Morphological Biomarkers Related to Visual Acuity in Patients With Radiation Retinopathy Treated With Intravitreal Ranibizumab.

BACKGROUND AND OBJECTIVE: Our objective was to monitor variables via spectral-domain optical coherence tomography (SD-OCT) and identify the most relevant biomarkers related to best-corrected visual acuity (BCVA) in radiation retinopathy (RR). PATIENTS AND METHODS: A post-hoc analysis of the two-year Ranibizumab for Radiation Retinopathy (RRR) trial analyzed vision and OCT parameters including intraretinal fluid, ellipsoid zone (EZ) disruption, retinal pigment epithelium atrophy, hard exudates, retinal hemorrhage, retinal neovascularization, and subfoveal fluid. BCVA and SD-OCT parameters were evaluated by univariate analysis and a mixed-effects model. RESULTS: Forty eyes from the RRR trial were included. Intraretinal cyst vertical size (week 24: P = 0.032; week 48: P = 0.021), neovascularization (week 48: P = 0.028; week 72: P = 0.025), and EZ disruption (week 72: P = 0.029; week 104: P = 0.019) were the clinical parameters most relevant to BCVA by univariate analysis in at least two time points. The mixed-effects model confirmed the relevance of intraretinal cyst vertical size (P = 0.001) and neovascularization (P = 0.001) but not EZ disruption (P = 0.119) over the course of the study. CONCLUSIONS: This study characterizes the course of visual loss in RR by identifying intraretinal cyst vertical size, neovascularization, and EZ disruption as biomarkers of poor BCVA over a span of two years. Larger multicenter studies are needed to confirm these findings. [Ophthalmic Surg Lasers Imaging Retina 2024;55:255-262.].

Impact of Prefilled Syringes and Masking on Postintravitreal Injection Endophthalmitis.

Purpose: To compare rates of endophthalmitis (1) following intravitreal injection of antivascular endothelial growth factor therapies with glass-vial preparation (GVP) vs prefilled syringes (PFS) and (2) before and after masking protocols were implemented. Methods: Medical records within a multicenter retina practice in Houston, Texas, from January 2015 to August 2021 were retrospectively reviewed. The primary outcome was rate of endophthalmitis after intravitreal injection. Results: A total of 307 349 injections were performed during the study period and 101 cases of endophthalmitis were identified (0.033%). PFS use was associated with a decreased risk of endophthalmitis (relative risk [RR], 0.320; 95% CI, 0.198-0.518, P < .001); 54 cases of endophthalmitis occurred in the GVP group of aflibercept and ranibizumab (0.052%) compared with 24 in the PFS group (0.017%). There was no difference in the endophthalmitis rates with or without universal masking (RR, 0.953; 95% CI 0.616-1.473, P = .91). Discussion: PFS use was associated with a significant reduction in the rate of endophthalmitis while the use of surgical face masks did not appear to significantly impact the rate of endophthalmitis.

Assessment of Visual Acuity Outcomes in Ocular Syphilis Treated With Adjunctive Topical or Oral Steroids.

PURPOSE: There is no consensus surrounding adjunctive steroid use in the treatment of ocular syphilis. We evaluated clinical outcomes of patients with ocular syphilis who were treated with penicillin plus either topical or oral steroids. METHODS: Nine male patients aged 26 to 72 years with a diagnosis of ocular syphilis were retrospectively identified (18 eyes). All patients were treated with penicillin and adjunctive topical or oral steroids. Visual acuity reported as the logarithm of the minimum angle of resolution (logMAR) and slit lamp findings were documented at presentation, short-term follow-up (<7 days after initiating therapy), and long-term follow-up (day 7+). Visual acuity outcomes were compared between eyes treated with topical versus oral steroids as well as eyes treated simultaneously with adjunctive steroids and penicillin versus patients treated with steroids after penicillin. RESULTS: At short-term follow-up, the mean logMAR (SD, Snellen fraction) visual acuity for eyes treated with topical steroids 0.93 (0.53, 20/170) was significantly lower than that for the oral steroid group 0.23 (0.09, 20/110; p=0.0075). Similarly, at long-term follow-up, the topical steroid group had a significantly lower visual acuity of 0.75 (20/112) compared to a visual acuity of 0.07 (20/25) for the oral steroid group (p=0.0022). Moreover, the oral steroid group displayed significant improvement in visual acuity at long-term follow-up compared to baseline while the topical steroid group did not demonstrate the same effect (p=0.0406 and p=0.5945, respectively). Initiation of steroid treatment simultaneously with penicillin did not result in better visual acuity than delayed steroid treatment (p>0.05). CONCLUSIONS: Steroids are an effective adjunctive treatment for patients with ocular syphilis. Oral steroids may be superior to topical steroids for improving visual function, especially in patients with a severe inflammatory component. Patients treated with oral or topical steroids and penicillin simultaneously did not demonstrate better visual acuity outcomes than patients treated with oral or topical steroids after penicillin was initiated.

