Transitioning from Pediatric to Adult Epilepsy Care

Transitioning from pediatric to adult care is a major milestone for individuals with epilepsy and their families. Unfortunately, this process can be delayed due to the multitude of health and comorbid conditions which can accompany epilepsy, as well as the personal bond between the family and their pediatric care team.

This webinar discusses how epilepsy patients, their families, and pediatric neurologists can develop a plan to prepare for the transition of care. The presenter, Dr. Joseph Sirven, explores what factors to consider when transitioning care, established research guidelines for transitioning care, and the resources available to assist everyone involved.

This webinar is conducted by Dr. Joseph Sirven, Professor of Neurology and Chair Emeritus in the Department of Neurology and Director of the Epilepsy Program at the Mayo Clinic’s Arizona Campus. Dr. Sirven serves as editor-in-chief at www.epilepsy.com.

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Audience Q&A with Dr. Joseph Sirven

If you have a neurology team that really hasn’t been following this plan, then how do you actually communicate this as a need as the parent?

This is considered a vital aspect of the care of a child with epilepsy or with any neurological condition. And so, it’s important to know that this is what Dr. Sirven and CURE Epilepsy and other teams are putting together. Hey, what a cool concept. This is actually considered a guideline of standard of care. And so, if you’re not having this discussion, I would say you’ve got to bring this up. You’ve got to ask, say, “Can we have a formal transition type of meeting?” Now to a pediatrician, they’re probably going to get that and they’ll understand.

But maybe you’re not seeing a pediatric neurologist. Maybe you’re seeing an adult neurologist already because that’s who’s in the community, or you’re seeing your family care. This is to be brought to them. That’s why I gave you some of those resources. Some of those are actually handouts you can print out, especially at the transition site, that you can actually even bring to your physicians with questions so you can begin answering these.

So as I mentioned earlier, a lot of this has to do with self-advocating and also planning. Like any good parent, ask the questions. If they’re not coming to you with this, know that by the age of 13, this should begin to be brought up and bring this up, because even for busy clinicians, they will stop, they care, they want to help. They just needed to be reminded sometimes, because you’re so busy and focused on the acute issue that you forget that there’s a future big picture that we need to address. Sometimes asking for a time appointment for that is going to be the way that you get there.

Are there already insurance issues or even possible legal ramifications, if people wish to stay with actually their pediatric clinicians if they’re very comfortable with them?

Yeah. There’s no insurance ramification per se. The pediatricians will be covered under the same plans as an adult neurologist. I’ve not seen in my career a situation where I have seen lack of payment or not paying because an adult is with a pediatric neurologist. It doesn’t work that way. It certainly doesn’t work that way in the current laws. Having said that, there are some pragmatic issues, and I’m delighted for the person who has that pediatric neurologist. But the fact of the matter is if there is a huge shortage of pediatric neurologists, and then if you expand that out, there’s an even bigger shortage of pediatric epilepsy neurologist out in the United States.

And so, oftentimes you may see that it’s not that the pediatrician wants to let go of you or anything along those lines. Most pediatricians, they love taking care of their patients. It’s just that, at some point, because the lines are so long and there are so few of us, so few of those physicians out there, that the transition may come up to you. Now maybe you’re in a community that that’s who you’re going to see because that’s all you have, but know that that’s the reality. Insurance sticks its neck in many things, but, fortunately, has not stuck its head in this equation just yet.

What do you suggest if your pediatric team has not yet identified, an adult neurologist and does insurance play a role in choosing those physicians?

First of all, you ask the pediatric team to help choose who are my choices out there. You don’t have to ask them for a specific person, even though you’re going to get one, but can you give me a list of names that you think may be good for my transition? Now insurance, they indirectly play a role here. One of the things that is occurring in modern healthcare now is fairly large networks of doctors. If you think about it, most of us get insurance through our employers, and employers, they get their insurance coverage through a network. So you work for a company, the company has networks.

Well, the network may say, “These are the people in my plan.” So you may be on the kid plan, the pediatric plan, these are the doctors on it. But then for adults, the plan is whatever they spelled out that they’re going to cover as being within network. So I guess, indirectly, how your insurance is structured, how tight do you have to go with the network. If you have a PPO insurance, that means you get to choose fairly broadly. If you’re in a health maintenance organization or a version of that type of organization, you may not have a broad choice as that, and that may impact how much out-of-pocket you have to put out for continued care in the hospital. So the network, the insurance plan may not do it, but the network may. I hope that I picked out that nuance for the listener out there.

To what extent are records transferred over to you providers? Do they have to handle this or does their pediatric neurologist take care of this?

That should be a simple answer, and it’s not going to be. So I’m going to try and talk it through at the end.

Medical records are technically owned by the patient, but housed by the physician, hospital, and all those folks. They can only travel to a new doctor with the permission of the patient. So the patient has to give permission. Patient or parent, whoever is in charge, have to give permission for those records to travel from doctor A to doctor B, from pediatrician to adult. So that has to be instituted from there.

In some cases, it’s really easy. For instance, where I work, I’m on a large electronic medical record known as Epic. One of the benefits of Epic is the fact that anyone who’s on Epic, by clicking a button with the patient, the records will automatically open up from one institution to a completely different institution if they’re both on. Now if you’re not on Epic, then physical records have to be sent, either paper or electronically, to the doctor in some way. But the permission, regardless if it’s electronic or paper, is the same. It has to come from the patient. The patient technically owns those records.

Is a legal power of attorney required for joining her adult child who’s over the age of 18 at her doctor’s appointments?

Well, the fact of the matter is that at the age of consent or the age of majority, which is defined state-by-state. 18 is the typical one for most states in the United States. I can’t think of one that isn’t, so I’ll just say age 18. They’re legally adults unless there’s a power of attorney that says that someone else is there. Now to your listener’s question, if they don’t have a power of attorney and the child or your child, even though as a parent, they’re always your children, but your child can say they don’t want you there and the healthcare group has to honor that.

So to your listener, yes, legally, if they’re 18 and the child has consent regardless and there’s no power of attorney, it’s up to the child to say whether they want them there or not. That’s legally. I mean it doesn’t have to be ugly or anything along those lines, but, yes, that is true from a legal perspective.

Are there different steps involved when transitioning a child who might be diagnosed with both epilepsy and autism spectrum disorder?

I get a lot of kids or young adults that have both. In fact, as an adult epileptologist, autism comes into the exam room, the clinic office very frequently together. What the transition is in that situation is that you spelled out not just what you’re doing for the epilepsy, but what’s the plan for the autism, because we focus so much on the epilepsy that sometimes the autism piece gets almost placed on the side, and yet that may be the bigger issue and the epilepsy’s not such a huge one.

So the short answer to the question is that those have to both be laid out. What do we do when there’s issues with behavior? What do we do when there’s issues with regards to management? That has to be spelled out because oftentimes they get conflated in the exam room, in the office, and they’re not. It’s just laying out what’s my course of action for each of these. That’s important because the management are very different, and understanding where the medications may play a role, what’s been tried, what’s worked, laying those things out can be a godsend in that reaction.

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.

Webinar: Epilepsy, Pregnancy, and Contraception

Pregnancy and contraception can be a difficult subject for women with epilepsy to discuss with their doctors, however it is critical for reproductive health.

Women with epilepsy must face certain considerations when starting a family. This webinar focuses on the research surrounding epilepsy and pregnancy, as well as provides strategies to help minimize risks for both mother and baby.

This webinar is conducted by Dr. Elizabeth Gerard, Associate Professor of Neurology with a specialty in epilepsy at Northwestern University. Her clinical focus is contraceptive and pre-conception counseling as well as the management of epilepsy during pregnancy.

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Plus, hear how one mom navigated epilepsy and pregnancy safely in this episode of the Seizing Life podcast.

Audience Q&A with Dr. Elizabeth Gerard

Are there a lot of known genes, like filamin-A where you have a 50% chance of actually passing on that particular mutation to your child?

Yeah, there are. There are a growing number of genes where we know that they can be passed on what’s called an autosomal dominant form. So the one that I showed was an X linked form, but there is a growing number of autosomal dominant genes that can be passed on. One of the ones was actually a CURE Epilepsy email today about the SCN1A gene. That’s a very complicated gene because you have a 50% of chance of passing it on, but the symptoms in somebody who inherits it can vary. So somebody who can inherit it could be very normal with just febrile seizures, and another person who inherits it could have a more severe epileptic encephalopathy known as dravet syndrome.

So that’s an example of an autosomal dominant gene, where you have a 50% chance of passing it on, and it’s also an example of what makes it very difficult to do genetic counseling and genetic testing pre-pregnancy. There are growing number, still small, but a growing number of genes that are autosomal dominant, and I typically look in an adult population that can be passed on. So one of the ones is the LGI1 gene, which is associated with focal temporal lobe epilepsy with auditory features. So a lot of patients will hear symptoms before their seizures. It’s traditionally a pretty mild syndrome. Then there are the gator complex genes.

So DEPDC5, NPL3, NPL2. These are just some examples and I don’t have a specific number for you at this time of the number of autosomal dominant genes, but it’s growing. And so that’s an important thing to look at. Signs that you might have an autosomal dominant gene in your family, although it could always start with the individual who has epilepsy, but signs that it might be in your family are if you have several close relatives, usually first degree relatives in your family. And that would be one of the things that would, if patients see me elevate my recommendation to consider genetic testing.

if you’re no longer looking to become pregnant, what are the reasons to stay on folic acid?

