Cenobamate: A New Treatment Option for Partial-Onset (Focal) Seizures

Approximately 30% of epilepsy patients have epilepsy that is considered refractory, or resistant to current treatment options. Therefore, it is critical that new and improved anti-epileptic drugs be developed. Cenobamate (XCOPRI®) is an FDA-approved drug made available to patients in 2020 and is approved for the treatment of partial-onset (also referred to as “focal”) seizures. Learn what is known about how cenobamate reduces seizure activity, and why it is a safe and effective treatment of partial seizures. Also discussed are the potential side effects that patients and caregivers should be aware of when considering this treatment option.

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About the Speaker
This webinar is presented by Dr. Michael Sperling, the Baldwin Keyes Professor of Neurology and Vice Chairman for Clinical Affairs in the Department of Neurology at Thomas Jefferson University in Philadelphia, PA. He is the Director of the Jefferson Comprehensive Epilepsy Center and the Clinical Neurophysiology Laboratory at Thomas Jefferson University Hospital. His primary research interests include surgical treatment of epilepsy, mortality in epilepsy, epilepsy genetics, and clinical neurophysiology.

The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified health care professionals who are familiar with individual medical conditions and needs. CURE strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified health care professionals who are familiar with the individual’s specific health situation.

This webinar is supported with funding from SK Life Science
SK Life Sciences

Q&A with Dr. Michael Sperling

Is this medication suitable for occipital lobe epilepsy?

Dr. Michael Sperling: It is approved and has been studied in all of the focal epilepsies. So, if you have occipital, or parietal, or frontal, or temporal, evidence exists that it works for focal epilepsy and occipital is a focal epilepsy. Is it good for generalized epilepsy, if you have Lennox-Gastaut syndrome, for example, or Dravet syndrome? Is it good if you have an idiopathic generalized epilepsy like juvenile myoclonic epilepsy or childhood absence epilepsy, or juvenile absence, or just generalized epilepsy with tonic-clonic seizures? It has not been studied in that. Studies need to be done.

There was a similar question somebody is asking about frontal lobe epilepsy.

Dr. Michael Sperling: Frontal lobe epilepsy is a focal epilepsy, absolutely appropriate.

What other medications are good to be paired with cenobamate?

Dr. Michael Sperling: I am not a huge fan of pairing medicines. I do it more than I should, as do many doctors. But in the best of all possible worlds, you would be on only one drug because then you have less side effects. If you’re going to pair it, however, drugs that work via a similar mechanism are probably not ideal because you’re more likely to get side effects. If you take a drug that’s a sodium channel blocker already, and then a new drug is added, which also blocks sodium channels, you’re more likely to have side effects. So you have to discuss with your doctors what’s suitable for what you have. But drugs like lacosamide (brand name Vimpat), carbamazepine, which is Tegretol but basically Trileptal, and some others, like lamotrigine also (Lamictal brand name) are sodium channel blockers.

When you add cenobamate you’re more likely to get side effects. You can pair it but I routinely have people start lowering their other drugs somewhat–usually by 50 or 100 milligrams a day, depending on how much they’re taking when they’re starting–to try to block side effects. I tell them that if you start seeing side effects, you can start lowering it sooner. Drugs with a different mechanism of action–so levetiracetam (which is Keppra), brivaracetam (which is Briviact), perampanel (which is Fycompa)–they’re probably going to be a bit less likely. There haven’t been great studies on that. Some analyses have been done looking at side effects and there have been some formal studies, but that’s a general rule that one can follow. The details of the studies are almost irrelevant in some sense, because it’s the dose that you’re on that makes a difference more than anything.

You’ve mentioned felbamate and that this is possibly viewed as a newer version of felbamate, but how does the effectiveness of cenobamate compare to felbamate?

Dr. Michael Sperling: Felbamate was studied in Lennox-Gastaut syndrome. There aren’t formal studies in focal epilepsy so we can’t really compare it quite as well. Now, many people, myself included, used it in focal epilepsy somewhat, but then felbamate was discovered to cause potentially fatal liver reactions and bone marrow reactions where people became profoundly anemic within a year of its appearance. So people use it very infrequently these days and mostly it’s used in Lennox-Gastaut. So we don’t have a good idea. We all thought that felbamate was a strikingly effective agent, however.

You mentioned the issues with felbamate and liver toxicity. There is no worry about cenobamate in liver toxicity in this case?

Dr. Michael Sperling: You can do the numbers: 930 plus 1,339. We have over 2,200 people and there’s been no significant abnormalities of liver reported with this. Does that mean that a less rare or less common reaction might not happen? It’s possible. So, felbamate in the trials looked, say, for liver abnormalities also. It wasn’t until it started being prescribed that liver problems resulted.

Keep in mind that when you start a new drug that just came out, we have reasonable evidence about it being effective. We have really modest evidence about safety. There’s nothing gross and horrible, but if one person out of 5,000 has a serious liver reaction and a serious bone marrow reaction, you have to have 25,000 people get the drug before you can be reasonably confident that the rate is at least 1 in 5,000. If the rate’s 1 in 50,000, a quarter of a million people have to have it. When drugs are approved after only 2,000 and 3,000 have had it, we know the risk is not large, it’s going to be small, but it doesn’t mean that there couldn’t still be a 1 in a 1,000 or 1 in 5,000 or 1 in 10,000 reaction. Time will tell.

We don’t routinely order liver function tests when starting people on this drug. We just ask them how they feel and keep an eye on things. We don’t order any blood tests with regularity because it’s not that the blood tests really predict it. And if you have what’s known as an idiosyncratic reaction, there’s no evidence that monitoring in advance actually makes a difference. The body’s exposed to it, something happens, and whether you take it for an extra one day or seven days probably doesn’t make a difference. What’s going to be is going to be at that point. And it’s when people don’t feel well that then we have to investigate more.

In terms of metabolic pathways, does cenobamate share a pathway with CBD? We know a lot of people are on CBD, whether it’s the approved version, the FDA version, or medications or substances that are purchased at dispensaries. Is there any known interaction with CBD?

Dr. Michael Sperling: A lot of people are taking it with CBD and products that contain CBD. Medical marijuana has many chemicals, one of which is presumably CBD. The enzymes in the liver that metabolize cenobamate also will metabolize CBD and other marijuana constituent chemicals. Does cenobamate alter the metabolism of CBD? Cenobamate does inhibit one of the enzymes within the liver that helps metabolize some compounds. It’s a 2C-19 compound. There’s a potential for an effect on that. How significant is it? We don’t know, and there really haven’t been great studies in people. In all those studies that were done, there’s not a whole lot of measurement of CBD that we can know. This is one of the things that needs to be studied. I’m sure there will be data that’s out there. In fact, I wouldn’t be surprised that there’s a paper or two published addressing this that I haven’t noticed yet. In practice, we start a new drug, and if there are side effects that start to develop, it’s common to start learning about other drugs and other medications.

Again, for focal epilepsy, I would point out that there is no scientific evidence in humans that CBD has benefit. There’s no data. People can try it. I have many patients who have given it a try, so give it a try see if it helps. But there’s actually no scientific data that it works. What the effect of CBD in people with focal epilepsy who have this drug is still needs further information and a large tail cross of people. Because they’re not just on CBD, they’re on usually one or two other drugs, or sometimes three other drugs. And it’s the whole mixture of the gemisch that we need to understand that adding one more drug into the mix may not enlighten us as much as we’d like.

Do you know if there are any studies on tuberous sclerosis and cenobamate, or if there’s anything in the works?

Dr. Michael Sperling: Many seizures in tuberous sclerosis are focal. So I would expect that for focal seizures in tuberous sclerosis this will be beneficial. I don’t think there are any formal randomized controlled trials like I showed you, but I’m certain that some people in tuberous sclerosis centers are starting to use this drug and tracking how their patients are doing. I would expect that we’ll see some results relatively soon.

Are there any reactions with warfarin (Coumadin)?

Dr. Michael Sperling: None that have been significant and been reported to date. I would still be cautious in the sense of checking the INR in people on warfarin when starting any new drug that can interact with liver enzymes because you can always be unpleasantly surprised. I would hope that most of the time we would be pleasantly surprised that it shouldn’t make a difference with warfarin. But it’s one of those things we want to keep an eye on.

Do you have any recommendations for patient compliance in a digital world where there are virtual visits?

Dr. Michael Sperling: For encouraging compliance, we talk to each other and we can talk to each other through computers or phones, which is how most of my patient visits are done during the pandemic. The vast majority are done that way. I think it’s the same conversation we have. One of the things that we, as doctors, have to do is understand our patient’s motivations.