Risk Factors for the Development of Fellow Eye Horseshoe Retinal Tears Following Horseshoe Retinal Tear in the Presenting Eye.

BACKGROUND: This study investigated factors associated with fellow eye horseshoe retinal tear (HST) development in consecutive patients with a presenting eye HST. MATERIALS AND METHODS: Medical records were reviewed for patients with initial HSTs between 2015 and 2017 and 24 factors were analyzed. Logistic regression was used to assess factors associated with fellow eye HST development. RESULTS: In total, 242 patients with an HST were identified with mean follow-up of 68.3 months. Four associations with fellow eye HST development were identified: (1) presence of fellow eye lattice degeneration, (2) subsequent presenting eye HSTs, (3) fellow eye vitreous hemorrhage at presenting eye HST occurrence, (4) OCT-determined stage 3 fellow eye posterior vitreous detachment at presenting eye HST occurrence. CONCLUSION: Four clinical findings associated with fellow eye HST development following presenting eye HST were identified. These factors may be important considerations during management patients with HST. [Ophthalmic Surg Lasers Imaging Retina 2023;54:338-345.].

OCT Risk Factors for Development of Atrophy in Eyes with Intermediate Age-Related Macular Degeneration.

PURPOSE: To determine the frequency of multiple OCT biomarkers of intermediate age-related macular degeneration (iAMD) and their relationship with the development of complete retinal pigment epithelium and outer retinal atrophy (cRORA) after 2 years. DESIGN: Retrospective cohort study. PARTICIPANTS: This retrospective analysis included 330 eyes of 330 consecutive patients with iAMD in ≥ 1 eye who had 24 months of follow-up data. METHODS: Spectralis OCT volume scans (49 B-scans over 6 × 6 mm, automatic real time = 6, fovea-centered) at baseline were evaluated for the previously described iAMD biomarkers, including a high-central drusen volume (DV; ≥ 0.03 mm3), intraretinal hyper-reflective foci (IHRF), subretinal drusenoid deposits (SDDs), hypo-reflective drusen cores (hDCs), and a thin or thick (multilayered) double-layer sign (DLS). The age-related macular degeneration (AMD) status in the fellow eye was also assessed and classified as normal or early AMD, iAMD, exudative macular neovascularization, or cRORA. MAIN OUTCOME MEASURES: Incidence of cRORA, odds ratio for demographics, and OCT features. RESULTS: At month 24, 16.36% (54/330) of the iAMD eyes developed cRORA. Several baseline features, including high-central DV, IHRF, SDD, hDC, thin DLS, and cRORA in the fellow eye, were associated with a significantly greater risk for development of cRORA at 2 years. The odds ratio, 95% confidence interval, P value, and baseline frequencies of these biomarkers were DV (6.510, 2.467-17.176, P < 0.001, 49.1%), IHRF (12.763, 4.763-34.202, P < 0.001, 38.8%), SDD (2.307, 1.003-5.304, P = 0.049, 34.2%), hDC (3.012, 1.152-7.873, P = 0.024, 13.0%), thin DLS (4.517, 1.555-13.126, P = 0.006, 11.8%), and cRORA in the fellow eye (7.184, 1.938-26.623, P = 0.003, 8.2%). CONCLUSIONS: In addition to the 4 previously reported factors that are present in a significant proportion of iAMD (DV, IHRF, hDC, and SDD), a thin DLS and cRORA in the fellow eye were associated with an increased risk of progression to cRORA over 2 years. These biomarkers may aid in prognostication, risk stratification, and selection of patients for clinical trials. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Optical Coherence Tomography Biomarkers for Conversion to Exudative Neovascular Age-related Macular Degeneration.

