Ophthalmic Surgery, Lasers and Imaging Retina

Imaging Review Open Access

Protecting Vision in Patients With Diabetes With Ultra-Widefield Imaging: A Review of Current Literature

Rishi P. Singh, MD; Jessica Hsueh; Michael M. Han; Ajay E. Kuriyan, MD; Felipe F. Conti, MD; Nathan Steinle, MD; Christina Y. Weng, MD, MBA; Robert W. Wong, MD; Jose A. Martinez, MD; Charles C. Wykoff, MD, PhD

  • Ophthalmic Surgery, Lasers and Imaging Retina. 2019;50(10):639-648
  • https://doi.org/10.3928/23258160-20191009-07
  • Posted November 6, 2019

Abstract

Ultra-widefield fundus imaging (UWFI) is a relatively new technology capable of capturing 200° images of the retina. Since vision changes can be irreversible in diabetic retinopathy (DR), recognition of prognostic biomarkers in the peripheral retina may prove invaluable toward optimizing the management and reducing the societal burden of this blinding disease. Following a bibliographic review using Pubmed, OVID Medline, Embase, and the Cochrane Library, the current review systematically examined 13 studies that compared UWFI to conventional screening techniques such as seven standard field (7SF) Early Treatment In Diabetic Retinopathy Study (ETDRS) and non-mydriatic multifield fundus photography (NMFP), as well as their scientific level of evidence. Overall, UWFI had good agreement with 7SF ETDRS and NMFP, and moderate agreement with dilated fundus examination. Seven additional studies were examined that considered the significance of peripheral lesions found on UWFI. These studies demonstrated that UWFI captured additional DR pathology in the peripheral retina that may not be evident if evaluation is limited to the posterior pole and may be relevant to patient outcomes. Future directions include but are not limited to the potential of UWFI to track the progression of DR with treatment.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:639–648.]

Abstract

Ultra-widefield fundus imaging (UWFI) is a relatively new technology capable of capturing 200° images of the retina. Since vision changes can be irreversible in diabetic retinopathy (DR), recognition of prognostic biomarkers in the peripheral retina may prove invaluable toward optimizing the management and reducing the societal burden of this blinding disease. Following a bibliographic review using Pubmed, OVID Medline, Embase, and the Cochrane Library, the current review systematically examined 13 studies that compared UWFI to conventional screening techniques such as seven standard field (7SF) Early Treatment In Diabetic Retinopathy Study (ETDRS) and non-mydriatic multifield fundus photography (NMFP), as well as their scientific level of evidence. Overall, UWFI had good agreement with 7SF ETDRS and NMFP, and moderate agreement with dilated fundus examination. Seven additional studies were examined that considered the significance of peripheral lesions found on UWFI. These studies demonstrated that UWFI captured additional DR pathology in the peripheral retina that may not be evident if evaluation is limited to the posterior pole and may be relevant to patient outcomes. Future directions include but are not limited to the potential of UWFI to track the progression of DR with treatment.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:639–648.]

Introduction

Diabetes and its complications represent a looming public health crisis. As of 2017, 23.1 million people in the U.S. population have diabetes, and an estimated 7.2 million people are undiagnosed.1 Diabetic retinopathy (DR) is one of the leading causes of adult vision loss in the developed world. Furthermore, at-risk populations, including low-income, inner-city ethnic patients with diabetes, have higher rates of DR, lower rates of screening and/or eye care utilization, and greater severity of disease than the general diabetic population.2,3 Lack of accessibility of eye care professionals in certain communities and transportation challenges contribute to barriers to care for minority populations.1,4,5 These barriers to the delivery of routine screening and standard of care must be addressed to decrease DR disparities.

