Retinal vein occlusion-related macular edema: An updated review of current evidence and future directions

Abstract

Macular edema is the leading cause of visual impairment in retinal vein occlusion (RVO). Management has evolved significantly with advances in retinal imaging and the recognition of vascular endothelial growth factor (VEGF) as a key pathogenic mediator. Anti-VEGF agents are now the mainstay of treatment, supported by robust evidence from randomized clinical trials and real-world studies. Intravitreal corticosteroids play a selective role in patients with suboptimal anti-VEGF responses or contraindications to anti-VEGFs, while the role of laser photocoagulation has become limited. Optical coherence tomography remains central to diagnosis, monitoring, and prognostication. Fluorescein angiography and optical coherence tomography have a role in assessing retinal perfusion, including the macula. Emerging therapies, including biosimilars and long-acting delivery systems, aim to increase accessibility and durability of treatment in RVO-related macular edema (RVO-ME). This review summarizes current evidence and future directions in the management of RVO-ME.

Retinal vein occlusion (RVO) is the second most common retinal vascular disorder, after diabetic retinopathy, and a significant cause of vision loss worldwide. RVO is clinically classified into branch retinal vein occlusion (BRVO) – major and macular, hemiretinal vein occlusion (HRVO), and CRVO (ischemic and nonischemic), each with distinct natural histories and prognoses.[1] Pooled population-based data estimate a global prevalence of approximately 0.5%, with CRVO being less frequent but more visually disabling than BRVO.[2,3] Visual morbidity in RVO is predominantly driven by macular edema (ME) and ischemic complications, which can result in irreversible vision loss if untreated. While most clinical trials address typical BRVO and CRVO, clinicians frequently encounter complex phenotypes, such as combined CRVO with arterial occlusion, inflammatory periphlebitis-associated RVO, and thrombophilia associations. Even though these entities carry distinct prognostic and therapeutic considerations, management still revolves around the prevention and management of treatable complications like ME and neovascularization.[4]

Therapy for RVO-related macular edema (RVO-ME) has evolved substantially over the past two decades. Earlier management strategies relied on laser photocoagulation and observation, guided by landmark trials such as the branch vein occlusion study (BVOS) and central vein occlusion study (CVOS), respectively.[5,6] However, advances in the understanding of retinal vascular biology—particularly the central role of vascular endothelial growth factor (VEGF)—have transformed treatment paradigms. Anti-VEGF agents are now the cornerstone of therapy, supported by robust randomized clinical trial data and real-world evidence.

Given the expanding therapeutic armamentarium—including newer anti-VEGF molecules, intravitreal corticosteroid implants, and emerging long-acting delivery systems—an updated synthesis of evidence is warranted. This review aims to comprehensively summarize current and emerging therapies for RVO-ME, integrating evidence from landmark trials and contemporary guidelines.

Methods

A narrative literature review was conducted using PubMed, MEDLINE, and Embase databases. The search covered studies published from January 1980 to December 2025. Keywords included retinal vein occlusion, branch retinal vein occlusion, central retinal vein occlusion, macular edema, anti-VEGF, corticosteroids, laser photocoagulation, and vitrectomy. Randomized controlled trials, systematic reviews, meta-analyses, and major clinical guidelines were included. Case reports and small uncontrolled series were excluded unless relevant to emerging or surgical therapies. References were selected based on methodological rigor, relevance to clinical management, and citation frequency.

Pathophysiology and Natural History

The pathogenesis of RVO involves multiple factors. It usually occurs due to thrombosis within the vein or external compression of the vein. This typically occurs at arteriovenous crossing points in BRVO or at the level of the lamina cribrosa in CRVO.[7] This blockage raises venous pressure, leading to capillary nonperfusion and triggering retinal hypoxia. The lack of oxygen drives the increase of hypoxia-inducible factor-1α (HIF-1α), which boosts the production of VEGF and placental growth factor (PlGF).[8] These proteins are the main drivers behind the breakdown of the blood–retinal barrier, causing ME. In eyes with severe ischemia, neovascularization of the retina or iris can also occur.[8,9]

