There’s a number of patients that will be, if it’s again trying to target the muscle or cardiovascular, things like that where we don’t have a validated route of administration that we’re leveraging as part of n Lorem.
Are n-Lorem applications only available for patients that reside in the US?
Yeah, it’s an important question. And right now we only have F D A guidance to under which these patients can be treated. We have significant efforts at this point with Canada and the UK to really evaluate and try to really forge the path in partnership with those regulatory agencies, to define a path based on other partnerships in those countries. We do have a lot of patients actually starting to apply or physicians from other countries that were, I think, trying to assess on almost a case-by-case basis. But for the most part, and it’s only if we already have an ASO for that particular mutation, which is highly unlikely, but I think the goal is to help as many patients as we can, but we have to start somewhere and that’s here in the US.
What is the current cost structure for patients and what do you foresee for the future?
So ultimately the patients don’t have any obligation for the cost of these drugs and the physicians themselves. N-Lorem covers all of the costs from the point of patient acceptance through to all of the drug discovery and development and talk studies, as well as manufacturing. The physicians and the institutions are then required and obligated to support from the treatment on, and so that’s what we’re working through. So typically this should not be, and most physicians are having insurance will be billed for what can be billed and institutions will cover some of the other costs. Some others have philanthropic funds. I think the reality is that each institution is handling this differently and that every institution needs funding for it and they all should get funding for it, honestly. I think one of the biggest challenges that we continue to see with the physicians is that they’re doing this in their nights and weekends time, physicians who are entirely clinical who don’t have any research time.
And I think for someone who’s not necessarily in that space, we all cannot appreciate how busy, how many individuals, like our loved ones that they’re caring for, and then to say, okay, well, and in my own personal family time, I’m going to spend on this particular patient for n-Lorem. So I think that’s what we’re trying to really understand, and I’m personally spending a lot of time right now is trying to understand what are the costs, specifically? What does that actually entail and should this be integrated into what the cost structure could look like for these treatments moving forward? Because ultimately the patient should not have to carry the burden for these costs. But at a minimum, I can say there is no cost for the drug itself.
The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified healthcare professionals who are familiar with individual medical conditions and needs. CURE Epilepsy strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified healthcare professionals who are familiar with the individual’s specific health situation.
In the United States alone, approximately 4,000 surgeries are performed each year to treat epilepsy. In comparison, an estimated 100,000-200,000 patients may benefit from epilepsy surgery 1 . This significant gap between the number of surgeries performed and the number for whom it could reduce or eliminate seizures could be filled by procedures that can more easily identify patients who are good candidates for surgery. Magnetoencephalography (MEG) is the newest, most advanced technology that can help close this gap. MEG can pinpoint the source of abnormal brain activity and seizures 2, is painless, safe, and requires only 1.5-2 hours to perform. Ultimately, MEG can help surgeons decide whether a patient should pursue surgery. Use of MEG may allow more patients to be identified for surgery, and potentially lead to greatly reduced or no seizures.
In this webinar, viewers will learn how MEG is a key part of the epilepsy surgery evaluation, including information about the basics and safety of a MEG study, and hear about how MEG can help the surgeon by mapping key functions (speech, motor, and vision) onto their MRI for use in the operating room.
The webinar is intended for people living with epilepsy, their family members and caregivers, and anyone seeking to learn more about mental health and epilepsy.
1 Institute of Medicine (IOM) Epilepsy across the spectrum: Promoting health and understanding. The National Academic Press; Washington, D.C: 2012.
2 Gill MM et al. The use of PET/CT in pregnancy: A case report of malignant parathyroid carcinoma and a review of the literature. Obstet Med. 2018 Mar;11(1):45-49. doi: 10.1177/1753495X17724950. Epub 2017 Oct 9. PMID: 29636815; PMCID: PMC5888841.
About the Speaker:
Dr. James Wheless is a neurologist and researcher whose research is focused on pediatric anti-epileptic drug development, the ketogenic diet, epilepsy surgery, and non-invasive brain mapping (TMS, MEG). Dr. Wheless is the Professor and Chief of Pediatric Neurology and the Le Bonheur Chair in Pediatric Neurology at the University of Tennessee Health Science Center (UTHSC) in Memphis. He also serves as Director of the Neuroscience Institute and the Le Bonheur Comprehensive Epilepsy Program for the Le Bonheur Children’s Hospital (LCH). Dr. Wheless is also an Adjunct Clinical Faculty Member in the Department of Pediatric Medicine at St. Jude Children’s Research Hospital.
Q&A with Dr. Wheless
Can a MEG scan identify a misconnection with a hemispherectomy?
If someone’s had a hemispherectomy, just to make sure everybody understands that, it’s a big surgery, but basically what you’ve done is you’ve disconnected, if you will, one half of the brain and parts of that brain from the other half. You may have abnormal tissue that’s still in place. It can still generate a seizure. But the way I describe it to patients, it’s kind of like it’s on an island. It can’t spread from there to the rest of the brain or to the body, so it’s not really causing a seizure, even though it may have nothing but abnormal activity. It’s been disconnected, if you will, from the rest of the brain.
