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Rare Look at Dravet Syndrome

Renowned neurologist Scott Perry M.D., Medical Director, Cook Cook Children's Genetic Epilepsy Clinic, takes us into the rare world of Dravet Syndrome patients and the exciting new treatments available now and on the horizon. Also, peek into the wide range of research, medications that are making a difference in seizures. He also does a deep dive into current research methods, including how zebra fish are helping to find more medications that work.


Meet the speaker

Meet Dr. Perry


Related information

More on Dravet syndrome

Cook Children’s Comprehensive Epilepsy program

Cook Children’s Neurosciences

The Arcuate


Transcript

00:00:01

Host: Today we're talking to Dr. Scott Perry about the ongoing study and research into Dravet syndrome and the hopeful horizon for children with this rare and often severe form of epilepsy. But before we get to that, here's a little background on Dr. Perry. He is currently the medical director of neurology and the genetic epilepsy clinic at Cook Children’s. Dr. Perry is also the co-director of the Jane and John Justin Neurosciences Center. His research interests focus on the treatment of childhood epilepsy, and he cares for a number of patients with epilepsy secondary to genetic cause. In addition to his work and research, I Cook Children’s Dr. Perry serves on several local national and international committees dedicated to improving the care of childhood onset epilepsy. And as a member of the Dravet Syndrome Foundation's medical advisory board. We're so happy that you could take the time to visit with us today. Welcome. Thank you. So Dr. Perry Dravet syndrome is a fairly rare form of epilepsy. Can you talk a little bit about what it is? What makes it rare and certain children predisposed to Dravet syndrome?

00:01:09

Dr. Perry: Absolutely. You know, Dravet syndrome is, is rare because it occurs somewhere between one and 15,000 to 20,000 kids. So it's not something that most doctors are going to see, uh, maybe at all in their career or if they do see it, it's going to be quite rare. So the ability to recognize it early on, uh, will become very important, which is why it's important we're having this conversation today. There are certain kids that will be more likely to have Dravet syndrome or will develop Dravet syndrome. And that's because they harbor a specific genetic mutation in a gene called the SCN1A gene that results in this epilepsy syndrome.

00:01:44

Host: I just wanted to clarify the number that you gave is that globally, or is that here in the U.S.?

00:01:49

Dr. Perry: It really is from a variety of different studies. So when you look at how common Dravet syndrome is, it will come from a variety of different studies from different countries. So, you know, in Norway, for example, there may be a study that showed it was one in 25,000 in another country. It may be one in 15, another one in 20. Another country may be more than that. So kind of globally, we say it's about one in 15 to 20,000 fact is it may be even more than that because you need specific genetic testing often to kind of confirm this diagnosis and genetic testing is not necessarily commonly available throughout the world. There may be many more patients out there with Dravet syndrome that just aren't yet diagnosed. And I suspect we'll see the number continue to rise to some degree because that's what we've seen over time, just here in the United States.

00:02:35

Host: So how is Dravet syndrome diagnosed? What specific symptoms for instance, should a primary care physician look for and when should they refer?

00:02:44

Dr. Perry: Dravet syndrome is first and foremost, a clinical syndrome. And that there is kind of a specific presentation that you will often run into. So for a primary care physician, this epilepsy syndrome commonly begins with febrile seizures. Now, febrile seizures are a very common thing. So seizures in the setting of fever, we see that in children all the time, and it's often very benign, but in Dravet syndrome, these seizures tend to be different. So what are some of the different things? Number one, kids with Dravet syndrome will have oftentimes very prolonged febrile seizures. So febrile seizures, 15 minutes, sometimes 30 minutes or longer, the seizures tend to occur every time the kid is sick. So every time a child has a fever or, you know, just a mild illness or commonly, these will occur after immunizations, you'll see seizures. So, you know, some of the red flags I tell pediatricians and other primary care providers to look for is they see a kid that's coming in multiple times with febrile seizures …

00:03:39

you've got to at least raise some concern. Initially these children are completely normally developed. Their EEG, if you do, one is probably going to be normal, but over time, and generally by the age of one, you start to see seizures in the absence of fever. You see continued admissions with prolonged seizures or status epilepticus, it's at that time that the EEG becomes abnormal often, uh, and you start to see a pause in the development or a stagnation in the development, and then maybe even developmental decline. The initial seizures that people often see are Hemiclonic. So that's a seizure where just one half of the body may be rhythmically shaking. And one time they may present with primarily left sided shaking. The next time they present, primarily right-sided shaking. After age one other seizure types will appear. Myoclonic type seizures,

00:04:26

grand mal, or what we call generalized tonic clonic seizures, absence seizures are what people used to call petit mal seizures, very brief periods of staring myoclonic seizures, tonic seizures, focal seizures, basically any seizure type, generally can begin to appear after that first year of life.

