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Purpose To explore whether phenotypes in geographic atrophy (GA) secondary to age-related macular degeneration can be separated into 2 or more partially distinct subtypes and if these have different genetic associations. This is important because distinct GA subtypes associated with different genetic factors might require customized therapeutic approaches. Design Cluster analysis of participants within a controlled clinical trial, followed by assessment of phenotype–genotype associations. Participants Age-Related Eye Disease Study 2 participants with incident GA during study follow-up: 598 eyes of 598 participants. Methods Phenotypic features from reading center grading of fundus photographs were subjected to cluster analysis, by k-means and hierarchical methods, in cross-sectional analyses (using 15 phenotypic features) and longitudinal analyses (using 14 phenotypic features). The identified clusters were compared by 4 pathway-based genetic risk scores (complement, extracellular matrix, lipid, and ARMS2). The analyses were repeated in reverse (clustering by genotype and comparison by phenotype). Main Outcome Measures Characteristics and quality of cluster solutions, assessed by Calinski-Harabasz scores, unexplained variance, and consistency; and genotype–phenotype associations, assessed by t test. Results In cross-sectional phenotypic analyses, k-means identified 2 clusters (labeled A and B), whereas hierarchical clustering identified 4 clusters (C-F); cluster membership differed principally by GA configuration but in few other ways. In longitudinal phenotypic analyses, k-means identified 2 clusters (G and H) that differed principally by smoking status but in few other ways. These 3 sets of cluster divisions were not similar to each other (r ≤ 0.20). Despite adequate power, pairwise cluster comparison by the 4 genetic risk scores demonstrated no significant differences (P > 0.05 for all). In clustering by genotype, k-means identified 2 clusters (I and J). These differed principally at ARMS2, but no significant genotype–phenotype associations were observed (P > 0.05 for all). Conclusions Phenotypic clustering resulted in GA subtypes defined principally by GA configuration in cross-sectional analyses, but these were not replicated in longitudinal analyses. These negative findings, together with the absence of significant phenotype–genotype associations, indicate that GA phenotypes may vary continuously across a spectrum, rather than consisting of distinct subtypes that arise from separate genetic causes.

BACKGROUND Treatment options for severe ocular von Hippel-Lindau (VHL) disease are limited. This trial evaluated preliminary safety and potential efficacy of combination intravitreous injection with ranibizumab, a vascular endothelial growth factor (VEGF) inhibitor, and E10030, a PDGF inhibitor, for eyes with VHL disease-associated retinal hemangioblastoma (RH) not amenable or responsive to thermal laser photocoagulation. METHODS This was a prospective, single-arm, open-label phase 1/2 study, comprised of three adults with VHL-associated RH and vision loss. Intravitreous injections of ranibizumab (0.5 mg) and E10030 (1.5 mg) were given unilaterally every 4 weeks in the study eye through 16 weeks, then every 8 weeks through 48 weeks. Supplementary standard care therapies were allowed without restriction after 40 weeks. The primary outcome was the ocular and systemic adverse effect profile at 52 weeks. Secondary outcomes included changes in best-corrected visual acuity (BCVA), RH size, exudation, epiretinal proliferation and retinal traction, and need for ablative treatment of RH or ocular surgery at week 52. RESULTS Three participants each received nine injections prior to week 52 and were followed for 104 weeks. One participant manifested mild episodic ocular hypertension in the study eye. Change in BCVA in the study eye at week 52 for the three participants was -5, -12 and +2 letters. No reduction in RH size was measured at 52 weeks. Variable mild improvements in exudation in two participants at week 16 were not sustained through week 52. CONCLUSIONS Combination intravitreous injection with ranibizumab and E10030 demonstrated a reasonable preliminary safety profile, but limited treatment effect.

Purpose To examine whether the rate of geographic atrophy (GA) enlargement is influenced by subsequent exudative neovascular age-related macular degeneration (nAMD) and hence, to explore indirectly whether nonexudative nAMD may slow GA enlargement. Design Post hoc analysis of a controlled clinical trial cohort. Participants Age-Related Eye Disease Study 2 participants 50 to 85 years of age. Methods Baseline and annual stereoscopic color fundus photographs were evaluated for (1) GA presence and area and (2) exudative nAMD presence. Two cohorts were constructed: eyes with GA at study baseline (prevalent cohort) and eyes in which GA developed during follow-up (incident cohort). Mixed-model regression of the square root of GA area was performed according to the presence or absence of subsequent exudative nAMD. Main Outcome Measures Change over time in square root of GA area. Results Of the 757 eyes in the incident GA cohort, over a mean follow-up of 2.3 years (standard deviation [SD], 1.2 years), 73 eyes (9.6%) demonstrated subsequent exudative nAMD. Geographic atrophy enlargement in these eyes was significantly slower (0.20 mm/year; 95% confidence interval [CI], 0.12–0.28 mm/year) compared with the other 684 eyes in which subsequent exudative nAMD did not develop (0.29 mm/year; 95% CI, 0.27–0.30 mm/year; P = 0.037). Of the 456 eyes in the prevalent GA cohort, over a mean follow-up of 4.1 years (SD, 1.4 years), 63 eyes (13.8%) demonstrated subsequent exudative nAMD. Geographic atrophy enlargement in these eyes was similar (0.31 mm/year; 95% CI, 0.24–0.37 mm/year) compared with the other 393 eyes in which subsequent exudative nAMD did not develop (0.28 mm/year; 95% CI, 0.26–0.29 mm/year; P = 0.37). Conclusions In eyes with recent GA, GA enlargement before the development of exudative nAMD seems slowed. This association was not observed in eyes with more long-standing GA, which have larger lesion sizes. Hence, perilesional nonexudative choroidal neovascular tissue (presumably present before the development of clinically apparent exudation) may slow enlargement of smaller GA lesions through improved perfusion. This hypothesis warrants further evaluation in prospective studies.

Purpose To develop deep learning models for detecting reticular pseudodrusen (RPD) using fundus autofluorescence (FAF) images or, alternatively, color fundus photographs (CFP) in the context of age-related macular degeneration (AMD). Design Application of deep learning models to the Age-Related Eye Disease Study 2 (AREDS2) dataset. Participants FAF and CFP images (n = 11 535) from 2450 AREDS2 participants. Gold standard labels from reading center grading of the FAF images were transferred to the corresponding CFP images. Methods A deep learning model was trained to detect RPD in eyes with intermediate to late AMD using FAF images (FAF model). Using label transfer from FAF to CFP images, a deep learning model was trained to detect RPD from CFP (CFP model). Performance was compared with 4 ophthalmologists using a random subset from the full test set. Main Outcome Measures Area under the receiver operating characteristic curve (AUC), κ value, accuracy, and F1 score. Results The FAF model had an AUC of 0.939 (95% confidence interval [CI], 0.927–0.950), a κ value of 0.718 (95% CI, 0.685–0.751), and accuracy of 0.899 (95% CI, 0.887–0.911). The CFP model showed equivalent values of 0.832 (95% CI, 0.812–0.851), 0.470 (95% CI, 0.426–0.511), and 0.809 (95% CI, 0.793–0.825), respectively. The FAF model demonstrated superior performance to 4 ophthalmologists, showing a higher κ value of 0.789 (95% CI, 0.675–0.875) versus a range of 0.367 to 0.756 and higher accuracy of 0.937 (95% CI, 0.907–0.963) versus a range of 0.696 to 0.933. The CFP model demonstrated substantially superior performance to 4 ophthalmologists, showing a higher κ value of 0.471 (95% CI, 0.330–0.606) versus a range of 0.105 to 0.180 and higher accuracy of 0.844 (95% CI, 0.798–0.886) versus a range of 0.717 to 0.814. Conclusions Deep learning-enabled automated detection of RPD presence from FAF images achieved a high level of accuracy, equal or superior to that of ophthalmologists. Automated RPD detection using CFP achieved a lower accuracy that still surpassed that of ophthalmologists. Deep learning models can assist, and even augment, the detection of this clinically important AMD-associated lesion.

Background: Group A β-hemolytic streptococcus (GAS) and Group B streptococcus (GBS) are two common pathogens that are associated with many diseases in children. Severe infections as a result of these two streptococci are albeit uncommon but associated with high mortality and morbidity, and often necessitate intensive care support. This paper aims to review mortality and morbidity severe infection associated with GAS and GBS isolations at a Pediatric Intensive Care Unit (PICU). Methods: All children admitted to PICU of a teaching hospital between October 2002 and May 2018 with laboratory-proven GAS and GBS isolations were included. Results: There were 19 patients (0.7% PICU admissions) with streptococcal isolations (GAS, n=11 and GBS, n=8). Comparing to GAS, GBS affected infants were younger (median age 0.13 versus 5.47 years, 95% CI, 1.7-8.5, p=0.0003), and cerebrospinal fluids more likely positive (p = 0.0181). All GAS and GBS were sensitive to penicillin (CLSI: MICs 0.06 – 2.0 μg/mL), with majority of GAS sensitive to clindamycin and erythromycin, and half of the GBS resistant to clindamycin and erythromycin. Co-infections were prevalent, but viruses were only isolated with GAS (p=0.024). Isolation of GAS and GBS was associated with nearly 40% mortality and high rates of mechanical ventilation and inotropic supports. All non-survivors had high mortality (PIM2) and sepsis scores. Conclusions: Severe GAS and GBS are rare but associated with high mortality and rates of mechanical ventilation and inotropic supports in PICU. The streptococci are invariably sensitive to penicillin. The high PIM2 and Sepsis scores suggest that prompt recognition of sepsis and timely judicious institution of antibiotics and intensive care support may be life-saving for these devastating infections.

