Chiari II Brain Malformation: The Role of Cerebrospinal Fluid in Neurodevelopmental Defects Associated With Spina Bifida
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 18
- 主要终点
- Identification of Proteins in Cerebrospinal Fluid (CSF)
研究概览
简要总结
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.
详细描述
Study Population and Methodology
This prospective case-control study will involve the collection of CSF samples from several groups, including:
- Newborns with open spina bifida undergoing postnatal surgery.
- Fetuses undergoing prenatal surgery for spina bifida.
- Newborns with hydrocephalus undergoing shunt surgery (control group).
- Infants undergoing spinal surgery for conditions unrelated to spina bifida (control group).
- Age-matched fetuses obtained from the Human Developmental Biology Resource (HDBR) as controls.
- 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.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Prospective
入排标准
- 年龄范围
- — 至 1 Year（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newborns with Spina Bifida (Postnatal Closure)
- •Diagnosed with open spina bifida (myelomeningocele).
- •Scheduled for postnatal surgical closure of the spinal lesion at Great Ormond Street Hospital (GOSH).
- •Age: Between 1 day to 1 year old.
- •Control Group 1 (Newborns with Hydrocephalus)
- •Newborns scheduled for shunt surgery for hydrocephalus unrelated to spina bifida.
- •Age and sex matched to the spina bifida newborns as closely as possible.
- •Age: Between 1 day to 1 year old.
- •Control Group 2 (Infants with Spinal Conditions Unrelated to Spina Bifida)
- •Infants undergoing paned spinal surgery for conditions such as spinal lipoma, fatty filum, tethered cord, etc.
- •Age and sex matched to the spina bifida newborns as closely as possible.
- •Age: Between 1 day to 1 year old. Fetuses with Spina Bifida (Prenatal Closure)
- •Prenatal diagnosis of spina bifida (myelomeningocele) and scheduled for fetal surgery at UCLH.
- •Reviewed by Mr Thompson at his outpatient clinic at GOSH
- •Gestational age: Between 22 and 24 weeks.
- •Control Fetal Samples
- •Aborted fetuses within the gestational age range of 22-24 weeks.
- •Samples obtained through the Human Developmental Biology Resource (HDBR).
- •Mouse Models
- •Genetic mouse model of spina bifida (Cdx2Cre x Pax3flox).
- •At embryonic day (E)13.5 (end of the embryonic period) and E18.5 (just before birth)
- •Control Mouse Models
- •Normal (wild-type) mice to serve as controls.
- •Normal brain development
- •At embryonic day (E)13.5 (end of the embryonic period) and E18.5 (just before birth)
排除标准
- •Newborns with Spina Bifida (Postnatal Closure)
- •Newborns who have undergone previous surgical intervention.
- •Presence of additional unrelated congenital anomalies that could affect cerebrospinal fluid (CSF) composition like meningitis or intraventricular bleeding
- •Older than 1 year and 1 month of age.
- •Parents refused to participate
- •Native language different to English with no translation services available
- •Control Group 1 (Newborns with Hydrocephalus)
- •Newborns with hydrocephalus caused by spina bifida.
- •Presence of intraventricular infection or haemorrhage.
- •Older than 1 year and 1 month of age.
- •Parents refused to participate
- •Native language different to English with no translation services available
- •Control Group 2 (Infants with Spinal Conditions Unrelated to Spina Bifida)
- •Infants who were born with spina bifida
- •Infants with coexisting conditions that could affect CSF composition like intraspinal tumours, empyema or haemorrhage.
- •Older than 1 year and 1 month of age.
- •Parents refused to participate
- •Native language different to English with no translation services available
- •Fetuses with Spina Bifida (Prenatal Closure)
- •Fetuses with additional major anomalies unrelated to spina bifida like diaphragmatic hernia.
- •Gestational age outside the range of 22-24 weeks.
- •Surgery performed by other neurosurgery team (not GOSH)
- •Parents refused to participate
- •Native language different to English with no translation services available
- •Control Fetal Samples
- •Poorly preserved aborted fetuses not suitable for CSF collection.
- •Gestational age outside the range 22-24 weeks.
- •Mouse Models
- •Mice with any genetic modifications other than those specified for the spina bifida model.
- •Mice with other congenital or acquired anomalies affecting the central nervous system.
- •Control Mouse Models
- •● Mice with any genetic modifications or health conditions that could influence the study's outcomes.
结局指标
主要结局
Identification of Proteins in Cerebrospinal Fluid (CSF)
时间窗: 1 year
The presence of specific proteins in cerebrospinal fluid (CSF) will be identified through proteomic analysis. This outcome will focus on categorizing which proteins are present in the CSF samples from patients with spina bifida and control participants.
Quantification of Protein Concentrations in Cerebrospinal Fluid (CSF)
时间窗: 1 year
The concentration of each identified protein in cerebrospinal fluid (CSF) will be measured using proteomic analysis. This outcome will report the amount of each protein present in the CSF, expressed in micrograms per milliliter (µg/mL) or nanograms per milliliter (ng/mL), allowing for comparison between patients with spina bifida and controls.
次要结局
- Measurement of Neurogenesis in Median Ganglionic Eminence (MGE) Cultures(1 year)
- Measurement of Neuronal Migration in Median Ganglionic Eminence (MGE) Cultures(1 year)
研究者
Amparo Saenz
PhD student and pediatric neurosurgeon
University College, London