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Seizure-Related Biomarkers of Sudden Unexpected Death in Epilepsy (SUDEP) in Drug-Resistant Focal Epilepsy (REPO2MSE): A Prospective, Multicentre Case-Control Study Ryvlin P, Huot M, Valton L, Maillard L, Bartolomei F, Derambure P, Hirsch E, Michel V, Chassoux F, Petit J, Crespel A, Biraben A, Navarro V, Kahane P, De Toffol B, Thomas P, Rosenberg S, Bernini A, Charlois AL, Craciun L, Chorfa F, Ducouret P, Ferreira A, Leclercq M, Marty M, Mercedes Alvarez B, Sampaio M, Spahr A, Timestit-Kurland N, Touya M, Roy P, Rheims S; REPO2MSE study group. Lancet Neurol. 2026;25(1):50-60. doi: 10.1016/S1474-4422(25)00379-5. Epub 2025 Nov 21. PMID: 41285145. Background: Novel biomarkers of the risk of sudden unexpected death in epilepsy (SUDEP) are needed to better inform people with epilepsy of their individual risk and identify those at a high risk. The aim of this study was to identify such biomarkers, particularly with the exploration of seizures characteristics that have not been previously investigated, including peri-ictal peripheral oxygen saturation (SpO 2 ) and site of seizure onset. Methods: We conducted a nested case–control study of SUDEP within a dedicated nationwide prospective cohort. Eligible participants were adults with drug-resistant focal epilepsy undergoing in-hospital seizure monitoring at 16 epilepsy monitoring units in France. Clinical data, results from presurgical investigations, and raw recordings from video electroencephalogram, electrocardiogram, and SpO 2 were collected until the end of the recruitment period. The French National Directory of Natural Persons Identification was queried annually to identify deaths. The SUDEP cases were adjudicated on the basis of medical records and interviews documenting the circumstances of death. Each SUDEP case was matched to 4 controls on the basis of study center and date of inclusion. The SUDEP risk factors were identified using LASSO-penalized conditional logistic regression. Findings: From May 18, 2010, to August 23, 2015, we enrolled a total of 1074 participants and followed their vital status until the end of 2018, yielding a total of 6828 patient-years of follow-up. A total of 42 participants died during follow-up, including 18 cases of definite or probable SUDEP, resulting in a SUDEP rate of 2.64/1000 patient-years (95% CI 1.36-3.92). Four risk factors were significantly associated with the risk of SUDEP: an extratemporal epileptogenic zone (OR 37.8, 95% CI 3.21-446.2, P = .0039), a BMI of 30 or higher (26.0, 2.0-339.6, P = .013), male sex (12.6, 1.5-106.8, P = .0201), and predominantly nocturnal seizures (6.0, 1.2-28.7, P = .026). In contrast, the presence of peri-ictal SpO 2 of less than 80% during focal seizures, the frequency of focal-to-bilateral tonic-clonic seizures, heart rate variability, age at epilepsy onset, number of antiseizure medications, and history of depression were not significantly associated with SUDEP. Interpretation: Extratemporal epilepsies involving the perisylvian region or frontal lobe appear to be associated with an increased risk of SUDEP. This finding warrants confirmation in larger cohorts and underscores the need to improve the diagnosis and surgical management of extratemporal epilepsies, which might contribute to improved SUDEP risk stratification and prevention.