The natural history varies between subtypes. It often depends on the level and severity of block and the development of compensatory collateral vessels. In BRVO, especially the macular variant, ME sometimes resolves on its own. In contrast, CRVO has a varied natural history. While the nonischemic CRVO might have a mild course, there is a significant risk of transitioning to the ischemic type (~30% over 3 years).[10] Ischemic CRVO often presents with severe ME and often has underlying macular ischemia as well.[3,11]

Diagnostic Evaluation and Imaging

Optical coherence tomography

Optical coherence tomography (OCT) is the primary imaging modality for structural evaluation and longitudinal monitoring of RVO-ME. In addition to objective quantification of macular thickness, OCT provides qualitative anatomic biomarkers that offer insights into visual potential, treatment response, refractoriness, and long-term outcomes.[12,13,14,15]

Ciulla et al.[12] reported that greater central subfield thickness, ellipsoid zone disruption, and persistent or worsening intraretinal fluid were negatively correlated with post-treatment visual acuity following combined intravitreal anti-VEGF and suprachoroidal triamcinolone therapy. In a cohort treated with dexamethasone intravitreal implant, Castro-Navarro et al.[13] found significantly worse baseline visual acuity in eyes which had external limiting membrane disruption, more than 20 hyperreflective foci, and disorganization of the retinal inner layers (DRIL); however, no OCT biomarker independently predicted final visual outcomes. Lent-Schochet et al.[14] observed that none of the OCT features were predictive of successful treatment discontinuation within 2 years, although central subfield thickness and DRIL were associated with long-term visual acuity.

Fundus fluorescein angiography

Fundus fluorescein angiography (FFA) plays an important complementary role in the evaluation of RVO, particularly by providing functional information on retinal perfusion that cannot be fully captured by structural imaging alone. FFA is useful in demonstrating features like delayed arteriovenous transit, venous staining, capillary nonperfusion, vascular leakage, and collateral vessel formation, which are hallmark features of RVO.[16]

In RVO-ME, FFA is useful for characterizing the pattern and source of macular leakage, including diffuse capillary leakage, focal leakage from microaneurysms, and associated macular ischemia.[17] This helps in planning macular laser treatment in cases with recalcitrant/recurrent ME. Importantly, FFA remains the reference standard for differentiating ischemic from nonischemic RVO, based on the extent of capillary nonperfusion. This distinction has major prognostic significance, particularly in CRVO, where extensive nonperfusion is associated with poor visual outcomes and a high risk of neovascular complications.[10] Ultra-widefield fluorescein angiography (UWFA) provides perfusion assessment of the retinal periphery and helps better explain persistent or recurrent edema by identifying extensive peripheral nonperfusion and leakage. This will also help in the stratification of patients at risk of developing neovascular complications.[18]

OCT-angiography

One of the principal contributions of OCT-angiography (OCTA) in RVO is the evaluation of macular ischemia. It allows delineation of capillary dropout, and enlargement or irregularity of the foveal avascular zone (FAZ), particularly within the deep capillary plexus, which is often more severely affected in RVO.[19,20]

OCTA also facilitates longitudinal monitoring of microvascular changes during treatment. Reduction in OCTA parameters such as vessel density (VD) and vessel skeletonized density (VSD) is associated with a higher injection burden and poorer visual outcomes on long-term follow-up.[21] Doppler OCT is emerging as an investigational tool to characterize retinal hemodynamics in vivo. If validated, it may complement OCTA by providing quantitative data for treatment planning.[22]

However, OCTA has important limitations in RVO-related macular edema. Segmentation errors, motion artifacts, and signal attenuation due to intraretinal fluid can affect image quality and quantitative measurements, particularly in eyes with significant edema.[23]

