Activity Transcript

Gregory Krauss, MD: Hello, I'm Gregory Krauss, Professor of Neurology at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Welcome to this program titled, "Expert Perspectives on Raising the Bar in Epilepsy, Treatment Selection, Dosing Considerations, and Interactions."

Joining me today are Steve Chung, who's a Professor of Neurology at the University of Arizona School of Medicine in Phoenix, and Michael Privitera, who's a Professor of Neurology at the University of Cincinnati and the Gardner Neuroscience Institute in Cincinnati, Ohio. Welcome.

In this program, we will discuss the following: the consequences of poorly controlled seizures in patients with focal epilepsy; clinical data regarding seizure freedom rates for currently approved antiseizure medications; how to titrate newer medications to reduce the occurrence of adverse events; and how to identify the need for dosing changes amongst current antiseizure medicines when a new antiseizure medicine is added and we're converting or adding therapies.

Impact of Uncontrolled Seizures

The CDC estimates that approximately 3.4 million people in the United States have active epilepsy. That includes about 3,000,000 adults and 470,000 children. Numerous effective treatments are available to help patients with epilepsy; however, approximately 40% of people with epilepsy continue to have seizures despite treatment with 2 or more antiseizure medicines. We call this "drug-resistant epilepsy," and this equates to approximately 1,000,000 people in the United States having what's classified as "drug-resistant epilepsy." This is the failure, again, of adequate trials of optimized antiseizure medicines that are tolerated and appropriately chosen.

The goal is to achieve seizure freedom, and that's part of our definition of success in terms of treatment. When we look at patients who are newly treated with epilepsy, a large number fail first- and second-line monotherapy treatments. In this large study from the United Kingdom, 47% of patients failed treatment with the first antiseizure medicine that was tried. When patients went on to try a second drug, only 13% became seizure-free with that treatment after 6 months or more, and only 4% of patients developed seizure freedom with the third drug monotherapy or with combined drug therapy. So, 36% of patients had drug-resistant epilepsy despite treatment with several antiseizure medicines.

Our treatment goals for epilepsy are to try to achieve seizure freedom for patients so they don't have any disability associated with their seizures or antiepileptic drugs. Some of them, particularly in combination, can cause adverse events like sedation and other symptoms, and those can impact patients' quality of life. So, we want to control seizures quickly without drug side effects.

Now, it's difficult to get many patients to the level of complete control of their seizures, particularly without side effects, but that's our goal and something that we should target in our therapy. That's what we'll be talking about today.

The consequences of uncontrolled seizures or mortality, like sudden unexpected death in epilepsy with accidents and suicide rates are increased in this population. Morbidity is common with seizures, with risk of injuries, burns, and effects of repetitive seizures on underlying disorders and cognition. The unpredictability of seizures can disrupt people's lives and cause problems at work. There are psychosocial consequences from having seizures or medication side effects, including depression, interference with driving, and vocational limitations. These things together can contribute to reduced quality of life in patients who have uncontrolled seizures.

Now, when you ask patients, what is of critical importance in terms of becoming completely seizure-free, driving is number 1. The impact of seizures can interfere with independence, work abilities, or job selection. Embarrassment is common with seizures. Medication dependence is sometimes a concern of patients, but many patients have mood and stress problems with epilepsy and sometimes with medications, and there are safety issues with having uncontrolled seizures.

When you look at tabulations of quality of life and what affects the quality of life in epilepsy the most, surprisingly drug side effects are 1 of the major contributors to reduced quality of life in patients. In particular, we see patients who have polytherapy or sometimes treatment with older medicines, where they'll sometimes get grogginess or sedation or have other problems, and that can reduce their quality of life.

Depression also can markedly reduce the quality of life in epilepsy. It's very important that we target drug side effects and minimize those, target treatment for depression, and try to control seizures, because there's a correlation between having drug-resistant epilepsy and depression. Seizures can contribute to reduced quality of life, and the comorbidities and associated disability with seizures are a major factor in patients sometimes losing their quality of life.

Now, a major issue that's been identified in the last several years is a big problem in patients with uncontrolled tonic-clonic seizures, which is a high risk of SUDEP, or sudden unexpected death in epilepsy. About 1 in 500 patients per year who have uncontrolled seizures can die suddenly, typically in the postictal phase. It's particularly a major risk in those with uncontrolled tonic-clonic seizures, so when you're looking at patients who are having uncontrolled seizures despite treatment with several anticonvulsants, you want to pick something that can control tonic-clonic seizures. That's an important goal to try to minimize the risk of SUDEP.

