Assessing CSF flow dynamics in pediatric hemorrhagic hydrocephalus

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Pediatric hydrocephalus affects 400,000 new children annually around the world. The primary etiology in the developed world is neonatal post-hemorrhagic hydrocephalus (PHH), affecting around 1 in 16 premature babies born at less than 29 weeks. Arising from the initial insult of intraventricular hemorrhage, subsequent neuroinflammation, and disruption of the choroid plexus epithelium, PHH is manifested by progressive ventricular dilation and increased intracranial pressure. PHH that can lead to significant disability and even death. The incomplete and evolving understanding of cerebrospinal fluid (CSF) flow dynamics limit the development of improved strategies to prevent and treat PHH. Traditional bulk CSF flow models consider hydrocephalus to be a plumbing problem with a mismatch in the rate of CSF generation and extracranial outflow. Several preclinical studies have shown that neuroinflammation disrupts CSF-lymphatic extracranial outflow. We hypothesize that in infants with PHH, impaired extracranial CSF outflow into the peripheral lymphatics contributes to a vicious cycle of increasing neuroinflammation that may be responsible for initial treatment failures and progressive insults that ensure irreversible brain injury. In this pilot project, we will deploy a new technique, called fluorescence, cap-based transcranial optical tomography (fCTOT) to understand the relationship between ventricular and lymphatic CSF dynamics, measures of neuroinflammation, and outcomes to standard-of-care CSF diversion as well as endoscopic third ventriculostomy and choroid plexus coagulation. Our specific aims are to: (1) Conduct point-of-care, fCTOT imaging of ventricular Inodcyanine green (ICG)-CSF dynamics in infants with progressing PHH; (2) Measure ICG-CSF clearance into lymph/blood from point-of-care, non-invasive diffuse reflectance measurements using NIRF-LI; and (3) Correlate fCTOT-derived ICG-CSF dynamics, ICG-CSF clearance into lymph/blood, and CSF biomarkers of inflammation with treatment outcomes. If successful, this application will provide novel, critical information on the role of CSF dynamics for the development of future prevention, progression, and treatment strategies for PHH. The study will be co-directed by Manish Shah, MD, a neurosurgeon overseeing the care of a large PHH patient population; by Eva Sevick, PhD., a biomedical engineer and early pioneer of near-infrared fluorescence optical tomography; and by Banghe Zhu, PhD., an optical engineer who translated a non-contrast versus CTOT for rapid, whole-brain tomography of PHH infants.