Intravitreal Injection of Anti-Vascular Endothelial Growth Factors Combined with Corticosteroids for the Treatment of Macular Edema Secondary to Retinal Vein Occlusion: A Systematic Review and Meta-Analysis.

PURPOSE: To evaluate the efficacy and safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) and corticosteroid combination therapy for the management of treatment-naïve or recurrent/refractory macular edema caused by retinal vein occlusion (RVO) in comparison with anti-VEGF monotherapy. METHODS: In this systematic review and meta-analysis study, the data from publications in the electronic databases including PubMed, Embase, Cochrane Library Central Register of Controlled Trials, ISI and Scopus from January 1, 2007, through November 20, 2020, were compiled. Heterogeneity was statistically quantified by the I2 statistic, and meta-analysis was performed using a random-effects model. RESULTS: Twenty-four related studies were identified, including a total of 1280 eyes, which consisted of 685 and 507 patients with central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO), respectively. This study demonstrated a greater improvement in best-corrected visual acuity (BCVA) in the combination group compared to anti-VEGF monotherapy for both CRVO and BRVO cases at 6 months after initiating therapy. The improvement in vision was more notable in BRVO cases than in CRVO cases. However, the changes in central macular thickness (CMT) did not differ significantly between the different treatment approaches, and the results were inconclusive. Including all cases with RVO, there was no inferiority in terms of BCVA improvement and CMT reduction in the triamcinolone subgroup compared with the slow-release dexamethasone implant subgroup. A greater improvement was noticed in terms of BCVA in the sequentially treated subgroup compared to the simultaneous treatment subgroup, while there was a greater reduction in CMT in the simultaneous subgroup with the highest reduction recorded at 1 month after treatment. CONCLUSIONS: This study suggests that combination therapy with intravitreal anti-VEGF and corticosteroid (such as intravitreal or subtenon triamcinolone or dexamethasone implant) has a slightly better effect on improving BCVA in cases with BRVO or CRVO at 6 months compared to monotherapy.

Characterization of Central and Nasal Orbital Adipose Stem Cells and their Neural Differentiation Footprints.

BACKGROUND: The unique potential of stem cells to restore vision and regenerate damaged ocular cells has led to the increased attraction of researchers and ophthalmologists to ocular regenerative medicine in recent decades. In addition, advantages such as easy access to ocular tissues, non-invasive follow-up, and ocular immunologic privilege have enhanced the desire to develop ocular regenerative medicine. OBJECTIVE: This study aimed to characterize central and nasal orbital adipose stem cells (OASCs) and their neural differentiation potential. METHODS: The central and nasal orbital adipose tissues extracted during an upper blepharoplasty surgery were explant-cultured in Dulbecco's Modified Eagle Medium (DMEM)/F12 supplemented with 10% fetal bovine serum (FBS). Cells from passage 3 were characterized morphologically by osteogenic and adipogenic differentiation potential and by flow cytometry for expression of mesenchymal (CD73, CD90, and CD105) and hematopoietic (CD34 and CD45) markers. The potential of OASCs for the expression of NGF, PI3K, and MAPK and to induce neurogenesis was assessed by real-time PCR. RESULTS: OASCs were spindle-shaped and positive for adipogenic and osteogenic induction. They were also positive for mesenchymal and negative for hematopoietic markers. They were positive for NGF expression in the absence of any significant alteration in the expression of PI3K and MAPK genes. Nasal OASCs had higher expression of CD90, higher potential for adipogenesis, a higher level of NGF expression under serum-free supplementation, and more potential for neuron-like morphology. CONCLUSION: We suggested the explant method of culture as an easy and suitable method for the expansion of OASCs. Our findings denote mesenchymal properties of both central and nasal OASCs, while mesenchymal and neural characteristics were expressed stronger in nasal OASCs when compared to central ones. These findings can be added to the literature when cell transplantation is targeted in the treatment of neuro-retinal degenerative disorders.

Ocular posterior segment complications following COVID-19 vaccination.