We traditionally recommend to all of our women who might get pregnant to be on some folic acid. Again, how much varies for patients who are still of reproductive age, before menopause, I usually have my patients on one milligram, although if they’re not really planning pregnancy, we can usually go down to the lower amount that’s in a women’s multivitamin or prenatal vitamin. Some people feel it’s good for hair and nails and stuff like that, but there’s not really any strong evidence to treat the epilepsy or other symptoms that a woman needs to continue on folic acid, other than planning pregnancy. We just traditionally continue it. We don’t usually continue it after menopause.

What are some strategies for women with epilepsy during labor or are C-sections more recommended/common?

We actually do not recommend C-sections for women with epilepsy. There isn’t any indication that just because of having a seizure disorder or having epilepsy that you need a C-section in our MONEAD trial, they’re looking at this data, but they’re very few in academic centers who know this information. It’s very rare to have C-sections done for purposes of epilepsy. So we don’t consider it a risk for C-sections. There have been studies that have shown in our country and other countries that C-sections are more commonly done for patients with epilepsy, but we suspect that this is more of just providers thinking that they need to do that rather than any kind of clear indication that needs to be done.

This question deals with a model that this woman follows called the Creighton Model. And she wanted to know if there are studies being done on this methodology and it’s use as a better understanding of women in epilepsy?

I don’t know the Creighton method per se, but I can speak to the issue of what’s known as catamenial epilepsy if that’s the question, but I’m not sure about the Creighton Model. It’s long been known that epilepsy can respond to hormonal fluctuations. So I had a few slides on that, but about 30% of women with epilepsy will find that in some way, their seizure frequency syncs up with their cycles. Usually in my experience, not exclusively that, but if you have more seizures during certain periods of the month, often it’s a few days before the period leading into the few days afterwards. I may actually show something.

So there’s a couple of different periods that people seem to be vulnerable to seizures. Again, 30% of women and those tend to be about ovulation or towards the end of the cycle. These patterns have been designed by Dr. Herzog. And so yes, for many of my patients, there’s different ways. This is an ovulation tracker that you can follow your period. This is actually a way we used to do in our clinic where we followed temperatures. And your temperature goes up when you ovulate and through the end of the cycle. So you can see for this patient, this is her temperatures. This is likely where she ovulated, and this is where her periods started and she had more seizures. This is the period here. She had more seizures, both around the time of ovulation and then leading up to her period.

Treatment for hormonally sensitive epilepsy. I’m not a believer that hormones cause the epilepsy, but that it’s one of many triggers that can trigger people’s epilepsy, just like sleep deprivation or alcohol or stuff like that. And so recognizing these kinds of patterns, I’m not sure of the Creighton method, but any other method can be very useful for women first just to identify the vulnerable periods of the month, and then there’s other strategies that are usually add-on strategies to try to control catamenial seizures. So this is my patient’s seizures here. I like to stress that I don’t think that hormonal treatments or approaches to hormonal modifications typically replace standard epilepsy treatments.

We still do first line treatments, anti-seizure medication, surgery if appropriate, but sometimes there are hormonal treatments that are given in addition to standard therapies. The evidence for this though is very limited. And then the other thing you can do though, and that I often do is that if you can recognize the pattern, which may be the participant was asking about, you can often give time to extra medications at the vulnerable periods of the cycle, and that can be very useful as well.

For women with epilepsy, what resources are available that can help them really track their seizures and track their menstrual cycles?

So seizuretracker.com, I know that they have been developing… it’s a great way to track your seizures and you can share with your doctor. There’s also the ability to put in your periods as well. Many of my younger patients just find that period tracker apps, there’s a ton of them available. They just do that and you can put symptoms in there as well. But seizure tracker is nice if you are in a computer. I know they were working on it, I don’t know if you can yet actually put the information in on your phone. That’s the only limitation for your periods, but they were working on developing that and right now on a computer, at least you can put in your periods as well as your seizures, and you can print out that information and provide it to your doctor.

Why is PCOS more common in women with epilepsy?

It’s not completely known. There’s some interesting research on that, but one of the reasons that we feel is actually early exposure to valproic acid or Depakote. So women who are exposed to valproic acid or Depakote in their teens are much higher risk of having a polycystic ovary syndrome, but there’s some other research in animals that there may be something to the epilepsy itself and to the frequency of seizures that may predispose to polycystic ovary syndrome, not just the valproic acid explanation and some of it is may be because seizures, particularly temporal lobe seizures involve the temporal which is right near, it gives feedback to the hypothalamus and pituitary, which then regulate ovulation. And so there are some theories about that, but there may be a direct effect on hormonal function that may lead to it. But those are the two main theories. One is valproic acid and then the other is this regulation of cycles.

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.

Webinar: Separating Stigma from Truth: Epilepsy Research and Resources

Have you ever been afraid to talk about your epilepsy to friends and coworkers for fear of repercussions? Epilepsy stigma is prolific and can affect all aspects of a person’s life. Approximately 50% of people in the US and Europe report feeling stigmatized because of their epilepsy diagnosis, according to recent studies.

Discover research findings about the public attitudes and beliefs about epilepsy, as well as how likely people with epilepsy are to encounter stigma due to negative public attitudes. We review how these harmful stereotypes affect quality of life, and explore what recent evidence suggests communities can do to improve public attitudes and reduce epilepsy stigma.

Let’s end these epilepsy stereotypes and shine a light on the truth.

This webinar is presented by Dr. Ann Jacoby, Professor Emerita in the Department of Public Health and Policy at the University of Liverpool, UK.

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Audience Q&A with Dr. Jacoby on Epilepsy Stigma

How can individuals overcome epilepsy stigma related to employment, the workplace, and co-workers? Are there strategies people can use?

The Epilepsy Action group is asked quite often on how to position telling your employer about your epilepsy. “If I’m going to be interviewed for a job, do I tell the potential employer that I have epilepsy?” The position people tend to take is not to disclose having epilepsy immediately. Sometimes you will be asked a question on an application form and you may have to then say something, but the epilepsy should not be the foremost thing. The question is, do you have the qualities and qualifications you need to do the job? We perhaps need to be more active by going to employers and presenting ourselves to them in a robust way as a person who has the skills that are needed.

Now, in the UK (and I suspect it’s the same in the US under the Americans with Disabilities Act) employers do have to make certain provisions for people who have long-term health conditions. When my team did the survey asking members of the general public in the UK about their attitudes and knowledge of epilepsy, we also did one with employers. We found that employers were a strange mixture of willingness to adapt and still holding negative attitudes. But they were willing to consider things like letting people do shorter days, letting them come in later in the morning if they needed to or leaving earlier, and so on.

Overall, employers surveyed were willing to consider adapting the work environment to fit the needs of people with epilepsy. I think that’s a really helpful thing to know and perhaps we need to just have that conversation with employers much more than we have so far to move their thinking along.

Are people with epilepsy who need to take time off for doctor’s appointments covered under the Americans with Disabilities Act?

I’m not familiar enough with the Americans with Disabilities Act to know whether these individuals are protected to go to doctor’s appointments. I would say that anyone who has an illness of any sort may need to see a doctor from time to time for a regular checkup or for treatment adjustments and so on. I think that employers would recognize that sometimes people have to take time off and that applies to anybody. To me, to you, to anyone.

I think we need to be firm about our rights as employees, but we also can turn to acts like the UK and the US Act and look at how those acts protect us in difficult situations where employers are being unreasonable.

How do we really change people’s attitudes in regards to cognitive ability?

Again, I think there is this problem that people always link having epilepsy with having conditions which may occur in people with epilepsy or without epilepsy. We do know that in people with very severe epilepsy, there may be cognitive problems, but we also know that the drugs people take to control their seizures may create some cognitive difficulties. Quite often people talk about having memory problems – they feel they aren’t as alert and so on.

These are difficulties, but the important message is they are not necessarily happening for every person with epilepsy. It’s the conflation of the notion that, if you have epilepsy, you must also have cognitive difficulties that we need to really need to change thinking about. That change requires a lot of educational efforts not only in general populations but also in particular subgroups like lawyers.

Do you know if countries are combating stigma by actually helping educate people about epilepsy in school-age children and adolescence?

There are projects to do that, but I think our difficulty is that these projects are often very small scale. It’s actually quite difficult to get funds to do those sorts of projects, which is where I think charities and their fundraising efforts have a big role to play. It can be quite difficult to convince teachers, school boards, and so forth that epilepsy awareness is an important part of educating of young and teenage children. Buy, yes, there are small scale initiatives doing that kind of work and perhaps we can use the outcomes from those initiatives to convince funders this is a really worthwhile educational activity.

Earlier you mentioned the difference between the developed and the developing world in regards to stigma. What are some of the principal differences?

The answer goes back to understanding how different cultures think about epilepsy. A few years ago, the US National Institute of Health had my team to look at the nature of epilepsy stigma in China and Vietnam. We explores what things cause epilepsy and how it can be treated, and then looked at how that differed from the way the public thinks epilepsy is treated. In those two countries, people’s understanding about what causes epilepsy are not hostile ideas, the sort that I mentioned in which people think someone with epilepsy is possessed by evil spirits.

