Causes of Childhood Blindness in the United States Using the IRIS® Registry (Intelligent Research in Sight).

PURPOSE: To investigate causes of childhood blindness in the United States using the IRIS® Registry (Intelligent Research in Sight). DESIGN: Cross-sectional study. PARTICIPANTS: Patients ≤ 18 years of age with visual acuity (VA) 20/200 or worse in their better-seeing eye in the IRIS Registry during 2018. METHODS: Causes of blindness were classified by anatomic site and specific diagnoses. MAIN OUTCOME MEASURES: Percentages of causes of blindness. RESULTS: Of 81 164 children with 2018 VA data in the IRIS Registry, 961 (1.18%) had VA 20/200 or worse in their better-seeing eye. Leading causes of blindness were retinopathy of prematurity (ROP) in 301 patients (31.3%), nystagmus in 78 patients (8.1%), and cataract in 64 patients (6.7%). The retina was the leading anatomic site (47.7%) followed by optic nerve (11.6%) and lens (10.0%). A total of 52.4% of patients had treatable causes of blindness. CONCLUSIONS: This analysis offers a unique cross-sectional view of childhood blindness in the United States using a clinical data registry. More than one-half of blind patients had a treatable cause of blindness. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Artificial Intelligence for Retinopathy of Prematurity: Validation of a Vascular Severity Scale against International Expert Diagnosis.

PURPOSE: To validate a vascular severity score as an appropriate output for artificial intelligence (AI) Software as a Medical Device (SaMD) for retinopathy of prematurity (ROP) through comparison with ordinal disease severity labels for stage and plus disease assigned by the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), committee. DESIGN: Validation study of an AI-based ROP vascular severity score. PARTICIPANTS: A total of 34 ROP experts from the ICROP3 committee. METHODS: Two separate datasets of 30 fundus photographs each for stage (0-5) and plus disease (plus, preplus, neither) were labeled by members of the ICROP3 committee using an open-source platform. Averaging these results produced a continuous label for plus (1-9) and stage (1-3) for each image. Experts were also asked to compare each image to each other in terms of relative severity for plus disease. Each image was also labeled with a vascular severity score from the Imaging and Informatics in ROP deep learning system, which was compared with each grader's diagnostic labels for correlation, as well as the ophthalmoscopic diagnosis of stage. MAIN OUTCOME MEASURES: Weighted kappa and Pearson correlation coefficients (CCs) were calculated between each pair of grader classification labels for stage and plus disease. The Elo algorithm was also used to convert pairwise comparisons for each expert into an ordered set of images from least to most severe. RESULTS: The mean weighted kappa and CC for all interobserver pairs for plus disease image comparison were 0.67 and 0.88, respectively. The vascular severity score was found to be highly correlated with both the average plus disease classification (CC = 0.90, P < 0.001) and the ophthalmoscopic diagnosis of stage (P < 0.001 by analysis of variance) among all experts. CONCLUSIONS: The ROP vascular severity score correlates well with the International Classification of Retinopathy of Prematurity committee member's labels for plus disease and stage, which had significant intergrader variability. Generation of a consensus for a validated scoring system for ROP SaMD can facilitate global innovation and regulatory authorization of these technologies.

Effect of Intravitreal Aflibercept vs Laser Photocoagulation on Treatment Success of Retinopathy of Prematurity: The FIREFLEYE Randomized Clinical Trial.

