Ultra-widefield Imaging Research Articles

PRPH2-Associated Retinopathy: Novel Variants and Genotype–Phenotype Correlations

A broad spectrum of autosomal-dominant inherited retinal diseases (IRDs), ranging from mild macular pattern dystrophy to severe cone-rod degeneration, is associated with PRPH2 variants (peripherinopathies). We present detailed clinical and molecular characterization of patients affected by peripherinopathies, aiming to expand the mutational spectrum, and propose novel genotype-phenotype correlations. Observational, retrospective case series. Patients with an IRD related to a molecularly proven PRPH2 variant. Data from ophthalmic examinations and retinal imaging were collected for each follow-up visit. The standard imaging protocol included OCT, blue-light autofluorescence, near-infrared autofluorescence, and ultra-widefield fundus imaging. Genetic analysis was performed with a genomic approach by next-generation sequencing. Results of ophthalmic examination, retinal imaging, and molecular genetic analysis. Overall, a total of 19 patients with an IRD and a (likely) pathogenic PRPH2 variant were identified. Their age at presentation had a median of 48 years, whereas the symptomatic disease onset was in their 30s or 40s in 74% of cases. The median follow-up time was 4 years. Clinically, 6 patients were diagnosed with cone-rod dystrophy and 13 with pattern dystrophy. Among the 13 PRPH2 pathogenic variants identified in our cohort, 7 were missense, 3 nonsense, 2 frame shifting, and 1 splice site. Missense variants in the D2 loop were associated with cone-rod dystrophies and poor visual prognosis, whereas predicted loss-of-function alleles with pattern dystrophies and retention of a good visual function into adulthood. Overall, the following 7 variants were novel and never associated to a clinical phenotype: c.68delT, c.290G>A, c.413T>G, c.642C>G, c.702_706dupCAGTT, c.771_772delinsGA, and c.850C>G. Here, we report the findings of a retrospective case series that provided a detailed clinical and molecular characterization of 19 patients harboring 13 different PRPH2 pathogenic variants, 7 of which were previously unreported, expanding the mutational spectrum of the PRPH2 gene. Loss-of-function variants might be preferentially associated with mild-pattern dystrophies, whereas missense dominant-negative variants might be preferentially associated with severely blinding cone-rod degenerations. Further studies are needed to better define the pathogenetic mechanisms and the functional effects of most variants to allow the development of successful gene therapy. Proprietary or commercial disclosure may be found after the references.

Deep-learning-based AI for evaluating estimated nonperfusion areas requiring further examination in ultra-widefield fundus images

We herein propose a PraNet-based deep-learning model for estimating the size of non-perfusion area (NPA) in pseudo-color fundus photos from an ultra-wide-field (UWF) image. We trained the model with focal loss and weighted binary cross-entropy loss to deal with the class-imbalanced dataset, and optimized hyperparameters in order to minimize validation loss. As expected, the resultant PraNet-based deep-learning model outperformed previously published methods. For verification, we used UWF fundus images with NPA and used Bland–Altman plots to compare estimated NPA with the ground truth in FA, which demonstrated that bias between the eNPA and ground truth was smaller than 10% of the confidence limits zone and that the number of outliers was less than 10% of observed paired images. The accuracy of the model was also tested on an external dataset from another institution, which confirmed the generalization of the model. For validation, we employed a contingency table for ROC analysis to judge the sensitivity and specificity of the estimated-NPA (eNPA). The results demonstrated that the sensitivity and specificity ranged from 83.3–87.0% and 79.3–85.7%, respectively. In conclusion, we developed an AI model capable of estimating NPA size from only an UWF image without angiography using PraNet-based deep learning. This is a potentially useful tool in monitoring eyes with ischemic retinal diseases.

Classification of diabetic retinopathy: Past, present and future.