Purpose: To assess the utility of deep learning in the detection of geographic atrophy (GA) from color fundus photographs; secondary aim to explore potential utility in detecting central GA (CGA). Design: A deep learning model was developed to detect the presence of GA in color fundus photographs, and two additional models to detect CGA in different scenarios. Participants: 59,812 color fundus photographs from longitudinal follow up of 4,582 participants in the AREDS dataset. Gold standard labels were from human expert reading center graders using a standardized protocol. Methods: A deep learning model was trained to use color fundus photographs to predict GA presence from a population of eyes with no AMD to advanced AMD. A second model was trained to predict CGA presence from the same population. A third model was trained to predict CGA presence from the subset of eyes with GA. For training and testing, 5-fold cross-validation was employed. For comparison with human clinician performance, model performance was compared with that of 88 retinal specialists. Results: The deep learning models (GA detection, CGA detection from all eyes, and centrality detection from GA eyes) had AUC of 0.933-0.976, 0.939-0.976, and 0.827-0.888, respectively. The GA detection model had accuracy, sensitivity, specificity, and precision of 0.965, 0.692, 0.978, and 0.584, respectively. The CGA detection model had equivalent values of 0.966, 0.763, 0.971, and 0.394. The centrality detection model had equivalent values of 0.762, 0.782, 0.729, and 0.799. Conclusions: A deep learning model demonstrated high accuracy for the automated detection of GA. The AUC was non-inferior to that of human retinal specialists. Deep learning approaches may also be applied to the identification of CGA. The code and pretrained models are publicly available at https://github.com/ncbi-nlp/DeepSeeNet., Comment: Accepted for publication in Ophthalmology

Background: Viral infections of the respiratory tract represent a major global health concern. Co-infection with bacteria may contribute to severe disease and increased mortality in patients. Nevertheless, viral-bacterial co-infection patterns and their clinical outcomes have not been well characterized to date. This study aimed to evaluate the clinical features and outcomes of patients with viral-bacterial respiratory tract co-infections.Methods: We included 19,361 patients with respiratory infection due to respiratory viruses [influenza A and B, respiratory syncytial virus (RSV), parainfluenza] and/or bacteria in four tertiary hospitals in Hong Kong from 2013 to 2017 using a large territory-wide healthcare database. All microbiological tests were conducted within 48 h of hospital admission. Four etiological groups were included: (1) viral infection alone; (2) bacterial infection alone; (3) laboratory-confirmed viral-bacterial co-infection and (4) clinically suspected viral-bacterial co-infection who were tested positive for respiratory virus and negative for bacteria but had received at least four days of antibiotics. Clinical features and outcomes were recorded for laboratory-confirmed viral-bacterial co-infection patients compared to other three groups as control. The primary outcome was 30-day mortality. Secondary outcomes were intensive care unit (ICU) admission and length of hospital stay. Propensity score matching estimated by binary logistic regression was used to adjust for the potential bias that may affect the association between outcomes and covariates.Findings: Among 15,906 patients with respiratory viral infection, there were 8451 (53.1%) clinically suspected and 1,087 (6.8%) laboratory-confirmed viral-bacterial co-infection. Among all the bacterial species, Haemophilus influenzae (226/1,087, 20.8%), Pseudomonas aeruginosa (180/1087, 16.6%) and Streptococcus pneumoniae (123/1087, 11.3%) were the three most common bacterial pathogens in the laboratory-confirmed co-infection group. Respiratory viruses co-infected with non-pneumococcal streptococci or methicillin-resistant Staphylococcus aureus was associated with the highest death rate [9/30 (30%) and 13/48 (27.1%), respectively] in this cohort. Compared with other infection groups, patients with laboratory-confirmed co-infection had higher ICU admission rate (p < 0.001) and mortality rate at 30 days (p = 0.028), and these results persisted after adjustment for potential confounders using propensity score matching. Furthermore, patients with laboratory-confirmed co-infection had significantly higher mortality compared to patients with bacterial infection alone.Interpretation: In our cohort, bacterial co-infection is common in hospitalized patients with viral respiratory tract infection and is associated with higher ICU admission rate and mortality. Therefore, active surveillance for bacterial co-infection and early antibiotic treatment may be required to improve outcomes in patients with respiratory viral infection.

In assessing the severity of age-related macular degeneration (AMD), the Age-Related Eye Disease Study (AREDS) Simplified Severity Scale predicts the risk of progression to late AMD. However, its manual use requires the time-consuming participation of expert practitioners. Although several automated deep learning systems have been developed for classifying color fundus photographs (CFP) of individual eyes by AREDS severity score, none to date has used a patient-based scoring system that uses images from both eyes to assign a severity score. DeepSeeNet, a deep learning model, was developed to classify patients automatically by the AREDS Simplified Severity Scale (score 0-5) using bilateral CFP. DeepSeeNet was trained on 58,402 and tested on 900 images from the longitudinal follow-up of 4549 participants from AREDS. Gold standard labels were obtained using reading center grades. DeepSeeNet simulates the human grading process by first detecting individual AMD risk factors (drusen size, pigmentary abnormalities) for each eye and then calculating a patient-based AMD severity score using the AREDS Simplified Severity Scale. DeepSeeNet performed better on patient-based classification (accuracy = 0.671; kappa = 0.558) than retinal specialists (accuracy = 0.599; kappa = 0.467) with high AUC in the detection of large drusen (0.94), pigmentary abnormalities (0.93), and late AMD (0.97). DeepSeeNet demonstrated high accuracy with increased transparency in the automated assignment of individual patients to AMD risk categories based on the AREDS Simplified Severity Scale. These results highlight the potential of deep learning to assist and enhance clinical decision-making in patients with AMD, such as early AMD detection and risk prediction for developing late AMD. DeepSeeNet is publicly available on https://github.com/ncbi-nlp/DeepSeeNet., Accepted for publication in Ophthalmology

Purpose To investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD). Design Retrospective analysis of a prospective cohort study. Participants Of the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED. Methods Baseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen ≥433 μm in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan–Meier analyses and multivariable proportional hazard regressions were performed. Main Outcome Measures Progression rates to late AMD and decrease of ≥3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype. Results Mean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98–2.82; P Conclusions This study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression.

Purpose To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. Design Prospective cohort study within a controlled clinical trial. Participants Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50–85 years. Methods Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. Main Outcome Measures (1) Presence or development of GA; (2) change in the square root of GA area over time. Results At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27–0.30) and incident GA (0.28 mm/year; 0.27–0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P Conclusions Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

Objective Reticular pseudodrusen (RPD), a key feature of age-related macular degeneration (AMD), are poorly detected by human experts on standard color fundus photography (CFP) and typically require advanced imaging modalities such as fundus autofluorescence (FAF). The objective was to develop and evaluate the performance of a novel multimodal, multitask, multiattention (M3) deep learning framework on RPD detection. Materials and Methods A deep learning framework (M3) was developed to detect RPD presence accurately using CFP alone, FAF alone, or both, employing >8000 CFP-FAF image pairs obtained prospectively (Age-Related Eye Disease Study 2). The M3 framework includes multimodal (detection from single or multiple image modalities), multitask (training different tasks simultaneously to improve generalizability), and multiattention (improving ensembled feature representation) operation. Performance on RPD detection was compared with state-of-the-art deep learning models and 13 ophthalmologists; performance on detection of 2 other AMD features (geographic atrophy and pigmentary abnormalities) was also evaluated. Results For RPD detection, M3 achieved an area under the receiver-operating characteristic curve (AUROC) of 0.832, 0.931, and 0.933 for CFP alone, FAF alone, and both, respectively. M3 performance on CFP was very substantially superior to human retinal specialists (median F1 score = 0.644 vs 0.350). External validation (the Rotterdam Study) demonstrated high accuracy on CFP alone (AUROC, 0.965). The M3 framework also accurately detected geographic atrophy and pigmentary abnormalities (AUROC, 0.909 and 0.912, respectively), demonstrating its generalizability. Conclusions This study demonstrates the successful development, robust evaluation, and external validation of a novel deep learning framework that enables accessible, accurate, and automated AMD diagnosis and prognosis.