Therapeutic Goals and General Management Principles

The therapeutic goals in RVO-associated macular edema are to restore and maintain visual acuity, resolve macular edema, prevent neovascular complications, and reduce long-term treatment burden. Management should be individualized by RVO subtype and ischemic status, guided by baseline visual acuity and OCT-derived edema activity/photoreceptor integrity. Intravitreal anti-VEGF therapy is the first-line for center-involving edema, with intravitreal corticosteroids reserved for selected patients. Systemic risk-factor optimization by controlling blood pressure, blood glucose, and other risk factors through coordinated care with physicians is essential.[24,25,26] For impending CRVO/BRVO presentations without definite ME, a reasonable strategy is close observation with appropriate systemic control.[27]

Anti-VEGF Therapy – Mainstay of Treatment

Rationale and mechanism

Upregulation of VEGF is central to the pathogenesis of ME in RVO, driven by retinal hypoxia and venous congestion. VEGF increases vascular permeability, disrupts the blood–retinal barrier, and promotes inflammatory and angiogenic cascades. Sustained intraocular VEGF suppression has been shown to rapidly reduce macular edema, improve visual acuity, and decrease the risk of neovascular complications across RVO subtypes.[26]

Anti-VEGF therapy is therefore recommended as first-line treatment for vision-impairing (typically center-involving) RVO-associated ME with retreatment and follow-up primarily guided by BCVA and OCT evidence of disease activity, while concurrently monitoring for ischemia and neovascular complications.[24,25]

Ranibizumab

Ranibizumab was the first anti-VEGF approved for the treatment of RVO-ME. The pivotal BRAVO trial established the efficacy of ranibizumab for ME secondary to BRVO.[28] A total of 397 eyes were randomized to receive monthly intravitreal ranibizumab (0.3 mg or 0.5 mg) or sham injections for 6 months. Ranibizumab-treated eyes achieved substantial visual improvement, with mean gains of 16.6 letters in the 0.3-mg group and 18.3 letters in the 0.5-mg group at month 6, compared with a gain of 7.3 letters in the sham arm. Following the 6-month primary endpoint, all participants became eligible for as-needed ranibizumab 0.5 mg through month 12. Eyes initially assigned to sham injections showed visual improvement after crossover to active treatment; however, their final visual outcomes remained inferior to those of eyes treated with ranibizumab from baseline. The CRUISE trial similarly assessed ranibizumab in CRVO-related ME. At 6 months, patients receiving monthly ranibizumab achieved a mean visual acuity gain of approximately 12.7 letters in the 0.3-mg group and 14.9 letters in the 0.5 mg group, compared with 0.8 letters in the sham group.[29] Deferring anti-VEGF therapy in center-involving RVO-ME carries a risk of poor visual gain from secondary photoreceptor injury. In BRAVO and CRUISE, eyes initially assigned to sham that crossed over to ranibizumab after month 6 improved but did not fully match the visual outcomes achieved with prompt initiation, underscoring the importance of early treatment when vision is affected.[27,28] Also, the BRAVO study does not provide a clean head-to-head comparison of ranibizumab versus optimal early grid laser. However, in clinical practice, this limitation is less clinically significant because anti-VEGF is generally considered first-line, while laser is reserved as adjunctive therapy in selected cases.[28]

Aflibercept

The efficacy of aflibercept in CRVO-ME was established by the pivotal phase III COPERNICUS trial, which compared monthly intravitreal aflibercept 2 mg with sham injections. A gain of at least 15 ETDRS letters was observed in 56.1% of the eyes treated with aflibercept compared to 12.3% in the sham group.[30] The GALILEO study also showed similar results in CRVO-related ME (60.2% of the eyes treated with aflibercept gained ≥15 ETDRS letters compared to 32.4% in the sham group).[31]

In BRVO, the role of aflibercept was evaluated in the VIBRANT trial, a randomized, double-masked phase III study that directly compared intravitreal aflibercept 2 mg with grid laser photocoagulation. Aflibercept demonstrated superior visual acuity gains and greater reductions in macular thickness relative to laser therapy, establishing pharmacologic VEGF inhibition as a more effective first-line approach for BRVO-associated ME.[32,33] A newer advancement is higher-dose aflibercept (8 mg; “Eylea HD”), which has received regulatory approval for RVO-ME. This approval was based on the Phase 3 QUASAR trial, which showed noninferior visual acuity gains of 8 mg aflibercept (3 or 5 monthly injections followed by every 8 weeks) compared to monthly aflibercept 2 mg.[34]

