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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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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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