BACKGROUND: The SARS-CoV-2 pandemic has had a significant impact on healthcare, including eye care, worldwide. Effective and safe vaccines have been developed using both conventional and novel technologies to combat SARS-CoV-2 infection. While vaccination has been shown to be remarkably effective in reducing the spread and associated morbidity and mortality of COVID-19 disease, there have been reports of complications to the posterior segment of the eye. METHODS: We present a case-based analysis of reported complications of COVID-19 vaccination to the posterior segment of the eye. The study aims to highlight the diversity of possible complications and discuss the plausible involved pathophysiologic mechanisms. RESULTS: The most significant complications reported were retinal macro or microvascular occlusions, uveitis, and central serous chorioretinopathy. These complications are rare but require prompt diagnosis and management to prevent serious visual morbidity. CONCLUSIONS: Our study highlights the need for ophthalmologists to be aware of possible complications related to COVID-19 vaccination and the importance of prompt diagnosis and management. The findings of this study may help ophthalmologists to better understand and manage these rare complications.

Intra-stromal injection of honey-treated keratocytes as a cell-based therapy for experimental corneal laceration.

OBJECTIVES: This study aimed to investigate the potential of honey-supplemented medium (HSM) for expanding corneal keratocytes and its transplantation in a model of corneal laceration. METHODS: Keratocytes were cultured in 1 % HSM- or 10 % fetal bovine serum (FBS)-supplemented medium for 24 h. The effect of HSM on keratocyte proliferation was evaluated using the MTT assay. The relative expression of Lum, Kera, and ALDH3A1, known markers of native keratocytes, was quantified by real-time PCR. The safety and efficacy of HSM-treated keratocyte intrastromal injection in a rabbit model of corneal laceration were also evaluated. RESULTS: The MTT assay showed that HSM treatment did not significantly affect cell viability compared to FBS-supplemented medium (84.71 ± 2.38 vs. 100.08 ± 10.92, respectively; p=0.076). Moreover, HSM-treated keratocytes had significantly increased expression of Lum, Kera, and ALDH3A1 compared to cells treated with FBS, while the expression of the proliferation biomarker Thy-1 did not significantly differ between the two treatments. Intrastromal injection of HSM-treated keratocytes in the laceration animal model was safe and uneventful, resulting in less stromal inflammation and neovascularization, and consequently, better final architecture with less residual haze compared to the group injected with FBS-treated keratocytes. CONCLUSIONS: These findings suggest that honey is a suitable supplement for keratocyte treatment and corneal cell therapy. The use of HSM may have potential applications in the treatment of corneal injuries and diseases.

Human Wharton's Jelly Mesenchymal Stem Cell Secretome Modifies the Processes of Neuroprotection and Epithelial-Mesenchymal Transition in Retinal Pigment Epithelium at Transcriptional Level.

BACKGROUND: Retinal pigment epithelium (RPE) cells are potential targets for treating retinal detachment (RD) and proliferative vitreoretinopathy (PVR), considering the importance of neuroprotection and epithelial-mesenchymal transition (EMT) of RPE in these conditions. This study investigated the effect of human Wharton's jelly mesenchymal stem cell secretome (WJMSC-S) on the expression of genes involved in both neuroprotection and EMT in RPE cells in vitro (TRKB, MAPK, PI3K, BDNF, and NGF). METHODS: RPE cells from passages 5-7 were treated with WJMSC-S (or the vehicle culture medium as control) for 24 h at 37◦C and subsequently subjected to RNA extraction and cDNA synthesis. Gene expression level was evaluated using real-time PCR in the treated versus control cells. RESULTS: The results of our study showed that WJMSC-S led to a significant downregulation in three out of five studied gene expression (MAPK, TRKB, and NGF), and simultaneously, remarkably upregulated the expression of the BDNF gene. CONCLUSIONS: According to the present data, WJMSC-S can affect the EMT and neuroprotection processes at the mRNA level by suppressing EMT and promoting neuroprotection in RPE cells. This finding may have positive clinical implications in the context of RD and PVR.

Variance in the macular sublayers' volume as a diagnostic tool for primary open-angle glaucoma.

