The review 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.
Abstract
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.
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
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
Abstract Autoimmune epilepsy, once regarded as a rare and poorly understood subset of seizure disorders, has now emerged as a clinically significant and potentially reversible cause of epilepsy. Advances in neuroimmunology have substantially broadened the spectrum of neural autoantibodies implicated in epileptogenesis—particularly those directed against neuronal cell surface and synaptic proteins, such as the N-methyl-D-aspartate receptor (NMDAR), leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and glutamic acid decarboxylase 65 (GAD65). Distinct autoantibody profiles are now recognized to correlate with characteristic clinical syndromes, facilitating earlier and more targeted diagnosis. For instance, faciobrachial dystonic seizures are highly suggestive of LGI1 antibody-mediated encephalitis, while neuropsychiatric manifestations and movement disorders are typical of NMDAR antibody encephalitis, and chronic temporal lobe epilepsy frequently accompanies GAD65 autoimmunity. Early identification of these immune-mediated forms is critical, as antibody-mediated epilepsies involving cell surface antigens often respond favorably to immunotherapy, leading to substantial recovery. In contrast, epilepsies associated with intracellular antigen targets or cytotoxic T-cell–driven mechanisms, such as Rasmussen encephalitis, typically show poor therapeutic response due to irreversible neuronal injury. Some autoimmune encephalitides also occur as paraneoplastic syndromes, underscoring the importance of comprehensive oncological evaluation in affected patients. Moreover, immune dysregulation has been implicated in catastrophic epileptic conditions such as new-onset refractory status epilepticus and febrile infection-related epilepsy syndrome, further broadening the clinical spectrum of autoimmune-mediated seizures. Although seizures may arise from diverse etiologies, immune mechanisms have gained increasing recognition as an important and potentially modifiable contributor to epileptogenesis. This recognition has been formally endorsed by the International League Against Epilepsy, which classifies autoimmune epilepsy as a distinct diagnostic entity. Nevertheless, true autoimmune epilepsy, in which seizure susceptibility persists after resolution of encephalitic activity, remains relatively uncommon. In most cases, seizures associated with autoimmune encephalitis are acute and reversible with timely immunotherapy. Thus, precise terminology—differentiating acute symptomatic seizures from chronic autoimmune-associated epilepsy—is essential for appropriate management, prognostication, and research standardization.
Monika Singla, Abhishek Dixit, M. Mehndiratta· International Journal of Epi...· 0 citations
This work proposes a threshold management framework for DRE, built on a revised reservoir model, and translates 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.
Alexander Trofimov, Ksenia Shcherbakova, Alexander Schwarz et al.· International Journal of Mol...· 0 citations
Sudden Unexpected Death in Epilepsy (SUDEP) represents a leading cause of epilepsy-related mortality, reflecting a severe disruption of systemic physiology that remains challenging to address using standard clinical protocols. Although generalized tonic–clonic seizures (GTCS) and pharmacoresistance are established risk indicators, current clinical risk stratification frequently lacks the predictive granularity required to anticipate individual cardiorespiratory collapse. This review provides a comprehensive synthesis of the SUDEP pathophysiological framework, aiming to bridge the gap between retrospective clinical observation and proactive precision medicine. We delineate a translational framework focused on the intrinsic biological susceptibility of the neuro-cardiac axis, particularly the genetic “dual pathology” of channelopathies and structural cardiac remodeling. Furthermore, we evaluate the transition from reactive risk identification toward multimodal “digital phenotyping” leveraging artificial intelligence. Finally, we assess the developmental trajectory of “secondary prevention” strategies, such as automated neurostimulation, designed to interrupt the terminal cascade. By integrating genomic vulnerability with emerging preventative technologies, this review outlines a multidisciplinary approach to transforming SUDEP into a more predictable and preventable clinical entity.
Chenxi Xu, Yi-Yuan Wang, Su-Ping Nie et al.· Frontiers in Neurology· 0 citations
Every revision of the seizure classification-most recently the 2025 International League Against Epilepsy (ILAE) update-refines terminology, yet it is worth asking whether patients are treated better because their seizures were renamed. The focal versus generalized dichotomy has organized epilepsy classification since the 1960 s and is grounded in a pharmacologic rationale, but head-to-head data from the SANAD trials show that efficacy differences between individual antiseizure medications frequently equal or exceed differences across the focal/generalized boundary. Meanwhile, the distinction that is genuinely transformative-whether an epilepsy is surgically remediable-produces seizure-freedom differences of an entirely different order of magnitude, and yet epilepsy surgery remains among the most underutilized evidence-based treatments in medicine. We argue that classification should elevate therapeutic trajectory over electroclinical phenomenology, and we propose an Interventional Axis built around three pathways: focal resection, neuromodulation, and palliative surgery, operating in parallel with pharmacotherapy rather than after its serial failure. Refining terminology improves communication, but the ultimate metric of a classification is outcome, not taxonomic elegance.
Felix Benninger, Ilan Goldberg· Epilepsy & Behavior· 0 citations