The Treatment Landscape of Dravet Syndrome & LGS

Anup Patel, MD: Speaking of treatment, let’s talk a little bit about the historical treatments in Dravet syndrome. What’s commonly used? And what do you use in your practice?

Elaine C. Wirrell, MD: I think that the historical treatments for Dravet have been very challenging. It’s a difficult epilepsy, but I think our usual antiseizure medicines have really not worked very well. I think traditionally people want to use, for Dravet syndrome, a broad-spectrum medication. Importantly, we talked about making the diagnosis early and avoiding things that make things worse. The usual group of medications that make Dravet much worse are the sodium channel agents. So oxcarbazepine, carbamazepine, phenytoin, lamotrigine, those should be avoided in children with Dravet syndrome. And that’s a reason to make an early diagnosis.

Typically when we’re starting medication for a child with Dravet, we often will start with clobazam or valproate and then add the other one in if the first one isn’t working. But we know that our ability to actually get successful seizure control even with that combination of medicine is very low. So it’s a very exciting time actually in Dravet syndrome to see some of the newer therapies that are coming in. Other therapies that we have traditionally used for Dravet syndrome, topiramate, and that does have some efficacy. The ketogenic diet, I’m also a zealot for the ketogenic diet in Dravet syndrome and Lennox-Gastaut. I think that that can have a very tremendous benefit for a subgroup of kids.

Anup Patel, MD: Speaking of treatments, let’s talk about what’s old is new, and stiripentol. Tell me about that medication and your experience. But now where are we today with that medication being available?

Elaine C. Wirrell, MD: Stiripentol was initially studied in France and in Italy back around 2000. The studies that they did were very small numbers of patients, but they had a robust statistical significance when they looked at efficacy. In those studies, about 70% of children with Dravet syndrome who had stiripentol added to a combination of valproate and clobazam were responders, meaning that they had a greater than 50% reduction in their seizures. So this is a medicine that has actually been used in France for many years.

Even in the United States, stiripentol was recently approved by the FDA in August and has just now become available for prescription. But even prior to that, many centers in the United States were actually using stiripentol for their Dravet patients. It’s important to recognize that you can’t use it on its own. You need to use it with clobazam in the United States, stiripentol must be combined with clobazam for it to work. But it seems to be very effective. The one thing you have to watch is if you add stiripentol to clobazam, you do need to drop your clobazam dose way down because there is an inhibition there, otherwise you’re going to have a child who becomes toxic on their clobazam.

Anup Patel, MD: What else as far as the medicine, how does it work, do we know a mechanism of action?

Elaine C. Wirrell, MD: It probably works by, as in many medications, several mechanisms. Probably the biggest way that it works is the GABAergic activity, and it seems to be different than your typical benzodiazepines because you actually get additional benefit if you use it with one of the benzodiazepines. There’s also some suggestion that it may also have a neuroprotective benefit as well, and so that is I think enticing for Dravet syndrome where they are having recurrent, often prolonged seizures. And then, as I’ve mentioned, there is the pharmacokinetic interaction with clobazam. And so you see elevations in clobazam and elevations in the metabolite N-desmethylclobazam as well.

Anup Patel, MD: Ian, in your practice, with that interaction, why is it important to have stiripentol with clobazam?

Ian Miller, MD: I think the biggest issue with stiripentol is that that’s the context in which the drug has been studied, and so that’s been an add-on requirement that the regulatory agencies have carried forward. And they said if your data include those medications, then your prescription needs to include those medications. I’m interested to see some of the newer studies that are being done, and I think we’re going to talk about fenfluramine and cannabidiol, and things like that. I think one open question is how those interact or what the relationship is, in terms of efficacy between, fenfluramine, cannabidiol, stiripentol plus all the old medications that we’ve been using for a long time because we didn’t have any other alternatives.

Anup Patel, MD: How do you start a patient on stiripentol if that’s what you think is best for them?

Ian Miller, MD: Like Elaine said, it’s really important to lower the clobazam, but in my experience, you also want to think about lowering the divalproex or the valproic acid if they’re on that as well. It is an extremely tricky medication, I guess. I would say I learned to respect it the hard way by having kids have a lot of adverse effects to it if I am not paying close attention and seeing them frequently and moderating the doses of those other medications.

Anup Patel, MD: Talk a little bit about some of those challenges. Like what do you monitor for?

Ian Miller, MD: Mainly it’s clinical toxicity. I think medication levels can be helpful, but it’s much less meaningful than simply watching to see if they’re having temperature instability, or somnolence, or GI [gastrointestinal] upset or anything like that.

Anup Patel, MD: And how would you handle that, would you lower the clobazam dosing more or would you lower the stiripentol dosing?

Ian Miller, MD: If we’re at the point where we’re adding stiripentol, my strategy has always been to lower the clobazam or the valproic acid, depending on which one seems like it’s more compatible with the toxicities that we’re seeing.

Anup Patel, MD: You know, Elizabeth, you are nodding in agreement. Any other insights that you would want to give other providers who are starting this path?

