Angiographic characteristics and treatment approach in patients undergoing intra-arterial chemotherapy for retinoblastoma.

PURPOSE: To identify the specific clinical and angiographic variables that determine the success of intra-arterial chemotherapy (IAC) in a patient with retinoblastoma. METHODS: Medical records from patients undergoing intra-arterial chemotherapy for the treatment of retinoblastoma between January 2015 and June 2020 within a large academic ocular oncology practice were retrospectively reviewed. Demographics were recorded together with clinical, ocular, and angiographic variables such as the diameter of the ophthalmic artery (OA), angle of ophthalmic artery takeoff, and branching pattern of ophthalmic vasculature. RESULTS: Forty-four eyes from 33 patients with retinoblastoma treated with IAC were identified. Over the total 32 mean months of follow-up, these patients received 144 total catheterizations and a mean of 3.2 IAC cycles for each eye. The number of IAC cycles and the chemotherapeutic agent used did not vary significantly with worsening International Classification of Retinoblastoma (ICRB) groups (P > 0.1). Cumulative dose did not vary with the ICRB group for eyes treated with melphalan, topotecan, or carboplatin (P > 0.1). A higher ICRB group was associated with a smaller mean ophthalmic artery diameter across all procedures (P = 0.016), and femoral artery diameter did not vary significantly between ICRB groups (P = 0.906). A higher cumulative dose of IAC was significantly associated with a smaller takeoff angle of the OA (melphalan, P = 0.011; topotecan, P = 0.009; carboplatin, P = 0.031) in patients who underwent successful IAC procedures. Ophthalmic artery diameter and femoral artery diameter did not have a significant association (P > 0.1) with higher IAC doses in successful IACs. Cumulative IAC dose was not significantly associated with ophthalmic vasculature branching pattern, presence of choroidal blush, temporary OA vasospasm reported during the procedure, and OA occlusion upon microcatheter placement. CONCLUSION: In this study, neurosurgical angioanatomy appeared to influence the cumulative dose of chemotherapy needed during IAC for retinoblastoma. In the future, these anatomic variables may be used to guide the frequency of monitoring, dosing, and estimation of recurrence risk.

Progressive inner retinal neurodegeneration in non-proliferative macular telangiectasia type 2.

PURPOSE: Patients with non-proliferative macular telangiectasia type 2 (MacTel) have ganglion cell layer (GCL) and nerve fibre layer (NFL) loss, but it is unclear whether the thinning is progressive. We quantified the change in retinal layer thickness over time in MacTel with and without diabetes. METHODS: In this retrospective, multicentre, comparative case series, subjects with MacTel with at least two optical coherence tomographic (OCT) scans separated by >9 months OCTs were segmented using the Iowa Reference Algorithms. Mean NFL and GCL thickness was computed across the total area of the early treatment diabetic retinopathy study grid and for the inner temporal region to determine the rate of thinning over time. Mixed effects models were fit to each layer and region to determine retinal thinning for each sublayer over time. RESULTS: 115 patients with MacTel were included; 57 patients (50%) had diabetes and 21 (18%) had a history of carbonic anhydrase inhibitor (CAI) treatment. MacTel patients with and without diabetes had similar rates of thinning. In patients without diabetes and untreated with CAIs, the temporal parafoveal NFL thinned at a rate of -0.25±0.09 µm/year (95% CI [-0.42 to -0.09]; p=0.003). The GCL in subfield 4 thinned faster in the eyes treated with CAI (-1.23±0.21 µm/year; 95% CI [-1.64 to -0.82]) than in untreated eyes (-0.19±0.16; 95% CI [-0.50, 0.11]; p<0.001), an effect also seen for the inner nuclear layer. Progressive outer retinal thinning was observed. CONCLUSIONS: Patients with MacTel sustain progressive inner retinal neurodegeneration similar to those with diabetes without diabetic retinopathy. Further research is needed to understand the consequences of retinal thinning in MacTel.

