Based on the assumptions that literature content can be represented by selected MeSH terms, research status of a specific theme can be revealed by an aggregation of MeSH terms. Statistical evaluation using BICOMB software indicates that the overall trend of research articles on “retinal vein occlusion” [MeSH] is featured as an increase peaked in 2015. Furthermore, US and England are identified as the two countries with the most publications on RVO, and one of the reasons for this could be that their native language is English.
With the focus on investigating the structures of RVO knowledge systemically, co-word evaluation, biclustering examination, strategic diagram and bibliometric SNA were included in this study. Clusters were formed and identified with MeSh terms that are associated closely through the co-word and biclustering evaluation. Cluster 1 was identified to be associated with studies on the complications of RVO, the etiology of macular edema and the therapeutic use of monoclonal/humanized antibodies, corticosteroids and anti-inflammatory agents. Age and systemic disorders were identified as the top two risk factors for RVO. RVO prevalence increases significantly with age but does not differ by gender [6], probably due to atherosclerosis. Systemic diseases such as hypertension, diabetes mellitus, hyperlipidemia, thrombophilia, hypercoagulation and inflammatory diseases are strongly associated with RVO [7]. RVO patients may suffer a variety of complications, the most significant of which is macular edema. Other serious complications include vascularization of the retina and optic disc (which can result in vitreous hemorrhage), retinal detachment, neovascular glaucoma and even blindness [8]. Cystoid macular edema (CME), which is caused by capillary congestion, may result in the metamorphopsia and even loss of visual acuity. A multicenter, randomized clinical trial examined the efficacy and safety of 1-mg and 4-mg doses of intravitreal triamcinolone acetonide (IVTA) in comparison with standard grid photocoagulation for BRVO. Investigators reported similar improvement in OCT thickness over 1-year observation in all groups. In terms of complications, cataract progression rate was higher in the 4mg IVTA group, thus IVTA is less commonly used than anti-VEGF therapy [9]. VEGF is an inflammatory cytokine that promotes vascular permeability and is upregulated in eyes with vein occlusion [10]. Ranibizumab and bevacizumab are humanized monoclonal antibodies that are active against the VEGF-A molecule. Different clinical trials on anti-VEGF injections suggest that intraocular anti-VEGF injection can significantly improve vision acuity in eyes with BRVO [11]. These topics in Cluster 1, positioned in Quadrant I, are the centralized and matured hotspots in the RVO field.
Cluster 0 is associated with research on epidemiology and the metabolism of RVO. The prevalence of RVO has been reported to range between 0.4% and 4.6%. Of the two main types of RVO, BRVO is four to six times more prevalent than CRVO [12]. The balance between inflammatory cytokines and angiogenesis in eye fluid is disturbed in patients with RVO. Exposure of endothelial cells to proinflammatory cytokines can cause oxidative stress and apoptosis, aggravating leukocyte efflux and thrombosis. Significantly increased concentrations of IL-1α, -6, and -8; IP-10; and PDGF-AA were observed in RVO patients when compared to control patients [10]. Macular edema secondary to RVO is associated with increased levels of VEGF in the aqueous humor. Therefore, the management of macular edema secondary to RVO, especially in the presence of capillary con-perfusion areas, should aim at reducing ocular VEGF concentration [13]. Cluster 3 relates to genetic studies on RVO. Thrombophilic diseases like factor V Leiden mutation, hyperhomocysteinemia and anticardiolipin antibodies increase the risk of RVO [14]. Proteomic studies suggest that RVO is associated with the remodeling of the extracellular matrix and adhesion processes. However, many areas of proteome changes in RVO remain unstudied. Future studies may address long-lasting retinal changes following intervention with anti-VEGF agents, such as dexamethasone intravitreal implants [15]. These two clusters, assigned to Quadrant III, represents research hotspots which are marginal and immature, and future research on these topics is suggested.
Cluster 2 relates to the surgical treatment of RVO. Macular grid laser photocoagulation is an effective treatment for macular edema in patients with BRVO. Other treatment options for reducing edema are intravitreal steroids, anti-VEGF drugs and vitrectomy. It has also been reported that vitrectomy is effective for reducing macular edema and improving visual acuity in patients with BRVO. Vitrectomy probably reduces macular edema by allowing oxygenated fluid to circulate in the vitreous cavity, improving perifoveal microcirculation, and increasing the clearance of VEGF in the vitreous cavity. A five-year follow-up of vitrectomy for macular edema associated with BRVO revealed that vitrectomy may evade the risks associated with repeated injections; however, the incidences of postoperative RD were higher than that of intravitreal injections [16]. Cluster 4 is associated with the pathophysiology and RVO diagnosis. In RVO patients, signs of oxidative stress, such as enhanced plasma lipid peroxidation and decreased antioxidant activity of paraoxonase, have been reported [17]. M. Becatti, et al. compared ROS production and membrane lipid peroxidation in RVO patients and control subjects. The results indicated that erythrocyte oxidative stress is an essential factor in the pathogenesis of RVO disease [18]. Suzuki et al. reported that anti-VEGF therapy might improve retinal deep ischemia in the retinal deep layer of patients with RVO [19]. In clinical practice, treatment decisions commonly depend on OCT measurements. OCT provides high-resolution imaging of the fovea and is helpful in detecting the presence of macular edema, vitreoretinal interface changes, neurosensory retinal detachment and subretinal fluid. Optical coherence tomography angiography (OCTA) can evaluate the retinal hemodynamics in patients with RVO. FFA is able to detect peripheral capillary nonperfusion, macular ischemia, and subtle neovascularization. Eyes with more capillary nonperfusion have a greater risk of ocular neovascularization. FFA may also help to distinguish collateralization from neovascularization, since the former does not leak fluorescein, whereas the latter does [20]. These two clusters are assigned to Quadrant IV and include immature but centralized research topics.
According to the RNA analytical outcome, MeSH terms ranked the top three are “Macular edema/drug therapy”, “Antibody, monoclonal, humanized/therapeutic use” and “Retinal vein occlusion/drug therapy”, showing high degree centralities. These MeSH terms are with the most directly links with other components, pioneering the progress of the RVO research. With regard to the betweenness centrality analysis, “Retinal vein occlusion/complications”, “Retinal vein occlusion/diagnosis” and “Retinal vein occlusion/physiopathology” are identified to be located at the network center, representing the key components with the highest influence in the determination of other components’ co-occurrence. “Retinal vein/pathology” and “Retina/pathology” are among the top ten MeSH terms with betweenness centrality; however, these two components are located in the IV quadrant and are not included in the MeSH terms listed with the top ten high-reoccurrence. This demonstrates that although these two components are important in the network stability, but the research on this topic is not well developed.