The importance of early detection of DR is the potential to prevent vision loss. DR has few visual symptoms until vision loss occurs. Thus, it is important to identify and treat DR patients early in their natural history. Yearly eye exams are recommended for diabetic patients to evaluate for the presence of treatable retinopathy.6

Novel imaging devices such as ultra-widefield fundus imaging (UWFI) technology with confocal laser scanning ophthalmoscopy have made it possible to capture high-resolution, widefield images (200°) of the retina. Confocal scanning laser ophthalmoscopy uses a laser to scan the retina point by point to capture the reflected light through a confocal pinhole. The pinhole suppresses light scattered from outside the focal plane to produce a high-contrast image. With UWFI, red and green lasers penetrate the retina to different depths, including below the retinal pigment epithelium. Combining these lasers with ellipsoid mirror technology allows for maximization of the retinal area captured in a single image. A panel of imaging experts were convened recently to recommend a definition for the term “widefield” to refer to images capturing retinal anatomy beyond the posterior pole, but posterior to the vortex vein ampulla in all four quadrants. The term “ultra-widefield” was recommended to describe images capturing retinal anatomy anterior to the vortex vein ampullae in all four quadrants.7 The advantage of this type of imaging technology is visualization of the retina without chemical dilation, which is beneficial for diabetics who do not have adequate response to dilating drops.8 Additionally, UWFI can often image the retina even in patients with media opacities, a task that is difficult using traditional fundus photography.9 Thus, UWFI appears to be more convenient and practical for both patients and clinicians while still providing high quality images.

UWFI has shown utility in teleophthalmology screening programs, reducing screening and image evaluation time, increasing detection of pathology, and lowering the proportion of ungradable images.10,11 UWFI may also capture lesions not seen in the seven standard fields (7SF) Early Treatment In Diabetic Retinopathy Study (ETDRS) protocol, such as peripheral lesions in the anterior retina. Peripheral lesions identified on UWFI are changing the way disease severity is evaluated and have shown to be predictive of the risk of disease progression.12 This may facilitate both earlier diagnosis and the screening of more patients, particularly in at-risk populations.

Despite evidence on the utility of UWFI, there is a lack of information on the level of scientific evidence of the reported studies.13 Understanding the utility of UWFI in screening and management of DR, and also in identifying new biomarkers of DR pathology, is critical toward maximizing the benefits from this imaging technique. The current manuscript reviews the utility of UWFI for these multiple purposes in prospective and retrospective studies involving patients with DR.

Patients and Methods

Search Strategy

We conducted a literature search of the Cochrane Library, OVID Medline, Embase, and PubMed databases using the key words “retinopathy,” “ultra,” and “widefield” with the Boolean operator “AND” between each field. The citations of identified articles were reviewed for additional sources. This review included studies published from April 2009 through October 2018 and did not include abstracts or case reports. All searches were restricted to articles published in English.

Eligibility Criteria

This review considered both prospective and retrospective studies that reported on the utility of UWFI for screening and management of DR, and any new biomarkers indicative of DR pathology on imaging. Studies utilizing ultra-widefield fluorescein angiography were included. Key inclusion criteria were as follows: (1) minimum “n” (eyes) of 100 and (2) considers utility of UWFI for either screening, follow-up, or new biomarkers of pathology of DR. Any study with a level of evidence of five was excluded. The search was limited to peer review publications and those published in English.

Data Extraction

The authors independently screened abstracts, excluded ineligible publications, reviewed studies, and extracted data. The selected studies were evaluated for study design, sample size, type of UWFI utility (screening, management, or biomarkers), and magnitude of findings.

Level of Evidence

Studies were considered as having high to low levels of evidence in the following order: randomized control trial or meta-analysis of RCT with homogenous results (level 1), prospective comparative study, meta-analysis of level 2 studies or level 1 studies with inconsistent results (level 2), retrospective cohort or case control studies, or meta-analysis of level 3 studies (level 3), case reviews or cross sectional studies (level 4), and case reports or expert opinions (level 5).

