RARE DISEASE
Epilepsy syndrome
Epilepsy syndrome
Epilepsy syndrome
Drug discovery
7
drugs
With orphan designations
Overview
Epilepsy is a chronic neurological disorder characterized by recurrent, unprovoked seizures due to abnormal neuronal activity. It affects all ages and has diverse etiologies, including genetic, structural, and unknown causes. While ~70% achieve seizure control with antiseizure medications (ASMs), 30% develop drug-resistant epilepsy, requiring advanced therapies. The condition carries significant mortality risks, including SUDEP (sudden unexpected death in epilepsy) [4][6][16].
Population
Global: Affects ~51.7 million people (24.2 million idiopathic; 27.5 million secondary) [9][19], with age-standardized prevalence of 307.38/100,000 [2].
Demographics: Highest incidence in children (0–14 years: 61/100,000) [2][19]; mortality peaks in adults ≥70 years (5.67/100,000) [2][19].
Disparities: 80% of cases occur in low- and middle-income countries, with treatment gaps exceeding 75% in some regions [16][19].
Burden
Mortality: Age-standardized death rate of 1.74/100,000 globally [2][19]; SUDEP accounts for 1/1,000 annual deaths in epilepsy patients [4][6].
Disability: 177.85 DALYs/100,000 globally, with males disproportionately affected (201.29 vs. 154.25 in females) [2][19].
Comorbidities: 20–30% have depression/anxiety; 27-fold higher sudden death risk vs. general population [6][16].
Therapies
First-line: ASMs (levetiracetam, valproate) control seizures in ~67% of patients [1][8][16].
Advanced options: Surgical resection, neurostimulation (vagus nerve stimulation, responsive neurostimulation), and ketogenic diet for drug-resistant cases [3][8][13].
Emerging therapies: Cenobamate, cannabidiol, and non-invasive neuromodulation (e.g., transcranial magnetic stimulation) [3][13][18].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
3,271 drug discovery papers about Epilepsy syndrome, with 2 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,271 drug discovery papers about Epilepsy syndrome, with 2 first-in-class and 10 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | Severe Epilepsy Syndromes in Childhood: A Comprehensive Review of Clinical Features, Etiologies, and Advancing Therapeutic Landscapes
Severe childhood epilepsy syndromes, encompassing the developmental and epileptic encephalopathies together with related drug-resistant electroclinical constellations, remain among the most challenging conditions in paediatric neurology. They combine frequent, treatment-resistant seizures with developmental impairment, substantial comorbidity, and elevated premature mortality. The past two decades have transformed the field: a revised syndrome classification, an expanding catalogue of monogenic causes, and a succession of syndrome-specific and mechanism-based therapies have altered both diagnosis and management. This critical narrative review synthesises evidence on the clinical features, aetiologies, and therapeutic options for these syndromes, and evaluates the strength, consistency, and limitations of that evidence rather than cataloguing individual studies. Literature was selected from bibliographic searching, citation chaining, and appraisal of consensus statements and clinical guidelines, with every cited reference and its digital object identifier independently verified. Several themes emerge. Aetiological diagnosis, particularly through broad genetic testing, now carries direct management consequences, yet a diagnostic gap persists and genotype does not map cleanly onto phenotype or treatment response. Syndrome-specific pharmacotherapy is supported by robust randomised evidence for a small number of agents in Dravet syndrome, Lennox-Gastaut syndrome, and CDKL5 deficiency disorder, but head-to-head comparisons, long-term developmental outcomes, and effects on the encephalopathy itself remain poorly characterised. Mechanism-based and disease-modifying strategies, including mammalian target of rapamycin inhibition, pre-emptive treatment, and antisense oligonucleotides, represent a conceptual shift from seizure suppression toward disease modification, though the durability and developmental impact of these approaches are not yet established. Sudden unexpected death in epilepsy and other causes of early mortality remain insufficiently mitigated. The available evidence supports cautious optimism: outcomes are improving, but confidence in many conclusions is constrained by small samples, heterogeneous endpoints, short follow-up, and reliance on seizure count as the dominant outcome. Priorities include earlier aetiological diagnosis, developmentally meaningful outcome measures, and trials designed to test disease modification rather than seizure frequency alone.
2026-08-09 | Total bilirubin-to-albumin ratio and systemic immune inflammation index as prognostic indicators in children with febrile infection-related epilepsy syndrome.
