Ketones Are Changing Your Brain in Epilepsy - Dr. Manny Bagary, Birmingham and Solihull Mental Health NHS Foundation Trust, UK
Medical ketogenic therapy can reduce seizures in some people with epilepsy - but how does it actually work? Dr. Manny Bagary explores how ketones may affect brain excitability, neurotransmitters, mitochondria, inflammation and even the gut microbiome. He also talks about why ketogenic therapy might improve cognition in some people, when a person should be offered it, and how it can help with status epilepticus. Watch/listen here 👇!
This episode is sponsored by Kanso, a brand by Dr. Schär who’s had no influence over the editorial content or discussion. Learn more about Kanso here.
Episode Highlights
What are ketogenesis, ketosis, ketone bodies
Impacts on seizures, anxiety, depression, and cognition
Forms of the medical ketogenic diet in adults
Ketogenic therapy for status epilepticus
About Dr. Manny Bagary
Dr. Manny Bagary is consultant epileptologist, somnologist and neuropsychiatrist. His medical training was in London, graduating from St Marys Hospital and Imperial College Medical School. His psychiatry training was on the Charing Cross and Maudsley rotations, London. He has held Wellcome Research Fellow posts at the MRC Cyclotron Unit, Imperial College and the Institute of Neurology, UCL/National Hospital for Neurology and Neurosurgery, Queen Square, London completing a PhD in neurological sciences. His epilepsy training was at the National Hospital for Neurology and Neurosurgery and the National Society for Epilepsy and he took a consultant post in Birmingham in 2004 and established a ketogenic diet service for adults with drug resistant epilepsy in 2009.
Full profile: Manny Bagary
Topics mentioned
ketogenic diet
modified ketogenic diet
seizure control
metabolism
glycemic index
cholesterol
quality of life
cognition
obesity
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Trailer
00:00 Manny Bagary
“And 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. 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.”
Intro
00:32 Torie Robinson
Welcome to Epilepsy Sparks Insights! I’m your host, Torie Robinson, and today we are joined by Epileptologist, Somnologist & Neuropsychiatrist Dr. Manny Bagary! Manny will be talking about the science and clinical evidence behind medical ketogenic therapy for epilepsy in adults! We arel 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 in to the broader epilepsy treatment pathway. This is our second of 3 episodes exploring medical ketogenic therapy in the epilepsies from different clinical and scientific perspectives.
If you’re new here, please subscribe so you don’t miss future conversations - and let’s get into today’s episode - presented in partnership with Kanso, by Dr. Schär.
Meet Manny
01:29 Torie Robinson
So, thank you for joining us, Manny. Could you tell us a bit about yourself, what you do, and where you're from?
01:33 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 3 adult services across the country.
What are ketogenesis, ketosis, ketone bodies, etc.?
02:03 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? And what changes are made into the brain when these ketones become a major energy source?
02:17 Manny Bagary
So 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. The clinical scenario is 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 is 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 antiseizure medicines or neurostimulation such as vagal nerve stimulation. There are 3 principal ketones without getting too complicated about it. We've got acetoacetate and 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 if somebody's on a ketogenic diet treatment, we understand what level of ketones they have in their system.
What makes ketosis stop seizures (in some people)?
04:17 Torie Robinson
When you speak of seizures, obviously we want to reduce seizures or get rid of them entirely, ideally. Is that with the ketogenic diet, is that about the ketosis itself or are there several things, mechanisms involved in the process?
04:30 Manny Bagary
We don't know. We think the ketogenic diet has multimodal mechanisms of action. So, if we think of ketone bodies themselves, there's a huge 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 - 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. 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 neural 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 cerebral spinal 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 some of the other mechanisms which are important, we know leptin increases, this is an appetite regulator and is also involved in energy homeostasis 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. And 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 ketogenic diet it’s 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.
07:29 Torie Robinson
This is fascinating. There's such detail. It's also exciting that we don't actually know enough yet. The perfect example why we need more funding for research into this. It's amazing how something as “simple” (in inverted commas) as diet change can change your metabolic function and the way your brain operates. And also, it can decrease excess activity when we're talking about seizures, but can also increase activity in other ways, often in cognition, right?
Impacts on anxiety, depression, cognition and more
08:00 Manny Bagary
Often when we do studies on ketogenic diets, there's much more of an evidence-based in children than in adults. We use primary endpoints of seizure frequency or we're looking for seizure freedom, we're looking as a secondary marker of 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. And 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. 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.
09:22 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? And does it also differ between people who are, for instance, being fed via, what's the word - “Enterol”; is that how you pronounce it, haha?
09:40 Manny Bagary
Enterol.
09:41 Torie Robinson
Enterol!