Importance: Laser photocoagulation, which is the standard treatment for retinopathy of prematurity (ROP), can have adverse events. Studies of anti-vascular endothelial growth factor injections have suggested efficacy in the treatment of ROP, but few studies have directly compared them with laser treatments. Objective: To compare intravitreal aflibercept vs laser photocoagulation in infants with ROP requiring treatment. Design, Setting, and Participants: This noninferiority, phase 3, 24-week, randomized clinical trial was conducted in 27 countries (64 hospital sites) throughout Asia, Europe, and South America. Overall, 118 infants (gestational age ≤32 weeks at birth or birth weight ≤1500 g) with ROP severity (zone I stage 1+ [stage 1 plus increased disease activity], zone I stage 2+, zone I stage 3, zone I stage 3+, zone II stage 2+, or zone II stage 3+) requiring treatment or with aggressive posterior ROP in at least 1 eye were enrolled between September 25, 2019, and August 28, 2020 (the last visit occurred on February 12, 2021). Interventions: Infants were randomized 2:1 to receive a 0.4-mg dose of intravitreal aflibercept (n = 75) or laser photocoagulation (n = 43) at baseline. Additional treatment was allowed as prespecified. Main Outcomes and Measures: The primary outcome was the proportion of infants without active ROP and unfavorable structural outcomes 24 weeks after starting treatment (assessed by investigators). The requirement for rescue treatment was considered treatment failure. Intravitreal aflibercept was deemed noninferior if the lower limit of the 1-sided 95% bayesian credible interval for the treatment difference was greater than -5%. Results: Among 118 infants randomized, 113 were treated (mean gestational age, 26.3 [SD, 1.9] weeks; 53 [46.9%] were female; 16.8% had aggressive posterior ROP, 19.5% had zone I ROP, and 63.7% had zone II ROP) and 104 completed the study. Treatment (intravitreal aflibercept: n = 75; laser photocoagulation: n = 38) was mostly bilateral (92.9%), and 82.2% of eyes in the intravitreal aflibercept group received 1 injection per eye. Treatment success was 85.5% with intravitreal aflibercept vs 82.1% with laser photocoagulation (between-group difference, 3.4% [1-sided 95% credible interval, -8.0% to ∞]). Rescue treatment was required in 4.8% (95% CI, 1.9% to 9.6%) of eyes in the intravitreal aflibercept group vs 11.1% (95% CI, 4.9% to 20.7%) of eyes in the laser photocoagulation group. The serious adverse event rates were 13.3% (ocular) and 24.0% (systemic) in the intravitreal aflibercept group compared with 7.9% and 36.8%, respectively, in the laser photocoagulation group. Three deaths, which occurred 4 to 9 weeks after intravitreal aflibercept treatment, were considered unrelated to aflibercept by the investigators. Conclusions and Relevance: Among infants with ROP, intravitreal aflibercept compared with laser photocoagulation did not meet criteria for noninferiority with respect to the primary outcome of the proportion of infants achieving treatment success at week 24. Further data would be required for more definitive conclusions regarding the comparative effects of intravitreal aflibercept and laser photocoagulation in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT04004208.

Pentosan Polysulfate Sodium Exposure and Drug-Induced Maculopathy in Commercially Insured Patients in the United States.

PURPOSE: To determine the association and cumulative dose-response pattern between pentosan polysulfate sodium (PPS) use for interstitial cystitis (IC) and maculopathy. DESIGN: Large, multicenter, retrospective cohort study of commercially insured patients in the MarketScan database (Truven Health Analytics, San Jose, CA). PARTICIPANTS: Two hundred twenty-seven thousand three hundred twenty-five patients with IC who were enrolled continuously in the MarketScan database. METHODS: Cox proportional hazards models (controlling for patient gender, age at index diagnosis of IC, and diagnosis with diabetes mellitus) followed up patients from index diagnosis of IC for 5 years, or until patients discontinued insurance coverage, or until patients' first diagnosis with a maculopathy. As a sensitivity analysis, we re-estimate all models after excluding all patients with diabetes. To assess for dose response, we calculated the total days of PPS prescriptions filled and created a categorical variable indicating total exposure. MAIN OUTCOME MEASURES: The primary outcome measure was association between binary PPS exposure and any maculopathy. Secondary outcome measures included exposure between binary and categorical, time-dependent, exposure to PPS and to drusen, nonexudative age-related macular degeneration (AMD), exudative AMD, hereditary maculopathy, and toxic maculopathy. RESULTS: The most common diagnoses of maculopathy in patients with IC were exudative AMD (1.5%), drusen (0.8%), nonexudative AMD (0.3%), toxic maculopathy (0.1%), and hereditary dystrophy (0.04%). In unadjusted analyses, the percentage of patients who filled a PPS prescription and were diagnosed later with a maculopathy (2.37%) was very similar to the percentage of patients who did not fill a prescription (2.77%). Survival models using a binary variable indicating PPS exposure showed no significant associations between PPS exposure and diagnosis of drusen, nonexudative AMD, exudative AMD, toxic maculopathy, hereditary dystrophy, or an aggregate variable of any maculopathy. Similarly, there was no dose-dependent relationship between PPS exposure and diagnosis of any maculopathy. These findings remained stable in sensitivity analysis models that excluded patients with diabetes mellitus. CONCLUSIONS: In this large, commercial claims database analysis, no association was found between PPS exposure and subsequent diagnosis of maculopathy.

