 Thanks very much, and I'd really like to thank the organizers for allowing me to come talk about the use of diet and epilepsy. My, I'm a pediatric epileptologist and for many years now have been a zealot for dietary therapy and epilepsy. So it's great to have the opportunity to share with you the experience of dietary therapy as a medical treatment in this area. So what I'd like to do first is kind of just briefly give an overview of what epilepsy is because there is a very significant health issue and not only in the United States but in the world, not only for children but for people of all ages. And then I'd like to talk a little bit about the classic ketogenic diet, particularly given the ancestral nature of this group, focusing a lot on the history of dietary therapy, how it's formulated and what the clinical experience has been, and then briefly where we are on the ketogenic diet in 2012. And then I'll just very briefly in interest of time talk about two variations on a theme that have been developed over the past ten years making this diet less restrictive and more tolerable, both the modified Akins diet and then low glycemic index treatment, and then finally at the end talk about dietary therapy as over the past few years, as Tom just discussed, there has been expanding interest and expanding anecdotal experience of the use of diet as a medical treatment in disorders other than epilepsy. So first of all, epilepsy, very significant health issue, affects, epilepsy is defined just as a seizure disorder. So if I had two seizures of any type, even if I'd pause briefly twice while talking to you in those seizures, then that would be called epilepsy. Epilepsy affects one to two percent of the worldwide population, both children and adults, and it is the most common neurologic disorder in children. And unfortunately, one-third of children as well as one-third of adults who develop epilepsy develop what is called or termed medically refractory or intractable epilepsy, which means that the medications just don't work. So kids or adults will continue to having seizures, oftentimes 100 times per day, even though they've been on five to six to 10 to 12 medications. So clearly there's a need for things other than medical therapy and epilepsy. So then turning to the dietary, history of dietary therapy in epilepsy, and this is always very humbling to me because this is not a new concept. In fact, Hippocrates wrote about in his famous book, Sacred Disease, he wrote that modification of the diet was actually required to treat epilepsy. And he based that on his belief that the epileptic patient's body was polluted and that modification of the diet would allow purification. Aristostratus then in the third century BC, so again not too recently, wrote that one inclining to epilepsy should be made to fast without mercy and be put on short rations. And I especially like this because that's basically what we're still doing with these kids in 2012. And he also based this on a belief that there was a connection between epilepsy, the bowels, and the digestive organs. And then epilepsy dietary therapy is also discussed in the Bible, which especially in the ketogenic diet world for epilepsy is often referred to. More in the modern literature in 1911 was the first description of the use of epilepsy by French, and they described their experience with 20 patients, both children and adults. They used what they called a detoxification diet, which was reduced calorie vegetarian diet, with sporadic periods of fasting and purging. And what they found is that overall it was too difficult to enforce. People really had difficulty with these restrictions and the purging. But a few patients had significant results. What they also found interestingly, which has also been seen still in 2012, is that in addition to effects on epilepsy, they noted greatly improved cognitive skills of many of their patients. In the United States, the first discussion or description of the use of diet and treatment of epilepsy was in 1921. And that was when Ray Galen talked to the AMA about the experience of the osteopath in Michigan by the name of Hugh Conklin. Similarly to Hippocrates, Conklin thought that there was some kind of relationship between epilepsy and the gut, and he believed that it was due to the intoxication of the pyrus patches of the intestines. So he developed a program in which he put the intestines to rest. He would fast patients, both children and adults, as long as they could tolerate it. So the longest a child went was 25 days with nothing but water, no chloric intake whatsoever. And then when the child or the adult could take it no longer would feed, and then as soon as they were able to refast. And he quoted cure rates of 90% in juvenile patients and 50% in adults. So that was pretty wicked exciting back then, because as you'll see, there were very limited medications. And so there was a lot of interest, what about fasting, effectively reduced seizure frequency. And as you guys all know, when you fast, you start breaking down your fat stores and burning fats as the energy supply. And so at that time, kind of the thought was, well, can we trick the body and develop a diet that basically mimics starvation and yet still provides adequate chloric