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

脑积水（HC）是一种常见的使人衰弱的神经系统疾病，发病率高达1/500。 腹腔分流术（VPS）已成为标准治疗方法超过60年，但分流率仍然很高。 问题，具有不可接受的高故障率，并且通常导致复杂的神经外科手术的终身 在乎内窥镜第三脑室造口术（ETV）是分流术的替代方法，但对婴儿的疗效有限。 在ETV中增加脉络丛烧灼术（CPC）似乎是分流婴儿的可行替代方案。尽管 结果相互矛盾，ETV-CPC目前在全球范围内定期提供，并且了解有限 这种手术对大脑发育的风险或益处。缺乏对外科手术和 ETV-CPC的生理后果构成了广泛接受这一点的重大障碍 procedure.例如，切除脉络丛的影响，脉络丛是一个主要的自我平衡器官， 神经发生和神经发育尚未确定。需要实验研究来确定 ETV和ETV-CPC在临床实践中的作用，但缺乏适当的，有效的大型动物模型， 来测试这些技术在大脑生理学上的作用，更重要的是，在大脑发育上的作用，从来没有被研究过。 我们的假设驱动的建议建立在我们的基础工作，开发了一个大型的，临床相关的动物 在幼年家猪中建立HC模型，并证明了ETV+CPC和VPS的可行性，从而继续 NIH PA-180-623，“加强产前和小儿脑积水研究的工具”的目标。三个具体 目的是检验我们的中心假设，即与VPS相比，ETV+CPC通过以下方式损害大脑发育： VZ/SVZ和PVWM前体生物学和CSF稳态与促炎信号传导的破坏：目的 1 -比较VPS和ETV+CPC对VZ/SVZ和PVWM的细胞学作用;目的2 -确定VPS和ETV+CPC对VZ/SVZ和PVWM的作用。 VPS和ETV+CPC对脉络丛和CSF的影响;目的3 -比较神经行为和认知功能 用VPS和ETV+CPC处理的HC动物的结果。支持这些目标的出版物和初步 显示以下脑室下区（SVZ）和室周白色物质（PVWM）中细胞病理学的数据 用VPS和ETV+CPC治疗，心室区（VZ）破坏，SVZ/PVWM细胞死亡，胶质细胞活化，和 异位、PVWM胶质细胞活化和少突胶质细胞祖细胞减少、流式细胞术和单细胞RNA 小胶质细胞和前体谱系的测序差异，CSF细胞和蛋白质改变， 认知评估将在治疗后30天和90天进行分析。猪被选中， 研究它们与人类神经解剖学和生理学的密切同源性以及使用标准临床 神经外科技术成功完成拟议的研究将填补HC研究的一个关键空白 通过对新兴外科手术和损伤机制的严格测试， HC临床管理的最佳神经外科实践。

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.