Secondary epilepsy is a common manifestation of infiltrative gliomas and occurs in high-grade gliomas less commonly than in low-grade gliomas; however, the reason for this is still unclear (1). Patients with temporal and frontal gliomas are more likely to experience seizures, and low-grade gliomas with oligodendroglial pathology are strongly associated with preoperative seizures (16). Approximately 30% of gliomas are drug-resistant even after resection (2) (3); however, the underlying mechanisms of this are still poorly understood. It is likely that epilepsy occurrence rates are not merely explained by peritumoral changes and that the internal relationship of genetic factors of the peritumoral brain tissue could be responsible for these seizures (4). Multiple studies suggested that epileptogenesis is actually influenced by tumor molecular genetic markers (5) (6) (1). Another study also found that tumor growth may stimulate the epileptic focus, suggesting that the two conditions may share common pathogenic mechanisms that influence each other (5).
Another possible explanation is the association of gliomas with the IDH1 mutation. Studies showed that mutant IDH1 gliomas are more likely to cause seizures than wt IDH1 (6) (7) (8). IDH1 is a metabolic enzyme located in the cytosol catalyzing the oxidative decarboxylation of isocitrate to α-ketoglutarate. The mutant enzyme reduces α-ketoglutarate to D-2-hydroxyglutarate. Hence, overproduction of D-2-hydroxyglutarate and its structural similarity to glutamate may be involved in the mechanism of neuronal excitation leading to seizures (7) (Fig. 1). Exposure to exogenous D-2-hydroxyglutarate increased the duration of synchronized network burst firing, and this was subsequently blocked by a selective N-methyl-D-aspartate receptor (NMDA) antagonist (1).
While the association of the IDH1 mutation with preoperative seizures was extensively reported, the influence of the IDH1 mutation in the postoperative glioma microenvironment is yet to be clarified. Chen et al. found that seizures are more likely to be present in low-grade gliomas with the IDH1 mutation and 1p19q codeletion than in high-grade gliomas with the IDH1 mutation. However, epilepsy during the end-of-life phase in glioblastoma patients became uncontrolled (17). Yang et al. studied the relationship of 172 gliomas with epilepsy (18) and found that 27% of glioblastomas were associated with epilepsy but that 64% of these epilepsy patients had low-grade gliomas. Furthermore, IDH1-mutant gliomas were associated with preoperative seizure mainly in cases of grade II gliomas (73%) but not glioblastomas. Our current study also found that the IDH1 mutation is significantly associated with controlled epilepsy in glioblastoma patients.
Currently, multimodal strategies fail to control seizures in up to a third of patients (9). Thus, a better understanding of the risk factors and mechanisms associated with glioma-associated epilepsy are needed to improve patient quality of life. To the best of our knowledge, although gliomas with MGMT gene promoter methylation are known to be more treatment-sensitive to TMZ chemotherapy [10], the association of glioma-associated epilepsy and MGMT promotor methylation has never been extensively studied. The relationship between preoperative and postoperative seizure control, in regard to MGMT gene promotor methylation status, is also limited. Patients with low expression of MGMT protein or MGMT methylated gliomas had more frequent postoperative seizure control than those with non-methylated MGMT or high MGMT protein activity (11) (8). The observed favorable postoperative seizure control in those with MGMT gene promotor methylation could stem from the better response to adjuvant chemoradiation therapy in this patient population (8). Nevertheless, these findings did not clarify whether MGMT methylation was the main reason for postoperative seizure control or whether anti-epileptic drugs act as potent MGMT methylation inhibitors. The results of our current study have demonstrated that the unmethylated MGMT promotor had more significant seizure control.
Bobustuc et al. reported that levetiracetam was the most potent MGMT inhibitor among several anti-epileptic medications with diverse MGMT regulatory actions and is thus considered the first-line drug to control seizure in glioma patients receiving TMZ (12). This is because levetiracetam enhances P53-mediateed MGMT inhibition, which sensitizes glioblastoma cells to TMZ (17) (12). This mechanism has never been investigated thoroughly, and thus further studies are necessary.
Scattered studies found that levetiracetam and valproic acid are the main anti-epileptic drugs that exhibit antitumor effects and have shown an actual decrease in the mortality rate among glioblastoma patients with epilepsy (13) (14) (15). Valproic acid exhibits antitumor effects via inhibition of mSin3A/histone deacetylase 1 and modulation of the mitogen-activated protein kinase pathway. Additionally, owing to the radio-sensitizing properties of valproic acid, radiotherapy with valproic acid is more effective than radiotherapy with other drugs (19). Another study on 418 patients with glioblastoma-associated seizures in Korea found that levetiracetam treatment in cases with the methylated MGMT promoter positively influenced the overall survival rate. In our study, we also found that levetiracetam is the first-line drug for glioblastoma-associated epilepsy. However, we reject the idea that levetiracetam sensitizes glioblastoma cells to chemotherapy, as there was no significant relationship with tumor recurrence interval when both anti-epileptic drugs and chemotherapies were used in glioblastoma patients.