Abstract
Cerebrospinal fluid is the metabolic powerhouse for the brain: a comparison of normal and Parkinson’s brain tissues
1Division of Neuroscience, Faculty of Biology, Medicine & Health, The University of Manchester, UK
Cerebrospinal fluid has been viewed as a waste disposal pathway for metabolism occurring in the brain. Little attention has been paid to its role in nutrient supply or neurotransmitter metabolism. The presence of folate metabolic enzymes and enzymes for neurotransmitter synthesis, including ALDH1L1, MTHFD1, MTHFR, DHFR and Tyrosine hydroxylase (TH), together with our previous studies showing dramatic changes in the metabolic profile of CSF in hydrocephalus, led us to explore whether metabolism was occurring in CSF and how this related to tissue metabolism.
Western blotting identified the presence or absence of enzymes in CSF and tissue. Enzyme assays for CSF and brain tissue lysates were conducted by adding the substrate and energy source for each enzyme and monitoring the reaction using a multiplate reader.
In normal brains MTHFD1and MTHFR were low in tissue, but ALDH1L1, DHFR and TH were high. ALDH1L1 and TH also showed activity in CSF and tissue. MTHFR, MTHFD1 and DHFR activity were present in CSF but not in tissue. We also investigated Parkinson’s disease (PD) as it has been associated with normal pressure hydrocephalus. MTHFD1, MTHFR and DHFR were deficient in PD CSF and tissue, but ALDH1L1 and TH were present in high amounts in CSF and low in tissue. Surprisingly, only ALDH1L1 had demonstrable enzyme activity in PD with no activity detectable for other enzymes in either CSF or tissue.
The presence and activity of enzymes involved in important metabolism in CSF as compared to tissue demonstrates that CSF plays a significant role in metabolism and production of essential metabolites required by neurons. From our data we can hypothesize that there is an error/block in these pathways preventing enzyme activity and resulting in the metabolic faults responsible for PD. Absence of CSF DHFR activity was surprising and suggests a possible role in transport of its metabolite from CSF to tissue.
Deciphering the potential fault in hepatic folate metabolism in a rat model of spina bifida with hydrocephalus comorbidity
1Healthcare Biotechnology Department, Atta-ur-Rehman School of Applied Biosciences, National University of Sciences and Technology (NUST), Islamabad, Pakistan
Folate, a water-soluble B vitamin, plays a vital role in DNA synthesis, metabolism, and neural tube development. Folic acid, a synthetic form of folate, requires conversion to tetrahydrofolate (THF) for cellular processes. Maternal folate deficiency is associated with developmental defects like spina bifida (SB) and hydrocephalus (HC). SB is caused by incomplete neural tube fusion, often comorbid with HC and treated clinically with folic acid. Maternal folic acid supplementation is reported to reduce the occurrence of SB, yet approximately 300,000 cases with 88,000 deaths occurs per year worldwide. This study hypothesized that there might be a potential fault in the hepatic folic acid metabolism affecting THF conversion and aims to analyze it in a rat model of SB-HC comorbidity. Furthermore, it aims to compare the maternal bioactive folate supplementation to the folic acid supplementation impact on SB-HC susceptibility. Therefore, a rat model was generated using valproic acid (VPA). Animals were categorized into three groups; healthy control (untreated), diseased control (treated with VPA on embryonic day (E) 10), and diseased treatment group. The diseased treatment group was subcategorized into folic acid, folinic acid and a combination of folinic acid and THF. These folates were administered subcutaneously one week before mating and throughout the pregnancy alongside VPA at E10. Dams were sacrificed at E20 and samples were collected.
Biochemical profile of maternal serum indicated an upregulation of bilirubin, alanine aminotransferase, alkaline phosphate, uric acid, urea, and creatinine in diseased group, indicating the detrimental impact of VPA during pregnancy. However, treatment groups, notably combination showed downregulation of serum profile, indicating a maximum efficacy against VPA. SB-HC comorbidity was confirmed with fetus gross appearance. Hematoxylin and eosin (H&E) staining validated the disease comorbidity with enlarged ventricles, reduced cortical thickness, CSF accumulation and the presence of spinal sac. However, abnormalities were reduced in treatment groups. The H&E of fetal liver tissue showed morphological differences, but treatment with bioactive folates restored these. Further analysis using WB and immunohistochemistry will evaluate folate metabolism changes.
Non-invasive MRI of blood-CSF-barrier function: A novel tool for assessment of pharmacological management of intracranial pressure and in an experimental model of hydrocephalus
1Centre for Advanced Biomedical Imaging, University College London, London, UK; 2UCL Queen Square Institute of Neurology, University College London, London, UK; 3Centre for Cardiovascular and Metabolic Neuroscience, University College London, London, UK
Raised intracranial pressure (ICP) is a defining feature of idiopathic intracranial hypertension (IIH) as well as common forms of hydrocephalus. Hypersecretion of cerebrospinal fluid (CSF) at the blood-CSF-barrier (BCSFB) in the choroid plexus has been implicated in the development of these neurologic conditions. There is currently an absence of non-invasive means of measuring BCSFB function, preventing effective monitoring of CSF-production targeted therapy. In this study, we demonstrate how a novel and non-invasive MRI method can capture changes in BCSFB function that underlie pharmacological modulation of ICP and pathological development in a preclinical model of hydrocephalus.