Results

The literature search yielded a total of 303 records: four from Cochrane Library, 203 from OVID Medline/Embase, and 96 from PubMed. We rejected 265 records for lack of relevance to the utility of UWFI for diagnosing and assessing DR. Of the 38 remaining records, we excluded 18 studies that did not meet sample size requirements.

Utility of UWFI for Screening and Diagnosis of DR

There was a similar concordance in the detection of DR by UWFI as compared to numerous reference standards across eight prospective studies and one retrospective study Kernt et al.,14 Rasmussen et al,15 and Aiello et al.16 reported the number of DR cases detected by UWFI versus 7SF ETDRS (84.7% vs. 84.0%, 96.3% vs. 97.9%, and 99.1% vs. 98.8%, respectively). Liegl et al.17 reported 83.9% by UWFI versus 86.0% by EURODIAB photography, a two-field 45° fundus photography standard. Manjunath et al.18 reported 88.6% by UWFI versus 86.3% by slit-lamp exam. Of two prospective studies with multiple comparisons, Silva et al.19 compared UWFI versus 7SF ETDRS (86.9% vs. 87.5%) and to dilated fundus exam (DFE) (87.3% vs. 85.9%), whereas another prospective study by Silva et al.20 also compared UWFI versus 7SF ETDRS (90% vs. 87.5%) and to DFE (90.3% vs. 85.9%). In a retrospective study by Silva et al.10 it was reported that DR detection rate was 24.2% by UWFI versus 11.7% by nonmydriatic multifield fundus photography (NMFP).

Agreement with International Clinical Diabetic Retinopathy (ICDR) severity grades between UWFI and multiple reference standards across studies was variable. Kappa (κ) values were consistently used across studies as a measure of agreement. Both retrospective and prospective studies comparing UWFI to 7SF ETDRS demonstrated moderate to high levels of agreement. κ values of 0.80 (weighted), 0.93, 0.71, 0.85 (weighted), 0.84 (weighted), and 0.70 were reported by Price et al.,21 Kernt et al.,14 Rasmussen et al.,15 Silva et al.,19 Silva et al.20 and Wilson et al.,22 respectively. Aiello et al.16 reported 86.3% agreement of DR severity between UWFI and 7SF ETDRS. However, one prospective study18 comparing UWFI to DFEs demonstrated low level of ICDR agreement with a κ = 0.39, and two other studies19,20 found moderate weighted κ = 0.77 and κ = 0.69. Another prospective study comparing UWFI to EURODIAB photography17 reported a κ = 0.54.

Ungradability rates of images between UWFI and multiple reference standards were variable depending on the reference standard. Both retrospective and prospective studies comparing UWFI versus 7SF ETDRS demonstrated lower levels of ungradability by UWFI. Kernt et al.14 reported 5.7% by non-mydriatic UWFI versus 10.4% by 7SF ETDRS. Silva et al.10 reported ungradability rate of 2.8% by non-mydriatic UWFI versus 26.9% by NMFP. However, Silva et al.19 reported 4.5% by non-mydriatic UWFI versus 0% by ETDRS. Aiello et al.16 reported 1.6% by mydriatic UWFI vs 1.7% by simulated 7SF ETDRS. Four prospective studies comparing ungradability of UWFI to DFEs demonstrated higher ungradability by UWFI. Manjunath et al.18 reported an ungradability rate of 1.1% by mydriatic UWFI versus 0.3% by DFE. Silva et al.19 reported an ungradability rate of 4.4% by non-mydriatic UWFI versus none by DFE. Silva et al.20 reported an ungradability rate of 1.0% by mydriatic UWFI versus none by DFE. Wilson et al.22 reported an ungradability rate of 10.8% by non-mydriatic UWFI versus 3.3% by DFE.

Utility of UWFI for Following DR Progression or DR Treatments

No studies relating to the utility of UWFI for following DR or DR treatments met the inclusion criteria.