In my experience, there are three main reasons people don’t take their drugs. The most common is it bothers them. They have side effects from it so they’ll skip a dose now and then because they don’t feel well. If doctors don’t ask about that, we don’t know, and then we don’t adjust. Or you don’t tell me that you’re skipping it every now and then because it bothers you because you don’t want to disappoint me. You’re not disappointing me. I want to know if you’re having a problem; let me know and I’ll adjust your doses. We want you to feel well. The idea is to take the pill, but otherwise not notice that it’s there. In my experience, I think a lot of it has to do with the drugs causing people not to feel well. They don’t want to embarrass their doctors by making them feel bad that I gave them a drug that makes them feel bad. It’s fine. I won’t feel bad. I want you to feel well. Tell me. That’s one reason.

The second reason, unfortunately, is affordability. We live in practically the only advanced country in the world–advanced economy, I should say–advanced economy where healthcare and drugs aren’t covered and drugs can be very expensive. Insurance companies have learned that your copay can be $10 a month for the generic, and they can make it $200 a month or a $100 a month if you’re on the brand. If drugs are on brand, suddenly it’s too expensive and people wind up skipping doses or taking less than they should. So, cost makes it different. Again, have a conversation with a doctor. If it’s too expensive, you need to be on a different drug. Some of the companies have programs to provide drugs for free for people who have certain income qualifications who otherwise couldn’t afford it. We need our health system fixed where people with chronic conditions don’t have to pay money to take drugs. Right now, I have patients who are on atorvastatin (Lipitor) for cholesterol lowering. If you’re on a generic, there’s no copay at all. If you have epilepsy, you really shouldn’t have a copay. There should be no barriers. So, that’s the barrier.

The third barrier–which I’ve been guilty of too–is that every once in a while, people forget, right? We all forget. We stay up late. We were out late in the pre-pandemic world more than now, but we’re out late, we’re doing something and we go to bed and we forget our medicine. We wake up in the morning, we’re rushing, we’re late for work. We have to go somewhere. We forget our medicine.

That, you can try to do something about. I always encourage people to brush their teeth twice a day and keep your medicine with your toothbrush next to the toothbrush. It’s there in the morning, it’s there at night, if you’re doing it once a day or twice a day. Set an alarm on your phone to ring. Set two alarms. One, if you’re supposed to take your medicine at 10:00 at night, have it ring at 10:00 and then have it ring at five after 10:00 to nag you. You’ll get in the habit and then you won’t need the alarm anymore. It just becomes automatic. So there are a few techniques could be done. Most important, frankly, is to make sure that the drug doesn’t bother you.

Additional Q&A not included in webinar, but answered by our webinar expert:

What are the similarities and differences between cenobamate and felbamate? How does the effectiveness of cenobamate compare to felbamate? The risks of felbamate were not discovered until after trials. The trial numbers don’t seem particularly large to identify issues either. How can we be confident about the safety issues? Would a patient change from felbamate to cenobamate and how would one do that (e.g, taper felbamate while starting Cenobamate)?

Dr. Michael Sperling: We do not yet fully understand the differences between felbamate and cenobamate, but the drug response seems different. We will not have full information about risks of any new drug until at least 50,000 to 100,000 people have been treated with that drug. That is why brand new drugs are often best reserved for people who have not responded to at least several other medications. It is possible to consider transitioning from felbamate to cenobamate, but there is no evidence about how this would work yet as it has not been reported.

With consideration to your comment on “needing new more effective drugs,” what are the ways to increase awareness of new drug adoption by doctors as well as patients, with Xcopri as an example?

Dr. Michael Sperling: The best way to increase awareness is by offering lectures at professional meetings to educate physicians and other health care providers about new treatments. Patient education is equally important as they can ask their physicians about new medications.

Were the patients in the placebo group taking other anti-seizure medications (ASMs)? If yes, what do you think was the effect of these other ASMs? How was that controlled for?

Dr. Michael Sperling: People in the placebo group were all taking their baseline ASMs. Improvement in seizure control occurs in some patients in the placebo arm during trials, and may relate to both more careful adherence to medication regimens and positive psychological effect.

Since cenobamate alters flow of sodium into neurons, are there side effects or precautions athletes should keep in mind, such as changes to the amount or type of fluid they should drink during a workout (water, Gatorade, etc.)?

Dr. Michael Sperling: There are no established precautions for athletes. There’s no need to alter the amount of fluid or type of liquids.

Does cenobamate have any synergistic effects with any other medications?

Dr. Michael Sperling: There may be synergistic effects, but this has not been studied enough to know.

Does cenobamate have any reaction to warfarin (Coumadin)?

Dr. Michael Sperling: Cenobamate does not appear to interact with warfarin/coumadin and doses do not appear to need to be changed in the preliminary studies. However, INR should be closely monitored as these preliminary studies are limited.

How does this interact with onfi (Clobazam)? I am experiencing major side effects and wonder if a large part is withdrawal from onfi.

Dr. Michael Sperling: People taking onfi may become more sleepy and the onfi dose may need to be lowered.

Will cenobamate substitute for both Vimpat and Keppra?

Dr. Michael Sperling: Cenobamate might be substituted for either of these drugs, carefully reducing their dose after the drug is started.

Are there any drug interactions with Vimpat, Banzel or Oxtellar?

Dr. Michael Sperling: There are potential interactions with oxcarbazepine (Oxtellar). Studies are needed for rufinamide (Banzel) but there is probably no interaction. There is probably no effect on Vimpat levels.

Will doctors have information on how to dose this drug? Is there a concern about a patient who already takes four medications adding this to the regimen?

Dr. Michael Sperling: If someone is on four medications, adding a fifth is usually problematic. It is best to be on fewer drugs before trying to add in cenobamate or any other drug.

Does this work better than polypharmacy with a combination of a sodium channel blocker and GABA modulator?

Dr. Michael Sperling: This is not better with polypharmacy. It probably works as well by itself but has not been tested that way. However, there is no reason to think that it would not work well if given by itself.

Is this suitable for epilepsies for SCN1A genes?

Dr. Michael Sperling: That’s not known at this time.

Can you explain drug reaction with eosinophilia and systemic symptoms (DRESS) for the skin rash reaction?

Dr. Michael Sperling: DRESS is a serious, potentially life threatening allergic reaction with inflammation in multiple organs, rash, and fever. The chance that it will occur is reduced by starting at a low dose and gradually increasing the dose over two to three months.

Does this medication have a prescription assistance program for patients?

Dr. Michael Sperling: Yes.

I also have hypothyroidism. Is there any risk in taking this drug?

Dr. Michael Sperling: No, there’s no problem for hypothyroidism.

Can the drug level be checked in blood work?

Dr. Michael Sperling: Yes, but the therapeutic range is not well characterized, so checking the level is not terribly helpful.

What kinds of blood work or other testing is required or recommended prior to starting cenobamate? An EKG to check for long QT syndrome, for example?

Dr. Michael Sperling: No blood work is required. An EKG is not required either. It has the potential to slightly shorten the QT, so having long QT should not be an issue. If long QT syndrome is present, however, then pre-treatment and post-treatment EKG is advisable.

Fenfluramine for Dravet: An Old Drug with a New Purpose

Epilepsy research has given the once-popular weight loss drug fenfluramine a new  purpose. Fenfluramine (Fintepla®) is now FDA-approved to treat Dravet syndrome, a rare, catastrophic form of  pediatric epilepsy. In this webinar, you will learn why doctors explored fenfluramine as a possible therapeutic option for epilepsy, and why it is safe and effective treatment for epilepsy in children with Dravet, as well as the potential side effects caregivers should know.

Our webinar presenter is leading-expert Dr. Joseph Sullivan, pediatric neurologist and Director of the UCSF Pediatric Epilepsy Center. He specializes in evaluating and treating children with epilepsy, particularly for those with epilepsies that do not respond to medications. In addition, he runs a specialized Dravet/PCDH19 clinic, where he cares for a large cohort of children with these types of genetic epilepsies.

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Audience Q&A with Dr. Sullivan

Can you talk about other syndromes or epilepsy types that Fintepla might be useful for or is being tested for?

There is a completed Phase 3 study with published results in Lennox-Gastaut syndrome, which also showed efficacy compared to placebo. It wasn’t as dramatic as what was seen in Dravet syndrome, but Lennox-Gastaut syndrome is a very different syndrome than Dravet syndrome. My understanding is that Zogenix will be submitting for labeling for the use of Fenfluramine in Lennox-Gastaut syndrome. I think that it definitely warrants additional study in terms of whether there are other epilepsy syndromes that this could be effective for. My colleague Elizabeth Dr. Thiele has a small study in sunflower syndrome that has also shown efficacy.

Those are three very different epilepsy syndromes. It’s very possible that fenfluramine could be a broad spectrum antiepileptic drug with sort of these favorable or more enriched responder rates in some of these syndromes. It’s our job as the clinical pediatric epilepsy community to try and figure out what would be the next target syndrome to go after.

Are there medications that help kids who have seizures related to heat or rapid body temperature changes?

We definitely know that patients with Dravet syndrome and who have SCN1A mutations do have temperature sensitivity. That’s been well documented in animal models. Interestingly, this temperature sensitivity does tend to wane over time. Adults tend not to be as temperature sensitive.

