The proposed phase-I STTR research is an interdisciplinary effort to develop more effective clinical managementof Status Epilepticus (SE) in collaboration with one of the leading neurological institutes in the world, the BarrowNeurological Institute in Phoenix, Arizona. SE is a life-threatening neurological emergency that can occur withoutwarning 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 biggerin patients with epilepsy (20% of epilepsy patients will experience SE at some point in their lives). Given the levelof its severity, relatively high mortality rate during and after an episode of SE (up to 40% in refractory SE), andthe high probability of its occurrence in epilepsy patients, SE is of a significant concern in ambulatory settingsand epilepsy medical centers. Timing and type of intervention to abate SE significantly influence patientoutcomes. However, there are currently no biomarkers to rapidly, quantitatively and objectively predict theeffectiveness of an intervention to disrupt SE, guide subsequent medication choices, or predict neurologicoutcome. 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 previouslydeveloped linear multivariate and nonlinear univariate measures of dynamics will be applied to long-term EEGand 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 substantialdatabase of feature values derived from measures of brain and heart dynamics. Specific Aim 2: Development and validation of biomarkers for the effectiveness of treatment ofSE. From the database of feature values per patient in Specific Aim 1, and based on our previous results fromlinear and non-linear measures of SE dynamics, we will derive biomarkers (SE indices) for monitoring the brain'sdynamics of the patient under treatment in real time, and an algorithm which will issue warnings (Wineff) onineffectiveness of treatment, i.e. when there is no statistically significant (p>0.05) resetting of the observedpathological dynamics following intervention. We will validate the generated SE index values and Wineffwarnings 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, weexpect that our developed biomarkers would exhibit high sensitivity and specificity for real time assessment ofthe effectiveness of the administered treatment of SE in an ambulatory or hospital environment, and will thusconstitute 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.
Public Health Relevance Statement: Timing and type of intervention to abate the life-threatening neurologic emergency of status epilepticus (SE)
significantly influence patient outcomes. However, despite the availability of expanding EEG analysis tools,
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. This proposal
aims to develop and validate such biomarkers, which could help shorten the duration of SE, reduce morbidity
and mortality after SE, as well as serve as surrogate endpoints in clinical trials for new treatments of SE.
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