Pars plana vitrectomy for retinal detachment using perfluoro-n-octane as intraoperative tamponade:a multicenter,randomized,non-inferiority trial

AIM:To evaluate the efficacy and safety of perfluoro-n-octane(PFO)for ophthalmic surgery versus F-Octane as an intraoperative tamponade in pars plana vitrectomy(PPV)in management of retinal detachment.METHODS:This multicenter,prospective,randomized,double-masked,parallel-controlled,non-inferiority trial was conducted in three ophthalmology clinical centers in China.Patients with retinal detachment,who were eligible for PPV were consecutively enrolled.Participants were assigned to PFO for ophthalmic surgery or F-Octane for intraocular tamponade in a 1:1 ratio.Best-corrected visual acuity(BCVA),intraocular pressure(IOP)measurement,and dilated fundus examination were performed preoperatively and at 1,7±1,28±3d postoperatively.The primary outcome was complete retinal reattachment rate at postoperative day one.The non-inferiority margin was set at 9.8%.The secondary outcomes included intraoperative retinal reattachment rate,and mean changes in IOP and BCVA from baseline to 1,7±1,28±3d postoperatively,respectively.Safety analyses were presented for all randomly assigned participates in this study.RESULTS:Totally 124 eligible patients completed the study between Mar.14,2016 and Jun.7,2017.Sixty of them were randomly assigned to the PFO for ophthalmic surgery group,and 64 were assigned to the F-Octane group.Baseline characteristics were comparable between the two groups.Both groups achieved 100%retinal reattachment at postoperative day one(difference 0,95%CI:-6.21%to 5.75%,P=1).The pre-defined noninferiority criterion was met.No significant difference was observed in intraoperative retinal reattachment rate(difference 1.77%,P=0.61),mean changes in IOP(difference 0.36,-0.09,2.22 mm Hg at 1,7±1,28±3d postoperatively,with all P>0.05)and BCVA(difference 0.04,-0.02,0.06 logMAR at 1,7±1,28±3d postoperatively,all P>0.05)between the two groups.No apparent adverse events related to the utilization of PFO were reported.CONCLUSION:In patients with retinal detachment undergoing PPV,PFO for ophthalmic surgery is non-inferior to F-Octane as an intraocular tamponade,and both are safe and well-tolerated.

Inflammation in diabetic retinopathy: possible roles in pathogenesis and potential implications for therapy

Diabetic retinopathy, characterized as a microangiopathy and neurodegenerative disease, is the leading cause of visual impairment in diabetic patients. Many clinical features observed in diabetic retinopathy, such as capillary occlusion, acellular capillaries and retinal non-perfusion, aggregate retinal ischemia and represent relatively late events in diabetic retinopathy. In fact, retinal microvascular injury is an early event in diabetic retinopathy involving multiple biochemical alterations, and is manifested by changes to the retinal neurovascular unit and its cellular components. Currently, intravitreal anti-vascular endothelial growth factor therapy is the firstline treatment for diabetic macular edema, and benefits the patient by decreasing the edema and improving visual acuity. However, a significant proportion of patients respond poorly to anti-vascular endothelial growth factor treatments, indicating that factors other than vascular endothelial growth factor are involved in the pathogenesis of diabetic macular edema. Accumulating evidence confirms that low-grade inflammation plays a critical role in the pathogenesis and development of diabetic retinopathy as multiple inflammatory factors, such as interleukin-1β, monocyte chemotactic protein-1 and tumor necrosis factor-α, are increased in the vitreous and retina of diabetic retinopathy patients. These inflammatory factors, together with growth factors such as vascular endothelial growth factor, contribute to blood-retinal barrier breakdown, vascular damage and neuroinflammation, as well as pathological angiogenesis in diabetic retinopathy, complicated by diabetic macular edema and proliferative diabetic retinopathy. In addition, retinal cell types including microglia, Müller glia, astrocytes, retinal pigment epithelial cells, and others are activated, to secrete inflammatory mediators, aggravating cell apoptosis and subsequent vascular leakage. New therapies, targeting these inflammatory molecules or related signaling pathways, have the potential to inhibit retinal inflammation and prevent diabetic retinopathy progression. Here, we review the relevant literature to date, summarize the inflammatory mechanisms underlying the pathogenesis of diabetic retinopathy, and propose inflammation-based treatments for diabetic retinopathy and diabetic macular edema.

