RVO is the second leading retinal vascular disease that can induce visual loss behind DR. According to the manifestations of retinal ischemia, RVO can be divided into ischemic and non-ischemic types. ME secondary to RVO is the major cause of visual loss, while long-term ME could induce visual cells apoptosis, consequently leading to permanent visual loss. Therefore, active application of effective methods to treat RVO-ME has important clinical significance for improving patients' visual acuity.
Currently, the treatments for RVO-ME in clinical practices mainly include drug therapy and laser photocoagulation. Sustained-release DEX is a water-soluble drug that can effectively enter the vitreous body. Previous studies have demonstrated that intravitreal injection of sustained-release DEX in RVO patients could alleviate ME and increase the visual acuity . VEGF has various homologous isoforms, such as VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor (PLGF). Among them, VEGF-A played an important role in angiogenesis and increasing vascular permeability , mainly by binding to vascular endothelial growth factor receptor (VEGFR). CBC is the fusion protein of the extracellular region of human VEGF receptor-1 (VEGFR-1), VEGFR-2, and human IgGFc fragment. It could competitively bind to VEGFA, VEGFB and PIGF to antagonize the effects of VEGF on promoting the proliferation of vascular endothelial cells, thereby inhibiting angiogenesis and reducing vascular leakage. Photocoagulation, which aims to reduce retinal edema and improve visual acuity, could destroy the photoreceptors in the retinal anoxic region and consequently reduce the retinal oxygen demand. In addition, photocoagulation could also reduce the release of angiogenic factors induced by anoxia, thereby preventing or reducing angiogenesis. Furthermore, photocoagulation could help reconstruct the internal and external blood-retinal barrier, and reduce macular capillary leakage, thereby reducing or preventing cystoid macular edema. In this study, the BRVO eyes were divided into DEX group (30 eyes), CBC group (51 eyes), combination group (29 eyes), and laser group (49 eyes)according to the treatment, respectively, then the BCVA, CFT, and HRD changes were assessed at 12 months after treatment. Our findings showed that intravitreal injection of CBC, sustained-release DEX or both drugs in patients with ME secondary to BRVO could effectively alleviate ME, reduce CFT (P<0.01), and increase the patient’s visual acuity (P<0.01).
The pathogeneses of ME have been mainly associated with the high expression of VEGF and the release of inflammatory mediators after retinal occlusion, retinal ischemia and hypoxia. Previous studies have demonstrated that there was already an imbalance between pro- and anti- inflammatory factors in the retina, and inflammatory reactions already occurred even before the appearance of microangiopathy . HRD has been considered as a sign of active inflammation , which refers to the small (diameters ≤30 μm) diffused dotty lesions with clear boundaries and the signal intensity equal to or higher than the retinal pigment epithelium shown by SD-OCT [3,4]. HDR could be found in patients with various diseases of the ocular fundus, such as RVO, AMD, DR/DME, Stargardt disease, and retinitis pigmentosa. They could also be found in the whole retina but were mainly clustered in the external layer. Professor Coscas firstly reported HRD in 2009 [5,6] and described it as dotty hyper-reflective material with small volumes distributed throughout the entire retina, but mainly in the exterior layer, and in the cystoid macular edema between retinal layers of AMD patients. Numerous studies in wAMD, DR, and DME have shown that HRD could be activated microglial cells [3,8,9], which is a marker of active retinal inflammation. During RVO, microglia can migrate from the interior retinal layer to the external retinal layer and release IL-6, TNF, NO, VEGF, and MCP-1 to promote inflammatory responses, disrupt the blood-retinal barrier, and induce macular edema . Our findings showed that HRD was found in the retina of all RVO patients before treatment, suggesting that inflammatory responses participated in the ME in RVO, while intravitreal injection of both sustained-release DEX and CBC significantly reduced the number of HRD in the retina (P<0.01). Further analysis showed that all three groups, including the DEX group, CBC group, and combination group, could be divided into responsive and non-responsive subgroups, while the HRD numbers were significantly higher in the non-responsive subgroups compared to responsive subgroups, thus suggesting that patients with higher baseline HRD numbers responded poorly to the treatment, and also had poorer visual outcomes.
In summary, all chronic retinal stresses could induce various sub-clinical molecular changes and cellular inflammatory responses, which consequently induced the development and progression of ME and seriously affected the vision of patients. Inflammatory factors participated in the development of ME secondary to RVO, while HRD could be used to identify inflammatory factors. Intravitreal injection of sustained-release DEX, CBC, or combined treatment could reduce the number of HRD in the retina, alleviate ME, and increase patients' visual acuity. The patients with higher baseline HRD numbers had a poorer response to the treatment, the treatment efficacy was suboptimal, and the visual prognosis were also poor.