Hydrocephalus is characterized by excessive amounts of cerebrospinal fluid (CSF) accumulating within the brain ventricles resulting in an increased intracranial pressure [
The systematic literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [
Studies were included in the review if they were (1) original research, (2) written in English, and (3) available in full text. Studies were excluded from the review if they (1) were reviews, meta-analyses, conference abstracts, comments, notes (i.e. gray literature), case reports, duplicates, or not published in English; (2) were not available in full text; (3) were animal or postmortem studies; (4) did not focus on patients with hydrocephalus; (5) did not analyze CSF for presence of inflammatory markers; (6) did not include a control group; (7) did not separate patients with hydrocephalus of different etiologies into separate groups; or (8) did not make a statistical comparison between patients with hydrocephalus and control subjects (Figure
PRISMA flow diagram of the literature search strategy. The database search identified 1198 studies, and 3 additional studies were identified from reference lists. Screening by title and abstract led to the exclusion of 1002 studies. Full-text review for eligibility of the remaining 199 studies resulted in a final inclusion of 22 studies for the review.
PubMed and Embase were searched for relevant studies published before December 3rd 2020. The following search terms were applied in all four searches: “hydrocephalus” AND “cerebrospinal fluid” OR “CSF” OR “cerebrospinal fluid” AND “inflammation” OR “inflammatory” OR “inflammatory marker” OR “biomarker” OR “marker” OR “cytokine.” A unique search term was, in addition, applied to each of the four searches.
The following data were extracted from each study: first author’s name, publication year, study design, patient groups, number of patients in each group, diagnostic criteria including inclusion and exclusion criteria, age, sex, type of medication given, type of surgery performed, CSF source, preanalytical CSF handling, analytical method, CSF marker(s) analyzed, and result of CSF analysis.
Authors SDL, NR, MJ, AS, and NM designed the protocol and search strategy.
Initially, authors SDL and NR independently screened the studies by title and abstract. Studies that clearly violated the eligibility criteria were excluded. Afterwards, SDL and NR independently assessed the studies for eligibility by full-text review. After the independent assessment, SDL and NR collectively selected the studies for the final analysis. Authors SDL and EKO extracted data from relevant studies independently. After independent data collection, SDL and EKO collectively screened the extracted data, discussed any disagreements, and corrected any inconsistencies.
Inflammatory markers were separated into two categories based on the degree of consistency in results among studies. Inflammatory markers were categorized as having
The potential risk of bias was assessed by the evaluation of the following data from each study: study design, sample size, age and sex, diagnostic criteria, inclusion and exclusion criteria, medication, circumstances of CSF sampling, pre-analytical CSF handling, selection of inflammatory markers for CSF analysis, and analytical methods.
The PubMed and Embase search identified 1198 potential studies for the review, and 3 additional studies were identified from relevant reference lists. The initial search thus revealed 1201 potential studies for the review. Screening by title and abstract resulted in an exclusion of 1002 studies. Full-text review for eligibility of the remaining 199 studies led to the exclusion of 177 further studies. Hence, 22 studies were included in the final analysis (Figure
The 22 studies included in the review were cross-sectional, case-control studies. Five studies were prospective [
The 22 studies applied different analytical methods to detect presence of inflammatory markers in the CSF samples. The analytical methods included enzyme-linked immunosorbent assays (ELISAs) [
CSF from iNPH patients was screened for presence of 36 inflammatory markers spread across 11 studies [
Inflammatory markers in iNPH patients.
Result | Marker | References |
---|---|---|
↑↑ | IL-6 | [ |
IL-1 | [ | |
LRG | [ | |
SP-G | [ | |
T | [ | |
TIMP-4 | [ | |
→ → | IL-8 | [ |
TNF- | [ | |
CCL-2/MCP-1 | [ | |
IL-4 | [ | |
IL-33 | [ | |
sCD40L | [ | |
→ | IL-12 | [ |
IL-12p40 | [ | |
L-selectin | [ | |
MMP-9 | [ | |
TGF- | [ | |
TIMP-1 | [ | |
TIMP-2 | [ | |
YKL-40 | [ | |
Contr | IL-21 | [ |
TGF- | [ | |
IL-12p70 | [ | |
IL-17A | [ | |
IL-22 | [ | |
IL-31 | [ | |
IL-10 | [ |
↑↑ = most evidence: significantly increased in iNPH patients in two or more studies, and maximum one study reports a contradictory result. ↑ = limited evidence: significantly increased in iNPH patients in a single study. ↓ = limited evidence: significantly decreased in iNPH patients in a single study. → → = most evidence: no significant difference in two or more studies, and maximum one study reports a contradictory result. → = no significant difference in a single study. Contr = contradicting results. Abbreviations: IL: interleukin; LRG: leucine-rich
IL-6, IL-1
CSF from PHH patients was screened for presence of 37 inflammatory markers spread across 12 studies [
Inflammatory markers in PHH patients.