Morphological characteristics of eyes with neovascular age-related macular degeneration and good long-term visual outcomes after anti-VEGF therapy.

PURPOSE: To analyse the morphological characteristics of eyes with neovascular age-related macular degeneration (AMD) with good long-term visual acuity after anti-VEGF (vascular endothelial growth factor) therapy. METHODS: Retrospective, observational study of 175 patients with neovascular AMD with >5 years of follow-up after initiating anti-VEGF therapy. Spectral-domain optical coherence tomography images were assessed for thickness of pigment epithelial detachment (PED), subretinal hyper-reflective material (SHRM), subretinal fluid and subfoveal choroidal, as well as the integrity of the outer retinal bands. RESULTS: The final analysis cohort included 203 eyes (175 patients) followed for a mean of 7.84±1.70 years (range: 5-11). The maximum PED thickness in the foveal central subfield (FCS) was significantly lower (p<0.001) in the poor vision group (13.11 µm) compared with the intermediate (86.25 µm) or good (97.92 µm) vision groups, respectively. In contrast, the maximum thickness of SHRM in the FCS was significantly thicker (p<0.001) in eyes with poor vision (149.46 µm) compared with eyes with intermediate vision (64.37 µm) which in turn were significantly thicker (p<0.001) than eyes with good vision (9.35 µm). The good vision group also had better continuity of all outer retinal bands (external limiting membrane, ellipsoid zone, and retinal pigment epithelium) compared with the other two groups (all p<0.001). CONCLUSION: A thicker PED and thinner SHRM were correlated with better vision in eyes with neovascular AMD following long-term anti-VEGF therapy. If replicated in future prospective studies, these findings may have implications for design of optimal anatomic endpoints for neovascular AMD treatment.

Association of Ultrasound Features in Uveal Melanoma With Metastatic Risk as Defined by Preferentially Expressed Antigen in Melanoma Status.

BACKGROUND AND OBJECTIVE: The purpose of this study was to evaluate the association between clinical and ultrasound features of uveal melanoma and preferentially expressed antigen in melanoma (PRAME), given its role as a biomarker for metastatic mortality. MATERIALS AND METHODS: Ultrasonographic characteristics and PRAME expression status of patients with uveal melanoma (2016 to 2021) were retrospectively analyzed using univariate and multivariate regression. RESULTS: Of the 81 eyes included, 49 (60%) were PRAME negative and 32 (40%) were PRAME positive. Univariate analysis showed that only largest basal diameter (LBD) was significantly associated with PRAME positivity (P = .006). There was a borderline association between shape and PRAME positivity (P = .054), whereas height, internal reflectivity, vascularity, and location showed no effect. Multivariate regression identified LBD as the sole significant predictor of PRAME positivity (odds ratio, 1.196; 95% CI, 1.055 to 1.379; P = .008). CONCLUSION: In this cohort, ultrasonographic LBD was significantly associated with PRAME status. No other clinical or ultrasound variables were predictive of molecular testing results. The results of this PRAME analysis are like prior reports, which suggested a strong association between gene expression profiling class 2 and increasing LBD. [Ophthalmic Surg Lasers Imaging Retina 2022; 53:374-378.].

Long-Term Retinal Vascular Changes in Age-Related Macular Degeneration Measured Using Optical Coherence Tomography Angiography.

