Stereoscopic Color Fundus Photographs Research Articles

Association of Visceral Obesity Indices With Incident Diabetic Retinopathy in Patients With Diabetes: Prospective Cohort Study.

Visceral adipose tissue plays an active role in the pathogenesis of type 2 diabetes and vascular dysfunction. The lipid accumulation product (LAP), visceral adiposity index (VAI), and Chinese VAI (CVAI) have been proposed as simple and validated surrogate indices for measuring visceral adipose tissue. However, the evidence from prospective studies on the associations between these novel indices of visceral obesity and diabetic retinopathy (DR) remains scant. This study aimed to investigate the longitudinal associations of LAP, VAI, and CVAI with incident DR in Chinese patients with diabetes. This was a prospective cohort study conducted in Guangzhou in southern China. We collected baseline data between November 2017 and July 2020, while on-site follow-up visits were conducted annually until January 2022. The study participants consisted of 1403 patients with a clinical diagnosis of diabetes, referred from primary care, who were free of DR at baseline. The LAP, VAI, and CVAI levels were calculated by sex-specific equations based on anthropometric and biochemical parameters. DR was assessed using 7-field color stereoscopic fundus photographs and graded according to the modified Airlie House Classification scheme. Time-dependent Cox proportional hazard models were constructed to estimate the hazard ratios with 95% CIs. Restricted cubic spline curves were fitted to examine the dose-response relationship between the 3 indices of visceral obesity and new-onset DR. Subgroup analyses were performed to investigate the potential effect modifiers. The mean age of study participants was 64.5 (SD 7.6) years, and over half (816/1403, 58.2%) were female. During a median follow-up of 2.13 years, 406 DR events were observed. A 1-SD increment in LAP, VAI, or CVAI was consistently associated with increased risk for new-onset DR, with a multivariable‑adjusted hazard ratio of 1.24 (95% CI 1.09-1.41; P=.001), 1.22 (95% CI 1.09-1.36; P<.001), and 1.48 (95% CI 1.19-1.85; P=.001), respectively. Similar patterns were observed across tertiles in LAP (P for trend=.001), VAI (P for trend<.001), and CVAI (P for trend=.009). Patients in the highest tertile of LAP, VAI, and CVAI had an 84%, 86%, and 82% higher hazard of DR, respectively, compared to those in the lowest tertile. A nonlinear dose-response relationship with incident DR was noted for LAP and VAI (both P for nonlinearity<.05), but not for CVAI (P for nonlinearity=.51). We did not detect the presence of effect modification by age, sex, duration of diabetes, BMI, or comorbidity (all P for interaction>.10). Visceral obesity, as measured by LAP, VAI, or CVAI, is independently associated with increased risk for new-onset DR in Chinese patients with diabetes. Our findings may suggest the necessity of incorporating regular monitoring of visceral obesity indices into routine clinical practice to enhance population-based prevention for DR.

Macular Telangiectasia Type 2: A Classification System Using MultiModal Imaging MacTel Project Report Number 10.

To develop a severity classification for macular telangiectasia type 2 (MacTel) disease using multimodal imaging. An algorithm was used on data from a prospective natural history study of MacTel for classification development. A total of 1733 participants enrolled in an international natural history study of MacTel. The Classification and Regression Trees (CART), a predictive nonparametric algorithm used in machine learning, analyzed the features of the multimodal imaging important for the development of a classification, including reading center gradings of the following digital images: stereoscopic color and red-free fundus photographs, fluorescein angiographic images, fundus autofluorescence images, and spectral-domain (SD)-OCT images. Regression models that used least square method created a decision tree using features of the ocular images into different categories of disease severity. The primary target of interest for the algorithm development by CART was the change in best-corrected visual acuity (BCVA) at baseline for the right and left eyes. These analyses using the algorithm were repeated for the BCVA obtained at the last study visit of the natural history study for the right and left eyes. The CART analyses demonstrated 3 important features from the multimodal imaging for the classification: OCT hyper-reflectivity, pigment, and ellipsoid zone loss. By combining these 3 features (as absent, present, noncentral involvement, and central involvement of the macula), a 7-step scale was created, ranging from excellent to poor visual acuity. At grade 0, 3 features are not present. At the most severe grade, pigment and exudative neovascularization are present. To further validate the classification, using the Generalized Estimating Equation regression models, analyses for the annual relative risk of progression over a period of 5 years for vision loss and for progression along the scale were performed. This analysis using the data from current imaging modalities in participants followed in the MacTel natural history study informed a classification for MacTel disease severity featuring variables from SD-OCT. This classification is designed to provide better communications to other clinicians, researchers, and patients. Proprietary or commercial disclosure may be found after the references.

