This comparative case-control study evaluates the association of dilation and manual eyelid lifting with visible retinal area on ultra-widefield imaging as well as the association of visible retinal area with diabetic retinopathy severity and detection of predominantly peripheral lesions among patients with diabetes.
Key Points
Question
Are dilation and manual lifting of the upper eyelid during ultra-widefield (UWF) imaging in a telemedicine setting associated with increased visible retinal area (VRA) and detection of pathology in patients with diabetes?
Findings
In this comparative case-control study, both dilation and manual eyelid lifting during UWF imaging were associated with increased VRA and the detection of retinal pathology. Increased VRA was also associated with worse diabetic retinopathy severity grading, and both associations were statistically significant.
Meaning
These findings suggest that VRA and diabetic retinopathy lesion identification may be increased by dilation and a simple eyelid lifting maneuver during UWF imaging.
Abstract
Importance
Methods that increase visible retinal area (VRA; measured in millimeters squared) may improve identification of diabetic retinopathy (DR) lesions.
Objective
To evaluate the association of dilation and manual eyelid lifting (MLL) with VRA on ultra-widefield imaging (UWFI) and the association of VRA with grading of DR severity and detection of predominantly peripheral lesions (PPLs).
Design, Setting, and Participants
Retrospective, comparative case-control study at the Joslin Diabetes Center, Boston, Massachusetts. Nonmydriatic UWFI with MLL was acquired from a DR teleophthalmology program (Joslin Vision Network [JVN]). A second cohort of mydriatic UWFI was acquired at an academic retina practice (Beetham Eye Institute [BEI]) from November 6, 2017, to November 6, 2018, and with MLL thereafter until November 6, 2019. Fully automated algorithms determined VRA and hemorrhage and/or microaneurysm (HMA) counts. Predominantly peripheral lesions and HMAs were defined as present when at least 1 field had greater HMA number in the peripheral retina than within the corresponding Early Treatment Diabetic Retinopathy Study field. Participants included 3014 consecutive patients (5919 eyes) undergoing retinal imaging at JVN and BEI.
Exposures
Dilation and MLL performed at the time of UWFI.
Main Outcomes and Measures
Visible retinal area, DR severity, and presence of PPLs.
Results
Of the 3014 participants, mean (SD) age was 56.1 (14.5) years, 1302 (43.2%) were female, 2450 (81.3%) were White, and mean (SD) diabetes duration was 15.9 (11.4) years. All images from 5919 eyes with UWFI were analyzed. Mean (SD) VRA was 665.1 (167.6) mm2 for all eyes (theoretical maximal VRA, 923.9 mm2), 550.8 (240.7) mm2 for nonmydriatic JVN with MLL (1418 eyes [24.0%]), 688.1 (119.9) mm2 for mydriatic BEI images (3650 eyes [61.7%]), and 757.0 (69.7) mm2 for mydriatic and MLL BEI images (851 eyes [14.4%]). Dilation increased VRA by 25% (P < .001) and MLL increased VRA an additional 10% (P < .001). Nonmydriatic MLL increased VRA by 11.0%. With MLL, HMA counts in UWFI fields increased by 41.7% (from 4.8 to 6.8; P < .001). Visible retinal area was moderately associated with increasing PPL-HMA overall and in each cohort (all, r = 0.33; BEI, r = 0.29; JVN, r = 0.36; P < .001). In JVN images, increasing VRA was associated with more PPL-HMA (quartile 1 [Q1], 23.7%; Q2, 45.8%; Q3, 60.6%; and Q4, 69.2%; P < .001).
Conclusions and Relevance
Using fully automated VRA and HMA detection algorithms, pupillary dilation and eyelid lifting were shown to substantially increase VRA and PLL-HMA detection. Given the importance of HMA and PPL for determining risk of DR progression, these findings emphasize the importance of maximizing VRA for optimal risk assessment in clinical trials and teleophthalmology programs.