Diabetic retinopathy (DR) is a leading cause of visual impairment and blindness worldwide. Since DR was first recognized as an important complication of diabetes, there have been many attempts to accurately classify the severity and stages of disease. These historical classification systems evolved as understanding of disease pathophysiology improved, methods of imaging and assessing DR changed, and effective treatments were developed. Current DR classification systems are effective, and have been the basis of major research trials and clinical management guidelines for decades. However, with further new developments such as recognition of diabetic retinal neurodegeneration, new imaging platforms such as optical coherence tomography and ultra wide-field retinal imaging, artificial intelligence and new treatments, our current classification systems have significant limitations that need to be addressed. In this paper, we provide a historical review of different classification systems for DR, and discuss the limitations of our current classification systems in the context of new developments. We also review the implications of new developments in the field, to see how they might feature in a future, updated classification.

Detecting multiple retinal diseases in ultra-widefield fundus imaging and data-driven identification of informative regions with deep learning

Detecting multiple retinal diseases in ultra-widefield fundus imaging and data-driven identification of informative regions with deep learning

Comparison of Widefield Laser Ophthalmoscopy and ETDRS Retinal Area for Diabetic Retinopathy

To evaluate agreement of nonmydriatic confocal scanning laser ophthalmoscopy (SLO; EIDON [CenterVue]) and the 7-standard field ETDRS area on ultrawide-field (UWF) SLO imaging for identification of diabetic retinopathy (DR) severity. Single-site, prospective, comparative, instrument validation study. One hundred ten eyes of 55 patients with diabetes mellitus were evaluated. Each patient underwent nonmydriatic, nonsimultaneous stereoscopic imaging using the EIDON camera and 4 fields of 60°× 55° were acquired (macula centered, disc centered, temporal macula, superotemporal). Mydriatic UWF retinal images were acquired using a nonsimultaneous stereographic protocol with UWF imaging (California; Optos plc). Before grading, a standardized ETDRS 7-field image mask was applied to all UWF retinal images. Images from each device were graded independently by 2 masked graders using the ETDRS clinical DR classification. Any discrepancy in DR grading between the devices was adjudicated by a third grader. κ Levels of agreement, sensitivity, and specificity for DR thresholds. Severity by ETDRS grading was as follows: no DR, 10.9%; mild nonproliferative DR (NPDR), 45.5%; moderate NPDR, 16.5%; severe NPDR, 11.8%; proliferative DR, 12.7%; high-risk proliferative DR, 2.7%; and ungradable, 0%. After adjudication, the level of DR identified on EIDON images agreed exactly with that of UWF ETDRS imaging in 87% of eyes (n= 96) and was within 1 step in 99.1% of eyes (n= 109) with a simple κ value of 0.8244 ± 0.0439 (95% confidence interval [CI], 0.7385-0.9104) and weighted (linear) κ value of 0.9041 ± 0.0257 (95% CI, 0.8537-0.9545). Sensitivity and specificity compared with ETDRS field grading for any DR were 0.96 and 0.75, for moderate NPDR or worse were 0.96 and 0.97, and for severe NPDR or worse were 0.91 and 1.00, respectively. Nonmydriatic 4-field stereoscopic widefield imaging using the EIDON device was comparable with the DR severity identified within the ETDRS 7-standard field area of UWF images. Future studies will need to evaluate the applicability of this device as a clinical and research tool and the impact of different widefield coverage areas.