Usually, the best strategy for saying are we confident that’s disconnected is to do what we call a tractography. It’s a type of MRI imaging where they actually look at the pathways from those disconnected areas and they can see have they all been cut. And that’s probably the best way to look at those, because MEG picks up abnormal electrical activity, and that abnormal electrical activity is still going to be sitting there because it hasn’t left that area. The question is, is it confined there, and that’s where the tractography helps us better.
This individual writes about having a pacemaker and also having a MEG test. One of the concerns is that the device may cause too much noise for the MEG and how well can the MEG reading be cleaned up if a device like that is present?
Yeah, that’s a great question and an area that I didn’t touch on that I probably should have for purpose of the time. But their question is great because they’ve picked up on what I was saying at the beginning that the MEG is detecting these magnetic signals and anything that’s metal generates a magnetic signal, which is why we all know if you take a magnet, you go around, you can pick up other things that are metal, right? Pacemaker nowadays, most modern pacemakers and other metal implants, if you think about dental fillings, more common than pacemakers even, as well could have an associated magnetic field with them.
The brain is small by comparison. They can overshadow, if you will, the brain. In the past, those were a huge problem. With modern software, we usually, I almost say 100%, but we usually can filter the noise out from those and still get the data that we want in patients that have those. Whereas in the past, we kind of said, “Gosh, that’s a deal breaker, unfortunately.” Nowadays, we say, “You know what? Let’s look at it. Let’s get you in the room. Let’s see what we’re recording.” Even if it’s somebody that we can just kind of… I guess you would say get in the room and try it.
We’re not doing the full recording, but just say, “Let’s make sure we’re not overwhelmed by the noise,” we can just test them, if you will, to see because it’s easy to do. You just go in the room and lie down. It’s pretty simple to do. But most of the time, nowadays with our current machines and the software improvements, we’re able to record.
Is having MEG done something that insurance will cover if a patient is not wanting surgery, but wants to identify where the seizures are coming from?
Obviously, today’s focus was on patients with surgery, but many patients get MEG that are not surgery candidates where it’s still helpful. For example, for some patients that we say, “Gosh, we think we know your seizure type, but you’re responding a little bit differently than the normal person with this.” Sometimes using the MEG with EEG really helps refine, are we on the right track for what we think is the type of seizures that they have? It’s been used there.
It’s been used some in folks that have seizures, probably mainly in childhood where the seizures also may be associated with kind of developmental or language changes that are negative to say, “Okay, let’s see if we can tease out the relationship of these two to each other.” Obviously, today’s focus was surgery, but has it been used in other aspects of epilepsy aside from surgery? Yes, as well. The question they asked about insurance, at least at our center and I think most centers, obviously like any test we do pre-approvals so somebody’s not out of pocket, a surprise. None of us like that.
I get it. I don’t like that either. Usually, that’s not a barrier. I know when we see patients, even if they’re from other centers, I mean, I didn’t mention this either, but the nice thing is the MEG data can all be kind of put on disk, if you will, or printed out in picture form. It can go back to referring neurologists, neurosurgeon, whoever, for them to pull up. We can even put it on disk so they can pull it up on their own inter-operative equipment to register in their own OR as well. It’s portable from that standpoint.
If seizures are coming from scar tissue left from a Gamma Knife surgery in middle age following an AVM removal at 15, so long time ago, could MEG be useful?
Yeah, I think MEG could be, because a couple things with that kind of surgery is, one, if it was near critically functional areas, so language, motor, vision, it could help figure out that relationship. Even if it was not in one of those areas, if around where the prior abnormality is on MRI, if all of those make dipoles line up all around that, it’s really telling you, it’s like a big arrow saying, “This is the problem. This is why you’re still having seizures.” And then obviously that’s a discussion with what are my options to get rid of that problem.
I’m amazed at the resolution that MEG has. This person is asking about the precision. I mean, clearly, it’s very precise, but is it ever inconclusive?
There are times. Just like any test, can you have an inconclusive test? Sure, you can. I would say the benefit of the MEG is that that happens. I will say I’ve not done this a lot, but we’ve done this some, we’ve had patients, their first has been inclusive. We really thought, gosh, we really need to get this data. We’ve literally brought back the patient a little while later and said, “Let’s just redo it and see for whatever reason we can get better data that day,” and we’ve got wonderful data that’s fit.
The analogy I would give folks, it’s kind of like many of our patients that have seizures have gone for EEGs and at some point in their life they say, “I have several normal EEGs or inconclusive, if you will, and then I finally got the one that showed my doc, yes, I have epilepsy. This is an abnormal EEG.” Can that happen to us? Yes, it can. But the nice thing is, especially if the person can do it without sedation or anything, is it’s an easy test to repeat.
Are you able to see the dendrites from the machine to determine damage to these after prolonged seizures?