Utility of UWFI for Capturing Biomarkers of DR Pathology

Ultra-widefield is defined as the area outside of the 7SF ETDRS territory up to the 200° field captured by devices such as the Optos P200 (Optos, Dunfermline, UK). Several studies focused on identifying pathology “outside,” “anterior,” or “peripheral” to the border of the 7SF ETDRS as biomarkers of DR pathology (Figure 1). For example, two retrospective case reviews23,24 reported that 10.7% and 10.1% of detected DR cases presented with lesions only outside of the 7SF. Bae et al. also reported that the incidence of anterior DR was correlated with lower hemoglobin A1C levels (7.03% in anterior DR versus 7.99% in posterior DR) and higher high density lipoprotein levels (51.2 mg/dL in anterior DR versus 49.7 mg/dL in posterior DR).23 Two prospective, cross-sectional studies20,25 reported that 10.7% and 11.7% were additional cases of DR found by UWFI.

Ultra-widefield fundus imaging (UWFI) with predominantly peripheral lesions (PPLs). UWFI of a patient with diabetic retinopathy (DR) demonstrating hemorrhages in a predominately peripheral distribution. Such PPLs have been associated with increased risk of DR progression and progression to proliferative DR.

Figure 1.

Ultra-widefield fundus imaging (UWFI) with predominantly peripheral lesions (PPLs). UWFI of a patient with diabetic retinopathy (DR) demonstrating hemorrhages in a predominately peripheral distribution. Such PPLs have been associated with increased risk of DR progression and progression to proliferative DR.

The remaining studies did not report a number of additional cases but instead reported a risk of increased DR severity associated with specific biomarkers. One cross-sectional study (DRCR protocol AA) studied the effects of peripheral lesions on disease progression and reported peripheral lesions exist in 41% of eyes studied and that 11% have implied worse DR severity as assessed by UWFI. Another longitudinal cohort by Silva et al.26 compared eyes with and without predominantly peripheral lesions (PPLs). For a specific field, a lesion was defined as predominantly peripheral if more than 50% of the lesion being graded was in the retinal peripheral field compared with a modified ETDRS field as seen in Figure 1. Any DR lesions type that was present predominantly in any peripheral field was defined as a PPL. Eyes with PPLs had a 3.2-fold increased risk of two-step or more DR progression and a 4.7-fold increased risk for progression to proliferative DR (PDR). The mean time from baseline to follow-up was 4.2 years ± 0.3 years. Finally, one retrospective case review27 compared the mean number of “white dots” on UWFI in diabetic and nondiabetic patients. White dots in this study were delineated by higher signal levels on only green laser images and were distinguished from hard exudates, drusen, and dot-like artifacts before manual counting. Although the authors of this study did not characterize the pathology of white dots, 31.6% (interquartile range: 21.2% to 52.0%) of the white dots corresponded to microaneurysms, which appeared as hyperfluorescent dots on the fluorescein angiography (FA) images, and most white dots around the boundary of nonperfused areas corresponded to microaneurysms. White dots were higher in eyes with DR (n = 100) than in eyes with no DR (P < .001), and the number of white dots also increased with DR severity in mild versus moderate nonproliferative DR (NPDR) (P = .006), versus severe (P = .001), and versus PDR (P < .001).

Utility of UWF in Telemedicine Programs for DR Screening

Digital retinal photography and telemedicine offer an alternative or valuable adjunct to dilated eye exams and may be effective as a screening tool for DR, especially in areas with poor access to eye care. Telemedicine programs like the Joslin Vision Network (JVN) have already tested the viability of using UWFI against other simplified protocols utilizing NMFP. In addition to having similar incidences of DR between cohorts examined by UWFI or NMFP, JVN found additional peripheral findings in 71 (14.1%) of the 502 eyes with diagnosed DR, which as stated in the previous section, has the potential to suggest advancement of disease in those with PPLs versus those without PPLs.20 They also highlighted logistical benefits such as speed of acquisition and grading and patient comfort in their study.28

