Comparative Effectiveness of Hyaluronidase Injections in Carpal Tunnel Syndrome: A Systematic Review and Meta-Analysis.

Carpal tunnel syndrome (CTS) is a common entrapment neuropathy associated with pain, sensory disturbances, functional impairment, and reduced quality of life. Hyaluronidase, an enzyme capable of degrading hyaluronic acid and facilitating perineural hydrodissection, has emerged as a potential minimally invasive treatment option for CTS. This systematic review and meta-analysis evaluated the effectiveness of hyaluronidase injections in CTS compared with other injection therapies. This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review and meta-analysis was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420251046156). PubMed, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched, supplemented by Google Scholar, Ovid Discovery, and ClinicalKey. Randomized controlled trials comparing hyaluronidase injections with control interventions in adults with CTS were included. Primary outcomes included symptom severity scale (SSS), functional status scale (FSS), sensory nerve conduction velocity (SNCV), and distal motor latency (DML). Secondary outcomes included visual analogue scale (VAS) and cross-sectional area (CSA) of the median nerve. Random-effects meta-analysis was performed using IBM SPSS Statistics for Windows, Version 31.0 (IBM Corp., Armonk, New York, United States). Risk of bias and certainty of evidence were assessed using the revised Cochrane Risk of Bias tool for randomized trials (RoB 2) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, respectively. Four randomized controlled trials involving 230 participants were included. Primary pooled analyses demonstrated directional trends favoring hyaluronidase for SSS at three months (MD=-0.17; 95% CI=-0.65 to 0.31) and six months (MD=-0.42; 95% CI=-1.29 to 0.45), FSS at three months (MD=-0.23; 95% CI=-0.95 to 0.49) and six months (MD=-0.30; 95% CI=-1.13 to 0.54), DML at three months (MD=-0.21 ms; 95% CI=-0.68 to 0.25) and six months (MD=-0.55 ms; 95% CI=-1.14 to 0.03), and SNCV at three months (MD=0.56 m/s; 95% CI=-3.57 to 4.69) and six months (MD=2.23 m/s; 95% CI=-2.88 to 7.34); however, none of these primary outcomes reached statistical significance. Pooled analysis demonstrated a statistically significant reduction in VAS scores at six months favoring hyaluronidase (MD=-1.97; 95% CI=-3.88 to -0.06; p=0.04). Subgroup analyses demonstrated significantly greater improvement with hyaluronidase compared with dexamethasone for SSS, FSS, and DML at the six-month follow-up. Considerable heterogeneity was observed across most pooled analyses, and sensitivity analyses identified one study as the principal contributor to heterogeneity. The certainty of evidence for primary outcomes was low. Current evidence does not demonstrate a consistent or statistically robust benefit of hyaluronidase injection in improving symptom severity, functional status, DML, and SNCV in CTS, although directional trends and subgroup findings suggest potential benefit in specific comparisons, particularly against dexamethasone. Further high-quality, adequately powered randomized controlled trials with standardized outcome measures are required to establish its effectiveness.