Central retinal vein occlusion (CRVO) causes macular edema and subsequent vision loss and is common in people with diseases such as arteriosclerosis and hypertension. Various treatments for CRVO-associated macular edema have been trialed, including laser photocoagulation, with unsatisfactory results. However, when the important pathogenic role of vascular endothelial growth factor (VEGF) in macular edema was identified, the treatment of CRVO was revolutionized by anti-VEGF therapy. However, despite the success of intraocular injection of anti-VEGF agents in many patients with CRVO, some patients continue to suffer from refractory or recurring edema. In addition, the expression of inflammatory cytokines increases over time, causing more severe inflammation and a condition that is increasingly resistant to anti-VEGF therapy. This indicates that the pathogenesis of macular edema in CRVO is more complex than originally thought and may involve factors or cytokines associated with inflammation and ischemia other than VEGF. CRVO is also associated with leukocyte abnormalities and a gradual reduction in retinal blood flow velocity, which increase the likelihood of it developing from the nonischemic type into the more severe ischemic type; in turn, this results in excessive VEGF expression and subsequent neovascular glaucoma. Here, we review the role of different factors and cytokines involved in CRVO pathogenesis and propose a mechanism that holds promise for the development of novel therapies.

Branch retinal vein occlusion (BRVO) often results in macular edema, which is the chief cause of visual impairment in patients with BRVO. Although the pathogenesis of macular edema in these patients is unclear, retinal changes due to BRVO (including hemorrhage) are known to cause local inflammation. After retinal vein occlusion, there is increased rolling and adhesion of leukocytes to the retinal vein walls that lead to stagnation of blood flow,¹ so inflammation may play a key role in the pathogenesis of BRVO. The role of inflammation is supported by reports that intravitreal injection of triamcinolone acetonide lessens macular edema in patients with BRVO² and that the aqueous flare value is significantly higher in patients with retinal vein occlusion than in healthy individuals.³

Diabetic macular edema (DME) is a critical complication of diabetic retinopathy, a condition that arises from the breakdown of the blood–retinal barrier and the consequent increase in vascular permeability. Over the years, attempts have been made to treat DME by various approaches, including laser photocoagulation, steroid triamcinolone acetonide, and vitrectomy. However, treatment was unsatisfactory until research identified vascular endothelial growth factor (VEGF) as a factor in the pathogenesis of DME. Intraocular anti-VEGF agents show good efficacy in DME. Nevertheless, in some patients the condition recurs or becomes resistant to treatment, suggesting that other factors may be involved. Because inflammation and retinal hypoxia are seen in DME, research has examined the potential role of cytokines and other inflammatory mediators. In this review, we provide an overview of this research and describe feedback mechanisms that may represent a target for novel treatments.

Branch retinal vein occlusion (BRVO) is a very common retinal vascular problem in patients with lifestyle-related diseases, such as hypertension and arteriosclerosis. In patients with BRVO, development of macular edema is the main cause of visual impairment. BRVO is still a controversial condition in many respects. Over the years, various methods such as laser photocoagulation have been tried to treat macular edema associated with BRVO, but the results were not satisfactory. After vascular endothelial growth factor (VEGF) was found to have an important role in the pathogenesis of macular edema in BRVO patients, treatment of this condition was revolutionized by development of anti-VEGF therapy. Although macular edema improves dramatically following intraocular injection of anti-VEGF agents, repeated recurrence and resistance of edema is a major problem in some BRVO patients. This suggests that factors or cytokines other than VEGF may be associated with inflammation and retinal hypoxia in BRVO and that the pathogenesis of macular edema is complicated. The present review assesses the role of various factors and cytokines in the pathogenesis of macular edema associated with BRVO. We present a mechanism that is not only plausible but should also be useful for developing new therapeutic strategies.

Purpose.: The association between aqueous humor levels of various growth/inflammatory factors or cytokines and the severity of macular edema was investigated in patients with central retinal vein occlusion (CRVO). Methods.: Aqueous humor levels of 11 factors or cytokines were measured in CRVO patients with macular edema (n = 38) and in cataract patients (n = 15) as controls. Aqueous humor samples were obtained from the patients during surgery and the levels of VEGF, its receptors, and other factors or cytokines were measured by the suspension array method. The severity of macular edema was determined by measuring the central macular thickness, neurosensory retinal thickness, and subfoveal serous retinal thickness with optical coherence tomography. Results.: Aqueous humor levels of growth factors, soluble VEGF receptor 1 (sVEGFR-1), sVEGFR-2, and inflammatory factors or cytokines were significantly higher in the CRVO group than in the control group. The aqueous level of sVEGFR-1 was significantly correlated with the neurosensory retinal thickness, as well as with the levels of growth factors (VEGF, placental growth factor, and platelet-derived growth factor-AA) and inflammatory factors/cytokines (monocyte chemotactic protein-1, interleukin-6, and interleukin-8). Aqueous humor levels of the three growth factors also were significantly correlated with each other, as were levels of the two sVEGFRs. Conclusions.: These findings suggest that growth/inflammatory factors and cytokines have an important role in macular edema associated with CRVO. Better understanding of the mechanisms involved may lead to development of new treatments, such as anti–VEGFR-1 therapy.