Utility of UWFI for Screening and Diagnosis of DR Utility of UWFI for Screening and Diagnosis of DR

Table 1:

Utility of UWFI for Screening and Diagnosis of DR

Utility of UWFI for Capturing Biomarkers of DR Pathology

Table 2:

Utility of UWFI for Capturing Biomarkers of DR Pathology

Discussion

The utility of UWFI for screening and diagnosis of DR has been widely studied. However, there has been a need for information on the level of scientific evidence of these studies. In order to maximize the benefits of UWFI aimed at improving patient care delivery, we reviewed the utility of UWFI for the purposes of screening, diagnosing, and managing DR in prospective and retrospective studies with sufficient levels of scientific evidence. Several level 4 studies indicate that UWFI has good DR severity agreement with 7SF ETDRS and NMFP and moderate agreement with DFE, and thus can be a sufficient imaging modality to screen and diagnose DR.14,15,20–22 UWFI also shows promising utility in long-term management of DR, as new biomarkers of DR pathology can be documented “outside,” “anterior,” or “peripheral” to the border of 7SF ETDRS.23–27,29

UWFI appears to have similar or higher rates of DR detection as reported by five level 4 studies14,15,19,20,16 when compared to the gold standard of DR diagnosis, 7SF ETDRS. This affirms UWFI use as a diagnostic tool for DR in place of traditional fundus imaging systems. Although UWFI has comparable DR detection rates to other imaging methods, the rates are not identical, and surprisingly, UWFI detection rates are sometimes slightly lower.15,17,19 There are many potential reasons for why this might be. We hypothesize that since DR pathology is centered on the posterior pole of the retina, it may cause similar detection rates between UWFI and other imaging methods. Additionally, when ETDRS criteria were first developed, imaging of the peripheral retina was not yet available, thus ETDRS grading may not sufficiently evaluate pathology on UWFI. Finally, resolution of Optos devices varied between included studies and may account for slight differences in detection rates. As compared to DFE DR detection rate, it is unclear as to how UWFI DR detection rates would differ. Since DFEs are more clinically relevant in terms of DR detection than the ETDRS 7SF, which require skilled technicians to perform, and because UWFI has demonstrated at least similar detection rates to DFEs, it stands to reason that UWFI offers a comparable method of DR detection that is both accurate and easy to perform.

Agreement of DR severity (based on ICDR severity scales) between UWFI and 7SF ETDRS across multiple studies is high (κ = 0.71–0.93), whereas agreement between UWFI and DFE is variable (κ = 0.39–0.7). We hypothesize this is because the 7SF ETDRS reference standard is more objective and has more regimented severity scales than clinical assessment on DFE despite the standardized method in which these DFEs were performed.

Interestingly, when comparing the ungradability of images, UWFI appears to have lower rates compared to 7SF ETDRS, but higher rates compared to DFEs. We hypothesize this may be because DFEs are routinely done by providers who can spend additional time on the exam, whereas UWFI and 7SF ETDRS are performed less commonly and by technicians. In addition, the positioning during the examination for some patients might be easier with a DFE versus UWFI.

Although no studies considering UWFI for following DR progression and DR treatments met the current inclusion criteria due to small sample size, three studies reported preliminary evidence for the utility of UWFI in following DR treatment. Levin et al.30 performed a retrospective review of 16 eyes that received UWFI pre- and post-anti-vascular endothelial growth factor treatment. UWFI was able to detect reperfusion of ischemic areas both within 7SF FA and in the periphery outside the 7SF, suggesting that UWFI has utility in capturing peripheral areas of ischemia that can possess viable, salvageable tissue with the potential to re-perfuse.30 Kim et al. documented the possible role of peripheral lesions in recurrent post-vitrectomy diabetic vitreous hemorrhage. After examining 46 eyes, they found significantly greater neovascularization, nonperfusion, and vascular leakage in the periphery beyond the 7SF for the 22 eyes with recurrent vitreous hemorrhage.31 Nicholson et al. performed a prospective, randomized study of 40 eyes that demonstrated there was utility in UWF in following the effect of DR treatment in the peripheral retina with either panretinal photocoagulation or aflibercept injections.32

