Structural Brain Networks and the Seizure-Survival Paradox in Glioblastoma

Background: In glioblastoma, tumor-related epilepsy (TRE) is paradoxically associated with longer survival, but the mechanism is unclear. We hypothesized that structural connectivity is associated with seizure susceptibility and survival, and tested whether these associations are independent or mediated. Methods: We retrospectively studied glioblastoma patients with preoperative diffusion-weighted MRI. Fractional anisotropy-weighted connectivity matrices were constructed using lesion-aware tractography. Mean edge weight and local efficiency were computed per Yeo 7-network and with global efficiency at hemisphere and whole-brain levels. Associations with TRE, overall survival (OS), and progression-free survival (PFS) were assessed using logistic regression and Cox proportional hazards models with false discovery rate correction. Causal mediation analysis tested whether connectivity and TRE mediate each other's relationship with overall survival. Results: We included 420 glioblastoma patients. Of 406 classifiable for TRE, 217 (53%) had TRE. TRE was associated with higher local efficiency across all seven contralateral networks (d=0.42-0.49, q<0.010) and five of seven ipsilateral networks (d=0.44-0.49, q<0.050). In adjusted models, higher contralateral global efficiency was associated with longer OS (HR 0.84, q=0.021), with no metric associated with PFS. TRE did not mediate the connectivity-OS relationship. Contralateral local efficiency partially mediated the TRE-OS association when postoperative KPS was excluded from the model (ACME 16.6 days, 7.8% mediated, p=0.029), though this was attenuated when KPS was included (p=0.074). Conclusions: Structural connectivity partially mediates the seizure-survival association, suggesting preserved network architecture may contribute to why seizure patients survive longer, though the majority of the effect operates through other pathways.