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  • Review Article
  • Published:

Seizures and gliomas — towards a single therapeutic approach

Nature Reviews Neurology volume 12, pages 204–216 (2016)Cite this article

Subjects

Key Points

  • Gliomas are commonly associated with the development of epilepsy; the two conditions share common pathogenic mechanisms and influence each other

  • Excessive glutamate release and activation of glutamate receptors promotes glioma growth, cell death and epileptic activity

  • GABAergic signalling is antiproliferative, whereas chloride accumulation is required for mitosis and migration of tumour cells, and is responsible for epileptogenic depolarizing GABAergic activity in neurons

  • The molecular target of rapamycin (mTOR) signalling pathway and epigenetic abnormalities are also involved in epileptogenesis and tumour growth

  • As a result of the shared pathogenic mechanisms, antiepileptic drugs can have antitumour effects, and antitumour therapy can control seizures

  • Single drug therapies targeting the shared mechanisms are now being assessed for combined seizure and tumour control, and have the advantage of lower risks of adverse effects and drug interactions

Abstract

Epilepsy often develops in patients with glioma, and the two conditions share common pathogenic mechanisms. Altered expression of glutamate transporters, including the cystine–glutamate transporter (xCT) system, increases concentrations of extracellular glutamate, which contribute to epileptic discharge, tumour proliferation and peripheral excitotoxicity. Furthermore, mutation of the isocitrate dehydrogenase 1 gene in low-grade gliomas causes production of D-2-hydroxyglutarate, a steric analogue of glutamate. Dysregulation of intracellular chloride promotes glioma cell mitosis and migration, and γ-aminobutyric acid (GABA) signalling suppresses proliferation. In neurons, however, chloride accumulation leads to aberrant depolarization on GABA receptor activation, thereby promoting epileptic activity. The molecular target of rapamycin (mTOR) pathway and epigenetic abnormalities are also involved in the development of tumours and seizures. Antitumour therapy can contribute to seizure control, and antiepileptic drugs might have beneficial effects on tumours. Symptomatic treatment with antiepileptic drugs carries risks of adverse effects and drug interactions. In this Review, we discuss the potential for single therapeutic agents, such as the xCT blocker sulfasalazine, the chloride regulator bumetanide, and the histone deacetylase inhibitor valproic acid, to manage both gliomas and associated epilepsy. We also provide guidance on the evidence-based use of antiepileptic drugs in brain tumours. The development of solo therapies to treat both aspects of gliomas promises to yield more-effective treatment with fewer risks of toxicity and drug interactions.

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Figure 1: Glutamatergic signalling promotes oncogenesis and epileptogenesis.
Figure 2: Dysregulation of intracellular Cl− and consequent defects in GABAergic signalling favour oncogenesis and epileptogenesis.

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References

  1. Noebels, J. L. et al. (eds) Jasper's Basic Mechanisms of the Epilepsies 4th edn, (OUP USA, 2012).

    Book  Google Scholar 

  2. Kerkhof, M. & Vecht, C. J. Seizure characteristics and prognostic factors of gliomas. Epilepsia 54 (Suppl. 9), 12–17 (2013).

    Article  PubMed  Google Scholar 

  3. van Breemen, M. S., Wilms, E. B. & Vecht, C. J. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol. 6, 421–430 (2007).

    Article  PubMed  Google Scholar 

  4. Buckingham, S. C. & Robel, S. Glutamate and tumor-associated epilepsy: glial cell dysfunction in the peritumoral environment. Neurochem. Int. 63, 696–701 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Pallud, J. et al. Cortical GABAergic excitation contributes to epileptic activities around human glioma. Sci. Transl. Med. 6, 244ra89 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gerin, C. et al. Quantitative characterization of the imaging limits of diffuse low-grade oligodendrogliomas. Neuro Oncol. 15, 1379–1388 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pallud, J. et al. Diffuse low-grade oligodendrogliomas extend beyond MRI-defined abnormalities. Neurology 74, 1724–1731 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Robert, S. M. et al. SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma. Sci. Transl. Med. 7, 289ra86 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Buckingham, S. C. et al. Glutamate release by primary brain tumors induces epileptic activity. Nat. Med. 17, 1–7 (2011).

    Article  CAS  Google Scholar 

  10. Hirsch, J. F., Buisson-Ferey, J., Sachs, M., Hirsch, J. C. & Scherrer, J. Electrocorticogram and unitary activites with expanding lesions in man. Electroencephalogr. Clin. Neurophysiol. 21, 417–428 (in French) (1966).

    Article  CAS  PubMed  Google Scholar 

  11. Tran, T. A. et al. Significance of spikes recorded on intraoperative electrocorticography in patients with brain tumor and epilepsy. Epilepsia 38, 1132–1138 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Venkatesh, H. S. et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161, 803–816 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Marcus, H. J., Carpenter, K. L., Price, S. J. & Hutchinson, P. J. in vivo assessment of high-grade glioma biochemistry using microdialysis: a study of energy-related molecules, growth factors and cytokines. J. Neurooncol. 97, 11–23 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Ye, Z. C., Rothstein, J. D. & Sontheimer, H. Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange. J. Neurosci. 19, 10767–10777 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Takano, T. et al. Glutamate release promotes growth of malignant gliomas. Nat. Med. 7, 1010–1015 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Savaskan, N. E. et al. Small interfering RNA-mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema. Nat. Med. 14, 629–632 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. de Groot, J. & Sontheimer, H. Glutamate and the biology of gliomas. Glia 59, 1181–1189 (2011).