ICP was measured from the lateral ventricles using a fluid-filled pressure sensor (Digitimer) in isoflurane-anaesthetised male C57BL6J mice. Hydrocephalus was induced by intracerebroventricular injection of 2mM FeCl3. We recently developed an MRI technique to assess BCSFB-function which measures the rate of flux of labelled blood-water into CSF. BCSFB-function and ventricular volume were acquired at 9.4T (Bruker) using BCSFB-ASL and high resolution T2-weighted imaging. In order to try to reduce ICP and hydrocephalus pathology, aminophylline was administered following baseline recordings or surgery.
Aminophylline administration resulted in a dose dependent decrease in ICP with concomitant decrease in non-invasive MRI measures of BCSFB function. In the hydrocephalus model, defined by ventriculomegaly, BCSFB-function was increased relative to baseline but decreased following aminophylline treatment.
Here we demonstrate that we are now able to measure the action of drugs to decrease ICP by targeted downregulation of BCSFB function using non-invasive and translational MRI methods. Secondly, our data suggests that the MRI method can capture upregulation of BCSFB function in an experimental model of hydrocephalus together with modulation by aminophylline treatment. As such, this translational method may therefore have potential to inform therapy for IIH and hydrocephalus.
Distribution and localisation of the water channel, AQP4, in organotypic brain slice cultures
1School of Biosciences, College of Health and Life Sciences, Aston University, UK; 2Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, UK
Aquaporins (AQP) are water channels found throughout the body. In the brain, AQP1 is expressed in choroid plexus epithelial cells and ependymal cells, and AQP4 in astrocytes. Astrocytes regulate brain water homeostasis by relocalising AQP4 from intracellular vesicular pools to the cell surface, with the highest density of AQP4 found at the astrocyte endfeet covering cerebral blood vessels. This subcellular relocalisation of AQP4 has a crucial role in the regulation of AQP4 function that is independent of AQP4 expression.
The glymphatic system contributes to clearing waste products and neurotoxic agents, such as amyloid-β from the brain, and its dysfunction has been implicated in pathological conditions such as Alzheimer’s disease, haemorrhagic stroke and hydrocephalus. Due to the enrichment of AQP4 localisation on astrocyte endfeet at the blood brain barrier, AQP4 is thought to have a role in glymphatic function, especially as a lack of AQP4 has been shown to reduce fluid clearance.
Recently, organotypic brain slice cultures (OBSCs) have been used to model diverse diseases in vitro. Although we cannot model the glymphatic system in vitro, we can modulate its cellular and structural elements. However, we do not fully understand the implications of having no blood flow through cerebral blood vessels in OBSCs, and AQP4 localisation in astrocytes may be affected. To investigate this, the distribution and localisation of AQP4 were compared between acute OBSCs and those that had been cultured (with no blood flow) for 8 days. Immunohistochemistry was performed to visualise and quantify the changes in the distribution and localisation of AQP4 in astrocytes between acute and cultured OBSCs.
Understanding the distribution and localisation of AQP4 in response to the lack of blood flow in the OBSC model will aid in future research using OBSCs to investigate elements of the glymphatic system and contribute to the development of therapies to promote fluid clearance.
An in vitro model of post-haemorrhagic hydrocephalus
1Inflammation and Ageing, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, UK
Post-haemorrhagic hydrocephalus (PHH) is a serious, life-threatening condition, typically caused by haemorrhagic stroke, including sub-arachnoid haemorrhage (SAH) and intraventricular haemorrhage (IVH). PHH has been shown to exacerbate secondary brain injury, but also has been associated with advanced brain ageing and the onset of age-related neurodegenerative disorders, including dementia. PHH is hypothesised to be triggered by fibrosis of cerebrospinal fluid (CSF) outflow channels along the dural lymphatic and glymphatic pathways, though the mechanism underlying this is unclear.
The present work employed organotypic brain slice cultures (OBSCs) from adult rats as an in vitro model of haemorrhagic stroke to build understanding of the mechanisms behind blood-induced fibrosis. Cultures were maintained at the air-liquid interface in a novel serum-free media formulation for 7 days prior to exposure to autologous blood for 6, 24 and 48 hours. Immunohistochemistry was performed on OBSCs to assess the viability of slices, levels of laminin and fibronectin expression around cortical blood vessels along the glymphatics pathways, and the expression of connective tissue growth factor (CTGF), a potent fibrogenic molecule. Finally, the effects of decorin, a TGF-β1 antagonist that has previously shown promise in reducing fibrosis in a kaolin model of juvenile communicating hydrocephalus, will be assessed in the OBSC cultures.
Developing an in vitro model of haemorrhagic stroke will enable us to further our understanding of pathological mechanisms and assess the efficacy of potential therapeutic agents in vitro before moving them into in vivo PHH models.
