OK, so I've mentioned that I study the anticonvulsant effects of the
ketogenic diet. I thought I'd review some of the more popular theories on "how the diet works". Although the exact mechanism isn't clear, we know that shifting the body's metabolism toward using fats (instead of carbohydrates) plays a critical role. This causes numerous adaptations in the body, which may contribute to the diet's anticonvulsant effects. I apologize if some of this gets "thick"- it would take a 30 page post to describe everything in non-scientific terms. Plough through and let me know if I can clarify anything, or if you have any general questions.
****************************KETOGENIC DIET: PROPOSED MECHANISM OF ACTIONThe Brain Lipids TheoryClinically, the ketogenic diet (KD) has been shown to increase blood cholesterol and triglyceride levels. It was hypothesized that this increase in lipid levels contributes to the anticonvulsant actions of the KD. One study, for instance, suggested that lipids are incorporated in the brain and subsequently alter the structure and function of neuronal membranes, causing changes to membrane fluidity, ion channel functioning and receptor-ligand affinities. They suggest these changes have anticonvulsant effects.
A major problem with this hypothesis is that not all KDs elevate lipid levels in a similar fashion. For example, the medium chain triglyceride KD does not elevate blood triglyceride levels, but it still has good anticonvulsant activity.
The pH Theory / Keto-acidosis Theory"Acidosis" (acidification, or pH lowering in the brain) was first hypothesized as the anticonvulsant mechanism of action for the KD in 1931 by Bridge and Iob. When started on the KD, the patient’s metabolism switches from the using carbohydrate to using ketone bodies as an energy substrate. The ketone bodies acetoacetate and beta-hydroxybutyrate, which are mild acids, were hypothesized to lower blood pH in patients on the KD. This decrease in pH was hypothesized to confer the diet’s anticonvulsant effects. For example, low pH has been shown to inhibit pH-sensitive NMDA-type glutamate receptors (excitatory receptors in the brain) and pH sensitive gap junctions (these are electrical synapses, vs. chemical ones), causing a decrease in neural excitation.
The acidosis hypothesis has largely been abandoned, however, as clinical studies have failed to show long-term, KD-induced changes in pH. Animal studies have confirmed this finding by demonstrating that there is no change of brain pH in the animals fed a KD.
The GABA Shunt TheoryThe GABA shunt theory suggests that the KD leads to higher levels of GABA (the brain's major inhibitory chemical) in the brain. It has been argued that the KD causes increased levels of α-ketoglutarate (this is a chemical precursor to GABA) in the brain. Excess α-ketoglutarate can be used to produce more GABA via the GABA shunt. Elevated GABA levels would then elevate seizure threshold in the brain, reducing the brain's susceptibility to seizures.
One of the strongest lines of reasoning opposing the GABA shunt theory is that the KD is often successful in patients that have already failed the anticonvulsant medications that elevate GABA levels in the brain -- e.g. phenobarbital (Luminal®), primidone (Mysoline®), topiramate (Topamax®), diazepam (Valium®) and tiagabine (Gabitril®). Therefore, if GABA agonists do not control the patient’s seizures and the KD does, it would not follow logically that the KD works by elevating GABA levels.
Another argument against the GABA shunt theory is that animal studies have shown that GABA levels are not increased in the brains of rats fed the KD.
The Energy Substrate TheoryAnaerobic metabolism—or metabolism in the absence of oxygen—occurs when glucose molecules are broken down into two pyruvate molecules outside of the mitochondria. This process, known as “glycolysis”, yields a small but immediately available source of energy for the cell (~8 moles of adenosine triphosphate per mole of glucose, ATP --- ATP is the cell's form of energy). Aerobic metabolism, however, requires oxygen and occurs in mitochondria via the Krebs cycle and the electron transport chain. Under normal conditions, most of the brain’s energy is derived from the aerobic oxidation of glucose, which provides higher levels of ATP (~30 moles). When dietary carbohydrates are scarce—such as in individuals on a KD—the brain begins to use ketone bodies for energy. Ketone bodies can be converted to acetyl CoA, which can subsequently be used in the Krebs cycle and the electron transport chain to make ATP. The conversion of ketone bodies to acetyl CoA, however, does not release ATP like glycolysis does.
Normally, glucose serves as the preferred energy substrate for the brain. In patients fed a KD, however, ketones can supply the brain with up to 60% of its energy needs. A study in 2003 hypothesized that glucose generates both “slow” energy (via Krebs cycle) and “fast” energy (via glycolysis). Ketones, however, yield only “slow” energy (via Krebs cycle). The energy substrate hypothesis suggests, therefore, that although ketones provide sufficient energy for regular brain activity, they do not provide enough “fast” energy to sustain seizure activity.
This theory is currently receiving widespread attention. I believe that this theory is getting very close to the heart of the matter. Unfortunately, this is also the most complex theory. I tried to give some detail without swamping those of you that aren't biologists. Essentially, there is something about burning fat for fuel (in the brain) that beats burning carbs when it comes to suppressing seizures.
The Ketonemia Theory & Acetone HypothesisThree ketone bodies, beta-hydroxybutyrate (βOHB), acetoacetate (ACAC) and acetone are significantly elevated in patients on the KD. The ketonemia theory postulates that ketone bodies themselves are anticonvulsant, and that the KD is effective because it elevates ketone bodies in the blood and brain. No specific mechanism of action, however, has been suggested (i.e. no “receptor” is known that ketones might bind, to confer their anticonvulsant activity. Some clinical studies and animal studies have reported significant correlations between levels of βOHB or ACAC and seizure protection. Other studies, however, have reported a lack of correlation between βOHB or ACAC and seizure protection. At present, the relationship between ketosis and seizure control remains unclear.
Opponents to the ketonemia theory have argued that βOHB or ACAC are elevated rapidly in patients on the KD, but seizure control can take some weeks to develop (although, it has been suggested, however, that it may take the brain a few weeks to adjust to the elevated ketone bodies before anticonvulsant effects are seen).
Historically, however, researchers have neglected the possible role of acetone in the anticonvulsant mechanism of the KD.
Acetone is a ketone elevated in patients on the KD (it's also the "active ingredient" in nail polish remover). The idea that acetone has anticonvulsant properties was first proposed by Helmholtz and Keith in 1930. The idea was then ignored for some years. Recently, however, it was reported that acetone was elevated in the brains of children on the KD. Also, a Toronto-based research group found that acetone had a wide spectrum of anticonvulsant effects in various seizure models. This led to the “acetone hypothesis”, which states that acetone plays a role in the anticonvulsant mechanism of the KD.
There are two lines of evidence for the acetone hypothesis. Firstly, acetone is elevated in fasted patients and patients fed the KD. It is known that both fasting and the KD have anticonvulsant properties. Secondly, acetone has been shown to have a broad spectrum of anticonvulsant action, similar to that of the KD, using experimental seizure models.
People are reluctant to accept this theory as we've come to know acetone as "glass cleaner" or "nail polish remover". However, our bodies continually make it (naturally) and it has a very apparent effect on brain activity when it accumulates in the blood. What isn't known, however, is whether elevations in blood acetone correlate with seizure suppression in kids on the KD.
****************************Is there anything that you'd like to know about epilepsy?
If so, please let me know and I'll do a post on it.
Have a great day,
Kirk.