Background: Viral infections of the respiratory tract represent a major global health concern. Co-infection with bacteria may contribute to severe disease and increased mortality in patients. Nevertheless, viral-bacterial co-infection patterns and their clinical outcomes have not been well characterized to date. This study aimed to evaluate the clinical features and outcomes of patients with viral-bacterial respiratory tract co-infections. Methods: We included 19,361 patients with respiratory infection due to respiratory viruses [influenza A and B, respiratory syncytial virus (RSV), parainfluenza] and/or bacteria in four tertiary hospitals in Hong Kong from 2013 to 2017 using a large territory-wide healthcare database. All microbiological tests were conducted within 48 hours of hospital admission. Four etiological groups were included: (1) viral infection alone; (2) bacterial infection alone; (3) laboratory-confirmed viral-bacterial co-infection and (4) clinically suspected viral-bacterial co-infection who were tested positive for respiratory virus and negative for bacteria but had received at least four days of antibiotics. Clinical features and outcomes were recorded. The primary outcome was 30-day mortality. Secondary outcomes were intensive care unit (ICU) admission and length of hospital stay. Propensity score matching estimated by binary logistic regression was used to adjust for the potential bias that may affect the association between outcomes and covariates. Findings: Among 15,906 patients with respiratory viral infection, there were 8,451 (53.1%) clinically suspected and 1,087 (6.8%) laboratory-confirmed viral-bacterial co-infection. Among all the bacterial species, Haemophilus influenzae (226/1,087, 20.8%), Pseudomonas aeruginosa (163/1,087, 16.9%) and Streptococcus pneumoniae (123/1,087, 11.3%) were the three most common bacterial pathogens in the laboratory-confirmed co-infection group. Respiratory viruses co-infected with non-pneumococcal streptococci or methicillin-resistant Staphylococcus aureus was associated with the highest death rate [9/30 (30%) and 13/48 (27.1%), respectively] in this cohort. Compared with other infection groups, patients with laboratory-confirmed co-infection had higher ICU admission rate (p < 0.001) and mortality rate at 30 days (p = 0.012), and these results persisted after adjustment for potential confounders. Furthermore, patients with laboratory-confirmed co-infection had significantly higher mortality compared to patients with bacterial infection alone. Interpretation: In our cohort, bacterial co-infection is common in hospitalized patients with viral respiratory tract infection and is associated with higher ICU admission rate and mortality. Therefore, active surveillance for bacterial co-infection and early antibiotic treatment may be required to improve outcomes in patients with respiratory viral infection. Funding Information: Commissioned Programmes for Influenza Research, Health and Medical Research Fund (HMRF), FHB (Ref. No.: INF-CUHK-2); National Natural Science Foundation of China (81873560); Shenzhen Science and Technology Programme, Shenzhen Science and Technology Innovation Commission (JCYJ20180307150626228); Health and Medical Research Fund (18170092). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: Ethics approval was obtained from the Chinese University of Hong Kong.

Multiple lines of investigation have demonstrated that inflammation plays significant roles in etiology of age-related macular degeneration (AMD). Although interventional trials in AMD therapy targeting inflammatory pathways have been conducted, they have not yet been successful and a detailed understanding as to why some have failed is still elusive. One limitation is the relative dearth of information on how immune cells interact with retinal cells to generate AMD phenotypes at each disease stage. Here, we summarize current research evidence and hypotheses regarding potential pathogenic roles of innate immune cells in the eye, which include resident retinal microglia, macrophages derived from infiltrating systemic monocytes, and macrophages resident in the choroid. We relate recent findings regarding the physiology, function, and cellular interactions involving innate immune cells in the retina and choroid to AMD-related processes, including: (1) drusen formation and regression, (2) the onset and spread of degeneration in late atrophic AMD, and (3) the initiation, growth, and exudation of neovascular vessels in late "wet" AMD. Understanding how innate immune cells contribute to specific AMD phenotypes can assist in generating a comprehensive view on the inflammatory etiology of AMD and aid in identifying anti-inflammatory therapeutic strategies and selecting appropriate clinical outcomes for the planned interventions.

In macula-wide analyses, spectral-domain (SD) optical coherence tomography (OCT) features including drusen volume, hyperreflective foci, and OCT-reflective drusen substructures independently predict geographic atrophy (GA) onset secondary to age-related macular degeneration (AMD). We sought to identify SD OCT features in the location of new GA before its onset.Retrospective study.Age-Related Eye Disease Study 2 Ancillary SD OCT Study participants.We analyzed longitudinally captured SD OCT images and color photographs from 488 eyes of 488 participants with intermediate AMD at baseline. Sixty-two eyes with sufficient image quality demonstrated new-onset GA on color photographs during study years 2 through 7. The area of new-onset GA and one size-matched control region in the same eye were segmented separately, and corresponding spatial volumes on registered SD OCT images at the GA incident year and at 2, 3, and 4 years previously were defined. Differences in SD OCT features between paired precursor regions were evaluated through matched-pairs analyses.Localized SD OCT features 2 years before GA onset.Compared with paired control regions, GA precursor regions at 2, 3, and 4 years before (n = 54, 33, and 25, respectively) showed greater drusen volume (P = 0.01, P = 0.003, and P = 0.003, respectively). At 2 and 3 years before GA onset, they were associated with the presence of hypertransmission (P0.001 and P = 0.03, respectively), hyperreflective foci (P0.001 and P = 0.045, respectively), OCT-reflective drusen substructures (P = 0.004 and P = 0.03, respectively), and loss or disruption of the photoreceptor zone, ellipsoid zone, and retinal pigment epithelium (RPE, P0.001 and P = 0.005-0.045, respectively). At 4 years before GA onset, precursor regions were associated with photoreceptor zone thinning (P = 0.007) and interdigitation zone loss (P = 0.045).Evolution to GA is heralded by early local photoreceptor changes and drusen accumulation, detectable 4 years before GA onset. These precede other anatomic heralds such as RPE changes and drusen substructure emergence detectable 1 to 2 years before GA. This study thus identified earlier end points for GA as potential therapeutic targets in clinical trials.

PURPOSE: To investigate how choroidal features vary with age-related macular degeneration (AMD) severity in early-intermediate disease. METHODS: One hundred fifty-one eyes of 151 participants >50 years with no to intermediate AMD were analyzed with enhanced depth imaging optical coherence tomography. Mean macular choroidal thickness (CT), choroidal vascular thickness (CV), and choroidal vascularity index (CVI) were determined, and statistical associations were calculated. RESULTS: Decreased CT and CV were associated with increased axial length (+30 and +14 μm/mm, respectively; P < 0.0001 each), whereas decreased CVI was associated with increased age (+0.1%/year; P = 0.004). Compared with eyes with no/early AMD (Group 0), eyes with large drusen without late AMD in the fellow eye (Group 1) showed increased CV and CVI (+22 μm, P = 0.03 and +2.2%, P = 0.02, respectively). However, eyes with large drusen and late AMD in the fellow eye (Group 2) resembled Group 0. Eyes with subretinal drusenoid deposits demonstrated lower mean CT/CV/CVI than Group 0 (−57 μm, P = 0.02; −31 μm, P = 0.02; −3.6%, P = 0.007). CONCLUSION: Early AMD progression seems associated with biphasic alterations in choroidal dimensions, increasing during early drusen formation but decreasing thereafter. Subretinal drusenoid deposits are independently associated with marked reductions in all choroidal parameters. Changes in choroidal vascular anatomy may drive or reflect the pathobiology of AMD progression.

The choroid, which provides vascular supply to the outer retina, demonstrates progressive degeneration in aging and age-related macular degeneration (AMD). However mechanisms that maintain or compromise choroidal homeostasis are obscure. We discovered that the ablation of choroidal macrophages via CSF1R blockade was associated with choroidal vascular atrophy and retinal pigment epithelial (RPE) changes including structural disruption, downregulation of visual cycle genes, and altered angiogenic factor expression. Suspending CSF1R blockade following ablation enabled spontaneous macrophage regeneration, which fully restored original macrophage distributions and morphologies. Macrophage regeneration was accompanied by arrested vascular degeneration and ameliorated pathological RPE alterations. These findings suggest that choroidal macrophages play a previously unappreciated trophic role in maintaining choroidal vasculature and RPE cells, implicating insufficiency in choroidal macrophage function as a factor in aging- and AMD-associated pathology. Modulating macrophage function may constitute a strategy for the therapeutic preservation of the choroid and RPE in age-related retinal disorders.

