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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Videos

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. 

Impact of Dravet Syndrome on the Caregiver and Family 

 Elizabeth had made a comment on having some patients on both, referring to fenfluramine. Elaine, going in the order of how these medications went into clinical trials and gained FDA approval, could you also walk us through the data supporting fenfluramine’s efficacy and your personal experience with it?

 Sure. Fenfluramine is a serotonergic agent, but it also a positive modulator of the sigma-1 receptor. I’m not sure anybody exactly knows how that translates into improved seizure control, but it’s a novel mechanism. It’s an interesting story. Fenfluramine had been used by the group in Belgium for quite some time. It was actually initially used before we even realized that Dravet syndrome was Dravet syndrome and was associated with SCN1A pathogenic variants. When they looked at their data of patients who were treated many years ago, dating to the early 1990s, they saw that the kids who were treated and responded were kids who ultimately were found to have Dravet syndrome and that SCN1A pathogenic variant. I find that really cool.

There was actually a royal decree made by the king of Belgium so could continue to use this very effective medication. This led to the clinical trials. There were 2 main publications. The first was a trial of kids with Dravet syndrome who were not on stiripentol but were on other cotherapies. They looked at higher-dose fenfluramine, which was 0.7 mg/kg per day, compared with lower-dose 0.2 mg/kg per day, compared with placebo. They found there were significantly better outcomes in kids who were treated with fenfluramine and that the higher dose worked better. They saw a 50% reduction in seizures and a 70% reduction on the higher dose. It was a 41% reduction on the lower dose and about 7% on placebo.

The other cool thing from that study is they looked at those with much more significant response. They looked at patients with a 75% reduction in seizures. They found that nearly half of patients in the high-dose group had a greater than 75% reduction in seizures and about a quarter of patients were near seizure-free. That was very exciting. A second study was done that included kids who were on stiripentol. Fenfluramine was added to stiripentol and, because of the pharmacokinetic interaction between stiripentol and fenfluramine, they just compared 1 dose of fenfluramine that was essentially equal to the higher dose that was used in the first study. They found significant benefits. Those who were in the fenfluramine group had a 53% reduction in seizures compared with those who were treated with placebo, who had just a 7% reduction.

We all get into these percentages and responder rates. Can you put that in context? For neurologists who are watching, we’re used to hearing about the 50% responder rate. These aren’t comparative head-to-head trials, but if we look at the value of a specific patient population, are all phenotype seizures are being counted in the same way? I pitch it to my families by providing the data from multiple sides. Can you put that into perspective for us comparing it with some of the other treatments?

 Yes. This 1 was certainly better than any of the version 1.0 treatment guidelines. This was better than any of our first-line therapies that we had suggested there. For me, what’s really intriguing is the proportion of patients who have a much more significant benefit. Patients had to have at least 1 seizure per week to get into the trial. Over 3 months, a quarter of the patients had between 0 and 1 seizures. Many of those patients were able to go a much longer time without any breakthrough seizures. That improves quality of life if you can get that to happen.

I couldn’t agree more that these responder rates, 75% reduction, are something that we don’t often see in epilepsy drug trials, certainly in a patient population that’s so treatment resistant. To have any percentage of them that are near seizure-free is unprecedented. Elizabeth, can you comment on the idea of this being a syndrome diagnosis and beyond seizures? In your experience, I’m sure you’re seeing that in some of your patients. What is that translating into for the everyday lives of these patients?

 When those trial results were released, we were all pretty impressed and very excited. It paralleled the efficacy seen in the Belgium experience, suggesting that this is going to be a very important drug in the management of seizures in Dravet syndrome. If I had a child with Dravet, a 70% reduction in seizures would be life transforming. I hear that from some of our kids who’ve responded beautifully to it—CBD [cannabidiol], or other treatments, really changes their life. The ability to leave the room and not worry that your child will have a bad seizure is freeing in many ways. It also buys the child a little more independence. A 70% reduction is still not what would be ideal seizure control, but it’s better than we’ve been able to do before with many of these patients. I’m really excited about the possible role of CBD, fenfluramine, and stiripentol in the treatment of these kids. We have many better options now than we did 5 years ago.

