The Role of CSF in Chiari II Brain Malformation

August 19, 2024 updated by: Amparo Saenz, University College, London

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

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

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.

Study Type

Observational

Enrollment (Estimated)

18

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child

Accepts Healthy Volunteers

N/A

Sampling Method

Non-Probability Sample

Study Population

  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

Description

Inclusion Criteria:

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)

Exclusion Criteria:

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Case group 1: Children with Open Spina Bifida and Chiari II Malformation
CSF will be collected during postnatal surgical repair at Great Ormond Street Hospital (GOSH)
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
Control group 1: Newborns with hydrocephalus undergoing shunt surgery, unrelated to spina bifida
CSF will be collected during suregry at GOSH
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
Control group 1bis: Infants undergoing spinal surgery for conditions other than SB
CSF will be collected during surgery at GOSH.
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
Case group 2: Fetuses Undergoing Prenatal Surgery for Spina Bifida
CSF will be collected during prenatal surgery at University College London Hospitals (UCLH).
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
Control group 2: Aborted fetuses within the gestational age range of 22-24 weeks,
CSF will be collected from fetuses provided by the Human Developmental Biology Resource (HDBR).
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
Case group 3: mouse model of spina bifida (Cdx2Cre x Pax3flox)
CSF will be collected
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
Control group 3: normal (wild-type) mice
CSF will be collected
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Identification of Proteins in Cerebrospinal Fluid (CSF)
Time Frame: 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.
1 year
Quantification of Protein Concentrations in Cerebrospinal Fluid (CSF)
Time Frame: 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.
1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Measurement of Neurogenesis in Median Ganglionic Eminence (MGE) Cultures
Time Frame: 1 year
The rate of neurogenesis in the median ganglionic eminence (MGE) of embryonic brain slice cultures will be measured following exposure to cerebrospinal fluid (CSF) from patients with Chiari II malformation and control subjects. The outcome will focus on the number of proliferating neurons per unit area, measured in cells per square millimeter (cells/mm²).
1 year
Measurement of Neuronal Migration in Median Ganglionic Eminence (MGE) Cultures
Time Frame: 1 year
The distance of neuronal migration in the median ganglionic eminence (MGE) of embryonic brain slice cultures will be measured following exposure to cerebrospinal fluid (CSF) from patients with Chiari II malformation and control subjects. The outcome will report the migration distance of neurons, measured in micrometers (µm).
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University College, London

Collaborators

University College London Hospitals
Great Ormond Street Hospital for Children NHS Foundation Trust

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

September 1, 2024

Primary Completion (Estimated)

September 1, 2025

Study Completion (Estimated)

August 1, 2027

Study Registration Dates

First Submitted

August 12, 2024

First Submitted That Met QC Criteria

August 15, 2024

First Posted (Actual)

August 19, 2024

Study Record Updates

Last Update Posted (Actual)

August 21, 2024

Last Update Submitted That Met QC Criteria

August 19, 2024

Last Verified

August 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 23DD12
  • 344434 (Other Identifier: IRAS Number)
  • Z6364106/2024/08/97 (Other Identifier: UCL Data Protection registration number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Becuase the infromation provided comes from susceptible (children) population, information won't be shared

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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