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，每500人中就有1人受到影响。 60年来，脑室-腹膜分流术(VPS)一直是标准治疗方法，但分流率仍然很高。 有问题的，故障率高得令人无法接受，通常会导致终身复杂的神经外科 关心。内窥镜第三脑室造口术(ETV)是分流手术的一种替代方法，但对婴儿的疗效有限。 在ETV的基础上加用脉络丛烧灼术(CPC)似乎是一种可行的替代婴儿分流的方法。尽管 结果相互矛盾，ETV-CPC目前正在全球范围内例行提供，但了解有限 这种程序对大脑发育的风险或好处。缺乏对这两种外科手术的了解 而ETV-CPC的生理后果构成了广泛接受这一点的重大障碍 程序。例如，消融脉络丛的影响，脉络丛是调节体内平衡的主要器官 神经发生和神经发育，尚未确定。需要进行实验研究才能确定 ETV和ETV-CPC在临床实践中的作用，但缺乏合适的、经过验证的大动物模型 用什么来测试这些技术在大脑生理学上，更重要的是，在大脑发育方面，从来没有研究过。 我们的假设驱动的建议建立在我们的基础工作之上，该工作开发了一种与临床相关的大型动物 在仔猪中建立HC模型，并论证了ETV CPC和VPS的可行性，从而继续 NIH PA-180-623的目标，“加强产前和儿童脑积水研究的工具”。三个具体的 AIMS将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前体生物学和脑脊液动态平衡的破坏与促炎信号：目的 1-比较VPS和ETV CPC对VZ/SVZ和PVWM的细胞学影响；目标2-确定影响 VPS和ETV CPC对脉络丛和脑脊液的影响；目标3-比较神经行为和认知 接受VPS和ETV CPC治疗的HC动物的结果。支持这些目标的出版物和初步报告 显示以下脑室下区(SVZ)和脑室周围白质(PVWM)的细胞病理学数据 VPS和ETV CPC治疗、室区(VZ)破坏、SVZ/PVWM细胞死亡、胶质细胞激活和 异位、PVWM胶质细胞活化和少突胶质细胞前体细胞减少、流式细胞术和单细胞RNA 小胶质细胞和前体细胞系的测序差异，脑脊液细胞和蛋白质的变化，以及减少 认知评估。分析将在治疗后30天和90天进行。猪被选为 它们与人类神经解剖学和生理学的同源性以及使用标准临床的能力的研究 神经外科技术。拟议研究的成功完成将填补HC研究中的一个关键空白 通过对新出现的手术程序和损伤机制进行严格测试，这对于识别 临床处理HC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.