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）是一种常见且令人衰弱的神经系统状况，影响了500个人中有1个。 心室旋转分流（VPS）已成为60年以上的标准治疗方法 有问题的，出现高功能率的高功能率，通常会导致复杂的神经外科治疗寿命 关心。内窥镜第三室造口术（ETV）是分流的替代方法，但婴儿的效率有限。 将脉络丛烧伤（CPC）添加到ETV中似乎是分类婴儿的可行替代品。尽管 相互矛盾的结果，目前正在定期和全球提供ETV-CPC，并且有限的理解 该程序对大脑发育的风险或好处。缺乏有关手术的知识 ETV-CPC的身体后果构成了广泛接受此事的重大障碍 程序。需要实验研究来确定ETV和ETV-CPC在临床实践中的作用，但是 缺乏适当的，经过验证的大型动物模型，在其中测试这些技术在脑生理学上以及， 至关重要的是，关于大脑发育，从未研究过。例如，消融脉络丛的影响， 调节神经发生和神经发育的主要稳态器官尚未确定。这 NIH通过启动资助机会PA-18-- 623，“增强产前和小儿脑积水研究的工具”，促进应用程序 设计“用于改变产前和/或儿科脑积水研究的领域，通过生成包括 动物...模型...了解疾病机制和/或发展治疗。我们的需求基于和 假设驱动的建议利用我们在ETV，ETV-CPC和VP的基础工作来解决目标 具有3个特定目的的PA-180-623：（1）开发与临床上的大型动物模型以比较 ETV，ETV-CPC和VPS； （2）在猪模型中定义成功ETV，ETV-CPC和VPS的标准 并确定这些程序对周围微观结构和海马的影响 体积; （3）检查ETV，ETV-CPC和VPS对婴儿仔猪认知功能的影响 HC。为此模型选择了猪，因为它们与人类神经解剖学和生理学的密切同源以及 使用标准临床神经外科技术的能力。这些新颖的治疗模型的开发 婴儿HC将填补HC研究中的关键空隙，并对新兴手术程序进行严格测试和 损伤机制，这对于确定最佳神经外科实践至关重要 HC。将实现PA-18-623的目标，因为该模型将由其他模型自由共享和实施 调查人员和教育计划。