    Article  PubMed  Google Scholar 

  18. Yuen, T. I. et al. Glutamate is associated with a higher risk of seizures in patients with gliomas. Neurology 79, 883–889 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Kandil, S., Brennan, L. & McBean, G. J. Glutathione depletion causes a JNK and p38MAPK-mediated increase in expression of cystathionine-γ-lyase and upregulation of the transsulfuration pathway in C6 glioma cells. Neurochem. Int. 56, 611–619 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Noch, E. & Khalili, K. Molecular mechanisms of necrosis in glioblastoma: the role of glutamate excitotoxicity. Cancer Biol. Ther. 8, 1791–1797 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Duran-Peña, A. et al. IDH1 mutation in low-grade gliomas related to epilepsy as initial symptom. Neuro Oncol. 16 (Suppl. 2), ii39–ii40 (2014).

    Article  PubMed Central  Google Scholar 

  22. Stockhammer, F. et al. IDH1/2 mutations in WHO grade II astrocytomas associated with localization and seizure as the initial symptom. Seizure 21, 194–197 (2012).

    Article  PubMed  Google Scholar 

  23. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sanson, M. et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J. Clin. Oncol. 27, 4150–4154 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Andronesi, O. C. et al. Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Sci. Transl. Med. 4, 116ra4 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Elkhaled, A. et al. Characterization of metabolites in infiltrating gliomas using ex vivo1H high-resolution magic angle spinning spectroscopy. NMR Biomed. 27, 578–593 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lyons, S. A., Chung, W. J., Weaver, A. K., Ogunrinu, T. & Sontheimer, H. Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res. 67, 9463–9471 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. D'Onofrio, M. et al. Pharmacological blockade of mGlu2/3 metabotropic glutamate receptors reduces cell proliferation in cultured human glioma cells. J. Neurochem. 84, 1288–1295 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Stepulak, A. et al. Expression of glutamate receptor subunits in human cancers. Histochem. Cell Biol. 132, 435–445 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Colman, H. et al. A multigene predictor of outcome in glioblastoma. Neuro Oncol. 12, 49–57 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Ishiuchi, S. et al. Blockage of Ca2+-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat. Med. 8, 971–978 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Rzeski, W., Turski, L. & Ikonomidou, C. Glutamate antagonists limit tumor growth. Proc. Natl Acad. Sci. USA 98, 6372–6377 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ishiuchi, S. et al. Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J. Neurosci. 27, 7987–8001 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. de Groot, J. F., Piao, Y., Lu, L., Fuller, G. N. & Yung, W. K. Knockdown of GluR1 expression by RNA interference inhibits glioma proliferation. J. Neurooncol. 88, 121–133 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Grossman, S. A. et al. Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin. Cancer Res. 16, 2443–2449 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Iwamoto, F. M. et al. Phase 2 trial of talampanel, a glutamate receptor inhibitor, for adults with recurrent malignant gliomas. Cancer 116, 1776–1782 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. US National Library of Science. ClinicalTrials.gov [online], (2015).

  38. Yohay, K. et al. Efficacy of local polymer-based and systemic delivery of the anti-glutamatergic agents riluzole and memantine in rat glioma models. J. Neurosurg. 120, 854–863 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. US National Library of Science. ClinicalTrials.gov [online], (2015).

  40. Ching, J. et al. The peroxisome proliferator activated receptor gamma agonist pioglitazone increases functional expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in human glioblastoma cells. Oncotarget 6, 21301–21314 (2015).

    PubMed  PubMed Central  Google Scholar 

  41. Ellis, H. P. & Kurian, K. M. Biological rationale for the use of PPARγ agonists in glioblastoma. Front. Oncol. 4, 52 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Puligheddu, M. et al. PPAR-alpha agonists as novel antiepileptic drugs: preclinical findings. PLoS ONE 8, e64541 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Saha, L., Bhandari, S., Bhatia, A., Banerjee, D. & Chakrabarti, A. Anti-kindling effect of bezafibrate, a peroxisome proliferator-activated receptors alpha agonist, in pentylenetetrazole induced kindling seizure model. J. Epilepsy Res. 4, 45–54 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  44. de Groot, J. F., Liu, T. J., Fuller, G. & Yung, W. K. The excitatory amino acid transporter-2 induces apoptosis and decreases glioma growth in vitro and in vivo. Cancer Res. 65, 1934–1940 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Grommes, C., Conway, D. S., Alshekhlee, A. & Barnholtz-Sloan, J. S. Inverse association of PPARγ agonists use and high grade glioma development. J. Neurooncol. 100, 233–239 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Arcella, A. et al. Pharmacological blockade of group II metabotropic glutamate receptors reduces the growth of glioma cells in vivo. Neuro Oncol. 7, 236–245 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rothstein, J. D. et al. β-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433, 73–77 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626–630 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bianchi, L. et al. Extracellular levels of amino acids and choline in human high grade gliomas: an intraoperative microdialysis study. Neurochem. Res. 29, 325–334 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Haglund, M. M. et al. Changes in gamma-aminobutyric acid and somatostatin in epileptic cortex associated with low-grade gliomas. J. Neurosurg. 77, 209–216 (1992).

