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PURPOSE: To evaluate progressive changes in retinal nerve fibre layer (RNFL), ganglion cell layer/inner plexiform layer (GCL/IPL) and visual function in thyroid eye disease (TED) patients with and without orbital decompression. METHODS: Sixty TED patients (105 eyes) were included. All patients were divided into mild, moderate-to-severe and dysthyroid optic neuropathy (DON) groups. Orbital decompression was performed in the moderate-to-severe and DON groups. Optic coherence tomography (OCT), visual field (VF) and best-corrected visual acuity (BCVA) were performed pre- and postoperatively. Preoperative follow-up was performed in the mild group and in part of the moderate-to-severe and DON groups. RESULTS: After decompression, the thickness of GCL/IPL and RNFL significantly decreased in DON group (p < 0.05), with varying degrees of decrease in eyes with optic disc swelling, atrophy and normal appearance. The mean GCL/IPL thickness significantly decreased in moderate-to-severe group (p < 0.05), the mean RNFL thickness slightly decreased with no statistical significance (p = 0.07). During the preoperative follow-ups, the mean GCL/IPL thickness significantly decreased (p = 0.04), whereas the mean RNFL thickness tended to increase (p = 0.13) in DON group. The thickness of GCL/IPL and RNFL did not change significantly in the mild and moderate-to-severe groups (p > 0.05). BCVA and VF did not change significantly in any group (p > 0.05) preoperatively. CONCLUSION: Swelling and degeneration of retinal ganglion cells (RGCs) may coexist in DON eyes, leading to continuous changes in the RNFL and GCL/IPL thickness either before or after decompression. Slight swelling and degeneration of RGCs may exist in moderate-to-severe TED eyes, although OCT measurements and visual functions remain stable before surgery.

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PURPOSE: This single-arm, prospective, exploratory study investigated the effectiveness of ultra-low-dose radiotherapy in the treatment of ocular adnexal lymphoma (OAL). PATIENTS AND METHODS: Patients with pathologically confirmed ocular adnexal low-grade non-Hodgkin lymphoma (predominantly mucosa-associated lymphoid tissue, MALT or follicular lymphoma) were included and treated with ultra-low-dose radiotherapy consisting of 2 successive fractions of 2 Gy at our institution between 2019 and 2021. Disease response was assessed clinically and radiographically within 4 months and at 3 to 6-month intervals after treatment. Data collected included rates of overall response, complete response (CR), partial response (PR), lesion size, and acute/chronic ocular toxic effects. RESULTS: Sixteen patients with median age of 63 years (range 23-86 years) were included in the study. The histological subtypes included MALT (11 patients; 69%); follicular lymphoma (2 patients; 12%); Lymphoid hyperplasia (3 patient, 19%). At a median follow-up time of 15.5 months (range 5.0-30.0 months), the overall response rate was 88%, with a CR rate of 75% (n = 12) and a PR rate of 13% (n = 2). The average lesion area was reduced from 117.9 ± 60.4 mm2 before radiation therapy to 38.7 ± 46.0mm2 at initial evaluation post radiation therapy (P = 0.002, n = 16), and to 8.5 ± 21.2 mm2 (P < 0.001 compared with postoperative lesion area) in patients with response at one year (n = 11). Disease progression was noted in 2 patients (12%). The 1-year rates of local progression-free survivals (LPFS) and overall survival (OS) were 85% and 100%, respectively. No distant relapses were observed in any of the patients. No acute or late toxic effects were noted. CONCLUSION: Ultra-low-dose radiotherapy in patients with OAL is associated with excellent local disease control and long-term survival with no significant acute or late toxicities.

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AIM: To investigate whether the subtle change of choroidal/retinal vessel densities and volumes in thyroid-associated ophthalmopathy (TAO) could be an early sign to detect dysthyroid optic neuropathy (DON). METHODS: This was a retrospective cross-sectional study, and a total of 98 eyes from 50 subjects were enrolled under certain criteria. Thirty-four eyes of normal controls and 64 eyes of TAO, including 39 eyes of DON and 25 eyes of TAO without DON, underwent optical coherence tomography angiography (OCTA) scanning. All the tested parameters of OCTA scanning including choroid radial peripapillary capillaries (RPC), retinal nerve fiber layer (RNFL), and macular ganglion cell complex (GCC) were compared among groups, and the correlation between OCTA parameters and visual function parameters was also investigated. RESULTS: Whole choroidal RPC was significantly reduced in DON (48.24%±0.4978%) compared to normal (50.33%±0.3173%) and TAO without DON (49.16%±0.5463%; P=0.0041). The reduction of whole choroidal RPC was also correlated with visual field (VF) defect in DON (r=0.5422, n=39). Although vision acuity and VF were improved in all the patients with DON after being treated with medical and surgical decompression, the reduction of RPC density were not reversed. CONCLUSION: There is a notable reduction in choroidal RPC in DON, which is correlated with VF defect. The reduction of RPC density could not be reversed immediately by medical and surgical decompression even when vision and VF were improved. These findings suggest that choroidal RPC could be a useful parameter to diagnose and monitor early stage of DON.

