In this systematic review, 15 articles focusing on the role of epilepsy at clinical presentation in the prognosis of patients with GBM in terms of PFS and OS were analyzed. The sample size ranged from 46 to 867 adult patients. The percentage of patients with seizures at onset ranged from 9 to 36%. Only six studies reported information on seizure semiology [11, 12, 14, 18, 20, 24], and only two reported results by seizures type with inconsistent results [14, 20]. Seven studies did not reported any data regarding the biomolecular characterization of GBM [10,11,12,13,14,15,16], whereas four studies included both IDH-wild type and IDH-mutated tumors in survival analysis [17,18,19,20]. Among these, IDH mutation status was not included in the multivariate analysis except for the study conducted by Ahmadipour et al. in 2021 [20]. Nevertheless, in this particular study, the IDH 1–2 mutation status was unavailable for 311 out of 867 patients (35.9%). Finally, four studies specifically focused on IDH-wild type glioblastomas [21,22,23,24].

Seizures at clinical onset were considered a favorable prognostic factor in six studies [10, 11, 13, 17, 18, 20], whereas 8 studies did not find any differences in terms of overall survival between patients with seizures and patients with other presenting symptoms [14,15,16, 19, 21,22,23,24]. One study found a favorable prognostic role of seizures at onset, which was lost if other symptoms developed after epileptic onset [12]. This underscores that when there is a delay between the clinical onset of seizures and surgical intervention, the prognostic advantage of pre-operative seizures appears to diminish significantly.

It is notable that there is a paucity of reporting of subgroup analysis by combination of seizures and other presenting symptoms, as well as by type of seizures, which constrains the possibility of exploring the causal pathway linking pre-operative seizures with early diagnosis and prognosis.

Seizures are the presenting symptom of GBM in approximately 25–30% of patients [6]. Epileptogenesis in GBM is a dynamic process occurring within the peritumoral cortex. Here, the establishment of a microenvironment abundant in cytokines, chemokines, and growth factors plays a pivotal role, contributing not only to epileptogenesis but also to tumor proliferation and invasiveness [8, 25]. Moreover, specific molecular alterations in tumor cells can have a crucial impact on both tumor growth and seizure risk [6]. For instance, several mutations in genes that determine aberrant glutamate release by glioblastoma cells, and an excess of glutamatergic activity in the tumor environment, may favor epileptogenesis as well as tumor growth and invasiveness [8]. Indeed, several anti-glutamatergic drugs, such as the selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel, have demonstrated robust anti-epileptic activity, but also a potential anti-tumor effect according to several preclinical in vitro studies [26].

Therefore, it would be expected that the development of epilepsy in the pre-surgical phase should be associated with a higher rate of tumor growth and invasiveness. However, most of the studies conducted until 2018 demonstrated a favorable prognostic role of seizures at clinical onset in terms of overall survival. These studies presented some confounding factors, such as the inclusion of participants with differences in terms of tumor volume and location (lobar and midline or subtentorial tumors, the latter often linked to a poorer prognosis and infrequently associated with epilepsy), extent of tumor resection, and adjuvant therapies. Most importantly, most studies conducted until 2018 included both IDH wild-type and IDH-mutated glioblastomas.

It is widely recognized that mutations in the IDH gene are associated with an elevated risk of seizures both before and after surgery. Specifically, the R132H mutation of the IDH1 gene leads to a gain of gene function, resulting in the accumulation of D-2-hydroxyglutarate (D-2-HG), a compound structurally analogous to glutamate [27]. Furthermore, the IDH1-2 mutation is linked to a more favorable prognosis, evidenced by a median overall survival of 32 months compared to 23 months for GBM with MGMT gene promoter methylation and 12 months for unmethylated GBM [28]. Other patient-related and tumor-related factors are associated with both early seizures and better survival. For instance, early seizures in GBM are often associated with younger age and small cortical lesions, more often located in temporal or frontal lobe, which are more easily attacked by surgery and therefore more susceptible to complete excision [29].

With the advent of the new 2021 classification of primary tumors of the central nervous system, mutation of the IDH gene has become an exclusion factor for the diagnosis of glioblastoma [5], and most studies from 2021 onwards excluded IDH mutated tumors from survival analyses. At the same time, these studies found no differences in survival between patients with seizures at onset and seizure-free patients.

In the context of the meta-analysis, despite the comprehensive pooled analysis suggesting a potential beneficial prognostic influence linked to seizures at the onset of glioblastoma, the subgroup examination reveals an absence of identifiable impact from preoperative seizures within studies confined to wild-type cases. Notably, the hazard ratio demonstrates a diminishing trend in association with an increasing prevalence of IDH-mutated cases. According to the subgroup analysis, an effect modification of IDH-mutation status could also not be excluded. Moreover, studies such as that by Toledo et al. have reported that seizures at the time of diagnosis were the sole predictor of extended survival among patients aged 60 years and below. In contrast, for patients over 60 years, neither seizures nor other factors were linked to prolonged survival [18]. Given that IDH mutations are more commonly found in younger patients, it is possible that the potential inclusion of some IDH-mutant cases could have contributed to the survival differences observed, particularly in younger patients with seizures.

Therefore, studies with more reliable data on IDH mutation status are needed to disentangle the prognostic value of peri-operatory seizures.

Furthermore, additional limitations are evident, particularly regarding the heterogeneity in the extent of surgery and adjuvant treatments administered to participants across various studies. Notably, only the investigations conducted by Zhao et al. [23] and Pesce et al. [24] exclusively enrolled patients who underwent total or subtotal resection of lesions, followed by a standard Stupp protocol.

Moreover, potential limitations encompass the retrospective design (except for the study conducted by Toledo and coworkers [18]), and the absence of PFS as a survival outcome (with the exception of the studies by Jilla et al. [16] and Pesce et al. [24]). Using PFS as a prognostic marker would provide more specific insights into the role of epilepsy in tumor progression, as OS may be influenced by diverse factors such as initial performance status, post-therapeutic complications, or the superimposition of other diseases during the clinical course.

Therefore, prospective studies involving homogeneous cohorts of IDH-wild type GBM patients are imperative to delineate more accurately the role of seizures at clinical onset in glioblastoma patients, focusing on both OS and PFS. A limitation of the review process is the lack of a review protocol registered before the start of the review process given by an oversight during the project initiation phase. Despite this, no deviations from the intended protocol occurred.