Multi-modal retinal scanning to measure retinal thickness and peripheral blood vessels in multiple sclerosis

Our purpose was to investigate changes to the retina in multiple sclerosis (MS) using established and novel modes of retinal image acquisition and analysis. 72 participants with MS and 80 healthy volunteers underwent retinal scanning with optical coherence tomography (OCT) and ultra-widefield (UWF) scanning laser ophthalmoscopy (SLO), over a two-year period. Changes in retinal nerve fibre layer (RNFL) thickness, macular volume and retinal blood vessel diameter were measured and parameters were then tested for associations with MS. Measurements from OCT showed that individuals with MS had a thinner RNFL and reduced macular volume when compared to healthy volunteers. On UWF images, participants with MS had reduced arterial widths in the inferior nasal quadrant of both eyes and reduced venous widths in the inferior nasal quadrant of right eyes. Longitudinal analysis showed that participants with MS had an accelerated annual rate of RNFL thinning in several regions of the retina. In conclusion, the assessment of OCT showed thinning of the RNFL and macula in concordance with previous reports on MS, while analysis of blood vessels in the retinal periphery from UWF-SLO images revealed novel changes.

LAC-GAN: Lesion attention conditional GAN for Ultra-widefield image synthesis

Automatic detection of retinal diseases based on deep learning technology and Ultra-widefield (UWF) images plays an important role in clinical practices in recent years. However, due to small lesions and limited data samples, it is not easy to train a detection-accurate model with strong generalization ability. In this paper, we propose a lesion attention conditional generative adversarial network (LAC-GAN) to synthesize retinal images with realistic lesion details to improve the training of the disease detection model. Specifically, the generator takes the vessel mask and class label as the conditional inputs, and processes the random Gaussian noise by a series of residual block to generate the synthetic images. To focus on pathological information, we propose a lesion feature attention mechanism based on random forest (RF) method, which constructs its reverse activation network to activate the lesion features. For discriminator, a weight-sharing multi-discriminator is designed to improve the performance of model by affine transformations. Experimental results on multi-center UWF image datasets demonstrate that the proposed method can generate retinal images with reasonable details, which helps to enhance the performance of the disease detection model.

Ethnic Variation in Diabetic Retinopathy Lesion Distribution on Ultra-widefield Imaging

To evaluate whether the distribution of diabetic retinopathy (DR) lesions differs among various ethnicities. Multi-center, retrospective cohort study. We accrued a cohort of 226 eyes with DR consisting of 51 East Asian eyes, 102 South Asian eyes, 30 Caucasian eyes, and 43 Latino eyes, all evaluated with ultrawide field pseudocolor images. Images were manually annotated for DR lesions and were classified as having predominantly peripheral lesions (PPL) or predominantly central lesions (PCL) using 4 quantitative methods. The percent distribution of PCL to PPL was compared among different ethnicities. Using a single-field lesion frequency-based method, East Asian eyes more frequently demonstrated a PPL distribution (86.3%), whereas South Asian eyes more frequently demonstrated a PCL distribution (64.7%). These findings were also observed when considering only the subset of treatment-naïve eyes. Furthermore, in treatment-naïve eyes without proliferative DR, the percent distribution of PPL to PCL in East Asian eyes was significantly different when compared to other ethnicities (P < .0001 South Asian, P=.035 Caucasian, P=.0003 Latino). The majority of patients (60%-78%) in all ethnic groups had moderate nonproliferative diabetic retinopathy(NPDR), and the same difference between East Asian and South Asian eyes was observed in this subgroup. The distribution of DR lesions appears to vary among different ethnicities. DR lesions tend to be distributed more peripherally in East Asian eyes compared to other ethnic groups, particularly South Asian eyes, which tend to have more central disease. The prognostic implications of these ethnic differences in DR lesion distribution require further investigation.

Effectiveness of Non-mydriatic Ultra-widefield Retinal Imaging to Screen for Diabetic Eye Disease: A Randomized Controlled Trial (Clearsight)

Suboptimal diabetic eye disease screening is a major cause of preventable vision loss. Screening barriers include mydriasis and need for dedicated screening appointments. The Clearsight trial assessed whether non-mydriatic ultra-widefield (NM UWF) screening on the day of a diabetes clinic visit improved detection of clinically important eye disease vs usual screening. This single-centre, randomized, parallel-group controlled trial was conducted at St. Joseph’s Health Care, London, Canada. Adults with diabetes due for screening were randomized to same-day On-Site Screening (NM UWF imaging) on the day of a scheduled diabetes clinic visit or Usual Screening (encouraged to arrange optometric screening).

