Article

Ultrawidefield Imaging for Diabetic Retinopathy

Extending the edge of discovery.

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There is a worldwide epidemic of diabetes mellitus. It is estimated that the global prevalence of diabetes in adults is 422 million, a number that is projected to rise to 629 million by 2045.1,2 Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and a primary cause of visual loss worldwide, and 95% of the visual loss cases due to DR can be prevented if detected and treated early.3 Currently, most screening programs employ color fundus photography to identify referable DR, and fundus imaging plays an integral role in the diagnosis, management, and follow-up of DR. A single-field fundus photograph covers the area between optic nerve and macula with a 20° to 50° field of view. Although this is certainly the most vital part of the fundus, a significant portion of the fundus remains uncovered, and as such peripheral DR lesions are excluded.

ETDRS 7 STANDARD FIELDS IMAGING

To address the limitations of single-field fundus imaging, a montage image combining disparate fields was developed with small areas of overlap to facilitate alignment. For the past 2 decades, the gold standard for assessing severity of DR has been the protocol established by the Early Treatment Diabetic Retinopathy Study (ETDRS) with the modified Airlie House classification. In this imaging protocol, retinal lesions are evaluated in the posterior pole using 7 stereoscopic pairs of 30-degree colour fundus photographs per eye (7 standard fields), encompassing a 75-degree horizontal fundus viewing angle.4 This system of montaged images has been found reliable for the assessment of DR and is the basis for nearly all modern formal imaging assessments of DR. However, it is laborious and time-consuming, and it requires a skilled photographer. Furthermore, the ETDRS 7 standard fields only comprise about 34% of the total retinal surface, and substantial diabetic changes can occur outside of this area that may be critical for optimal assessment of diabetic retinal diseases.

DEFINING ULTRAWIDEFIELD IMAGING

According to the Diabetic Retinopathy Clinical Research network (DRCR.net ), fundus imaging with a field of 100-degree or more is considered ultrawidefield (UWF).5 This definition is debated and is based on a “field-of-view” (FOV) approach. Recently, the International Widefield Imaging Study Group recommended using anatomical landmarks rather than FOV to define the terms widefield and UWF.6 Their rationale for this approach rests upon the concept that clinicians examine patients using anatomic landmarks to guide their exam and, as such, these definitions should follow a similar course. Furthermore, because field of view can be calculated using an internal or external angle of the eye, these differences in capture techniques could be unified by focusing on the end result of said imaging: anatomy. Thus, the group defined a widefield image as the retina up to and including the vortex vein ampullae in all 4 quadrants obtained in a single capture. An ultrawidefield image was defined as the retina beyond the vortex vein ampullae in all four quadrants obtained in a single capture.

The advent of modern wide and ultrawidefield imaging devices has expanded our view of the peripheral retina and thus our perspective on DR. The Optos (Daytona; Optos), Clarus 500 (Carl Zeiss Meditec), and Clarus 700 (Carl Zeiss Meditec) are currently available widefield imaging platforms that both enable widefield imaging either in single capture or image montage.5 Optos is a scanning laser ophthalmoscope that produces retinal images of up to 200° in nonmydriatic eyes, representing more than three times the retinal surface of traditional ETDRS 7-field photos. This allows for identification of peripheral DR lesions that cannot be seen on conventional fundus photos. The recently released Clarus 500 and Clarus 700 capture “true-color” images that may potentially enable more accurate identification of DR lesions, although this has yet to be demonstrated in clinical trials.

DETECTION AND CLASSIFICATION OF DIABETIC RETINOPATHY

Single-center studies have shown moderate to substantial agreement between the ETDRS 7-field system and UWF imaging in assessing DR severity.7-9 In a recent cross-sectional study comparing the 2 imaging systems using 37 DRCR.net sites, Aiello et al found that 59% of eyes had exact agreement and 97% of eyes were within 1 step of agreement.10 These findings may justify UWF imaging for assessing the severity of DR endpoints in future clinical trials. In other studies, DR was classified at a higher retinopathy level in the UWF view compared to ETDRS standard fields.11,12 Detection of retinal nonperfusion and neovascularization was also higher in UWF images, and the study authors suggested that improved retinal visualization may lead to more precise grading of disease compared to non-UWF images.