 I agree. And not only as we’ve all spoken about efficacy and tolerability—there are adverse-effect profiles for any medication—but it seems that fenfluramine and cannabidiol have very attractive adverse-effect profiles. Further expanding on that with fenfluramine, included in the studies was this measure of executive function, mainly to see if this drug had a negative impact in executive function. It was included as a safety measure. Then looking at some of the results of those surveys, in patients who had the 75% reduction in seizures, about 25% to 30% of them had clinically meaningful improvements in their behavior and executive function. Is that only seizures? Is it something about the medication? The jury is still out on that, but it highlights that more seizure control is often better, as long as it doesn’t come at the expense of moderate or severe treatment-related adverse effects.

I’m sure that this happens in your practices too. You’re talking about a new treatment and the family says, “Yes, but we’ve been there. We always get the drug, and it works great for the first couple of months and there’s the honeymoon effect. I don’t know if my emotions can tolerate another honeymoon effect.” For a lot of these drugs, we now have some longer-term open-label data. Trevor, would you mind commenting on what we’ve seen with fenfluramine and its longer-term use?

That question is brought up by every patient . The open-label extension demonstrated the 3 or 4 things we really want to see. One is that the effect is sustained. Another is you don’t have any new tolerability issues you didn’t get when you had a relatively shorter maintenance period. Third, the gorilla in the room for fenfluramine was the question of valvular heart disease. It demonstrated no red flags in the open-label extension study in more patients over a longer period of time. It’s very important in terms of real-world experience after having a control study showing that everything we’re seeing in the cannabidiol study was substantiated and validated with a robust seizure response. It’s a very valuable addition to our armamentarium.

 Absolutely. We’re looking at a group study that’s not immune to the honeymoon effect, but it’s comforting to see from those data that there does appear to be a durability of response. As we said with cannabidiol, it’s safe and appears to be well tolerated. Right now, fenfluramine does have an indication for treatment of seizures associated with Dravet syndrome in ages 2 and older. Maybe we’ll comment on this in our 2.0 guidelines. We’re all excited to see what impact these more syndrome-specific treatments can have if we have earlier diagnosis and earlier syndrome-specific treatment.

 You have to pause and think how wicked exciting this has been for the Dravet community within the past 5 years. Suddenly we have 3 FDA-approved medications for a disorder where there were no FDA-approved specific treatments. That doesn’t happen very often, so it’s incredibly exciting.

That coupled with our ability to do genetic testing and make an earlier diagnosis. I think back to fellowship. I saw 1 kid with Dravet syndrome, which means I missed a lot. The 1 we saw turned into a grand rounds type of thing. Fast-forward 15 years, and to your point, there are 3 FDA-approved medications and the ability to make a new diagnosis.

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Elaine Wirrell, MD, provides background on fenfluramine, results from 2 clinical trials, and compares it to other treatment therapies.  

Fenfluramine as a Treatment Option for Dravet Syndrome 

 If we think back to the first clinical trial that was done in the United States for Dravet syndrome using a purified formulation of pure cannabidiol [CBD]—it’s just a fascinating story of how social media and all the observations from this patient population happened because they were desperate, looking for other opportunities, and giving up on the long list of medications that we just discussed. Lo and behold, there was a company that already had a purified version of cannabidiol. For the purposes of this conversation, we’re speaking about that formulation and not many of the other artisanal derivations.

Elizabeth, you were a principal investigator in many of those trials. Could you walk us through a little of your experience and give your thoughts on the efficacy and adverse effects? With a lot of the medicines we use, we don’t fully understand the mechanism of action. That’s true for cannabidiol as well, but I know there have been some theories as to how that works. Let’s have an open CBD discussion here.

The past 8 years of me thinking about CBD in campus has probably been 1 of the most important aspects of my career. It’s an example where it does come from people commenting on positive responses to things instead of just the negatives. As I tell medical students and residents, we don’t practice medicine by anecdote, but listening and paying attention to anecdotes can be extremely helpful. This is a very good example. On social media there was a buzz once medical marijuana became available in Colorado and California. People wondered, “Is this effective?” You have the survey of a Dravet family saying, “Yes, it can be effective,” which is really what led to the development of this purified formulation of CBD.

Based on what I’ve learned from using this as a treatment for children with Dravet syndrome and other epilepsies over the past 8 years, it can be effective. It’s not a silver bullet for epilepsy, as many people in the press and elsewhere would have led us to believe for not only epilepsy but for many ailments. But clearly, it’s an important addition to our toolbox of treatments for children with Dravet syndrome, LGS [Lennox-Gastaut syndrome], TSC [tuberous sclerosis complex], and likely other epilepsies.

