3.1.1. Triamcinolone Acetonide

Triamcinolone is a type of steroid hormone commonly used in ophthalmology for intraocular treatment. Its main purposes are to inhibit proliferation, reduce edema, and suppress the formation of new blood vessels. The therapeutic effect of triamcinolone on RVO is mainly achieved by reducing the permeability of retinal capillaries and inhibiting the expression of VEGF factors. The standard treatment for RVO compared with corticosteroid treatment (Standard Care vs. Corticosteroid for Retinal Vein Occlusion, SCORE) investigated the role of 1 mg or 4 mg of triamcinolone in the vitreous cavity and macular grid laser photocoagulation (GLP) in BRVO. The study included 411 BRVO patients and allowed re-treatment every 4 months according to the PRN standard. There was no statistically significant increase in visual acuity at the 12th month: the percentages of patients with an increase of 15 letters or more in visual acuity from baseline to the 12th month were 26.0% (1 mg), 27.0% (4 mg), and 29.0% (GLP), the average change in BCVA was 5.7 (1 mg), 4.0 (4 mg), and 4.2 (GLP), and the central foveal thickness of the macula measured by OCT decreased by 149 μm (1 mg), 170 μm (4 mg), and 224 μm (GLP) compared to the baseline. In the 4 mg triamcinolone group (41%), antihypertensive drugs were more common than the 1 mg triamcinolone group (7%) and the GLP group (2%) within 12 months. 25% (1 mg), 35% (4 mg), and 13% (GLP) of patients experienced progression of cataracts [8]. The SCORE study also included 271 patients with CRVO who received intravitreal injections of 1 mg or 4 mg of triamcinolone acetonide for comparison. The same PRN standard allowed for re-treatment every 4 months. From baseline to the 12th month, the proportion of patients with an increase of ≥15 letters in BCVA was 26.5% (1 mg), 25.6% (4 mg), and 6.8% (observation), which was similar to the average loss of 12 letters in the observation group. The stable vision in the 1 mg and 4 mg triamcinolone acetonide groups was −1.2 and −1.2, respectively. The central point thickness measured by OCT was reduced by 196 μm (1 mg), 261 μm (4 mg), and 277 μm (observation) from the baseline. In the 4 mg triamcinolone acetonide treatment group (35%), the frequency of starting to use eye pressure-lowering drugs within 12 months was higher compared to the 1 mg triamcinolone acetonide treatment group (20%) and the observation group (8%), with 26% (1 mg), 33% (4 mg), and 18% (observation) of patients experiencing progression of cataracts [9]. Whether it is posterior vitreous injection or intravitreal injection of triamcinolone acetonide, both can alleviate macular edema in the short term and improve patients’ vision. However, they may also aggravate the formation of cataracts, cause increased intraocular pressure, and lead to related complications such as endophthalmitis. Therefore, their use should be carefully considered based on the patient’s condition.

3.1.2. Dexamethasone Implant

Ozurdex® (dexamethasone intravitreal implant) is a dexamethasone carrier developed in the form of a biodegradable intravitreal implant, which can deliver a 700μg dose of the drug to the retina and vitreous. It has been approved by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Swiss Medical Council for the treatment of ME associated with RVO [10] and non-infectious posterior uveitis [11]. Since inflammation is the key factor causing RVO-ME, Ozurdex® directly targets a series of inflammatory mediators. By inhibiting the proliferation and migration of various inflammatory cells and blocking the potential mechanisms of RVO-ME early on, it achieves protection of photoreceptor cells and effectively reduces macular edema. Ozurdex® can also be used in cases where the effect of anti-VEGF drugs has not been fully determined, namely ischemic retinopathy. There have been prospective studies proving its effective action for more than 12 months in ischemic RVO (although due to the ischemic state, the function is limited) [12][13]. In the case of anti-VEGF treatment for retinal vascular diseases, the efficacy of dexamethasone implants in treating refractory macular edema has been proven [14]. For patients who have experienced cardiovascular events and are unable to tolerate monthly anti-VEGF drug treatment or follow-up, Aduris® can also be considered. Additionally, assessing the degree of ischemia in patients is a very important factor to consider. Not only the macular area should be focused on, but also the peripheral area. If macular edema is combined with ischemic factors, hormone combined with laser treatment can be considered. The impact of Ozurdex® on the recovery of the retinal vascular barrier in patients with RVO is related to its effects on vision and central retinal thickness [15]. The main risk of complications from intravitreal dexamethasone implants is an increase in intraocular pressure, which reaches its peak 1 to 2 months after the first treatment. There have been no reports of an increase over time or with an increase in the number of injections. Monitoring and controlling intraocular pressure should be done within 4 weeks after implantation [16][17]. At the same time, dexamethasone implants may also cause other complications such as cataracts and glaucoma. Although studies have confirmed that dexamethasone implants have a good therapeutic effect on RVO-ME and have a long-lasting effect in the vitreous cavity, which can significantly reduce the number of injections, due to the risks of these complications, further research is still needed for the use of dexamethasone implants.

