Advances in Treatment for Epilepsy-Use of Dietary Therapies in the Management of Refractory Status Epilepticus

Video Transcription

So I'm going to talk about my favorite topic in the entire world, which is use of dietary therapies in the management of refractory status epilepticus.  Thank you so much for the opportunity to come today and wow, oh my goodness, there are so many people in this room.  And thank you all very much for being here as well to listen to these wonderful presenters.  So here are my disclosures. The disclosures I have that are relevant to the talk that I'm going to be giving today.  I do have disclosures with Nutritia and with Vitaflow, which are both companies that produce ketogenic formulas.  And I will be talking about dietary therapies and ketogenic formulas. However, I won't mention particular ones by name. All of my other disclosures are not relevant to this talk.  The learning objectives for today are to define the potential role of dietary therapies, and in particular ketogenic diet,  in the management of refractory and super refractory status epilepticus,  and to incorporate current recommendations and identify pearls and pitfalls in utilizing these therapies in a critical care setting.  Now, you heard in the poster session this concept of time is brain because we just learned that the longer status epilepticus goes on,  you have these changes that happen in the brain, and we've known this for a very long time.  We have learned as neurologists that you're supposed to treat stroke urgently. Time is brain.  And I'm not sure why that hasn't caught on as quickly when we're thinking about status epilepticus, but we are still trying to move forward with that.  And as you heard, going from 30 minutes to 5 minutes with the definition of status epilepticus is a good first step.  And what has evolved over time are a variety of treatment algorithms that we all are familiar with for first line, second line therapies for status epilepticus,  and really the ESET trial was very instrumental in helping us figure out what some of these therapies might be, what doses to use,  and so now you can see just an example of some of these algorithms that are currently being used.  Now, once those first and second line therapies fail, as you all know, then we kind of call it the wild, wild west, right?  So we start, we intubate patients, we sedate them with general anesthetics. This is just an example from 2011 of some of the drugs. This was over 10 years ago.  We're still using these same drugs, same doses, trying to sedate patients and hope that when we take away those anesthetic drugs that, in fact, the seizures have gone away.  And so that is kind of the current state of affairs with regards to refractory status epilepticus. And these numbers haven't changed too much since 2011.  So what we know is that with refractory status epilepticus, I think of it as a third, a third, a third, about a third of patients will die,  about a third of patients will survive but will have significant disabilities, and about a third of patients will actually leave the hospital and be able to return to baseline.  And when we say baseline, a lot of those patients still have chronic epilepsy following discharge from the hospital,  so really sometimes not even to that point where, how they came in initially. And then with super refractory status epilepticus, so we wait 24 hours.  We either try really hard to sedate the patient and to suppress the seizures and we're not able to do so in those 24 hours,  or after the 24 hours we take away the medicine and find out that the seizures just come right back.  Actually, about 50% of those patients will die of super refractory status epilepticus. The problem is this is not a sustainable disease.  You have to keep treating it, and there's no way to really be able to sustain life unless you're able to control it.  And so there has been, and I'll come back to this later, a clinical trial that attempted to treat super refractory status epilepticus,  and around 40% of the placebo group responded and around 40% of the treatment group responded, and that was with allopregnenolone.  And so that at least gives us a picture of what our expectation is with regards to the current therapies  or the current management that we have when we're talking about super refractory status epilepticus.  So I just want to point out, take a moment to think about a patient who is sedated, who's intubated. Usually that patient also gets a feeding tube.  That usually happens around the time of intubation. Some interesting things happen in the critical care setting.  So we don't always feed patients right away, but actually just feeding patients, there's a lot of really good evidence that feeding patients can actually improve outcomes,  but often we put the tube in and they hang out for a little while. So what you see here is kind of what a standard enteral formula is. It's sort of like the standard American diet.  The majority of that formula is carbohydrate and a smaller percentage fat and protein.  Now my suggestion, something for us to think about as a group, well, could we order a different formula maybe? We know that ketogenic diet works for kids and adults with epilepsy.  Why would we be giving them this high carbohydrate formula when we just have to go and place that order? So just something to think about. Now I want to talk about ketogenic diet.  It used to be I would talk about ketogenic diet and no one had ever heard of it.  Now I talk about ketogenic diet and people will say, oh, I'm on that or my grandmother's on that or somebody is on that.  So I just want to now tell you guys what the ketogenic diet actually is because it is different and we actually use the term ketogenic diet therapy among our group or therapies  because these are really treatments, they're not fad diets. And so with the classic ketogenic diet, we talk about it in ratios.  