We don’t visualize the actual structure, which is what they’re asking. We’re looking at function, if you will. We can get an idea if function has been changed in some other ways that I didn’t talk about today. There’s other ways we can use the MEG technology to look at function if it’s been altered. In the example I would give folks, again, if we look at analogies is I could give my car detail, take a picture of it, make it look great and show it to you, and then say, “Do you want to buy it?” You’d probably say, “Well, wait a minute, can I drive it first? Can I see if the air conditioning works?”
But if some of those functions weren’t quite so hot, that might change your thinking, right? They’re looking for, is there a change in structure? Whereas often what we really want to know is, is the function different in the patient, right? I mean, structure, yes, but we want to know how things are functioning.
Are there patients that cannot have MEG?
They’re rare in the modern era. The biggest ones I would say, and they’re pretty rare because the technology has shifted for a lot of our implants, I would say if a patient has had, gosh, probably like a really horrible head trauma where they had to have some kind of large bone flap that was metal plate because their head trauma was so bad and they had seizures from that. Even in the modern era, a lot of the ways that surgeons are doing that are compatible because they’ve gotten away from some of the older fashion kind of metal ones, because even with MRIs that’s a problem. They’ve kind of had to adapt for more current imaging where that’s less of an issue for us as well.
There are rare folks, to be candid. Even some of our patients that have cognitive issues that make it hard for them to understand the testing, if we can do sedation, unless they’re just behaviorally and cognitively so challenging that literally the parents tell us, the caregivers, it’s hard to even get them in a car to get to a hospital. Short of that, we can do it. There really are pretty rare exceptions in the modern world. I mean, we call patients, we kind of say, “Here’s what’s going to happen. Tell us about you,” most of those, if there’s any odd one there, we can tease it out before a patient’s driven to get a MEG or gone through the process, if you will.
Can you use prior MRI to superimpose the MEG or do you have to have sort of coincident testing done?
Prior MRI, I will say, sometimes can be used. Political answer here. The reason I say sometimes is it depends how it was done. To get the degree of resolution I showed you, we need what are called really thin cuts of the MRI to be done. Sometimes if they’re just doing what I would call a regular run-in-the-mill MRI, say you have headaches and got MRI, the cuts are much thicker. They don’t give us the details that we need to put our data on top of the structural picture.
That’s when we end up just saying we can just do part of the MRI over. We just need to do our structural part. We don’t need to do the whole 45-minute to hour MRI. It may just take us 10 minutes to do our part, for example. But if they’ve had a good structural MRI and we look at it, yeah, we can use that. Even my own patients, if they’ve had one six months, a year ago, as long as it wasn’t so long ago that we say, “Okay, things may have changed,” we can use those.
The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified health care professionals who are familiar with individual medical conditions and needs. CURE Epilepsy strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified health care professionals who are familiar with the individual’s specific health situation.
Studies show that people with epilepsy are more sedentary than the general population. This is partly due to concerns about having a seizure while playing sports or exercising and the fact that healthcare professionals previously advised against physical activity. Many people with epilepsy, caregivers, and even some doctors are unaware of the research surrounding physical activity for those living with epilepsy. Unfortunately, studies have shown that up to 80% of people with epilepsy exhibit some form of cardiovascular disease 1 , and people with epilepsy have a threefold increased risk of sudden cardiac death 2. These statistics suggest the need for more physical activity among those with epilepsy, a fact that is reinforced by recent research.
This free webinar will explain the difference between exercise and physical activity, summarize the health issues faced by manypeople with epilepsy and discuss who may benefit from physical activity. Viewers will also hear the current consensus among medical professionals on the safety of different types of physical activity and exercise for people with epilepsy. Finally, viewers will learn practical tips for how to safely engage in physical activity for those living with epilepsy.
The webinar is intended for people living with epilepsy, their family members and caregivers, and anyone seeking to learn more about mental health and epilepsy.
1 Verrier RL, Pang TD, Nearing BD, Schachter SC. Epileptic heart: A clinical syndromic approach. 2021;62(8):1780-1789
2 Bardai A, Blom MT, van Noord C, Verhamme KM, Sturkenboom MC, Tan HL. Sudden cardiac death is associated both with epilepsy and with use of antiepileptic medications. 2015;101(1):17-22.
About the Speaker:
Dr. Halley Briglia Alexander is an Assistant Professor of Neurology at Wake Forest School of Medicine. She is board certified in the areas of epilepsy and clinical neurophysiology. Her research focuses on evaluating the effects of physical activity in people with epilepsy on seizure control and epilepsy-associated comorbidities. Dr. Alexander is working to develop physical activity programs that are accessible to those with epilepsy, taking into account the unique barriers to exercise that people with epilepsy may face.
Q&A with Dr. Halley Briglia Alexander
One of the most challenging obstacles to getting enough exercise and activity is the feeling of constantly being fatigued and a sense of being sedated from the antiseizure medications. Is there anything that can be done to address this issue?
