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  • Periodic Report Summary 3 - EPISTOP (Long-term, prospective study evaluating clinical and molecular biomarkers of epileptogenesis in a genetic model of epilepsy – tuberous sclerosis complex)

Periodic Report Summary 3 - EPISTOP (Long-term, prospective study evaluating clinical and molecular biomarkers of epileptogenesis in a genetic model of epilepsy – tuberous sclerosis complex)

Project Context and Objectives:
Epilepsy affects 1% of the world’s population. In Europe, 6 million people have epilepsy (World
Health Organization, 2010). Despite great progress in the management of epilepsy and increasing
numbers of antiepileptic drugs, 30-40% of epilepsy patients are refractory to all available
medications and many suffer from epilepsy-related comorbidities (Jensen, 2011). Given these data
and the leading position of European epileptology centres, the Consensus Document of European
Brain Research in 2011 recommended research focused on preventing epilepsy development to be
supported by European funding (Di Luca, 2011).
In more than 65% of patients, epilepsy begins in childhood and the incidence of epilepsy is highest in
the first year of life (Hauser, 1993). In children, the problem of epilepsy is far beyond seizures, as
about 50% of children with epilepsy suffer from psychiatric and behavioural comorbidities, including
developmental delay, learning disabilities, and autism spectrum disorder (Ono, 2012). Furthermore,
early onset of seizures is regarded as one of the major risk factors for development of drug-resistant
Epilepsy differs from many other neurological conditions due to its extreme heterogeneity in
aetiologies and phenotypes. Thus, studies of epilepsy risk factors might be uniquely enabled by
analyses in young children where the influence of the external, environmental factors is lower than in
Tuberous Sclerosis Complex (TSC) is a genetically determined neurocutaneous syndrome affecting 1
child in 6,000 (Curatolo, 2008). TSC is often considered an excellent clinical model of severe focal
epilepsy, as 70 to 90% of patients are affected by epilepsy and in most cases the seizures are
drug-resistant. In the majority of patients epilepsy manifests in the first months of life and half of
patients develop cognitive impairment, autism spectrum disorder or other neurodevelopmental
disturbances (Jozwiak, 1998). Therefore TSC is an excellent model for both focal epilepsy and
infantile spasms. Although there is definite clinical heterogeneity, TSC represents a relatively
homogenous group of patients for the studies of epileptogenesis, who are at high risk of this disease.
Recent studies (Jozwiak, 2011) demonstrated that in infants with paroxysmal discharges on EEG it is
possible to modify the outcome of the disease by antiepileptic treatment before the onset of clinical
seizures. EPISTOP model gives us a unique opportunity to investigate whether clinically successful
epilepsy prevention is possible, and to explore the molecular mechanisms of this effect.
The aim of EPISTOP is to better understand the pathophysiology of epilepsy and its consequences, to
develop a preventative strategy for epilepsy, to identify new biomarkers of epilepsy, and to develop
new therapeutic targets to block or otherwise modify epileptogenesis in humans.
To achieve this aim, the risk factors and biomarkers of epilepsy are being identified by a
multidisciplinary, systematic approach in three settings:
- a prospective study of epilepsy development in infants with TSC, using a wide range of clinical,
neuroimaging, and genetic analyses
- prospective clinical study of TSC infants treated with antiepileptic drugs at the onset of subclinical
seizures in comparison to children treated only after clinical seizures appear
- analysis of biomarkers of epileptogenesis and drug-resistant epilepsy in epileptogenic brain
specimens obtained from patients with TSC
To achieve this goal 16 partners created EPISTOP Consortium – 10 clinical sites, 5 laboratories
performing state of the art analysis and 1 financial consultant. During 54 months of project implementation all goals for this period have been achieved and cooperation between partners is successful in terms of project objectives

