Higher-Order Assessment of OCT in Diabetic Macular Edema from the VISTA Study: Ellipsoid Zone Dynamics and the Retinal Fluid Index

Abstract

Purpose: To investigate retinal fluid features and ellipsoid zone (EZ) integrity dynamics on spectral-domain OCT (SD-OCT) in eyes with diabetic macular edema (DME) treated with intravitreal aflibercept injection (IAI) in the VISTA-DME study.

Design: A post hoc subanalysis of a phase III, prospective clinical trial.

Participants: Eyes received either IAI 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly doses (2q8).

Methods: All eyes from the VISTA Phase III study in the IAI groups imaged with the Cirrus HD-OCT system (Zeiss, Oberkochen, Germany) were included. The OCT macular cube datasets were evaluated using a novel software platform to generate retinal layer and fluid boundary lines that were manually corrected for assessment of change in EZ parameters and volumetric fluid parameters from baseline. The retinal fluid index (i.e., proportion of the retinal volume consisting of cystic fluid) was also calculated at each time point.

Main outcome measures: The feasibility of volumetric assessment of higher-order OCT-based retinal parameters and its correlation with best-corrected visual acuity (BCVA).

Results: Overall, 106 eyes of 106 patients were included. Specifically, 52 eyes of 52 patients were included in the IAI 2q4 arm, and 54 eyes of 54 patients were included in the IAI 2q8 arm. Ellipsoid zone integrity metrics significantly improved from baseline to week 100, including central macular mean EZ to retinal pigment epithelium (RPE) thickness (2q4: 26.6 μm to 31.6 μm, P < 0.001; 2q8: 25.2 μm to 31.4 μm, P < 0.001). At week 100, central macular intraretinal fluid volume was reduced by >65% (P < 0.001) and central macular subretinal fluid volume was reduced by >99% in both arms (P < 0.001). Central macular retinal fluid index (RFI) significantly improved in both arms (2q4: 17.9% to 7.2%, P < 0.001; 2q8: 19.8% to 4.2%, P < 0.001). Central macular mean EZ-RPE thickness (i.e., a surrogate for photoreceptor outer segment length) and central RFI were independently correlated with BCVA at multiple follow-up visits.

Conclusions: Intravitreal aflibercept injection resulted in significant improvement in EZ integrity and quantitative fluid metrics in both 2q4 and 2q8 arms and correlated with visual function.

Figure 1.. A representative case with diabetic macular edema treated with intravitreal aflibercept injection demonstrating a longitudinal change in en face retinal thickness mapping, ellipsoid zone (EZ) mapping, intraretinal/subretinal fluid mapping, and horizontal OCT B-scan image.

The left eye from a 51-year-old female patient in the 2q4 arm. Among 10 follow-up time points that have been evaluated in this subanalysis, 8 selected time points are shown in the figure including the baseline (farthest left column), week 4, 8, 12, 24 28, 52 and 100 (farthest right column). An inner circle represents the macular radius of 0.5 mm (corresponds to central subfield) and an outer circle represents the macular radius of 1.0 mm (corresponds to central macula) in en face macular map. (Top row) En face retinal thickness mapping. (Second row) En face EZ mapping representing the topographical thickness between EZ and retinal pigment epithelium (RPE). EZ-RPE attenuation mainly localized within the central macular area gradually decreased its size through week 52. (Third row) Intraretinal and subretinal fluid mapping. Intraretinal fluid within central macula (an area filled in blue) and subretinal fluid (an area filled in green). (Bottom row) Horizontal B-scan crossing the central fovea displaying semi-automatically segmented retinal layer boundaries and visually discernable fluid. The internal limiting membrane (blue line), EZ band (yellow line), RPE (turquoise line), intraretinal fluid within central macula (an area filled in blue) and subretinal fluid (an area filled in green). Each boundary was verified by trained reviewers, and segmentation errors were carefully corrected manually.

Figure 2.. Longitudinal changes in best corrected visual acuity and selected OCT parameters from baseline to week 100 in 2q4 and 2q8 arms.

2q4 arm received intravitreal aflibercept injection (IAI) every 4 weeks from baseline to week 100, while 2q8 am received IAI every 4 weeks from baseline to week 16 (5 injections) followed by dosing every 8 weeks through week 100. The error bars indicate the standard errors of the mean. A, Mean change in best corrected visual acuity (ETDRS letters) from baseline through week 100 in 2q4 and 2q8 arms. B, Central macular mean ellipsoid zone (EZ) to retinal pigment epithelium (RPE) thickness. C, The area coverage of EZ-RPE thickness < 20 μm. D, Actual central macular mean retinal tissue thickness. E, Central macular retinal fluid index. F, Central macular subretinal fluid volume.

Figure 3.. A heat map representing the Pearson correlation coefficients between best corrected visual acuity (ETDRS letters) and OCT retinal parameters from baseline through week 100.

Each colored rectangle represents the degree of correlation coefficient at specific week; positive correlations are filled in red whereas negative correlations are filled in blue. Correlation coefficients are depicted according to the shown color scale shown at the bottom. Superimposed asterisk indicates the statistical significance of P < .05. At week 24, separate 2q4 and 2q8 arms are also shown. Central subfield and central macular ellipsoid zone (EZ) to retinal pigment epithelium (RPE) parameters demonstrate a consistent moderate correlation with best corrected visual acuity (BCVA) at given week. Actual central subfield and central macular retinal tissue thickness/volume parameters demonstrate a weak positive correlation beyond week 4.

Figure 4.. Multivariate linear regression analysis on BCVA (ETDRS letters) from baseline to week 100 in all study eyes.

Independent variables included actual central macular mean retinal tissue thickness, central macular mean ellipsoid zone (EZ) to retinal pigment epithelium (RPE) thickness, and transformed central macular retinal fluid index. Adjusted R-squared (R²), a forest plot, adjusted coefficient with 95% confidence interval (CI) and P values for each variable at given week are shown. P values in bold letters indicate statistical significance of less than .05.

Figure 5.. Scatterplot showing the relationship between actual central macular mean retinal tissue thickness and best corrected visual acuity (ETDRS letters) at week 20 (include both 2q4 and 2q8 arms).

The actual mean retinal tissue thickness represents mean retinal tissue thickness excluding both intraretinal and subretinal fluid (i.e., equivalent to the mean retinal thickness of diffuse, non-cystic retinal thickening). The graph demonstrate a weak positive correlation between two parameters (the regression coefficient is r = 0.264, P = .007) at week 20.