At present, intravitreal injection of anti-VEGF drugs has become the preferred treatment method for RVO [18][19].

3.2.1. Bevacizumab

Bevacizumab is a recombinant humanized monoclonal antibody targeting all subtypes of VEGF. Epstein et al. [20] evaluated the efficacy of intravitreal injection of Avastin in treating patients with CRVO-induced macular edema for more than 12 months. Sixty patients were assigned to receive intravitreal injection of Avastin or sham injection every 6 weeks for 6 months. All patients received intravitreal injection of Avastin every 6 weeks starting from the 6th month, and this continued for another 6 months. At the 12th month, the BCVA of the bz/bz group improved by 16.0 letters, while the sh/bz group improved by 4.6 letters. In the last follow-up, 18 out of 30 patients in the bz/bz group (60%) increased by 15 letters, and 10 out of 30 patients in the sh/bz group (33.3%) increased by 15 letters. The sh/bz group showed a reduction of 404 μm in CMT, while the bz/bz group had an average reduction of 435 μm in CMT. Intravitreal injection of Avastin can improve vision and alleviate macular edema. However, the visual improvement in patients receiving delayed treatment is limited. Other studies have also reported some side effects of Avastin’s anti-VEGF treatment, such as damage to the macular microcirculation and retinal blood supply, and promotion of retinal vascular occlusion in RVO eyes [21]. Compared with ranibizumab, bevacizumab is less costly, but its overall therapeutic effect and safety are inferior to that of ranibizumab. Currently, the clinical application of intravitreal injection of bevacizumab is relatively rare.

3.2.2. Ranibizumab

Ranibizumab is a second-generation recombinant humanized monoclonal antibody Fab fragment with a relative molecular weight of 48,000. It can bind with high affinity to various isoforms of VEGF-A (VEGF165, VEGF121 and VEGF110) [22][23]. The BRAVO study [24] (Evaluation of the efficacy and safety of ranibizumab in treating macular edema caused by BRVO) enrolled 397 patients and randomly divided them into the Lucentis (0.3 mg) group, the Lucentis (0.5 mg) group, and the sham injection group. After 6 months, they were switched to the PRN regimen. At the 12th month, the percentages of patients in the Lucentis (0.3 mg) group, Lucentis (0.5 mg) group, and sham injection group who achieved a BCVA improvement of ≥ 15 letters were 56.0%, 60.3%, and 43.9%, respectively. The CMT reduction values were 313.6 μm, 347.4 μm, and 273.7 μm, respectively. Moreover, no new adverse events were found in this study. In the HORIZON trial, the open-label extension of the BRAVO study confirmed that the therapeutic benefits were typically maintained [25]. The CRUSE study [26] (Retinal vein occlusion (CRVO) with macular edema treated with ranibizumab: Efficacy and safety assessment) A total of 392 patients were included, who received monthly intravitreal injections of 0.3 mg or 0.5 mg ranibizumab or placebo for 6 months. Subsequently, PRN treatment with 0.3 mg or 0.5 mg ranibizumab and placebo was administered for 6 to 12 months. At 6 months, the average improvement in best corrected visual acuity (BCVA) score in the ranibizumab group was 12.7 (0.3 mg) and 14.9 (0.5 mg), while in the placebo group it was 0.8 letters; the proportion of patients with BCVA increase of ≥15 letters was 46.2% (0.3 mg), 47.7% (0.5 mg), and 16.9% (placebo); the average reduction in central foveal thickness (CMT) was 434 μm (0.3 mg), 452 μm (0.5 mg), and 168 μm (placebo). At 12 months, the average change in BCVA was 13.9 (0.3 mg), 13.9 (0.5 mg), and 7.3 (placebo/0.5 mg); the proportion of patients with BCVA increase of ≥15 letters at 12 months was 47.0% (0.3 mg), 50.8% (0.5 mg), and 33.1% (placebo/0.5 mg); CMT decreased to 452 μm (0.3 mg), 462 μm (0.5 mg), and 427 μm (placebo/0.5 mg), and no ocular adverse events occurred. This study confirmed the efficacy and safety of ranibizumab.

