Epilepsy Currents – Episode 3 "Keto Is Not Just for Kids: A Randomized Trial of a Modified Atkins Diet for Adolescents and Adults With Anti-Seizure Medication Resistant Epilepsy"

Join Dr. Bermeo in a conversation with Dr. Mackenzie Cervenka and Dr. Manjari Tripathi as they discuss the article, " Keto is Not Just for Kids: A Randomized Trial of a Modified Atkins Diet for Adolescents and Adults With Anti-Seizure Medication Resistant Epilepsy ".

Click here to read the article.

This podcast was sponsored by the American Epilepsy Society.

We’d also like to acknowledge contributing editor Dr. Rohit Marawar, and the team at Sage Publishing.

 

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Five Key Takeaways:

 

1. Effectiveness of Modified Atkins Diet (MAD): The research conducted by Dr. Manjari Tripathi found that 26% of the people who supplemented their drug therapy with the MAD experienced a more than 50% reduction in seizure frequency compared to only 2.5% of people who used only drug therapy. Importantly, some patients even became seizure-free.
2. Improved Quality of Life: Along with a significant decrease in seizures, patients following the MAD also reported improved quality of life and behavior.
3. Difference in Adherence Between Adolescents and Adults: The study found that adults were more likely to adhere to the diet than adolescents, possibly due to a combination of food preferences and possible differences in gut microbiota.
4. Potential Long-Term Effects of Ketogenic Diets: While ketogenic diets can be effective in managing epilepsy, there are potential long-term side effects to consider, such as vitamin and mineral deficiencies, bone loss, risk of nephrolithiasis (kidney stones), and hyperlipidemia (high levels of lipids in the blood), which may lead to cardiovascular and cerebrovascular diseases.
5. Approach to Weaning off the Diet: Dr. Mackenzie Cervenka suggests that weaning off the diet should be considered in a similar manner to removing anti-seizure medication. The decision should be made considering the side effects and the overall burden of the therapy on the patient. Abrupt discontinuation of the diet can result in an increase in seizures, hence the diet should be gradually reduced.

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Dr. Adriana Bermeo (00:06):

Hello, and welcome to episode three of Epilepsy Currents podcast. I am your host, Adriana Bermeo. I am the senior podcast editor for Epilepsy Currents, the official journal of the American Epilepsy Society. It is my pleasure to welcome today's guest to talk about the use of ketogenic diets in the treatment of refractory epilepsy in adolescents and adults. First, I want to welcome our contributing editor for epilepsy current, Dr. Mackenzie Cervenka, who wrote a commentary titled "Keto Is Not Just For Kids: a randomized trial of a modified Atkins diets for adolescents and adults with anti-seizure medication resistant epilepsy". This was published online first in the March, 2023 issue of Epilepsy Currents. Dr. Cervenka is Professor of Neurology at John Hopkins School of Medicine. She's the medical director of the Adult Epilepsy Diet Center and the Adult Epilepsy Monitoring Unit. She developed the John Hopkins Adult Epilepsy Dietary Center in 2010 and has treated nearly 450 adults with epilepsy using ketogenic diet. Dr.Cervenka, welcome to Epilepsy Currents podcast.

Dr. Mackenzie Cervenka (01:16):

Thank you so much Dr. Bermeo for inviting me as a guest today at the Epilepsy Currents Podcast.

Dr. Adriana Bermeo (01:22):

It's a pleasure to have you. I also want to specially welcome Dr. Manjari Tripathi, who is the senior author of the publication that inspired this commentary titled "Safety, efficacy, and Tolerability of Modified Atkins Diet in Persons with Drug-Resistant Epilepsy." This was published in Neurology in March of 2023. Dr. Tripathi is a professor of neurology and epilepsy at the All India Institute of Medical Sciences, where she serves as director of the Epilepsy, Behavioral Neurology, and Sleep Medicine Programs. Dr. Tripathi, it's a pleasure to have you.

Dr. Manjari Tripathi (01:57):

Hi. Thank you. Great being here.

