[Biomechanics of diabetic vitreopapillary traction syndrome]. / Biomekhanika diabeticheskogo vitreopapillyarnogo traktsionnogo sindroma.

Diabetic vitreopapillary traction syndrome (VPT) is a variant of diabetic retinopathy (DR) that can lead to vision loss in advanced stages. This review reports on the biomechanics of the vitreous in the pathogenesis of proliferative DR, in particular diabetic VPT. The article analyzes and summarizes literature data, presents the views of different authors on this problem, and provides the results of Russian and foreign scientific research on this pathology. It is concluded that further research in this area can lead to a significant improvement in the results of therapy, timely diagnosis, and preservation of vision in patients with DR.

Traumatic terson syndrome with a peculiar mass lesion and tractional retinal detachment: a case report.

BACKGROUND: To report a case with bilateral Terson syndrome presented with a unique mushroom-like mass lesion on the optic disc along with proliferative vitreoretinopathy and tractional retinal detachment. CASE PRESENTATION: A 33-year-old man was injured during a traffic accident and had diffuse brain swelling and intraocular hemorrhage. Poor vision in both eyes was noted after the patient regained consciousness. B-scan ultrasonography showed extensive vitreous opacity with a posterior vitreous detachment and without obvious retinal detachment. Vitrectomy was performed in both eyes five months after the accident. After clearing up the vitreous opacity, a peculiar pigmented mushroom-like mass lesion was noted in the posterior pole and had severe adhesion to the underneath optic disc. Extensive multilayered peripapillary epiretinal membrane was found covering the posterior pole and led to tractional retinal detachment around the macula. The mass was presumed to be an organized vitreous hemorrhage originated from the optic disc. The extensive and adherent epiretinal membrane together with the mass lesion were removed as much as possible and silicon oil was injected for tamponade. However, in the right eye, the retina redetached under silicon oil, whereas in the left eye, his vision improved to 20/100. CONCLUSIONS: Terson syndrome usually has a favorable prognosis but may be complicated by proliferative vitreoretinopathy and tractional retinal detachment. Careful monitoring is warranted and early vitrectomy should be considered in cases suspecting additional pathologies.

Anti-inflammatory potential of simvastatin and amfenac in ARPE-19 cells; insights in preventing re-detachment and proliferative vitreoretinopathy after rhegmatogenous retinal detachment surgery.

PURPOSE: Rhegmatogenous retinal detachment is a severe vision-threatening complication that can result into proliferative vitreoretinopathy (PVR) and re-detachment of the retina if recovery from surgery fails. Inflammation and changes in retinal pigment epithelial (RPE) cells are important contributors to the disease. Here, we studied the effects of simvastatin and amfenac on ARPE-19 cells under inflammatory conditions. METHODS: ARPE-19 cells were pre-treated with simvastatin and/or amfenac for 24 h after which interleukin (IL)-1α or IL-1ß was added for another 24 h. After treatments, lactate dehydrogenase release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) processing, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity, prostaglandin E2 (PGE2) level, and extracellular levels of IL-6, IL-8, monocytic chemoattractant protein (MCP-1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor, as well as the production of reactive oxygen species (ROS) were determined. RESULTS: Pre-treatment of human ARPE-19 cells with simvastatin reduced the production of IL-6, IL-8, and MCP-1 cytokines, PGE2 levels, as well as NF-κB activity upon inflammation, whereas amfenac reduced IL-8 and MCP-1 release but increased ROS production. Together, simvastatin and amfenac reduced the release of IL-6, IL-8, and MCP-1 cytokines as well as NF-κB activity but increased the VEGF release upon inflammation in ARPE-19 cells. CONCLUSION: Our present study supports the anti-inflammatory capacity of simvastatin as pre-treatment against inflammation in human RPE cells, and the addition of amfenac complements the effect. The early modulation of local conditions in the retina can prevent inflammation induced PVR formation and subsequent retinal re-detachment.

Vitreous Olink proteomics reveals inflammatory biomarkers for diagnosis and prognosis of traumatic proliferative vitreoretinopathy.