The obvious advantage of UWFI is in documenting lesions more peripheral to the visual territories of other imaging modalities. Bae et al. demonstrated the possible importance of peripheral lesions and their correlation with lower HbA1c and higher high-density lipoprotein levels. The increased sensitivity of UWFI may also strengthen relationships between retinopathies and other systemic conditions. Wessel et al. quantified the additional amount of information available on UWFA as being 3.2-times the area of 7SF ETDRS, especially important due to the majority of retinal nonperfusion occurring in the mid-periphery.33,34 Talks et al.25 used standard UWFI and UWFA to identify additional patients with neovascularization as compared to 7SF ETDRS.

Nonetheless, it cannot be assumed that DFE alone or UWFI alone is a substitute for a diabetic exam. Comprehensive examinations involve the assessment of the entire eye including corneal, cataract, optic nerve, and other important structures affected in the diabetic eye. The American Academy of Ophthalmology still maintains in their most recent preferred practice pattern on DR that photographic evaluation is not a substitution for an eye examination.

In summary, UWFI has demonstrated significant strengths in aspects of DR. The benefit of peripheral documentation has been studied and includes the identification and documentation of additional pathology with prognostic value, a reduction of ungradable image rates in telemedicine programs, and an increase in accessibility for patients through decreased screening time and patient discomfort. On-going and planned studies evaluating the utility of UWFI may add additional support to an expanded role in the clinical management of DR moving forward. The CLEAR SIGHT trial35 is currently in progress and might lend more information as to the future directions for UWFI.

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Utility of UWFI for Screening and Diagnosis of DR