Comprehensive assessment of growth factors,inflammatory mediators, and cytokines in vitreous from patients with proliferative diabetic retinopathy

AIM: To assess alterations in growth factors, inflammatory mediators, and cytokines associated with vitreous-retinal diseases in vitreous humor from patients with proliferative diabetic retinopathy(PDR), and to identify potential new treatment targets and strategies.METHODS: Control vitreous samples were collected from patients with macular hole, epiretinal membranes, or rhegmatogenous retinal detachments, and PDR samples from patients with complications of PDR, who required pars plana vitrectomy. Specimens were stored at-80℃ and then investigated by Luminex multi-factor assay. Parametric and nonparametric analyses of demographic characteristics and cytokine expression levels were conducted using SPSS.RESULTS: There were no significant differences in demographic characteristics between patients with and without PDR. Expression levels of growth factors [plateletderived growth factor(PDGF)-AA, glial cell line-derived neurotrophic factor(GDNF), and vascular endothelial growth factor A(VEGFA)], inflammatory mediators [interleukin(IL)-8, IL-11, and tumor necrosis factor-α(TNF-α)] and cytokines [chemokine C-X-C ligand(CXCL)10, interferon-γ(IFN-γ), and granulocyte macrophage-colony stimulating factor(GM-CSF)] were significantly elevated in vitreous humor from patients with PDR compared with those in the control group(all P<0.05). Further, VEGFA levels were lower in patients with PDR treated with anti-VEGF injection than those who were not(P<0.05), and there was no difference between the PDR group treated with anti-VEGF and controls(P>0.05).CONCLUSION: This proof-of-concept study demonstrates the potential for combinational therapeutic strategies to ameliorate diabetic retinopathy progression by targeting growth factors, inflammatory factors, and cytokines, in addition to VEGFA.

Epigenetic modifications and metabolic memory in diabetic retinopathy:beyond the surface

Epigenetics focuses on DNA methylation,histone modification,chromatin remodeling,noncoding RNAs,and other gene regulation mechanisms beyond the DNA sequence.In the past decade,epigenetic modifications have drawn more attention as they participate in the development and progression of diabetic retinopathy despite tight control of glucose levels.The underlying mechanisms of epigenetic modifications in diabetic retinopathy still urgently need to be elucidated.The diabetic condition facilitates epigenetic changes and influences target gene expression.In this review,we summarize the involvement of epigenetic modifications and metabolic memory in the development and progression of diabetic retinopathy and propose novel insights into the treatment of diabetic retinopathy.

Quantitative analysis of retinal intermediate and deep capillary plexus in patients with retinal deep vascular complex ischemia

AIM: To quantitatively analyze the retinal intermediate and deep capillary plexus(ICP and DCP) in patients with retinal deep vascular complex ischemia(RDVCI), using 3D projection artifacts removal(3D PAR) optical coherence tomography angiography(OCTA).METHODS: RDVCI patients and gender-and agematched healthy controls were assessed and underwent OCTA examinations. The parafoveal vessel density(PFVD) of retinal deep vascular complex(DVC), ICP, and DCP were analyzed, and the percentage of reduction(PR) of PFVD was calculated.RESULTS: Twenty-four eyes in 22 RDVCI patients(20 in acute phase and 4 in chronic phase) and 24 eyes of 22 healthy subjects were enrolled as the control group. Significant reduction of PFVD in DVC, ICP, and DCP was observed in comparison with the controls(DVC: acute: 43.59%±6.58% vs 49.92%±5.49%, PR=12.69%;chronic: 43.50%±3.33% vs 51.20%±3.80%, PR=15.04%. ICP: acute: 40.28%±7.91% vs 46.97%±7.14%, PR=14.23%;chronic: 41.48%±2.87% vs 46.43%±3.29%, PR=10.66%. DCP: acute: 45.44%±8.27% vs 51.51%±9.97%, PR=11.79%;chronic: 37.78%±3.48% vs 51.73%±5.17%, PR=26.97%;all P<0.05). No significant PR difference was found among DVC, ICP, and DCP of RDVCI in acute phase(P=0.812), but significant difference in chronic phase(P=0.006, DVC vs DCP, ICP vs DCP). No significant difference in PR between acute and chronic phases in the DVC(P=0.735) or ICP(P=0.681) was found, but significant difference in the DCP(P=0.041).CONCLUSION: The PFVD of DVC, ICP, and DCP in RDVCI is significantly decreased in both acute and chronic phases. ICP impairment is stabilized from acute to chronic phase in RDVCI, whereas subsequent DCP impairment is uncovered and can be explained by ischemia-reperfusion damage.

A novel surgical technique of internal limiting membrane peeling for high myopic foveoschisis:a wide range of whole piece consecutive peeling without preservation of epi-fovea

AIM:To demonstrate an improved surgical technique of whole piece consecutive internal limiting membrane(ILM) peeling without preservation of the epi-fovea to treat high myopic foveoschisis(MF).METHODS:A 23-gauge 3-port pars plana vitrectomy was performed on 16 patients with high MF.A parallel arc line along the vascular arcades was scraped out with a curved membrane scraper DSP.Next,an ILM forceps was used to catch hold of the incisal edge of the ILM flap,and the action of releasing and separating was subsequently taken toward the direction of the macular fovea.Next,the ILM forceps was used to grasp the released area,and the whole area coherent ILM peeling covering the macular fovea was implemented thereafter.Finally,the ILM was folded backwards and peeled off in the arc direction.RESULTS:At the final visit,the average central macular thickness decreased remarkably from 423.76±177.67 to 178.24±66.21 μm.The mean logarithm of the minimum angle of resolution best-corrected visual acuity of 1.37±0.59 was significantly alleviated to 0.74±0.59.CONCLUSION:The wide range of whole piece consecutive ILM peeling without preservation of the epifovea is proven to be effective and significantly reduced the occurrence of retinal tear and macular hole.