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PURPOSE: We aimed to investigate the performance of T1 mapping and its histological correlation with extraocular muscle fibrosis in thyroid-associated ophthalmopathy (TAO). METHODS: We prospectively recruited 12 cases of active TAO, 12 cases of inactive TAO, and 15 cases of control subjects. All participants underwent magnetic resonance imaging (MRI) scan with pre-/postcontrast T1 mapping and short-time inversion-recovery (STIR) sequence. The images were analyzed to obtain precontrast T1, extracellular-volume (ECV) fraction on T1 mapping, and signal-intensity ratio (SIR) on STIR for each rectus. Muscle biopsy was performed at lateral rectus to quantify-collagen volume fraction, glycosaminoglycan (GAG)-volume fraction, and extracellular space component. The relationship between MRI and histopathology was examined with Pearson correlation coefficient. RESULTS: The active TAO group was characterized with GAG accumulation, while the inactive TAO group presented with substantial fibrosis. The MRI parameters achieved acceptable interobserver and intraobserver agreement. The precontrast T1 and ECV remarkably increased in the TAO groups than the control group, and ECV positively correlated with collagen-volume fraction (r = 0.913) and extracellular-space component (r = 0.886) in the inactive TAO group. The SIR statistically increased in the active TAO group, and SIR positively correlated with GAG-volume fraction in all three groups. The performance of ECV (cutoff > 48.1%) to screen out extraocular muscle fibrosis in inactive TAO was 60.9% sensitivity and 93.3% specificity. CONCLUSIONS: The ECV parameter on T1 mapping MRI is a reliable tool to quantify extraocular muscle fibrosis, providing insights into noninvasive evaluation of pathological changes in TAO orbit. TRIAL REGISTRATION NUMBER: ChiCTR2000040394; Date of registration: 28 November 2020.

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Purpose: The aim of this study is to evaluate the expression of osteopontin (OPN) and its relationship with relative cytokines in patients with Graves' ophthalmopathy (GO), and to observe the effect of OPN on orbital fibroblasts (OFs) proliferation, migration, and the expression of relative cytokines, as well as the signaling pathways involved in its effect. Methods: The orbital adipose connective tissue was obtained from 24 patients with GO (12 cases of active GO, and 12 cases of inactive GO) and 12 healthy controls. OFs were isolated from orbital tissues obtained from patients with active GO who were undergoing orbital decompression surgery. Quantitative PCR and Western blot were performed to detect RNA and protein expression. The proliferation and cell migration rates of OFs were measured by methylthiazol tetrazolium (MTT) and the cell scratch test. Signaling pathway inhibitors, such as OPN monoclonal antibody 1A12, ERK1/2 inhibitor PD98059, and PI3K inhibitor LY294002, were applied to determine the involved pathways. Results: The mRNA and protein levels of OPN were increased in orbital adipose connective tissue from patients with active GO than those from patients with inactive GO (2.83-fold increase, P < 0.001; 1.91-fold increase, P < 0.05). The OPN mRNA level was positively correlated with CD40 ligand (CD40L) and hyaluronan synthases 2 (HAS2) mRNA in patients with GO. OPN promoted proliferation and migration rate of OFs and induced vascular endothelial growth factor (VEGF) and collagen I mRNA expression, and the effects were inhibited by 1A12 or LY294002. Conclusions: OPN in orbital adipose connective tissues were significantly increase in active GO, and there were significant correlations of OPN with CD40L and HAS2 mRNA levels in patients with GO. OPN promoted proliferation and migration of OFs and induced VEGF and collagen I mRNA expression in OFs through PI3K/Akt signaling pathway. This suggested a role for OPN in the pathogenesis of GO through the activation of OFs.