intake and energy supply. So the ketogenic diet was actually developed and first described in 1924, so almost 90 years ago. First described at the Mayo Clinic, and then there was also reports from Harvard University of Rochester. And as I said at that time, only two medications were available, phenobarbital and bromides. We now have close to 20 medications. So there were a lot of people with uncontrolled epilepsy. And so the ketogenic diet was widely used both in the United States and around the world. However, in 1938, diphenylhydantoin or dilantin was introduced. And so the ketogenic diet largely fell out of favor because compared to dilantin, which was considered the beginning of the pharmaceutical era in epilepsy, even though it was 30 years before another medication was available, the diet was viewed as being too rigid, too difficult and too expensive. But interestingly, largely in the United States, the diet continued to be used in various places with still documented efficacy. And the world kind of changed in the field of epilepsy in 1997 with this story. And the story behind this very briefly is a movie producer named Jim Abrams who produced Airplane in the Naked Gun series. I had a son, Charlie, who developed highly refractory epilepsy and Charlie was seen at six different pediatric epilepsy programs around the country. And Jim and his wife were given no hope. They were told palliative care may be possible, no hope. And Jim was distraught both at Charlie's epilepsy and the effect of Charlie's epilepsy on the entire family. So he started researching. And remember, this is pre-internet. So he really worked hard to research and look for alternative options. And he read about this ketogenic diet and learned that Hopkins was doing the diet. When to Hopkins, Charlie started the ketogenic diet and Charlie has subsequently been seizure free. And he's now been off the diet for about seven years. Charlie recently graduated from high school. So Jim became what he describes himself, the angry parent. He had never been given this as an option, never even told of this as an option. So he was on Primetime Live with Diane Sawyer and with his friend Meryl Streep also made this movie about the diet called First Do No Harm. And what this did for the first time in my career created a huge outcry in the part of the healthcare consumer. Families were calling angry that why wasn't my child given this option and why do you have my child on these poisons instead. So what was done as a result of that is a multi-center study was organized in the United States to learn how to do the start the ketogenic diet. And the results of that study are similar to the results that have been seen since this diet's been used. And so what is done is interesting. So as 1997, Jim also started a foundation called the Charlie Foundation to increase awareness about the use of dietary therapy in epilepsy. And then we often view the importance of something in the medical literature and medical world by how often it's cited in the medical literature. So this is just interesting. Medline was created in 1965. So if you look at 1965 to 1995, there were only 56 citations about dietary therapy in 31 years. Then if you go to 1996 to 2010, 840 in 14 years. And our big journal in epilepsy is called Epilepsia and you honestly cannot pick up a monthly issue of epilepsy and now without there being at least one paper on dietary therapy. Also the popular vacan's diet in the United States I think has made this seem like it's possibly more acceptable and doable for kids. So this just shows you what the ketogenic diet is. As you guys all know, Americans really like carbohydrates. Our ketogenic diet is largely fat and how it is formulated is formulated individually and specifically for each child. And it is formulated. These kids are on meal plans. They're weighing out meals on gram scales. And the calories are based on age, ideal body weight and current intake. Cause as you can imagine, a hyperactive six year old is gonna have very different caloric needs in a non-ambulatory six year old. Kids get the RDA or above a protein and they get the RDI of items and minerals. And then each child is put on what is referred to as a ketogenic diet ratio. And that's a ratio by grams of fats, two proteins and carbohydrates. And most children are put on a four to one ratio which means of course they get four grams of fat to every one gram of combined protein and carbohydrate. This diet is also used in adults. It is not as effective. Adults have a harder time complying. Plus their ratio is limited because adults are bigger so have a higher protein requirement but it can still be very effective. What kids get to eat on the ketogenic diet is cream and lots of cream. Fats, fruits and vegetables and proteins. But what they don't get obviously is what makes this difficult. No bread, pasta, grains, no sugar and no starchy fruits or vegetables. And what families and kids have to learn on this diet is they have to be wicked and vigilant and excluding or monitoring extra carbohydrates because carbohydrates are everywhere. These children are all on medications. Most meds have carbohydrates. Non-nutritious sweeteners have carbohydrates. And as far as I'm aware, Tom's of Maine continues to be the only