What is Occluding Our Understanding of Retinal Vein Occlusion?

Key Summary Points

The prevalence of retinal vein occlusion (RVO) is rising, driven by its association with age and cardiovascular disease.

RVO pathogenesis is complex, and the patient population is heterogeneous.

To optimize treatment strategies, it is essential to understand and address unmet needs within the RVO patient journey.

We must leverage recent advancements including imaging and serologic biomarkers, data linkage and artificial intelligence, and patient-reported outcome tools, as well as novel treatments targeting multiple pathways, to achieve a future where treatment is individualized and streamlined to optimize visual outcomes for all patients with RVO.

Introduction

Retinal vein occlusion (RVO) remains a significant cause of visual impairment and is the second most common retinovascular disease after diabetic retinopathy [1, 2]. Although the exact etiology remains elusive, RVO is thought to occur because of thrombus formation occluding the central, hemi-retinal, or branch retinal vein restricting normal blood flow and typically results in sudden, painless vision loss in the affected eye [1–5]. Despite first being described in the nineteenth century [1], and the advances in diagnostic modalities and novel therapies since, large gaps persist in our understanding of the pathophysiology and optimal management of RVO. Hence, the patient journey for RVO is not well defined [3, 5].

With the prevalence and burden of RVO rising, largely driven by its association with age and cardiovascular disease [6, 7], it is now imperative to identify and address the unmet needs that remain in the RVO patient journey. By harnessing modern tools, such as novel imaging modalities, the application of artificial intelligence to large imaging datasets and routinely collected clinical data, and novel tools for patient-reported outcomes and experiences, we can aim to better target the primary dysfunctions in the pathogenesis of RVO. These may deliver solutions with the potential to prevent disruption to retinal function from RVO before it occurs and ameliorates vision loss, through earlier diagnosis alongside the use of effective, individualized treatment strategies for patients.

Below, we set out key knowledge gaps in our current understanding of RVO, as well as areas where the associated patient journey remain unclear and must be addressed at pace to lead us towards this envisioned future. We must ask: what is occluding our understanding of RVO and the patient journey for this condition?

What Is Our Current Understanding of the Pathogenesis of RVO?

The pathogenesis of RVO is multifactorial, involving a combination of vascular, anatomic, and biochemical mediators associated with systemic diseases, that result in occlusion or thrombus formation [3, 4, 8, 9]. RVO encompasses a spectrum of diseases depending on where the obstruction in the retinal venous occurs, and is therefore subdivided into central, hemi, or branch RVO [3]. Both central RVO (CRVO) and branch RVO (BRVO) can be further classified into ischemic and non-ischemic types based on the area of capillary non-perfusion [2, 3]. However, it should be noted that this distinction of ischemic CRVO was arbitrarily defined by the Central Retinal Vein Occlusion study (CVOS) in the 1990s as 10 or more disc areas of capillary non-perfusion on standard fluorescein angiography (FA) [2, 3, 10]. We need to consider whether making diagnoses and dividing patients into subgroups that can define treatment strategies based on this arbitrary definition are still appropriate given the availability of more advanced widefield and ultra-widefield imaging techniques, or whether a revision of this definition is urgently required.

We know that the subtypes of RVO occur at different rates, with CRVO being 3–4 times less prevalent than BRVO and typically having a poorer prognosis [2, 11]. However, the leading causes of the occlusion and the extent to which they vary between these different subtypes have not yet been clearly defined [12]. In particular, CRVO is no longer viewed as a simple thrombotic disorder, with alteration of blood flow velocity and impaired vessel integrity now also considered important to its occurrence [12]. Even fundamental facts, such as the site of occlusion in CRVO, are disputed, with some believing it occurs at the lamina cribosa and others suggesting it occurs posterior to the lamina cribosa [13]. This is important, as the site of occlusion influences potential therapeutic interventions considered, such as surgical decompression of the central retinal vein if at the lamina cribosa [14].

Who Is at Risk of Developing RVO?

The complex pathogenesis of RVO results in a heterogeneous patient population with a variety of underlying systemic causal factors, the contributions of which are poorly understood. What we do know from large longitudinal population studies is that RVO demonstrates an increasing prevalence with age, particularly over 70 years, with seemingly no predilection by gender and apparent increased prevalence of BRVO in Asian and Hispanic individuals [15–17]. There is, however, a well-recognized cohort of younger people that develop RVO, but the underlying cause of this phenomenon is still unclear, requiring broader systemic investigations [3, 18]. RVO in these eyes is more likely to be non-ischemic and resolve spontaneously, and is therefore potentially more prone to under-reporting [2, 3]. Yet, RVO is not always benign in this young cohort, with at least 20% developing poor visual outcomes due to severe neovascular complications [2, 18].