Top five legal pitfalls in retinopathy of prematurity.

PURPOSE OF REVIEW: This review highlights the common areas of medicolegal risk during retinopathy of prematurity (ROP) screening. RECENT FINDINGS: Most malpractice risk in ROP comes from systemic errors that ultimately result in failure to screen the patient in a timely fashion, resulting in failures to intervene and/or refer in a timely fashion. Currently, the emphasis is engaging the family members, the hospital staff, and clinic staff to pro-actively manage ROP patients and ensure that they are screened in a timely fashion. Coordinating care between multiple caregivers can minimize risk. Risk increases when practitioners do not stay up to date on current screening and treatment guidelines or on the most recent study recommendations. Finally, it is important to maintain a high level of suspicion when dealing with infants is known to be predisposed to poor outcomes. SUMMARY: Premature infants with short gestation and very low birthweights need to have structured screening coordinated between the hospital, the clinic, the physicians, and the family in order to minimize medicolegal risk and maximize beneficial outcomes.

A novel classification of high myopia into anterior and posterior pathologic subtypes.

PURPOSE: High myopia and pathologic myopia are common causes of visual morbidity. Myopic pathology can affect all regions of the retina, though there is currently no classification system to distinguish anterior (peripheral) and posterior (macular) pathology. We hypothesize that these classifications are characterized by distinct demographic and refractive features, highlighting the disparity in types of pathologic myopia. METHODS: Institutional retrospective cohort study. The Stanford University Medical Center Clinical Data Warehouse was used to identify patients with high myopia by ICD-9 and ICD-10 codes. Predetermined ICD diagnoses were then used to classify patients with high myopia into isolated high myopia (IHM), anterior pathologic myopia (APM), posterior pathologic myopia (PPM), and combined pathologic myopia (CPM). A cohort of this population was then manually reviewed to gather refractive data and confirm accuracy of ICD coding. RESULTS: Patients (3274) were identified with high myopia. Overall, 22.1% individuals met criteria for APM, 10.7% for PPM, 17.0% for CPM, and 50.2% for IHM. We identified a significantly higher frequency of females with PPM compared to APM (62.3 vs. 48.3%; OR, 1.73; 95% CI, 1.34 to 2.25), Asian patients with PPM as compared to APM (42.9 vs. 33.3%; OR, 1.50; 95% CI, 1.16 to 1.95), and younger patients with APM compared to PPM (median 45.3 vs. 63.4 years). The refractive error was significantly more myopic in the CPM (median - 9.8D; interquartile range, IQR 6.7) and PPM (median - 10.5D; IQR 9.8) subgroups as compared to the APM (median - 8.1D; IQR 3.5), and IHM (median - 8.2D; IQR 4.1) subgroups (p = 0.003). CONCLUSIONS: High myopia may be divided into four distinct subgroups based on presence and location of pathology, which is associated with differences in age, gender, race, and refractive error.

Predictors of treatment-warranted retinopathy of prematurity in the SUNDROP cohort: influence of photographic features.

