Identifying Potential Therapeutic Targets for Abusive Head Trauma

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PROJECT SUMMARY The pathophysiology of hemispheric hypodensity is unknown. It is a pattern of brain damage only occurring in young children, often resulting from abuse, where the majority of the hemisphere underlying the subdural hematoma appears hypodense on computed tomography spanning multiple vascular territories. When the subdural hematoma is over one hemisphere, the damage is predominantly unilateral. Recently, we successfully induced unilateral hemispheric hypodensity in piglets developmentally similar to human toddlers by re-creating the clinical characteristics of this injury: mechanical trauma, midline shift, subdural hematoma, seizures, apnea, and hypoventilation. This model results in an age-dependent neurologic impairment, metabolic acidosis, and unilateral hypoxic-ischemic-type injury encompassing most of the cortex underlying the subdural hematoma. The pattern of damage, degree of vasogenic edema, and upregulation of matrix metalloproteinases are age-dependent. The percentage of hemispheric damage is positively correlated with hemorrhage area and seizure duration. Our long-term goal is to understand the age- and injury-specific pathophysiology to develop therapies that halt or inhibit the progression of tissue damage after abusive head trauma. The overall objective in this application is to determine the contribution of seizures and hemorrhage in the development of the damage and if the cascades of injury can be aborted. Our central hypothesis is that the large forces generated from abuse causes extensive tissue damage that is primarily driven by an interplay between focal seizures and hemorrhage and that the resultant damage cascades can be arrested with anti- epileptic drugs. The rationale is that by understanding the pathophysiology and determining if the tissue is salvageable, then therapeutics that potentially halt the damage can be tested. We will test our central hypothesis with two specific aims:1.) Determine the contribution of seizures and hemorrhage to the development of unilateral hemispheric hypodensity; and 2.) Determine if stopping seizures at a time when children present to the emergency department prevents the extensive damage. Our contribution is the first model of hemispheric hypodensity that replicates the potentially synergistic multifactorial injury cascades within comparable developmental stages and brain morphology of human infants and toddlers where the pathophysiology and contribution of seizures can be determined. This approach is innovative as it departs from the status quo of using a single injury to induce “severe traumatic brain injury”; instead, we study the synergistic interplay of multiple injuries and insults and manage 30 hours of critical care using standard pediatric critical care protocols with clinically relevant outcomes. The proposed contribution is significant because age-specific therapies that abort the cascades of the pathophysiology of abusive head trauma might reduce the severity of neural damage and reduce the number of infants that die or are permanently disabled.