Cerebrospinal Fluid Biomarkers of Neuroinflammation in Children with Hydrocephalus and Shunt Malfunction
Authors: Harris Carolyn A , Morales Diego M. , Arshad Rooshan , McAllister James P. , Limbrick David D. 
Published: October 2020

Abstract
Background: Cerebrospinal fluid (CSF) shunt systems fail approximately 30% of the time within the first year of shunt implantation, while 98% of all patients with hydrocephalus (HCP) will suffer shunt failure in their lifetime. Perhaps due to the heterogeneity in etiology or the unique environment housing CSF shunt systems, the underlying reasons for shunt failure continue to elude researchers and clinicians. Still, obstruction remains the most common reason for shunt failure and it is vital to understand what factors may be contributing or driving shunt failure for improving patient outcomes and ultimately quality of life.Methods: Using multiplex ELISA, this study first examined the protein concentration profiles of select pro-inflammatory and anti-inflammatory cytokines, as well as select matrix metalloproteinases (MMPs) in 38 pediatric patients and their CSF obtained at shunt revision operation; all patients pediatric (<18). Shunt failure was further examined for interdependencies between the past number of previous revisions, length of time implanted, patient age, and the surgeon-described reason for revision noted as obstruction or non-obstruction. The pro-inflammatory cytokines were IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12, IL-17, TNF-α, GM-CSF, IFN-γ. The anti-inflammatory cytokines were IL-4 and IL-10, and the MMPs are MMP-2, MMP-3, MMP-7, MMP-9. protein concentration is reported as pg/mL for each analyte. Results: IL-10, IL-6, IL-8 and MMP-7 demonstrated significantly increased concentrations in patient CSF for the non-obstructed subgroup compared to the obstructed subgroup (p=<0.05). Under generalized etiology, these analytes present within communicating HCP cases (15 of which were diagnosed with PHH) compared to non-communicating HCP or traumatic brain injury (TBI) cases. Further examination revealed that CSF IL-6 was significantly increased in both obstructed and non-obstructed cases, predominately for PHH and congenital HCP patients while IL-8 was significantly higher only in PHH patients. In terms of number of past revisions, IL-10, IL-6, IL-8, MMP-7 and MMP-9 significantly and progressively increased from zero to two past revisions and then significantly declined and remained low for subsequent revisions (p=<0.05). In terms of implantation time, CSF from shunts implanted for three months or less show significantly increased concentration for IL-6, IL-8, and MMP-7 (p=<0.05). Lastly, Six months or less was the age identified to coincide with significantly increased concentration of IL-6, IL-8, and MMP-7 (p=<0.05). Conclusion: Of all the cytokines and MMPs tested, IL-10, IL-6, IL-8, MMP-7 and MMP-9 were significantly elevated compared to other cytokines and MMPs in the various dependencies evaluated. IL-6 and IL-8 stand out in our study with significantly increased concentration in select etiologies, age, length of time implanted. The aforementioned cytokines and MMPs all showed an interesting relation with number of past revisions which warrants further examination. Non-obstruction cases were determined to be accompany significantly higher CSF cytokine MMP presence compared to obstructive cases. This suggests closer examination to the extent of the role neuroinflammation plays for causing obstruction in HCP patients. Additionally, IL-10 was associated with the length of time implanted as well as number of past revisions, and higher in non-obstructed cases compared to obstructed cases. A severity-dependent interplay between IL-10, IL-6 and IL-8 is an area for expansion and may provide foundation for therapeutic control of neuroinflammation.Trial registration: Not applicable.