OBJECTIVE 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. METHODS 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 < 0.05. RESULTS 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). CONCLUSIONS 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.

Cellular signal transduction is defined as the conversion of an extracellular signal to a response within a cell. Commonly referred to as forward signalling, this extracellular signal often comes in the form of a soluble ligand that binds to a membrane‐spanning receptor. However, many ligands or their precursors are also transmembrane or membrane associated. It is now appreciated that these ligands may also act as receptors in a process referred to as reverse signalling. There is a growing body of evidence that reverse signalling occurs for several classes of ligands including: ephrins, semaphorins, interleukins, tumour necrosis factor family members and Notch‐associated ligands. This type of signalling has been linked to immune responses, axon guidance, cell proliferation and differentiation. Here we review reverse signalling of ligands categorised by how they associate with the membrane: transmembrane type 1 (TM1), transmembrane type 2 (TM2), or GPI‐linked. Within this structure we will emphasize the physiological and pathological roles of reverse signaling. Key Concepts Ligand classes that possess the ability to reverse signal include, but are not limited to, members of the tumour necrosis factor superfamily (TNFSF), ephrin family, semaphorin family, interleukin family and Notch‐associated ligands. These ligands can be categorized into the following subgroups: transmembrane type 1 (TM1), transmembrane type 2 (TM2), and GPI‐linked. Ligands can reverse signal by directly recruiting adaptor or effector proteins, acting in concert with coreceptors or by liberation of the intracellular domain to influence transcription. Reverse signalling has been shown to be involved in processes including axon guidance, tissue development and immune responses. Ectopic regulation of reverse signalling is associated with a range of pathologies including cancer, developmental defects and osteoporosis.

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