    Article  CAS  PubMed  Google Scholar 

  51. Marco, P., Sola, R. G., Ramón y Cajal, S. & DeFelipe, J. Loss of inhibitory synapses on the soma and axon initial segment of pyramidal cells in human epileptic peritumoural neocortex. Brain Res. Bull. 44, 47–66 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Köhling, R. & Avoli, M. Methodological approaches to exploring epileptic disorders in the human brain in vitro. J. Neurosci. Methods 155, 1–19 (2006).

    Article  PubMed  Google Scholar 

  53. Chang, W. S. et al. Decreased inhibitory neuronal activity in patients with frontal lobe brain tumors with seizure presentation: preliminary study using magnetoencephalography. Acta Neurochir. (Wien) 155, 1449–1457 (2013).

    Article  Google Scholar 

  54. Smits, A. et al. GABA-A channel subunit expression in human glioma correlates with tumor histology and clinical outcome. PLoS ONE 7, e37041 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Labrakakis, C., Patt, S., Hartmann, J. & Kettenmann, H. Functional GABAA receptors on human glioma cells. Eur. J. Neurosci. 10, 231–238 (1998).

    Article  CAS  PubMed  Google Scholar 

  56. Young, S. Z. & Bordey, A. GABA's control of stem and cancer cell proliferation in adult neural and peripheral niches. Physiology (Bethesda) 24, 171–185 (2009).

    CAS  Google Scholar 

  57. Habela, C. W., Ernest, N. J., Swindall, A. F. & Sontheimer, H. Chloride accumulation drives volume dynamics underlying cell proliferation and migration. J. Neurophysiol. 101, 750–757 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Habela, C. W., Olsen, M. L. & Sontheimer, H. ClC3 is a critical regulator of the cell cycle in normal and malignant glial cells. J. Neurosci. 28, 9205–9217 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Watkins, S. & Sontheimer, H. Hydrodynamic cellular volume changes enable glioma cell invasion. J. Neurosci. 31, 17250–17259 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Haas, B. R. & Sontheimer, H. Inhibition of the sodium–potassium–chloride cotransporter isoform-1 reduces glioma invasion. Cancer Res. 70, 5597–5606 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ernest, N. J., Weaver, A. K., Van Duyn, L. B. & Sontheimer, H. W. Relative contribution of chloride channels and transporters to regulatory volume decrease in human glioma cells. Am. J. Physiol. Cell Physiol. 288, C1451–C1460 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Garzon-Muvdi, T. et al. Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation. PLoS Biol. 10, e1001320 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Algharabil, J. et al. Inhibition of Na+–K+−2Cl− cotransporter isoform 1 accelerates temozolomide-mediated apoptosis in glioblastoma cancer cells. Cell. Physiol. Biochem. 30, 33–48 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Cuddapah, V. A. et al. Kinase activation of ClC-3 accelerates cytoplasmic condensation during mitotic cell rounding. Am. J. Physiol. Cell Physiol. 302, C527–C538 (2012).

    Article  CAS  PubMed  Google Scholar 

  65. McCoy, E. & Sontheimer, H. Expression and function of water channels (aquaporins) in migrating malignant astrocytes. Glia 55, 1034–1043 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Cuddapah, V. A., Turner, K. L., Seifert, S. & Sontheimer, H. Bradykinin-induced chemotaxis of human gliomas requires the activation of KCa3.1 and ClC-3. J. Neurosci. 33, 1427–1440 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Huberfeld, G., Blauwblomme, T. & Miles, R. Hippocampus and epilepsy: findings from human tissues. Rev. Neurol. (Paris) 171, 236–251 (2015).

    Article  CAS  Google Scholar 

  68. Huberfeld, G. et al. Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy. J. Neurosci. 27, 9866–9873 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Palma, E. et al. Anomalous levels of Cl− transporters in the hippocampal subiculum from temporal lobe epilepsy patients make GABA excitatory. Proc. Natl Acad. Sci. USA 103, 8465–8468 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Muñoz, A., Méndez, P., DeFelipe, J. & Alvarez-Leefmans, F. J. Cation–chloride cotransporters and GABA-ergic innervation in the human epileptic hippocampus. Epilepsia 48, 663–673 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Cepeda, C. et al. Enhanced GABAergic network and receptor function in pediatric cortical dysplasia type IIB compared with tuberous sclerosis complex. Neurobiol. Dis. 45, 310–321 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Talos, D. M. et al. Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. Ann. Neurol. 71, 539–551 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Campbell, S. L. et al. GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy. Glia 63, 23–36 (2015).

