Branched Chain Amino Acids as Adjunctive Therapy to Ketogenic Diet in Epilepsy: Pilot Study and Hypothesis

Abstract

A pilot prospective follow-up study of the role of the branched chain amino acids as additional therapy to the ketogenic diet was carried out in 17 children, aged between 2 and 7 years, with refractory epilepsy. All of these patients were on the ketogenic diet; none of them was seizure free, while only 13 had more or less benefited from the diet. The addition of branched chain amino acids induced a 100% seizure reduction in 3 patients, while a 50% to 90% reduction was noticed in 5. Moreover, in all of the patients, no reduction in ketosis was recorded despite the change in the fat-to-protein ratio from 4:1 to 2.5:1. Although our data are preliminary, we suggest that branched chain amino acids may increase the effectiveness of the ketogenic diet and the diet could be more easily tolerated by the patients because of the change in the ratio of fat to protein.

Interactions in the Metabolism of Glutamate and the Branched-Chain Amino Acids and Ketoacids in the CNS

“…In recent years, however, considerable research has focused on the possibility that less onerous increases of branched-chain amino acids and ketoacids might prove beneficial in preventing brain injury, possibly by subtly modulating intra-cerebral levels of glutamate and/or glutamine. To this end, investigators have scrutinized the therapeutic potential of dietary branched-chain amino acid supplementation in diverse pathologic conditions, among them hepatic encephalopathy (Dam et al, 2013; Bak et al, 2013), fatigue (Newsholme and Blomstrand, 2006; Choi et al, 2013; Gluud et al, 2013), traumatic brain injury (Cole et al, 2010); appetite and energy sensing (Schwartz, 2013), obesity (Drgonova, 2013) and epilepsy (Evangeliou et al, 2009). It is probable that future investigation will broaden this repertoire still more.…”

Non-ketogenic combination of nutritional strategies provides robust protection against seizures

“…(2015) 4 , it is indeed likely that the nutritional strategies employed in our CD concur to downregulate the LDH metabolic pathway, a component of the astrocyte-neurone lactate shuttle. It also remains probable that other mechanisms act in parallel to dampen neuronal excitation, such as for instance reduced glutamate level in the brain that could result from a high BCAA/AAA ratio 19, 20 , or neuronal hyperpolarization induced by polyunsaturated fatty acids though modulation of voltage gated ion channels 39 , or the increase in adenosine receptors activation under medium-chain triglycerides treatment, which reduces probability of neurotransmitter release 40 .…”

“…Also supporting this approach, glycolytic inhibition with 2-deoxyglucose administration has proved effective in reducing seizure occurrence in epilepsy models 17, 18 . Finally, interesting data suggest that the proportion of branched-chained (BCAA) vs aromatic amino acids (AAA) in the blood can influence excitability of central neuronal networks 19, 20 . The BCAAs leucine, isoleucine and valine would indeed favour ketosis and GABA synthesis while reducing glutamate levels 19, 21 .…”

“…Finally, interesting data suggest that the proportion of branched-chained (BCAA) vs aromatic amino acids (AAA) in the blood can influence excitability of central neuronal networks 19, 20 . The BCAAs leucine, isoleucine and valine would indeed favour ketosis and GABA synthesis while reducing glutamate levels 19, 21 . Thus, a higher BCAA/AAA blood ratio has been proposed to decrease brain excitability, thereby favouring seizure control 20 .…”

Dietary therapies for epilepsy: Future research

“…With a therapy as carefully calculated as the KD, it is natural for parents and dietitians to want to attempt many dietary modifications, especially when seizures recur after initial improvement. A single study recently suggested that adding branched-chain amino acids to the KD might improve efficacy [26]. However, the cohort chosen had already improved to some degree with the KD.…”