toothpaste available in the United States that does not contain carbohydrates. So very strict. But it works. And this just is a busy slide but this just shows series looking at the efficacy of this diet since 1925 to the present. And basically the bottom line is four children who go on the diet and the majority of these children have been on four to six seizures per day. Many of these children having hundreds of seizures per day. One third of people who go on this diet become completely seizure free. One third have a greater than 50% reduction in seizures and one third it doesn't work and oftentimes that's because it's not tolerated. So I believe that this almost inarguably means that dietary therapy is the most effective treatment for epilepsy. So then just briefly, it is restrictive. Parents are having to weigh up foods. Kids do get admitted to the hospital to start this diet. As over the past 10 years, as I said, two different diets have been developed. Both of these diets now being used both around the United States and internationally with similar efficacy. The modified Akin's diet was developed by Eric Kosov and his colleagues and we've also developed a diet that we refer to as low glycemic index treatment. And this just basically shows you our diet. So here's the ketogenic diet and American diet. So our diet you can see is still largely fat but kids are getting more carbohydrates as opposed to the 10 grams of carbohydrates on keto. They're getting 40 to 60 grams per day but those are low GI carbs. So carbs with a glycemic index of less than 50. So the ketogenic diet, as I said, I believe is the most effective treatment for epilepsy that LGIT and MAD diet appear almost as effective if not as effective as the classic ketogenic diet. But then I think the question kind of, I'm sure also you guys would all be interested in is is there a role for dietary therapy other than epilepsy? And this has been a really exciting time and I think will continue to be a very exciting time. Tom just talked about the experience and the possibilities of using cancer and there's increasing interest in that not only in brain cancer but in prostate cancer and other types of cancer. There is now anecdotal evidence that it may have a beneficial role in Alzheimer's disease as well as Parkinson's disease and there is currently now a multi-center trial with a diet very similar to the ketogenic diet in ALS or Lou Gehrig's disease. Also some thought that head injury it might be a good treatment for head injury to reduce morbidity and also animal model work that it may be effective in diabetic neuropathy and I think that this is just the beginning of an expansion of the use of dietary therapy as an overall medical treatment. But kind of implementing this, as Tom said the IRBs are an issue with clinical research but there are also other significant roadblocks. The restrictedness of this diet does significantly impact particularly children who are then unable to eat their birthday cake, have snacks at school, et cetera. So that can be very difficult and then also doing this diet safely particularly in growing children but also adults. I believe required skilled dietitians and there's a very limited number of people able to do these diets and also with our current insurance system this is not a billable or reimbursable service. So any epilepsy program that has a dietary program is coming up with funds independently in order to make that program work. And then also in Western medicine there are a lot of disbelievers of the use of diet as a medical therapy. I'm largely in part because we all feel pretty comfortable where a lot of this Western world feels very comfortable swallowing pills and so if we could formulate the diet into a pill it probably would be easier to sell. Anyway, I'd like to thank you guys for your attention. We have a huge, we have probably over 350 kids on dietary therapy right now at the MGH of both the LGIT and ketogenic diet and we have had a long experience of it being miraculous for many children. So as I said earlier I am a huge zealot for this is a medical therapy in epilepsy and beyond. So thank you very much. Yeah, I'm just wondering, I've worked in addictions for a few years and I see quite a few of my clients who have seizures as a result of drug addiction and even like one year sober still having seizures and I'm wondering if ketogenic therapy might be something that would work for them or if they just maybe have brain damage and it's permanent and. So the ketogenic diet or LGIT or anything can work for epilepsy of any cause and any type of seizure. It's wicked effective across the board. So it could be effective. I mean sometimes with drug addiction they're withdrawal seizures and that's not the same as epilepsy but if they continue to have seizures afterwards and that would be considered epilepsy and absolutely. Ketogenic diet might be tough especially that's kind of a vulnerable population of people and so it might be that low glycemic would be a more tolerable diet for them because it is much less restrictive. There's more flexibility, more wiggle room with that. Okay, great, thank you. I was wondering as you're pointing out the ketogenic diet is obviously a large portion fat but what's the research about the