Mechanism of Ketosis and Seizure Control in Pediatric Drug-Resistant Epilepsy: Insights from an Indianized Ketogenic Diet

Introduction: Drug-resistant epilepsy (DRE) is a challenging neurological condition among the pediatric population, prompting the exploration of alternatives like the ketogenic diet (KD), which shifts metabolism from glucose to ketones. Ketone bodies, mainly beta-hydroxybutyrate and acetoacetate, enhance mitochondrial function and gamma-aminobutyric acid [(GABA) ergic] transmission, promoting seizure control. Despite its efficacy, the exact mechanisms behind KD’s antiseizure effects remain unclear. Objective/Aim: This study examines the link between urine ketone levels and seizure outcomes in children with DRE on an Indianized KD. Methods: A prospective observational study was conducted among 55 children less than 5 years of age diagnosed with DRE. Initially at baseline, all participants followed a normal high-carbohydrate, moderate-protein, low-fat diet providing 60% carbohydrates, 20% protein, and 20% fat before transitioning to an Indianized version of KD, which was high in fat, moderate in protein, and very low in carbohydrates, providing 80% fat, 15% protein, and 5% carbohydrate. All participants began with a 2:1 ketogenic ratio, which was adjusted based on metabolic response and tolerance. Urine ketones were monitored using a urine ketone dipstick thrice daily by parents, who documented the results in a urine ketone diary, and seizure frequency was recorded over 6 months. Statistical analyses included mean, standard deviation, chi-square testing, and P -values, with statistical significance defined as P < 0.05. Results: The study cohort included 55 children (mean age 2.5 ± 1.1 years), with the majority aged 1 to 3 years [35 (63.6%)] and diagnosed primarily with infantile spasms [39 (70.9%)]. At baseline, urine ketone levels were −41.25 ± 17.67 mg/dL, indicative of a carbohydrate-based diet, while seizure frequency was 26 ± 39.31 episodes/day. After 6 months on KD, urine ketone levels significantly increased to 141.82 ± 39.5 mg/dL, coinciding with a marked reduction in seizure frequency to 3.26 ± 4.99 episodes/day ( P < 0.05). A significant inverse correlation was observed between urine ketone levels and seizure frequency ( χ 2 = 12.36, P < 0.001), reinforcing the biochemical role of ketosis in seizure control. A ketogenic ratio-dependent increase in urine ketone levels was noted, with the highest concentrations recorded at a 2.4:1 ratio ( χ 2 = 8.72, P = 0.03). All participants exhibited improvements in nutritional status, achieving normal parameters at the study endpoint ( χ 2 = 10.45, P = 0.001). Electroencephalogram (EEG) abnormalities, present in 100% of participants at baseline, showed partial improvement in 78% and complete normalization in 22% ( χ 2 = 9.88, P = 0.002), suggesting a positive correlation between ketosis and neurophysiological stabilization. Conclusion: This study supports ketosis as a key mechanism in seizure control, highlighting ketone metabolism’s role in enhancing mitochondrial function and reducing excitability. Optimizing the ketogenic ratio is crucial for sustained ketosis, correlating with therapeutic efficacy and improved EEG patterns. Increased GABA synthesis, reduced glutamatergic activity, and metabolic shifts suggest further benefits, warranting future research on blood ketone monitoring for better protocol refinement. This work also aligns with the United Nations Sustainable Development Goal 3, which emphasizes ensuring healthy lives and promoting well-being for all at all ages.