PURPOSE: The Stanford University Network for the Diagnosis of Retinopathy of Prematurity (SUNDROP) initiative-an ongoing telemedicine-based initiative for in-hospital screening of high-risk infants for treatment-warranted ROP (TW-ROP)-has been shown to be a safe, reliable, and cost-effective supplement to the efforts of ROP specialists. We utilized data collected in the SUNDROP initiative to determine demographic (birth weight, sex, multiplicity), weight gain, and ocular imaging (media haze, peripapillary atrophy, fundus pigmentation) predictors of TW-ROP. METHODS: This was a retrospective nested case-control study. Cases and controls were selected from a cohort of 843 low birth weight, premature newborns who survived to an estimated gestational age of 31 weeks and underwent screening through the SUNDROP initiative. Infants were screened at one of six neonatal intensive care units from December 1, 2005, to April 1, 2016. Cases (n = 37) were newborns with TW-ROP who underwent retinal ablative therapy. Two controls (n = 74) without TW-ROP were matched to each case by gestational age. One reviewer graded media haze, presence of peripapillary atrophy, and fundus pigmentation in images taken at the baseline exam for each newborn. The main outcome measure was association of TW-ROP with predictive factors. RESULTS: In the SUNDROP trial, 37 out of 843 (4.4%) newborns developed TW-ROP. In a multivariable model, birth weight (OR, 0.32; 95% CI, 0.15-0.70) was inversely associated with TW-ROP. In contrast to prior reports, we found no significant difference in sex, multiplicity, or fundus pigmentation at baseline exam in those with TW-ROP as compared to controls. High levels of media haze (>2, scale 0 to 5) were found in the majority of cases (67.6%, 25/37) and controls (65.7%, 44/67). Presence of peripapillary atrophy did not improve prediction of the development of TW-ROP compared to birth weight and weight gain rate alone. CONCLUSIONS: The finding of high levels of media haze at baseline ROP screening exams is novel. This study supports the current model for detection of TW-ROP using birth weight, gestational age, and weight gain rate. We found no significant difference between newborns with TW-ROP and controls in baseline presence of media haze, fundus pigmentation or peripapillary atrophy.

NONDAMAGING RETINAL LASER THERAPY FOR TREATMENT OF CENTRAL SEROUS CHORIORETINOPATHY: What is the Evidence?

PURPOSE: To summarize the literature addressing subthreshold or nondamaging retinal laser therapy (NRT) for central serous chorioretinopathy (CSCR) and to discuss results and trends that provoke further investigation. METHODS: Analysis of current literature evaluating NRT with micropulse or continuous wave lasers for CSCR. RESULTS: Sixteen studies including 398 patients consisted of retrospective case series, prospective nonrandomized interventional case series, and prospective randomized clinical trials. All studies but one evaluated chronic CSCR, and laser parameters varied greatly between studies. Mean central macular thickness decreased, on average, by ∼80 µm by 3 months. Mean best-corrected visual acuity increased, on average, by about 9 letters by 3 months, and no study reported a decrease in acuity below presentation. No retinal complications were observed with the various forms of NRT used, but six patients in two studies with micropulse laser experienced pigmentary changes in the retinal pigment epithelium attributed to excessive laser settings. CONCLUSION: Based on the current evidence, NRT demonstrates efficacy and safety in 12-month follow-up in patients with chronic and possibly acute CSCR. The NRT would benefit from better standardization of the laser settings and understanding of mechanisms of action, as well as further prospective randomized clinical trials.

Chronic Vascular Arrest as a Predictor of Bevacizumab Treatment Failure in Retinopathy of Prematurity.