One reason why we think that physical activity could be good for people with epilepsy is because of these medication side effects. And there’s been at least one study that I can think of off the top of my head that showed that people reported a reduction in their medication side effects after they started exercising. So my recommendation would be to try not to let it keep you from starting the physical activity. That’s a lot easier said than done. But I think if you can make yourself just start somewhere, like I said, a few minutes a day, you should find that increasing your physical activity, even though it’s going to be hard at first because of those side effects, will probably reduce the side effects that you’re experiencing. And then, therefore, it will kind of just get easier day after day.
The other thing that I’ll say is that it could be worth talking to your neurologist about your medications, because we don’t want anyone to have to live with side effects. And we have over 25 medications for epilepsy now. So, it’s possible that they may be willing to work with you to try adjusting medications and finding a regimen where maybe you don’t feel so fatigued.
Another question came in that relates to a very tragic event that happened very recently with regard to a surfer. This is a surfer who died potentially from seizure while surfing, and this is a very scary possibility.
The person who posed the question also enjoys surfing and has epilepsy. And generally, they feel better physically after surfing and believes that the additional ATP produced in the body might help with brain health. So, I want to get a perspective on that. What are the thoughts on ATP production from exercise? Will it help reduce seizures at all? Are there other things that the body produces during exercise that might help reduce the chances of seizures?
That’s a great question. And that’s all kind of research that we don’t have answers to right now, but they are being looked at. We do have data outside of epilepsy and some from other neurological diseases even, especially in the Alzheimer’s realm, where they’ve looked at what is actually changing in the body when people exercise and how might that be benefiting brain health. So, there are some neurotransmitters that they’ve looked at. Something that comes up a lot is BDNF, which is brain-derived neurotrophic factor, which is thought to increase plasticity of the brain, so kind of improving the health of neurons. But specifically in epilepsy, it really hasn’t been looked at. So, there’s many theories about what could be happening in the brain, different levels of different hormones, and again, neurotransmitters. And it’s probably some combination of all of those things that’s happening, but we don’t have all the answers to that right now.
Here’s a question about weightlifting, which was included in the moderate risk category, but the CDC recommends including strength training two times per week. Can you clarify or share your opinion on this?
Another good point. So, it is definitely recommended to do some weight resistance-type exercise. But of course, that is slightly increased risk in people with epilepsy because of the fact that if you’re lifting a 30-pound weight, or lifting it over your head, if you are to have a seizure, there’s a more significant risk of injury there compared to just walking or running.
And so, as far as I know, there aren’t any official guidelines or recommendations about that. But one thing that I think would be safer if you want to incorporate resistance training and you’re having frequent seizures is possibly using resistance bands, because you can get the same idea, same kind of effect on the muscles as weight lifting, but it’s a little bit safer in that you’re not lifting a weight that could drop, you’re just working with the resistance of the band.
I’m not a personal trainer, so I can’t suggest any specific exercises with the bands. And of course, I don’t know the context of this person’s specific epilepsy, but that might be somewhere to start.
So, should someone try to target a specific level of exertion or increase in heart rate? And along the same lines, can you speak to the idea of too much exercise? So, in this person’s case, they’ve always run marathons, and have become afraid of going too hard and toned it down to half marathons as a compromise, which I still think is amazing. So again, what level of exertion is reasonable?
Another good question and congratulations to that person for being so active. It’s very impressive. And afraid the answer is that there is no one level necessarily. Exercise is one of those things that the more you do it, you kind of buildup gradually. And then, the more that you’re able to do. So, for somebody who’s training to do a marathon, for them to go actually run the marathon doesn’t quite take the same amount of exertion and toll on the body as it would for somebody who hasn’t been training to go run the marathon. That could actually be disastrous for that person. So, there’s not necessarily a level of exertion that is appropriate for everyone or everyone with epilepsy.
I’m trying to think of the best way to answer the question. I think, again, it has to be individualized. But for that person, listening to their body is probably a good way to start. If they’re a marathon runner, they’re probably familiar with the feeling of a good type of hard workout and a bad type of hard workout, where hard feels too hard.
So again, I can’t give a definite answer to them, but I think that working with their neurologist and just listening to their body. But I will say, running and that type of high-intensity exercise… High intensity, so that means the intensity of the exercise in that moment was not shown to increase seizures. But when we’re talking about marathon running, we’re actually talking about low-intensity exercise over a longer period of time. And that, I don’t think has been looked at in people with epilepsy and probably won’t be. We won’t be making them run long duration to test that, so we don’t have the data there.
Are there any limitations on exercise when you have a VNS?
The reason I say that though is that some of the newer VNSs, they can be set to go off if they detect increased heart rate. The reason for that is that a lot of seizures present with increased heart rate or a fair amount of them do, so the idea is that the device can actually detect that and then go ahead and give a stimulation to help abort that seizure. So of course when you exercise, your heart rate will go up. So, in those cases, again, it still wouldn’t necessarily mean that you couldn’t exercise, but you might want to be aware of that and be prepared for the idea that your device might go off a lot more.
And if you’re somebody who wants to engage in exercise regularly, depending on your seizures and your type of epilepsy, it might be something that your neurologist could adjust. They might be willing to adjust it so that it doesn’t go off every time your heart rate increases a little bit.
