Epilepsy in gliomas: recent insights into risk factors and molecular pathways.

Abstract

The purpose of this review is to discuss the molecular pathways governing the development of seizures in glioma patients. The intrinsic epileptogenicity of the neuronal component of glioneuronal and neuronal tumors is the most relevant factor for seizure development. The two major molecular alterations behind epileptogenicity are the rat sarcoma virus (RAS)/mitogen-activated protein kinase / extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol-3-kinase / protein kinase B / mammalian target of rapamycin (P13K/AKT/mTOR) pathways. The BRAFv600E mutation has been shown in experimental models to contribute to epileptogenicity, and its inhibition is effective in controlling both seizures and tumor growth. Regarding circumscribed astrocytic gliomas, either BRAFv600E mutation or mTOR hyperactivation represent targets of treatment. The mechanisms of epileptogenicity of diffuse lower-grade gliomas are different: in addition to enhanced glutamatergic mechanisms, the isocitrate dehydrogenase (IDH) 1/2 mutations and their product D2-hydroxyglutarate (D2HG), which is structurally similar to glutamate, exerts excitatory effects on neurons also dependent on the presence of astrocytes. In preclinical models IDH1/2 inhibitors seem to impact both tumor growth and seizures. Conversely, the molecular factors behind the epileptogenicity of glioblastoma are unknown. This review summarizes the current state of molecular knowledge on epileptogenicity in gliomas and highlights the relationships between epileptogenicity and tumor growth.