Bevacizumab

A prospective randomized controlled trial in CRVO demonstrated that bevacizumab significantly improved both visual acuity and macular thickness compared with sham injections, with 60% of treated eyes achieving ≥15-letter gains at 6 months.[35] Multiple meta-analyses and real-world studies suggest that bevacizumab achieves visual outcomes broadly comparable to approved anti-VEGF agents in many clinical settings, although durability may differ.[36] Bevacizumab remains particularly relevant in resource-limited settings, where cost considerations strongly influence treatment access and adherence.

Faricimab

Faricimab is a novel bispecific monoclonal antibody designed to simultaneously inhibit VEGF-A and angiopoietin-2 (Ang-2). The phase III BALATON (BRVO) and COMINO (CRVO) trials demonstrated that faricimab was noninferior to aflibercept with respect to visual acuity gains at 24 weeks.[37] Notably, a higher proportion of faricimab-treated eyes showed the absence of macular leakage, suggesting superior anatomic vascular stabilization. These findings suggest faricimab as a promising newer therapy, particularly for patients with persistent leakage or high treatment burden.

Choice of anti-VEGF agents

Multiple randomized controlled trials and meta-analyses have shown the superiority of anti-VEGF agents over other available treatment modalities (intravitreal steroids and macular grid laser). The SCORE 2 study compared monthly intravitreal bevacizumab and aflibercept for CRVO-ME. At 6 months, intravitreal bevacizumab was noninferior to aflibercept with respect to visual acuity.[38] The LEAVO trial was a multicenter, three-arm, noninferiority trial comparing ranibizumab, aflibercept, and bevacizumab for the treatment of ME due to CRVO. At 100 weeks, aflibercept was noninferior to ranibizumab for visual acuity outcomes and required fewer injections, suggesting greater durability. Bevacizumab did not meet the predefined noninferiority margin compared with ranibizumab, although it still produced meaningful visual gains. While aflibercept and ranibizumab offer comparable visual efficacy, aflibercept may require fewer injections; bevacizumab, although not meeting predefined noninferiority margins, remains a cost-effective alternative in clinical practice.[39] A recent systematic review of international clinical practice guidelines confirmed a broad consensus that anti-VEGF therapy represents first-line treatment for RVO-related ME.[40] Most guidelines do not recommend one specific agent over another, instead advocating individualized agent selection based on disease severity, response, cost considerations, and access. Switching anti-VEGF agents can be considered if there is a “suboptimal response” after adequate induction in eyes with persistent ME or high treatment burden.[41] Transition to intravitreal corticosteroids can be considered in pseudophakic eyes, anti-VEGF nonresponders, or inflammatory RVOs or when regular compliance is an issue.[42] Adjunctive focal/grid laser in selected recalcitrant RVO cases may help reduce recurrence or injection burden.[43] Table 1 summarizes the key clinical trials of intravitreal anti-VEGF therapy for RVO-ME.

Table 1.

Key clinical trials and real-world evidence of intravitreal anti-VEGF therapy for retinal vein occlusion-related macular edema