Now we'd like to review some of the issues of how to manage epilepsy using currently approved antiseizure medicines and we have a couple of case studies that illustrate issues on how to optimize treatment. Steve Chung is going to start with a discussion about how to select and manage antiseizure medicines.

Selecting Antiseizure Medications

Steven Chung, MD: Sure. Thanks, Greg. As you had mentioned, we have so many medication choices and there are so many patients still experiencing seizure after seizure. You mentioned about 30% to 40% of the US population with seizures are still having uncontrolled seizures daily or monthly. So, we have to think about how we're going to be individualizing our treatment for patients, not only the refractory population but also selecting the first medication when they're newly diagnosed with epilepsy.

The good news is we have more than 30 medications available for the treatment of epilepsy or seizures. Among them, I think about 20 medications are commonly used, including some of the older medications, such as carbamazepine or valproate, depending on seizure type. Oftentimes, if you look at the literature, first-line or second-line medications include not only carbamazepine and valproate, but lamotrigine, levetiracetam, zonisamide, and some other medications.

On top of that, there are so many new medications that came out in the last 10 years which actually add benefit towards the seizure control and possibly control those in the refractory population better.

The real question is then, out of all these medications, how are we going to choose a medication? First, we have to know what type of seizures we're dealing with. Focal epilepsy vs generalized epilepsy, we tend to choose different medications.

Not only that, but we have to know their individual side effects. What are the things that patients are most concerned about as potential side effects? What are the ones they're willing to take as potential side effects? Ultimately, we want to control their seizures, not just to make the seizure go away, but to improve their quality of life.

Greg, you mentioned how important it is to control their seizures and minimize the side effect to improve their quality of life. Those are really important issues. To do that, you have to know your patient well, not only their seizure types and comorbid conditions, but what other medications they are taking. Also, you have to understand the pros and cons of each medication, including older medication and new medication together. When you combine medication, you have to consider the pharmacodynamic and pharmacokinetic interactions. For example, drug-to-drug interactions could be due to enzyme-inducing effects lowering or increasing each drug's serum levels, so we have to know that when we combine medications. We also need to know the pharmacodynamic effects. For example, if you combine a sodium channel blocking agent with another sodium channel blocking agent, they tend to have an increased incidence of dizziness. We refer to that as a "pharmacodynamic effect." Even without changing their serum level, they can have compounded side effects together, so all of this should be considered.

Efficacy is another very important thing. We have to know what type of seizures they have so that we choose appropriate medications. Even with focal seizures, they may have different types of focal seizures and we must address them all.

One hundred percent seizure freedom is what we want. Ironically, if you look at the clinical studies, the primary measurement or primary outcome is oftentimes how much seizure reduction was seen. Not seizure freedom necessarily. This is sometimes referred to as the "responder rate"—what percentage of people reduce their seizures by 50% or more. We want seizure freedom, but the information that we have is usually the seizure reduction percentage, not seizure freedom.

If you look at seizure freedom, it's not that promising. Historically, the medications that I mentioned, plus many others, the clinical studies show seizure freedom to run between about 2% and 6%, depending on the studies. We always want the medication, even in the refractory population, to provide a much higher percentage of seizure freedom. Again, that's something that we're striving for.

There's 1 medication, cenobamate, the most recently approved medication, that has shown a higher percentage of seizure freedom in their pivotal trials. This was seen not only during the 12-week maintenance period but also when they looked at longer durations. At 25 to 30 months, about 20% of patients at the dosage of 400 milligrams per day of cenobamate would maintain seizure freedom.

Dr Krauss: Thank you, Steve. Michael, you recently co-authored a meta-analysis to compare the 50% responder rates for cenobamate made against a variety of antiseizure medicines. What did you find?

Michael D. Privitera, MD: We did a meta-analysis, which is a way to combine the results of different studies, and we looked at 21 different randomized control trials with maintenance phases that lasted 12 weeks. We looked at cenobamate, which was the newest drug, compared to 7 other drugs, including brivaracetam, eslicarbazepine, lacosamide, perampanel, lamotrigine, levetiracetam, and topiramate. We looked at all doses. We looked at FDA-approved doses and we looked at the maximum dose and the minimum dose to see if we could find much difference.

