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EPISTOP Report Summary

Project ID: 602391
Funded under: FP7-HEALTH
Country: Poland

Periodic Report Summary 2 - 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.
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 adults.
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 first 36 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. In this reporting period the specific objective was to update a project website and to arrange project meetings as well as everyday project management and partners’ support. All objectives were successfully implemented. Consortium is also supported by Scientific Advisory Board members. Within WP2 which is connected to EEG analysis. We have noticed that 45% of the children had an abnormal EEG already within the first 2-3 months of life. Moreover the proportion of normal EEGs dramatically decreases with age, with only maximum 20% normal EEGs above the age of 12 months. Most seizures occurred within the first 6 months of life. This shows that any possible preventive treatment has to start early on, and again that if EEG would be used to select the patients at risk for seizures, we need to perform very early and more frequent EEGs. Molecular analysis (WP3 and WP5) are not available yet however we have performed Whole Genome Sequencing of DNA of most of the patients and identified TSC mutations. Within WP4 which focuses on MRI analysis some work has been done in order to define criteria of the variety of MRI abnormalities. As a result of WP6 we have noticed that children treated before clinical seizures occurrence seem to develop clinical seizures later in comparison to standard care group (treated after the onset of seizures). These results have to be confirmed on the whole cohort. As a result of work performed within WP7 neuropsychological evaluations of EISTOP patients have been collected. Preliminary data from BSID are showing that normal cognitive and language developmental quotients decrease over time with a concomitant increase of mild delay. The rate of belonging to a specific risk class for autism spectrum disorder according to ADOS results has been studied at different ages. Preliminary results reveal a trend toward the increase of the rate of children with high risk of autism spectrum disorder over time. Tasks within WP8 were focused on EPISTOP project promotion and dissemination. In this reporting period over 30 lectures have been given as well as over 30 publications and posters have been presented acknowledging or promoting EPISTOP.
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 implemented.
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 resistance.
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.
List of Websites:


Iwona Nowak
Tel.: +48 22 815 11 24
Fax: +48 22 815 11 43


Life Sciences
Record Number: 199763 / Last updated on: 2017-06-21
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