Ask the Mito Doc – September 2025 Q&A
All answers today are based on personal experience of the participants. As always, please consult your personal physician prior to taking any action.
Topic: Seizure Management in Patients with Mitochondrial Disease
Clinician:
- Russell Saneto, DO, PhD, Seattle Children’s Hospital, Seattle, Washington
Q: Do you think a ketogenic diet is beneficial in controlling seizures/ movements in mito patients? What factors should be made in considering that diet?
A: For one, whether you’re G-tube fed or an oral eater will dictate the different types of high-fat diets that you may be able to tolerate. In a 4-to-1 diet, which is the classic ketogenic diet, if you just go in your cupboard and pull out one Triscuit, that one Triscuit has all the carbohydrates you’re allowed per day. Everything else has to be fat. So you can tell that that’s going to be hard to do. But you can do that through G-tube feeding very easily. Now, whether you tolerate it or not, that’s a different story. For oral eaters, we often do the modified Atkins diet, which allows you 20 to 30 grams of carbohydrate per day, and then you can mix your meals, and it’s a per day thing. Most of our patients, if seizures are reduced they buy into the modified Atkins diet and do pretty well. We use Keto for Ph deficiency right away. We’ve been using the ketogenic diet in that syndrome for a long time. What we’re finding is that some of the mtRNA synthetase drugs or genetic defects can be helped by the ketogenic diet. We just published a paper looking at VARS-2 and the tissue culture cells do much better on keto. So, we’re starting to see more precision medicine there. Alpers-Huttenlocher Syndrome is a work in progress. We’re trying to manipulate different inhibitors and enhancers of glutamate versus GABA. Since we are doing this, that’s more precision medicine. What we also know is that the ketogenic diet has a mTOR enhancement or inhibitory part of it. But it can also enhance mTOR in a certain population. So in the Leigh Syndrome mouse model if you give mTOR stimulators, you can alter the disease course, and you can help with seizures. And so, oftentimes, in Leigh Syndrome, we think of a ketogenic diet.
Phenoquinone did not get FDA approved either, but that’s a really good medication that we found for seizure control, but hopefully we’ll figure out another drug like it. So, the ketogenic diet can be helpful.
Q: My 17 year old takes Keppra, Clonazepam, and Depakene to control his movements; I’m concerned about the side effects of these medications. What can patient families do to limit the side effects or make them less?
A: Well, one is to use less of them. We try to use no more than 2 to 3 seizure medications at one time. Seizure medications, because they were invented to treat focal versus generalized, they are shotguns. They’re heavy hitters. They really do their job well. Because they do their job well the normal activity of neurons talking to other neurons is also altered. So, for instance, let’s say you’re learning to write ‘cat’, C-A-T, you’re stimulating certain neurons in your hippocampus. And you’re stimulating them over and over again, and when you stimulate them over and over again, you’re increasing their activity until it becomes so entrained that you think of cat, and in your mind you see a cat, and you can write it. And that’s what we call making synaptic connections. When you have seizures, what happens is those synaptic connections are frayed, and you lose them so you lose that memory. Well our drugs are developed for epilepsy to inhibit the synchronization of networks. Stimulating particular networks that induce synaptic connections to allow you to have more seizures. That’s called Kindle. So, learning and reducing seizures are part of the same process to different degrees. Epilepsy drugs can be very cognitive challenging to a patient, because we’re inhibiting the learning process of stimulating particular networks of neurons to learn a new task. You don’t want to use too many, because you’re causing the diminishing of those networks to be stimulated. The benefit of the third generation drugs is that it minimizes side effects. If possible, you want to use the third generation medications more than the second generation drugs.
Q: What causes the lesions in metabolic strokes and is there a document describing this phenomenon?
A: Essentially, yes. You can tell that you get tissue death by the MRI findings. And there’s a mixed vasogenic signal that we see in MELAS and stroke-like episodes. It’s the lack of oxygen to that area that’s causing breakdown and cell swelling. We sort of know what’s causing them, they’re not getting enough energy. They’re not getting enough fuel so the cells die. By MRI scans you can see they don’t get enough oxygen, you don’t get enough nutrients into the brain because you’ve got a thrombus, in this case, and not the capillaries that are arterials that are tied so that area dies. And on MRI scan, you can see It means diffusion-weighted, and so you get a mixed vasogenic diffusion-weighted abnormality in the area of the stroke-like episode so you sort of know what happens. The same thing would happen in a regular stroke. So one is due to a thrombus of some sort, and the other one is due to this mismatch of oxygen-nutrient need, and not enough blood vessel to get it there. The end product is pretty similar, and that’s why they call it stroke-like.