PURPOSE: To describe a pattern of retinopathy of prematurity (ROP) disease regression and chronic vascular arrest after intravitreal bevacizumab treatment that is not observed after peripheral laser ablation. DESIGN: Single-institution retrospective cohort study. PARTICIPANTS: Consecutive sample of 58 eyes in 30 patients treated for type 1 ROP. METHODS: Initial treatment with either a single intravitreal injection of bevacizumab in off-label use (n = 33 eyes) or peripheral laser ablation (n = 25 eyes) as part of standard clinical care. There was bias in recommending off-label bevacizumab for smaller infants with type 1 ROP. MAIN OUTCOME AND MEASURES: Reactivation or persistence of ROP, as determined by clinical examination, fundus photography, and fluorescein angiography. RESULTS: All eyes treated initially with bevacizumab demonstrated irregular progression of the leading vascular edge in a stereotyped pattern, suggestive of scalloped regression. Recurrence, based on angiographic demonstration of leakage, or chronic vascular arrest, confirmed based on angiographic demonstration of peripheral ischemia, was noted in 30 eyes (91%) in the bevacizumab group, at a median interval of 14.9 weeks after injection (corrected gestational age, 49.3 weeks). Univariate logistic regression indicated that the need for rescue treatment was associated with decreased birth weight (odds ratio [OR], -0.007; P = 0.04) and age of initial treatment (OR, -0.35; P = 0.05), but not gender, race, or gestational age. Multivariate logistic regression indicated that only decreased birth weight (OR, -0.018; P = 0.04) was associated with need for rescue treatment. CONCLUSIONS: Treating ROP with intravitreal bevacizumab results in a characteristic scalloped regression pattern that is highly associated with treatment using biologic anti-vascular endothelial growth factor agents. The presence of this pattern in conjunction with chronic vascular arrest and peripheral retinal ischemia persisting beyond standard screening timelines has significant implications for the management of ROP. Fluorescein angiography is important in assessing vascular maturation in these infants.

Retinal and Optic Nerve Hemorrhages in the Newborn Infant: One-Year Results of the Newborn Eye Screen Test Study.

PURPOSE: To report the birth prevalence, risk factors, characteristics, and location of fundus hemorrhages (FHs) of the retina and optic nerve present in newborns at birth. DESIGN: Prospective cohort study at Stanford University School of Medicine. PARTICIPANTS: All infants who were 37 weeks postmenstrual age or older and stable were eligible for screening. Infants with known or suspected infectious conjunctivitis were excluded. METHODS: Infants born at Lucile Packard Children's Hospital (LPCH) from July 25, 2013, through July 25, 2014, were offered universal newborn screening via wide-angle digital retinal photography in the Newborn Eye Screen Test study. Maternal, obstetric, and neonatal factors were obtained from hospital records. The location, retinal layer, and laterality of FH were recorded by 1 pediatric vitreoretinal specialist. MAIN OUTCOME MEASURES: Birth prevalence of FH. Secondary outcomes included rate of adverse events, risk factors for FH, hemorrhage characteristics, and adverse events. RESULTS: The birth prevalence of FH in this study was 20.3% (41/202 infants). Ninety-five percent of FHs involved the periphery, 83% involved the macula, and 71% involved multiple layers of the retina. The fovea was involved in 15% of FH cases (birth prevalence, 3.0%). No cases of bilateral foveal hemorrhage were found. Fundus hemorrhages were more common in the left eye than the right. Fundus hemorrhages were most commonly optic nerve flame hemorrhages (48%) and white-centered retinal hemorrhages (30%). Retinal hemorrhages were found most frequently in all 4 quadrants (35%) and more often were multiple than solitary. Macular hemorrhages most often were intraretinal (40%). Among the risk factors examined in this study, vaginal delivery compared with cesarean section (odds ratio [OR], 9.34; 95% confidence interval [CI], 2.57-33.97) showed the greatest level of association with FH. Self-identified ethnicity as Hispanic or Latino showed a protective effect (OR, 0.43; 95% CI, 0.20-0.94). Other study factors were not significant. CONCLUSIONS: Fundus hemorrhages are common among newborns. They often involve multiple areas and layers of the retina. Vaginal delivery was associated with a significantly increased risk of FH, whereas self-identified Hispanic or Latino ethnicity was protective against FH in this study. The long-term consequences of FH on visual development remain unknown.

Expanded Spectrum of Congenital Ocular Findings in Microcephaly with Presumed Zika Infection.

