Are 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.

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.

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.

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.