Ratios are the ratio of fat to carbohydrate and protein combined in grams. And so when we think of it that way, they're almost like doses.  So a 3 to 1 ratio is a lower dose ketogenic diet than a 4 to 1 ratio. If we're talking about a patient who is able to communicate with us, who is able to swallow and eat by mouth,  we would actually be weighing those foods with a gram scale in order to create the ratio that's appropriate for that patient.  In the setting of status epilepticus, we pick out a formula, we order it, and the formula is ready to be used.  Some centers and some protocols will use a fast at the onset of using the ketogenic diet.  It takes about 24 hours for people to be able to use up their glycogen stores to start to get into ketosis. And so sometimes a fast can actually kickstart that.  If you look at patients who are intubated and sedated in an ICU setting, often they have been fasting for a period of time. So that sort of kicks off the ketosis.  And in fact, in our center, when we were first starting to look at this, I just looked at patients in their first 24 hours in the ICU.  And they were in ketosis, about 14% of them, when we hadn't even started using the diet yet. And so just something to keep in mind. And so there are commercial tube feeds.  And one of the advantages, several advantages, they contain multivitamins, calcium, vitamin D. So they're nutritionally complete.  Potassium citrate is something that you want in your ketogenic formula because it can prevent kidney stones.  And then carnitine supplements as if you're going to be using the diet long term. Fiber can help with reducing issues like gastroparesis and constipation.  And then medium chain triglyceride oil is something that is in some ketogenic formulas or you can add to ketogenic formulas.  Medium chain triglycerides actually can be metabolized through the liver into beta-hydroxybutyrate, acetoacetate, acetone,  so the basic ketone bodies, much more quickly than other forms of fatty acids. And so this is one way in order to be able to really boost ketosis.  And when we talk about ketosis, what we're talking about is producing ketone bodies and achieving the state.  Now, this is another question I'm going to get to is what should our definition of ketosis be? We were talking about this earlier today. We really don't know.  We talk about the diet like a dose of medication, but we actually don't know just yet what the therapeutic level is with using a ketogenic diet.  Now, if patients have intolerances, allergies, you can also use the diet with blenderized foods.  And so with regards to anti-seizure mechanisms of action, I am not going to actually delve into this.  I'm going to refer you to this wonderful review article by Rowe and colleagues because as you can see,  these are just topics of different ways in which the diet works, and underneath each of these topics are about four or five subtopics because the diet is not like anything else.  That's why you keep hearing about it being used for everything is because it does so many different things.  And what it does for epilepsy and status epilepticus is different than what it does for Alzheimer's disease or what it does for brain tumors.  And so please take a look at that article, which is just fantastic. Now, one of the mechanisms of action that I was most skeptical about in the context of status epilepticus  is this concept that actually it alters the gut microbiome and actually increases the proportions of acromantia and parabacteroides in the gut,  and that elevates the GABA to glutamate levels, and that can suppress seizures. And when I heard this, I'm like, that is fantastic. That makes perfect sense.  Of course, this is why it works. But then I'm like, is it going to do it that quickly?  And so I've been pestering the researchers that have done this work, and they tell me that this happens in a matter of hours.  Now, this is in animal models, but it can happen in a matter of hours. And so possibly it still could be a potential mechanism in status epilepticus.  Now, the other mechanism that I just want to draw your attention to is anti-inflammatory properties.  So when we think about our patients with encephalitis, when we think about patients with Nourse in particular,  we're looking at a lot of different therapies that you're going to hear about in just a moment.  But one of the things that the diet has been shown to do in a variety of different conditions and models is to reduce pro-inflammatory cytokines and chemokines.  It actually reduces local inflammation. And one of the reasons that we see that it does this is this elegant study that was done looking at actual beta-hydroxybutyrate itself,  one of the ketone bodies that blocks the NLRP3 inflammasome, which decreases the production of these pro-inflammatory cytokines.  And so you'll hear again about some of these different strategies for reducing inflammation. But guess what? The diet does it too. So like I said, the diet does everything, right?  So how do we use the diet? Obviously, not everyone here works with a dietician.  Not everyone here has a center where they can just start the diet and push the button and order the ketogenic diet and everything works perfectly.  So what is the protocol for incorporating it in the setting of refractory and super refractory status epilepticus? It is an adjunct to anti-seizure medications.  I just point that out because sometimes people get confused. They think, oh, we'll just start the diet and we'll take away all these other things. That's not how the diet works.  As I mentioned, it takes at least 24 hours to be able to start getting into a state of ketosis. We don't know exactly how much ketosis is needed to suppress seizures.  So you always want to still have the anti-seizure medicines.  You always want to have the anesthetic on board and then start to take it away once you see that the patient has reached a state of ketosis.  