Diagnostic accuracy of disorganization of the retinal inner layers in detecting macular capillary non-perfusion in diabetic retinopathy.

BACKGROUND: Disorganization of the retinal inner layers (DRIL) on optical coherence tomography (OCT) is thought to represent retinal capillary non-perfusion (CNP) in eyes with diabetic retinopathy. This study was designed to evaluate the ability of DRIL to accurately predict CNP. DESIGN: Retrospective masked reliability and diagnostic accuracy study performed in the National Institute for Health Research (NIHR) Moorfields Biomedical Research Centre, London, UK SAMPLES: Retinal images of patients with diabetic retinopathy METHODS: The OCT images from 90 separate areas of angiographically confirmed perfused and non-perfused areas of the macula from 37 eyes of 31 patients were anonymized and coded. Two masked graders independently graded these OCT scans for the presence or absence of DRIL to determine the intergrader reliability. The diagnostic accuracy of DRIL in identifying CNP was evaluated from the results obtained. MAIN OUTCOME MEASURES: Sensitivity and specificity of DRIL in accurately detecting CNP RESULTS: The intergrader agreement was high with a Cohen's kappa of 0.909. DRIL was present in 84.4% (38/45) of non-perfused retina and none in perfused retina (0/45). The sensitivity and specificity of DRIL in detecting angiographic evidence of CNP was 84.4% and 100%, respectively. The positive predictive value was 100% and the negative predictive value was 86.5%. CONCLUSIONS: The presence of DRIL is a reliable predictor of areas of macular CNP. However, DRIL is not a universal finding of non-perfusion, with some cases exhibiting absence of DRIL despite angiographic CNP.

Recurrent superior orbital fissure syndrome associated with VEXAS syndrome.

PURPOSE: To describe a case of recurrent orbital inflammation and superior orbital fissure syndrome associated with VEXAS (vacuoles, E1 enzyme, X-linked, auto-inflammatory, somatic) syndrome. CASE PRESENTATION: VEXAS syndrome is a recently identified multi-system inflammatory disease of late adult onset. The authors describe the case of a 76-year-old man who presented with recurrent episodes of orbital inflammation, with superior orbital fissure syndrome, dacryoadenitis and orbital myositis. He had a constellation of systemic disorders including recurrent chest infections, congestive cardiac failure, pulmonary emboli and skin rashes. The underlying diagnosis of VEXAS syndrome was confirmed by genetic testing, which revealed the UBA1 mutation. CONCLUSION: VEXAS syndrome should be considered in the differential diagnosis of orbital inflammatory disease associated with multi-system inflammatory disorders.

Visual Outcomes Associated With Patterns of Macular Edema Resolution in Central Retinal Vein Occlusion Treated With Anti-Vascular Endothelial Growth Factor Therapy: A Post Hoc Analysis of the Lucentis, Eylea, Avastin in Vein Occlusion (LEAVO) Trial.

IMPORTANCE: It is unclear how visual outcomes vary between patterns of macular edema (ME) resolution in eyes with central retinal vein occlusion (CRVO). OBJECTIVE: To assess best-corrected visual acuity (BCVA) outcomes at 100 weeks based on macular fluid resolution patterns by 52 and 100 weeks among patients receiving anti-vascular endothelial growth factor therapy for CRVO-related ME. DESIGN, SETTING, AND PARTICIPANTS: Post hoc analysis of the prospective, 3-arm, double-masked, randomized noninferiority trial Lucentis, Eylea, Avastin in Vein Occlusion (LEAVO), which evaluated intravitreal aflibercept (2.0 mg/0.05 mL), bevacizumab (1.25-mg/0.05 mL), or ranibizumab (0.5 mg/0.05 mL) over 100 weeks in adult patients (18 years and older) with CRVO-related ME with BCVA Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 19 to 78 in the study eye (approximate Snellen equivalent, 20/400 to 20/32, respectively) from December 2014 to December 2016 at 44 UK National Health Service ophthalmology departments. A total of 140 of 154 eyes were randomized to aflibercept, 144 of 154 randomized to bevacizumab, and 141 of 155 randomized to ranibizumab. Data were analyzed from January 2019 to March 2019. EXPOSURES: Persistent ME included eyes with central subfield thickness (CST) 320 µm or greater, and persistently dry macula (no ME) included eyes with CST less than 320 µm at 52 and 100 weeks. Recurrent ME included eyes that did not meet the criteria for persistently dry or wet. If CST was missing, the closest intervening visit was carried forward. MAIN OUTCOMES AND MEASURES: Adjusted mean BCVA at 100 weeks. RESULTS: The mean (SD) age of the 425 included participants was 69.2 (12.7) years, and 243 participants (57.2%) were men. A total of 425 eyes from 425 participants were included. By 100 weeks, 117 eyes (28.5%) were persistently dry, 44 (10.7%) were persistently wet (with ME), and 250 (60.8%) had recurrent ME. Persistent ME at 100 weeks was associated with worse VA compared with dry macula (adjusted difference, -10.98 ETDRS letters; 95% CI, -16.19 to -5.76; P < .001) and recurrent ME (adjusted difference, -5.39 letters; 95% CI, -10.15 to -0.64; P = .03). By 52 weeks, individuals with persistent ME also had poorer 100-week BCVA compared with individuals with dry macula (adjusted difference, -7.39; 95% CI, -11.72 to -3.05; P < .001) and recurrent ME (adjusted difference, -3.92; 95% CI, -8.05 to 0.20; P = .06). By 100 weeks, more eyes treated with bevacizumab had persistently wet macula than those treated with aflibercept (26 of 140 [18.6%] vs 7 of 134 [5.2%]; difference, 13.3%; 95% CI, 5.9 to 20.8; P < .001) or ranibizumab (11 of 137 [8%]; difference, 10.5%; 95% CI, 2.7 to 18.4; P = .01). CONCLUSIONS AND RELEVANCE: These findings suggest that attempts should be made to maintain persistently fluid-free macula for optimal visual acuity outcomes.