BACKGROUND AND OBJECTIVE: To determine if age-related macular degeneration (AMD) status affects longitudinal retinal vessel changes. PATIENTS AND METHODS: Retrospective, cohort study of 125 eyes (75 patients) with AMD, following retinal vessel density (VD) and foveal avascular zone (FAZ) measurements using optical coherence tomography angiography (OCT-A) over 24 months. RESULTS: FAZ area (P < .001) and perimeter (P < .001) increased over 2 years, with no difference between nonexudative and exudative AMD (P = .134-.976). Eyes with geographic atrophy (GA) showed greater progressive VD loss (P = .023-.038), and greater increase in FAZ area (P = .044) and perimeter (P = .040) compared to eyes without GA. Neither baseline nor 2-year change in vascular parameters were associated with choroidal neovascularization (CNV) or GA incidence in nonexudative AMD, or anti-VEGF injection frequency in exudative AMD (P = .070-.952). CONCLUSION: AMD eyes with GA undergo more rapid loss of retinal vessel density and FAZ enlargement over 2 years, suggesting a relationship between the retinal vasculature and AMD pathophysiology. [Ophthalmic Surg Lasers Imaging Retina 2022;53:529-536.].

The visual consequences of virtual school: acute eye symptoms in healthy children.

PURPOSE: To investigate acute eye symptoms in healthy children after a typical day of virtual school during the COVID-19 pandemic. METHODS: The study population included 110 healthy children 10-17 years of age who were enrolled in full-time or hybrid virtual school. Children with a history of central nervous system or ocular pathology, recent concussions, reported poor vision, convergence insufficiency, history of orthoptic therapy, strabismus, amblyopia, or learning disorders were excluded. Background information was collected, including demographics, family and personal ocular history, and virtual school specifications. Eligible children completed a modified convergence insufficiency symptom survey (CISS) and an asthenopia survey before and after a virtual school session. CISS and asthenopia survey symptoms were scored, and the differences in symptomatology before and after school were calculated. RESULTS: The average sum of the CISS scores increased from 5.17 before school to 9.82 after (P < 0.001), with 61% of children recording an increase in convergence insufficiency symptoms and 17% experiencing severe convergence insufficiency symptoms after school. Average asthenopia symptom scores increased from 1.58 to 2.74 (P < 0.001), with 53% of children recording an increase in asthenopia symptoms. Significant increases were seen in 12 of 15 CISS questions and in 4 of 5 asthenopia questions. CONCLUSIONS: In this study cohort, otherwise healthy children experienced acute ocular symptoms following virtual school.

Research Funding, Income, and Career Satisfaction Among Clinician-Scientists in Ophthalmology in the United States.

PURPOSE: The purpose of this study was to characterize clinician-scientists in ophthalmology and identify factors associated with successful research funding, income, and career satisfaction. DESIGN: Cross-sectional study. METHODS: A survey was conducted of clinician-scientists in ophthalmology at US academic institutions between April 17, 2019, and May 19, 2019. Collected information including 1) demographic data; 2) amount, type, and source of startup funding; first extramural grant; and first R01-equivalent independent grant; 3) starting and current salaries; and 4) Likert-scale measurements of career satisfaction were analyzed using multivariate regression. RESULTS: Ninety-eight clinician-scientists in ophthalmology were surveyed across different ages (mean: 48 ± 11 years), research categories, institutional types, geographic regions, and academic ranks. Median startup funding ranged from $50-99k, and median starting salaries ranged from $150-199k. A majority of investigators (67%) received their first extramural award from the National Eye Institute, mainly through K-award mechanisms (82%). The median time to receiving their first independent grant was 8 years, mainly through an R01 award (70%). Greater institutional startup support (P = .027) and earlier extramural grant success (P = .022) were associated with earlier independent funding. Male investigators (P = .001) and MD degreed participants (P = .008) were associated with higher current salaries but not starting salaries. Overall career satisfaction increased with career duration (P = .011) but not with earlier independent funding (P = .746) or higher income (P = .300). CONCLUSIONS: Success in research funding by clinician-scientists in ophthalmology may be linked to institutional support and earlier acquisition of extramural grants but does not impact academic salaries. Nevertheless, career satisfaction among clinician-scientists improves with time, which is not necessarily influenced by research or financial success.

Noncompliance in Prospective Retina Clinical Trials: Analysis of Factors Predicting Loss to Follow-up.

