Review articleHow does the ketogenic diet induce anti-seizure effects?

- Clinical and experimental interest in the ketogenic diet has grown rapidly over the past decade.
- Ketone bodies have been linked to inhibitory neurotransmitter release and activation of ATP-sensitive potassium channels.
- The ketogenic diet enhances overall cellular bioenergetics and reduces oxidative stress.
- Glycolytic diversion and/or restriction may play an important role in the clinical activity of the ketogenic diet.
- Modulation of tricarboxylic acid cycle flux may also underlie ketogenic diet effects.

The high-fat ketogenic diet (KD) is a remarkably effective treatment for medically intractable epilepsy and has been part of the clinical armamentarium for nearly a century. However, the mechanisms underlying the KD's actions have remained elusive. Over the past decade, there has been phenomenal international growth of clinical centers offering metabolism-based therapies for epilepsy, and rapidly expanding research into the cellular and biochemical effects induced by the KD. At present, there are many hypotheses regarding KD action, and while each is uniquely compelling, it is becoming more apparent that the KD likely works through multiple mechanisms that target fundamental biochemical pathways linked to cellular substrates (e.g., ion channels) and mediators responsible for neuronal hyperexcitability. This is not altogether surprising given the complexity of the epileptic brain, and the many different pathophysiologic mechanisms that underlie seizure genesis and epileptogenicity. The scientific literature involving the KD strongly supports the notion that epilepsy may indeed in part represent a “metabolic disease”, and that this concept could serve as a novel framework for the development of more effective anti-seizure drugs.