Trevor J. Resnick, MD

Before we wrap up, let’s talk about 1 more thing. Are these types of therapies going to be appropriate for older children or even adults? We don’t have any data. The preclinical model is all in mice. But any thoughts about if it’s ever going to be too late to intervene for some of these patients? Trevor, if these treatments get approved, would you recommend it for your 25-year-old patient if they were shown to be safe and effective?

It’s an issue that requires a conversation. Obviously, if you’re having that conversation with parents of a 1-year-old, it’s a very different conversation from 1 with parents of a 25-year-old. If there’s a treatment that’s effective, even if it can mitigate some of the progression, it’s worth doing. Every parent will want to know that, even if it’s late in the game. If it may make some positive difference, I want it for my child. Under those circumstances, I would absolutely recommend it.

 Elaine or Elizabeth, what are your thoughts?

 The other potential issue is that we know SUDEP [sudden unexpected death in epilepsy] doesn’t go away. SUDEP is a risk that continues through adulthood. If this really significantly reduces seizures and gets rid of that SUDEP risk or markedly reduces it, that’s very exciting as well. As Trevor says, it needs to be a conversation. But I certainly would not exclude adults from this treatment.

 I completely agree. Sure, there’s great excitement that if we can identify Dravet early—after that first seizure with a gene panel, and treat early with a genetic therapy—could that be life transforming and changing? Hopefully it can be. But even if I had a 25-year-old or a 40-year-old who I knew had Dravet, if it was an effective therapy—and as Elaine said, would reduce or eliminate the SUDEP risk—I’d absolutely want it to be available for that patient as well.

There’s this theme that it’s never too late, right? The brain always has the ability to learn, adapt, and develop. If you look at some of the clinical trials we’ve talked about, the mean age in a lot of these trials is 9 or 10 years. Hundreds if not thousands of seizures have passed in these poor children’s lives, yet we were able to see improvements in behavior and executive function by giving symptomatic seizure relief. Imagine if we can give symptomatic seizure relief plus get at the underlying etiology. We all agree that earlier is going to be better but that at the same time, it’s never too late.

To close, for all our neurologists watching, I wonder if we could go around and each give 1 tip or helpful piece of advice for them if they’re treating patients with Dravet syndrome. Elaine, I’ll start with you.

 One thing we hadn’t talked much about was having a really good rescue plan. We know that this group of patients is very susceptible to prolonged seizures and breakthrough seizures, so it’s important to have a clear rescue plan at home and medication. Typically, in young persons with Dravet syndrome who tend to have a high risk of going into status epilepticus, we say that if you see a convulsive seizure, don’t wait the 5 minutes. Just give the rescue medication. But you should also have a plan for what should happen if that rescue medication doesn’t work. It gets tougher because there’s a lot more individuality between what works for status epilepticus or prolonged seizures after the rescue medication has failed. It’s important to develop that as the neurologist who knows that patient best.

 These are just pragmatic suggestions. For a number of patients, the triggers are the major issue. Having a preventive plan for the triggers is also really important, especially for hypothermia. Be able to address it when they begin to see it. That gives parents some element of control over the risk for status epilepticus. Obviously, some kids have different triggers. It’s important to be able to talk with families about what triggers their child has and to help obviate that as much as possible. Each individual trigger and trial can be an episode of status epilepticus, and if you can stop just 1 or 2, you’ve made a difference. Having the parents involved in that process is so important.

 One would be to recognize it; especially child neurology. You’re right. Everyone knows Dravet syndrome. There’s been a lot of excitement, particularly for recent trials and FDA approval, but I still see kids who could have been diagnosed earlier. More available access of genetic testing, which should definitely become standard of care for epilepsies in childhood with these more specific treatments, is very important.

