Eval, Pathogenesis, Outcome of Subjects with or Suspected Traumatic Brain Injury

National Institute Of Neurological Disorders And Stroke

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Abstract

Each year, at least 1.4 million people sustain TBI, with over 1.1 million treated and released from the emergency department (ED). Approximately 125,000 patients with TBI, typically those more severely injured, experience permanent disability as a result of damage to the brain. On the other hand, mild TBI, accounting for at least 75% of all TBI, results in more subtle functional and cognitive deficits that often go undetected in the acute setting. These patients can experience drastic changes in their quality of life, have difficulties returning to daily activities and may be unable to return to work for weeks or months. It is estimated that mild TBI alone costs the United States in excess of $17 billon per year in long-term care and lost productivity. Lack of objective criteria for diagnosing TBI presents a significant impediment to developing therapies and improving clinical outcomes . Patients with a history of head injury often receive a screening brain scan using computed tomography (CT) in the ED despite a low sensitivity for detecting mild injury. The objective of this project is to generate natural history data for cohort-based comparisons to serve as the basis for future hypothesis-driven protocols and to contribute to the clinical and physiological understanding of traumatic brain injury (TBI) through the description of manifestations of the injury and the relationship among radiological, hematological, clinical variables and standard functional/cognitive outcome measures. In particular, the use of MRI to identify biomarkers, diagnose acute TBI, and predict outcome is being study. This is a prospective study of subjects with known and suspected non-penetrating acute traumatic brain injury who are enrolled in one of two IRB approved protocols. Subjects presenting to the emergency department or trauma service at participating hospitals with a history of recent head injury are studied during the course of their hospital stay and after discharge using radiological, hematological, clinical and functional/cognitive outcome measures. In addition to patients presenting to our local hospitals for acute care, there is an option to recruit subjects from beyond the local hospitals to be brought to the NIH Clinical Center for a more comprehensive battery of assessments and referral to other studies. Subjects are stratified according to findings into cohorts for comparison. The design is intentionally broad in scope to allow acquisition of initial data for the development of future hypothesis-driven protocols. Research performed under this protocol does not interfere with standard of care and subjects are not treated with experimental therapies as part of the research study. Data collected under this research study is shared without personal identifiers with other researchers if subjects approve this option on the informed consent. To date, nearly 2000 adult subjects with history of recent head injury with or suspected non-penetrating acute TBI have been enrolled in one of two protocols. Subjects having varying degrees of TBI severity have been recruited from the collaborative programs between NIH and non-NIH hospitals. Approximately 80% of subjects are classified as mild TBI, concussion, or no injury, with approximately one half of subjects enrolled being discharged directly from the emergency department. Subjects were offered the option of coming to the NIH Clinical Center to be imaged at very high fields (7T), imaged with positron emission tomography (PET), and some have been followed for up to 5 years under a collaborative project. The project was part of the NIH Uniform Services University - Center for Neuroscience and Regenerative Medicine (CNRM) and supported through the CNRM Acute Studies core. In 2019, support for the core was discontinued, enrollment was halted, and data was cleaned and locked. Work continues to analyze and publish data as part of the NINDS effort and through continued collaboration with CNRM. During the past year, we have focused on the following areas: Traumatic microbleeds: We have previously demonstrated the prevalence and persistence of small hemorrhagic lesions: traumatic microbleeds or TMB. They are found in up to 20% of patients with mild TBI we have studied and are suggestive of microvascular injury based on our pathology work. They are predictive of worse outcome. We have recently finished a study demonstrating the association between TMBs and areas of cytotoxic edema, essentially small, stroke-like appearing lesions. Independent of other baseline factors, evidence of cytotoxic edema seen on acute MRI is predictive of persistent deficits at 30-90 days. Traumatic meningeal enhancement: Our largest study of approximately 650 patients is complete and the manuscript in preparation. The meninges are injured in nearly 1 of 2 patients with TBI. The severity of the injury we detect on MRI is predictive of persistent enhancement of the meninges at 30 days, suggesting failure to repair as was seen in the mouse model (Dorian McGavern, PI). Collaborative science: As part of the Department of Defense CNRM, we continue to make data available through direct collaboration. This year collaborative projects have included blood-based biomarker characterization of TBI (Jessica Gill, PI), focal cortical atrophy and generalized brain atrophy (John Butman, PI), and the start of a collaboration with colleagues at the Hospital of the University of Pennsylvania on the epidemiology of TBI.