The choroid of the eye provides necessary vascular supply to the outer retina across the retinal pigment epithelial (RPE) layer and is a locus of progressive degenerative change in aging and age-related macular degeneration (AMD). Cellular mechanisms that maintain or compromise choroidal vasculature homeostasis are not well understood, complicating therapeutic efforts. We discover here that pharmacological ablation of macrophages normally resident in the adult mouse choroid via blockade of the CSF1 receptor resulted in progressive thinning of the choroid layer and atrophy of the choriocapillaris. Concurrently, choroidal macrophage ablation also induced structural disorganization of the RPE cell layer, downregulation of RPE visual cycle genes, and altered RPE angiogenic factor expression. Suspension of CSF1R blockade following ablation conversely enabled spontaneous regeneration of the choroidal macrophage population, restoring original macrophage distribution and morphological features. Macrophage repopulation significantly ameliorated the ablation-induced changes in RPE structure and angiogenic factor expression and arrested choroidal vascular atrophy. These findings reveal a previously unsuspected trophic function of resident choroidal macrophages in the maintenance of choroidal vasculature and the RPE layer, suggesting that insufficiency of macrophage function may contribute to age- and AMD-associated pathology. Modulating choroidal macrophage support function can constitute a strategy for therapeutic preservation of the choroid and RPE in AMD prevention and treatment.Significance StatementChoroidal atrophy is associated with normal aging and progression in age-related macular degeneration (AMD), a leading cause of blindness. Herein, we identify the choroidal macrophage as a critical player in the homeostatic maintenance of choroid-RPE complex of the eye. Depletion of choroidal macrophages resulted in progressive vascular atrophy, altered structure of retinal pigment epithelial (RPE) cells, and dysregulated RPE expression of visual cycle protein and angiogenic factors, VEGF and PEDF. We discovered that choroidal macrophages can regenerate and repopulate the choroid following depletion, ameliorating RPE alterations and arresting vascular atrophy. Our results suggest that insufficiency of macrophage function may contribute to age- and AMD-associated pathology, and modulation of macrophage support functions may be therapeutically useful in AMD prevention and treatment.

BACKGROUND Sepsis is a systemic host response to an infection leading to organ failure. This is associated with dynamic expression of endogenous host defense peptides. Dysregulation of these peptides is associated with septic morbidity and mortality. METHODS We performed a systematic search of articles indexed in Pubmed, ISI Web of Knowledge, EmBase and Scopus database from inception to October 2016. Both preclinical and clinical studies investigating the role of host defense peptides in pathogenesis and as biomarkers for sepsis were included. RESULTS Of the available literatures, cathelicidin, defensin and hepcidin are amongst the best-characterized peptides. These regulate immune response, and crosstalk with pyroptosis and coagulation cascades. The applicability of these peptides as septic biomarkers has been investigated in vitro and in vivo studies. However, numerous studies were based on endotoxemia without an infection, jeopardizing interpretation of the outcomes. Cathelicidin and defensin were frequently reported in adult sepsis while hepcidin in neonatal sepsis. The expression level of these peptides is significantly associated with septic condition. Most of the studies employed a cross-sectional design, precluding the establishment of a temporal relationship between candidate peptide biomarkers and sepsis. CONCLUSIONS Innate defense peptides have been insufficiently evaluated as either diagnostic or prognostic biomarkers. In the future, evaluation of host defense peptides as septic biomarkers may employ a longitudinal design and consider a panel of multiple peptides.

Purpose To describe the clinical course of advanced juxtapapillary retinal capillary hemangioblastomas (RCHs) associated with von Hippel-Lindau (VHL) disease treated with systemic sunitinib malate, an agent that inhibits both anti–vascular endothelial growth factor and anti–platelet-derived growth factor signaling. Design Observational case review. Participants Three patients with advanced VHL-related juxtapapillary RCHs treated with systemic sunitinib malate. Methods Patient 1 was followed routinely every 4 months while on systemic sunitinib prescribed by her oncologist for metastatic pancreatic neuroendocrine and kidney tumors. Patients 2 and 3 were part of a prospective clinical trial evaluating the use of systemic sunitinib for ocular VHL lesions during a period of 9 months. Visual acuity, size of RCHs, and degree of exudation were recorded at each visit. Optical coherence tomography and fluorescein angiography were also obtained at some visits. Main Outcome Measures Visual acuity, size of RCHs, and degree of exudation. Results Three patients with advanced VHL-associated juxtapapillary RCHs were treated with systemic sunitinib malate. Although none of the patients lost vision during therapy, treatment with sunitinib malate did not improve visual acuity or reduce the size of RCHs. Improvements in RCH-associated retinal edema were observed in 2 patients. All patients experienced multiple adverse effects, including thyroid toxicity, thrombocytopenia, nausea, fatigue, jaundice, and muscle aches. Two of the 3 patients had to discontinue treatment prematurely and the third required dose reduction. Conclusions Systemic sunitinib malate may be useful in slowing progression of ocular disease from VHL-associated RCHs. However, significant systemic adverse effects limited its use in this small series, and systemic sunitinib malate may not be safe for treatment of RCHs when used at the doses described in this report. Further studies are required to determine if this medication, used at lower doses with different treatment strategies; other medications in the same class; or drugs directed at multiple targets in the tumor may be safer and more effective for the treatment of advanced VHL-associated RCHs.

Purpose To evaluate the risk factors, incidence, and rate of progression of geographic atrophy (GA) in eyes with neovascular age-related macular degeneration (nAMD) treated with ranibizumab. Design Post hoc analysis of a prospective clinical study. Participants There were 69 participants with nAMD in ≥1 eye. Methods Participants were prospectively treated in the study eye with 0.5 mg intravitreal ranibizumab. Study eyes received 4 monthly injections followed by pro re nata injections until a fluid-free macula was achieved on optical coherence tomography. Risk factors assessed included baseline demographics, treatment, and ocular characteristics on imaging. Eyes were evaluated on fundus autofluorescence for GA. The rate of GA area growth in study and fellow eyes was analyzed by linear regression of square root transformed areas. Main Outcome Measures Development of new-onset GA and rate of GA area growth measured on ocular imaging, including fundus autofluorescence images of the study eyes. Results Sixty-nine participants (mean age, 78.8±7.8 years) with an average of 40.0±13.6 months of follow-up were analyzed. Twenty-two of the 69 study eyes (32%) were treatment naive. During their first year of the study, participants received an average of 9.2±3.3 injections in the study eye. Of 63 study eyes with quality baseline images, 22 (35%) had preexisting GA. Of the remaining 41 eyes, 7 (17%) developed new-onset GA during study follow-up. Those who developed new GA were older (all ≥79 years old) and had received fewer study injections on average (6.9 vs. 10.4 injections at 1 year) compared with those who did not develop new GA. Of the 12 treatment-naive study eyes without GA at baseline, 1 (8.3%) developed new GA during the study. In 21 study eyes with quantifiable GA area, eyes with GA present at baseline (16/21) enlarged by 0.34±0.26 mm/y, compared with 0.19±0.12 mm/y in eyes developing new-onset GA (5/21). Conclusions Although 17% of study eyes without GA present at baseline receiving ranibizumab developed new GA, the role of ranibizumab in the development of GA is unclear. Further prospective longitudinal studies are required to determine the eyes most at risk of developing GA in the setting of anti–vascular endothelial growth factor treatment.

Background Although the evidence suggests that general fatigue is a strong indicator of rapid aging, frailty, and disability, general fatigue is undertreated in gerontological care. Objective The aim of this study is to investigate whether an individualized exercise program with and without behavioral change enhancement (BCE) strategies for older people who are frail and have general fatigue will reduce their fatigue and symptoms of frailty. Design A 3-arm, single-blind, cluster randomized controlled trial registered with ClinicalTrials.gov (NCT03394495) will be conducted. Setting The study will be conducted in a community setting. Participants Two hundred eighty-five community-dwelling older people with general fatigue will be recruited from 12 district community health centers. Intervention People from each center will be randomized to one of three groups. The combined group will receive a 16-week combined intervention consisting of individualized exercise training and the BCE program, plus two booster sessions at 2 and 6 months after the program. The exercise group will receive exercise training and health talks only. The control group will receive health talks only. Measurements Outcome measures will be collected at baseline, at the midpoint (week 8) of the program, and then at 1 week, 6 months, and 12 months after the end of the program. The primary outcome---level of fatigue---will be measured using the Multidimensional Fatigue Inventory. Secondary outcomes will include the participants’ frailty status, strength, mobility, exercise self-efficacy, and habitual physical activity. Limitations A self-reported level of fatigue will be used. Conclusions The effect of exercise and BCE strategies on general fatigue among older people who are frail is not known. This study will be a pioneering interventional study on how general fatigue among older people who are frail can be managed and how fatigue-related frailty can be prevented or minimized.

