Despite decades of research, exactly how the ketogenic diet works to stop seizures remains unclear. We do know that breaking down fat for energy produces side-products called ketone bodies. High levels of these produce a metabolic state called ketosis which inhibits seizures. Three studies published in the last month have investigated the multiple chemical processes behind the protective effect of ketosis.

The glutamate system
Glutamate is the main excitatory neurotransmitter in the brain. It is transported around cells by a number of special transporter proteins. Reduced rates of glutamate transport are associated with epilepsy; these can be caused by abnormalities in the levels of both glutamate and transporter proteins.

Dr KJ Bough and colleagues at Emory University in Atlanta, USA, theorised that, since reduced glutamate transport is associated with epilepsy, the ketogenic diet might work by increasing glutamate transport, particularly by increasing the levels of the transporter proteins present in the brain. They investigated the levels of the transporter proteins in brain tissue exposed to the ketogenic diet and compared it to levels in brains not treated with the diet. They found no difference in levels between the two types. This shows that this is probably not the mechanism by which the ketogenic diet has its effect.

This is an example of a negative study, where the researchers' starting theory was found to be incorrect. These types of study are just as important as positive ones for advancing what's known about epilepsy. The study was published in the journal Epilepsy Research in April 2007.

Also working on the glutamate system are another research group at the Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, USA. Writing in the Annual Review
of Nutrition in last month, Dr M Yudkoff and colleagues put forward a theory for a different effect of the ketogenic diet. Glutamate is used in the normal glucose-fuelled functioning mode of the brain, but under ketotic conditions, more glutamate is available to the chemical pathway that makes GABA, the major inhibitory neurotransmitter of the brain. The diet may also favour the synthesis of glutamine, another chemical that is needed to make GABA.

Acetone and its breakdown products
Acetone is one of the principal chemicals produced by the breakdown of fats in the liver. Acetone levels are higher in patients during treatment with the ketogenic diet. Acetone is a powerful anticonvulsant, but exactly how it interacts with cells to reduce excitability is unknown.

Scientists at the US National Institute of Neurological Disorders and Stroke Bethesda, USA, investigated whether acetone's effect is due to the activity of the chemical itself or to its own breakdown products. They tested each of these at various dose levels separately, to find out how much they inhibited seizures.

None of the breakdown products had any effect except at massively higher doses than would be caused by the breakdown of acetone. These high levels also caused side effects such as motor impairment which were not seen with acetone dosing. This establishes that it's acetone itself, not its breakdown products, that has the anticonvulsant effect. This research was published in the journal Epilepsia in March 2007.

What is the ketogenic diet?
The ketogenic diet is high in fat, low in carbohydrate and contains an adequate amount of protein. It works well to treat paediatric epilepsy but is not effective in adults (for reasons that are unknown). Whatever mechanisms are involved, they are not the same as those by which any currently-available anti-epileptic drugs work.

Under normal dietary conditions, the body burns glucose for energy. This process does not produce ketone bodies. Under ketogenic diet conditions, the normal glucose breakdown processes are inhibited.

More information about the ketogenic diet can be found here
and here