Different types of ketogenic diet
09:42 Manny Bagary
You may have come across this in the literature. There are different types of ketogenic diet 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 diets. 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 a classical ketogenic diet, we've got ratios of 4:1 fat to carbohydrate protein, 3:1, 2:1. We've got something called the MCT diet, the medium chain triglyceride diet. That ratio is 3:1. And we use MCT because it seems to 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 diets. I think those terms are interchangeable. So, what we do with that particular diet, the ratio of fat to protein carbohydrate is 1:1. And we're using a carbohydrate restriction of usually 20 grams a day, but it can vary to 10 and 30 grams. And then we have something called the low glycaemic index diet, and that ratio is 0.6 to 1. So, the carbohydrate restriction may be 40 to 60 grams a day and the glycaemic index less than 50. And the difference between these diets is to generate ketones. The more fat that is in the diet, generally the more the more ketotic that diet is going to be. So, a 4:1 diet will reduce ketosis fairly quickly; probably to a much higher degree than something like the low GI diets, 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. And if we have different clinical scenarios, for example, in an outpatient setting, what 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. So, in outpatient setting, we might want to start the modified ketogenic diet. That's that 1:1 ratio with a 20-gram carbohydrate restriction. And the reason we want to start that, it’s that it's still, it may not be as effective as a classical ketogenic diet, we don't quite know that, but it, but it works, 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 have phased in, they don't really drop out because of tollerability reasons. Whereas if we had a slightly different scenario where we had a patient on ITU with super refractory status epilepticus, who are PEG fed, they're tube fed, and 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 4:1 or a 3:1 to get ketosis fairly quickly, and then 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.
Ketogenic therapy for status epilepticus
13:17 Torie Robinson
It's interesting you mentioned the status epilepticus, but 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.
13:29 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 antiseizure medicines and some benzodiazepines, and it becomes super-refractory if after 24 hours of sedation with an anaesthetic we still have seizures or if we try and withdraw the anaesthetic the seizures come back. And certainly, for super-refractory status epilepticus, it's really high morbidity. The mortality is about 30 - 40%. 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. 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 the 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 FIRES in paediatric services and some adult studies. Response rates, we're talking in the region of 70 -80% respond.
14:44 Torie Robinson
Wow.
14:45 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 diet 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 we 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, ITU patient, in super-refractory status because the outcomes are so poor. And only for FIRES, I think we've got good data that ketogenic diet is really effective.
Ketogenic diet in adults
16:31 Torie Robinson
We don't have much data or evidence to support - [well,] there’s some - we'll talk, speak about your work, but much evidence about… into the benefits of ketogenic diets for adults. Why has it been so difficult to date 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?
16:57 Manny Bagary
Yeah, again, it's 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 was felt there was enough evidence to use ketogenic 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 ketogenic diet would stop working.
17:41 Torie Robinson
Huh, fair!
17:43 Manny Bagary
For those paediatric syndromes where it's proven that ketogenic diet is really effective, response rates are up to 70%, it's like some of the metabolic syndromes like GLUT1 and PDH, they still need those treatments as they hit adult services. And we potentially withdrawing those treatments because there isn't adult provision, I would think it's probably medically negligent. So, we really need to develop these adult services for… certainly for paediatric patients who are stabilised and are transitioning to adult services. We need to think about services on ITU, certainly in refractory status for FIRES, and probably other refractory status epilepsy syndromes. I suppose I'm slightly biased because I've been doing this for quite a long time [but] 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 30% of our patients who are really struggling to respond to antiseizure medicines.
Forms of treatment - when does the ketogenic diet come in?
19:10 Manny Bagary
And what tends to happen is we cycle through a series of antiseizure medicines and we try and rationalise using antiseizure medications with different mechanisms of action, although the evidence-based data is quite limited. And 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 hard to treat epilepsy, it's drug-resistant, and there's an ILAE definition, 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? What do we think about non-drug treatments? Do we think about neurostimulation? Do we think, know, VNS? We've got the new EASEE device. We don't really use deep brain stimulation in the UK; they do in America. And they've got responsive neuro stimulation in the States. And then, you know, are we thinking about surgical options? Has our patient got a lesion that might respond well to all 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. And 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 neuro-stimulation pathway, or are you going to think about ketogenic diets?
21:07 Torie Robinson
I agree. As, personally, as a somebody who has an epilepsy, I agree. I would say that if there's a chance that one may have one’s seizures controlled without removing brain tissue, why not give it a shot? It's not the same for everybody, of course, but it seems maybe I'm being very biased here, but it does seem kind of a good idea, no?
21:29 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, you know, temporal lobe 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 3-month outcomes predict the 12-month outcomes. And this is what a lot of studies are finding, that if ketogenic diet works, it doesn't suddenly stop working. So, a 3-month trial of ketogenic diet would really be merited before you progress down perhaps an uncertain surgical outcome.
Closing thoughts & thanks
22:28 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; from energy metabolism and neurotransmission 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’ll carry out 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. Schar, for partnering with Epilepsy Sparks. If you found today’s discussion interesting, please subscribe so 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. Thanks so much for joining us - and I’ll see you next time.