Peripapillary Microvasculature Predicts the Incidence and Development of Diabetic Retinopathy: An SS-OCTA Study

To examine the associations of peripapillary microvascular metrics with diabetic retinopathy (DR) incidence and development using swept-source optical coherence tomography angiography (SS-OCTA). Prospective cohort study. A total of 1033 eyes from 1033 patients with type 2 diabetes mellitus (T2DM) were included, with 2-year follow-up. The peripapillary microvascular metrics at the superficial capillary plexus (SCP) were measured by SS-OCTA at the baseline, including peripapillary vascular density (pVD) and peripapillary vascular length density (pVLD). The DR incidence and progression were evaluated with 7 standard fields of stereoscopic color fundus photographs. The associations were tested with logistic regression models after adjusting for established risk factors and confounding factors. The prediction value of OCTA metrics was examined with the elevation of area under the receiver operating characteristic curve (AUROC). The 2-year incidence of diabetic retinopathy (DR) was 25.1% (n=222) in non-DR (NDR) eyes, 7.4% DR progression (n=11) in DR eyes, and 4.17% RDR eyes (n=43) in all eyes. After adjusting for established factors, lower whole-image pVD (wi-pVD) (relative risk [RR]=0.81; 95% CI=0.68-0.96; P=.015), circular pVD (circ-pVD) (RR=0.79; 95% CI=0.66-0.95; P=.013), whole-image pVLD (wi-pVLD) (RR=0.79; 95% CI=0.67-0.94; P=.008), and circular pVLD (circ-pVLD) (RR=0.76; 95% CI=0.63-0.91; P=.003) were significantly associated with increased risk of DR incidence; wi-pVD (RR=0.48; 95% CI=0.35-0.67; P < .001), circ-pVD (RR=0.65; 95% CI=0.45-0.94; P=.023), and wi-pVLD (RR=0.46; 95% CI=0.33-0.66; P < .001) were associated with incident risk of RDR. Both pVD and pVLD of SCP were not significantly associated with DR progression. The AUROC for the DR incidence risk prediction model increased from 0.631 to 0.658 (4.28%; P=.041) by circ-pVLD; the AUC of the RDR incidence risk prediction model increased from 0.631 to 0.752 by wi-pVD (19.18%; P=.009), to 0.752 by circ-pVD (19.18%; P=.009), and to 0.752 by wi-pVLD (19.18%; P=.009). Lower pVD and pVLD of SCP are associated with 2-year incident DR and RDR among the T2DM population. The peripapillary metrics imaged by SS-OCTA can provide additional value to the prediction of DR incidence and development.

Progression of Geographic Atrophy with Subsequent Exudative Neovascular Disease in Age-Related Macular Degeneration: AREDS2 Report 24

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. Post hoc analysis of a controlled clinical trial cohort. Age-Related Eye Disease Study 2 participants 50 to 85 years of age. 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. Change over time in square root of GA area. 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). In eyes with recent GA, GA enlargement before the development of exudative nAMD seemsslowed. This association was not observed in eyes with more long-standing GA, which have larger lesionsizes. Hence, perilesional nonexudative choroidal neovascular tissue (presumably present before the development of clinically apparent exudation) may slow enlargement of smaller GA lesions through improvedperfusion. Thishypothesis warrants further evaluation in prospective studies.

Grading Diabetic Retinopathy from Stereoscopic Color Fundus Photographs — An Extension of the Modified Airlie House Classification: ETDRS Report Number 10

The modified Airlie House classification of diabetic retinopathy has been extended for use in the Early Treatment Diabetic Retinopathy Study (ETDRS). The revised classification provides additional steps in the grading scale for some characteristics, separates other characteristics previously combined, expands the section on macular edema, and adds several characteristics not previously graded. The classification is described and illustrated and its reproducibility between graders is assessed by calculating percentages of agreement and kappa statistics for duplicate gradings of baseline color non- simultaneous stereoscopic fundus photographs. For retinal hemorrhages and/ or microaneurysms, hard exudates, new vessels, fibrous proliferations, and macular edema, agreement was substantial (weighted kappa, 0.61 to 0.80). For soft exudates, intraretinal microvascular abnormalities, and venous beading, agreement was moderate (weighted kappa, 0.41 to 0.60). A double grading system, with adjudication of disagreements of two or more steps between duplicate gradings, led to some improvement in reproducibility for most characteristics.

