Imaging Biomarkers “Significant Predictors” of Worsening Diabetic Macular Edema

Fundus oculi of a patient suffering from retinal edema. (Photo by: BSIP/Universal Images Group via Getty Images)
Researchers used data from the VISTA clinical trial to show how imaging technologies can foretell worse leakage and poorer visual acuity.

Both early and cumulative retinal fluid index volatility significantly predicted the worsening of diabetic macular edema (DME) and visual acuity in certain patients in a sub-analysis of the VISTA phase III trial, potentially offering new imaging biomarkers for best treatment interval extension, according to the study published in the American Journal of Ophthalmology.

The purpose of the study, a post hoc sub-analysis of the VISTA trial, was to look at longitudinal retinal fluid dynamics with spectral domain optical coherence tomography (SD-OCT) to find imaging biomarkers that could potentially determine DME progression. It took place during interval extension of anti-vascular endothelial growth factor (VEGF) therapy. 

Researchers examined patients in 2 groups, 55 eyes that received intravitreal aflibercept injection 2 mg every 4 weeks (2q4), and 58 eyes that received intravitreal aflibercept injection every 8 weeks after 5 initial monthly injections (2q8). All eyes were imaged with SD-OCT. In the study, investigators evaluated retinal images with a novel software platform that found retinal fluid features including retina fluid index, which is the percentage of retina volume that’s “occupied by intraretinal fluid.” In addition, the macular cube was analyzed at 10 time-points, baseline to week 100.

They found that early retina fluid index volatility that had a retina fluid index increase of 5 points or more from week 4 to 8 (P =.004) and cumulative retina fluid index volatility that had an aggregate increase in macular retina fluid index by 10 points or more with increased retina fluid index between baseline to week 20 (P =.005) were significant predictors that DME and visual acuity would worsen in the 2q8 group when the treatment interval was extended to 8 weeks.

“Eyes with these risk factors might be regarded as poor candidates for extending treatment interval with a higher risk of losing vision between the injections and might provide unique opportunity for patient education/prognostication. In addition, identifying these at-risk eyes might facilitate clinical trial enrichment for emerging molecules and therapeutics,” they report.

They also successfully classified eyes based on treatment response in central macular retina fluid index. “By this definition, roughly one in two eyes were classified as early responders, and of those, 94% of eyes achieved central macular [retina fluid index] <10% and 43% achieved very good BCVA at week 100. Eyes in this category might be candidates for early treatment interval extension,” investigators say.

The study did have limitations, including its smaller sample size than the original study the post-hoc exploratory subanalysis was based on, as well as some on the technical side with OCT and these measurements.

“Further validation and enhanced automation of calculating this imaging biomarker may provide an important opportunity for clinical trial utilization and potentially deployment to clinical care,” they report. 


Ehlers JP, Uchida A, Sevgi DD, et al. Retinal fluid volatility associated with interval tolerance and visual outcomes in diabetic macular edema in the VISTA phase III trial

Am J Ophthalmol. 2020. doi: 10.1016/j.ajo.2020.11.010