Abstract
Stroke remains a leading cause of long-term disability in adults, with many survivors experiencing persistent neurological and functional deficits. Conventional rehabilitation offers limited benefit once recovery plateaus. Biological therapies targeting chronic mechanisms of neural dysfunction, such as perispinal etanercept (PSE), a tumor necrosis factor-alpha (TNF-α) inhibitor, have been proposed as potential alternatives. This systematic review evaluates the safety and effectiveness of PSE for neurological recovery in adults with chronic post-stroke deficits. A comprehensive search of PubMed, Embase, MEDLINE, Cochrane Library, Scopus, and Web of Science identified human studies assessing PSE in stroke ≥six months post-event. Two reviewers independently screened, extracted data, and assessed bias using the risk of bias 2 (RoB 2), Newcastle-Ottawa Scale, and Joanna Briggs Institute (JBI) tools. Eligible studies included randomised trials, non-randomised trials, and case-based reports describing neurological, functional, cognitive, or safety outcomes. Five studies met the inclusion criteria: two randomised controlled trials, one large observational cohort, one case series, and one case report. The available evidence showed variable outcomes. Some studies reported short-term improvements in pain and motor function, whereas others found no significant overall functional or quality-of-life gains. Reported benefits, when observed, were typically domain-specific and not consistently sustained. Treatment was well tolerated, with no major safety concerns reported. Robust, large-scale trials are still needed to establish consistent functional benefits and long-term efficacy. Future research should focus on optimising treatment protocols and identifying responsive patient phenotypes through neuroimaging and inflammatory biomarkers. Well-designed multicenter trials with standardised stroke-specific endpoints and extended follow-up are essential to determine the true therapeutic value of PSE before routine clinical adoption.