Sickle cell retinopathy is the ocular manifestation of sickle cell disease (SCD), a group of hereditary hemoglobinopathies. It is identified by ICD-10-CM diagnostic code H36.
Retinal hemorrhage associated with SCD was first reported by Cook in 1930. In 1937, Harden described dilation and tortuosity of retinal vessels, and in 1942, Ray and Cecil proposed the basic pathology of microvascular occlusion by sickled red blood cells.
Hemoglobin consists of two alpha chains and two beta chains. A single nucleotide substitution (GAG to GTG) at codon 6 of the beta chain results in the replacement of glutamic acid with valine. Homozygosity for this mutation leads to HbSS (sickle cell disease), while heterozygosity leads to HbAS (sickle cell trait). Compound heterozygosity with other beta chain mutations results in HbSC disease and HbS thalassemia (HbSThal).
The incidence of genotypes among African Americans in North America is as follows:
| Genotype | Incidence | PSR Frequency |
|---|---|---|
| HbAS (trait) | Approximately 8% | Low |
| HbSS | 0.4% | Approximately 3% |
| HbSC | 0.2% | Approximately 33% |
In a Jamaican cohort study, the prevalence of PSR by age 20.5 years was 43% for HbSC and 14% for HbSS. The annual incidence was 2.5% for HbSC and 0.5% for HbSS, with age, extent of retinopathy, and status of the contralateral eye associated with progression.
In HbSS, systemic anemia and vaso-occlusive crises are severe, so patients are managed early due to systemic symptoms. On the other hand, HbSC patients have relatively good general health, live longer, and are thought to accumulate ischemic changes in the eye more easily. Additionally, HbSC red blood cells have high viscosity and tend to cause occlusion of small peripheral retinal vessels.
Many patients maintain good vision for a long time, but if the following symptoms appear, they may be signs of vitreoretinal traction or retinal detachment.
Characterized by vascular occlusion and ischemic changes mainly in the peripheral retina.
Salmon Patch
Appearance: Round to oval superficial retinal hemorrhage. Elevated or flat.
Color change: Initially red. Changes to salmon color due to hemolysis of red blood cells.
Outcome: May appear normal after absorption, or leave an iridescent spot.
Iridescent spots
Cause: After absorption of salmon patches, hemosiderin and macrophages deposit directly beneath the internal limiting membrane.
Appearance: Observed as refractive, shiny deposits.
Black sunbursts
Cause: Migration and proliferation of retinal pigment epithelium (RPE) in response to hemorrhage.
Appearance: Radial black pigmented spots, commonly in the peripheral retina.
Other NPDR findings:
PSR is classified into the following 5 stages by Goldberg 1).
| Stage | Findings | Notes |
|---|---|---|
| I | Peripheral arterial occlusion | Earliest change |
| II | Peripheral arteriovenous anastomosis | Dilation of existing capillaries, hairpin loops |
| III | Neovascularization and fibrous proliferation (sea fan) | Occurs at the posterior border of non-perfused areas |
| IV | Vitreous hemorrhage | Due to rupture of sea fan |
| V | Tractional retinal detachment | Most severe stage |
Stage III “sea fan” is observed as a “white sea fan” when neovascularization undergoes auto-infarction. Unlike diabetic retinopathy, neovascularization in PSR originates from the periphery, not the center.
Capillaries of the bulbar conjunctiva (surface of the white of the eye) show a characteristic comma shape due to accumulation of sickle cells. This can be observed with a slit lamp microscope and is a finding suggestive of sickle cell disease.
HbS (sickle hemoglobin) produced by the GAG→GTG mutation at the 6th position of the β chain polymerizes under hypoxic conditions, causing red blood cells to become sickle-shaped. These deformed red blood cells cannot pass through small blood vessels, leading to vascular occlusion.
The incidence of PSR is significantly higher in patients with HbSC and HbSThal (33% and 14%, respectively) than in HbSS patients (3%). It is important to note that the severity of systemic complications does not necessarily correlate with the risk of ocular complications2).
Confirming a history of sickle cell disease is the first step. Comma-shaped vessels in the bulbar conjunctiva provide a diagnostic clue.
The following 12 diseases need to be differentiated. A history of sickle cell disease is useful for differentiation, but these may also coexist with SCR.
OCTA can noninvasively visualize retinal capillaries and identify early retinal ischemic changes that are difficult to detect with FA. Since it shows significant changes even in children without obvious structural damage, it is expected to be used for early screening.
Currently, there is no specific treatment for NPSR. Regular observation is the mainstay, and patients with sickle cell disease are recommended to have at least one complete eye examination per year.
