Subthreshold micropulse laser combined with anti-vascular endothelial growth factor therapy for diabetic macular edema: a systematic review and meta-analysis.

PURPOSE: To evaluate the effects of subthreshold micropulse laser (SML) in addition to anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). METHODS: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were systematically searched for studies that compared anti-VEGF with SML and anti-VEGF monotherapy for DME. Outcome measures were best-corrected visual acuity (BCVA), central macular thickness (CMT), and the number of anti-VEGF injections. RESULTS: Eight studies including 493 eyes were selected. Four studies were randomized controlled, and the other four were retrospective. Meta-analysis showed that there was no significant difference in BCVA (mean difference [MD] -0.04; 95%CI -0.09 to 0.01 logMAR; P = 0.13;). CMT was thinner in the group of anti-VEGF with SML (MD -11.08; 95%CI -21.04 to -1.12 µm; P = 0.03); however, it was due to a single study that weighed higher, and the sensitivity and subcategory analyses did not support the finding. The number of anti-VEGF injections was significantly decreased in the group of anti-VEGF with SML (MD -2.22; 95%CI -3.02 to -1.42; P < 0.0001). CONCLUSION: Current evidence indicates that adding SML to anti-VEGF therapy could significantly reduce the number of anti-VEGF injections compared to anti-VEGF monotherapy, while achieve similar BCVA and CMT.

RECENT TRENDS IN THE CUMULATIVE INCIDENCE AND INTERVENTION PATTERNS OF RETINOPATHY OF PREMATURITY IN JAPAN: A Multicenter Analysis, 2011-2020.

PURPOSE: To investigate recent trends in the cumulative incidence and treatment patterns of retinopathy of prematurity (ROP) in Japan. METHODS: A retrospective multicenter cohort was conducted from 2011 to 2020 using the Diagnosis Procedure Combination inpatient database. Preterm newborns with birth weight <2,500 g were categorized by birth weight. The cumulative incidence of ROP, treatment patterns, and association between treatment and birth weight were investigated. RESULTS: A total of 82,683 preterm infants were identified, of whom 9,335 (11.3%) were diagnosed with ROP. The cumulative incidence of ROP increased by 15% in those with birth weight <500 g over the study period. Among the ROP infants, 20.2% received treatment, including laser photocoagulation (94.8%), intravitreal injection (3.8%), or both (1.8%). The proportion receiving laser photocoagulation decreased followed by an increase in intravitreal injection. This shift in intervention pattern was most conspicuous for those with birth weight 750 to 1,249 g. The risk ratio of receiving laser and intravitreal injection for those weighing <500 g was 24.7 (95% confidence interval, 10.5-58.2) and 28.4 (5.8-138.1), respectively, as compared with infants weighing >1,500 g. CONCLUSION: The cumulative incidence of ROP increased in infants with birth weight <500 g. A shift from laser photocoagulation to intravitreal injection was observed in the more recent years.

Mitochondrial glutathione peroxidase 4 is indispensable for photoreceptor development and survival in mice.

Glutathione peroxidase 4 (GPx4) is known for its unique function in the direct detoxification of lipid peroxides in the cell membrane and as a key regulator of ferroptosis, a form of lipid peroxidation-induced nonapoptotic cell death. However, the cytosolic isoform of GPx4 is considered to play a major role in inhibiting ferroptosis in somatic cells, whereas the roles of the mitochondrial isoform of GPx4 (mGPx4) in cell survival are not yet clear. In the present study, we found that mGPx4 KO mice exhibit a cone-rod dystrophy-like phenotype in which loss of cone photoreceptors precedes loss of rod photoreceptors. Specifically, in mGPx4 KO mice, cone photoreceptors disappeared prior to their maturation, whereas rod photoreceptors persisted through maturation but gradually degenerated afterward. Mechanistically, we demonstrated that vitamin E supplementation significantly ameliorated photoreceptor loss in these mice. Furthermore, LC-MS showed a significant increase in peroxidized phosphatidylethanolamine esterified with docosahexaenoic acid in the retina of mGPx4 KO mice. We also observed shrunken and uniformly condensed nuclei as well as caspase-3 activation in mGPx4 KO photoreceptors, suggesting that apoptosis was prevalent. Taken together, our findings indicate that mGPx4 is essential for the maturation of cone photoreceptors but not for the maturation of rod photoreceptors, although it is still critical for the survival of rod photoreceptors after maturation. In conclusion, we reveal novel functions of mGPx4 in supporting development and survival of photoreceptors in vivo.