Background: The aim of this study was to identify inflammatory biomarkers in traumatic proliferative vitreoretinopathy (TPVR) patients and further validate the expression curve of particular biomarkers in the rabbit TPVR model. Methods: The Olink Inflammation Panel was used to compare the differentially expressed proteins (DEPs) in the vitreous of TPVR patients 7-14 days after open globe injury (OGI) (N = 19) and macular hole patients (N = 22), followed by correlation analysis between DEPs and clinical signs, protein-protein interaction (PPI) analysis, area under the receiver operating characteristic curve (AUC) analysis, and function enrichment analysis. A TPVR rabbit model was established and expression levels of candidate interleukin family members (IL-6, IL-7, and IL-33) were measured by enzyme-linked immunosorbent assay (ELISA) at 0, 1, 3, 7, 10, 14, and 28 days after OGI. Results: Forty-eight DEPs were detected between the two groups. Correlation analysis showed that CXCL5, EN-RAGE, IL-7, ADA, CD5, CCL25, CASP8, TWEAK, and IL-33 were significantly correlated with clinical signs including ocular wound characteristics, PVR scoring, PVR recurrence, and final visual acuity (R = 0.467-0.699, p < 0.05), and all with optimal AUC values (0.7344-1). Correlations between DEP analysis and PPI analysis further verified that IL-6, IL-7, IL-8, IL-33, HGF, and CXCL5 were highly interactive (combined score: 0.669-0.983). These DEPs were enriched in novel pathways such as cancer signaling pathway (N = 14, p < 0.000). Vitreous levels of IL-6, IL-7, and IL-33 in the rabbit TPVR model displayed consistency with the trend in Olink data, all exhibiting marked differential expression 1 day following the OGI. Conclusion: IL-7, IL-33, EN-RAGE, TWEAK, CXCL5, and CD5 may be potential biomarkers for TPVR pathogenesis and prognosis, and early post-injury may be an ideal time for TPVR intervention targeting interleukin family biomarkers.

TGF-ß2-induced alterations of m6A methylation in hTERT RPE-1 cells.

N6-methyladenosine (m6A) is a major type of RNA modification implicated in various pathophysiological processes. Transforming growth factor ß2 (TGF-ß2) induces epithelial-mesenchymal transition (EMT) in retinal pigmental epithelial (RPE) cells and promotes the progression of proliferative vitreoretinopathy (PVR). However, the role of m6A methylation in the EMT of human telomerase reverse transcriptase (hTERT) retinal pigmental epithelium (RPE)-1 cells has not been clarified. Here, we extracted RNA from RPE cells subjected to 0 or 20 ng/mL TGF-ß2 for 72 h and identified differentially methylated genes (DMGs) by m6A-Seq and differentially expressed genes (DEGs) by RNA-Seq. We selected the genes related to EMT by conjoint m6A-Seq/RNA-Seq analysis and verified them by qRT-PCR. We then confirmed the function of m6A methylation in the EMT of RPE cells by knocking down the methyltransferase METTL3 and the m6A reading protein YTHDF1. Sequencing yielded 5814 DMGs and 1607 DEGs. Conjoint analysis selected 467 genes altered at the m6A and RNA levels that are closely associated with the EMT-related TGF-ß, AGE-RAGE, PI3K-Akt, P53, and Wnt signaling pathways. We also identified ten core EMT genes ACTG2, BMP6, CDH2, LOXL2, SNAIL1, SPARC, BMP4, EMP3, FOXM1, and MYC. Their RNA levels were evaluated by qRT-PCR and were consistent with the sequencing results. We observed that METTL3 knockdown enhanced RPE cell migration and significantly upregulated the EMT markers N-cadherin (encoded by CDH2), fibronectin (FN), Snail family transcription repressor (SLUG), and vimentin. However, YTHDF1 knockdown had the opposite effects and decreased both cell migration and the N-cadherin, FN, and SLUG expression levels. The present study clarified TGF-ß2-induced m6A- and RNA-level differences in RPE cells, indicated that m6A methylation might regulate EMT marker expression, and showed that m6A could regulate TGF-ß2-induced EMT.

PI3Kδ Mediates Fibrosis by Patient-Derived Vitreous.