Result | Marker | Reference |
---|---|---|
↑↑ | IL-6 | [ |
↑ | CCL-3/MIP-1 | [ |
↓ | TIMP-4 | [ |
→ → | TGF- | [ |
→ | CXCL-11 | [ |
Contr | CCL-2/MCP-1 | [ |
↑↑ = most evidence: significantly increased in PHH patients in two or more studies, and maximum one study reports a contradictory result. ↑ = limited evidence: significantly increased in PHH patients in a single study. ↓ = limited evidence: significantly decreased in PHH patients in a single study. → → = most evidence: no significant difference in two or more studies, and maximum one study reports a contradictory result. → = no significant difference in a single study. Contr = contradicting results. Abbreviations: IL: interleukin; VEGF: vascular endothelial growth factor; CCL: C-C motif chemokine ligand; MIP: macrophage inflammatory protein; CXCL: C-X-C motif chemokine ligand; IP: interferon gamma inducible protein; HGF: hepatocyte growth factor; HMGB1: high-mobility group box 1; L1CAM: L1 cell adhesion molecule; MMP: matrix metalloproteinase; FasR: Fas receptor; sFas: soluble Fas; SP-G: surfactant protein-G; sRAGE: soluble receptor for advanced glycation end products; TGF: transforming growth factor; TIMP: tissue inhibitor of metalloproteinases; XCL: X-C motif chemokine ligand; SCF: stem cell factor; FasL: Fas ligand; sFasL: soluble fas ligand; MCP: monocyte chemoattractant protein; IFN: interferon; TNF: tumor necrosis factor.
IL-6, IL-18, and VEGF showed most evidence of increased levels in CSF from PHH patients compared to control subjects [
Sixteen inflammatory markers, CCL-3/MIP-1
CSF from the mixed patient group with other hydrocephalus diagnoses was screened for presence of 30 inflammatory markers spread across seven studies [
Further, VEGF was found increased over that of control subjects in congenital hydrocephalus, spina bifida, and hydrocephalus associated with tuberculous meningitis [
Sources of bias that could potentially influence the findings presented in the review are assessed in the following.
Ideally, the sample size should be large enough to detect differences that are clinically relevant [
Studies are generally recommended to match for age and sex to control for confounding elements and increase study efficiency [
Ideally, patients should not receive medication that is expected to influence the levels of the investigated inflammatory markers [
In the current review, we systematically evaluated the existing literature on inflammatory markers in CSF from patients with hydrocephalus. We sought to identify promising inflammatory markers for future experimental research that aims to elucidate whether inflammatory markers can alter CSF dynamics and contribute to hydrocephalus development and progression. If neuroinflammation is involved in the pathogenesis of hydrocephalus, inflammatory markers may serve as novel disease biomarkers. Modulation of inflammatory pathways affects a range of systemic illnesses [
Activation of the NF-
LRG (leucine-rich
The molecular mechanisms underlying choroidal CSF secretion are still investigated [
The systematic review included patients with hydrocephalus of various etiologies. Although the term “hydrocephalus” applies to all, the clinical presentations, radiological features, and etiologies vary between age groups. The classification of hydrocephalus is complex and ambiguous and thus an obvious challenge for a review of the present type, as the same clinical condition may be classified in more than one way—and the same classification can apply to different clinical conditions. In this review, we sought to overcome this by choosing etiologies as our defining parameter. Even though the results were separated into three main categories, patient heterogeneity within each category may have influenced the results. The category that comprised patients with other hydrocephalus diagnoses may especially have suffered from variations related to patient heterogeneity. Discrepancies in the diagnostic criteria combined with general lack of the stringent inclusion and exclusion criteria may also have contributed to patient heterogeneity. The control subjects were likewise heterogeneous in health status. The included studies had variations in sample sizes, and the majority of studies did not match patient groups on age and sex, which may also have influenced the results of the review. In addition, recruitment of patients from specialized clinics such as hydrocephalus units may have resulted in selection bias of patients with more pronounced cognitive and physiological impairments than encountered on average. The included studies analyzed CSF from children and adults, but the results were not separated accordingly. The inflammatory CSF profile of children and adults could possibly differ, and such information may thus have been lost. The category comprising PHH patients may have been particularly prone to variations related to age differences (preterm infants to adults). However, as some studies failed to report an age distribution or compared CSF from a mix of children and adults, results separated according to age would likewise have been associated with certain limitations.
Another limitation of this review is the heterogeneity in sampling and handling of CSF across the included studies. Several studies directly compare lumbar CSF with ventricular CSF which may have influenced the results due to differences in the protein content from the ventricles to the lumbar space. The influence of sample time on CSF protein concentration remains debatable [
The review included inflammatory markers both directly and indirectly linked to inflammation. The definition of an indirect inflammatory marker falls within a grey area. Hence, some of the indirect inflammatory markers might be more relevant than others. The current review included indirect inflammatory markers that appeared relevant based on the identified studies in the original search. Regarding medication, it is surprising that only one study comment on the use of medication in relation to the investigated outcome [
Despite the limitations, this systematic review presents a currently needed overview of the relevant literature and enables identification of promising inflammatory markers for future experimental research. In the current systematic review, we evaluated the existing literature on inflammatory markers in CSF from patients with hydrocephalus. We identified six inflammatory markers, IL-6, IL-1
All data is available on request.
The authors declare that they have no conflicts of interest.
Sara Diana Lolansen and Nina Rostgaard contributed equally to this work.
This study is supported by a Tandem grant from the Novo Nordisk Foundation [grant number NNF17OC0024718 to N.M. and M.J.], IMK Almene Fond (to N.M.) and the Absalon Foundation (to A.H.S.).
Supplemental Table 1: overview of all inflammatory markers investigated in CSF from iNPH patients. Supplemental Table 2: overview of all inflammatory markers investigated in CSF from PHH patients. Supplemental Table 3: overview of all inflammatory markers investigated in CSF from patients with other hydrocephalus diagnoses.