title: Mutant IDH1 and seizures in patients with glioma.
abstract: OBJECTIVE
  Because the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1mut) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1mutincreases 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 IDH1mutstatus. 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 (IDH1wt) patients and in 59%-74% of IDH1mutpatients (p< 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1mutwas 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 IDH1mutmay increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1mutgliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1mutinhibitors may improve antiepileptic therapy in patients with IDH1mutgliomas.
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Judkins
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Cheddhi
authors.initials: C
authors.lastname: Thomas
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Meijing
authors.initials: M
authors.lastname: Wu
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Laith
authors.initials: L
authors.lastname: Khoury
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Carolina G
authors.initials: CG
authors.lastname: Benjamin
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Donato
authors.initials: D
authors.lastname: Pacione
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: John G
authors.initials: JG
authors.lastname: Golfinos
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Priya
authors.initials: P
authors.lastname: Kumthekar
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Farhad
authors.initials: F
authors.lastname: Ghamsari
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Pamela
authors.initials: P
authors.lastname: Lein
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Dane M
authors.initials: DM
authors.lastname: Chetkovich
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington.
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.affiliation: From the University of California, Davis (H.C., P.L.), CA; Departments of Neurosurgery (M.W., C.H.), Neurology (L.C., D.M.C.), Physiology (D.M.C.), and Pathology (C.H.), Feinberg School of Medicine (J.J., F.G.), Northwestern University, Chicago, IL; Departments of Pathology (C.T., M.S.) and Neurosurgery (C.G.B., D.P., J.G.G.), Langone School of Medicine, New York University, New York; and Departments of Neurosurgery (L.K.) and Cancer Biostatistics (P.K.), University of Kentucky, Lexington. craig.horbinski@northwestern.edu.
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1; D005260:Female; D005910:Glioma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D005977:Glutarates / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D017207:Rats, Sprague-Dawley; D012189:Retrospective Studies; D012640:Seizures / Q000235:genetics* / Q000503:physiopathology / Q000601:surgery
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human