The only grouping that showed a difference was the 50% responder rate at the FDA-recommended dose of cenobamate. But none of the other dose comparisons were statistically significant. When we looked at discontinuations, those were the same across all the different drugs.

Dr Krauss: What do you mean FDA-recommended doses? Were you looking at a broad range of doses for other medicines compared to cenobamate?

Dr Privitera: Yeah. If you look at the prescribing information for each of these drugs, there's a range that the FDA approves for use, but in clinical trials, they may have been tested at lower doses or at higher doses than what's in the prescribing information as a recommended dose.

Dr Krauss: Okay, thank you, Michael. Steven, can you introduce our first case so that we can put some of what we've learned regarding treatment selection into practice?

Early Treatment of Focal-Onset Epilepsy

Dr Chung: Sure. I'll be happy to. I'll share this case that I saw recently. This person's name is José. He's a 35-year-old investment banker working hard, and he decided one weekend, "I can just take a weekend off and take the ATV out in the desert." Unfortunately, his ATV got flipped over and he had head injuries and subsequently developed seizures.

In terms of seizure semiology, his seizures usually start with a right-hand tingling sensation followed by some dystonic or jerking motion on the right side of his face, which rarely, but indeed, progressed to convulsions several times. Initially, he's been treated with antiseizure medication, which I will mention in a second. But the focal motor seizures became a lot more common, counting about 2 to 3 times per week. However, the convulsive seizures were in control better, but not fully: 2 times per year. We're not happy with it, but he used to have a lot more seizures.

We have something to do here. He recognized that working too hard with the stress at work or home, drinking alcohol, and lack of sleep as trigger factors for his seizures.

His initial MRI scan shows some diffuse axonal injury involving the left hemisphere and the subsequent MRI scan did show some mild degree of diffuse atrophy without showing the visual temporal sclerosis on the left side. Outpatient EEG did show some epileptic form discharges arising from the left temporal region. Later on, he did get the video EEG monitoring study, mainly because he wanted to know whether he was having any seizures while sleeping. He had been waking up really tired, to the point that he could not go to work early in the morning. As you know, he's a stock trader.

The video EEG monitoring study captured 2 seizures. Both were obscured by the muscle artifact because he was chewing or the dystonia involving the face. But 1 of them did show that right before the onset of the clinical event, rhythmic discharges were arising from the left temporal lobe. We didn't have a good target with an MRI scan, so we decided to treat him with another medication.

Levetiracetam was initially selected by another physician. By the time I saw him, he was taking levetiracetam extended-release up to 3000 mg per day. There was some attempt made to increase the levetiracetam, but he could not tolerate this due to the cognitive, maybe sedating side effects, and lethargic feeling, especially in the morning. He preferred to take medication once daily, but he was somewhat open to taking it twice a day if the medication provides good benefit. At this point, there are a lot of different medication choices that we can make. Levetiracetam, being cleared by the kidneys, does not have a sodium channel blocking effect.

We thought it would be a good idea to add a sodium channel blocking agent to his regimen, but it could have been any medication added to it. The intention was if the second medication works well, then eventually we'll do the conversion to monotherapy of that medication.

After a long discussion about his preference and checking some of the insurance company coverage, we decide to add a small dose of lacosamide. We started at the small dosage, which would be ramped up. When he reached about 100 mg twice a day of lacosamide, along with his levetiracetam, he did have some more mood changes. It wasn't clear whether he was getting it from levetiracetam, lacosamide, or maybe a combination of those. But it did affect him. Not only that he feels tired now, but he felt a little bit of moodiness. On top of that, he did admit that he will often forget to take the morning dose of lacosamide because right after getting up, he's sitting in front of the computer and looking at the trades in the market.

Dr Krauss: How did you decide to do an add-on therapy versus just adding the lacosamide and taking away the levetiracetam?

Dr Chung: We decided that whatever we're going to do, we don't want to have any kind of a further increase of convulsive seizures. We thought that it would be safer to add the second medication and only if the second medication completely controls the seizures, then we'll consider withdrawing the first medication. The intention was to have a second monotherapy, but a lot of times, from my experience with other patients, they actually end up sticking with the combination therapy. In those cases, they're usually on moderate doses of 2 medications. If they are doing well and are not having much of a side effect, they prefer to continue their medication combination rather than completely converting over to the second agent.

