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Introduction Epilepsy surgery is the only curative treatment for patients with drug-resistant focal epilepsy. Stereoelectroencephalography (SEEG) is the gold standard to delineate the seizure-onset zone (SOZ). However, up to 40% of patients are subsequently not operated as no focal non-eloquent SOZ can be identified. The 5-SENSE Score is a 5-point score to predict whether a focal SOZ is likely to be identified by SEEG. This study aims to validate the 5-SENSE Score, improve score performance by incorporating auxiliary diagnostic methods and evaluate its concordance with expert decisions.Methods and analysis Non-interventional, observational, multicentre, prospective study including 200 patients with drug-resistant epilepsy aged ≥15 years undergoing SEEG for identification of a focal SOZ and 200 controls at 22 epilepsy surgery centres worldwide. The primary objective is to assess the diagnostic accuracy and generalisability of the 5-SENSE in predicting focality in SEEG in a prospective cohort. Secondary objectives are to optimise score performance by incorporating auxiliary diagnostic methods and to analyse concordance of the 5-SENSE Score with the expert decisions made in the multidisciplinary team discussion.Ethics and dissemination Prospective multicentre validation of the 5-SENSE score may lead to its implementation into clinical practice to assist clinicians in the difficult decision of whether to proceed with implantation. This study will be conducted in accordance with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (2014). We plan to publish the study results in a peer-reviewed full-length original article and present its findings at scientific conferences.Trial registration number NCT06138808.

ObjectivesNew-onset refractory status epilepticus (NORSE) is associated with high morbidity and mortality. Despite extensive work-up, the underlying etiology remains unknown in 50% of affected individuals. Mitochondrial disorders represent rare causes of NORSE. Biallelic variants in FASTKD2 were reported as a cause of infantile encephalomyopathy with refractory epilepsy.Case descriptionIn the study, we report a previously healthy 14-year-old with a new, homozygous FASTKD2 variant presenting with NORSE. Following a seizure-free period of 7 years, he experienced another super-refractory SE and subsequently developed drug-resistant focal epilepsy, mild myopathy, optic atrophy, and discrete psychomotor slowing. Structural MRI at the time of NORSE showed right temporo-parieto-occipital FLAIR hyperintensity and diffusion restriction, with extensive right hemispheric atrophy at the age of 22 years. Whole-exome sequencing revealed a novel homozygous loss of function variant [c.(1072C>T);(1072C>T)] [p.(Arg358Ter);(Arg358Ter)] in FASTKD2 (NM_001136193), resulting in a premature termination codon in the protein-coding region and loss of function of FASTKD2. Oxidative phosphorylation (OXPHOS) in muscle and skin fibroblasts was unremarkable.ConclusionThis is the first case of a normally developed adolescent with a new homozygous loss of function variant in FASTKD2, manifesting with NORSE. The phenotypical spectrum of FASTKD2-related mitochondrial disease is heterogeneous, ranging from recurrent status epilepticus and refractory focal epilepsy in an adolescent with normal cognitive development to severe forms of infantile mitochondrial encephalopathy. Although mitochondrial diseases are rare causes of NORSE, clinical features such as young age at onset and multi-system involvement should trigger genetic testing. Early diagnosis is essential for counseling and treatment considerations.

Introduction: Epilepsy surgery is the only curative treatment for patients with drug-resistant focal epilepsy. Stereoelectroencephalography (SEEG) is the gold standard to delineate the seizure-onset zone (SOZ). However, up to 40% of patients are subsequently not operated as no focal non-eloquent SOZ can be identified. The 5-SENSE Score is a 5-point score to predict whether a focal SOZ is likely to be identified by SEEG. This study aims to validate the 5-SENSE Score, improve score performance by incorporating auxiliary diagnostic methods and evaluate its concordance with expert decisions., Methods and Analysis: Non-interventional, observational, multicentre, prospective study including 200 patients with drug-resistant epilepsy aged ≥15 years undergoing SEEG for identification of a focal SOZ and 200 controls at 22 epilepsy surgery centres worldwide. The primary objective is to assess the diagnostic accuracy and generalisability of the 5-SENSE in predicting focality in SEEG in a prospective cohort. Secondary objectives are to optimise score performance by incorporating auxiliary diagnostic methods and to analyse concordance of the 5-SENSE Score with the expert decisions made in the multidisciplinary team discussion., Ethics and Dissemination: Prospective multicentre validation of the 5-SENSE score may lead to its implementation into clinical practice to assist clinicians in the difficult decision of whether to proceed with implantation. This study will be conducted in accordance with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (2014). We plan to publish the study results in a peer-reviewed full-length original article and present its findings at scientific conferences., Trial Registration Number: NCT06138808., Competing Interests: AA-R has no conflict of interest related to this work. Outside of the submitted work, she acted as a paid consultant for Epilog and received travel support and speaker's honoraria from Eisai. PP has received speaker honoraria or consultancy fees to his institution from Chiesi, Eisai, LivaNova, Novartis, Sun Pharma, Supernus and UCB Pharma, outside the submitted work. He is an Associate Editor for Epilepsia Open. Furthermore, he is supported by an Emerging Leadership Investigator Grant from the Australian National Health and Medical Research Council (APP2017651), The University of Melbourne, Monash University, the Austin Medical Research Foundation and the Norman Beischer Medical Research Foundation. VV has participated in advisory boards and symposium organised by Angellini, Bial, Biocodex, Eisai, Jazz Pharmaceuticals, Novartis, Paladin, Takeda, UCB, Xenon. AU has served as a consultant for Neuropace. JC serves on the scientific advisory board at NeuroOne Medical Technologies. SS received speaker honoraria and consultancy fees from Greenwich, Neurelis, SK Life Science, Bioserenity, Monteris and UCB outside the submitted work. ASM has received speaker honoraria and consultancy fees from Paladin and Jazz Pharmaceuticals, outside the submitted work. GZ gratefully acknowledges the support of the WISS 2025 project ‘IDA-Lab Salzburg’ (20204-WISS/225/197-2019 and 20102-F1901166-KZP). ET reports personal fees from EVER Pharma, Marinus, Argenix his institution has received grants from Biogen, UCB Pharma, Eisai, Red Bull, Merck, Bayer, the European Union, FWF Österreichischer Fond zur Wissenschaftsforderung, Bundesministerium für Wissenschaft und Forschung and Jubilaumsfond der Österreichischen Nationalbank outside the submitted work. BF has no conflict of interest in relation to this work. Outside of this work, she received honoraria for speaking engagements/advisory board meetings from UCB, UNEEG, Paladin labs, Eisai and Natus. Furthermore, she received a project grant from the Canadian Institutes of Health Research (PJT-175056) as well as Start-up Funding from Duke University. All other coauthors report no conflict of interest related to this work., (Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)