Evolution of the inflammatory and edematous processes in the periventricular area during the onset of experimental posthemorrhagic hydrocephalus. Effect of a stem cell-based therapy
1Departamento de Fisiologia Humana, Histologia Humana, Anatomia Patologica y Educacion Fisica y Deportiva. Universidad de Malaga. Spain; 2Instituto de Investigacion Biomedica de Malaga- Plataforma BIONAND, Spain; 3Departamento de Biologia Celular, Genetica y Fisiologia Animal. Universidad de Malaga, Spain
Germinal matrix and intraventricular hemorrhages often lead to posthemorrhagic hydrocephalus (PHH), a severe cause of morbidity and mortality in premature neonates. Hemorrhages disrupt the ependyma, causing dysfunction in cerebrospinal fluid homeostasis, circulation, and in neurogenesis. Also, blood products from the bleeding and ependyma disruption shoot an inflammatory process. Together, these processes lead to a severe modification of the periventricular brain tissue: loss of ependyma lining, reaction of periventricular astrocytes that form a new layer, activation of microglial cells with inflammatory activity, degeneration of the periventricular tissue, and an increasing brain parenchyma edema.
So, ependyma restoration and modulating the inflammatory process have evolved as central actors in the look for new non-surgical treatments in the PHH.
Experimental pediatric PHH was induced using collagenase injection in the germinal matrix. As stem cell therapy, we used a combination of mesenchymal stem cells and ependymal progenitors injected into the lateral ventricles.
The inflammatory process was studied using specific cell markers and confocal microscopy. The edema’s extension, severity, and evolution were analyzed and quantified using an Evans Blue Assay.
Differences in the distribution and morphology of microglial cells can be detected between periventricular areas with an ependyma lining, areas without ependyma, and without ependyma but with an astrocytic glial scar. Differences in the severity of edema can also be found. Stem cell-based therapy also affects edema and inflammatory reactions in experimental pediatric PHH.
Interaction between ependymal, astroglial, and microglial cells are modified with the stem cell treatment in PHH.
Human Mesenchymal Stem Cells and its Exosomes in Posthemorrhagic Hydrocephalus: A Focus on Edema and Ependymal Repair
1Departamento de Biologia Celular, Genetica y Fisiologia Animal. Universidad de Malaga. 29071, Spain; 2Instituto de Investigacion Biomedica de Malaga - IBIMA, Spain; 3Departamento de Fisiologia Humana, Histologia Humana, Anatomia Patologica y Educacion Fisica y Deportiva. Universidad de Malaga, Spain
Germinal matrix hemorrhages and intraventricular hemorrhages (GMH/IVH) often lead to posthemorrhagic hydrocephalus (PHH), a severe cause of morbidity and mortality in premature neonates. GMH/IVH is known to disrupt the ependyma, which forms a functional and physical barrier between the cerebrospinal fluid (CSF) and the brain tissue. Consequently, CSF circulation and physiology are severely affected; and thus, ependyma is a chiefly important target when it comes to designing PHH treatments. Bone marrow-derived mesenchymal stem cells (MSCs) are extremely effective anti-inflammatory agents which have already shown positive results regarding PHH treatment. However, there is no therapy to recover the ependyma in humans.
Human MSCs were cultured under inflammatory or non-inflammatory conditions to extract and purify their correspondent exosomal fraction through sequential centrifugation steps. The effect on the ependymal differentiation and ciliogenesis was tested in vivo and in vitro. Also, the effect on the parenchymal edema was assesed in vivo on a PHH surgical model. Conditioned and non-conditioned exosomes were used. Ventricular wall explants were analysed through confocal microscopy. The exosomes were functionally characterised through proteomics.
Firstly, no rejection of the human MSCs nor of their exosomes is observed. Both MSCs and exosomes have a posititve effect on ciliogenesis and edema proportion and severity. This also indicates that exosomes are able to partially reproduce the human MSCs therapeutic effect in vitro and in vivo. Functional enrichment of proteomics gives some insight on the mechanism that makes the therapy possible.
Transition of hydrocephalus patients from paediatric to adult neurosurgery: long term outcomes and single institution experience
1Department of Neurosurgery, The National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, United Kingdom; 2UCL Institute of Neurology, University College London, United Kingdom; 3University College London Medical School, London, United Kingdom
The transition process from paediatric to adult neurosurgery is an essential part of patient’s care. This study aims to report long-term outcomes of patients with hydrocephalus as well as our institution’s experience with the transition process.
This is a single centre retrospective case series study involving patients with paediatric hydrocephalus transitioned to adult neurosurgery. Demographic, clinical and imaging data was derived from the patients’ charts. Data collection centers on the three overarching categories: paediatric past medical history, the transition process, and long-term outcomes which are reinforced through the use of interview surveys.
A total of 227 patients were included with a mean age of 32 years (range: 16-68 years; SD+/-11.9). 122 patients were transitioned from the nearest paediatric center, Great Ormond Street Hospital and 105 from other national and international hospitals. The most common aetiology was post-haemorrhagic hydrocephalus (19.8%) followed by hydrocephalus in the context of dysraphism (12.7%), aqueduct stenosis (12.7%) and congenital hydrocephalus (8.81%). In 16.7% no cause could be identified, due to insufficient documentation. 171 (75.3%) patients were seen electively, whereas 37 (16.3%) presented with suspicion of acute shunt dysfunction. Further 19 (8.4%) were referred by other specialists after the patients were lost to follow up. Patients presenting acutely were more likely to come from other centers (26.7%) compared to Great Ormond Street Hospital (7.37%) (p<0.005; Wilcoxon Signed Rank). 66/227 (29%) patients underwent at least a CSF diversion intervention in adulthood and 76.2% of the initial conservatively managed patients required surgery. Up to 70% of the patients experience symptoms such as headaches and fatigue.
