3D Ultrasound in the Management of Post Hemorrhagic Ventricle Dilatation

Enlargement of the cerebral ventricles is relatively common among extremely preterm neonates born before 28 weeks gestational age. One common cause of ventricle dilatation is post hemorrhagic ventricle dilatation following a bleed in the cerebral ventricles. While many neonates with PHVD will have spontaneous resolution of the condition, severe, persistent PHVD is associated with a greater risk of brain injury and morbidity later in life and left untreated can cause death. The current clinical management strategy consists of daily measurements of head circumference and qualitative interpretation of two-dimensional US images to detect ventricular enlargement and monitoring vital signs for indications increased intracranial pressure (i.e. apnea, bradycardia). Despite the widespread clinical use of these indicators, they do not have the specificity to reliably indicate when an intervention to remove some CSF is required to prevent brain damage. Early recognition of interventional necessity using quantitative measurements could help with the management of the disease, and could lead to better care in the future. Our objective was to develop and validate a three-dimensional ultrasound system for use within an incubator of neonates with PHVD in order to accurately measure the cerebral ventricle volume. This system was validated against known geometric phantoms as well as a custom ventricle-like phantom. Once validated, the system was used in a clinical study of 70 neonates with PHVD to measure the ventricle size. In addition to three-dimensional ultrasound, clinical ultrasound images, and MRIs were attained. Clinical measurements of the ventricles and three-dimensional ultrasound ventricle volumes were used to determine thresholds between neonates with PHVD who did and did not receive interventions based on current clinical management. We determined image based thresholds for intervention for both neonates who will receive an initial intervention, as well as those who will receive multiple interventions. Three-dimensional ultrasound based ventricle volume measurements had high sensitivity and specificity as patients with persistent PHVD have ventricles that increase in size faster than those who undergo resolution. This allowed for delineation between interventional and non-interventional patients within the first week of life. While this is still a small sample size study, these results can give rise to larger studies that would be able to determine if earlier intervention can result in better neurodevelopmental outcomes later in life

Cranial ultrasound findings in preterm germinal matrix haemorrhage, sequelae and outcome

Germinal matrix-intraventricular haemorrhage (GMH-IVH), periventricular haemorrhagic infarction (PHI) and its complication, post-haemorrhagic ventricular dilatation (PHVD), are still common neonatal morbidities in preterm infants that are highly associated with adverse neurodevelopmental outcome. Typical cranial ultrasound (CUS) findings of GMH-IVH, PHI and PHVD, their anatomical substrates and underlying mechanisms are discussed in this paper. Furthermore, we propose a detailed descriptive classification of GMH-IVH and PHI that may improve quality of CUS reporting and prediction of outcome in infants suffering from GMH-IVH/PHI

An Examination of Lumbar and Ventricular Cerebrospinal Fluid Findings in Children with Tuberculous Meningitis and Hydrocephalus

