Hydrocephalus (HC) is a common and debilitating neurological condition affecting up to 1 in 500 individuals. Ventriculoperitoneal shunting (VPS) has been the standard treatment for >60 years but shunts remain highly problematic, with an unacceptably high malfunction rate and often lead to a lifetime of complex neurosurgical care. Endoscopic third ventriculostomy (ETV) is an alternative to shunting but has limited efficacy in infants. Adding choroid plexus cauterization (CPC) to ETV seems to be a viable alternative to shunting infants. Despite conflicting outcomes, ETV-CPC is currently being offered routinely and globally, and with limited understanding of the risks or benefits of this procedure on brain development. The lack of knowledge about both the surgical and physiological consequences of ETV-CPC constitutes a significant barrier to broad acceptance of this procedure. Experimental studies are needed to determine the role of ETV and ETV-CPC in clinical practice, but the lack of appropriate, validated large animal models in which to test these techniques on brain physiology and, critically, on brain development, has never been studied. For example, the impact of ablating the choroid plexus, a major homeostatic organ which regulates neurogenesis and neurodevelopment, has yet to be determined. The NIH has responded to the unmet need for appropriate animal models by initiating Funding Opportunity PA-18- 623, ?Tools to Enhance the Study of Prenatal and Pediatric Hydrocephalus?, which promotes applications designed ?to transform the field of prenatal and/or pediatric hydrocephalus research by generating tools including animal?models?to understand disease mechanisms and/or developing therapeutics?. Our needs-based and hypothesis-driven proposal leverages our foundational work on ETV, ETV-CPC, and VPS to address the goals of PA-180-623 with 3 Specific Aims: (1) Develop a clinically-relevant, large animal model of HC to compare ETV, ETV-CPC, and VPS; (2) Define criteria for successful ETV, ETV-CPC, and VPS in the porcine model and determine the effects of these procedures on periventricular microstructure and hippocampal volume; and (3) Examine the effect of ETV, ETV-CPC, and VPS on cognitive function in piglets with infant HC. Pigs were chosen for this model both for their close homology to human neuroanatomy and physiology and the ability to use standard clinical neurosurgical techniques. Development of these novel treatment models of infant HC will fill a critical void in HC research and enable rigorous testing of emerging surgical procedures and injury mechanisms, which is essential to identifying best neurosurgical practices for the clinical management of HC. The goal of PA-18-623 will be achieved because this model will be freely shared and implemented by other investigators and educational programs.
This project will address the lack of large animal model systems to test ?developing therapeutics? in pediatric hydrocephalus. The successful completion of these studies will fill a critical void in hydrocephalus research and will provide evidence-based criteria for the clinical management of hydrocephalus.