00:04:43

Host: So how do you treat Dravet syndrome?

Dr. Perry: Well, traditionally Dravet syndrome has been, you know, treated with medications to control the seizures. And these medications were not specifically tested in Dravet syndrome. They were simply medicines that based on expert consensus were probably the most useful drugs. So those drugs would have been valproic, clobazam, and another medicine called stiripentol. Those were the really the three medications that we considered the primary medications to treat this disorder. Stiripentol has not been available in the United States until just recently. It was FDA approved last year and is now available in the U.S., but before that, we had to import it to be able to treat these kids.

00:05:23

What has happened more recently is that we do have new medicines that are at least been specifically tested in Dravet syndrome. And there's been a lot of excitement over the last couple of years is the new studies that are being directed specifically at this disorder, so we have some good evidence of what can treat these kids. I should say, there are certain medications that they should avoid. So it's very important that you understand which medicines make them better, but what's also very important is make sure you understand which medicines you should avoid that will worsen this epilepsy. So drugs that work on the sodium channel, which is what the SCN1A gene encodes, will make these children worse. And that's important because many drugs used to treat epilepsy are sodium channel drugs, and they are medications that are traditionally used to treat focal seizures. So you can imagine if a kid comes in with their first seizure and they have one side of the body jerking, that's a focal seizure. So doctors are reasonably going to consider these medicines. So finito and oxcarbazepine, carbamazepine, lamotrigene, are all sodium channel drugs. There's actually many more that need to be avoided in these kids so that you don't make them worse.

00:06:29

Host: So when should a pediatrician or a primary care physician refer a child?

00:06:34

Dr. Perry: When you look at seizures in the setting of fever, a primary care physician should become suspicious and probably refer to a neurologist for further evaluation if the child is presenting with repeated prolonged febrile seizures. So, you know, 15 minutes, as I said, 30 minutes long, those would be of concern. If you have a child who, every time they get sick, every time they have a fever, they're having a seizure – that is concerning. Even if the kid is normally developing, it's at least worth a visit to the neurologist to talk about it. If you have a child who has had febrile seizures and has had seizures in the absence of fever, that is definitely a reason to refer them for evaluation as well. I guess one last would be if sometimes this happens, you might be seeing a child who has had febrile seizures and has been put on a medicine and you've noticed they have become worse. So if they've been put on a sodium channel drug and their worse, that is concerning for Dravet syndrome.

00:07:29

Host: So what happens if a child who has Dravet is put on a sodium channel drug, what are the implications of that?

00:07:36

Dr. Perry: A child treated with a sodium channel drug with Dravet syndrome will first and foremost have probably more frequent seizures and is more likely to go into status epilepticus. Whether that has impact down the road is somewhat debatable. There are definitely studies that have shown that children that were exposed to sodium channel drugs early, before they had the diagnosis of Dravet syndrome, they do worse cognitively later on than children who were not exposed to those drugs early on. I can say at least anecdotally in my own population, I would agree with that. Um, children that I follow that were diagnosed late in life seemed to cognitively probably be a little worse off. Uh, and it's not just because their age, it’s because they had many more bouts of status when they were kids and they were exposed to the wrong medicines. Whereas now that, you know, we're more attuned to this disease, we diagnose it early on and avoid those drugs. I do feel like the patients are cognitively developing better.

00:08:34

Host: So what research and novel treatments are in the works and how are they changing the way we approach treating Dravet syndrome?

00:08:41

Dr. Perry: Well, over the last several years, the interest in evaluating and treating Dravet syndrome has grown significantly such that we've really seen some of the first drug trials specific to Dravet syndrome. And when I say it's specific to Dravet syndrome, I don't mean that these drugs have been developed specifically to treat the disease, but they are being specifically tested in the disease. So that just indicates there is interest in this population and trying to help this epilepsy syndrome. The first drug that was studied and has recently become FDA approved is Epidiolex. That is a first-in-class medication derived from the cannabis plant. So it is purified cannabidiol or what people call CBD a suspended in oil. I, and we completed a multiple phase three trials here at Cook Children’s over the last couple of years to evaluate that medication. Those trials were well-designed double blind placebo controlled trials that showed Epidiolex was superior to placebo in the reduction of convulsive seizures in children with Dravet syndrome.