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METHODS: Thirty studies with 1308 eyes were identified and included in this study. The primary outcome measures were best-corrected visual acuity (BCVA), and secondary outcomes were optical coherence tomography characteristics and polyp regression rates. The pooled results were calculated by the random-effect or fixed-effect model according to the heterogeneity of the data. RESULTS: Despite a large standard deviation in means (SMD) improvement for BCVA and central retinal thickness (CRT) in the conbercept group, there was no statistically significant difference in the other outcomes compared to ranibizumab and aflibercept. However, there was a greater polyp regression rate in the conbercept group at 12 months. CONCLUSIONS: This systematic review indicates that conbercept may achieve similar BCVA and CRT improvements as ranibizumab and aflibercept, with a superior rate of polyp regression at 12 months.

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BACKGROUND: Orbital invasive aspergillosis infection is rare life-threatening infection, most commonly seen in immunocompromised patients and extremely rare in individuals without risk factors. Here we present a rare case of bilateral cellulitis caused by invasive aspergillosis associated with bilateral intraorbital abscesses in a female patient. CASE PRESENTATION: A 49-year-old woman presented with a 3-month history of painful proptosis and periorbital swelling of bilateral eyes. She was initially diagnosed as bilateral orbital cellulitis complicated with cavernous sinus thrombosis and was treated with antibiotic medication for 1 month, but her symptoms persisted. MRI demonstrated orbital masses behind both globes. The lesion in right orbit was biopsied with a diagnosis of orbital granulomatosis with invasive aspergillosis infection. The patient was healed after receiving antifungal treatment. CONCLUSIONS: This is an unusual case about bilateral orbital abscesses with invasive fungal infection. Fungal infection of the orbit should be considered when patient does not respond to combination of anti-inflammatory and antibiotic therapies, even in some cases without any risk factors.

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BACKGROUND: Fibrofolliculoma is a benign, perifollicular, connective tissue tumor, and it usually arises in the form of multiple lesions, but rarely as a solitary lesion. We report a case of solitary fibrofolliculoma on the eyelid. CASE PRESENTATION: A 68-year-old female presented with an asymptomatic mass on the right upper eyelid. The lesion appeared as a flesh-colored, dome-shaped, smooth nodule being the size of 5 × 5 × 4 mm, with eyelashes protruding from the surface, and located on the upper lid margin. Shave excision was performed, and the diagnosis of fibrofolliculoma was confirmed finally through histological exam. CONCLUSIONS: Solitary fibrofolliculomas rarely arises on the eyelid. However, it should be suspected when a flesh-colored and doom-shaped lesion of the eyelid is encountered. The benign tumor on the lid margin can be removed by shave biopsy.

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AIM: To evaluate the benefit and harms of high-dose intravenous glucocorticoids (IVGC) as first-line treatment for Graves' ophthalmopathy (GO). METHODS: A systematic review and Meta-analysis of randomized clinical trials (RCTs) comparing IVGC for the treatment of GO, with placebo or other treatments, were conducted. Electronic databases were searched, and standard methodological guidance of Cochrane Handbook for Systematic Reviews of Interventions was used. The primary outcome was overall response, and secondary outcomes included the improvement and change in clinical activity score (CAS), and adverse events. RESULTS: Ten RCTs were included in the Meta-analysis. Low quality evidence (one trial) showed that participants receiving IVGC achieved significantly higher response compared to participants receiving placebo [risk ratio (RR) 7.50, 95% confidence interval (CI) 1.14 to 49.26]. Moderate quality evidence (four trials) support appreciable benefit of IVGC in response compared with oral glucocorticoids (OGC), with of RR being 1.51 (95%CI 1.25 to 1.83). There was low quality evidence (one trial) compatible with appreciable benefit for IVGC plus orbital radiotherapy in response (RR 1.38, 95%CI 1.07 to 1.79), compared with OGC plus orbital radiotherapy. One IVGC versus rituximab trial provided moderate quality evidence suggesting that participants using IVGC achieved significantly lower response compared to participants using rituximab (RR 0.70, 95%CI 0.50 to 0.98). One IVGC versus mycophenolate mofetil (MMF) trial provided moderate quality evidence suggesting that participants using IVGC achieved significantly lower response compared to participants using MMF (RR 0.74, 95%CI 0.63 to 0.88). Very low quality evidence (one trial) showed that participants with dysthyroid optic neuropathy (DON) receiving IVGC were more likely to achieve response compared to participants receiving orbital decompression (RR 3.33, 95%CI 0.51 to 21.89). CONCLUSION: The current evidence is moderate quality, which is sufficient to support IVGC to be as the first-line treatment for moderate-to-severe GO, and the use of rituximab or MMF to be the second-line treatment instead of IVGC. However, the evidence is very low quality, which is insufficient to support the use of IVGC or orbital decompression as the first-line treatment of DON.