Dr. Adriana Bermeo (02:00):

Dr. Cervenka, I want to start with you. Our listeners may or may not be familiar with the concept of ketogenic diets for the treatment of epilepsy in adults particularly, but they may not know that there are different options for treatment. Can you please give us an overview of the principles of these dietary treatments and tell us what options can we can offer to our patients

Dr. Mackenzie Cervenka (02:21):

In our field? We refer to ketogenic diets for epilepsy actually as ketogenic diet therapies. And we do this to distinguish them from ketogenic diets that we typically hear about being used for weight loss or for other purposes, and that are not necessarily recommended or monitored by clinicians or treating teams. Technically, a ketogenic diet therapy is any dietary manipulation that can produce a state of nutritional ketosis, and that is a state where the body metabolizes fatty acids into ketone bodies. Those are beta hydroxybutyrate, acetoacetate, and acetone. There are a whole variety of ketogenic diet therapies, and these include what are called the classic or classical ketogenic diet. This was first described over one century ago. There are also modified versions of this classic ketogenic diet, specifically the Modified Atkins diet and a modified ketogenic diet. In addition to that, there is a low glycemic index diet or treatment, and that can also produce a state of ketosis, although it is not the primary goal of that particular diet, and any of these diets can be supplemented with medium chain triglyceride oil, and that is readily metabolized into ketone bodies. So that can be added to any of these other diets that I mentioned. Finally, these diets can also be combined with fasting, which also, encourages ketosis as well.

Dr. Adriana Bermeo (03:51):

Thank you so much, Dr. Tripathi. Do different options fit different demographics? Particularly I’m curious of why did your team choose to try specifically the modified Atkins diet in adults and adolescents with refractory epilepsy as opposed to other options as Dr. Cervenka was describing?

Dr. Manjari Tripathi (04:10):

So this is a very pertinent question. We need to give something which is acceptable, accessible, and affordable. Now, if you look at the traditional classic ketogenic diet, as Dr. Cervenka described it, it's a very restrictive diet, and it's rigid. It's rigid in terms that it restricts the calories and the fluids. It often requires weighing of food, at least in our center, the ketogenic diet requires the patient to be admitted for a washout and monitoring before the diet is started, whereas a modified Atkins diet does not restrict calories. However, it produces the same effect that is ketosis. So, it's more flexible, it's easier on the gut and the palate, and we know that adults and adolescence can be picky eaters and choosy. As you get older, you also get conditioned on the kind of foods that you eat. So in factoring all this, we decided that it'll be easier on our patients to have the modified Atkins diet, which is less rigid than the ketogenic diet. And hence we undertook the study with drug resistant epilepsy patients as compared to the classic ketogenic diet.

Dr. Adriana Bermeo (05:38):

Dr. Cervenka, how well accepted do you find these dietary treatments for among patients when you start them on, but also among neurologists and epileptologists? What, what do you think are the greatest barriers right now for them to be used more broadly in the clinic?

Dr. Mackenzie Cervenka (05:57):

I think it's interesting to look back at kind of the historical perspective of how the ketogenic diet evolved over time, because when it was initially introduced back in the 1920s, it was the only real treatment for epilepsy that was being looked at the time, and it was very popular then. It was being used for children, it was being used for adolescents and adults, and then anti-seizure medications became more readily available around the 1930s, and it really stopped being used for, for many decades, and it sort of reemerged in the late 1900s. However, when it reemerged, it was primarily in children. And so when you ask the question, how accepted is it as a treatment for epilepsy, I think it varies tremendously because I think now if you look in curricula for pediatric neurology residents, you'll see that ketogenic diet therapy is listed in that curriculum for pediatric neurology residents for a treatment of pediatric epilepsy.

Dr. Mackenzie Cervenka (07:01):

However, that may not necessarily be the case for adult epilepsy. And when I was in training and when I was learning about this I learned about ketogenic diet therapies from my pediatric epilepsy colleagues and wondered why it was not necessarily being used in adults and asked that question of my pediatric and adult colleagues and really did not have a good understanding of why that was the case. So I kind of delved into that a little bit deeper and discovered that there were plenty of epilepsy syndromes and seizure disorders that, that we knew the ketogenic diet was very effective for in children that adults also had. However, they were not necessarily being offered this therapy. And so really it has not been as well accepted in the adult population as it has been in children up until really the last couple of decades, to be honest.

