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(Abst. 2.121), 2019

Prevention of Epilepsy in Infants with Tuberous Sclerosis Complex: Results from a Prospective, Multicenter, Double Arm EPISTOP Study
Authors: Katarzyna Kotulska-Jóźwiak, The Children's Memorial Health Institute; Paolo Curatolo, Tor Vergata University, Rome; Bernhard Weschke, Charite University Miedicine; Kate Riney, Queensland Children’s Hospital, South Br; Floor Jansen, Brain Center UMC Utrecht,; Martha Feucht, Medical University Vienna.; Pavel Krsek, Motol University Hospital, Charles Unive; Rima Nabbout, Reference Centre for Rare Epilepsies and; Anna Jansen, U Brussels; Konrad Wojdan, Transition Technologies; Kamil Sijko, Transition Technologies; Jagoda Głowacka, The Children's Memorial Health Institute; Julita Borkowska, The Children's Memorial Health Institute; Krzysztof Sadowski, The Children's Memorial Health Institute; The Children's Memorial Health Institute Romina Moavero, Tor Vergata University; Christoph Hertzberg, Charité University Medicine; Brain Center UMC Utrecht Sharon Samueli, Medical University Vienna; David Kwiatkowski, Brigham and Women Hospital, Harvard Medi; Eleonora Aronica, Amsterdam UMC, University of Amsterdam; Brigham and Women Hospital, Harvard Medi Lieven Lagae, KUL Leuven; Sergiusz Jozwiak, The Children's Memroial Health Institute
Content: Rationale: Tuberous Sclerosis Complex (TSC) is a genetically determined neurocutaneous disorder affecting 1 child in 6,000. Epilepsy develops in 80-90% of patients with TSC and is frequently resistant to medical treatment. Seizures usually manifest in infancy and half patients develop intellectual disability and autism spectrum disorder. In TSC, the cascade of epileptiform changes on EEG followed by focal seizures evolving into infantile spasms has been reported. Due to multisystemic presentation, TSC can be diagnosed early, even prenatally, enabling tracking of epileptogenesis before the presentation of clinical seizures.Preliminary open label study showed that antiepileptic treatment introduced before clinical seizures might prevent epilepsy in TSC.  Methods: In this multicenter study, infants with TSC were followed with serial vEEG before the onset of seizures. Standard antiepileptic treatment started after the first subclinical or clinical seizure was compared to preventive antiepileptic treatment, started at the onset of pre-seizure epileptiform activity on EEG. In the randomized arm, children were randomly allocated to treatment in a 1:1 ratio and the treating physicians were blinded to treatment. In the observational arm, the open-label treatment allocation was fixed at site level. Participants were followed up until the age of 2 years. The primary end point was the time to the first clinical seizure. Secondary endpoints included the risk of drug resistant epilepsy and infantile spasms, and neuropsychological outcome at the age of 2 years.  Results: Of a total of 97 children, 54 were included in the randomized arm and 47 in the observational arm. The time to the first clinical seizure was longer with preventive than conservative treatment (randomized arm: 297 vs. 124 days, P=0.013; observational arm: 397 vs. 73 days, P=0.014). At 24 months, a pooled analysis showed that preventive treatment reduced the risks of clinical seizures (odds ratio, 0.33, P=0.036), drug resistant epilepsy (odds ratio, 0.26, P=0.013), and infantile spasms (odds ratio, 0, p = 0.003). The risks of autism and intellectual disability was 31.8% and 37.9%, respectively and was not significantly different between treatment groups. These risks were lower than reported in TSC before, suggesting the beneficial effect of early monitoring and treatment in EPISTOP protocol.  Conclusions: Presymptomatic electroencephalographic monitoring and preventive treatment modified the natural course of the disease and reduced the risk of seizures and severity of epilepsy in infants with TSC.  Funding: The work was financed by the EC Seventh Framework Programme (FP7/2007-2013; EPISTOP, grant agreement no. 602391), the Polish Ministerial funds for science (years 2013-2019) for the implementation of international co-financed project.  
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