Prevalence of Age-related Maculopathy: The Beaver Dam Eye Study

The relationships of retinal drusen, retinal pigmentary abnormalities, and macular degeneration to age and sex were studied in 4926 people between the ages of 43 and 86 years who participated in the Beaver Dam Eye Study. The presence and severity of various characteristics of drusen and other lesions typical of age-related maculopathy were determined by grading stereoscopic color fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. One or more drusen were present in the macular area of at least 1 eye in 95.5% of the population. People 75 years of age or older had significantly higher frequencies (P < 0.01) of the following characteristics than people 43 to 54 years of age: larger sized drusen (>125 /μm, 24.0% versus 1.9%), soft indistinct drusen (23.0% versus 2.1%), retinal pigment abnormalities (26.6% versus 7.3%), exudative macular degeneration (5.2% versus 0.1%), and geographic atrophy (2.0% versus 0%). These data indicate signs of age-related maculopathy are common in people 75 years of age or older and may pose a substantial public health problem.

Visual Acuity Outcomes after Anti–Vascular Endothelial Growth Factor Treatment for Neovascular Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report Number 19

To analyze best-corrected visual acuity (BCVA) outcomes after anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (AMD). Prospective cohort study of participants enrolled in a clinical trial of oral supplements and receiving anti-VEGF therapy in routine clinical practice. Age-Related Eye Disease Study 2 (AREDS2) participants (50-85 years of age) whose eyes met AREDS2 inclusion criteria at baseline (no late AMD, BCVA ≥20/100, no previous anti-VEGF injections) but received at least 1 anti-VEGF injection for incident neovascular AMD during follow-up. Participants underwent refracted BCVA testing, ophthalmoscopic examination, and stereoscopic color fundus photography at baseline and annual study visits over 5 years. Self-reports of anti-VEGF injections (numbers, dates, and names of drug) were collected at baseline and annual study visits and during telephone calls every 6 months. Primary outcome measures were mean refracted BCVA and proportions of eyes with BCVA of 20/40 or better and 20/200 or worse. An exploratory outcome measure was the mean number of self-reported anti-VEGF injections. One thousand one hundred five eyes of 986 AREDS2 participants met the inclusion criteria; of these, 977 participants (99.1%) underwent at least 1 posttreatment visit. At the first and subsequent annual examinations after the first injection, mean refracted BCVAs were 68.0 letters (Snellen equivalent, 20/40), 66.1 letters, 64.7 letters, 63.2 letters, and 61.5 letters (Snellen equivalent, 20/60). Proportions of eyes with BCVA of 20/40 or better were 59.3%, 55.1%, 53.5%, 50.6%, and 49.7%, and those with BCVA of 20/200 or worse were 5.5%, 8.6%, 9.4%, 12.4%, and 14.4%. Mean annual numbers of self-reported anti-VEGF injections per eye were 2.9, 3.9, 3.3, 3.1, and 3.0. Refracted BCVA data were obtained in a clinical trial environment but were related to anti-VEGF treatment administered in normal clinical practice. Visual outcomes declined slowly with increased follow-up time: mean BCVA decreased by approximately 1.5 to 2 letters per year. At 5 years, half of eyes achieved BCVA of 20/40 or better, but approximately one sixth showed BCVA of 20/200 or worse. These data may be useful in assessing the long-term effects of anti-VEGF therapy.

Evaluation of choroidal thickness in different stages of diabetic retinopathy

Purpose: to assess changes of choroidal thickness (CT) in diabetic patients in different stages of diabetic retinopathy and diabetic macular edema using spectral domain optical coherence tomography. Patients and methods: One hundred and sixty three subjects were enrolled: 113 diabetic patients (186 eyes) and 50 normal individuals as controls. Eyes were divided into two groups according to age; group A from 35 to 50 years and group B from 51 to 65 years. Both groups classified according to retinopathy grade: DR1 (no DR), DR2 (mild- moderate nonproliferative diabetic retinopathy (NPDR)), DR3 (severe NPDR), DR4 (untreated proliferative diabetic retinopathy (PDR)) and DR5 (previously treated PDR). All participants underwent full ophthalmic examination, stereoscopic color fundus photography, and spectral domain optical coherence tomography (RS-3000; Nidek). Spectral domain optical coherence tomography examination consisted of linear scans, 6 mm in length, centered onto the fovea, and macula multi scans. Choroidal thickness was measured manually at the fovea and at 500, 1000, and 1500 um distance along all scans in the macula. Results: Mean age was not significantly different between patients with diabetes and controls. In the macular area, CT was significantly lower in the nasal quadrant versus all other quadrants (P, 0.0001), in both groups. No significant CT difference was found between controls and diabetic eyes without detectable DR. Diabetic macular edema did not influence CT. In early NPDR (mild and moderate) and treated PDR the mean choroidal thickness was significantly decreased than control. In severe NPDR and treated PDR, the mean subfoveal choroidal thickness was not different than control. There was a statistically significant increase in choroidal thickness in PDR when compared with the mild NPDR group (P=0.027). DME was associated with a non-statistically significant increase in choroidal thickness compared with eyes without DME (P=0.13). Conclusion: Choroidal thickness is reduced in diabetic eyes. Subfoveal choroidal thickness increased with the severity of diabetic retinopathy but showed no statistically significant association with the presence of DME. Spectral domain optical coherence tomography clearly confirms in vivo previously reported histopathologic observations. The role of choroid in the pathophysiology of DR needs to be adequately investigated.

