Project title: Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy – Tuberous sclerOsis comPlex

Acronym: EPISTOP

Project summary

• About epilepsy

Epilepsy affects 1% of the world’s population. In Europe, 6 million people have epilepsy (World Health Organization, 2010). 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).

• About Tuberous Sclerosis Complex

Tuberous Sclerosis Complex (TSC) is a genetically determined neurocutaneous syndrome affecting 1 child in 6,000 (Curatolo, 2008). Molecular genetic studies have shown that there are two genes that cause TSC, TSC1 and TSC2, both of which are subject to heterozygous inactivating mutations in TSC. 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). Epilepsy in TSC is often focal initially, but in many cases infantile spasms follow or coexist with focal seizures. Thirty-eight percent of TSC patients experience infantile spasms, and TSC accounts for 10% of all infantile spasms cases (Osborne, 2010). 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.

• About prevention of epileptogenesis

It is now widely accepted that clinical seizures are preceded by a latent period of epileptogenesis (Pitkanen, 2011, Rakhade, 2009). This cascade of cellular and molecular events may be triggered by diverse brain insults, including trauma, infection or genetic predisposition, and leads to the formation of hyperexcitable neural networks ultimately resulting in spontaneous epileptiform activity. This process continues with onset of clinical seizures, leading to the development of established, drug-resistant epilepsy, and secondary comorbidities. In humans, epileptogenesis studies are difficult because the patients usually present after seizures and little is known about the earlier stages of the disease. The molecular changes occurring during epileptogenesis in animal models are still not fully understood, but are known to include changes in gene expression, activation of several immune and inflammatory processes, and others. It has been shown in multiple animal models of epilepsy that interventions applied prior to the onset of clinical epilepsy can prevent or delay the development of seizures. Even if seizures occur, they may be seen at reduced frequency, may be of shorter duration, or of milder severity (Galanopoulou, 2012, Zeng, 2008). Attempts at preventative treatment for epilepsy in humans have been inconsistent, mainly due to the extreme heterogeneity of epilepsy mechanisms in different patients and the difficulty of identifying patients at risk. However, two recent studies of children with epileptiform activity recorded on electroencephalography (EEG) indicate that patients treated with standard antiepileptic drugs before the onset of clinical seizures may benefit from this approach (Jozwiak, 2011, van Rooij, 2010). Our study showed that treatment before onset of clinical seizures appeared to not only reduce the risk of clinical seizures, but also to modify the later phases of epileptogenesis, reducing the risk of both drug-resistance and neurodevelopmental delay associated with epilepsy (Jozwiak, 2011). Increasing numbers of TSC patients are diagnosed prenatally or soon after birth, through increasing awareness of this syndrome, and early detection of cardiac rhabdomyomas which are often detected on routine prenatal echocardiography. These tumours are present in over 80% of foetuses with TSC. When cardiac rhabdomyomas are detected, prenatal or neonatal brain MRI can be performed to confirm the diagnosis of TSC. This early diagnosis enables serial clinical observation BEFORE the onset of epilepsy, which usually starts at the age of 4-6 months. A prospective study of TSC infants before clinical seizures has been published by the Coordinating Investigator, Professor Sergiusz Jóźwiak, proving the feasibility of this approach. This study showed that 71% of all TSC infants develop epilepsy in the first 24 months of life.

Epileptogenesis progress. Brain insult (e.g., injury, genetic predisposition, experimental status epilepticus)  induces a cascade of  cellular and molecular  events  leading to the clinical manifestation of seizures. This process can be tracked on EEG. Epileptogenesis  extends beyond the first seizure and contributes to  the development of neuropsychiatric  comorbidities of epilepsy.