    Article  PubMed  Google Scholar 

  74. Conti, L. et al. Anomalous levels of Cl− transporters cause a decrease of GABAergic inhibition in human peritumoral epileptic cortex. Epilepsia 52, 1635–1644 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Aronica, E. et al. Differential expression patterns of chloride transporters, Na+–K+–2Cl−-cotransporter and K+–Cl−-cotransporter, in epilepsy-associated malformations of cortical development. Neuroscience 145, 185–196 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Coull, J. A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Lee, H. H., Deeb, T. Z., Walker, J. A., Davies, P. A. & Moss, S. J. NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents. Nat. Neurosci. 14, 736–743 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Haas, B. R. et al. With-no-lysine kinase 3 (WNK3) stimulates glioma invasion by regulating cell volume. Am. J. Physiol. Cell Physiol. 301, C1150–C1160 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhu, W. et al. WNK1–OSR1 kinase-mediated phospho-activation of Na+–K+–2Cl− cotransporter facilitates glioma migration. Mol. Cancer 13, 31 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhang, X. et al. The effect of bumetanide on photodynamic therapy-induced peri-tumor edema of C6 glioma xenografts. Lasers Surg. Med. 46, 422–430 (2014).

    Article  PubMed  Google Scholar 

  81. Dzhala, V. I. et al. Progressive NKCC1-dependent neuronal chloride accumulation during neonatal seizures. J. Neurosci. 30, 11745–11761 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Nardou, R. et al. Neuronal chloride accumulation and excitatory GABA underlie aggravation of neonatal epileptiform activities by phenobarbital. Brain 134, 987–1002 (2011).

    Article  PubMed  Google Scholar 

  83. Rheims, S., Represa, A., Ben-Ari, Y. & Zilberter, Y. Layer-specific generation and propagation of seizures in slices of developing neocortex: role of excitatory GABAergic synapses. J. Neurophysiol. 100, 620–628 (2008).

    Article  PubMed  Google Scholar 

  84. Kilb, W., Sinning, A. & Luhmann, H. J. Model-specific effects of bumetanide on epileptiform activity in the in-vitro intact hippocampus of the newborn mouse. Neuropharmacology 53, 524–533 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Kahle, K. T., Barnett, S. M., Sassower, K. C. & Staley, K. J. Decreased seizure activity in a human neonate treated with bumetanide, an inhibitor of the Na+–K+–2Cl− cotransporter NKCC1. J. Child Neurol. 24, 572–576 (2009).

    Article  PubMed  Google Scholar 

  86. Eftekhari, S. et al. Bumetanide reduces seizure frequency in patients with temporal lobe epilepsy. Epilepsia 54, e9–e12 (2013).

    Article  CAS  PubMed  Google Scholar 

  87. US National Library of Science. ClinicalTrials.gov [online], (2015).

  88. Pressler, R. M. et al. Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility Phase 1/2 trial. Lancet Neurol. 14, 469–477 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Töllner, K. et al. A novel prodrug-based strategy to increase effects of bumetanide in epilepsy. Ann. Neurol. 75, 550–562 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Gagnon, M. et al. Chloride extrusion enhancers as novel therapeutics for neurological diseases. Nat. Med. 19, 1524–1528 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hamidi, S. & Avoli, M. KCC2 function modulates in vitro ictogenesis. Neurobiol. Dis. 79, 51–58 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lyons, S. A., O'Neal, J. & Sontheimer, H. Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin. Glia 39, 162–173 (2002).

    Article  PubMed  Google Scholar 

  93. Sontheimer, H. An unexpected role for ion channels in brain tumor metastasis. Exp. Biol. Med. (Maywood) 233, 779–791 (2008).

    Article  CAS  Google Scholar 

  94. Lui, V. C., Lung, S. S., Pu, J. K., Hung, K. N. & Leung, G. K. Invasion of human glioma cells is regulated by multiple chloride channels including ClC-3. Anticancer Res. 30, 4515–4524 (2010).

    CAS  PubMed  Google Scholar 

  95. Lipton, J. O. & Sahin, M. The neurology of mTOR. Neuron 84, 275–291 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Baybis, M. et al. mTOR cascade activation distinguishes tubers from focal cortical dysplasia. Ann. Neurol. 56, 478–487 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Mohamed, A. R. et al. Intrinsic epileptogenicity of cortical tubers revealed by intracranial EEG monitoring. Neurology 79, 2249–2257 (2012).

    Article  PubMed  Google Scholar 

  98. Weston, M. C., Chen, H. & Swann, J. W. Multiple roles for mammalian target of rapamycin signaling in both glutamatergic and GABAergic synaptic transmission. J. Neurosci. 32, 11441–11452 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bateup, H. S. et al. Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron 78, 510–522 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lozovaya, N. et al. Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model. Nat. Commun. 5, 4563 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Knobbe, C. B., Merlo, A. & Reifenberger, G. Pten signaling in gliomas. Neuro Oncol. 4, 196–211 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chakravarti, A. et al. Prognostic and pathologic significance of quantitative protein expression profiling in human gliomas. Clin. Cancer Res. 7, 2387–2395 (2001).

    CAS  PubMed  Google Scholar 

  103. Prabowo, A. S. et al. BRAF V600E mutation is associated with mTOR signaling activation in glioneuronal tumors. Brain Pathol. 24, 52–66 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Penman, C. L., Faulkner, C., Lowis, S. P. & Kurian, K. M. Current understanding of BRAF alterations in diagnosis, prognosis, and therapeutic targeting in pediatric low-grade gliomas. Front. Oncol. 5, 54 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Franz, D. N. et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann. Neurol. 59, 490–498 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Krueger, D. A. et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N. Engl. J. Med. 363, 1801–1811 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Sami, A. & Karsy, M. Targeting the PI3K/AKT/mTOR signaling pathway in glioblastoma: novel therapeutic agents and advances in understanding. Tumour Biol. 34, 1991–2002 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. US National Library of Science. ClinicalTrials.gov [online], (2016).