Macular and peripapillary retinal nerve fiber layer thinning in eyes with prediabetes in the elderly population: OTASSHA study.

PURPOSE: To investigate retinal thickness parameters in the elderly with prediabetes mellitus (preDM) and type 2 DM without retinopathy (non-diabetic retinopathy [NDR]). METHODS: This cross-sectional study included a total of 1273 eyes without retinal pathologies of 699 volunteers aged ≥ 65 years were included. The eyes were categorized into non-DM (606 eyes), preDM (480 eyes), and NDR (187 eyes) groups according to their HbA1c levels. Fundus photography, swept-source optical coherence tomography, and comprehensive systemic examination were conducted. The thicknesses of the retinal nerve fiber layer in the macula (mRNFL) and peripapillary (pRNFL), ganglion cell complex (GCC), and ganglion cell inner plexiform layer (GCIPL), as well as central subfield thickness (CST) and central foveal thickness (CFT) were investigated for their association with DM stage using linear mixed model. RESULTS: A statistically significant thinning of mRNFL was observed in preDM vs. non-DM and in NDR vs. preDM in 3/6 sectors. A significant thinning of pRNFL was observed in preDM vs. non-DM and in NDR vs. preDM in 2/12 sectors. Such DM stage-dependent thinning of RNFL was observed mainly in the temporal and superior sectors. GCIPL and GCC were less sensitive to reflect DM-dependent inner retinal thinning. CST and CFT were not significantly associated with different DM stages. CONCLUSION: The thinning of mRNFL in the temporal and superior sectors might be a sensitive parameter associated with early neurodegeneration in preDM and NDR.

ASSOCIATION OF PREDIABETES WITH RETINAL MICROVASCULATURE ON SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN THE ELDERLY: OTASSHA Study.

PURPOSE: To investigate the retinal microvasculature in the elderly persons with prediabetes mellitus (preDM) and type 2 DM. METHODS: This cross-sectional study included a total of 452 eyes without retinal pathologies of 301 elderly volunteers aged ≥65 years, and they were categorized into nonDM (225 eyes), preDM (177 eyes), and DM (50 eyes) groups based on their HbA1c. Fundus photography, swept-source optical coherence tomography and angiography, and comprehensive systemic examinations were conducted. Vessel density (VD) and foveal avascular zone in superficial and deep retinal microvasculature were investigated for their association with DM stages using linear mixed model. RESULTS: Superficial VD (sVD) mean values in nonDM, preDM, and DM groups were 35.2%, 34.9%, and 34.8%, respectively. sVD in preDM was equivalent to sVD in DM, whereas significantly lower compared with sVD in nonDM (difference [95% CI] -0.19 [-0.33 to -0.049], P = 0.009). Deep VD (dVD) mean values in nonDM, preDM, and DM groups were 35.0%, 35.0%, and 34.4%, respectively. dVD in preDM was equivalent to dVD in nonDM, whereas significantly higher compared with dVD in DM (difference [95% CI] 0.31 [0.046-0.57], P = 0.02). There was no significant association between foveal avascular zone area and DM stages. CONCLUSION: Retinal microvasculature may be affected at the prediabetic stage in the elderly.

RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization.

