Towards a patient-friendly ketogenic diet for epilepsy Development and preclinical validation

Epilepsy is one of the most common neurological disorders, affecting approximately 1% of the global population. The classic ketogenic diet (KD), a high-fat, low-carbohydrate diet, offers an alternative treatment option for patients that do not respond adequately to anti-seizure medication. However, its restrictive nature and high fat content (~90% of calories) limit compliance and can cause acute and chronic fat-related side effects. This thesis describes the development of a novel KD with a reduced fat content and added nutrients to maintain therapeutic efficacy. In vitro hepatocyte assays identified ketogenesis stimulating nutrients, while parallel primary neuroglial rat culture studies identified nutrients that could dampen neuronal hyperexcitability. The efficacy of the novel KD was compared to a rodent-adapted classic KD and a control diet in the rapid kindling rat model of epileptogenesis. The classic KD did not affect seizure severity and we observed liver triglyceride accumulation after three weeks of dietary treatment. Conversely, rats fed with the novel KD required more stimulations to reach severe seizure stages and no liver fat accumulation was observed. Both diets shortened EEG after-discharges and preserved hippocampal neurons, notably the novel KD achieved these effects with modest ketosis levels. Furthermore, the novel KD altered the gut microbiome composition, maintained short-chain fatty acid production, while increasing the abundances of microbiota genera that could be correlated to improved seizure scores and reduced liver triglyceride levels. These findings highlight a promising novel strategy for managing epilepsy with the potential to improve patient safety and compliance.