Enhancing Diabetic Macular Edema Treatment Outcomes: Exploring the ESASO Classification and Structural OCT Biomarkers

Abstract

Introduction: This study assessed the European School of Advanced Studies in Ophthalmology (ESASO) classification's prognostic value for diabetic macular edema (DME) in predicting intravitreal therapy outcomes.

Methods: In this retrospective, multicenter study, patients aged > 50 years with type 1 or 2 diabetes and DME received intravitreal antivascular endothelial growth factor (anti-VEGF) agents (ranibizumab, bevacizumab, and aflibercept) or steroids (dexamethasone). The primary outcome was visual acuity (VA) change post-treatment, termed as functional response, measured 4-6 weeks post-third anti-VEGF or 12-16 weeks post-steroid injection, stratified by initial DME stage.

Results: Of the 560 eyes studied (62% male, mean age 66.7 years), 31% were classified as stage 1 (early), 50% stage 2 (advanced), 17% stage 3 (severe), and 2% stage 4 (atrophic). Visual acuity (VA; decimal) improved by 0.12-0.15 decimals in stages 1-2 but only 0.03 decimal in stage 3 (all p < 0.0001) and 0.01 in stage 4 (p = 0.38). Even in eyes with low baseline VA ≤ 0.3, improvements were significant only in stages 1 and 2 (0.12 and 0.17 decimals, respectively). Central subfield thickness (CST) improvement was greatest in stage 3 (-229 µm, 37.6%, p < 0.0001), but uncorrelated with VA gains, unlike stages 1 and 2 (respectively: -142 µm, 27.4%; - 5 µm, 12%; both p < 0.0001). Stage 4 showed no significant CST change. Baseline disorganization of retinal inner layers and focal damage of the ellipsoid zone/external limiting membrane did not influence VA improvement in stages 1 and 2. Treatment patterns varied, with 61% receiving anti-VEGF and 39% dexamethasone, influenced by DME stage, with no significant differences between therapeutic agents.

Conclusion: The ESASO classification, which views the retina as a neurovascular unit and integrates multiple biomarkers, surpasses single biomarkers in predicting visual outcomes. Significant functional improvement occurred only in stages 1 and 2, suggesting reversible damage, whereas stages 3 and 4 likely reflect irreversible damage.

Keywords: Anti-VEGF; Diabetic macular edema; ESASO classification; OCT Biomarkers; Optical coherence tomography; Retinal Neurovascular Unit; Steroid; Treatment outcomes in DME.

Fig. 1

Illustrations of ESASO DME classification stages. Early diabetic maculopathy (stage 1) includes: a Small cystoid spaces near the fovea, with all retinal layers intact and normal central subfoveal thickness and macular volume. TCED-HFV: T = 1; C = 1; E = 0; D = 0; H = 0; F = 0; V = 0. b Multiple perifoveal cystoid spaces with mild macular thickening and incomplete vitreous detachment; over 30 hyperreflective foci. TCED-HFV: T = 1; C = 2; E = 0; D = 0; H = 1; F = 0; V = 1. c Mild macular edema with intact retinal profile, cystoid spaces, and initial epiretinal membrane; over 30 hyperreflective foci. TCED-HFV: T = 1; C = 2; E = 0; D = 0; H = 1; F = 1; V = 4. Advanced diabetic maculopathy (stage 2) includes: d cystoid spaces with retinal thickening and central macrocyst; damaged subfoveal ellipsoid zone. TCED-HFV: T = 2; C = 3; E = 1; D = 0; H = 1; F = 0; V = 0. e Intermediate cystoid spaces with disrupted external limiting membrane and visible internal retinal layers; no adhesion or traction. TCED-HFV: T = 2; C = 2; E = 1; D = 0; H = 0; F = 1; V = 0. f Large pseudocyst in the fovea with parafoveal cystoid spaces; damaged subfoveal external limiting membrane and partial vitreous detachment. TCED-HFV: T = 2; C = 3; E = 1; D = 1; H = 0; F = 0; V = 1. g Large cystoid spaces with shallow subfoveal detachment; non-gradable ellipsoid zone and discontinuous external limiting membrane; visible inner retinal segmentation and slightly elevated vitreous. TCED-HFV: T = 2; C = 3; E = 1; D = 0; H = 1; F = 1; V = 1. Severe diabetic maculopathy (stage 3) includes: h multiple central macrocysts with inner retinal layer disorganization; absent subfoveal external limiting membrane and ellipsoid zone. TCED-HFV: T = 2; C = 3; E = 2; D = 1; H = 0; F = 0; V = 1. i Central macrocyst with large surrounding cystoid spaces, severe DRIL, and incomplete vitreous detachment; absent subfoveal external limiting membrane and ellipsoid zone. TCED-HFV: T = 2; C = 3; E = 2; D = 1; H = 0; F = 0; V = 1. j Central macrocyst and multiple large cysts with a few hyperreflective foci; damaged but visible retinal inner layers and normal vitreoretinal relationship. Atrophic diabetic maculopathy (stage 4) includes: k Central retinal thinning with DRIL, atrophic retinal pigment epithelium, and below-normal thickness and volume; some parafoveal microcysts and peripheral cystoid spaces. TCED-HFV: T = 0; C = 1; E = 2; D = 1; H = 1; F = 0; V = 0. l Central thinning with DRIL, irregular and focally atrophic retinal pigment epithelium, and below-normal thickness and volume, but with some moderate intraretinal cysts. TCED-HFV: T = 0; C = 1; E = 2; D = 1; H = 0; F = 0; V = 0. Adapted from reference [4]. DME diabetic macular edema, DRIL disorganization of the inner retinal layers, ESASO European School of Advanced Studies in Ophthalmology, TCED-HDF Thickening–cysts–ellipsoid–DRIL–hyperreflective foci–fluid (subretinal)–vitreoretinal relationship

Fig. 2

Treatment patterns in diabetic macular edema. VEGF vascular endothelial growth factor

Fig. 3

Mean VA improvement after the loading phase, any therapy (a), and absolute mean VA improvement after the loading phase, any therapy (b). VA visual acuity

Fig. 4

VA improvement in the function of VA from baseline (a), stratified by ESASO DME classification in eyes with VA < 0.3 decimal at baseline (b). DME diabetic macular edema, ESASO European School of Advanced Studies in Ophthalmology, VA visual acuity

Fig. 5

Correlation between ESASO DME stage and changes in CST at the end of follow-up. CST central subfield thickness, DME diabetic macular edema, ESASO European School of Advanced Studies in Ophthalmology

Fig. 6

Absolute variation in VA in DRIL at baseline and in DRIL at the end of the treatment period (a), stage 2 and in stage 3 (b), VA in EZ/ELM Grade1 (n = 224), in EZ/ELM grade 2 (c), and VA in stage 2 and stage 3. DRIL disorganization of the inner retinal layers, EZ ellipsoid zone, ELM external limiting membrane, VA visual acuity

Fig. 7

Absolute difference in (VA) according to stage and treatment naivety. VA visual acuity