The epithelial-mesenchymal transition (EMT) is a fundamental process in developing fibrotic diseases, including forming epiretinal membranes (ERMs). ERMs can result in irreversible vision loss. Previous research has demonstrated that vitreous (VIT) derived from patients with proliferative diabetic retinopathy can stimulate angiogenesis through the Axl/PI3K/Akt pathway. Building upon this knowledge, we aimed to explore the influence of VIT from patients with macular membranes in ARPE-19 cells. Our findings reveal that patient-derived VIT from individuals with macular membranes promotes EMT and phosphoinositide 3-kinase-delta (PI3Kδ) expression in ARPE-19 cells. To elucidate the function of PI3Kδ in the ERM, we conducted experiments involving the knockout of p110δ, a key subunit of PI3Kδ, and observed that its absence hinders EMT induced by patient-derived VIT. Moreover, p110δ depletion reduces cell proliferation and migration in ARPE-19 cells. Remarkably, these effects were further corroborated by applying the p110δ inhibitor idelalisib, which blocks fibrosis in the laser-induced fibrosis model. Collectively, our results propose that p110δ plays a critical role in the progression of ERMs. Consequently, targeting p110δ emerges as a promising therapeutic approach for mitigating fibrosis. These findings contribute to a better understanding of the underlying mechanisms involved in ERM formation and highlight the potential for p110δ-directed antifibrotic therapy in retinal diseases.

Bone morphogenetic protein 6 (BMP6) antagonises experimental proliferative vitreoretinopathy established by TGF-ß2 stimulation in retinal pigment epithelial cells through modulation of the p38 and JNK MAPK pathways.

The formation of the epiretinal fibrotic membrane by retinal pigment epithelial (RPE) cells is a primary pathological change for proliferative vitreoretinopathy (PVR). Bone morphogenetic protein 6 (BMP6) is an antifibrogenic factor in various cells. To date, it is still unknown whether BMP6 can interfere with the fibrogenesis of RPE cells during the progression of PVR. This work aimed to address the relationship between BMP6 and transforming growth factor-ß2 (TGF-ß2)-elicited fibrogenesis of RPE cells, an experimental model for studying PVR in vitro. The BMP6 level was down-regulated, while the TGF-ß2 level was up-regulated in the vitreous humor of PVR patients. The BMP6 level was down-regulated in human RPE cells challenged with TGF-ß2. The treatment of RPE cells with TGF-ß2 resulted in significant increases in proliferation, migration, epithelial-to-mesenchymal transition (EMT), and extracellular matrix (ECM) remodelling. These effects were found to be inhibited by the overexpression of BMP6 or exacerbated by the knockdown of BMP6. BMP6 overexpression reduced the phosphorylation of p38 and JNK in TGF-ß2-stimulated RPE cells, while BMP6 knockdown showed the opposite effects. The inhibition of p38 or JNK partially reversed the BMP6-silencing-induced promoting effects on TGF-ß2-elicited fibrogenesis in RPE cells. Taken together, BMP6 demonstrates the ability to counteract the proliferation, migration, EMT, and ECM remodelling of RPE cells induced by TGF-ß2. This is achieved through the regulation of the p38 and JNK MAPK pathways. These findings imply a potential connection between BMP6 and PVR, and highlight the potential application of BMP6 in therapeutic interventions for PVR.

ADDITIONAL PNEUMATIC RETINOPEXY IN PATIENTS WITH PERSISTENT RETINAL DETACHMENT AFTER SCLERAL BUCKLING.

PURPOSE: To investigate the efficacy, safety, and indications for additional pneumatic retinopexy (PR) in patients with persistent retinal detachment after scleral buckling. METHODS: This retrospective study included patients who underwent additional PR after scleral buckling for primary rhegmatogenous retinal detachment (n = 78). We defined "inadequate buckle" as retinal detachment persistence because of low buckle height despite accurate buckle placement and "buckle misplacement" as an uncovered tear because of incorrect buckle placement. RESULTS: The anatomical success rate after additional PR was 52.6%. Development of proliferative vitreoretinopathy Grade B (hazard ratio, 5.73; P < 0.001) and inferior retinal tears (hazard ratio, 2.12; P = 0.040) were significant risk factors for anatomical failure. The most common cause of anatomical failure was proliferative vitreoretinopathy (19 of 37; 51.4%), and epiretinal membrane formation was a common complication after additional PR (22 of 78; 28.2%). The anatomical success rate with additional PR was significantly higher in the inadequate buckle group than in the misplacement group (8 of 9 [88.9%] vs. 1228 [42.9%]; P = 0.023). CONCLUSION: Development of proliferative vitreoretinopathy Grade B and inferior retinal tears were significantly associated with anatomical failure after additional PR. Additional PR may benefit patients with superior retinal tears or low buckle height and those without proliferative vitreoretinopathy.