PURPOSE: To assess the variance of macular sublayers' volume in glaucoma patients compared with normal individuals. METHODS: This case-control observational study included 63 cases of primary open-angle glaucoma and 57 healthy controls. Macular volumetric scans were captured at the 6 mm ETDRS circle for each retinal sublayer using Spectralis OCT2. The studied macular sublayers included the retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer, outer plexiform layer, outer nuclear layer, and outer retinal layers (external limiting membrane to the retinal pigment epithelium). Standard deviation (SD) and coefficient of variation (CoV) of macular sublayers' volume were calculated. An unpaired Student t test (or its nonparametric equivalent) was used to compare each variable between groups. The receiver operating characteristic curve (ROC) was used to investigate the discriminative ability of each parameter. RESULTS: There was no significant difference for age or sex between the groups. The SD (of all sublayers' volume) was greater in the glaucomatous eyes compared with controls (0.620 ± 0.073vs.0.524 ± 0.056  mm3, respectively; P < 0.001). The same pattern was observed for CoV (7.890 ± 0.979vs.6.128 ± 0.583; P < 0.001). The area under curves (AUCs) for SD and CoV were 0.855and0.930, respectively (P = 0.05). The best cutoff value for the CoV was 6.712. The CoV and ganglion cell layer (GCL) volume revealed similar sensitivity (80.75) at 95% specificity for diagnosing glaucoma. The CoV detected 5 patients with glaucoma who had normal GCC volume. CONCLUSION: This study showed that the macular sublayers' volume variance parameters could be viable OCT biomarkers for detecting glaucomatous changes.

Agreement of ocular response analyzer cornea compensated IOP with corvis ST biomechanical IOP following Femtosecond Laser-assisted LASIK.

OBJECTIVES: To compare intraocular pressure (IOP) measurement by ORA-IOPcc and Corvis-bIOP after femtosecond laser-assisted LASIK (FS-LASIK). METHODS: In this prospective cohort study, 56 eyes from 56 consecutive patients scheduled for FS-LASIK were enrolled. All patients had IOP measurement with ORA and Corvis ST by two blinded independent expert examiners. IOP examinations were conducted between 8 and 11 A.M. Data were collected at baseline and 3 months after FS-LASIK. RESULTS: The mean age of the participants was 29.1 ± 6.3 years, and 42 (75%) were female. The average of central corneal thickness (CCT) decreased from 537 ± 23 µm at baseline to 458 ± 31 µm after FS-LASIK. The mean postoperative change of IOP was 0.0 ± 2.1 for bIOP and -2.5 ± 3.2 mmHg for IOPcc. The corresponding 95% limits of agreement (LoA) was -4.1 to 4.1 mmHg and -3.8 to 8.8 mmHg, respectively. Both methods showed no significant correlation between ∆IOP and ∆CCT. The 95% LoA between bIOP and IOPcc after FS-LASIK was -4.8 to 9.1 mmHg. CONCLUSIONS: Compared to the ORA-IOPcc, the Corvis-bIOP showed less variation after FS-LASIK and might be a more appropriate choice for measuring IOP in this condition. The agreement of bIOP vs. IOPcc after FS-LASIK is below the clinically acceptable level, and the two methods could not be regarded as interchangeable.

An Update on Anti-Vascular Endothelial Growth Factor Treatment for Retinopathy of Prematurity.

Purpose: To present updated information on the role of anti-vascular endothelial growth factor (anti-VEGF) therapy for treating retinopathy of prematurity (ROP). Methods: We searched through PubMed and Scopus databases using the keywords of this article and gathered relevant published articles from the year 2005 to December 2022. The selected articles were classified and summarized, and reasonable conclusions were made accordingly. Results: Considering the current evidence, anti-VEGF agents are superior to laser therapy for the initial treatment of type 1 ROP in zone 1 or posterior zone 2. However, there is a substantial risk of reactivation or persistent avascular retina after solo treatment with anti-VEGFs, and many cases may require laser therapy within the following weeks or months. Thus, vigilant follow-up examinations are mandatory. Conclusions: The role of anti-VEGF agents in the treatment of ROP is indispensable. However, future studies are required to improve indications and dosage and determine long-term ocular and systemic safety.

A Review on the Application of Stem Cell Secretome in the Protection and Regeneration of Retinal Ganglion Cells; a Clinical Prospect in the Treatment of Optic Neuropathies.

