Experimental Studies of Endoscopic Third Ventriculostomy and Choroid Plexus Cauterization in Hydrocephalus

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. For example, the impact of ablating the choroid plexus, a major homeostatic organ which regulates neurogenesis and neurodevelopment, has yet to be determined. 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. Our hypothesis-driven proposal builds on our foundational work that developed a large, clinically-relevant animal model of HC in juvenile domestic pigs and demonstrated feasibility of ETV+CPC, and VPS, thus continuing the goals of NIH PA-180-623, “Tools to Enhance the Study of Prenatal and Pediatric Hydrocephalus”. Three Specific Aims will test our Central Hypothesis that, compared with VPS, ETV+CPC impairs brain development through disruption of VZ/SVZ and PVWM precursor biology and CSF homeostasis with pro-inflammatory signaling: Aim 1 - compare the cytological effects of VPS and ETV+CPC on VZ/SVZ and PVWM; Aim 2 - determine the effect of VPS and ETV+CPC on choroid plexus and CSF profile; Aim 3 - compare neurobehavioral and cognitive outcomes in HC animals treated with VPS and ETV+CPC. Supporting these aims are published and preliminary data showing cytopathology in the subventricular zone (SVZ) and periventricular white matter (PVWM) following treatment with VPS and ETV+CPC, ventricular zone (VZ) disruption, SVZ/PVWM cell death, glial activation, and heterotopia, PVWM glial activation and reduced oligodendrocyte progenitors, flow cytometry and single cell RNA sequencing differences in microglia and precursor lineages, CSF cellular and protein alterations, and reduced cognitive assessments. Analyses will be performed at 30- and 90-days post-treatment. Pigs were chosen for studies for their close homology to human neuroanatomy and physiology and the ability to use standard clinical neurosurgical techniques. Successful completion of the proposed studies will fill a critical void in HC research through rigorous testing of emerging surgical procedures and injury mechanisms, which is essential to identifying best neurosurgical practices for the clinical management of HC.