Vitreous Biomarkers for Proliferative Vitreoretinopathy Prognostication in Patients Undergoing Primary Retinal Detachment Repair.

Purpose: To compare baseline levels of exploratory biomarkers in the vitreous fluid of patients with primary retinal detachment who subsequently develop proliferative vitreoretinopathy (PVR) versus those who do not. Methods: In this exploratory case-control study, we evaluated the baseline protein biomarker levels from a biobank containing the vitreous fluid of patients who had undergone primary pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment. Undiluted samples were collected at the time of PPV and stored at -80°C. Samples from 13 patients who developed PVR within 6 months (PVR group) and 13 age- and gender-matched controls who did not develop PVR (control group) were included. Protein abundance levels were evaluated using a proximity extension assay, and a confirmatory enzyme-linked immunosorbent assay (ELISA) was used to measure the concentration of vimentin. Results: Baseline vimentin (Normalized Protein eXpression [NPX], 8.6 vs. 6.4, P < 0.0001) and heme oxygenase 1 (NPX 8.9 vs. 7.0, P < 0.001) levels were found to be elevated in vitreous fluid of patients who subsequently developed PVR compared to those who did not. Confirmatory analysis using ELISA demonstrated mean vimentin concentrations of 7254 vs. 2727 ng/mL in the PVR versus control groups (P = 0.0152). The odds ratio for developing PVR was 14 (confidence interval, 1.4-168; P = 0.03), assuming a baseline vimentin threshold of 7500 ng/mL. Conclusions: Vimentin is an intermediate filament protein expressed by retinal glial cells, and our data combined with prior evidence suggest that it may serve as an early vitreous biomarker for subsequent PVR formation and reactive gliosis. Furthermore, we found, for the first time, elevated baseline levels of heme oxygenase 1, a measurable indicator of oxidative stress. Translational Relevance: Our positive findings could impact clinical care for retinal detachment patients by facilitating risk stratification for targeted interventions or closer monitoring in those at the highest risk of developing PVR.

Risk factors for surgical failure after primary scleral buckling for rhegmatogenous retinal detachment.

OBJECTIVE: To identify risk factors for surgical failure after scleral buckling (SB) for primary rhegmatogenous retinal detachment (RRD) repair. DESIGN: Single-centre retrospective consecutive case series. PARTICIPANTS: All patients who underwent SB for repair of primary RRD at Wills Eye Hospital between January 1, 2015, and December 31, 2018, were included. METHODS: Single-surgery anatomic success (SSAS) rate and risk factors associated with surgical failure were evaluated. A multivariable logistic regression model was completed to assess the effect of demographic, clinical, and operative variables on SSAS rate. RESULTS: A total of 499 eyes of 499 patients were included. Overall SSAS rate was 86% (n = 430 of 499). Using multivariate analysis, surgical failure was more likely in males (adjusted odds ratio [adjusted OR] = 2.98; 95% CI, 1.58-5.62; p = 0.0007) with a macula-off status on preoperative examination (adjusted OR = 2.15; 95% CI, 1.10-4.20; p = 0.03) and preoperative proliferative vitreoretinopathy (adjusted OR = 4.26; 95% CI, 1.10-16.5; p = 0.04). Time interval between initial examination and surgery (p = 0.26), distribution of buckle or band material used (p = 0.88), and distribution of tamponade used (p = 0.74) were not significantly different between eyes with and without surgical failure. CONCLUSION: Male sex, macula-off status, and preoperative proliferative vitreoretinopathy were factors with increased odds of surgical failure after SB for primary RRD repair. Operative characteristics, such as type of band or use of tamponade, were not associated with surgical failure.