Introduction
Prior to ultra-widefield (UWF) imaging, traditional fundus photography provided a limited view of the retinal periphery. Ultra-widefield retinal imaging has allowed the retinal periphery to be readily evaluated in clinical and research settings. However, with UWF imaging, there can be significant variability in the extent of visible retinal area (VRA) between images. Some of this variability is due to artifacts resulting from the patient’s eyelashes and eyelids. Thus, ungradable rates are 2- to 3-fold higher in inferior fields compared with temporal and superior fields.1 Ultra-widefield imaging offers a large retinal area over which pathology may be identified, but this may be compromised when the extent of the imaged retina is reduced. Reductions in VRA may lead to missing important retinal pathology in the retinal periphery and introduce variability in the assessment of diabetic retinopathy (DR) severity. This problem might be minimized by improved patient positioning and imaging setup. Given the importance of maximizing VRA, manual eyelid lifting (MLL) was implemented at our institution, the Joslin Diabetes Center, Boston, Massachusetts. This study evaluated the association of dilation and MLL with UWF VRA and assessed the association of VRA with detection of clinically relevant lesions and grading of DR severity.
Methods
This retrospective, comparative case-control study reviewed all optomap plus (Optos plc) retinal images acquired at the Beetham Eye Institute (BEI) of the Joslin Diabetes Center from November 6, 2017, to November 6, 2019. Approval for this retrospective review was obtained through the Committee on Human Studies of the Joslin Diabetes Center, which also waived the need to obtain informed consent from the participants because only deidentified retinal images were evaluated in this retrospective review. The waiver of consent was granted by the Committee of Human Studies of Joslin Diabetes Center and did not affect the patients’ rights and welfare. The reporting of study data was in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.2 All nonmydriatic teleophthalmology images (Joslin Vision Network [JVN] images) were with MLL and evaluated at a central reading center for DR severity and predominantly peripheral lesions (PPLs).3 A second cohort of clinical mydriatic images was acquired at an academic retina practice (BEI images) during the same period. These images were acquired without MLL from November 6, 2017, until November 6, 2018, with all subsequent images using MLL if more than 10% of the retina was obscured by eyelid or eyelash artifacts. Figure 1 demonstrates the standard MLL technique used in this study. All images were processed with automated algorithms to determine VRA (performance dice coefficient: 0.848 vs manual VRA annotations) and hemorrhage and/or microaneurysms (HMAs) (area under the curve: 0.90-0.95 for images with nonproliferative DR) counts.4 Automated PPL-HMAs were defined as present when at least 1 field had a greater HMA number in the peripheral retina than within the Early Treatment Diabetic Retinopathy Study (ETDRS) fields using the automated HMA algorithm. When multiple images were taken of each eye, only the image with the largest VRA was processed. The primary outcomes were extent of VRA (millimeters squared) before and after implementation of MLL and corresponding detection rates of HMA, PPL, and DR severity.
Figure 1. Eyelid Lifting Technique During Ultra-Widefield Image Capture.
Montage showing technique of manual lifting of the upper eyelid. The index and middle finger are used to provide countertraction against eyelid closure (A and C) and are positioned carefully between the patient and the imaging device during capture (B and D). Compare the lifted eye against the nonlifted eye in the photographs (A and C). The eyelashes are directed upward and outside the imaging field with eyelid lifting, while in the natural position they are directed slightly downward, obstructing retinal visualization.
Nonparametric analyses (Wilcoxon rank sums) were used to compare the distributions of continuous variables. The χ2 test was used to compare frequencies of categorical variables. We evaluated the effect of each VRA quartile on PPL, PPL-HMA, and DR severity. P values were 2-sided and not adjusted for multiple analysis. P < .05 was considered statistically significant. All analyses were performed using SAS, version 9.4 (SAS Institute Inc).