PURPOSE: To identify optical coherence tomography (OCT) biomarkers, including thin and thick double-layer sign (DLS) for the progression from intermediate AMD (iAMD) to exudative macular neovascularization (MNV) over 24 months. DESIGN: Retrospective cohort study. METHODS: Setting: Retina consultants of Texas. PATIENT POPULATION: 458 eyes of 458 subjects with iAMD in at least 1 eye with 24 months of follow-up data. MAIN OUTCOMES MEASURES: The following biomarkers were assessed at baseline: high central drusen volume (≥0.03 mm3), intraretinal hyper-reflective foci (IHRF), subretinal drusenoid deposits, hyporeflective drusen cores, thick DLS, thin DLS, and central choroidal thickness. A binary logistic regression was computed to investigate the association between baseline OCT covariates and the conversion to exudative MNV within 24 months. In addition, fellow eye status was also included in the model. RESULTS: During follow-up, 18.1% (83 of 458) of eyes with iAMD progressed to exudative MNV. Thick DLS, IHRF, and fellow eye exudative MNV were found to be independent predictors for the development of exudative MNV within 2 years. The baseline frequencies, odds ratios, 95% confidence intervals, and P values for these biomarkers were as follows: thick DLS (9.6%, 4.339, 2.178-8.644; P < .001), IHRF (36.0%, 2.340, 1.396-3.922; P = 0.001), and fellow eye exudative MNV (35.8%, 1.694, 1.012-2.837; P = .045). CONCLUSIONS: Thick DLS, IHRF, and fellow eye exudative MNV were associated with an increased risk of progression from iAMD to exudative MNV. These biomarkers, which are readily identified by the review of OCT volume scans, may aid in risk prognostication for patients and for identifying patients for early intervention trials.

Scleral Buckling Alone or in Combination with Pars Plana Vitrectomy for Rhegmatogenous Retinal Detachment Repair: A Meta-Analysis of 7,212 Eyes.

PURPOSE: The efficacy and safety of scleral buckling (SB) versus combination SB and pars plana vitrectomy (SB + PPV) for rhegmatogenous retinal detachment (RRD) repair remains unclear. METHODS: A systematic review and meta-analysis was conducted to identify comparative studies published from Jan 2000-Jun 2021 that reported on the efficacy and/or safety following SB and SB + PPV for RRD repair. Final best-corrected visual acuity (BCVA) represented the primary endpoint, while reattachment rates and ocular adverse events were secondary endpoints. A random-effects meta-analysis was performed, and 95% confidence intervals were calculated. RESULTS: Across 18 studies, 3912 SB and 3300 SB + PPV eyes were included. Final BCVA was nonsignificantly different between SB and SB + PPV (20/38 vs. 20/66 Snellen; WMD = -0.11 LogMAR; 95% CI: [-0.29, 0.07]; p = 0.23). Primary reattachment rate was similar between procedures (p = 0.74); however, SB alone achieved a significantly higher final reattachment rate (97.40% vs. 93.86%; RR = 1.03; 95% CI: [1.00, 1.06]; p = 0.04). Compared to SB + PPV, SB alone had a significantly lower risk of postoperative macular edema (RR = 0.69; 95% CI: [0.47, 1.00]; p = 0.05) and cataract formation (RR = 0.34; 95% CI: [0.12, 0.96]; p = 0.04). The incidence of macular hole, epiretinal membrane, residual subretinal fluid, proliferative vitreoretinopathy, elevated intraocular pressure, and extraocular muscle dysfunction were similar between SB and SB + PPV. CONCLUSIONS: There was no significant difference in final BCVA between SB + PPV and SB alone in RRD. SB alone offers a slightly higher final reattachment rate along with a reduced risk of macular edema and cataract. Primary reattachment rate and the incidence of other complications were similar between the two procedures.

Pars Plana Vitrectomy with and without Supplemental Scleral Buckle for the Repair of Rhegmatogenous Retinal Detachment: A Meta-analysis.