In my opinion, fenfluramine is not necessarily being effective in just those patients that have temperature sensitivities. I think this may be something where, again, there’s that enriched responder rate for Dravet syndrome, but that’s independent of this temperature sensitivity, but it’s an interesting question to ask as to whether or not there are other temperature-sensitive seizure syndromes that may be a target.

In my practice, when Dravet patients actually have a fever, even though we have no evidence to support this, we do try temperature reduction reducing measures, and for some kids we even try to give sort of benzodiazepines for 24 to 48 hours to bridge them through their fever. Again, isolated patients say, “Yes, that’s effective for my child,” but that’s not something that I recommend with every patient and certainly don’t have any scientific data to support those recommendations that I’m making.

Do you have any concerns recommending this treatment for kids with minor cardiac regurgitation after study Fintepla? My child couldn’t get into the clinical trial because of this issue.

Even in the placebo group, we saw this regurgitation. This actually created some anxiety for some of our patients who were left wondering, “Oh, no. Does my child need to see a cardiologist?” The answer is no and we’ve asked cardiologists this all across the country. Your child’s heart is normal if they have trace regurgitation, and that should not be a precaution for starting Fenfluramine now in the post-studies commercialization phase.

We don’t really see any signal to suggest that trace regurgitation – again, because it’s a normal physiologic finding – would be a risk factor for the development of valvulopathy. That finding going to be followed over time and is why I feel very comfortable that this REMS program is going to allow us to start this drug in more patients and follow that safety signal over time.

Could this drug be used in a child who is weaning off phenobarbital?

Our goal is seizure control and minimizing side effects and maximizing quality of life. I think you’d have to ask yourself, how is your child or your patient doing on phenobarbital? Phenobarbital certainly gets a bad reputation, but it does work for some patients. I would say if the patient is doing whatever you determine is okay, then I would not rock the boat. Go with what you know because while fenfluramine was effective in the majority of patients, there are some patients it’s not necessarily going to work for.

I said my new bar is 75% reduction of seizures. If the child is still having a high seizure burden and you’re questioning whether or not they are phenobarbital-related side effects, I think it would certainly be the right next step to add fenfluramine to that regimen. If the patient improves, then very, very slowly taper off some of the background drugs, That’s true for phenobarbital and that’s true for valproic acid. It’s true for any background drug.

If I’m adding a second or a third or a fourth drug to a regimen, I’m acknowledging that drugs one, two, and three are not getting that person to where they want to be. We see dramatic improvement after taking the new drug, we then have to ask ourselves, “Is the majority of that improvement all being realized from the additional drug? Can I reduce background drugs?” Unfortunately, I showed you that list of drugs that were in the Phase 3 trials. Even though there were only four to five drugs that were the most commonly used, we cannot tease out whether or not there’s like a combination that was more effective than others and I think we’ll just sort of have to realize that as more patients get started on these over time.

Are patients on Fintepla also on Epidiolex?

Epidiolex was not yet FDA-approved during our Phase III program, and any other investigational drug was not allowed in the double-blind placebo-controlled trials. Even on the open label extension, for the first six months, we really couldn’t make any changes to background medications – specifically adding of drugs because then that actually really confounds the open label extension data. Then, it just happened to align that as once Epidiolex was approved and we had more patients in the open label extension, and again, even if you were considered one of those super responders and had a 75% reduction of seizures, if you were still having seizures, the investigators did have the ability to ask the medical monitor for permission to start the drug.

In the expanded access program, I certainly have a handful of patients who are on both. It’s still been a relatively short period of time for me to be able to say with confidence how that combination working. It seems at first glance to be well tolerated. There does not seem to be significant drug-to-drug interactions, but ask me that question a year from now and I think it’s going to be exciting to report back whether or not we can see these incremental benefits of two drugs that have good Phase III controlled data to support their use in these patients.

This webinar is supported with funding from Zogenix

Webinar: Rescue Medication Delivery Methods and Future Therapies

Seizures can be both unpredictable and unrelenting. When a seizure becomes an emergency, rescue medications provide immediate relief and help prevent the need for emergency care. While existing therapies do stop these epilepsy emergencies in many patients, some are still searching for an option that works for them.

In the second part of this two-part webinar series, gain insight from Dr. Nathan Fountain of the University of Virginia on how different rescue medications can be administered, promising research, and what rescue therapies are currently in the pipeline. His presentation includes a look at the rescue medication pipeline and the new delivery methods which may become available to patients.

Dr. Nathan Fountain, Professor of Neurology and the Director of the Comprehensive Epilepsy Program at the University of Virginia.

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Audience Q&A with Dr. Fountain

Dr. Nathan FountainIs there any reason not to use Diastat before a seizure in a child who has been seizing for five minutes? And if so, how long should you wait?

There are exceptions to every single rule. As a general principle, if you’ve been prescribed rectal diazepam gel to stop seizures, and you have – let’s say – a child who’s been seizing for five minutes, there’d be few situations in which you wouldn’t give them the rectal diazepam gel. There’s a safety concern, and there’s a treatment concern in this circumstance.

The safety concern is; imagine that you’ve already given the child other benzodiazepines, let’s say clonazepam or lorazepam, or even diazepam in a pill form an hour ago. And so, it’s already in their blood. You might be hesitant to give them more without any kind of supervision. But as a general principle, we give rescue medications and tell them, “If you actually time a seizure, five minutes is a really long time.” We do this in the epilepsy monitoring unit. We admit people to the hospital and observe their seizures to figure out where they’re coming from and so forth.

A common exercise is to ask people when we watched the seizure on the video, “How long was that?” And they almost always say, “Oh, that was five minutes.” But you know what? It’s almost always under 90 seconds – a minute and a half. The point: while you’re watching someone seize for five minutes, it’s kind of forever, especially the big convulsive seizure. For convulsive seizures or medically serious seizures, you might say, usually we would advise giving the medicine after five minutes of seizure activity.

Now, if it’s a non convulsive seizure, or if you’re not sure it’s a seizure, that’s a different situation. I suppose we could imagine a situation where you wouldn’t give them medicine. It was in five minutes because it’s a non-convulsive seizure and you think it’s not causing any harm. Let’s say it’s just a staring seizure, an absence seizure. It is unusual to have one for more than five minutes, but there are specific situations when you might. Or if you’re not sure that it’s a seizure, so if you haven’t figured that out yet, then maybe it would be okay to not give the medicine if it’s something, as in, convulsive activity.

Are there any reasons to administer rescue medications to individuals who have one tonic clonic seizure without a cluster?

That goes back to really defining what it means to have a cluster. As a casual observation, we can easily make the statement, “Sure. Give the medicine to prevent the next seizure.” But if you think about this in detail as the FDA does when they think about exactly what the medicine is used for, this starts with a careful history to determine what is a typical seizure for that individual.

If that individual has big convulsive grand mal or generalized tonic clonic seizures typically lasting three minutes, but they suddenly have three in one day or even twice in one day and you want to prevent the next seizure. Usually you’d let that seizure complete because it would almost take three minutes just to administer whatever you’re going to administer. Typically, we’d let that seizure complete itself, then give whatever medicine is appropriate to prevent the next seizure.

I’m glad that question was asked because in general, we wouldn’t treat an acute seizure unless it lasted more longer than usual or more than five minutes. Now, as I said, five minutes is a long time. By three minutes, everybody’s getting all excited and getting ready to do something – call the rescue squad or given a board of therapy or do something – because it will take your five minutes to figure all that out. But for most people with epilepsy, they don’t have a seizure that lasts longer than three minutes. In fact, if you measure it, it’s usually less than 90 seconds and a half.

If you define the typical seizures as less than five minutes, we typically wouldn’t recommend the currently available abortive therapies. Maybe that’ll change. Maybe if it turns out intranasal medications really worked very quickly and are very effective and maybe we’ll get for ongoing seizures, but at the moment we would say no.

Do you have any suggestions for rescue therapies in children younger than two,  because the FDA approved cutoff for Diastat is two years old.

That’s a situation where you really need to talk to your doctor. There are alternatives. Everyone gets nervous when treating young children. When they’re less than two, it gets a little complicated because the dosing changes as well as the method of administration.

I’d say talk to your doctor about that. For a prolonged seizure in those who are less than two years old, we have the same concerns that we have in those older than two. Although the medications are only approved down to a certain age, doctors can use them in different situations. For example, the IV form of midazolam is definitely not approved to be blown up the nose until now. Still the IV form is not, but yet we would use that in certain situations when we knew the details warranted it. Being less than two, you could still use rectal Diastat for instance, or could use some other form.

Talk to your doctor about that and what might be best in that particular situation.

The CURE Leaders in Epilepsy Webinar Series has covered many topics related to epilepsy and innovations in research. Check out our full list of available webinars here.

