2026-02-12
Epilepsy: targeting the right mechanism to treat better?
Neurology
By Ana Espino | Published on February 12, 2026 | 3 min read
Epilepsy is a chronic neurological disorder characterized by abnormal electrical activity in the brain, leading to seizures that are often sudden and disabling. While the majority of patients respond to antiseizure medications, approximately 30% develop drug‑resistant epilepsy, defined by the failure of at least two appropriately chosen and well‑tolerated treatments. This refractory form is associated with a major deterioration in quality of life, an increased risk of psychiatric comorbidities, and premature mortality, notably due to SUDEP (sudden unexpected death in epilepsy).
Current management remains largely symptomatic, focusing on seizure reduction without addressing the underlying causes of the disease. Treatments remain ineffective in many genetic or syndromic epilepsies, for which no specific validated therapeutic approach is currently available. This lack of tailored solutions highlights the need to move beyond a one‑size‑fits‑all approach to antiseizure therapy.
In this context, the main therapeutic challenge lies in the development of individualized strategies capable of directly targeting the pathogenic mechanisms specific to each type of epilepsy. Precision medicine therefore emerges as a particularly promising avenue. This study was initiated to evaluate recent advances in targeted therapies in epilepsy, by analyzing available preclinical and clinical data in order to define their potential and limitations within the framework of personalized care.
The article is based on a structured narrative review of targeted therapies developed for rare or genetic epilepsies. The approach combines evidence from animal models, patient‑derived cellular studies, and available clinical trials. Several specific syndromes are explored, including pyridoxine‑dependent epilepsy, GLUT1 deficiency syndrome, tuberous sclerosis complex (TSC), and genetic epileptic encephalopathies related to SCN2A, KCNT1, and GRIN2B.
Some targeted treatments, such as pyridoxine or the ketogenic diet, demonstrated clinical efficacy early on, well before the underlying molecular mechanisms were fully understood. Everolimus, an mTOR pathway inhibitor, achieved significant results in TSC, with response rates close to 40% in phase III clinical trials. In SCN2A gain‑of‑function epilepsies, sodium channel blockers have shown clear clinical benefit, supported by both animal models and documented clinical cases. More experimental approaches are also discussed, including modulation of the glutamatergic pathway via GluN2C, as well as targeting neuro‑immune inflammation through mediators such as IL‑1β and CXCL10, paving the way for future combination therapies.
However, the inconsistent efficacy of certain options—such as quinidine in KCNT1‑related epilepsies—highlights the limitations of translating preclinical findings into clinical practice and underscores the need for rigorous methodological frameworks to validate these targeted approaches.
Drug‑resistant epilepsy is a severe neurological condition, marked by persistent seizure activity despite standard treatments. The central challenge remains the inability of current approaches to address underlying disease mechanisms, particularly in genetic or syndromic forms.
The objective of this study was to review recent advances in targeted therapies, drawing on preclinical and clinical evidence obtained in well‑defined subgroups of rare epilepsies. The findings confirm that precision medicine represents a credible therapeutic pathway, with demonstrated benefits in conditions such as TSC, GLUT1 deficiency, and SCN2A‑related epilepsies, while also highlighting the heterogeneity of responses and the complexity of clinical implementation.
However, limitations remain and justify further research. Future efforts should include large‑scale multicenter clinical trials, in‑depth functional characterization of genetic variants, and the development of standardized protocols for the use of targeted therapies in neurology. Identifying early therapeutic windows, integrating drug repurposing strategies, and strengthening collaboration between clinicians, geneticists, and researchers will be essential to accelerate the translation of discoveries into truly personalized epilepsy care.
About the author – Ana Espino
PhD in Immunology, specialized in Virology
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.
Epilepsy is a chronic neurological disorder characterized by abnormal electrical activity in the brain, leading to seizures that are often sudden and disabling. While the majority of patients respond to antiseizure medications, approximately 30% develop drug‑resistant epilepsy, defined by the failure of at least two appropriately chosen and well‑tolerated treatments. This refractory form is associated with a major deterioration in quality of life, an increased risk of psychiatric comorbidities, and premature mortality, notably due to SUDEP (sudden unexpected death in epilepsy).
Current management remains largely symptomatic, focusing on seizure reduction without addressing the underlying causes of the disease. Treatments remain ineffective in many genetic or syndromic epilepsies, for which no specific validated therapeutic approach is currently available. This lack of tailored solutions highlights the need to move beyond a one‑size‑fits‑all approach to antiseizure therapy.
In this context, the main therapeutic challenge lies in the development of individualized strategies capable of directly targeting the pathogenic mechanisms specific to each type of epilepsy. Precision medicine therefore emerges as a particularly promising avenue. This study was initiated to evaluate recent advances in targeted therapies in epilepsy, by analyzing available preclinical and clinical data in order to define their potential and limitations within the framework of personalized care.
Does targeting mean winning ?
The article is based on a structured narrative review of targeted therapies developed for rare or genetic epilepsies. The approach combines evidence from animal models, patient‑derived cellular studies, and available clinical trials. Several specific syndromes are explored, including pyridoxine‑dependent epilepsy, GLUT1 deficiency syndrome, tuberous sclerosis complex (TSC), and genetic epileptic encephalopathies related to SCN2A, KCNT1, and GRIN2B.
Some targeted treatments, such as pyridoxine or the ketogenic diet, demonstrated clinical efficacy early on, well before the underlying molecular mechanisms were fully understood. Everolimus, an mTOR pathway inhibitor, achieved significant results in TSC, with response rates close to 40% in phase III clinical trials. In SCN2A gain‑of‑function epilepsies, sodium channel blockers have shown clear clinical benefit, supported by both animal models and documented clinical cases. More experimental approaches are also discussed, including modulation of the glutamatergic pathway via GluN2C, as well as targeting neuro‑immune inflammation through mediators such as IL‑1β and CXCL10, paving the way for future combination therapies.
However, the inconsistent efficacy of certain options—such as quinidine in KCNT1‑related epilepsies—highlights the limitations of translating preclinical findings into clinical practice and underscores the need for rigorous methodological frameworks to validate these targeted approaches.
Personalizing epilepsy care: mission possible?
Drug‑resistant epilepsy is a severe neurological condition, marked by persistent seizure activity despite standard treatments. The central challenge remains the inability of current approaches to address underlying disease mechanisms, particularly in genetic or syndromic forms.
The objective of this study was to review recent advances in targeted therapies, drawing on preclinical and clinical evidence obtained in well‑defined subgroups of rare epilepsies. The findings confirm that precision medicine represents a credible therapeutic pathway, with demonstrated benefits in conditions such as TSC, GLUT1 deficiency, and SCN2A‑related epilepsies, while also highlighting the heterogeneity of responses and the complexity of clinical implementation.
However, limitations remain and justify further research. Future efforts should include large‑scale multicenter clinical trials, in‑depth functional characterization of genetic variants, and the development of standardized protocols for the use of targeted therapies in neurology. Identifying early therapeutic windows, integrating drug repurposing strategies, and strengthening collaboration between clinicians, geneticists, and researchers will be essential to accelerate the translation of discoveries into truly personalized epilepsy care.
About the author – Ana Espino
PhD in Immunology, specialized in Virology
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.
Source(s) :
Auvin S. Targeted therapies in epilepsies. Rev Neurol (Paris). 2025 May;181(5):450-455 ;
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