00:09:44

Now, following that was a study in a drug called fenfluramine. Fenfluramine was formerly a component of a diet pill called fen-phen. That was taken off the market many years ago because it had some adverse effects on the cardiac valves and the heart valves. But it was noted in Europe that children treated with fenfluramine that had Dravet syndrome significantly did better from a seizure standpoint. And so they took that drug and studied it really at its at a lower dose than they used previously when it was used for diet. And again, in a double blind placebo controlled trial have shown significant reduction in seizures in children with Dravet syndrome in this drug. So both of those drugs are likely going to be available. Epidiolex is available now, fenfluramine is currently awaiting evaluation by the FDA to see if it gets approved. Beyond that there are several other drugs coming down for investigation.

00:10:36

There's one called OV935 of which studies will open up later this year. That's a drug with yet another mechanism of action working on a cholesterol enzyme in the brain that appears to help control seizures. There are three different drugs that were discovered by examining medications used in zebra fish that have Dravet syndrome. And they are doing that screening of the zebra fish demonstrated that these drugs reduce the seizures in the fish. And as a result, those will now come to human study. So that will probably be early next year. And then beyond that, there are some very exciting, uh, genetic research, possibly some gene cures that are being developed.

00:11:17

Host: So talk a little bit about this, I find that very interesting that a fish could have Dravet syndrome and how that might be helpful to patients.

00:11:24

Dr. Perry: It is fascinating. So typically before a drug comes into human study, we've got to study in animals and see if it's safe and to see if it's effective in the condition. And so commonly, we have models that are mice models that have these diseases, and there is a mice model of Dravet syndrome. The thing about mice is that mice take up a lot of space. They're a decent sized animal. You need, you know, hundreds of animals to study. And so it can be difficult to study sometimes, uh, mice. So a researcher named Scott Baraban out in California, uh, has developed a zebra fish model of Dravet syndrome. So this is a very small fish, uh, you know, maybe a few inches in size when full grown that has Dravet syndrome and the fish all, uh, live in their small tanks that are filmed continuously throughout the day.

00:12:13

And the cameras detect the motion of the fish. And when the fish have seizures, they swim very erratically. And so the camera can pick up on this erratic swimming and know that the fish is having seizures. So what is special about zebra fish is that in the early period of their life, anything that's in their water is absorbed through their skin and into their body. So it is a very good way to test drugs. So what he's done is he took like 3,500 already available drugs and put them in the water individually and looked for drugs in which the fish swimming in that water started to swim more normally showing that their seizures were under better control. And by doing that, he identified an old anti-histamine from the 1950s. Uh, he identified a drug that is used for depression and anxiety currently, and he identified another drug that was used as a weight loss drug, all of which significantly improve the seizures in the zebra fish model and now is going to take those drugs and apply them to human study.

00:13:12

Host: Wow. Okay. So based on today's treatment protocols, how severe is the impact on a child's development and cognitive skills?

00:13:21

Dr. Perry: Dravet syndrome has significant impact on development and cognition. As I said, most of these kids are really all of these kids are normal in the first year of life, but after, on average, age one, you start to see really a pause in their development. Some of them will have decline, especially after a very long seizure after status epilepticus, they may lose skills like walking or maybe lose some of their talking that they had before. They may regain some of that, but they slide backwards after that bout of status, but they also just, as other kids around them are growing and developing their development kind of just pauses or at least slows down. And so over the years, the separation between a child with Dravet and a child that otherwise is healthy, becomes greater. There are some unique findings to children with Dravet, for instance, their gait changes.

00:14:10

So around the age of six, many children with Dravet start to take on a very particular gate in which they're kind of crouched a narrow based. And they kind of shuffle when they walk. These are kind of unique, developmental changes that we see in Dravet syndrome that are probably in part related to the epilepsy and the frequency of the seizures, but are also partly related to the sodium channel mutation itself. And so really that's why our goals, when we talk about treatment, treating the seizures is important and we want them to have less seizures and that's going to help some, but that's probably not what's going to ultimately be the thing that makes us better. We need to get at the genetic mutation itself and change that so that we can change some of these other, you know, developmental or motor findings that these kids have.

00:14:55

Host: So these challenges must be extremely difficult for patients and for their families. What is the medical community doing to help them cope? And what can we do better?