The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified health care professionals who are familiar with individual medical conditions and needs. CURE strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified health care professionals who are familiar with the individual’s specific health situation.

A doctor explains what epilepsy is and what causes it

Webinar: Epilepsy Emergencies and Current Rescue Medications

Seizures can be both unpredictable and unrelenting. When a seizure becomes an emergency, rescue medications provide immediate relief and help prevent the need for emergency care. While existing therapies do stop these epilepsy emergencies in many patients, some are still searching for an option that works for them.

In this webinar, Dr. Kamil Detyniecki of the University of Miami provides an overview of the different types of seizure emergencies, while also discussing the currently available rescue medications.

View our follow-up webinar on the latest advances in rescue medications.

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Dr. Kamil DetynieckiAre these medications combined with other treatments or solo treatments?

These medications are not supposed to replace the daily antiepileptic medications that you take. These are only to be used in situations of emergencies. When you are prescribed a rescue therapy, you continue taking your daily medications. Rescue meds are extra protection in case of a situation that requires treatment.

Are there differences in effectiveness between the different delivery methods of rescue medications such as buccal or nasal or…

The important thing is that these medications get to the system as fast as possible. There are not good studies comparing one to another, because it’s very hard to make a study like that unbiased and blinded (a blinded study is one in which the participants don’t know if they are taking a placebo or not). But there have been some studies comparing rectal diazepam with nasal midazolam, and they seem to be compatible.

During your presentation, you mentioned the side effects of some of the rescue medications. Does delivery method affect these side effects?

Yes, absolutely. So as I mentioned, the nasal administration has the potential for irritation in the nose. That’s one type of side effect. In addition, medications have different half lives, which means they may stay in your system for different lengths of time. For example, diazepam stays in your system longer. After taking it, the effect of sedation may last for a longer time than midazolam. In some patients this may be beneficial, because there maybe longer lasting protection. So one may be better for one patient then versus others.

Is current research suggesting that rescue medications, such as Nayzilam, will be effective?

Yeah, absolutely. For the nasal midazolam, there was a large, multicenter study comparing this medication with placebo. This study showed that the nasal midazolam was much more effective than using the dummy medication. That’s what we use and that’s what the FDA used to approve this medication.

When is a patient considered to be in status epilepticus? Does the length of time vary between children and adults?

Definitions have this problem that they’re never perfect and this is what we have right now. And I think that, again, in terms of when to treat, it’s different. One definition may say that status epilepticus is five minutes, but this doesn’t mean that we need to wait five minutes in order to start treatment.

That is what has been shown based on animal and human data; if a seizure goes for five minutes or longer, there’s a less likelihood that it will stop on its own. For some patients, if a seizure is one, two minutes long, it may be too long for them. Every patient is different, but not aware of any that we’re changing that definition.

What would you say to say school teachers or school personnel who refuse to administer a rectal medications?

There’s been a lot of debate about having the school administer those medications. I think that the problem with the rectal administration maybe resolved now that we have nasal. Again, rectal is troublesome in patients’ privacy. But now that we have the option of nasal, hopefully that won’t be a problem.

Can diastat be given twice at one time if the seizures persist after the first dose ? Or do you have to wait a certain period of time between doses?

Typically the dose is calculated by weight. There is a possibility of giving another dose, but I would normally wait at least 10 minutes or more to know if the first dose had an effect. We have to always assess whether the patient may be overly sedated, having any difficulty breathing, etc. But those discussions about the dose need to be specifically addressed with with the neurologist. I can’t give you an answer for everyone.

But to answer shortly. Yes. In some patients, we can.

Is there an average length for how long it takes a rescue medication to take effect?

Yes. And really it depends on the type of rescue medications. Oral medications can take much longer. That’s why we’re so excited to have different routes of administration. If you swallow a pill, it may take 20 minutes or more to start working. A convulsion going on for a long time, it’s unacceptable.

Nasal may work as fast as 10 minutes, and there are new medications that are being searched in and are being researched that may work even faster as fast as IV. So there’s different times depending on the type on the medication and the route of administration. But the fastest we have right now are the rectal and the nasal.

What are the differences between Versed and Nayzilam?

The active compound is the same. Versed is the brand name of midazolam, which is the same compound which in this brand name Nayzilam. The main difference is that when you use the off label midazolam, like I showed this picture of this young kid getting the Versed with a syringe or a spray. That is because we’re using a product that is being developed for IV, it’s very diluted. You need to use much more volume or much more amount of liquid that it actually doesn’t all get absorbed in the drips behind the nose, so it’s not ideal.

This product that was FDA approved, Nayzilam, is a much smaller concentration, so it’s just one dose, and so that is an improvement compared to the off label, but the actual medication that is being used is the same.

If you can use the nasal spray to stop a seizure and it’s not effective, can you switch rescue medications and give Diastat?

These are great questions and that’s why it’s important to have a rescue plan. Every rescue plan needs to have an option. What if the rescue medication doesn’t work? When can you use another dose, should you call 911… Again, this is not an answer for everyone, and it really depends on the age of the patient and the dose that is to be given.

Using different types of rescue medication at the same time is possible, but it’s unusual. There are rescue medications that you can repeat after five or 10 minutes. It’s not that commonly used but it’s possible. But this is something that should be discussed and patients should ask that of their neurologist.

Again important to have a rescue plan where we discuss these situations… what to do with one medication doesn’t work. Can I use a second dose? When should I call 911? And so on.

If a patient already has a benzo, such as Onfi, as part of their daily AED regime, are the rescue meds effected?

The good answer is: it’s possible. There’s a phenomenon of tolerance to benzodiazepines, and so if a patient is on Onfi or clobazam, it’s possible that they may require a higher dose of rescue medication.

And this is something that is going to need more research for the newer medications. For the new medication, Nayzilam, the patients in the study were not allowed to be on benzodiazepines. And so we need more information about it. It’s definitely not a contraindication, but it may be that the patients may notice that they may require a higher dose.

Are there resources available for school personnel or other professionals on how to use rescue medications? 

I think that the Epilepsy Foundation is a great resource. They have examples of rescue medication plans.

Are there sublingual rescue medications that would work more quickly than a pill?

People are using lorazepam or clonazepam buccally or sublingually. I think the exact absorption has not been studied as well, but there’s a potential that it works faster than swallowing the pill. Although many of these pills are not meant to be used sublingually, so they may not dissolve as fast.

There are companies trying to develop different products, for example, a film that goes into the cheek to get absorbed faster. It’s an active area of research looking for different routes of administration.

For a child who has had a history of refractory epilepticus, when would it be ideal to administer the rescue medications or call 911? This person in particular is not comfortable waiting five minutes.

So, the answer is right there. If you’re not comfortable waiting five minutes, you shouldn’t do that. There is not an answer for everyone. And that’s why I continue to mention that which rescue medication you use, when to administer it, etc. should be a decision between the patient, caregiver, and the doctor depending on the user’s seizures, what kind of seizures they have.

For example, you may be willing to wait longer if you’re having a focal motor seizure, which is a seizure where you have, for example, motor activity without loss of awareness. These seizures can go on for several minutes without causing any significant harm to the patient, but a tonic-clonic seizure going on for four or five minutes, it can be potentially a concern.

The CURE Leaders in Epilepsy Webinar Series has covered many topics related to epilepsy and innovations in research. Check out our full list of available webinars here.

The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified health care professionals who are familiar with individual medical conditions and needs. CURE strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified health care professionals who are familiar with the individual’s specific health situation.

Epilepsy Surgery: Advancements, Options, & Considerations

For some people with uncontrolled seizures, epilepsy surgery is an effective and important option to consider. This webinar will help patients and caregivers approach this difficult and sometimes confusing conversation with their doctors.

Webinar presenter Dr. Kate Davis explores recent advances in epilepsy surgery, which have increased not only the types of surgeries available to patients but expanded who is an appropriate candidate for surgery. Dr. Davis also discusses the different tests performed as part of an epilepsy surgical evaluation and review current surgical options including resective surgery, laser ablation, and implantable devices.

Dr. Kate Davis is Medical Director of the Epilepsy Surgical Program and Epilepsy Monitoring Unit at the University of Pennsylvania.

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Plus, get the patient perspective on epilepsy surgery from this episode of our Seizing Life podcast.

Audience Q&A with Dr. Davis

How do you make sure that someone won’t have any new problems with memory or function after surgery?

There are some parts of the brain that we don’t worry about it that much. However, there are a lot of parts that are really critical real estate. The neuropsychological testing is really helpful for us to determine whether there’s risk. There are also clinical factors that come into play. The age that the seizures started is really important. If seizure started really early in life, most people will have had a lot of reorganization of the brain and the areas of the seizures are usually not functioning. We can do some testing for that.