Progression of Geographic Atrophy in Age-related Macular Degeneration: AREDS2 Report Number 16

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. Prospective cohort study within a controlled clinical trial. Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50-85 years. 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. (1) Presence or development of GA; (2) change in the square root of GA area over time. 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 < 0.0001 for interaction in each case) but not with AREDS2 treatment assignment (P= 0.33) or smoking status (P= 0.05). Enlargement was significantly faster with ARMS2 risk (P < 0.0001), C3 non-risk (P= 0.0002), and APOE non-risk (P= 0.001) genotypes. 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.

The Relationship of Retinal Vessel Geometric Characteristics to the Incidence and Progression of Diabetic Retinopathy

To examine the relationships of retinal vessel geometric characteristics (RVGCs) to the incidence and progression of diabetic retinopathy (DR). Observational, prospective cohort study. Nine hundred ninety-six persons with type 1 diabetes mellitus (T1DM) and 1370 persons with type 2 diabetes mellitus (T2DM) seen at a baseline examination who were eligible for follow-up examinations at subsequent 5-year intervals. A total of 3846 person-interval data from these follow-up examinations are the basis for the analyses. Diabetic retinopathy and macular edema were assessed by grading of 30° stereoscopic color fundus photographs. Retinal vessel geometric characteristics were assessed using the Singapore I Vessel Assessment program from a digitized copy of 1 of the field 1 fundus photographs obtained at baseline and follow-up. The 5-year incidence of any DR, progression of DR, and incidence of proliferative diabetic retinopathy (PDR) and clinically significant macular edema (CSME) in right eyes. Incident DR occurred in 45%, progression in 32%, PDR in 10%, and CSME in 5%. While adjusting for glycated hemoglobin, duration of diabetes, and other factors, retinal arteriolar simple tortuosity was associated significantly with the incidence of any DR (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.01-1.35). Retinal venular branching angle was associated significantly with progression of DR (OR, 1.18; 95% CI, 1.03-1.36), retinal venular curvature tortuosity was associated significantly with the incidence of PDR (OR, 1.15; 95% CI, 1.01-1.30), and retinal venular branching angle (OR, 1.41; 95% CI, 1.10-1.82) was associated significantly with the incidence of CSME. There were no significant associations of other RVGCs with any of the DR outcomes in the full multivariate model. Inclusion of all possible RVGCs did not improve the predictive value of the models that already included retinal vessel diameter and baseline DR severity level. Retinal vessel geometric characteristics of the retinal venules were associated with progression of DR; however, most of the RVGCs measured from digitized fundus photographs added little to the assessment of risk of incidence and progression of DR when other risk factors were considered in T1DM and T2DM.

The Nine-Step Minnesota Grading System for Eyebank Eyes With Age Related Macular Degeneration: A Systematic Approach to Study Disease Stages.

To refine the Minnesota Grading System (MGS) using definitions from the Age-Related Eye Disease Studies (AREDS) into a nine-step grading scale (MGS-9). A nine-step grading scale descriptive analysis using three key phenotypic features (total drusen area, increased, and decreased pigmentation) of human eyebank eyes that were graded according to definitions from the AREDS criteria in order to harmonize studies of disease progression for research involving human tissue. From 2005 through February 2017, we have analyzed 1159 human eyes, procured from two eyebanks. Each macula was imaged using high-resolution, stereoscopic color fundus photography with both direct- and transillumination. Fundus images were digitally overlaid with a grading template and triangulated for foveal centration. We documented and stratified risk for each globe by applying the AREDS nine-step grading scale to the key clinical features from the MGS-9. We found a good distribution within the MGS categories (1-9) with few level eight globes. Eyes were processed within 12.1 ± 6.3, hours from the time of death through imaging, dissection, and freezing or fixation. Applying the MGS-9 to 331 pairs (662 eyes were simultaneously graded), 84% were within one-grading step and 93% within two steps of the fellow eye. We also document reticular pseudodrusen, basal laminar drusen, and pattern dystrophy. The MGS nine-step grading scale enables researchers using human tissue to refine the risk assessment of donor tissue. This analysis will harmonize results among researchers when grading human tissue using MGS criteria. Most importantly, the MGS-9 links directly to the known risk for progression from the AREDS.

