Toward a better understanding of the cellular basis for cerebrospinal fluid shunt obstruction: report on the construction of a bank of explanted hydrocephalus devices

Abstract

<jats:sec> <jats:title>OBJECTIVE</jats:title> <jats:p>Shunt obstruction by cells and/or tissue is the most common cause of shunt failure. Ventricular catheter obstruction alone accounts for more than 50% of shunt failures in pediatric patients. The authors sought to systematically collect explanted ventricular catheters from the Seattle Children's Hospital with a focus on elucidating the cellular mechanisms underlying obstruction.</jats:p></jats:sec> <jats:sec> <jats:title>METHODS</jats:title> <jats:p>In the operating room, explanted hardware was placed in 4% paraformaldehyde. Weekly, samples were transferred to buffer solution and stored at 4°C. After consent was obtained for their use, catheters were labeled using cell-specific markers for astrocytes (glial fibrillary acidic protein), microglia (ionized calcium-binding adapter molecule 1), and choroid plexus (transthyretin) in conjunction with a nuclear stain (Hoechst). Catheters were mounted in custom polycarbonate imaging chambers. Three-dimensional, multispectral, spinning-disk confocal microscopy was used to image catheter cerebrospinal fluid–intake holes (10× objective, 499.2-μm-thick z-stack, 2.4-μm step size, Olympus IX81 inverted microscope with motorized stage and charge-coupled device camera). Values are reported as the mean ± standard error of the mean and were compared using a 2-tailed Mann-Whitney U-test. Significance was defined at p &lt; 0.05.</jats:p></jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>Thirty-six ventricular catheters have been imaged to date, resulting in the following observations: 1) Astrocytes and microglia are the dominant cell types bound directly to catheter surfaces; 2) cellular binding to catheters is ubiquitous even if no grossly visible tissue is apparent; and 3) immunohistochemical techniques are of limited utility when a catheter has been exposed to Bugbee wire electrocautery. Statistical analysis of 24 catheters was performed, after excluding 7 catheters exposed to Bugbee wire cautery, 3 that were poorly fixed, and 2 that demonstrated pronounced autofluorescence. This analysis revealed that catheters with a microglia-dominant cellular response tended to be implanted for shorter durations (24.7 ± 6.7 days) than those with an astrocyte-dominant response (1183 ± 642 days; p = 0.027).</jats:p></jats:sec> <jats:sec> <jats:title>CONCLUSIONS</jats:title> <jats:p>Ventricular catheter occlusion remains a significant source of shunt morbidity in the pediatric population, and given their ability to intimately associate with catheter surfaces, astrocytes and microglia appear to be critical to this pathophysiology. Microglia tend to be the dominant cell type on catheters implanted for less than 2 months, while astrocytes tend to be the most prevalent cell type on catheters implanted for longer time courses and are noted to serve as an interface for the secondary attachment of ependymal cells and choroid plexus.</jats:p></jats:sec>

Cerebrospinal Fluid Shunting Complications in Children

“…However, it is important to recognize that up to 15% of shunted pediatric patients will have such profound alterations in brain compliance that their ventricles will not enlarge in the face of shunt failure and increased ICP [40]. Additionally, when comparing a patient’s ventricular size to baseline studies, interpretation should take into account that the decline in ventricular size following initial shunt placement does not reach a plateau until approximately 14 months, regardless of whether a standard differential-pressure, a siphon-reducing differential-pressure, or flow-limiting valve was employed [30].…”

“…Ventricular catheter obstruction with cells or tissue accounts for over 50% of shunt failures in the pediatric population [2, 31, 34, 40], although the literature has been mixed with respect to the cell types implicated in the pathophysiology of catheter obstruction [41]. Clinicians and scientists alike have observed an array of cells and tissues bound to CSF shunt catheter material, including choroid plexus, astrocytes, macrophages/microglia/foreign body giant cells/granulomatous reactions, eosinophils, lymphocytes, monocytes, brain parenchyma, ependyma, connective tissue and fibrin networks, leptomeninges, necrotic debris, hemorrhage, calcification, neoplastic cells, foreign bodies, and embolic material [42].…”

“…Work by our group, utilizing comprehensive multi-channel, 3-dimensional confocal microscopy imaging of explanted ventricular catheters from shunt-dependent Seattle Children’s Hospital patients further shifts the focus away from choroid plexus and narrows in on astrocytes and microglia, which are by far the most common cell types bound directly to catheter surfaces [40]. Based on this work, we have created an astrocyte/microglia centric model for ventricular catheter occlusion (Fig.…”

“…1). Our working model for noninfectious ventricular catheter occlusion can be conceptualized as a 5-stage process [40, 41]. First, within microseconds of catheter implantation, extracellular, CSF, and serum proteins are adsorbed on the poly(dimethylsiloxane) (silicone; PDMS) catheter surfaces, providing a chemically permissible substrate for cells to attach and migrate (Fig.…”

“…Although our model suggests that choroid plexus attachment is not the primary inciting event in the pathophysiology of shunt obstruction [40], it remains critical that the practicing neurosurgeon remain aware of the possibility of choroid plexus attachment when extracting long-term indwelling cathethers. Removal of these catheters can result in avulsion of a bound (secondary or otherwise), well-vascularized, pedicle of choroid plexus, resulting in an intraventricular hemorrhage.…”