The clinical relevance of ultra-widefield angiography findings in patients with central retinal vein occlusion and macular oedema receiving anti-VEGF therapy.

AIMS: To report, using ultra-widefield angiography (UWFA) the area, distribution, and change in retinal capillary nonperfusion (RCNP) at baseline and 100 weeks in eyes with central retinal vein occlusion (CRVO) receiving anti-VEGF for macula oedema. METHODS: Prospective longitudinal multi-centre cohort study. Adults with CRVO treated with anti-VEGF therapy for macular oedema underwent UWFA at baseline and week-100. The area, distribution, and change in total, peripheral and posterior pole RCNP were determined. RESULTS: Of 153 eyes at baseline, mean area of RCNP was 34.3DA and 12 (7.8%) had ≥75DA RCNP. More than 10DA RCNP was present in the temporal periphery in 75.8% of eyes vs. 10.5% in the nasal periphery. At week-100, mean RCNP was 42.1DA with a median change from baseline of 3.3DA 95% CI [0.4, 7.3]; p < 0.01. Of 146 eyes with ≤10DA of posterior pole RCNP at baseline, 16/146 (11.0%) progressed to >10DA at week-100. These eyes had a median increase in total RCNP of 69.7DA [95% CI 27.2-85.4] vs 0DA [0.0-1.4]; p < 0.001 for those who did not, and two developed neovascular glaucoma. Larger baseline area of RCNP and history of glaucoma were risk factors for posterior pole RCNP developing. CONCLUSIONS: With UWFA, significant baseline RCNP was identified in the majority of CRVO patients, notably in the temporal periphery, but large increases over 100 weeks were uncommon. Development of >10DA posterior pole RCNP is a marker for widespread RCNP and in such cases the risk of anterior segment neovascularisation is not abolished by concomitant anti-VEGF therapy.

Impact of injection frequency on 5-year real-world visual acuity outcomes of aflibercept therapy for neovascular age-related macular degeneration.

BACKGROUND: To evaluate the impact of injection frequency on yearly visual outcomes of patients treated with intravitreal aflibercept for neovascular age-related macular degeneration (nAMD) over a period of 5 years in a tertiary ophthalmic centre. DESIGN: Single centre, retrospective cohort study. PARTICIPANTS: Consecutive treatment-naive nAMD patients initiated on aflibercept injections 5 years ago. METHODS: The Moorfields OpenEyes database was searched for consecutive patients who were initiated on intravitreal aflibercept for nAMD in 2013-14 and the visual acuity (VA) in Early Diabetic Retinopathy Study (ETDRS) letters and injection records per year were recorded for a period of 5 years. Analyses of the whole cohort and a sub-sample of 5-year completers were done. The cohort was further grouped into Group A (on continuous treatment), Group B (early cessation of treatment) and Group C (interrupted treatment) to evaluate the relation between treatment frequency and visual outcomes. MAIN OUTCOME MEASURES: The primary end point was change in VA at 5 years; secondary outcomes included proportion of eyes that gained or maintained VA, number of injections received and the effect of treatment frequency. RESULTS: Data were collected on 468 patients (512 eyes). Sixty-six percent of the patients completed 5-year follow-up. The mean age of the whole cohort was 79.5 ± 8.5 years and the mean baseline VA was 58.3 ± 15.4 letters. Amongst the completers, final VA change was -2.9 (SD 23.4) ETDRS letters and the cumulative number of injections over 5 years was 24.2 (10.6). Group A had three letter gain and received significantly higher cumulative number of injections over 5 years than Group B and C (31.8, 14.6 and 18.4 respectively, p = 0.001). After adjusting for age and baseline VA, on average, final VA was +8.0 letters higher in the ≥20 injections group than the <20 group (p = 0.001). CONCLUSIONS: Aflibercept therapy results in sustained good visual outcome over 5 years in neovascular AMD eyes when early and persistent treatment is given.

