Long-term, prospective study evaluating clinical and molecular biomarkers of epileptogenesis in a genetic model of epilepsy - Tuberous Sclerosis Complex.

Despite a great progress in the management of epilepsy, still one third of
patients are refractory to available medications. The incidence of epilepsy is
highest in infancy and 50% of children experience epilepsy-related
comorbidities, such as developmental delay and autism. This is particularly
true for patients with tuberous sclerosis complex (TSC). The development of
epilepsy (epileptogenesis), extensively studied in animals, is barely studied
in humans, as patients usually present AFTER the seizure onset.

The primary objective of the clinical part of EPISTOP project is to identify
the clinical and molecular biomarkers of epileptogenesis in a prospective
clinical study of patients with TSC.
Secondary objective of the clinical part of EPISTOP is to compare the effects
of standard antiepileptic treatment in patients diagnosed as having epilepsy
after clinical seizures vs after electroencephalographical epileptiform
discharges, in a randomized trial in TSC patients.

This is a prospective study of epileptogenesis in TSC infants. Biomarker
analysis will be performed by a multidisciplinary, systematic approach in three
clinical settings:
a) Prospective study of epilepsy development in infants with TSC, including
analysis of clinical, neuroimaging, and molecular, blood-derived biomarkers at
predefined time points: before the onset of seizures, at the onset of
epileptiform discharges on EEG, at seizure onset and at the age of 24 months;
b) Prospective study of blood-based biomarkers in infants with TSC treated with
antiepileptic drugs prior to clinical seizure onset in comparison to children
treated only after clinical seizures appear.
c) Analysis of biomarkers of epileptogenesis and drug-resistant epilepsy in
brain specimens obtained from TSC patients who have had epilepsy surgery and
TSC autopsy cases.

A randomized controlled trial (RCT) will be undertaken to establish the most
optimal moment of starting anti-epileptic drug treatment: after
electroencephalographical epileptiform discharges or after clinical seizures.
Patients may be enrolled in the first part of the study only, or both the
follow up study and the RCT if applicable.
At baseline, all patients will undergo neuroimaging examination by means of
MRI, a battery of neuropsychological tests, blood biomarker sampling and the
review of medical history of the patient and the family. Blood samples for
biomarker studies will be collected in all patients participating in the
project (including children that only participate in the follow up study) at
study entry, at the onset of epileptiform discharges on vEEG or at the age of 6
months, whichever is applicable, at the onset of clinical seizures, and at the
end of follow-up (age 2 years).
At the age of 24 months, all TSC infants participating in the study will
undergo neuroimaging examination by means of MRI, a battery of
neuropsychological tests, and epilepsy analysis.
Epileptogenesis in TSC infants will be tracked by means of serial vEEG
recordings. In children with diagnosed epilepsy, standard therapy with
recommended first line antiepileptic drug will be given.
Infants that have epileptiform discharges on vEEG and no clinical seizures
will, if their parents/caregivers give consent, be randomized into two groups:
group A will be diagnosed as having epilepsy after epileptiform discharges, and
the patients in group B will be diagnosed with epilepsy only after clinical
seizures appear.

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Follow up of both medical history and ancillary investigations are part of
routine daily clinical practice, therefore no risks are anticipated. The burden
includes few more blood withdrawals that will be combined with necessary
bloodsamples as much as possible.
With respect to the RCT, children in group A will be prescribed the recommended
first line antiepileptic drug. Side effects will be monitored closely, though
anti-epileptic drugs are usually well tolerated in infants.
Identification of biomarkers enables assessment of prognosis, improving
monitoring children at risk of worse developmental outcome and ultimately
developing new treatment strategies to improve seizure control and development
in this high-risk group of patients.
Observational data has given support that preventative treatment is related to
improved outcome. This study aims to find ultimate evidence for preventative
treatment.