In this episode of Evidence Based Retina, Dr. Singh speaks with Jennifer K. Sun, MD, MPH, Chief at the Joslin Diabetes Center and Vice Chair of Clinical Research at Beth Israel Deaconess Medical Center, about the importance of assessing peripheral lesions in patients with diabetic retinopathy.
They discuss how these lesions may indicate a higher risk of disease progression, highlighting the need to refine staging systems to improve clinical management.
Historical context and technology
Drs. Singh and Sun begin their discussion by highlighting the historical interest in the retinal periphery regarding diabetic retinopathy and its importance for assessing the risk of worsening conditions, a focus dating back to the late 1960s.
While developing the initial classification system for diabetic retinopathy, researchers observed that the far periphery was critical. However, due to the technological limitations of that time, creating montaged images extending to the equator took up to 12 hours.
Currently, modern machines can image 80% of the retina in a quarter of a second, providing the necessary instrumentation to look at the periphery.1 Early studies, including those from the Joslin Diabetes Center, found that about 10% of eyes have more severe retinopathy when the periphery is included in ultra-widefield images.2
Defining ultra-widefield imaging
Ultra-widefield (UWF) cameras, such as the OPTOS machine, can capture images up to 200°. Other equipment, such as the Clarus machines, can image far into the periphery but may require montaging of a couple of images. Table 1 is a quick overview of two UWF systems.1
Table 1: Comparison of OPTOS and Clarus.1
| UWF System | Advantages | Tips for Use |
|---|---|---|
| OPTOS | Can take 200° images. | Optimizing images in the software is helpful, especially looking at the red-free channels, which make hemorrhages, microaneurysms, and difficult-to-see IRMA more visible. Optimizing visualization in OPTOS requires adjusting the contrast and gamma. |
| Clarus | Provides true color. Offers a beautiful view of the retina's appearance. | Will tend to need montaging of a couple of images to get far out. |
UWF systems do a reasonably good job of capturing diabetic retinopathy compared to the historical gold standard of seven standard fields done in stereo (which involved 14 to 15 sets of images per eye).1
UWF and diabetic retinopathy grading
It has been established that retinopathy grading is equivalent when comparing masked seven standard-field images to UWF images.1 Looking at the entire area visible with UWF, outside the seven fields, reveals additional lesions. In about 10% of eyes, these peripheral lesions push the grading to a more severe level of retinopathy.3
Predominantly peripheral lesions
"Predominantly peripheral lesions" are defined as any type of retinopathy lesion that is greater in extent or severity outside the seven-centered fields compared to within them. Initial studies suggested that identifying predominantly peripheral lesions could indicate eyes at higher risk of worsening diabetic retinopathy.3
The DRCR protocol AA, a multi-center study, did not find an association between predominantly peripheral lesions on color photos and worsening of diabetic retinopathy over 4 years. However, the DRCR protocol AA study did find a much higher rate of worsening in eyes with predominantly peripheral lesions on fluorescein angiography.
Approximately 50% of these eyes worsened over 4 years, compared with about 31% of eyes without predominantly peripheral lesions.4
Clinical management and future outlook
Management of diabetic retinopathy is still generally based on findings in the seven standard fields, but there is a move to redefine staging systems. Dr. Sun believes, "We're at a time now when we're really poised to start to redefine the staging systems."
Predominantly peripheral lesions likely reflect the same pathology as posterior lesions, such as nonperfusion retinal ischemia. These peripheral lesions confer a similar risk of worsening over time, indicating an underlying disease that puts a person at risk of increased retinopathy,5 or potential vision loss.
In practice, for an eye with mild non-proliferative retinopathy in the posterior pole but severe hemorrhages, microaneurysms, or IRMA in the periphery, Dr. Sun will follow the patient much more closely.
When to initiate anti-VEGF therapy to manage diabetic retinopathy
Dr. Sun uses anti-VEGF therapy for eyes with proliferative retinopathy, generally not sooner, because studies like DRCR protocol W and PANORAMA showed that while anti-VEGF led to anatomic benefits (reductions in proliferative retinopathy or central DME), the final visual outcomes were the same whether treatment was started early or held until vision-threatening complications occurred.6,7
Anti-VEGF treatment can improve retinal appearance, leading to regression in retinopathy severity, but studies have not shown a dramatic resolution of underlying nonperfusion and ischemia.
Dr. Sun will closely monitor an eye with many far peripheral lesions, and treatment may be initiated sooner, especially if very peripheral neovascularization is observed, which could lead to bleeding or traction.
Unanswered questions
One unanswered question is how to begin creating new staging systems for retinopathy to improve the ability to risk-stratify eyes for vision loss and treatment needs.
A major goal is to use long-term natural history studies with rigorous capture of UWF images and fluorescein angiography to develop new staging systems.
Future models should include strong predictors of worsening retinopathy and the need for treatment, such as baseline diabetic retinopathy severity, retinal nonperfusion, and leakage.5
