Postoperative risk of IDH-mutant glioma–associated seizures and their potential management with IDH-mutant inhibitors
Michael R. Drumm, … , Geoffrey T. Swanson, Craig Horbinski
Michael R. Drumm, … , Geoffrey T. Swanson, Craig Horbinski
Published April 27, 2023
Citation Information: J Clin Invest. 2023;133(12):e168035. https://doi.org/10.1172/JCI168035.
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Research Article Neuroscience Oncology

Postoperative risk of IDH-mutant glioma–associated seizures and their potential management with IDH-mutant inhibitors

Abstract

Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH–wild type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contributed to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures were often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, d-2-hydroxyglutarate, rapidly synchronized neuronal spike firing in a seizure-like manner, but only when non-neoplastic glial cells were present. In vitro and in vivo models recapitulated IDHmut glioma–associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibited seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.

Authors

Michael R. Drumm, Wenxia Wang, Thomas K. Sears, Kirsten Bell-Burdett, Rodrigo Javier, Kristen Y. Cotton, Brynna Webb, Kayla Byrne, Dusten Unruh, Vineeth Thirunavu, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Rimas V. Lukas, Joanna J. Phillips, Esraa Mohamed, John D. Finan, Lucas Santana-Santos, Amy B. Heimberger, Colin K. Franz, Jonathan Kurz, Jessica W. Templer, Geoffrey T. Swanson, Craig Horbinski

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Figure 3

D2HG requires glial cells to trigger neuronal firing in vitro.

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D2HG requires glial cells to trigger neuronal firing in vitro. (A and B)...
(A and B) Day 21 mouse neurons cultured with or without glia were recorded on a multi-electrode plate for 5 minutes, and then treated with vehicle or 1, 3, or 10 mM D2HG (vehicle –glia, n = 13; 1 mM D2HG +glia, n = 10; 3 mM D2HG –glia, n = 10; 10 mM D2HG –glia, n = 12; 3 mM D2HG +glia, n = 9). Experiment was repeated twice for a total of 3 times. Fold change after treatment was calculated for each well. Bars represent mean ± SEM. ***P = 0.002, ****P < 0.0001 by unpaired, 2-tailed t test (Bonferroni-adjusted P = 0.006). (C and D) Raster plots of wells with neurons only (C) or neurons with glia (D) treated with 3 mM D2HG at the time point indicated by the red arrows. Horizontal rows indicate firing activity of each electrode in a well (16 electrodes per well). Histogram above the rows depicts the summation of the firing activity of all electrodes in the well at a given time point. (E) Day 21 mouse neurons cultured with glia had baseline weighted mean firing rate recorded on a multi-electrode well plate for 5 minutes, then were treated with vehicle or 1, 3, or 10 mM D2HG (vehicle, n = 19; 1 mM D2HG, n = 15; 3 mM D2HG, n = 15; 10 mM D2HG, n = 17). Fold change of weighted mean firing rate for 5 minutes after treatment was calculated for each well. Bars represent mean ± SEM. *P < 0.05, ***P < 0.001 by 2-tailed t test. Experiment was repeated twice for a total of 3 times. (F and G) Neurons cultured with glia were recorded for 20 minutes following treatment with either 1 mM D2HG (n = 15) (F) or 3 mM D2HG (n = 15) (G), and fold change of weighted mean firing rate was calculated for each well in 5-minute intervals. Bars represent mean ± SEM. *P < 0.05, **P < 0.01 by unpaired, 2-tailed t test. Experiment was repeated twice for a total of 3 times. (H) Representative raster plot of well with neurons cultured with glia treated with 3 mM D2HG and recorded for 20 minutes following treatment.