A new handheld fundus camera combined with visual artificial intelligence facilitates diabetic retinopathy screening

AIM: To explore the performance in diabetic retinopathy(DR) screening of artificial intelligence(AI) system by evaluating the image quality of a handheld Optomed Aurora fundus camera in comparison to traditional tabletop fundus cameras and the diagnostic accuracy of DR of the two modalities. METHODS: Overall, 630 eyes were included from three centers and screened by a handheld camera(Aurora, Optomed, Oulu, Finland) and a table-top camera. Image quality was graded by three masked and experienced ophthalmologists. The diagnostic accuracy of the handheld camera and AI system was evaluated in assessing DR lesions and referable DR.RESULTS: Under nonmydriasis status, the handheld fundus camera had better image quality in centration, clarity, and visible range(1.47, 1.48, and 1.40) than conventional tabletop cameras(1.30, 1.28, and 1.18;P<0.001). Detection of retinal hemorrhage, hard exudation,and macular edema were comparable between the two modalities, in principle, with the area under the curve of the handheld fundus camera slightly lower. The sensitivity and specificity for the detection of referable DR with the handheld camera were 82.1%(95%CI: 72.1%-92.2%) and 97.4%(95%CI: 95.4%-99.5%), respectively. The performance of AI detection of DR using the Phoebus Algorithm was satisfactory;however, Phoebus showed a high sensitivity(88.2%, 95%CI: 79.4%-97.1%) and low specificity(40.7%, 95%CI: 34.1%-47.2%) when detecting referable DR.CONCLUSION: The handheld Aurora fundus camera combined with autonomous AI system is well-suited in DR screening without mydriasis because of its high sensitivity of DR detection as well as its image quality, but its specificity needs to be improved with better modeling of the data. Use of this new system is safe and effective in the detection of referable DR in real world practice.

Dynamic versus static ultra-widefield fluorescein angiography in eyes with diabetic retinopathy:a pilot prospective cross-sectional study

AIM:To analyze differences in ultra-widefield fluorescein angiography(UWFA)findings between dynamic and static images of eyes with diabetic retinopathy(DR).METHODS:This cross-sectional study included 28 eyes of 28 patients with DR undergoing UWFA.A series of UWFA images acquired from each patient were converted into a time-lapse video and used as a dynamic image.A single,clear,arteriovenous phase image was chosen as a static image.Non-perfusion index(NPI)and its correlation with vascular abnormalities in different zones were compared between dynamic and static UWFA imaging.RESULTS:NPI appeared to increase from the center to the far-periphery in both groups.Dynamic NPI was lower in the total retinal area(0.26 vs 0.29,P=0.009)and farperiphery(0.33 vs 0.36,adjusted P=0.042),which was contrary to the static NPI.Far-peripheral NPI was associated with intraretinal microvascular abnormality in the posterior area in both groups.CONCLUSION:Time-lapse dynamic UWFA imaging is a useful modality to differentially diagnose hypofluorescence in the most peripheral region.This modality could provide a reliable method for NPI measurement.

Reduced choroidal peripapillary capillaries in thyroid-associated ophthalmopathy with early stage of dysthyroid optic neuropathy

AIM: To investigate whether the subtle change of choroidal/retinal vessel densities and volumes in thyroidassociated 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.

Is Iba-1 protein expression a sensitive marker for microglia activation in experimental diabetic retinopathy?

