OBJECTIVE: Epilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants. METHODS: In this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open-label trial (OLT). Subjects were followed until 2 years of age. The primary endpoint was the time to first clinical seizure. RESULTS: In 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty-seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364 days (95% confidence interval [CI] = 223-535) vs 124 days (95% CI = 33-149); OLT: 426 days (95% CI = 258-628) vs 106 days (95% CI = 11-149)]. At 24 months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug-resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p < 0.001). No adverse events related to preventive treatment were noted. INTERPRETATION: Preventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2021;89:304-314.

Amsterdam UMC University of Amsterdam Department of Pathology Amsterdam Neuroscience Amsterdam The Netherlands

Brigham and Women's Hospital Harvard Medical School Boston MA USA

Child Neurology and Psychiatry Unit Systems Medicine Department Tor Vergata University Rome Italy

Child Neurology Unit Neuroscience and Neurorehabilitation Department Bambino Gesù Children's Hospital IRCCS Rome Italy

Department of Child Neurology Brain Center University Medical Center Utrecht Utrecht The Netherlands

Department of Child Neurology Charité University Medicine Berlin Berlin Germany

Department of Child Neurology Medical University of Warsaw Warsaw Poland

Department of Development and Regeneration Section Pediatric Neurology University Hospitals KU Leuven Leuven Belgium

Department of Neurology and Epileptology The Children's Memorial Health Institute Warsaw Poland

Department of Pediatric Neurology Reference Centre for Rare Epilepsies Necker Enfants Malades Hospital University Paris Descartes Imagine Institute Paris France

Department of Pediatrics University Hospital Vienna Vienna Austria

Motol University Hospital Charles University Prague 5 Czech Republic

Neurogenetics Research Group Vrije Universiteit Brussel Brussels Belgium

Neurosciences Unit Queensland Children's Hospital South Brisbane QLD Australia

Pediatric Neurology Unit UZ Brussel Brussels Belgium

School of Medicine University of Queensland St Lucia QLD Australia

Transition Technologies Warsaw Poland

Warsaw University of Technology Institute of Heat Engineering Warsaw Poland

Warsaw University of Technology The Faculty of Electronics and Information Technology Warsaw Poland

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