Comparison of two ultra-widefield color-fundus imaging devices for visualization of retinal periphery and microvascular lesions in patients with early diabetic retinopathy

Comparison of two ultra-widefield (UWF) color-fundus (CF) imaging devices in diabetic patients for visualization of retinal periphery and detection of early microvascular lesions. The total gradable areas (TGA) seen on non-mydriatic CF-images of two UWF-imaging devices (Optos Daytona P200T; Zeiss Clarus 700) were compared and differences in projected area measured. Retinal periphery outside the 7 standard fields (7SF) was divided into: F3 temporal, F4 superotemporal, F5 inferotemporal, F6 superonasal, F7 inferonasal. DR stage was evaluated in the 7SF and the TGA on images of both devices and compared using Cohens κ. 67 eyes of 67 patients (52.5 ± 15.3 years) were analysed. DR stages in the 7SF were no (n = 36 Optos, n = 35 Clarus), mild (n = 16 Optos, n = 17 Clarus), and moderate DR (n = 15). Optos depicted significantly more area in F3 (median [interquartile range]; 2.41% [1.06–4.11] vs 0% [0–0], P < 0.001) and Clarus in F7 (3.29% [0–7.69] vs 0% [0–3.27], P = 0.002). In 4 eyes DR-stage was higher using Optos due to peripheral lesions not seen on the Clarus. Interrater reliability of DR-stage on both devices was almost perfect in the 7SF (κ = 0.975) and the TGA (κ = 0.855). Reliability in detecting signs of early DR is high on both devices. Clarus allowed for better visualization of the inferonasal field, Optos of the temporal field.

A Blinding Glioma

A 12-year-old girl presented with no light perception in the right eye. Ultrawide-field retinal imaging (Fig A) revealed a grayish papillary mass expanding into the vitreous cavity, ghost retinal vessels, and deep retinal hemorrhages. Brain magnetic resonance imaging showed a left-sided parieto-occipital tumor crossing the midline (Fig B, arrows) with an enlarged right optic nerve (arrowhead). Pathologic examination found highly cellular glial and microvascular proliferation, palisading necrosis, numerous mitoses (Fig C, arrow) (Hemalun Phloxin Saffron staining, left), and diffuse expression of the mutation H3F3A G34R (right).

RETINAL VASCULAR BED AREA IN EYES WITH RETINAL VEIN OCCLUSION ON ULTRA-WIDEFIELD FLUORESCEIN ANGIOGRAPHY: WAVE Study.

To compute retinal vascular bed area (RVBA) in square millimeters on distortion corrected ultra-widefield fluorescein angiography images in eyes with retinal vein occlusion (RVO). Prospective observational study. The peripheral distortion of baseline ultra-widefield fluorescein angiography (Optos 200Tx) images of 30 patients with RVO from the WAVE study (NCT01710839) and 13 control eyes of normal subjects was corrected using the stereographic projection method to compute RVBA in square millimeters. In comparison with age- and sex-matched normal control eyes, eyes with RVO had a decreased global RVBA for the entire retina (50.5 ± 20.4 mm 2 vs. 62.6 ± 12.2 mm 2 , P = 0.023). Eyes with RVO and the unaffected fellow eye had a similar RVBA globally (50.5 ± 20.4 mm 2 vs. 46.2 ± 18.9 mm 2 , P = 0.523). The RVBA was observed to negatively correlate with nonperfusion area (R = -0.47, P = 0.009). However, RVBA was not related to the severity of macular edema ( P > 0.05). Eyes with RVO have a similar RVBA to the unaffected fellow eyes but with a reduction when compared with normal control eyes. Retinal vascular bed area appears to be a surrogate biomarker of retinal ischemia on ultra-widefield fluorescein angiography but not the extent of macular edema.