Dr Krauss: This patient is starting to display signs of being drug-resistant. They're having continued seizures on 2 medicines. They don't look like they're an optimal surgery candidate. They have a frontotemporal injury with focal motor seizures and kind of a broad EEG pattern. They could be a candidate, but they're not straightforward. You're probably going to be thinking about second-, third-generation medications at this point. When we think about that, there are a lot of options and ways to manipulate treatment.

Steve gave a good presentation on early treatment. Michael, can you present our second case, which is a patient who has very refractory seizures and we can kind of continue this conversation about how to treat people who are drug-resistant.

Dr Privitera: This second case is a 36-year-old woman who has refractory focal epilepsy and mild developmental delay. The seizures started when she was 10, and it appears that she had encephalitis, although this was well before I saw her. She presented with status epilepticus at seizure onset and then developed medication-refractory epilepsy pretty rapidly over the next several years. At another center, she underwent a left anterior temporal lobectomy at age 14, and it didn't help very much.

After 2 years, they tried some other medications. Then they tried a second surgery where they put intracranial subdural electrodes into the posterior temporal region behind where the initial resection occurred. They did an additional small resection plus multiple subpial transections. Because it was close to her language area, it helped a little bit, but never really stopped the seizures.

At the time of this presentation, when we're talking about her case now, she has about 5 to 10 focal seizures a month with a loss of awareness, plus additional seizures where she doesn't have a loss of awareness. Her tonic-clonic seizures were happening about once a year. She had pretty much failed everything. So, she had failed phenytoin and phenobarbital, valproate, lamotrigine, topiramate, zonisamide, and oxcarbazepine. She'd been on the ketogenic diet, which didn't help. Her medications at the time of her current presentation included brivaracetam 300 mg a day, lacosamide 700 mg a day, pregabalin 1500 mg a day, and then clobazam 20 mg a day. On top of the fact that she has a lot of seizures, her parents and the patient herself tell us that stress is a seizure trigger, so when stressful things are happening, she has even more seizures. She's having moderate side effects, but they were not too bad considering she's on 4 medications, which is a lot of medication.

Dr Krauss: And 2 of them are at very high doses: brivaracetam and lacosamide.

Dr Privitera: Right. So, the goal in the next step would be to try to get a medication that's going to help the seizures, but also to try to get her off some of these other medications. While I had not seen her for long, each time we tried to change one of her medicines, there might be a bump in seizures. Then she would say, "Look, Dr Privitera, I don't want to make any changes. Cutting those medicines is going to make me have more seizures." That was sort of a challenge.

We had quite a long discussion about the new medication, cenobamate. We said, "Okay, you're on a lot of medicine, so let's choose a lower target dose of 100 mg a day of cenobamate." Then we titrated up according to the prescribing information, which with cenobamate is very important.

She started at 12.5, then up to 25, then to 50, and then to 100 mg a day in 2-week intervals. Again, we use a slow titration and a lower target dose because I wanted to avoid side effects. She's on other medications and I wanted to be sure that we gave this drug an opportunity. I didn't want to hit her with a lot of side effects right away and have her say, "Oh, I don't want that medicine because it has too many side effects."

I just want to mention that titration of antiseizure medicines right at the beginning is critical. If you go too fast, you can give that patient too many side effects early on. Then they may say, "No, that drug was terrible. I'll never try it again." Even though a lot of these newer medicines, especially compared to the older medicines, have a better safety and tolerability profile, some medications can produce significant adverse effects that can even be life-threatening. So, again, "start low, go slow" with all antiseizure medicines is a good idea, including any recommended dosing for initiation, especially with the drugs that can produce these serious adverse effects, especially skin-related ones, or other things like DRESS. It's very important to follow the titration intervals and not exceed them because several medications can give us these immune-mediated, idiosyncratic adverse effects. We've seen Stevens-Johnson and toxic epidermal necrolysis. Then 1 that's less common, but can be even more serious, is something called DRESS. This is like a Stevens-Johnson, but you also get multiorgan involvement.

Early on, and we've seen this with other drugs, but early on in the studies of cenobamate, they saw a few cases of this. That's why they went back, changed the titration to a lower starting dose and slower titration, and that seems to have improved.