PURPOSE: Retinal ganglion cells (RGCs) are one the most specialized neural tissues in the body. They transmit (and further process) chemoelectrical information originating in outer retinal layers to the central nervous system. In fact, the optic nerve is composed of RGC axons. Like other neural cells, RGCs will not completely heal after the injury, leading to irreversible vision loss from disorders such as glaucoma that primarily affect these cells. Several methods have been developed to protect or regenerate RGCs during or after the insult has occurred. This study aims to review the most recent clinical, animal and laboratory experiments designed for the regeneration of RGC that apply the stem cell-derived secretome. METHODS: We extracted the studies from Web of Science (ISI), Medline (PubMed), Scopus, Embase, and Google scholar from the first record to the last report registered in 2022, using the following keywords; "secretome" OR "conditioned medium" OR "exosome" OR "extracellular vesicle" AND "stem cell" AND "RGC" OR "optic neuropathy". Any registered clinical trials related to the subject were also extracted from clinicaltrial.gov. All published original studies that express the effect of stem cell secretome on RGC cells in optic neuropathy, whether in vitro, in animal studies, or in clinical trials were included in this survey. RESULTS: In this review, we provided an update on the existing reports, and a brief description of the details applied in the procedure. Compared to cell transplant, applying stem cell-derived secretome has the advantage of minimized immunogenicity yet preserving efficacy via its rich content of growth factors. CONCLUSIONS: Different sources of stem cell secretomes have distinct implications in the management of RGC injury, which is the main subject of the present article.

Angle κ and its effect on the corneal elevation maps in refractive surgery candidates.

PURPOSE: To assess the associations of angle κ and Pentacam decentration indices with elevation maps in normal refractive surgery candidates. SETTING: Salouti Cornea Research Center, Salouti Eye Clinic, Shiraz, Iran. DESIGN: Retrospective observational study. METHODS: In this research, the right eyes of 173 refractive surgery candidates were assessed. Data of front and back corneal elevation maps, keratometric data, decentration indices, and corneal astigmatism obtained by Pentacam HR system and angle κ obtained by Orbscan IIz were extracted. Maximum elevation (or depression) for each of the 4 quadrants was recorded. Correlations of elevation values with angle κ, Pentacam decentration indices, keratometry, and astigmatism were examined by Pearson correlation coefficient. 148 age- and sex-matched cases with keratoconus grade 1 were selected as a positive control group, and Pentacam variables were compared between the groups. RESULTS: Overall, data from 173 eyes of 173 normal refractive surgery candidates and 148 eyes of 148 patients with keratoconus were recorded and analyzed. In normal refractive surgery candidates, the mean of angle κ was 5.32 ± 1.36 (SD) degrees. Angle κ had a positive correlation with front and back temporal elevations based on a best-fit sphere (BFS) ( r = 0.339, P = .001; r = 0.300, P < .001, respectively). Front and back keratometric astigmatisms were positively correlated with front and back nasal and temporal elevations ( r ≥ 0.543, P < .001) and negatively correlated with superior and inferior elevations ( r ≤ -0.547, P < .001). These associations no longer existed when using best-fit toric ellipse (BFTE) for calculating elevation data. The thinnest point to vertex decentration was significantly associated with the back temporal elevation (based on the BFTE) in both normal ( r = 0.311, P < .001) and keratoconus ( r = 0.190, P = .021) eyes. CONCLUSIONS: This study showed that elevation maps obtained by the Pentacam system using BFS might be affected by both the large angle κ and corneal astigmatism, confounding the preoperative assessment of refractive surgery candidates. Using BFTE as a reference for calculating elevation data should eliminate most diagnostic issues and thus is encouraged in this context.

Inferior Spear-like Lens Opacity as a Sign of Keratoconus.

PURPOSE: To report 21 cases of typical inferior feather-shape lens opacity associated with keratoconus. METHODS: In this cross-sectional study, we evaluated the association of keratoconus with inferior feather-shape lens opacity in refractive surgery candidates. Visual acuity, demographic, refractive, and topographic characteristics of 26 eyes of 21 patients with inferior feather-shape lens opacity were evaluated in detail. Pedigree analysis was also performed to assess possible inheritance. RESULTS: Overall, 2122 out of 33,368 cases (6.4%) without lens opacity had keratoconus, while 20 out of 21 patients (95.2%) with peculiar lens opacity had definite keratoconus (P < 0.001). Lens opacity was bilateral in 5 cases (24%), and keratoconus was bilateral in all 20 patients with lens opacity. Nine eyes out of thirty-six with a complete data record (25%) had a severe keratoconus and underwent deep lamellar keratoplasty, while 11 (31%) had forme fruste keratoconus. Pedigrees were drawn for eight patients, most families of whom suggested an X-linked recessive inheritance. CONCLUSION: The present study was the first to investigate patients with a peculiar inferior feather-shape lens opacity accompanied by bilateral keratoconus, which was observed in 95% of the patients. This finding should raise awareness as to the possibility of diagnosing keratoconus in the eyes of the patients with these characteristics.

