Retinal Ischaemia in Diabetic Retinopathy: Understanding and Overcoming a Therapeutic Challenge

Abstract

Background: Retinal ischaemia is present to a greater or lesser extent in all eyes with diabetic retinopathy (DR). Nonetheless, our understanding of its pathogenic mechanisms, risk factors, as well as other characteristics of retinal ischaemia in DR is very limited. To date, there is no treatment to revascularise ischaemic retina.

Methods: Review of the literature highlighting the current knowledge on the topic of retinal ischaemia in DR, important observations made, and underlying gaps for which research is needed.

Results: A very scarce number of clinical studies, mostly cross-sectional, have evaluated specifically retinal ischaemia in DR. Interindividual variability on its natural course and consequences, including the development of its major complications, namely diabetic macular ischaemia and proliferative diabetic retinopathy, have not been investigated. The in situ, surrounding, and distance effect of retinal ischaemia on retinal function and structure and its change over time remains also to be elucidated. Treatments to prevent the development of retinal ischaemia and, importantly, to achieve retinal reperfusion once capillary drop out has ensued, are very much needed and remain to be developed.

Conclusion: Research into retinal ischaemia in diabetes should be a priority to save sight.

Keywords: DMI; DR; FFA; OCT; OCT angiography; OCTA; UWF FFA; diabetes; diabetic macular ischaemia; diabetic retinopathy; optical coherence tomography angiography; retinal capillary dropout; retinal function; retinal ischaemia; retinal nonperfusion; ultra-widefield fluorescein angiography.

Figure 1

(a) Ultra-wide field pseudocolour image obtained from the right eye of a patient with diabetes with “no overt diabetic retinopathy”. Microaneurysms and small areas of capillary drop-out, however, are visible on the corresponding ultra-wide field fundus fluorescein angiogram (b). As an example, the two areas with no abnormalities are magnified as detected on the pseudocolour image (bottom left), which showed vascular changes on fluorescein angiography (bottom right).

Figure 2

Arterio-venous (a) and late (b) phases of the ultra-wide field fundus fluorescein angiogram obtained from the right eye of a patient with proliferative diabetic retinopathy (PDR). Note the relatively well-perfused retina, except for very small areas of retinal ischaemia (example in inset) but several mid-peripheral new vessels elsewhere. Findings are very suggestive that other mechanisms, besides retinal ischaemia (e.g., inflammation), contribute to new vessel formation. Furthermore, findings highlight the great variability on the extension of areas of retinal ischaemia required for the occurrence of PDR.

Figure 3

Venous phase of an ultra-wide field fundus fluorescein angiogram obtained from the right eye of a patient with non-proliferative diabetic retinopathy. Despite extensive midperipheral and peripheral retinal ischaemia, no new vessels are present. As findings show in Figure 2, this demonstrates also that there is great interindividual variability on the response of the retina to the insult of retinal ischaemia. Note the relatively well-preserved perifoveal capillaries (for details, see inset, right).

Figure 4

(a) Superficial and (b) deep retinal capillary plexuses as visualized using optical coherence tomography angiography (OCTA) and (c) corresponding fundus fluorescein angiogram (FFA). OCTA shows a well-preserved superficial capillary plexus (a) and what appears to be an area of capillary nonperfusion, supero-temporally to the foveal avascular zone (FAZ) and a microaneurysm temporally in the deep capillary plexus (b). FFA clearly shows multiple microaneurysms temporally to the FAZ ((c) and inset) not seen in the superficial capillary plexus on OCTA; one of these is imaged in the deep capillary plexus on OCTA imaging. This suggests that FFA, in contrast to what has been previously stated in the literature, is able to determine changes in the deep capillary plexus and, under certain circumstances at least (such as the case shown here), allows better visualization of retinal capillary changes than OCTA.

Figure 5

Venous phase of an ultrawide field fundus fluorescein angiogram obtained from three patients with non-proliferative diabetic retinopathy. Note in ((a) and corresponding inset) the lack of perfusion of the far peripheral temporal retina when compared with ((b) and corresponding inset) where blood vessels reached the far periphery. Interindividual differences with regard to the extension of the retinal vessels to the far peripheral retina may affect measures of retinal ischaemia if these areas of “nonperfusion” are considered “ischaemic”. In contrast, areas of ischaemia at other locations are usually well delineated and easier to identify, often surrounded by areas with multiple microaneurysms and microvascular changes ((c) and corresponding inset).

Figure 6

Ultrawide field fundus fluorescein angiogram (a) and same image with superimposed sensitivity values as derived from the Metrovision automated perimeter (57-point static test) (b). In green are depicted points with normal sensitivity; in light pink are those with deficits from 4 to 8 dB; in dark pink are deficits of >8 dB; and in red absolute deficits, when compared with those obtained in the corresponding locations in an age-matched group of healthy volunteers.