different types of dietary fatty acids in this diet? Specifically I'm curious about medium chain triglycerides because of their benefit for the mitochondria and gene regulation and things like that. So that's a fantastic idea. So kind of in the 1970s there was an introduction of MCT oils to try and make it then those are more ketogenic so maybe you could make the diet less restrictive. It's actually very difficult for many people to tolerate a lot of MCT, it's tough on the gut. So they are combined and it's a mixture and my dietitian could tell you this probably much better than I could but typically it's a mixture but then when we're fine tuning the diet if we don't have optimal seizure control we often do try increasing MCTs if tolerated. So again it's very independent for each person. And does that also mean so when you're saying you, it's the other types of fats that you have in there do you tend to go more saturated fats or what else is? I think it's a mixture but we do use a lot of saturated. Thank you. Ketogenic diets are actually also recommended in Scandinavian by official nutritionists. They are doing research now on using ketogenic diets and it's incredible to read these anti-fat, the anti-fat establishment using several pages in their nutritional official magazine to recommend and to advise on ketogenic diets. That's at least happening in Scandinavia also. I was wanting to ask if, what do you think is the reason why ketogenic diets are being accepted in these disorders and then rejected in many other diseases? So being a zealot in this, I would not say they're being accepted in these disorders. I think if you poll 100 neurologists and ask them what about dietary therapy for epilepsy? They say, oh yeah that might have been used decades ago. So and that is something that's maddening for us who are zealots about this and Tom can tell you because he's also in the key to world for epilepsy drives us nuts. 80 years, 90 years of data that this is the best treatment and yet I often see kids who've been on 11 medications and sometimes the parents have even asked the neurologist what about dietary therapy and the neurologist says, oh no, no, no that's not for this type of epilepsy. Oh no, no, no that's too hard. And as one mother recently said, nothing is as hard as watching your kid have a seizure. How about other psychiatric diseases? Is there any work going on at your center? For example in schizophrenia or? You know I think it's a brilliant idea. We're pretty overwhelmed with kids having seizures but I think that we're very interested about the possible role of the diet in autism in children with autism without epilepsy. And we think also a lot in the folks at Harvard Medical School we're working with trying to figure out the mechanisms of the diet but I think probably there could be potential benefit in any health disorder. The lack of insurance reimbursement seems to be a major problem here and then in other treatment with dietary therapy. Is it just that the insurance companies are non-believers? I mean what is the issue here? The efficacy seems to be pretty good although I don't know exactly what the relative efficacy is of drugs. So it's better than drugs? I mean drugs can work. 50% of people will respond to a drug but it's better than drugs. So there are layers of difficulty with that. Part of it is that when the whole health care got organized many years ago nutritional care was considered to be part of the hospital care. So if I'm in there for pneumonia nutrition should be covered. So that use of as dietary therapy as a medical therapy it's just not there yet. So we're working extremely hard and we wanna do a meta-analysis because really what you wanna show is the health insurance companies look hey this works and this ends up saving money. Our kids aren't on these expensive medications or our kids aren't in the hospital having status. I mean so I think it's really a matter of proof to get that to say that. Because honestly I think this is an audience that really wants medical therapy, medical dietary therapy. It's only gonna be possible if dieticians are reimbursed. I mean the MGH has been nice to me to help me cover the cost of my dietician because otherwise we wouldn't be able to do this. In one of the studies you mentioned that a third of the children was intolerable of the diet. Was that largely intolerable by the gut or was that execution and staying strict to it? That's a really good question. It's probably a mixture. And those are retrospective studies so it's kinda hard. We have prospectives going now for the LGIT both in kids and adults so we'll have a better sense. Oftentimes it's that the kids just can't tolerate. I had a kid once he went on the diet went from 100 seizures a day to two. But then his class went on camping trip and his class had some ores. And the kid could not have some ores. So the kid came off the diet. So I think it's a mixture. Sometimes it is, the kids are just too acidotic but we're pretty good at balancing and managing that now so we can troubleshoot a lot of the side effects of the diet. It oftentimes is just the child's inability or the family's inability because it's a lot to be weighing out your kid's food if you're feeding three other people in your family. Okay, thank