Experimental endoscopic third ventriculostomy with choroid plexus cauterization and its effects on brain development

实验性内镜第三脑室造口术结合脉络丛烧灼及其对大脑发育的影响

• 批准号: 9896631
• 负责人: David Delmar Limbrick
• 金额: $ 25.05万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896631
• 关键词: Address; Adolescent; Affect; Aftercare; Age; Anatomy; Animal Model; Animals; Ataxia; Autologous; Bilateral; Binaural; Biological; Biological Markers; Biological Models; Blood; Brain; Caring; Cauterize; Cerebrospinal Fluid; Child; Childhood; Clinical; Clinical Management; Clinical/Radiologic; Cognition; Cognitive; Complement; Complex; Conflict (Psychology); Creation of ventriculo-peritoneal shunt; Development; Disease; Dose; Etiology; Experimental Models; Family suidae; Foundations; Funding Opportunities; Goals; Gold; Hippocampus (Brain); Histologic; Human; Hydrocephalus; Impairment; Individual; Infant; Injections; Intraventricular Injections; Kaolin; Knowledge; Lead; Lethargies; Magnetic Resonance Imaging; Measures; Medical Device; Methods; Modeling; Neuroanatomy; Neuroepithelial; Neurologic; Operative Surgical Procedures; Organ; Outcome; Pattern; Perioperative; Physiological; Physiology; Postoperative Period; Procedures; Process; Research; Research Personnel; Risk; Role; Shunt Device; Structure of choroid plexus; Surgical Injuries; Techniques; Testing; Therapeutic; Treatment Failure; United States National Institutes of Health; Ventricular; Ventriculostomy; Work; base; clinical practice; clinically relevant; cognitive function; design; evidence base; experimental study; glial activation; in vivo monitoring; indexing; memory recognition; migration; monolayer; neurodevelopment; neurogenesis; novel; patient subsets; precursor cell; prenatal; programs; research clinical testing; standard care; subventricular zone; success; tool

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.

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。还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、经过验证的大型动物模型来测试这些技术的大脑生理学和， 关键的是，对大脑发育的研究从未被研究过。例如，消融脉络丛的影响， 调节神经发生和神经发育的主要动态平衡器官尚未确定。这个 美国国立卫生研究院通过发起资助机会PA-18来回应对适当动物模型的未得到满足的需求。 623，“加强产前和儿科脑积水研究的工具”，促进应用 旨在通过以下方式转变产前和/或儿科脑积水研究领域 动物…型号…了解疾病机制和/或开发治疗方法“。我们以需求为基础的 假设驱动的提案利用我们在ETV、ETV-CPC和VPS方面的基础工作来实现这些目标 PA-180-623的3个具体目标：(1)建立临床相关的HC大动物模型，以比较 ETV、ETV-CPC和VPS；(2)在猪模型中定义成功的ETV、ETV-CPC和VPS的标准 并确定这些手术对脑室周围微结构和海马区的影响 (3)ETV、ETV-CPC和VPS对哺乳仔猪认知功能的影响 啊哈。猪被选为这一模型的原因是它们与人类的神经解剖学和生理学非常相似，而且 使用标准临床神经外科技术的能力。这些新的治疗模式的发展 婴儿HC将填补HC研究中的一个关键空白，并使对新出现的外科程序和 损伤机制，这对于确定临床处理的最佳神经外科实践是必不可少的 啊哈。PA-18-623的目标将会实现，因为该模型将由其他人自由共享和实施 调查人员和教育项目。