Introduction
Epileptic encephalopathy embodies the notion that the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone (e.g., cortical malformation).6
Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by a mutation in one of the two genes, TSC1 or TSC2, leading to a overactivation of the mammalian target of rapamycin (mTOR).18 mTOR is a serine/threonine kinase playing a crucial role in cell growth and proliferation, and it exerts its activity in response to nutrients and growth factors.15 “mTORopathies” are a group of conditions in which TSC is best known, but also includes focal cortical dysplasia and hemimegalencephaly, and are characterized by a disruption of the brain architecture.14 mTOR dysregulation in TSC determines an alteration in cellular morphology with cytomegalic neurons, altered synaptogenesis and an imbalance between excitation/inhibition, thus providing a likely neuroanatomical substrate for the early appearance of refractory seizures.36 Also neurodevelopmental deficits may be the result of signaling abnormalities, deriving from the alteration of the cascade of events subsequent to the TSC gene mutation, and the severity of symptoms may depend on which structural and functional sites are impaired by an individual mutation.21 Indeed, mTOR overactivation is also responsible of altered long term potentiation and connectivity abnormalities, which might be responsible per se of neurodevelopmental problems.29
TSC is frequently associated with seizures, which are present in up to 85% of patients. Seizure onset is observed in the first year of life in about 67% of affected children. About half of the children remain resistant to the current available treatment options.13 Furthermore, learning disability is present in about half of patients affected by TSC, with a considerable proportion with severe/profound ID.33 A higher tuber burden is associated with a higher risk of ID, and the presence of tubers in the temporal lobes may increase the risk for autism spectrum disorders.16, 8, 31
A significant relationship between early age at seizure onset and poor developmental outcomes has been established.25, 31 However, it is still unclear whether epilepsy in TSC is simply a marker of infants who are destined to develop an encephalopathic process or seizures play a causal role in developing an encephalopathy.
A European workshop in the context of a Steering Committee Meeting of a multicenter trial (EPISTOP project) was held in Rome on June 19th 2015 with the aims of discussing the current knowledge on early onset epilepsy and encephalopathy in TSC, including the possible relationship between seizures and neurodevelopmental phenotype – cause or consequence. This paper reports the main points discussed at this workshop, and review the experimental evidences in support of the two theories.