If I had to give 1 piece of advice in addition to what Elaine and Trevor said, it would be to recognize the impact on the family. That’s where epilepsy centers can be helpful, because epilepsy centers I know about have a better infrastructure for providing support for families and siblings and resources to refer people to than many child neurologists who are treating everything we’re able to. The impact on the siblings and parents is incredibly profound. I feel very passionate that we should not only treat seizures but also take care of patients and families.

 You took the words right out of my mouth. With a lot of my child neurology colleagues, epilepsy seizures is half of what they do. Sometimes there may be this reticence, like “I got this.” Many times you do. But as we’ve hopefully shown, there’s so much value in making a precise diagnosis, making it as early as possible, and using the available literature for some new therapies to help optimize the treatment. Equally important, we close with these clinical trials. The way these trials are going to be successful, and the way we’re going to get them in the hands and brains of the patients who need them, is for them to be aware of the trials and these comprehensive epilepsy centers where we all take care of more than a handful of these patients. That’s going to allow these patients and their families the best opportunity for improvement in their overall quality of life as we work toward a cure.

Thank you, all. This has been a lively discussion. I look forward to doing this in person soon. To our observers and attendees, thank you for watching this 

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The panelists discuss the possibility of treating Dravet syndrome in older children and adults and the effects if the therapies were effective.  

Therapies for Children and Adults with Dravet Syndrome 

We’re going to move on to our last topic, which is exciting things on the horizon. Elizabeth, you mentioned that it’s wicked cool that we have 3 FDA-approved drugs for the treatment of seizures. Some are showing improvements in executive function and quality of life. But we still need something that gets at the underlying cause and is potentially disease modifying. I’m wondering if you can start us out with what things are on the horizon. We can have an open discussion of how we feel about these and where they may fit into this patient population.

There’s an enormous amount of excitement and interest, in both the patient community and the academic community, about the role of genetic therapies. I find that the patients with Dravet syndrome are very sophisticated compared with many of my other patients. Patients are coming in and asking about these therapies. In some cases, they’re explaining to me how the therapies work.

I was at a meeting several years ago about the future of pediatric trials and treatment. It was an interesting meeting because there were the patient advocacy groups, government agencies, pharmaceutical companies, and a group of academic epileptologists. It was clear from the patient communities that they want a cure. It’s really exciting we have these FDA-approved medications that show pretty good efficacy in treating seizures in Dravet syndrome, but families consider the seizures a symptom of having Dravet. They view genetic therapy as more of a possible cure. I get that. I’m also wicked excited about seeing whether they’re effective therapies. Will the efficacy be maintained? Are we able to disease modify in a profound way by early identification and treatment of the whole disorder rather than the symptoms of the disorder?

Absolutely. As you said, seizures are just 1 symptom of the syndrome. I’ve often said that even when someone is having very frequent seizures, if you add up the number of minutes or hours in their week or month, the majority of the time, they’re not seizing. But those are the times when they have to be watched 24-7 or are impulsive or hyperactive. Not until we get at that underlying cause can begin to address some of those things.

I’m with you, Elizabeth. When patients would ask me about gene therapy a few years ago, I really felt like, “I don’t see it.” I was trying to understand based on what I learned in medical school. How are you going to get this gene into the right neurons? Then, all of a sudden, we go to some of these talks and you’re like, “Wow, I wasn’t taught that in medical school.” Maybe we can talk a little about the 2 that are truly on the horizon. There’s 1 in a phase 1/2 clinical trial with Stoke Therapeutics, using this antisense oligonucleotide. Elaine, do you want to talk a little about your knowledge of that? We can all provide some color as best as we understand it.

 Yes. It’s exciting because it’s targeting the underlying pathophysiological mechanism. It really targets the channelopathy. The hope is that you will improve not only seizures but also these other comorbidities. It’s an antisense oligonucleotide that actually prevents the nonsense-mediated decay of the mRNA strand and restores the haploinsufficiency of Nav1.1, the protein. Work in animal models has shown that it can almost essentially prevent SUDEP [sudden unexpected death in epilepsy], which is very exciting. That’s in clinical trials. We’ll see what the impact is on not only seizures but development and other comorbidities, including things like SUDEP. That’s a therapy that’s probably going to need to be given every several months. I don’t think we know the frequency of that, but it’s very exciting.