Febrile infection-related epilepsy syndrome (FIRES) is associated with high mortality and poor neurological outcomes, yet reliable prognostic indicators are lacking. This study aimed to evaluate the prognostic value of inflammatory indexes in FIRES and to explore their potential role in guiding clinical management. Children with FIRES hospitalized at the Children's Hospital affiliated to Chongqing Medical University between November 2015 and April 2024 and followed for more than 6 months were retrospectively included. Inflammatory indexes were analyzed at admission and after immunotherapy. Patients were categorized into death, KD, and non-KD survival groups according to clinical course and treatment pathway. Multivariate logistic and sequential logistic regression analyses were performed to identify prognostic factors. Receiver operating characteristic (ROC) curves and Gordon's coefficient were used to determine cut-off values. Sankey diagrams and nomograms were applied to validate prognostic stratification. Thirty-six children with FIRES were included (22 males; mean age 6.67 ± 3 years). Nine patients died, none of whom received KD. The KD group had significantly higher 6-month Glasgow Outcome Scale (GOS) scores than the non-KD survival and death groups (4 ± 1 vs. 3 ± 1 vs. 1 ± 0, p < 0.001). Multivariate analyses showed that total bilirubin-to-albumin ratio (TAR) at admission (18.48, 95% CI 6.86∼30.09, p = 0.002) and systemic immune inflammation index (SII) after immunotherapy (-0.001, 95% CI -0.001-0, p = 0.003) were independently associated with prognosis. Cut-off values of 0.145 and 0.195 for TAR and 1292 and 1892 for SII stratified patients into distinct severity groups. Higher TAR values and lower SII values were associated with milder disease and better outcomes. Sankey diagrams and nomograms further illustrated the prognostic stratification based on TAR and SII. TAR at admission and SII after immunotherapy are practical inflammatory indexes associated with disease severity and prognosis in FIRES. These findings support further investigation of early KD initiation, particularly in patients with low TAR at admission or persistently elevated SII after immunotherapy.
2026-07-29 | Therapeutic Use of Medical Cannabis Beyond Pain Management in Physical Medicine and Rehabilitation.
Medical cannabis has emerged as a rapidly evolving therapeutic modality with expanding clinical interest beyond its traditional role in pain management. Particularly relevant to Physical Medicine and Rehabilitation (PM&R), where the focus extends beyond symptom control to functional restoration and optimal quality of life, key non-pain indications described in the literature include management of spasticity, neurologic and seizure disorders, sleep disturbances, and chemotherapy-induced nausea and vomiting (CINV). This PM&R-centered narrative review synthesizes current evidence on the efficacy, mechanisms, and clinical implications of cannabis use for non-pain conditions, with emphasis on its interaction with the endocannabinoid system, including CB1- and CB2-receptor-mediated pathways influencing neuromodulation, inflammation, and homeostasis. Across multiple conditions, cannabinoids demonstrate modest benefits in symptom reduction, including improvements in patient-reported spasticity in multiple sclerosis, significant seizure reduction in treatment-resistant pediatric epileptic syndromes, antiemetic effects in refractory CINV, and appetite stimulation in cachectic states. Additionally, subjective improvements in sleep quality have been observed, though objective changes in sleep architecture remain inconsistent. However, there remains limited evidence supporting meaningful improvements in functional outcomes and quality of life. Cannabis use may negatively impact rehabilitation through dose-dependent cognitive impairment, sedation, impaired motor learning, and increased fall risk. Significant challenges persist, including lack of standardized dosing, variability in formulations and THC:CBD ratios, inconsistent product labeling, and limited high-quality randomized controlled trials assessing long-term functional outcomes. Regulatory barriers, including discrepancies between federal and state laws, further complicate clinical implementation and research. This review highlights the gap between symptomatic relief and functional recovery, emphasizing the need for PM&R-specific research focused on rehabilitation-relevant outcomes that objectively measure functional independence and quality of life. Bridging this gap will be critical to defining a role for medical cannabis within rehabilitation medicine and optimizing patient-centered care that maximizes function.
2026-07-17 | The role of Vagus nerve stimulation in epilepsy with eyelid myoclonia - A case series.