TOPIC: It is unclear whether there are differences in safety and efficacy between pars plana vitrectomy (PPV) alone and PPV with a supplemental scleral buckle (SB; PPV-SB) for the treatment of rhegmatogenous retinal detachment. CLINICAL RELEVANCE: This meta-analysis aimed to compare the safety and efficacy of these surgical procedures. METHODS: In this meta-analysis, Ovid MEDLINE, Embase, and Cochrane Library were systematically searched (January 2000-June 2021). The primary outcome was the final best corrected visual acuity (BCVA), whereas the secondary outcomes were reattachment rates and complications. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized controlled trials (RCTs) and the risk of bias in nonrandomized studies of interventions tool for nonrandomized studies. RESULTS: This study included 15 661 eyes from 38 studies (32 observational studies and 6 RCTs). The median follow-up duration was 6 months. The final BCVA was similar between PPV and PPV-SB (weighted mean difference [WMD], -0.03 logarithm of the minimum angle of resolution [-0.14 to 0.07]; P = 0.55). There was a significant difference in the single-operation success rate (SOSR) (88.2% versus 86.3%; relative risk [RR], 0.97 [0.95-1.00]; P = 0.03), favoring PPV-SB; however, there was no significant difference in the final reattachment rate (RR, 1.00 [0.99-1.01]; P = 0.56). Pars plana vitrectomy required a significantly higher number of operations to achieve final anatomical reattachment (WMD, 0.13 [0.02-0.24]; P = 0.02). In terms of complications, PPV was significantly less likely to be associated with macular edema (RR, 0.47 [0.25-0.88]; P = 0.02) and epiretinal membrane formation (RR, 0.70 [0.52-0.94]; P = 0.02), but these differences were no longer significant in studies published after 2010 or in RCTs. Significant proliferative vitreoretinopathy, lens status, and macular attachment status did not mediate differences in these effects. CONCLUSIONS: There were no significant differences in the final visual acuity outcomes between PPV and PPV-SB. Pars plana vitrectomy with supplemental SB was associated with a greater SOSR than standalone PPV, although the magnitude of the effect was small, with a high number needed to treat. The final reattachment rate was similar. In recent studies and in RCTs, the risk of complications was similar between the procedures.

Final Outcomes from the Randomized RECOVERY Trial of Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy.

PURPOSE: Retinal nonperfusion (RNP) is an important biomarker for diabetic retinopathy (DR). Data suggest that consistent anti-VEGF pharmacotherapy can slow RNP development. The RECOVERY trial evaluated the impact of aflibercept (Eylea, Regeneron) on RNP among eyes with proliferative DR (PDR). DESIGN: Prospective, randomized clinical trial with treatment crossover in the second year. SUBJECTS: Eyes with PDR and RNP. METHODS: At baseline, the subjects were randomized 1:1 to monthly (arm 1) or quarterly (arm 2) intravitreal 2 mg aflibercept. At the beginning of year 2, the treatment arms were crossed over so that the monthly-dosed subjects subsequently received quarterly dosing and the quarterly-dosed subjects subsequently received monthly dosing. MAIN OUTCOME MEASURES: Change in total RNP area (mm2) through year 2. Secondary outcomes included Diabetic Retinopathy Severity Scale (DRSS) scores; best-corrected visual acuity; central subfield thickness; additional measures of RNP, including ischemic index (ISI); and adverse event incidence. Means and 95% confidence intervals were calculated. RESULTS: Among all subjects, from baseline to year 2, the mean RNP increased from 235 mm2 to 402 mm2 (P < 0.0001), and the ISI increased from 25.8% to 50.4% (P < 0.0001). Increases in the mean RNP (P < 0.0001) and ISI (P < 0.0001) were also observed from year 1 to year 2. The mean total RNP increased from 264 mm2 at baseline to 386 mm2 (P < 0.0001) at year 2 in arm 1 and from 207 mm2 at baseline to 421 mm2 (P < 0.0001) at year 2 in arm 2 (P = 0.023, arm 1 vs. arm 2). Increases in the mean RNP for both treatment arms (P < 0.0001) were also specifically observed within year 2 (P = 0.32, arm 1 vs. arm 2). Compared with baseline, the DRSS scores at the end of year 2 improved in 82% (n = 27) of subjects and remained stable in 18% (n = 6), with no subjects experiencing worsening; at 2 years, the DRSS scores had improved by 2 or more steps in 65% (n = 11) and 81% (n = 13) of subjects in arms 1 and 2, respectively. CONCLUSIONS: Through year 2 of the RECOVERY trial, both treatment arms experienced significant increases in RNP. Despite the expansion of the RNP area in nearly all subjects, 82% of subjects demonstrated an improvement in DRSS levels from baseline, with no subjects experiencing worsening in DRSS scores.

Outcomes of Eyes Undergoing Multiple Surgical Interventions after Failure of Primary Rhegmatogenous Retinal Detachment Repair.

