NCT06560788

The Role of CSF in Chiari II Brain Malformation

Chiari II Brain Malformation: The Role of Cerebrospinal Fluid in Neurodevelopmental Defects Associated With Spina Bifida

• Status: Not Yet Recruiting
• Phase: —
• Study type: Observational
• Enrollment: 18 (estimated)
• Sponsor: University College, London · Academic / Other
• Sex: All
• Age: 1 Year
• Healthy volunteers: —

Summary

Spina bifida, particularly its most severe form known as open spina bifida (myelomeningocele), is a significant congenital disorder that results in profound neurological impairments, including Chiari II malformation. This malformation is associated with the downward displacement of the cerebellum and brainstem into the spinal canal, often leading to hydrocephalus, a condition where cerebrospinal fluid (CSF) accumulates in the brain1. These conditions can result in a range of complications, including cognitive and motor disabilities, learning difficulties, and, in severe cases, early mortality1,2. While surgical interventions, including prenatal and postnatal surgeries, have been developed to manage the physical manifestations of spina bifida and Chiari II malformation, these procedures have not been fully successful in addressing the associated brain anomalies3. This study aims to explore the hypothesis that the composition of CSF plays a critical role in the development of these brain defects. Specifically, it is hypothesized that the rapid replenishment of CSF, due to its leakage from the open spine in spina bifida, results in a "less mature" fluid composition, which negatively affects neurogenesis and neuronal migration during critical periods of brain development.

Detailed description

Study Population and Methodology This prospective case-control study will involve the collection of CSF samples from several groups, including: 1. Newborns with open spina bifida undergoing postnatal surgery. 2. Fetuses undergoing prenatal surgery for spina bifida. 3. Newborns with hydrocephalus undergoing shunt surgery (control group). 4. Infants undergoing spinal surgery for conditions unrelated to spina bifida (control group). 5. Age-matched fetuses obtained from the Human Developmental Biology Resource (HDBR) as controls. 6. Mouse models: This includes a genetic mouse model of spina bifida (Cdx2Cre x Pax3flox) and normal (wild-type) mice as controls These samples will be analyzed using mass spectrometry-based proteomics to identify differences in protein composition and concentrations between the groups. Additionally, brain slices from human embryos and mouse models will be cultured in the presence of these CSF samples to assess the impact on neurogenesis and neuronal migration. Expected Benefits The findings from this study are expected to provide new insights into the pathogenesis of Chiari II malformation and other associated brain anomalies in children with spina bifida. By understanding how CSF composition influences brain development, the study could pave the way for novel therapeutic strategies aimed at modifying CSF composition during early pregnancy. This could potentially prevent or mitigate the neurological impairments associated with spina bifida, ultimately improving the quality of life for affected individuals. Impact on Clinical Practice and Policy Should the study confirm the hypothesis, it could lead to changes in clinical practices concerning the management of spina bifida and Chiari II malformation. For instance, it might inform the development of new prenatal treatments or interventions designed to normalize CSF composition before significant brain damage occurs4-6. This would represent a significant advancement in fetal surgery and pediatric neurosurgery, with the potential to influence guidelines and policies within the NHS and other healthcare systems globally. Relation to Academic Qualification This study is being conducted as part of the Lewis Spitz PhD program at University College London (UCL) and Great Ormond Street Institute of Child Health (GOSH ICH). The research builds upon previous studies sponsored by UCL-ICH/GOSH, particularly those investigating the neurodevelopmental consequences of spina bifida and related congenital conditions.

Conditions

• Myelomeningocele
• Brain Malformation
• Chiari Malformation Type 2

Interventions

Type	Name	Description
OTHER	collection of cerebrospinal fluid	CSF is collected as part of routine care in any of the surgeries listed in the control or cases groups. We will take part of that CSF for proteomic analysis

Timeline

• Start date: 2024-09-01
• Primary completion: 2025-09-01
• Completion: 2027-08-01
• First posted: 2024-08-19
• Last updated: 2024-08-21