  109. US National Library of Science. ClinicalTrials.gov [online], (2012).

  110. US National Library of Science. ClinicalTrials.gov [online], (2016).

  111. US National Library of Science. ClinicalTrials.gov [online], (2016).

  112. US National Library of Science. ClinicalTrials.gov [online], (2015).

  113. US National Library of Science. ClinicalTrials.gov [online], (2012).

  114. US National Library of Science. ClinicalTrials.gov [online], (2015).

  115. US National Library of Science. ClinicalTrials.gov [online], (2013).

  116. US National Library of Science. ClinicalTrials.gov [online], (2015).

  117. US National Library of Science. ClinicalTrials.gov [online], (2015).

  118. US National Library of Science. ClinicalTrials.gov [online], (2016).

  119. Meikle, L. et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J. Neurosci. 28, 5422–5432 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zeng, L. H., Xu, L., Gutmann, D. H. & Wong, M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann. Neurol. 63, 444–453 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Krueger, D. A. et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann. Neurol. 74, 679–687 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Wiegand, G. et al. Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option? Eur. J. Paediatr. Neurol. 17, 631–638 (2013).

    Article  PubMed  Google Scholar 

  123. Cardamone, M. et al. Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex. J. Pediatr. 164, 1195–1200 (2014).

    Article  CAS  PubMed  Google Scholar 

  124. US National Library of Science. ClinicalTrials.gov [online], (2016).

  125. US National Library of Science. ClinicalTrials.gov [online], (2015).

  126. Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  127. Bangert, A. et al. Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP. Oncogene 31, 4677–4688 (2012).

    Article  CAS  PubMed  Google Scholar 

  128. Cipro, Š., Hr˘ebac˘ková, J., Hrabe˘ta, J., Poljaková, J. & Eckschlager, T. Valproic acid overcomes hypoxia-induced resistance to apoptosis. Oncol. Rep. 27, 1219–1226 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Van Nifterik, K. A. et al. Valproic acid sensitizes human glioma cells for temozolomide and γ-radiation. J. Neurooncol. 107, 61–67 (2012).

    Article  CAS  PubMed  Google Scholar 

  130. Chen, C. H., Chang, Y. J., Ku, M. S., Chung, K. T. & Yang, J. T. Enhancement of temozolomide-induced apoptosis by valproic acid in human glioma cell lines through redox regulation. J. Mol. Med. (Berl.) 89, 303–315 (2011).

    Article  CAS  Google Scholar 

  131. Brodie, S. A. & Brandes, J. C. Could valproic acid be an effective anticancer agent? The evidence so far. Expert Rev. Anticancer Ther. 14, 1097–1100 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Weller, M. et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 77, 1156–1164 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kerkhof, M. et al. Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. Neuro Oncol. 15, 961–967 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Krauze, A. V. et al. A Phase 2 study of concurrent radiation therapy, temozolomide, and the histone deacetylase inhibitor valproic acid for patients with glioblastoma. Int. J. Radiat. Oncol. Biol. Phys. 92, 986–992 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Happold, C. et al. Does valproic acid improve survival in glioblastoma? A meta-analysis of randomized trials in newly diagnosed glioblastoma [abstract]. Neuro Oncol. 17 (Suppl. 5), v12 (2015).

    PubMed Central  Google Scholar 

  136. Bobustuc, G. C. et al. Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide. Neuro Oncol. 12, 917–927 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kim, Y. H. et al. Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme. Cancer 121, 2926–2932 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. Grossman, S. A. et al. Talampanel with standard radiation and temozolomide in patients with newly diagnosed glioblastoma: a multicenter Phase II trial. J. Clin. Oncol. 27, 4155–4161 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Thom, M., Blümcke, I. & Aronica, E. Long-term epilepsy-associated tumors. Brain Pathol. 22, 350–379 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Englot, D. J., Berger, M. S., Barbaro, N. M. & Chang, E. F. Factors associated with seizure freedom in the surgical resection of glioneuronal tumors. Epilepsia 53, 51–57 (2012).

    Article  PubMed  Google Scholar 

  141. Pallud, J. et al. Epileptic seizures in diffuse low-grade gliomas in adults. Brain 137, 449–462 (2014).

    Article  PubMed  Google Scholar 

  142. Englot, D. J., Han, S. J., Berger, M. S., Barbaro, N. M. & Chang, E. F. Extent of surgical resection predicts seizure freedom in low-grade temporal lobe brain tumors. Neurosurgery 70, 921–928 (2012).

    Article  PubMed  Google Scholar 

  143. Luyken, C. et al. The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects. Epilepsia 44, 822–830 (2003).

    Article  PubMed  Google Scholar 

  144. Chang, E. F. et al. Seizure characteristics and control following resection in 332 patients with low-grade gliomas. J. Neurosurg. 108, 227–235 (2008).

    Article  PubMed  Google Scholar 

  145. Chaichana, K. L., Parker, S. L., Olivi, A. & Quiñones-Hinojosa, A. Long-term seizure outcomes in adult patients undergoing primary resection of malignant brain astrocytomas. J. Neurosurg. 111, 282–292 (2009).

