The clinical efficacy of the ketogenic diet (KD) has now been well-documented. However, the underlying bases of KD antiepileptic efficacy are still a matter of speculation. A number of suggestions regarding underlying mechanisms have been offered, but all require rigorous testing. Development of appropriate animal model systems, and clear statement of experimentally testable hypotheses, are needed. Among the general hypotheses of interest are the following: (1) the KD alters the nature, and/or degree, of energy metabolism in the brain -- therefore altering brain excitability; (2) the KD leads to changes in cell (neuronal and perhaps glial) properties, which decrease excitability and dampen epileptiform discharge; (3) the KD induces changes in neurotransmitter function and synaptic transmission -- thus altering inhibitory-excitatory balance and discouraging hyper-synchronization; (4) the KD is associated with changes in a variety of circulating factors which act as neuromodulators that can regulate CNS excitability; and (5) the KD gives rise to alterations in brain extracellular milieu, which serve to depress excitability and synchrony. An understanding of the mechanism underlying KD antiepileptic efficacy will help us not only to optimize the clinical use of the ketogenic diet, but also to develop novel antiepileptic treatments.
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