All patients with diabetes are at risk of developing diabetic macular edema, which is painless and usually insidious. Diabetic retinopathy is increasingly prevalent with long-standing diabetes, higher incidence baseline A1C levels, hypertension, hyperlipidemia, diabetic nephropathy and diabetic neuropathy—all of which are significant predictors of progression to DME.1,2

DME is an accumulation of fluid resulting from an imbalance of multiple and intricate mechanisms involved in hydro-ionic homeostasis, their molecular and cellular basis, and inner and outer blood retinal barrier disruption driven by Starling’s law.3

Although these risk factors are well known, an additional question is whether retinal imaging in its current state can provide risk factors for progression from DR to DME. Here, we examine the role optical coherence tomography, OCT angiography and ultra-widefield fluorescein angiography (UWFA) can play in identifying predictors of DME, and we report findings from our own small study of these imaging modalities.

Role of OCT angiography
OCT provides a topographical and structural analysis of DR microvascular abnormalities. It can help to identify and characterize complications such as neovascularization, DME, and quantitative and qualitative assessment of macular perfusion.4

Most studies agree that a relationship exists between macular perfusion and stage of DR. OCTA can also reveal alterations in density and morphology of the macular microvasculature in the deep (DCP) and superficial capillary plexus (SCP), as well as correlate the number of microaneurysms in the DCP to the presence of DME. However, OCT has not been able to provide definitive risk factors for progression to DME.5,6

Imaging of the peripheral retina
Imaging the peripheral retina is crucial in the effective diagnosis, management and prognosis of DR, and for quantifying and documenting retinal pathology more precisely than conventional FA. Patients with predominately peripheral lesions have been reported to have a fourfold risk of progressing to proliferative disease than those with more centrally located retinopathy.7,8

Furthermore, identification of the retinal nonperfusion area and calculation of the ischemic index evaluating peripheral nonperfusion using UWFA have been shown to correlate with the severity of DR, as well as defining the presence of peripheral lesions being a risk factor for progression of DR.

The data regarding the ability of UWFA in predicting progression to DME are conflicting. In a retrospective case series, Scott Oliver, MD, and Steven Schwartz, MD, at UCLA did not find a correlation between peripheral nonperfusion and DME, but did create a term, “peripheral vessel leakage” (PVL), to describe late leakage from retinal vessels extending beyond the vessel wall, and found a correlation with PVL and focal DME.9

Figure 1. Ultra-widefield angiography (A) shows nonperfusion and neovascularization, while optical coherence tomography (B) of the same patient shows no diabetic macular edema.

In contrast, Szilard Kiss, MD, and col- leagues at Weill Cornell Medical College found a positive correlation between peripheral nonperfusion (ischemic index) and DME. They reported that peripheral ischemia was an independent risk factor for DME development.10

Findings on OCT
Many biomarkers, including subretinal fluid (SRF), inner segment/outer segment (IS/OS) continuity, absence of hyperreflective foci, attached vitreoretinal interface, central subfield thickness (CST), cube average thickness, disruption of external limiting membrane (ELM) and ellipsoid zone (EZ) have been evaluated to identify early phases of DR and progression of DR.11,12

Although these biomarkers have been correlated to severity of DR and visual acuity changes, no strong evidence exists that they correlate to progression of DME. However, changes in these bio- markers are seen with DME and therefore are presumed to be indicators of worsening DR and DME.

Hyperreflective foci correlate with lipoprotein extravasation after breakdown of the inner blood-retinal barrier in the initial stage of developing hard exudates. Researchers in South Korea determined that hyperreflective foci on spectral-domain OCT are markers of increased DME activity.13 They proposed that hyperreflective foci were lipoprotein, migrated microglia or a combination of both.

Our study of UWFA and OCT
We retrospectively evaluated 48 eyes of 24 consecutive patients who underwent UWFA for very severe nonproliferative or proliferative DR, grading for DME, neovascularization, peripheral perfusion ischemic index and PVL. Grading was masked, and both ischemic index and PVL were grouped into mild, moderate and severe categories. OCT of each eye was then evaluated to confirm the presence or absence of DME. Ischemic index and PVL category were then correlated with the patients’ OCT, and statistical analysis was performed


A higher ischemic index was not associated with DME (p=0.62), while higher PVL was correlated with DME (p=0.01) (Table). Our findings are similar to those Drs. Oliver and Schwartz reported.9

We retrospectively evaluated 44 eyes of 22 consecutive patients with severe NPDR without DME on initial OCT. Initial OCT was then correlated to OCT taken at a mean of 24 months later (range, 18 to 27 months), with respect to hyperreflective foci, SRF, IS/OS continuity, disruptions of ELM and EZ, CST, cube average thickness and the development of DME. The later OCT was graded in a masked fashion. DME was judged to be either present or absent on the later OCT.

Statistical analysis was used to compare the initial OCT to the later OCT using chi square testing. We found that only hyperreflective foci correlate with progression to DME (p=0.03) (Table). Our findings are consistent with the initial findings of the previously mentioned researchers in Korea.13

Bottom line
Findings on retinal imaging, including OCT hyperreflective foci and UWFA peripheral vessel leakage, may predict progression from DR to DME in our study. Other studies have found a positive correlation between peripheral nonperfusion and DME. Although development of DME is a multifactorial process that comprises systemic health, metabolic control, cytokines, growth factors and other mechanisms violating the blood retinal barrier, further studies with a larger number of patients would validate the utility for OCTA, OCT and UWFA to elucidate additional risk factors for development of DME.

Figure 2. Baseline optical coherence tomography (A) shows hyperreflective foci. Eighteen months later, OCT (B) exhibits diabetic macular edema.

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