The functional MRI can look at where language is. We can also look at where motor function is, or what allows you to move your hands or your legs. With patients who have intracranial EEG, we can use those electrodes to map function. We do a combination of these things, plus our knowledge of what brain regions do in most people’s brains, and that can help us make an assessment of risk. Then that should be discussed by your treatment team with the family and the patient, if there is risk.

Are the ketogenic diet and AEDs are tried before surgery even becomes an option?

I briefly mentioned that the ketogenic (keto) diet is mostly used in pediatrics. I’m not a pediatric epilepsy specialist, but many pediatric patients will try the keto diet with seizure medications before considering surgery. Not all. That’s something definitely should be discussed with your treatment team. In adults, there’s very little evidence that the keto diet and other dietary therapy substantially helps with seizure. We do not have a trial of a diet therapy before we consider surgery because the data is really not there to support that decision.

Can deep brain stimulator (DBS) or RNS can ever be implanted in pediatric patients?

I don’t know the specific age cutoffs because I don’t treat pediatrics, but the NeuroPace device is designed for the skull or the head of a seven-year-old or older. I think they are trying to change labeling to push the age back to pediatrics, and there are some centers that are implanting NeuroPace devices in pediatric patients. It is being done. Some of it is off label use, meaning it’s not under the FDA-approved label. The deep brain stimulator device is much newer, and I honestly don’t know if there are pediatric sites that are implanting that yet. I’m sure that we’ll learn that soon. I know that the pediatric epileptologists are very passionate about bringing these kind of technologies to their patients when they think it’s indicated.

Can you ever skip any of the tests, or is there a certain order that you always have to go through?

In the presentation, I went through a whole laundry list of tests. Not every patient needs each one of those tests. There is some variation in what centers use which tests. Some centers may not have availability of some tests, or have more experience with certain ones.

One test that I did not cover is a Wada test, which is done less frequently, but still at many centers is done. We will sometimes do Wadas in some patients. We will frequently do a functional MRI before doing that. Wada, just as an offside, is a test that’s been done for a very long time in epilepsy that is more invasive than the functional MRI, and that’s really one of the reasons there’s a move away from that test. Because it involves an injection of a drug that puts one side of the brain to sleep for a few minutes, during which time the neuropsychologist can do testing to look at function. Then you do it for the other side of the brain. That can give us information trying to determine the risk of the memory or language problems after a surgery, going back to the first question. In isolated cases, we are still doing Wadas.

I hesitate to say there’s a certain group of tests that each patient really needs. At a minimum, a brain MRI and EEG data is really done I think at every center. Then there’s some variation.

The CURE Leaders in Epilepsy Webinar Series has covered many topics related to epilepsy and innovations in research. Check out our full list of available webinars here.

The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified health care professionals who are familiar with individual medical conditions and needs. CURE strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified health care professionals who are familiar with the individual’s specific health situation.

A cute little girl in a yellow shirt holding a tomato in front of a bowl of salad.

Epilepsy and Dietary Therapies: How What You Eat May Help Control Seizures

For individuals with epilepsy – particularly refractory epilepsy – change of diet can be a recommended therapy for seizure control. While the ketogenic diet has been around for almost a century and is the arguably the most well-known dietary treatment option, today, there are multiple diets used to treat specific epilepsy types and syndromes.

In this webinar, two neurologists present both the research and clinical perspectives of dietary therapies. Dr. Jong Rho speaks to the science backing the use of dietary therapies to control seizures, and Dr. Eric Kosoff discusses how doctors determine which patients to recommend these therapies for, as well as how patients can work with their doctors to navigate these options.

Dr. Jong Rho is Professor of Pediatrics, Clinical Neurosciences, and Physiology and Pharmacology at the University of Calgary and Dr. Eric Kossoff is Professor of Neurology and Pediatrics at Johns Hopkins Children’s Center.

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Plus, listen to our Seizing Life podcast episode featuring registered dietician Robyn Blackford and advanced practice nurse Breanne Fisher for more information about using the ketogenic diet to treat epilepsy.

Audience Q&A with Dr. Kossoff and Dr. Jong Rho

How long does the average person stay on the ketogenic diet? And then, the second part of that question is, what are some of the factors that that you look into when coming off the ketogenic diet?

The duration of the ketogenic diet is a question that has been looked at with some research both in terms of the minimum time, how long you should give it and perhaps the case where it’s not effective. But also, maybe more interestingly, the maximum time at which point is maybe the ketogenic diet outlived its usefulness or maybe it’s led to the benefit you’re going to see and you can come off the diet without negative effects. And so, most of the time, we will tell families give the diet at least two to three months.

There is some scientific evidence that if you’re having seizures frequently enough, even within two to three weeks, you’re going to see potential benefit. Unlike some therapies, the ketogenic diet seems to work relatively quickly, maybe again within a week or two. And so, we generally do still recommend for families that make the commitment and engage in the ketogenic diet as a therapy to give it two to three months before giving up if they perhaps don’t see any benefit. On the opposite end in terms of how long to stay on the diet, the tradition, at least in the pediatric world is two years similar to medications. So, if you’re doing well or especially if you’re seizure free, at about two years on the ketogenic diet will often check in EEG. And if you have an epilepsy that potentially could be outgrown, we will slowly wean the diet by reducing the ratio usually every week or two until the diet has been stopped and you’re back on regular foods.

For certain epilepsies like Glute 1 deficiency where diet may be helpful even into adulthood, you may stay on the diet much, much longer. For some epilepsies like infantile spasms, there was a randomized trial comparing six months to two years and they found six months was just as effective in terms of diet duration. For that epilepsy, we may go shorter periods of time. But in general, on average, it’s about one or two years in the pediatric world. In the adult world, they often stay on for longer if it’s helping. But in pediatrics about two years.

What are the steps that someone might take to initiate the diet? Meaning, blood work, other tests, et cetera.

It really is important that this should be done with supervision at an epilepsy center. We do have families that are starting on their own and sometimes it works out, but other times they can have adverse effects or even just not the efficacy they were hoping for. So, it really should be done in an epilepsy center. There are labs that are recommended to be done in advance to make sure there’s no reason that the diet could potentially cause a problem.

As Dr. Rho mentioned it is a metabolic big change to the neurons into your body. And so, it can have some adverse effects if there is a problem in metabolizing the fats. So, we usually recommend labs to be done in advance. We usually as well spend a lot of time talking to the families just about goals, expectations. What’s going to happen during the week, maybe changing their medications to a tablet formulation, so there’s less carbohydrates. We often will do that. And so, there’s a fair bit that goes in before the ketogenic diet is started. And a lot of that does involve neurologists, it involves dieticians and really families just reading and getting information before jumping down the road of the ketogenic diet.

Is there potential harm be it cardiovascular risks, renal risks, hepatic risks of somebody on the ketogenic diet long term?

This is actually a topic that we’re really actively looking at. There are a lot of investigators trying to look into the long-term side effects. At least right now, the three major long term effects that have at least been reported are bone density changes and bone fractures can happen if you’re on ketogenic diets for over five to six years. This is true for a lot of our anticonvulsant drugs. And it may be, again, as many patients are on both more related to drugs. But we do certainly see that this can happen with ketogenic diet therapy. So, bone health is one. Growth is something that we do see as a problem in children who were on ketogenic diets for prolonged periods of time.

This may have more to do with again the bones than the actual diet components. But children who are on the ketogenic diet, sometimes their height velocity can be affected if they’re on it for many years. And then, the last one, at least so far appears to be kidney stones. And so, if you’re on the diet for long periods of time, we make sure that your kidneys are being monitored. We often will use a supplement called polycitra to help prevent kidney stones. And so, those are the three at least current in 2019 long term side effects that we’re aware of. But there’s a lot of research being done looking at cardiovascular health, carotid artery changes and looking at long term effects that we really just don’t know about. But not knowing doesn’t mean it’s not a potential risk or side effect. So, stay tuned. And I think we’ll have more research in this to come.

If there has been success on a medically managed ketogenic diet i.e. they’ve become seizure free on the die, has there been any research or does science suggest that a person could have a higher chance of experiencing seizures again?

There’s been a little research into how you wean the diet and what happens. And before I jump to that question I guess, most of the studies would say about 80% of the time, what happens on the diet will remain when you come off a diet. So, for example, if you’re seizure free, you stop the diet, and this is again in pediatrics. 80% of the time, your seizures will remain gone when you come off the diet. And if you’re 90% better and you wean the diet in odds, you’ll stay 90% better without it. But there certainly are children, it tends to be more in the short term as you wean the diet, their seizures can get worse and you go back on the diet.

There are some patients who maybe years later depending on the epilepsy they have may have a recurrence. We are certainly seeing in our adult epilepsy diet center some patients who were on the ketogenic diet when they were young children were taken off the diet, maybe tried a few more medications over their adolescence. Now, they’re adults and they go back on the diet in adulthood. It’s a small number of patients, but certainly, it happens in the diet. Again, it seems to be equally effective in adults as in children.

Are there ways to increase ketosis when you follow a diet that’s more based on meat?