Study (Author)	RVO Type	Agent and Dose	Sample Size	Primary Outcome Measure	Visual Outcomes	Key Anatomical Outcomes
BRAVO (Campochiaro et al.)[28]	BRVO	Ranibizumab 0.3/0.5 mg monthly vs sham	397	Mean BCVA change at 6 months	+16.6 (0.3 mg group); +18.3 (0.5 mg group) ETDRS letters vs +7.3 (sham)	Superior CRT reduction: -337 μm (0.3 mg); -345 μm (0.5 mg) vs 158 μm (sham)
CRUISE (Brown et al.)[29]	CRVO	Ranibizumab 0.3/0.5 mg monthly vs sham	392	Mean BCVA change at 6 months	+12.7 (0.3 mg group); +14.9 (0.5 mg group) letters vs +0.8 (sham)	Superior CRT reduction: -434 μm (0.3 mg); -452 μm (0.5 mg) vs 168 μm (sham)
COPERNICUS (Brown et al.)[30]	CRVO	Aflibercept 2 mg monthly vs sham	189	≥15 ETDRS letter gain at 24 weeks	56.1% vs 12.3% (sham)	-
GALILEO (Korobelnik et al.)[31]	CRVO	Aflibercept 2 mg every 4 weeks vs sham	177	≥15 ETDRS letter gain at 52 weeks	60.2% vs 32.4% (sham)	Superior CRT reduction: -423.5 μm vs -219.3 μm (sham)
VIBRANT (24 wk) (Campochiaro et al.)[32]	BRVO	Aflibercept 2 mg every 4 weeks vs grid laser	183	≥15 ETDRS letter gain at 24 weeks	52.7% vs 26.7% (laser)	Superior CRT reduction: -280.5 μm vs -128.0 μm (laser)
VIBRANT (52 wk) (Clark et al.)[33]	BRVO	Aflibercept 2 mg q4w through week 24; then q8w through week 48 vs grid laser	183	≥15 ETDRS letter gain at 52 weeks	57.1% vs 41.1% (laser)	Superior CRT reduction: -283.9 μm vs -249.3 μm (laser)
Epstein et al.[35]	CRVO	Bevacizumab 1.25 mg vs sham	60	≥15-letter gain at 6 months	60% gained ≥15 letters vs 20% (sham)	Superior CRT reduction: -426 μm vs -102 μm (sham)
BALATON (Tadayoni et al.)[37]	BRVO	Faricimab 6 mg vs Aflibercept 2 mg every 4 weeks for 24 weeks	553	Change in BCVA from baseline to week 24	Non-inferior BCVA gains (+16.9 vs +17.5 letters)	Comparable CRT reduction (-311.4 μm vs -304.4 μm)
COMINO (Tadayoni et al.)[37]	CRVO	Faricimab 6 mg vs Aflibercept 2 mg every 4 weeks for 24 weeks	729	Change in BCVA from baseline to week 24	Non-inferior BCVA gains (+16.9 vs +17.3 letters)	Comparable CRT reduction (-461.6 μm vs -448.8 μm)
Scott IU et al. (SCORE2)[38]	CRVO/HRVO	Bevacizumab vs Aflibercept	362	RCT; non-inferiority at 6 months	Mean BCVA gain +18.6 vs +18.9 letters (non-inferior)	Similar reduction in central retinal thickness
Hykin P et al. (LEAVO)[39]	CRVO	Ranibizumab vs Aflibercept vs Bevacizumab	463	RCT; noninferiority at 100 weeks	Aflibercept noninferior to ranibizumab; bevacizumab did not meet noninferiority	Comparable visual outcomes; fewer injections with aflibercept
Pearce I et al. (LUMINOUS)[45]	BRVO	Ranibizumab	405	Prospective real-world study; 1-year outcomes	Mean BCVA gain ~10–12 letters at 1 year	Higher visual gains were achieved in patients who received more injections and those with poor baseline vision
Lotery A et al. (LUMINOUS)[46]	CRVO	Ranibizumab	476	Prospective real-world study; 1-year outcomes	Mean BCVA gain ~9–10 letters at 1 year	Clinically meaningful visual gains over 5 years; better visual gains in patients receiving loading doses

RVO, retinal vein occlusion; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; ME, macular edema; anti-VEGF, anti-vascular endothelial growth factor; BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study

Treatment protocols

Current clinical practice typically involves fixed monthly loading doses, followed by PRN or treat-and-extend regimens, with retreatment guided by OCT evidence of recurrent or persistent edema and visual outcomes.[24,25] Early initiation and avoidance of undertreatment remain important determinants of long-term visual success.

