Ivie Itua¹, Mohammed-Sherrif Fuseini², Zulfiya Emefa Gbedemah², Joan Efua Hanson³

¹Clinical Research Fellow, Imperial College London, London, UK
²Korle Bu Teaching Hospital, Accra, Ghana
³Department of Ophthalmology, University Hospitals 

Summary

Sickle cell retinopathy (SCR) is a major ocular manifestation of sickle cell disease (SCD), arising from vaso-occlusion, ischemia, and retinal neovascularisation. Historically, scatter and focal laser photocoagulation formed the mainstay of treatment for proliferative sickle cell retinopathy (PSCR). However, the advent of anti-vascular endothelial growth factor (anti-VEGF) therapy, micro-incision vitrectomy and multimodal imaging, enhanced by artificial intelligence (AI), has transformed disease management. This review critically appraises current and emerging interventions for SCR, evaluating evidence, limitations, and implications for ophthalmology trainees. Regional disparities and future directions for global ophthalmic care are also discussed.

Introduction

Sickle cell disease (SCD) encompasses inherited haemoglobinopathies in which sickle haemoglobin (HbS) polymerises under hypoxic stress, leading to erythrocyte rigidity, vaso-occlusion, and haemolysis (1). Sickle cell retinopathy (SCR), one of its ocular manifestations, represents a spectrum of retinal microvascular pathology ranging from non-proliferative changes, such as salmon patch haemorrhages and iridescent spots, to proliferative stages involving neovascularisation and tractional retinal detachment (2). The genotypes most associated with ocular involvement are HbSS, HbSC, and HbS/β-thalassaemia, with HbSC paradoxically showing more severe retinopathy despite milder systemic disease (1).

Goldberg’s five-stage classification of proliferative sickle cell retinopathy (PSCR) remains central to clinical staging (2):

• Peripheral arteriolar occlusion
• Arteriovenous anastomoses
• Neovascular “sea-fan” formation
• Vitreous haemorrhage
• Tractional or rhegmatogenous retinal detachment.

This framework has evolved, from a descriptive tool to a therapeutic guide, where laser, pharmacologic and surgical decisions are stratified according to the extent of ischemia and proliferative change. The overarching therapeutic goal is to prevent or regress neovascularisation and preserve macular integrity. Accordingly, contemporary management has shifted from destructive peripheral ablation to precision-guided, imaging-informed approaches that balance efficacy with retinal preservation.

This review appraises the evidence base for current PSCR management, tracing its evolution from laser photocoagulation to anti-VEGF therapy and modern vitreoretinal surgery. It also discusses disparities in access to care and the emerging tecniques shaping future practice.

Laser Photocoagulation

Peripheral scatter laser photocoagulation was the first evidence-based treatment for PSCR. Condon and Serjeant (3) reported regression of neovascular “sea-fans” in 63% of treated eyes versus 22% of untreated controls after argon laser. Welch and Goldberg (4) found a 50% reduction in vitreous haemorrhage incidence after sectoral photocoagulation. These landmark studies provided early proof that ablation of ischemic retina diminishes VEGF-driven angiogenesis.

Argon and, later, diode lasers became the mainstay of therapy, delivered either via slit-lamp or indirect ophthalmoscope using sectoral scatter photocoagulation to treat ischemic areas adjacent to neovascular complexes. Compared with pan retinal approaches, the sectoral technique limits damage to functional retina while effectively reducing angiogenic drive. However, both early trials were small, non-randomised, and focused on anatomical rather than visual outcomes. Downes et al. later demonstrated a 30% recurrence rate after 10 years (5), underscoring that PSCR is chronic and prone to relapse. Laser complications such as peripheral field constriction, scotomas, and inadvertent foveal burns are uncommon but remail clinically relevant (6).

Recent refinements, including pattern-scan and navigated laser systems, have improved delivery precision and reduced collateral damage by standardising burn placement and integrating real-time imaging, though high-quality comparative data remain limited. Mastery of safe sectoral laser technique remains a key skill for ophthalmology trainees to obtain, particularly in resource-limited settings, where conventional scatter photocoagulation continues to represent first-line treatment.

Study	Design	Eyes (n)	Intervention	Outcome	Limitations
Condon & Serjeant (1981) (3)	Controlled cohort	72	Argon scatter laser	63% regression vs 22% untreated	Non-randomised; short follow-up
Welch & Goldberg (1983) (4)	Prospective	40	Sectoral photocoagulation	↓ vitreous haemorrhage by 50%	No visual-function data
Downes et al. (2005) (5)	Retrospective	97	Argon laser	30% recurrence @ 10 yrs	Observational; no control group

Table 1: summary of evidence for laser techniques

Anti-VEGF Therapy

Vascular endothelial growth factor (VEGF) is central to ischemia-driven angiogenesis. Elevated intraocular VEGF in SCD provides strong biological rationale for pharmacologic inhibition (7). Mansour et al. (8) first reported complete regression of neovascular complexes within one month after intravitreal bevacizumab. Jampol et al. (9) observed improved intraoperative visualisation and reduced bleeding when bevacizumab preceded vitrectomy. Recurrence within 3-6 months is common, underscoring that VEGF blockade addresses consequence, not cause. This may suggest the need for regular administration which may increase the likelihood of side effects.

Small case series with ranibizumab and aflibercept also show short-term anatomical improvements (11, 12), though absence of control arms and brief follow-up limit interpretation. No large randomised controlled trials (RCTs) compare anti-VEGF monotherapy with laser or observation in SCR. Moreover, Spaide (13) cautioned that VEGF suppression may worsen ischemia by impeding physiological vascular maintenance.

