New biomarker may predict treatment response in DME

Researchers have identified a new biomarker they believe can be used as a predictor of vision change in patients with diabetic macular edema, either during the natural history of the disease or after undergoing anti-VEGF therapy. The biomarker is disorganization of the retinal inner layers, or DRIL.

Take-home: Researchers have identified a new biomarker they believe can be used as a predictor of vision change in patients with diabetic macular edema, either during the natural history of the disease or after undergoing anti-VEGF therapy. The biomarker is disorganization of the retinal inner layers, or DRIL.

Reviewed by Jennifer K. Sun, MD, MPH

In many patients, eyes treated with an anti-VEGF agent for diabetic macular edema (DME) resolve the edema and improve their vision. However, there are eyes where the edema resolves over the course of anti-VEGF therapy but the vision remains the same or worsens, and there are eyes that have persistent or even worsening edema, with excellent visual acuity outcomes. 

There is an inexact correlation between central subfield thickness and visual acuity, so researchers are looking into using biomarkers of vision, which might improve methods for evaluating potential new therapies.

Many parameters evaluated to this point (such as presence or absence of epiretinal membranes, presence and extent of intraretinal cysts, hyper-reflective foci, presence of microaneurysms, extent of subretinal fluid, and measures of outer layer disruption, reflectivity, or thickness) have not been shown to be strongly correlated with or predictive of vision.

Jennifer K. Sun, MD, MPH and colleagues at the Joslin Diabetes Center, Boston, have identified a new biomarker called disorganization of the retinal inner layers (DRIL). The researchers looked for DRIL within the central 1-mm foveal zone.In eyes with no DRIL, researchers were able to segment the inner retinal layer boundaries, but in eyes with DRIL they were unable to segment these layers. They found DRIL could be evaluated not just within the entire extent of the 1-mm zone, but also in terms of portions of the 1-mm zone being affected. DRIL can be present or absent in eyes with resolved as well as current DME.


Eyes with edema that do not have disruption of the boundaries of the inner retinal layers often have good vision, even despite the presence of large intraretinal cysts. However, eyes with DRIL in either resolved or current edema often have poor vision.

The researchers initially identified the DRIL parameter in an early cross-sectional study that looked at a number of parameters seen on spectral-domain optical coherence tomography (SD-OCT) in eyes with DME (80 eyes in 58 patients).

In the study, the patients were split into groups of those with the expected relationships between retinal thickness and visual acuity, and those with paradoxical, or unexpected, relationships between thickness and visual acuity.

“Both in the entire cohort when we looked, and in an analysis evaluating just the groups of eyes with current edema and good vision, versus those with resolved edema, but unfortunately poor vision, we found that DRIL of all the SD-OCT parameters was the most robustly associated with visual acuity outcomes,” Dr. Sun explained, “where the presence of DRIL affecting 50% or more of the central 1-mm zone was more likely to be seen in eyes with worse vision.”

The researchers then looked at longitudinal studies, examining DRIL and other SD-OCT parameters in terms of early change within 4 months. They looked to see how these correlated with visual acuity outcomes at 8 months.

They found that even when adjusting for central retinal thickness and outer layer characteristics, DRIL was still the most robust SD-OCT parameter associated with visual acuity change over time.  Early, 4-month change in DRIL was predictive of visual acuity outcomes at the 8-month time period.

Though DRIL can worsen and persist, it can also resolve, and reverse. In the researchers’ study, 66% of eyes with baseline DRIL had DRIL improvement in the 8-month study.  When DRIL decreased by 50 µm or more at 4 months, visual acuity was stable or increased in 97% of eyes.

In eyes where DRIL decreased by a larger threshold of 250 µm over 4 months, none had vision decline of a line or more, but 78% percent visual acuity increase of a line or more at 8 months.

“These data suggest that perhaps over time we might be successful in finding thresholds of DRIL that are highly correlated with percent chances of visual acuity gain or worsening over the long term,” Dr. Sun said.

The researchers went on to look at other aspects of visual function–retinal sensitivity as measured by microperimetry in the LUCIDATE study, which randomized 33 participants to ranibizumab, or macular laser for treatment of DME.


They looked at the entire panel of SD-OCT parameters and again found that DRIL was highly correlated with improvements in central microperimetry over 0-12 and 0-24 weeks. In contrast, other SD-OCT measures, including central retinal thickness, were not correlated with microperimetry outcomes at any one of the time points in this 48-week study.

“DRIL change within the central foveal zone is a stronger predictive biomarker for both visual acuity and retinal sensitivity, than either retinal thickness, or outer layer changes,” Dr. Sun said. “Thresholds of early DRIL change may prove in the future to be useful for predicting functional improvement, or worsening, for an individual eye.”

For now, evaluation of DRIL and other SD-OCT variables is primarily a research tool in eyes with DME. There are studies ongoing to attempt to validate DRIL and these other parameters as predictors of vision.

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