To speak of that, to get it into the brain, it’s not a pill. It’s a lumbar puncture. It’s given into that space so it can go into the spinal fluid and circulate around in the brain. In the phase of the clinical trials it’s in, this is different from any other pediatric epilepsy treatment we’ve had before, where there are some safety data in adults. We don’t have the luxury of signing up healthy adults to undergo a lumbar puncture. This first trial is somewhat of a safety trial because we need to understand what doses, just like any other drug we talk about. Of course, we hope we get some signal based on the efficacy. Stay tuned for that. There will hopefully be some exciting data in the coming years.

There’s another approach that I’ll speak to and ask others if they want to chime in. Encoded Therapeutics is also working on a genetic therapy that uses an AAV, or an adeno-associated virus. As it turns out, the SCN1A gene is too big to fit inside 1 of these viruses in the classical sense, where you can give the virus and it gets inserted into the patient’s—in this case—neurons. They’ve developed a very slick approach where a promoter is inserted into the virus and it binds to the working copy—the nonmutated copy—of the SCN1A gene. It binds upstream, telling that gene to make more of the messenger RNA transcripts. The result is hopefully the same: More of the transcript gets translated into the protein, and then you restore the function of those inhibitory interneurons.

The difference with this therapy is that it has to be given directly into the ventricular system for it to be more widely distributed through the central nervous system. But on the positive side, it would be a single dose. The dose is correct. It would be a single procedure. That promoter would bind to that wild-type allele and tell it to keep making that messenger RNA. Those trials are planning to start up within the next 6 to 12 months, so that’s another exciting approach that we hope will get all the syndromes and other symptoms and issues that these patients have.

The panel discusses future gene therapies in development for Dravet syndrome. 

Looking to the Future of Dravet Syndrome Therapies  

 Trevor, you mentioned your 25-year-old patient. I always feel that, as a pediatric epileptologist, I don’t want to ignore that this is a childhood-onset epilepsy. But these children do become young adults, and that is often a difficult time as we pass the torch to our adult epilepsy colleagues. It’s not only difficult for the adult epilepsy colleagues who are often on the receiving end, but very difficult for the family to be under our care for 15 or 20 years and then have to switch. Elaine, can you share your experience or comment on what you feel are some of the most important things that we need to be mindful of when we think about that transition?

You’re right. It is a very worrisome time for many families. They know us. We’ve been with them typically since the beginning. They know that we are involved in different research. They know we’ve been involved with other families who have a child with Dravet syndrome. They look at us as somebody who knows a fair bit about Dravet syndrome, so moving on to a new person is pretty anxiety-provoking. The important thing about transition is that we do this as a well-organized process. It’s not something that happens in a single day, where you suddenly stop seeing me and you go and see one of my adult colleagues. It’s a process that happens over months to years.

It’s important to work with families to help them understand why that process is important. There are 2 big reasons why it’s important. First of all, your young adult with Dravet syndrome is going to develop medical problems that are more in keeping with an adult than a child. As a child neurologist, I do not feel well empowered to deal with hypertension or a lot of the adult-onset medical issues that those patients will get. Secondly, many of our pediatric hospitals have an upper age limit, beyond which we cannot admit. It’s crucial for these families to have that adult team set up before they’re in a medical crisis. We don’t want those patients being admitted to an adult center where we can’t actually see them and we don’t have any hospital privileges, and they’re having to meet a new adult team in that moment of crisis. If we can plan and do that ahead of time, that’s important.