Inflammation plays an important role in pathological angiogenesis. Receptor-interacting protein 1 (RIP1) is highly expressed in inflammatory cells and is known to play an important role in the regulation of apoptosis, necroptosis, and inflammation; however, a comprehensive description of its role in angiogenesis remains elusive. Here, we show that RIP1 is abundantly expressed in infiltrating macrophages during angiogenesis, and genetic or pharmacological inhibition of RIP1 kinase activity using kinase-inactive RIP1K45A/K45A mice or necrostatin-1 attenuates angiogenesis in laser-induced choroidal neovascularization, Matrigel plug angiogenesis, and alkali injury-induced corneal neovascularization in mice. The inhibitory effect on angiogenesis is mediated by caspase activation through a kinase-independent function of RIP1 and RIP3. Mechanistically, infiltrating macrophages are the key target of RIP1 kinase inhibition to attenuate pathological angiogenesis. Inhibition of RIP1 kinase activity is associated with caspase activation in infiltrating macrophages and decreased expression of proangiogenic M2-like markers but not M1-like markers. Similarly, in vitro, catalytic inhibition of RIP1 down-regulates the expression of M2-like markers in interleukin-4-activated bone marrow-derived macrophages, and this effect is blocked by simultaneous caspase inhibition. Collectively, these results demonstrate a nonnecrotic function of RIP1 kinase activity and suggest that RIP1-mediated modulation of macrophage activation may be a therapeutic target of pathological angiogenesis.

Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina.

The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the Lamp2 gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch's membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD-namely, the accumulation of APOE, APOA1, clusterin, and vitronectin-adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch's membrane were reduced in Lamp2 knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.

Lysosome-associated membrane protein-2 deficiency increases the risk of reactive oxygen species-induced ferroptosis in retinal pigment epithelial cells.

Lysosome-associated membrane protein-2 (LAMP2), is a highly glycosylated lysosomal membrane protein involved in chaperone mediated autophagy. Mutations of LAMP2 cause the classic triad of myopathy, cardiomyopathy and encephalopathy of Danon disease (DD). Additionally, retinopathy has also been observed in young DD patients, leading to vision loss. Emerging evidence show LAMP2-deficiency to be involved in oxidative stress (ROS) but the mechanism remains obscure. In the present study, we found that tert-butyl hydroperoxide or antimycin A induced more cell death in LAMP2 knockdown (LAMP2-KD) than in control ARPE-19 cells. Mechanistically, LAMP2-KD reduced the concentration of cytosolic cysteine, resulting in low glutathione (GSH), inferior antioxidant capability and mitochondrial lipid peroxidation. ROS induced RPE cell death through ferroptosis. Inhibition of glutathione peroxidase 4 (GPx4) increased lethality in LAMP2-KD cells compared to controls. Cysteine and glutamine supplementation restored GSH and prevented ROS-induced cell death of LAMP2-KD RPE cells.

Oxidative stress induces ferroptotic cell death in retinal pigment epithelial cells.

The dysfunction and cell death of retinal pigment epithelial (RPE) cells are hallmarks of late-stage dry (atrophic) age-related macular degeneration (AMD), for which no effective therapy has yet been developed. Previous studies have indicated that iron accumulation is a source of excess free radical production in RPE, and age-dependent iron accumulation in RPE is accelerated in patients with dry AMD. Although the pathogenic role of oxidative stress in RPE in the development of dry AMD is widely accepted, the mechanisms of oxidative stress-induced RPE cell death remain elusive. Here, we show that ferroptotic cell death, a mode of regulated necrosis mediated by iron and lipid peroxidation, is implicated in oxidative stress-induced RPE cell death in vitro. In ARPE-19 cells we observed that the ferroptosis inhibitors ferrostatin-1 and deferoxamine (DFO) rescued tert-butyl hydroperoxide (tBH)-induced RPE cell death more effectively than inhibitors of apoptosis or necroptosis. tBH-induced RPE cell death was accompanied by the three characteristics of ferroptotic cell death: lipid peroxidation, glutathione depletion, and ferrous iron accumulation, which were all significantly attenuated by ferrostatin-1 and DFO. Exogenous iron overload enhanced tBH-induced RPE cell death, but this effect was also attenuated by ferrostatin-1 and DFO. Furthermore, mRNA levels of numerous genes known to regulate iron metabolism were observed to be influenced by oxidative stress. Taken together, our observations suggest that multiple modes of cell death are involved in oxidative stress-induced RPE cell death, with ferroptosis playing a particularly important role.

