J. Peter Campbell

Visualization of 3 Distinct Retinal Plexuses by Projection-Resolved Optical Coherence Tomography Angiography in Diabetic Retinopathy

Importance Projection artifacts in optical coherence tomography angiography (OCTA) blur the retinal vascular plexuses together and limit visualization of the individual plexuses. Objective To describe projection-resolved (PR) OCTA in eyes with diabetic retinopathy (DR) and healthy eyes. Design, Setting, and Participants In this case-control study, patients with DR and healthy controls were enrolled in this observational study from January 26, 2015, to December 4, 2015, at a tertiary academic center. Spectral-domain, 70-kHz OCT obtained 3 × 3-mm macular scans. The PR algorithm suppressed projection artifacts. A semiautomated segmentation algorithm divided PR-OCTA into superficial, intermediate, and deep retinal plexuses. Two masked graders examined 3-layer PR-OCTA and combined angiograms for nonperfusion and abnormal capillaries. Main Outcomes and Measures Retinal nonperfusion and capillary abnormalities and the diagnostic accuracy of detecting DR. Results Twenty-nine eyes of 15 healthy individuals (mean [SD] age, 36.2 [13.4] years; 11 women) and 47 eyes of 29 patients with DR (mean [SD] age, 55.5 [11.9]; 10 women) underwent imaging. PR-OCTA revealed 3 distinct retinal plexuses in their known anatomical locations in all eyes. The intermediate and deep plexuses of healthy eyes revealed capillary networks of uniform density and caliber, whereas the superficial plexus revealed vessels in the familiar centripetal branching pattern. In eyes with DR, 3-layer PR-OCTA disclosed incongruent areas of nonperfusion and varied vessel caliber and density in the deeper plexuses. Masked grading of capillary nonperfusion on 3-layer PR-OCTA detected DR with 100% sensitivity (95% CI, 90.8%-100%) and 100% specificity (95% CI, 85.4%-100%). With unsegmented retinal angiograms, the sensitivity and specificity were 78.7% (95% CI, 63.9%-88.8%) and 100% (95% CI, 85.4%-100%), respectively (P = .002 for sensitivity). On 3-layer PR-OCTA, sensitivity was 72.2% (95% CI, 54.6%-85.2%) for severe nonproliferative DR and proliferative DR eyes with generalized nonperfusion in 2 or more individual plexuses, but on combined angiogram, sensitivity was 25.0% (95% CI, 12.7%-42.5%) for generalized nonperfusion (P < .001). PR-OCTA disclosed dilated vessels in the intermediate and deep plexuses in 23 eyes (100%) with proliferative DR, 13 eyes (100%) with severe nonproliferative DR, 8 eyes (73%) with mild to moderate nonproliferative DR, and 0 control eyes. Conclusions and Relevance By presenting 3 retinal vascular plexuses distinctly, PR-OCTA reveals capillary abnormalities in deeper layers with clarity and may distinguish DR from healthy eyes and severe DR from mild DR with greater accuracy compared with conventional OCTA.

Injection frequency and anatomic outcomes 1 year following conversion to aflibercept in patients with neovascular age-related macular degeneration