So, to some of the data that were presented, on the mood graph, why didn’t exercise or activity decrease fatigue in relationship to non-exercisers? Both groups scored the same regardless of activity.
Good question. And I don’t know the answer to that, but I can offer a few points of speculation. So, it’s possible that the group that was exercising… I believe in that study it was either six weeks or 12 weeks. But when you first start an exercise regimen, you might actually be a little bit more tired because your body is working harder to adapt, which in the end is good, but in the short term could cause a little bit more fatigue. So it could be partly due to that.
Could be, again, like somebody has already mentioned, that sometimes the seizure medications are contributing to some kind of fatigue or sleepiness. And so, it might be that in that study, the exercise group, despite reporting that they had more vigor, we saw that component had gone up, that maybe that wasn’t enough to overcome… That their medications were still making them feel a little bit fatigued. And I don’t know how those two terms are perceived differently, vigor and fatigue.
So again, I’m speculating on that, but I think it could be a lot of different variables. But we do have data from other studies and from that study, showing the vigor, where people have perceived that their energy levels are increasing. And so, I didn’t show those graphs, but when we look at the quality of life scales and epilepsy, they have subdomains. So, a lot of them will look at physical function or energy level as a subdomain of the quality of life scores. And so, with exercise, in a couple of studies, people have reported improvement in the energy or the physical function domain of those subscores. So again, I can’t explain that one study, but I do think in general people have been reporting feeling improvement in their energy with exercise.
Is there a difference between physical activity indoors versus outdoors?
That’s a good question. I guess, it depends on what you’re looking at, a difference in what exactly? But being outdoors has been shown to improve mood, even if you’re not exercising. Being outdoors in the sunshine and the fresh air, that does seem to do a lot of good for a lot of people. So, I would say if the weather’s okay and you’re able to and you have the choice between the two, then going outdoors probably would have more benefits for you health-wise.
However, if we’re talking about a dangerous outdoor situation, maybe it’s not safe to walk in that neighborhood, or the weather’s bad, or being at home and doing a stationary bike means you can have family members nearby who could help you if you were to have a seizure, whereas if going outdoors, your only option is to ride the bicycle, which that was a group two sport because you’re out in traffic and everything, then looking at the difference between those two, it certainly would be safer to do the stationary bike inside. So probably depends on what you’re trying to see a difference in, but there are differences between the two. But then, at the end of the day, physical activity is physical activity. So whichever way you can safely get it would be what I would recommend doing
And just want to be clear that while some of the data focused on mesial temporal lobe epilepsy, this is broad advice for anyone with epilepsy, it’s not just restricted to mesial temporal lobe, correct?
Yes. Thank you for clarifying that. So, most of the studies looked at adults and kids, focal types of epilepsy, general type of epilepsy, some specific syndrome. So, it’s broad advice for all epilepsy.
Are there any mitochondrial effects from exercises that could be a part of the benefits to epileptics from exercise?
Yes is the short answer. They’ve looked at the mitochondrial effects of exercise in humans and a lot of other disease in the general population, in other neurological diseases. Again, as far as I know, we don’t have published data on that in people with epilepsy. But most likely, any of that, that’s affecting brain health is probably going to be beneficial for people with epilepsy.
The reason why we still need to specifically look at it in the epilepsy population, and we can’t just assume, “Oh, it’s good for brain health in Alzheimer’s, it’s probably good for epilepsy,” is that epilepsy is somewhat unique than other neurological diseases, in that it’s increased brain activity, increased signaling. And so, some of these neurotransmitters and things that might be more activating in the brain, which might help dementia or memory loss, we don’t really know necessarily the effect it would have in epilepsy.
So for example with BDNF, that increases synaptic plasticity and neurogenesis, but that’s not always beneficial in people with epilepsy. So, if you have new neuronal connections being made, it’s possible that kind of aberrant sprouting could actually be part of what could be related to the seizures themselves. So, we don’t know any of that, but that’s why we need to look at it in epilepsy, even though we’ve looked at it in other populations. And right now, we don’t have those answers.
The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified health care professionals who are familiar with individual medical conditions and needs. CURE Epilepsy strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified health care professionals who are familiar with the individual’s specific health situation.
Sudden Unexpected Death in Epilepsy (SUDEP) affects approximately 1 in 1,000 people with epilepsy, regardless of age 1,2. While lack of seizure control and seizure severity are the most common concerns for increased risk of SUDEP, there is also a concern that certain genetic mutations may increase SUDEP risk.
This webinar will discuss what we know about SUDEP, specifically in the rare epilepsy community, as well as what parents and caregivers of children with rare epilepsies should know about SUDEP prevention and ways to mitigate risk. Presenters will share ideas on how to discuss SUDEP with doctors, from both the perspective of a physician and a parent of a child diagnosed with a rare genetic epilepsy who has educated themselves about SUDEP and taken steps to reduce the risk of SUDEP for their child. Attendees will have the opportunity to ask questions to all presenters. The webinar will also include a discussion about the latest advancements in basic and clinical epilepsy research focused on SUDEP risk and prevention.