you. You mentioned IRBs. IRBs don't like to approve this or what? So the Institutional Review Board, so as a medical treatment, if I wanna use this as a treatment, I don't need the IRB involvement. But for instance, if we want to do a study, especially trying to say really, why does this work, how is it tolerated? Then it would be good to do a clinical study. So to get things through IRBs is difficult. The problem we've had, honestly, both when I was at Children's Hospital, MGH, is I think that there's a bias against the word diet. And so this is the thing, because if you take people who are kind of, then look at diets, lots of diets fail. So we now refer to this as a medical therapy or medical treatment. And our things are getting through the IRB much more readily. The IRB, first time we tried to put an IRB through on dietary stuff, they came back and they said, are you screening these kids for eating disorders? And I said, these kids have epilepsy. I'm trying to treat that. So I think if we're trying to make them think that, look, we're not talking diet, we're not wanting these kids to lose weight, we're talking this as a medical therapy, is really helping us. I think a big kind of elephant in the room with the ketogenic diet. Last week I presented my high-grade glioma study ketogenic diet. And on the last day of the conference, the head of a major cancer organization said, this is a protocol, the ketoacidotic diet for high-grade glioma. And I think it's a big issue where in medicine, I think greater than 50% of physicians out there don't know the difference between a ketotic diet and a ketoacidotic diet. And so, ketoacidotic is a fatal thing and they don't know the difference. So until we actually teach this in medical school, which is not taught, and I'm saying five out of 10, I know my colleague is probably less than that. No, I would agree. Well, I think a lot of people, I can't remember when in medical school I took biochemistry, but it was early on, way early on. So I think that a lot of people don't really realize that G ketone bodies can be used as substrates. And interestingly, they are used as substrates. So a time when ketone bodies are highly used or when fetuses are being delivered. So during labor and delivery, which is a stressful time, the fetal brain starts burning ketones for energy. So I think that's what a lot of people don't remember. And I honestly think we need to move away from the concept of diet and more the concept of therapy. Because I think, especially if you're a traditional Western medicine person looking at something, we think medical therapy and then you hear diet. And there's so many alternative things that people are doing and you hear diet and it's like, oh no, here we go again. So I think treatment or therapy is where we need to focus it. Lustig San Francisco, one of the things that you left off your history was the fact that patients with diabetic ketoacidosis would stop their seizures during their DKA. That then addressed the question of mechanism. One possibility is that it's low blood glucose, but of course DKA is high blood glucose. The fact that you're using a low glycemic index diet suggests that it's probably not carbohydrate specific. And I wondered, first of all, how that affected your ketogenesis, the LGIT. And could it possibly be insulin suppression itself that's actually changing seizure frequency? That is a wicked, wicked good question. And kind of there is increasing, like Gary's lab and there's increasing other very good basic science going looking at what is the mechanism this. You are correct and our low glycemic diet, by and large, the kids are not spilling ketones. Now if they're not spilling ketones and they don't have elevated beta-hydroxybuty in their blood, that does not mean they don't, at the neuronal level, have a slightly elevated beta-hydroxybutyrate. But my gut is, and I've always thought this, because this diet, LGIT, works wicked fast. You take a kid who had 200, 100 seizures a day, put them on our diet in two weeks or seizure-free. So that's pretty fast. So I do think that there's some kind of, and how we came to that is kids on the ketogenic diet have an extremely stable glucose level. Whether they're eating or not, whether they go several days with that caloric intake, their blood glucose is like this. So we thought, well maybe that's one of the mechanisms, because you stabilize blood glucose, you stabilize insulin, you stabilize lots of other things. And so that's how we came up with the low glycemic index treatment is to try and approximate that. So there are a lot of people. Gary's lab actually just had a beautiful paper come out in Nature Neuroscience. And they think that maybe somehow there's an effect of ATP levels helping modulate a potassium channel that's sensitive ATP and involved in neural excitability. And then you could say, well, G. glycolysis societal plasmics, so the ATP's there, whereas fatty acid, you know, metabolism's mitochondrial, so then the ATP is in the mitochondrial, so maybe that. But there's a lot of really good science now. It's really cool actually, because increasingly very, very powerful neuroscientists and biochemists thinking about this. All right, that's all the time we have. And thank you, Dr. Shearer.