So, there are several ways you could do that. Obviously, fasting calorie restriction is the classic way you induce ketosis. If you take the diet and it’s high in fats then the fatty acid oxidation will produce the ketone bodies. There’s a growing number of sources for ketone supplements that are currently available through the web. And the number of experimental studies looking at various formulations of ketone bodies such as ketone esters that have been shown in animal models to be effective. We don’t have any human data yet, but those are being planned. The ketone esters are interesting because they’re orally ingestible. They can be broken down by the body through enzymes that are resident in the gut as well as in the bloodstream, the so-called ester ACES.

And that what that does is it produces ketones to be elevated in your blood. There are also certain foods that have a higher tendency, perhaps to produce ketone bodies, the so-called MCT diet, for example, has been historically observed to maybe induce greater ketosis. But again, in terms of whether that’s a proven fact or not. I think Eric can certainly comment on that better than I can. So, I think ketones because of their pleiotropic mechanisms that have been described in the last five years, there’s a growing interest in trying to figure out a way of providing ketone supplements, enhancing ketosis without necessarily going to the traditional diets themselves.

It’s still early days. I would be cautious in the sense that not all available formulations are necessarily safe in large quantities and these things are constructed also with various salts and ways of making them ingestible. So, they may produce some degree of toxicity as well. And keep also in mind that the relative amount of ketosis is important. Mild to moderate degrees of ketosis that we see in clinical therapy with the diet is tolerated. Although, certainly diabetics who go into major ketoacidosis, something we don’t see in ketogenic diet treatments, high levels can actually induce health problems and in the extreme case, coma. So, dose does differentiate a remedy from a poison. So, as a famous pharmacologist from centuries ago would say.

Is there research into the effectiveness of the diet for those who experience nocturnal seizures versus those who experienced seizures during the day?

It hasn’t really been looked at in that manner before. We certainly see a lot of pediatric patients who have more seizures at night than during the day. And the diet seems to be effective for those types of epilepsies as well as those that have more during the day. It doesn’t seem to make much of a difference. We do sometimes target the way we provide the diet based on when the seizures are happening. So, in some children who have predominantly nocturnal seizures, we may give a higher ratio or an extra fat supplement at bedtime to try to get their ketones higher during the evening that can sometimes be successful. But to my knowledge, I don’t know if Jong knows. I don’t know anyone who’s looked specifically at treating those only with nocturnal seizures versus those with daytime or with maybe a combination. I think we just don’t know that yet.

It’s a very interesting question, certainly. The topic for more focused future clinical studies. What I can say from the basic science side is that it’s known that the epileptic brain has derangements in sleep wake cycling and rest activity cycling. So, there’s perturbations that occur and it’s not surprising that many forms of epilepsy actually manifest at night for example or during sleep wake transitions. When you actually feed epileptic mice or animals with the ketogenic diet, there are restoration of the sleep wake cycling and the rest activity cycling such that the prediction would be that would have perhaps efficacy, perhaps on those that tend to manifest mostly during sleep, for example. But we don’t have any real strong clinical data to show that, that’d be a subject for an interesting clinical study for sure.

Are there quantifiable EEG changes once somebody is on the diet?

Yeah, that’s actually somewhat controversial topic. There has been some evidence that supports that. That suggests that there can be changes in the EEG sometimes within a few weeks. There’s one study out of Texas that suggested that if there was a decrease in the amount of slowing, slowing someone suggesting a diffuse change to the brain, not necessarily an epilepti-form one. But if there were changes to slowing within that first month, they were much more likely to respond in terms of seizure reduction later on to the ketogenic diet. And there have been some studies that have looked at certain epilepsies where they follow the EEG and shown that yes, the EEG can improve just like the clinical seizures can improve.

On the other hand, there actually have been other papers that have really said there’s a big disconnect. The seizures may seem like they’re clinically improved but the EEG may actually not have changed very much. There’s one epilepsy called ESES or Epilepsy with Status Epilepticus and Sleep. Where really the goal of that treatment for that condition is to improve the nocturnal EEG. And the data is actually relatively mixed about how just affected the diet is and improving that EEG. Patients may be better but the EEG doesn’t always change very much. So, it’s a hot topic. There’s a lot of debate and discussion. When we see families and we talk to them about the ketogenic diet at our center, we really focus primarily on the clinical seizures. And actually, there’s some good data now about cognitive benefits out of the Netherlands. But usually, we don’t promise or guarantee for any patient that the EEG is necessarily going to change.

Based off the effectiveness of the ketogenic diet with certain medicines and things of that nature. Has there been research into the use of the ketogenic diet with AEDS? And also, does the ketogenic diet work when somebody is not on any AEDs?

It’s usually a partnership. We tell families that for most patients, and actually we have a recent study that suggests that it’s again, about 82%, 83% of our families still remain on medications, it might be fewer medications, but it’s usually not the ketogenic diet by itself. Although, that did happen in about 20% of patients who usually did very well. We were able to wean them off their medications. But we tell families for the most part, it is a partnership. There is no one drug that is negatively interacted per se by the ketogenic diet.

We know that certain drugs you have to be a little bit more cautious for side effects. So, topiramates, zonisamide, you have a slightly higher chance of acidosis. Valproic, you may see a higher chance of carnitine deficiency. You might see reduced ketosis if you’re on valproic. But these drugs are not contra indicated so to speak, it’s not a situation where they have to stop those medications. And on the other hand, we also don’t have any evidence that any one drug seems to be really effective with the ketogenic diet.

There are lots of drugs often tried. But we don’t have any one drug in particular, that seems to be particularly beneficial. If anything, we have some older data that the Vagus nerve stimulator may in combination with the ketogenic diet be potentially synergistic, but that’s obviously not a medication. So, I think as more patients are put on different therapies, we can look for those beneficial synergistic effects. But at least right now, we tell families that any drug is fine, no drug is perfect with the diet, and we’ll just do it case by case.

Is there a range that’s recommended for ketosis in terms of blood meters?

I think much like when we use anti-seizure drugs and we do blood levels of the drugs, we have a rough idea based on clinical experience where patients should be or could be, but these are guides. There are no absolute numbers and everyone’s response is going to be a little bit different. In fact, the same level in two different patients, one may tolerate very well, the other one may get very sleepy or tired. So, I think the levels themselves are really a guide. We tell families that the ketone levels are like a drug level and every child is different. Some children only need to have relatively low ketone levels and the low glycemic index, which is one of our dietary therapies.

You have extremely low ketone levels and actually in the urine, they’re undetectable, yet these children do very well. And so, I think, especially when we hear the mechanistic potential options for why the diet works as Dr. Rho presented, there’s so many mechanisms at work that ketones may just be part of it. And it may suggest the body has made this metabolic change but it may not really be the true aspect of why the diet’s effective. So, I think every child is different. We try to keep a calendar of what their ketone levels are, and in a sense for where maybe, okay, the ketone levels seem to correlate with seizure control and try to achieve that for every child individually.

For somebody who is considering the ketogenic diet or is maybe new to the ketogenic diet, what resources are available to those patients and to those families?

One major website that I would recommend is the Charlie foundation for ketogenic therapies website. So, https://charliefoundation.org. All one word, charliefoundation. It’s a good place to start. They’ve been around for a long, long time. And the fact the Charlie Foundation was founded in the mid-1990s. And it was really seminal in catalyzing both clinical interest in research in the ketogenic diet. And we’ve actually looked at this in a research way and really families find out about the ketogenic diet from the internet nowadays is not all from books and magazines and other resources. It really is the internet. So, I always recommend the Charlie Foundation webpage.

There’s another organization in England called Matthews Friends. It’s site, S-I-T-E, .matthewsfriends.org. That like the Charlie Foundation is a parent support with great resources and articles that patients can download. I also have helped the Epilepsy Foundation through their webpage, which is epilepsy.com. Good information about ketogenic diet along with all the other therapies as well. But those are probably my top three.

The CURE Leaders in Epilepsy Webinar Series has covered many topics related to epilepsy and innovations in research. Check out our full list of available webinars here.

The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified health care professionals who are familiar with individual medical conditions and needs. CURE strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified health care professionals who are familiar with the individual’s specific health situation.

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Epilepsy Devices & Technology

Devices and technologies can help patients and caregivers track seizures, and send an alert to caregivers when a seizure happens. These tools also help track medications and potential seizure-triggers.

This webinar features Dr. Robert Fisher, who discusses the newest devices and technologies are in development. Dr. Fisher is the Maslah Saul MD Professor and Director of the Stanford Epilepsy Center and EEG lab. He has published over 200 peer-reviewed articles and three books, and he has received numerous awards for his work nationally and internationally. In addition, he is a past president of the American Epilepsy Society.

His recent research is on new devices to detect and treat seizures. Dr. Fisher has won many teaching awards and also has an active clinical practice at the Stanford Epilepsy Clinic.