Background: Childhood tuberculous meningitis (TBM) has poor outcomes. These are often associated with delayed diagnosis because early diagnosis and treatment is challenging. Existing diagnostic criteria use CSF characteristics to suspect TBM. However, lumbar and ventricular CSF may differ. These differences have not been well characterised Sometimes only ventricular CSF is available and decisions about surgical treatment may be influenced by CSF characteristics. This study examined CSF parameters from lumbar and ventricular compartments in patients with TBM and hydrocephalus who required neurosurgical procedures, their CSF temporal profiles, differentials between compartments, and factors that may influence these results. Methodology: A descriptive cross-sectional study was conducted including data from two prospective TBM studies. Children treated for TBM and hydrocephalus at Red Cross War Memorial Children’s Hospital with lumbar and/ or ventricular samples were selected. Pooled lumbar verses ventricular samples and paired time-linked samples in individual patients were analysed. Differences in CSF cell counts and biochemistry parameters across compartments were analyzed using Wilcoxon signed rank test, and temporal profiles graphically presented. Associations between laboratory, clinical and radiological data were analyzed using Mann-Whitney’s U test. To test for associated factors, results of the nature of hydrocephalus (level of CSF obstruction) and spinal imaging were analyzed where available. Association between CSF parameters and morbidity was analyzed. Results: Eighty-one patients were studied, 29 had time-linked paired CSF. The mean patient age was 36 months (2- 156 months), 93% were HIV-uninfected, and the mortality rate was 13.6%. Seventy-two percent had communicating hydrocephalus, 16% non-communicating, and 12% uncertain (unable to demonstrate level of block). Medians of admission lumbar CSF showed low glucose (2.2 mmol/L), low chloride (112 mmol/L), raised protein (2g/L) and elevated white cell count (165 x 106 /L). Corresponding values for admission ventricular CSF were minimally affected glucose (3mmol/L), mildly low to normal chloride (114.5mmol/L), normal to mildly raised protein (0.5g/L) and less elevated white cell count (22 x 106 /L). In paired samples, all parameters were significantly different between lumbar and ventricular CSF. Ventricular CSF showed milder aberrations than lumbar CSF: lower protein and total white cell count, higher glucose and chloride. All paired samples showed higher lumbar CSF protein; lower lumbar CSF chloride in almost 80%; lower lumbar CSF glucose in 96%. Analysis of possible factors was limited by the small patient numbers who had full brain and spine imaging, and also paired CSF samples (n=17). However, maximum lumbar CSF protein was associated with severity of spinal disease on imaging. The lymphocyte ratio between lumbar and ventricular CSF was higher in patients with non-communicating and uncertain hydrocephalus. CSF parameters normalized slowly. White cell count and lymphocyte CSF differential were associated with favorable outcome in survivors. Conclusion: Lumbar CSF depicted a typical TBM pattern. Ventricular CSF differed: CSF parameters were less abnormal in both pooled analysis and across individual paired samples. Spinal disease severity and nature of hydrocephalus may affect this differential. The CSF compartment sampled is therefore clinically relevant when interpreting CSF characteristics for diagnostic and treatment decisions. Studies of TBM diagnosis, pathophysiology, biomarkers and drug concentrations should consider these differences

Diffusion tensor imaging with direct cytopathological validation: Characterisation of decorin treatment in experimental juvenile communicating hydrocephalus

BACKGROUND: In an effort to develop novel treatments for communicating hydrocephalus, we have shown previously that the transforming growth factor-β antagonist, decorin, inhibits subarachnoid fibrosis mediated ventriculomegaly; however decorin’s ability to prevent cerebral cytopathology in communicating hydrocephalus has not been fully examined. Furthermore, the capacity for diffusion tensor imaging to act as a proxy measure of cerebral pathology in multiple sclerosis and spinal cord injury has recently been demonstrated. However, the use of diffusion tensor imaging to investigate cytopathological changes in communicating hydrocephalus is yet to occur. Hence, this study aimed to determine whether decorin treatment influences alterations in diffusion tensor imaging parameters and cytopathology in experimental communicating hydrocephalus. Moreover, the study also explored whether diffusion tensor imaging parameters correlate with cellular pathology in communicating hydrocephalus. METHODS: Accordingly, communicating hydrocephalus was induced by injecting kaolin into the basal cisterns in 3-week old rats followed immediately by 14 days of continuous intraventricular delivery of either human recombinant decorin (n = 5) or vehicle (n = 6). Four rats remained as intact controls and a further four rats served as kaolin only controls. At 14-days post-kaolin, just prior to sacrifice, routine magnetic resonance imaging and magnetic resonance diffusion tensor imaging was conducted and the mean diffusivity, fractional anisotropy, radial and axial diffusivity of seven cerebral regions were assessed by voxel-based analysis in the corpus callosum, periventricular white matter, caudal internal capsule, CA1 hippocampus, and outer and inner parietal cortex. Myelin integrity, gliosis and aquaporin-4 levels were evaluated by post-mortem immunohistochemistry in the CA3 hippocampus and in the caudal brain of the same cerebral structures analysed by diffusion tensor imaging. RESULTS: Decorin significantly decreased myelin damage in the caudal internal capsule and prevented caudal periventricular white matter oedema and astrogliosis. Furthermore, decorin treatment prevented the increase in caudal periventricular white matter mean diffusivity (p = 0.032) as well as caudal corpus callosum axial diffusivity (p = 0.004) and radial diffusivity (p = 0.034). Furthermore, diffusion tensor imaging parameters correlated primarily with periventricular white matter astrocyte and aquaporin-4 levels. CONCLUSIONS: Overall, these findings suggest that decorin has the therapeutic potential to reduce white matter cytopathology in hydrocephalus. Moreover, diffusion tensor imaging is a useful tool to provide surrogate measures of periventricular white matter pathology in communicating hydrocephalus. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12987-016-0033-2) contains supplementary material, which is available to authorized users