The general notions in China and Vietnam were much more aligned with traditional Chinese medicine ideas about imbalance in the body systems. Epilepsy and seizures were perceived to be caused by bodily imbalance and treatments were focused on reducing those imbalances. In China, for example, people with epilepsy do take modern western drugs, but these individuals often thought the drugs were there to stop seizures and traditional medicine was needed to realign the body to rid you of epilepsy.

These are very benign ideas and there was a great sense of care towards people with epilepsy, but there was also a recognition that they presented danger to themselves, if not to others. For example, they couldn’t work in rice paddy fields, because they might have a seizure and drown. People were worried about them having seizures outside in the community and being treated badly, so caregivers tended to keep family members with epilepsy at home and isolated from others. People with epilepsy in China and Vietnam were not considered particularly good marriage partners because they were believed to be unable to perform tasks, like childcare, that marriage expects of them.

These ideas were very different from ancient ideas, but the impact tended to be the same. In fact, you see this kind of evolution of ideas continue to have negative impacts on people with epilepsy in other cultures, even though the ideas themselves are very different. If you look at some countries in Africa, you see very different ideas about causes of epilepsy compared to China. In these countries, sin and possession by evil spirits still are held to be important causes of epilepsy and ideas about the condition are very hostile. People with epilepsy are treated quite poorly in quite a lot of African countries. In some countries, epilepsy is referred to as the “burning disease” because… People believe you can’t touch someone who is having a seizure because they think epilepsy is contagious, so individuals fall into open fires and get burned.

So, I think those cultural ideas are really important and they do emphasize that you need to understand the ideas underlying epilepsy in order to develop educational programs.

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.

Epilepsy Genetics

Plus, discover the latest in genetic testing advances in this episode of our Seizing Life podcast.

To learn more about CURE Epilepsy’s EGI initiative please visit the links below.

EGI Overview

EGI Initiative

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Audience Q&A with Dr. Dan Lowenstein

What are the different types of genetic tests that are out there right now?

The most common test involves taking a taking DNA, taking a blood sample and applying it to what we call an array. An array is essentially a matrix that includes a panel, if you will, of the most common types of genes that have thus far been associated with various genetic forms of epilepsy. So a DNA panel will include, whether it’s 50 or 100, or 50 or 500 genes in which there is evidence that there is an association with epilepsy, and it will test specifically for those genes. On the other end of the spectrum is called, is something called whole exome sequencing. Now, if I use the term whole genome sequencing, I think most of you would probably appreciate that that means that the process involves sequencing our entire genome. The three billion base pairs of our genome. But it turns out that only a very small percentage of our genome actually encodes proteins themselves. And that part of the genome that encodes proteins is called an exome.

So whole exome sequencing is much less costly and much more efficient. And so we’re turning more and more to doing whole exome testing so that we have a chance to, I say, the entire exome of an individual rather than just being limited to the DNA panels or arrays. These are carried out by clinical testing labs all across the country and in the world now. And the main limitation at this point for people in which there is a reasonable chance that a genetic cause might be identified. The real challenge that we’re currently having at the moment is getting health insurance to cover the cost of that testing. You heard from Laura before that the epilepsy genetics initiative is a large national, international effort to try and collect as much of the data that is being produced in these clinical testing labs as well as research labs. So that we can deepen our understanding of the complexity of the exome and discover more and more epilepsy genes.

Can you speak briefly about some of the environmental factors that can actually modify genes?

Yeah, we have a fairly limited understanding of that to date. I think the most obvious environmental factor that we know can mutate DNA is actually sunlight. So we know that ultraviolet exposure and extreme sunlight can directly damage DNA and the evidence for that is that as we age, we have more and more of a predisposition for skin cancer. Especially any of us who have not taken a caution on using proper protection lotion throughout our life. So light itself is directly damaging. There’s also evidence, clear evidence of various toxins to be damaging to DNA, so called teratogens. And in some cases that’s even been associated with certain drugs. We know that a very significant number of environmental toxins associated with pesticides can be DNA damaging as well. But this is an area that I think has received relatively limited study to date. And my hope is that we’re going to make significant advances in the years ahead in that regard.

Can you just clarify again, some about how a child can inherit epilepsy from a parent and the parent be unaffected, even though it did come from them?

Yes. So in the most well understood case, the parents may be unaffected, but there may be other members of the family that are affected. So that goes back to the family tree that I showed before. So in that case, if the parent is carrying one copy of the gene that person won’t be affected. But if they happen to have a child with a partner who also carries that gene, then the child would receive both copies and be affected. So that’s the most straightforward case. But I think the questioner is asking what about if there’s not any epilepsy that’s evident in the family? And especially in the case where you can really trace the family tree on both sides. And that individual may be carrying a mutation that is not causing epilepsy. But the child, in fact, does then develop epilepsy.

We don’t completely understand this yet. But that gets back to the previous figure, where I showed that we believe that many, many cases in which there’s a genetic influence on the epilepsy is due to polygenic changes or small change, relatively small changes in the various proteins. But many proteins because a number of different genes are affected, so it’s not a single gene mutation. Of course, the other very important reason for a child developing epilepsy born today to both parents who don’t have any evidence of epilepsy is what I talked about before. And that’s this idea of de novo mutations. In other words, the mutation in the child was not inherited from the DNA from the parents, it appeared only in the sperm and the egg. And so this is not something that would be inherited. Now, that child now does carry that mutation. And if that child had children, depending on the mutation and severity, it could theoretically be passed on to the children of that particular child.

If EGI has a population of 700 plus participants, how many are needed to do an effective population level genetic analysis of epilepsy?

The vast majority of cases of people who have epilepsy, in which there’s a genetic, a primary genetic cause or genetic influence, have that epilepsy because of sometimes subtle mutations in many, many genes. The only way that we’re going to be able to figure this out is by doing a genetic analysis by doing sequencing, whole exome and whole genome sequencing on hundreds of thousands of people with particular, with epilepsy or whatever the disease type it is. We now are appreciating just how complex the genetics is in the majority of cases. And we now believe that it’s going to take certainly many, many, many tens of thousands of people. And ultimately I believe it’s going to be hundreds of thousands of people for us to really decipher this.

So EGI is a kind of approach that we need to have, where we bring together the different data-sets that are being produced all around the globe. Again, whether it’s from individual clinical testing labs or large research groups that are doing sequencing on hundreds of people or thousands of people. If we can work out the arrangement to be able to bring all that data into one common data set. I don’t have any question that we have the capacity for being able to do an analysis on hundreds of thousands of people from around the world, which is going to be the critical step for understanding the complexity of this type of genetic influence on epilepsy.

Does the genetic testing have to be done with just the person who has epilepsy, or does it have to include other family members’ DNA as well?

In many cases, it’s the ideal is to have the DNA from the affected person and both parents. But this is actually changing, in part because of the creation of larger and larger data sets. The statistical geneticists are working out approaches that allow a comparison between just a single individual and the increasingly large data sets that contain sequence from both affected. And in our case, epilepsy patients. And very, very large, quote, “normal population controls”. So at the moment, again, depending on the situation, the clinician ordering the test will prefer getting DNA from the affected person and both parents. But I think that this is changing and over time, just getting individual DNA will be sufficient.

What percentage of epilepsy cases do you expect that will be identified by whole exome sequencing in the future?

Well, that’s a tough one. It’s a fool’s errand to predict the future in this way. But, I mean, given that we believe that roughly two-thirds of all the epilepsies have some type of genetic influence. And, by the way, I should also say that we think that in some cases of so called acquired epilepsy, that you’re genetic makeup also helps determine your likelihood of developing epilepsy. For example, everyone probably appreciates that traumatic brain injury, such as what can occur in a terrible car accident can lead to epilepsy. And in that case, we believe that the main event is the fact that there’s been a direct injury to the brain. But there is evidence to suggest that that individual’s genetic makeup may make it more or less likely. Just depending on their, the nature of their DNA. So in those cases as well, I think that we’ll get to the point where whole exome sequencing will allow us to essentially define what the map is of variations in DNA or mutations, that are the determinants of a person’s disease.

And I’m not going to say that it’s going to necessarily be two-thirds of all patients with epilepsy, but I would think that conservatively that it’ll be 50%. And there will be a day when we’re going to have an entire map of our own DNA with the predictions of how various mutations might affect our likelihood of developing epilepsy. But more importantly by having that map, we will be able to come up with very specific precise approaches to therapy that are tailored to the specific genetic basis of that person’s epilepsy.

Is it more difficult to determine mutations in generalized ability given that the brain is firing neurons from all over?

We have not figured that out yet. I’ve had the good fortune of being involved in a very large study called Epi4K that has involved hundreds of scientists and study coordinators throughout the world, in which we’ve collected and sequenced many thousands of patients with various forms of epilepsy. And we actually have attempted to answer that very specific question of what’s the likelihood of finding a causative mutation in patients who have generalized epilepsies versus those with focal epilepsies. And somewhat to our surprise in our first main study, we were able to identify a larger number of causative mutations in the focal epilepsy. So that actually went against our hypothesis and I think what the questioner is asking. But I don’t think this chapter has come to a close yet. I think there’s a lot more research that needs to go into this. And I suspect that we’ll be making advances in identifying mutations in both cases.

Is it possible for an individual to have a known genetic mutation, but not actually have the disease?

Yes. So I alluded to this before, I didn’t emphasize it. But all of us are walking around with variations. There are mutations, there are differences in DNA from one another. And some of us have variants that really are quite different from the normal population. And yet for reasons sometimes that we do and sometimes don’t understand that variation does not lead to any significant abnormal structure or function of the protein. Or it may lead to an abnormal protein but nature has come up with some other ways of covering the deficit that might occur from that protein. And so we have our normal health. So yes, we’re filled with variations in our DNA that fortunately more often than not actually don’t cause disease.