Background/Aim To evaluate the clinical, anatomic and functional effects of conversion to aflibercept following ranibizumab and/or bevacizumab in patients with neovascular age-related macular degeneration (AMD). Methods A retrospective review of patients with neovascular AMD treated with intravitreal ranibizumab and/or bevacizumab who were switched to aflibercept was performed. The primary outcome was change in injection frequency in the year following the change. Secondary outcomes included change in central macular thickness (CMT) at 6 months and 1 year, presence of intraretinal and subretinal fluid at 6 months and visual acuity at 1 year. Results A total of 109 eyes with neovascular AMD were switched to aflibercept and met inclusion criteria. Overall, aflibercept injection frequency was unchanged with patients receiving 7.4 antivascular endothelial growth factor (VEGF) injections the year prior to conversion compared with 7.2 aflibercept injections in the year following (p=0.47). However, the change to aflibercept was associated with improvement in CMT from 324 to 295 μm (p=0.0001) at 6 months and 299 μm (p=0.0047) at 1 year. There was no effect on visual acuity at 1 year. In a subgroup analysis, patients who had received ≥10 anti-VEGF injections in the year prior had fewer injections (11.1 to 8.4, p<0.0001) and clinic visits (13.9 to 9.6, p<0.0001) as well as a significant decrease in CMT (−35 μm, p=0.02). Conclusions In our population, switching to aflibercept therapy was not associated with a change in injection frequency nor improved visual acuity, but was associated with improved CMT at 6 months and 1 year. In patients who received at least 10 anti-VEGF injections in the year prior, transitioning to aflibercept was associated with a reduced injection frequency and CMT, suggesting potential cost savings in this population.

Expert Diagnosis of Plus Disease in Retinopathy of Prematurity From Computer-Based Image Analysis

IMPORTANCE Published definitions of plus disease in retinopathy of prematurity (ROP) reference arterial tortuosity and venous dilation within the posterior pole based on a standard published photograph. One possible explanation for limited interexpert reliability for a diagnosis of plus disease is that experts deviate from the published definitions. OBJECTIVE To identify vascular features used by experts for diagnosis of plus disease through quantitative image analysis. DESIGN, SETTING, AND PARTICIPANTS A computer-based image analysis system (Imaging and Informatics in ROP [i-ROP]) was developed using a set of 77 digital fundus images, and the system was designed to classify images compared with a reference standard diagnosis (RSD). System performance was analyzed as a function of the field of view (circular crops with a radius of 1-6 disc diameters) and vessel subtype (arteries only, veins only, or all vessels). Routine ROP screening was conducted from June 29, 2011, to October 14, 2014, in neonatal intensive care units at 8 academic institutions, with a subset of 73 images independently classified by 11 ROP experts for validation. The RSD was compared with the majority diagnosis of experts. MAIN OUTCOMES AND MEASURES The primary outcome measure was the percentage of accuracy of the i-ROP system classification of plus disease, with the RSD as a function of the field of view and vessel type. Secondary outcome measures included the accuracy of the 11 experts compared with the RSD. RESULTS Accuracy of plus disease diagnosis by the i-ROP computer-based system was highest (95%; 95% CI, 94%-95%) when it incorporated vascular tortuosity from both arteries and veins and with the widest field of view (6-disc diameter radius). Accuracy was 90% or less when using only arterial tortuosity and 85% or less using a 2- to 3-disc diameter view similar to the standard published photograph. Diagnostic accuracy of the i-ROP system (95%) was comparable to that of 11 expert physicians (mean 87%, range 79%-99%). CONCLUSIONS AND RELEVANCE Experts in ROP appear to consider findings from beyond the posterior retina when diagnosing plus disease and consider tortuosity of both arteries and veins, in contrast with published definitions. It is feasible for a computer-based image analysis system to perform comparably with ROP experts, using manually segmented images.

