Will New Research Redefine Epilepsy?

Animal and human studies suggest that there is variability in neuronal excitation during seizures, with some neurons firing more, some less and others intermittently. “Seizures aren’t what textbooks would suggest – events with highly coordinated activity among neurons. At the level of individual neurons, different dynamics and behaviors occur during seizures; this offers a new way of understanding the mechanisms of seizures and how we might control them,” says Sydney S. Cash, MD, PhD, Principal Investigator of the MGH Cortical Physiology Laboratory.

The MGH Cortical Physiology Laboratory is the first to demonstrate this heterogeneity among neurons in humans. The Laboratory uses various microelectrode, macroelectrode and non-invasive recording techniques to study how the brain works under both normal and pathological conditions. Its epilepsy research focuses on the neurophysiology of epilepsy, with the goals of developing new methods for identifying the sites of onset and targets of propagation of epileptic activity to facilitate epilepsy surgery and targeted delivery of treatment. Precise localization of seizure onset zones will support the use of new optigenetic techniques, viral-vector mediated gene therapy and focal electrical stimulation to stop seizures before they become clinically apparent and interrupt normal behavior.

“Dr. Cash’s work provides a new conceptual framework for epilepsy that will translate into thinking differently about how to treat seizures. It may lead to new medications with different mechanisms of action than current medications which typically slow or block neuronal activity,” says Andrew J. Cole, MD, Director of the Epilepsy Service.

In related research, Cash Laboratory investigators have found that inhibitory neurons stop firing midway through a seizure, suggesting another mechanism for stopping seizures at an early stage. They have also studied how seizures spontaneously terminate; their work suggests that focal seizures terminate through a critical transition at multiple macroscopic spatial scales that is consistent with other critical transitions in natural and social systems. It may be possible to develop new drugs or devices that promote the biophysical processes that produce the critical transition to a non-seizure state.

The Laboratory’s future plans are to conduct studies of seizure mechanisms with larger numbers of patients, measuring patient data continuously, with the goal of developing an algorithm that could reliably indicate seizure onset.

Wide-Ranging Epilepsy Research

The Cortical Physiology Laboratory is one area of epilepsy research at MGH. The MGH Epilepsy Service conducts extensive research, including clinical trials and studies of healthcare outcomes and advanced neuroimaging techniques and basic molecular research on the mechanisms of disease.
 
A significant MGH Epilepsy Research Laboratory study found that early-life seizures predispose the brain to the damaging effect of seizures later in life, proposing a “two-hit hypothesis” for the development of epilepsy. “It takes two injuries to convert a brain from normal to epileptic; an initial insult at a young age can have serious consequences later on,” says Dr. Cole, who was principal investigator for the study.

The Epilepsy Service is currently recruiting patients for the Human Epilepsy Project (HEP), a five-year, prospective, observational study of patients with new-onset or recently diagnosed focal epilepsy. The study aims to identify characteristics and biomarkers predictive of disease outcome, progression and treatment response. Other research projects are focusing on understanding neuronal injury following seizures and developing strategies for neuroprotection that may lead to the development of new treatments.

Comprehensive Clinical Trials

The first epilepsy center to administer a new drug, SAGE-547, for status epilepticus (SE), the MGH Epilepsy Service is currently recruiting participants for an interventional study of the drug. Developed by Sage Therapeutics, SAGE-547 is a potent positive allosteric modulator (PAM) of both synaptic and extra-synaptic GABA receptors. Early findings on SAGE-547 have been robust. “Existing treatments for SE are often ineffective. Based on our preliminary experience, we are excited about launching the first clinical trials of SAGE-547,” says Dr. Cole.

MGH Chief of Pediatric Neurology, Kevin J. Staley, MD, Ph.D, is leading another study at MGH to evaluate bumetanide as an add-on therapy with phenobarbital to treat newborn seizures caused by hypoxic-ischemic encephalopathy (HIE), focal or multi-focal stroke, or intracranial hemorrhage. Dr. Staley has studied bumetanide in pre-clinical work and shown it to be effective in reducing seizures in neonatal animals by blocking a specific chloride transporter that is highly expressed in the brain in neonates, but not in children and adults. “Rapid translation of Dr. Staley’s work into a human clinical trial illustrates the power of the bench to bedside mindset and we have across Neurology at MGH” notes Dr. Cole.
 
The NeuroPace responsive neurostimulator system (RNS) device, was tested at MGH and recently received FDA approval; it is now available clinically and  provide an additional treatment option for epilepsy patients (for more information, see epilepsy surgery article). Noteably, after enrolling eight patients into the RNS pivotal trial required for FDA approval, the MGH Epilepsy Service has recently implanted the device into our first post-approval patient. 

For information about other clinical trials that are recruiting patients, visit rally.partners.org.

Genetics Research and the BioBank

Genetics is an explosive area of epilepsy research. Working with the Partners Healthcare Biobank, which collects patients’ DNA, the Epilepsy Service is assembling a resource of DNA samples and phenotypes which can be accessed by investigators to answer specific questions. “If we can match phenotype with genotype, it can help us identify genes important in this disease and genetic markers that influence prognosis and patient response to treatments,” says Dr. Cole.
Upcoming Studies and Future Plans

The Epilepsy Service recently added a new faculty member, Lidia Moura, MD, with expertise in outcome measures who will be looking at how best to measure quality in epilepsy care. Future plans include “hiring additional faculty members with expertise in genetics, functional anatomy, and clinical trials to complement our existing faculty and advance our cutting edge program to translate scientific understanding into meaningful treatments for patients,” says Dr. Cole.