BACKGROUND This study identifies potential pitfalls in incorporating plasma Epstein-Barr virus (EBV) DNA into the management of nasopharyngeal carcinoma (NPC). METHODS A total of 208 NPC patients without distant metastasis who received radical treatment and had measurements of EBV DNA at baseline, 8 weeks and 26 weeks postradiotherapy were analyzed. Prognostic and predictive values at each time-point were compared. RESULTS Risk stratification by pretreatment level failed to identify a poor prognostic group. Detectable EBV DNA at 8 weeks and 26 weeks postradiotherapy were both associated with significantly poorer 5-year disease-free survival (HR 0.30, P

Purpose To characterize functional and structural changes in hydroxychloroquine (HCQ) retinal toxicity after drug cessation. Methods Twenty-two patients (91% female; mean age 58.7 ± 11.4 years; mean duration of HCQ treatment 161.1 ± 90 months; mean dose 5.9 ± 1.9 mg/kg) with detected HCQ retinopathy were monitored for 6 months to 82 months after HCQ cessation with multimodal imaging including spectral domain optical coherence tomography and fundus autofluorescence imaging at 488 nm (standard) and 787 nm (near-infrared autofluorescence). Tests of visual function including visual acuity, Humphrey visual field testing, and multifocal electroretinography (mfERG) were performed. Study eyes were categorized into four separate severity stages by qualitative grading of spectral domain optical coherence tomography macular scans taken at the time of HCQ cessation. Changes in outcome measures between drug cessation and last follow-up visit were computed and compared between eyes of different severity stages. Results Study eyes (n = 44) were categorized based on optical coherence tomography criteria into: Stage 1 (subtle changes confined to parafoveal region; n = 14), Stage 2 (clear localized changes in parafovea; n = 17), Stage 3 (extensive parafoveal changes; n = 7), and Stage 4 (foveal involvement, n = 6). Visual acuity measurements across follow-up were stable in Stage 1 and Stage 2 eyes but decreased significantly in Stage 3 and 4 eyes. Humphrey visual field measures were also stable in stages 1 and 2 but deteriorated in Stage 3 eyes. mfERG testing demonstrated significant improvement in the R1/R2 ratio after HCQ cessation in Stage 1 eyes (mean change = -0.86 ± 0.79, P = 0.03) but did not change significantly in eyes of higher stages. Decreases in macular thickness in ≥1 of 9 Early Treatment Diabetic Retinopathy Study subfields on spectral domain optical coherence tomography were found in eyes of all stages, with Stage 2 eyes demonstrating thinning in most subfields (eight of nine subfields). In eyes with a measurable central foveal ellipsoid zone band island (9 of 17 Stage 2 eyes and 7 of 7 Stage 3 eyes), progressive decrease in the foveal ellipsoid zone band length was observed in 6 of 9 (67%) Stage 2 eyes and 6 of 7 (86%) Stage 3 eyes. Changes indicative of progressing retinopathy were detected in 17% of Stage 1 eyes, 46% of Stage 2 eyes, and 43% of Stage 3 eyes on standard fundus autofluorescence imaging, and in 17% of Stage 1 eyes, 38% of Stage 2 eyes, and 14% of Stage 3 eyes on near-infrared autofluorescence imaging. Conclusion Eyes with detected HCQ retinopathy do not demonstrate general stability in retinal structure and function after HCQ cessation but instead demonstrate a range of changes during follow-up whose magnitudes correlate with retinopathy severity at the time of cessation. After cessation, eyes with only subtle and localized retinopathy were mostly stable and may show some functional improvement, whereas more severely affected eyes continued to progress. These findings provide evidence that early detection and prompt cessation in HCQ retinopathy may be needed to arrest retinopathy progression and to optimize long-term outcomes.

Constitutive TGFβ signaling is important in maintaining retinal neurons and blood vessels and is a factor contributing to the risk for age-related macular degeneration (AMD), a retinal disease involving neurodegeneration and microglial activation. How TGFβ signaling to microglia influences pathological retinal neuroinflammation is unclear. We discovered that ablation of the TGFβ receptor, TGFBR2, in retinal microglia of adult mice induced abnormal microglial numbers, distribution, morphology, and activation status, and promoted a pathological microglial gene expression profile. TGFBR2-deficient retinal microglia induced secondary gliotic changes in Müller cells, neuronal apoptosis, and decreased light-evoked retinal function reflecting abnormal synaptic transmission. While retinal vasculature was unaffected, TGFBR2-deficient microglia demonstrated exaggerated responses to laser-induced injury that was associated with increased choroidal neovascularization, a hallmark of advanced exudative AMD. These findings demonstrate that deficiencies in TGFβ-mediated microglial regulation can drive neuroinflammatory contributions to AMD-related neurodegeneration and neovascularization, highlighting TGFβ signaling as a potential therapeutic target.

PurposeBlood vessels of the retina provide an easily-accessible, representative window into the condition of microvasculature. We investigated how retinal vessel structure captured in fundus photographs changes with age, and how this may reflect features related to patient health, including blood pressure.ResultsWe used two approaches. In the first approach, we segmented the retinal vasculature from fundus photographs and then we correlated 25 parameterized aspects ("traits")-comprising 15 measures of tortuosity, 7 fractal ranges of self-similarity, and 3 measures of junction numbers-with participant age and blood pressure. In the second approach, we examined entire fundus photographs with a set of algorithmic CHARM features. We studied 2,280 Sardinians, ages 20-28, and an U.S. based population from the AREDS study in 1,178 participants, ages 59-84. Three traits (relating to tortuosity, vessel bifurcation number, and vessel endpoint number) showed significant changes with age in both cohorts, and one additional trait (relating to fractal number) showed a correlation in the Sardinian cohort only. When using second approach, we found significant correlations of particular CHARM features with age and blood pressure, which were stronger than those detected when using parameterized traits, reflecting a greater signal from the entire photographs than was captured in the segmented microvasculature.ConclusionsThese findings demonstrate that automated quantitative image analysis of fundus images can reveal general measures of patient health status.

Introduction Patients with pulmonary large-cell carcinoma (LCC) have poor prognosis and limited treatment options. The identification of clinically actionable molecular alterations helps to guide personalized cancer treatment decisions. Patients and Methods A consecutive cohort of 789 resected NSCLC cases were reviewed. Fifty-nine NSCLC cases lacking morphologic differentiation, accounting for 7.5% of all resected NSCLCs, were identified and further characterized by immunohistochemistry according to the 2015 WHO lung tumor classification. Molecular alterations were investigated by multiple technologies including target capture sequencing, immunohistochemistry, and fluorescence in situ hybridizations. Results Of 59 NSCLC cases lacking morphologic differentiation, 20 (33.9%) were reclassified as adenocarcinoma (LCC-AD), 14 (23.7%) as squamous cell carcinoma (LCC-SqCC), and 25 (42.4%) as LCC-Null. Approximately 92% of LCC-Null, 95% of LCC-AD, and 86% of LCC-SqCC harbored clinically relevant alterations. Alterations characteristic of adenocarcinoma (EGFR, KRAS, ALK receptor tyrosine kinase [ALK], ROS1, and serine/threonine kinase 11 [STK11]) were detected in the LCC-AD subgroup but not in LCC-SqCC, whereas squamous-lineage alterations (phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha [PIK3CA], SRY-box 2 [SOX2], fibroblast growth factor receptor 1 [FGFR1], and AKT1) were detected in the LCC-SqCC subgroup but not in the LCC-AD group. Although some LCC-Null tumors displayed a genetic profile similar to either adenocarcinoma or squamous-cell carcinoma, more than half of the LCC-Null group were completely devoid of recognizable lineage-specific genetic profiles. High programmed death ligand 1 expression and high frequency of cell cycle regulatory gene alterations were found in the LCC-Null group offering alternative options of targeted therapy. Conclusions This comprehensive molecular study provided further insight into the genetic architecture of LCC. The presence of clinically actionable alterations in a majority of the tumors allowed personalized treatment to emerge.

Introduction: von Hippel-Lindau (VHL) disease is an autosomal dominant, inherited multisystem cancer syndrome involving mutations in the VHL tumor suppressor gene. The hallmark lesion in ocular VHL disease is the retinal capillary hemangioblastoma (RCH), a benign vascular tumor capable of causing visual loss through exudative changes.Areas covered: Combining epidemiological and clinical data with an analysis of recent treatment and outcomes literature, this review aims to update the clinician on research findings and upcoming potential therapies. We describe the clinical features of ocular VHL disease and the factors that can help prognose visual outcome in affected patients and provide a summary of current treatment modalities.Expert commentary: We provide an update on the advent of genetic testing for pathogenic mutations in the VHL gene which has enabled earlier diagnoses and more detailed prognoses in affected patients, and have opened the way to future potential treatments aimed at the downst...

Purpose To investigate the comparative efficacy of bevacizumab (Avastin) and ranibizumab (Lucentis; both Genentech, Inc, South San Francisco, CA) for diabetic macular edema (DME) using a crossover study design. Design Randomized, double-masked, 36-week, 3-period crossover clinical trial. Participants Fifty-six subjects with DME involving the center of the macula in one or both eyes. Methods Monthly intravitreous injections of bevacizumab (1.25 mg) or ranibizumab (0.3 mg). Main Outcome Measures Comparison of mean changes in visual acuity and central retinal thickness, tested using a linear mixed-effects model. Results Based on the linear mixed-effects model, the 3-month estimated mean improvement in visual acuity was 5.3 letters for bevacizumab and 6.6 letters for ranibizumab (difference, 1.3 letters; P = 0.039). Estimated change in optical coherence tomography (OCT) central subfield mean thickness (CSMT) was −89 μm for bevacizumab and −137 μm for ranibizumab (difference, 48 μm; P Conclusions This trial demonstrated a statistically significant but small relative clinical benefit of ranibizumab compared with bevacizumab for treatment of DME, using a markedly reduced sample size relative to a full comparative efficacy study. The effects on visual acuity and central retinal thickness for the 2 drugs are consistent with those reported at 1 year for the concurrent parallel-group trial by the Diabetic Retinopathy Clinical Research Network testing bevacizumab, ranibizumab, and aflibercept for DME. The 3-period crossover design allowed for meaningful and efficient comparison, suggesting that this approach may be useful for future comparative efficacy studies of anti–vascular endothelial growth factor drugs for DME.

