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Sparking interest and understanding in the epilepsies whilst bridging the communication gap between epilepsy patients, clinicians, scientists, geneticists – and the world. Hosted by Torie Robinson.
**NOT FOR CLINICAL OR PATIENT DECISION-MAKING*
Visit www.torierobinson.com & www.epilepsysparks.com.
Within my own experience, patients who go on to ketogenic diet therapies often report that their processing speed, their speed of concentration, their memory, their alertness is much better. What we don't know if this is due to a reduction in seizures, an improvement in sleep, an improvement in anxiety or depression, or a direct effect of the ketone bodies themselves. But there's definitely a signal there that we need to explore further.
Torie Robinson:Welcome to Epilepsy Sparks Insights. I'm your host, Torie Robinson. And today we are joined by epileptologist, somnologist and neuropsychiatrist, Doctor. Manny Bagary. Manny will be talking about the science and clinical evidence behind medical ketogenic therapy for epilepsy in adults.
Torie Robinson:We are gonna go through the biological mechanisms behind ketosis, how ketones can affect brain excitability, our neurotransmitters, mitochondria, inflammation and even our gut microbiome and of course how the therapy may reduce seizures. We'll also go into how the diet can positively affect cognition, be used to treat status epilepticus and where it could fit into the broader epilepsy treatment pathway. This is our second of three episodes exploring medical ketogenic therapy in the epilepsies from different clinical and scientific perspectives. If you're new here, please subscribe so that you don't miss future conversations. And let's get into today's episode presented in partnership with Kanso by Dr. Schär. So thank you for joining us Manny. Could you tell us a bit about yourself, what you do and where you're from?
Manny Bagary:Yeah, no, thank you for inviting me on your podcast. So I work in adult epilepsy and sleep medicine. So I'm a neuropsychiatrist by training and I've been running an epilepsy service in Birmingham since 2004. And since around 2009 I've been running a ketogenic diet service for drug resistant epilepsy. And I think we're one of only three adult services across the country.
Torie Robinson:Some people say they've heard of the ketogenic diet, but to start off with, what does ketosis actually mean and what does it mean biologically? What changes are made into the brain when these ketones become a major energy source?
Manny Bagary:Just to go through some terminology. So what we mean by ketogenesis is when we produce ketone bodies and these are produced in the liver through fat metabolism. We can produce ketones if we fast for a few days, if we don't have enough glycogen. Our normal energy stores are in glycogen, either in the liver or in muscle, and we break this down for glucose for energy. And what we mean by ketosis is when we substitute the glucose for ketone bodies which are derived from fat metabolism.
Manny Bagary:The clinical scenarios whereby you might get ketosis is one is in diabetes which some of your listeners may have come across: diabetic ketoacidosis. This is a medical emergency. And the other clinical scenario might be if somebody's on a ketogenic diet. Lots of people are on ketogenic diets for health reasons, but our ketogenic diet is specifically for patients with drug resistant epilepsy. It's a medical therapy as opposed to a diet and I think it should be thought of as a medical therapy akin to using anaesthesia medicines or neurostimulation such as vagal nerve stimulation.
Manny Bagary:There are three principal ketones without getting too complicated about it. We've got acetoacetate, then we've got beta hydroxybutyrate. These are quite long names. When we measure ketones in the blood with pinprick testing, what we're measuring is Beta hydroxybutyrate levels and they give us an indicator of how ketotic somebody might be. Just as you might measure blood glucose levels if you're diabetic, we can measure ketone levels the same way just to make sure that if somebody's on a ketogenic diet treatment we understand what level of ketones they have in their system.
Torie Robinson:When you speak of seizure, seizures obviously we want to reduce seizures or get rid of them entirely ideally. With the ketogenic diet, is that about the ketosis itself or are there several things, mechanisms involved in the process?
Manny Bagary:We don't know. We think the ketogenic diet has multimodal mechanisms of action. So if we think of ketone bodies themselves, huge there's metabolic shift when we develop ketone bodies. We're shifting away from glucose as an energy source to ketone bodies as an energy source. And ketone bodies can then supply maybe 60% to 70% of brain energy requirements and indirectly ketone bodies seem to reduce neuronal excitability, they enhance brain energy reserves, they increase chemicals like ATP and KATP and these in themselves reduce neuronal excitability.
