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Principal Investigator: Beth A Costine-Bartell
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $335,881
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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.
Terms: <0-11 years old><Abusive head injury><Abusive head trauma><Accident and Emergency department><Accidents><Acquired brain injury><Acute><Admission><Admission activity><Age><Anesthesia><Anesthesia procedures><Anti-epileptic><Apnea><Area><Biological Markers><Bleeding><Blood Vessels><Body Tissues><Brain Hypoxia-Ischemia><Brain Injuries><Brain Trauma><Brain region><CAT scan><CT X Ray><CT Xray><CT imaging><CT scan><Characteristics><Child><Child Youth><Childhood><Childhood Injury><Children (0-21)><Clinical><Clinical Management><Computed Tomography><Contralateral><Craniocerebral Injuries><Craniocerebral Trauma><Critical Care><Death Rate><Depressed mood><Development><Digenic Acid><Dysfunction><Elements><Emergency Department><Emergency room><Event><Evolution><Focal Seizure><Functional disorder><Future><General Radiology><Goals><Guidelines><Head Injuries><Head Trauma><Hemorrhage><Hospital Admission><Hospitalization><Hospitals><Hour><Human><Hypoventilation><Image><Impairment><Infant><Injury><Intensive Care><Kainic Acid><Location><MMPs><Matrix Metalloproteinases><Mechanics><Metabolic acidosis><Modeling><Modern Man><Multiple Injuries><Multiple Trauma><Neurologic><Neurologic status><Neurological><Neurological status><Outcome><Pattern><Pediatric Intensive Care Units><Physiopathology><Protocol><Protocols documentation><Radiology><Radiology Specialty><Seizures><Severities><Shaken baby syndrome><Shaken impact syndrome><Subarachnoid Hemorrhage><Subdural Hematoma><Subdural Hemorrhage><Testing><Therapeutic><Time><Tissues><Toddler><Tomodensitometry><Trauma><Traumatic Brain Injury><Up-Regulation><Upregulation><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><age associated><age correlated><age dependent><age linked><age related><age specific><ages><anti-epileptic agents><anti-epileptic drugs><bio-markers><biologic marker><biomarker><blood loss><brain atrophy><brain damage><brain morphology><brain-injured><catscan><cerebral atrophy><clinical relevance><clinically relevant><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><cortical atrophy><critical injury><depressed><devastating injury><develop therapy><developmental><disability burden><disabled><hemisphere damage><hypoxia/ischemia><imaging><injured child><injured children><injuries><injury in children><innovate><innovation><innovative><intervention development><kids><mechanic><mechanical><mortality><mortality rate><mortality ratio><neural><non-contrast CT><noncontrast CT><noncontrast computed tomography><partial seizure><pathophysiology><pediatric><pediatric injury><permissiveness><polytrauma><prevent><preventing><sadness><severe injury><therapeutic target><therapy development><time interval><tissue trauma><traumatic brain damage><treatment development><vascular><vasogenic edema><whiplash shaken infant><youngster>