CBD is a really interesting chemical. It’s important to know that it doesn’t have any psychoactive properties like THC [tetrahydrocannabinol]. There’s a lot of work being done to figure out the mechanisms of action. The best thought now is it’s GPR55, a G-binding protein that regulates neuronal excitability as well as modulation of the TRPV1 ion channels. It may also modulate adenosine. Like many of our medications, there are several mechanisms of action in the treatment of epilepsy. Importantly, it doesn’t seem to work via the endocannabinoid system. The first thought was, “Here’s a phytocannabinoid. Does it interact with the endocannabinoids?” Knowing that’s not true is important. It will be important to try to delineate the mechanisms as well as the efficacy in other epilepsies and disorders.

One of the things I’ve been most impressed with is the safety tolerability profile. When I discuss treatment options with my Dravet families, and we talk about CBD compared with the other medications, safety-wise, other than the drug interactions that have been pretty well characterized—particularly with clobazam and valproate—it’s very well tolerated. One of the main adverse effects is loose stool or diarrhea. Many of my Dravet families and other families view that as a positive adverse effect, because many of these kids have such significant constipation and elaborate bowel regimens that they’re able to back down on those.

It has an important role to consider as a treatment option in the management of children with Dravet. We’re going to talk about the other options. We don’t have any data suggesting 1 is better than the other. In reality, I already have a lot of my patients on both, and that will be how we manage Dravet syndrome. Even if I get a 50% or 60% reduction in seizures with 1 treatment option, I’m not at my ideal goal, so I would try the other options.

 I agree. I always say this in the talks I give to residents. Why does the brain follow mathematics? You start out with 10 seizures, you get a 50% reduction. Now you’re on 5 seizures and you get another 50% reduction. Our goal is to try to get as much reduction as possible. Could you make a few more comments on dosing? You were involved with the TSC studies and the higher doses that were different from the Dravet study. Do you have any thoughts on what your starting dose is for cannabidiol and what the sweet spot has been? Maybe I’ll ask others to comment as well.

I agree with the FDA labeling of starting at 5 mg/kg per day and then titrating up. I pretty much follow those. In the TSC trial, as well as an expanded-access program, we did use higher dosing. We learned from all the trials that CBD, like many of our medications, has a broad dose range. That’s a good thing to know. Many people respond very well to the lower doses. Sometimes response is even better at the lower doses than the higher doses.

In the TSC trial, we learned that even though going to 50 mg/kg per day didn’t have the dose response with regard to efficacy, there was safe passage. Even though there were more adverse events at the higher doses, as expected, it was still pretty well-tolerated. Some patients do better and need the higher dose. Through the different dose ranges of the different trials, we learned a lot, but I believe I achieve efficacy with most of my patients within the recommended dosing.

Any comments, Elaine and Trevor? Do you agree or disagree?

 I agree. I typically work them up to about 10 mg/kg per day, and then I assess if we need to go higher. Many patients get better efficacy as we go higher, but tolerability seems to be a little better at lower doses, so that’s typically where I start.

 Ditto for everything that Elizabeth said. One thing I’ve found in a few patients is if the response improves or continues to improve as you go to higher doses, then it’s worthwhile continuing to increase. But if you hit a plateau, I’d say the vast majority of my patients get their response somewhere between 10 and 20 mg/kg. It’s the minority that you have to go up, where going up higher actually helps.

 I was going to close with that because it’s nice to have the safe passage. When you look at a study of 120 patients, there may be 5 who did do better at the higher dose. But when you look at a group analysis, it doesn’t shut out. The bars look the same. But if you have 1 patient who’s sitting in front of you and they’re having a dose-related response and improvement, then we know that 50 mg/kg has been tolerated. You certainly can go in that direction if necessary.

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Elizabeth Thiele, MD, PhD, reviews cannabidiol oral solution as treatment of seizures associated with Dravet syndrome and the safety profile and dosing associated with it.  

Cannabidiol as a Treatment Option for Dravet Syndrome 

 I keep reiterating this theme that it’s extremely valuable to have a specific diagnosis. It is mixed seizures. We know that our different antiseizure medications have maybe differential efficacy against different seizure types. Trevor, how much experience have you had with stiripentol? Then maybe look into that third tier before we get into some of the new medications that we generally don’t think of as being syndrome-specific, like vagal nerve stimulation [VNS] and zonisamide. Pick one and let me know your thoughts on that.

