Harnessing Metabolism to Treat Post-Traumatic Epilepsy

Dr Dulla’s lab focuses on the molecular and cellular underpinnings of epilepsy, with a particular emphasis on injury, astrocytes, and glutamate. Using a combination of advanced imaging approaches, genomics, and electrophysiology, the Dulla Lab studies the progression of epilepsy. His current work aims to use metabolic modulation of neuronal excitability to tackle pathologies linked to brain injury.

Dr Dulla will outline his experiments into inhibiting glycolysis after brain injury to prevent the loss of inhibitory GABAergic neurons. He will also describe novel single cell transcriptomics approaches that may shed light on how we might harness metabolism to prevent post-traumatic epilepsy.

Critical Care EEG Monitoring: A Practical Update

Talk Summary

Dr. Hirsch will provide an update in diagnosing and managing seizures, including nonconvulsive ones, and related EEG patterns in critically ill patients. This talk will benefit any member of the health care team involved in inpatient care of patients with altered mental status, including MDs, nurses, PA’s, APRNs, and EEG technologists.

Objectives:

  • To learn which patients are at risk of nonconvulsive seizures and warrant EEG monitoring
  • To learn how to understand EEG reports and which findings require urgent or aggressive treatment
  • To learn how to treat clinical and nonconvulsive seizures in the critically ill most effectively.

Status Epilepticus Research: My Adventures

Talk Summary

The goal of this talk is to highlight importance of novel scientific approaches and team science in epilepsy research. Changing focus from the role GABA -mediated inhibition to AMPA mediated excitatory transmission allowed us to use novel brain mapping techniques and genetic tools to gain novel insights into pathophysiology of status epilepticus.

In an effort to improve patient care, we organized a large, 60 -site clinical trial to investigate treatment of benzodiazepine-refractory status epilepticus, called Established Status Epilepticus Treatment Trial (ESETT). Organization and execution of such a large study required participation of a multidisciplinary team consisting of adult and pediatric ED physicians, adult and pediatric neurologists, trial design experts, biostatisticians , database experts, pharmacists and pharmacologists, and most importantly clinical research coordinators. Team science is critical to improving patient outcomes.

The Indisputable Dawn of Precision Medicine in Epilepsy

Talk Summary

Despite remarkable advances in basic and clinical neuroscience, and the introduction of many new pharmacological treatments, the overall impact of care for patients with epilepsy has not significantly changed for the past 50 years – until now.

Our increasing ability to define the “Knowledge Network” that includes the multi-layered determinants of health and disease in large populations is beginning to translate into more and more precise, individualized diagnostics and therapeutics. In epilepsy, genetics is leading the way, but this is only the dawn of what will, thankfully, be a new era in our ability to treat and eventually cure patients with epilepsy and other brain network disorders.

Preventing SUDEP (Sudden and Unexpected Death in Epilepsy) and How to Build Research Around SUDEP

Talk Summary

Individuals with epilepsy, particularly those with uncontrolled epilepsy, are at a much greater risk of premature death than those without. In fact, the standardized mortality ratio in those with epilepsy is between 2 and 3.

In the UK, the most common cause of epilepsy-related death is due to Sudden Unexpected Death in Epilepsy (SUDEP), which accounts for up to one-fifth of deaths in some series. SUDEP is more common in those with frequent convulsive seizures (particularly nocturnal seizures) and in those with drug-resistant epilepsy.

While the causes of SUDEP are unknown, the most commonly suggested underlying mechanisms are cardiac arrhythmias, respiratory depression and “cerebral shutdown”. Because no preventative measures currently exist, an understanding of SUDEP risk factors, potential mechanisms and the effectiveness of preventative measures is essential. To this end, there are a multitude of opportunities available in the field of SUDEP research and these opportunities will be interactively discussed during the presentation.

Thalamocortical Tonic Inhibition, Absence Epilepsy and Sleep

Talk Summary

Absence epilepsy is characterized by EEG spike-and-wave discharges (SWDs) and behavioral arrests.

