The Potential Effect of the IDH1 Mutation and MGMT Gene Promotor Methylation on the Control of Glioblastoma-Associated Epilepsy in Patients Receiving Anti-Epileptic Agents and Chemotherapies

Abstract

Objective: (a) To assess the control of glioblastoma-associated seizure in patients receiving different anti-epileptic drugs and chemotherapies after total resection and its association with O-methylguanine-DNA methyltransferase (MGMT) promotor methylation and the isocitrate dehydrogenase 1 (IDH1) mutation; (b) to determine which anti-epileptic drug exerts the best effective control on glioblastoma-associated epilepsy; (c) to identify the relationship between seizure control and different anti-epileptic drugs and recurrence interval.

Methods: This was a retrospective cohort study of patients with postoperative glioblastoma-associated epilepsy in the period between 2014 and 2019. The correlations between the IDH1 mutation and MGMT promotor methylation with anti-epileptic drugs, chemotherapy type, seizure control, and recurrence interval were analyzed using different statistical methods.

Results: This study included 53 adult patients with glioblastoma-associated epilepsy. The IDH1 mutation was present in 20 patients, and MGMT promotor methylation was present in 13 patients. Out of 53 patients, 37 cases received chemoradiotherapy while 16 cases receive only radiotherapy. Levetiracetam was the most prescribed anti-epileptic drug (n= 36, 60%), and 36 and 16 patients had controlled and uncontrolled seizures, respectively. The IDH1 mutation and unmethylated MGMT promotor were significantly present in cases with controlled epilepsy (P < 0.05). Among the anti-epileptic drugs, levetiracetam showed significantly better seizure control in cases with the IDH1 mutation and unmethylated MGMT promotor (P < 0.05). Patients did not show significant differences in either seizure control or the tumor recurrence interval (P > 0.05).

Conclusion: (a) Glioblastoma-associated epilepsy can be better controlled in patients with the IDH1 mutation and unmethylated MGMT promotor compared with patients with the methylated MGMT promotor, (b) Levetiracetam is considered the first-line anti-epileptic drug for controlling seizures but may not enhance the sensitivity of glioblastomas to chemotherapies, (c) Lack of seizure control in glioblastoma patients may not be related to tumor recurrence despite one-year treatment with anti-epileptic drugs, (d) Better understanding of the risk factors and mechanisms associated with glioma-associated epilepsy are needed to improve patient quality of life.

Introduction

Glioblastoma-associated epilepsy is an uncommon manifestation of infiltrative gliomas, and approximately 30% of cases are drug-resistant even after glioma resection (1) (2) (3). The cause of this is still unclear; however, it is likely that genetic factors of the peritumoral brain tissue are responsible for these seizures (1) (4) (5) (6). There is evidence that tumor growth may stimulate the epileptic focus, suggesting that the two conditions may share common pathogenic mechanisms and influence each other (5). Another possible explanation is the association of gliomas with the isocitrate dehydrogenase 1 (IDH1) mutation. Previous studies showed that IDH1-mutant gliomas are more likely to cause seizures than IDH1-wildtype (wt) gliomas (6) (7) (8), as the mutant enzyme reduces α-ketoglutarate to D-2-hydroxyglutarate. Hence, D-2-hydroxyglutarate overproduction and its structural similarity to glutamate have been suggested to play a role in the neuronal excitation leading to seizures (6). While the association of the IDH1 mutation with preoperative seizures has been previously reported, the influence of the IDH1 mutation in the postoperative glioma microenvironment is yet to be clarified. Multimodal strategies fail to control seizures (9), and a better understanding of the risk factors and mechanisms of glioma-associated epilepsy are needed to improve patient quality of life.

Gliomas with O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation are more treatment-sensitive to temozolomide (TMZ) chemotherapy (10). However, the association of glioma-associated epilepsy with MGMT promotor methylation has not been extensively studied. Patients with MGMT methylated gliomas show more seizure control than those with non-methylated MGMT (11) (8). In this study, we assessed seizure control among glioblastoma patients, after total resection, receiving different anti-epileptic drugs and chemotherapies and investigated its associations with MGMT promotor methylation and the IDH1 mutation. Levetiracetam is the most potent MGMT inhibitor among several anti-epileptic medications with diverse MGMT regulatory actions and is considered the first-line drug to control seizures in glioma patients (12). Multiple studies concluded that levetiracetam and valproic acid are the main anti-epileptic drugs that exhibit antitumor effects and decrease the mortality rate among glioblastoma patients with epilepsy (13) (14) (15). In this study, we also have investigated which anti-epileptic drug exerts the best effective control of glioblastoma-associated epilepsy in Saudi Arabia and have also identified the relationship of seizure control with different anti-epileptic drugs and the recurrence interval. The only limitations we faced in this current study were the limited number of glioblastoma-associated seizure and the unknown biological cause of seizure progression or patient death when they showed late recurrence.