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AIMS: To examine possible benefits of intravitreal anti-vascular endothelial growth factor (VEGF) agent treatment immediately after cataract surgery for patients with diabetic retinopathy (DR). METHODS: A comprehensive literature search was performed using the Cochrane collaboration methodology to identify randomized controlled trials (RCTs) and comparative studies of cataract surgery with or without anti-VEGF agent treatment for any diabetic retinopathy. Meta-analyses were performed for clinical outcome parameters including changes in macular thickness (MT), best-corrected visual acuity (BCVA), incidence of diabetic retinopathy and maculopathy progression, laser treatment rate, and other complications. RESULTS: Nine RCTs and 3 nonrandomized comparative studies were identified and used for comparing cataract surgery with intravitreal bevacizumab (IVB) or intravitreal ranibizumab (IVR) treatment (338 eyes, intervention group) to cataract surgery alone (329 eyes, control group). Analysis of all data showed that the mean BCVA at 1 week postoperatively had no statistically significant difference in the two groups, but at 1, 3, and 6 months postoperatively, the mean BCVA was statistically significantly better in the anti-VEGF treatment group than that in cataract surgery alone group. Analysis of all data showed that the mean MT was statistically significantly less in the anti-VEGF treatment group at 1 week and 1, 3, and 6 months postoperatively (P=0.05, P=0.006, P=0.0001, and P=0.0001, respectively); but postoperative clinical outcomes were differentiated from the type of anti-VEGF agents, IVB or IVR, and the existing macular edema preoperatively. Intravitreal anti-VEGF agent treatment statistically significantly reduced the incidence of diabetic retinopathy progression and maculopathy progression compared to the control group (P=0.0003, P < 0.00001, respectively). CONCLUSION: IVB or IVR treatment immediately after cataract surgery may represent a safe and effective strategy to prevent postoperative macular thickening or reduce macular edema and result in greater mean improvements in visual acuity for diabetic patients.

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BACKGROUND Thyroid-associated ophthalmopathy (TAO) is a common endocrine autoimmune disease. The present study explored corneal nerve changes in TAO patients. MATERIAL AND METHODS Thirty-eight Chinese TAO patients and 20 healthy individuals were included in the study. Central corneal subbasal nerve density and morphology were evaluated with in vivo laser scanning confocal microscopy and quantified using automated CCmetrics software. RESULTS The values of the central corneal subbasal nerve plexus parameters of both active and inactive TAO patients were significantly decreased compared with those of controls, including corneal nerve fiber density (CNFD) (P<0.001 for both), corneal nerve branch density (CNBD) (P<0.001 for both), corneal nerve fiber length (CNFL) (P<0.001 for both), corneal nerve fiber total branch density (CTBD) (P<0.001 for both), corneal nerve fiber area (CNFA) (P<0.001 for both), corneal nerve fiber width (CNFW) (P=0.046, P=0.027, respectively), and corneal nerve fiber fractal dimension (ACNFrD) (P<0.001 for both). In addition, CNFD and ACNFrD values were significantly lower in the active TAO patients compared with those in the inactive TAO patients (P=0.020, P=0.002, respectively). There were significant correlations between CNFD, CNBD, CNFL, CTBD, CNFA, and ACNFrD and the ocular surface parameters and activity assessment items. CONCLUSIONS Abnormal corneal subbasal nerves were observed in both active and inactive Chinese TAO patients, suggesting that nerve degeneration is associated with the disease. However, the exact underlying mechanisms remain to be elucidated.