There are a whole list of labs up here, and that is because there are contraindications to the diet. So I said, oh, let's put everyone on the diet.  That's not true because there are, for instance, metabolic conditions that are very serious in children, and if you put them on the ketogenic diet, they will die.  So that's where we see things like plasma acyl carnitine levels, urine, and plasma amino acids.  Those are measured in children before they are started on a ketogenic diet if it's a young child  and there's any concern about one of these metabolic abnormalities because you really cannot start those patients on the diet.  Some of these other things are just to make sure there's no underlying deficiency that needs to be addressed,  and then urine HCG is because we do not know if the diet has any teratogenic effects.  If we're using it in refractory status epilepticus, we're probably using it for a short period of time,  and there may be other concerns that we have on our minds as well, but we still just don't have an answer to that question yet. We always want a nutrition consult.  We want to remove dextrose from IV fluids, change all medications to low-carbohydrate preparation,  and start a nutritionally complete enteral ketogenic formula meeting estimated caloric needs.  Now I'll show you a couple of recommendation papers, one of which says use a three-to-one ratio diet in children under 18 months  and a four-to-one ratio diet in children over 18 months or in some cases two years and over.  I'm just quickly going to go through these slides because each year I add a few more studies to it, and these are the studies that have come about in 2020 onward.  If anyone has done any studies that I've missed, I apologize and come talk to me afterwards, but these are the ones that I found.  And what you'll notice in the very, very, very small print that you probably can't see is that these studies are looking at the feasibility and safety of using a ketogenic diet  in the setting of refractory or super refractory status epilepticus. The largest study is in 16 individuals.  There are some in children, there are some in adults, there are some in both. Most are retrospective, and they are not comparison trials. They are safety and feasibility trials.  So I will just briefly touch on a few of them. This was a study that we conducted with collaborators from Rochester,  from the Queens Medical Center in Oahu, and also Thomas Jefferson. And what we found is that in 15 adults, this was a prospective study,  all were able to achieve a state of metabolic ketosis on a four-to-one ratio ketogenic diet with a median of 10 days after the onset of super refractory status epilepticus  and 73% of enrolled participants had resolution of super refractory status epilepticus. Remember, that's compared to 40% with these clinical trials that have taken place.  This is another study that was done more recently looking at refractory status epilepticus. So these are patients that actually started the diet much earlier.  So they started it after the anesthesia was begun. And you can see the majority were able to achieve ketosis in one day, almost all of them,  a 10 out of 11, and 73% of enrolled participants had resolution. Well, gosh, that number sounds very, very similar. And here's another one. So this is a study done in 14 children.  93% achieved ketosis, and their ratios were anywhere from three-to-one to five-to-one, and 71% of enrolled patients had resolution of refractory status epilepticus.  So one of the authors is here in the audience, Neha Kal, and so these are some practical considerations and practical recommendations  about how to manage refractory and super refractory status epilepticus in the pediatric and in the adult population. So a few important points as we're wrapping up.  First of all, time is brain. I think I've said that enough times, so I can move on. The second thing is if you are trying to induce ketosis and you're having difficulty,  consider medium-chain triglyceride oil, palm kernel oil, coconut oil, and then get pharmacy involved.  This is a multidisciplinary approach to the management of super refractory status epilepticus. So either avoid or account for lipid content in ibupropofol.  There is one study that actually showed a propofol infusion syndrome that resulted in the death of a child when it was combined with ketogenic diet.  So just make sure that if you're considering using propofol that you're really taking into consideration that lipid content.  IV drugs can have propylene glycol, which can suppress ketosis. We don't know if that affects the seizures or not.  We have no idea, but those can be IV phenytoin and pentobarbital in some cases, and we do know that that can suppress ketosis.  Tablets and IV medications have lower carbohydrate content in general than liquids and syrups,  and just make sure if you have those perfect when you leave for the day that they stay perfect overnight  because there can be well-meaning people that might change things around in the middle of the night not realizing why you did that.  So having order sets available, actually putting in that the patient is allergic to dextrose,  those can be ways that can trigger your electronic medical record to not let that happen. And then you have to treat if the CO2 levels go down  because otherwise the patients can experience acidosis. And then finally, hypoglycemia. We actually don't know how much hypoglycemia we're willing to tolerate and when,  so we don't know the exact cutoffs for when to treat. But if you overtreat, it takes another day to get back into ketosis. It's totally unfair.  It's really hard to get into ketosis, and it's really easy to get out of it. So time is brain. A ketogenic diet can be safe to start in patients of all ages  with refractory and supra-refractory status epilepticus. However, randomized clinical trials examining the efficacy of a ketogenic formula  and the management of RSE and SRSE are needed. Thank you very much.