3.2.3. Conbercept

Conbercept is a new type of anti-VEGF drug. It is a fusion protein with a relative molecular weight of 143,000. Its composition structure consists of the immunoglobulin-like region 2 of human VEGFR1 (FLt-1) and the immunoglobulin-like regions 3 and 4 of VEGFR2, and fuses them with the Fc segment of human IgG1, making it have high affinity and a longer half-life. Studies have shown that the extracellular domain of VEGFR2 in Conbercept can significantly reduce the activity of new blood vessels, and at the same time enhance the binding of Conbercept to VEGF [27]-[29]. In the study by Huang YK et al. [30], compared with the normal control group matched by age and gender, the average BCVA, retinal vascular density and blood perfusion of 12 patients (12 eyes) with non-ischemic BRVO-ME were lower, while the CMT and the area of the foveal avascular zone (FAZ) were larger. These BRVO-ME patients received monthly intravitreal injections of Conbercept for 3 consecutive months. The results showed that after the injection of Conbercept, BCVA, retinal vascular density, blood perfusion increased, CMT significantly decreased, and macular edema was alleviated. This confirmed the definite efficacy of Conbercept in the treatment of non-ischemic BRVO-ME. These results were consistent with most previous studies. Compassip has more binding sites, higher affinity, and even a longer half-life compared to monoclonal antibody anti-VEGF drugs [31][32]. Therefore, it is questionable whether Conbercept causes more severe retinal vascular events than monoclonal antibody anti-VEGF drugs. In the study by Li FJ et al. [33], the treatment strategy for BRVO secondary to ME adopted a 1 + PRN approach. The results showed that BCVAs significantly improved (p < 0.05), and the average CMT significantly decreased (p < 0.001). At any follow-up time, there were no statistically significant differences in the improvement of BCVA, reduction of CMT, and injection frequency between the two groups. Therefore, the efficacy of conbercept and ranibizumab in treating BRVO secondary to ME was comparable. Additionally, during the follow-up period, no serious adverse events (systemic or focal) occurred in either group, such as stroke, arterial thrombosis, intraocular inflammation, cataract or lens damage, retinal detachment, retinal tear, or vitreous hemorrhage. The data indicate that intravitreal injection of conbercept for treating BRVO-ME is safe. Since conbercept has a stronger binding affinity to VEGFA than ranibizumab, it may be more effective in treating BRVO secondary to ME. Although the research data indicate that these two drugs have similar efficacy in treating BRVO secondary to ME, it is likely that the smaller molecular weight of ranibizumab enhances its penetration at the action site compared to conbercept, thereby offsetting its relatively lower binding affinity. Studies have shown that patients with RVO-ME who presented with serous macular edema characterized by retinal thickening before treatment, showed significant reduction in retinal thickness and improvement in macular edema after continuous injection of Conbercept for 3 months. No adverse reactions such as endophthalmitis or vitreous hemorrhage occurred. This proves the effectiveness and safety of Conbercept in the treatment of RVO [34]. In conclusion, intravitreal injection of Conbercept for the treatment of RVO is safe and effective.

