Ketone Bodies in Epilepsy
Seizures that are resistant to standard medications remain a major clinical problem. One underutilized option for patients with medication-resistant seizures is the high-fat, low-carbohydrate ketogenic diet. The diet received its name based on the observation that patients consuming this diet produce ketone bodies (e.g., acetoacetate, β-hydroxybutyrate, and acetone).
Although the exact mechanisms of the diet are unknown, ketone bodies have been hypothesized to contribute to the anticonvulsant and antiepileptic effects. In this review, anticonvulsant properties of ketone bodies and the ketogenic diet are discussed (including GABAergic and glutamatergic effects).
Because of the importance of ketone body metabolism in the early stages of life, the effects of ketone bodies on developing neurons in vitro also are discussed. Understanding how ketone bodies exert their effects will help optimize their use in treating epilepsy and other neurological disorders.
A growing amount of in vivo and in vitro data show that ketone bodies can alter neuronal activity and protect against seizures. The mechanisms through which ketone bodies may confer an anticonvulsant effect are still debated. The potential mechanisms discussed in this review center around neurotransmitters and the resting neuronal membrane potential (Fig. 2). Moving forward, work will need to be completed exploring how physiological levels of ketone bodies affect these systems. The exact targets of ketone bodies still are unknown and may be direct (i.e., binding to a specific neuronal target, as demonstrated for acetoacetate in VGLUT), or indirect (i.e., supplying carbon equivalents to the Krebs cycle or an antioxidant effect).
Given both the success of AC-1202 (an oral ketogenic compound that rapidly elevates β-hydroxybutyrate levels) in improving cognitive outcomes in Alzheimer disease patients (Henderson et al.2009) and the success of a ketogenic diet in treating children with medically intractable epilepsy, there is significant interest in pursuing these types of compounds for epilepsy therapies.
However, the contribution of ketone bodies to the anticonvulsant effects of the ketogenic diet remains elusive. Because of study design issues and the amount of overlap between values in different patient groups, the relationship between seizure control and serum levels of β-hydroxybutyrate remains unclear (Gilbert et al. 2000). Many other studies have failed to show that the levels of serum or urine ketosis correlate with seizure protection in animal models (Likhodii et al. 2000, Bough et al. 2000) or patients (Ross et al. 1985, Fraser et al. 2003).
Breath acetone levels correlate with plasma levels of all three ketone bodies but not with seizure control (Musa-Veloso et al. 2006). Some of these studies highlight the potential difference between administration of ketone bodies versus a ketogenic diet (understanding the former as a product of the latter). Together, some of the data discussed here suggest the ketogenic diet may have anticonvulsant effects via mechanisms other than elevated ketone body levels, even though ketone bodies have numerous potential beneficial effects. Therefore, based on current data, ketone bodies may represent a unique, additional therapeutic modality to optimize for patients with epilepsy and possibly other neurological disorders. Further studies are required to understand how using these compounds may help these populations.