Morphological assessment of the retina in uveitis.

BackgroundThe objective of this study is to describe a system for color photograph evaluation in uveitis and report baseline morphologic findings for the Multicenter Uveitis Steroid Treatment (MUST) Trial.Four-hundred seventy-nine eyes of 255 subjects with intermediate, posterior, and panuveitis had stereoscopic color fundus photographs obtained by certified photographers and evaluated by certified graders using standardized procedures to evaluate morphologic characteristics of uveitis. The posterior pole was evaluated for macular edema, vitreoretinal interface abnormalities, and macular pigment disturbance/atrophy; the optic disk was assessed for edema, pallor, or glaucomatous changes. The presence of neovascularization, vascular occlusion, vascular sheathing, and tractional retinal changes was determined. A random subset of 77 images was re-graded to determine the percentage agreement with the original grading on a categorical scale.ResultsAt baseline, 437/479 eyes had images available to grade. Fifty-three eyes were completely ungradable due to media opacity. Common features of intermediate and posterior/panuveitis were epiretinal membrane (134 eyes, 35 %), and chorioretinal lesions (140 eyes, 36 %). Macular edema was seen in 16 %. Optic nerve head and vascular abnormalities were rare. Reproducibility evaluation found exact agreement for the presence of chorioretinal lesions was 78 %, the presence and location of macular edema was 71 %, and the presence of epiretinal membrane was 71 %. Vertical cup-to-disk ratio measurement had intra-class correlation of 0.75.ConclusionsThe MUST system for evaluating stereoscopic color fundus photographs describes the morphology of uveitis and its sequelae, in a standardized manner, is highly reproducible, and allows monitoring of treatment effect and safety evaluation regarding these outcomes in clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s12348-016-0103-2) contains supplementary material, which is available to authorized users.

Effects of Prior Intensive Insulin Therapy and Risk Factors on Patient-Reported Visual Function Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Cohort.

Preservation of vision in patients with diabetes mellitus is critical. Interventions to improve glycemic control through early intensive treatment of diabetes reduce rates of severe retinopathy and preserve visual acuity. To assess the effects of prior intensive insulin treatment and risk factors on patient-reported visual function in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Cohort study of 1184 participants with type 1 diabetes from the DCCT/EDIC study (randomized clinical trial followed by an observational follow-up study) who completed the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) during EDIC years 17 through 20 (September 1, 2009, through April 30, 2014) in 28 institutions across the United States and Canada. The primary outcome was the composite NEI-VFQ-25 score. Secondary outcomes were visual acuity (measured by the Early Treatment Diabetic Retinopathy Study protocol), retinopathy level (determined by masked grading of stereoscopic color fundus photographs), and NEI-VFQ-25 subscale scores. The composite NEI-VFQ-25 scale and its subscales were scored 0 to 100, corresponding to poor to excellent function, respectively. The overall average NEI-VFQ-25 score for 1184 DCCT/EDIC participants (mean [SD] age, 52.3 [6.9] years; 48% female) with a 30-year duration of diabetes was high (all participants: median, 91.7; interquartile range [IQR], 89.7-96.9; intensive treatment [n = 605]: median, 94.7; IQR, 91.0-97.2; conventional treatment [n = 579]: median, 94.0; IQR, 88.4-96.1; P = .006 for intensive vs conventional). After adjustment for sex, age, hemoglobin A1c level, and retinopathy level at DCCT baseline, the former intensive treatment group had a significant, albeit modest, improvement in overall NEI-VFQ-25 score compared with the former conventional diabetes treatment group (median difference, -1.0; 95% CI, -1.7 to -0.3; P = .006). This beneficial treatment effect was fully attributed to the prior glycemic control in DCCT (explained treatment effect: 100%). Those with visual acuity worse than 20/100 reported the largest decline in visual function (median difference, -21.0; 95% CI, -40.5 to -1.6; P = .03). In the DCCT/EDIC cohort, patient-reported visual function remains high in both treatment groups, comparable to previous reports of overall health-related quality of life. Intensive diabetes therapy modestly improved NEI-VFQ-25 score 30 years after the start of the DCCT, the benefit underestimated owing to more nonparticipants from the conventional treatment group. Visual acuity had the greatest effect on patient-reported visual function from among all risk factors. clinicaltrials.gov Identifiers: NCT00360815 and NCT00360893.