Retinal changes of primary vitreoretinal lymphoma after intravitreal methotrexate

BackgroundTo identify retinal changes using spectral-domain optical coherence tomography (SD-OCT) and ultra-widefield images in eyes with primary vitreoretinal lymphoma (PVRL) during intravitreal methotrexate (MTX) treatment. MethodsThis study retrospectively reviewed 111 eyes of 58 patients with vitreous cytology-proven confirmed PVRL, who received intravitreal injections of MTX.ResultsAt the initial visit, the OCT manifestations included vitreous cells (105 eyes, 94.6%), intraretinal infiltration (44 eyes,39.6%), subretinal infiltration (45 eyes, 40.5%,), retinal pigment epithelium (RPE) abnormalities (66 eyes, 59.5%), disruption of the ellipsoid zone (58 eyes, 52.3%), subretinal fluid (4 eyes, 3.6%), RPE detachment (PED) (28 eyes, 25.2%), epiretinal membrane (ERM) (8 eyes, 7.2%), macular edema (10 eyes, 9%). After therapy, tumor regression was achieved in all eyes. Between the initial presentation and regression, the vitreous cells (94.6% vs. 0%, P < 0.001), intraretinal infiltration (39.6% vs. 0%, P < 0.001), RPE abnormalities (59.5% vs.19.8%, P < 0.001), PED (25.2% vs.0%, P < 0.001), and subretinal infiltration (40.5%vs.16.2%, P < 0.001) were significantly reduced. The fundus photography findings all improved after therapy. The mean Logarithm of the Minimum Angle of Resolution (logMAR) for the best corrected visual acuity (BCVA) at presentation was 0.79 ± 0.81 (range, 0–2.9), which improved to 0.70 ± 0.97 (range, 0–2.9, P = 0.01) at the final visit.ConclusionsSD-OCT combined with ultra-widefield imaging, which can reflect retinal changes, are valuable tools for monitoring the effect of PVRL treatment.

Visualization and Grading of Vitreous Floaters Using Dynamic Ultra-Widefield Infrared Confocal Scanning Laser Ophthalmoscopy: A Pilot Study.

Purpose: To describe the appearance of vitreous opacities using dynamic ultra-widefield infrared confocal scanning laser ophthalmoscopy (IRcSLO). Design: Retrospective case series. Methods: Eyes of patients complaining of myodesopsia were analyzed using dynamic ultra-widefield IRcSLO imaging (Nidek Mirante, Nidek Co., Ltd., Gamagori, Japan), and classified according to a vitreous opacity severity scale. Results: Thirty eyes of 21 patients were included in this study. The average age was 56 years. Symptom duration ranged from 1 to more than 365 days. The most common cause of vitreous floaters was posterior vitreous detachment (63.3%), followed by vitreous syneresis (23.3%), asteroid hyalosis (10%) and vitreous hemorrhage (3.3%). Opacities were classified as Grade 1 in three eyes (10%), Grade 2 in 10 eyes (33.3%), Grade 3 in 11 eyes (36.6%), Grade 4 in two eyes (6.6%) and Grade 5 in four eyes (13.3%). Patients with Grade 1 opacities were younger than patients with opacities Grade 2 or greater. A visible Weiss ring could be identified in 0% of eyes with Grade 1 opacities, 40% of eyes with Grade 2 opacities, 100% of eyes with Grade 3 opacities, and 100% of eyes with Grade 4 opacities. In patients with Grade 5 opacities, a Weiss ring could not be identified. Conclusion: Dynamic ultra-widefield IRcSLO imaging is a useful tool to evaluate patients with vitreous floaters. It allows for accurate visualization of the number, density, and behavior of the shadows that vitreous opacities project over a very wide area of the retina, which has a positive correlation with patient perception of floaters.

A cascade eye diseases screening system with interpretability and expandability in ultra-wide field fundus images: A multicentre diagnostic accuracy study.