00:15:06

Dr. Perry: Well, the medical community is doing a lot, but before we talk about the medical community, we'll talk about the parent community who is really doing what is necessary to make this syndrome better. Families of children with Dravet syndrome are one of the best organized and committed groups of families I've ever encountered. The Dravet Syndrome Foundation, which you mentioned I'm on the medical advisory board, does an outstanding job raising awareness for this syndrome and helping new families that are diagnosed with this become familiar and ready to deal with this syndrome as their child experiences that. It's thanks to the Dravet Syndrome Foundation and advocates for this, that the medical community has taken notice of this syndrome and has become more familiar with this syndrome. It is thanks to the family advocates that pharmaceutical companies have decided that Dravet syndrome is a worthy syndrome for evaluation. They are very engaged in research and supporting research, which is why all these strides we've talked about already today have happened.

00:16:06

Host: So looking ahead, do you see a cure in the future for kids with Dravet syndrome? And if so, how far off are we?

00:16:14

Dr. Perry: I do think there will be a cure for Dravet syndrome in the future. And I don't think it's as far off, as you know, you might think. We know the gene that causes the disorder and the overwhelming majority of kids with Dravet syndrome. And so what we have to do is figure out how to correct it. So the problem here is that so every human has two versions of SCN1A and you need them both to function normally and not have Dravet syndrome. So if you have a damaged copy, so one of the copies is damaged. You will not have enough SCN1A and you will present most likely with Dravet syndrome. So what we have to do is figure out genetically how to either turn up the good copy and make more SCN1A out of that, or find ways to diminish the production of bad copies …

00:17:01

… so that only good copies get made. There's a couple of different approaches you could take. And that's really where the science is going right now. There are pieces of genetic material that are in charge of telling how much of the SCN1A channel to be made. And so some of the new treatments are guided at trying to activate that genetic material to turn on that signal, to make the good SCN1A develop. That's an area of hot research right now, there are multiple companies that are developing treatments of that type. They are, you know, right now in a process of trying to make sure they understand how to get the genetic material to the right place and to get it to do the right thing. You might not want to make too much SCN1A, we don't know what happens if you have too much SCN1A, so you have to, you know, figure out how to get it to the right place and how to get it to do what you want it to do to gene.

00:17:49

But there will probably be in the coming years, some early studies in humans to show how that would work, and then it would be more large-scale study after that. Right now they've done some small studies where they use mice and they've shown that using this treatment in the mouse model does result in improvement in the amount of SCN1A made in the mice. And I've also showed that one of the significant problems in Dravet syndrome, which is SUDEP or sudden unexpected death in epilepsy, they've shown that that is reduced significantly in the mouse model when we use this treatment. So that suggests that this treatment can be very effective. There are a couple other genetic approaches. One is using a virus to carry in the genetic material. And the problem is, is the SCN1A gene is a very large gene. And so to put it into a virus to then send into a human is difficult.

00:18:38

So it has to be broken into two parts, but there are some proof of concept studies where they've shown they could divide it into pieces and put it back together once it's been taken in. That's something on the horizon. And there's also a drug that was originally developed for the treatment of muscular dystrophy, which basically jumped over the genetic abnormality so that the rest of the gene can be transcribed. That's also being looked at in the study. So there's, there's multiple different angles people are taking to the genetic reason for this, that may result in a cure. And when it does, I think it may hold the key to multiple other genetic epilepsies, which are also caused by single gene mutation. And we can apply the same science to other disorders and hopefully reverse them or cure them as well.

00:19:21

Host: So, after everything we've talked about today, why should people care about improving the quality of life for people with Dravet syndrome?

00:19:28

Dr. Perry: The answer to that question, and then maybe the question to that question is why should people not want to improve the quality of life of people with all kinds of epilepsy, not just Dravet syndrome, right? Epilepsy is a very unpredictable disorder with seizures that can strike at any time. So no matter how frequent or infrequent your seizures are, epilepsy significantly can affect your quality of life. We have opportunities. If we can gain seizure control to significantly improve people's quality of life, to improve their safety, to improve, not just their quality of life, but their family's quality of life who also have to live with this chronic disorder. So really continuing to do research and find cures for all forms of epilepsy are incredibly important.

00:20:14

Host: One more question, Dr. Perry, where can people go if they want to learn more about the research that you're doing on Dravet and other epilepsy conditions?

00:20:23

Dr. Perry: People can follow me on social media. I'm on Twitter at the notorious EEG. You can also follow us on our website, the arcuate.org.

00:20:32

Host: Dr. Perry, thank you for taking time out from your super busy schedule to talk about Dravet syndrome and the great things that are happening here at Cook Children’s and in other places as well. We certainly do appreciate the incredible work you're doing to help patients, not only at cook, but across the country and the globe. Thank you so much. Thank you. Thanks for tuning in to Physician {erspectives recorded in the Child Life studios at Cook Children’s. If you'd like to learn more about our program and research at Cook Children’s visit our website at Cook Children’s dot org.