Manny Bagary:They stimulate mitochondrial biosynthesis it's the mitochondria that make the ATP we need for energy and they reduce some chemicals, for example, like BDNF and NTRK2, and this is due to reduced glycolysis, and this reduces neuronal excitation. And we want to dampen down that excitation to try and reduce the risk of further seizures. A second sort of major component of the mechanisms is enhanced what you might term as GABAergic inhibition. GABA is an inhibitory neurotransmitter and this helps to dampen down seizure activity. And we know that with ketogenic diet we've got a decreased concentration of reactive oxygen species, we've got increased GABA in the cerebrospinal fluid, and some of the components within the diet like decanoic acid that's a medium chain triglyceride refining coconut oil that can directly affect AMPA receptor inhibition and polyunsaturated fatty acids have some direct effects on sodium channels, potassium channels and calcium channels which can be helpful in dampening seizures down. And of the other mechanisms which are important: know leptin increases this is an appetite regulator and is also involved in energy homestasis. And there's interest in epigenetics: Ketogenic diet seems to alter histone proteins which can then switch genes on and off, and we've got increased adenosine which reduces DNA methylation, and that reverses some of the increased methylation that we see in chronic seizures in some animal models. Perhaps most complicated is the changes to the gut microbiome. There's lots of interest in the gut microbiome for lots of different conditions. In Ketidaitis complex There are some increases, some decreases and we don't really understand what these changes mean, but we do think some of these might be relevant to the efficacy of the ketogenic diet.
Torie Robinson:This is fascinating. There's such detail. It's also exciting that we don't actually know enough yet. It's a perfect example why we need more funding for research into this. It's amazing how something as simple, in a vertic commerce, as diet change can change your metabolic function and the way your brain operates.
Torie Robinson:And also it can decrease excess activity when we're talking about seizures, but can also increase activity in other ways, often in cognition.
Manny Bagary:Often when we do studies on ketogenic diet, there's much more of an evidence base in children than adults. We use primary endpoints of seizure frequency or we're looking for seizure freedom, we're looking as a secondary marker a 50% reduction in seizures, Then we've got lots of other outcomes that we're interested in: things like neuropsychiatric morbidity, anxiety, depression. We're looking at bone metabolism, we're looking at renal function, and we're looking at cognition. And most studies have touched on some of these secondary outcomes but haven't measured them systematically. And we're now beginning to do those things.
Manny Bagary:Within And my own experience, patients who go on to ketogenic diet therapies often report that their processing speed, their speed of concentration, their memory, their alertness is much better. And what we don't know if this is due to a reduction in seizures, an improvement in sleep, an improvement in anxiety or depression, or a direct effect of the ketone bodies themselves. But there's definitely a signal there that we need to explore further.
Torie Robinson:People with an epilepsy were all incredibly different. There'll be some similarities, but each case is very different. Is this related to why adherence is different amongst people? Does it also differ between people who are, for instance, being fed via what's the word? Enterol?
Torie Robinson:Is that how you pronounce it?
Manny Bagary:Enterol.
Torie Robinson:Enterol.
Manny Bagary:You may have come across this in the literature. There are different types of ketogenic diets and that can be quite confusing. So if I just go through what the different diets are, there's the what we call the classical ketogenic diet, and essentially the way all the diets differ is the amount of fat as opposed to the amount of carbohydrates as opposed to fat and protein. So with the classical ketogenic diet we've got ratios of four:one fat to carbohydrate protein three:one, two:one. We've got something called the MCT diet, the medium chain triglyceride diet.
Manny Bagary:That ratio is three:one, And we use MCT because it seems to be more ketogenic than some of the long chain triglycerides. Then we've got what's something called either the modified Atkins or the modified ketogenic diet. I think those terms are interchangeable. So what we do with that particular diet, the ratio of fat to protein carbohydrate is one to one, and we're using a carbohydrate restriction of usually twenty grams a day, but it can vary to ten and thirty gs. And then we have something called the low glycaemic index diet, and that ratio is 0.6:one, so the carbohydrate restriction may be forty-sixty gs a day and the glycemic index less than 50.