Results
Of the 3014 participants, mean (SD) age was 56.1 (14.5) years, 1302 (43.2%) were female, 2450 (81.3%) were White, and mean (SD) diabetes duration was 15.9 (11.4) years. All images from 5919 eyes with UWFI were analyzed. The mean (SD) VRA was 665.1 (167.6) mm2 for all eyes (N = 5919), 550.8 (240.7) mm2 for nonmydriatic JVN images with MLL (1418 eyes [24.0%]), 688.1 (119.9) mm2 for all mydriatic-only BEI images (3650 eyes [61.7%]), and 757.0 (69.7) mm2 for all mydriatic and MLL BEI images (851 eyes [14.4%]). The theoretical maximal UWF image VRA is 923.9 mm2.5,6 Results before and after implementation of MLL are summarized in the Table and the eTable in the Supplement. The method of MLL is shown in Figure 1, and images before and after eyelid lifting are shown in Figure 2.
Table. Outcomes for Mydriatic BEI UWFI Taken During Routine In-Clinic Patient Visitsa.
| Variable | Mydriatic BEI UWFI, Mean (SD) | |||
|---|---|---|---|---|
| No eyelid lifting | Eyelid lifting | Change, % | P value | |
| VRA, mm2 | 688.1 (119.9) | 757.0 (69.7) | 10 | <.001 |
| Total automated HMA count | 8.1 (13.9) | 9.4 (15.9) | 16 | <.001 |
| HMA | ||||
| In ETDRS 7 fields | 3.3 (7.1) | 2.6 (7.5) | –21.2 | .56 |
| In periphery | 4.8 (8.1) | 6.8 (9.9) | 41.7 | <.001 |
| Automated PPL-HMA, % | 69.7 | 85.4 | 15.7 | <.001 |
Abbreviations: BEI, Beetham Eye Institute; ETDRS, Early Treatment Diabetic Retinopathy Study; HMA, hemorrhages/microaneurysms; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; PPL, predominantly peripheral lesions; Q, quarter; UWFI, ultra-widefield imaging; VRA, visible retinal area.
Eyelid lifting was instituted on November 6, 2018, for BEI mydriatic retinal imaging. Median visual acuity in the BEI cohort was 20/20 (Q1, 20/16; Q2, 20/20; Q3, 20/25; and Q4, 20/200). For the BEI cohort (n = 4501), distribution was 45.6% with no DR (n = 2052); 28.8% with mild NPDR (n = 1296); 7.1% with moderate NPDR (n = 320); 2.5% with severe NPDR (n = 113); and 16.0% with PDR (n = 720).
Figure 2. Ultra-Widefield (UWF) Images of an Eye Without Diabetic Retinopathy and an Eye With Diabetic Retinopathy, Taken Without and With Upper Eyelid Lifting.
A, Ultra-widefield retinal image captured without manual eyelid lifting (MLL) in an eye without diabetic retinopathy. B, Image captured with MLL of the same patient taken at the same session. C and D, Image masks obtained following automated visible retinal area (VRA) measurement. Substantially more area is seen in the inferior retinal periphery after eyelid lifting (VRA without MLL, 529.47 mm2; with MLL, 779.87 mm2). E, Ultra-widefield retinal image captured without MLL in an eye with diabetic retinopathy. F, Image captured with MLL of the same patient taken at the same session. The arrowhead shows significantly more retinal hemorrhages and microaneurysms with predominantly peripheral lesions uncovered only after MLL in the superior and nasal quadrant. G and H, Image masks obtained following automated VRA measurement. Substantially more VRA is seen after MLL (VRA without MLL, 421.8 mm2; with MLL, 677.69 mm2).
The implementation of MLL guidelines for BEI images increased VRA by 10.0% (mean [SD], 688.1 [119.9] mm2 to 757.0 [69.7] mm2; P < .001). Manual eyelid lifting increased the mean number of HMAs identified overall by 16.0% (from 8.1 to 9.4; P < .001) and those identified in the retinal area peripheral to the ETDRS standard fields by 41.7% (from 4.8 to 6.8; P < .001). There was no significant difference in the number of HMAs identified in the combined ETDRS 7-field area (3.3 vs 2.6; P = .56). Evaluating the distribution of PPL-HMAs in each VRA quartile of the cohort, the trend for more PPL-HMAs with increasing VRA was significant (quartile 1 [Q1], 49.8%; Q2, 58.8%; Q3, 72.2%; and Q4, 78.7%; r = 0.29; P < .001). This correlation was seen in the overall cohort as well (r = 0.33; P < .001). In a small cohort of undilated eyes (20 eyes; 10 patients) tested with and without MLL, MLL increased VRA by 11.0% (mean [SD], 658.3 [102.6] mm2 to 715.1 [47.1] mm2; P < .001).
