Biomarkers for Brain Resetting as an Assistive Tool in the Treatment of Status Epilepticus

The proposed phase-I STTR research is an interdisciplinary effort to develop more effective clinical management of Status Epilepticus (SE) in collaboration with one of the leading neurological institutes in the world, the Barrow Neurological Institute in Phoenix, Arizona. SE is a life-threatening neurological emergency that can occur without warning and is characterized by recurrent seizures without recovery of normal brain function between seizures. The incidence rate of SE in the general public is 10 to 41 per 100,000 individuals per year, but it is much bigger in patients with epilepsy (20% of epilepsy patients will experience SE at some point in their lives). Given the level of its severity, relatively high mortality rate during and after an episode of SE (up to 40% in refractory SE), and the high probability of its occurrence in epilepsy patients, SE is of a significant concern in ambulatory settings and epilepsy medical centers. Timing and type of intervention to abate SE significantly influence patient outcomes. However, there are currently no biomarkers to rapidly, quantitatively and objectively predict the effectiveness of an intervention to disrupt SE, guide subsequent medication choices, or predict neurologic outcome. Development and validation of such biomarkers could help shorten the duration of SE, reduce patients’ morbidity and mortality, as well as serve as surrogate endpoints in new clinical trials for treatment of SE.Specific Aim 1: Measurement of brain and heart dynamics during SE treatment. Our previously developed linear multivariate and nonlinear univariate measures of dynamics will be applied to long-term EEG and ECG recordings from a large number of SE patients (~100) treated at the Epilepsy Monitoring Unit (EMU), Intensive Care Unit (ICU) or Emergency Room (ER) of the Barrow Neurological Institute, generating a substantial database of feature values derived from measures of brain and heart dynamics.Specific Aim 2: Development and validation of biomarkers for the effectiveness of treatment of SE. From the database of feature values per patient in Specific Aim 1, and based on our previous results from linear and non-linear measures of SE dynamics, we will derive biomarkers (SE indices) for monitoring the brain’s dynamics of the patient under treatment in real time, and an algorithm which will issue warnings (Wineff) on ineffectiveness of treatment, i.e. when there is no statistically significant (prt0.05) resetting of the observed pathological dynamics following intervention. We will validate the generated SE index values and Wineff warnings based on the clinical state of the patient over time, corroborated by collaborating physicians.Based on our preliminary results from a relatively small cohort of human and animal SE cases so far, we expect that our developed biomarkers would exhibit high sensitivity and specificity for real time assessment of the effectiveness of the administered treatment of SE in an ambulatory or hospital environment, and will thus constitute the basis for an assistive, robust and objective commercial tool for the clinical management of SE, much to the benefit of patients undergoing SE treatment and the society at large.