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. As cerebrospinal fluid (CSF) builds up in the brain, intracranial pressure increases and brain development is adversely affected, leading to disability or even death. There is no medical treatment for PHH and surgical treatments are often impermanent with potentially life-threatening failure. The development of improved treatment strategies is complicated by the incomplete and evolving understanding of CSF flow physiology as well as a lack of definitive diagnostics for use in infants. While we and others have demonstrated the ability to image CSF outflow in rodent models of disease, there has been no prior approach to image larger, more relevant models. In preliminary studies using custom-built near-infrared (NIR) fluorescence instrumentation in adult cancer patients and normal volunteers, we have demonstrated the ability to non-invasively image the deep jugular lymphatic channels that are the predominant drainage pathways for extracranial CSF flow. Using a similarly sensitive, but non-contrast, fiber-optic, cap-based NIR tomographic system, we furthermore demonstrated mapping of whole-brain oxygenation in an awake infant with PHH. Given the enabling technological advances that allowed these measurements, we now expect to be able to non-invasively map CSF dynamics in infants with PHH following NIR contrast administration into the CSF. However, before securing FDA clearance for these studies, we seek to first demonstrate the feasibility for mapping of CSF dynamics in a closely sized model of pediatric patients under PA-18-623 “Tools to enhance the study of prenatal and pediatric hydrocephalus.” Specifically, our aims are to non-invasively image circulatory CSF flow dynamics in cynomolgus macaques following intraventricular and intrathecal administration of fluorescent contrast as well as develop an understanding of dosing amounts that would be necessary for subsequent safety and toxicity studies. If successful, this exploratory grant will develop “novel methods and/or innovative technologies to accelerate the understanding of prenatal and/or pediatric hydrocephalus,” but to do so in the context of its clinical management. Our translational team consists of collaborative basic science and clinical investigators who (i) direct surgical management of PHH patients at Children's Memorial Hermann Hospital; (ii) engineered NIRF lymphatic imaging in over 600 human subjects under the FDA experience and established NIRF imaging of CSF outflow; and (iii) established the feasibility of whole-brain NIR tomography in a PHH patient.

Surgical treatment for post-hemorrhagic hydrocephalus (PHH) of premature infants is limited by our understanding of cerebrospinal fluid (CSF) production and circulation. Armed with technological knowledge from past studies in adult humans and a PHH infants, we propose to develop and deploy near-infrared fluorescence imaging of CSF in infant-sized cynomolgus macaques as the first step towards development of a real-time tool to direct endoscopic third ventriculostomy and choroid plexus coagulation, and diagnose ventriculoperitoneal shunt failure.