Hydrocephalus is a condition that requires lifelong neurosurgical follow up and individuals with hydrocephalus may exhibit heightened rates of seeking medical attention. A more structural approach towards transition is needed.
Waite Hydrocephalus Student Bursary Award 2023: Investigating the therapeutic potential of bioactive folates in spina bifida with hydrocephalus comorbidity
1Atta Ur Rehman School of Applied Biosciences, National University of Science and Technology, Islamabad (44000), Pakistan
Folate is an umbrella term used collectively for synthetic folic acid (FA) and bioactive forms like tetrahydrofolate (THF), and folinic acid (FLA). Folates are crucial compounds to the entire process of pregnancy. Reduced maternal folate levels are associated with neural tube defects (NTDs) such as spina bifida which is often comorbid with hydrocephalus. Maternal folic acid supplementation is reported to reduce the occurrence of spina bifida, yet its annual cases are approximately 300,000 with 88,000 annual deaths worldwide. This highlights a need to look for something more promising than folic acid supplementation. The main objective of the current study is to understand the cause of spina bifida comorbid with hydrocephalus and to investigate whether this comorbidity can be prevented using bioactive folates.
For that purpose, a rat model was generated using valproic acid (VPA), an effective antiepileptic drug, yet, its use during pregnancy leads to increased risk of teratogenesis such as NTDs. Animals were categorized into three groups; healthy control (untreated), diseased control (treated with VPA at embryonic day10 (E10)), and diseased treatment group. The diseased treatment group was subcategorized into three groups that received FA, FLA and a combination of FLA and THF respectively. Folates were administered subcutaneously one week before mating and throughout the pregnancy, in addition to the VPA administration at E10.
Dams were sacrificed at E 20 and fetus were collected. Hematoxylin and eosin (H&E) staining was performed on the sagittal sections of the fetus. The results indicated an altered brain morphology, increased ventricle size, decreased cortical thickness and presence of a sac in diseased control group. FA and FLA supplementation partially restored the fetal brain morphology, cortical thickness, spina bifida sac with an increase in cellular proliferation. However, brain and spine morphology was completely morphologically restored in the fetuses of group treated with FLA and THF. These initial finding suggests that a combination of bioactive folates such as FLA and THF might be more efficient and effective in preventing spina bifida comorbid with hydrocephalus. Molecular assays are underway to further corroborate these findings and to understand the cause that leads to this comorbidity.
Waite Hydrocephalus Student Bursary Award 2023: Characterising IVH-induced Hydrocephalus using Surface-Enhanced Raman Spectroscopy (SERS)
1Leeds General Infirmary, LTHT, England, UK; 2Neurosurgery Department, SUNY Upstate Medical University, New York, USA; 3Biomedical Engineering Department, SUNY Binghamton University, New York, USA; 4Siena College, New York, USA
Hydrocephalus is a neurological disorder characterized by excessive accumulation of cerebrospinal fluid (CSF) in the ventricles, affecting approximately 85 per 100,000 individuals worldwide. It can lead to severe cognitive and physical impairments. This study aims to investigate whether the composition of CSF in hydrocephalus differs from normal conditions using Surface-Enhanced Raman Spectroscopy (SERS). The hypothesis is that hydrocephalus results from impaired clearance of macromolecules, leading to altered CSF composition.
An intraventricular haemorrhage (IVH)-induced hydrocephalus model was developed in rats. CSF samples were collected and analysed using Raman spectroscopy at varying laser wavelengths. Gold nanoparticles (AuNP) were used to enhance signal acquisition, and samples were processed using commercial SERS substrates to ensure uniform signal detection. Data analysis included principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) to identify spectral differences between normal and hydrocephalic CSF.
Spectral analysis revealed distinct differences between normal and hydrocephalic CSF samples. Specific biomarkers associated with protein aggregation and macromolecule retention were identified, supporting the hypothesis of altered CSF composition in hydrocephalus. The study also observed the “coffee ring” effect on SERS substrates, indicating uneven protein distribution, which was accounted for during analysis.
The findings demonstrate that SERS is a viable tool for characterizing CSF composition changes in hydrocephalus. The observed spectral differences provide insights into the pathophysiology of hydrocephalus and may contribute to early diagnostic methods. The study’s approach, combining Raman spectroscopy with nanomaterial-enhanced detection, offers a non-invasive and sensitive method for CSF analysis.
This study highlights the potential of SERS as a diagnostic tool for hydrocephalus by detecting macromolecular retention in CSF. Future research should focus on clinical validation and potential translation into patient diagnostics.
Waite Hydrocephalus Student Bursary Award 2023: Hypoxia results in ventricular enlargement in adult mice mimicking normal pressure hydrocephalus
1University of Manchester, Manchester, UK; 2University of Seville, Seville, Spain
30% of neonates suffering birth asphyxia develop hydrocephalus while the remainder show ventricular enlargement and/or life-long neurological issues including cerebral palsy. In later life, up to one third of adults show ventricular enlargement and suffer normal pressure hydrocephalus (NPH) and dementia. We used a mouse model of hypoxia developed by the group at Seville to understand how such an insult can cause ventricular enlargement and/or hydrocephalus, as well as investigating changes to the cerebral folate system.
