Purpose Structural and compositional heterogeneity within drusen comprising lipids, carbohydrates, and proteins have been previously described. We sought to detect and define phenotypic patterns of drusen heterogeneity in the form of optical coherence tomography–reflective drusen substructures (ODS) and examine their associations with age-related macular degeneration (AMD)–related features and AMD progression. Design Retrospective analysis in a prospective study. Participants Patients with intermediate AMD (n = 349) enrolled in the multicenter Age-Related Eye Disease Study 2 (AREDS2) ancillary spectral-domain optical coherence tomography (SD OCT) study. Methods Baseline SD OCT scans of 1 eye per patient were analyzed for the presence of ODS. Cross-sectional and longitudinal associations of ODS presence with AMD-related features visible on SD OCT and color photographs, including drusen volume, geographic atrophy (GA), and preatrophic features, were evaluated for the entire macular region. Similar associations were also made locally within a 0.5-mm-diameter region around individual ODS and corresponding control region without ODS in the same eye. Main Outcome Measures Preatrophy SD OCT changes and GA, central GA, and choroidal neovascularization (CNV) from color photographs. Results Four phenotypic subtypes of ODS were defined: low reflective cores, high reflective cores, conical debris, and split drusen. Among the 349 participants, there were 307 eligible eyes and 74 (24%) had at least 1 ODS. The ODS at baseline were associated with (1) greater macular drusen volume at baseline (P < 0.001), (2) development of preatrophic changes at year 2 (P = 0.001–0.01), and (3) development of macular GA (P = 0.005) and preatrophic changes at year 3 (P = 0.002–0.008), but not development of CNV. The ODS at baseline in a local region were associated with (1) presence of preatrophy changes at baseline (P = 0.02–0.03) and (2) development of preatrophy changes at years 2 and 3 within the region (P = 0.008–0.05). Conclusions Optical coherence tomography–reflective drusen substructures are optical coherence tomography–based biomarkers of progression to GA, but not to CNV, in eyes with intermediate AMD. Optical coherence tomography–reflective drusen substructures may be a clinical entity helpful in monitoring AMD progression and informing mechanisms in GA pathogenesis.

IMPORTANCE: Measurable competence derived from comprehensive and advanced training in grading digital images is critical in studies using a reading center to evaluate retinal fundus images from infants at risk for retinopathy of prematurity (ROP). Details of certification for nonphysician trained readers (TRs) have not yet been described. OBJECTIVE: To describe a centralized system for grading ROP digital images by TRs in the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity (e-ROP) Study. DESIGN, SETTING, AND PARTICIPANTS: Multicenter observational cohort study conducted from July 1, 2010, to June 30, 2014. The TRs were trained by experienced ROP specialists and certified to detect ROP morphology in digital retinal images under supervision of an ophthalmologist reading center director. An ROP reading center was developed with standard hardware, secure Internet access, and customized image viewing software with an electronic grading form. A detailed protocol for grading was developed. Based on results of TR gradings, a computerized algorithm determined whether referral-warranted ROP (RW-ROP; defined as presence of plus disease, zone I ROP, and stage 3 or worse ROP) was present in digital images from infants with birth weight less than 1251 g enrolled from May 25, 2011, through October 31, 2013. Independent double grading was done by the TRs with adjudication of discrepant fields performed by the reading center director. EXPOSURE Digital retinal images. MAIN OUTCOMES AND MEASURES: Intragrader and intergrader variability and monitoring for temporal drift. RESULTS: Four TRs underwent rigorous training and certification. A total of 5520 image sets were double graded, with 24.5%requiring adjudication for at least 1 component of RW-ROP. For individual RW-ROP components, the adjudication rate was 3.9%for plus disease, 12.4% for zone I ROP, and 16.9%for stage 3 or worse ROP. The weighted κ for intergrader agreement (n = 80 image sets) was 0.72 (95%CI, 0.52-0.93) for RW-ROP, 0.57 (95%CI, 0.37-0.77) for plus disease, 0.43 (95%CI, 0.24-0.63) for zone I ROP, and 0.67 (95%CI, 0.47-0.88) for stage 3 or worse ROP. The weighted κ for grade-regrade agreement was 0.77 (95%CI, 0.57-0.97) for RW-ROP, 0.87 (95%CI, 0.67-1.00) for plus disease, 0.70 (95%CI, 0.51-0.90) for zone I ROP, and 0.77 (95%CI, 0.57-0.97) for stage 3 or worse ROP. CONCLUSIONS AND RELEVANCE: These data suggest that the e-ROP system for training and certifying nonphysicians to grade ROP images under the supervision of a reading center director reliably detects potentially serious ROP with good intragrader and intergrader consistency and minimal temporal drift.

