Dietary Intervention in Children with Refractory Epilepsy and Inherited Metabolic Disease: An Observational Study on Ketogenic Diet Therapy.

Purpose: Ketogenic Diet Therapies (KDT) are well established, non-pharmacologic treatments for children with refractory epilepsy and inherited metabolic diseases. Ketosis is achieved via dietary carbohydrate restriction and drastic increase of fat. Several studies suggest that the proportion of branched chain amino acids (BCAA: isoleucine, leucine, valine) vs aromatic amino acids (ARAA: phenylalanine, tyrosine) can influence excitability of central neuronal networks. In patients, undergoing KDT, there is limited clinical evidence on the changes of BCAA and ARAA. We aim to analyze alterations in plasma amino acid (pAA) concentrations in pediatric patients undergoing KDT, based on routine care data.
Methods: Routinely acquired data from 53 patients before and after onset of KDT between 01/01/2010 and 12/31/2020 were analyzed retrospectively using descriptive statistics. Generalized estimating equations (GEE) were used to investigate the effect of KDT on changes in pAA concentrations. Amino acid concentrations were determined by ion exchange chromatography with post column derivatisation with ninhydrine (Biochrom 30+, Laborservice Onken, Germany). Fisher’s ratio was calculated as BCAA:ARAA. β-hydroxybutyric acid was measured via enzymatic essays (Wako Chemicals, Germany).
Results: We report specific alterations in pAA profiles of 53 patients (26/49% male, 27/51% female) undergoing KDT (10/19% classical KDT, 43/81% modified Atkins diet) due to structural anomaly (n=6/11%), metabolic disease (n=7/13%), genetic disease (n=11/21%), epileptic syndrome (n=26/49%) and unclear primary diagnosis (n=3/6%). In our cohort, KDT led to ketosis resulting in a significant positive effect on the Fisher’s ratio. Mean baseline Fisher’s ratio was within reference range (M=3.84, SD=1.6, reference range: 2.10-4.00). GEE shows a significant effect of KDT on the Fisher’s ratio over the subsequent follow up measurements (p <0.001).
Conclusion: In our cohort, an increase of the Fisher’s ratio was observed during KDT. These metabolic adaptions might be linked to stabilizing mechanisms of action, in patients with refractory epilepsy and inherited metabolic disease. As the mechanistic effects of KDT are not yet fully understood and might be relevant to a variety of other diseases (e.g. obesity, Alzheimer’s disease, multiple sclerosis), further investigations in prospective randomized trials comprising complete metabolomic assessment in addition to classical clinical endpoints, coupled with causal mediation analysis are needed.