SummaryBackgroundClinical application of artificial intelligence is limited due to the lack of interpretability and expandability in complex clinical settings. We aimed to develop an eye diseases screening system with improved interpretability and expandability based on a lesion-level dissection and tested the clinical expandability and auxiliary ability of the system.MethodsThe four-hierarchical interpretable eye diseases screening system (IEDSS) based on a novel structural pattern named lesion atlas was developed to identify 30 eye diseases and conditions using a total of 32,026 ultra-wide field images collected from the Second Affiliated Hospital of Zhejiang University, School of Medicine (SAHZU), the First Affiliated Hospital of University of Science and Technology of China (FAHUSTC), and the Affiliated People's Hospital of Ningbo University (APHNU) in China between November 1, 2016 to February 28, 2022. The performance of IEDSS was compared with ophthalmologists and classic models trained with image-level labels. We further evaluated IEDSS in two external datasets, and tested it in a real-world scenario and an extended dataset with new phenotypes beyond the training categories. The accuracy (ACC), F1 score and confusion matrix were calculated to assess the performance of IEDSS.FindingsIEDSS reached average ACCs (aACC) of 0·9781 (95%CI 0·9739-0·9824), 0·9660 (95%CI 0·9591-0·9730) and 0·9709 (95%CI 0·9655-0·9763), frequency-weighted average F1 scores of 0·9042 (95%CI 0·8957-0·9127), 0·8837 (95%CI 0·8714-0·8960) and 0·8874 (95%CI 0·8772-0·8972) in datasets of SAHZU, APHNU and FAHUSTC, respectively. IEDSS reached a higher aACC (0·9781, 95%CI 0·9739-0·9824) compared with a multi-class image-level model (0·9398, 95%CI 0·9329-0·9467), a classic multi-label image-level model (0·9278, 95%CI 0·9189-0·9366), a novel multi-label image-level model (0·9241, 95%CI 0·9151-0·9331) and a lesion-level model without Adaboost (0·9381, 95%CI 0·9299-0·9463). In the real-world scenario, the aACC of IEDSS (0·9872, 95%CI 0·9828-0·9915) was higher than that of the senior ophthalmologist (SO) (0·9413, 95%CI 0·9321-0·9504, p = 0·000) and the junior ophthalmologist (JO) (0·8846, 95%CI 0·8722-0·8971, p = 0·000). IEDSS remained strong performance (ACC = 0·8560, 95%CI 0·8252-0·8868) compared with JO (ACC = 0·784, 95%CI 0·7479-0·8201, p= 0·003) and SO (ACC = 0·8500, 95%CI 0·8187-0·8813, p = 0·789) in the extended dataset.InterpretationIEDSS showed excellent and stable performance in identifying common eye conditions and conditions beyond the training categories. The transparency and expandability of IEDSS could tremendously increase the clinical application range and the practical clinical value of it. It would enhance the efficiency and reliability of clinical practice, especially in remote areas with a lack of experienced specialists.FundingNational Natural Science Foundation Regional Innovation and Development Joint Fund (U20A20386), Key research and development program of Zhejiang Province (2019C03020), Clinical Medical Research Centre for Eye Diseases of Zhejiang Province (2021E50007).

Association of Predominantly Peripheral Lesions on Ultra-Widefield Imaging and the Risk of Diabetic Retinopathy Worsening Over Time