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BACKGROUND: Thyroid associated ophthalmopathy (TAO) is an autoimmune disease, which involves inflammation and tissue remodeling. Pentraxin-3 (PTX3) is a component of innate immune system and recently implicated in autoimmunity. This observation may indicate that PTX3 participates in the inflammatory process of TAO. METHODS: All studies were performed on TAO patients and healthy controls (45: 28 in total). RNA-seq was used to detect differential gene expression of orbital adipose-connective tissue. Quantitative PCR was performed to verify the results. PTX3 protein in orbital adipose-connective tissues was visualized by immunohistochemistry (IHC). PTX3 concentration in serum was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: RNA-seq showed 1.86-log⁡2FC higher PTX3 expression in the orbital adipose-connective tissues from TAO group than controls (FDR = 0.0059). qPCR confirmed the difference (5.59-fold increase, p = 0.0012). The presence of PTX3 protein was demonstrated. Orbital adipose tissue from healthy controls showed weak staining for PTX3 while tissue from TAO group was strongly positive. Serum PTX3 concentration was significantly elevated in patients when compared to the control group (1.9-fold increase; p < 0.0001). CONCLUSIONS: Patients with TAO showed increased presence of PTX3 in orbital tissue and serum, which may suggest a potential relationship of PTX3 and TAO.

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BACKGROUND/AIMS: Activating transcription factor 4 (ATF4) is a member of the activating transcription factor family which regulates the expression of genes involved in amino acid metabolism, redox homeostasis and ER stress responses. ATF4 is also over-expressed in human solid tumors, although its effect on responsiveness to radiation is largely unexplored. METHODS: Real-time PCR was used to detect ATF4 mRNA levels in cells treated with different doses of 60Coγ radiation. Cell viability was assayed using a cell counting kit. The cell cycle was analyzed using flow cytometry, and cell apoptosis was assayed using Annexin V-PI double labeling. Small interfering RNA (siRNA) against ATF4 was transfected into ECV304 cells using Lipofectamine 2000. An ATF4 over-expression plasmid (p-ATF4-CGN) was transfected into HEK293 cells that endogenously expressed low levels of ATF4. The levels of intracellular reactive oxygen species (ROS) were measured using CM-H2DCFDA as a probe. RESULTS: ATF4 mRNA and protein expression levels were higher after radiation and increased in a dose- and time-dependent manner in AHH1 lymphoblast cells (P < 0.05). An increase in ATF4 levels was also observed after radiation in primary murine spleen cells, human endothelial ECV304 cells, human liver LO2 cells, breast cancer MCF7 cells, and human hepatocellular carcinoma HEPG2 cells. No change was observed in human embryonic kidney 293 (HEK293) cells. Over-expressing ATF4 in HEK293 cells inhibited cell proliferation, increased cell apoptosis and significantly increased the proportion of cells in G1 phase. Conversely, when ATF4 expression was knocked down using siRNA in ECV304 cells, it protected the cells from radiation-induced apoptosis. These findings suggest that ATF4 may play a role in radiation-induced cell killing by inhibiting cell proliferation and promoting cell apoptosis. CONCLUSIONS: In this study, we found that radiation up-regulated the expression of ATF4. We used ATF4 knockdown and over-expression systems to show that ATF4 may play a role in radiation-induced cellular apoptosis.

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PURPOSE: To examine the density and morphology of Langerhans cells (LCs) in the cornea of patients with thyroid-associated ophthalmopathy (TAO). METHODS: Forty patients with TAO and 20 healthy volunteers were studied. All subjects underwent a thorough ophthalmic examination of both eyes. The ocular surface status was assessed by Ocular Surface Disease Index (OSDI) symptom questionnaires, tear break-up time (BUT), fluorescein staining and the Schirmer test. Laser scanning in vivo confocal microscopy was applied to evaluate the LC density and morphology in both central and peripheral cornea. The correlations between confocal microscopy data and clinical data were also analyzed. RESULTS: The OSDI and fluorescein staining values were significantly higher, while BUT and Schirmer test scores were lower in both active and inactive TAO patients compared to the controls. Central LC densities of patients with active TAO (76.38 ± 67.77 cell/mm(2)) and inactive TAO (47.49 ± 38.58 cell/mm(2)) were both significantly higher than those of the controls (21.46 ± 21.74 cell/mm(2)). The number of LCs in the peripheral cornea was also significantly increased in the active TAO group (131.53 ± 74.18 cell/mm(2)) compared to the control group (70.21 ± 37.76 cell/mm(2)). Central LC morphology (LCM) values were significantly higher in both active (1.77 ± 0.63) and inactive (1.51 ± 0.63) TAO groups compared to the control group (1.01 ± 0.80), whereas peripheral LCM scores of the two TAO groups were increased without statistical significance. There were significant correlations between both central LC density and central LCM scores and clinical data, including clinical activity score, OSDI and Schirmer test scores, and between peripheral LC density and OSDI and Schirmer test scores. No significant correlations were found between peripheral LCM scores and clinical data. CONCLUSIONS: The increase of corneal LCs in density and maturation in patients with TAO reflects an activated state of the local immune system, which indicates an inflammatory process in the cornea of TAO.