A Diagnostic Odyssey: Early Genetic Testing in Epilepsy

Plus, discover the latest in genetic testing advances in this episode of our Seizing Life podcast.

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Audience Q&A with Dr. Porter and Ms. Nye

We had one question that asked, ‘I am 66 and I’ve had epilepsy since I was 13. Is genetic testing important at my age? I have children age 31 and 28 who do not have epilepsy.’

Yeah. I think there’s a lot of detail that would have, to be fair, to have to determine if genetic testing would be helpful in this situation. I guess I don’t really feel confident in coming out strongly one way or the other, but I will say that genetic epilepsies are complicated. Mrs. Nye had the situation where her husband and her both have mutations in this particular gene and they’re completely healthy, and it was only when they came together that they had a child who had mutations in both copies of the gene. There’s other situations where a single mutation is new de novo in the child, and that won’t be passed on necessarily to the next child from the parents. I don’t feel very comfortable in saying that, but it’s something you can certainly talk to your epileptologist about.

What does Dr. Porter see as the major barriers to genetic testing in epilepsy?

Sometimes cost is as an issue. We have sometimes difficulty getting insurance to cover it or to cover all the testing costs, but many of the companies, including Invitae, but other ones as well are making the testing quite reasonable, meaning that there are programs for patients that are on Medicaid to help them fund the testing. Some of the companies have like a cutoff where you can’t be required to pay more than a certain amount for testing. That’s number one. I would say number two is sometimes interpreting the results. There, I’m very lucky cause I have a lot of genetics colleagues. I have a genetic counselor for just this situation, but we do come down to sometimes being not absolutely sure that the differences in the genetic testing are really causal.

I don’t think that that should deter you from testing because I think, as time goes on, it’ll become more clear whether differences are in fact causal, but costs and interpretation, I think, are still two issues that we face. The final thing though, is that there are patients that I know, I absolutely, in my heart, know have genetic epilepsy and we still cannot find a mutation. That’s why the EGI program is in existence, because if your exome sequencing, meaning the parts of the gene that make proteins don’t have a finding in them, the data can be uploaded to EGI, and it will continually be investigated.

I think in the future, some changes in certain genes that we don’t know right now cause epilepsy will be identified as causing epilepsy. So, it’s important to not think of this as a static question. Your gene testing is negative. Well, it’s negative at this moment. It doesn’t mean it’s going to be negative in a year or two.

Are there any consensus statements or practice guidelines that can be used to help support the need for early genetic testing in epilepsy when working with insurance or institutional send out labs?

Yes. I don’t know who sent that, but if you want to send me an email, I can send you a generic version of a letter that we use. I think the Lennox-Gastaut Syndrome also has some generic wording on some letters. I will not say that they’re always successful, but I think it’s a worthy cause, so it’s worth trying to do that. Feel free to just send me an email and I’ll give you our generic a letter. But again, some of the companies now have very low copays, or even an amount that you don’t have to pay over if the insurance refuses to pay for it. I think there’s ways to work around the insurance companies, to some extent, but I do have some generic letters I could send you.

If I don’t have many genetic colleagues at my institution, can I ask for guidance and testing and interpretation from the genetic testing lab?

Yes. They all have genetic counselors, at least when you say that. I’m almost positive they all have genetic counselors, at least in my experience they do. They can walk you through some of the interpretations. If that’s not fruitful, I think referring to some of the epilepsy genetics clinics that have been kind of springing up around the country, or to somebody that has more expertise in epilepsy genetics would be another reasonable option, even if it’s not at your institution. Sometimes families are willing to travel for something so important.

Do you recommend biochemical testing for metabolic disorders prior to genetic testing for epilepsy or should these be done simultaneously?

Yeah. We’ve spent a lot of time working up a protocol that we’re instituting here on how to work up a child, in this case, with suspected genetic epilepsy, including metabolic epilepsies. We have decided to kind of take a multi-pronged approach. So, we do metabolic testing, often simultaneous with the genetic testing. I would say there are certain circumstances where we might vary that slightly. It also depends a little bit on the patient’s situation. So, if it’s a very severe catastrophic epilepsy and they have features that make us highly suspect metabolic diseases, then we would definitely push for that more strongly. If the epilepsy seems to not be as severe or we think, it’s much more likely, it falls into a certain genetic syndrome, then we might skip the metabolic testing. But right now, our pathway is to do them simultaneously.

How do you broach the topic of genetic testing with a patient given that their diagnostic odyssey might already be expensive?

At our institution, MRIs are extremely expensive, especially if there’s a need for sedation. I think we just need to get our head around the fact that we don’t blink too much at the expense for that MRI, and our genetic testing is about a 10th of that. So, I agree medicine’s very expensive, but the yield from genetic testing is quite a bit higher frequently than an MRI, and I don’t really worry about the $10,000, $20,000 MRI. So, doing an exome sequencing seems like a bargain to me.

How early is too early for genetic testing in epilepsy?

If they were going to go forth and multiply again, I would guess maybe they would do testing in utero, now that they know what they’re looking for. If you don’t have a clear cut epilepsy gene that you’re looking for in a pregnancy, I don’t know that I would test the baby. That’s probably not reasonable in utero. We send genetic testing on neonates a couple of days old if we think they have a neonatal epilepsy.

Do you think it makes more sense to start with an epilepsy panel or whole exome sequencing?

So we still use epilepsy panels before we do exome. I don’t know when the tipping point is going to come when we stop doing epilepsy panels and we flip over to just doing exome, or then, now some of my patients get a whole genome if the exome has been negative. I guess for right now, anyway, I usually start with a panel because the yield is pretty high in many of my patients. But some of them that are negative, we do go on to do exome, or as I said, rarely now we’re doing whole genome.

How did you know which steps to take, to establish your foundation and work towards discovering treatment for your children’s condition?

I was really lucky to have friends that I had met along the way who also were dealing with rare diseases or had started foundations of their own. I was actually hesitant to do it. We tried triheptanoin first. We thought there was a treatment out there, and so we’ve tried the treatment before we started the foundation. It was only when it became clear that the gut instincts of treatments weren’t working that we decided to take a step back and formalize and organize everything. We continue to be close partners with other organizations. There’s a lot work to do. We certainly still work with CURE Epilepsy and other organizations that are also fighting the epilepsy battle. But I think it does just depend if you have enough patients and if there seems to be enough information to gather and enough work to do.

This is Brenda. I would just say that, of my families that I give them a diagnosis, I tell them to go out there and look. There’s almost always a Facebook page or some other group that they can meet with and start to talk about what their children have or how they’ve dealt with certain situations. So, getting together with other families that are sharing all the things that you’re going through is really important. Mrs. Nye is amazing, because she has taken it an extra step and raised money to really work on epilepsy that her children have, but even just getting together with other families is so helpful. It’s helpful to me sometimes in taking care of the kids, because the parents will say, “Oh, we talked to this family in Brazil and they tried this and it seemed to help their child. Can we talk about that?” That’s something I might not have known had they not been in contact with another family?

How do you know which epilepsy center is the best, and how do you find the best neurologist for your child near your home? How did you come to seek out epileptologists around the world?

I guess we tried to find the neurologist that had maybe seen something similar to what we thought we were dealing with. It might not be the same doctor or the same place for every family, but I tried to get an idea of what neurologists or epileptologists or geneticists might have seen something like this before.

I think seeing large numbers of patients with epilepsy and genetic epilepsies is very helpful. You start to see patterns. I can almost always pick up a kid now. Well, I shouldn’t say this, but usually I can pick up a kid with a glucose transporter, because I’ve seen enough of them over the years, fairly successfully. I think it’s a little bit just seen a lot of kids with genetic epilepsies that allows you to see patterns. People who specialize in epilepsy as opposed to some general neurologist who see some epilepsy, but maybe specialize in headache, they may not be the right person to take care of a child with really complicated epilepsy.

We would see a great doctor, that doctor would maybe have three or four ideas. We would try those three or four ideas, and then maybe it was time to seek out another opinion to see if anybody else had the next three or four ideas. As a parent, you don’t really have the option of giving up, so you just keep going and keep talking and trying to find a doctor who has an idea that hopefully moves the child’s health in the right direction.

I think also the idea that in some places there may not be a lot of specialists, but if your physician is willing to work with somebody else that’s more at a distance, that that’s always very reassuring. I certainly have people that I think of as colleagues around California, for example, or Hawaii I talk to about patients. They’ll send me some information and I’ll try to assist them as best I can. Even if your local physician may not be the world’s expert in X disease, they can certainly reach out to someone who is, and it is a collaborative environment for the most part.

How do you find support from other families if you don’t know your child’s genetic diagnosis?

I would say that there are both broad and specific diagnoses. While we went on a 10 year odyssey to find the genetic marker for the type of epilepsy that the two of my kids have, we had other diagnoses along the way. Epilepsy, in and of itself, is something of a diagnosis. So, there are certainly support groups for other families dealing with epilepsy. We seem to collect different labels. As the years went on, things like CP or ataxia or apraxia, or just developmental delay. There are support groups for all of those more clinical descriptions of what’s going on. I think families do find some comfort in those groups as well.