Prevalence of vitreoschisis-induced vitreous cortex remnants over the peripheral retinal surface in eyes undergoing vitrectomy for primary rhegmatogenous retinal detachment.

PURPOSE: Unremoved vitreoschisis-induced vitreous cortex remnants over the peripheral retinal surface posterior to the vitreous base (pVCR) may increase the risk of surgical failure after primary rhegmatogenous retinal detachment (RRD) repair. The purpose of this study was to validate our previous findings on pVCR prevalence during vitrectomy for RRD and to examine their association with proliferative vitreoretinopathy (PVR) and surgical failure. METHODS: Prospective observational multisurgeon study of 100 eyes of 100 consecutive patients who underwent vitrectomy for RRD by one of four vitreoretinal surgeons. Collected data included detected pVCR and known PVR risk factors. Pooled analysis with our previous retrospective study (251 eyes of 251 patients) was also performed. RESULTS: Initial PVR (≥C) was present and removed in 6/100 (6%) patients, pVCR were detected in 36/100 (36%) patients, pVCR were removed in 30/36 (83%) patients with pVCR, and 4/36 (11%) patients with pVCR were high myopes (≤-6D). Six per cent (6/100) developed a retinal redetachment, of which 3/6 (50%) had initial PVR (≥C). Surgical failure rates in eyes with and without pVCR were 17% (6/36) and 0% (0/64), respectively. In eyes with pVCR and surgical failure, pVCR were not or not completely removed during the first surgery. Overall analysis showed that pVCR were statistically significantly associated with PVR. CONCLUSIONS: This study confirms our previous findings: a pVCR prevalence of around 35% and an association between pVCR, PVR formation and surgical failure in patients undergoing vitrectomy for RRD. More research is needed to determine which patients would benefit most from pVCR removal.

LATE RECURRENCE OF RETINAL DETACHMENT: Incidence, Clinical Features, and Surgical Outcomes.

PURPOSE: To describe and evaluate demographics, clinical features, prognostic factors, rate of success of surgery, incidence, and visual outcomes in patients with a late recurrence of rhegmatogenous retinal detachment over a 10-year period at a large tertiary referral eye center. METHODS: A retrospective, observational case series of patients with late recurrence of retinal detachment, defined as redetachment after at least six months of total reattachment in non-proliferative vitreoretinopathy (PVR) rhegmatogenous retinal detachment, after pars plana vitrectomy (PPV) surgery with gas tamponade. RESULTS: Thirty-nine patients had a late recurrence of rhegmatogenous retinal detachment of 16,396 rhegmatogenous retinal detachment operations. The mean of time between the first retinal detachment (RD) surgery and redetachment was 122.7 (SD 115) weeks. On presentation with late recurrence, 72% of eyes were pseudophakic and 64% were macula-off. In 28 eyes, small breaks were found. Thirty-eight percent had established PVR (PVR-C in 80%). Ninety-five percent underwent PPV. Gas was used in 61%. The initial secondary success rate was 64%. Initial best-corrected visual acuity was 1.32 logarithm of the minimum angle of resolution (logMAR) (6/120) and final was 0.8 logMAR (6/38; P value 0.002). CONCLUSION: Late recurrence of retinal detachment is rare. It is characterized by small retinal breaks that may be difficult to visualize. Although cases can be treated with favorable anatomical results, visual outcomes are often less good and the success rate is lower.

Retinal Detachments after Open-Globe Injury: Risk Factors and Outcomes.

