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Introduction: To assess the effectiveness and safety of intranasal tear neurostimulation in the treatment of dry eye disease. Methods: We performed a meta-analysis of four databases from their inception to October 2022 without language restrictions. Randomized controlled trials and non-randomized controlled trials meeting the inclusion criteria were included in this review and were quality appraised. The risk of bias was evaluated by two independent reviewers using the Cochrane Collaboration Tool and Methodological Index for Non-Randomized Studies. The random-effect model or fixed-effect model was adopted to estimate the pooled effect sizes. Results: Fifteen published studies consisting of 17 clinical trials with a total of 901 patients were analyzed. Schirmer II test scores were significantly higher after intranasal tear neurostimulation in patients with dry eye disease (mean difference = 14.12 mm, 95% confidence intervals (8.93, 19.31), P < 0.001). Intranasal tear neurostimulation increased the meibomian gland areas (mean difference = − 251.79 μm2, 95% confidence intervals (− 348.34, − 155.23), P < 0.001), but no significant difference was found in meibomian gland perimeters before and after stimulation (mean difference = 3.72 mm, 95% confidence intervals (− 22.14, 29.59), P = 0.78). All adverse events were mild or moderate, and no serious adverse events were reported. Conclusions: This meta-analysis provides promising evidence for the controversial effectiveness of intranasal tear neurostimulation in the treatment of dry eye disease, along with useful information for guiding intranasal tear neurostimulation in future clinical trials. Trial Registration: This meta-analysis was registered on the Prospective Register of Systematic Reviews (PROSPERO) (CRD42021284214). [ABSTRACT FROM AUTHOR]

Jonathan Lilley,1 Erin C O’Neil,1 Vatinee Y Bunya,1 Kennedy Johnson,1 Gui-Shuang Ying,2 Peiying Hua,2 Mina Massaro-Giordano1 1Department of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 2Center for Preventive Ophthalmology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USACorrespondence: Mina Massaro-GiordanoDepartment of Ophthalmology, Scheie Eye Institute, Perelman School of Medicine at the University of Pennsylvania, 51 N. 39th Street, Philadelphia, PA, 19104, USATel +1 215-662-9393Email mina@pennmedicine.upenn.eduPurpose: To assess the efficacy and safety of an intranasal tear neurostimulator (ITN) device in Sjögren syndrome (SS) patients.Methods: This was a two-visit prospective, randomized, controlled, same-day crossover study in participants with SS. Inclusion criteria were assessed at a baseline screening visit and included an Ocular Surface Disease Index (OSDI) score ≥ 13, and a Schirmer with anesthesia ≤ 10 mm/5 min (in at least one eye), with a cotton swab stimulation induced increase of ≥ 4 mm in the same eye. Participants returned for the application visit, where they received intranasal and extranasal applications of the ITN in random sequence, separated by at least 60 min. Schirmer scores were measured in both eyes after each application and compared to baseline values. Generalized linear models were performed to compare the change in Schirmer scores from baseline, and generalized estimating equations were used to account for correlations from repeated measurements in the same eye and measurements from two eyes of the same patient.Results: Fifty-five participants were screened and 35 were enrolled (all female), ranging in age from 31 to 72 years (mean, 57 years). The baseline OSDI score ranged from 14 to 91 (mean, 50.5), and the baseline Schirmer score had a mean (SD) of 6.4 (3.5) ranging from 0 to 20 (mm/5min). Improvement in Schirmer scores was significantly greater for intranasal device application (13.5 mm/5min, 95% CI: 10.4, 16.5) compared to extranasal device application (0.8mm/5min, 95% CI: − 0.9, 2.4) (p< 0.0001). The effects of the intranasal device application were significant regardless of the participant’s baseline Schirmer score and systemic SS medication usage (p< 0.05).Conclusion: Intranasal application of the ITN device significantly increased tear production in a subset of SS patients compared to baseline and was more effective than extranasal application. While production of the ITN device was recently discontinued, our findings suggest that other therapies that neurostimulate the lacrimal function unit may be effective in a subset of SS patients.Keywords: Sjögren syndrome, intranasal tear neurostimulation, tear production