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.