Author, Year Study Design and Level of Evidence Number of Eyes Ref Std Summary of Clinical Findings
Retrospective % of DR Cases Identified by Non-Mydriatic UWFI vs. Ref Std ICDR Severity Grade Agreement With Ref Std Ungradability Rate of UWFI vs. Ref Std
Price, 201521 Case review, 4; Optos P200 266 7SF ETDRS (simulated) Simple κ = 0.74 (95% CI, 0.67–0.81); Weighted κ = 0.80 (95% CI 0.74–0.86)
DR severity was higher in 40 (15%) UWF images (P < .0001); 18 eyes were designated as mild NPDR instead of very mild, 18 eyes as moderate NPDR instead of mild, and four eyes as severe NPDR instead of moderate.
Silva, 201610 Cross-sectional, 4; Multiple models 16,218 NMFP 24.2% vs. 11.7% (P < .0001) 2.8% vs. 26.9% (P < .0001)
In eyes with DR imaged by UWFI, the presence of predominantly peripheral lesions suggested a more severe level of DR in 282 (7.2%) of 3,926 eyes.
Prospective
Hussain, 201736 Cross-sectional, 4; Optos 200Tx 2,048 165 eyes were identified to have DR. Image acquisition with UWF camera by trained nursing personnel is feasible as only one image was deemed ungradable.
Kernt, 201214 Cross-sectional, 4; Optos P200 144 7SF ETDRS 84.7% vs. 84.0% 95.8%, κ = 0.93 5.7% vs. 10.4%
Liegl, 201317 Cross-sectional, 4; Optos P200 143 EURODIAB photography 83.9% vs. 86.0% κ = 0.54 (P < .001)
Liu, 201735 Randomized Control Trial, 1; Optos 200Tx n/a DFE* CLEAR SIGHT trial in progress
Manjunath**, 201518 Cross-sectional, 4; Optos P200 2,047 DFE 88.6% vs. 86.3% κ = 0.39 1.1% vs. 0.3%
Rasmussen, 201415 Cross-sectional, 4; Optos 200Tx 190 7SF ETDRS 96.3% vs. 97.9% κ = 0.71 (95% CI, 0.63–0.78) 0% vs. 0%
Silva, 201219 Cross-sectional, 4; Optos P200MA 200 7SF ETDRS 86.9% vs. 87.5% Simple κ = 0.79 (95% CI, 0.73–0.86); Weighted κ = 0.85 (95% CI, 0.8–0.91) 4.5% vs. 0.5%
206 DFE 87.3% vs. 85.9% Simple κ = 0.61 (95% CI, 0.53–0.69); Weighted κ = 0.77 (95% CI, 0.71–0.84) 4.4% vs. 0%
Silva**, 201320 Cross-sectional, 4; Optos P200MA 200 7SF ETDRS 90.0% vs. 87.5% Simple κ = 0.74 (95% CI, 0.67–0.81); Weighted κ = 0.84 (95% CI, 0.79–0.89) 0% vs. 0%
206 DFE 90.3% vs. 85.9% Simple κ = 0.47 (95% CI, 0.39–0.56); Weighted κ = 0.69 (95% CI, 0.62–0.76) 1% vs. 0%
Silva, 201511 Cross-sectional, 4; Optos P200MA and P200C 3,978 Evaluation of UWFI images by non-physicians had sensitivity and specificity of 0.95 (95% CI, 0.94–0.97) and 0.84 (95% CI, 0.82–0.85), respectively
Wilson, 201022 Cross-sectional, 4; Optos P200 380 DFE 42.9% vs. 42.4% κ = 0.7 (95% CI, 0.63–0.78) 10.8% vs. 3.3%
Aiello** 201816 Cross-sectional, 4; Optos 200Tx 752 7SF ETDRS (simulated) 99.1% vs. 97.9%. 86.3% agreement (95% CI, 83.4–88.7%) 1.6% vs. 1.7%
752 7SF ETDRS 99.1% vs. 98.8% 1.6% vs. 1.6%

Utility of UWFI for Capturing Biomarkers of DR Pathology

Author, Year Study Design and Level of Evidence Number of Eyes Biomarker “Outside,” “Anterior,” or “Peripheral” to the Border of the ETDRS 7SF Additional Cases of DR Detected by UWFI and Summary of Clinical Findings
Retrospective
Bae, 201623 Case review, 4; Optos P200MA 234 Diabetic retinal changes anterior to imaginary border of ETDRS 7SF 25 (10.7%) eyes with lesions only outside of 7SF. The incidence of anterior DR positively correlated with lower hemoglobin A1c levels and with greater high-density lipoprotein levels following multiple logistic regression analysis (P < .001).
Dodo, 201627 Case review, 4; Optos P200MA 125 White dots (which were delineated by higher signal levels on green but not red laser images) Mean number of white dots was higher in eyes with DR (n = 100) than in eyes with no DR (P < .001). Number of white dots also increased with DR severity, in mild vs. moderate NPDR (P = .006), vs. severe (P = .001), and vs. PDR (P < .001).
Wessel, 201224 Case review, 4; Optos P200A 218 Diabetic retinal changes anterior to imaginary border of ETDRS 7SF using UWFI 22 eyes (10.1%) with lesions only outside of 7SF: 13 eyes (8%) nonperfusion, 9 eyes (17%) neovascularization, 0 eyes (0%) PRP
Prospective
Silva**, 201320 Cross sectional, 4; Optos P200MA 206 Hemorrhage, microaneurysm, venous beading, intraretinal microvascular abnormality, and new vessels elsewhere. 22 eyes (10.7%); Distribution of lesions outside of ETDRS were: hemorrhage/microaneurysm (30%), intraretinal microvascular abnormality (27%), and new vessels elsewhere (34%) This lead to increased severity in 20 eyes.
Silva, 201512 Longitudinal cohort, 3; Optos P200MA 200 DR with a greater distribution outside of the ETDRS 7SF, predominantly peripheral lesions (PPLs) and risk to 2 or more steps progression after 4 years. Compared with eyes without PPLs, eyes with PPLs had a 3.2-fold increased risk of 2-step or more DR progression (6 [11%] vs. 19 [34%]; P = .005) and a 4.7-fold increased risk for progression to PDR (3 [6%] vs. 14 [25%]; P = .005).
Talks, 201525 Cross-sectional, 4; Optos P2000 1,562 Neovascularization anterior to imaginary border of ETDRS 7SF and two-field using steered UWFI 25 (24.5%) and 12 (11.7%) additional eyes compared to two-field and seven-field ETDRS, respectively.
Aiello**, 201816 Cross sectional, 4; Optos 200Tx 749 Hemorrhage and/or microaneurysms, intraretinal microvascular abnormality, neovascularization of the disc, neovascularization elsewhere, venous beading. 308 (41.1%) of eyes showed predominantly peripheral lesions with 83 (11.1%) of eyes demonstrating more severe grading as a result.
Authors

