First Results of the EPISTOP Study

Objectives: Children with Tuberous Sclerosis Complex (TSC) have a 70–80% risk of developing epilepsy , often already in the first year of life, and a high risk for developmental delay (DD) and/or autism spectrum disorder (ASD). The aims of the EPISTOP study are (1) to identify clinical, metabolic and molecular genetic biomarkers of epileptogenesis in children with TSC in their first 2 years of life, and (2) to test the hypothesis that preventive treatment with vigabatrin (VGB) previous to seizure onset can decrease the risk to develop DD and ASD. Here, we present first results.

Material and Methods: Between 2014 and 2018, 101 children with clinically and/or genetically proven TSC up to 4 months of age who were so far seizure-free were recruited for EPISTOP (Epileptogenesis in a Genetic Model of Epilepsy – Tuberous sclerosis Complex), a study sponsored by the 7th framework program of the EU and perfomed by a consortium of 16 partners. Patients included were monitored closely clinically, by Video-EEG, cerebral MRI (at least at study entry and at 24 months age), and psychometric testing (BSID at 6, 12, 18 and 24 months; ADOS at 12,18 and 24 months). In case EEGs showed at least focal interictal epileptiform discharges (IED) in > 1% of the recording time they were either treated with VGB preventively or only after a first clinical seizure (standard treatment). In those centers where it had been approved by local authorities, the children were randomized to preventive and standard treatment, respectively. Blood samples were taken at study entry, at the time the children fulfilled a randomization criterium or at age 6 months, when the first seizure occured, and at age 24 months. If epilepsy surgery was performed, a brain biopsy was taken.

Results: (1) Close video-EEG-monitoring enabled us to identify children with TSC at risk for future epilepsy. (2) EEG dysmaturity was associated with an increased risk for ASD. (3) A high lesion load in the cMRI at the age < 4 months was correlated with higher prevalence and severity of epilepsy (drug refractoriness) and with cognitive developmental delay at age 24 months. (4) Preventive treatment with VGB starting at the occurence of IED in the EEG reduced the risk of epilepsy at 24 months, deferred the start of epilepsy in others, and reduced the risk of infantile spasms as well as drug refractoriness. (5) Later epilepsy onset was associated with better cognitive outcomes.

Discussion: Video-EEG monitoring proved to be a valuable biomarker for epileptogenesis in children with TSC. As to preventive treatment, our results confirm those of a previous observational study (Jozwiak 2011). Although developmental outcome in these patients depend on multiple factors like TSC mutation and lesion load, it can be significantly improved by preventing epilepsy.

Conclusion: Children with TSC should be diagnosed as early as possible, closely monitored by video-EEG, and treated preventively with VGB at the occurence of IED in the EEG.

No conflict of interest has been declared by the author(s).