Light Stress-Induced Increase of Sphingosine 1-Phosphate in Photoreceptors and Its Relevance to Retinal Degeneration.

Sphingosine 1-phosphate (S1P) is a potent lipid mediator that modulates inflammation and angiogenesis. In this study, we investigated the possible involvement of S1P in the pathology of light-induced retinal degeneration in vivo and in vitro. The intracellular S1P and sphingosine kinase (SphK) activity in a photoreceptor cell line (661W cells) was significantly increased by exposure to light. The enhancement of SphK1 expression was dependent on illumination, and all-trans-retinal significantly promoted SphK1 expression. S1P treatment reduced protein kinase B (Akt) phosphorylation and increased the protein expression of cleaved caspase-3, and induced photoreceptor cell apoptosis. In vivo, light exposure enhanced the expression of SphK1 in the outer segments of photoreceptors. Intravitreal injection of a SphK inhibitor significantly suppressed the thinning of the outer nuclear layer and ameliorated the attenuation of the amplitudes of a-waves and b-waves of electroretinograms during light-induced retinal degeneration. These findings imply that light exposure induces the synthesis of S1P in photoreceptors by upregulating SphK1, which is facilitated by all-trans-retinal, causing retinal degeneration. Inhibition of this enhancement may be a therapeutic target of outer retinal degeneration, including age-related macular degeneration.

Visual acuity improvement after phacoemulsification cataract surgery in patients aged ≥90 years.

BACKGROUND: Visual acuity (VA) outcomes after phacoemulsification cataract surgery in the very elderly (≥90 years) compared to those in younger patients remain unclear till date. METHODS: We retrospectively investigated 138 (group 1) and 152 (group 2) eyes in patients aged ≥90 and < 80 years, respectively, with senile cataracts who underwent phacoemulsification and intraocular lens implantation between 2014 and 2016. Four highly experienced ophthalmic surgeons performed the procedures. Intra- and post-operative complications were compared between the two groups. To investigate the effectiveness of cataract surgery in improving best-corrected VA (BCVA) at 1 and 3 months postoperatively, multiple regression analysis was performed with variables of age, cataract grades, sex, and history of diabetes mellitus (DM) and hypertension. RESULTS: The intra- and post-operative complication rates were similar between the two groups. After adjusting for the difference in cataract grades, multiple regression analysis indicated that BCVA improvement was equally favorable in both groups at 1 and 3 months postoperatively but was less favorable in patients with a history of DM at 3 months postoperatively (P = 0.042). CONCLUSION: Phacoemulsification in patients aged ≥90 years improves VA as effectively and safely as it does in younger patients, at least when performed by experienced surgeons.

EFFECTS OF INTERNAL LIMITING MEMBRANE PEELING COMBINED WITH REMOVAL OF IDIOPATHIC EPIRETINAL MEMBRANE: A Systematic Review of Literature and Meta-Analysis.

PURPOSE: To evaluate the effects on postoperative prognosis of internal limiting membrane (ILM) peeling in conjunction with removal of idiopathic epiretinal membranes (ERMs). METHODS: MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE were systematically searched for studies that compared ILM peeling with no ILM peeling in surgery to remove idiopathic ERM. Outcome measures were best-corrected visual acuity, central macular thickness, and ERM recurrence. Studies that compared ILM peeling with no ILM peeling for the treatment of idiopathic ERM were selected. RESULTS: Sixteen studies that included 1,286 eyes were selected. All the included studies were retrospective or prospective comparative studies; no randomized controlled study was identified. Baseline preoperative best-corrected visual acuity and central macular thickness were equal between ILM peeling and no ILM peeling groups. Postoperatively, there was no statistically significant difference in best-corrected visual acuity (mean difference 0.01 logarithm of the minimum angle of resolution [equivalent to 0.5 Early Treatment Diabetic Retinopathy Study letter]; 95% CI -0.05 to 0.07 [-3.5 to 2.5 Early Treatment Diabetic Retinopathy Study letters]; P = 0.83) or central macular thickness (mean difference 13.13 µm; 95% CI -10.66 to 36.93; P = 0.28). However, the recurrence rate of ERM was significantly lower with ILM peeling than with no ILM peeling (odds ratio 0.25; 95% CI 0.12-0.49; P < 0.0001). CONCLUSION: Currently available evidence in the literature indicates that additional ILM peeling in vitrectomy for idiopathic ERM could result in a significantly lower ERM recurrence rate, but it does not significantly influence postoperative best-corrected visual acuity and central macular thickness.