Pathogenesis of optic disc edema in raised intracranial pressure.

Optic disc edema in raised intracranial pressure was first described in 1853. Ever since, there has been a plethora of controversial hypotheses to explain its pathogenesis. I have explored the subject comprehensively by doing basic, experimental and clinical studies. My objective was to investigate the fundamentals of the subject, to test the validity of the previous theories, and finally, based on all these studies, to find a logical explanation for the pathogenesis. My studies included the following issues pertinent to the pathogenesis of optic disc edema in raised intracranial pressure: the anatomy and blood supply of the optic nerve, the roles of the sheath of the optic nerve, of the centripetal flow of fluids along the optic nerve, of compression of the central retinal vein, and of acute intracranial hypertension and its associated effects. I found that, contrary to some previous claims, an acute rise of intracranial pressure was not quickly followed by production of optic disc edema. Then, in rhesus monkeys, I produced experimentally chronic intracranial hypertension by slowly increasing in size space-occupying lesions, in different parts of the brain. Those produced raised cerebrospinal fluid pressure (CSFP) and optic disc edema, identical to those seen in patients with elevated CSFP. Having achieved that, I investigated various aspects of optic disc edema by ophthalmoscopy, stereoscopic color fundus photography and fluorescein fundus angiography, and light microscopic, electron microscopic, horseradish peroxidase and axoplasmic transport studies, and evaluated the effect of opening the sheath of the optic nerve on the optic disc edema. This latter study showed that opening the sheath resulted in resolution of optic disc edema on the side of the sheath fenestration, in spite of high intracranial CSFP, proving that a rise of CSFP in the sheath was the essential pre-requisite for the development of optic disc edema. I also investigated optic disc edema with raised CSFP in patients, by evaluating optic disc and fundus changes by stereoscopic fundus photography and fluorescein fundus angiography. Based on the combined information from all the studies discussed above, it is clear that the pathogenesis of optic disc edema in raised intracranial pressure is a mechanical phenomenon. It is primarily due to a rise of CSFP in the optic nerve sheath, which produces axoplasmic flow stasis in the optic nerve fibers in the surface nerve fiber layer and prelaminar region of the optic nerve head. Axoplasmic flow stasis then results in swelling of the nerve fibers, and consequently of the optic disc. Swelling of the nerve fibers and of the optic disc secondarily compresses the fine, low-pressure venules in that region, resulting in venous stasis and fluid leakage; that leads to the accumulation of extracellular fluid. Contrary to the previous theories, the various vascular changes seen in optic disc edema are secondary and not primary. Thus, optic disc edema in raised CSFP is due to a combination of swollen nerve fibers and the accumulation of extracellular fluid. My studies also provided information about the pathogeneses of visual disturbances in raised intracranial pressure.

MACULAR AND PERIPAPILLARY CHOROIDAL THICKNESS IN DIABETIC PATIENTS

To investigate macular and peripapillary choroidal thickness (CT) in diabetic patients with and without diabetic retinopathy (DR). One hundred and fifty subjects were enrolled: 102 diabetic patients (102 eyes) and 48 normals, as controls. Exclusion criteria were previously treated DR, refractive error higher than ± 3 diopters, and treated or untreated glaucoma. All patients underwent full ophthalmic examination, stereoscopic color fundus photography, and spectral domain optical coherence tomography (RS-3000; Nidek). Spectral domain optical coherence tomography examination consisted of linear scans, 6 mm in length, centered onto the fovea, and circle scan positioned around the optic disk (3.46 mm in diameter). Choroidal thickness was measured manually at the fovea and at 1, 2, and 3 mm distance along all scans in the macula. Peripapillary CT was measured at eight points along the circle scan. All measurements were performed independently by 2 masked graders. Mean age was not significantly different between patients with diabetes and controls. In the macular area, CT was significantly lower in the nasal quadrant versus all other quadrants (P < 0.0001), in both groups. In the peripapillary area, CT was significantly lower in the inferior quadrant versus all other quadrants (P < 0.05), in both groups. Mean macular and peripapillary CT progressively and significantly decreased with increasing level of DR (nonproliferative and proliferative DR vs. controls, P < 0.05). No significant CT difference was found between controls and diabetic eyes without detectable DR. Diabetic macular edema did not influence CT. Interobserver coefficient of repeatability was 28.8 (95% confidence interval, 24.8-32.8) for foveal measurements and 13.0 (95% confidence interval, 11.2-14.8) for peripapillary measurements. Pearson correlation coefficient was 0.99, and P <0.0001 for all measurements. Choroidal thickness is reduced in diabetic eyes and parallels appearance and evolution of DR. Spectral domain optical coherence tomography clearly confirms in vivo previously reported histopathologic observations. The role of choroid in the pathophysiology of DR needs to be adequately investigated.