That’s the catch-as-catch-can. A very good point you just made is that, especially after the first year of life, the different seizure types dictate your choices. Even though you have this list of guidelines, which we follow, a lot of the choices that come afterward in the second and third line are choices dictated by the predominant seizure type that affects that specific child. Our experience with stiripentol has been pretty much as adjunctive therapy, and it certainly has not been a knock-your-socks-off response. Some children have responded quite well with the adjunctive treatment with stiripentol. The treatment we have found to be gratifying has been the ketogenic diet. Even though we don’t start with the ketogenic diet, we often find that we fall back onto it pretty quickly. I almost feel that if you look at the list of clobazam and valproate as first-line treatments, the ketogenic diet is often the secondary treatment if one of those fail. I don’t know if everybody else has had a similar experience.

I probably have about 7 or 8 teenagers who have vagal nerve stimulators. I have personally never recommended a vagal nerve stimulator to be placed for any of my patients with Dravet syndrome. These are patients who I either inherited or came to me. When they’ve been through 7 or 8 different medications, just like we do with all of our other refractory epilepsies, and they didn’t have a Dravet syndrome diagnosis, they’re like, “Let’s try VNS.” It’s effective. It can have a 50% reduction in seizures. Then the families feel like it worked. Getting back to the different stages of the disease, they would say, “Well, they didn’t end up going into status [epilepticus] anymore.” I have no data to back this, but I wonder if that was more the natural history. They put the VNS in maybe when they were 5 years old, and then over the next few years, their episodes of status decreased. It’s important, though, because when it comes time for the battery to be replaced, it’s always a difficult decision to give families counsel. Do you replace it or do you not? I’m curious to hear other people’s opinions about VNS.

 I agree exactly. I never know whether it’s the natural history of the disease or the specific treatment, especially when it’s done at a specific age. I don’t know how valuable that discussion is with the parents, because they only see what’s happened to their child, and it’s a very difficult discussion to have.

 We’ve had the VNS longer than we’ve had SCN1A gene testing. I have several patients with VNS who ended up having Dravet syndrome. For some of them, it has been effective. I agree that with any kid who gets VNS, how do you know if it’s really the VNS or the natural history of their epilepsy? When the generator is reaching end of service, I discuss with the family to see what happens with seizures. A couple of my kids with Dravet syndrome have had an increase in seizures, and sure enough, the battery is low. They replace the battery, and their seizure control improves again. It can be effective, but it’s like what Trevor said about stiripentol. It’s definitely not a silver bullet, but I don’t think it’s usually effective in this patient population.

A lot of kids who are coming to battery end of life would now have the opportunity to be on some newer, more effective agents. Before you jump in and replace that battery, it’s very reasonable to see if the seizures worsen.

Absolutely. I have a closing comment about the medications we’ve talked about so far. This is anecdotal, when we sit around the table and talk, especially with our European colleagues who have had stiripentol for 2 decades. The stage-specific nature of the disease and the different seizure types that occur at that first stage in episodes of status [epilepticus] are very common. I certainly have experienced that with stiripentol. Some of our colleagues said that they don’t go to the ICU [intensive care unit] anymore. It may not reduce the overall frequency in such a significant manner where it’d be measurable in a clinical trial, but keeping them out of the emergency department and keeping them from calling 911 and getting into the PICU [pediatric intensive care unit] has certainly been my experience.

Experts in the field discuss second- and third-line treatment options for Dravet syndrome such as stiripentol and vagal nerve stimulation and the effects they’ve seen on patients. 

Second- and Third-Line Treatments for Dravet Syndrome  

 We’ve been talking, somewhat skirting around expectations about our treatment goals. We now have a lot of options available to us. Let’s switch to all the treatment options we have available, how we go through those, how much of it is practically limiting, and how we have that conversation. Elaine, you and I and many of our colleagues worked on a consensus statement a few years ago and are working on the version 2.0 as we speak. Could you start with why we felt we needed consensus guidelines? These aren’t protocols. These are just meant to give some guidance. Why did we feel as a community that this was necessary?