The process we initially go through with the transition is making sure families understand how Dravet syndrome evolves as the child goes from a child to a teenager and from a teenager to an adult. We see a difference in seizures. In young adulthood, many of the patients are having briefer convulsive seizures at night as opposed to absences, myoclonic, or prolonged seizures. They become much less frequent. They can develop more gait issues and Parkinsonian features. They can develop behavioral issues. Those are all important to address to ensure families understand what to expect at the different ages.

The other important thing is having them work with a social worker who is very knowledgeable in working with children with developmental and epileptic encephalopathies, so they understand the importance of guardianship to make sure they’re not cut off from medical records when the child turns 18 and they understand the insurance changes when you become a young adult. We don’t want any lapse in insurance trust funds, if those need to be set up.

As far as what we can do to make that process easier, if you look at 1 emergency department visit, that probably generates 100 pages of medical records. If we’re sending these patients on to our adult colleagues, it’s important that we provide them with a succinct transition document—a 2 to 3 page summary that summarizes this patient well—and that they have that before they meet the patient. It should summarize what medications they are on, which ones they have been on previously, and why those were stopped. Did they have [adverse] effects? Are they on dietary therapy? That will need to be planned for when they go to the adult side. What other comorbidities do they have? If we can provide that 2 to 3 page summary document, that’s super helpful for our adult colleagues.

I agree completely. We’re working on that, along with one of our residents who is trying to do a transition toolkit, which is a living document that lives as we update it. Getting back to that caregiver impact, those things often don’t get included in the handoff in terms of maybe the PTSD [post-traumatic stress disorder] that some of these families are feeling and where they are in terms of their psychological well-being. That’s going to be very important as an adult neurologist tries to pivot and make another treatment recommendation but doesn’t have that relationship. It’s important for them to understand that context.

I’ll just make one other comment about adulthood. It’s a little related in the sense that it’s now our job as a Dravet community to try to educate our adult neurologists about what the signs are of someone they have in their clinic who could have undiagnosed Dravet syndrome. We would all agree it morphs and maybe looks like a more nondescript epilepsy. We often don’t have the luxury of having the early childhood history that we started with. In a lot of ways, if you have a young adult with refractory epilepsy and intellectual disability and you don’t know why, that patient needs genetic testing. Some of them are going to have SCN1A mutations, and then you go back and ask the questions, and they are going to fulfill criteria for Dravet syndrome. Now more than ever with these newer therapies, it can really make a difference in terms of how we treat them.

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Elaine Wirrell, MD, reviews the transition of care into adulthood of patients with Dravet syndrome and how this transition can affect the patient, caregiver, and care provider.  

Transitioning Into Adulthood With Dravet Syndrome 

We’ve talked a lot about seizures and quality of life. Let’s segue into the impact this has on the family and the caregiver. We’re all epileptologists. In most situations, when I try to talk to my patient, who is a child, I feel like I have 2 or 3 patients with each visit because the caregivers are needing just as much of our support as the child themselves. Elizabeth, could you give us a summary of what you feel in your experience is the caregiver burden for these families? It’s one form of a catastrophic epilepsy that probably shares a lot of similarities to other epilepsies. What’s your experience with this patient population?

Joe, what you said is absolutely right. Pediatric epileptologists don’t just treat seizures; we take care of children and families. Most of my practice, as all of ours, consists of treating children with refractory epilepsy. As you said, for the families of all those children, there’s incredible pressure, tension, and emotional weight for siblings, parents, etc. Maybe the families of patients with Dravet syndrome are even harder hit, with the frequency of the seizures, the triggers, the anxiety of what’s going to happen at night, and the increased risk of SUDEP [Sudden Unexpected Death in Epilepsy]. Studies have looked at the impact on parents needing to quit a job to stay home and take care of the child, the impact on the siblings, and the incidence of depression and anxiety in siblings. It’s profound.