There are, that I know of, support groups for infantile spasms, Lennox-Gastaut Syndrome. These are all seizure types, or seizure syndromes, and all of those organizations have networks. The Lennox-Gastaut Syndrome foundation is having a meeting in Orlando next month that I’m going to. If you find the type of seizure your child has, often they’ll be a group. Then locally, the epilepsy foundation of America has local chapters all over. For instance, the one in Northern California has a very … well, I think most of them around the country have the very nice camp for kids that gives them a sense of inclusion. They have a parent support groups they help with as well.

If there’s a family history of a genetic epilepsy and another child is born with the same genetic condition, would you start antiepileptic medication before seizures begin, or do you need to wait for symptoms to become apparent?

We do not have epilepsy prevention therapies. I work on a trial right now trying to look at that in tuberous sclerosis, whether we can actually prevent the development of epilepsy and autism in children with tuberous sclerosis, treating them before they develop seizures. But for the most part, right now, we don’t have therapies focused on the prevention of epilepsy. I personally, if I know that a child is at high risk for epilepsy, I often use EEG to try to make sure I’m not missing any seizures that are subtle, or just present on the EEG, but that is a conversation you would need to have with your physician to determine whether your child would benefit from frequent EEGs.

This is also important to note that some genetic predisposition to epilepsy does not absolutely say that child will have epilepsy. There are certain mutations that it’s highly likely they will have epilepsy, and there are certain mutations where some small percentage of patients have epilepsy and others don’t. So, it really depends on the specific situation.

Do you think that technologies such as antisense oligonucleotide therapies and gene therapy using the new vectors provide hope for various types of genetic epilepsies, or will these type of advances take many more years?

They definitely provide hope. I think that the timing of when these kind of therapies will be available is much more challenging. The neuromuscular field is obviously ahead of us as far as getting across the finish line with antisense or vector-based approaches for gene therapy. I don’t think epilepsy is that far behind, but it is a little bit more complicated in some situations about how to get the protein and all the cells in the brain, how to get it early enough. There are a lot of challenges, I think it’s coming and it probably isn’t fast enough for anybody that’s on the phone with a child with epilepsy, but I don’t know when, but just take heart that it’s coming. I just don’t know when.

What would you say to a mom who’s just beginning the diagnostic odyssey for their child with epilepsy?

I would say that there’s going to be some good days and an awful lot of bad days where you want to just give up, but I just take a step back, take a deep breath, and then when I’m ready to go at it again, you just keep trying. I think that you can’t just make the diagnostic odyssey the whole goal. A diagnosis helps certain parts, but it doesn’t actually change your child. Your child is the same child the day before you receive a diagnosis, as he or she is the day after. Even though continuing this research and finding a diagnosis are really important to me, and I think they are to a lot of parents and families, the majority of my time is still spent doing physical therapies and occupational therapies and figuring out IEPs at schools, and just trying to make sure my kids have hobbies that give them something to look forward to.

I think the diagnostic odyssey or a diagnosis in general is like a piece of the puzzle, but it’s not the whole puzzle. So, try not to just completely go down that rabbit hole, and try to have fun with your kid because you don’t get these days back.

What is the yield for a multi-gene panel and for exome sequencing for a patient with epilepsy? What would the yields be if the patient has additional features?

I’ve seen papers trying to address this question, and I think it’s extremely challenging because it all comes down to the denominator like what kind of patients you include in that group. I’ve seen 30% for a panel. Again, though, it really depends on the denominator. When did the patient develop epilepsy? What kind of epilepsy do they have? Do they have some other syndrome features? Syndromic features, meaning their ears are set differently, their eyes are set differently, their MRI has an abnormality on it that’s frequently associated with a certain genetic disease. I don’t know the specific answer, but I think it’s not 1%, and it’s probably not 100% percent. It’s probably somewhere less than 50%, but in the 10s to 20s to 30%, so good we’re doing, I think.

I just wanted to say that I liked Mrs. Nye’s description of ending on this that, understanding your child’s epilepsy is so important, but having fun with your child and doing things that you and your child both can enjoy is so important. The families that I see in clinic that really take that to heart and do things with their kids that their kids can enjoy, and that they can enjoy watching their kids enjoy is so important. Maybe your child’s not going to be able to play regular soccer. I had a patient last week that is playing in the special Olympics soccer team, and he absolutely loves it. He’s so happy with it, and his parents were really enjoying it too. That is so important, to taking care of a child with special needs, is finding out what they like to do and helping them do that. It just is a nice way to end, I think.

Panels & Exomes: Diagnostic Yield & Detection of Childhood Epilepsy

Plus, discover the latest in genetic testing advances in this episode of our Seizing Life podcast.

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Audience Q&A with Dr. Swaroop and Dr. Sullivan

Would you wait until the patient has had at least two seizures before considering genetic testing? Or would you consider genetic testing after a single seizure?

I think you really do need to wait for that second seizure, specifically in Dravet syndrome, we’re really trying to arrive at a very early diagnosis and we’ve actually looked to see if genetic testing should be sent after a young child under the age of one has had their first episode of prolonged convulsive status. That may be an isolated situation where I think a single seizure could be argued, but other than that, I think you really need to wait for that second seizure.

The table showed a relatively high yield of TPP1, can you speak to this?

Yeah, absolutely. And this was surprising to us as well and a couple of them were actually… It turned out a couple of them were actually because of signatures that are associated with TPP1 related Neuronal Ceroid Lipofuscinosis. So there was a prior probability that we would discover it. But in several of those other ones, we actually didn’t expect those. And so it may be that as rare as this disorder is, and perhaps it is under diagnosed. And some of you may know that there’s a program that BioMarin has that is looking at these individuals with mutations in TPP1 and seeing who may be eligible for a drug therapy. And I think it appears that this disorder may not be as rare as we’ve thought before. But really, I mean, even in the quarter of 2000 children we’re seeing a number but I would really be interested in seeing a much larger cohort and seeing if this number really holds true.

How difficult has it been for you to get genetic testing approved for your patients with epilepsy?

It really does depend on the type of insurance coverage. But it also depends on the attitude of the person on the other end of the line when you’re calling in to get the prior authorization. I would say that in my practice, because we still serve about 50% of our patient population is state-insured or under-insured, Medicaid Medical, that it is still very challenging, but I know that there are a lot of companies that are working with us to try and come up with an arrangement so that those patients who could benefit the most can get testing but that’s a process in evolution right now.

Is it best to order a panel that includes deletion duplication studies performed simultaneously with the sequencing? Or does it make more sense to see what the findings of the sequencing are and then only order deletion duplication for the genes indicated based on the sequencing results?

Yeah. I think that’s a good question for a couple of reasons. One, I think it’s fair to say that we really didn’t appreciate how prevalent these exonic copy number variants are in disease genes, aside from maybe a handful like Duchenne muscular dystrophy, or some of the other ones. But where we’re really seeing this evolve to is being able to detect a much broader spectrum of variants, including single nucleotide variants, indels, exonic, copy number variants, etc, all within a single test.

And so it should be, we should all be moving towards being able to get all those pieces of information together from a single test. And we’re finding through internal analysis of our data, that the prevalence and frequency of these exonic copy number variants is actually pretty high that it accounts for almost 10% of all the pathogenic variants that we’ve ever reported from Invitae. So it’s clearly a high proportion of clinically important findings. So my opinion, is that these tests should be looking at exonic copy number variants at the same time as sequence variants so we have the most optimal clinical sensitivity of testing.

When would you recommend testing an adult patient and is that something that you need to consider with a higher concern if they have relapsed? And what would your recommendations be for them?

I’m glad that this is being asked. I think that because I commented that a lot of the early onset epilepsies have a very high diagnostic yield, if an adult being seen in an adult epilepsy practice, had an infantile onset epilepsy, and there still is not a known cause, I would say that those group of patients actually represent a very rich group where the yield could be exceedingly high. Especially if the clinician has the time to go back and take that early childhood history, I’m convinced that there are hundreds of patients sitting in an adult epilepsy clinic with SCN1A mutations that had Dravet syndrome but then when they turned into adults they have a little bit more of a nondescript phenotype and our adult epilepsy colleagues may not have that index of suspicion. But I still think that those group of patients just to summarize, are those with infantile or childhood onset who continue to have seizures and have no known cause.

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.

Infantile Spasms

Plus, learn more about this severe form of pediatric epilepsy from Child Neurology Foundation Executive Director Amy Brin in this episode of our Seizing Life podcast.

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Audience Q&A with Dr. Jeff Noebels

Do all IS cases have a genetic cause? And if they don’t, what are some of the other presumed causes?

Right. So, IS, it’s not incredibly rare, but it’s uncommon. And among those who have it, we have now discovered that there are certain genes that are now well known that can underlie the syndrome. I mentioned tuberous sclerosis and Arx. There are some others. I won’t give you their names. But there are probably five to ten genes that we know about and we can look for in the case. And that can likely explain features of the syndrome that the infant has. As far as acquired causes, I mentioned perinatal insults and maternal CNS infections have been associated with it. Beyond that, that seems like a general category. We don’t know specifically which viruses, what kind of insults, because they often created a lot of damage in the developing brain, and so we can’t always predict what kind of epilepsy will emerge from that. So there are both genetic and acquired causes of this syndrome.

I understand that IS results secondary to a brain injury. Does the research differentiate between genetic causes of IS and those secondary to a brain injury?