Materials And Methods

Results

1. Descriptive analysis

In total, 53 postoperative patients with glioblastoma-associated seizures were included in this study (36 men and 17 women). The mean age was 51 years. The predominant locations were the frontal (n = 21, 39.6%) and temporal lobes (n = 17, 32.1%). We observed the IDH1 mutation in 20 patients (37.7%), MGMT methylation in 13 patients, and the unmethylated MGMT promotor in 40 patients. Furthermore, 37 patients received a standard treatment protocol of chemoradiotherapy, whereas 16 patients received only radiotherapy. Of those who received chemotherapy, 29 (78.4%) patients received TMZ alone, and 8 (21.6%) patients received TMZ together with other chemotherapies. Epilepsy was controlled in 36 patients (69.2%), and 16 patients (30.8%) had uncontrolled epilepsy. Table 1 and Fig. 2 summarize the descriptive distribution of the data and the study plan.

Discussion

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.

Conclusion

Our study has come to three main conclusions. First, glioblastoma-associated epilepsy can be better controlled in patients with the IDH1 mutation or unmethylated MGMT promotor than in patients with the methylated MGMT promotor. Second, levetiracetam can be considered the first-line anti-epileptic drug for controlling seizures yet may not enhance the sensitivity of glioblastomas to chemotherapies. Third, the lack of seizure control in glioblastoma patients is not related to tumor recurrence despite one-year treatment with anti-epileptic drugs. We recommend using IDH1 and the MGMT gene promotor as parameters in seizure control. We also recommend using levetiracetam as first-line treatment, regardless of the type of chemotherapeutic agent.

Declarations

Note

Unknown cases are not included in this table. Pearson's Chi-squared test¹

Note

Unknown cases are not included in this table. Pearson's Chi-squared test¹

Funding:

No funding received for the current study.

Consenting

The study did not include any patient information required consent for publications.

Authors' contributions:

MK, idea, IRB submission, writing, study design and data, and histological analysis; NS, Statistical analysis; SB, data provider, writing, and analysis; BG, study design, writing, and editing; YM, data entry, tissue collection, and writing; AB, data entry, and tissue collection; RS, data entry, tissue collection, and writing; FA, Histological and data analysis, NA, Data collection, MB: IHC analysis and histological correlation; AS, data provider, writing, and histological revision; AL, data provider, and IRB submission; TA, Clinical information provider.

Acknowledgment:

none.

References

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Tables

Table 1. Characteristics of patients and therapies. Isocitrate dehydrogenase 1 mutation (IDH1); O-methylguanine-DNA methyltransferase (MGMT).

Table 2. Seizure control in cases with IDH1 mutation and MGMT promotor methylation. There were no significant differences between seizure control and IDH1 status among cases with glioblastoma-associated epilepsy. However, a significant relationship in seizure control was found between different groups of MGMT methylation.                                                                            

Note: Unknown cases are not included in this table. Pearson's Chi-squared test¹

Table 3. The relationship of anti-epileptic drugs and seizure control, regardless of the status of the IDH1 mutation and MGMT promotor methylation. There were no significant differences in seizure control among cases treated with levetiracetam, phenytoin, or levetiracetam with phenytoin.

Pearson's Chi-squared test¹

Table 4. The relationship between anti-epileptic drugs and chemotherapies with seizure control. Patients with glioblastoma-associated epilepsy, regardless of the type of anti-epileptic drugs and chemotherapies, showed no significant differences in seizure control.                                                                

Note: Unknown cases are not included in this table. Pearson's Chi-squared test¹

Table 5. The relationship between seizure control in glioblastoma patients and tumor recurrence interval. Patients with glioblastoma-associated epilepsy, regardless of the status of seizure control, showed no significant differences in the recurrence interval.

Pearson's Chi-squared test¹