The webinar is intended for people living with epilepsy, their family members and caregivers, and anyone seeking to learn more about mental health and epilepsy.
This webinar is conducted in partnership with our friends at PAME and Wishes for Elliott.
The mission of Partners Against Mortality in Epilepsy (PAME) is to convene, educate and inspire all stakeholders – from the bereaved to those living with epilepsy, to health care professionals, advocates, clinical and basic scientists, and death investigators – to promote understanding and drive prevention of epilepsy-related mortality.
Wishes for Elliott is a non-profit organization dedicated to supporting research to improve the lives and prognosis of children struggling with SCN8A mutations and similar rare epilepsies. Their collaborative DEE-P Connections project partners with more than 40 rare epilepsy groups to help educated and bring critical resources to families who have children severely affected by these disorders.
1 Sveinsson O, Andersson T, Carlsson S, Tomson T. The incidence of SUDEP: A nationwide population-based cohort study. Neurology. 2017 Jul11;89(2):170-177.
2 Keller AE, Whitney R, Li SA, Pollanen MS, Donner EJ. Incidence of sudden unexpected death in epilepsy in children is similar to adults. Neurology. 2018 Jul 10;91(2):e107-e111.
About the Speaker: Dr. Lhatoo is aneurologist and neurophysiologist with expertise in the medical and surgical management of intractable epilepsy. He has been a director for Level-IV epilepsy centers inthe UK and USA since 2006 and an instructor for the International Stereo EEG course since its inception in 2010. Dr. Lhatooserves as the head of the International League Against Epilepsy’s Task Force for Big Data in Epilepsy. He has a particular interest in the epidemiology, phenomenology, and pathogenesis of SUDEP. His published work has described potential biomarkers of SUDEP, including post-ictal generalized EEG suppression (PGES) in SUDEP cases, post-ictal hypotension, post-convulsive central apnea, and ictal central apnea.
Q&A with Dr. Lhatoo
How did you find out about SUDEP?
I’ll tell you just now is what I’ve learned about SUDEP was right here on this call with you. I didn’t think it applied to us. It wasn’t until my son’s third birthday when another one of our little buddies in our group, Emma, passed away in her sleep. She had a seizure, and they found her, I think, with her head in the pillow, and it was devastating. It was that point on that my husband and I started monitoring Lincoln, and we had a hospital grade monitor. We hooked him up every night. It used to be that we would only monitor his breathing when he was sick, when we knew that he was compromised, but from that night on, we have put Lincoln on his stat monitor every single night.
I didn’t even know that it was because of SUDEP, still. I wasn’t associating that with Emma’s passing or anything like that. We just knew we needed to monitor him. It’s not a conversation that we had with our doctors. Honestly, I thought that Lincoln has lived through so many thousands of seizures that one couldn’t possibly be the one to take him out, for lack of better terminology. I think I thought that was a non-issue. Like, “No, he’s just had lots of seizures, and he’s okay. He comes out of them.”
I’m realizing now, thanks to the doctor’s presentation, that Lincoln fits all those boxes, and we’re not going to have seizure freedom. We’re going to keep working for it, but he is very high risk. I’m comforted knowing that we’re doing what we can, and I even have questions for the doctor myself. We happened upon a solution. We can’t prevent it, but monitoring Lincoln and keeping him in our room is something that we’re comfortable with in doing what we can
Can you comment on successful ways that parents have brought this issue to your attention. I know you’re very attuned to all of this, but what recommendations do you have for parents who want to talk about this and don’t know how to bring it up?
I think the way in which patients have proactively asked me, it’s often me discussing SUDEP with patients and their carers, but every once in a while a proactive parent or a proactive carer or a patient himself or herself will bring this up to me. It’s a very direct and inoffensive question, which is, “What is the risk of something bad happening to me?” It’s a straightforward question that deserves a straightforward answer.
Most of us who have observed a grand mal seizure to occur will know that a lot of the time patients do turn a little blue around the lips and don’t breathe very well after a seizure. What does that mean to that individual? I think it’s a very important question to be asked and to be addressed. A lot of the time is the answer is reassuring. Sometimes it is okay. These are the specific things that need to look out for, and this is how you can be careful.
What do you recommend for children and teens who want to sleep alone? Is there a specific type of monitoring device, either that they wear or that is connected to the bed, that’s helpful?
That’s a very, very important question. I think there was a time when we were very careful about making overbearing recommendations because teenagers in particular have to live their lives. There’s a quality of life issue, et cetera, et cetera. But we know from recent scientific studies that one of the most powerful factors that prevents death probably is the presence of somebody else in the room; whether somebody else is in the room sleeping with that particular individual or not. There’s something to be said about that kind of observation.
