Ketogenic diet (KD) has been used to treat epilepsy for 100 years. It is a high-fat, low-carbohydrate, and sufficient-protein-for-growth diet that mimics the metabolic changes occurring during starvation. Except for classic KD, its modified counterparts, including modified Atkins diet and low-glycemic-index treatment, have gained grounds to increase palatability and adherence. Strong evidence exists that the KD offers protection against seizures in difficult-to-treat epilepsy and possesses long-lasting anti-epileptic activity, improving long-term disease outcome. The KD can also provide symptomatic and disease-modifying activity in a wide range of neurodegenerative diseases. In an era of highly available new anti-seizure medications (ASMs), the challenge of refractory epilepsy has still not been solved. This metabolic therapy is increasingly considered due to unique mechanisms and turns out to be a powerful tool in the hands of a skillful team. Despite decades of extensive research to explain the mechanism of its efficacy, the precise mechanism of action is to date still largely unknown. The key feature of this successful diet is the fact that energy is derived largely from fat but not from carbohydrates. Consequently, fundamental change occurs regarding the method of energy production that causes alterations in numerous biochemical pathways, thus restoring energetic and metabolic homeostasis of the brain. There are barriers during the use of this special and individualized therapy in many clinical settings worldwide. The aim of this review is to revisit the current state of the art of therapeutic application of KD in refractory epilepsy.

The ketogenic diet (KD) is a high-fat, adequate-protein, and low-carbohydrate diet that has been used successfully in the treatment of refractory epilepsies for almost 100 years. There has been accumulating evidence to show that the KD may provide a therapeutic benefit in autism spectrum disorders, albeit by a yet-unknown mechanism. We report a case of a 6-year-old patient with high-functioning autism and subclinical epileptic discharges who responded poorly to several behavioural and psychopharmacological treatments. The patient was subsequently placed on the KD due to significant glucose hypometabolism in the brain as revealed by an 18FDG PET. As soon as one month after starting the KD, the patient’s behavior and intellect improved (in regard to hyperactivity, attention span, abnormal reactions to visual and auditory stimuli, usage of objects, adaptability to changes, communication skills, fear, anxiety, and emotional reactions); these improvements continued until the end of the observation period at 16 months on the KD. The 18FDG PET, measured at 12 months on the KD, revealed that 18F-FDG uptake decreased markedly and diffusely in the whole cerebral cortex with a relatively low reduction in basal ganglia in comparison to the pre-KD assessment. It warrants further investigation if the 18FDG PET imaging could serve as a biomarker in identifying individuals with autism who might benefit from the KD due to underlying abnormalities related to glucose hypometabolism.

Targeting mechanisms that result in increased concentrations of kynurenic acid (KYNA) in the brain has been considered as a therapeutic approach for the treatment of epilepsy and certain neurodegenerative disorders. Recently, KYNA has been implicated in the effects produced by the high-fat and low-protein/carbohydrate ketogenic diet (KD) in a report demonstrating an increased production of KYNA in vitro by one of the ketone bodies, β-hydroxybutyrate, elevated by the KD. To further explore this association, brain concentrations of KYNA were compared in young (3 weeks old) and adult (8–10 weeks old) rats that were chronically exposed to the KD and regular diet. Exposure to the KD resulted in the anticipated elevations of β-hydroxybutyrate with accompanying decreases in glucose concentrations. In comparison to rats fed the regular diet, KYNA concentrations were significantly (p < 0.05) increased in the hippocampus (256 and 363% increase in young and adult rats, respectively) and in the striatum (381 and 191% increase in young and adult rats, respectively) in KD-fed rats. KD-induced increases in KYNA concentrations in young versus adult rats in the hippocampus and striatum were comparable (p > 0.05). Exposure to the KD had no effect on KYNA concentrations in the cortex of young and adult rats (p > 0.05). In summary, chronic exposure to the KD resulted in several-fold increases in KYNA concentrations in discrete brain structures in the rats. Thus, the relevant clinical question for further exploration is whether KD-induced increases in KYNA concentrations can translate into clinically significant improvements in neuropsychiatric diseases associated with KYNA hypofunction.