To study the effectiveness of vagus nerve stimulation (VNS) in patients with epilepsy with eyelid myoclonia (EEM, previously known as Jeavons Syndrome). EEM is an epilepsy syndrome characterized by eyelid myoclonia, eyelid closure-induced generalized EEG paroxysms or seizures, and photosensitivity. Many patients have drug-resistant epilepsy; however, the effectiveness of VNS in this epilepsy syndrome has not been well studied. This is a single institution retrospective observational study of patients with EEM. Among a database of 134 patients with EEM, we identified those treated with VNS. Epilepsy history, VNS parameters, and response to VNS were abstracted. We identified 12 patients who were treated with VNS (50% female). The median age of epilepsy onset was 5 (range 4-14) years; age of VNS implantation was 16 (range 6-33) years, and median duration of VNS treatment was 13.5 (range 0-24) years. Four patients (33.3%) were responders reporting greater than 50% improvement in seizure frequency. All four patients (33.3%) showed response with generalized tonic-clonic seizures, myoclonic seizures, and three patients (25%) reported response with eyelid myoclonia and absence seizures. One patient had the VNS explanted due to lack of efficacy and one had it turned off for enrollment in a clinical trial. The median maximum tolerated output current settings for our cohort were 1.75 mA (IQR 1.38-1.94; range 0.75-2.25) with an OFF time of 1.8 min (IQR 1.1-3, range 0.2-3) and median duty cycle of 24% (IQR 16-29; range 12-58). From this small case series of patients with EEM, four (33.3%) were responders to VNS, with improvement noted in multiple seizure types. This indicates the potential role of VNS for patients with EEM.
2026-07-05 | Cenobamate use in super-refractory status epilepticus: A report of three cases.
Super-refractory status epilepticus (SRSE) is a neurological emergency with high morbidity and mortality. Cenobamate, a novel antiseizure medication, may be helpful in managing SRSE, but evidence is limited. This retrospective case series reports the use of cenobamate as add-on therapy in the management of three cases of SRSE. Median age at status epilepticus (SE) onset was 28 years (range 27-75). The etiologies of SRSE included one case of febrile infection-related epilepsy syndrome (FIRES), one patient with a probable genetic etiology (SCN7A variant of uncertain significance), and one case of unknown etiology. Cenobamate was introduced at a median of 27 days (range 13-103) after SE onset. Resolution of SRSE was observed after a median of 7 days (range 3-30) once cenobamate was started. Median dose of cenobamate at SRSE cessation was 25 mg/day (range 12.5-50 mg/day), and the median maintenance dose at the time of discharge was 200 mg/day (range 100-400 mg/day). Two patients died and one patient achieved functional independence. No severe medication side effects, specifically drug reaction with eosinophilia and systemic symptoms (DRESS), were observed. Cenobamate may have a role in the management of SRSE. Further studies are needed to define the optimal timing of initiation, titration strategy, and target dose of cenobamate in the context of SE.
2026-08-11 | Severe Epilepsy Syndromes in Childhood: A Comprehensive Review of Clinical Features, Etiologies, and Advancing Therapeutic Landscapes
Severe childhood epilepsy syndromes, encompassing the developmental and epileptic encephalopathies together with related drug-resistant electroclinical constellations, remain among the most challenging conditions in paediatric neurology. They combine frequent, treatment-resistant seizures with developmental impairment, substantial comorbidity, and elevated premature mortality. The past two decades have transformed the field: a revised syndrome classification, an expanding catalogue of monogenic causes, and a succession of syndrome-specific and mechanism-based therapies have altered both diagnosis and management. This critical narrative review synthesises evidence on the clinical features, aetiologies, and therapeutic options for these syndromes, and evaluates the strength, consistency, and limitations of that evidence rather than cataloguing individual studies. Literature was selected from bibliographic searching, citation chaining, and appraisal of consensus statements and clinical guidelines, with every cited reference and its digital object identifier independently verified. Several themes emerge. Aetiological diagnosis, particularly through broad genetic testing, now carries direct management consequences, yet a diagnostic gap persists and genotype does not map cleanly onto phenotype or treatment response. Syndrome-specific pharmacotherapy is supported by robust randomised evidence for a small number of agents in Dravet syndrome, Lennox-Gastaut syndrome, and CDKL5 deficiency disorder, but head-to-head comparisons, long-term developmental outcomes, and effects on the encephalopathy itself remain poorly characterised. Mechanism-based and disease-modifying strategies, including mammalian target of rapamycin inhibition, pre-emptive treatment, and antisense oligonucleotides, represent a conceptual shift from seizure suppression toward disease modification, though the durability and developmental impact of these approaches are not yet established. Sudden unexpected death in epilepsy and other causes of early mortality remain insufficiently mitigated. The available evidence supports cautious optimism: outcomes are improving, but confidence in many conclusions is constrained by small samples, heterogeneous endpoints, short follow-up, and reliance on seizure count as the dominant outcome. Priorities include earlier aetiological diagnosis, developmentally meaningful outcome measures, and trials designed to test disease modification rather than seizure frequency alone.
