We estimate 250,000 new infants develop hydrocephalus, most commonly following neonatal infection, in sub- Saharan Africa (SSA) each year. Most have poor access to treatment. We developed and validated a novel operative treatment for infant hydrocephalus combining endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC) that avoids shunt dependence in the majority. Our prior collaborative work at CURE Children’s Hospital of Uganda (CCHU) supported equipoise between shunt placement and ETV/CPC in regard to 5-year survival and development. That ETV/CPC prevents shunt dependence among those with no urgent access for shunt malfunction is compelling, but we do not know which treatment optimizes development. We seek to confirm the optimal treatment selection paradigm. Using CT-based measures we found that brain and CSF volume discriminated neurocognitive outcome, providing a promising objective measure of hydrocephalus treatment efficacy. Preliminary data from our R-21 and R01 funded randomized controlled trial (RCT) of ETV/CPC vs. shunt for PIH treatment (ClinicalTrials.gov registration NCT01936272) have shown no important differences at one year in regard to safety, efficacy, developmental outcome, or brain growth Those achieving normal or near-normal brain volume by 1 year, regardless of preop volume, had the best outcome. The current proposal seeks to accomplish the following aims: 1) test the hypothesis that endoscopic treatment of PIH is better than or equal to shunt placement in regard to five-year neurocognitive development; 2) further develop CCHU as a neuroscience research facility; 3) develop the in-country capacity for sustainable ultra-low-field (ULF) MRI imaging; 4) install optimized ULF-MRI at CCHU; 5) Correlate MRI-derived brain/CSF volume metrics with long-term neurocognitive development following PIH treatment. As planned, the RCT patient study cohort will undergo further developmental assessment using the Bayley Scales of Infant Development (BSID-III) at 24 months post- operatively along with repeat CT-based brain and CSF volume metrics. In the current proposal, developmental assessment will be conducted at 5 years post-treatment using the Vineland-III, as well as an assessment of quality of life. After developing Mbarara University of Science and Technology (MUST) as an ULF-MRI demonstration and resource center, ULF-MRI will be installed at CCHU for evaluation as a volumetric and diagnostic tool compared to CT. Neurocognitive outcome will be correlated with pre- and post-operative MRI- based brain/CSF volumes and treatment modality. Extension of the study will determine whether non-inferiority of ETV/CPC to shunt in regard to developmental outcome and brain growth persists at 5 years post-treatment, whether MRI-based volume metrics effectively supplant CT-based measures, and whether brain and CSF volumetrics prove useful in guiding optimal clinical management. The proposed project will determine whether ETV/CPC is the preferred initial treatment and will further develop research capacity at CCHU.

Project Narrative We have established neonatal postinfectious hydrocephalus (PIH) as a major public health problem in East Africa for which there are two strategies of treatment – shunting versus endoscopic third ventriculostomy + choroid plexus cauterization (ETV/CPC), which we developed – with no definitive evidence supporting which therapy is optimal. Our randomized controlled trial of ETV/CPC vs. shunt for PIH has shown no difference in success rate, developmental outcome or brain growth at one year following treatment, with better outcome among those demonstrating “catch-up” brain growth after treatment. We here propose extended follow up of the existing study cohort to analyze early childhood development at 5 years after treatment and to implement new sustainable ultra-low-field MRI technology for brain and CSF volume metrics to provide an evidence- based foundation for better treatment of such children.