Ultra-widefield (UWF) imaging improves the ability to identify peripheral diabetic retinopathy (DR) lesions compared with standard imaging. Whether detection of predominantly peripheral lesions (PPLs) better predicts rates of disease worsening over time is unknown. To determine whether PPLs identified on UWF imaging are associated with increased disease worsening beyond the risk associated with baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) score. This cohort study was a prospective, multicenter, longitudinal observational study conducted at 37 US and Canadian sites with 388 participants enrolled between February and December 2015. At baseline and annually through 4 years, 200° UWF-color images were obtained and graded for DRSS at a reading center. Baseline UWF-color and UWF-fluorescein angiography (FA) images were evaluated for the presence of PPL. Data were analyzed from May 2020 to June 2022. Treatment of DR or diabetic macular edema was at investigator discretion. Predominantly peripheral lesions were defined as DR lesions with a greater extent outside vs inside the 7 standard ETDRS fields. Primary outcome was disease worsening defined as worsening 2 steps or more on the DRSS or receipt of DR treatment. Analyses were adjusted for baseline DRSS score and correlation between 2 study eyes of the same participant. Data for 544 study eyes with nonproliferative DR (NPDR) were analyzed (182 [50%] female participants; median age, 62 years; 68% White). The 4-year disease worsening rates were 45% for eyes with baseline mild NPDR, 40% for moderate NPDR, 26% for moderately severe NPDR, and 43% for severe NPDR. Disease worsening was not associated with color PPL at baseline (present vs absent: 38% vs 43%; HR, 0.78; 95% CI, 0.57-1.08; P = .13) but was associated with FA PPL at baseline (present vs absent: 50% vs 31%; HR, 1.72; 95% CI, 1.25-2.36; P < .001). Although no association was identified with color PPL, presence of FA PPL was associated with greater risk of disease worsening over 4 years, independent of baseline DRSS score. These results suggest that use of UWF-FA to evaluate retinas peripheral to standard ETDRS fields may improve the ability to predict disease worsening in NPDR eyes. These findings support use of UWF-FA for future DR staging systems and clinical care to more accurately determine prognosis in NPDR eyes.

Association of Ultra-Widefield Fluorescein Angiography–Identified Retinal Nonperfusion and the Risk of Diabetic Retinopathy Worsening Over Time

Presence of predominantly peripheral diabetic retinopathy (DR) lesions on ultra-widefield fluorescein angiography (UWF-FA) was associated with greater risk of DR worsening or treatment over 4 years. Whether baseline retinal nonperfusion assessment is additionally predictive of DR disease worsening is unclear. To assess whether the extent and location of retinal nonperfusion identified on UWF-FA are associated with worsening in Diabetic Retinopathy Severity Scale (DRSS) score or DR treatment over time. This cohort study was a prospective, multicenter, longitudinal observational study with data for 508 eyes with nonproliferative DR and gradable nonperfusion on UWF-FA at baseline. All images were graded at a centralized reading center; 200° ultra-widefield (UWF) color images were graded for DR at baseline and annually for 4 years. Baseline 200° UWF-FA images were graded for nonperfused area, nonperfusion index (NPI), and presence of predominantly peripheral lesions on UWF-FA (FA PPL). Treatment of DR or diabetic macular edema was at investigator discretion. Association of baseline UWF-FA nonperfusion extent with disease worsening, defined as either 2 or more steps of DRSS worsening within Early Treatment Diabetic Retinopathy Study fields on UWF-color images or receipt of DR treatment. After adjusting for baseline DRSS, the risk of disease worsening over 4 years was higher in eyes with greater overall NPI (hazard ratio [HR] for 0.1-unit increase, 1.11; 95% CI, 1.02-1.21; P = .02) and NPI within the posterior pole (HR for 0.1-unit increase, 1.35; 95% CI, 1.17-1.56; P < .001) and midperiphery (HR for 0.1-unit increase, 1.08; 95% CI, 1.00-1.16; P = .04). In a multivariable analysis adjusting for baseline DRSS score and baseline systemic risk factors, greater NPI (HR, 1.11; 95% CI, 1.02-1.22; P = .02) and presence of FA PPL (HR, 1.89; 95% CI, 1.35-2.65; P < .001) remained associated with disease worsening. This 4-year longitudinal study has demonstrated that both greater baseline retinal nonperfusion and FA PPL on UWF-FA are associated with higher risk of disease worsening, even after adjusting for baseline DRSS score and known systemic risk. These associations between disease worsening and retinal nonperfusion and FA PPL support the increased use of UWF-FA to complement color fundus photography in future efforts for DR prognosis, clinical care, and research.