With such a heterogeneous patient population, how might one improve the patient journey to diagnosis? Timely diagnosis is vital in RVO as early treatment is critical for optimal outcomes; delaying treatment leads to a lower likelihood of clinically significant visual improvement [19, 20]. However, the visual impairment in RVO, particularly BRVO, is often subtle at early stages, and many patients are asymptomatic, with problems only being detected at routine check-ups, thereby potentially delaying diagnosis [1, 6]. In addition to this, there is a general lack of awareness of the disease by non-ophthalmologic clinicians who might see patients early in the disease for systemic problems underlying RVO (e.g., cardiologists). If awareness of RVO and the diagnostic criteria can be increased in this wider community, there may be multiple points of referral for a patient to see a retinal specialist, thereby leading to an earlier diagnosis and potential to start treatment early in the disease progression, resulting in improved vision.

Another significant challenge in the current patient journey is the variability and unpredictability of disease occurrence. While many systemic factors have been inconsistently associated with developing RVO, their importance in individual cases and our understanding of the interplay of implicated systemic factors are, at best, rudimentary. Underlying systemic factors may contribute to alterations in vascular homeostasis that eventually trigger the acute RVO event, analogous to the way in which the progression of atherosclerosis can lead to events that might trigger myocardial infarction and stroke [21]. Unfortunately, documentation of detailed systemic data in patients with RVO is not a routine feature of most ophthalmology practices, and comprehensive systemic data are often siloed and therefore not a consistent feature of recent RVO clinical trials. There is, therefore, limited characterization of the causative role and interplay between myriad systemic factors that contribute to the development of RVO and its subtypes.

How Can We Improve Investigations at the Level of the Individual Patient?

Advanced retinal imaging techniques have enabled more detailed assessments of eyes presenting with RVO. These include semi-histologic detail of the macula from optical coherence tomography (OCT), with fluid compartments delineated exquisitely and structural changes observable in the outer and inner retina [22]. Further advancements with OCT angiography (OCTA) detail capillary non-perfusion at the macula, while ultra-wide field OCTA (UWF-OCTA) captures capillary non-perfusion in the peripheral retina [23]. Ultra-wide fundus photography FA can capture >80% of the total retina surface compared to only ~30% captured in standard fundus photos [24, 25]. Despite this, FA is not routinely performed in many clinical practices because of time pressures, staffing costs, its invasive nature, and the readily available OCT for detecting macular edema [24, 25]. Yet, determining the extent of peripheral ischemia may improve individualized patient treatment [25].

Furthermore, as prognostic risk in RVO has traditionally been based on the area of peripheral ischemia, it is crucial to determine the impact of larger areas of ischemia and peripheral vascular leakage on optimal treatment type, response to treatment, and prognosis. The ability to predict who will convert from non-ischemic to the more severe ischemic type of RVO remains an unmet need. Similarly, determining which eyes will resolve spontaneously and quickly, and which eyes will respond better to different types of therapy (e.g., steroidal, intravitreal anti-vascular endothelial growth factor [anti-VEGF], or dual anti-VEGF and anti-angiopoietin-2 [anti-Ang-2] inhibition therapy) is also beyond the limits of current understanding.

How Can We Address the Biomarker Gap to Deliver Individualized Care to Patients with RVO?

In ocular diseases, the aqueous humor can accurately reflect the internal environment of the eye and provide insights into the pathologic pathways implicated in disease. Numerous studies have demonstrated associations between aqueous humor inflammatory cytokine levels and RVO disease status [8, 26]. However, these tests are not feasible for use in daily clinic as current aqueous humor collection techniques are not suitable for routine outpatient use and inconsistencies introduced by the breakdown of intraocular cytokines during storage can affect the reliability of their measurements [8, 27]. Thus, there remains a critical need for validated non-invasive serologic and imaging biomarkers that can accurately prognosticate visual function, optimal treatment options, and treatment response in individual patients with RVO.

Several investigators have postulated that imaging biomarkers may predict poor visual prognosis [28, 29], but none have yet undergone rigorous clinical validation. We are now able to access and collect a vast amount of detailed information with the imaging modalities at our disposal and the use of accessible technology to link to clinical data, including within primary care. We need to organize and capitalize on this wealth of information to identify serologic and imaging biomarkers and develop individualized risk assessment and prognostic tools that could substantially transform the patient journey.

