Glial Neurovascular Unit Protein Dysregulation and Risk of Idiopathic Intracranial Hypertension: A Systematic Review and Meta-Analysis

Background:Idiopathic intracranial hypertension is a neurological disorder of unclear etiology that primarily affects young adults. Although several therapeutic options are available, many patients continue to experience persistent visual impairment and headaches, suggesting that key disease mechanisms remain poorly understood. Emerging evidence implicates dysfunction of the glial neurovascular unit (gNVU) in the pathogenesis of IIH. Objective:To systematically evaluate the association between alterations of gNVU-related proteins, specifically aquaporin-4, glial fibrillary acidic protein, fibrinogen, and neurofilament light chain, with the risk of IIH. Methods:A comprehensive literature search of PubMed, EMBASE, Cochrane Library, Scopus, and Web of Science was conducted through August 2025. Studies comparing patients with IIH to control participants and reporting gNVU-related biomarkers in cerebrospinal fluid, plasma, serum, or brain tissue were included. Data extraction and quality assessment were performed independently using the Newcastle-Ottawa Scale. Pooled standardized mean differences with 95% confidence intervals were calculated using random-effects models. Results:Ten studies comprising 327 patients with IIH and 216 controls met the inclusion criteria, with seven studies contributing to quantitative synthesis. Levels of CSF Nf-L and plasma fibrinogen were significantly higher in IIH patients, indicating neuroaxonal injury and a hypercoagulable state (Nf-L: SMD=0.78, 95% CI 0.51-1.05; fibrinogen: SMD=0.66, 95% CI 0.08-1.23). Findings for AQP4 and GFAP were inconsistent across studies. Higher BMI was also associated with an increased risk of IIH (SMD=0.80, 95% CI 0.17-1.44). Study quality did not significantly influence effect estimates.