The ketogenic diet is a specialized diet that involves highly restricted intake of carbohydrates and proteins and a high proportion of fat consumption. It has proven to be used in the treatment of drug-resistant epilepsy because the mechanism of action of the diet causes changes in the levels of ketones and other substances in the body, reducing the frequency of seizures.
Pathophysiology of Seizures
A complex network of neurons that transmit nerve impulses and signals is evident in the brain. Neurotransmitters play an important role in the propagation of these impulses, responsible for carrying the message across the synapse of the neurons.
Neurotransmitters are generally known to be excitatory or inhibitory, according to the effect they have on the firing of impulses. Glutamate is a common excitatory neurotransmitter that promotes the propagation of impulses, whereas GABA is primarily responsible for the inhibition of nerve impulses.
A seizure can occur when there is a disruption in the balance between the neurotransmitters in the brain, particularly due to the over-excitation of the nerves and excessive nervous messages being fired. For this reason, typical anticonvulsant drugs tend to increase the inhibitory neurotransmitter, GABA, helping to control the frequency of seizures.
Ketogenic Diet Action
The precise mechanism of action of the ketogenic diet is not known, although many possible explanations have been proposed. There are many changes that occur in the body and brain as a result of the diet, but it is unclear which of these alterations is responsible for the anticonvulsant effect. This is expected, however, as the mechanism of action of many pharmacological anticonvulsant drugs is similarly a mystery.
The key aspect of the ketogenic diet involves the restriction of carbohydrates, which are no longer able to be converted to glucose and provide for the body’s metabolic and energy needs. To compensate for this, fatty acids are converted into the fuel sources through a process of oxidation in the mitochondria.
In the absence of glucose due to lack of carbohydrates in the diet, the ketone bodies β-hydroxybutyrate, acetoacetate and acetone are synthesized and are able to cross the blood-brain barrier to provide an alternative source of energy for the brain. These ketone bodies are thought to possess anticonvulsant properties, as both acetoacetate and acetone have been shown to protect against seizures in animal models.
The stabilization of the neurons and the propagation of nervous messages may occur as a result of the efficiency of the ketone bodies as a fuel source, increasing the number of mitochondria as the body adapts to converting the fatty acids to generate ketone bodies for energy.
Neither pharmacological anticonvulsants nor the ketogenic diet is able to cure epilepsy but work due to their ability to suppress epileptic seizures. However, unlike medication options, the ketogenic diet has been shown in a study of rats to have anti-epileptogenic properties and inhibit the development of epilepsy.
There are several other theories about the mechanism of action of the ketogenic diet, including the increased acidity in the blood known as systemic acidosis, electrolyte changes and hypoglycemia. These hypotheses have not, however, been proven to be accurate and there is some evidence to indicate they are not involved in the mechanism of action.
References
Further Reading
How a ketogenic diet could reduce autoimmune disease severity through host-microbiome interactions