All experiments were performed under European 2010/63/EU and Spanish RD/53/2013 directives on the protection of animals used for scientific purposes. The study was approved by the Animal Research Committee of Virgen del Rocío University Hospital (26/01/ 2017/017; University of Seville). 4 pregnant dams were kept in controlled conditions (temperature 22C, 12hr light-dark cycle) until they delivered their 14 pups. 2 mothers plus 7 pups remained in normal conditions (normoxia, NX), and 2 mothers plus 7 pups in hypoxia (HX) conditions (with 10% oxygen) in a hermetically sealed chamber in which they stayed for 5 days. The pups were sacrificed on P8 and rapidly frozen for cryosectioning and immunohistochemistry. Sections were stained onto nitrocellulose membrane, glass slides, and free-floating. They were stained for glial fibrillary acidic protein (GFAP), folate receptor 1 (FOLR1), aldehyde dehydrogenase 1 family member L1 (ALDH1L1), and folate.
In the HX membrane samples, a notable increase in both 5-methyltetrahydrofolate (5MTH) and folate receptor-alpha (FR-alpha) suggests a heightened response to hypoxia which potentially indicates a regulatory mechanism or adaptive response to low oxygen levels. The absence of 10-formyltetrahydrofolate dehydrogenase (FDH) in cerebrospinal fluid (CSF) of HX samples (where only astrocyte end processes are stained) aligns with observations in human asphyxia cases, where zero FDH is typically found in the CSF. This further shows the specificity of using FDH as a marker for hypoxia-related conditions. In contrast, the NX membrane samples showed the presence of FDH (lower levels than HX samples), and less GFAP was staining in NX compared to HX samples. These findings would suggest that under NX conditions, the cellular response involves maintaining some level of FDH expression whilst modulation astrocyte activity (possibly to counteract the effects of lower oxygen availability). It also supports the notion that hypoxia affects the folate system and suggests a compensatory response or adaptive mechanism to the mice attempting to maintain folate homeostasis under NX. The decreased expression of key markers in HX samples (especially in membrane HX) highlights the impact of hypoxia on the folate system and specific protein markers. The limited staining observed from the samples collected onto glass slides is due to only tissue being visible (no CSF) on the glass, compared to the membranes (CSF visible). The link between hypoxia and ventricular enlargement presents a plausible mechanism for how hypoxia may contribute to compromised CSF drainage and associated disruptions in folate availability associated with birth asphyxia and later-life NPH.
What are the current risks from audiological transducer on programmable ventriculoperitoneal shunts?
1Manchester Centre for Audiology and Deafness, University of Manchester, UK
Hearing assessment involves the use of headphones, insert earphones and bone-conduction devices all of which are place on the head of the person being assessed. Individuals with hydrocephalus frequently require hearing assessed particularly in the newborn period. Following concerns raised about the possibility of accidental reprogramming of ventriculoperitoneal shunts, the British Society of Audiology published guidance in 2019 for audiology professionals to minimise this risk when assessing hearing. In recent years, the concerns about this risk have changed, and manufacturers of some audiological devices have highlighted devices which they report do not carry this risk. This has prompted a study which aims to contribute to updating the position of the British Society of Audiology on this issue.
Research Question: Do current clinically available transducers used in audiological assessment cause programmable shunts to be reprogrammed?
In an electrically shielded room the magnetic field strength (mT) of a range of clinically available transducers is measured from a range of distances and positions using a direct current (DC) magnetic field measurement probe. These transducers are also positioned directly on the valves to assess whether the settings for valves are adjusted for a range of stimulus intensities, site positions and movements that are typically associated with transducer placement during hearing assessment.
Outcomes of measures will be presented and discussed in the context of recommendations that can be made for audiological assessment.
Norman Guthkelch Award 2024 Plenary Presentation: Analyzing cerebrospinal fluid dynamics in ventricular catheters for pediatric hydrocephalus
1Wayne State University, Detroit, Michigan, US
Hydrocephalus treatment involves the implantation of a silicone ventricular catheter (VC) into the ventricles to drain excess fluid. However, the VC failure rate is 50% within two years due to mechanical obstructions of the drainage holes. Incremental progression has been made with VC design apart from antibiotic impregnation. Prior work using computational fluid dynamics (CFD) has used a cylinder to replicate a hydrocephalic ventricle to study cerebrospinal fluid (CSF) behavior in VCs. Accurate representation of (CSF) flow patterns is complex in these models because of the need for dynamic ventricular shapes. Capturing the complex ventricular morphology is imperative to investigate CSF flow patterns. We conducted a comprehensive analysis to explore how cerebrospinal morphological changes influence ventricle fluid flow. Using patient-specific ventricles generated from MRIs, we investigate the impact of ventricular size and shape on flow dynamics inside VC drainage holes and lumen by quantifying mass flow rate, shear stresses, and pressure gradients over the cardiac cycle. We will elucidate the influence of ventricular size and surgical trajectory on these parameters to optimize VC design. We answer the clinical question of how ventricular morphology affects CSF flow rate in catheters over time. By understanding how ventricular size and shape changes influence flow dynamics, we can provide neurosurgeons with insights into expected shunt performance and potential failure. This analysis will improve clinical prediction how ventricular changes over a patient’s life impact catheter function, guiding more effective treatments for hydrocephalus.