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Audience Q&A with Dr. Robert Fisher

Do all devices have to undergo FDA approval? Why does the process seem to be much longer in the US than in other nations?

The FDA classifies devices as type I, II, or III. Type I, like a tongue depressor or a bedpan, do not have to go through approval processes. Type II are items with some risk. Type III is high risk. An implanted brain device would be in the type III category, and therefore require pretty extensive evidence of safety and efficacy in medical trials. It probably does take the FDA longer to approve drugs and devices than it takes agencies in other countries. I can’t speak really for the FDA, I can only say that they require a device to be safe, effective, and have a clinically meaningful benefit. I think all of the devices that I spoke about today have potential, but I can’t promise that all of them will be approved. I can never really speak from the FDA’s timeline.

Are there any studies going on to determine if wearable devices will ever be able to predict non-convulsive seizures?

I think wearable devices will be able to predict non-convulsive seizures. We’re looking for good ideas and good strategies on that, and we can take advantage of tailoring an intelligent device to a person’s particular seizure type. Let’s imagine, for example, that someone has a complex partial seizures (and I apologize for the name change. The seizure name just changed this year, so that’s also a focal impaired awareness seizure) and the person might always say, “Help me, help me, help me,” or some other stock phrase at the start of a seizure. We could tailor a device to recognize that behavior at the start of the seizure.

Prediction is a little bit harder. That mostly seems to be based on EEG, though some studies say measuring brain blood flow can be used for prediction. We’re still looking for a way to have wearable, non-invasive predictive devices. I think we can probably do it with invasive and maybe we can do in non-invasive.

Are there any statistics on how predictive wearable devices have the potential to be or is that information really not available yet?

By wearable devices, we’re currently talking about shake detector watches or the shake detector Brain Sentinel EMG. Sentinel device had pretty good sensitivity for picking up seizures. The watches usually have pretty good sensitivity, meaning they pick up the shaking, but they also pick up a large number of non-seizure events, for example, brushing your teeth. Devices therefore need a cancel button, so that a false alarm can be prevented. If you use the cancel function, then both the sensitivity and the specificity of these devices in small studies can be above 75, 80%. Now, large studies like the EpiWatch Apple study will give us the more definitive answer to the question you asked.

Promising Anti-Epileptic Drugs in Development

This free webinar outlines therapies in development for epilepsy and seizures, including promising therapies for patients with treatment-resistant epilepsy and children with severe epilepsy. The webinar also focuses on drugs that may not only reduce seizures, but improve treatment of the underlying disease.

The webinar is presented by Dr. Jacqueline French, a professor of Neurology in the Comprehensive Epilepsy Center at NYU Langone School of Medicine and Founder/Director of the Epilepsy Study Consortium. Dr. French’s presentation was followed by an interactive Q&A session.

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Audience Q&A with Dr. Jacqueline French

You mentioned schedule 1 and schedule 2. Can you explain these different stages a little bit further?

There are drugs that are considered to be controlled substances, which means that people can become dependent or get addicted to them. The more likelihood that there is that people will get addicted to them, the higher the level of control that the government puts on the distribution of those drugs. We all think of drugs like heroin and morphine. Heroin, in fact, is the most controlled of drugs because it is so addictive and also because it has no medicinal use. The drugs that are in the schedule 1 are considered to be highly addictive and have no medicinal use whatsoever. People are surprised to know cocaine, for example, is not schedule 1 because there is a use of cocaine for some eye diseases, so it’s actually scheduled 2.

It’s extremely difficult to even do research on schedule 1 compounds because they are so highly regulated by the government and very difficult, obviously, you can’t prescribe them because they have no medicinal use. Once a drug is known to have a medicinal use and it becomes schedule 2, then it is much more easier to move that product around to have it in pharmacies without like 10,000 locks on every door where this substance is being held and it just makes things much, much easier. Then you go down the line. For example, many of our epilepsy drugs are on the schedule of potentially addictive drugs.

You’d be surprised, drugs that perhaps people who take them would say, “I can’t imagine anybody would use these if they didn’t have to.” There is some evidence that in fact people do try and get them for recreational use and not for medicinal use and that includes drugs such as Pregabalin or Lyrica drugs such as a Vimpat or Lacosamide. Yes, those are restricted to some degree, but they’re only scheduled 4, so they’re lightly restricted. As you go up to schedule 3, schedule 2 and schedule 1, you get more and more and more restriction.

A drug such as Epidiolex and Fenfluramine and drugs that are being developed for Dravet Syndrome for instance, will they be available to others with similar seizures, but may not have the Dravet or that clinical diagnosis?

In the United States specifically, the FDA doesn’t put restrictions on doctors to say, “You can only prescribe a drug for what it has been FDA approved for and is on the FDA label.” The studies that are done and the diseases that are studied in the trials, will lead to a label that says, “This has been shown to be safe and effective in condition A, B, or C.” I could prescribed that drug for condition, D, E and F, but there are a couple of issues that I would have to have in mind as a physician.

Number one is that, there is a certain amount of liability because I am going what’s called off-label. My patient that I’m treating might say, “I came to some harm from what you did and really you weren’t doing the proper thing because the FDA didn’t say it was approved for this particular indication.” You were taking on some risk when you prescribed off-label, although many, many, many people do it. It’s done all the time.

The second thing is that, your insurance company might say, “Hey, this is a reasonably expensive drug and nobody has said that for your condition it’s effective, so why are we going to pay for it?” One or two things can happen. It may be that your doctor can then appeal to the insurance company and provide extra information and the insurance company can eventually agree to pay for it or they may just completely not agree under any circumstances. We have had that issue arise with one of our other drugs that is only approved for what we call an orphan condition and that is a Clobazam or Onfi. It’s a reasonably expensive drug and it’s only approved for Lennox-Gastaut Syndrome and sometimes I can get it for my patients and sometimes the insurance company will just completely stonewall and say, “No, you can’t have it.”

Do you know what the mechanism of action in the Cenobamate trial that you referenced earlier is?

Cenobamate, we do not specifically know the mechanism of action. However, it is in the class of drugs called carbamate. There was one other drug that was approved for epilepsy that’s in that class and that is Felbamate. We do not know its mechanism. We know that it is somewhat related. It’s a second cousin or a third cousin of Felbamate. Felbamate was a very effective drug for many people with epilepsy, but as a many of the audience may know, it is used very rarely now because it caused serious liver problems and a plastic anemia which has not been seen with this drug. If it was as efficacious as Felbamate, that would be a good thing and perhaps in some conditions it’s more and the rest remains to be seen.

Do we know whether there are targeted treatments for those epilepsies in development?

The first answer is yes. On the slide that I showed, there were a couple of genetic conditions that there are targeted treatments. Excuse me. Glut-1 deficiency is a great example where these are children who have a genetic defect that prevents their brains from turning glucose into energy. They have an energy defect in the brain and over time, that leads to seizures as well as an increase in cognitive dysfunction. There is a targeted therapy of a drug that can be used by the brain to produce energy that’s not glucose and therefore could reverse the specific problem in these children. That is one example of a treatment that is specifically targeting one genetic condition.

There is a drug called Ganaxolone that is being tried specifically in children with CDKL-5, which is another specific genetic defect. It doesn’t reverse the specific issue in CDKL-5, but there are reasons to believe it might be effective in CDKL-5. There are a number of drugs that are specifically targeting genetic defects. I think that what you may also be asking is, are we trying to reverse the genetic defect that caused the epilepsy to begin with, as was the case with the tuberous sclerosis and Everolimus? There are some attempts at that. They’re a little bit further away probably from the clinic, but, for example, there’s a drug called Endololin being tested in children with genetic code problems where there’s a certain part of the gene that’s supposed to create a protein that is very important for the development or the running of the brain. When that gene is being read, it comes upon a mutation and that whole mechanisms stops. It’s called the stop codon and that protein can’t be created.

This drug actually allows the information in the gene to be read even when that mutation is in the middle of it and that protein to be created. That would be really amazing if that works and it might actually be able to prevent the disease if it was given early enough to a child who had that genetic defect. These are the almost science fiction things that are turning into reality in clinical trials.

When you said the period of follow up is eight weeks or 12 weeks, are they on drug during those eight to 12 weeks or do they stop taking drugs and see what happens in the next eight to 12 weeks?

The way trials work is, usually, they start with what’s called the baseline period, which is just a period where we can figure out what the frequency, the typical frequency of seizures is. Let’s say an individual has four seizures a month or five seizures a month or 10 seizures a month, whatever that number is, it’s determined during an eight-week baseline. Then at the end of that baseline, they get randomized and they continue on there. During the baseline and during the study, they’re continuing to take whatever medication their physician has given them, a combination of medications that is the best control that they can get.