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BACKGROUND: Trabeculectomy is performed as a treatment for glaucoma to lower intraocular pressure (IOP). The surgical procedure involves creating a channel through the wall of the eye. However scarring during wound healing can block this channel which will lead to the operation failing. Anti-vascular endothelial growth factor (VEGF) agents have been proposed to slow down healing response and scar formation. OBJECTIVES: To assess the effectiveness of anti-VEGF therapies administered by subconjunctival injection for the outcome of trabeculectomy at 12 months follow-up and to examine the balance of benefit and harms when compared to any other anti-scarring agents or no additional anti-scarring agents. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2015, Issue 10), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 12 November 2015. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of anti-VEGF therapies administered by subconjunctival injection compared to any other anti-scarring agents or no additional anti-scarring agents (no treatment or placebo) in trabeculectomy surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcome was successful trabeculectomy at 12 months after surgery which was defined as achieving a target IOP (usually no more than 21 mm Hg) without any additional intervention. Other outcomes included: qualified success (achieving target IOP with or without additional intervention), mean IOP and adverse events. MAIN RESULTS: We included five RCTs (175 participants, 177 eyes) that met the inclusion criteria in this review.One trial conducted in Iran (37 participants, 37 eyes) compared anti-VEGF (bevacizumab 0.2 mg) versus control (sham injection) in people with refractory glaucoma. We judged this study to be at low risk of bias.The primary outcome of this review was not reported; mean IOP at three months was 15.1 mm Hg (standard deviation 1.0) in both anti-VEGF and control groups.Four trials compared anti-VEGF to mitomycin C (MMC) (138 particpants, 140 eyes). These studies were conducted in India, Iran, Turkey and the USA. The anti-VEGF agent used in these four trials was bevacizumab 2.5 mg (two trials), bevacizumab 1.25 mg three times and ranibizumab 0.5 mg. Two trials were at high risk of bias in two domains and one trial was at high risk of bias in four domains.Only one of these trials reported the primary outcome of this review (42 participants, 42 eyes). Low quality evidence from this trial showed that people receiving bevacizumab 2.5 mg during primary trabeculectomy were less likely to achieve complete success at 12 months compared to people receiving MMC but the confidence interval (CI) was wide and compatible with increased chance of complete success for anti-VEGF (risk ratio (RR) 0.71, 95% CI 0.46 to 1.08), Assuming that approximately 81% of people receiving MMC achieve complete success, the anticipated success using anti-VEGF agents would be between 37.2% and 87.4%. The same trial suggested no evidence for any difference in qualified success between bevacizumab and MMC (RR 1.00, 95% CI 0.87 to 1.14, moderate quality evidence). Two trials of primary trabeculectomy provided data on mean IOP at 12 months; one trial of bevacizumab 2.5 mg and one trial of ranibizumab 0.5 mg. Mean IOP was 1.86 mm Hg higher (95% CI 0.15 to 3.57) in the anti-VEGF groups compared to the MMC groups (66 people, low quality evidence). Data were reported on wound leak, hypotony, shallow anterior chamber and endophthalmitis, but these events occurred rarely and currently there are not enough data available to detect any differences, if any, between the two treatments. AUTHORS' CONCLUSIONS: The evidence is currently of low quality which is insufficient to refute or support anti-VEGF subconjunctival injection for control of wound healing in glaucoma surgery. The effect on IOP control of anti-VEGF agents in glaucoma patients undergoing trabeculectomy is still uncertain, compared to MMC.Further RCTs of anti-VEGF subconjunctival injection in glaucoma surgery are required, particularly compared to sham treatment with at least 12 months follow-up.