Deidentified, patient-specific MRI scans were used to create 3D ventricular renders for CFD simulation. Commercial catheters from a pediatric patient biobank were scanned under confocal microscopy to create 3D renders of the catheters. Catheters were inserted into the lateral ventricles using Kocher’s, Keen’s, and Frazier’s landmark trajectories. Boundary conditions such as CSF secretion from the choroid plexus, cardiac-driven ventricular pulsations, and intracranial pressure were assigned to the ventricular domain with a constant pressure outlet at the VC exit. A laminar transient flow model was assigned to the simulation. Flow parameters, including mass flow rate, velocity, shear stresses, pressure gradients, and velocity streamlines, were quantified in the catheter drainage holes and lumen during the cardiac cycle.
Data analysis reveals that catheters positioned using Kocher’s approach are associated with significant reductions in mass flow rates, shear stress, and pressure gradients at the catheter holes during transient ventricular size changes. In contrast, catheters placed at Frazier’s and Keen’s points exhibit stable flow rates under similar conditions. Placement at Kocher’s point causes the catheter to contact the ventricular wall and parenchyma, inducing turbulent mixing at the catheter holes, which affects mass flow distribution into the drainage holes. Moreover, catheters inserted into the ventricular horns via Kocher’s point increase contact with the parenchyma as the ventricles decrease in size, affecting more drainage holes compared to placements at Frazier’s and Keen’s points, where catheters remain within the ventricular cavity. This placement leads to unsteady velocities, particularly when some holes shear the roof of the frontal horn and become partially exposed to brain parenchyma. This exposure impedes proper flow output and necessitates CSF flow redistribution to other drainage holes.
Morphological changes in the ventricles impact cerebrospinal fluid flow dynamics in VCs, particularly when the ventricular wall contacts the ventricular catheter. These insights underscore the importance of considering patient-specific ventricular characteristics in optimizing ventricular catheter design and placement strategies to mitigate failure.
Preclinical models of the ciliated ependyma
1Institute of Child Health, University College London, UK
The walls of the ventricular system within the brain are lined by cilia which project into the cerebrospinal fluid (CSF). Multiple motile cilia project out from the ependymal cells, and, through coordinated and rhythmical beating, are thought to play a role in maintaining laminar flow across the ventricular surface. Non motile cilia, arising from neural stem progenitor cells (NSPC) (within the subventricular zone (SVZ)) and CSF contacting neurons, whilst less common, are similarly seen lining the ventricle and are thought to play a role in controlling NSPC division and differentiation within the SVZ and brain homeostasis respectively.
The ciliated ventricular border thus plays a critical role in the developing brain and beyond, acting as both a protector and gatekeeper to the underlying parenchyma, controlling influx and efflux across the CSF to brain interstitial fluid interface.
Whilst damage to the ventricular cilia, in both transgenic mouse models and following intraventricular injection (e.g., blood, collagenase etc), has been shown to cause hydrocephalus, the role of ventricular cilia in the evolution of hydrocephalus in the human brain remains contentious. However, damage to the ventricular lining, with denudation of the ependyma, is commonly seen at autopsy, for example following intraventricular haemorrhage or ventriculitis, and protection and or replacement of the ependyma is now recognised as a key potential future therapy, both to prevent the evolution of hydrocephalus and to improve neurological outcome following insult.
Despite its seemingly critical function and potential for therapeutic intervention, in comparison to other ciliated interfaces within the body, research into the ependymal cilia remains minimal. In this presentation I will present my work exploring preclinical models of the ciliated ependyma, focusing on the use of high-speed video microscopy, electron microscopy (including 3-view scanning), ependymal cell culture and immunohistochemistry.
Sleep stages variation in intracranial pressure and pulse amplitude
1Victor Horsley Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, UK; 2Department of Clinical and Experimental Epilepsy, National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, UK; 3Department of Neuroanaesthesia and Intensive Care, National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, UK
It is thought that CSF pulsatility has an important role in brain physiology during sleep. Yet few studies have looked into changes of ICP and pulsatility during sleep. This study’s objective was to elucidate whether there is sleep stage related variability in intracranial pressure and pulse amplitude.
A single centre prospective cohort study. Patients undergoing 24h ICP monitoring for suspected CSF dynamic disorders underwent concomitant polysomnography. Clinical and radiological presentation were derived from the patient’s records. Aggregate mean ICP and pulse amplitude (mPA) values were recorded for each sleep stage. Sleep staging was performed in conformity with the AASM guidelines. Within subject values were compared using repeated-measures, one-way ANOVA. Post-hoc paired t-tests were used to compare sleep stages between groups corrected for multiple comparisons (Benjamini-Hochberg method).
A total of 12 patients (10 females, 2 males; mean age 40.8 years, SD+/- 12.9) with complete data were analysed. There were significant differences in mean ICP between sleep stages (F(3,33)=10.7, p< 0.00001). Post-hoc paired t-tests revealed significant differences between rapid eye movement (REM; mean ICP 14.4mmHg) and all other sleep stages (mean ICP/N1=12.0mmHg, t=-3.6, p=0.004; ICP/N2=11.8mmHg, t= -4.3, p=0.001; ICP/N3=12.3mmHg, t=-3.5, p=0.004). Significant differences were also found in mPA between sleep stages (F(3,33)= 5.7, p=0.003) confirmed on post-hoc paired t-tests: REM (mean mPA 5.5mmHg and all other sleep stages: mPA/N1=4.7mmHg, t=-2.3, p=0.04; mPA/N2=4.3mmHg, t=-2.7, p=0.02; mPA/N3=4.5mmHg, t=-2.3, p=0.04).