PURPOSE: Noncompliance during prospective studies can bias results and limit conclusions. The current study retrospectively investigated the relationship between study subject characteristics and rates of noncompliance in interventional trials involving common causes of blindness. DESIGN: Retrospective analysis of 10 randomized clinical trials. METHODS: Subjects were enrolled in investigator-initiated trials studying proliferative diabetic retinopathy, neovascular age-related macular degeneration, diabetic macular edema, and retinal venous occlusive disease. Records were reviewed for hypothesized risk factors of noncompliance and rates of noncompliance, which were defined as at least 1 missed visit or exiting the study early. Demographic information, systemic medical history, and ocular medical history, including visual acuity and central retinal thicknesses, were examined retrospectively using Student t test, Pearson χ2 test, and logistic regression. RESULTS: Of 390 subjects included, 212 (54.4%) were compliant with all scheduled study visits and 178 (45.6%) met criteria for noncompliance, with 53 (13.6%) subjects exiting early. Regression models identified 17 variables that were significant in determining subject noncompliance. Among those, distance, comorbidities, diabetic status, concomitant medications, previous clinic visits, length of study, disease under study, and severe adverse events were highly significant risk factors of noncompliance. CONCLUSION: The current research identified a substantial proportion of subjects who met the criteria for noncompliance within the trials analyzed. The factors identified in the current work are consistent with published clinical observations and the results of previous clinical trials. These results highlight the importance of considering study design and medical history when designing prospective clinical trials in an attempt to minimize data loss.

Association of Intravitreal Aflibercept With Optical Coherence Tomography Angiography Vessel Density in Patients With Proliferative Diabetic Retinopathy: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Although previous studies have evaluated the association between anti-vascular endothelial growth factor therapy and macular vessel density, they were confounded by the presence of macular edema, which may be associated with artifacts and segmentation errors in optical coherence tomography angiography (OCTA). Objective: To evaluate the association of intravitreal aflibercept with changes in macular vascular density using OCTA in patients with proliferative diabetic retinopathy without diabetic macular edema. Design, Setting, and Participants: This post hoc analysis of a randomized clinical trial used data on 40 eyes of 40 patients with proliferative diabetic retinopathy without diabetic macular edema who were enrolled in the Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy (RECOVERY) clinical trial from August 1, 2016, to June 31, 2017. Three patients were lost to follow-up at month 12, and 5 patients were excluded from analysis because of poor OCTA image quality, leaving 16 patients in each cohort in the final analysis. Data analysis was performed from March 1, 2018, to January 15, 2019. Intervention: In the RECOVERY trial, patients were randomized into cohorts receiving 2 mg of aflibercept injections monthly (n = 20) or quarterly (n = 20) and treated for 12 months. Main Outcomes and Measures: The percentage of vascular density (in total scan and foveal and parafoveal regions) was compared before and after 12 months of therapy. Results: The sample for this OCTA analysis included 32 eyes from 32 patients (mean [SD] age, 48.37 [12.30] years; 17 [53.1%] male). The mean (SD) total scan vascular density for the superficial vascular complex was 42.28% (4.03%; 95% CI, 40.63%-43.93%) at baseline and 39.64% (4.01%; 95% CI, 37.91%-41.37%) at month 12 (P = .69). For the deep vascular complex, the mean (SD) vascular density was 48.42% (4.99%; 95% CI, 46.36%-50.47%) at baseline and 45.69% (4.63%; 95% CI, 43.69%-47.70%) at month 12 (P = .40). For the choriocapillaris, the mean (SD) vascular density was 64.42% (3.36%; 95% CI, 63.04%-65.81%) at baseline and 62.55% (4.79%; 95% CI, 60.48%-64.62%) at month 12 (P = .16). There was no difference in vascular density parameters between monthly and quarterly injection arms at month 12. Conclusions and Relevance: In this study, macular vascular density did not change after 12 months of intravitreal aflibercept therapy. Because nonperfusion is expected to progress in diabetic retinopathy, this finding may represent a beneficial association between anti-vascular endothelial growth factor therapy and macular vascular density. Trial Registration: ClinicalTrials.gov Identifier: NCT02863354.