Safety profile

Intravitreal anti-VEGF agents are generally well tolerated, with a favorable ocular and systemic safety profile. Although systemic VEGF inhibition raises theoretical concerns regarding arterial thromboembolic events, pooled evidence from randomized trials and meta-analyses in RVO and other retinal diseases has not demonstrated a significant increase in major cardiovascular events.[47]

Long-term outcomes of anti-VEGF therapy in RVO-ME

Long-term data indicate that RVO-ME frequently demonstrates a chronic and relapsing course, necessitating prolonged therapy in a substantial proportion of patients. In the RETAIN study, Campochiaro et al.[48] reported outcomes over a mean follow-up of approximately 4 years in eyes treated with ranibizumab for RVO-ME. Sustained resolution of ME was achieved in a higher proportion of eyes with BRVO compared with CRVO, while nearly half of all treated eyes continued to exhibit persistent or recurrent edema requiring ongoing intermittent treatment. Importantly, continued anti-VEGF therapy was associated with maintenance of meaningful visual acuity gains relative to baseline, underscoring the efficacy of long-term treatment despite the need for retreatment. Similar long-term observational studies have corroborated these findings, demonstrating that while anti-VEGF therapy can provide durable visual benefits, a significant proportion of patients, particularly those with CRVO, require prolonged, individualized treatment to control edema and preserve vision even after 8 years of commencing treatment.[49]

Biosimilars

Anti-VEGF biosimilars have emerged as a viable and cost-effective alternative to innovator molecules in the management of RVO-ME, particularly in resource-constrained settings. Real-world studies from India have consistently demonstrated that Razumab, the first approved ranibizumab biosimilar, has shown improvements in BCVA and central retinal thickness comparable to the innovator molecule.[50,51] Comparative real-world analyses have shown similar short-term visual and anatomical outcomes between ranibizumab biosimilars, innovator ranibizumab, and bevacizumab, without significant safety concerns.[52,53] Collectively, available evidence supports ranibizumab biosimilars as effective and safe alternatives. Taken together, the available evidence suggests that ranibizumab biosimilars represent a practical, effective, and safe alternative to the innovator drug, which may improve treatment accessibility and adherence in RVO-ME. In addition to ranibizumab biosimilars, aflibercept biosimilars are increasingly available and can be used for RVO-ME effectively bringing down the cost of treatment. Some of the aflibercept biosimilars include Yesafili, Opuviz, Ahzantive, and Afqlir, which have been approved by various international drug approval regulators.[54] Fig. 1 discusses a case of RVO-ME treated with Ranibizumab biosimilar.

Figure 1.

Role of anti-VEGF biosimilars in treatment of RVO-ME. (a) A case of right eye major BRVO with macular edema. (b) OCT showing cystoid edema. The patient was initiated on three monthly intravitreal injections of ranibizumab biosimilar injections. (c-e) Progressive resolution of macular edema. (f-i) The patient was put on pro re nata regimen with resolution of edema after injections and vision maintained at 6/9. (j) Fundus photo 6 months after treatment initiation showing reduction of retinal hemorrhages and sclerosed vessels

Corticosteroid Therapy

Intravitreal corticosteroids reduce ME by stabilizing the blood–retinal barrier and suppressing inflammatory mediators. They are particularly useful in patients with inadequate response to anti-VEGF therapy, pseudophakic eyes, or those unable to adhere to frequent visits. Table 2 summarizes major clinical trials and real-world evidence of intravitreal corticosteroid therapy for RVO-ME.

Table 2.

Major clinical trials and real-world evidence of intravitreal corticosteroid therapy for retinal vein occlusion-related macular edema