Diagnostic Discrepancies in Retinopathy of Prematurity Classification

PURPOSE To identify the most common areas for discrepancy in retinopathy of prematurity (ROP) classification between experts. DESIGN Prospective cohort study. PARTICIPANTS A total of 281 infants were identified as part of a multicenter, prospective, ROP cohort study from 7 participating centers. Each site had participating ophthalmologists who provided the clinical classification after routine examination using binocular indirect ophthalmoscopy (BIO) and obtained wide-angle retinal images, which were independently classified by 2 study experts. METHODS Wide-angle retinal images (RetCam; Clarity Medical Systems, Pleasanton, CA) were obtained from study subjects, and 2 experts evaluated each image using a secure web-based module. Image-based classifications for zone, stage, plus disease, and overall disease category (no ROP, mild ROP, type II or pre-plus, and type I) were compared between the 2 experts and with the clinical classification obtained by BIO. MAIN OUTCOME MEASURES Inter-expert image-based agreement and image-based versus ophthalmoscopic diagnostic agreement using absolute agreement and weighted kappa statistic. RESULTS A total of 1553 study eye examinations from 281 infants were included in the study. Experts disagreed on the stage classification in 620 of 1553 comparisons (40%), plus disease classification (including pre-plus) in 287 of 1553 comparisons (18%), zone in 117 of 1553 comparisons (8%), and overall ROP category in 618 of 1553 comparisons (40%). However, agreement for presence versus absence of type 1 disease was >95%. There were no differences between image-based and clinical classification except for zone III disease. CONCLUSIONS The most common area of discrepancy in ROP classification is stage, although inter-expert agreement for clinically significant disease, such as presence versus absence of type 1 and type 2 disease, is high. There were no differences between image-based grading and clinical examination in the ability to detect clinically significant disease. This study provides additional evidence that image-based classification of ROP reliably detects clinically significant levels of ROP with high accuracy compared with the clinical examination.

Pro-Permeability Factors After Dexamethasone Implant in Retinal Vein Occlusion; the Ozurdex for Retinal Vein Occlusion (ORVO) Study

PURPOSE To correlate aqueous vasoactive protein changes with macular edema after dexamethasone implant in retinal vein occlusion (RVO). DESIGN Prospective, interventional case series. METHODS Twenty-three central RVO (CRVO) and 17 branch RVO (BRVO) subjects with edema despite prior anti-vascular endothelial growth factor (VEGF) treatment had aqueous taps at baseline and 4 and 16 weeks after dexamethasone implant. Best-corrected visual acuity (BCVA) and center subfield thickness were measured every 4 weeks. Aqueous vasoactive protein levels were measured by protein array or enzyme-linked immunosorbent assay. RESULTS Thirty-two vasoactive proteins were detected in aqueous in untreated eyes with macular edema due to RVO. Reduction in excess foveal thickness after dexamethasone implant correlated with reduction in persephin and pentraxin 3 (Pearson correlation coefficients = 0.682 and 0.638, P = .014 and P = .003). Other protein changes differed among RVO patients as edema decreased, but ≥50% of patients showed reductions in hepatocyte growth factor, endocrine gland VEGF, insulin-like growth factor binding proteins, or endostatin by ≥30%. Enzyme-linked immunosorbent assay in 18 eyes (12 CRVO, 6 BRVO) showed baseline levels of hepatocyte growth factor and VEGF of 168.2 ± 20.1 pg/mL and 78.7 ± 10.0 pg/mL, and each was reduced in 12 eyes after dexamethasone implant. CONCLUSIONS Dexamethasone implants reduce several pro-permeability proteins providing a multitargeted approach in RVO. No single protein in addition to VEGF can be implicated as a contributor in all patients. Candidates for contribution to chronic edema in subgroups of patients that deserve further study include persephin, hepatocyte growth factor, and endocrine gland VEGF.

Plus Disease in Retinopathy of Prematurity: Improving Diagnosis by Ranking Disease Severity and Using Quantitative Image Analysis.