    Article  PubMed  Google Scholar 

  146. Englot, D. J., Berger, M. S., Barbaro, N. M. & Chang, E. F. Predictors of seizure freedom after resection of supratentorial low-grade gliomas. A review. J. Neurosurg. 115, 240–244 (2011).

    Article  PubMed  Google Scholar 

  147. van den Bent, M. J. et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366, 985–990 (2005).

    Article  CAS  PubMed  Google Scholar 

  148. Rudà, R. et al. Seizure control following radiotherapy in patients with diffuse gliomas: a retrospective study. Neuro Oncol. 15, 1739–1749 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Pace, A. et al. Temozolomide chemotherapy for progressive low-grade glioma: clinical benefits and radiological response. Ann. Oncol. 14, 1722–1726 (2003).

    Article  CAS  PubMed  Google Scholar 

  150. Rudà, R., Bello, L., Duffau, H. & Soffietti, R. Seizures in low-grade gliomas: natural history, pathogenesis, and outcome after treatments. Neuro Oncol. 14 (Suppl. 4), iv55–iv64 (2012).

    PubMed  PubMed Central  Google Scholar 

  151. Koekkoek, J. A. et al. Seizure outcome after radiotherapy and chemotherapy in low-grade glioma patients: a systematic review. Neuro Oncol. 17, 924–934 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Kaloshi, G. et al. Temozolomide for low-grade gliomas: predictive impact of 1p/19q loss on response and outcome. Neurology 68, 1831–1836 (2007).

    Article  CAS  PubMed  Google Scholar 

  153. Sherman, J. H. et al. Impact of temozolomide chemotherapy on seizure frequency in patients with low-grade gliomas. J. Neurosurg. 114, 1617–1621 (2011).

    Article  PubMed  Google Scholar 

  154. Roelcke, U. et al. Amino acid positron emission tomography to monitor chemotherapy response and predict seizure control and progression-free survival in WHO grade II gliomas. Neuro Oncol. http://dx.doi.org/10.1093/neuonc/nov282 (2015).

  155. Koekkoek, J. A. et al. Seizure reduction is a prognostic marker in low-grade glioma patients treated with temozolomide. J. Neurooncol. 126, 347–354 (2016).

    Article  CAS  PubMed  Google Scholar 

  156. Krumholz, A. et al. Evidence-based guideline: management of an unprovoked first seizure in adults: report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 84, 1705–1713 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Glantz, M. J. et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Neurology 54, 1886–1893 (2000).

    Article  CAS  PubMed  Google Scholar 

  158. Soffietti, R. et al. Guidelines on management of low-grade gliomas: report of an EFNS–EANO Task Force. Eur. J. Neurol. 17, 1124–1133 (2010).

    Article  CAS  PubMed  Google Scholar 

  159. Glauser, T. et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 54, 551–563 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. Karceski, S., Morrell, M. J. & Carpenter, D. Treatment of epilepsy in adults: expert opinion, 2005. Epilepsy Behav. 7 (Suppl. 1), S1–S64 (2005).

    Article  PubMed  Google Scholar 

  161. Maschio, M. et al. Levetiracetam monotherapy in patients with brain tumor-related epilepsy: seizure control, safety, and quality of life. J. Neurooncol. 104, 205–214 (2011).

    Article  CAS  PubMed  Google Scholar 

  162. Rosati, A. et al. Efficacy and safety of levetiracetam in patients with glioma: a clinical prospective study. Arch. Neurol. 67, 343–346 (2010).

    Article  PubMed  Google Scholar 

  163. Helmstaedter, C. & Witt, J. A. The effects of levetiracetam on cognition: a non-interventional surveillance study. Epilepsy Behav. 13, 642–649 (2008).

    Article  PubMed  Google Scholar 

  164. de Groot, M. et al. Levetiracetam improves verbal memory in high-grade glioma patients. Neuro Oncol. 15, 216–223 (2013).

    Article  CAS  PubMed  Google Scholar 

  165. Mbizvo, G. K., Dixon, P., Hutton, J. L. & Marson, A. G. Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review. Cochrane Database Syst. Rev. 9, CD001901 (2012).

    Google Scholar 

  166. Benit, C. & Vecht, C. J. Seizures and cancer: drug interactions of anticonvulsants with chemotherapeutic agents, tyrosine-kinase inhibitors and glucocorticoids. Neuro Oncol. Pract. http://dx.doi.org/10.1093/nop/npv038 (2015).

  167. Wick, W. et al. Pharmacotherapy of epileptic seizures in glioma patients: who, when, why and how long? Onkologie 28, 391–396 (2005).

    CAS  PubMed  Google Scholar 

  168. Bodalia, P. N. et al. Comparative efficacy and tolerability of anti-epileptic drugs for refractory focal epilepsy: systematic review and network meta-analysis reveals the need for long term comparator trials. Br. J. Clin. Pharmacol. 76, 649–667 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Bromley, R. et al. Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child. Cochrane Database Syst. Rev. 10, CD010236 (2014).