Purpose To investigate how macular thickness varies with intermediate age-related macular degeneration (iAMD) severity and the presence of subretinal drusenoid deposits (SDDs). Methods A longitudinal prospective study of 143 participants >50 years of age with no to intermediate AMD who were followed with multimodal imaging and functional testing. Participants were stratified by iAMD severity according to imaging features. Macular thicknesses measurements over the central circles with 1-mm, 3-mm, and 6-mm diameters obtained from ocular coherence tomography imaging were compared across severity categories using cross-sectional (143 eyes) and longitudinal (subset of 77 eyes followed for 4 years) multivariate analyses. Results Compared with control eyes without large drusen or SDDs (Group 0), central maculas of lower risk eyes with unilateral large drusen (Group 1) were thicker (P = 0.014), whereas higher risk eyes with SDDs (Group SDD) were thinner (P = 0.02) in cross-sectional multivariate analyses. In longitudinal analyses, maculas with SDDs thinned more rapidly over 4 years relative to control eyes (P = 0.0058), which did not show significant thinning. More rapid central macular thinning was associated with worse baseline best-corrected visual acuity (BCVA) (P = 0.016) and more rapid BCVA decline (P = 0.0059). Conclusions Macular thickness in iAMD varies with disease severity, showing small increases in eyes with large drusen and decreases in eyes with SDDs. Active processes possibly related to neuroinflammation and neurodegeneration may be contributory. Longitudinal central macular thickness evaluation is an accessible outcome measure relevant to functional measures and is potentially useful for iAMD interventional studies.

Purpose The contribution of adjuvant chemotherapy after chemoradiation therapy (CRT) in nasopharyngeal cancer (NPC) remains controversial. Plasma Epstein-Barr virus (EBV) DNA is a potential biomarker of subclinical residual disease in NPC. In this prospective, multicenter, randomized controlled trial, we used plasma EBV DNA to identify patients with NPC at a higher risk of relapse for adjuvant chemotherapy. Patients and Methods Eligible patients with histologically confirmed NPC of Union for International Cancer Control stage IIB to IVB, adequate organ function, and no locoregional disease or distant metastasis were screened by plasma EBV DNA at 6 to 8 weeks after radiotherapy (RT). Patients with undetectable plasma EBV DNA underwent standard surveillance. Patients with detectable plasma EBV DNA were randomly assigned to either adjuvant chemotherapy with cisplatin and gemcitabine for six cycles (arm 1) or observation (arm 2). Patients were stratified for primary treatment (RT v CRT) and stage (II/III v IV). The primary end point was relapse-free survival (RFS). Results Seven hundred eighty-nine patients underwent EBV DNA screening. Plasma EBV DNA was undetectable in 573 (72.6%) and detectable in 216 (27.4%); 104 (13.2%) with detectable EBV DNA were randomly assigned to arms 1 (n = 52) and 2 (n = 52). After a median follow-up of 6.6 years, no significant difference was found in 5-year RFS rate between arms 1 and 2 (49.3% v 54.7%; P = .75; hazard ratio for relapse or death, 1.09; 95% CI, 0.63 to 1.89). The level of post-RT plasma EBV DNA correlated significantly with the hazards of locoregional failure, distant metastasis, and death. Conclusion In patients with NPC with detectable post-RT plasma EBV DNA, adjuvant chemotherapy with cisplatin and gemcitabine did not improve RFS. Post-RT plasma EBV DNA level should be incorporated as the selection factor in future clinical trials of adjuvant therapy in NPC.

Purpose To investigate the natural history of dark adaptation (DA) function as measured by the change in rod intercept time (RIT) over 4 years and to correlate RIT change with age-related macular degeneration (AMD) severity. Design Longitudinal, single-center, observational study. Participants A total of 77 participants aged ≥50 years with a range of AMD severities. Methods Participants each contributing a single study eye to the analysis were assigned into person-based AMD severity groups based on fundus characteristics (drusen, pigmentary changes, late AMD, and subretinal drusenoid deposits [SDDs]). The DA function was assessed in study eyes at baseline and 3, 6, 12, 18, 24, 36, and 48 months. Mean change in DA function over time was calculated using the slope of linear regression fits of longitudinal RIT data. Patient-reported responses on a Low Luminance Questionnaire (LLQ) were obtained at baseline and yearly. Nonparametric statistical testing was performed on all comparisons. Main outcome measure The RIT, defined as the time taken after a photobleach for visual sensitivity to recover detection of a 5×10-3 cd/m2 stimulus (a decrease of 3 log units), was monitored in study eyes over 4 years, and the mean rate of change was computed. Results Longitudinal analysis of 65 study eyes followed on the standard testing protocol (mean age, 71±9.3 years; 49% were female) revealed that higher rates of RIT prolongation were correlated with AMD severity group assignment at baseline (P = 0.026) and with severity group assignments at year 4 (P = 0.0011). Study eyes that developed SDD during follow-up demonstrated higher rates of RIT prolongation relative to those that did not (P Conclusions Longitudinal decline in DA function, which correlated with patient-reported functional deficits, was accelerated in eyes with greater AMD severity and especially in eyes with SDD both at baseline and at 4 years. The RIT prolongation as a measure of changing DA function may be a functional outcome measure in AMD clinical studies.

Author(s): Allahdina, Ali M; Stetson, Paul F; Vitale, Susan; Wong, Wai T; Chew, Emily Y; Ferris, Fredrick L; Sieving, Paul A; Cukras, Catherine | Abstract: Purpose:As optical coherence tomography (OCT) minimum intensity (MI) analysis provides a quantitative assessment of changes in the outer nuclear layer (ONL), we evaluated the ability of OCT-MI analysis to detect hydroxychloroquine toxicity. Methods:Fifty-seven predominantly female participants (91.2% female; mean age, 55.7 ± 10.4 years; mean time on hydroxychloroquine, 15.0 ± 7.5 years) were enrolled in a case-control study and categorized into affected (i.e., with toxicity, n = 19) and unaffected (n = 38) groups using objective multifocal electroretinographic (mfERG) criteria. Spectral-domain OCT scans of the macula were analyzed and OCT-MI values quantitated for each subfield of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid. A two-sample U-test and a cross-validation approach were used to assess the sensitivity and specificity of toxicity detection according to OCT-MI criteria. Results:The medians of the OCT-MI values in all nine of the ETDRS subfields were significantly elevated in the affected group relative to the unaffected group (P l 0.005 for all comparisons), with the largest difference found for the inner inferior subfield (P l 0.0001). The receiver operating characteristic analysis of median MI values of the inner inferior subfields showed high sensitivity and high specificity in the detection of toxicity with area under the curve = 0.99. Conclusions:Retinal changes secondary to hydroxychloroquine toxicity result in increased OCT reflectivity in the ONL that can be detected and quantitated using OCT-MI analysis. Analysis of OCT-MI values demonstrates high sensitivity and specificity for detecting the presence of hydroxychloroquine toxicity in this cohort and may contribute additionally to current screening practices.

Purpose The activation of microglia, the primary innate immune cell resident in the retina, produces inflammatory mediators, which underlie changes in diabetic retinopathy including increased vascular permeability. This study evaluates the safety and efficacy of dextromethorphan, a drug capable of inhibiting microglial activation, in the treatment of diabetic macular edema (DME). Methods A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with macular involving DME who received oral dextromethorphan 60 mg twice daily for 6 months as monotherapy. Main outcome variables included central retinal subfield thickness (CST), best-corrected visual acuity (BCVA), macula sensitivity, and late leakage on fluorescein angiogram (FA). Results The study drug was well tolerated. At the primary end point of 6 months, mean CST decreased by -6.3% ± 6.8% and BCVA increased by +0.6 ± 5.11 (mean ± SEM) letters. Late leakage on FA was scored as improved in four of five study eyes. These findings were not correlated with changes in hemoglobin A1c (HbA1c), creatinine, or blood pressure. Conclusions In this proof-of-concept study, dextromethorphan administration as the primary treatment for DME was associated with decreased vascular leakage, suggesting possible therapeutic effects. Additional studies investigating the modulation of microglial activation is warranted. Translational relevance These findings highlight microglial modulation as a potentially useful therapeutic strategy in the treatment of diabetic macular edema.

