Association between accumulation of 2-hydroxyglutarate detected by MR spectroscopy and preoperative seizure in IDH-mutant glioma

Abstract

Objective: Epileptic seizures are common in patients with gliomas, and their control represents an important aspect of treatment. The oncometabolite 2-hydroxyglutarate (2HG), produced by mutant isocitrate dehydrogenase (IDH), is thought to be associated with seizures due to its structural similarity to the excitatory neurotransmitter glutamate. Using 3T MR spectroscopy (MRS), the authors investigated whether 2HG accumulation might indicate preoperative glioma-associated seizures.

Methods: The authors included 196 consecutive patients with diffuse glioma who underwent preoperative MRS and neurological surgery from August 2013 to August 2022. IDH mutation status was confirmed by immunohistochemical analysis and direct DNA sequencing. Concentrations of metabolites, including 2HG, were measured by 3T MRS. The authors set a single voxel (15 mm × 15 mm × 15 mm) and used LCModel software to obtain the quantitative information of the metabolites. They assessed the correlations of preoperative seizures with patient characteristics, tumor size and location, metabolite concentration on MRS, histopathological diagnosis, WHO grade, and IDH-mutant status.

Results: Preoperative seizures were observed in 57.8% of patients with IDH-mutant glioma and in 15.2% of patients with IDH-wildtype glioma (p < 0.0001). MRS indicated a higher glutamate concentration in IDH-wildtype gliomas (n = 132) than in IDH-mutant gliomas (n = 64, p < 0.0001). The 2HG concentrations were higher in IDH-mutant tumors than in IDH-wildtype tumors (median 0.71 mM vs 0 mM, respectively; p < 0.001). Glutamate was not associated with a high frequency of preoperative seizures in patients with either IDH-mutant or IDH-wildtype gliomas. In IDH-mutant glioma, 2HG levels were higher in the group with preoperative seizures than in the group without preoperative seizures (median 1.429 mM and 0.187 mM, respectively; p = 0.0231). Multivariate analysis revealed that 2HG concentration was associated with preoperative seizures in IDH-mutant glioma (OR 4.164, 95% CI 1.320-14.50).

Conclusions: An elevated 2HG concentration on MRS could be associated with preoperative seizure, suggesting that 2HG accumulation increases the risk of preoperative seizures in IDH-mutant gliomas.

Keywords: 2-hydroxyglutarate; 2HG; IDH mutation; glutamate; magnetic resonance spectroscopy; seizure; tumor.