Novel machine learning approaches are relevant to this endeavor. These techniques have been increasingly used in biomedical research to devise multi-risk factor predictive models from large datasets in diverse areas of healthcare, including COVID-19 and retinopathy of prematurity [30, 31]. Unlike traditional machine learning approaches, which rely heavily on expert-driven feature engineering, deep learning models (e.g., graph neural networks) can automatically extract meaningful latent feature representations from complex raw data [32]. As such, linkage of large, routinely collected clinical datasets with associated imaging data would create an enriched resource that can be utilized to build highly accurate predictive models to define the expected disease course and support risk-stratification for the individual patient. It is possible that these models can then be extended to predict whether eyes are more likely to respond to particular therapies, and even therapy regimes.

How Can We Address the Limitations of Current Interventions?

Anti-VEGF therapy has become a mainstay approach for patients with RVO, with early treatment being critical for optimal outcomes (as demonstrated in prior clinical trials, including the CRUISE, BRAVO, VIBRANT, COPERNICUS, and GALILEO trials) [19, 33]. However, there are intra- and inter-regional inequalities and unwarranted variation in the access to prompt healthcare, which need to be addressed to optimize the RVO patient journey wherever patients may reside.

Fundamentally, there are gaps in our understanding of structure-function correlations in RVO and limitations associated with the most commonly used functional test in the assessment of RVO in clinic and in clinical trials—best-corrected visual acuity (BCVA). BCVA does not often capture the full spectrum of visual dysfunction suffered by patients with macular edema secondary to RVO [13], with only a modest correlation between BCVA and central retinal thickness at presentation and during treatment [34]. After fluid resolution, some patients continue to suffer visual impairment despite objectively good BCVA, reflecting damage to the retinal architecture away from the foveal center point. This visual dysfunction is often ignored in the current management paradigm, emphasizing BCVA change and fluid resolution on OCT only. Qualitative studies, patient-reported outcome measures, and exploration of functional tests that capture the visual impact more comprehensively are required to fully address the impact of RVO on visual function. Similarly, the functional impact of peripheral retinal ischemia and, by extension, the impact of current therapies on peripheral retinal ischemia, is not routinely evaluated in clinic or clinical trials.

Patients treated with anti-VEGF therapy need repeated injections, and, as anti-VEGF therapy does not address the events leading up to the occlusive event and cannot prevent RVO recurrence, long-term treatment is required in most cases [12, 35, 36]. This treatment burden, and the inability of many healthcare systems to meet it, often results in undertreatment in the real world, and therefore suboptimal functional and anatomical outcomes compared to clinical trials. Many patients also have a variable and suboptimal response to anti-VEGF therapy [26, 37], with up to 70% of eyes having persistent or recurrent macular fluid on anti-VEGF therapy up to 100 weeks in the LEAVO trial [38], highlighting the clear unmet need for more efficacious RVO treatments.

The identification of other mediators beyond VEGF that may play a role in the pathogenesis of RVO is thus crucial. For example, steroids have been used to treat macular edema secondary to RVO because of their ability to reduce the elevated retinal capillary permeability resulting from RVO pathogenesis, with their efficacy demonstrated in numerous trials (including the SCORE and GENEVA trials) [19]. Intravitreal steroids are thought to act through inhibition of the VEGF pathway as well as VEGF-independent pathways involving inflammatory cytokines associated with macular edema secondary to RVO (e.g., tumor necrosis factor-α, interleukin [IL]-1, monocyte chemoattractant protein-1, IL17-E) [2, 19]. Therefore, steroids are an important treatment option for many patients with RVO, particularly as a second-line option for those who have a suboptimal response to anti-VEGF therapy or who are unable to commit to an initial monthly injection regime [19].

Another mediator implicated as important in the pathogenesis of RVO is Ang-2. Among patients with various retinal diseases, patients with RVO have some of the highest levels of Ang-2 in the vitreous humor [39]. The expression of Ang-2, a marker of endothelial instability, is increased with tissue ischemia and inflammation, as well as by mechanical traction on endothelial cells, caused by increased venous pressure during the initial event in RVO [8, 40–42]. It is thought that the overexpression of Ang-2, caused by these various pathologic processes, drives disease progression alongside VEGF, as upregulation of Ang-2 leads to vascular instability, permeability, and inflammation [39, 42, 43]. If these primary causative factors are not reversed, RVO may become a chronic condition that responds poorly to various treatments. Therefore, targeting these additional pathways may improve and prolong the duration of treatment response [39, 43, 44].

The BALATON and COMINO Clinical Trials Reveal New Information about RVO

The recent BALATON and COMINO trials investigated faricimab, a bispecific antibody that acts through dual inhibition of both VEGF-A and Ang-2, in patients with RVO [45, 46]. Data from these trials demonstrated the efficacy of faricimab through gains in BCVA and reductions in central subfield thickness (CST) from baseline maintained through to Week 72, with a reduced need for frequent injections (>45% of patients were on faricimab dosing every 12 weeks or longer at Week 68) [46]. Faricimab was also well tolerated, and the safety profile was consistent with previous studies [45, 46].

