Thread by @AvrahamCooperMD

1/🧵
Why is a ketogenic diet a potentially effective treatment for refractory epilepsy?

There's something almost magical about the idea that a specific type of diet could reduce the risk of epileptic seizures.

Let's explore why that might be.

#medtwitter #tweetorial

2/
First let's define a ketogenic diet.

Ketogenic diets have ⬆️ fat and ⬇️ carbohydrates. This leads to ⬆️ serum free fatty acids and ketone body production by the liver (acetoacetate, acetone, beta-hydroxybutyrate) for use as cellular fuel.

pubmed.ncbi.nlm.nih.gov/17241207/

3/
Ketogenic diets induce a pseudostarvation state, as carbohydrates = typical primary cellular fuel.

In the 1900s it was noted that fasting helped control epileptic seizures.

By 1921, RM Wilder proposed that ketogenic diets might replicate this effect.

neslazeno.cz/wilder-1921-th…

4/
The first clinical trial of a ketogenic diet as an anti-seizure intervention occurred in 1924.

Of 17 patients treated w/ a ketogenic diet, 10 responded and became seizure free.

jamanetwork.com/journals/jamap…

5/
Subsequent studies have confirmed the efficacy of ketogenic diets in reducing seizure burden in epilepsy, particularly in children.

💥This Cochrane Review analysis found a Risk Ratio benefit of 5.8 for 50% seizure reduction in kids.

ncbi.nlm.nih.gov/pmc/articles/P…

6/
Returning to our original question, why would a ketogenic diet protect against seizures?

Let's examine 3 proposed mechanisms:

🧠The metabolic hypothesis
🧠GABA shunting
🧠The acetone hypothesis

7/
Let's first look at the metabolic hypothesis.

This theory focuses on the idea that decreasing glucose-based metabolism in the brain may have anticonvulsant effects.

ncbi.nlm.nih.gov/pmc/articles/P…

8/
There is animal data supporting the anticonvulsant effects of avoiding glucose-based metabolism in the brain.

For example, administering 2-Deoxy-D-Glucose (which inhibits glycolysis) to rats protects against seizures.

pubmed.ncbi.nlm.nih.gov/17041593/

9/
The basis for the metabolic hypothesis = "fast" vs "slow" neuronal cellular fuel:

Glucose = rapidly available fuel source via glycolysis (+slower fuel via Krebs cycle) which can support seizures

Ketones = slower fuel source (Krebs only), ⬇️ seizures

pubmed.ncbi.nlm.nih.gov/12859666/

10/
And there is some clinical data supporting the metabolic hypothesis.

💡In a small clinical trial, the majority of patients w/ intractable epilepsy placed on a low-glycemic-index diet experienced a decrease in seizure frequency.

pubmed.ncbi.nlm.nih.gov/16344529/

11/
Next let's examine the GABA shunt hypothesis.

🔑Recall that GABA is a primary inhibitory neurotransmitter, and increased GABA signaling can suppress seizures.

More on GABA ⬇️

https://twitter.com/AvrahamCooperMD/status/1353394078604533761?s=20&t=EDt6l6OPa96cPqSw9LSu-A

12/
Ketones are converted to both glutamine and acetyl-CoA in the brain, and both raise CNS GABA levels.

Glutamine becomes glutamate and then GABA, and having more acetyl-CoA around drives that conversion even more (aka shunting ketones into GABA).

ncbi.nlm.nih.gov/pmc/articles/P…

13/
The final possible explanation we will examine is the acetone hypothesis.

While multiple types of ketones are generated by a ketogenic diet, only acetone has evidence of anticonvulsant properties.

ncbi.nlm.nih.gov/pmc/articles/P…

14/
Administration of acetone to rats protects against multiple seizure types.

And acetone protected against seizures w/ a dose-response relationship, suggesting that it may have a direct anticonvulsant effect in the brain.

pubmed.ncbi.nlm.nih.gov/12891674/

15/
It's also possible that an acetone metabolite, rather than acetone itself, mediates any anticonvulsant action.

Minimal human data exists, but acetone does cross the blood-brain barrier more easily than other ketones.

pubmed.ncbi.nlm.nih.gov/14769491/

16/
Let's end with a neat historical reflection.

As of 500 BC, dietary therapy for epilepsy was actually mentioned in the Hippocratic collection.

Treating epilepsy with dietary changes is, in a way, one of the oldest medical interventions in existence.

pubmed.ncbi.nlm.nih.gov/19049574/

17/SUMMARY
🧠Ketogenic diets are often effective in refractory epilepsy
🧠Proposed mechanisms include:
🔺"Slower" metabolic fuel sources
🔺Increased GABA
🔺Anticonvulsant effects of acetone

Thank you so much to @RGottliebSmith and @JulieZiobro for thoughtful peer review of this #tweetorial!

Also thank you to @AdamRodmanMD for help with the Hippocrates source!