Advancing the Paradigm of Temporal Lobe Epilepsy as a Network Disease: The Promise of Biomarkers and Targeted Disease Modification
- 1Department of Physiology, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș, 540142 Târgu Mureș, Romania
- 2Department of Pharmacology and Clinical Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, 540142 Târgu Mures, Romania
- 3Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureș, 540142 Târgu Mureș, Romania
Abstract
Temporal lobe epilepsy (TLE) is increasingly conceptualized not as an isolated hippocampal lesion, but as a complex, multiscale limbic network connectomic disorder. Despite advances in pharmacological management, over 30% of patients experience drug-resistant epilepsy, underscoring the urgent need to shift from symptomatic seizure control to mechanism-directed disease modification. This review comprehensively synthesizes the pathophysiological architecture of epileptogenesis in TLE, spanning mitochondrial bioenergetic alterations, chronic neuroinflammation, synaptic reorganization, and ionic plasticity resulting from ion-channel dysregulation. We evaluate diagnostic advancements, highlighting how invasive stereo-EEG disambiguates pathological high-frequency oscillations from physiological ripples, how structural HARNESS-MRI maps anatomical substrates, and how AI-driven algorithms analyze ultra-long-term EEG streams for continuous seizure forecasting. Additionally, peripheral biofluid proteins and microRNAs provide noninvasive windows into active neuroinflammation and network remodeling, serving as valuable tools for longitudinal disease monitoring rather than primary screening. Therapeutically, the field is evolving beyond empirical antiseizure medications toward mechanism-based rational drug design and precision interventions. Dual-mechanism agents enhance seizure freedom, while antisense oligonucleotides, microRNA antagomirs, and cation-chloride cotransporter modulators target underlying genetic and biophysical drivers. Minimally invasive ablation, AI-guided closed-loop neuromodulation, targeted anti-inflammatory biologics, and patient-derived 3D cerebral organoid platforms further expand the translational frontier. Ultimately, bridging these experimental modalities through prospective clinical validation may provide a viable path toward interrupting epileptogenesis and realizing true disease modification in human TLE.
Related
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BibTeX
@article{orbankis2026advancing,
title = {{Advancing the Paradigm of Temporal Lobe Epilepsy as a Network Disease: The Promise of Biomarkers and Targeted Disease Modification}},
author = {Károly Orbán-Kis and Krisztina Kelemen and Rita-Judit Kiss and Zsolt Gáll and Zsolt András Nagy and Anna Fehér and Nándor Todor and Ádám Szentes and Júlia Erzsébet Metz and Tibor Szilágyi},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27188328},
url = {https://www.mdpi.com/1422-0067/27/18/8328},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Advancing the Paradigm of Temporal Lobe Epilepsy as a Network Disease: The Promise of Biomarkers and Targeted Disease Modification
AU - Károly Orbán-Kis
AU - Krisztina Kelemen
AU - Rita-Judit Kiss
AU - Zsolt Gáll
AU - Zsolt András Nagy
AU - Anna Fehér
AU - Nándor Todor
AU - Ádám Szentes
AU - Júlia Erzsébet Metz
AU - Tibor Szilágyi
PY - 2026
DA - 2026/09/19
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27188328
UR - https://www.mdpi.com/1422-0067/27/18/8328
AB - Temporal lobe epilepsy (TLE) is increasingly conceptualized not as an isolated hippocampal lesion, but as a complex, multiscale limbic network connectomic disorder. Despite advances in pharmacological management, over 30% of patients experience drug-resistant epilepsy, underscoring the urgent need to shift from symptomatic seizure control to mechanism-directed disease modification. This review comprehensively synthesizes the pathophysiological architecture of epileptogenesis in TLE, spanning mitochondrial bioenergetic alterations, chronic neuroinflammation, synaptic reorganization, and ionic plasticity resulting from ion-channel dysregulation. We evaluate diagnostic advancements, highlighting how invasive stereo-EEG disambiguates pathological high-frequency oscillations from physiological ripples, how structural HARNESS-MRI maps anatomical substrates, and how AI-driven algorithms analyze ultra-long-term EEG streams for continuous seizure forecasting. Additionally, peripheral biofluid proteins and microRNAs provide noninvasive windows into active neuroinflammation and network remodeling, serving as valuable tools for longitudinal disease monitoring rather than primary screening. Therapeutically, the field is evolving beyond empirical antiseizure medications toward mechanism-based rational drug design and precision interventions. Dual-mechanism agents enhance seizure freedom, while antisense oligonucleotides, microRNA antagomirs, and cation-chloride cotransporter modulators target underlying genetic and biophysical drivers. Minimally invasive ablation, AI-guided closed-loop neuromodulation, targeted anti-inflammatory biologics, and patient-derived 3D cerebral organoid platforms further expand the translational frontier. Ultimately, bridging these experimental modalities through prospective clinical validation may provide a viable path toward interrupting epileptogenesis and realizing true disease modification in human TLE.
SN - 1422-0067
ER -