Scatter laser photocoagulation is the standard treatment for sea fans in PSR stage III. The current standard technique is to perform scatter laser around the sea fans 3).
In a randomized clinical trial in Jamaica, the treatment group that received scatter photocoagulation had a significantly lower frequency of long-term vision loss and vitreous hemorrhage compared to the control group. Laser treatment outcomes are shown below 3).
| Outcome measure | Treatment group | Control group |
|---|---|---|
| Incidence of new sea fans | 34.4% | 41.3% |
| Long-term vision loss due to vitreous hemorrhage | 1% | 6.7% |
However, because new blood vessels may spontaneously regress (auto-infarction), treatment decisions are made on an individual basis. Feeder vessel photocoagulation is now mainly of historical significance.
For complications of PSR (risk of vitreous hemorrhage and tractional retinal detachment), intravitreal injection of anti-VEGF drugs may induce regression of new blood vessels. It is sometimes used in combination with laser therapy.
Hydroxyurea
Mechanism of action: Increases production of fetal hemoglobin (HbF), reducing the proportion of HbS.
Indication: Has been shown to prevent sickle cell retinopathy in children.
Current status: Widely used systemic drug therapy.
Casgevy (approved in 2023)
Technology: Uses CRISPR-Cas9 to edit the patient’s hematopoietic stem cells, increasing HbF production.
Approval: FDA approved in December 2023.
Pretreatment: Requires myeloablative conditioning.
Lyfgenia (approved in 2023)
Technology: Lentiviral vector modifies hematopoietic stem cells to produce a hemoglobin A-like molecule.
Approval: FDA approved in December 2023.
Preconditioning: Myeloablative therapy is required.
Surgical indications:
Intraoperative management requires optimization of oxygen administration and fluid replacement, as well as strict monitoring of intraocular pressure. Care should be taken when using scleral buckling to reduce the risk of anterior segment ischemia. Preoperative consultation with a hematologist should be considered.
In African American patients with traumatic hyphema, testing for sickle cell hemoglobinopathy is necessary. Acetazolamide is contraindicated for intraocular pressure management; instead, methazolamide should be used. Acetazolamide can induce systemic acidosis and promote sickling of red blood cells, which may lead to serious complications.
Normal red blood cells are flexible and round to oval in shape, allowing them to pass easily through small blood vessels. In patients with SCD, local hypoxia causes soluble HbS to irreversibly convert into crystalline hemoglobin, producing rigid sickle-shaped red blood cells. Changes in the adhesive properties of vascular endothelial cells due to hypoxia lead to reduced blood flow and vascular occlusion.
Sickle cells become trapped in the small blood vessels of the anterior and posterior segments of the eye, causing characteristic damage.
Unlike diabetic retinopathy, the neovascularization in PSR originates from the periphery because occlusion by sickle cells occurs in peripheral capillaries.
In December 2023, two types of gene therapy for sickle cell disease were approved by the FDA. Both involve collecting, modifying, and transplanting the patient’s own hematopoietic stem cells under myeloablative conditioning.
Casgevy (exagamglogene autotemcel): Uses CRISPR-Cas9 technology to edit the BCL11A gene in hematopoietic stem cells, reactivating fetal hemoglobin (HbF) production. It was approved as the world’s first CRISPR gene therapy. In the phase 3 CLIMB SCD-121 trial, 97% of participants with sufficient follow-up achieved freedom from severe vaso-occlusive crises for at least 12 months4).
Lyfgenia (lovotibeglogene autotemcel): Uses a lentiviral vector to insert the βT87Q-globin gene, producing a hemoglobin A-like molecule (HbAT87Q).
These treatments aim to fundamentally address sickle cell disease and are expected to prevent ocular complications including retinopathy in the long term. However, challenges remain, including the risks of myeloablative chemotherapy required for conditioning, high costs, and limited long-term efficacy data.
Beyond Casgevy, research is progressing on multiple approaches to increase HbF production, such as targeted editing of the BCL11A enhancer. Strategies combining pharmacological HbF increase with hydroxyurea and genetic HbF increase via CRISPR are also being explored.
OCTA can capture capillary-level changes more noninvasively than FA. Since significant changes can be detected even in children without structural damage, its use as an indicator for early intervention is being studied.
Although FDA-approved in 2023, both treatments require advanced facilities and specialized teams. Myeloablative conditioning is mandatory, and treatment costs are extremely high. Currently, they are only available at specialized hematology centers and are not standard treatments available at general eye clinics or hospitals.