Figure 1. Asymmetric ultrawidefield fluorescein angiogram (Optos California) of a 54-year-old male with proliferative diabetic retinopathy demonstrating widespread nonperfusion and neovascularization.

PREDICTION OF DIABETIC RETINOPATHY PROGRESSION

In clinical practice, the integration of UWF imaging enhances the ability to visualize the retinal periphery and may improve rates of DR detection. Recent studies suggest that the presence of predominantly peripheral lesions (PPL) on UWF imaging is highly associated with increased risk of DR worsening and the onset of proliferative DR. Predominantly peripheral lesions have been defined as microaneurysms, hemorrhages, venous beading, intraretinal microvascular abnormalities, and new vessels elsewhere in eyes with DR with more than 50% of the graded lesion located outside the 7 standard ETDRS fields.12,13 Using UWF imaging, Silva et al showed that eyes with PPLs have a 3.2-fold increased risk of 2-step or more of DR progression and a 4.7-fold increased risk for progression to proliferative disease, independent of baseline DR severity and HbA1C levels.14 These findings demonstrate that evaluation of the peripheral retina using UWF imaging provides important information for assessing the risk of DR progression that cannot be assessed by ETDRS 7-field imaging. The use of UWF imaging also may be important in clinical trial settings requiring precise assessment of prospective DR progression rates, in clinical care for accurate patient counseling, and in teleophthalmology programs to improve risk assessment and triage in eyes that otherwise would not have the peripheral retina evaluated.

TARGETED RETINAL LASER PHOTOCOAGULATION

Improved detection of peripheral DR lesions and areas of nonperfusion allows for their more selective treatment through targeted laser photocoagulation (TRP). Using UWF-guided TRP, Mugit et al showed a regression in 76% of patients at 12 weeks and complete disease regression in 37% of patients at 24 weeks.15 The same group also conducted a randomized clinical trial (PETER PAN study) that demonstrated a significant reduction in central retinal thickness in the TRP group compared to the minimally traumatic panretinal photocoagulation group, although the rates of progression to proliferative DR was similar.16 A phase 1/2, multicenter, randomized, study of the efficacy and safety of ranibizumab injection monotherapy vs a combination therapy of ranibizumab plus Optos UWF-guided TRP in patients with center involving diabetic macular edema (clinicaltrials.gov identifier: NCT01552408) is ongoing.

LIMITATIONS OF ULTRAWIDEFIELD IMAGING

As a relatively new and evolving imaging modality, many of the current studies are performed in the setting of a dedicated image grading center. Additional investigations may determine if these data hold true in a clinical setting. If so, the major constraint to widespread adoption of UWF systems such as the Optos and Clarus is largely financial. Such instruments cost an order of magnitude more than conventional fundus camera setups. Despite impressive outcomes from studies, it remains unclear whether the additional information UWF adds to clinical practice is sufficient to justify the financial outlay, and cost-effectiveness analysis may be needed. However, as technology improves and equipment costs fall, UWF imaging should become increasingly accessible. Other limitations of UWF systems include low portability, difficult service, and the need for extensive imager training.17 As with most imaging modalities, obtaining high-quality UWF images require good patient cooperation, and image quality and FOV may be affected by artifacts from the eyelids and lashes. From a technical perspective, a major technical limitation inherent to any widefield imaging system is the nonlinear warp at the periphery, which is a result of digital projection of a 3-dimensional surface to 2-dimensional image. Because the angle of view changes when moving from the center of the image toward the periphery, more peripheral structures will appear to be larger when stereographically projected. However, the latest software on Optos instruments for example has tried to address this problem, and the size and location of peripheral lesions can now be calculated in anatomically correct physical units.18

SUMMARY

The potential benefits are evolving when it comes to the diagnosis, classification, and management of DR. Advances in UWF imaging technology now allows for 80% of the retinal surface to be imaged within a single capture in a quarter-second. From a research standpoint, UWF imaging is providing us with a better understanding of disease mechanisms, specifically the relationship between peripheral diabetic changes and the severity and progression of DR. From a clinical standpoint, visualization of the retinal periphery provides important information in the detection and management of diabetic eye diseases. It is an exciting time in retinal imaging, and this new imaging modality holds promise for providing improved care of patients with diabetes worldwide. RP

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