We've seen this with lamotrigine. Early on, lamotrigine was used at much higher doses and had faster titration. Once we slowed down the titration, we saw fewer cases of Stevens-Johnson. And then the other issue with lamotrigine, as you may know, is when you use it with valproate, you have to be especially careful because the risk of rash is higher.

With DRESS in cenobamate, they switched from 50 mg or 100 mg as a starting dose to 12.5 mg. Once they changed that protocol in the subsequent 2000 patients, there were no more cases of DRESS. Now, we have about 20,000 long-term exposures with cenobamate, and no additional cases of DRESS have been reported to the FDA.

Going back to our case, Jasmine was titrated to reach 100 mg daily. I concomitantly reduced the lacosamide, mostly because they're both sodium channel drugs, to try to avoid some of the dizziness and blurred vision side effects. I reduced some of the pregabalin because we felt the pregabalin wasn't helping that much and she'd been eager to get off it. We didn't make a change to her brivaracetam or her clobazam, even though some people might say, "Well, clobazam, there's a pharmacokinetic interaction, you might want to reduce that." At this point, with her being on 4 drugs, we were reducing 2, and I thought that was adequate in terms of this titration.

Polytherapy is potentially a problem, but we also want to make sure patients come off medications in a slow and careful way. In this case, we were reducing 2 of the drugs, but the other 2 drugs we were going to keep the same. One of the important things that we see sometimes is when people add a new drug and they see adverse effects, the first reaction is to reduce the new drug. But very often when we start a new drug and see adverse effects, it's useful to reduce older medications instead. For example, when you have 2 drugs that are sodium channel drugs, reducing the older drug can reduce those adverse effects. You'll never be able to give the new drug a chance for seizure control unless you can reduce some of the adverse effects. That's why we were being more aggressive about reducing lacosamide in our patient. We know this from other drugs, too. If you look back at clinical trials of multiple different new drugs, when concomitant drugs are reduced, generally those drugs are better tolerated.

In our case, in January 2021, that's 3 months after cenobamate was initiated, she had almost complete cessation of her seizures, but she still felt pretty sleepy. To address the sleepiness, we tried to get rid of the rest of the pregabalin. She was down to 1 seizure over the previous 2 months when I saw her again in April. So, I said, "Let's try increasing the cenobamate a little bit more from 100 to 150." Then we titrated her down to get rid of the rest of the lacosamide.

In October when we saw her, she was not seizure-free, although she had been for the first 3 months, but was better than 90% seizure reduced. We were still trying to get her off more of the lacosamide. She was a little bit resistant to increasing the cenobamate because she was still kind of sleepy. The other thing that was quite interesting is that her parents and the patient said, "The effect of stress triggering the seizures seems to have stopped." We seem to have blunt blunted that effect, and everybody was happy because the patient and the family said this was the lowest seizure frequency that the patient had had over a 6-month period since the onset of her seizures that, as I mentioned, started with an episode of status epilepticus.

Dr Krauss: Well, thanks very much. That patient had highly drug-resistant epilepsy and did very well. Probably, in the future, it may be even possible to charge up to a higher dose of cenobamate and convert additional medicines. One I often convert is clobazam, because the clobazam metabolite is increased when combined with cenobamate, but she's done remarkably well, and thanks for reviewing that.

In wrapping up this program, there are a few key points to keep in mind. One is that poorly controlled seizures have many consequences, including a large number of effects on people's lives that can cause disability and reduce quality of life. There's a risk of SUDEP, particularly with persisting tonic-clonic seizures, which is important to target in treating.

There are no extensive head-to-head trials comparing antiseizure medicines. Meta-analyses have shown seizure freedom is possible for some patients, particularly with newer agents. To reduce the risk of adverse events, most antiseizure medicines should be started at low doses and slowly titrated to achieve target maintenance doses. I think it's particularly important to consider switching and converting between medicines to avoid polytherapy, which often multiplies the risk for side effects.

We generally find, as you go higher to reach target doses of newer medicines, if the new drug is effective, then often you can lower these other previously ineffective drugs and reduce toxicity. So, as we're titrating on newer drugs, and as Dr Privitera mentioned, if they're getting CNS-related side effects, often those go away if you down titrate on the older drugs. I think that's a good thing to emphasize.

Steve and Michael, thank you for the great discussion and thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

Transcript edited for style and clarity.