From Case Western Reserve University School of Medicine, Cleveland, Ohio (RPS, JH, MH); Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio (RPS, FFC); the Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio (RPS, FFC); Flaum Eye Institute, University of Rochester Medical Center, Rochester, New York (AEK); California Retina Consultants, Santa Barbara, California (NS); Cullen Eye Institute, Baylor College of Medicine, Houston, Texas (CYW); Austin Retina Associates, Austin, TX and Department of Ophthalmology, Dell Medical School, University of Texas at Austin, Austin, Texas (RWW, JAM); Retina Consultants of Houston, Blanton Eye Institute, Houston Methodist Hospital & Weill Cornell Medical College, Houston, Texas (CCW).

Dr. Singh has received personal fees from Optos and Zeiss during the conduct of the study, as well as grants and personal fees from Regeneron, Novartis/Alcon, and Genentech and personal fees from Bausch + Lomb outside the submitted work. Dr. Kuriyan has received personal fees from Allergan, Alimera Sciences, and Regeneron, and grants from Genentech, Second Sight, and Bayer outside the submitted work. Dr. Weng has received personal fees from Allergan and Alimera Sciences outside the submitted work. Dr. Wykoff has received grants from Adverum Biotechnologies, Aerpio Therapeutics, Alcon Laboratories, Aldeyra Therapeutics, Allegro, Apellis Pharmaceutical, Astellas Pharma, Aura Biosciences, Boehringer Ingelheim, Chiltern International, Heidelberg Engineering, Iconic Therapeutics, inc Research, Johns Hopkins University, NEI, OHR Pharmaceuticals, Ophthotech Corp, Regenxbio, SciFluor Life Sciences, Taiwan Liposome Company and Tyrogenex; personal fees from Alimera Sciences, Alnylam Pharmaceuticals, Bayer, CORCEPT, DORC International, Evolve Medical Education, k2c Medical Communications, Kodiak Sciences, Notal Vision, ONL Pharmaceuticals, and PRIME Educations; and grants and personal fees from Clearside Biomedical, EyePoint (formerly pSivida), Genentech, Novartis, Regeneron Pharmaceuticals, and Santen outside the submitted work. The remaining authors report no relevant financial disclosures.

Dr. Singh did not participate in the editorial review of this manuscript.

Address correspondence to Rishi P. Singh, MD, 9500 Euclid Avenue, Desk i32, Cleveland, OH 44195; email: SINGHR@ccf.org.

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (https://creativecommons.org/licenses/by/4.0). This license allows users to copy and distribute, to remix, transform, and build upon the article, for any purpose, even commercially, provided the author is attributed and is not represented as endorsing the use made of the work.
Received: November 16, 2018
Accepted: March 25, 2019

10.3928/23258160-20191009-07

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