Project Results:
EPISTOP project consists of 8 work packages (WP). Each WP is devoted for specified tasks which are related to overall study objectives. After 36 months of study duration the project reached the recruitment target of 100 patients. At the end of August 2016 the recruitment period has been closed with the result of 101 patients included. Final results will be known after study completion however preliminary analysis in particular WPs are promising. Consortium is also supported by Scientific Advisory Board members. The objective of WP2 is to determine electroencephalographic biomarkers of epileptogenesis, and to randomize patients into group A and B (WP6). In the analysis phase, the systematic database was used to analyze the actual EEGs in detail. Molecular analysis (WP3 and WP5) are not available yet however we have performed Whole Genome Sequencing of DNA and Deep (> 1000x read depth) next gen sequencing (NGS) of TSC1 and TSC2. We also performed a systematic evaluation on a large cohort of TSC brain lesions and cortical tubers and perituberal cortex for biomarkers of epileptogenesis and molecular targets for antiepileptogenesis therapy. The objective of WP4 is to deliver the neuroimaging biomarkers of epileptogenes. MRIs were visually analysed by the work package leader. Quantification methods for MRI characteristics are under development (volume measures of structural visible abnormalities, DTI measures, ASL measures). In this reporting period continuous collection of clinical data and biological specimen were performed as well as interim analysis of data collected. Interim analysis, in concordance with the protocol, was made on 70% patient completion of the study. The whole dataset was analyzed for a better understanding of the data and the patient cohort. There was a close examination of the study dynamics and patient medical history. WP7 conducted a preliminary analysis of neuropsychological examinations from EPISTOP patients.
Tasks within WP8 were focused on EPISTOP project promotion and dissemination. In this reporting period over 50 lectures have been given as well as 29 publications and posters have been presented acknowledging or promoting EPISTOP.
From an administrative and financial point of view, the main action that has to be reported was an extension of the duration of the project for 6 months.

Potential Impact:
EPISTOP is aimed to better understand the complex pathophysiology of epilepsy in order to develop
novel preventative strategies in at risk patients, improve diagnostic methods and develop more
effective therapeutic strategies. We expect that the project will generate significant and valuable new
knowledge of potential use in clinical practice in the care of epilepsy patients:
- insight into the development of EEG changes before the onset of clinical seizures
- insight into epileptogenesis and molecular biomarkers of epilepsy
- possible new targets for novel antiepileptic and antiepileptogenic drugs
- potential prevention of epilepsy by introducing antiepileptic drugs in patients at risk
- molecular mechanisms of epileptogenesis that might be modified by epilepsy prevention
- clinical risk factors for epilepsy and its neuropsychiatric consequences
- mechanisms of drug-resistant epilepsy, to identify new therapeutic strategies
The primary clinical endpoint of this study will be the decrease in epilepsy severity and the clinically
active epilepsy incidence in the preventatively treated group in comparison to the group treated after
the onset of clinical seizures. EPISTOP will be the first prospective study of epileptogenesis in
humans, starting before seizures and expanding beyond the point when drug-resistant epilepsy and
epilepsy comorbidities can be assessed. If favorable EPISTOP will change the approach to treatment
of early childhood epilepsy in TSC, breaking new ground in preventative approaches for epilepsy.
The secondary endpoints will be the changes in biomarkers between two groups.
EPISTOP will be the first study to provide detailed molecular insight into the progress of epileptogenesis in humans. We will compare the molecular biomarkers of epileptogenesis at four
time points: before seizures and any abnormalities on EEG (at baseline); after the appearance of EEG
abnormalities, but before the onset of clinical seizures; at the onset of clinical seizures; and the age of
24 months, when a significant percentage of TSC patients already have drug-resistant epilepsy.
Ideally these studies will help define the time point when preventative treatment should be
The major advantage of EPISTOP is the comprehensive panel of molecular investigations in
epileptogenesis. Two work packages are designed to look for molecular signals of epileptogenesis in
the blood (WP3), and to examine brain samples to better understand epilepsy development in TSC
(WP5). Studies of biomarkers in drug-resistant patients’ blood and brain specimens may help
recognize targets for drugs decreasing drug resistance risk.
Altogether EPISTOP will provide insights into novel diagnostic laboratory tests to predict epilepsy
onset, and clinical recommendations to identify patients at high risk of epilepsy development before
epilepsy is clinically active.
We expect to identify clinically applicable risk factors for early identification of drug-resistant
patients, as well as to discover the potential targets for novel therapies reducing the risk of drug
EPISTOP aims to identify the risk factors of autism and mental retardation in epilepsy patients. WP 7
is devoted to the research on the correlation between the neurodevelopmental outcome and clinical,
neuroimaging, and molecular biomarkers. Given that the biomarkers will be collected prospectively,
we expect also to reveal the mechanisms of development of neuropsychiatric consequences of
epilepsy and to identify the possible targets for therapeutic strategies and novel drugs. An important
advantage of EPISTOP is the opportunity to study the impact of preventative treatment on the
neurodevelopmental outcome in TSC patients. This approach should help us delineate a potentially
reversible mechanism of mental retardation associated with epilepsy in children.

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