Anup Patel, MDAnup Patel, MD
Epilepsy specialists are faced with treating several disease variations that all present unique challenges, including a pair of rare, early-onset syndromes: Dravet and Lennox-Gastaut. In a NeurologyLiveTM Peer Exchange panel discussion, a group of epileptologists explored the spectrum of obstacles they face when treating these severe syndromes, including creating the correct cocktail of medications to control seizures and making sure that patients adhere to therapy.

Led by Anup Patel, MD, section chief of pediatric neurology at Nationwide Children’s Hospital and associate professor of neurology and clinical pediatrics at The Ohio State University College of Medicine in Columbus, the panel began by covering the current treatment landscape, including the drawbacks to some of the current pharmaceutical therapies, and the challenges that providers and caregivers have to overcome to address adherence to these treatments.

The Current Treatment Landscape

“Historical treatments for Dravet syndrome have been challenging,” Elaine Wirrell, MD, director of pediatric epilepsy and professor of neurology at Mayo Clinic in Rochester, Minnesota, said.

“It’s a difficult epilepsy, and I think our usual antiseizure medicines have really not worked very well. Traditionally, people want to use a broad-spectrum medication.”

She noted how early diagnosis is extraordinarily important in Dravet syndrome, as is avoiding medications that may worsen symptoms, which means avoiding sodium channel agents such as oxcarbazepine, carbamazepine, phenytoin, and lamotrigine. Often, physicians start with clobazam or valproate, following up with the other as an add-on if the response is poor.

“We know that our ability to actually get successful seizure control, even with that combination of medicine, is very low,” Wirrell said. “So it’s actually a very exciting time to be in Dravet syndrome and see some of the newer therapies that are coming in.” She also advocated for topiramate, which can have some effi- cacy in this population, as well as treatment with alternative thera- peutic approaches, namely the ketogenic diet.

As stiripentol was only recently approved by the FDA, although it has been used off label, the panel focused on the anticonvulsant. In European studies from the early 2000s, the therapy showed ≥50% response among roughly 70% of patients when added to a combination of valproate and clobazam, Wirrell said.

“Stiripentol must be combined with clobazam for it to work. But it seems to be very effective,” she explained. “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.”

Ian Miller, MD, medical director of the Comprehensive Epilepsy Clinic at Nicklaus Children’s Hospital in Miami, Florida, remarked that the biggest issue with stiripentol has been the context in which it was studied—as an add-on— that resulted in its specific indication.

“One open question is how those interact or what the relationship is, in terms of efficacy, between fenfluramine, cannabidiol, [and] stiripentol, plus all the old medications that we’ve been using for a long time because we didn’t have any other alternatives,” Miller said.

Patel and Miller dove into the process of starting a patient on stiripentol, noting that lowering doses of other medications, such as clobazam, divalproex, and valproic acid is essential, as stiripentol can be a fickle medication.

“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,” Miller noted.

He explained that monitoring clinical toxicity—temperature instability, somnolence, or gastrointestinal upset, among others—is paramount. Miller suggested that to handle these issues, his strategy is often to adjust the medication stiripentol is being added to.

“In any patient, if we’re adding a new medication, it’s because there’s an unmet need and uncontrolled seizures,” Elizabeth Thiele, MD, PhD, director of the Pediatric Epilepsy Program and Herscot Center for Tuberous Sclerosis Complex at Massachusetts General Hospital, and professor of neurology at Harvard Medical School, both in Boston, said. “So if I add a new medication, I always look at what are the coexisting medications and try to drop one of those, rather than the new medicine, to help optimize tolerability and give the new medicine a chance to see how effective it can be.”

Positing about the optimal dosing, Patel asked Wirrell to talk the panelists through her step-based approach for stiripentol. Wirrell explained that dosing is done milligram per kilogram, typically administered twice daily, although it isn’t a cookie-cutter situation. Stiripentol is available in 250- and 500-mg sachets, and the recommended dose is roughly 50 mg/kg. Wirrell said that she usually spends 3 to 4 weeks getting to that point, additionally monitoring liver enzymes and complete blood counts.

“For those older kids, probably, your target should be 25 mg/kg per day. For the younger kids, I think you can certainly go up to 50 mg/kg per day, but I would start at maybe 10 to 15 mg/kg and sort of take your time getting there,” she explained. “One of the big adverse effects that we see, as Dr Miller 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.”

"If I add a new medication, I always look at what are the coexisting medications and try to drop one of those, rather than the new medicine, to help optimize tolerability and give the new medicine a chance to see how effective it can be," said Elizabeth Thiele, MD, PhD.

Tackling Treatment Adherence

While working up to and settling on an optimal dose is essentially clearing 1 hurdle, getting the patient to remain adherent to that treatment presents a whole new category of challenges to both providers and caregivers.

“For a lot of patients, there are several barriers, starting with the fact that most of these kids are on more than 1 medication. If we stop and think about the number of pills we’re actually asking them to take a couple of times per day, it’s sometimes shockingly overwhelming to me that it’s quite a large number. And oftentimes, it’s a problem,” Thiele said. “Some kids can’t swallow pills, some refuse to swallow pills, and some might just have difficulty with oral motor function. So our nurses are actually very good at working with patients and trying to figure out what strategies will work, and I’m always impressed that parents can also be pretty creative.”

Sharing some of her personal patient experience, Thiele recalled a patient who takes 4 medications per day, but will only do so if the parents crush and combine the pills into 1 capsule.

“That’s a huge amount of effort for that family every day, which is I think one reason we and the pharmaceutical industry realizes that we need formulations other than pills for many of our patients,” she said.

With drug levels so important to seizure control, Patel added that these alternative ways of getting patients to take medications can introduce dosing issues. For instance, if a caregiver is mixing the medication with food and the patient doesn’t eat the whole portion, their drug levels may be off and it may leave them more vulnerable for seizure.

Turning to Jesus Eric Pina-Garza, MD, director of pediatric epilepsy at TriStar Medical Group Children’s Specialists in Nashville, Tennessee, Patel wondered what his thoughts were on new drug formulations aimed at improving administration and adherence.

“One of the delivery systems that is new and could potentially be helpful, not just for anticonvulsants but for medications in general, is the film delivery, and I have actually tested it in several patients with Lennox-Gastaut because they offer a particular challenge,” Pina-Garza said. “Just like any other kid, they don’t like to take medications, and sometimes if they’re cognitively impaired, which is often a comorbidity [in Lennox-Gastaut], they don’t understand why it’s so important. And then we talk about dysphasia, and dysphasia with liquid is worse. So liquid is just a possible option for the person that prefers liquid over tablet, which is usually a child, but not one with dysphasia. So the fact of having a film tech- nology that dissolves on your tongue and you’re not able to spit it out is incredible. That hopefully will be something that expands to other medications.”

Pina-Garza noted that there is much potential for medication given by oral film, and that although the current focus is on improving medication absorption through the gastrointestinal tract, in the future, this route of administration may be particularly helpful as a rescue medication that can be administered safely. You can be confident that the person is ingesting it and the treatment is being absorbed.