Abstract
OBJECTIVE: Drug-resistant epilepsy (DRE) is defined as the failure of two antiseizure medications (ASMs) to achieve complete seizure control, affecting approximately 30% of epilepsy patients. In some cases, additional ASMs and surgical approaches are also unsuccessful. Ultra-Refractory Epilepsy (URE) is a newly described entity, characterized by the failure of six distinct epilepsy treatment strategies, including ASMs, surgical resection, and neurostimulation techniques. This study aimed to analyze demographic and clinical data of URE patients managed at the Brno Epilepsy Center, a member of the European Reference Network (ERN)-EpiCARE. METHODS: We conducted a retrospective cohort study with a prospective follow-up component. Adult patients hospitalized for epilepsy at the Brno Epilepsy Center between 2017 and 2023 were retrospectively identified, and their outcomes were prospectively assessed in February 2025 through medical record review and structured telephone interviews. URE patients were identified, and their demographic and clinical data were analyzed. RESULTS: In this study, 1034 patients' charts were reviewed, and 62 patients (6%) met the criteria for URE. In the URE cohort, the median age of epilepsy onset was 9 years (range 1-60 years), and the median age at the time of evaluation was 35 years (range 21-67 years). The median seizure frequency was nine seizures per month (range 1-900), with 26 (42%) of patients experiencing extremely high seizure frequencies (>20 seizures/month). Structural etiology was the most common cause (29 [47%] patients). Among the cohort, 57 (92%) patients received a combination of ASMs, surgical resection, or neurostimulation, while only 5 (8%) patients were managed exclusively with ASMs. SIGNIFICANCE: URE represents an extreme therapeutic challenge within epilepsy centers. The high seizure burden and limited treatment response in this population highlight the urgent need for novel therapeutic strategies and further research into this newly defined entity. PLAIN LANGUAGE SUMMARY: Ultra-refractory epilepsy (URE) is a newly described form of extremely difficult-to-treat epilepsy. In our study of 62 patients, all had already failed at least six different treatment attempts, including medications, brain surgery, or nerve stimulation. Most patients continued to have frequent seizures despite all available therapies, and only a small minority achieved long-term seizure freedom. These findings show that URE is a severe condition with a major unmet medical need, highlighting the importance of developing new treatment strategies.