Patterns of treatment discontinuation in patients receiving anti-vascular endothelial growth factor for neovascular age-related macular degeneration.

Purpose: To report the reasons for treatment discontinuation within 5 years in patients receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy for neovascular age-related macular degeneration (nAMD). Methods: A retrospective case-notes review of patients commenced on anti-VEGF for nAMD who failed to complete 5 years of follow-up was undertaken. The reasons for treatment discontinuation, baseline age, baseline visual acuity (VA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and the VA change at the last follow-up were recorded. Age-specific all-cause mortality was calculated for deceased patients. Results: Of the 1177 patients, 551 patients (46.8%) failed to complete the 5-year follow-up. The reasons for treatment discontinuation were death (251), early discharge due to stable disease (110), further treatment deemed futile (100), failure to attend (15), ill health (14), patient choice (7), and transfer of care (1). In 53 patients, no reason was documented. The mean baseline age of those who completed the 5-year follow-up (77.4 ± 7.8 years, 95% confidence interval (CI): 76.8-77.9) was significantly lower than those who discontinued the treatment for any reason (82 ± 7.7 years, 95% CI: 81.4-82.6) (P < 0.0001). Survival analysis showed that baseline VA was not a factor in treatment discontinuation; however, visual stability (±5 letters from baseline) was associated with treatment continuation. The age-specific all-cause mortality in deceased patients was lower than that in the general population. Conclusion: At 5 years, only 53% of patients remained in active care, and death was the most common reason for treatment discontinuation. Lower baseline age and VA stability during therapy were associated with treatment continuation.

Ten-year outcome of anti-vascular endothelial growth factor treatment for neovascular age-related macular degeneration.

PURPOSE: The aim of this study was to report the 10-year visual outcome in eyes treated with anti-vascular endothelial growth factor (anti-VEGF) agents for neovascular age-related macular degeneration (nAMD) and to assess the impact of switching treatment as part of routine clinical care. METHODS: Electronic records of treatment-naïve eyes initiated on intravitreal ranibizumab between January and December 2009 were accessed. The primary outcome measured was the change in visual acuity (VA) in Early Treatment of Diabetic Retinopathy Study letters. The frequency and reasons for treatment discontinuation during each year of follow-up and the impact of switching from ranibizumab to aflibercept were some of the secondary outcomes. RESULTS: Of the 223 eyes (203 patients), 60 eyes completed 10 years of continuous follow-up. After a mean follow-up of 121.4 months, VA declined by 5.6 letters (95% confidence interval [CI] -0.25 to -11.1, P = 0.04). Final VA of ≥70 letters was seen in 20% of eyes and 35% had VA ≤ 35 letters. VA gain of ≥10 letters was seen in 23% and loss of ≥10 letters was seen in 40% of the eyes. Twenty-nine eyes remained on ranibizumab monotherapy and 31 switched to aflibercept. Switched eyes showed a visual decline of 7.1 letters (5.5 letters in monotherapy eyes, P = 0.32) and received a significantly higher number of injections (39.6 ± 9.9 vs. 24.4 ± 13.1, P < 0.0001). Patients discontinuing treatment were older and had lower baseline vision compared to completers. CONCLUSION: VA declined below the baseline after 10 years of follow-up and switching did not have any effect on the final visual outcome.

Reliability of Retinal Pathology Quantification in Age-Related Macular Degeneration: Implications for Clinical Trials and Machine Learning Applications.

Purpose: To investigate the interreader agreement for grading of retinal alterations in age-related macular degeneration (AMD) using a reading center setting. Methods: In this cross-sectional case series, spectral-domain optical coherence tomography (OCT; Topcon 3D OCT, Tokyo, Japan) scans of 112 eyes of 112 patients with neovascular AMD (56 treatment naive, 56 after three anti-vascular endothelial growth factor injections) were analyzed by four independent readers. Imaging features specific for AMD were annotated using a novel custom-built annotation platform. Dice score, Bland-Altman plots, coefficients of repeatability, coefficients of variation, and intraclass correlation coefficients were assessed. Results: Loss of ellipsoid zone, pigment epithelium detachment, subretinal fluid, and drusen were the most abundant features in our cohort. Subretinal fluid, intraretinal fluid, hypertransmission, descent of the outer plexiform layer, and pigment epithelium detachment showed highest interreader agreement, while detection and measures of loss of ellipsoid zone and retinal pigment epithelium were more variable. The agreement on the size and location of the respective annotation was more consistent throughout all features. Conclusions: The interreader agreement depended on the respective OCT-based feature. A selection of reliable features might provide suitable surrogate markers for disease progression and possible treatment effects focusing on different disease stages. Translational Relevance: This might give opportunities for a more time- and cost-effective patient assessment and improved decision making as well as have implications for clinical trials and training machine learning algorithms.

