Epileptogenesis and Tumorigenesis in Glioblastoma: Which Relationship?

Abstract

Epilepsy is reported in 29–52% of patients with glioblastoma (GBM) and has an important role in the natural history of this tumor and patients’ life quality. Although GBM is less epileptogenic than lower-grade gliomas, seizures are usually more difficult to control with common antiseizure medications; drug resistance is found in 20% of cases. Recent studies suggest that seizures at the onset of GBM could be a possible favorable independent prognostic factor in patients. Moreover, a growing body of evidence shows that many molecular mechanisms that influence epileptogenesis often regulate GBM growth and invasiveness, sometimes favoring or counteracting the tumor, respectively. The better-characterized players include glutamate, γ-aminobutyric acid, aquaporin-4, and hypoxia-activated molecules. However, currently available data on the molecular basis of epileptogenesis, tumorigenesis, and their relationship is incomplete or discordant and further research is urgently needed on this topic.

Focal-to-bilateral tonic-clonic seizures and High-grade CMV-infection are poor survival predictors in Tumor-related Epilepsy Adult-type diffuse gliomas—A single-center study and literature review

“…TRE is a well-recognized condition in low-grade gliomas. The prevalence of epilepsy in GB patients has been previously reported to fluctuate between 25 and 50% [ 23 , 44 ]. Epilepsy in patients with GB plays an important role with impact in their quality of life and also appears to affect the survival of these patients.…”

Efficacy and Tolerability of Perampanel in Brain Tumor-Related Epilepsy: A Systematic Review

“…However, due to the high rate of IDH1 mutant tumors within the study population (7/8 patients), sampling error could not be excluded [ 19 ]. It is common knowledge that the R132H mutation of the IDH1 gene results in a gain of function and promotes the accumulation of D-2-hydroxyglutarate (D-2-HG), which is structurally similar to glutamate [ 5 ]. The mutation in the IDH gene is associated with an increased risk of seizures preoperatively and postoperatively, and this may be a reason for the higher incidence of epilepsy in astrocytoma and oligodendroglioma compared to GBM [ 5 ].…”

“…It is common knowledge that the R132H mutation of the IDH1 gene results in a gain of function and promotes the accumulation of D-2-hydroxyglutarate (D-2-HG), which is structurally similar to glutamate [ 5 ]. The mutation in the IDH gene is associated with an increased risk of seizures preoperatively and postoperatively, and this may be a reason for the higher incidence of epilepsy in astrocytoma and oligodendroglioma compared to GBM [ 5 ]. Moreover, PER showed a safety profile that is consistent with that demonstrated in the phase 3 studies and their extension [ 10 , 11 , 21 , 22 ] as well as in real-life studies [ 23 ].…”

“…A growing body of evidence suggests that the pathogenesis of BTRE is predominantly related to an excess of glutamatergic activity in the tumor microenvironment, resulting from excessive glutamate secretion by tumor cells and reduced glutamate clearance as well as from an increased expression of ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors at the level of tumor cells and peritumoral astrocytes [ 5 ]. Moreover, excessive glutamatergic tone might also favor tumor growth and invasiveness as well as excitotoxicity, an effect that leads to neurodegeneration and cognitive deterioration [ 5 ]. The role of glutamate in brain tumor-related epileptogenesis is widely known for gliomas [ 6 ], but have been established in other histotypes including meningiomas [ 7 ] and brain metastases [ 8 ].…”

Surgical management of Glioma Grade 4: technical update from the neuro-oncology section of the Italian Society of Neurosurgery (SINch®): a systematic review

“…Although GG4 are less epileptogenic than lower-grade gliomas, seizures are usually more difficult to control with common ASMs and drug resistance reported in 20% of cases [ 120 – 122 ].…”