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PURPOSE: Nonarteritic anterior ischemic optic neuropathy (NAION) is a multifactorial disease, and recently epidemiologic studies have investigated the association between obstructive sleep apnea (OSA) and NAION. A systematic review of the association of OSA and NAION has not been performed. Therefore, the current meta-analysis was performed to assess such potential association between OSA and risk of NAION. METHODS: A systematic search of PubMed and EMBASE databases was performed for published studies evaluating the association between OSA and NAION. The summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for categorical risk estimates. Sensitivity analyses and subgroup analyses were also performed to assess the robustness of pooled outcomes. RESULTS: A total of four prospective cohort studies and one case-control study met our inclusion criteria. The pooled OR of developing NAION in the subjects with OSA was 6.18 (95% CI, 2.00-19.11) versus non-OSA controls. Sensitivity analyses showed that no matter one study excluded, the pooled OR did not change significantly, which indicated that the evidence was robust. In subgroup analyses, a significant association was seen in studies matched systemic risk factors (OR, 5.00; 95% CI, 2.22-11.25), but not in those non-matched. The magnitude and direction of effects were also affected by methodological variability, including study design, and diagnosis of OSA. CONCLUSIONS: The findings from this meta-analysis supported the robust evidence that OSA was a strong independent risk factor of NAION. Relative to non-OSA controls, the subjects with OSA were found to have a more than sixfold risk of NAION. In future, more well-designed studies are needed to confirm these findings.

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BACKGROUND: Several immunosuppressive therapeutic regimens are widely used to treat Graves' ophthalmopathy (GO), including oral glucocorticoids (OGC), intravenous glucocorticoids (IVGC), retrobulbar injections of glucocorticoids (ROGC) and orbital radiotherapy (OR). The priority among these is unknown. This meta-analysis investigated the efficacy and tolerability of the above regimens. METHODS: The PubMed, EMBASE, and Cochrane Library databases and the Chinese Biomedicine Database were searched up to November 18, 2014. Randomized controlled trials (RCTs) comparing monotherapies (OGC, IVGC, ROGC and OR) in patients with moderate-to-severe active GO were selected. The main efficacy measures were the response rate, the standard mean difference (SMD) in the reduction in the clinical activity score (CAS) and the mean difference (MD) in proptosis from baseline to the end of treatment. The main tolerability measure was the risk ratio (RR) for adverse events. The pooled estimates and 95% confidence intervals (95% CIs) were calculated using the RevMan software, version 5.1. RESULTS: Seven published RCTs involving 328 participants were included in the present meta-analysis, including IVGC versus OGC (3 trials), ROGC versus OGC (3 trials) and OR versus OGC (1 trial). IVGC was more effective than OGC in response rate (RR = 1.48, 95% CI = 1.18-1.87) and had an obvious CAS reduction (SMD = 0.69, 95% CI = 0.13-1.25). IVGC caused fewer adverse events than OGC. ROGC and OGC had no statistically significant difference in response rate (RR = 1.16, 95% CI = 0.94-1.42). OR also did not differ significantly compared with OGC (RR = 0.93, 95% CI = 0.54-1.60). ROGC and OR had fewer adverse events, such as weight gain, compared with OGC. CONCLUSIONS: For patients with GO in the moderate-to-severe active phase, current evidence gave priority to IVGC, which had a statistically significant advantage over OGC and caused fewer adverse events. ROGC and OR did not provide greater efficacy than OGC, although better tolerability and fewer adverse events were shown.

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OBJECTIVE: This meta-analysis was designed to assess the efficacy, as well as the safety of loteprednol etabonate (LE) ophthalmic suspension compared with placebo and other commonly used eye drops for treatment of allergic conjunctivitis. METHODS: Comprehensive searches of randomized controlled trials were carried out in a database of Medline, Embase, and the Cochrane Library. Eight qualified studies were included. This study assessed the reduction from baseline in scores of cardinal signs and symptoms, proportion of patients with improvement of allergic signs and symptoms, and incidence of clinically significant intraocular pressure (IOP) elevation (IOP elevation ≥10 mmHg). RESULTS: The results showed that topical LE was significantly superior to placebo in reduction from baseline in signs scores (standardized mean difference [SMD] = -0.48; 95% confidence interval [CI] = -0.65 to -0.32) and symptoms scores (weighted mean difference [WMD] = -0.51; 95% CI = -0.64 to -0.38) of allergic conjunctivitis, and as effective as olopatadine and fluorometholone acetate. Topical LE was associated with a higher improvement rate of signs (risk ratio [RR] = 1.53; 95% CI = 1.26-1.86; I (2 )= 57%) and symptoms (RR = 1.29; 95% CI = 1.15-1.46; I (2 )= 54%) than placebo and the positive control treatment. Clinically significant IOP elevation was more frequent in the group of LE than the group of control treatment (pooled odds ratio = 3.03; 95% CI = 1.04-8.80), which was affected by the response to corticosteroid of the individual patient and the wearing of contact lenses. CONCLUSIONS: Topical LE is effective in treating allergic conjunctivitis. However, it should be used with caution due to the higher incidence of IOP elevation compared with placebo and olopatadine. A large-scale trial would be required to confirm the effect of different concentrations of LE on IOP.

