Characterizing Seizure-Onset Patterns With the Responsive Neurostimulation System.

PURPOSE: The responsive neurostimulation system (RNS) aims to improve seizures by delivering electrical stimulation in response to epileptiform patterns detected by electrocorticograms. Seizure-onset patterns (SOPs) correspond to outcomes in intracranial EEG (IC-EEG), although whether this is true for RNS is unknown. This study characterizes common RNS SOPs and correlates them with seizure outcomes. METHODS: Among 40 patients with RNS implants, long-episode electrocorticogram characteristics of each patient's seizures were classified by visual analysis as one of the eight patterns previously described in IC-EEG. Correlation between each type of SOP and eventual seizure outcome was analyzed, with ≥50% improvement in a number of patient-reported seizure counts defined as a favorable outcome. RESULTS: Across 263 LEs analyzed, the most common SOP observed was low-voltage fast activity. There was no difference between the distribution of RNS SOPs and that of IC-EEG SOPs described in the literature (Kolmogorov-Smirnov test, P = 0.98). Additionally, there was no correlation between any particular SOP and favorable outcomes (Fisher's omnibus test, P = 0.997). CONCLUSION: This initial description of RNS SOPs finds them to be similar to previously described IC-EEG SOPs, which suggests similar prognostic/therapeutic potential. However, we found that RNS efficacy is independent of patient SOP, suggesting that RNS is likely an equally effective treatment for all SOPs. Future research on stimulation parameters for particular RNS SOPs and correlation with IC-EEG SOPs in the same patients would be instrumental in guiding personalized neurostimulation.

Molecular and behavioral consequences of Ube3a gene overdosage in mice.

Chromosome 15q11.2-q13.1 duplication syndrome (Dup15q syndrome) is a severe neurodevelopmental disorder characterized by intellectual disability, impaired motor coordination, and autism spectrum disorder. Chromosomal multiplication of the UBE3A gene is presumed to be the primary driver of Dup15q pathophysiology, given that UBE3A exhibits maternal monoallelic expression in neurons and that maternal duplications typically yield far more severe neurodevelopmental outcomes than paternal duplications. However, studies into the pathogenic effects of UBE3A overexpression in mice have yielded conflicting results. Here, we investigated the neurodevelopmental impact of Ube3a gene overdosage using bacterial artificial chromosome-based transgenic mouse models (Ube3aOE) that recapitulate the increases in Ube3a copy number most often observed in Dup15q. In contrast to previously published Ube3a overexpression models, Ube3aOE mice were indistinguishable from wild-type controls on a number of molecular and behavioral measures, despite suffering increased mortality when challenged with seizures, a phenotype reminiscent of sudden unexpected death in epilepsy. Collectively, our data support a model wherein pathogenic synergy between UBE3A and other overexpressed 15q11.2-q13.1 genes is required for full penetrance of Dup15q syndrome phenotypes.