PURPOSE: To describe the ocular findings of 3 cases of suspected congenital Zika viral infection with microcephaly and maculopathy. DESIGN: Retrospective, consecutive case series. PARTICIPANTS: Three male infants born in northern Brazil whose mothers demonstrated a viral syndrome during the first trimester and who subsequently were born with microcephaly. METHODS: Observational report of macular findings. MAIN OUTCOME MEASURES: Continued observation. RESULTS: Three male infants were born with microcephaly to mothers who had a viral syndrome during the first trimester of gestation in an area that subsequently has demonstrated epidemic Zika infection, a flavivirus related to Dengue. Ocular examination was performed. All 6 eyes demonstrated a pigmentary maculopathy ranging from mild to pronounced. In 4 eyes, well-delineated macular chorioretinal atrophy with a hyperpigmented ring developed. Three eyes demonstrated vascular tortuosity and 2 eyes demonstrated a pronounced early termination of the retinal vasculature on photographic evaluation. Two eyes demonstrated a washed out peripheral retina with a hypolucent spot. One eye had scattered subretinal hemorrhages external to the macula. Finally, 1 eye demonstrated peripheral pigmentary changes and clustered atrophic lesions resembling grouped congenital albinotic spots (polar bear tracks). CONCLUSIONS: Zika virus has been linked to microcephaly in children of mothers with a viral syndrome during the first trimester of pregnancy. Ocular findings previously described a pigmentary retinopathy and atrophy that now can be expanded to include torpedo maculopathy, vascular changes, and hemorrhagic retinopathy. Ophthalmologic screening guidelines need to be defined to determine which children would benefit from newborn screening in affected regions.

Visual acuity measured with a smartphone app is more accurate than Snellen testing by emergency department providers.

PURPOSE: To assess the accuracy of best-corrected visual acuity (BCVA) measured by non-ophthalmic emergency department (ED) staff with a standard Snellen chart versus an automated application (app) on a handheld smartphone (Paxos Checkup, San Francisco, CA, USA). METHODS: The study included 128 subjects who presented to the Stanford Hospital ED for whom the ED requested an ophthalmology consultation. We conducted the study in two phases. During phase 1 of the study, ED staff tested patient BCVA using a standard Snellen test at 20 feet. During phase 2 of the study, ED staff tested patient near BCVA using the app. During both phases, ophthalmologists measured BCVA with a Rosenbaum near chart, which was treated as the gold standard. ED BCVA measurements were benchmarked prospectively against ophthalmologists' measurements and converted to logMAR. RESULTS: ED logMAR BCVA was 0.21 ± 0.35 (approximately 2 Snellen lines difference ± 3 Snellen lines) higher than that of ophthalmologists when ED staff used a Snellen chart (p = .0.00003). ED BCVA was 0.06 ± 0.40 (less than 1 Snellen line ± 4 Snellen lines) higher when ED staff used the app (p = 0.246). Inter-observer difference was therefore smaller by more than 1 line (0.15 logMAR) with the app (p = 0.046). CONCLUSIONS: BCVA measured by non-ophthalmic ED staff with an app was more accurate than with a Snellen chart. Automated apps may provide a means to standardize and improve the efficiency of ED ophthalmologic care.

AFLIBERCEPT FOR THE TREATMENT OF RETINAL PIGMENT EPITHELIAL DETACHMENTS.

PURPOSE: To compare anatomical and visual acuity outcomes of eyes with persistent pigment epithelial detachments (PEDs) secondary to exudative age-related macular degeneration despite ranibizumab or bevacizumab treatment. METHODS: After institutional review board approval, 40 eyes with PEDs switched from ranibizumab or bevacizumab to intravitreal aflibercept were compared for logMAR visual acuity, central subfield thickness on spectral domain optical coherence tomography, and PED height. Using paired t-tests, these parameters at baseline, after 3 consecutive injections, and 1 year after the switch were compared. RESULTS: Baseline visions of 20/61 ± 3.99 lines declined after 3 injections with aflibercept by 0.39 ± 2.43 lines (P = 0.32) and continued to fall after 1 year by 1.27 ± 3.48 lines (P = 0.03). Central subfield thickness was reduced after 3 injections (9.1 ± 52.0 µm, P = 0.27) and after 1 year (24.4 ± 55.3 µm, P = 0.01). The height of PEDs decreased by 31.7 ± 71.53 µm (P = 0.008) after 3 injections and by 47.81 ± 77.94 µm (P < 0.001) after 1 year. CONCLUSION: Switching to aflibercept from ranibizumab or bevacizumab resulted in a reduction in the height of PED and central subfield thickness, but a trend toward worse visual acuity 1 year after the switch.