Elizabeth A. Thiele MD, PhD: No, I would agree with Ian. I think if we ever add, in any patient if we’re adding a new medication, it’s because there’s an unmet need and uncontrolled seizures. And so if you add a new medication, I always also look what are the coexisting medications and try to drop one of those rather than the new medicine to kind of optimize tolerability and giving the new medicine a chance to see how effective it would be.

Anup Patel, MD: Elaine, this is a new day for folks, that they can prescribe this without some of the challenges and hurdles we’ve had to overcome in getting an IND [Investigational New Drug permission], etcetera. How would they start the dosing, is it mg per kg, is it daily, is it twice daily? People are going to need to know this.

Elaine C. Wirrell, MD: Typically we give it twice a day. And it is a mg per kg to a certain degree. I think the sachets and the pills come in 250 mg and 500 mg, so you kind of have to, you almost guess your best dose that is going to be compatible with the pill size or the sachets that you have. Typically, the recommended dose is about 50 mg per kg. I usually spend about 3 or 4 weeks getting there. And in many kids, particularly in older kids, older children or adolescents, 50 mg per kg is probably going to be too high for them. So I think for those older kids, probably your target should be 25 mg per kg per day. For the younger kids, I think you can certainly go up to 50 mg per kg per day, but I would start at maybe 10 to 15 mg per kg and sort of take your time getting there. One of the big adverse effects that we see, as Ian has already alluded to, is the sedation and bit of ataxia that is probably clobazam related. But stiripentol itself can also cause kids to not be very hungry, to have a decreased appetite, and that can be a challenge as well. So taking a little bit of time to get there makes sense.

Anup Patel, MD: What about monitoring? Should we be careful about liver enzymes, blood counts? What sort of monitoring do you do?

Elaine C. Wirrell, MD: It’s recommended generally that you would do every 3 months liver enzymes and CBCs [complete blood counts]. But I must say, I have not seen any big concerns with that. There have been some reported reversible neutropenias associated with that, but that’s not been a reason that I’ve ever had to stop stiripentol.

Anup Patel, MD: That’s great.

Elaine C. Wirrell, MD: Yes.

Anup Patel, MD: Eric, comment a little bit on some other treatments that are potentially not medicine-related, like the vagus nerve stimulator or other devices, and do they have a role in treating Dravet or LGS [Lennox-Gastaut syndrome]?

Jesus Eric Pina-Garza, MD: Everything has a role when you still have a problem. That’s the reason we have these medications because we’re trying to develop solutions for a problem that has been in existence for centuries. So one of the things with the trials of stiripentol and cannabidiol that we learn is that we never reach the maximum of clobazam. Both trials show that some patients would benefit from having even higher levels of clobazam. So when we look at the dose response curves of clobazam, we saw that the curve kept ascending to the maximum approved dose by FDA. And we know that higher doses produce toxicity. But both the stiripentol and cannabidiol raised that even further. For some patients, you don’t need to reduce the clobazam if you’re not toxic and you seek further benefit.

For cannabidiol, clearly the post hoc analysis by the FDA shows that there was a separation from the cannabidiol component. For stiripentol, probably there is some separation but not enough in the post hoc. That’s why we have to prescribe it with clobazam. But even with all these drugs, the key to me is maybe a little bit earlier…I think like anything in medicine, the most effective we are is when we intervene early. To me, you start calling a spectrum of Lennox-Gastaut. So LGS, capital; small s, but the small s is a spectrum, so it’s bigger. And what it tells you is that when you have an epilepsy that’s resistant to treatment early in life, and you start seeing these generalized discharges, it’s not a primary generalized epilepsy. This is the symptomatic generalization. That’s when you have to start worrying about LGS. You still don’t have drop attacks, you still don’t have all the multiple seizures. But that’s the beginning. If you track every patient in LGS, EEG [electroencephalogram]-wise, you find that is a little signal to tell you. That is why the spectrum is probably more helpful. This is anecdotal but just looking at my own charts.

I always say that if you’re refractory to treatment as child, you’re better being refractory to a wide spectrum medication than to a narrower spectrum. Because at least the wide spectrum medication may protect you from the syndrome fully developing. So I think we have start very early, but I don’t have the data to tell if you that if we start everybody early in the spectrum, you can prevent everybody, I don’t think it’s possible. You still get to that point where you have to do occasionally palliative care like callosotomies. Why, because drop attacks kill people. People fall with these terrible injuries, and you wonder why they have facial lacerations. Because when you fall from your height without tone, your head is completely unprotected, different from falling in the tonic posture, where your shoulders shield your head.

It’s an incredible cause of death, fatalities. I like to use the mathematical role to help adult neurologists acknowledge Lennox-Gastaut, which is if you look at our open-label trials, about 1% of the patients died a year. It’s a high fatality rate, which means about 80% become adults. So when you ask an adult and they say, “I don’t have Lennox-Gastaut,” that’s magic. It’s like you disappeared them by not acknowledging. So clearly, a lot of patients are potentially healthier early, but we still have to rescue them because we’re in a transition of awareness. All this adult population that still is refractory to not adequate treatments. So we have a big test.