Role of GPx4 in human vascular endothelial cells, and the compensatory activity of brown rice on GPx4 ablation condition.

Oxidative stress is implicated in the pathologies of vascular endothelial cells. However, the importance of specific antioxidant enzymes in vascular endothelial cells is not fully understood. The purpose of this study was to elucidate the importance of Glutathione peroxidase 4 (GPx4), and the involvement of ferroptosis on cell death induced by GPx4 loss in human vascular endothelial cells. In addition, we examined the compensatory activity of brown rice on GPx4 ablation condition. Human umbilical vein endothelial cells were transfected with GPx4 or scramble control siRNA. GPx4 knockdown caused the increase in the levels of lipid oxidation, and induced cytotoxicity. On the other hand, α-tocopherol (vitamin E) and extract of brown rice, ameliorated lipid peroxidation, cytotoxicity, and delay of proliferation induced by GPx4 knockdown. Furthermore, ferrostatin-1, inhibitor of ferroptosis, also prevented cytotoxicity and delay of proliferation. In conclusion, our data demonstrated that GPx4 is an essential antioxidant enzyme for protecting lipid peroxidation, and is a regulator of ferroptosis in vascular endothelial cells. Furthermore, vitamin E rich food, such as brown rice, can compensate for GPx4 loss by protecting cells against lipid peroxidation.

Factors Associated With the Efficacy of Probing for Adult Patients With Lacrimal Duct Obstruction.

PURPOSE: To investigate the factors associated with the effectiveness of probing for epiphora in adults with lacrimal duct obstruction. METHODS: This was a cross-sectional retrospective study involving 116 eyes of 82 patients (26 males and 56 females) with a primary acquired lacrimal duct obstruction who received a probing from June 2007 to October 2013. The influences of age, gender, the duration of the symptom before probing, the number of probing treatments during the follow-up period, locations of the obstructions, and the presence of mucopurulent discharge upon irrigation of the lacrimal sac on the efficacy of probing were evaluated. RESULTS: Obstructions were observed in the nasolacrimal duct, common canaliculus, canaliculus, and punctum for 76% (88/116), 22% (26/116), 4% (5/116), and 3% (3/116), respectively. The overall efficacy of probing was 52% (60/116). Between the effective group and the noneffective group, 77% (20/26) of the common canaliculus obstructions were found in the effective group (p = 0.0039), whereas 67% (29/43) of the cases with discharge from the lacrimal sac were found in the noneffective group (p = 0.0020). On logistic regression analysis, the efficacy of probing was increased by the presence of common canaliculus obstruction (odds ratio = 6.0408; 95% confidence interval = 1.1255-48.9179, p = 0.0353), but was decreased by the presence of discharge from the lacrimal sac (odds ratio = 0.3508; 95% confidence interval = 0.1425-0.8345, p = 0.0176). CONCLUSION: Probing can be a therapeutic choice for lacrimal duct obstructions, particularly when there is a common canaliculus obstruction and no discharge from the lacrimal sac.

BRILLIANT BLUE G-ASSISTED INTERNAL LIMITING MEMBRANE PEELING FOR MACULAR HOLE: A Systematic Review of Literature and Meta-Analysis.