Objective: To describe presenting clinical features and surgical techniques that are associated with successful surgical repair of pediatric rhegmatogenous retinal detachment (RRD). Design: Retrospective interventional case series. Subjects: 212 eyes of 191 patients, aged 0–18 years, undergoing surgical repair for RRD between 2001 and 2015 with a minimum follow up of 3 months. Methods: Patients were divided into three age groups (0–6 years, 7–12 years, 13–18 years) and comparisons were made using bivariate and multivariable generalized estimating equation models. A mixed means model was used to examine visual acuity in each age group over time. Main Outcome Measures: Complete reattachment of the retina at final follow up. Results: Of a total of 212 eyes, 166 (78%) achieved total reattachment at final follow up. Mean follow up was 36.3 months. RRD associated with Stickler syndrome was more likely to occur in the younger cohorts (odds ratio [OR] 0.45, 95 % confidence interval [CI] 0.22 – 0.91), while RRD associated with blunt trauma was more likely to occur in the oldest cohort (OR 2.3, 95% CI 1.2–4.4). Subtotal RRD was more likely to be successfully repaired than total RRD (OR 3.6, 95% CI 1.5 – 8.4, p = 0.0100), and eyes with previous vitreoretinal surgery were less likely to have successful repair (OR 0.30, 95% CI 0.12 – 0.78, p = 0.0258). There was no significant difference between age groups in the rate of surgical success (p = 0.55). There was a significantly higher success rate with primary scleral buckle (SB) (63%, OR 2.2, 95% CI 1.1–4.5) and combined scleral buckle/vitrectomy (SB/PPV) (68%, OR 2.3 95% CI 1.1–5.1) compared to vitrectomy (PPV) alone (51%). Conclusions: Most pediatric patients with RRD achieved complete reattachment with surgery. Success was more common in patients with a subtotal RRD at presentation. Previous vitreoretinal surgery was a risk factor for failure. Younger patients were more likely to present with RRD involving the macula but there was no difference between age groups in successful reattachment at final follow up. Primary PPV had a lower rate of success than SB or combined SB/PPV.

With fewer than 100 peer-reviewed cases reported in the world to date, the underlying etiology of torpedo maculopathy has remained elusive. In this literature review, we provide new evidence to better support, reject and unify claims regarding cause, diagnosis, and proper clinical management of this disease. We reviewed 44 case reports and case series, which included 77 patients (after exclusions). We additionally introduced 3 new cases from our clinical practice for a total of 80 cases. Ages at presentation ranged from 6 months old to 73 years old (mean: 24.2 years old). The nasal aspects of torpedo maculopathy lesions pointed toward the optic disc and localized to a kite-shaped region of the temporal macula, correlating with the anatomic junction of the superior arcuate, inferior arcuate, and papillomacular bundles of retinal nerve fiber layer distribution. No patterns were observed among the temporal aspects of the lesions. These findings support a congenital etiology of torpedo maculopathy and a possible influence of the retinal nerve fiber layer in the development of mature retinal pigment epithelium.