In practice anti-VEGF agents are best used adjunctively, either to facilitate surgery or when media opacity precludes laser. Combined therapy appears to yield faster regression and fewer recurrences than either alone (14, 15), but long-term outcomes remain uncertain. Trainees should view anti-VEGF as a temporising measure rather than a cure.

Surgical Management

Non-clearing vitreous haemorrhage and tractional retinal detachment are vision-threatening PSCR complications. Early 20-gauge vitrectomy carried substantial risk of intraoperative bleeding and postoperative rebleeding (16). Transition to small-gauge (23–25 G) micro-incision systems has improved safety and visual outcomes (17). During the procedure, three self-sealing sclerotomies are created for the infusion cannula, light source, and vitrector, allowing removal of opacified vitreous and fibrovascular membranes under widefield viewing. Endolaser photocoagulation is typically applied intraoperatively to residual ischemic retina, and a gas or silicone oil tamponade may be used to reattach the retina or stabilise postoperative haemostasis.

Recent reports show visual improvement in 70–85% of cases (18,19). Pre-operative bevacizumab administered several days before surgery reduces intraoperative bleeding and enhances visualisation (20), though optimal timing, dosage, and cost-effectiveness remain under study. There are still Inequalities in access in many most affected areas of the world, where scarcity of vitreoretinal surgeons and surgical facilities delays intervention until fibrosis or detachment is advanced (21). For trainees, understanding such global disparities highlights the broader responsibilities of ophthalmologists in capacity building and advocacy.

Imaging and Artificial Intelligence

Modern imaging has revolutionised understanding of SCR pathophysiology. Optical coherence tomography angiography (OCTA) enables non-invasive mapping of capillary dropout, while widefield fluorescein angiography (FA) visualises peripheral ischemia beyond the posterior pole (22, 23). Quantitative OCTA biomarkers, such as vessel density and non-perfusion index, offer objective disease metrics (24). However, variability among imaging systems and small study sizes limit standardisation.

Artificial intelligence (AI) is now emerging as a diagnostic adjunct. A deep-learning model by Falavarjani et al. achieved 93% accuracy distinguishing proliferative from non-proliferative SCR on ultra-widefield FA (25). Such models could enable automated screening in high-burden, low-resource settings. Yet, algorithmic bias remains a concern since most datasets derive from non-African populations. Researchers and policy makers should critically appraise dataset diversity and clinical applicability before deploying AI systems.

Global Disparities and Emerging Collaborations

Despite scientific progress, inequity in SCR care remains pronounced. In high burden settings, access to laser, anti-VEGF agents, or vitrectomy is limited by infrastructure and cost (26). In contrast, routine retinal screening and early intervention in high-income countries have markedly improved outcomes (27).

Teleophthalmology initiatives using portable fundus cameras and smartphone-based imaging are bridging diagnostic gaps (28). Integrating such tools into haematology clinics could enable sustainable surveillance, identifying at risk individuals early and preventing expensive sight threatening complications.

The Sickle Cell Retinopathy Network (SCR.net) has launched a Delphi consensus to develop global guidelines for screening and management (29). This inclusive collaboration, engaging ophthalmologists, haematologists, and patient advocates from diverse regions, sets a new precedent for equity-driven research. Participation in such networks offers trainees valuable insight into international clinical guideline development.

Educational and Research Implications

For ophthalmology trainees, sickle cell retinopathy (SCR) provides an instructive clinical model that integrates systemic haematology, retinal vascular biology, imaging interpretation, and microsurgical decision-making. Understanding its natural history reinforces fundamental principles also applicable to diabetic and venous occlusive retinopathies.

In the clinical setting, SCR encourages a multidisciplinary mindset that links systemic disease control, retinal pathophysiology and visual prognosis. Trainees gain exposure to the rationale behind targeted photocoagulation, pharmacologic VEGF inhibition, and timing of vitreoretinal intervention. Moreover, interpretation of multimodal imaging including optical coherence tomography angiography (OCTA) and fluorescein angiography, builds analytical proficiency essential for modern ophthalmic practice.

From an academic perspective, SCR highlights the limitations of the current evidence base. Most published studies are small, single-centre and observational, limiting generalisability and external validity. The field would benefit from multicentre randomised controlled trials comparing laser, anti-VEGF and combined treatment strategies with long-term visual outcomes. Future research should also evaluate systemic modifiers such as hydroxyurea or emerging gene therapies on ocular disease progression, validate OCTA and AI-derived biomarkers across diverse populations and assess the cost-effectiveness of screening and treatment approaches in resource-limited settings.

Embedding such projects within existing sickle cell disease (SCD) networks and international collaborations could accelerate evidence generation while providing ophthalmology trainees with valuable experience in research design, data collection and critical appraisal. By engaging in these initiatives, future clinicians will not only refine their understanding of retinal vascular disease but also contribute to equitable global ophthalmic care.

Conclusion

Management of sickle cell retinopathy has evolved from empirical laser ablation to a multimodal approach incorporating pharmacologic, surgical, and imaging advances. Laser photocoagulation remains foundational, while anti-VEGF therapy and micro-incision vitrectomy improve outcomes when applied judiciously. Emerging imaging technologies and AI-driven analysis herald an era of precision ophthalmology, but equitable implementation remains critical. For ophthalmology trainees, SCR illustrates the convergence of systemic medicine, retinal science and health equity, skills integral to becoming thoughtful, globally aware clinicians.

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