Mutant IDH1 and seizures in patients with glioma

Objective: Because the D-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1(mut)) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1(mut) increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons. Methods: Three WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1(mut) status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5. Results: Preoperative seizures were observed in 18%-34% of IDH1 wild-type (IDH1(wt)) patients and in 59%-74% of IDH1(mut) patients (p, 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1(mut) was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6-3.9, p < 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5. Conclusions: The D2HG product of IDH1(mut) may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1(mut) gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1(mut) inhibitors may improve antiepileptic therapy in patients with IDH1(mut) gliomas.