Structural Brain Networks and the Seizure-Survival Paradox in Glioblastoma
- 1University of Pennsylvania
Abstract
BackgroundIn 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.
MethodsWe 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 others relationship with overall survival.
ResultsWe 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).
ConclusionsStructural connectivity may partially mediate the seizure-survival association, suggesting preserved network architecture may contribute to longer survival in glioblastoma patients with TRE, though most of the effect operates through other pathways.
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BibTeX
@misc{zhou2026structural,
title = {{Structural Brain Networks and the Seizure-Survival Paradox in Glioblastoma}},
author = {D. J. Zhou and M. Jaskir and J. Gal and Y. Fonkeu and A. J. Lucas and Q. Cao and C. Davatzikos and M. P. Nasrallah and J. Garcia and R. Xing and R. E. Phillips and C. A. Ellis and S. Das and J. J. Gugger and N. Sinha and J. M. Stein and K. A. Davis},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.26362299},
url = {https://www.medrxiv.org/content/10.64898/2026.09.04.26362299v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Structural Brain Networks and the Seizure-Survival Paradox in Glioblastoma
AU - D. J. Zhou
AU - M. Jaskir
AU - J. Gal
AU - Y. Fonkeu
AU - A. J. Lucas
AU - Q. Cao
AU - C. Davatzikos
AU - M. P. Nasrallah
AU - J. Garcia
AU - R. Xing
AU - R. E. Phillips
AU - C. A. Ellis
AU - S. Das
AU - J. J. Gugger
AU - N. Sinha
AU - J. M. Stein
AU - K. A. Davis
PY - 2026
DA - 2026/09/04
PB - medRxiv
DO - 10.64898/2026.09.04.26362299
UR - https://www.medrxiv.org/content/10.64898/2026.09.04.26362299v1
AB - BackgroundIn 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. MethodsWe 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 others relationship with overall survival. ResultsWe 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). ConclusionsStructural connectivity may partially mediate the seizure-survival association, suggesting preserved network architecture may contribute to longer survival in glioblastoma patients with TRE, though most of the effect operates through other pathways.
ER -