Introduction: The branched-chain amino acids (BCAAs) valine, leucine and isoleucine are thought to play an important role in the metabolism of the excitatory transmitter glutamate in the central nervous system. The goal of the present study was to explore the relationships among BCAAs, glutamate, and seizures in humans with localization-related epilepsies.

Methods: Intracerebral microdialysis combined with tandem mass spectrometry was used to measure extracellular levels of glutamate, glutamine, and BCAAs in epileptogenic and non-epileptogenic brain areas in 30 patients with medically refractory localization-related epilepsies. Electroencephalogram recordings from depth electrodes attached to 73 microdialysis catheters were used to identify the epileptogenic and non-epileptogenic areas. Basal samples were collected 1 day after electrode implantation and at least 6 hours away from a seizure. Seizure-associated samples were collected every hour starting 6 hours before a seizure and ending 6 hours after a seizure.

Results: Basal levels of extracellular glutamate, valine, leucine and isoleucine were significantly correlated (p < 0.0001). All amino acids levels except glutamine were significantly higher in epileptogenic vs. non-epileptogenic brain areas (Fig. 1A, p < 0.05 for all). The ratios of BCAAs (2:2:1, valine:leucine:isoleucine) were constant across brain regions and time points. Preliminary studies indicate that glutamate, valine, leucine and isoleucine increase in the hours before a seizure in epileptogenic brain areas (Fig. 2A and 2B).

Conclusions: Our data suggest that BCAAs are implicated in the regulation of extracellular brain glutamate and in the initiation of seizures in patients with medically refractory localization-related epilepsies. However, further studies are required to establish a causal relationship between increased BCAAs, glutamate, and seizures. In the event that such a cause-effect relationship can be determined, BCAAs can be considered as a potential diagnostic or therapeutic target for the treatment of localization-related epilepsy.

Patient Care: This research may lead to the use of BCAAs as a biomarker to improve the localization of a seizure focus for epilepsy surgery, and may serve as a target for the development of novel therapeutic interventions in medically refractory localization-related epilepsy.

Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe baseline differences of BCAAs and glutamate in epileptogenic vs. non-epileptogenic areas, 2) Discuss, in small groups, seizure-associated changes in glutamate, BCAAs, and glutamine, 3) Discuss possible clinical implications of BCAAs in localization-related epilepsy.

References: 1) Lieth E, LaNoue KF, Berkich DA, Xu B, Ratz M, Taylor C, Hutson, SM. Nitrogen shuttling between neurons and glial cells during glutamate synthesis. J. Neurochem. 2001;76:1712–1723. 2) Skeie B, Petersen AJ, Manner T, Askanazi J, & Steen PA. Effects of Valine, Leucine, Isoleucine, and a Balanced Amino Acid Solution on the Seizure Threshold to Picrotoxin in Rats. Pharmacol. Biochem. And Behavior 1994;48:101-103.