Video Summary

The presentation explores the use of ketogenic diets in managing refractory and super refractory status epilepticus, highlighting dietary therapies as adjuncts to conventional treatments. The speaker emphasizes the critical nature of timely intervention, drawn from the "time is brain" concept, and challenges the traditional high-carbohydrate nutritional practices in critical care settings. The ketogenic diet, known for its roles in various medical conditions, is portrayed not as a fad but as a structured treatment involving ratios of fat to carbs and proteins. Studies show the diet's feasibility and safety; however, large-scale, comparison-specific trials are scarce. Despite promising results, further research is warranted to solidify understanding of its efficacy and optimal application parameters. Key considerations include patient monitoring for ketosis, managing nutrition-related complications, and integrating multidisciplinary approaches to ensure proper diet implementation alongside other anti-seizure measures.

Asset Subtitle

Presenter

Mackenzie Cervenka, MD, is a Professor of Neurology at Johns Hopkins School of Medicine. She completed her undergraduate studies at the University of Virginia and received her medical degree from the University of Virginia School of Medicine. She then completed neurology residency training at the University of Maryland Medical Center followed by a 2 year fellowship in epilepsy at Johns Hopkins University School of Medicine. As a faculty member of the Johns Hopkins Department of Neurology, Dr. Cervenka is Medical Director of the Johns Hopkins Adult Epilepsy Diet Center and the Johns Hopkins Adult Epilepsy Monitoring Unit. Her clinical research focuses on the feasibility, safety, and efficacy of ketogenic diet therapies in the management of adults with epilepsy and refractory status epilepticus as well as other neurologic disorders.

Keywords

ketogenic diet

status epilepticus

dietary therapies

critical care

patient monitoring