PURPOSE To determine expert agreement on relative retinopathy of prematurity (ROP) disease severity and whether computer-based image analysis can model relative disease severity, and to propose consideration of a more continuous severity score for ROP. DESIGN We developed 2 databases of clinical images of varying disease severity (100 images and 34 images) as part of the Imaging and Informatics in ROP (i-ROP) cohort study and recruited expert physician, nonexpert physician, and nonphysician graders to classify and perform pairwise comparisons on both databases. PARTICIPANTS Six participating expert ROP clinician-scientists, each with a minimum of 10 years of clinical ROP experience and 5 ROP publications, and 5 image graders (3 physicians and 2 nonphysician graders) who analyzed images that were obtained during routine ROP screening in neonatal intensive care units. METHODS Images in both databases were ranked by average disease classification (classification ranking), by pairwise comparison using the Elo rating method (comparison ranking), and by correlation with the i-ROP computer-based image analysis system. MAIN OUTCOME MEASURES Interexpert agreement (weighted κ statistic) compared with the correlation coefficient (CC) between experts on pairwise comparisons and correlation between expert rankings and computer-based image analysis modeling. RESULTS There was variable interexpert agreement on diagnostic classification of disease (plus, preplus, or normal) among the 6 experts (mean weighted κ, 0.27; range, 0.06-0.63), but good correlation between experts on comparison ranking of disease severity (mean CC, 0.84; range, 0.74-0.93) on the set of 34 images. Comparison ranking provided a severity ranking that was in good agreement with ranking obtained by classification ranking (CC, 0.92). Comparison ranking on the larger dataset by both expert and nonexpert graders demonstrated good correlation (mean CC, 0.97; range, 0.95-0.98). The i-ROP system was able to model this continuous severity with good correlation (CC, 0.86). CONCLUSIONS Experts diagnose plus disease on a continuum, with poor absolute agreement on classification but good relative agreement on disease severity. These results suggest that the use of pairwise rankings and a continuous severity score, such as that provided by the i-ROP system, may improve agreement on disease severity in the future.

Randomized Trial of High Dose Azithromycin Compared to Standard Dosing for Children with Severe Trachoma in Tanzania

Background: Children with a heavy load of C. trachomatis infection may continue to be infected following a single dose of 20 mg/kg of azithromycin. We compared the C. trachomatis infection rates at six weeks post-treatment of children randomized to 30 mg/kg single dose of azithromycin versus 20 mg/kg single dose of azithromycin. Methods: Ninety-nine children with severe trachoma (defined as either trachoma intense or follicular trachoma with ten or more follicles) were enrolled and randomly assigned. Baseline data on age, sex, and trachoma status was obtained, and swabs for determination of C. trachomatis were taken. Dosing was weight-based and observed. Children were followed up at six weeks for trachoma and infection. The laboratory was masked to treatment assignment. Results: Both groups experienced reductions in infection and in severe trachoma. Twelve percent of the 20 mg/kg group were PCR positive at 6 weeks, compared with 69% at baseline, an 82% reduction (p-value < .001). In the 30 mg/kg group, 15% were infected, compared with 62% at baseline, a 76% reduction (p < .001). The rate of infection comparing treatment groups was not significantly different at 6 weeks (p = 0.71). Analyses on children who were infected at baseline showed those remaining positive at six weeks were 18%, and 14% in the standard and high dose groups, respectively. Conclusion: Increasing the single dose of azithromycin to 30 mg/kg in children with severe trachoma did not result in significantly less infection at six weeks post-treatment compared to 20 mg/kg.

Handheld optical coherence tomography angiography

We developed a handheld optical coherence tomography angiography (OCTA) system using a 100-kHz swept-source laser. The handheld probe weighs 0.4 kg and measures 20.6 × 12.8 × 4.6 cm3. The system has dedicated features for handheld operation. The probe is equipped with a mini iris camera for easy alignment. Real-time display of the en face OCT and cross-sectional OCT images in the system allows accurately locating the imaging target. Fast automatic focusing was achieved by an electrically tunable lens controlled by a golden-section search algorithm. An extended axial imaging range of 6 mm allows easy alignment. A registration algorithm using cross-correlation to register adjacent OCT B-frames with propagation from the central frame was used to effectively minimize motion artifacts in volumetric OCTA images captured in relatively short durations of 1 and 2.1 seconds. 2.5 × 2.5 mm (200 × 200 pixels) and 3.5 × 3.5 mm (300 × 300 pixels) retinal angiograms were demonstrated on two awake adult human subjects without the use of any mydriatic eye drops.

