Improving infant hydrocephalus outcomes in Uganda: Predicting developmental outcomes and identifying patients at risk for early treatment failure after ETV/CPC

项目总结/摘要 婴儿脑积水是一个严重的全球性健康问题，估计每年有40万新病例。近 其中一半发生在撒哈拉以南非洲，新生儿感染是那里最常见的原因。未经治疗， 脑积水导致进行性脑损伤甚至死亡。长期以来， 脑室腹腔分流（VPS）的放置，但这些设备需要终身维护，几乎所有 失败多次。正因为如此，分流依赖在LMIC中更危险，因为在LMIC中， 神经外科护理是困难的或不可能的。乌干达CURE儿童医院（CCHU）开发了一种替代方法， 内镜下第三脑室底造瘘术联合脉络丛烧灼术（ETV/CPC） 患者无分流的生活。一项NIH资助的随机对照试验，比较了ETV/CPC与VPS治疗后 CCHU的感染性脑积水（PIH）在治疗后一年的脑内无显著差异 增长或发展成果。治疗失败是一个重要的问题，发生在第三个。 发育结果与大脑生长量有关，但与传统的 头部或心室大小。治疗一直集中在控制心室大小，但这几乎没有关联 有结果。大脑发育是一个更好的指标，我们假设在妊高征，它部分取决于完整性 感染后潜在的大脑物质的变化，以及部分脑循环支持再生的能力。 因此，我们假设脑血流量和代谢更能代表疾病的严重程度 和治疗反应。我们开发了一种新的，结合频域近红外和漫反射 相关光谱（FDNIRS/DCS）技术测量脑血流量（CBF）和氧 代谢（CMRO 2）在床边非侵入性。在BCH和CCHU的试点研究中，我们发现未经治疗的 脑积水逐渐阻碍脑灌注并抑制代谢，而成功的治疗 立即恢复CBF和CMRO 2。此外，术后即刻较大的CMRO 2与以下因素相关： 六个月后大脑发育更好我们现在建议在一个更大的群体中验证这些结果，目标是 引导脑积水治疗远离目标脑室大小，而是将其导向可测量的 改善大脑的生理健康。这样的范式转变将在临床上产生重大影响， 发展中国家，美国和世界其他地区。

Project Summary/Abstract Infant hydrocephalus is a serious global health problem, with an estimated 400,000 new cases annually. Nearly half of these occur in sub-Saharan Africa, with neonatal infection being the most common cause there. Untreated, hydrocephalus causes progressive brain injury and even death. The standard treatment has long been placement of a ventriculoperitoneal shunt (VPS) but these devices require life-long maintenance and nearly all fail multiple times. Because of this, shunt-dependence is more dangerous in LMIC where emergency access to neurosurgical care is difficult or impossible. CURE Children’s Hospital of Uganda (CCHU) developed an alternate treatment combining endoscopic third ventriculostomy with choroid plexus cauterization (ETV/CPC) to give patients a shunt-free life. An NIH-funded, randomized controlled trial of ETV/CPC vs VPS for infants with post- infectious hydrocephalus (PIH) at CCHU found no significant difference at one-year post-treatment in brain growth or developmental outcomes. Treatment failure is a significant problem for both, occurring in a third. Developmental outcomes were associated with the amount of brain growth, but not with traditional metrics of head or ventricle size. Treatment has always focused on controlling ventricle size, but this has little association with outcomes. Brain growth is a better indicator, and we hypothesize in PIH it depends in part on the integrity of the underlying brain matter after infection and in part on the cerebral circulation’s ability to support regrowth. Consequently, we hypothesize cerebral blood flow and metabolism are more representative of disease severity and treatment response. We developed a novel, combined frequency-domain near-infrared and diffuse correlation spectroscopies (FDNIRS/DCS) technology to measure cerebral blood flow (CBF) and oxygen metabolism (CMRO2) non-invasively at the bedside. In pilot studies at BCH and CCHU, we found untreated hydrocephalus progressively impedes cerebral perfusion and depresses metabolism, while successful treatment immediately restores CBF and CMRO2. Moreover, greater CMRO2 immediately after surgery correlated with better brain growth six months later. We now propose validating these results in a larger group with the goal of leading hydrocephalus treatment away from targeting ventricle size and directing it instead towards measurable improvements in the brain’s physiological health. Such a paradigm shift will have substantial clinical impact in developing countries, the United States, and the rest of the world.