RPE based gene and cell therapy for inherited retinal diseases: A review.

The Retinal Pigment Epithelium (RPE) is the supportive layer located beneath the neural retina. Its health is essential for the proper function of photoreceptors. Indeed, any condition involving the RPE has the potential to induce an antegrade degeneration of the photoreceptors and inner retinal layers. Traditionally, degenerative disorders of the neural retina have been considered untreatable. However, the advent of gene and cell replacement therapies brings hope to halt or even cure retinal degenerative diseases. This study aims to review the most recent clinical trials registered on the RPE-based gene/cell intervention for the treatment of inherited retinal diseases (IRD). In this review, we provided an update on the clinical studies on the RPE-based gene/cell therapy for the treatment of IRD, summarized recent studies in this regard, and present the results of the corresponding clinical trials. A brief description of the details applied in the techniques, the advantages and withdraws of the utilized strategies were also included. This study provided evidence to show that gene therapy and cell replacement therapy have a great potential to become a successful treatment for IRD in the following decades, however, future studies should focus on novel methods to increase the safety and efficacy of the treatment.

Comparison of retinal vascular arcade trajectory between eyes with an idiopathic macular hole and the healthy fellow eye.

PURPOSE: We aimed to present a method to evaluate the retinal arcade vascular trajectory by measuring the distance between the retinal veins in eyes with idiopathic macular hole (IMH) and comparing this measurement with healthy fellow eyes. METHODS: In this cross-sectional study 18 patients with unilateral IMH were enrolled. We used standard fundus photographs, which were obtained from each eye with a digital fundus camera using a 55-degree lens. The calculation of the retinal arcade vascular trajectories was done by drawing and measuring five vertical lines within the macular area. RESULTS: The mean age of the patients was 65 ± 9 years. The between-groups differences of each vertical line were not statistically significant, except for the differences between the most temporal line, which was greater in the diseased group (9388 vs. 8322 µm; P = 0.034). The ratio between the fifth (most temporal) and the third (fovea-center) vertical lines was greater than 1 (V-shape) in 72% of eyes with a macular hole, whereas it was less than one (U-shape) in 78% of control eyes (P = 0.003). CONCLUSIONS: We demonstrated that in eyes with an IMH the vascular arcade has more tendency to diverge on its path temporal to the fovea.

Ocular manifestations of endocrine disorders.

Endocrinopathies are prevalent diseases that typically affect multiple organs, and the eye and orbital tissues are often involved in endocrine disorders. Some conditions, such as diabetes and thyroid gland dysfunction, may cause serious eye pathology and even blindness. A clear insight into the pathogenesis of endocrinopathies and their ocular manifestations would enhance preventive and therapeutic measures and reduce the incidence of sight-threatening complications. This review discusses the ocular manifestations of several endocrine disorders that eye care providers are likely to encounter in clinical practice.

Effects of the secretome of human Wharton's jelly mesenchymal stem cells on the proliferation and apoptosis gene expression of the retinal pigmented epithelium.

