Reduction of Macular Edema and Pro-permeability Factors after Dexamethasone Implant Injection in Retinal Vein Occlusion; the Ozurdex for Retinal Vein Occlusion (ORVO) Study

Abstract

Purpose: To measure changes in aqueous levels of vasoactive proteins in patients with macular edema due to retinal vein occlusion (RVO) after injection of a dexamethasone implant and correlate them with changes in edema.

Methods: Twenty-three subjects with central RVO (CRVO) and 17 with branch RVO (BRVO) who had persistent/recurrent edema despite prior injections of a vascular endothelial growth factor (VEGF)-neutralizing protein had an aqueous tap at baseline, 4 weeks and 16 weeks after intraocular injection of a dexamethasone implant. At each study visit, patients had best-corrected visual acuity (BCVA) measured by Early Treatment Diabetic Retinopathy Study protocol and measurement of center subfield thickness (CST) by spectral domain optical coherence tomography. Aqueous levels of vasoactive proteins were measured by protein array or enzyme-linked immunosorbent assay (ELISA). The main outcome was correlation of changes between baseline and week 4 in aqueous levels of vasoactive proteins with changes in edema.

Results: Thirty-two of a possible 55 vasoactive proteins were detected in the aqueous at baseline. Four weeks after injection of a dexamethasone implant, hepatocyte growth factor (HGF), endocrine gland-vascular endothelial growth factor (EG-VEGF), insulin-like growth factor binding proteins (IGFBPs) 1, 2, and 3, activin-A and endostatin were reduced by ≥30% in at least 4 of 11 eyes with BRVO and at least 4 of 11 eyes with CRVO. In 18 RVO eyes (12 CRVO, 6 BRVO) baseline levels of HGF and VEGF measured by ELISA were 168.2 ± 20.1 pg/ml and 78.7 ± 10.0 pg/ml; in association with reduced edema at week 4, HGF was reduced in 12 of 18 eyes and VEGF was reduced in 10 of 17. There was a correlation between reduction in persephin (PCC=0.638, p=0.003) and pentraxin 3 (PCC=0.682, p=0.014) with reduction in excess foveal thickening.

Conclusions: Dexamethasone implants reduce levels of several proteins that may have pro-permeability activity, potentially an appealing multitargeted approach for patients with macular edema. It would be valuable to identify proteins that contribute to chronic edema to gain insight into molecular mechanisms. This study has identified candidates that deserve further study including HGF, EG-VEGF and activin-A. The potential effects of changes in IGFBPs and persephin also deserve investigation.