What we know from these and the research is usually the firmest information we can get is from animal models at a very basic level. So we don’t have too many of those models in the animal. There are various drugs that can be injected into a developing brain that seem to produce spasms and even the EEG counterpart, the abnormality, the hypsarrhythmia to study. But we’re not confident always that those are the same as what happens in human. It’s just a model. They allow us to study basic parameters of this disorder without really telling us this is what any child might have. So there are ways of approaching this scientifically. The genes are probably the clearest and most reproducible way of learning more about each child with infantile spasms.

Do infantile spasms have an autoimmune etiology? And have auto antibody prevalence been studied in this population?

So in the group that CURE Epilepsy brought together, we’re a group of scientists and clinicians, and we sat down and quickly realized that there are many questions we don’t understand. The autoimmune concept, just to explain to people, is that the nervous system in the body will start to generate antibodies against itself. Obviously a very dangerous chain of events, because you begin to attack normal structures in your brain. And there are several forms of childhood epilepsies in particular that have this autoimmune cause, where if you look at the cerebrospinal fluid, you can find antibodies directed against the very molecules that you need to properly signal the brain. These receptors can become degraded by your immune system and seizures can result. I’m not certain that we have a clear knowledge base on whether this is one form, whether infantile spasms can arise from it, but it’s a very tempting hypothesis that deserves to be explored. The forms that I’m aware of don’t cause infantile spasms, but they do cause seizures.

Now on the other side of the question, is that well why does prednisone and ACTH these steroids, why are they so effective as treatments? Because we know that they do impair, they tune down the inflammatory response in your body. That’s why they’re usually prescribed. So therefore, does that mean that the infantile spasms was an inflammatory disorder? Not necessarily, because these steroids have many other effects, including actually acting on GABA receptors which is the target for many of our best antiepileptic drugs. So there is some evidence that perhaps there could be an inflammatory response. I don’t believe it’s ever been well studied or firmly demonstrated. But just because a prednisone works so well when it does in blocking infantile spasms, doesn’t mean that that’s the mechanism for generating.

How often are anti inflammatory drugs used in this population?

Well in the sense of that prednisone is the front line treatment for these infants, so I would suspect that whenever it’s properly diagnosed and the prednisone is available, that is the first medicine that the child will see. It doesn’t always work. Also as I mentioned, infantile spasms sometimes can go away anyway without treatment. Another interesting aspect of the infantile spasms part of this syndrome, it’s what brings the child to the doctor’s attention. It is not necessarily itself a epileptic seizure in the sense that it may not actually be damaging the brain. So as I mentioned, one of the fascinating features of this is that it looks like a normal reflex. It’s just present in the nervous system at an age when that normal reflex would have disappeared. There’s no sign in the EEG, in the rest of the brain, of a seizure when this happens.

And so to my mind, we don’t have to worry as much as we do with convulsive seizures about whether the event itself is actually damaging to the brain. We would like it to go away, wish it wasn’t there in the first place, but it’s really just a tell tale that something developmentally is wrong in the wiring of the brain that these reflexes persist in some way or return. And as nice as it is to get rid of them, the infantile spasms themselves to me aren’t as much of a danger as just an important warning sign that there’s something else the matter, and if we know how to treat seizures that are to come, maybe we can prevent them.

Do you know whether combination treatment with estradiol and ACTH or vigabatrin will provide a greater level of effect?

Some of those studies are ongoing. So one of the things we decided among the CURE Epilepsy group would be to find out if in our model does our mouse model respond to prednisone, and we found out that it does. But what we haven’t done yet is to combine the two, prednisone plus estradiol, and see if that would really allow us to either use smaller doses or treat for a shorter period of time. Those are studies that we would really like to complete and get an answer for.

Do you think that there would be a difference in the actions in males compared with females in your study?

Well that’s interesting, because this was an excellent gene. And for everyone, that means that males will only have a single X chromosome. If they have the mutation on that chromosome that they inherited, they will have the disease. Whereas a female has only 50% chance and possibly no chance because she has a second normal X chromosome that could protect her from the disorder. Whereas the male has only one X chromosome to rely on, and if it has the mutation, you’re affected. So all of our studies are actually, and for this particular gene, are done in males, because they’re the only ones that are affected. Now other genes may not show that sex difference and they’ll be very interesting to see if estrogen levels, which might be different in females, are actually protective in that sense. So we don’t know the answer to that question, but it’s interesting.

Do we know what proportion of patients with IS have a TSC mutation? And on these lines, could you share your thoughts on the potential of mTOR inhibitors for the treatment of IS?

I’m sorry, I don’t know the answer. This is still really rare, and I’m sure there’s some studies that could answer that, your first question. But I don’t have that fact at my fingertips. But we’re talking about an uncommon … both disorders are somewhat uncommon. You hear about them a lot because we have the genes and we’re working on them intensively. But I don’t have the epidemiology of that question yet. But the mTOR inhibition issue is certainly an interesting one, and just like the estradiol, mTOR inhibition seems to be remarkably effective in certain kinds of epilepsy, including TS. But I don’t know whether it’ll be effective in all forms, or even same forms as the ones where estradiol will work. So again, these are open questions, and see how well we can prevent damage using these different sort of targeted therapies for very specific molecular pathways and cells.

What is your opinion on the existence of truly idiopathic infantile spasms where they were normal prior to diagnosis, rapid response to treatment, and normal tests, and normal developmental outcome?

Well my opinion, that word idiopathic helps a lot of people out because it’s a Greek term. That means we have no idea of what’s going on. So idiopathic infantile spasms up until recently was all of them were idiopathic. Now we have a few genes for some of them. But I can’t really comment as a group on what the natural history of idiopathic infantile spasms are. If you go into the old literature of infantile spasms before we knew these subtypes, then everything you read would be true, because they couldn’t distinguish between different types. Now you wonder whether something is idiopathic because you haven’t looked for all the things that we do know about yet. So you begin to question the use of the term idiopathic because we know there are certain answers. And in fact, the field of epilepsy as a whole has seemed to move away from the term idiopathic epilepsy, and now they call it genetic epilepsy under what I guess is the optimistic assumption that everything that doesn’t have an observable cause during the lifetime must be genetic, and therefore has a discoverable genetic problem.

We won’t probably ever be able to discover every single gene that contributes to epilepsy in every single person. But there is a sense that the entire field is now assuming that most cases, the more we study them, if we can get a pure culture of a specific type of epilepsy and study it intensely, we will find the cause of that particular type. But I think all of our listeners know that epilepsy comes in so many varieties. Different ages of onset, different seizure types, different responses to antiepileptic therapy, that we know we’re dealing with a very complicated disorder. Certainly it’s as complicated as all the cancers you’ve heard about, and that we just need to learn a lot more about these disorders and we need to split them apart and look at them, and then see if we can lump them back together.

Do you know of chloride regulation deficits in interneurons that impair migration or development of interneurons to cause infantile spasms?

Most ion channel mutations, chloride channel is one of them, are not known to interfere terribly with migration. At the moment, there’s a migration disorder in one of a number of forms is probably the best explanation for infantile spasms as far as I know. So of the chloride channels, I can’t think of one. There’s one in mice that obliterates the hippocampus, and that’s not anything like what you see in infantile spasms. But the other ones that are either triggered by electricity or opened by GABA inhibitory transmitter, I don’t know that there are … there should be defects in migration. I don’t know of a specific model where that’s been shown, and it shows to have the infantile spasms phenotype, but I would not be surprised if there’s one about to be reported.

The next question actually is regarding CURE Epilepsy’s team science approach to the IS initiative. And the question is can you explain what this means and do you think that this approach may lead to discoveries that could lead to breakthroughs sooner?

Yes, absolutely. And this is something that I think is happening all over science, but really needs to happen fast in disease or oriented sciences because we’re all counting on these breakthroughs to come. And what’s happening in science right now is the enormous growth of very powerful tools, both ways of manipulating brain cells at the molecular level and of tracking their functions with amazing tools of micro imaging and electrophysiology of single cells and of large groups and networks of cells. We’re really starting to be able to powerfully examine the nervous system, when it works and when it doesn’t work properly. So all of those techniques require time and skill, and no one laboratory really can do it. The ones that really have a tool that they can perform correctly don’t know as much about disease, and the people with a lot of disease background don’t necessarily have all the tools. So the idea of getting together with a focus group and attacking a problem, such as was done with the CURE Epilepsy initiative, was really a smart thing to do, and I think we need to see a lot more of it in the future.

Has the ketogenic diet been used as a first line approach to treatment for these babies?

I’m not a pediatric neurologist, I’m an adult neurologist studying the developing brain. So I don’t have firsthand information. The ketogenic diet keeps coming up in every form of epilepsy where the conventional drugs don’t work well is not the front line treatment for infantile spasms, but it is certainly something to try if the front line treatments haven’t given the desired effects. It’s a difficult treatment. I think it’s been tried in most different forms of epilepsy. I don’t know that anyone is claiming that it is the second line, but it’s certainly available and could work in some cases.

Webinar: Targeted Treatments for the Genetic Epilepsies – Clinical Cases

Plus, learn more about genetic forms of epilepsy in this episode of our Seizing Life podcast.

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Audience Q&A with Dr. Katie Angione and Dr. Lacey Smith

At what point in the diagnostic work up of patient with epilepsy would it be appropriate to order genetic testing? For instance, do you need to wait until the patient has failed at least two different anti-epileptic medications?