REM is characterized by higher ICP and mPA values, result confirmed in near-normal patients included in this cohort.
Performance of the Segment Anything Model for Ventricular Segmentation in Normal Pressure Hydrocephalus
1Johns Hopkins Hospital, Baltimore, US
Normal pressure hydrocephalus (NPH) is a disorder characterized by the accumulation of cerebrospinal fluid in the lateral ventricles resulting in a treatable form of dementia. Deep learning models may facilitate earlier and more accurate diagnosis of NPH by estimating ventricular volume. The Segment Anything Model (SAM) is the first foundational model for general imaging segmentation. We hypothesize that SAM will improve ventricular segmentation performance compared to FreeSurfer, a commonly used segmentation algorithm in neuroimaging.
18 cases of NPH (9 with shunt and 9 without) were identified in the electronic medical record. The corresponding T1 MR data was downloaded from PACS and pre-processed for segmentation. Ventricular segmentation was performed using 3D-Slicer by a radiology resident and post-doctoral fellow. All masks were segmented using SAM and FreeSurfer. Dice scores were calculated for SAM and FreeSurfer masks. An Evan’s index was then calculated from the ground truth, SAM, and FreeSurfer masks.
For non-shunted cases of NPH, the mean Dice for SAM was 0.90 vs 0.39 for FreeSurfer (p<.001). In shunted cases of NPH, the mean Dice for SAM was 0.91 vs 0.21 for FreeSurfer (p<0.001). For shunted or non-shunted NPH, the mean Dice for SAM was 0.91 vs 0.30 for FreeSurfer (p<.001). There was no statistically significant difference between SAM masks in shunted vs non-shunted cases (p=0.36), while there was for FreeSurfer masks (p=0.012).
For calculated Evan’s index, in shunted NPH, SAM vs FreeSurfer mean was 0.44 and 0.24 respectively (p=.019). In non-shunted cases, SAM vs FreeSurfer mean was 0.51 vs 0.39 (p=0.027). There was no significant difference between SAM and the ground truth Evan’s index (p=.283 for shunted and p=.226 for no shunt), but there was for FreeSurfer (p=.039 for shunted and p=.012 for no shunt).
SAM masks have higher Dice scores and a closer Evan’s index to ground truth masks. Since there is a statistically significant difference between FreeSurfer masks with and without shunt, this suggests FreeSurfer is more sensitive to artifact than SAM. SAM’s generalizability, particularly in cases where artifact is introduced, makes it an attractive option for segmentation in medical imaging.
SRHSB/Integra Travelling Fellowship Award 2023: Observership in paediatric neurosurgery: A comparison of the management of hydrocephalus associated with paediatric brain tumours
1National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
Brain tumours in children are frequently associated with hydrocephalus. This may either be obstructive hydrocephalus – when the tumour and associated mass effect blocks CSF pathways, or communicating hydrocephalus – when hydrocephalus exists despite successful tumour resection.
The risk of long-term hydrocephalus in children after tumour resection, as reported in the literature, is of the order of 15-30%. I performed a retrospective study to evaluate the same in 125 consecutive cases at my previous hospital (Queen’s Medical Centre, Nottingham, UK) and had found our rate of persisting, long-term hydrocephalus in this group to be 44%.
To learn more about how to mitigate this risk, I undertook a travelling fellowship, generously funded by Integra and the Society of Research into Hydrocephalus and Spina Bifida at the Sree Chitra Tirunal Institute of Medical Sciences and Technology (SCTIMST) in Kerala, India. The Department of Neurosurgery at SCTIMST is a high volume neurosurgical centre that provides a tertiary, national and international referral service for various advanced neurosurgical conditions.
The main purpose of my visit was to learn more about the management of brain tumours in children, especially details of surgical and peri-operative strategies, because their rates of post-operative hydrocephalus are low. Over a two week period (Jan-Feb 2024), I participated in 44 neurosurgical operations, including 7 operations to resect paediatric brain tumours.
I learned several valuable lessons in paediatric brain tumour surgery, which may seek to reduce the risk of post-operative hydrocephalus. These include pre-operative use of high dose steroids; avoidance of external ventricular drainage when possible; meticulous microsurgical technique, especially avoiding unnecessary prolongation of surgery to prevent CSF seeding; meticulous wound closure and many others.
This travelling fellowship has resulted in a significant amount of research, which has resulted in a few papers that are at various stages of publication. With my experience of paediatric hydrocephalus I was selected to join Harry’s Hydrocephalus Awareness Trust (Harry’s HAT) as Clinical Trustee. Work carried out during the travelling fellowship has resulted in a national level prize – the SBNS Sir Hugh Cairns prize. It is hoped that there will continue to be ongoing international collaboration in the true spirit of global neurosurgery.