PURPOSE: To assess outcomes among eyes undergoing surgery for recurrent rhegmatogenous retinal detachment (RRD) and investigate variables that correlate with visual and anatomic outcomes. DESIGN: Retrospective, consecutive case series. PARTICIPANTS: Eyes in which initial RRD repair failed that underwent ≥2 surgeries for RRD repair between January 1, 2016, and December 31, 2020. METHODS: A retrospective analysis of eyes that underwent ≥2 RRD repairs. Eyes with etiologies of retinal detachment other than RRD, previous vitreoretinal surgery, and proliferative diabetic retinopathy were excluded. One-way analysis of variance with Tukey honestly significant difference testing and multivariate regression analyses were used to assess statistical significance. MAIN OUTCOME MEASURES: Anatomic success rate and habitual best recorded visual acuity (VA) at postoperative time intervals and at final follow-up. RESULTS: The single-operation success rate (SOSR) among eyes that underwent primary RRD repair over a 5-year period was 92.4% (2021 of 2187 eyes). The remaining 166 eyes (164 patients) in which primary RRD repair failed were included in this study. Although the anatomic success rates after the second and third RRD repairs were lower than the SOSR (71.7% and 68.1%, respectively), the final anatomic success rates did not significantly differ between eyes that underwent ≥2 RRD repairs (range, 90.6%-100%) (P > 0.05), and final anatomic success was achieved in 95.8% of the eyes. The average VA at both postoperative time intervals and final follow-up decreased with an increased total number of RRD repairs. Eyes that received silicone oil endotamponade during the second RRD repair were 20.3% (P = 0.03) and 38.4% (P = 0.04) less likely to require a third RRD repair compared with eyes that received octafluoropropane and sulfur hexafluoride gases, respectively. Eyes that developed a third RRD due to proliferative vitreoretinopathy (PVR) (n = 43) were 110% more likely to require a fourth RRD repair than eyes that developed a third RRD due to a new tear or failure to reattach (n = 4) (P = 0.04). CONCLUSIONS: In this series, the rates of anatomic success appeared consistent after each surgery when multiple reoperations were required for RRD. The VA decreased with an increased total number of RRD repairs, and the endotamponade choice might have affected the risk of additional reoperations. Proliferative vitreoretinopathy was a significant prognostic factor for RRD recurrence.

Retinal non-perfusion in diabetic retinopathy.

Diabetic retinopathy is a major cause of vision loss worldwide and areas of retinal non-perfusion (RNP) are a key pathologic feature of the vascular component of diabetic retinopathy. While there is a need for a more complete understanding of the natural history of RNP development and progression, overall, increasing RNP has been closely linked with worsening DR severity. Both traditional and novel approaches to quantitative image assessment are being explored to advance our understanding of the vascular, physiologic and functional changes associated with progressive RNP. Retinal ischemia secondary to RNP leads to tissue hypoxia and changes in the expression of a host of signalling molecules. Current anti-vascular endothelial growth factor and steroid pharmaceutical agents appear to be unable to reperuse areas of RNP, but may be able to slow the progressive longitudinal accumulation of RNP with regular retreatments. There remains a tremendous unmet need for pharmacotherapies that can slow RNP progression and ultimately reperfuse areas of the non-perfused retina. Towards this end, novel targets including the semaphorin family are being investigated.

Two-year results for ranibizumab for radiation retinopathy (RRR): a randomized, prospective trial.

PURPOSE: To assess the efficacy of a treat-and-extend strategy with intravitreal ranibizumab for radiation-related macular edema. METHODS: Forty eyes with radiation-induced macular edema and decreased visual acuity were enrolled in the phase IIb, prospective clinical trial and randomized into 3 cohorts: (A) monthly ranibizumab, (B) monthly ranibizumab with targeted retinal photocoagulation (TRP), or (C) as-needed ranibizumab and TRP. In year 2, all subjects entered a treat-and-extend protocol for ranibizumab. The primary outcome measure was mean change in early treatment diabetic retinopathy study (ETDRS) best-corrected visual acuity (BCVA) from baseline. RESULTS: Through year 1, the mean change in ETDRS BCVA was significantly different between the three cohorts (p < 0.001); cohort A saw the largest gain with + 4.0 letters. Significant anatomic improvements were also seen in all cohorts. Comparatively, through year 2, cohorts A, B, and C had a mean change in ETDRS BCVA of - 1.9, - 3.9, and + 1.3 letters, respectively; additionally, no significant differences were found in absolute ETDRS BCVA across time (ANOVA, p = 0.123). Overall, 90% of eyes maintained VA 20/200 or better and 33.3% of subjects gained at least one line of vision. There were no significant differences in mean central macular thickness for any cohort compared to baseline (p = 0.09). The presence of retinal hemorrhage and intraretinal exudates stayed consistent from year 1 to year 2 for all cohorts. CONCLUSIONS: Among eyes with radiation-related macular edema, a treat-and-extend regimen with ranibizumab may not result in as many visual and anatomic improvements as monthly injections. However, treat-and-extend still may prevent serious visual complications compared to historical controls. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02222610.

