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
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/
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…
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…
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…
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
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…
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/
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/
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/
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 ⬇️
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…
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…
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/
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/
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/
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
🧠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!
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