Q: Can metabolic strokes occur in ocular vascular territories or in the occipital lobe and involve yellow tint, grainy vision alternating with clear vision?
A: Since the capillary beds are where the mitochondrial are dysfunctional, little arterials, that probably is engrossed and dies. So downstream, you’re losing all the brain matter because those don’t exist anymore. And so you’re losing the mechanism to get blood to that area, in other words, nutrients to that area to function. So, theoretically, like in Moyamoya, you might be able to bypass some of that by producing more blood vessels around the stroke-like area.
Q: Do medications differ between children and adults?
A: Only the amount. We dose children by their weight. In adults, we figured they’re all fat, and so we just give them a dose that’s been shown in a normal weight adult to be effective. We start there, and then you add or subtract depending upon side effects.
Q: Are there things that people with mitochondrial conditions who are not affected by epilepsy can do to prevent the development of epilepsy? Or is the development of epilepsy random among those with mitochondrial conditions?
A: Just like any disease process; 1. A good diet. The folks at CHOP have shown that for
mitochondrial disease patients have core diets. 2. A good sleep. If you do a sleep study, most of them have fragmented sleep so we need to figure out how to get people better sleep. And I think that’s an area that hopefully, over time, we’ll learn more about, especially in mitochondrial disease. Not much is known about sleeping, other than it’s fragmented. Nutrition, good sleep, and healthy habits. You just have to live a good, balanced life.
Q: What is the progression of the stroke like episodes as far as the effects on the blood vessels? How is a stroke-like episode and a seizure the same and how are they different?
A: Well, usually when you have a stroke-like episode, downstream brain is demanding more energy and that extra demand is causing more blood flow to try to go to that area. But the mitochondrial dysfunctional within the capillary beds, the arteries that take the blood to that portion of the brain, that’s not getting enough oxygen now and glucose is starting to die off. And so, the manifestation of the stroke is actually where the stroke happens. And if it’s in delicate neurons in a particular region that can reduce seizures, that’s where you get seizures. Now, there’s something that I’ve wanted to try, and I’m starting to try in my MELAS patients. There’s a genetic type of vascular vasculopathy, which is what we would call MELAS, and we’re seeing benefits using Epidiolex. The Epidiolex works really well in the Sturge-Weber group. And it’s the same problem with imbalance between how the brain is demanding energy and this loss of vasculature around that brain area. So Epidiolex may be a good medication for MELAS once you start to have seizures. We don’t know yet but etiology-wise, it’s starting to make more sense to try Epidiolex as first line. Now, the problem is, Epidiolex is only FDA approved for Dervais and Lennox-Gastaut syndrome and Tuberous sclerosis complex (TSC). So you have to fight your insurance companies, but it’s a pretty easy sale if you just give your insurance company the data suggesting that it could be helpful for vasculopathies, since MELAS is a vasculopathy. Epidiolex doesn’t have very many side effects, so it’s a good mechanism.
Q: Can oxidative stress, as measured by glutathione (reduced to oxidized ratio) and ketone tests, be an underlying mechanism for seizures? Can a Nav1.8 inhibitor like suzetrigine, which is an inducer of CYP3A4, reduce the effective dose of oxcarbazepine which is a substrate of CYP3A4, thereby triggering seizures?
A: The short answer to that is yes. The long answer is, it’s likely due to a process called ferroptosis. And it’s GPX4 driven. We need better drugs to treat GPX4 and enhance its activity. That would reduce the glutathione loss that is eaten up by Oxidative stress in the lipids. We’re starting to get drugs that are somewhat beneficial for GPX4. One of which was Phenoquinone, which didn’t get FDA approval. Researchers like Stockwell at Columbia University are really into this, looking at small molecules. And in one patient who had a primary GPS defect they passed 10,000 different compounds, and he actually found one that worked. So, it’s just a matter of effort, right now. We’re learning more about it, we’ll find better medications for GPX 4 enhancement. And I think down the road, that’s going to be helpful for a lot of different syndromes there. We’re dealing with that can cause seizures.
Q: I feel like I’m about to blackout from time to time, but I snap out of it after a quarter of a second, is that seizure activity?
A: Likely not. We all have those moments when we’re sort of fog-ish, going into a brain pop, and then you kind of snap out of it .Sometimes related to lack of sleep, sometimes related to just being super tired. You know, big day, and you’re kind of decompressing. Other times, let me say this to parents. You know, little Sally is really bright, and her teacher’s really boring, and she’s just checking out, because, you know what? Teacher’s boring and she’s not learning anything. And there’s bird on the tree outside her window is much more interesting than her teacher. Now, the teacher would say, I give such good lectures kids love me, and they always pay attention. Sally is having a seizure. We could go on. So, there are a lot of other circumstances that are just normal little glitches that we all go through that aren’t seizures, but sometimes can concern you.
