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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
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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
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
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
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
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
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
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
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
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
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
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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
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
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
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
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
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
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 ⬇️
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
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
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
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
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
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
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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
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
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
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
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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