Quantification of Key Retinal Features in Early and Late Age-Related Macular Degeneration Using Deep Learning.

PURPOSE: We sought to develop and validate a deep learning model for segmentation of 13 features associated with neovascular and atrophic age-related macular degeneration (AMD). DESIGN: Development and validation of a deep-learning model for feature segmentation. METHODS: Data for model development were obtained from 307 optical coherence tomography volumes. Eight experienced graders manually delineated all abnormalities in 2712 B-scans. A deep neural network was trained with these data to perform voxel-level segmentation of the 13 most common abnormalities (features). For evaluation, 112 B-scans from 112 patients with a diagnosis of neovascular AMD were annotated by 4 independent observers. The main outcome measures were Dice score, intraclass correlation coefficient, and free-response receiver operating characteristic curve. RESULTS: On 11 of 13 features, the model obtained a mean Dice score of 0.63 ± 0.15, compared with 0.61 ± 0.17 for the observers. The mean intraclass correlation coefficient for the model was 0.66 ± 0.22, compared with 0.62 ± 0.21 for the observers. Two features were not evaluated quantitatively because of a lack of data. Free-response receiver operating characteristic analysis demonstrated that the model scored similar or higher sensitivity per false positives compared with the observers. CONCLUSIONS: The quality of the automatic segmentation matches that of experienced graders for most features, exceeding human performance for some features. The quantified parameters provided by the model can be used in the current clinical routine and open possibilities for further research into treatment response outside clinical trials.

Progression from Early/Intermediate to Advanced Forms of Age-Related Macular Degeneration in a Large UK Cohort: Rates and Risk Factors.

PURPOSE: To estimate rates and risk factors for progression to geographic atrophy (GA) or choroidal neovascularization (CNV) among eyes diagnosed with early or intermediate age-related macular degeneration (AMD) in clinical practice. DESIGN: Retrospective cohort analysis of a multicenter electronic medical record (EMR) database from the United Kingdom. PARTICIPANTS: Patients aged 50 years or more with diagnosis of early/intermediate AMD in at least 1 eye (the study eye) and no evidence of CNV or GA in the study eye, from 10 clinical sites using the EMR. METHODS: Anonymized data for 40 543 patients with a diagnosis of early/intermediate AMD were extracted between October 2000 and February 2016 from EMR database records held in the 10 sites. A sample of records randomly selected from each center was used to validate disease definitions. Records were analyzed by subgroup, based on the AMD status of the fellow eye. Multivariate Cox regression models identified other predictors of disease progression. MAIN OUTCOME MEASURES: Progression rate (per 100 person-years) to GA or CNV in study eyes with early/intermediate AMD by fellow eye status and identified risk factors for progression. RESULTS: Study eyes with early/intermediate AMD and a diagnosis of CNV in the fellow eye progressed to CNV fastest (at a rate of 15.2 per 100 person-years), and those with a diagnosis of GA in the fellow eye progressed to GA fastest (11.2 per 100 person-years), compared with the rates per 100 person-years of progression to CNV (3.2-11.9) or GA (2.0-7.8) in the other subgroups. In individuals with bilateral early/intermediate AMD, rates of progression to GA or CNV were 2.0 and 3.2 per 100 person-years, respectively. In the multivariate model, age, female sex, and cardiovascular disease were associated with an increased risk for progression to advanced AMD, whereas diabetes and glaucoma were associated with a decreased rate of progression (hazard ratios, 0.45 and 0.64, respectively). CONCLUSIONS: Progression to GA or CNV was observed frequently in eyes with early/intermediate AMD, with the status of the fellow eye affecting the rate of progression. Novel associations with risk factors were observed and require replication in other cohorts.

Direct Ophthalmic Healthcare Resource Use among Patients with Geographic Atrophy in a Large Cohort from the United Kingdom.

PURPOSE: To estimate the direct ophthalmic healthcare resource use in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: Retrospective analysis of anonymized data derived from electronic medical records (EMRs) acquired at 10 clinical sites in the United Kingdom. PARTICIPANTS: Patients aged ≥50 years with ≥1 eye with a clinical record of GA or, for comparison, bilateral early/intermediate AMD. Four subgroups were identified: GA in both eyes (GA:GA); GA in 1 eye, choroidal neovascularization (CNV) in the fellow eye (GA:CNV); GA in 1 eye with early or intermediate AMD in the fellow eye (GA:E); and early/intermediate AMD in both eyes (E:E). METHODS: The EMRs were analyzed to derive the median number of visits over the first 2 years after diagnosis of GA or early/intermediate AMD. Clinical tests recorded at visits were used to calculate estimated costs (payer perspective) of monitoring. Analyses were restricted to patients with an initial diagnosis on or after January 1, 2011, to represent present day monitoring and costs associated with AMD. MAIN OUTCOME MEASURES: Median number of visits and estimated monitoring costs per patient (in £) over the first 2 years among patients with ≥2 years of follow-up and in the individual subgroups. Intravitreal treatment costs in the GA:CNV group were excluded. RESULTS: For all 3 GA subgroups (n = 1080), the median number of visits over the first 2 years was 5, and monitoring costs were £460.80 per patient. The GA:CNV subgroup (n = 355) had the highest number of visits (median, 15), with a cost of £1581, compared with the GA:E subgroup (n = 283; median 4 visits; cost ∼£369) and the GA:GA subgroup (n = 442; median 3 visits; cost ∼£277). Ophthalmic tests were conducted most frequently in the GA:CNV subgroup. Visits and costs in the E:E subgroup (n = 6079) were lower. CONCLUSIONS: Resource use in patients with GA varies considerably and is strongly influenced by the concomitant presence of CNV and lack of monitoring strategies for GA.