Of course, as you’ve already alluded to, there’s the in between of monitoring devices and a lot of my patients do use them successfully. There are a couple of FDA approved devices that are out there on the market. I personally don’t have shares in either, but there is the Empatica, the Embrace device. There’s Brain Sentinel. They both use different approaches. What they don’t do is prevent SUDEP. What they do, do is let the designated carer or person know that a seizure is occurring or has occurred. I’m an advocate for the use of whatever technology is available for mitigating risk.
Have there been any studies with SUDEP and VNS patients? If so, are there any differences in the rate of SUDEP?
Yes. Great question. There is actually a very well-known study where several thousand patients who had had VNS devices implanted were studied over a period of time. It looked as though the rate of SUDEP over a prolonged period of time actually went down in the VNS population. Over a long period of time, it may be protective against SUDEP.
This is obviously one study, but it was sufficiently powered, I think, because there were thousands of patients who were studied to say that there is probably something there. When you couple that with the fact that VNS in some individuals reduces seizure frequency, then there’s a case to be made for doing VNS in patients who have not responded to other measures. [But] I wouldn’t say that VNS alone is completely protective.
Can a CPAP or other oxygenation aid device help those with SUDEP risk factors at night during sleep?
That’s a pretty nuanced question, I have to say. When it comes to improving sleep quality in patients with epilepsy, yes, absolutely. CPAP and those things might be useful because sleep deprivation, poor sleep quality, et cetera, et cetera. These are all linked to seizure frequency, and of course, seizure frequency is linked to SUDEP.
In somebody who’s having a seizure and may be likely to suffer from SUDEP, would CPAP prevent that? Probably not, and I say that for number reasons. Chief among those being that, in a convulsive seizure, you can have all monitoring devices, they become dislodged, there’s a lot of movement, shaking, et cetera, et cetera. So I wouldn’t rely on CPAP for preventing SUDEP directly like that.
Should electrical stimulation of the medulla, and maybe you can explain where the medulla is, be more widely used to study or to prevent SUDEP?
The medulla is part of the brain stem, the same structure that I was talking about, and medulla probably is the most important part of the brain stem for a final common pathway to controlling breathing and cardiac rhythm and blood pressure. A very important structure. It’s a very challenging part of the brain to study in humans because to stimulate the medulla, you have to put electrode into the brain stem, and that always carries a risk of bleeding hemorrhage and so forth. The outcome of bleeding in that part of the brain stem would be catastrophic, would be death. To my knowledge, nobody has done that in humans yet, but there are researchers who are looking at stimulating other parts of the brain stem; parts of the brain stem that are maybe less risky, but at the same time, likely to impact breathing and cardiac function. There’s more to come. In the next few years, I think we will hear a lot more about brain stem stimulation
For uncontrolled seizure patients, how often would you recommend doing an EMU stay? I know that the MORTEMUS study was done using patients in the EMU.
The EMU has a very specific role. We either send patients there for diagnostic assessment. Here, we’re trying to figure out if the patient has epilepsy or a related disorder. Or, we’re trying to see what kind of epilepsy it is. That’s diagnostic EMU assessment.
Then there’s the other kind of EMU assessment, which is the presurgical assessment; studying the seizure in order to do brain surgery. It’s the latter type in which we’ve become more and more practiced at assessing cardiac and breathing function, as well. There isn’t much point in repeated EMU assessments for assessing risk. Usually, if intractability or lack of control through medication surgery has been established, then one EMU assessment where cardiac and breathing function are looked at as well is probably enough.
Here’s a question related to the rare epilepsy categorization. “Is Lennox-Gastaut a part of this group of rare epilepsies that are impacted more significantly by SUDEP?
Yes. I would say that it is. It’s one of the commoner varieties of the rare epilepsies, but Lennox-Gastaut really is a syndrome. It’s not really one specific genetic condition. Within the LennoxGastaut rubric, we actually have dozens of other conditions that make up the syndrome complex that we call Lennox-Gastaut.
You’ve talked a lot about people who may have had longterm epilepsy, lots of seizures, but there are instances where after just a handful of seizures, somebody has passed due to SUDEP. We think of some more public cases like Cameron Boyce who passed away, but there are others. Is it possible to die from SUDEP without either a diagnosis of epilepsy or a first tonic clonic seizure?
Absolutely, yes. Happily, I would say that that kind of situation where it’s not uncontrolled epilepsy is extremely rare, but it does happen. As recently as two months ago, I was contacted by colleagues in another part of the country who had just such a patient who passed after a second tonic clonic seizure. We’ve come to understand that SUDEP is actually a heterogeneous phenomenon. It’s not just one thing, and there isn’t just one prototype patient that fits that mold. There’s actually a variety of types. There are tragic cases where a first ever or a second ever seizure kills, but I have to say that that is very, very rare.
You’ve talked about the cardiac disturbances, but could you talk a little bit more about that? Does that mean cardiac arrest, or what do you mean by a cardiac disturbance or arrhythmia?
