Age-dependent factors in treatment of epileptic encephalopathies: a bridge between research and clinical approaches

Epilepsy is a common neurological disorder in childhood. Defined as a disease characterized by a persistent predisposition to generate epileptic seizures, along with the neurobiological, cognitive, psychological, and social consequences of this condition, epilepsy encompasses more than just the recurrence of seizures. Seizures are undoubtedly the hallmark and most obvious and frightening manifestation of epilepsy; however, concomitant neurodevelopmental symptoms and their psychological and social implications often contribute equally to the overall burden. The relationship between epilepsy and neurodevelopmental disorders is current topic of ongoing research. The relationship and the pathophysiological mechanisms that link epileptic activity with neurodevelopmental disorders are not completely understood and various related hypotheses exist. In epileptic encephalopathies brain function disruption, leading to the onset of psychomotor/cognitive dysfunction, is ascribed to the active phase of epilepsy which manifests itself with frequent seizures or even just with the presence of abundant epileptic activity detected on electroencephalograms. The advances in knowledge of the genetic aetiologies of epilepsies have highlighted how, particularly in early-onset severe epilepsies, the epileptic activity can represent a superimposed part of an underlying genetic condition which can independently cause the neurodevelopmental disorder. Defining the contribution of different aspects represents a real challenge in clinical practice moving in the direction of personalized medicine. This challenge does not concern exclusively the most severe forms of epilepsy. A neurodevelopmental involvement, emerging in the early school years and manifested by impaired executive and learning functions, frequently accompanies also the most common forms of child epilepsy in which seizures have an age-specific presentation and resolve spontaneously. In these "self-limiting" epilepsies, presumed genetic factors play an important etiological role. However, no specific genetic variants have been identified so far in this multidimensional condition in which maturational and age-related factors influence the clinical outcome. This doctoral thesis presents research experience resulting from two seemingly contrasting perspectives: that of rare epilepsies and that of common epilepsies, each highlighting the challenges and opportunities associated with the connection between research and clinical practice. The presentation of the results of the work conducted in recent years at our Institute (Burlo Garofolo, Trieste) in the field of rare genetic epilepsies highlights the importance of a strong and consistent integration between clinical and research approaches. Multidisciplinarity, which unites and enhances the clinical characterization of the phenotype and molecular research, in a multidimensional and longitudinal perspective is fundamental to improve the effectiveness of the diagnostic process, with significant implications for therapeutic interventions.