Purpose We investigate whether ocular and person-based characteristics were associated with dark adaptation (DA). Design Cross-sectional, single-center, observational study. Participants One hundred sixteen participants older than 50 years of age with a range of age-related macular degeneration (AMD) severity. Methods Participants underwent best-corrected visual acuity (BCVA) testing, ophthalmoscopic examination, and multimodal imaging. Presence of reticular pseudodrusen (RPD) was assessed by masked grading of fundus images and was confirmed with optical coherence tomography. Eyes also were graded for AMD features (drusen, pigmentary changes, late AMD) to generate person-based AMD severity groups. One eye was designated the study eye for DA testing. Nonparametric statistical testing was performed on all comparisons. Main Outcome Measures The primary outcome of this study was the rod intercept time (RIT), which is defined as the time for a participant's visual sensitivity to recover to a stimulus intensity of 5×10 −3 cd/m 2 (a decrease of 3 log units), or until a maximum test duration of 40 minutes was reached. Results A total of 116 study eyes from 116 participants (mean age, 75.4±9.4 years; 58% female) were analyzed. Increased RIT was associated significantly with increasing AMD severity, increasing age ( r = 0.34; P = 0.0002), decreasing BCVA ( r = −0.54; P P = 0.03), and decreasing subfoveal choroidal thickness ( r = −0.27; P = 0.003). Study eyes with RPD (15/116 [13%]) had a significantly greater mean RIT compared with eyes without RPD in any AMD severity group ( P Conclusions Impairments in DA increased with age, worse visual acuity, presence of RPD, AMD severity, and decreased subfoveal choroidal thickness. Analysis of covariance found the multivariate model that best fit the data included age, AMD group, and presence of RPD ( R 2 = 0.56), with the presence of RPD conferring the largest parameter estimate.

BACKGROUND AND OBJECTIVE: To evaluate scaling and measurement differences between flash and scanning laser fundus images. PATIENTS AND METHODS: The authors analyzed fundus autofluorescence images of patients with geographic atrophy secondary to age-related macular degeneration imaged with both 30º confocal scanning laser ophthalmoscope (cSLO) and 50º flash fundus camera (FFC). Multiple vessel-crossing points served as landmarks. RESULTS: The mean (± SD; range) scaling factor between cSLO and FFC images (by GRADOR) for the horizontal dimension was 1.217 (± 0.0487; 1.0474-1.272) versus 1.138 (± 0.0311; 1.0841-1.193) for the vertical dimension. The mean percentage difference between horizontal and vertical scaling factors was 7.48 (± 2.29; 2.30–10.70). Refractive error (focus) and aperture size (or field of view of the image) were positively correlated and aspect ratio was negatively correlated with landmark pair measurements. CONCLUSION: Inherent image-scaling differences between fundus autofluorescence imaging systems are not restricted to simple pixel-to-millimeter calibration variances, but appear to vary depending on measurement orientation. Differences should be considered when comparing measurements obtained using different imaging systems, particularly for clinical trials. [ Ophthalmic Surg Lasers Imaging Retina . 2015;46:872–879.]

Purpose To investigate whether the 2-year change in lens opacity severity on the Age-Related Eye Disease Study (AREDS) lens grading scale predicts progression to cataract surgery or loss of visual acuity by 5 years. Design Prospective cohort study within a randomized clinical trial of oral supplements. Participants The AREDS participants whose eyes were phakic at baseline and free of late age-related macular degeneration throughout the study. Methods Baseline and annual lens photographs of AREDS participants (n = 3466/4757; 73%) were graded for severity of cataracts using the AREDS system for classifying cataracts from photographs. Clinical examinations conducted semiannually collected data on cataract surgery and visual acuity. Association of the change in lens opacities at 2 years with these outcomes at 5 years was analyzed with adjusted Cox proportional hazard models. Main Outcome Measurements Progression of lens opacities on stereoscopic lens photographs at 2 years, cataract surgery, and visual acuity loss of 2 lines or more at 5 years. Results The adjusted hazard ratios (HRs) for association of progression to cataract surgery at 5 years were: nuclear cataract increase of 1.0 unit or more compared with less than 1.0-unit change at 2 years, 2.77 (95% confidence interval [CI], 2.07–3.70; P P = 0.002); and posterior subcapsular cataract increase of 5% or more versus less than 5% in the central 5 mm of the lens, 8.25 (95% CI, 5.55–12.29; P P P = 0.519); and posterior subcapsular cataract, 3.05 (95% CI, 1.79–5.19; P Conclusions Two-year changes in severity of lens opacities on the AREDS lens grading scale are predictive of long-term clinically relevant outcomes, making them potential surrogate end points in follow-up studies.

Resident microglial cells can be regarded as the immunological watchdogs of the brain and the retina. They are active sensors of their neuronal microenvironment and rapidly respond to various insults with a morphological and functional transformation into reactive phagocytes. There is strong evidence from animal models and in situ analyses of human tissue that microglial reactivity is a common hallmark of various retinal degenerative and inflammatory diseases. These include rare hereditary retinopathies such as retinitis pigmentosa and X-linked juvenile retinoschisis but also comprise more common multifactorial retinal diseases such as age-related macular degeneration, diabetic retinopathy, glaucoma, and uveitis as well as neurological disorders with ocular manifestation. In this review, we describe how microglial function is kept in balance under normal conditions by cross-talk with other retinal cells and summarize how microglia respond to different forms of retinal injury. In addition, we present the concept that microglia play a key role in local regulation of complement in the retina and specify aspects of microglial aging relevant for chronic inflammatory processes in the retina. We conclude that this resident immune cell of the retina cannot be simply regarded as bystander of disease but may instead be a potential therapeutic target to be modulated in the treatment of degenerative and inflammatory diseases of the retina.

Purpose The purpose of this 1-year prospective study was to investigate how induction/pro re nata ranibizumab intravitreal treatment of eyes with neovascular age-related macular degeneration affects the anatomy of choroidal neovascularization (CNV) and the overlying outer retinal tissue. Methods High-speed indocyanine green (HS-ICG) angiography measurements provided quantification of the CNV size in 60 patients followed for 1 year. Minimum intensity projection optical coherence tomography (MinIP OCT), a novel algorithm assessing minimum optical intensity between the internal limiting membrane and retinal pigment epithelium, measured the area of outer retinal disruption overlying the CNV. Fluorescein angiography was also assessed to evaluate late retinal leakage. Results After 1 year, the mean area of CNV measured with indocyanine green angiography decreased by 5.8%. The mean area of MinIP OCT of outer retinal disruption overlying the CNV decreased by 4.2%. Mean area of fluorescein angiography leakage decreased by 6.3%. Both the area of outer retinal disruption measured with MinIP OCT and the area of leakage on fluorescein angiography typically exceeded the area of CNV on indocyanine green angiography at baseline and 1 year. Conclusion Choroidal neovascularization treated with induction/pro re nata intravitreal ranibizumab for 1 year essentially remained static. Minimum intensity projection optical coherence tomography suggests that the area of outer retinal disruption overlying the CNV may be greater than the CNV itself and often correlates with the leakage area on fluorescein angiography. Additionally, there was minimal change in the area of outer retinal disruption on MinIP OCT even when fluid resolved. Measurements of the extent of CNV lesions based on indocyanine green angiography and MinIP OCT may provide useful outcome variables to help assess the CNV complex longitudinally and warrant further validation.

von Hippel-Lindau (VHL) disease is an autosomal-dominant tumor predisposition syndrome characterized by the development of highly vascularized tumors and cysts. LOH of the VHL gene results in aberrant upregulation of hypoxia-inducible factors (HIF) and has been associated with tumor formation. Hemangioblastomas of the central nervous system and retina represent the most prevalent VHL-associated tumors, but no VHL animal model has reproduced retinal capillary hemangioblastomas (RCH), the hallmark lesion of ocular VHL. Here we report our work in developing a murine model of VHL-associated RCH by conditionally inactivating Vhl in a hemangioblast population using a Scl-Cre-ERT2 transgenic mouse line. In transgenic mice carrying the conditional allele and the Scl-Cre-ERT2 allele, 64% exhibited various retinal vascular anomalies following tamoxifen induction. Affected Vhl-mutant mice demonstrated retinal vascular lesions associated with prominent vasculature, anomalous capillary networks, hemorrhage, exudates, and localized fibrosis. Histologic analyses showed RCH-like lesions characterized by tortuous, dilated vasculature surrounded by “tumorlet” cell cluster and isolated foamy stromal cells, which are typically associated with RCH. Fluorescein angiography suggested increased vascular permeability of the irregular retinal vasculature and hemangioblastoma-like lesions. Vhl deletion was detected in “tumorlet” cells via microdissection. Our findings provide a phenotypic recapitulation of VHL-associated RCH in a murine model that may be useful to study RCH pathogenesis and therapeutics aimed at treating ocular VHL. Significance: This study describes a model that phenotypically recapitulates a form of retinal pathogenesis that is driven by genetic loss of the VHL tumor suppressor, providing a useful tool for its study and therapeutic intervention. Cancer Res; 78(5); 1266–74. ©2018 AACR.