Exploring the angiographic-biologic phenotype in the IMAGINE study: quantitative UWFA and cytokine expression.

BACKGROUND: This study investigates the association of intraocular cytokine expression and ultrawide-field fluorescein angiography (UWFA) quantitative imaging biomarkers and their association with angiographical feature response after antivascular endothelial growth factor (VEGF) therapy in diabetic macular oedema (DME). METHODS: The IMAGINE DME study is a post hoc imaging biomarker and intraocular cytokine assessment from the DAVE study, a prospective DME clinical trial that included aqueous humour sampling and UWFA imaging. Fifty-four cytokines associated with inflammation and angiogenesis were evaluated through multiplex arrays. UWFA parameters were assessed using an automated feature analysis platform to determine ischaemic and leakage indices and microaneurysm (MA) count. Eyes were classified into UWFA responder or non-responder groups based on longitudinal quantitative UWFA parameter improvement. Cytokine expression was correlated with UWFA metrics and evaluated in the context of therapeutic response. RESULTS: Twenty-one eyes were included with a mean age of 55±10 years. Increased panretinal leakage index correlated with VEGF (r=0.70, p=0.0005), angiopoietin-like 4 (r=0.77, p=4.6E-5) and interleukin (IL)-6 (r=0.64, p=0.002). Panretinal ischaemic index was associated with tissue inhibitor of metalloproteinases 1 (TIMP-1, r=0.49, p=0.03) and peripheral ischaemia correlated with VEGF (r=0.45, p=0.05). MA count correlated with increased monocyte chemotactic protein-4 (MCP-4, r=0.60, p=0.004) and platelet and endothelial cell adhesion molecule 1 (PECAM-1, r=0.58, p=0.005). Longitudinal MA reduction was associated with decreased baseline VEGF and urokinase receptor (uPAR) (p<0.05). High baseline VEGF and IL-6 were associated with dramatic reduction in macular leakage (p<0.05). CONCLUSIONS: Baseline and longitudinal quantitative UWFA imaging parameters correlated with multiple aqueous humour cytokine concentrations, including VEGF and IL-6. Further research is needed to assess the possible implications of using these findings for evaluating treatment response.

Expanded Clinical Spectrum of Pentosan Polysulfate Maculopathy: A Macula Society Collaborative Study.

PURPOSE: Explore the spectrum of clinical manifestations of pentosan polysulfate sodium (PPS) maculopathy observed across a range of practice settings. DESIGN: Multi-institutional retrospective study. PARTICIPANTS: Patients exhibiting findings suggestive of PPS maculopathy identified from April 30, 2019, to December 4, 2020. METHODS: Members of the Macula Society submitted cases of presumed PPS maculopathy for consideration in this series. Diagnosis was confirmed by masked review of fundus imaging. Clinical characteristics of confirmed cases were summarized with descriptive statistics. MAIN OUTCOME MEASURES: Pentosan polysulfate exposure characteristics and fundus imaging features. RESULTS: There were 74 patients with PPS maculopathy included in the current study. Median (interquartile range) age at diagnosis was 62.0 years (56.0-65.8). The median duration of exposure to PPS was 14.0 years (10.2-18.9), with a median cumulative exposure of 1.5 kg (0.9-2.4). The most common presenting symptom was decreased or blurry vision (66.2%), followed by prolonged dark adaption or nyctalopia (32.4%). The most common referral diagnosis was age-related macular degeneration (54.1%); 16.2% of patients were referred for suspected PPS maculopathy. Novel imaging findings emerged, including highly asymmetric disease in 2 patients and a prominent vitelliform maculopathy in 2 patients. CONCLUSIONS: Most patients with PPS maculopathy exhibit characteristic findings on multimodal fundus imaging in the setting of high cumulative exposure to the oral drug. Some patients in the current study manifested novel imaging findings, expanding our understanding of the phenotypic spectrum of this condition. We recommend considering standardized ophthalmic screening of patients treated with PPS.

Real-Time Diabetic Retinopathy Severity Score Level versus Ultra-Widefield Leakage Index-Guided Management of Diabetic Retinopathy: Two-Year Outcomes from the Randomized PRIME Trial.