Longitudinal Evaluation of an N-Ethyl-N-Nitrosourea-Created Murine Model with Normal Pressure Hydrocephalus

Normal-pressure hydrocephalus (NPH) is a neurodegenerative disorder that usually occurs late in adult life. Clinically, the cardinal features include gait disturbances, urinary incontinence, and cognitive decline.Herein we report the characterization of a novel mouse model of NPH (designated p23-ST1), created by N-ethyl-N-nitrosourea (ENU)-induced mutagenesis. The ventricular size in the brain was measured by 3-dimensional micro-magnetic resonance imaging (3D-MRI) and was found to be enlarged. Intracranial pressure was measured and was found to fall within a normal range. A histological assessment and tracer flow study revealed that the cerebral spinal fluid (CSF) pathway of p23-ST1 mice was normal without obstruction. Motor functions were assessed using a rotarod apparatus and a CatWalk gait automatic analyzer. Mutant mice showed poor rotarod performance and gait disturbances. Cognitive function was evaluated using auditory fear-conditioned responses with the mutant displaying both short- and long-term memory deficits. With an increase in urination frequency and volume, the mutant showed features of incontinence. Nissl substance staining and cell-type-specific markers were used to examine the brain pathology. These studies revealed concurrent glial activation and neuronal loss in the periventricular regions of mutant animals. In particular, chronically activated microglia were found in septal areas at a relatively young age, implying that microglial activation might contribute to the pathogenesis of NPH. These defects were transmitted in an autosomal dominant mode with reduced penetrance. Using a whole-genome scan employing 287 single-nucleotide polymorphic (SNP) markers and further refinement using six additional SNP markers and four microsatellite markers, the causative mutation was mapped to a 5.3-cM region on chromosome 4.Our results collectively demonstrate that the p23-ST1 mouse is a novel mouse model of human NPH. Clinical observations suggest that dysfunctions and alterations in the brains of patients with NPH might occur much earlier than the appearance of clinical signs. p23-ST1 mice provide a unique opportunity to characterize molecular changes and the pathogenic mechanism of NPH

Clinical application of 3D ultrasound in neonatal intraventricular hemorrhage

Preterm neonates are at risk for intraventricular hemorrhage (IVH) and subsequent post-hemorrhagic hydrocephalus (PHH). A well-accepted interventional therapy for PHH is ventricular tap (VT). Permanent treatment, ventriculo peritoneal shunt surgery (VPS) is required in the case of some neonates under some conditions (weight, immunological status, CSF protein level) who receive multiple interventions. The objective of this study was to apply a 3D ultrasound system clinically to determine CSF volume within the ventricle, to guide the neurosurgeon regarding the amount of CSF should be removed during every intervention, which lateral ventricle is better to intervene and to predict the possibilities of the requirement of the shunt. After ethics approval and parental consent, this 3D US system was used in a clinical study where data of 70 neonates having IVH were analyzed retrospectively and 22 preterm neonates were recruited prospectively. 3D US system was used to measure the ventricle volume of the neonates. In addition, we have changed the posture of some neonates to find the volume variation in two lateral postures. We found that 3D US ventricle volume had a higher correlation (Pearson correlation 0.739) with the amount of CSF removed in each tap than other parameters (weight, age, head circumference). After changing the posture of the neonates, we did not find any significant volume change of two lateral ventricle volumes (P-value was 0.353 in case of the right ventricle in two different postures and 0.473 in case of the left ventricle in two different postures). We also found more volume change after VT in those patients who required VPS than who did not need a VPS (volume change was18.70 ± 10.98 cm3 in shunt treated patients and 7.52 ± 3.35 cm3 in patients with no shunt where P- value was 0.0001). Therefore, our study suggests that a volumetric measurement of total lateral ventricles by the 3D US could be used concurrently with other physical parameters for better management of the neonates having PHH