I think in most cases, it’s completely reasonable to order genetic testing pretty early on in the work up. Unless there’s a very clear structural cause on a brain MRI, genetic testing is reasonably high yield, especially if it’s very early onset, so infantile onset epilepsy. Because there’s the potential for identifying a treatable condition, I think it should be an important part of the work up.

As we kind of went over, a lot of the conditions, earlier you start treatment, the better the response and the better the developmental outcome. Then there’s also the potential for helping with medication selection. I don’t think that there’s really a need to wait until they failed medication and put the patients unnecessarily through that trial and error, because genetic testing can potentially give us some evidence to support a particular medication.

I’ll expand on that too and we talked a lot about treatment, but there are certainly other benefits for genetic testing and diagnosis outside of treatment, right? You don’t necessarily need to fail two epilepsy medications in order to start pursuing genetic testing. If families are interested in recurrence risk or are thinking about having additional children and wanting to figure out what the likelihood of having another child with this condition is, it can be part of the work up. As I mentioned earlier, it could reduce the number of tests that are warranted.

If you have a SLC2A1 variant, you may not need to do an LP for that for a small child. It could certainly reduce the number of tests during the diagnostic workup.

How do you know which epilepsy panel is best for your patients?

I think it depends on the patient obviously, which is often our answer. Sometimes a very specific phenotype or maybe you’ve done some biochemical testing, that may be pointing you in the direction of a certain gene or a class of gene. I think in those cases, it might make sense to start with a smaller panel, maybe even a single gene and then reflex to something larger if that’s negative. But for a lot of our patients, maybe even the majority, we don’t really have enough evidence to point us in any particular direction. There is a lot of phenotypic overlap in genetic epilepsy disorders. I think doing a slightly more comprehensive panel is, in most cases, going to be the best bang for your buck.

That way, you’re not extending the time it takes to reach that diagnosis. I would also say as far as which panel is best, which panel to order, there is a lot of options out there and that’s always changing. Labs are always expanding their panels, adding new panels, different options for rapid options. So, there’s really a lot to navigate. I think some of the important things to keep in mind are how big is the panel, what genes are included. If you do a bigger panel, maybe you’re increasing the chances of getting variants of uncertain significance which can be hard to navigate. But you’re going to be better at catching more rare disorders and maybe newer disorders, especially if the lab is kind of continually updating their panels as new genes are discovered. Then I think you also want to think about what is the coverage of the panel? What’s the minimum depth of coverage and the average depth of coverage? Because that’s telling you what’s the quality of that test? Are you going to miss something? Is there any chance of detecting higher level mosaicism?

Then the parental testing policies I think are something to be aware of as well because that’s going to help to resolve any variance. It might help to see if there is a recurrence risk, if it’s a recessive disorder, and then just overall how comfortable you are with the lab. Is there good communication? Is there a report that you’re able interpret well and feel comfortable sharing with families? A lot of things to take into account and I think it definitely depends on your specific institution and the patient population you’re seeing, but I think it’s something to look into and make sure you’re evaluating the panels that you’re ordering and asking questions of the lab, working with the lab to make sure you’re getting the best testing for yourself and for your patients.

Is deletion, duplication, and copy number detection important for genetic epilepsies or should that be left as a secondary option after sequencing?

I think it’s important to include deletion duplication at the onset. We typically order panels that include both sequencing and deletion duplication. I think that if you’re really doing a sequencing only panel, you’re missing the potential for a diagnosis there and just by doing it sequentially, you’re just expanding the time to a diagnosis for these patients.

I think I’ve definitely heard people kind of maybe arguing against deletion duplication and saying, “We don’t see a lot of evidence of deletion or duplications in a lot of these genes,” but I think honestly, we don’t really have enough data at this point to say that it’s not an important thing to do, especially for some of the more recently discovered genes.

Maybe we’ve only seen sequencing changes so far, but that doesn’t mean that there’s not the potential for deletion or duplication. As Lacey said, it would kind of be a shame to miss that by just doing sequencing and then have to go back just to make sure that you’re not missing anything.

Was the exome resequenced in order to find the PROSC gene? What changed in the analysis?

Affirmative. Sammy’s DNA wasn’t resequenced, but rather the lab just re-analyzed the sequencing data that was already available. I think it was a combination of factors. I think that the lab, in the time between the initial exome and the time that we got our re-analysis done, they may have changed their policy on reporting out candidate genes. Some labs are more proficient at reporting out candidate genes, so genes that really may not have been associated with any particular disease or disorder, but maybe it’s expressed in the brain, for example, and it’s a neurological phenotype. They may report those out with the caveat that it is a candidate gene and we know nothing about this, but just to keep this on your radar. As you saw shortly thereafter, we had the publication that came out. That’s helpful.

Doing a re-analysis of exome either on a clinical or research basis, the data’s there. It’s just our understanding of the genes. We have so many genes that we just don’t know what they do and what their involvement is in the human body, so our understanding changes over time. It’s not a change in technology, per se, in most cases. It’s really just our ability to interpret it and draw conclusions from that.

What can we do to keep drugs like ezogabine on the market so they’re available for patients? Is it a regulatory issue or an insurance coverage issue?

I think it’s different for different drugs that are available. Sometimes, for ezogabine, I think it was more of a financial issue. Ezogabine does have some side effects. Physicians were pretty reluctant to prescribe it, unless there was a pretty difficult to control epilepsy. I think for ezogabine, it was a situation where just not enough patients were on it for it to be marketable by the company, which is unfortunate but a reality. I think that really it’s been the families I’ve seen who have put in a lot of effort and advocacy and putting the information out there on how important this is and some labs and others are starting to catch on.

Are there foundations or patient groups that can help pay for enzyme replacement therapy?

I think there’s definitely a lot of advocacy groups out there. As far as how powerful they can be, that’s kind of another story. There’s so many rare diseases out there and all of these families are advocating for their children, their families, and there’s a lot to be overcome. I think it’s definitely a great thing to do to get involved with those programs. Honestly, the more people that do get involved, especially those that I think are in healthcare and are connected in a different way than the families, it’s certainly really helpful. Honestly, I don’t know the specifics but it goes a long way, just getting involved and even reaching out to advocacy groups, writing letters to politicians. Those things, they sound like they don’t make a big difference for something so rare, but you put enough doctors, enough families together doing those things and that’s our hope is that we can get to the point that we don’t have to deny a life-saving treatment because of insurance coverage.

Would specific EEG patterns, apart from hypsarrhythmia, give you an idea of which genetic etiology could be causing a person’s seizures?

There have been some cases that neurologists have come forward with a specific EEG pattern that’s directed very targeted treatments, so hypsarrhythmia as Katie mentioned, there’s the burst suppression in Ohtahara that I mentioned. We recently had a case, I don’t remember the exact EEG pattern but it was really suggestive of a POLG related epilepsy so they were looking for that and there was a hit on POLG. So I think that there are some patterns but even when you do have a specific EEG pattern, so if you have hypsarrhythmia and you have spasms, there are a variety of underlying genetic causes of infantile spasms.

That may help the clinical diagnosis and give a general direction for genetic testing. There’s still, as Katie mentioned, so much overlap with the genes and the phenotypes for epilepsy. Yeah, very true. CDKL5, ARX can cause infantile spasms. I think there’s a list of maybe 15 or 20 different genes, so genetic testing definitely still is an important part of that work up, even if the EEG maybe points you in a certain direction.

Do you have studies on isodicentric 15Q?

I’m not aware of any off the top of my head, but that doesn’t mean that there aren’t available. I would say clinicaltrials.gov is usually my go-to for specific disorder targeted studies. Beyond that, I would say maybe one of the patient advocacy or support groups would be a good place to go. Honestly, Facebook groups a lot of the time can get you in touch with new research studies. Families are definitely very good at staying up to date on what’s going on and what studies are available.

Genetic Testing to Develop Personalized Medicine for Epilepsy

This webinar recorded at Columbia University in New York City, focuses on “Genetic Testing to Develop Personalized Medicine in Epilepsy”. In this webinar, learn more about the importance of genetic testing in epilepsy, the different diagnoses you can receive from genetic testing, and what options are available after your testing results. Also, learn how CURE’s Signature Program, the Epilepsy Genetics Initiative or EGI, is helping push the precision medicine movement in epilepsy forward.

The webinar is presented by Dr. David Goldstein, Director of the Institute of Genomic Medicine at Columbia, and also features a Q&A portion. Some of the questions you might hear addressed include:

What is the value of genetic testing?
How do I go about getting testing ordered for me and/or my child?
What type of results can I expect if I do have genetic testing completed?
How can knowing the cause of my/my child’s epilepsy help with the available treatment options?
How is epilepsy research, like that involved in EGI, helping end the diagnostic odyssey that many patients face?

Plus, learn how genetic causes of epilepsy occur in this episode of our Seizing Life podcast.

Download Full Transcript

Audience Q&A with Dr. David Goldstein

Where can patients get information on clinical trials?

You can go to a government website which lists the clinical trials that are ongoing, clinicaltrials.gov. And that is a comprehensive listing of ongoing clinical trials, meaning that when the compounds get in demand, they’ll be there. Trials that are being planned, but aren’t at the stage of being tested in people. It’s much harder to get a sense of what’s coming. And that’s actually one of the things that I think would be good to try to organize information around too to really try to figure out what’s coming down the pipe. But for things that are being tested one you go to that government website.

Are there any consequences of whole exome sequencing or any adverse situations that one would be aware of?

