Novel Ultrasound Indices of Intracranial Pressure and Brain Ischemia in Neonatal Hydrocephalus

Novel Ultrasound Indices of Intracranial Pressure and Brain Ischemia in Neonatal Hydrocephalus Project Summary Neonatal hydrocephalus affects 1-2 of every 1000 live births and results in neurologic deficits in up to 78% of treated patients. A wide spectrum of etiologies including intraventricular hemorrhage, congenital aqueduct stenosis, myelomeningocele, and brain tumors cause an abnormal accumulation of cerebral spinal fluid (CSF) in this disease, resulting in cerebral ventricular dilatation and elevated intracranial pressure (ICP). While ventricular shunting is used as a surgical treatment for CSF diversion, the decision to shunt is based on ventricular size and clinical judgement which are not sensitive markers of ICP and brain health. Thus, delayed diagnosis of elevated ICP and surgical shunting can result in permanent brain damage and long-term neurologic deficits. Invasive ICP monitors are not routinely inserted due to the associated risk of bleeding and regional brain ischemia in the vulnerable neonatal brain. To provide a solution to a significant gap in clinical care of neonatal hydrocephalus, we utilize the contrast-enhanced ultrasound (CEUS) technique for noninvasive detection of ICP and brain ischemia in a well-established porcine model of hydrocephalus. CEUS uses intravascular injection of microbubbles of 2-3 µm in average size for assessment of tissue perfusion. With the use of the novel particle tracking method (so-called particle image and/or tracking velocimetry), the underlying spatial and temporal changes in cerebral microcirculation can be quantified for assessment of elevated ICP and brain ischemia. To this end, the previous R01 cycle validated a promising cerebral microvascular flow marker of ICP and brain ischemia in the acute porcine hydrocephalus model. This renewal R01 will focus on expanding the imaging biomarker repertoire and applicability to hydrocephalus of varying duration and etiology. The central hypothesis of the proposal is that CEUS will be a robust biomarker of ICP, brain ischemia and oxygenation in neonatal hydrocephalus. The overall goal of the proposal is therefore to 1) expand the novel CEUS biomarker repertoire and applicability beyond the acute phase of elevated ICP and to 2) explore the complementary use of macro- vascular diagnostic tools. As an exploratory aim, we will conduct a pilot Investigational New Drug (IND) approved clinical study as a continuous laboratory-to-clinical and reverse feedback learning and improvement mechanism in biomarker development. Our work will set the stage for clinical translation of a new noninvasive tool for assessment of ICP and brain ischemia in neonatal hydrocephalus, which can ultimately improve the guidance of shunting and long-term neurologic outcomes.