Q: Is it possible that valproic acid taken for a year could trigger LHON and become affected in someone who didn’t know they were a carrier? And what medications and/or interventions work best in people with LHON and epilepsy?
A: Well, anything’s possible, but we don’t know why there’s such a penetrance difference between patients who have like the 11778 mutation. Why is it mostly guys that get it and not women? Estrogen protective, it’s testosterone causative. We do know that smoking is a trigger for many patients and why we really don’t know. Mark Tarnopolsky thinks that sunlight can be a trigger in some patients. So he recommends sunglasses depending upon where you live. That’s a work in progress, and we need to learn more about what is actually the trigger. You’re not going to be on valproic acid unless you have seizures. So I don’t know the data on seizures and then propagating typical retinal optic nerve findings in Leber’s. So it is possible but I have no data on.
Q: A surprisingly high number of people with an LHON mutation report seizures. Many more report epilepsy. Do you have any specific recommendations for those individuals?
A: That’s an interesting question. There’s never been a study. The 11778 mutation that’s most common that causes Leber’s hereditary optic neuropathy I would say, just in my own mind. It’ll be interesting to see what gene transfer does once it becomes clinically available. Because that is a genetic, that’s been tested through a Phase III trial. And hopefully that’ll be accepted. And hopefully, using that will help seizures. Certainly, we don’t know. And certainly you would go through and try to use the least offensive.
Q: Is neurosurgery sometimes an option for individuals with mitochondrial disease? If so, do patients tend to recover well and are there positive outcomes as far as seizure control?
A: We are learning and starting to do this at Seattle Children’s, looking at deep brain stimulation for intractable epilepsy for children that are older. Also for dystonia. There is literature in mitochondrial disease.
Q: In mitochondrial disease, we see interneuron deficits and excitatory, inhibitory imbalance driving seizures, but also depression, anxiety, and cognitive symptoms. In LHON for example, mental health challenges are common even without seizures. How might precision interventions being developed for seizure control also inform strategies to address these psychiatric and cognitive outcomes? And what would it take to design an implementation approach… Approaches that integrate both. Basically, do you think that some of the mental health pieces would improve?
A: It’s a difficult question to answer, because a lot of the behavioral problems we don’t really understand the etiology. We don’t understand in totality why mitochondrial patients are more likely to have certain types of neuropsychological problems like chronic depression, bi-polar disease, schizophrenia-like symptoms. It depends actually on what neurons, what brain area, and the population of neurons within that brain area. What’s living and what’s being pruned away. And that’s something we don’t know. And if you don’t understand how a process occurs, then treating it is like you’re just throwing things at it. We learn some things, like in chronic depression it is likely a serotonin depletion problem. And you give SSRIs, which are serotonin and reuptake inhibitors. You increase the serotonin and depression gets better. We know the constant stress from having a chronic disease depletes your serotonin. So, patients need more serotonin. And then they don’t sleep well because melatonin is made from serotonin, and melatonin gets you to sleep but if you don’t have enough serotonin because you’re stressed out, you don’t sleep well, which stresses you more which depletes your melatonin more, and so it’s a cycle. So you need to start treating some of that. But from the etiology point, nobody really understands.
Q: Is PNES (Psychogenic Nonepileptic Seizures) more likely to be diagnosed in mitochondrial disease?
A: So that’s when you have what looks like a seizure, but isn’t driven by cortical activity. There are a lot of movement disorders in mitochondrial disease that look like seizures but they aren’t. And so a parent looking at their child would think it looks like epilepsy and they would bring the child in, we would get an EEG, and we would capture the movement, and it’s just myoclonus so it’s not driven by the cortex, so theoretically, it’s not a seizure. But it looks just like a seizure. When you do that enough to a particular provider, he’s going to call it a functional neurological condition, which is a non-epileptic event. But it’s the provider that needs to show the parent that it is not driven by the cortical activity. It’s driven by something deeper in our brain or spinal cord and it’s a self-activation, a quick jerk. Essentially, we all have those. It’s called Sleep Myoclonus, and we all jerk as we go to sleep. So those aren’t seizures, those are driven by just abnormal stimulation of dorsal root ganglion cells or just kind of jerk a little bit. The same thing can happen when you’re concentrating…and somebody comes at the door and you get a startle reflex. So there are things that look like epilepsy that aren’t, that can get called PNES but they’re just sometimes part of your disease, sometimes it’s part of something else so that’s why we bring you into the EMU, hook you up, and try to reproduce one of your symptoms, because then we could tell it’s not functional it’s just something else. It’s a startle. Or it’s a benign sleep myoclonus, or something like that.