The prospective PRIME trial applied real-time, objective imaging biomarkers to determine individualized retreatment needs with intravitreal aflibercept injections (IAI) among eyes with diabetic retinopathy (DR). 40 eyes with nonproliferative or proliferative DR without diabetic macular edema received monthly IAI until a DR severity scale (DRSS) level improvement of ≥2 steps was achieved. Eyes were randomized 1:1 to DRSS- or PLI- guided management. At the final 2-year visit, DRSS level was stable or improved compared to baseline in all eyes, and mean PLI decreased by 11% (p = 0.73) and 23.6% (p = 0.25) in the DRSS- and PLI-guided arms. In both arms, the percent of pro re nata (PRN) visits requiring IAI was significantly higher in year 2 versus 1 (p < 0.0001). The percent of PRN visits receiving IAI during year 1 was significantly correlated with the percent of PRN visits with IAI during year 2 (p < 0.0001). Through week 104, 77.4% of instances of DRSS level worsening in the DRSS-guided arm were preceded by or occurred alongside an increase of PLI. Overall, consistent IAI re-treatment interval requirements were observed longitudinally among individual patients. Additionally, PLI increases appeared to precede DRSS level worsening, highlighting PLI as a valuable biomarker in the management of DR.

Investigational Agents in Development for the Treatment of Geographic Atrophy Secondary to Age-Related Macular Degeneration.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration, a late-onset, complex, genetic degenerative disease of the retina. Multiple environmental and genetic factors have been implicated in the development of GA, a pathology ultimately defined by loss of photoreceptors and the underlying retinal pigment epithelium and choriocapillaris. The personal burden of GA has been documented to have a substantial negative impact on quality of life, with progressive and cumulative loss of visual function each year. Currently, there are no treatments to prevent or slow the development or progression of GA. Multiple genetic and histopathologic studies have implicated dysregulation of the complement cascade in GA pathogenesis, leading to the development of several investigational pharmaceuticals targeting key factors in this inflammatory pathway. Several other biochemical pathways have also been implicated in GA development and progression, such as mitochondrial components, mediators of apoptosis and molecules involved in extracellular matrix remodeling, many of which are also being investigated for their potential value as therapeutic targets for GA treatment. Recent advancements in our understanding of GA pathogenesis and the progression of multiple potential therapeutics into later-stage human clinical trials hold great promise for a clinically effective therapeutic for patients with GA to emerge within the near future.

Real-Time Photographic- and Fluorescein Angiographic-Guided Management of Diabetic Retinopathy: Randomized PRIME Trial Outcomes.

PURPOSE: To assess the safety and efficacy of as-needed (PRN) intravitreal aflibercept injections (IAI) in managing diabetic retinopathy (DR) guided by the real-time DR severity scale (DRSS) level or panretinal leakage index (PLI) assessment among eyes without diabetic macular edema (DME). DESIGN: Prospective, randomized phase 2 trial (PRIME). METHODS: A total of 40 eyes with nonproliferative (NPDR) or proliferative DR (PDR) received monthly IAIs until a DRSS improvement of ≥2 steps was achieved and eyes were randomized (1:1) to DRSS-guided or PLI-guided management strategies graded by a central reading center. Main outcome measurements included safety and changes in DRSS and PLI. RESULTS: Through week 52, 95% of eyes achieved a DRSS improvement of ≥2 steps. Following DRSS improvement, 97% of eyes required at least 1 PRN IAI. In eyes requiring PRN IAI and completing week 52, 100% and 59% experienced DRSS worsening (P = .01) in the DRSS- and PLI-guided arms, respectively. Through week 52, mean PLI decreased 18.2% (P = .49) and 54.6% (P <.0001), respectively, in the DRSS- and PLI-guided arms. NPDR versus PDR eyes at baseline achieved a DRSS improvement of ≥2 steps after a mean 4.9 and 3.6 IAIs (P = .03). Two eyes developed a PDR event at week 52 following 5 months of quiescence. CONCLUSIONS: The randomized PRIME study analyzed 2 imaging-based biomarkers to guide PRN management with IAI of DR without DME: DRSS level and PLI. Within the context of this study with limitations, most patients required IAI re-treatment every 3-4 months, and deterioration of PLI appeared to precede DRSS level worsening. Finally, these findings reaffirm the fact that close clinical follow-up is important even among eyes that achieve substantial DRSS improvements with apparently quiescent disease.

Effect of Aflibercept on Diabetic Retinopathy Severity and Visual Function in the RECOVERY Study for Proliferative Diabetic Retinopathy.

