Current Series: Treatment Advances In Dravet And Lennox Gastaut Syndrome


Anup Patel, MD: With Dravet syndrome, Elaine mentioned that there’s the recent FDA approval of stiripentol. We’re going to talk about some of the other recent FDA approved medications. With Lennox-Gastaut though we have more approved medications, and I don’t know if you can speak about some of those approved medications and how they are utilized in your practice for Lennox-Gastaut syndrome [LGS].

Elizabeth A. Thiele, MD, PhD: Sure. Lennox-Gastaut is in a better place because there are several medications that have an FDA approval, including rufinamide and clobazam, and that was the initial approval for those medications in the United States. There’s also Valproate, lamotrigine, topiramate, Felbatol, VNS [vagus nerve stimulation]. So we do have in the armamentarium toolbox for LGS more options than there have been for Dravet. But even with those it’s kind of humbling that we still have an incredible unmet need that these kids, if you look at the data from any of the trials, even though sometimes there’s a nice response and a seizure reduction, seizure freedom is rarely attained. And even if we get a 50% reduction in seizures for one of our patients, they’re still going to have a seizure burden that we’re going to continue to work on.

I think most of us use the medications, and probably each of us have our favorite ones in which we’d go to first with our experience on how effective, how well tolerated, etcetera. As I said, I use diet very frequently. I know Elaine does as well. So the armamentarium in the toolbox is there, but there continues to be a significant unmet need for this patient population as well as for the Dravet population, as well as for most of the kids I take care of, for safe and well tolerated medications.

Anup Patel, MD: I think it’s really important that when you look at the literature, there was a great article that says, “What are our first-line treatments,” and it was sent out to all neurology providers. And valproic acid was traditionally the one that rose to the top, which is ironic since it doesn’t actually have an FDA approval for Lennox-Gastaut syndrome, but that’s what most people use. I’d love to hear, what do you start with as far as treatments for a new onset Lennox-Gastaut syndrome? And I’m going to ask all of you to comment on that because I think there is variability.

Ian Miller, MD: I think that can be a little bit tricky because even though it does have kind of a classical edge at onset, sometimes you don’t know at the onset that it is LGS. And so it’s very different than Dravet, again, because in Dravet you have some clues in terms of temperature sensitivity, etcetera, and the quality of the seizure. But for Lennox-Gastaut I find that more difficult. So if the seizure sounds like it’s generalized, I’m probably more likely to use levetiracetam. If it sounds like it’s focal I might use oxcarbazepine, but that’s kind of prior to the light bulb going off and realizing that I’m dealing with Lennox-Gastaut.

Anup Patel, MD: How about you, Elizabeth?

Elizabeth A. Thiele, MD, PhD: For me by the time we see these kids, either we’ve been following them or other people have and they’ve already been on some of these medicines. So I think once you recognize the seizure, mixed seizure type, we all think broad spectrum medication. And then for me it’s honestly what medications has the child been on, what medications have they not been on.

We use a lot of lamotrigine, levetiracetam, clobazam, and rufinamide. We have a lot of kids on Felbatol. We have a lot of kids on dietary therapy. We have a lot of kids on VNS. And now with the recent approval of CBD [cannabidiol], I think we’re also going to have a lot of kids on cannabidiol. And I know we’re going to talk about that later but, again, we’re in a fortunate place, and I think it will depend a lot on what the kid has been on and what the kid’s tolerated, not tolerated, and what my options are for further treatment.

Anup Patel, MD: Elaine, what about you, what’s your first go-to medication for Lennox-Gastaut syndrome?

Elaine C. Wirrell, MD: I fully agree with Elizabeth. By the time we’re seeing these kids they’ve often been on numerous other medications, and many of them are coming in with large amounts of medications. So I think first of all before you start adding new things is to figure out what are they on, what is working, what is clearly not working and try and simplify things. Make sure that you’ve actually maximized your current treatments, and that’s typically what we do. Removing medications that we think are going to make things worse is also important.

I like Valproate. I think that’s a medication that many people are still a little scared to use. But I think it’s a nice medication because you can get the dose up fairly quickly. I think it’s very efficacious. I also like lamotrigine. The concern with lamotrigine is if you’re having very frequent seizures, particularly if you’re adding it to Valproate, it takes a long time to get into the therapeutic range. So that would be sort of a concern there.

I think in addition to the medications that Elizabeth already alluded to, really looking at our other treatments that we have. So if they’ve already been on 2 to 3 to 4 medications, and those have been maximized and they’re appropriate for LGS and they’re not working, then maybe try and look at bringing in things like ketogenic diet as well. Or thinking about vagus nerve stimulation.

Anup Patel, MD: Eric, what about you? And then we’re going to talk about that specifically, because I’d love to get into some of the second-, third-line treatments that we go to. But you’ve got a kid, he’s 6 years old, he’s in your office and you say, “Oh, this is Lennox-Gastaut syndrome,” what’s your go-to?

Jesus Eric Pina-Garza, MD: It varies a lot, I agree with everybody. But there’s the LGS that I’m brewing. It happened in front of me. That’s the one that I consider the early spectrum, and that’s the best opportunity to treat. There’s the kid who gets referred after having LGS for some time. So the one that is developing, which I can intervene with my pick, I would say clobazam, rufinamide, and cannabidiol are very attractive.

We cannot separate medications a lot based on efficacy, but we can separate them on tolerability and safety. And in my first 10 years of practice one of the things that I used to see frequently was pathological fractures of the spine, and things like that. So I’m so happy that we went away from the liver enzyme induction—carbamazepine, phenobarbital—and also from Valproate, which is through an insulin growth factor, it’s a different mechanism, but it also causes osteoporosis.   

So I’m thinking about these kids. These kids become adults. And the fatality may be higher even from the adverse effects of the osteoporosis. People die from hip fractures at a very high rate, and falls cause fractures. So I’m thinking more about that. I’m thinking about topiramate also works at the high dose, but these kids’ populations are already cognitively impaired. That’s one of the possible tolerability issues. So that’s why the other 3 become attractive, and every time I can I try them. Again, I’ll have patients who don’t respond to that, but at least you give them the best chance at having something that they can tolerate and not hurt them.

Anup Patel, MD: I think that’s an important concept. That we don’t just pick treatments because they may work for a seizure type, but we also have to look at the comorbidities and tolerability and safety. Elizabeth, comment on women and Valproate and why that’s such an important aspect for us to monitor and to consider.

Elizabeth A. Thiele, MD, PhD: Well Valproate is one of our medications that’s known to have teratogenic effects. So particularly in adolescent women, if they need to be on a medication long term, you have to think hard about that. Valproate also for me is tough in adolescent women. It’s good to hear Elaine’s thought on this because there can be significant weight gain, and that’s very tough for an adolescent, tougher for adolescent girls with epilepsy than boys. And then there also is this…question of the role of Valproate in women with epilepsy developing poly….

Jesus Eric Pina-Garza, MD: Boys also care about how we look.

Elizabeth A. Thiele, MD, PhD: I know boys do. So I kind of would like to see how Elaine feels about that because I think that you probably use more Valproate than I do, maybe for some of those reasons.

Elaine C. Wirrell, MD: I think you’re right. I think when you look at adolescents, and I would say both boys and girls, but if you’re seeing a patient who already has a body mass index that’s above the 90th or certainly above the 95th percentile, I think the risk of using Valproate in those patients is much higher. And I think that you can try and control the diet and things like that, but many of these kids already have significant behavior issues. And if you try and add that to the plate of the family; I’m going to put them on this medication that’s going to increase their appetite, and here I want you to really regulate and feed them carrot sticks, that’s just not going to happen.