Manny Bagary:And the difference between these three diets is to generate ketones. The more fat that is in the diet, more the more ketotic that diet is going to be. So a four:one diet will reduce ketosis fairly quickly and probably to a much higher degree than something like the low GI diet, but that's reversibly linked to tolerability. So the higher the fat component, the lower the carbohydrate component, the harder it is to tolerate some of these diets. If we have different clinical scenarios, for example in an outpatient setting, we want to do is give patients the best quality of life they can and we want patients to be able to tolerate the ketogenic diet.
Manny Bagary:So in that patient setting we might want to start the modified ketogenic diet. That's that one to one ratio with a 20 gram carbohydrate restriction. And the reason we want to start that is that it's still it may not be as effective a classical ketogenic diet. We don't quite know that. But it works.
Manny Bagary:We know it works. But it's really well tolerated and we can phase that in in an outpatient setting. And certainly in our experience, once patients are phased in they don't really drop out because of tolerability reasons, whereas if we had a slight different scenario where we had a patient on ITU with super refractory status epilepticus who are PEG fed or they've got or they're tube fed there's a gastric tube and there's a jejunal tube For those patients, they're unconscious of course, we might want to start a classical ketogenic diet at a four:one or a three:one to get ketosis fairly quickly. Hopefully our patient will respond, and if they have responded and they're stepping down from ITU down to a ward, then we might want to switch that classical diet to a modified Atkins because it's just much better tolerated.
Torie Robinson:It's interesting you mention the status epilepticus, because I don't hear many people speak about that so often, but so ketogenic diet can be used as a potential treatment for what is otherwise refractory status epilepticus.
Manny Bagary:Absolutely. So status epilepticus is if we've got prolonged seizures or repeated seizures without recovery and it becomes refractory if we've tried a couple of antisia medicines and some benzodiazepines, and it becomes super refractory if after twenty four hours of sedation with an anaesthetic we still have seizures or if we try and withdraw the anaesthetic the seizures come back. Certainly for super refractory status epilepticus, it's really high morbidity. The mortality is about thirty-forty percent and most patients who enter super refractory status end up with a neurological deficit. So our treatments we do try all sorts of treatments for super refractory status, but it's essentially an evidence free zone.
Manny Bagary:We've got a really complex presentation with lots of treatments being tried and you never quite know which is the most important in getting resolution. But there is good data now in paediatric services, particularly for a condition called FIRES, which is a subset of NORSE (new onset refractory status epilepticus), and FIRES is febrile illness related status epilepticus. The response rates seem to be very good for FIS in paediatric services and some adult studies. Response rates we're talking in the region of seventy to eighty percent respond.
Torie Robinson:Wow!
Manny Bagary:So in a lot of paediatric status protocols, ketogenic diet is in there amongst a mix of treatments that you can use, but there's a lot of variability as to when you should introduce it And who you should introduce it to? One of the things about ketogenic diets is we need to understand which patients it might be contraindicated in, And those patients who've got an abnormal carnitine profile or an abnormality of fatty acid metabolism, you wouldn't want to be using a ketogenic diet in those patients. But when we send off those laboratory tests, sometimes it takes a while to get those back, and in paediatric patients you probably want to wait for those tests to be returned before you start the diet. But in adults, if you've got a patient who's had normal development and was reasonably fit and healthy before the onset of a refractory status, you don't necessarily need to wait for those results to come back because they're very unlikely, this sort of carnitine abnormality and fatty acid abnormalities they're unlikely to present de novo in an adult who's previously healthy. So the risk benefit changes and also the decision to use ketogenic diet changes from an outpatient population to an inpatient, high ITU patient in suprarefractured status because the outcomes are so poor.
Manny Bagary:And only for FIRES, I think we've got good data that ketogenic diet is really effective.
Torie Robinson:We don't have much data or evidence to support [well,] there's some - we'll speak about your work but much evidence into the benefits of ketogenic diets for adults. Why has it been so difficult today to generate that evidence? And at what point are we going to have, or when would clinicians think this is enough evidence for us to be helping more and more adults via the ketogenic diet?
Manny Bagary:Yeah, again, a really good question. And I think internationally it's been really difficult to get funding for RCTs in adults on ketogenic diets in children's services. They've got good studies, prospective studies, but some of those studies in children included adults. There are 66 patients in some of the studies reviewed by Cochrane back in 2018 where it felt there was enough evidence to use Kidney Shake Diet in paediatrics. And intuitively there's no reason to think that once a child has turned into an adult aged 18 that suddenly the Kidney Shake Diet would stop working.
