Is epileptogenesis a key to treatment of childhood epileptic encephalopathies?

Abstract

D espite the recent discovery of many newer and safer antiepileptic drugs (AEDs) the number of patients with drug resistant epilepsy remains at about 30%. Epilepsy is particularly devastating in the first years of life often causing mental retardation and autistic behavior, usually leading to epileptic encephalopathies. A better understanding of epilepsy development (epileptogenesis) in this group of patients may lead to successful prevention of drug-resistant epilepsy and its comorbidities (Barker-Haliski et al., 2015; Chapman et al., E-pub ahead of print). Scientific basis for possible intervention has been established in recent animal genetic models of epilepsy. In their study, Yan et al. (2005) used an epileptic double mutant rat (SER; zi/zi, tm/tm) which after age 7–8 weeks spontaneously exhibits tonic and absencelike seizures in response to mild sensory stimulation. Three weeks before the expected time of seizure onset, from postnatal weeks 5 to 8, rats received levetiracetam at 80 mg/kg/day (i.p). The seizure assessment has been carried out in weeks 12 and 13 (5 weeks after termination of the administration), by clinical evaluation and conventional EEG recordings. The incidence of both tonic and absence-like seizures was significantly lower in levetiracetam treated group comparing with the control animals. This effect was suggested to be due to an antiepileptogenic rather than an antiseizure effect, as the half-life time of levetiracetam in plasma is short (2–3h in rats) after single and long term administration (Yan et al, 2005). Another group of researchers performed the experiment in a genetic model of human absence epilepsy. Wistar Albino Glaxo/Rij rats, that exhibit spontaneous spike-wake complexes on electroencephalography and seizures at 3 moths of life, were administered oral ethosuximide from day 21 to 5 months of age. On follow-up at 8 months, after several months of discontinuation of the treatment, the significant suppression of discharges and lower number of seizures was still documented (Blumenfeld et al., 2008). Both Yan et al. (2005) and Blumenfeld et al. (2008) studies demonstrated that epilepsy prevention may be possible and that such a strategy could be considered in susceptible human cohorts. Indeed similar studies in humans carried out in selected groups of patients in the first year of life with a high risk of epilepsy, seem to corroborate the results obtained in animals. Ville et al. (2002) identified a group of 16 infants with Sturge-Weber syndrome, the condition characterized by early onset of seizures and poor mental outcome. Preventative treatment of this group with phenobarbitone, the drug frequently used for neonatal seizures, resulted in decreased epilepsy (p < 0.01) and mental retardation (p < 0.05) incidence in comparison to 21 children treated in the standard manner (i.e. after the onset of clinical seizures). The results are concordant with our results obtained in tuberous sclerosis complex (TSC) (Jozwiak et al., 2011). In a prospective study of 14 young infants who underwent regular EEG assessments every 4–6 weeks until 24 month of age, ten patients received a treatment with vigabatrin due to paroxysmal multifocal activity on EEG. The treatment was discontinued at 24 month, if no clinical seizures appeared. Six out of 10 children developed epilepsy despite of the medication. However, we demonstrated a lower incidence of drug-resistant