Two-Day Dosing versus One-Day Dosing of Azithromycin in Children with Severe Trachoma in Tanzania

Purpose: To determine whether 2-day dosing of azithromycin may improve the efficacy of azithromycin dosing in children with severe trachoma. Methods: Fifty children with severe trachoma (defined as either trachoma intense or follicular trachoma with ten or more follicles) were enrolled from five villages in Kongwa, Tanzania. Enrollment occurred within 1 month and within the same district as the historical control population of 99 children with severe trachoma, all of whom received 1-day dosing. Baseline data on age, sex, and trachoma status were obtained, and swabs for determination of Chlamydia trachomatis were taken. All 50 children received 20 mg/kg azithromycin daily for 2 days, which was directly observed. Children were followed up at 6 weeks for trachoma and infection. The laboratory was masked to treatment assignment. Results: Baseline characteristics were similar between the treatment group and the control group. A total of 1/46 (2.2%) of children in the treatment group were polymerase chain reaction (PCR)-positive at 6 weeks, a 96.3% reduction from baseline, compared to 13/96 (13.5%) in the historical control group, an 89.4% reduction. This difference was statistically significant. However when modeled using logistic regression and accounting for age, gender, weight, and baseline percent PCR positivity, the difference was not significant. Prevalence of clinical trachoma did not differ between the groups at 6 weeks. Conclusion: For children with severe trachoma, a randomized controlled trial of 2-day versus 1-day treatment may be warranted.

Automated Diagnosis of Plus Disease in Retinopathy of Prematurity Using Deep Convolutional Neural Networks

Importance Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide. The decision to treat is primarily based on the presence of plus disease, defined as dilation and tortuosity of retinal vessels. However, clinical diagnosis of plus disease is highly subjective and variable. Objective To implement and validate an algorithm based on deep learning to automatically diagnose plus disease from retinal photographs. Design, Setting, and Participants A deep convolutional neural network was trained using a data set of 5511 retinal photographs. Each image was previously assigned a reference standard diagnosis (RSD) based on consensus of image grading by 3 experts and clinical diagnosis by 1 expert (ie, normal, pre–plus disease, or plus disease). The algorithm was evaluated by 5-fold cross-validation and tested on an independent set of 100 images. Images were collected from 8 academic institutions participating in the Imaging and Informatics in ROP (i-ROP) cohort study. The deep learning algorithm was tested against 8 ROP experts, each of whom had more than 10 years of clinical experience and more than 5 peer-reviewed publications about ROP. Data were collected from July 2011 to December 2016. Data were analyzed from December 2016 to September 2017. Exposures A deep learning algorithm trained on retinal photographs. Main Outcomes and Measures Receiver operating characteristic analysis was performed to evaluate performance of the algorithm against the RSD. Quadratic-weighted &kgr; coefficients were calculated for ternary classification (ie, normal, pre–plus disease, and plus disease) to measure agreement with the RSD and 8 independent experts. Results Of the 5511 included retinal photographs, 4535 (82.3%) were graded as normal, 805 (14.6%) as pre–plus disease, and 172 (3.1%) as plus disease, based on the RSD. Mean (SD) area under the receiver operating characteristic curve statistics were 0.94 (0.01) for the diagnosis of normal (vs pre–plus disease or plus disease) and 0.98 (0.01) for the diagnosis of plus disease (vs normal or pre–plus disease). For diagnosis of plus disease in an independent test set of 100 retinal images, the algorithm achieved a sensitivity of 93% with 94% specificity. For detection of pre–plus disease or worse, the sensitivity and specificity were 100% and 94%, respectively. On the same test set, the algorithm achieved a quadratic-weighted &kgr; coefficient of 0.92 compared with the RSD, outperforming 6 of 8 ROP experts. Conclusions and Relevance This fully automated algorithm diagnosed plus disease in ROP with comparable or better accuracy than human experts. This has potential applications in disease detection, monitoring, and prognosis in infants at risk of ROP.