United Kingdom Diabetic Retinopathy Electronic Medical Record (UK DR EMR) Users Group: report 4, real-world data on the impact of deprivation on the presentation of diabetic eye disease at hospital services.

AIM: To assess the impact of deprivation on diabetic retinopathy presentation and related treatment interventions, as observed within the UK hospital eye service. METHODS: This is a multicentre, national diabetic retinopathy database study with anonymised data extraction across 22 centres from an electronic medical record system. The following were the inclusion criteria: all patients with diabetes and a recorded, structured diabetic retinopathy grade. The minimum data set included, for baseline, age and Index of Multiple Deprivation, based on residential postcode; and for all time points, visual acuity, ETDRS grading of retinopathy and maculopathy, and interventions (laser, intravitreal therapies and surgery). The main  outcome measures were (1) visual acuity and binocular visual state, and (2) presence of sight-threatening complications and need for early treatment. RESULTS: 79 775 patients met the inclusion criteria. Deprivation was associated with later presentation in patients with diabetic eye disease: the OR of being sight-impaired at entry into the hospital eye service (defined as 6/18 to better than 3/60 in the better seeing eye) was 1.29 (95% CI 1.20 to 1.39) for the most deprived decile vs 0.77 (95% CI 0.70 to 0.86) for the least deprived decile; the OR for being severely sight-impaired (3/60 or worse in the better seeing eye) was 1.17 (95% CI 0.90 to 1.55) for the most deprived decile vs 0.88 (95% CI 0.61 to 1.27) for the least deprived decile (reference=fifth decile in all cases). There is also variation in sight-threatening complications at presentation and treatment undertaken: the least deprived deciles had lower chance of having a tractional retinal detachment (OR=0.48 and 0.58 for deciles 9 and 10, 95% CI 0.24 to 0.90 and 0.29 to 1.09, respectively); in terms of accessing treatment, the rate of having a vitrectomy was lowest in the most deprived cohort (OR=0.34, 95% CI 0.19 to 0.58). CONCLUSIONS: This large real-world study suggests that first presentation at a hospital eye clinic with visual loss or sight-threatening diabetic eye disease is associated with deprivation. These initial hospital visits represent the first opportunities to receive treatment and to formally engage with support services. Such patients are more likely to be sight-impaired or severely sight-impaired at presentation, and may need additional resources to engage with the hospital eye services over complex treatment schedules.

Characterizing Disease Burden and Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration.

PURPOSE: To understand levels of disease burden and progression in a real-world setting among patients from the United Kingdom with bilateral geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: Retrospective cohort analysis of a multicenter electronic medical record (EMR) database. PARTICIPANTS: Patients who were aged ≥50 years with bilateral GA and no history of choroidal neovascularization (CNV) and who attended 1 of 10 clinical sites using the EMR. METHODS: A deidentified data set was constructed from the records held at the 10 sites. An algorithm was used to extract cases with a GA diagnosis, of which 1901 had bilateral GA and form the basis of this report. A sample of records randomly selected from each center was used to validate disease definitions. MAIN OUTCOME MEASURES: Progression to blindness (visual acuity [VA] <20 letters or Snellen 3/60 in the better-seeing eye), driving ineligibility (VA ≤70 letters or Snellen 6/12 in the better-seeing eye), progression to CNV, loss of 10 or more letters, and mean change in VA over time. RESULTS: At first record of GA, 7.1% had a VA in the better-seeing eye equal to or lower than the cutoff for blindness registration and 71.1% had a VA that would have rendered them ineligible to drive. Over time, 16% became legally blind (median time to outcome, 6.2 years) and 66.7% became ineligible to drive (median time to outcome, 1.6 years). In the worse-seeing eye, 40.1% lost ≥10 letters in 2.4 years. Among patients with baseline and 24-month VA measurements, mean VA decline was 6.1 letters in the worse-seeing eye (n = 413) and 12.4 letters in the better-seeing eye (n = 414). The rate of progression to CNV in either eye was 7.4% per patient-year. CONCLUSIONS: At initial diagnosis, based on VA in the better-seeing eye, a high proportion of patients with bilateral GA were ineligible to drive and approximately 7% were eligible for UK blindness registration. The subsequent reduction in VA that occurred in the better-seeing eye would render a further two-thirds ineligible to drive. These findings emphasize the severity of the visual disability associated with GA secondary to AMD.