    Google Scholar 

  170. Christensen, J. et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 309, 1696–1703 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Vecht, C. J., Kerkhof, M. & Duran-Pena, A. Seizure prognosis in brain tumors: new insights and evidence-based management. Oncologist 19, 751–759 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Brodie, M. J. & Sills, G. J. Combining antiepileptic drugs — rational polytherapy? Seizure 20, 369–375 (2011).

    Article  PubMed  Google Scholar 

  173. French, J. A. & Faught, E. Rational polytherapy. Epilepsia 50 (Suppl. 8), 63–68 (2009).

    Article  CAS  PubMed  Google Scholar 

  174. Otoul, C., Arrigo, C., van Rijckevorsel, K. & French, J. A. Meta-analysis and indirect comparisons of levetiracetam with other second-generation antiepileptic drugs in partial epilepsy. Clin. Neuropharmacol. 28, 72–78 (2005).

    Article  CAS  PubMed  Google Scholar 

  175. Prust, M. J. et al. Standard chemoradiation for glioblastoma results in progressive brain volume loss. Neurology 85, 683–691 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Kaminski, R. M., Matagne, A., Patsalos, P. N. & Klitgaard, H. Benefit of combination therapy in epilepsy: a review of the preclinical evidence with levetiracetam. Epilepsia 50, 387–397 (2009).

    Article  CAS  PubMed  Google Scholar 

  177. Ricard, D., Taillia, H. & Renard, J. L. Brain damage from anticancer treatments in adults. Curr. Opin. Oncol. 21, 559–565 (2009).

    Article  CAS  PubMed  Google Scholar 

  178. Klein, M. et al. Epilepsy in low-grade gliomas: the impact on cognitive function and quality of life. Ann. Neurol. 54, 514–520 (2003).

    Article  PubMed  Google Scholar 

  179. Correa, D. D. et al. Cognitive functions in low-grade gliomas: disease and treatment effects. J. Neurooncol. 81, 175–184 (2007).

    Article  PubMed  Google Scholar 

  180. Correa, D. D. et al. Longitudinal cognitive follow-up in low grade gliomas. J. Neurooncol. 86, 321–327 (2008).

    Article  PubMed  Google Scholar 

  181. Witt, J. A. & Helmstaedter, C. Monitoring the cognitive effects of antiepileptic pharmacotherapy — approaching the individual patient. Epilepsy Behav. 26, 450–456 (2013).

    Article  PubMed  Google Scholar 

  182. Helmstaedter, C. & Witt, J. A. The longer-term cognitive effects of adjunctive antiepileptic treatment with lacosamide in comparison with lamotrigine and topiromate in a naturalistic outpatient setting. Epilepsy Behav. 26, 182–187 (2013).

    Article  PubMed  Google Scholar 

  183. Brodie, M. J. & Yuen, A. W. Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res. 26, 423–432 (1997).

    Article  CAS  PubMed  Google Scholar 

  184. Saria, M. G. et al. Retrospective analysis of the tolerability and activity of lacosamide in patients with brain tumors: clinical article. J. Neurosurg. 118, 1183–1187 (2013).

    Article  CAS  PubMed  Google Scholar 

  185. Riechelmann, R. P. Drug combinations with the potential to interact among cancer patients. Support. Care Cancer 15, 1113–1114 (2007).

    Article  PubMed  Google Scholar 

  186. Relling, M. V. et al. Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia. Lancet 356, 285–290 (2000).

    Article  CAS  PubMed  Google Scholar 

  187. Brodie, M. J. et al. Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia 54, 11–27 (2013).

    Article  CAS  PubMed  Google Scholar 

  188. Gilbert, M. R. & Armstrong, T. S. Management of patients with newly diagnosed malignant primary brain tumors with a focus on the evolving role of temozolomide. Ther. Clin. Risk Manag. 3, 1027–1033 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Maschio, M. et al. Temozolomide treatment does not affect topiramate and oxcarbazepine plasma concentrations in chronically treated patients with brain tumor-related epilepsy. J. Neurooncol. 90, 217–221 (2008).

    Article  CAS  PubMed  Google Scholar 

  190. Coulter, D. W. et al. Valproic acid reduces the tolerability of temsirolimus in children and adolescents with solid tumors. Anticancer Drugs 24, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Bourg, V., Lebrun, C., Chichmanian, R. M., Thomas, P. & Frenay, M. Nitroso-urea-cisplatin-based chemotherapy associated with valproate: increase of haematologic toxicity. Ann. Oncol. 12, 217–219 (2001).

    Article  CAS  PubMed  Google Scholar 

  192. Gerstner, T. et al. Valproate-associated coagulopathies are frequent and variable in children. Epilepsia 47, 1136–1143 (2006).

    Article  PubMed  Google Scholar 

  193. Psaras, T. et al. Quantitative assessment of postoperative blood collection in brain tumor surgery under valproate medication. Zentralbl. Neurochir. 69, 165–169 (2008).

    Article  CAS  PubMed  Google Scholar 

  194. Simó, M. et al. Impact of antiepileptic drugs on thrombocytopenia in glioblastoma patients treated with standard chemoradiotherapy. J. Neurooncol. 108, 451–458 (2012).

    Article  CAS  PubMed  Google Scholar 

  195. Tinchon, A. et al. Haematological toxicity of valproic acid compared to levetiracetam in patients with glioblastoma multiforme undergoing concomitant radio-chemotherapy: a retrospective cohort study. J. Neurol. 262, 179–186 (2015).

