Postoperative risk of IDH-mutant glioma–associated seizures and their potential management with IDH-mutant inhibitors
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
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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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 5

IDHmut glioma causes TAE in mice.

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IDHmut glioma causes TAE in mice. (A) Mice were engrafted with either ID...
(A) Mice were engrafted with either IDHmut or IDHwt glioma. Four mice per group were euthanized on days 6, 12, 15, and 18. Intracranial tumor size at each time point was histologically measured as maximum tumor diameter. Data points represent mean ± SEM. Data were analyzed with 2-way ANOVA. (B) Top trace is EEG1, middle trace is EEG2, bottom trace is EMG. Red arrows indicate representative epileptiform spike. (C and D) Mice engrafted with IDHwt (n = 12) or IDHmut (n = 8) glioma had recordings taken at days 6, 12, and 18. EEGs were scored for percentage of 10-second epochs that contained epileptiform spikes and normalized to the tumor size in IDHwt or IDHmut glioma at day 6, 12, or 18, respectively (C), as well as directly compared (D). Bars represent mean ± SEM. Data were analyzed with unpaired, 2-tailed t test (C) or 2-way ANOVA (D). (E) Dentate gyrus of mice engrafted with either IDHwt or IDHmut glioma, stained with NeuN (1:400; ab104224, red), cFOS (1:500; ab190289, green), and MAP2 (1:1,000; ab5392, blue). (F) Percentage of NeuN colocalized with cFOS in the dentate gyrus of mice engrafted with either IDHwt (n = 3) or IDHmut (n = 4) glioma. Bars represent mean ± SEM. Data were analyzed with unpaired, 2-tailed t test. (G) Cortex contralateral to IDHwt- or IDHmut-engrafted glioma, stained with GFAP (1:500; CP040A). (H) Quantification of GFAP positivity in contralateral cortex of mice engrafted with IDHwt glioma within 12–18 days after engraftment (n = 6) or 19+ days after engraftment (n = 5) and of mice engrafted with IDHmut glioma within 12–18 days after engraftment (n = 4) or 19+ days after engraftment (n = 4) using pixel thresholding in QuPath. Scale bars in E and G: 100 μm. Bars represent mean ± SEM. **P < 0.01, ***P < 0.001 by unpaired, 2-tailed t test.