 When we look at kids with Dravet syndrome, some medications make things worse. We know that as epileptologists, but when many of these children are initially treated, they may not be seeing an epileptologist. It’s important to be very clear that there are certain medications that should be avoided. There really weren’t data in the literature. There are data now, thankfully, but there weren’t many data in the literature on efficacy of medications. When that happens, sometimes we work together and try to get expert consensus on what a group of epileptologists agree would be the best therapy. That was the goal of that document, and also that it could then be provided to parents. They would have access to that and know the appropriate therapies to potentially ask their clinicians about. The document also addressed what we didn’t know, which was a lot. Hopefully version 2.0, which we’re working on now, will bring us forward a little.

 As we reflect on that process, I remember when we were going through the literature, it was a lot of anecdotes and expert opinions, including ours. Could you walk through what we came to believe is the first-line treatment? Even though we’re making this diagnosis earlier and earlier, these kids, even in their classical presentation, don’t come in with, “I have Dravet syndrome” written on their forehead. Even in the best hands, they’re often given an epilepsy diagnosis, and they’re treated not necessarily within in the framework of a Dravet syndrome diagnosis. Can you talk about what we felt were the first-line therapies?

 We thought valproic acid or clobazam would be reasonable in the first line, but when we looked at the data to support that, these were open-label and often retrospective studies with very small numbers of patients. There were actually very few studies. If you look at the data, the responder rates, which are the proportion of kids having a greater than 50% reduction in seizures, the rates for those medications were only between 25% and 50%. Although we put them down as first-line medications because we didn’t have a whole lot more at that point, we recognized that they were not very effective medications for most kids with Dravet syndrome.

We thought topiramate was a second-line agent. There have been a few studies showing marginal response rates in those patients. About half of kids will have a nice response to the ketogenic diet, although usually not seizure-free. Then we addressed stiripentol, although that was not yet available in the United States when we did our consensus.

 I certainly have patients who are on fill-in-the-blank medication. As long as it’s not a contraindicated medication, as Trevor brought up, and they’re doing OK, I personally don’t rock the boat. I wait until they fall into the parameter that we and the family consider not well controlled and then look to these guidelines. Elizabeth, can you expand a little on your other experience with the ketogenic diet or stiripentol and how those fit into your treatment algorithm?

 Treatment guidelines in disorders like this are really important because with many neurologists and even some epileptologists, you might see 1 or 2 kids with a certain disorder. You might not get a sense of what works more effectively here or there. When guidelines are available, it really helps, especially with our growing number of possible treatment options. If we can say, “Here are all the options we have, but this one might be better in this situation,” it’s good for us and really good for the patient.

I’m a zealot for dietary therapy. If the first-line therapy doesn’t work or even if you know a child has Dravet syndrome, I would consider the ketogenic diet in the first line because it’s pretty easy to do in that age range. Many people think the ketogenic diet is difficult. I’m still seeing patients who are told it’s much too difficult. It was the mother of a patient with Dravet, Lori O’Driscoll, who told me many years ago that when she brought up the ketogenic diet to her neurologist, the neurologist’s response was, “Oh, that’s much too difficult.” To which she responded, “Nothing is as difficult as watching your child have seizures.” I am a big zealot for dietary therapy.

We use topiramate, which can be effective, but there are possible cognitive [adverse] effects and acidosis that can be seen with that. I don’t have as much experience with stiripentol, because unlike Elaine and others, we did not have great luck in the Massachusetts area getting payer approval or coverage of that before it was FDA approved. For many of my families, it was cost prohibitive. But we do put that in a regimen, in the list of possible therapies, especially because there is known efficacy in Dravet syndrome. I agree with you. If a patient comes into us on levetiracetam who we now know has an SCN1A mutation and Dravet syndrome, why rock the boat if the child’s doing well? But if the seizures break through or there’s any problem, I follow those guidelines. They’re very helpful, so I’m looking forward to version 2.0.

A panel discussion on the North American Consensus statement on treating Dravet syndrome and the approved therapies like clobazam, ketogenic diets, and other first- and second-line therapies. 

Treatment Therapies for Dravet Syndrome  

Let’s say a patient’s not doing well in our opinion and we recommend a treatment change, and the response is, “I read that when someone did that for their child, it was horrible.” I’m wondering if we could each share some perceptions of some of our patients in terms of why they may be hesitant to make treatment changes, or why they may want to make a treatment change too quickly and not be patient with something we recently changed. Trevor, do you want to start that?