Inflammatory choroidal neovascular membrane in posterior uveitis-pathogenesis and treatment.

Choroidal neovascular membrane (CNVM) formation is a well-documented sight-threatening complication of posterior segment intraocular inflammation (PSII). The aim of this article is to review the basic and clinical science literature on the pathogenesis of CNVM formation in PSII and to present results of a case series. We searched the literature using the mesh terms- inflammation, CNVM, age-related macular degeneration, immunosuppression, photodynamic therapy, steroids, vascular endothelial growth factors and posterior uveitis. Additionally, we evaluated the visual outcome of and clinical response to our standard treatment protocol involving a combination treatment for young patients with inflammatory CNVM. The development of CNVM in PSII is promulgated by infiltrating myeloid cells as well as choroidal and retinal myeloid cell activation, subsequent vascular endothelial growth factors, cytokine and chemokine production and complement activation acting in consort to mediate angiogenic responses. No clear standard of care currently exists for the treatment of inflammatory CNVM and various combinations have been tried. Using our combination treatment, visual acuity improved in four, stabilized in one and worsened in four patients. Though significant advances have occurred in the understanding of the pathogenesis and management of this condition, optimizing therapeutic regimens will require further well-constructed prospective cohort series.

Confident complete excision of lid-margin BCCs using a marginal strip: an alternative to Mohs' surgery.

AIMS: To report a new technique of tissue preparation, using a marginal strip, after the excision of eyelid basal cell carcinomas (BCCs) and to report the long-term results of BCCs excised using this technique. METHOD: After the excision of eyelid BCC with a safety margin of 4 mm, a 1 mm strip was excised along the whole perimeter from the margin of the freshly excised specimen. This marginal strip had intact conjunctival mucosa along one edge and skin along the other. The marginal strip and the central tumour mass were then fixed immediately in formal saline and subjected to conventional histopathology. RESULTS: Of the 61 patients who completed a 5 years follow-up, the results of 28 eye-lid BCCs that were within 4 mm of the lid margin are reported. The marginal strip was clear in 22 specimens and had the presence of residual tumour in its margin in 6 specimens. These six 6 cases were further managed by observation (n = 2), by further surgical excision using marginal strip (n = 2) and by Mohs' surgery (n = 2). CONCLUSION: Marginal strip examines the entire resection margins analogous to Mohs' technique and we recommend its use in lid margin where tarsus is present throughout the specimen and >4 mm from the lid margin.

Early vitrectomy for fundus-obscuring dense vitreous haemorrhage from presumptive retinal tears.

BACKGROUND: Published literature on the management of patients with fundus-obscuring dense vitreous haemorrhage due to presumptive retinal tears is sparse and advocates waiting for spontaneous resolution. Surgery is indicated only when a definite retinal tear or retinal detachment is identified. METHODS: A retrospective review of all patients who underwent early vitrectomy for vitreous haemorrhage associated with posterior vitreous detachment was carried out. A comparison of initial visual acuity versus final visual acuity after vitrectomy was performed. The number of eyes that were found to have retinal tears and retinal detachment were documented. Initial and final Snellen acuities were used for statistical analysis. Categorical data were analysed using Fisher's exact test and statistical significance was considered to be p < 0.05. RESULTS: Sixteen eyes were identified and all these patients presented or were referred soon after the onset of vitreous haemorrhage. Associated ocular pathology (choroidal neovascular membrane, retinal branch vein occlu-sion, macroaneurysm) was suspected to be the source of the haemorrhage in 4 eyes. Vitrectomy was carried out in 12 eyes soon after presentation (mean time 6.3 days, range 1-28 days). Nineteen retinal breaks were seen in these eyes and 5 eyes had more than two breaks. None of the eyes were found to have proliferative vitreoretinopathy at the time of surgery. Two eyes needed repeat surgery for new retinal breaks. Excluding the eyes found to have an ocular pathology as the cause of vitreous haemorrhage, the mean visual acuity improved from hand movements to 6/12 (p < 0.001). CONCLUSIONS: Early vitrectomy for spontaneous dense fundus-obscuring vitreous haemorrhage and posterior vitreous detachment is safe. Since the number of patients in this study was small, a prospective randomised controlled study comparing early versus late vitrectomy is needed to see whether early surgery also prevents proliferative vitreoretinopathy formation.