AIM:To investigate the changes of Iba-1 and other potential markers for microglia activation in experimental diabetic retinopathy(DR).METHODS:Male Sprague-Dawley rats were rendered diabetes via intraperitoneal injection of streptozotocin.The retinas were harvested at 1 to 24 wk after diabetes onset.Hypoxia-treated mouse microglial cell line(BV2 cells)was employed as the in vitro model to mimic diabetic condition.The expressions of Iba-1,CD11 b,ICAM-1 as well as the inflammatory factors were examined with real-time polymerase chain reaction,Western blot and immunofluorescence both in vivo and in vitro.RESULTS:Compared with age-matched normal control,the number of microglia(Iba-1 positive immunostaining)in diabetic rat retinas was increased from 1 to 24 wk of diabetes,which was most obvious at 12 wk of diabetes.Iba-1 protein expression detected by Western blot was increased slightly in diabetic rat retinas compared with that in age-matched normal control;however,there was statistically significant between two groups only at 2 wk after diabetes onset.The m RNA expression of Iba-1 was decreased significantly at 2 and 4 wk of diabetic rat retinas,and remained unchanged at 8 and 12 wk of diabetes.In BV2 cells,there was no significant change for the Iba-1 protein expression between normoxia and hypoxia groups;however,its m RNA level was decreased significantly under hypoxia.To further characterize microglial activation,F4/80,CD11 b and inflammatory factors were detected both in vivo and in vitro.Compared with normal control,the expressions of F4/80 and CD11 b as well as the inflammatory factors,such as ICAM-1,i NOS,COX2,IL-1βand IL-6,were increased significantly both in vivo and in vitro.CONCLUSION:Iba-1 protein expression might not be a sensitive marker to evaluate the activation of microglia in experimental DR.However,Iba-1 immunostaining,in combination with other markers like CD11 b and ICAM-1,could be well reflect the activation of microglia.Thus,it is of great importance to explore other potential marker to evaluate the activation of microglia.

Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

Anti-VEGF reduces inflammatory features in macular edema secondary to retinal vein occlusion

AIM: To investigate the anti-inflammatory effect of intravitreal injection of anti-vascular endothelial growth factor(anti-VEGF) in patients with macular edema secondary to retinal vein occlusion(RVO-ME).METHODS: Twenty-eight eyes from twenty-eight treatment-na?ve patients(14 males and 14 females) with RVO-ME were included in this retrospective study.The retinal vein occlusion(RVO) was comprised of both central retinal vein occlusion(CRVO,n=14) and branch retinal vein occlusion(BRVO,n=14).Intravitreal injection of anti-VEGF reagents were administered monthly for three consecutive months,in which 18 patients were injected with ranibizumab and 10 patients were injected with conbercept.All eyes were imaged with optical coherence tomography angiography(OCTA) at baseline and 1wk after monthly intravitreal anti-VEGF injection.The visual acuity(VA),central macular thickness(CMT),the number of hyperreflective foci(HRF) recognized as an inflammatory sign in OCT images,and non-perfusion area(NPA),were compared before and after anti-VEGF treatments.RESULTS: The mean interval between baseline and follow-up was 29.4±0.79(range,27-48)d.Compared with the baseline,the VA improved(log MAR 1.5±0.1 vs 0.8±0.1,P<0.05) and CMT decreased(460±34.0 μm vs 268.8±12.0 μm,P<0.05),significantly,after antiVEGF treatment.The number of HRF was decreased significantly(76.5±4.8 vs 47.8±4.3,P<0.05) after antiVEGF treatment.CONCLUSION: Anti-VEGF therapy is effective in treating RVO-ME.The mechanisms for the decreased HRF and the reduction of NPA by anti-VEGF therapy merits further exploration.

The associations of lens power with age,axial length and type 2 diabetes mellitus in Chinese adults aged 50 and above

Background:To investigate the associations of lens power with age,axial length(AL),and Type 2 diabetes mellitus(DM)in Chinese adults aged 50 and above.Methods:Random clustering sampling was used to identify adults aged 50 years and above in urban regions of Shanghai.The participants underwent a comprehensive ophthalmic examination including subjective refraction,autorefraction,and IOL-Master.The crystalline lens power was calculated using Bennett’s formula.Results:A total of 4177 adults were included.A linear decrease in lens power was observed both with age and with AL,followed by a stop of lens power loss after the age of 70 or when AL≥25 mm,respectively.Participants with Type 2 DM presented higher lens power(0.43 diopter(D),p<0.001)and thicker lens thickness(0.06 mm,p<0.001).In multivariate regression models,there was a positive correlation between lens power and Type 2 DM when age<75 years(p<0.001)or AL<25 mm(p<0.001)after adjusting for other factors,while no significant association was found in participants aged≥75 years(p=0.122)or with AL≥25 mm(p=0.172).Conclusions:The lens power in adults aged 50 and above exhibited two stages with age and with AL.Type 2 DM caused an increase in lens power,which was not seen in participants aged≥75 years or with AL≥25 mm.

Artificial intelligence for diabetic retinopathy

Diabetic retinopathy(DR)is an important cause of blindness globally,and its prevalence is increasing.Early detection and intervention can help change the outcomes of the disease.The rapid development of artificial intelligence(AI)in recent years has led to new possibilities for the screening and diagnosis of DR.An AI-based diagnostic system for the detection of DR has significant advantages,such as high efficiency,high accuracy,and lower demand for human resources.At the same time,there are shortcomings,such as the lack of standards for development and evaluation and the limited scope of application.This article demonstrates the current applications of AI in the field of DR,existing problems,and possible future development directions.