Since first described by Friberg and Forrester in 2004,9
UWFA has proven to be a reliable method of retinal evaluation, having favourable sensitivity and specificity compared with other traditional methods.10–12
In some applications, including identification of diabetic pathology, it has proven to be superior to traditional methods, including 7SF. A recent comprehensive study of efficacy in detection of diabetic pathology found that UWFA was able to demonstrate retinal non-perfusion and neovascularisation in 10% of eyes that would have been missed by 7SF.13
To our knowledge, this study is one of the first and largest to use UWFA to evaluate retinal ischaemia and identify its relationship with DMO. This study also examined whether UWFA can be used as a complement to OCT to determine whether the degree of macular thickening correlates with the proportion of retinal ischaemia.
We demonstrate that patients with retinal ischaemia have a 3.75 times greater chance of having DMO. This observation has several important implications. First, it lends support to the growing data suggesting that retinal ischaemia and release of vasoproliferative growth factors play a role in the pathogenesis of DMO. Several recent studies, including the BOLT and PACORES study groups, have shown that anti-VEGF therapy is effective in treating DMO, even in cases where macular laser therapy has failed.14–16
In that retinal ischaemia is most likely driving the release of VEGF, and that patients with retinal ischaemia have a 3.75 times greater chance of developing DMO, detection and monitoring of peripheral retinal ischaemia could play an important role in the management of patients with diabetic retinopathy. For example, patients with retinal ischaemia on UWFA may necessitate closer monitoring and earlier follow-up than patients with no evidence of retinal ischaemia.
A second implication of our study is that new treatment modalities, such as targeted retinal photocoagulation (TRP) may prove efficacious in treating DMO. In early studies evaluating patients with proliferative diabetic retinopathy, it has been suggested that TRP may replace pan-retinal photocoagulation by directing therapy specifically at ischaemic parts of the retina to precisely eliminate the source of VEGF, thus minimising the sequelae of pan-retinal photocoagulation.17
In many of the eyes that we analysed, DMO was present despite minimal posterior diabetic pathology. In some of these eyes, UWFA was able to demonstrate anterior areas of retinal ischaemia (). In that the pathogenesis behind the formation of DMO is most likely related to peripheral retinal ischaemia in these cases, it would be reasonable to consider treating DMO by using UWFA and TRP. In combination with macular laser and anti-VEGF therapy, TRP could prove to be important in the growing arsenal of treatment modalities for DMO.
Figure 3 An ultra-widefield fluorescein angiogram with diabetic macular oedema and a peripheral area of ischaemia. Targeted photocoagulation treatment of this area could possibly prove to be another treatment choice if traditional methods were not efficacious. (more ...)
Interestingly, our study failed to detect an association between the amount of retinal ischaemia and the degree of macular thickening. While this might in part be attributable to the small number of patients who had both OCT and UWFA images performed at the time of their initial visit, it might also suggest that the degree of retinal ischaemia is not related to the extent of macular thickening. It is possible that only a small amount of retinal ischaemia is necessary for the causal factors of DMO to develop, and the macular thickness may be more attributable to local, structural and micro-anatomical factors than to the extent of released VEGF. Additional studies would be needed to explore this relationship further. Also, it was also noted that the proportion of retinal ischaemia was significantly related to the value of haemoglobin A1c (), but not with the presence of DMO. This could suggest that both DMO and ischaemia are related to the pathophysiology of diabetes, but by different mechanisms. Along with evaluating whether there is a direct association between ischaemia and DMO, it would be valuable to examine whether there is a threshold level of ischaemia at which DMO is induced.
We recognise there are limitations to the conclusions that can be drawn from our study. Although we attempted to use all UWFAs in the two-and-a-half-year time period, there was likely a significant selection bias given that physicians had multiple options of obtaining fluorescein angiograms in our clinic, only one of which was the Optos system. Given the retrospective nature of our study and the limited time span in which the study was conducted, we realise that not all results are generalisable. However, the large number of patients included in the study helps to mitigate this issue. While this is, to our knowledge, the largest study examining the correlation between retinal ischaemia and DMO, further studies with an increased number of patients would enhance our findings, and prospective trials could help validate these potential applications of UWFA in clinical practice. Additionally, we realise that measurements of a three-dimensional eye using a two-dimensional system are imprecise, and it is likely that peripheral pathology is over-represented. While not trivial, this discrepancy would not significantly alter the conclusions that can be drawn from our data. Finally, while identifying the presence of retinal ischaemia on UWFA imaging is fairly straightforward, variations in image quality could lead to some variability in quantifying the area of ischaemic retina in each image. These limitations were minimised by our large sample size and the use of two independent reviewers to evaluate each image.
Overall, the findings of this study suggest that there may be a role for UWFA in assessing retinal changes associated with DMO. UWFA may serve as a valuable tool for identifying diabetic patients at risk of developing DMO, for guiding management and follow-up protocols, and for potential new treatment options. As DMO contributes significantly to vision loss in patients with diabetes, the possibility of using UWFA to develop earlier and more precise detection and treatment strategies for DMO is encouraging.