Dr. Mackenzie Cervenka (08:01):

Now, something else happened that was very interesting, really around2017, and I refer to it as the keto craze, where the ketogenic diet suddenly became very popular for weight loss or different variations on the theme of the ketogenic diet. And I think this brought the concept of a ketogenic diet into the awareness of the general population such that there have even been individuals with epilepsy who started a diet for weight loss and then discovered that it helped with their seizures and began to investigate this and realized, oh, yes, it's been used to treat epilepsy for over a hundred years. So it's, it's a really interesting evolution. This has actually helped patients because those who have been treated with ketogenic diets have a lot more options with regards to foods that are available now because of the commercial availability of some of these foods being used for the purpose of weight loss. So I, do think that that has, has certainly helped with regards to barriers for the use more broadly in clinic the greatest barriers particularly for adults are the lack of familiarity of adults, neurologists, clinicians with diet therapies. So they have this discomfort just because they don't understand the diets or how to go about counseling patients for following these ketogenic diet therapies. Lack of nutritionist or dietician supports who work specifically with adults and also lack of reimbursement for these services. That is a very, very big barrier, particularly in the United States.

Dr. Adriana Bermeo (09:37):

Well, hopefully studies like the one we're discussing today will change some of those, you know, people getting more familiar and hopefully permeating all the way to finding more support and, different arenas. Dr. Tripathi, can you please give us an overview of the design and the results of this study you conducted among adolescents and adults with refractory epilepsy?

Dr. Manjari Tripathi (09:58):

Absolutely. So, when we are actually offering services of a drug-resistant epilepsy clinic, we are left with a large number of people with epilepsy who have been on many medications, typically two or more, and they still continue to have seizure and they cannot be offered epilepsy surgery because they have not been candidates for the same due to lack of a lesion or discordance of data. So we, in this study, prospectively enrolled patients who had been having seizures and they were having as many as 27 seizures per month. So when we enrolled these patients, when we analyzed the data, we found that they had at least 27 seizures per month. So that's a very high seizure frequency, and we followed up these patients for six months after initiating the diet. The patients were randomized into two groups, one group receiving the modified Atkins diet along with the conventional anti-seizure medication, which was not changed during the therapy.

Dr. Manjari Tripathi (11:12):

That means the patients were stabilized on anti-seizure medicines and they had a baseline seizure frequency before they were enrolled, and the other group continued to have their usual antiseizure medicines without the modified Atkins diet. Now, this diet is a medical diet, it needs monitoring, and our nutritionist and dietician was involved in monitoring these patients. But the assessment was done by a person other than us, and she was looking at the outcomes. We decided to take clinically meaningful outcomes, and in this case, of course, it'll be the reduction of seizures, which would be the primary outcome measure and secondary outcome measures would be change in behavior and quality of life. We also looked at their weight and their lipid profiles just to make sure that they weren't deranged by the end of the study. So basically it was a very well thought out and planned study and was undertaken after a lot of thinking to it as to what more can we offer our patients who are left without the option of surgery.

Dr. Manjari Tripathi (12:29):

So we had, as I told you, 160 people with epilepsy, which were drug resistant, having at least 27 seizures a month when we saw the results. And they had been having this resistant epilepsy for 10 years or more. So they were really, those, prolonged resistant epilepsy patients, and one doesn't know what to do with them when they're coming. And we've been taught ketogenic diet is for children. So we thought, you know, if we can't offer them something, they get enrolled into the study. What we found when we looked at the results at the end of the study was that 26% of the people who had taken both the drug therapy with modified Atkins diet had more than 50% reduction of seizures compared to only a minuscule 2.5% of people who had received drug therapy alone without the diet. And actually four people in the diet group became free of seizures.

Dr. Manjari Tripathi (13:32):

So you can imagine someone who's on four drugs or more having refractory epilepsy for 10 years or more, getting free of seizures. So four became seizure free. We found significant improvements in quality of life behavior. We did not find any per side effects. The diet was very well tolerated, and overall the patients felt a sense of improvement. However, a word of caution here, we were operating the trial during covid times, so we noted about a third of patients, 33% did not complete the study. However, we did an intention to treat analysis, which kind of overcomes the deficit of the dropouts, and most of them dropped out due to inability to follow up as a part of the COVID 19 pandemic. Some of them could not tolerate the diet, and some of them just dropped out because they felt it wasn't doing anything to them. So this was a limitation of the study, but I guess when we are doing studies which deal with something as a diet, this is bound to happen. So overall, it was a prospective randomized assessor blinded study, and it did pretty well for people who were refractory despite taking four or more medications.