    Article  CAS  PubMed  Google Scholar 

  196. Italiano, D. & Perucca, E. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age: an update. Clin. Pharmacokinet. 52, 627–645 (2013).

    Article  CAS  PubMed  Google Scholar 

  197. Johannessen Landmark, C. et al. Pharmacokinetic variability of four newer antiepileptic drugs, lamotrigine, levetiracetam, oxcarbazepine, and topiramate: a comparison of the impact of age and comedication. Ther. Drug Monit. 34, 440–445 (2012).

    CAS  PubMed  Google Scholar 

  198. de Wit, D., Guchelaar, H. J., den Hartigh, J., Gelderblom, H. & van Erp, N. P. Individualized dosing of tyrosine kinase inhibitors: are we there yet? Drug Discov. Today 20, 18–36 (2015).

    Article  CAS  PubMed  Google Scholar 

  199. Patsalos, P. N. Drug interactions with the newer antiepileptic drugs (AEDs) — part 1: pharmacokinetic and pharmacodynamic interactions between AEDs. Clin. Pharmacokinet. 52, 927–966 (2013).

    Article  CAS  PubMed  Google Scholar 

  200. Houillier, C. et al. IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 75, 1560–1566 (2010).

    Article  CAS  PubMed  Google Scholar 

  201. Ducray, F. et al. Predictive and prognostic factors for gliomas. Expert Rev. Anticancer Ther. 11, 781–789 (2011).

    Article  CAS  PubMed  Google Scholar 

  202. Liubinas, S. V. et al. IDH1 mutation is associated with seizures and protoplasmic subtype in patients with low-grade gliomas. Epilepsia 55, 1438–1443 (2014).

    Article  CAS  PubMed  Google Scholar 

  203. Zhang, C. B. et al. Correlation of IDH1/2 mutation with clinicopathologic factors and prognosis in anaplastic gliomas: a report of 203 patients from China. J. Cancer Res. Clin. Oncol. 140, 45–51 (2014).

    Article  CAS  PubMed  Google Scholar 

  204. Zhong, Z., Wang, Z., Wang, Y., You, G. & Jiang, T. IDH1/2 mutation is associated with seizure as an initial symptom in low-grade glioma: a report of 311 Chinese adult glioma patients. Epilepsy Res. 109, 100–105 (2015).

    Article  CAS  PubMed  Google Scholar 

  205. Kerkhof, M., Benit, C., Duran-Pena, A. & Vecht, C. J. Seizures in oligodendroglial tumors. CNS Oncol. 4, 347–356 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Berendsen, S. et al. Prognostic relevance of epilepsy at presentation in glioblastoma patients. Neuro Oncol. http://dx.doi.org/10.1093/neuonc/nov238 (2015).

  207. de Groot, M. et al. Overexpression of ADK in human astrocytic tumors and peritumoral tissue is related to tumor-associated epilepsy. Epilepsia 53, 58–66 (2012).

    Article  CAS  PubMed  Google Scholar 

  208. US National Library of Science. ClinicalTrials.gov [online], (2015).

  209. US National Library of Science. ClinicalTrials.gov [online], (2009).

  210. US National Library of Science. ClinicalTrials.gov [online], (2009).

  211. US National Library of Science. ClinicalTrials.gov [online], (2009).

  212. US National Library of Science. ClinicalTrials.gov [online], (2009).

  213. US National Library of Science. ClinicalTrials.gov [online], (2009).

  214. US National Library of Science. ClinicalTrials.gov [online], (2016).

  215. US National Library of Science. ClinicalTrials.gov [online], (2015).

  216. US National Library of Science. ClinicalTrials.gov [online], (2016).

  217. Booth, L. et al. HDAC inhibitors enhance the lethality of low dose salinomycin in parental and stem-like GBM cells. Cancer Biol. Ther. 15, 305–316 (2014).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors express their gratitude to Richard Miles (Institut du Cerveau et de la Moelle Epinière, Paris, France) and Johan Pallud (Neurosurgery Department, Paris Descartes University, Sainte-Anne Hospital, Paris, France) for reading the manuscript.

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Authors and Affiliations

  1. Sorbonne University, UPMC University Paris 06, Paris, F-75005, France

    Gilles Huberfeld

  2. Neurophysiology Department, UPMC, Centre Hospitalo-Universitaire Pitié-Salpêtrière, APHP, Paris, F-75013, France

    Gilles Huberfeld

  3. INSERM U1129 “Infantile Epilepsies and Brain Plasticity”, Paris, France

    Gilles Huberfeld

  4. Paris Descartes University, PRES Sorbonne Paris Cité; CEA, Gif sur Yvette, France

    Gilles Huberfeld

  5. Service de Neuro-oncologie Mazarin, UPMC, Centre Hospitalo-Universitaire Pitié-Salpêtrière, APHP, Paris, F-75013, France

    Charles J. Vecht

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G.H. has received consulting and speakers' fees from Eisai. C.J.V. has received consulting and speakers' fees from UCB.

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Huberfeld, G., Vecht, C. Seizures and gliomas — towards a single therapeutic approach. Nat Rev Neurol 12, 204–216 (2016). https://doi.org/10.1038/nrneurol.2016.26

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