Harry’s Hat Student Bursary Award 2023: Comparison of the awareness of hydrocephalus and spina bifida in South Asians living in the UK compared to those in South Asia and the determination of best methods to raise awareness and empower women with the knowledge to prevent and/or detect hydrocephalus and spina bifida early through the get ahead initiative
1Division of Neuroscience, University of Manchester, Manchester, UK
Folic acid (FA) is a synthetic version of vitamin B9 (folate) that is required for cell and tissue growth at all periods of life, including infancy, adolescence, parenthood, and old age. It lowers the incidence of neural tube abnormalities (NTDs) such as spina bifida, anencephaly, and hydrocephalus, and it works with vitamin B12 to form red blood cells, regulating iron levels in the body. Folate with vitamins D3 and B2 together also aids the production of neurotransmitters, for example, noradrenaline, dopamine, serotonin, and melatonin, preventing mood disorders such as depression, as well as nitric oxide, essential to cerebrovascular health. Many studies have revealed that ethnic minorities are uninformed of the numerous benefits of folate and are in critical need of this vital vitamin due to linguistic and educational limitations, as well as physiological needs. The purpose of this study is to discover the causes of low FA awareness and intake in East and Southeast (SE) Asian people in the United Kingdom (UK). The study will also cover the public’s opinion of FA fortification, general awareness of neural tube abnormalities, and the dietary habits of ethnic minorities. These variables taken together will aid in determining why folate and FA are deficient in the diets of ethnic minorities. A survey with 17 questions was created targeting educated ethnic minorities in the UK. The study outcomes revealed that many people from the British public do not take supplements, and if any, the popular supplements include vitamins D and B12. In addition, many survey respondents stated they are familiar with folic acid, but do not consume it daily, and are hesitant to purchase folate fortified foods. As a result, this study can help generate solutions to the lack of folate awareness in the UK population.
Dr Richard Morgan Prize: Implementation of the Ready Steady Go transition program for youth with spina bifida: user-friendliness and role in transition from a patient perspective
1Pediatric Neurology, Amsterdam UMC, Netherlands; 2Inholland University of Applied Sciences, Netherlands
An individualized transition plan contributes to the transition of patients from pediatric to adult care. To assess the patients’ needs during transition, questionnaires from the Ready Steady Go transition program were used. These questionnaires were developed for youth with chronic conditions. The questionnaires cover eight domains: knowledge and skills, self-advocacy, health and lifestyle, daily activities, school and your future, leisure time, managing emotions, and transition to adult care. Based on the completed questionnaires, the nurse practitioner engages in conversation with the patient and their parents to jointly create a plan to work towards independence.
Question: How user-friendly are the RSG questionnaires from a patient perspective, and what role do they play in the transition for patients with spina bifida and their parents? Method: This cross-sectional pilot study measured satisfaction with and user-friendliness of the RSG questionnaires using an evaluation questionnaire among a sample of 10 youth (aged 12-18 years, median 14.5 years) with spina bifida and their parents.
The median duration for completing the questionnaire is ten minutes. Children in special education were unable to complete the questionnaire independently, while children attending VMBO education could. All participants rated the topics covered as important. Most patients (9 out of 10) and all parents would recommend the RSG program to other youth and parents. For some patients (4 out of 10), the RSG questionnaire does not seem to be the tool to initiate a conversation with parents about becoming independent.
The use of the RSG questionnaires is generally positively evaluated by spina bifida patients and their parents and requires little time. Given the various tools available, it remains important to research the effectiveness of each transition program.
Coping with spina bifida: self-reported health-related quality of life and psychosocial needs among adult patients
1Neuro-e-Motion Research Team, Department of Psychology, Faculty of Health Sciences, University of Deusto, Bilbao, Spain; 2Department of Clinical and Health Psychology and Research Methodology, Faculty of Psychology, University of the Basque Country UPV/EHU, Donostia, Spain
A growing number of spina bifida (SB) patients survive into adulthood resultant of medical care advancements. These patients struggle with the management of this chronic condition since childhood, leading to poor psychosocial outcomes that remain in adult life. Thus, the aim of this study was to analyze the self-reported psychosocial status in a Spanish sample of adults with SB and compare their results with healthy controls.
Hospital Anxiety and Depression Scale (Zigmond & Snaith, 1983), WhoQoL-Bref (WHOQOL Group, 1998), Rosenberg’s Self-Esteem Scale (Rosenberg, 1965), Autoconcepto Forma-5 (García & Musitu, 1999), The Barthel Index (Mahoney & Barthel, 1965) and an ad hoc questionnaire to obtain sociodemographic and clinical data.
An exploratory cross-sectional study was conducted using a convenience sample, based on the characteristics of the SB population. The sample consisted of a clinical group conformed by 12 adults with SB and a control group of 12 healthy peers, all of them aged 21 to 40 years.
Adults with SB show a more negative self-concept, lower self-esteem, higher levels of depressive symptoms, and poorer health-related quality of life compared to their healthy peers. Since the depressive symptoms could be influencing the results obtained, its effect was controlled through a covariance analysis. Differences between both groups were still observed on the initially proposed variables except in one dimension of self-concept. Study variables appeared to be related to each other after showing significant correlations. Lastly, physical functionality and participation in active sports were identified as significant predictors of emotional and physical self-concept.
This study identifies some psychosocial concerns of adults with SB, which could help healthcare providers in developing interventions from a patient-centered care approach in order to improve these patients’ quality of life and psychological well-being.