2026-08-09 | Total bilirubin-to-albumin ratio and systemic immune inflammation index as prognostic indicators in children with febrile infection-related epilepsy syndrome.
Febrile infection-related epilepsy syndrome (FIRES) is associated with high mortality and poor neurological outcomes, yet reliable prognostic indicators are lacking. This study aimed to evaluate the prognostic value of inflammatory indexes in FIRES and to explore their potential role in guiding clinical management. Children with FIRES hospitalized at the Children's Hospital affiliated to Chongqing Medical University between November 2015 and April 2024 and followed for more than 6 months were retrospectively included. Inflammatory indexes were analyzed at admission and after immunotherapy. Patients were categorized into death, KD, and non-KD survival groups according to clinical course and treatment pathway. Multivariate logistic and sequential logistic regression analyses were performed to identify prognostic factors. Receiver operating characteristic (ROC) curves and Gordon's coefficient were used to determine cut-off values. Sankey diagrams and nomograms were applied to validate prognostic stratification. Thirty-six children with FIRES were included (22 males; mean age 6.67 ± 3 years). Nine patients died, none of whom received KD. The KD group had significantly higher 6-month Glasgow Outcome Scale (GOS) scores than the non-KD survival and death groups (4 ± 1 vs. 3 ± 1 vs. 1 ± 0, p < 0.001). Multivariate analyses showed that total bilirubin-to-albumin ratio (TAR) at admission (18.48, 95% CI 6.86∼30.09, p = 0.002) and systemic immune inflammation index (SII) after immunotherapy (-0.001, 95% CI -0.001-0, p = 0.003) were independently associated with prognosis. Cut-off values of 0.145 and 0.195 for TAR and 1292 and 1892 for SII stratified patients into distinct severity groups. Higher TAR values and lower SII values were associated with milder disease and better outcomes. Sankey diagrams and nomograms further illustrated the prognostic stratification based on TAR and SII. TAR at admission and SII after immunotherapy are practical inflammatory indexes associated with disease severity and prognosis in FIRES. These findings support further investigation of early KD initiation, particularly in patients with low TAR at admission or persistently elevated SII after immunotherapy.
2026-07-29 | Therapeutic Use of Medical Cannabis Beyond Pain Management in Physical Medicine and Rehabilitation.
Medical cannabis has emerged as a rapidly evolving therapeutic modality with expanding clinical interest beyond its traditional role in pain management. Particularly relevant to Physical Medicine and Rehabilitation (PM&R), where the focus extends beyond symptom control to functional restoration and optimal quality of life, key non-pain indications described in the literature include management of spasticity, neurologic and seizure disorders, sleep disturbances, and chemotherapy-induced nausea and vomiting (CINV). This PM&R-centered narrative review synthesizes current evidence on the efficacy, mechanisms, and clinical implications of cannabis use for non-pain conditions, with emphasis on its interaction with the endocannabinoid system, including CB1- and CB2-receptor-mediated pathways influencing neuromodulation, inflammation, and homeostasis. Across multiple conditions, cannabinoids demonstrate modest benefits in symptom reduction, including improvements in patient-reported spasticity in multiple sclerosis, significant seizure reduction in treatment-resistant pediatric epileptic syndromes, antiemetic effects in refractory CINV, and appetite stimulation in cachectic states. Additionally, subjective improvements in sleep quality have been observed, though objective changes in sleep architecture remain inconsistent. However, there remains limited evidence supporting meaningful improvements in functional outcomes and quality of life. Cannabis use may negatively impact rehabilitation through dose-dependent cognitive impairment, sedation, impaired motor learning, and increased fall risk. Significant challenges persist, including lack of standardized dosing, variability in formulations and THC:CBD ratios, inconsistent product labeling, and limited high-quality randomized controlled trials assessing long-term functional outcomes. Regulatory barriers, including discrepancies between federal and state laws, further complicate clinical implementation and research. This review highlights the gap between symptomatic relief and functional recovery, emphasizing the need for PM&R-specific research focused on rehabilitation-relevant outcomes that objectively measure functional independence and quality of life. Bridging this gap will be critical to defining a role for medical cannabis within rehabilitation medicine and optimizing patient-centered care that maximizes function.