When we approach the treatment of a child with Dravet syndrome, we also approach the management, understanding, and support of the families. I have one Dravet family with 4 children under the age of 12, including a child with Dravet with very frequent seizures and both parents trying to work. Especially during the COVID-19 pandemic, that was a real nightmare. I have another child with Dravet who has bright light-triggered seizures in a big way, so much so that even going outside into natural daylight will often trigger seizures. That’s a family that then basically stays inside and doesn’t go out. I find that these families really constrict their worlds to protect their child, minimize seizures, and minimize the trauma of having Dravet on their child. The impact on the whole family is really profound.

 Absolutely. I’m glad you brought up siblings, because not only are families dealing with Dravet, always on high alert with bags packed—a seizure happens and it’s off to the hospital—siblings are left feeling a little neglected. These parents are doing the best they can, but the siblings do deserve some attention there.

This has gone so far. In my practice, I’ve had a very generous family. The mom was a licensed therapist, an LCSW [licensed clinical social worker], and put together a deck of cards for life support for families living with epilepsy. It has very nuts-and-bolts information. My favorite one says, “What do you do when you get angry or frustrated with your neurologist?” When you flip over the card, it walks you through a couple of things that we’ve been talking about here. It’s a testament to trying to at least acknowledge the stress these families are under.

We touched upon it in our consensus guidelines, too. We tried to get a little beyond seizures to have some guidelines about some of the other issues that impact these patients, including behavior, sleep, and some of the motor problems. In a perfect world, it would be a multidisciplinary approach. Trevor, in a perfect world, if we were not resource-limited in our hospitals, how important is it to have this approach to caring for these patients?

It really is a multidisciplinary approach. As we mentioned earlier, depending on the child, each aspect of developmental regression or behavioral difficulty will be different. That’s why, if you have your group of therapists—including a behavioral therapist, physical therapist, occupational therapist—depending on the individual child, they may need to spend more time with one child as opposed to the other child in a specific area.

I have one child—he’s not a child anymore, he’s 25—with Dravet, who has the issue with the crouched gait. The apraxic difficulty has been such an issue for him. It’s almost like he has a visual perceptual problem when he walks. He’s planning for where he has to sit down, and how he has to turn around and sit down. He can’t do it. For him, that motoric disability is his biggest issue. It may not be the biggest issue for some of the other kids whose behavioral issues are greater, either regressive or aggressive behavior.

You have to have this team together. Depending upon the individual patient, 1 or 2 members of that team will be spending most of their time with the child. Elaine mentioned earlier the importance of having the Dravet Syndrome Foundation available for the parents to be able to not necessarily only listen to their own neurologist, but hear what everybody else is talking about. The fortunate thing with the foundation is that they are grounded in so much fact that you’re not going to hear the outrageous theories you sometimes hear in terms of what needs to be done for their child. It’s very helpful for parents to be able to be directed to a reliable place like that to get opinions and hear someone else talking.

After all, if you think about the name, it’s a syndrome. A syndrome is a constellation of signs and symptoms that go beyond just seizures. The Dravet Syndrome Foundation tries to identify Dravet centers of excellence, which are anchored in having at least some of these multidisciplinary providers. In a world of unlimited resources, we would have all of them. But as a Dravet community, we certainly feel that you at least need to have access to the ketogenic diet, physical therapists, and occupational therapists.

Getting back to how we started this conversation, the value of making a syndrome diagnosis is paramount. I know there are some groups around the world that are starting to look at these gait problems so we can better understand why they’re occurring and if there’s something we can do about it. We definitely know that orthopedic surgery is not the answer for it, but are there things like special gait training that could prevent this crouched gait and lead to improved mobility of these patients?

The panel discusses the impact on the family, siblings, or caregivers of patients with Dravet syndrome. 

Trevor J. Resnick, MD

Articles

Therapies for Children and Adults with Dravet Syndrome

Looking to the Future of Dravet Syndrome Therapies

Transitioning Into Adulthood With Dravet Syndrome

Impact of Dravet Syndrome on the Caregiver and Family