Quarterly Anti-Vascular Endothelial Growth Factor Dosing for Neovascular Age-Related Macular Degeneration: Real-World Clinical Outcomes.

BACKGROUND AND OBJECTIVE: Characterize eyes managed with quarterly intravitreal anti-vascular endothelial growth factor injections for neovascular age-related macular degeneration (nAMD). PATIENTS AND METHODS: Treatment-naïve nAMD eyes managed predominately using a treat-and-extend approach that received five or more consecutive quarterly injections from 2005 to 2017. RESULTS: One hundred fifty eyes were retrospectively identified. During quarterly dosing, a mean of 9.8 injections were given over a mean of 29 months. Ninety-one eyes (61%) had no exudative disease recurrence during quarterly dosing. Thirty-three eyes (22%) experienced exudative activity recurrence, with a mean cumulative yearly recurrence rate of 12% and a mean 6-letter loss of visual acuity (VA). Twenty-four eyes (16%) stopped quarterly treatments; nine (38%) of these subsequently experienced exudative activity recurrence with a mean 8-letter VA loss. CONCLUSION: In this real-world analysis of nAMD managed with quarterly dosing over a mean of more than 2 years' follow-up, 22% experienced disease recurrence during quarterly dosing, and 38% of eyes that stopped quarterly dosing experienced subsequent exudative disease recurrence. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e250-e256.].

Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy: Outcomes from the Randomized RECOVERY Trial.

PURPOSE: Evaluate the impact of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) on retinal nonperfusion (RNP) in eyes with proliferative diabetic retinopathy (PDR). DESIGN: Prospective, randomized clinical trial. PARTICIPANTS: Eyes with treatment-naïve PDR and extensive RNP without diabetic macular edema. METHODS: Patients were randomized 1:1 to intravitreal 2 mg aflibercept every 4 weeks (monthly) or every 12 weeks (quarterly). MAIN OUTCOME MEASURES: The primary outcome measure was change in total RNP area (in square millimeters) from baseline to year 1. Secondary outcomes included ischemic index (ISI), diabetic retinopathy severity scale (DRSS) scores, visual acuity, central retinal thickness, and adverse events. The mean and 95% confidence interval were calculated for each outcome. RESULTS: Through 1 year, the monthly (n = 20) and quarterly (n = 20) cohorts received 11.0 and 3.95 mean aflibercept injections, and DRSS scores improved 2 steps or more in 74% and 67% of patients, respectively. Among all patients through 1 year, mean total area of RNP increased from 235 mm2 to 266 mm2 (P = 0.18) and ISI increased from 25.8% to 31.9% (P = 0.004). Retinal nonperfusion outcomes favored monthly dosing. Mean total RNP increased from 207 mm2 at baseline to 268 mm2 (P = 0.01) at 1 year in the quarterly cohort and remained stable at 264 mm2 at baseline and 1 year (P = 0.70) in the monthly cohort (P = 0.05, monthly vs. quarterly cohorts). Although many eyes demonstrated increased areas of RNP longitudinally (n = 24 [66.7%]), this was more common with quarterly dosing (n = 14 [77.8%]), and a proportion of eyes (n = 12 [33.3%]) demonstrated localized areas of apparent reperfusion of nonperfused retina, more commonly in the monthly cohort (n = 8 [44.4%]). CONCLUSIONS: Widespread evidence of retinal reperfusion with aflibercept dosing of PDR eyes with extensive RNP was not identified, and therefore the primary outcome of the current study was not met. Nevertheless, zones of apparent reperfusion were detected in some patients, and a dose response was identified with a reduction of RNP progression with monthly compared to quarterly dosing.