Purpose: To evaluate the prevalence of retinal disease on fluorescein angiography (FA) in patients with incontinentia pigmenti (IP) and to compare the severity of retinal disease in those with and without known central nervous system (CNS) disease. Design: Multi-institutional consecutive retrospective case series. Subjects: New patients with a diagnosis of IP were seen at the Casey Eye Institute at the Oregon Health and Science University (OHSU), Moran Eye Center, University of Utah, or Bascom Palmer Eye Institute, University of Miami from December 2011 to September 2018. Methods: Detailed ophthalmoscopic examination and FA were recommended for all new patients and performed on every patient who had parental consent. Ophthalmoscopic findings and FA images were graded for severity by 2 masked graders on a 3-point scale: 0 = no disease, 1 = vascular abnormalities without leakage, 2 = leakage or neovascularization, and 3 = retinal detachment. The presence of known CNS disease was documented. Additional cases were obtained from a pediatric retina listserv for examples of phenotypic variation. Main Outcome Measures: The proportion of eyes noted to have disease on ophthalmoscopy compared with FA and the severity of retinal disease in those with and without known CNS disease. Results: Retinal pathology was detected in 18 of 35 patients (51%) by indirect ophthalmoscopy and 26 of 35 patients (74%) by FA (P = 0.048) in a predominantly pediatric population (median age, 9 months). Ten patients (29%) had known CNS disease at the time of the eye examination. A Wilcoxon rank-sum test indicated that the retinal severity scores for patients with CNS disease (median, 2) were significantly higher than the retinal severity scores for patients without CNS disease (median, 1), z = -2.12, P = 0.034. Conclusions: Retinal disease is present in the majority of patients with IP, and ophthalmoscopic examination is less sensitive than FA for detection of disease. There may be a correlation between the severity of retinal and CNS disease.

Morbidity and mortality associated with retinoblastoma have decreased drastically in recent decades, in large part owing to better prediction of high-risk disease and appropriate treatment stratification. High-risk histopathologic features and severe anaplasia both predict the need for more aggressive treatment; however, not all centers are able to assess tumor samples easily for the degree of anaplasia. Instead, identification of genetic signatures that are able to distinguish among anaplastic grades and thus predict high- versus low-risk retinoblastoma would facilitate appropriate risk stratification in a wider patient population. A better understanding of genes dysregulated in anaplasia also would yield valuable insights into pathways underlying the development of more severe retinoblastoma. Here, we present the histopathologic and gene expression analysis of 28 retinoblastoma cases using microarray analysis. Tumors of differing anaplastic grade show clear differential gene expression, with significant dysregulation of unique genes and pathways in severe anaplasia. Photoreceptor and nucleoporin expression in particular are identified as highly dysregulated in severe anaplasia and suggest particular cellular processes contributing to the development of increased retinoblastoma severity. A limited set of highly differentially expressed genes also are able to predict severe anaplasia accurately in our data set. Together, these data contribute to the understanding of the development of anaplasia and facilitate the identification of genetic markers of high-risk retinoblastoma.

Purpose: Retinoblastoma (RB) is most often diagnosed with clinical features and not diagnosed with tumor biopsy. This study describes tumor-derived analyte concentrations from aqueous humor (AH) liquid biopsy and its use in clinical assays. Design: Case series study. Participants: Sixty-two RB eyes from 55 children and 14 control eyes from 12 children from 4 medical centers. Methods: This study included 128 RB AH samples including: diagnostic (DX) samples, samples from eyes undergoing treatment (TX), samples after completing treatment (END), and during bevacizumab injection for radiation therapy after completing RB treatment (BEV). Fourteen-control AH were analyzed for unprocessed analytes (double-stranded DNA [dsDNA], single-stranded DNA [ssDNA], micro-RNA [miRNA], RNA, and protein) with Qubit fluorescence assays. Double-stranded DNA from 2 RB AH samples underwent low-pass whole-genome sequencing to detect somatic copy number alterations. Logistic regression was used to predict disease burden given analyte concentrations. Main Outcome Measures: Unprocessed analyte (dsDNA, ssDNA, miRNA, RNA and protein) concentrations. Results: Results revealed dsDNA, ssDNA, miRNA, and proteins, but not RNA, were quantifiable in most samples (up to 98%) with Qubit fluorescence assays. Median dsDNA concentration was significantly higher in DX (3.08 ng/μl) compared to TX (0.18 ng/μl; P < 0.0001) at an order of 17 times greater and 20 times greater than END samples (0.15 ng/μl; P = 0.001). Using logistic regression, nucleic acid concentrations were useful in predicting higher versus lower RB disease burden. Retinoblastoma somatic copy number alterations were identified in a TX, but not in a BEV sample, indicating the correlation with RB activity. Conclusions: Aqueous humor liquid biopsy in RB is a high-yield source of dsDNA, ssDNA, miRNA, and protein. Diagnostic samples are most useful for RB 1 gene mutational analyses. Genomic analysis may be more informative of tumor activity status than quantification alone and can be performed even with smaller analyte concentrations obtained from TX samples. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