Torie Robinson:Fair.
Manny Bagary:For those paediatric syndromes where it's proven that KitchenAid diet is really effective, response rates are up to seventy percent, some of the metabolic syndromes like GLUT1 and PDH, they still need those treatments as they hit adult services. Potentially withdrawing those treatments, because there isn't adult provision, would think is probably medically negligent. So we really need to develop these adult services certainly for paediatric patients who are stabilised and are transitioning to adult services. We need to think about services on ITU, certainly in the refractory status for fires and probably other refractory status epilepsy syndromes.
Manny Bagary:I suppose I'm slightly biased because I've been doing this for quite a long time. There's sufficient evidence to merit ketogenic diets in adult drug resistant epilepsy, because once we've made that diagnosis of drug resistant epilepsy, We're going to have thirty percent of our patients who are really struggling to respond to anaesthesia medicines, and what tends to happen is we cycle through a series of anaesthesia medicines and we try and rationalise using anaesthesia medicines with different mechanisms of action, although the evidence base to do that is quite limited. We try and ensure that we optimise quality of life and make sure we've got efficacy and we've got good tolerability, but we don't always get that balance right. And we should be having a conversation once we've understood that this is a hard to treat epilepsy, it's drug resistant, and there's an ILA definition, a really straightforward definition of what drug resistance is. We should be having a conversation with our patients and carers and families of where we go from this point and do we continue with other anti seizure medicines?
Manny Bagary:What do we think about non drug treatments? Do we think about neurostimulation? Do we think VNS? We've got the new EZ device. We don't really use deep brain stimulation in The UK, they do in America, and they've got responsive neurostimulation in The States.
Manny Bagary:And then, you know, are we thinking about surgical options? Has our patient got a lesion that might respond well to one of the surgical treatments? Is it a resective surgery? Or is there something palliative that we might be able to do? And then within that algorithm, we need to think about where ketogenic diet comes.
Manny Bagary:Probably every clinician will have a slightly different view as to where it comes. This is my personal view that it should probably come once you've got to drug resistance, and in that discussion between are you going down a surgical pathway, are you going down a neurostimulation pathway, or are you going to think about ketogenic diets?
Torie Robinson:I agree. Personally, as somebody who has an epilepsy, I agree. I would say that if there's a chance that one may have one seizure's controlled without removing brain tissue, why not give it a shot? It's not the same for everybody, of course.
Manny Bagary:Yeah, no, absolutely. I mean, I think probably the biggest block is the lack of service provision. For those surgical cases, if you've got temporal epilepsy non dominant, potentially you're going to get a really good outcome. Whereas if you've got surgical epilepsies that are perhaps more frontal, the outcomes are a little less certain, certainly consider a trial of ketogenic diet before you progress down that surgical pathway. Just in terms of morbidity, a ketogenic diet trial, we found that three month outcomes predict the twelve month outcomes.
Manny Bagary:And this is what a lot of studies are finding that if ketogenic diet works, it doesn't suddenly stop working. So a three month trial of ketogenic diet would really be merited before you progress down perhaps an uncertain surgical outcome.
Torie Robinson:Thank you so much, to Manny, for going into some of the nitty gritty of medical ketogenic therapy. I don't know about you, but I personally find the many potential mechanisms that may be involved absolutely fascinating because seriously from energy metabolism and urine transmission to mitochondrial function and the broader systems within our bodies that we just still don't fully understand. In our third and last episode about medical ketogenic therapy, we will carry on our chat with Manny, looking at the long term outcomes of the diet, how it can affect cognition and mood, some cholesterol concerns, contraindications, and some of the really big challenges when it comes to accessing professional support for adult therapy services around the world. Again, huge thanks to Kanso by Dr. Schär for partnering with Epilepsy Sparks.
Torie Robinson:If you found today's discussion interesting, please subscribe so that you don't miss the rest of this ketogenic therapy series. And if you work in epilepsy care, research or have personal experience with ketogenic therapy, I would genuinely love to hear your perspective below. Thank you so much for joining us and I'll see you next time.