Previous studies in several rodent models proposed that enhanced GABAergic thalamic tonic inhibition is “necessary and sufficient” to cause typical absence epilepsy. In contrast, here we show that knock-in mice expressing a human absence epilepsy mutation in the GABA-A receptor (?2R43Q) have typical absence seizures but have a complete loss, rather than enhancement, of tonic inhibition in principal cells of both thalamus and cortex. Furthermore, pharmacological blockade of tonic inhibition in wild type mice is sufficient to provoke SWDs, whereas pharmacological rescue of tonic inhibition in mutant mice suppresses SWDs by ~60%.

Like many humans with various epilepsies, ?2R43Q knock-in mice also have disrupted sleep cycles, with SWDs occurring preferentially within minutes after abrupt transitions from NREM to Wake stages. This sleep/seizure linkage appears to be reduced by rescue of tonic inhibition. Together with previous results, these data suggest that an optimal level of GABAergic tonic inhibition throughout the thalamocortical circuit is required for normal function and that deviation from this optimum in either direction results in pathological thalamocortical function including absence seizures and sleep disruptions. Pharmacological rescue of tonic inhibition is thus a potential treatment for certain subtypes of absence epilepsy and associated sleep disruption.

Deconstruction of Neural Circuits Underlying Dravet Syndrome

Talk Summary

Dr Paz was the first to reveal that seizures can be instantaneously aborted in real-time with closed-loop optogenetic control of a specific cell type. Her work led her to identify thalamo-cortical neurons as novel targets that control post-stroke seizures in real-time without side effects.

Integrating Brain Implants with Local and Distributed Computing Devices: A Next Generation Epilepsy Management System

Talk Summary

Brain stimulation has emerged as an effective treatment for a wide range of neurological and psychiatric diseases. Interfacing implantable brain devices with local and cloud computing resources has the potential to improve electrical stimulation efficacy, disease tracking and management.

Epilepsy, in particular, is a neurological disease that might benefit from integration of implanted devices with off-the-body computing for tracking disease and therapy. Recent studies have demonstrated seizure forecasting, seizure detection, and therapeutic electrical stimulation in patients with focal epilepsy.

In this talk, Dr Worrell will review progress on his Brain Initiative public-private-partnership with Medtronic Inc. to develop a next generation epilepsy management system in which low demand analytics requiring fast response times are embedded in the implanted device and more complex algorithms are implemented in off¬-the¬-body local and distributed cloud computing environments.

Instability in Epileptic Networks: Initiation, Termination, Interruption

Talk Summary

Historically, neuroscience research has provided mechanistic insights regarding ways in which neural circuitry may become dysfunctional in the context of epileptic seizures. For example, a rich history of studies in isolated rodent brain slices has provided a window into neural function during seizure-like events, but these studies are often artificially produced in vitro (out of the living organism). These in vitro studies allow for easier access to intracellular recordings and other advanced neurophysiological approaches whose results support roles for individual neurons and synapses in provoking and preventing seizure states.

Now, advances in scientific methods allow for real-time modulation of specific neural activity in behaving animals experiencing seizures. In this talk I will present recent in vivo (live animal) studies from our laboratory and others that validate some, but not all, of the mechanistic models obtained from simple ex vivo approaches and discuss how an integrated in vitro/in vivo approach may lead to a powerful translational path.

Cannabinoids in Epilepsy

Talk Summary

Using cannabinoids in the treatment of epilepsy is an area that is controversial, yet holds much promise. This talk will review the biology of cannabis – both the botany and human cannabinoid system – and then review the preclinical data on cannabidiol (CBD) and other cannabinoids. An overview of the neurological uses of cannabis will be presented, with a focus on the current data for the use of CBD and other cannabinoid preparations in epilepsy. The talk will then end with a summary of the current data and future directions regarding epilepsy in the cannabinoid space.