Saturday, May 17, 2025
5/17/2025
Eye as a Window into Brain Health in Pediatric Hydrocephalus - Eye as a Window into Brain Health in Hydrocephalus Project Summary Hydrocephalus is a debilitating condition caused by excess buildup of cerebrospinal fluid (CSF) in the cerebral ventricles. The overall global prevalence of hydrocephalus in children is 88 out of 100,000, with the mortality rate of untreated hydrocephalus reaching up to 87%. Most pediatric hydrocephalus cases (>90%) are managed operatively, using a ventricular shunt to divert CSF. Unfortunately, timing of shunting is guided by gross measures of intracranial pressure (ICP) and brain health including ventricular size and clinical signs. Delaying CSF diversion can lead to elevated ICP and irreversible brain injury. Invasive ICP monitoring, while more precise, is not routinely adopted in children due to the risks of hemorrhage and brain injury. This proposal bridges a significant clinical gap in care by validating ocular blood flow as a precise biomarker of ICP and brain ischemia that can negate the need for invasive ICP monitoring. As a direct extension of the brain, the eye has served as a window into studying ICP, but to date none of the noninvasive approaches evaluating ocular hemodynamics has proven as reliable as invasive ICP monitoring. In our proposed study, ocular contrast-enhanced ultrasound (CEUS) using a high-speed ultrasound system is performed in a high-fidelity pediatric porcine model of hydrocephalus to validate ocular blood flow markers of ICP and brain ischemia. CEUS uses intravenously injected microbubbles of 2-3 µm in size, smaller than red blood cells, that can be tracked across multiple ultrasound frames using an advanced particle tracking method (called particle image and/or tracking velocimetry or PIV/PTV). As a result, spatial and temporal changes in ocular microcirculation can be quantified for assessment of elevated ICP and brain ischemia. While the CEUS technology is FDA-approved for pediatric applications, specifically for evaluation of focal liver lesions and vesicoureteral reflux, ocular CEUS is off-label. The investigative team stands ready for clinical translation following this proposal, as the PI currently leads the first FDA-regulated, Investigational New Drug (IND)-approved clinical trials applying CEUS in infants with brain injury and necrotizing enterocolitis. The central hypothesis of the proposal is that ocular CEUS will provide accurate biomarkers of ICP and brain ischemia. The overall goal of the proposal is therefore to 1) validate and refine the accuracy and reproducibility of the PIV/PTV for eye imaging using phantom models mimicking the complex ocular microvascular networks and spontaneous eye movement, 2) validate ocular CEUS indices of ICP and brain ischemia using an established pediatric porcine model of hydrocephalus and 3) assess in vivo safety of the optimized ocular CEUS protocol. Our work will set the stage for clinical translation of a new noninvasive tool for assessment of ICP and brain ischemia in pediatric hydrocephalus, which could ultimately impact survival and long-term outcomes of affected children.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).