Electrographic seizures (ESz) and high-frequency periodic discharges (HF-PD) are present in approximately 30% of severe traumatic brain injury (sTBI) patients and are associated with poor outcomes across a range of acute brain injuries. ESz and HF-PD are associated with hypermetabolism that demands more energy than supplied, particularly in patients vulnerable from acute brain injury. A gap in knowledge exists regarding whether ESz and HF-PD result in secondary brain injury in sTBI and are treatment-responsive. To date, no existing treatment guidelines are available regarding which epileptiform abnormalities result in secondary brain injury or respond to treatment after sTBI. Thus, our central hypothesis is that ESz and HF- PD represent a treatable biomarker of metabolic crisis and secondary brain injury in at-risk tissue. The long- range goal of our research program is to improve the outcomes of sTBI patients by developing treatment strategies that reduce acute secondary brain injury. The proposed project is significant because it will 1) establish if ESz and HF-PD exposure is linked with metabolic crisis, 2) quantify the impact of ESz and HF-PD on clinical outcome, and 3) investigate the effect of clinical treatment on ESz and HF-PD exposure in a large, generalizable population of sTBI patients. BOOST-3 (Brain Oxygen Optimization in Severe TBI Phase 3 trial, U01 NS099946) is a multicenter clinical trial to evaluate the clinical efficacy of a treatment strategy using invasively monitoring to optimize PbtO2 and ICP compared to ICP alone. It offers a unique infrastructure in a codified cohort to quantify the complex relationship between EEG abnormalities, PbtO2, ICP, clinical outcomes, and treatment. We will evaluate our central hypothesis in 250 BOOST-3 patients from selected BOOST-3 sites performing continuous EEG (cEEG) as standard of care in sTBI patients undergoing invasive multimodality monitoring. We will address the following specific aims:
Specific Aim 1 : Demonstrate the influence of ESz and HF-PD on brain tissue oxygenation after sTBI. We will establish the relationship between ESz, HF-PD, brain hypoxia, and elevated ICP to determine if ESz and HF-PD are a dynamic biomarker of secondary brain injury related to metabolic crisis after sTBI.
Specific Aim 2 : Quantify the effect of ESz and HF-PD exposure on functional outcome after sTBI. We will determine the effect of elevations in the peak exposure to ESz and HF-PD on functional outcome measured by Glasgow Outcome Scale ? Extended (GOSE) 6 months after sTBI.
Specific Aim 3 : Quantify the effect of ESz and HF-PD exposure on functional outcome after sTBI. We will evaluate the change in ESz and HF-PD exposure after anti-seizure drug intervention. Further, we will measure the change in quantitative measures of EEG frequency and networks as well as Glasgow Coma Scale (GCS) score trends before and after the administration of anti-seizure drugs. The findings from this study will lead to future clinical trials of interventions targeting disrupted metabolism associated with ESz and HF-PD, in order to improve patient outcomes after sTBI.

Public Health Relevance

Electrographic seizures (ESz) and some epileptiform abnormalities (e.g. high-frequency periodic discharges HF-PD) captured on continuous EEG (cEEG) are common after severe traumatic brain injury (sTBI) and are associated with supply-demand mismatch, in-hospital neurologic deterioration, and outcome in a variety of conditions. A gap in knowledge exists in the treatment of sTBI patients regarding whether ESz and HF-PD result in secondary brain injury and respond to anti-seizure drug treatment. The goal of this project is to link the relationship between established biomarkers of metabolic demand (PbtO2), EEG abnormalities (ESz and HF- PD), clinical outcome, and treatment, to identify dynamic EEG biomarkers of secondary injury that will power future interventional trials targeting hypermetabolism to improve functional outcomes for sTBI patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Bellgowan, Patrick S F
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Yale University
Schools of Medicine
New Haven
United States
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