A key finding was that a greater proportion of patients in the faricimab versus 2 mg aflibercept arm achieved absence of macular leakage at Week 24, suggesting that the Ang-2 inhibition component of faricimab’s dual mechanism of action may provide additional benefit to patients over VEGF inhibition alone [45]. How might one build upon these results to further explore faricimab’s impact on the underlying disease mechanisms in RVO and the potential long-term treatment strategy? Ultra-wide field fluorescein angiography (UWF-FA) and/or UWF-OCTA could be used to determine whether faricimab extends its effects to reduce ischemia in the periphery as this could have an impact on disease prognosis. The impact of faricimab on macular ischemia and retinal thinning over time in RVO eyes will also provide additional insights into the modification of natural history and prognosis with intervention.

The dual action of faricimab on two different pathways implicated in RVO pathogenesis may provide improved disease control in patients whose condition cannot be managed at present even with frequent anti-VEGF injections. The anti-inflammatory properties of Ang-2 blockade may be of particular advantage in RVO, given the significant increase in pro-inflammatory cytokines in RVO eyes [47]. These promising results highlight the need to further investigate our understanding of multi-pathway targeting, with the potential to benefit a more heterogeneous group of patients with RVO.

Despite this, given that RVO is a chronic disease requiring long-term monitoring [19], a critical need for guidance on how to optimize patient management in the long term remains. If patients are responding particularly well to treatment, can treatment frequency be reduced or can they discontinue injections altogether? A resolution needs to be put in place to address these possibilities and ensure that long-term monitoring is individualized, balancing effective disease management with practicability.

A Call to Action

RVO is a heterogeneous group of disorders which require nuanced and individualized diagnostic investigations, treatment strategies, and patient care. With the increasing prevalence and burden of RVO [6], it is critical to identify and address the key unmet needs in the patient journey (Fig. 1). We need to harness novel deep learning techniques in combination with large-scale linked datasets to further our understanding of the systemic factors associated with RVO, thereby helping us better predict who is at risk.

Fig. 1.

A schematic overview of the patient journey in retinal vein occlusion (RVO). *Data from Romano et al. 2023 [3]. ^†Data from Minaker et al. 2020, Jumper et al. 2018, Gurudas et al. 2022 [26, 37, 38]. RVO retinal vein occlusion

To holistically address visual impairment due to RVO, we need to challenge the current paradigm of what good functional outcomes with treatment look like, perhaps through the use of patient-centered evaluation of the structure-function correlation and patient-reported outcome measures specifically designed for people affected by RVO. We also need to advance our knowledge of imaging and serologic biomarkers and further investigate novel treatments targeting multiple pathways to improve our ability to choose the right treatment and treatment strategy for the heterogeneous groups of patients with RVO to achieve the best patient outcomes.

Using real-world and collated data from recent studies such as BALATON and COMINO, combined with the benefits of advances in retinal imaging and deep learning techniques, we foresee powerful new insights into the treatment of RVO. An optimized patient pathway may well be within reach.

Declarations

Conflict of Interest

Christiana Dinah: Consultant for Astellas, Boehringher Ingelheim, Johnson & Johnson, and Roche; Research grants from Apellis, Roche, and Topcon; speaker fees and honoraria from Apellis, Bayer, Heidelberg, Roche, and Topcon; Andrew Chang: Consultant for Alcon, Allergan, Apellis, Astellis, Bayer, Novartis, Roche/Genentech Inc., and Zeiss,; received grants or contracts from Allergan, Bayer, and Novartis; received payment or honoraria for lectures, presentations, speaker bureaus, or educational events from Alcon, Allergan, Apellis, Bayer, Nidek, Novartis, Roche/Genentech, Inc., and Zeiss; received support for attending meetings and/or travel from Bayer; Junyeop Lee: Consultant for AbbVie/Allergan, AMC sciences, Bayer, Curacle, Novartis, and Roche; received grants/research support from Bayer and Novartis; William W. Li has nothing to disclose; Rishi Singh: Personal fees from Alcon, Apellis, Bausch and Lomb, Eyepoint, Genentech, Iveric Bio, Regeneron, Regenxbio, and Zeiss, and research grants from Janssen; Lihteh Wu: Consultant for Apellis, Astellas, Bayer, Lumibird Medical, and Roche; David Wong: Consultant for AbbVie, Alcon, Apellis, Bausch Health, Bayer, Biogen, F. Hoffmann La-Roche, Novartis, Regeneron, Ripple Therapeutics, and Zeiss; grant support from Bayer, F. Hoffmann La-Roche, and Novartis; Insaf Saffar: Employee of F. Hoffmann La-Roche.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.