2026-07-17 | The role of Vagus nerve stimulation in epilepsy with eyelid myoclonia - A case series.
To study the effectiveness of vagus nerve stimulation (VNS) in patients with epilepsy with eyelid myoclonia (EEM, previously known as Jeavons Syndrome). EEM is an epilepsy syndrome characterized by eyelid myoclonia, eyelid closure-induced generalized EEG paroxysms or seizures, and photosensitivity. Many patients have drug-resistant epilepsy; however, the effectiveness of VNS in this epilepsy syndrome has not been well studied. This is a single institution retrospective observational study of patients with EEM. Among a database of 134 patients with EEM, we identified those treated with VNS. Epilepsy history, VNS parameters, and response to VNS were abstracted. We identified 12 patients who were treated with VNS (50% female). The median age of epilepsy onset was 5 (range 4-14) years; age of VNS implantation was 16 (range 6-33) years, and median duration of VNS treatment was 13.5 (range 0-24) years. Four patients (33.3%) were responders reporting greater than 50% improvement in seizure frequency. All four patients (33.3%) showed response with generalized tonic-clonic seizures, myoclonic seizures, and three patients (25%) reported response with eyelid myoclonia and absence seizures. One patient had the VNS explanted due to lack of efficacy and one had it turned off for enrollment in a clinical trial. The median maximum tolerated output current settings for our cohort were 1.75 mA (IQR 1.38-1.94; range 0.75-2.25) with an OFF time of 1.8 min (IQR 1.1-3, range 0.2-3) and median duty cycle of 24% (IQR 16-29; range 12-58). From this small case series of patients with EEM, four (33.3%) were responders to VNS, with improvement noted in multiple seizure types. This indicates the potential role of VNS for patients with EEM.
2026-07-05 | Cenobamate use in super-refractory status epilepticus: A report of three cases.
Super-refractory status epilepticus (SRSE) is a neurological emergency with high morbidity and mortality. Cenobamate, a novel antiseizure medication, may be helpful in managing SRSE, but evidence is limited. This retrospective case series reports the use of cenobamate as add-on therapy in the management of three cases of SRSE. Median age at status epilepticus (SE) onset was 28 years (range 27-75). The etiologies of SRSE included one case of febrile infection-related epilepsy syndrome (FIRES), one patient with a probable genetic etiology (SCN7A variant of uncertain significance), and one case of unknown etiology. Cenobamate was introduced at a median of 27 days (range 13-103) after SE onset. Resolution of SRSE was observed after a median of 7 days (range 3-30) once cenobamate was started. Median dose of cenobamate at SRSE cessation was 25 mg/day (range 12.5-50 mg/day), and the median maintenance dose at the time of discharge was 200 mg/day (range 100-400 mg/day). Two patients died and one patient achieved functional independence. No severe medication side effects, specifically drug reaction with eosinophilia and systemic symptoms (DRESS), were observed. Cenobamate may have a role in the management of SRSE. Further studies are needed to define the optimal timing of initiation, titration strategy, and target dose of cenobamate in the context of SE.
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Drug Discovery Landscape
7 orphan drug designations for Epilepsy syndrome, including 2 approved therapies.
7 orphan drug designations for Epilepsy syndrome, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
diazepam | small molecules | FDA | 2016-11-10 | — | Aquestive Therapeutics |
topiramate injection | small molecules | FDA | 2013-07-24 | — | CURx Pharmaceuticals, Inc. |
intravenous carbamazepine [CARNEXIV] | small molecules | FDA | 2013-06-27 | 2016-10-07 | Lundbeck LLC |
diazepam auto-injector | small molecules | FDA | 2013-05-30 | — | Meridian Medical Technologies, Inc. |
midazolam | small molecules | FDA | 2006-05-08 | — | UCB, Inc |
Stiripentol [Diacomit] | small molecules | EMA | 2001-12-05 | — | Biocodex |
Diazepam viscous solution for rectal administration [Diastat] | small molecules | FDA | 1992-02-25 | 1997-07-29 | Valeant Pharmaceuticals |
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