Dr. Adriana Bermeo (14:54):

It's an, amazing design and study and really, really encouraging results. We noticed that the adult group in your study did better than the adolescents in regards to outcomes. Do you have any ideas of what, what would that have happened?

Dr. Manjari Tripathi (15:10):

Yeah, so at the end of six months in adolescence, about 36% of the patients who were on the diet had greater than 50% reduction, whereas in the adults it was 57%. Now, there could be several reasons for this, and I think the most important is that if anyone has dealt with this particular age bracket of adolescence, it's a difficult age. Generally, they're very picky about their food. They tend to like their carbs, they tend to binge on fast food, at least in India. The adolescents are typically into an American diet where they would want to have burgers and, you know, cola and, and chips. So, it's very difficult for us to consent them into the diet and any study cannot be done without consenting. So, one is of course that, and the second is, I guess though they were monitored for their compliance and their ketosis. There could be certain gut microbiome differences. We know that the diet works while acting at the neurotransmitters, whether it's promoting the inhibitory neurotransmitters, antioxidant mechanisms, anti-inflammatory mechanisms. It also works through there is a gut microbiome hypothesis for the mechanism of action of the diet. So there could be several other reasons, r this effect that we saw.

Dr. Adriana Bermeo (16:45):

I am convinced just to hear about the adherence in adolescence. I have a pre-teen at home. Dr. Cervenka. Can you talk to us a little bit about what considerations do we have for adults particularly following ketogenic diet therapies in regards to maybe long-term side effects or anything that they should be particularly wary of? Is there a specific time to them or liberalize the diet or discontinue them? And any practical points for, for our audience in regards adults in this therapy?

Dr. Mackenzie Cervenka (17:19):

I think it's really important to consider the differences between children and adults when you're considering how to manage the diet long-term. For instance, pediatric epilepsy syndromes may resolve in childhood, and many children are taken off of ketogenic diet therapies within a year or two of after starting them. Often they're taken off of their medicines, they're taken off of therapies, and we really don't have to think about these, what I call long, long side effects. I think particularly about individuals with glucose transporter type one deficiency syndrome, when I get concerned about long, long-term side effects because those are individuals that we believe are going to need to be on diet therapy long-term or perhaps lifelong. And some of those considerations include vitamin and mineral deficiencies. So, in particular zinc selenium, vitamin D carnitine deficiencies, we know that in children, even over the two years that they would typically be on a ketogenic diet therapy, you can see bone loss in those children.

Dr. Mackenzie Cervenka (18:28):

Typically, once the diet is stopped that reverses itself. However, if you're thinking about an adult who over time is at risk for progressive bone loss, you may be concerned that over time that can accelerate with the ketogenic diet therapy and there's mounting evidence that that could indeed be the case. We also know that nephrolithiasis is a risk with ketogenic diet therapies both in children and adults. And so of course for the longer that you're on a diet, the longer that you're at risk for having that occur. And then there's a body of literature looking at hyperlipidemia and potential risks for cardiovascular and cerebrovascular disease. One of the physicians here at Johns Hopkins investigator Dr. Tanya McDonald is looking into this at Johns Hopkins. And then there are researchers worldwide who are act actively investigating this topic as well, because certainly we're treating epilepsy, but we also don't want to be causing other long-term side effects over the course of a patient's lifetime that they're going to have to be dealing with later.

Dr. Mackenzie Cervenka (19:30):

So those are really the major ones that we are concerned about. Now with regards to weaning the diet in an adult, my particular approach is to think of it similarly to thinking of anti-seizure medications. So if there is an adult at an appropriate time for removing the anti-seizure medication, I would speak to them about removing the anti-seizure medicine, removing the diet, which of those things they would like to do first, we would look at the side effects and we would look at the overall burden of that therapy in deciding which of them we wanted to remove first if the patient was seizure free and if there was a good likelihood that they would remain seizure free after removal of that therapy. And then we would do that in a sequential fashion and we would wean rather than discontinuing it abruptly. And I think that's also very important because we have seen instances where if where a patient who abruptly stops the diet can suddenly begin to have a significant increase in their seizures, similarly to abruptly stopping an anti-seizure medication.