PURPOSE: To evaluate the effect of internal limiting membrane peeling with brilliant blue G (BBG) for the treatment of macular hole compared with peeling procedures with other dyes or without dye. METHODS: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) were systematically reviewed. Outcome measures were the primary closure rate and postoperative best-corrected visual acuity. RESULTS: Nine studies that included 846 eyes were selected. There was no significant difference in preoperative best-corrected visual acuity between the BBG and no BBG (i.e., other dyes or no dye) groups (mean difference -0.02 logMAR [equivalent to 1 Early Treatment Diabetic Retinopathy Study (ETDRS) letter]; 95% confidence interval -0.09 to 0.04 [-2-4.5 ETDRS letters]; P = 0.45). The macular hole closure rate using BBG was not significantly different from that using indocyanine green (odds ratio 1.98; 95% confidence interval 0.71-5.48; P = 0.19). The postoperative best-corrected visual acuity was more favorable with BBG than with indocyanine green (mean difference -0.10 logMAR [5 ETDRS letters]; 95% confidence interval -0.16 to -0.03 [1.5-8 ETDRS letters]; P = 0.004) or with no BBG (mean difference -0.11 [5.5 ETDRS letters]; 95% confidence interval -0.18 to -0.04 [2-9 ETDRS letters]; P = 0.003). CONCLUSION: BBG could contribute to better visual acuity outcome than other dyes for internal limiting membrane peeling in patients with macular hole; however, it does not significantly influence the closure rate.

EFFECT OF INTERNAL LIMITING MEMBRANE PEELING DURING VITRECTOMY FOR DIABETIC MACULAR EDEMA: Systematic Review and Meta-analysis.

PURPOSE: To evaluate the effect of internal limiting membrane (ILM) peeling during vitrectomy for diabetic macular edema. METHODS: MEDLINE, EMBASE, and CENTRAL were systematically reviewed. Eligible studies included randomized or nonrandomized studies that compared surgical outcomes of vitrectomy with or without ILM peeling for diabetic macular edema. The primary and secondary outcome measures were postoperative best-corrected visual acuity and central macular thickness. Meta-analysis on mean differences between vitrectomy with and without ILM peeling was performed using inverse variance method in random effects. RESULTS: Five studies (7 articles) with 741 patients were eligible for analysis. Superiority (95% confidence interval) in postoperative best-corrected visual acuity in ILM peeling group compared with nonpeeling group was 0.04 (-0.05 to 0.13) logMAR (equivalent to 2.0 ETDRS letters, P = 0.37), and superiority in best-corrected visual acuity change in ILM peeling group was 0.04 (-0.02 to 0.09) logMAR (equivalent to 2.0 ETDRS letters, P = 0.16). There was no significant difference in postoperative central macular thickness and central macular thickness reduction between the two groups. CONCLUSION: The visual acuity outcomes using pars plana vitrectomy with ILM peeling versus no ILM peeling were not significantly different. A larger randomized prospective study would be necessary to adequately address the effectiveness of ILM peeling on visual acuity outcomes.

SUPPLEMENTAL SCLERAL BUCKLE IN VITRECTOMY FOR THE REPAIR OF RHEGMATOGENOUS RETINAL DETACHMENT: A Systematic Review of Literature and Meta-Analysis.

PURPOSE: To evaluate the effect of supplemental scleral buckle (SB) in pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment. METHODS: MEDLINE, EMBASE, and CENTRAL were searched to identify studies comparing PPV with supplemental SB (PPV + SB) to PPV alone for the repair of rhegmatogenous retinal detachment. The outcome measures were primary and final reattachment rates, and postoperative complications. Odds ratio with 95% confidence interval in random effects for the comparison of outcomes between PPV + SB and PPV alone was calculated. RESULTS: Ten studies consisting of 1,704 patients were included. Meta-analysis showed that the overall primary reattachment rate was significantly higher in PPV + SB than PPV alone (odds ratio, 1.70; 95% confidence interval, 1.21-2.39; P = 0.002). The final reattachment rate was equally high in both groups. Postoperative development of epiretinal membrane was more frequent in PPV + SB than in PPV alone (odds ratio, 1.89; 95% confidence interval, 1.30-2.76; P = 0.001), whereas no significant difference in postoperative development of macular edema, proliferative vitreoretinopathy, or elevation of intraocular pressure was found. CONCLUSION: Supplemental SB increases the primary reattachment rate in PPV for rhegmatogenous retinal detachment, although final reattachment rate was equally high with or without SB.

Systemic vascular safety of ranibizumab for age-related macular degeneration: systematic review and meta-analysis of randomized trials.