PURPOSE: To evaluate the effect of intravitreal aflibercept on diabetic retinopathy (DR) severity and visual function in patients with proliferative DR (PDR) without diabetic macular edema (DME). DESIGN: Prospective, longitudinal, multicenter clinical trial. PARTICIPANTS: Forty eyes of 40 patients with PDR and no DME were enrolled in this study. Patients were randomized into monthly and quarterly 2-mg aflibercept injection cohorts and were treated over a period of 12 months. METHODS: All patients underwent ultra-widefield fundus imaging including pseudocolor and fluorescein angiography using an Optos 200Tx device. MAIN OUTCOME MEASURES: Severity of DR at baseline, month 6, and month 12 was evaluated using the DR severity scale (DRSS). The DRSS scores were correlated with the 25-item Visual Function Questionnaire (VFQ-25) and 39-item Visual Function Questionnaire (VFQ-39) scores at baseline and month 12. RESULTS: Mean age of the patients was 48.2 years (range, 25-75 years), mean duration of diabetes mellitus was 16.1 years (range, 2-36 years), and median glycated hemoglobin level was 8.8% (IQR, 7.4%-10%). Both monthly and quarterly groups demonstrated a statistically significant regression in DRSS from baseline to month 12 (P < 0.001). The monthly group demonstrated a statistically significant greater regression of DRSS score at the month 6 visit compared with the quarterly group (P = 0.019). However, the difference between the two groups became statistically insignificant at month 12 visit (P = 0.309). Also no difference was found in mean VFQ-25 and VFQ-39 composite scores between the monthly and quarterly groups at month 12 (P = 0.947 and P = 0.921, respectively). The improvement in mean VFQ-25 and VFQ-39 composite scores at month 12 was correlated significantly with improvement in DRSS score (r = 0.384 and P = 0.039, and r = 0.361 and P = 0.046, respectively). CONCLUSIONS: In this study of eyes with PDR without DME, both monthly and quarterly aflibercept injection groups showed significant improvement in DR severity at month 12 compared with baseline. The improvement in DRSS score was associated with an improvement in VFQ-25 and VFQ-39 composite score.

Aqueous Cytokine Expression and Higher Order OCT Biomarkers: Assessment of the Anatomic-Biologic Bridge in the IMAGINE DME Study.

PURPOSE: To identify biomarkers for predicting response to anti-vascular endothelial growth factor (VEGF) therapy in diabetic macular edema (DME) and evaluate any links between cytokine expression and optical coherence tomography (OCT) phenotype. DESIGN: The IMAGINE is a post hoc image analysis and cytokine expression assessment of the Efficacy & Safety Trial of Intravitreal Injections Combined With PRP for CSME Secondary to Diabetes Mellitus (DAVE) randomized clinical trial. METHODS: Subjects were categorized as anatomical responders or nonresponders, and within the responder group as rebounders and non-rebounders based on quantitative, longitudinal OCT criteria. Retinal layer and fluid features were extracted using an OCT machine-learning augmented segmentation platform. Responders were further sub-classified by rapidity of response. Aqueous concentrations of 54 cytokines were measured at multiple timepoints. Expression was compared between responder groups and correlated with OCT imaging biomarkers. RESULTS: Of the 24 eyes studied, 79% were anatomical responders with 38% super responders, 17% early responders, and 25% slow responders. Twenty-one percent were nonresponders. Super responders had increased baseline vascular endothelial growth factor (VEGF) (880.0 pg/mL vs 245.4 pg/mL; P = .012) and decreased monocyte chemotactic protein-1 (MCP-1) (513.3 pg/mL vs 809.5 pg/mL; P = .0.042) concentrations compared with nonresponders. Interleukin-6 (-24.9 pg/mL vs 442.8 pg/mL; P = .032) concentrations increased among nonresponders during therapy. VEGF concentrations correlated with central subfield thickness (r = 0.49; P = .01). Panmacular retinal volume correlated with increased interleuckin-6 (r = 0.47; P = .02) and decreased MCP-1 (r = -0.45; P = .03). Matrix metallopeptidase-1 correlated with subretinal fluid volume (r = 0.50; P = .01). CONCLUSIONS: OCT imaging biomarkers correlated with both intraocular cytokines and responsiveness to anti-VEGF therapy, which indicated a possible link to underlying pathways and their relevance to DME prognosis. Baseline concentrations of VEGF and MCP-1 are associated with anatomic response to anti-VEGF therapy.