Purpose: To report results of aflibercept therapy in eyes with neovascular age-related macular degeneration previously treated with bevacizumab, ranibizumab, or both. Design: Retrospective, interventional, noncomparative, consecutive case series. Methods: Ninety-six eyes from 85 patients with neovascular age-related macular degeneration who previously had received bevacizumab, ranibizumab, or both were treated with aflibercept monthly for 3 months followed by a fourth injection within 2 months. Outcomes were determined 4 ± 1 months after the first aflibercept dose and included: proportion of patients gaining or losing 2 lines or more of best-corrected visual acuity, proportion remaining within a gain or loss of 1 line, mean change in logarithm of the minimal angle of resolution visual acuity, mean change in central foveal thickness, mean change in macular cube volume, and qualitative anatomic response as assessed by spectral-domain optical coherence tomography. Results: At baseline, 82 (85%) eyes had signs of active exudation despite a mean of 17 previous anti-vascular endothelial growth factor injections. At final visit, 82 (85%) remained stable within a gain or loss of 1 line, 7 (7%) gained 2 lines or more, and 7 (7%) lost 2 lines or more of best-corrected visual acuity. Mean logarithm of the minimal angle of resolution visual acuity showed minimal change 0.02 (range, -0.46 to 0.70; P =.14). Mean central foveal thickness decreased -18 μm (range, -242 to 198 μm; P =.06). Mean macular volume decreased -0.27 mm3 (95% confidence interval, -0.4 to -0.1 mm3; P =.004). On qualitative analysis, 4 (5%) eyes had complete resolution of exudative fluid, 40 (49%) showed partial resolution, 26 (32%) remained unchanged, and 12 (14%) showed worsened exudative fluid. Conclusions: Aflibercept seems to be an effective alternative for neovascular age-related macular degeneration patients previously treated with bevacizumab, ranibizumab, or both at 4 months of follow-up. Most treated eyes demonstrated stable visual acuity and anatomic improvements by spectral-domain optical coherence tomography.

A 4-week-old boy with subependymal lesions consistent with tuberous sclerosis was evaluated for a large intraocular tumor in the left eye. The eye was enuclated and examination showed a retinal giant cell astrocytoma composed of giant, round cells and spindle-shaped cells, with associated aggregates of mononuclear inflammatory cells.

Purpose of review The surgical management of ROP continues to employ a paradigm of peripheral laser followed by vitrectomy for patients who develop retinal detachment. This review addresses significant advances that have been made in our understanding of the indications, timing, techniques, and outcomes of these interventions. Recent findings The indications for laser are highly dependent upon the diagnosis of plus disease. Recognition of plus disease is variable and subjective. Efforts are underway to develop more objective measures of plus using image analysis software. Intravitreal injection of bevacizumab is emerging as an adjunct to laser for aggressive posterior ROP. While vitrectomy for retinal detachment is effective in eyes without plus, management of eyes with retinal detachment and persistent plus continues to be a major challenge. Older children with regressed ROP may suffer from vitreous hemorrhage in the absence of retinal tears, detachments, or active neovascularization. Summary Our understanding of the best indications, timing and techniques for the surgical management of ROP continues to evolve and outcomes have improved in recent years. Areas that generate significant ongoing interest and investigation include the assessment of plus disease and the use of adjuncts for aggressive posterior ROP.