Abstracts

Rationale: Glutamine is critical for numerous brain functions such as ammonia detoxification and synthesis of the neurotransmitters glutamate and gamma-aminobutyric acid (GABA). Glutamine synthetase (GS) is the only enzyme capable of forming significant amounts of glutamine in mammals. GS is located in astrocytes, which when compromised have been implicated in playing a major role in epileptic conditions. In patients with drug-resistant epilepsy (MTLE), this enzyme is severely deficient in the seizure focus of the brain. However, glutamine levels are not significantly different between GS-deficient and -intact regions of the brain. Thus, suggesting robust mechanisms that may be responsible for normal glutamine levels despite GS loss. Furthermore, these findings highlight the importance of glutamine regulation in epilepsy. To this extent, we measured the glutamine levels of patients who eventually underwent epilepsy surgery and compared their glutamine levels with Engel class I (seizure-free), II, III, and IV outcomes.

Methods: Twenty-nine patients with drug-resistant focal epilepsies of different types were implanted with intracranial depth electrodes for seizure localization. A microdialysis catheter was inserted into the lumen of the depth electrodes. Sterile artificial cerebrospinal fluid was perfused through a microdialysis catheter, and the efflux was collected in 1- or 2-h aliquots. Glutamine was quantified in the dialysis samples using liquid chromatography-tandem mass spectrometry. Postoperative seizure outcome was assessed using the Engel scale. The student’s T-test was implemented to compare basal brain extracellular glutamine levels in patients with class I (seizure-free), II, III, or IV outcomes. Statistical analysis was done in Prism 9 and R 4.0.2.

Results: Extracellular fluid was collected from 66 depth electrodes from 29 patients. Between groups, there was no difference in the number of electrodes implanted in mesial and non-mesial regions and cortical and non-cortical regions. The patients were followed for a median period of 5.3 years. Eleven patients reported Engel class I outcomes. Next, we compared the basal glutamine levels between the two groups. Glutamine levels were significantly higher in patients with seizure-free outcomes versus other Engel class outcomes (791.3 vs. 510.6 μM, P = 0.021). Logistic regression revealed the patients with higher glutamine levels had significantly better odds of obtaining seizure-free outcomes (OR: 1.001, P = 0.027).

Conclusions: This pilot study implements basal glutamine levels with epilepsy surgery outcomes. Higher glutamine levels in patients with Engel class I outcomes underscore the importance of glutamine maintenance in epileptogenesis. Further studies in various animal models can help in understanding the role of glutamine homeostasis in epilepsy. In addition, more understanding of the mechanisms that up-regulate in the presence of abnormal glutamate-glutamine cycling, may help in understanding glutamine regulation in epileptic states.

Funding: Please list any funding that was received in support of this abstract.: MRS, ED and TE (Swebilius Foundation).