PURPOSE: We investigate whether responses on a Low Luminance Questionnaire (LLQ), in patients with a range of AMD severity, are associated with their performance on focal dark adaptation (DA) testing and with choroidal thickness. DESIGN: Cross-sectional, single-center, observational study. PARTICIPANTS: One hundred and thirteen participants older than 50 years of age with a range of age-related macular degeneration (AMD) severity. METHODS: Participants answered the LLQ on the same day that they underwent DA testing using a focal dark adaptometer measuring rod intercept time (RIT). We performed univariable and multivariable analyses of the LLQ scores and age, RIT, AMD severity, subfoveal choroidal thickness [SFCT], phakic status, and best-corrected visual acuity. MAIN OUTCOME MEASURES: The primary outcome of this study was the score on the 32-question LLQ. Each item in the LLQ is designated to one of six subscales describing functional problems in low luminance: driving, emotional distress, mobility, extreme lighting, peripheral vision, and general dim lighting. Scores were computed for each subscale, in addition to a weighted total mean score. RESULTS: Responses from 113 participants (mean age, 76.2 ± 9.3 years; 58.4% female) and 113 study eyes were analyzed. Univariable analysis demonstrated that lower scores on all LLQ subscales were correlated with prolonged DA testing (longer RIT) and decreased choroidal thickness. All associations were statistically significant except for the association of choroidal thickness and ‘peripheral vision’. The strongest association was the LLQ subscale of driving with RIT (r = −0.97, p

PurposeTo characterize longitudinal structural changes in early stages of late-onset retinal degeneration to investigate pathogenic mechanisms.MethodsTwo affected siblings, both with a S163R missense mutation in the causative gene C1QTNF5, were followed for 8+ years. Color fundus photos, fundus autofluorescence images, near-infrared reflectance fundus images, and spectral domain optical coherence tomography scans were acquired during follow-up.ResultsBoth patients, aged 45 and 50 years, had good visual acuities (>20/20) in the context of prolonged dark adaptation. Baseline color fundus photography demonstrated yellow-white, punctate lesions in the temporal macula that correlated with a reticular pattern on fundus autofluorescence and near-infrared reflectance imaging. Baseline spectral domain optical coherence tomography imaging revealed subretinal deposits that resemble reticular pseudodrusen described in age-related macular degeneration. During follow-up, these affected areas developed confluent thickening of the retinal pigment epithelial layer and disruption of the ellipsoid zone of photoreceptors before progressing to overt retinal pigment epithelium and outer retinal atrophy.ConclusionStructural changes in early stages of late-onset retinal degeneration, revealed by multimodal imaging, resemble those of reticular pseudodrusen observed in age-related macular degeneration and other retinal diseases. Longitudinal follow-up of these lesions helps elucidate their progression to frank atrophy and may lend insight into the pathogenic mechanisms underlying diverse retinal degenerations.

Background Sepsis coincides with altered gene expression in different tissues. Accumulating evidence has suggested that microRNAs, long non-coding RNAs, and circular RNAs are important molecules involved in the crosstalk with various pathways pertinent to innate immunity, mitochondrial functions, and apoptosis. Methods We searched articles indexed in PubMed (MEDLINE), EMBASE and Europe PubMed Central databases using the Medical Subject Heading (MeSH) or Title/Abstract words (“microRNA”, “long non-coding RNA”, “circular RNA”, “sepsis” and/or “septic shock”) from inception to Sep 2016. Studies investigating the role of host-derived microRNA, long non-coding RNA, and circular RNA in the pathogenesis of and as biomarkers or therapeutics in sepsis were included. Data were extracted in terms of the role of non-coding RNAs in pathogenesis, and their applicability for use as biomarkers or therapeutics in sepsis. Two independent researchers assessed the quality of studies using a modified guideline from the Systematic Review Center for Laboratory animal Experimentation (SYRCLE), a tool based on the Cochrane Collaboration Risk of Bias tool. Results Observational studies revealed dysregulation of non-coding RNAs in septic patients. Experimental studies confirmed their crosstalk with JNK/NF-κB and other cellular pathways pertinent to innate immunity, mitochondrial function, and apoptosis. Of the included studies, the SYRCLE scores ranged from 3 to 7 (average score of 4.55). This suggests a moderate risk of bias. Of the 10 articles investigating non-coding RNAs as biomarkers, none of them included a validation cohort. Selective reporting of sensitivity, specificity, and receiver operating curve was common. Conclusions Although non-coding RNAs appear to be good candidates as biomarkers and therapeutics for sepsis, their differential expression across tissues complicated the process. Further investigation on organ-specific delivery of these regulatory molecules may be useful. Electronic supplementary material The online version of this article (doi:10.1186/s13054-016-1555-3) contains supplementary material, which is available to authorized users.

Purpose To compare evaluation by clinical examination with image grading at a reading center for the classification of diabetic retinopathy and diabetic macular edema. Methods Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Family Investigations of Nephropathy in Diabetes (FIND) had similar methods of clinical and fundus photograph evaluation. For analysis purposes, the photographic grading scales were condensed to correspond to the clinical scales, and agreement between clinicians and reading center classification were compared. Results Six thousand nine hundred and two eyes of ACCORD participants and 3,638 eyes of FIND participants were analyzed for agreement (percent, kappa) on diabetic retinopathy on a 5-level scale. Exact agreement between clinicians and reading center on diabetic retinopathy severity category was 69% in ACCORD and 74% in FIND (kappa 0.42 and 0.65). Sensitivities of the clinical grading to identify the presence of mild nonproliferative retinopathy or worse were 0.53 in ACCORD and 0.84 in FIND. Specificities were 0.97 and 0.96, respectively. Diabetic macular edema agreement in 6,649 eyes of ACCORD participants and 3,366 eyes of FIND participants was similar (kappa 0.35 and 0.41). Sensitivities of the clinical grading to identify diabetic macular edema were 0.44 and 0.53 and specificities were 0.99 and 0.94, respectively. Conclusion The results support the use of clinical information for defining broad severity categories but not for documenting small-to-moderate changes in diabetic retinopathy over time.

Purpose To investigate pigment clumping in idiopathic macular telangiectasia type 2 (IMT2) for its incidence, development, and progression during the course of the disease.

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 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.

The purpose of this study was to quantify photoreceptor outer segment (PROS) length in 27 consecutive patients (30 eyes) with diabetic macular edema using spectral domain optical coherence tomography and to describe the correlation between PROS length and visual acuity.Three spectral domain-optical coherence tomography scans were performed on all eyes during each session using Cirrus HD-OCT. A prototype algorithm was developed for quantitative assessment of PROS length. Retinal thicknesses and PROS lengths were calculated for 3 parameters: macular grid (6 x 6 mm), central subfield (1 mm), and center foveal point (0.33 mm). Intrasession repeatability was assessed using coefficient of variation and intraclass correlation coefficient. The association between retinal thickness and PROS length with visual acuity was assessed using linear regression and Pearson correlation analyses. The main outcome measures include intrasession repeatability of macular parameters and correlation of these parameters with visual acuity.Mean retinal thickness and PROS length were 298 mum to 381 microm and 30 microm to 32 mum, respectively, for macular parameters assessed in this study. Coefficient of variation values were 0.75% to 4.13% for retinal thickness and 1.97% to 14.01% for PROS length. Intraclass correlation coefficient values were 0.96 to 0.99 and 0.73 to 0.98 for retinal thickness and PROS length, respectively. Slopes from linear regression analyses assessing the association of retinal thickness and visual acuity were not significantly different from 0 (P0.20), whereas the slopes of PROS length and visual acuity were significantly different from 0 (P0.0005). Correlation coefficients for macular thickness and visual acuity ranged from 0.13 to 0.22, whereas coefficients for PROS length and visual acuity ranged from -0.61 to -0.81.Photoreceptor outer segment length can be quantitatively assessed using Cirrus HD-OCT. Although the intrasession repeatability of PROS measurements was less than that of macular thickness measurements, the stronger correlation of PROS length with visual acuity suggests that the PROS measures may be more directly related to visual function. Photoreceptor outer segment length may be a useful physiologic outcome measure, both clinically and as a direct assessment of treatment effects.

Purpose To use multiple imaging methods to investigate patients with type 2 idiopathic macular telangiectasia (IMT) at different disease severity stages so as to characterize and categorize disease progression through the full spectrum of disease phenotypes. Design Observational case series. Methods Twelve patients with type 2 IMT (22 eyes) examined with fundus photography, angiography, optical coherence tomography imaging, fundus autofluorescence (FAF), and microperimetry testing in an institutional setting. Results Eyes examined by multiple imaging methods were classified into 5 proposed categories (0 through 4): category 0 (fellow) eyes had normal results on all imaging methods. Category 1 eyes had increased foveal autofluorescence on FAF imaging as the only imaging abnormality. Category 2 eyes had increased foveal autofluorescence together with funduscopic and angiographic features typical of type 2 IMT. Category 3 eyes had additional evidence of foveal atrophy on optical coherence tomography, and category 4 eyes had all the above features plus clinically evident pigment clumping. FAF signal increased in intensity in the foveal region from category 0 through category 3, whereas category 4 eyes demonstrated a mixed pattern of increased and decreased FAF signal. Conclusions The findings here outline a sequence of progressive changes seen with multiple imaging methods in advancing stages of disease. Increase in foveal autofluorescence is an early anatomic change in type 2 IMT that may precede typical clinical and angiographic changes. Loss of macular pigment density in the fovea and a changing composition of fluorophores in the retinal pigment epithelium may underlie these changes on FAF in the fundus.