Stereotactic radiotherapy for neovascular age-related macular degeneration: year 2 results of the INTREPID study.

PURPOSE: To determine the safety and efficacy of low-voltage, external-beam, stereotactic radiotherapy (SRT) for patients with neovascular age-related macular degeneration (AMD). DESIGN: Randomized, double-masked, sham-controlled, multicenter, clinical trial. PARTICIPANTS: A total of 230 participants with neovascular AMD who received ≥ 3 ranibizumab or bevacizumab injections within the preceding year and requiring treatment at enrollment. METHODS: Participants received 16 Gray, 24 Gray, or sham SRT. All arms received pro re nata (PRN) ranibizumab for 12 months, with PRN bevacizumab or ranibizumab thereafter. MAIN OUTCOME MEASURES: Mean number of PRN injections; best-corrected visual acuity (BCVA); loss of <15 Early Treatment of Diabetic Retinopathy Study letters; change in optical coherence tomography central subfield thickness; and change in angiographic total lesion area and choroidal neovascularization (CNV) area. RESULTS: At year 2, the 16 and 24 Gray arms received fewer PRN treatments compared with sham (mean 4.5, P = 0.008; mean 5.4, P = 0.09; and mean 6.6, respectively). Change in mean BCVA was -10.0, -7.5, and -6.7 letters for the 16 Gray, 24 Gray, and sham arms, respectively, with 46 (68%), 51 (75%), and 58 participants (79%), respectively, losing <15 letters. Mean central subfield thickness decreased by 67.0 µm, 55.4 µm, and 33.3 µm, respectively. Mean total active lesion area increased by 1.0, 4.2, and 2.7 mm(2), respectively. Mean CNV area decreased by 0.1 mm(2) in all groups. An independent reading center detected microvascular abnormalities in 6 control eyes and 29 SRT eyes, of which 18 were attributed to radiation; however, only 2 of these possibly affected vision. An exploratory subgroup analysis found that lesions with a greatest linear dimension ≤ 4 mm (the size of the treatment zone) and a macular volume greater than the median (7.4 mm(3)) were more responsive to SRT, with 3.9 PRN injections versus 7.1 in comparable sham-treated participants (P = 0.001) and mean BCVA 4.4 letters superior to sham (P = 0.24). CONCLUSIONS: A single dose of SRT significantly reduces intravitreal injections over 2 years. Radiation can induce microvascular change, but in only 1% of eyes does this possibly affect vision. The best response occurs when AMD lesions fit within the treatment zone and they are actively leaking.

Stereotactic radiotherapy for wet age-related macular degeneration (INTREPID): influence of baseline characteristics on clinical response.

PURPOSE: To determine which patients respond best to stereotactic radiotherapy (SRT) for neovascular age-related macular degeneration. METHODS: Participants (n = 230) receiving intravitreal anti-vascular endothelial growth factor injections for neovascular age-related macular degeneration enrolled in a randomized, double-masked sham-controlled trial comparing 16 Gray, 24 Gray, or Sham SRT. In a post hoc analysis, participants were grouped according to their baseline characteristics, to determine if these influenced SRT efficacy. RESULTS: At 52 weeks, SRT was most effective for lesions ≤4 mm in greatest linear dimension and with a macular volume greater than the median value of 7.4 mm. For 26% of the participants with both these characteristics, SRT resulted in 55% fewer ranibizumab injections (2.08 vs. 4.60; P = 0.0002), a mean visual acuity change that was 5.33 letters superior to sham (+2.18 vs. -3.15 letters; P = 0.0284), and a 71.1-µm greater reduction in mean central subfield thickness (-122.6 vs. -51.5 µm; P = 0.027). Other features associated with a positive response to SRT included pigment epithelial detachment and the absence of fibrosis. CONCLUSION: Stereotactic radiotherapy is most effective for neovascular age-related macular degeneration lesions that are actively leaking at the time of treatment, and no larger than the 4-mm treatment zone.