Human retinal pigmented epithelium (RPE) can undergo an uncontrolled proliferation in some disorders such as retinal detachment associated with proliferative vitreoretinopathy (PVR). The present study was conducted to evaluate the effect of the conditioned medium secreted by human Wharton's jelly mesenchymal stem cells (WJMSCs-CM) on the proliferation and apoptosis gene expression of the RPE. WJMSCs-CM was collected from WJMSCs after two periods of 24-h and 9-h culture in serum-free medium. RPE cells were cultured in WJMSCs-CM versus serum-deprived media for 24 h. The effect of WJMSCs-CM on RPE cell proliferation was determined using the MTT assay. Relative expression of apoptotic genes (Bcl2, Bax, and IL-1B) was also assessed by real-time PCR. MTT assay demonstrated that RPE cell viability was reduced significantly in WJMSCs-CM treated RPE cells compared to those cultured in serum-deprived medium (64.23 ± 2.44 vs 100.10 ± 5.68; P = 0.006). Moreover, the expression of anti-apoptotic Bcl2 was significantly decreased in WJMSCs-CM compared to serum-deprived medium (0.52 ± 0.06 in WJMSCs-CM vs 1.02 ± 0.2 in serum-free treatment; P = 0.03), while the expression of pro-apoptotic biomarkers of Bax and IL-1B was not significantly different between the two treatments. The represented data showed that WJMSCs-CM can induce apoptosis in RPE cells in vitro through activating apoptosis pathways. This proof-of-the-concept study provides basic evidence for the possible effect of WJMSCs-CM on preventing PVR.

Intraocular Pressure Changes after Water Drinking Test in Surgically Treated Primary Congenital Glaucoma.

PURPOSE: To assess intraocular pressure (IOP) changes after the water drinking test (WDT) in patients with primary congenital glaucoma (PCG). METHODS: In this prospective interventional study, 20 eyes of 20 patients with PCG were included. All patients had undergone trabeculotomy. Six out of twenty eyes had received a glaucoma drainage device (GDD) implantation. IOP was measured using an air-puff tonometer at baseline, and 15, 30, 45, and 60 min after WDT. The repeated-measures analysis of variance test was used to compare the mean IOPs at different time points. RESULTS: The mean ( ± standard deviation) of participants' age was 9.9 ± 2.7 years (range, 6 to 16 years), and 8 (40%) participants were male. The mean IOPs at baseline and 15, 30, 45, and 60 minutes after the WDT were 15.8 ± 3.7, 18.6 ± 3.4, 19.0 ± 3.8, 17.9 ± 3.8, and 16.9 ± 3.5 mmHg, respectively (P < 0.001). Pairwise comparisons revealed that the mean IOPs after 15 and 30 min were significantly greater than the baseline IOP (P < 0.001 and P = 0.002, respectively); however, the difference in mean IOPs after 45 and 60 min were not statistically significant from the baseline IOP. The averages of IOP peak and IOP fluctuation after the WDT were 20.0 ± 3.5 and 4.2 ± 2.9 mmHg, respectively. IOP fluctuation in those who underwent trabeculotomy alone was twice that of those with GDDs, but the difference was not statistically significant (5.0 vs 2.5 mmHg; P = 0.08). CONCLUSION: In patients with PCG, WDT induced significant IOP elevation 15 and 30 min after the test, which returned to pre-test values after 45 min.

Distribution of intraocular pressure in healthy Iranian children: the Shiraz Pediatric Eye Study.

PURPOSE: To describe the mean and normal range of intraocular pressure (IOP) and its associations in healthy Iranian school children using the noncontact tonometer. METHODS: In this cross-sectional study as part of the Shiraz Pediatric Eye Study, a stratified random sampling was performed among elementary school children of Shiraz, Iran. Basic demographics and socioeconomic status of households, past medical history, drug history, and eye health history were collected for each eligible student. Children underwent complete ophthalmic examination. Axial length, corneal curvature, and anterior chamber depth were measured using the IOL-Master 500. RESULTS: Of 2,001 eligible children, 1,901 (95.0%; 3,802 eyes) with a mean age of 9.1 ± 1.6 years (standard deviation; range, 6-12 years) had reliable IOP. The mean spherical equivalent refraction was 0.5 ± 1.3 D for the right eye and 0.6 ± 1.2 D for the left eye. Mean IOP in the right eye was 15.1 ± 2.5 mm Hg (median, 15.0; range, 8.0-27.0 mm Hg); in the left eye, 15.2 ± 2.5 mm Hg (median, 15.0; range, 9.0-28.0 mm Hg). In multiple regression analyses, the mean IOP was significantly lower among asthmatic children compared to normal participants (P = 0.007). The measured IOP was significantly higher in myopic participants than hyperopic patients (P = 0.003). CONCLUSIONS: This study provides a useful normative IOP database using the noncontact tonometer for healthy Iranian school children.