To some extent, it depends on your approach in the beginning. One thing I think is a good idea is to never say that a drug you’re going to use or a treatment approach is going to be the best treatment. I always speak to patients about a whole host of different available treatments that are effective to some extent, so that if I fail with the first one, they’re quite happy to move to the second one. There may be different reasons for why. Depending upon the presentation, parents may have a different attitude to switching. The example you brought up was a good one. Another I’ve had an experience with is when the presentation has been so devastating, with prolonged febrile, generalized, tonic-clonic seizures, status epilepticus, and admission to the hospital, that if they get onto medication A and they have seizures but they don’t come into the hospital, they’re very reticent to change because of their early experience with the seizures. It requires a lot of discussion about the consequences of the different seizure types and the goals in terms of where you want to get to, in order to get them to change. I get that reticence depending on where they come from, what they’ve read, and what their own experience is with their child’s seizures.

Elizabeth, any personal experiences with that?

 I agree completely. There’s a spectrum, not only with how the kids present, but the families’ attitudes and approaches. I was really impressed several years ago. We had a child come to see us who had their first seizure in the setting of fever, had the genetic panel sent, and was found to have a large deletion of SCN1A. They came to see us because they had read that the ketogenic diet could be very effective. Even though the child had only had 1 seizure and was on 1 medicine, they really wanted to start the ketogenic diet to try to be proactive. That child has done well. I have other families where the child may be having occasional brief seizures, but the family likes how alert the child is, how interactive, the gains they’re making, and they’re afraid to rock the boat. They’re afraid that any change could compromise how the child is doing overall. It’s very variable.

Along those lines, Elaine, have you had some experience with differential expectations from families? You and I have families like this, where I would never have thought of mentioning a ketogenic diet. Although anecdotally, if it is started early in this population, it could be potentially game-changing. How do you manage expectations when you have someone who’s seemingly well controlled yet they want better control? I have this scenario, too, where they read about the catastrophic stories and say, “My son’s actually not too bad,” yet they’re still having 5 convulsive seizures a month. I don’t know how to say this with the utmost respect; do you think they know what better is? I don’t want to be judgmental, but how can we help them get on a better path?

It’s an ongoing conversation that you have. When you’re making your initial diagnosis and when we’re following these kids, we see them pretty frequently in our offices. If new therapies come up, we have a conversation. “This is what this therapy potentially has to offer. These are the potential adverse effects.” But as I say, it is a conversation that you have with families. I do think families know their kids best. Sometimes families have come to me, and just like with Elizabeth’s example of the child with 1 seizure, who wanted to try the ketogenic diet, many families know their kids best, and so we need to listen to their concerns. It’s also important though if you have somebody who has poorly controlled seizures, that you work with the family and help them balance what the risks are: the risk of seizures, the risk of medication, and also the risk of SUDEP [sudden unexpected death in epilepsy]. In young children, we know that status epilepticus can also result, in rare cases, in severe brain edema and death. It’s important to help the families balance those risks. That’s a long conversation that you have, but it’s an important one. It’s part of what we really need to do.

There’s one caveat I sometimes use when families will cite what they read. Maybe this is changing a little now that social media is so pervasive, but I don’t often see many families writing about good things. They’re not like, “I started this, and….” It’s more like a restaurant review. You’re more likely to say that this was a terrible experience as opposed to saying it was fine, so I try to keep that in context. Getting back to the sense of connection and community, I do try to say, “Reach out.” I’ll even put them in touch with some of my other families and try to represent a balanced view with both sides, like someone who did well on valproate and someone who did not, so they don’t feel like I’m trying to force this upon them.

We’ve already mentioned that Dravet syndrome is pretty variable from patient to patient, but it’s also pretty variable within the same patient. You may have a kid who goes for 2 months relatively well controlled but then has a big bout of status epilepticus. You need to balance some of the little blips that happen as well and work with families to help them understand that there’s the background noise of Dravet. Just because you have a seizure when you’re on a low dose of whatever medication you’re starting, doesn’t mean that medication is going to worsen things. We sometimes need to give it a little longer.

 I try to practice some sense of vulnerability to say, “I might be wrong and you’re going to be right. I’m going to start this and Johnny’s going to do poorly.” To that point, just because we make a decision doesn’t mean that we’re not in constant contact. But try to hang in, not saying that with the first dose of the medication, everything goes awry, but to try to keep that conversation open and be flexible to pivoting. In the end, it’s about the quality of life. We’re going to get into it a bit more; it’s not just about seizures. Elizabeth, as you said, it’s seizures and adverse effects. If we have a kid who’s sleeping all day but seizure free, that’s no way for the child or the family to live.