Prevention of Age-Related Macular Degeneration–Like Retinopathy by Rapamycin in Rats

Age-related macular degeneration, a neurodegenerative and vascular retinal disease, is the most common cause of blindness in the Western countries. Evidence accumulates that target of rapamycin is involved in aging and age-related diseases, including neurodegeneration. The target of rapamycin inhibitor, rapamycin, suppresses the senescent cell phenotype and extends life span in diverse species, including mice. Rapamycin decreases senescence-associated phenotypes in retinal pigment epithelial cells in culture. Herein, we investigated the effect of rapamycin on spontaneous retinopathy in senescence-accelerated OXYS rats, an animal model of age-related macular degeneration. Rats were treated with either 0.1 or 0.5 mg/kg rapamycin, which was given orally as a food mixture. In a dose-dependent manner, rapamycin decreased the incidence and severity of retinopathy. Rapamycin improved some (but not all) histological abnormalities associated with retinopathy. Thus, in retinal pigment epithelial cell layers, rapamycin decreased nuclei heterogeneity and normalized intervals between nuclei. In photoreceptor cells, associated neurons, and radial glial cells, rapamycin prevented nuclear and cellular pyknosis. More important, rapamycin prevented destruction of ganglionar neurons in the retina. Rapamycin did not exert any adverse effects on the retina in control disease-free Wistar rats. Taken together, our data suggest the therapeutic potential of rapamycin for treatment and prevention of retinopathy.

Photographic Assessment of Baseline Fundus Morphologic Features in the Comparison of Age-related Macular Degeneration Treatments Trials

To describe the methods used for assessment of baseline fundus characteristics from color photography and fluorescein angiography (FA) in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and to describe the relationship between these characteristics and visual acuity. Randomized, masked, multicenter trial. This investigation included 1185 participants of the CATT study. Baseline stereoscopic color fundus photographs and FAs of participants in the CATT study were assessed at a central fundus photograph reading center by masked readers. Replicate assessments of random samples of photographs were performed to assess intragrader and intergrader agreements. The association of the lesion characteristics with baseline visual acuity was assessed using analyses of variance and correlation coefficients. Intragrader and intergrader reproducibility, visual acuity, and lesion characteristics. Intragrader and intergrader reproducibility showed agreements ranging from 75% to 100% and weighted κ values ranging from 0.48 to 1.0 for qualitative determinations. The intraclass correlation coefficients were 0.96 to 0.97 for quantitative measurements of choroidal neovascularization (CNV) area and total area of CNV lesion. The mean visual acuity varied by the type of pathologic features in the foveal center: 64.5 letters (standard error, 0.7 letters) for fluid only, 59.0 letters (standard error, 0.5 letters) for CNV, and 58.7 letters (standard error, 1.3 letters) for hemorrhage (P<0.001). Fibrotic or atrophic scar present in the lesion, but not under the center of the fovea, also was associated with a markedly reduced visual acuity of 48.4 letters (standard error, 2.2 letters; P<0.0001). Although total area of CNV lesion was correlated weakly with visual acuity when all participants were assessed (Spearman correlation coefficient, ρ = -0.16; P<0.001), the correlation was stronger within patients with predominantly classic lesions (ρ = -0.42; P<0.001). These results show that the methodology used for grading CATT fundus images has good reproducibility. As expected, larger total CNV lesion area and pathologic findings such as hemorrhage, fibrosis, and atrophy at baseline are associated with decreased visual acuity.

Increased Caucasian Prevalence of Medium and Large Drusen, Focal Pigment Abnormalities, and Advanced Age-related Macular Degeneration