Increased CSF aquaporin-4, and interleukin-6 levels in dogs with idiopathic communicating internal hydrocephalus and a decrease after ventriculo-peritoneal shunting

Background: Studies in animal models, in which internal hydrocephalus has been induced by obstructing the cerebrospinal fluid pathways, have documented an up-regulation of the concentrations of aquaporin-4 (AQP4) in the brain. In this study, the concentrations of aquaporin-1 (AQP1), AQP1, AQP4 and interleukin-6 (IL-6) were determined in the CSF of dogs with idiopathic communicating hydrocephalus before and after the reduction of intraventricular volume following ventriculo-peritoneal shunt (VP-shunt) treatment. Results: The concentrations of AQP4 and IL-6 were increased in the cerebrospinal fluid of dogs with hydrocephalus compared to controls. Both parameters significantly decreased after surgical treatment, accompanied by decrease of ventricular size and the clinical recovery of the dogs. AQP1 was not detectable in CSF. Conclusions: Brain AQP4 up-regulation might be a compensatory response in dogs with hydrocephalus. Future determination of AQP4 at the mRNA and protein level in brain tissue is warranted to substantiate this hypothesis

Preterm neonatal lateral ventricle volume from three-dimensional ultrasound is not strongly correlated to two-dimensional ultrasound measurements

The aim of this study is to compare longitudinal two-dimensional (2-D) and three-dimensional (3-D) ultrasound (US) estimates of ventricle size in preterm neonates with posthemorrhagic ventricular dilatation (PHVD) using quantitative measurements of the lateral ventricles. Cranial 2-D US and 3-D US images were acquired from neonatal patients with diagnosed PHVD within 10 min of each other one to two times per week and analyzed offline. Ventricle index, anterior horn width, third ventricle width, and thalamo-occipital distance were measured on the 2-D images and ventricle volume (VV) was measured from 3-D US images. Changes in the measurements between successive image sets were also recorded. No strong correlations were found between VV and 2-D US measurements (R-2 between 0.69 and 0.36). Additionally, weak correlations were found between changes in 2-D US measurements and 3-D US VV (R-2 between 0.13 and 0.02). A trend was found between increasing 2-D US measurements and 3-D US-based VV, but this was not the case when comparing changes between 3-D US VV and 2-D US measurements. If 3-D US-based VV provides a more accurate estimate of ventricle size than 2-D US measurements, moderate-weak correlations with 3-D US suggest that monitoring preterm patients with PHVD using 2-D US measurements alone might not accurately represent whether the ventricles are progressively dilating. A volumetric measure (3-D US or MRI) could be used instead to more accurately represent changes. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI

The pulsating brain: A review of experimental and clinical studies of intracranial pulsatility

The maintenance of adequate blood flow to the brain is critical for normal brain function; cerebral blood flow, its regulation and the effect of alteration in this flow with disease have been studied extensively and are very well understood. This flow is not steady, however; the systolic increase in blood pressure over the cardiac cycle causes regular variations in blood flow into and throughout the brain that are synchronous with the heart beat. Because the brain is contained within the fixed skull, these pulsations in flow and pressure are in turn transferred into brain tissue and all of the fluids contained therein including cerebrospinal fluid. While intracranial pulsatility has not been a primary focus of the clinical community, considerable data have accrued over the last sixty years and new applications are emerging to this day. Investigators have found it a useful marker in certain diseases, particularly in hydrocephalus and traumatic brain injury where large changes in intracranial pressure and in the biomechanical properties of the brain can lead to significant changes in pressure and flow pulsatility. In this work, we review the history of intracranial pulsatility beginning with its discovery and early characterization, consider the specific technologies such as transcranial Doppler and phase contrast MRI used to assess various aspects of brain pulsations, and examine the experimental and clinical studies which have used pulsatility to better understand brain function in health and with disease