Study (Author)	Agent and Dose	Sample Size	Primary Outcome Measure	Visual Outcomes	Anatomical Outcomes	Safety Profile
SCORE-CRVO (Ip et al.)[57]	Triamcinolone 1 mg/4 mg vs observation	271	≥15 ETDRS letter gain at 12 months	27% (1 mg); 26% (4 mg) vs 7% (observation)	Median decrease in CRT at the month 4 visit: -77 μm (1 mg); -196 μm (4 mg) vs -125 μm (observation)	IOP elevation and cataract incidence were comparable between observation and 1-mg groups, but increased with the 4-mg dose.
SCORE-BRVO (Scott et al.)[44]	Triamcinolone 1 mg/4 mg vs grid laser	411	≥15 ETDRS letter gain at 12 months	26% (1 mg); 27% (4 mg) vs 29% (laser)	Median decrease in CRT at the month 4 visit: -77 μm (1 mg); -142 μm (4 mg) vs -113 μm (laser)	IOP elevation and cataract rates were comparable in the standard care and 1-mg groups, but higher with the 4-mg dose.
GENEVA (Haller et al.) – BRVO/CRVO[55]	Dexamethasone implant 0.7 mg/0.35 mg vs sham	1267	Time to achieve a ≥15 ETDRS letter improvement in BCVA	Both dexamethasone implant groups achieved a ≥15-letter BCVA gain more rapidly than the sham group.	Mean decrease in CRT at 90 days: -208 μm (0.7 mg); -177 μm 0.35 mg) vs – 85 μm (sham)	IOP of ≥25 mmHg peaked at 16% at day 60 with dexamethasone (both doses) and returned to sham levels by day 180; cataract rates did not differ from sham.
Eter et al. (Real-world study)[56]	Dexamethasone implant (0.7 mg)	573	Mean change in BCVA at 12 weeks	+7.8 ETDRS letters	Mean CRT was significantly reduced at 12 weeks	Increased IOP in 5.8%

RVO, retinal vein occlusion; BRVO, branch retinal vein occlusion; CRVO, central retinal vein occlusion; ME, macular edema; BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study; IOP, intraocular pressure

Triamcinolone acetonide

The SCORE trials evaluated intravitreal triamcinolone acetonide. In the SCORE-BRVO trial, visual outcomes at 12 months were comparable between intravitreal triamcinolone (1 mg or 4 mg) and grid laser photocoagulation; however, steroid-treated eyes had significantly higher rates of cataract and IOP-related adverse events, supporting laser as the preferred option in perfused BRVO.[44] The SCORE-CRVO trial showed that triamcinolone resulted in superior visual gains compared with observation. IOP elevation and cataract rates were comparable in the standard care and 1-mg groups but higher with the 4-mg dose.[57] Based on the balance between efficacy and safety, the 1-mg dose was considered superior to the 4-mg dose.

Dexamethasone implant

The GENEVA trial demonstrated that the dexamethasone intravitreal implant provides rapid but transient visual and anatomical improvement in both BRVO and CRVO, with peak benefit at approximately 3 months and waning effect by 6 months, necessitating retreatment.[55] Real-world studies confirmed its effectiveness but highlighted the need for retreatment and monitoring for steroid-related complications.[56]

Direct comparisons between steroids and anti-VEGF agents and systematic reviews favor anti-VEGF therapy for superior visual and anatomical outcomes, with a more favourable safety profile. Thus, intravitreal corticosteroids can be reserved as second-line therapy for selected patients, such as those with inadequate anti-VEGF response or contraindications, pseudophakics, vitrectomized eyes (sustained release implant preferred over triamcinolone), and inflammatory vein occlusions (periphlebitis), with careful monitoring for ocular side effects.[24,58]

Role of Laser

In the anti-VEGF era, the role of laser photocoagulation in RVO-ME has become limited. The BVOS established grid laser photocoagulation as the standard treatment for ME secondary to BRVO, demonstrating superior visual outcomes compared with the natural history. With the availability of effective intravitreal treatment, grid laser is considered a second-line option in BRVO, reserved for eyes that show a suboptimal response to pharmacotherapy, or require repeat injections, or in situations where anti-VEGF agents are contraindicated [Fig. 2].[24,25] In contrast, grid laser is not a recommended treatment for CRVO-related ME, supported by evidence from CVOS.[6,24]

Figure 2.