I think it is fair to say that, that there can be concerns in performing whole exome sequencing. One example is that it is possible that you would find out something depending on what’s done with the whole exome sequence data that would cause anxiety without providing a compensatory benefit. In most cases where this kind of sequencing is performed to explain an indication, for example, to explain a patient’s seizures. In most such cases the patient and care provider in fact will only find out about genetic variants in the individual’s genome that either are responsible for the indication or that are on a particular list of genes that have been highlighted by the American College of Medical Genetics as being important to communicate results back for.

And these so-called incidental findings are communicated back because they represent genes that cause presentations that are not only serious but whether it’s something that the individual can do about it. So, for example, on that list are genes that cause cancers where there are certain screening regimes that are recommended. Genes on that list include genes that cause heart arrhythmias where there are certain interventions that are possible, and where certain kinds of evaluations, lifestyle changes are important. So usually those are the only things that individuals will hear about.

But in some settings they might hear about other things for whatever reason once the data have been generated. And there are examples of things that one might find in one’s genome that could cause anxiety without clearly providing benefit. A very famous example of that is whether individuals carry a relatively common and very strongly acting risk factor for Alzheimer’s disease where there really isn’t anything that you can do about it. In most settings it’s possible to choose what you would hear about and not hear about. And so there you can make a personal choice about whether you want to know about these other things that are not related, for example, to the reason for the sequencing.

Can you explain why you’d want to have a patient and possibly their parents sequenced?

There are really two ways in which we use family members. One is really just to better diagnose the affected individual. And there it really does boil down to finding out what’s in the child, for example, that’s not in the parents. And that could be, as I already highlighted a so-called de nova mutation. So a variant that’s not in the parents at all, or it could be a genotype where the child has two mutation, one from mom and one from dad and mom and mom and dad have only one. And so this is so-called recessive gene. And we can actually then use the fact that it’s not present in two copies in either of the parents to help reassure us that it’s actually responsible for disease.

In other cases, we might test other family members to help us, for example rule out a possible cause in an affected individual. If for example, there was an affected person with an unaffected siblings, we might test a candidate variant in the unaffected siblings. And if it’s present too, we might say that we’re disinclined to believe that that variant is causing disease. And of course, when there are multiple affected members of a family, then we’re looking for genotypes that are in common across the multiple members. The only final thing I’ll say about this is that there are in genetics always wrinkles in stories and often you need to do careful testing to see whether there are any wrinkles. I’ll just highlight one that’s important.

The so-called de novo mutations. Those actually often start in the gene cells of the parents. So in either cells leading to eggs or sperm, and sometimes the mutations that are in those cells of the parents are in other cells too, but just not all cells of the parents. And in those situations, we actually can sometimes in fact look for maybe even modest effects in the parents or the possibility, even though it’s say an apparently brand new mutation of transmission to other children. And so there’s a whole bunch of different contexts in which we would look more broadly through families.

If a family has had a single gene testing done or even a panel of genes for epilepsy, when should they or should they go on and have whole exome sequencing? And then also in that same vein with new genes being discovered, how often should a patient actually undergo testing?

So, in terms of the first part, if the test was either a gene or indeed even a large epilepsy panel and was negative, it really is clear that, that individual should have whole exome testing because none of the panels are absolutely complete for genes that cause epilepsy. If however, a single gene test or a panel test identified a clear cut cause that when vetted by people that know their way around the genome well, and the identification of pathogenic variants really does look like the cause, then in fact it’s not really necessary to perform whole exome sequencing.

If you for example, had a suspicion of Dravet and you had the SCN1A gene sequence, then there was a protein truncating variant found there really wouldn’t be any reason to sequence the rest of the genome in that context. As far as how often you want to reanalyze, given new genes are being discovered all the time. Even though it is tapering off as I said, in comparison to where we’re at a couple of years ago, it still is the case that new genes are being discovered all the time.

And in fact we’re learning more about how to recognize mutations in the already known genes. So therefore, it really is better to reanalyze as often as you can. There’s of course, of course a cost associated with the analysis and interpretation, and so, it’s a question of how often is manageable. We came to the view that every six months was a reasonable compromise and trying to make sure that we didn’t wait too long. If there was a new gene discovered that would make a difference in an individual patient’s genome. But having the re-analysis be generally manageable. And I think that, that’s probably reasonable overall something like every six months or a year for re-analysis.

Where can people get information on the cost? How do patients generally pay for their whole exome sequencing?

Yeah. So let me just clarify to a distinction between the actual generation of the data and the re-analysis. So in general, you actually don’t need to redo the generation of the data or get a new test unless you’ve only had a panel, or a single gene tested.

With the exception that if the sequence data regenerated a long time ago, there’ll be lower quality. And in this context, a long time ago probably means around three plus years ago, maybe a little bit more than that. All the exome data generate after that is pretty high quality. So, it’d be a matter of re-analysis as opposed to retesting or regenerating the data. As far as the costs go, it’s really difficult to say much about what the costs really are because it’s impossible to get one’s head around how costing actually works in the clinical space because the advertised costs have nothing to do with the real costs or even what providers are actually paid. And I really don’t understand the reimbursement landscape well at all.

But what I can say is that the cost to actually generate the sequence data in the first place forgetting clinical economy environment this testing happens in, the cost to generate the data in the first place is actually pretty modest now. So, here at Columbia, the costs for us to generate a whole exome sequence data is 300 and something dollars per individual, and so the actual cost of the data generation. And then once you have a reasonable scale of ration, the marginal costs of the analysis per individual are not that high either, but of course in the clinical environments, a whole bunch of other costs that get included including the final interpretation by a board certified individual and whether a mutation actually causes a disease or not.

With the re-analysis being obviously taking care of a group through the EGI initiative, how do patients enroll in EGI?

Patients can enroll in EGI with the support of their care providers and the genetic counselors here at Columbia. And as far as the starting point for those that are at academic medical centers that are already partners in EGI, it’s a straightforward process to be enrolled. And there’s a listing at CURE Epilepsy’s website of those partners for those that are not already at an academic medical centers starting point to approach CURE. So, for those that are not at one of the already participating academic medical centers the starting point would be to reach out to CURE for a discussion about how best to enroll.

If you contact CURE Epilepsy. It’s 1-844-EGI-CURE or you can just email directly at egicureepilepsy.org. So that it does get you in touch with the Columbia team and we can get you enrolled remotely, and actually from any part of the world.

Are there specific types of seizures identified with the information gained by genetic testing to date? And if so, is that an indication of who should be sequenced and who shouldn’t be?

In general, the answer is that it is the more severe and earlier onset epilepsies not specific seizure types, but really severity and age of onset where the genetic diagnostic yield is the highest. It’s not a zero in any of the so-called non acquired epilepsy. So when we sequence patients with more common forms of epilepsy such as genetic, generalized epilepsy, non-acquired focal epilepsy, we actually do still see apparently a contributing variants in a number of known epilepsy genes. And this is very strong statistical evidence that they do in fact contribute and if they’re not a sole causes. But if you consider those diagnoses, the diagnostic yield for those epilepsies is a much smaller proportion than the earlier onset, more severe epilepsy. So that’s where genetic testing is most strongly indicated.

There are a lot of genetic testing labs and diagnostic testing that are out there, are the known epilepsy genes, is that list, are they made available to those labs and are they aware of those new and current epilepsy genes?

I think that the labs actually do now a fairly good job of keeping up with the literature, a fairly good job when they interpret a patient’s exome. So I think in general, if there’s a mutation in a gene that is known in the scientific literature, most labs are going to catch that mutation and report on it. And as far as the lists go, the labs really do go to the scientific literature themselves and identify all of the genes that have been associated with epilepsy from the scientific literature. And now the scientific literature is relatively easy to interpret. There are some genes where when you actually look closely, you see that the strike revenues for them isn’t so strong in the literature but in most cases it’s relatively easy to interpret the literature.

Will there be a future in gene therapy with the database that you’ve collected?

Here at Columbia and I imagine other places, there are a wide range of views on that. My own personal view is that gene therapy in all of its various forms is something that we absolutely need to explore for serious neurological conditions including epilepsy. But I personally feel that in general, that’s going to be a pretty difficult path and that there’s not going to be a lot of effective gene therapies for epilepsies in the relatively near future. And I’m more optimistic of traditional pharmacological approaches that are targeted to the genetic cause. In the near term, and then gene therapy, just because it’s really hard. Whatever kind of gene therapy you’re talking about, to get the therapeutic agents to the right cells in the brain, it’s just a challenging thing to do.

Does EGI currently work with any pharmaceutical companies?

EGI currently doesn’t work directly with any of the pharmaceutical companies and above my pay grade to indicate whether or not we will. That sounds like Kate may want to say something about that, but what I can say is that there have been a number of conversations that a number of people have had with companies and I do think that there are a number of companies that are increasingly interested in seeing the development of an environment that will facilitate the kind of genetically targeted trials that I was describing earlier.

As far as future research with EGI and the data, is the database and how is it made available to the public?

The sequence data is available currently through (inaudible) I believe already. And so what that means is that you can apply to access the sequence data through (inaudible). And in addition the actual variants that we identified through our analyses are available on the webpage that I showed earlier. And the final thing I’d say is that EGI really is established on behalf of the broader community. And therefore, anyone who actually has suggestions of ideas of ways that the data in EGI should be analyzed, we are very receptive to discuss it.