Faculty Bibliography

BACKGROUND AND PURPOSE/OBJECTIVE:The increased severity of white matter disease is associated with worse outcomes and an increased rate of intracerebral hemorrhage in patients with ischemic stroke undergoing thrombolytic treatment. However, whether white matter disease is associated with outcomes in patients undergoing endovascular treatment remains unclear. MATERIALS AND METHODS/METHODS:In this prespecified exploratory analysis of our prospective multi-institutional study that enrolled consecutive adult patients with anterior circulation ischemic stroke undergoing endovascular treatment from November 2017 to September 2018, we compared the following outcomes between patients with none-to-minimal (van Swieten score, 0-2) and moderate-to-severe (van Swieten score, 3-4) white matter disease using logistic regression: 90-day mRS 3-6, death, intracerebral hemorrhage, successful recanalization, and early neurologic recovery. RESULTS:< .001). No associations between white matter disease severity and intracerebral hemorrhage, successful recanalization, and early neurologic recovery were observed. CONCLUSIONS:Moderate-to-severe white matter disease is associated with worse outcomes in patients undergoing endovascular treatment without a significant increase in hemorrhagic complications. Studies comparing patients with and without endovascular treatment are necessary to determine whether the benefit of endovascular treatment is attenuated with greater white matter disease.

Bioelectronic devices should optimally merge a soft, biocompatible tissue interface with capacity for local, advanced signal processing. Here, we introduce an organic mixed-conducting particulate composite material (MCP) that can form functional electronic components by varying particle size and density. We created MCP-based high-performance anisotropic films, independently addressable transistors, resistors, and diodes that are pattern free, scalable, and biocompatible. MCP enabled facile and effective electronic bonding between soft and rigid electronics, permitting recording of neurophysiological data at the resolution of individual neurons from freely moving rodents and from the surface of the human brain through a small opening in the skull. We also noninvasively acquired high-spatiotemporal resolution electrophysiological signals by directly interfacing MCP with human skin. MCP provides a single-material solution to facilitate development of bioelectronic devices that can safely acquire, transmit, and process complex biological signals.

Introduction: Antiseizure medications are the mainstay of epilepsy treatment. Currently therapies are not specific to epilepsy etiology, and control seizures in two thirds of cases. Drugs in clinical development aim to bridge that gap by targeting novel receptors and epileptogenesis. While currently approved antiseizure medications target focal or generalized epilepsies regardless of etiology, newly approved and investigational epilepsy drugs also target rare or orphan epilepsy syndrome indications, such as Lennox-Gastaut or Dravet syndrome. We identified investigational drugs through the Epilepsy Foundation pipeline tracker and conference proceedings of recent novel epilepsy drug conferences (XV AEDD, XIV EILAT).Areas Covered: We review antiseizure medications in clinical development and their targets (GABA, T-type calcium channels, 5-HT, potassium channels). We also discuss drugs with unknown or multiple mechanisms of action (cannabinoids, carisbamate, cenobamate). Therapies with potential disease-modifying effects in preclinical and clinical development are then outlined, ranging from gene-targeted treatments (antisense oligonucleotide, gene therapy, antisense transcript regulators) targeting specific genetic epilepsies, mTOR inhibitors, to inflammation-targeted treatments.Expert Opinion: Drugs to treat novel targets to control seizures as well as prevent epileptogenesis offer great promise. To assess disease modifying agents, we may need new clinical trial designs. Precision medicine therapies for genetic epilepsies may control seizures and restore brain health.

BACKGROUND:In neuromyelitis optica spectrum disorder (NMOSD), clinical disability in NMOSD patients is relapse-related and progressive phase is rare. This observation raises the question whether there is any radiographic disease activity. The aim of present study was to determine the longitudinal changes in cerebral lesion number, lesion size, lesion-to-venule relationship, and morphological patterns of lesions in NMOSD using multiparametric 7T MR imaging. We also aimed to assess brain volume changes in NMOSD. METHODS:A cohort of 22 patients with NMOSD underwent high-resolution 3D-susceptibility weighted imaging (SWI) and 2D-gradient-echo (GRE-T2*) weighted imaging on 7T MRI of brain at baseline and after ~2.8 years of follow-up. Morphologic imaging characteristics, and signal intensity patterns of lesions were recorded at both time points. Lesions were classified as "iron-laden" if they demonstrated hypointense signal on GRE-T2* images and/or SWI as well as hyperintense signal on quantitative susceptibility mapping (QSM). Lesions were considered "non-iron-laden" if they were hyperintense on GRE-T2*/SWI and isointense or hyperintense on QSM. Additionally, fractional brain parenchymal volume (fBPV) was computed at both time points. RESULTS:A total of 169 lesions were observed at baseline. At follow-up, 6 new lesions were found in 5 patients. In one patient, a single lesion could not be detected on the follow-up scan. No appreciable change in lesion size and vessel-lesion relationship was observed at follow up. All lesions demonstrated hyperintense signal intensity on GRE-T2* weighted images and isointense signal on QSM at both time points. Therefore, these lesions were considered as non-associated with iron pathology. Additionally, no significant change in brain volume was observed: fBPV 0.78 ± 0.06 at baseline vs. 0.77 ± 0.05 at follow up, p>0.05. CONCLUSION/CONCLUSIONS:Cerebral lesions in NMOSD patients remain 'inert' and do not show any substantial variations in morphological characteristics during a 2-3-year follow-up period.

