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.

Combining Human iPSC and Animal Models to Study Genetic Epileptic Encephalopathies

Talk Summary

Reprogramming somatic cells to a pluripotent state via the induced pluripotent stem cell (iPSC) method offers an unparalleled approach for neurological disease modeling using patient-derived neurons.

My laboratory has applied the iPSC approach in combination with genetically modified mice to model severe childhood genetic early infantile epileptic encephalopathies (EIEEs) with patient-derived cells. More recently, we developed other rodent genetic EE models by combining in utero electroporation with CRISPR gene editing (IUE-CRISPR).

The talk will describe our findings using these models to study three different EIEEs cause by mutations in SCN8A, SPTAN1 and STRADA. Our studies of mouse and patient iPSC models of EIEE13 due to de novo dominant SCN8A mutations show gain-of-function increased persistent or resurgent sodium current leading to neuronal hyperexcitability. We modeled EIEE5 SPTAN1-associated epilepsy with embryonic rat IUE-CRISPR and found that Sptan1 deletion altered cortical pyramidal cell morphology with loss of inhibitory innervation. Similar morphological defects were seen with overexpression of human mutant SPTAN1 and in EIEE5 patient iPSC-derived neurons.

In the last part of the talk, I will discuss our recent studies of PMSE (polyhydramnios, megalencephaly and symptomatic epilepsy) caused by autosomal recessive STRADA mutations, using patient-derived iPSCs grown in 2-D cultures and as cortical organoids. Taken together, our work suggests that combining human iPSC and animal models of EIEEs offers great promise for mechanistic understanding of these severe childhood genetic epilepsies, and should provide useful platforms to identify novel therapies.

SUDEP Family Panel

Understanding and Coping with the Risks of SUDEP

This was an exciting event which brought together health care providers, researchers, and advocacy groups to advance our understanding of SUDEP. The event welcomed patients and families living with the risks of SUDEP, and coping with the loss of a family member due to SUDEP.

The seminar features scientific and medical experts on various proposed causes for SUDEP, and new seizure detecting technologies. Dr. Cynthia Harden spoke on the practice guidelines for SUDEP incidence and risk factors, which she developed.

The program included:

  • Understanding and Coping with the Risks of SUDEP, which will teach you how to discuss SUDEP with your doctor
  • Guidelines for Assessing the Risks of Sudden Unexpected Death in Epilepsy (SUDEP), presented by Dr. Harden.
  • A presentation on NYS Legislation for Reporting of SUDEP (Senate Bill S2422)
  • A panel discussion by parents who lost a child to SUDEP

CURE’s Frontiers in Research Seminar Series is made possible by the generous support of Nussenbaum-Vogelstein family.