In nonmydriatic JVN images, MLL was used to reduce the presence of eyelid and eyelash artifacts. Increasing VRA was associated with more PPLs (Q1, 4.8%; Q2, 9.0%; Q3, 11.8%; and Q4, 9.0%; P = .01) and more PPL-HMAs (Q1, 23.7%; Q2, 45.8%; Q3, 60.6%; and Q4, 69.2%; r = 0.36; P < .001). The findings remained significant after correcting for diabetes duration and DR severity (more PPLs P = .03; more PPL-HMAs P < .001). A smaller VRA was associated with higher ungradable rates (Q1, 5.1%; Q2, 0.6%; Q3, 0.6%; and Q4, 0.6%; P < .001). In this cohort, a smaller VRA was associated with male sex (male, 529.9 mm2; female, 565.2 mm2; P = .001). There was no significant association between age and VRA (r = −0.03; P = .19).
Discussion
Maximizing visualization of the peripheral retina is important for optimal characterization of DR severity. Numerous studies have emphasized peripheral lesion association with longitudinal risk of DR progression and visual loss.3,7,8,9 The use of UWF imaging substantially increases the field of view acquired with a single image. However, eyelid and eyelash artifacts in the superior and inferior fields can substantially reduce the effective field of view. In prior studies,10,11 nearly 1 in 8 eyes had inferior fields that were ungradable for DR severity.
In this study, dilation increased VRA by 25% and simple eyelid lifting increased VRA an additional 10% (P < .001). Manual eyelid lifting improved VRA by 11.0% in the undilated eye.
Increased VRA was associated with detecting increased numbers of HMAs and a greater likelihood of identification of PPL-HMAs. The JVN cohort showed that increasing VRA was associated with greater identification of PPLs and PPL-HMAs. Lower VRA was associated with increased ungradable image rate, which is a key metric in telemedicine programs.12 Furthermore, PPL-HMAs are more common in all DR levels with mydriatic imaging compared with nonmydratic imaging (nonmydratic, 79.2%; mydratic, 59.0%; P = .001). This likely explains the lower rates of PPL identified on nonmydriatic programs compared with rates found in clinical trials that used mydriatic imaging.13 The reduction of ungradable rate translates to improved disease detection. In teleophthalmology programs, automated measures of VRA could be implemented to provide real-time feedback to improve image capture.
Prior reports in teleophthalmology programs that use nonmydriatic UWF imaging have reported PPL presence in 14.0% to 17.5% of eyes.12,14 This contrasts with clinical studies using mydriatic imaging reporting the presence of PPLs in 41% to 51% of eyes.3,13 These discrepancies suggest that, without mydriasis, a substantial number of PPLs and other DR lesions may be missed. Thus, methods to increase VRA, such as mydriasis and eyelid lifting, will be important in clinical trials and teleophthalmology settings.
Limitations
This study has limitations. We evaluated 2 different cohorts, and results within individual teleophthalmology programs may differ with varying populations and instrumentation. Furthermore, eyelid artifacts and palpebral fissure width may have different confounding effects dependent on different techniques and racial and ethnic populations.
Conclusions
The findings of this case-control study indicate that fully automated VRA and HMA detection algorithms, pupillary dilation, and MLL may be associated with increased VRA, HMA, and PPL-HMA detection. Given the importance of HMAs and PPLs for determining risk of DR progression, these findings emphasize the potential importance of maximizing VRA in addition to image quality for optimal risk assessment in clinical trials and teleophthalmology programs.
eTable. Outcomes for Nonmydriatic JVN Teleophthalmology UWFI Taken During Routine In-Clinic Patient Visits
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Associated Data
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Supplementary Materials
eTable. Outcomes for Nonmydriatic JVN Teleophthalmology UWFI Taken During Routine In-Clinic Patient Visits