We developed a neural network model that can account for major elements common to human focal seizures. These include the tonic-clonic transition, slow advance of clinical semiology and corresponding seizure territory expansion, widespread EEG synchronization, and slowing of the ictal rhythm as the seizure approaches termination. These were reproduced by incorporating usage-dependent exhaustion of inhibition in an adaptive neural network that receives global feedback inhibition in addition to local recurrent projections. Our model proposes mechanisms that may underline common EEG seizure onset patterns and status epilepticus, and postulates a role for synaptic plasticity in the emergence of epileptic foci. Complex patterns of seizure activity and bi-stable seizure end-points arise when stochastic noise is included. With the rapid advancement of clinical and experimental tools, we believe that this model can provide a roadmap and potentially an in silico testbed for future explorations of seizure mechanisms and clinical therapies.

Debates on six controversial topics on the network theory of epilepsy were held during two debate sessions, as part of the International Conference for Technology and Analysis of Seizures, 2019 (ICTALS 2019) convened at the University of Exeter, UK, September 2-5 2019. The debate topics were (1) From pathologic to physiologic: is the epileptic network part of an existing large-scale brain network? (2) Are micro scale recordings pertinent for defining the epileptic network? (3) From seconds to years: do we need all temporal scales to define an epileptic network? (4) Is it necessary to fully define the epileptic network to control it? (5) Is controlling seizures sufficient to control the epileptic network? (6) Does the epileptic network want to be controlled? This article, written by the organizing committee for the debate sessions and the debaters, summarizes the arguments presented during the debates on these six topics.

Lemborexant is a dual orexin receptor antagonist indicated for the treatment of adult and elderly individuals with insomnia. Some current pharmacologic treatments for insomnia cause respiratory depression, a serious safety concern, particularly for individuals with obstructive sleep apnea (OSA). This phase 1, randomized, double-blind, placebo-controlled, two-period crossover study examined respiratory safety parameters in individuals with mild OSA following treatment with lemborexant. Participants (n = 39) were randomized to one of two treatment sequences, including placebo and lemborexant 10 mg. Each treatment period lasted 8 days and was separated by a washout of at least 14 days. Following single or multiple doses, there were no significant differences in mean apnea-hypopnea index for lemborexant 10 mg versus placebo (least squares mean [LSM] difference [95% confidence interval {CI}]: day 1, -0.03 [-2.22, 2.17]; day 8, -0.06 [-1.95, 1.83]) or peripheral capillary oxygen saturation during sleep (LSM difference [95% CI]: day 1, 0.07 [-0.31, 0.46]; day 8, 0.25 [-0.11, 0.61]). There were no significant differences versus placebo for the percentage of total sleep time during which peripheral capillary oxygen saturation was <80% (LSM difference [95% CI]: day 1, 0.002 [-0.019, 0.023]; day 8, 0.006 [-0.015, 0.026]), <85% (LSM difference [95% CI]: day 1, 0.067 [-0.124, 0.258]; day 8, 0.056 [-0.117, 0.228]) or <90% (LSM difference [95% CI]: day 1, 0.312 [-0.558, 1.181]; day 8, 0.088 [-0.431, 0.607]). The incidence of treatment-emergent adverse events was low and similar for lemborexant and placebo. Lemborexant demonstrated respiratory safety in this study population and was well tolerated.

PURPOSE/OBJECTIVE:A phase I feasibility study to determine the accuracy of identifying seizures based on audio recordings. METHODS:We systematically generated 166 audio clips of 30 s duration from 83 patients admitted to an epilepsy monitoring unit between 1/2015 and 12/2016, with one clip during a seizure period and one clip during a non-seizure control period for each patient. Five epileptologists performed a blinded review of the audio clips and rated whether a seizure occurred or not, and indicated the confidence level (low or high) of their rating. The accuracy of individual and consensus ratings were calculated. RESULTS:The overall performance of the consensus rating between the five epileptologists showed a positive predictive value (PPV) of 0.91 and a negative predictive value (NPV) of 0.66. The performance improved when confidence was high (PPV of 0.96, NPV of 0.70). The agreement between the epileptologists was moderate with a kappa of 0.584. Hyperkinetic (PPV 0.92, NPV 0.86) and tonic-clonic (PPV and NPV 1.00) seizures were most accurately identified. Seizures with automatisms only and non-motor seizures could not be accurately identified. Specific seizure-related sounds associated with accurate identification included disordered breathing (PPV and NPV 1.00), rhythmic sounds (PPV 0.93, NPV 0.80), and ictal vocalizations (PPV 1.00, NPV 0.97). CONCLUSION/CONCLUSIONS:This phase I feasibility study shows that epileptologists are able to accurately identify certain seizure types from audio recordings when the seizures produce sounds. This provides guidance for the development of audio-based seizure detection devices and demonstrate which seizure types could potentially be detected.