Neurocognitive disabilities in developmental and epileptic encephalopathies - Can we do better ?

Administrator: Elaine Wirrell, US

Dr Nicola Specchio
Bambino Gesu Childrens Hospital
nicola.specchio@gmail.com
Autism in Tuberous Sclerosis Complex - Who is At Risk and Can We Prevent This?
The goals of this talk will be to elucidate the relationship between autism, epilepsy and tuberous sclerosis complex (TSC), define phenotypic, genetic, and neurological risk factors. Firstly, the frequency of both autism and epilepsy within the TSC population, based on large clinical cohorts will be reviewed. The features of autism and epilepsy in TSC will be carefully characterized in order to better understand the relationship between these conditions within individuals with TSC.
The prevalence of autism and epilepsy in TSC is much higher than that in the general population, both alone and as comorbid features. We will summarize the phenotypic, genetic, and neurological risk factors of autism and epilepsy, including the impact of infantile spasms and drug resistance, in TSC patients. Given the complex relationship between these three conditions, early identification and effective treatment of the risk factors (tuber size and location; infantile spasms/early onset seizures; TSC2 mutations) should be a priority in order to optimize favorable outcomes in this vulnerable population.
Finally, the results of recent clinical trials comparing preventative treatment vs symptomatic treatment of seizures will be summarized.

Dr Rima Nabbout
Necker Enfant Hospital for Children
rimanabbout@yahoo.com
Precision Targeting of Genetic Epilepsies - Impact on Neurodevelopment and Seizures or Just Seizures?
Description of talkMonogenetic causes for early-life Developmental and Epileptic encephalopathies are being increasingly identified. Some are associated with narrow phenotypic spectrums (etiology-specific syndromes) while others are phenotypically quite diverse. This talk will review our current understanding of the underlying etiology of neurodevelopmental delay in monogenic DEEs, addressing the concepts of both developmental encephalopathy and epileptic encephalopathy, and will summarize the correlation between seizure control and neurodevelopmental outcomes in several genetic DEEs of early childhood. Furthermore, the results of recent clinical trials with both novel clinical compounds (i.e. cannabidiol, stiripentol, ganoxolone) and repurposed therapies (i.e. fenfluramine, quinidine) in children with genetic DEEs will be summarized, with a specific focus on their impact on neurodevelopment. Additionally, emerging precision therapies, targeting specific synaptic targets or ion channels, and precision metabolic therapies will be discussed.

Dr. Aaron Warren
University of Melbourne
aaron.warren@unimelb.edu.au
Lennox Gastaut syndrome and Secondary Network Dysfunction
This talk will review recent advances in the brain network understanding of Lennox-Gastaut syndrome (LGS), and how this knowledge is informing novel network-based interventions. LGS is characterised by multiple, drug-resistant seizure types and specific EEG patterns including slow spike-and-wave and generalised paroxysmal fast activity. It typically is associated with significant co-morbidities including intellectual disability, behaviour problems, and sleep disorders.
Recent advances in neuroimaging have begun to uncover the brain network mechanisms of LGS. Studies using multi-modal functional neuroimaging, in particular combined EEG with functional MRI (EEG-fMRI), have revealed activation of specific cortical and subcortical circuits during patients’ interictal epileptiform discharges. Intriguingly, these activation patterns appear similar across individual patients with distinct aetiologies of LGS. This has led to the recent conceptualisation of LGS as a ‘secondary network epilepsy’ - abnormal expression of a shared brain network that develops secondarily to the specific aetiology.
Improvements in our network understanding of LGS have aided the development of several new therapies, including the recent “ESTEL” clinical trial of thalamic deep brain stimulation for LGS. Key insights from ESTEL included the identification of thalamocortical connectivity patterns than may underlie the antiseizure effects of deep brain stimulation.

Dr Scott Perry
Cook Childrens Hospital
Scott.Perry@cookchildrens.org
Resective Surgery for Early-Life Epilepsies - Impact on Neurodevelopment
Early-onset, drug-resistant epilepsy leads to functional network changes with adverse impact on cognition and development. Epilepsy surgery is one of the most effective therapies for achieving seizure freedom in infants with drug-resistant epilepsy, yet remains vastly underutilized world wide. This disconnect stems from a variety of barriers and knowledge gaps related to the efficacy, risks and benefits beyond seizure freedom, further complicated by heterogeneous patient characteristics which make prediction of outcome difficult. Too often, epilepsy surgery is regarded as a last resort, particularly for those with physical, cognitive or behavioral delays - all characteristics frequently encountered in the DEEs.
This talk will review the Pediatric Epilepsy Research Consortium's surgery database, which has prospectively collected common data elements in children referred for epilepsy surgery across 24 participating U.S. pediatric epilepsy centers. Results exploring evaluation and treatment trends in children with DEEs will be discussed and in addition, we will explore the outcome of procedures intended to be both curative and palliative to better understand their impact on seizure frequency and neurodevelopmental outcome.