By cardiac disturbance I mean cardiac rhythm dysfunction. Cardiac rhythm can be disturbed in a variety of ways during seizures. The heart can either be too fast or too slow. When it’s too fast, it can happen in a pathological fashion; conditions that we refer to as ventricular tachycardia, ventricular fibrillation, and things like that. Those are very dangerous. In the SUDEP context that seems to happen extremely, extremely rarely. What is more common is the heart beating too slow and maybe even stopping. That’s what we refer to as bradycardia and asystole. You can imagine that after a seizure, if a patient is not breathing too well and their heart’s not beating too fast either, that their blood pressure’s not going to be great. Of course, it sets a vicious spiral that can result in an unfortunate outcome
Abby, I know that you had some questions. Now that you’ve heard this discussion, as a parent, what do you think and what sorts of questions would you be coming to your physician with now?
Abby: First off, I’m like, “Wow! It’s a miracle my son is still here!” We have prolonged QTC. He has intractable epilepsy. He’s a boy. He has cluster seizures. I’m thanking God that he’s still here.
I feel like quite a few of the questions coming in were kind of along the lines of what I was thinking. My son has a VNS, so I was worried that might be a problem.
Somebody asked about the CPAP, that’s something that I have chosen not to put on my son, but I’m wondering if I should? I’m wondering if that makes a difference breathing-wise.
My question would be the sleep studies that my son had done seem like they’re separate from EKGs, like these are two different events. I’m wondering, do I need to pursue having them done together? I’m not even quite sure what my question is. It just seems that the breathing patterns that you’re looking for are maybe things my neurologist isn’t looking at. Is my neurologist looking at that, or my epileptologist, or are they just looking at seizure activity? Are they focused in on breathing patterns? How do I know if my son’s intractable epilepsy is causing breathing issues not related to just, “Oh, his SATs dropped”?
I don’t know if that was very clear cut, but that’s kind of where I’m going. How do we get everybody together on the same page to talk about this risk?
Dr. Lhatoo: If I may just make a comment, which is, I shared some of the recent research findings with you folks today, and it is always the case that clinical practice lags a little behind what comes out in research. That’s only correct because research findings need to be validated, replicated, reproduced, and so forth before they become standard clinical practice. It is not standard clinical practice in many places to routinely measure breathing. Cardiac rhythm is done. EKG is done in most places, but breathing is not routine. I believe that it should, and there are a group of us who are strong advocates for it. Over the coming months and years, you’ll see more and more folks who will begin to do it in their epilepsy monitor units. But in sleep studies, breathing is very carefully measured, so I would imagine that your child has had that done.
The questions below were answered by Dr. Lhatoo after the webinar had finished recording to answer some of the remaining questions submitted by attendees:
Why does the risk of SUDEP increase in people with nocturnal epilepsy or people who have seizures during sleep? What makes sleep or being isolated throughout the night a risk factor? Is there any recent research you could share?
Sleep onset seizures (particularly REM sleep) seem to cause more problems in animal models of SUDEP. Sleep phases may also be associated with more tendency to autonomic dysfunction [the autonomic nervous system is what controls and regulates involuntary physiologic presses such as heart rate, blood pressure, breathing, and digestion; I believe Dr. Lhatoo is saying during sleep, these processes slow down which can increase seizure severity] and post-seizure obtundation [reduced level of consciousness after a seizure]. In some people, getting tangled up in bedclothes face down may impair recovery fatally.
What are the most promising biomarkers to identify patients at SUDEP risk, and how do we implement these into clinical care (other than the biomarkers you discussed in the webinar—eg. genetic biomarkers)?
So far, there are no biomarkers that have been proven to be useful in systematic prospective studies [a study that focuses on the development of a disease and relates it to suspected risk or protection factors; usually involves watching subjects for a long period of time], but there are several for which there is some evidence of value. These include generalized convulsive seizure frequency and post convulsive [after a convulsive seizure] bradycardia/asystole [slow heartbeat/heart stops pumping entirely due to the electrical system failing] and central apnea [breathing repeatedly stops and starts because the brain doesn’t send proper signals to the muscles that control breathing]. The best way to identify these is an epilepsy monitoring unit assessment. There are several candidate genetic biomarkers but again, none with clinical utility yet.
Does SUDEP originate from specific lobes or areas of the brain (apart from the brain stem and uncontrolled epilepsy as mentioned in the webinar)? Do we know the percentage of SUDEP victims who suffered from seizures originating in these specific lobes?
There is reasonable evidence now to say that SUDEP can occur whether the seizures are of focal (any lobe) or of generalized onset, if seizures are uncontrolled.
Is the risk of SUDEP the same if a patient experiences ictal/postictal tachycardia instead of bradycardia during seizures? I understand that any cardiac arrhythmia is a risk factor for SUDEP but multiple review papers and studies have conflicting information about what type of arrhythmia is the most dangerous—could you please help clarify this??
Post-ictal bradycardia [slow heartbeat after a seizure] is likely more dangerous than tachycardia [rapid/increased heartbeat]. This is because postictal tachycardia is extremely common; the vast majority of patients who have this feature have no problems.
The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified health care professionals who are familiar with individual medical conditions and needs. CURE Epilepsy strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified health care professionals who are familiar with the individual’s specific health situation.
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