Dr. Adriana Bermeo (20:35):

Those are very, very really practical and, and useful considerations for us to manage patients in the clinic. Dr. Tripathi, we were particularly curious about the fact that you conducted this study in India, and we were wondering what particular challenges do you expect in different ethnic cultural populations? We imagine a good size of your, the population you deal with, maybe vegetarian. So what is your approach to handle this? Is it very prescriptive or do you give your patients freedom to find general rules of how to manage the diet?

Dr. Manjari Tripathi (21:12):

Well, it's not difficult at all. The key to success at least what we perceived in our study was a highly motivated caregiver team, and mostly it would be the mom. So many patients and their caregivers ask us, what can we give to eat to our child or to our patient with seizures? And previously, you know, when we weren't using diets, for reducing seizures, we would just brush the question aside and say, oh, the normal diet. But now when people or caregivers ask us that, is there any specific diet that's a good step where you then tell them about the possibility of manipulating the diet or modifying the diet in such a way that the proteins are more and the fats are more, and the carbs are really, really low, and that gets them interested. So rather than telling them straight away that it's a medical diet, we just give them a brief introduction and you'd be surprised how well they take it.

Dr. Manjari Tripathi (22:25):

For vegetarians, it's not a problem at all because majority of our people were vegetarian around 75%. And we do have very good protein options in you know, the vegetarian food particularly the soy protein, soy milk. And of course in India we have a lot of use of coconut oil too and other forms of healthy oils. So more and more, you know, mustard oil, olive oil, and we have particular form of fat, which we call the clarified butter, or ghee, which is made at home usually from the cream of the cow's milk. So many of our moms and caregivers are quite used to this kind of diet, even though they may be vegetarians. And if you look at the Indian scriptures, it's a little, you know, story I'm telling. We had one avatar, which was the Krishna avatar, and he thrived on stealing butter from and eating butter from the villagers' pots.

Dr. Manjari Tripathi (23:35):

So basically his diet was all ketogenic, it was high butter diet. So, when we tell them that the diet is going to be somewhat like what Krishna used to eat, they get even more thrilled. So, we did not find any kind of setback due to the vegetarian. The most important thing which we felt was to have a motivated caregiver, a motivated mom. And, you know, many of our people have heard of these diets reducing the weight, though we used to caution them that, you know, your weight may not reduce it may or may not, they would get all excited about it. And I think that was good too.

Dr. Adriana Bermeo (24:23):

Thank you so much for that perspective. Really interesting. Dr. Cervenka, we started with the history of these diets and definitely a rich history into them. But I would love to wrap up by asking you, what do you envision in our, in the future of these dietary therapies and how will they continue to be incorporated in our comprehensive epilepsy approach in the clinic? Do you see them becoming or be considered earlier, even before patients become refractory?

Dr. Mackenzie Cervenka (24:54):

So I've definitely envisioned several scenarios where that could be the case. I think the most obvious one that I had mentioned before would be glucose transporter type one deficiency syndrome. And I, I wouldn't say that that's really in the future. I think that that's happening now because we understand that ketogenic diet therapy is the gold standard for this condition. So as soon as patients are diagnosed, we place them on the diet. We understand that in fact, diet monotherapy in that case is going to be the most effective treatment. And so there are plenty of patients now with that particular syndrome that are on diet monotherapy and doing extremely well. So that's a very exciting example. There is also some evidence to suggest that certain generalized epilepsy, such as absence and juvenile myoclonic epilepsy that those patients respond very well to ketogenic diet therapies. So I can also envision scenarios where we might want to consider diet earlier in the management of those patients. In particular, whenever we're thinking about starting the diet in anti-seizure medication resistant patients with focal epilepsy, we do know that epilepsy surgery is more likely to produce seizure free then diet therapy. However, we don't have those options to offer patients with drug resistance generalized seizures. So I think we might want to consider diet therapy earlier in their management. That's one place that I can envision starting diet therapy earlier.

Dr. Adriana Bermeo (26:30):

Well, that's a wonderful place to end our conversation today. I want to really thank our guests for this fascinating conversation, and I want to thank our listeners for joining us today. We look forward to having you at our next episode. As always, please remember to subscribe to Epilepsy Currents podcast wherever you get your podcast, and send us your feedback, suggestions, or questions through our website, epilepsycurrents.org. And don't forget to follow us on Twitter at @AEScurrents. Until next time.