Mutant IDH1 and seizures in glioma patients

Seizures diminish the quality of life in patients with diffusely infiltrative gliomas. Over 50% of patients will experience at least one seizure during the course of their disease, and over 30% will develop tumor-associated epilepsy (TAE), defined as multiple seizures. Because the D-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1mut) is released by tumor cells into the microenvironment, and D2HG is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1mut increases the risk of seizures in glioma patients, and whether D2HG increases the electrical activity of neurons. To address this, three WHO grade II-IV glioma cohorts from separate institutions (total N=712) were retrospectively assessed for the presence of preoperative seizures. Preoperative seizures were observed in 18-34% of IDH1 wild-type (IDH1wt) patients and in 59-74% of IDH1mut patients (P<0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe tumor location, showed that IDH1mut was an independent correlate with seizures (OR=2.5, 95% CI=1.6-3.9, P<0.001). Furthermore, exogenous D2HG increased the synchronized firing rate of cultured rat cortical neurons several fold, but was completely blocked by the selective NMDA antagonist, AP5. We therefore hypothesize that the D2HG product of IDH1mut increases neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and that this is the reason why IDH1mut gliomas are more likely to cause seizures in patients. Our data has rapid translational implications for the personalized management of TAE, as targeted IDH1mut inhibitors may improve antiepileptic therapy in patients with IDH1mut gliomas.