At that point they’re randomized to either adding the new drug or adding a sugar pill. Then for eight to 12 weeks they carry on and they see whether the seizure frequency that was determined during the baseline, is actually going to go down or go up or whatever happens. That goes on for eight to 12 weeks. Then at the end of that the randomized portion of the trial is over and they go into what’s called the open-label extension. During that time, everybody can be on the medication. The doctor knows the dosage, they know that the medication is being administered, they can manipulate it, they can change the background medications or whatever is considered to be optimal for that individual. During the double-blind they may or may not be taking the study medication, but once they get to the open-label extension, everybody is given the study medication on top of the medication that they’re already taking.

Are these drugs safe to take while a woman is pregnant?

Pregnancy, we always advise that drugs that are in clinical trials, women should not go into clinical trials if they are planning pregnancy and in fact we have significant safeguards in place. People have to sign a consent that says that during the trial, they will use appropriate birth control, so that they will not get pregnant and we make sure that they or receiving a birth control that’s likely to be effective, so that they will not get pregnant because this is not the time when you want to be experimenting to see whether this medication will adversely affect the fetus. Because, first, you want to make sure that the drug actually works, is safe and effective. Once the drug is safe and effective and is approved and is then available to the public, then over time some women will take it and will become pregnant. Only then, can we really know entirely whether the drug is safe during pregnancy.

We have many pregnancy registries that accumulate data on the drugs once they are in the clinic, but it is unfortunately a very slow process. It may take decades before there are enough women in the registries that we have really good information about whether the drug is safe in pregnancy or not. Even some of the drugs that have been around for a really long time and Lacosamide is one good example, we don’t have enough information really to say for an absolute assuredness that it is safe in pregnancy. We do have information as immediately when the drug is approved, as to whether it’s caused birth defects in animals. The label that’s put on the drug by the FDA, will say either the drug has been shown to be safe in animals, but we don’t know about humans or the drug has been shown not to be safe in animals, but we don’t know about humans or the drug has been shown to be harmful in animals and harmful in humans, so that it gives them an A, B, C or D rating.

The higher the letter, the worse it is. A class D drug would be one where it’s been shown and this is, Valproic Acid or Depakote is in this class that is both harmful in animals and also has been shown to be harmful in people during pregnancy. The A designation is almost never given where we say, “Oh we absolutely know it’s as safe as houses and anybody can take it and it’s perfectly fine. Most seizure medications are either B or C.

Where do we get more information on clinical trials?

The Epilepsy Foundation actually has a lot of information on epilepsy.com. If people want to know whether there is a trial that they could sign up for then that is an excellent place to look, there is a section of epilepsy.com where the trials that are underway describe a little bit of information about what we know about the drug and what the trial would be like if you were to enroll in it. That’s one good thing that’s on epilepsy.com and there’s also a part of epilepsy.com where there is a pipeline. You can see all of the drugs that are currently in development and what stage of development they’re in, whether they’re in early development or they’re close to the clinic.

Webinar: Cannabidiol and Epilepsy: The Real Risks and Benefits

Recently there has been a great deal of focus on the uses and risks of marijuana in the field of epilepsy. Epidiolex, a  cannabidiol (CBD) treatment for epilepsy, gained FDA approval for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, two rare and severe forms of epilepsy. This is the first FDA-approved plant based treatment with greater than 98% CBD.

In this webinar, learn why CBD may be an effective treatment for certain types of epilepsy, what risks can be associated with CBD, and what the FDA approval of means for the future of epilepsy research and treatment.

This webinar is presented by Dr. Anup D. Patel, Section Chief of Pediatric Neurology at Nationwide Children’s and Associate Professor of Clinical Pediatrics and Neurology at The Ohio State University College of Medicine.

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Plus, get additional research insights from CURE Chief Scientific Officer Dr. Laura Lubbers in this episode of our Seizing Life podcast.

Audience Q&A with Dr. Patel

Dr. Anup PatelHow does Epidiolex differ from the medical marijuana patients can get from dispensaries in some states?

I think the biggest difference is that the Epidiolex product must contain 98% or more CBD and very little anything else. The products you can get from dispensaries do not have that same requirements, so they may not have as much CBD. In addition, they may contain other compounds from the plant or the other chemicals I mentioned during my presentation. It cannot have any chemicals that aren’t listed, any bacterial contamination, or a higher percentage of THC. All of this is not the case with the non FDA-approved products.

There are similarities, though: CBD is CBD. If these products contain a high level of CBD, it is the same CBD that is in the Epidiolex product. CBD is a chemical structure. There is a synthetic version of CBD being concurrently studied. It is going to be a laboratory-made CBD based on the same chemical structure. That product will be 100% CBD and will not have anything else in it, but it is not plant-based.

If you’re taking a THC/CBD product purchased through a dispensary, is there a test to find out the ingredient accuracy of the product?

Yes, there are some labs, depending on your location. There are labs now that will test your products. The key thing is to find a certified lab, so that you can be sure of the integrity of the laboratory testing process.

The danger is you would have to test every bottle you get, because the content of CBD, THC, and other chemical compounds will change from bottle to bottle and month to month. To do testing well, you must test all your products every time you get a new bottle, which is really difficult and not cost effective.

Can you speak to the integrity and consistency of the Charlotte’s Web product?

There have not been a lot of good studies to show that. The company does claim to test the product and check this on a regular basis. That being said, to my knowledge this testing is done locally and not through an outside, unbiased service. Therefore it’s hard to make good, accurate information about it.

I do hope they will use what has happened with the Greenwich product Epidiolex as an example and follow the same processes to hopefully get their product potentially FDA approved. But to do that, their product will have undergo the same tests and studies that the Epidiolex product did. But I’m hopeful that this will help spur on some of that work, either through this or some similar type of group.

How can patients who have similar phenotypes to Dravet syndrome and LGS, but don’t have a specific diagnosis, access Epidiolex? If they cannot, will there be a way to in the future?

I think that’s my most important question. I’m glad somebody asked us. The reason is that we anticipated this product or medication could be of benefit outside the actual FDA label of Dravet and Lennox-Gastaut. To get ahead of that, we published a lot of the related data through our expanded access program.

Normally when a medication is FDA-approved, it’s used on label and then neurologist, pediatric epileptologist, or adult epileptologist will use it “off label”, because they just want to help patients, and not everything is known from studies. The process will lead to publications being submitted to insurance companies that they’ll then use to potentially reimburse the medication off label. In this case, we’re hopeful. I cannot guarantee it, but we’re more hopeful because actually the way this story got told was we got the off label studies published that led to the on-label studies.

We’re sitting on mountains of publications that I really encourage medical providers to submit to try to get this medication authorized by insurance companies. Unfortunately there’s no guarantee, as it really will depend on your specific insurance company. But please know that these manuscripts are out there and can be submitted to change their decisions if they choose not to authorize this and pay for it. We don’t want patients having to be burdened by medical bills. This is one way we can get ahead of that and have their medical insurances pay for it.

The company has promised to run and have run patient assistance programs, so also look towards them to help. I don’t have any details. I don’t work with them on that, so I don’t know what they’re offering, but they have told me that they’re going to have these patient assistance programs. So please, if you’re going to get this medication or prescription, get your insurance to pay for it the best way you can and use the resources that are available to try to get it compensated and paid for.

Was there an interaction with those on Onfi and Valproate who were part of the extension studies? Were the interactions in the co-treatment or were the children allowed to be in the trial while on these medications?

In the trials, we saw the same thing we saw during the Expanded Access Program trials; in some cases there was an interaction – not necessarily with clobazam, but with broken down clobazam – causing kids to be tired. I will tell you in a lot of cases the answer was not to get rid of the Epidiolex or CBD product, it was to actually lower the clobazam dosing. It’s important to work with your medical provider to either lower one or both of the products. In many cases, excessive tiredness did go away.

There is a risk for increased liver enzymes with Epidiolex or CBD products in general, even if you’re not on valproic acid or Depakote. The risk was more commonly seen in patients who were on both  CBD and Valproate during the randomized double blind placebo controlled trials. In those cases, every single one of those patients had their liver enzymes returned back to normal by doing one of three things; getting rid of the Epidiolex, getting rid of the Valproate, or lowering either medications. In those three scenarios everybody, returned back to normal. But it is going to be recommended that a patient get baseline liver enzymes before going on Epidiolex. There will also be recommendations to be monitored while you’re on this medication, because we’re not able to predict if you’re going to have this interaction or not.

While we need more data to confirm this, we do feel there may be a good pattern in kids and adults who are on both Epidiolex and clobazam, meaning that perhaps those two medicines work better in combination than either of them separately. But again more information needs to be studied with that.

The CURE Leaders in Epilepsy Webinar Series has covered many topics related to epilepsy and innovations in research. Check out our full list of available webinars here.

The information contained herein is provided for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information as a substitute for consultations with qualified health care professionals who are familiar with individual medical conditions and needs. CURE strongly recommends that care and treatment decisions related to epilepsy and any other medical condition be made in consultation with a patient’s physician or other qualified health care professionals who are familiar with the individual’s specific health situation.