3.2.4. Aflibercept

Aflibercept is a recombinant protein composed of two protein sequences of VEGF receptors (VEGFR-1 and VEGFR-2) and the Fc portion of immunoglobulin G1. The GALILEO study enrolled 177 patients with macular edema secondary to CRVO. They received 2 mg aflibercept intravitreal injection or placebo injection every 4 weeks for 20 weeks. The aflibercept group was treated with the aflibercept as-needed (PRN) regimen, while the placebo group continued to receive placebo injections for 24 to 48 weeks. At 6 months, the average increase in letters was 18.0 for the aflibercept group and 3.3 for the placebo group; 60.2% of the aflibercept group achieved ≥15 letters, while 22.1% of the placebo group did. The average CMT decreased by 448.6 μm in the aflibercept group and 169.3 μm in the placebo group [35]. At the 12th month, the patients in the aflibercept group increased by 16.9 letters, while those in the sham injection group increased by 3.8 letters. The average percentage of patients in the aflibercept group who gained ≥15 letters was 60.2%, and that in the sham injection group was 32.4%. Compared with the sham injection group (−219.3 μm), the CMT in the aflibercept group (−423.5 μm) improved significantly [36]. From 12 to 18 months, the patients were monitored every 8 weeks. Both groups of patients received the Avastin PRN treatment regimen. During this period of 12 to 18 months, when the treatment interval was extended to 8 weeks, the visual and anatomical improvements were largely maintained [37]. No new adverse events were found during the follow-up period, confirming the safety and efficacy of Avastin treatment for RVO.

The combined surgery of vitrectomy and internal limiting membrane peeling can relieve the traction of the vitreous on the retina in the macular area, improve oxygen supply, thereby reducing exudation and eliminating macular edema, achieving the goal of effective treatment for RVO. In the study by Park DH et al. [38]. 20 patients with CRVO and HRVO secondary macular edema underwent vitrectomy including internal limiting membrane peeling. The average follow-up was 61.2 months. Before the surgery, the average BCVA of 20 eyes was (1.50 ± 0.83), which improved to 1.06 ± 1.08 after the surgery. The follow-up after 60 months of vitrectomy (p < 0.05). At 60 months, the best corrected visual acuity improved by 0.2 log units or more in 13 out of 20 eyes (65%), 1 eye (5%) improved by 0.2 log units, 5 eyes (25%) remained unchanged, and 1 eye (5%) worsened. Mandelcorn and Nrusimhadevara reported [39] that in 8 eyes with macular edema caused by CRVO, 62.5% of the patients had improved vision after vitrectomy and internal limiting membrane peeling, and the macular edema was alleviated. The results of the above studies were better than the natural history data described in the Central Vena Cava Occlusion Study Group. Liang et al. [40] also reported that 75% of the 8 eyes with macular edema caused by CRVO had significant improvement in visual acuity. However, their average follow-up period was 14 months, and it could not show the effectiveness of the surgery anatomically. This surgery is difficult and risky, and has not been widely used in clinical treatment of RVO yet.

Laser-induced chorioretinal venous anastomosis (L-CRA) refers to the process where, through the induction of laser, the obstructed veins, the Bruch membrane and the retinal pigment epithelium layer adjacent to the veins are simultaneously punctured, allowing the retinal veins in the fundus to be anastomosed with the choroid to form collateral circulation. This promotes the return of blood throughout the body, thereby improving the hypoxic state of the retina. In a randomized, controlled, multi-center, prospective clinical trial study [41]. The research results indicate that L-CRA has reasonable predictability. 76.4% of the patients achieved functional anastomosis, and surgical complications were effectively controlled. For patients who actually had anastomosis, significant visual results were observed, and the rate of converting to retinal ischemia was lower than that of patients receiving standard treatment. The most important surgical complication of L-CRA surgery is the occurrence of new blood vessels at the anastomosis site. Currently, this surgical method is less used in clinical practice.

BRVO refers to the obstruction of the branch veins of the retina. The obstruction mainly occurs at the intersection of the retinal arteries and veins. In theory, incising and reducing the sheath at this location can achieve the goal of improving blood circulation. The research results of Yamane S et al. showed that the arteriovenous sheath incision surgery significantly improved the BCVA of patients at 6 months and 12 months after the operation [42]. The results of a matched control study compared the effects of arteriovenous sheath incision surgery with that of observation alone and laser treatment in the matched control group. The results showed that the visual effect of the arteriovenous sheath incision surgery group was superior to that of the matched control group [43]. However, this surgical method has serious complications such as postoperative increase in intraocular pressure, retinal detachment, and rupture and bleeding of retinal blood vessels during the operation. Currently, this surgical method has been abandoned in clinical practice.