Recent advances in effective therapies slow the progression of intermediate AMD to advanced AMD and decrease the risk for moderate vision loss associated with the development of choroidal neovascularization (CNV). However, epidemiological investigations remain important to identify possible risk factors for the development or progression of AMD, to recognize susceptible individuals and populations, to promote screening, education, and prevention tools, and to generate hypotheses for disease pathogenesis. For instance, the strongest and most consistent association between incident and prevalent AMD and a modifiable risk factor has been tobacco use. 2 It is theorized that hypoxia stimulates vascular endothelial growth factor (VEGF) production, which in turn upregulates retinal endothelial cell proliferation, which fosters the development of CNV. 3 Smoking may potentiate hypoxic retinal conditions, thus contributing to the pathogenesis and progression of AMD. Identifying patients with this modifiable risk factor and educating them about the potential benefits of tobacco cessation may have a significant long-term impact on lowering the incidence and progression of AMD. Many of the landmark epidemiological studies concentrating on AMD have employed a standardized approach to identify ‘cases’ of AMD. Case recognition has involved the use of high-quality stereoscopic color fundus photographs, obtained by certified photographers adhering to a protocol, which are then graded by trained and experienced readers with systematic application of standard definitions and reference photographs to generate levels of specific AMD features and levels of disease. As many studies have used similar means of generating their data, pooling of databases has been facilitated and some comparisons can be made between studies to partially overcome the limitation that only a few investigations have involved populations with heterogeneous ethnic backgrounds. While there are minor distinctions from one population-based study to the next in terms of the characterization of specific ocular features that comprise the early, intermediate, and advanced stages of AMD, the descriptions that follow are generally accepted, and the prevalence of each level of AMD has repeatedly been shown to be age-related. The label ‘early’ AMD requires that an eye has, as its most advanced feature, the presence of at least one medium-sized druse, with a linear dimension that is at least 64µm and up to 125µm (including 125µm in some studies) within 3,000µm (two standard disc diameters) of the foveal center.

15-Year Cumulative Incidence and Associated Risk Factors for Retinopathy in Nondiabetic Persons

To investigate the relationship of systemic factors to the 15-year cumulative incidence of retinopathy in nondiabetic persons in the Beaver Dam Eye Study. Included were 4699 persons, 43 to 86 years of age at baseline examination in 1988-1990 and with follow-up in 1993-1995 and/or 1998-2000 and/or 2003-2005. Stereoscopic color fundus photographs were graded to determine the presence of retinopathy. The main outcome measure was cumulative incidence of retinopathy accounting for competing risk of death or diabetes mellitus. The 15-year cumulative incidence of retinopathy in the nondiabetic cohort was 14.2%. In multivariate analyses, older age (hazard ratio [HR] per age group, 1.13; 95% confidence interval [CI], 1.01-1.27), higher systolic blood pressure (HR per 10 mm Hg, 1.15; 95% CI, 1.07-1.20), presence of chronic kidney disease (HR, 1.51; 95% CI, 1.12-2.00), and wider retinal arteriolar diameter (HR per 10 μm, 1.17; 95% CI, 1.10-1.26) at baseline were associated with the incidence of retinopathy. In a separate model, the 15-year incidence of retinopathy was higher in those with uncontrolled hypertension compared with those who did not have hypertension (HR, 2.07; 95% CI, 1.51-2.83). There were no associations of body mass index, lipid levels, glycosylated hemoglobin level, smoking status, markers of inflammation, endothelial dysfunction and oxidative stress, and hematologic factors with retinopathy incidence. These data show 2 modifiable factors, uncontrolled hypertension and chronic kidney disease, are related to an increased incidence of retinopathy in nondiabetic persons and show that control of blood pressure is associated with a lower risk of incident retinopathy compared with uncontrolled blood pressure.

Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study System for Evaluation of Stereoscopic Color Fundus Photographs and Fluorescein Angiograms

To describe the procedures and reproducibility for grading stereoscopic color fundus photographs and fluorescein angiograms of participants in the SCORE Study. Standardized stereoscopic fundus photographs and fluorescein angiograms taken at 84 clinical centers were evaluated by graders at a central reading center. Type of retinal vein occlusion (RVO), area of retinal thickening, and area of retinal hemorrhage are evaluated from fundus photographs; area of fluorescein leakage and area of capillary nonperfusion are measured on fluorescein angiography. Temporal reproducibility consisted of annual regrading of a randomly selected dedicated subset of fundus photographs (60 subjects) and fluorescein angiograms (40 subjects) for 3 successive years. Contemporaneous reproducibility involved monthly regrading of a 5% random selection of recently evaluated fundus photographs (n = 73). The intergrader agreement for RVO type and presence of retinal thickening was greater than 90% in the 3 annual regrades. The intraclass correlation (ICC) for area of retinal thickening in the 3 years ranged from 0.39 to 0.64 and for area of retinal hemorrhage, 0.87 to 0.96. The ICC for area of fluorescein leakage ranged from 0.66 to 0.75 and for capillary nonperfusion, 0.94 to 0.97. The contemporaneous reproducibility results were similar to those of temporal reproducibility for all variables except area of retinal thickening (ICC, 0.84). The fundus photography and fluorescein angiography grading procedures for the SCORE Study are reproducible and can be used for multicenter longitudinal studies of RVO. A systematic temporal drift occurred in evaluating area of retinal thickening.