BACKGROUND: We conducted a meta-analysis of randomized trials of ranibizumab for age-related macular degeneration (AMD) to elucidate systemic vascular risk. CLINICAL RELEVANCE: Although intravitreal vascular endothelial growth factor inhibitors are widely used to treat AMD, whether they produce systemic adverse effects remains uncertain. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials through March 2014 to identify the randomized trials that compared systemic safety among different intensities of ranibizumab treatment for AMD. The outcome measures were the incidence of cerebrovascular accidents (CVAs), myocardial infarctions, nonocular hemorrhages, overall arterial thromboembolic events (ATEs), and all-cause mortality. We calculated the Peto odds ratio (OR) with 95% confidence interval for the comparisons between different intensities of regimens in terms of dose and retreatment frequency. RESULTS: Eleven trials comprising 6596 patients with AMD were included in the meta-analysis. A significant increase was observed in the following comparisons: 0.5 versus 0.3/0.0 mg for CVA (OR, 1.86; 95% CI, 1.05-3.29; P = 0.03), monthly versus pro re nata (PRN)/0.0 mg for CVA (OR, 1.89; 95% CI, 1.06-3.38; P = 0.03), and 0.3/0.5 versus 0.0 mg for nonocular hemorrhage (OR, 1.57; 95% CI, 1.01-2.44; P = 0.04). A nonsignificant increase was observed in the following comparisons: 0.5 versus 0.0 mg for CVA (OR, 2.27; 95% CI, 0.90-5.69; P = 0.08), monthly versus PRN for CVA (OR, 2.04; 95% CI, 0.94-4.45; P = 0.07), 0.5 versus 0.0 mg for nonocular hemorrhage (OR, 1.68; 95% CI, 0.98-2.88; P = 0.06), 0.3 versus 0.0 mg for nonocular hemorrhage (OR, 1.68; 95% CI, 0.95-2.98; P = 0.07), monthly versus PRN/0.0 mg for nonocular hemorrhage (OR, 1.54; 95% CI, 0.98-2.42; P = 0.06), monthly versus PRN for ATE (OR, 1.58; 95% CI, 0.96-2.61; P = 0.07), and monthly versus PRN/0.0 mg for ATE (OR, 1.42; 95% CI, 0.99-2.05; P = 0.06). Among the other analyses, no protective or harmful effects of ranibizumab were observed. CONCLUSIONS: In ranibizumab treatment for patients with AMD, a possible relationship of more intensive treatment to more systemic vascular adverse events was identified, but no relationship with mortality was identified.

Systemic safety of ranibizumab for diabetic macular edema: meta-analysis of randomized trials.

PURPOSE: To evaluate systemic safety of ranibizumab for diabetic macular edema. METHODS: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were systematically reviewed. Eligible studies were randomized trials on ranibizumab for diabetic macular edema with observation at least 6 months and ≥80% completion rate that reported systemic adverse events of cerebrovascular accident, myocardial infarction, vascular death, and overall mortality. The numbers of adverse events were compared between patients treated with ranibizumab and those without. Furthermore, dose-dependent effect of ranibizumab was estimated for overall mortality through Poisson meta-regression. RESULTS: Six trials with 2,459 patients were included. All trials had exclusion criteria on systemic vascular conditions for enrollment. Risk ratio for cerebrovascular accident, myocardial infarction, vascular death, and overall mortality were 0.80 (95% confidence interval, 0.37-1.73; P = 0.57), 0.91 (95% confidence interval, 0.46-1.80; P = 0.78), 1.29 (95% confidence interval, 0.58-2.86; P = 0.53), and 1.92 (95% confidence interval, 0.78-4.73; P = 0.16), respectively. Poisson regression model showed a significant dose-dependent increase in overall mortality in the largest randomized trial using monthly ranibizumab (P = 0.04). However, the significance disappeared (P = 0.133) when pooled with other studies using ranibizumab on pro re nata basis. CONCLUSION: Ranibizumab for diabetic macular edema is considered safe when the patients are carefully selected based on systemic vascular conditions and it is used on pro re nata basis. Further evaluation is necessary on more intensive use or on high-risk patients.