NeuroVoices: Orrin Devinsky, MD, on Metabolic Changes and Benefits of Modified Atkins Diet in Epilepsy Surgery

Orrin Devinsky, MD

Previous literature has shown that brain metabolism is altered in epilepsies, playing a role in seizure generation and also altered as a result of seizure activity. Variations of the ketogenic diet, including the more flexible modified Atkins diet (MAD), have been used to reduce seizure frequency in some treatment-resistant patients with epilepsy. Recently published in Epilepsia, a group of investigators assessed molecular mechanisms in brain tissue and plasma from adults with epilepsy after an average of 10 days of MAD prior to brain surgical resection compared with controls that consumed a non-modified, higher carbohydrate diet.

At surgerical resection, both peripheral blood and brain tissue were collected. All told, at the conclusion of the study, there were 13 increased metabolites in plasma that included a 4.10-fold increased ketone body 3-hydroxybutyric acid, decreased palmitic acid in cortex, and 11 decreased metabolites in hippocamps that had top associations with mitochondrial functions. Led by Orrin Devinsky, MD, the study also showed a 2.75-fold increased hippocampal MT-ND3 and trends in hippocampal NADH-related signaling pathways such as activated oxidative phosphorylation and inhibited sirtuin signaling.

Devinsky, director of NYU Langone’s Comprehensive Epilepsy Center, sat down as part of a new iteration of NeuroVoices to discuss the reasons for the study, and why these findings are so significant. He spoke specifically about the metabolic changes observed in patients with epilepsy and why these data provide greater insight and clarity on the steps prior to epilepsy surgery.

NeurologyLive^®: What were the origins of this study, and why did you feel as though you needed to conduct?

It’s a fascinating opportunity. Many centers throughout the United States and in the world are involved with epilepsy surgery in a subgroup of people with focal epilepsy whose seizures can be localized to a region that can be safely removed. That tissue has provided a wealth of information about both normal processes in the brain and the underlying mechanisms of epilepsy. Another opportunity is that we can use that tissue to look at changes in the brain or blood and compare them under a variety of different interventions from medications that might help reduce seizures, to drugs that might affect the mTOR pathway in people with tuberous sclerosis or cortical dysplasia.

In this case, we looked at the modified Atkins diet, which is a form of a low carbohydrate, ketogenic style diet, which we know alters brain metabolism. It's been studied in mice a lot, although we still don't have a clear understanding why it control seizures so well in some children and adults with epilepsy. This was one of those studies where we wanted to capitalize on this opportunity on people undergoing surgery, where we know ahead of time. They're often scheduled a month, 3 months out, and for those who are willing, it's a healthy diet.

In my view, I live trying to eat healthy during breakfast and lunch. At dinner, I sometimes veer off the path a bit, but it is something I believe in. Certainly, the amount of processed carbohydrates that modern societies consume contributes to their large burden of non-communicable diseases, from cancer and heart disease, to gout, diabetes, obesity, etc. The question was: what's going on in the brain of these people when they do want go on these diets?

In the results, was there anything that was unexpected?

There are so many enzymes and neurophysiologic systems involved in metabolism, and metabolism underlies everything. Our brain is one of the most metabolically expensive organs in the body. Intelligence is a great thing, but very few species have grown brains because they’re extraordinarily expensive. There’s a trade-off in natural selection. Humans have very big brains, they’re highly metabolic, but they’re costly. And so, one of the largest changes that we saw was in NADH, which is a critical enzyme in metabolism. It helps foster better use of bioactive molecules for energy generation.

Seeing some of those changes in the hippocampus—which happened to be one of the regions we were studying because those are the regions we take out, we couldn’t look at whole brains here—that was something that that intuitively made a lot of sense that would be something that would be changed by the diet. Because essentially, a diet changes an individual's brain's metabolism and some of the rest of their body from chewing up sugar and carbohydrates to chewing up fats and fat metabolism. I wouldn't say it's better or worse, but for seizure control, it seems to be better for many people. This is one of the places where we saw changes. We saw changes in a number of other metabolites in the brain as well as in the blood.

Are there any types of diet-related research in epilepsy you feel is needed?

it would be great if we had better ways to collect systematic data on our patients, what they eat and what their outcomes are. It's relatively low hanging fruit, no pun intended, this is not high tech data. But if we could integrate more systematic surveys, which are hard and probably need to be done more regularly. Some of the classic ones like the Nurses Health Study, and the Women's Health Initiative, which has given rise to a lot of the data on diet in America. People will often look back over the last year and say, how many apricots do you eat? No one can give an accurate number about that, and it's kind of insane. But I think you can get surveys that probably more accurately survey people.

You can see, for example, patients ask me all the time, is there a diet I can take that will help or hurt my epilepsy? I have to be honest, and say, yes, there's the modified Atkins and ketogenic, which certainly can help some people. Whether it will help you, I can't say, but there's no diet that we know make seizures worse. Fasting puts you into ketosis, and that has probably helped some people, but it may be stressful for others and make their seizures worse in some cases. I do think there's going to be a lot of individual variability, and we haven't even begun to systematically probe the bigger picture or the specific patient profiles. The technology is here to do that, it's just a question of collecting data prospectively and analyzing it.

Transcript edited for clarity.