A discussion on having conversations with the parents of patients with Dravet syndrome with regards to adjustments to therapy and managing their expectations. 

Managing Patient/Parent Expectations in Dravet  

Now we have a child’s family that has the diagnosis of Dravet syndrome, and they come to our clinic with lots of questions because they’ve been on the internet. If you go onto Google, the top 10 hits often say catastrophic. They’re already coming in with a pretty poor outlook on what is in store for their child. Elizabeth, I’m wondering how you approach that first visit in terms of how bad it’s going to be and what our reasonable treatment expectations are.

 That’s a good question. You’re right, the internet is very powerful, but it does take people to the edge of the cliff. The first thing I try to do is walk them back from the edge of the cliff and say that this is often catastrophic, but not always. Some of the children I take care of with Dravet syndrome are doing fairly well with regard to seizure control, cognition, etc. At the point I meet the child, there’s no way to know where on that spectrum they’re going to be, but I have to give the parents hope that there’s a chance the child could be at the better end of the spectrum.

Even though we know Dravet syndrome is a refractory, difficult to treat epilepsy, I approach the management of it as I do with my other patients with epilepsy. Maybe I’m an idealist, but my goal is always complete seizure control. I realize 0 seizures and 0 treatment adverse effects is ideal. Sometimes we can get there with our kids with epilepsy and some of our kids with Dravet syndrome. Sometimes it’s a matter of finding a balance between what would be acceptable seizure activity vs acceptable treatment adverse effects. Most of my parents of kids with Dravet syndrome are mainly worried about the seizures that occur at night, particularly with the increased incidence of SUDEP [sudden unexpected death in epilepsy]. They’re also worried about the prolonged atypical absence that prevents their child from functioning, interacting, and learning. It’s a discussion with each family, that we try to optimize seizure control and how their child is doing overall. The journey is often very different for different patients with regard to treatments, response, tolerability, etc.

Trevor, do you have anything to add in terms of treatment goals?

 It was pretty well covered. It’s very important to lay out the landscape of what Dravet syndrome is, but it’s also very important to talk about the variability in presentation and in evolution of the disorder. The parents have to have hope and you have to tell them the truth, but you have to say that there’s a lot of variability, there are new treatments, that we will work together to get the best possible outcome in terms of seizure control, and we will work with all the other ancillary services and the therapist to make sure the development is maximized. If you talk about it that way, which I know all of us do, it provides parents with a feeling of, “We’ve got a job to do. We’re all going to do it together. We’re all part of the same team.” That makes a big difference, as opposed to reading about it online and reading about, as you say, catastrophic this, catastrophic that. It’s the same story but with a different spin.

 As you mentioned earlier, having an early diagnosis and a more precise diagnosis allows us to construct some type of a roadmap of different ways this could go, which is incredibly valuable. That’s certainly the case for me as a clinician, as I am trying to be anticipatory, knowing that they’re entering that next stage. It’s also valuable for families so it doesn’t come out of the blue, to manage expectations, and to have hope that this fever sensitivity might lessen with time. Elaine, do you have anything else to say about how we set the stage of what our reasonable expectations are?

 I certainly agree with the variability. I talk to the families about how, in most cases, this is a drug-resistant epilepsy. Because although I’m also an idealist, the chance of getting that child completely seizure-free is not very high. The other thing when you’re making a diagnosis is ensuring that you give that family the option of contacting other families who also have children with Dravet syndrome. Things like the Dravet Syndrome Foundation can be very empowering. They’re a great organization. There’s a lot of support for families, and they have been very helpful for many of the families that have been diagnosed early. It’s a tough discussion to have at the first visit, but what’s important as well is that they understand the potential risk of SUDEP, because that is something that they will find online. It’s a much more reasonable discussion to have directly with a physician than for families to find online.

 We’ve all brought up the internet. It can be a powerful tool, but it’s a dangerous tool. I couldn’t agree more. I learn so much from my patients who, early in my Dravet experience, would say what they read online. I would always say, “Proceed with caution,” and I still do, but I do feel that the families can get a sense of connection.

A panel of experts discuss treatment goals for patients with Dravet syndrome and how to convey the variability of treatment to the parents of these patients.  