Predictors of Visual Acuity Outcomes after Anti-Vascular Endothelial Growth Factor Treatment for Macular Edema Secondary to Central Retinal Vein Occlusion.

PURPOSE: To evaluate whether baseline demographic, clinical, and OCT characteristics predict visual acuity (VA) outcomes in patients receiving anti-vascular endothelial growth factor (VEGF) therapy for macular edema (ME) due to central retinal vein occlusion (CRVO). DESIGN: Post hoc analysis of the randomized noninferiority trial (Lucentis, Eylea, Avastin in CRVO) LEAVO Study from December 12, 2014, to December 16, 2016, carried out across 44 UK National Health Service ophthalmology departments. PARTICIPANTS: Data on 267 participants with a baseline best-corrected mean visual acuity (BCVA) range of 19 to 78 Early Treatment Diabetic Retinopathy Study letter score (approximate Snellen equivalent, 20/32 to 20/320) who had central subfield thickness (CST) ≥ 320 µm on Spectralis OCT (Heidelberg Engineering) were analyzed. METHODS: Study participants were randomized to receive repeated intravitreal injections of ranibizumab (0.5 mg/50 µl), aflibercept (2.0 mg/50 µl), or bevacizumab (1.25 mg/50 µl), and a protocol-driven pro re nata re-treatment regimen at 4 to 8 weekly visits was followed up to week 100 after 4 mandated 4-weekly loading injections. MAIN OUTCOME MEASURES: Change in BCVA and percentage of patients gaining ≥ 10 letters and achieving BCVA letter score > 70 letters at 52 and 100 weeks. RESULTS: The analysis was adjusted for treatment effects and confirmed by sensitivity analysis. Age ≥ 75 years is a poor predictor for all 3 visual outcomes. Lower baseline BCVA predicted 10-letter gainers and higher gains in BCVA, although it is a poor predictor of achieving > 70 Early Treatment Diabetic Retinopathy Study letters. None of the baseline OCT morphologic characteristics except ellipsoid zone (EZ) integrity influenced any visual outcomes. Both baseline CST and total macular volume showed a nonlinear relation to 10-letter gainers, with CST > 900 µm being a poor prognostic indicator. Baseline CST and macular volume did not predict mean change in BCVA or BCVA > 70 letters at 52 and 100 weeks. The sensitivity analysis conclusions after removing iCRVO were similar. CONCLUSIONS: At presentation, younger age, higher baseline BCVA, and a definitely intact subfoveal EZ are predictors of BCVA score > 70 letters at 100 weeks.

Retinal Nonperfusion in the Posterior Pole Is Associated With Increased Risk of Neovascularization in Central Retinal Vein Occlusion.