Role of macular lasers in treatment of RVO-ME. (a) A case of left eye old macular BRVO showing circinate arrangement of hard exudates with multiple microaneurysms within the ring. There was a history of receiving 6 intravitreal bevacizumab injections in the past. (b) Fundus fluorescein angiography images showing enlarged foveal avascular zone and numerous microaneurysms. (c) Late phase leak from microaneurysms and superior macular capillary bed. (d) OCT showing cystoid edema and hard exudates. (e and f) Reduction in macular edema with two monthly intravitreal Ranibizumab injections. Grid laser and focal laser was done to reduce treatment burden. (g) Fundus photo 4 months post macular laser showing reduction in hard exudates and fundus autofluorescence photo showing laser scars (inset). (h-i) Follow-up OCT images showing progressive resolution of macular edema

Scatter laser to the peripheral retinal ischemic areas (targeted panretinal photocoagulation, TPRP) has been advocated as a measure to reduce the load of VEGF and thereby the recurrence of ME. However, the addition of TPRP does not translate into significant vision differences or a reduction in treatment burden compared to anti-VEGF therapy alone.[59]

Role of Vitrectomy

Pars plana vitrectomy has a selective and adjunctive role in specific clinical scenarios where ME is complicated by vitreoretinal interface abnormalities like epiretinal membrane formation, vitreomacular traction, macular hole, or macular tractional retinal detachment. In such cases, pars plana vitrectomy with membrane peeling can relieve mechanical traction, improve macular architecture, and facilitate anatomical resolution of edema [Fig. 3]. Visual outcomes, however, are dependent largely on preoperative photoreceptor integrity and the severity of macular ischemia. Vitrectomy may alter the pharmacokinetics of intravitreal drugs, potentially shortening the duration of action of anti-VEGF agents and increasing treatment burden postoperatively.[60]

Figure 3.

Role of vitrectomy in treatment of RVO-ME. (a) A case of lasered superotemporal major BRVO with neovascular complications (fibrovascular proliferation, vitreous hemorrhage, and tractional macular edema). (b) OCT showing thick epiretinal membrane causing spongiform thickening with neurosensory detachment. Patient underwent pars plana vitrectomy with membrane peeling. (c) One-month postoperative fundus photo showing retina on status and sclerosed vessels in the superotemporal quadrant. (d) OCT showing restoration of foveal contour and reduction of neurosensory detachment

Emerging and Future Therapies

Current anti-VEGF treatments are effective but pose a burden due to the need for administering repeated injections. Thus, the research on RVO is shifting from effectiveness to durability. The BEACON study on tarcocimab tedromer (KSI-301), a novel antibody biopolymer conjugate (ABC) that utilizes high-molar density VEGF inhibition, can perform comparably to aflibercept with much less frequent dosing in RVO (ClinicalTrials.gov ID: NCT04592419). At the same time, sustained delivery systems are emerging. The Port Delivery System (PDS) with ranibizumab, currently approved for wet age-related macular degeneration, provides an option for continuous drug release, potentially eliminating the fluctuating intraocular drug levels seen with regular injections.[61] Further down the line, gene therapy vectors aim to make the eye produce anti-VEGF proteins, possibly offering a one-time treatment solution.[62] Neuroprotective approaches, such as topical Caspase-9 inhibition, have shown potential in research models to reduce ME as well as protect retinal ganglion cells.[63]

Conclusions

Anti-VEGF therapy is the established first-line treatment for RVO-ME, with early initiation and appropriate retreatment essential for optimal visual outcomes. All the available anti-VEGFs provide comparable visual outcomes in most eyes when adequately dosed, with newer anti-VEGF agents like aflibercept and faricimab providing longer treatment-free intervals. The increasing availability of ranibizumab biosimilars has enhanced treatment accessibility in resource-limited settings. Intravitreal corticosteroids have a selective role in pseudophakics, anti-VEGF nonresponders, and situations where treatment burden is a concern, while laser photocoagulation now has a limited adjunctive role. Advances in multimodal imaging have improved disease characterization and prognostication, though retreatment decisions remain primarily guided by vision and optical coherence tomography. Emerging therapies and sustained drug delivery systems may further reduce treatment burden and refine individualized care in the future.

Authors’ contribution

Concept, design, definition of intellectual content: ST, GR, NS; Literature search, data acquisition: ST, GR, ADS; Data analysis: ST, GR, AKD,; Manuscript preparation: ST, GR, ADS; Manuscript editing and manuscript review: ST, AKD, NS.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.