In terms of postoperative management for diffuse glioma, there are many controversial issues that need to be clarified. The use of prophylactic AEDs in patients without preoperative GRE is definitely one of them 1. There is a plenty of evidences to prove that AED prophylaxis do not significantly reduce the incidence of postoperative seizures in brain tumor patients without preoperative seizures 10, 11. Accordingly, Many experts believe that routine prophylactic AED use has no benefit for this group of patients 12. However, in our opinion, AED prophylaxis is not meaningless for patients without preoperative GRE, as new-onset postoperative seizures can indeed be observed in some of them. A more plausible explanation is that for one subset of patients, routine AED prophylaxis is unnecessary or at least sufficient for postoperative seizure control; while for the other subset of patients, routine AED prophylaxis is insufficient and should be more aggressive. In consequence, the identification of markers for distinguishing between the two subsets is of great importance.
In the current study, we explored the risk factors of new-onset postoperative seizures in patients without preoperative GRE, and identified that IDH1 mutation was the only independent predictor for new-onset postoperative seizures by multivariate analysis. The result suggested that for patients with IDH1 mutant gliomas, more aggressive AED regimen should be adopted even if they did not have preoperative GRE. IDH1 mutation is considered as an early event in glioma-genesis, and has gained major importance in the 2016 WHO classification of diffuse gliomas 13. In addition, the close correlation of IDH1 mutation with preoperative GRE has already been confirmed 14. The accumulation of D-2-hydroxyglutarate (D2HG), which is structurally similar to the major excitatory neurotransmitter glutamate, is supposed to be a major mechanism behind such correlation. As an important metabolic enzyme, IDH1 can catalyze the oxidative decarboxylation of isocitrate to a-ketoglutarate. While mutant IDH1 can reduce a-ketoglutarate to D2HG, which results in the accumulation of D2HG in tumor microenvironment. The accumulation of D2HG can lead to overexcitation of neurons and thus induce epilepsy 15, 16. This mechanism can also explain the association between IDH1 mutation and new-onset postoperative seizures. Generally, we evaluate the EOR basing on tumor boundary seen on neuroimaging. However, a radiologically proven GTR does not mean that all tumor cells have been removed, and the presence of glioma cells outside the radiological tumor borders has been demonstrated 17. The remaining IDH1 mutant cells can still affect the surrounding microenvironment, and lead to new-onset seizures. Overall, in order to reduce the incidence of postoperative GRE, a GTR basing on the “epileptogenic boundary”, which is actually the histological boundary, can be more effective.
Another potential mechanism behind the correlation of IDH1 mutation with new-onset postoperative seizures is related to seizure spread network. It is reported that patients with IDH1 mutant gliomas have higher global functional connectivity, which is difficult to recover even after the tumor is removed 18, 19. In contrast, gliomas carrying wild-type IDH1 are often more aggressive and thus more likely to cause destruction of brain networks, which may add barriers to the spread of epileptic discharges 20.
We also found that WHO grade and Ki-67 expression were negatively associated with new-onset postoperative seizures. It has been widely accepted that patients with low-grade gliomas have a higher incidence of preoperative GRE 1. In the current study, we identified that low-grade glioma patients without preoperative GRE also have a higher incidence of new-onset postoperative seizures. IDH1 mutant status may be one of the decisive factors behind such relationship, because IDH1 mutation is frequently observed in diffuse gliomas but rarely seen in primary glioblastomas (WHO grade Ⅳ) 20. Maybe that was also why WHO grade showed no statistical significance in regression analysis. As for Ki-67, it is an effective biomarker to determine the proliferative activity of tumors 21. As mentioned above, tumors with stronger proliferation ability are more likely to cause damage to brain networks, and impede the spread of epileptic discharges. Therefore, it’s not difficult to understand the association between low Ki-67 expression and new-onset postoperative seizures.
The prognostic value of new-onset postoperative seizures was also investigated. In 2018, we performed a meta-analysis to determine the association between preoperative GRE and clinical outcomes, and identified that GRE at presentation is significantly correlated with prolonged OS in patients with diffuse glioma 14. Consistent with this previous study, here we also demonstrated that new-onset postoperative seizures could predict longer OS in patients without preoperative GRE. Given the correlation of new-onset postoperative seizures with the above proven positive prognostic factors, like lower WHO grade and IDH1 mutation, such result was predictable 22, 23. However, early postoperative seizures do not seem to predict a good prognosis. Dewan et al. reported that glioma patients with early postoperative seizures have a significant shorter median survival (3 months) than those without (15.6 months) 24. The worse prognosis of patients with early postoperative seizures may due to the hemorrhage and severe intracranial hypertension following epilepsy 25. For patients with early postoperative seizures, corresponding active examinations and treatments should be proceed in a timely manner.
The study has several limitations. For instance, as a proportion of patients were followed up by telephone interviews, EEG was not applied for the definite diagnosis of seizures in those patients. Moreover, the study was limited by its retrospective nature, the results need to be verified in a prospective set of patients. Efforts to further explore risk factors of new-onset postoperative seizures, and reduce the incidence of postoperative seizures through patient-tailored antiepileptic therapies should remain the priorities of future studies.