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BACKGROUND: Prostaglandin-timolol fixed combinations (PG-timolol FCs) are now widely used to reduce intraocular pressure in patients with glaucoma. The efficacy and tolerability of these drugs are worthy of further exploration. An updated systematic review and meta-analysis was performed to assess the clinical efficacy and tolerability of the three PG-timolol FCs. METHODS: Pertinent randomized, controlled trials were identified through systematic searches of PubMed, Embase, the Cochrane central register of controlled trials and the Chinese Biomedicine Database. The main efficacy measures were the weighted mean differences (WMDs) for the reduction from baseline to end of treatment in IOP at 9 am, 12 pm and 4 pm and diurnal curve. The main tolerability measures were the odds ratios (ORs) for the incidence of conjunctival hyperemia. RESULTS: Nine studies involving 991 patients were included in the meta-analysis. Latanoprost-timolol FC (LTFC) and travoprost-timolol FC (TTFC) were not significantly different in lowering IOP at diurnal mean, 9 am, 12 pm and 4 pm. Bimatoprost-timolol FC (BTFC) provided significantly greater efficacy in lowering IOP at the three measurement time points and over the mean diurnal curve than LTFC (diurnal curve: WMD = 0.88 mmHg [95% CI, 0.42 to 1.33]; 9 am: WMD = 1.27 mmHg [0.68 to 1.86]; 12 pm: WMD = 1.16 mmHg [0.85 to 1.46]; 4 pm: WMD = 0.61 mmHg [0.51 to 0.70]) and TTFC (diurnal curve: WMD = 1.94 mmHg [0.19 to 3.68]; 9 am: WMD = 0.68 mmHg [0.15 to 1.21]; 12 pm: WMD = 0.90 mmHg [0.41 to 1.39]; 4 pm: WMD = 1.06 mmHg [0.61 to 1.51]). The incidence of hyperemia was significantly higher with BTFC than LTFC (pooled ORs: 1.85 [1.09 to 3.13]). The incidence of hyperemia was not significantly higher with TTFC than LTFC (pooled ORs: 2.52 [0.85 to 7.46]), and was not significantly higher with BTFC than TTFC (pooled OR: 1.65 [0.48 to 5.70]). CONCLUSIONS: BTFC provided significantly greater efficacy in lowering IOP at diurnal mean, 9 am, 12 pm and 4 pm than LTFC and TTFC. LTFC was as effective as TTFC in lowering IOP at the four measurement time points and BTFC caused conjunctival hyperemia in more patients than LTFC. Further clinical trials are needed because of the limited number of studies.

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PURPOSE: The aim of this study was to detect the effect of the CD40 ligand (CD40L) on the expression of vascular cell adhesion molecule 1 (VCAM-1) and E-Selectin in orbital fibroblasts (OFs) from patients with Graves' orbitopathy (GO), as well as the signaling pathways involved in this effect. METHODS: OFs were isolated from orbital tissues obtained from patients with severe GO who were undergoing orbital decompression surgery. VCAM-1 and E-selectin RNA and protein expression levels were quantified in OFs stimulated with soluble CD40L (sCD40L). RNA and protein quantification was performed with real-time polymerase chain reaction (PCR) and western blot analysis. Cytoplasmic and nuclear fractions were isolated in order to detect the nuclear translocation of nuclear factor-κB (NF-κB). Signaling pathway inhibitors were applied to determine the pathways involved. RESULTS: Compared to unstimulated OFs, the mRNA and protein levels of VCAM-1 and E-selectin in OFs incubated with sCD40L were significantly increased. This was observed in dose- and time-course experiments, and the inductive effects of sCD40L were much weaker in OFs from healthy donors. At the same time, we observed that CD40L induced nuclear translocation of NF-κB, also in a dose- and time-dependent manner. The up-regulation of VCAM-1 and E-selectin, as well as the NF-κB nuclear translocation induced by CD40L, was significantly attenuated by inhibitors targeting mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3K), and NF-κB. CONCLUSIONS: CD40L demonstrated the ability to up-regulate the expression of VCAM-1 and E-selectin at the pre-translational level in OFs from patients with GO. The MAPK and PI3K pathways and NF-κB may play important roles in CD40L-induced VCAM-1 and E-selectin expression.

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