PURPOSE: To identify risk factors for retinal detachment (RD) after open-globe injury (OGI) and evaluate outcomes of RD repair after OGI. DESIGN: Case-control study. PARTICIPANTS: Overall, 769 patients presented with 786 OGIs, which were surgically managed with ≥ 30 days of follow-up. Of the 786 eyes, 223 developed RD, the other 551 served as controls, and RD status of 12 eyes was unknown. METHODS: A retrospective chart review was performed of all OGIs presented to the University of Michigan between 2000 and 2022. Multivariable regression identified risk factors for RD after OGI and predictors of poor vision after RD repair. Kaplan-Meier analysis estimated time from OGI to RD. MAIN OUTCOME MEASURE: Predictors of visual outcome after RD repair after OGI. RESULTS: After OGI, 223 (28.4%) of 786 eyes were diagnosed with RD, with > 73% diagnosed within a month. Predictors of RD include posterior injury (zone II vs. I odds ratio [OR], 1.60 [95% confidence interval {CI}, 1.04-2.46]; P = 0.0331; zone III vs. I OR, 2.29 [1.53-3.41]; P < 0.0001), vitreous hemorrhage (OR, 2.29 [1.54-3.1]; P < 0.0001), and presenting acuity worse than count fingers (CFs) (OR, 2.65 [1.69 - 4.16]; P < 0.0001). Retinal detachment repair took place in 142 of 223 eyes. The mean logarithm of minimal angle of resolution visual acuity (VA) improved from 2.3 ± 0.8 to 1.7 ± 0.9 after RD repair at 6-month follow-up, with 51.2% of eyes achieving CF or better vision. Single surgery anatomic success rate was 69.7% and final anatomic success was 88%. Predictors of vision worse than CF include history of ocular surgery (OR, 0.32 [0.11-0.94]; P = 0.039), proliferative vitreoretinopathy (PVR; OR, 0.39 [0.16 - 0.92]; P = 0.032), aphakia (OR, 0.25 [0.08 - 0.77]; P = 0.016), and redetachment (OR, 0.26 [0.1 - 0.63]; P = 0.003). CONCLUSIONS: Most RD occur within the first month after OGI. Patients with posterior injuries, vitreous hemorrhage, or poor presenting VA were more likely to develop RD after OGI. Anatomic success was achieved in the majority, as was final VA of CF vision or better. History of ocular surgery, PVR at time of repair, aphakia, and redetachment were risk factors for a poor outcome. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

PRESENTATIONS AND FACTORS AFFECTING OUTCOME OF RHEGMATOGENOUS RETINAL DETACHMENT WITH CHOROIDAL DETACHMENT: An Indo-Taiwanese Study.

PURPOSE: To report the clinical settings, management, and factors associated with outcomes of rhegmatogenous retinal detachment with concurrent choroidal detachment. METHODS: Retrospective, consecutive, multicenter case series from January 2014 to January 2021 were included. Cases were from a tertiary eye care center in India and Taiwan. RESULTS: Overall 303 eyes were included. Mean age was 43.72 ± 20.64 years (median 46). Best-corrected presenting visual acuity was 1.79 ± 0.92 logMAR (median 2.10) (Snellen 20/1,233). Forty-four patients (17.91%) received preoperative steroids. Final visual acuity was 1.33 ± 0.94 logMAR (median 1.10) (Snellen 20/427). Favorable anatomic outcome was seen in 200/303 (66%), whereas favorable functional outcome was seen in 128/303 (42.20%). Factors predicting favorable anatomic outcome were absence of phakic lens status (odds ratio [OR] 2.76), absence of proliferative vitreoretinopathy worse than Grade A (OR 7.69), use of preoperative steroids (OR 4.50), and use of an encircling band (3.85). Factors predicting favorable functional outcome were better presenting visual acuity (OR 3.03), absence of phakic lens status (OR 4.93), absence of proliferative vitreoretinopathy worse than Grade A (OR 10.41), and use of preoperative steroids (OR 7.24). CONCLUSION: Administration of preoperative steroids, use of an encircling band during surgery, and pseudophakic status of the eye were found to have better outcomes in rhegmatogenous retinal detachment with concurrent choroidal detachment.

Proliferative vitreoretinopathy: an update on the current and emerging treatment options.

Proliferative vitreoretinopathy (PVR) remains the main cause of failure in retinal detachment (RD) surgery and a demanding challenge for vitreoretinal surgeons. Despite the large improvements in surgical techniques and a better understanding of PVR pathogenesis in the last years, satisfactory anatomical and visual outcomes have not been provided yet. For this reason, several different adjunctive pharmacological agents have been investigated in combination with surgery. In this review, we analyze the current and emerging adjunctive treatment options for the management of PVR and we discuss their possible clinical application and beneficial role in this subgroup of patients.