Jun 2026· MedComm· Vol 7· 1 citation· 323 references
Medicine
TL;DR
Current evidence supports a shift from empirical seizure suppression toward mechanism‐guided and individualized care, and future progress will require closer integration of molecular discovery, validated biomarkers, and real‐world implementation to achieve earlier, more equitable, and potentially disease‐modifying treatment.
Abstract
Epilepsy is a common neurological disorder with a substantial global burden. Despite major advances in diagnosis and therapy, nearly one‐third of patients remain resistant to antiseizure medications, highlighting persistent gaps in understanding epileptogenesis and disease progression. Here, we review epidemiological evidence, time‐dependent seizure patterns, and pathogenic mechanisms that contribute to epilepsy. We discuss how genetic variants, ion‐channel dysfunction, altered synaptic transmission, neuroinflammation, metabolic and mitochondrial stress, structural remodeling, network reorganization, and epigenetic regulation converge to destabilize neural circuits. These processes interact across disease stages and promote persistent hyperexcitability. We further summarize how mechanistic advances are reshaping clinical management, including precision diagnostics, pharmacotherapy, surgery, neuromodulation, dietary and lifestyle intervention, chronotherapy, biomarker‐guided stratification, and emerging disease‐modifying approaches such as immunotherapy, pathway‐targeted treatment, RNA‐based therapeutics, and gene‐directed strategies. Data‐driven tools for seizure detection and forecasting are also discussed as complementary approaches for individualized care. Overall, current evidence supports a shift from empirical seizure suppression toward mechanism‐guided and individualized care. Future progress will require closer integration of molecular discovery, validated biomarkers, and real‐world implementation to achieve earlier, more equitable, and potentially disease‐modifying treatment.
Epilepsy is increasingly recognized as a multiscale network disorder rather than solely a condition of neuronal hyperexcitability, and the coordinated use of complementary human-relevant platforms may help incorporate multiscale mechanistic insights into therapeutic development and evaluation, narrow persistent translational gaps, and support more predictive and mechanism-informed treatment strategies.
Wonseok Chang, Amy Seomin Kwak, Seung Ho Han et al.· Pharmaceutics· 0 citations
Epilepsy is a multifactorial disorder, yet routine management still focuses on neuronal excitation and insufficient inhibition, with antiseizure medications (ASMs) as the primary therapeutic strategy. This approach fails in roughly one-third of patients who develop drug-resistant epilepsy (DRE). Converging evidence links DRE with neuroinflammation, oxidative stress (OS), and mitochondrial dysfunction—an interconnected distal pathophysiological triad that progressively lowers seizure thresholds yet remains peripheral to clinical epilepsy management. We map this triad mechanistically and show that ASMs modulate it beyond their anticonvulsant activity, while triad-targeting pharmacological, dietary, and botanical interventions independently reduce seizure susceptibility. Common precipitants are reinterpreted as acute activators of the distal triad, linking precipitant identification and patient agency to threshold elevation. Integrating these elements, we propose a threshold management framework for DRE, built on a revised reservoir model, and translate it into three structural priorities: mechanistic phenotyping to stratify patients by pathophysiological domain, dual-mechanism drug development, and trial designs suited to multicomponent, context-dependent interventions. Together, these proposals reframe epilepsy management from sequential pharmacological trials toward coordinated optimization of the full seizure threshold landscape.
Alexander Trofimov, Ksenia Shcherbakova, Alexander Schwarz et al.· International Journal of Mol...· 0 citations
This review synthesizes advances in neuroimmunology, clinical phenotyping, diagnostics, immunomodulatory and antiseizure therapies, neuromodulation, and patient and family centered outcomes, and outlines future directions focused on biomarker-driven precision medicine, disease-modifying strategies, and interdisciplinary care models.
Alica M. Goldman, Nora Wong, A. Vezzani et al.· Epilepsy Currents· 0 citations
This review synthesizes contemporary insights into the genetic and molecular pathophysiology of seizures and epilepsy, with emphasis on mechanisms that destabilize excitation–inhibition balance, promote epileptogenesis, and drive pharmacoresistance and supports more refined approaches to epilepsy classification and future precision medicine strategies.
Mohammad Reza Seyedtaghia, Jina Babanzadeh, Marcello Scala et al.· Epilepsia Open· 0 citations
Epilepsy is a heterogeneous neurological disorder affecting more than 70 million people worldwide, posing significant challenges for clinicians due to its complex etiology, diverse manifestations, variable treatment responses, and the inability to predict seizures or disease onset reliably. Despite advances in antiseizure medications, approximately 30% of patients remain treatment-resistant, highlighting the urgent need for therapies with antiepileptogenic or disease-modifying effects. To optimize and individualize strategies to predict and treat seizures and epilepsy, efforts to identify biomarkers of epilepsy risk, epileptogenesis, seizures, and therapy response are ongoing. This article reports key presentations and discussions from the 2023 Workshop on Neurobiology of Epilepsy (WONOEP XVII) in Kilkea, Ireland on novel epilepsy biomarkers and treatment strategies beyond the synapse and does not constitute a comprehensive review of biomarkers or treatment strategies. Much of the focus in epilepsy research has centered on identifying primarily neuronal processes or components. The 2023 WONOEP presentations discussed advances in plasma biomarkers for posttraumatic seizures and outcomes, perivascular spaces in posttraumatic epilepsy and poststroke epilepsy, imaging biomarkers of astrogliosis, and plasma microRNA biomarkers of intellectual disability and autism in tuberous sclerosis complex. Furthermore, research on immuno- and anti-inflammatory therapies and blood-brain barrier in drug-resistant focal epilepsies and infantile epileptic spasms syndrome was presented, as well as on the effects of antiseizure and cardioprotective medications on cardiac injury in temporal lobe epilepsy. The review also emphasizes the need for further interdisciplinary collaboration to accelerate the translation of these findings into clinical practice, ultimately improving outcomes and quality of life for people with epilepsy.
Mirte Scheper, Zining Liu, A. Galanopoulou et al.· Epilepsia· 0 citations