PURPOSE: To review the definition of ischaemic central retinal vein occlusion (CRVO) and stratify the risk of neovascular complication based on wider areas of visible retinal non-perfusion. DESIGN: Retrospective consecutive case series and image analysis study. METHODS: Setting: Moorfields Eye Hospital, London, United Kingdom. STUDY POPULATION: Forty-two consecutive treatment-naïve eyes with CRVO imaged with ultra-widefield angiography with a minimum of 12 months follow-up. OBSERVATION PROCEDURE: The spatial location and total area of retinal nonperfusion (measured in disc areas, DA) were determined using the validated concentric rings method. The area was corrected for projection distortion. The images were graded by 2 retinal physicians and average measurements used. MAIN OUTCOME MEASURES: Development of neovascular complications. RESULTS: The percentage of eyes developing new vessels increased from none in eyes with less than 10 DA of nonperfusion in total to 14.3% in eyes with 10-30 DA, 20.0% for 30-75 DA, and 80% risk with 75-150 DA of nonperfusion. From 13 (31.0%) eyes with a perfused posterior pole (an area encompassing a 5 disc diameter radius centered at the fovea) and more than 10 DA of nonperfusion isolated in the periphery (beyond the posterior pole), only 1 (7.7%) eye developed new vessels, odds ratio (OR) 0.12 [95% confidence interval (CI): 0.01, 1.03]. Comparatively, for 13 (31.0%) eyes with more than 10 DA of nonperfusion in the posterior pole, 11 (84.6%) developed new vessels, OR 74.25 [95% CI: 9.26, 595.30], P < .001. CONCLUSION: With ultra-widefield angiography, we have ascertained that posterior pole nonperfusion of more than 10 DA remains the key risk factor for new vessel development compared to areas of nonperfusion confined to the periphery.

Real-World Outcomes of Ranibizumab Treatment for Diabetic Macular Edema in a United Kingdom National Health Service Setting.

PURPOSE: To determine visual acuity (VA) and spectral-domain optical coherence tomography (OCT) outcomes with intravitreal ranibizumab for diabetic macular edema (DME) in a United Kingdom National Health Service clinical setting. DESIGN: Retrospective interventional case series. PARTICIPANTS: Consecutive patients with DME, treated with the first ranibizumab injection between August 2013 and March 2014 across 4 sites of Moorfields Eye Hospital, London. METHODS: Two hundred eyes of 164 consecutive patients with center-involving DME and VA ≤79 ETDRS letters, central subfield macular thickness (CST) ≥350 µm on Topcon 3D OCT 2000, initiated on a loading phase of 3 intravitreal ranibizumab injections and who had at least 6 months follow-up were reviewed. Subsequent retreatment was guided by VA and OCT with the aim of treating to stability. VA, OCT CST, and macular volume (MV) were recorded at baseline and monthly to 12 months. RESULTS: The mean VA, mean CST, and mean MV at baseline were 54.4 (± 15.26) letters, 490.16 (± 116.54) µm, and 10.46 (± 2.28) mm3. The mean VA change at 12 months was +6.6 (± 13.35) letters (P = .0003). A total of 40.3% of patients (n = 77) gained ≥10 letters and 25.1% (n = 48) gained ≥15 letters; 8.9% (n = 17) lost ≥10 letters and 6.3% (n = 12) lost ≥15 letters. At 12 months, the mean change in CST and MV were -133.9 (± 160.12) µm (P = .0001) and -1.5 (± 1.96) mm3 (P = .0001), respectively. An average of 7.2 (± 2.3) injections were given over 12 months. CONCLUSIONS: Outcomes with 3 loading injections of 0.5 mg ranibizumab given monthly followed by pro re nata retreatment in a clinical setting are comparable with outcomes from clinical trials.

Validation of Concentric Rings Method as a Topographic Measure of Retinal Nonperfusion in Ultra-Widefield Fluorescein Angiography.

PURPOSE: To validate the use of concentric rings as a method to measure topographic area of retinal nonperfusion in ultra-widefield angiography with the ischemic index method, which is the most frequently used method to measure nonperfusion in ultra-widefield angiography. DESIGN: Validation study and reliability analysis. METHODS: setting: Single-center study performed at National Institute for Health Research Moorfields Biomedical Research Centre, London, United Kingdom. STUDY POPULATION: Twenty-eight ultra-widefield angiogram images of eyes with central retinal vein occlusion. OBSERVATION PROCEDURE: The concentric rings method consists of 6 macula-centered concentric rings divided into 12 segments each. Each image was graded by 5 graders using both the concentric rings and the ischemic index methods. MAIN OUTCOME MEASURES: Agreement between the 2 methods was calculated using the intraclass correlation coefficient. Intertest agreement, intergrader agreement, test-retest reliability, and the time taken to grade using these 2 methods were compared. RESULTS: The intertest agreement between concentric rings method and ischemic index method was 0.965. The intergrader agreement was 0.910 for the concentric rings method and 0.898 with the ischemic index method. The test-retest reliability was 0.975 for the rings and 0.979 for the ischemic index. Average grading time per image was 187 s and 297 s for the concentric rings method and ischemic index method, respectively, P < .001. CONCLUSION: The concentric rings method has an "almost-perfect" intergrader agreement and intertest agreement with the ischemic index method, with a shorter grading time.