Thinking Outside the Circle—The Potential Value of Ultra-Widefield Imaging

Thinking Outside the Circle—The Potential Value of Ultra-Widefield Imaging

The Feasibility of Using Ultra-Widefield Retinal Imaging to Identify Ocular Pathologies amongst Those with Systemic Medical Disease Attending a Tertiary Healthcare Facility at a University Hospital

Aims: The aim of the study was to evaluate the feasibility of ultra-widefield (UWF) imaging to identify ocular pathologies amongst in- and out-patients in a tertiary university hospital. Methods: We followed a prospective double-blinded multicenter clinical study. In total, 634 patients from a university hospital with pulmonary, cardiovascular, and endocrine diseases were examined by two teams by conventional slit-lamp biomicroscopy (CBM). UWF images with Optos Tx200 were taken and subsequently graded independently by two retina specialists and graders from two reading centers for the presence of pre-defined pathologies. Interrater reliability was calculated using Fleiss statistical software. An independent, trained and certified ophthalmologist with retinal subspecialty (BL) classified all UWF images with retinal hemorrhages by severity and interrater agreement. Results: Complete data were available for 502 patients. The Moorfields Eye Hospital Reading Center, London, UK (RM), reported the highest number of cases with retinal pathologies (378), and the Reading Center GRADE Bonn, Germany (RB), did so for cases with optic disc cupping (466). Two retinal consultants (R1 and R2) from the Department of Ophthalmology, University Hospital Giessen and Marburg GmbH, Campus Giessen, Germany, noted optic disc pathologies. R1 reported 151 cases with optic disc pallor, while R2 reported only 39 disc pathologies. Both for clinical and for image readers, the early changes had equally low interrater reliability. The presence of at least 3 retinal hemorrhages had the highest interrater reliability (0.59). Conclusions: UWF imaging is convenient to identify overt retinal pathologies in patients at risk of ocular complications of their systemic disease who are attending hospital clinics. Imaging the eye allows for remote retinal assessment and for placing the patient into the appropriate clinical pathway for ophthalmology. Precis: UWF-imaging in a population of in- and out-patients at a university hospital who are at risk of retinal complications is effective to detect overt retinal pathologies and allows for tele-ophthalmology approaches to be enabled for placing the patients into the appropriate clinical pathways.

Predominant peripheral lesions in patients with diabetic retinopathy and its association with systemic comorbidities.

To determine the associations of predominant peripheral lesions (PPLs) with systemic comorbidities in individuals with diabetic retinopathy. This is a multicenter cross-sectional observational study conducted across three tertiary eye care centers in south India between January 2019 and July 2021. Ultra-widefield fundus images of consecutive patients with varying severity of diabetic retinopathy with data on systemic comorbidities were classified based on the presence or absence of PPL. Systemic comorbidities (hypertension, diabetic kidney disease, coronary artery disease, dyslipidemia, and anemia) were compared between the two groups. A total of 879 participants (70.1% males) were included in the study, of which 443 (50.4%) patients had PPL. The mean age of the study participants was 56 ± 10 years, mean age of onset of diabetes was 41.24 ± 11.6 years, and mean duration of diabetes was 15.39 ± 7.6 years. The number of PPL increased with increasing severity of DR. Of all the systemic comorbidities analyzed, we found that coronary artery disease (CAD) had a significant association with PPL (Odds ratio [OR]-1.69; 95% confidence interval [CI], 1.12-2.55; P = 0.013) after adjusting for diabetic retinopathy severity, duration of diabetes, and age of onset of diabetes. The presence of PPL is a marker for coronary artery disease and early referral to cardiology is warranted.