Sickle cell maculopathy (SCM) is a condition in which the macula becomes thinned in patients with sickle cell disease (SCD).
SCD is a hemoglobinopathy caused by a point mutation (Glu→Val) in the β-globin gene, leading to the production of HbS molecules. HbS molecules polymerize and form fibers under deoxygenation, causing red blood cells to deform into a crescent (sickle) shape. These deformed red blood cells occlude microvessels, causing ischemic changes in the eye as well as in systemic organs.
Proliferative sickle retinopathy (PSR) is widely known as an ocular complication, but SCM is characterized by its asymptomatic progression at an earlier stage than PSR. While PSR primarily involves neovascularization of the peripheral retina, SCM is essentially ischemia and thinning of the inner retinal layers (especially the deep capillary plexus) in the macula.
PSR is primarily caused by peripheral retinal ischemia leading to neovascularization, which can cause vision-threatening vitreous hemorrhage or tractional retinal detachment. SCM is primarily characterized by thinning of the inner retinal layers in the macula and often progresses asymptomatically. Both conditions can coexist in the same patient.
Most cases of SCM are asymptomatic. Visual acuity is often preserved over a long period, and the lesion progresses without the patient being aware of any abnormality.
When symptoms appear, the following may be observed:
Characteristic findings are obtained with the following examination modalities.
A comparison of OCT and OCTA findings is shown in the table below.
| Examination | Main Findings |
|---|---|
| OCT | Thinning of the inner retinal layers (RIPL) |
| OCTA | FAZ enlargement and capillary dropout |
OCT findings (retinal inner layer thinning: RIPL)
In 44–60% of SCM patients, thinning of the inner retinal layers in the macula (Retinal Inner Plexiform Layer thinning; RIPL) is observed. Selective thinning of the inner granular layer, inner plexiform layer, and ganglion cell layer is characteristic. In cases complicated by acute RAO, thinning and edema of the entire inner retina progress rapidly, eventually leading to permanent atrophy 1).
OCTA findings (changes in the perifoveal capillary network)
OCTA shows enlargement of the foveal avascular zone (FAZ) and dropout/coarsening of the perifoveal capillary network. These findings can be detected early, even before subjective symptoms appear, and are attracting attention as biomarkers reflecting disease activity.
The direct cause of SCM is occlusion of the macular capillaries by deformed red blood cells due to polymerization of HbS molecules. However, the risk of developing SCM varies greatly depending on the hemoglobin genotype 1).
The main risk factors and protective factors are shown in the table below.
| Factor | Description | Direction |
|---|---|---|
| HbSS type | Most severe genotype | Risk |
| HbF >15% | Suppresses sickling | Protective |
| Advanced age, long disease duration | Ischemic accumulation | Risk |
Diagnosis of SCM is primarily based on imaging findings during regular fundus examinations in SCD patients. Since subjective symptoms are scarce, active screening examinations are important 1).
Current standard screening test. It quantitatively evaluates the thickness of the inner retinal layers (ganglion cell layer, inner plexiform layer, inner nuclear layer). It can detect early thinning and is suitable for tracking changes over time.
It can visualize the parafoveal capillary network without contrast agents. It allows quantitative measurement of FAZ area and assessment of capillary dropout, making it excellent for disease severity evaluation. It is less invasive than fluorescein fundus angiography (FFA) and can be repeated, making it advantageous for follow-up.
Used for functional assessment. Even in early cases where OCT shows no clear morphological changes, a decrease in parafoveal amplitude may be detected. It is attracting attention in both research and clinical settings as an objective indicator of visual function.
Useful for direct visualization of capillary non-perfusion areas and vascular anastomosis. However, there are risks associated with contrast agent use, and OCTA is increasingly being used as an alternative.
Primary Prevention
Hydroxyurea: Induces HbF production and inhibits sickling. Reduces the risk of developing SCM. It is a mainstay drug for SCD management and early introduction is recommended from the perspective of preventing ocular complications.
Transfusion Therapy: Performed in severe cases or when drug therapy is insufficient. Reduces HbS ratio to suppress systemic and ocular ischemic events.
Existing Lesions
No Established Treatment: Currently, there is no treatment to improve macular thinning (RIPL) once it has occurred. The goal of treatment is to slow disease progression.
Acute RAO Complication: Requires urgent medical and ophthalmic management. Treatment follows that for ophthalmic artery occlusion, but effects are often limited.
Screening
Regular OCT Examination: Performed periodically in SCD patients, especially those with HbSS type, from adulthood onward.
Collaboration between ophthalmology and hematology: Collaboration between both departments is essential for managing SCM. Strengthening systemic management leads to prevention of ocular complications.
The central pathology of SCM is chronic ischemia in the deep capillary plexus (DCP) of the macula.
HbS molecules polymerize under deoxygenated conditions, causing red blood cells to deform and harden. These deformed red blood cells lack flexibility and cannot pass through capillaries with a diameter of 5–10 μm, leading to repeated micro-occlusions. In the macula, the temporal terminal arteriole (TTA) is the most peripheral location and is anatomically susceptible to ischemia.
When capillary non-perfusion occurs, oxygen and nutrient supply to neurons in the inner nuclear layer and inner plexiform layer is cut off, leading to selective cell death (apoptosis) 2). This process involves the following mechanisms.
The temporal terminal arteriole is a single blood flow pathway to the macula with poor collateral circulation. Therefore, occlusion at this site is reflected as FAZ enlargement and parafoveal capillary dropout.
FAZ area and capillary density index derived from OCTA are being studied as quantitative biomarkers of ocular microcirculation in SCD patients. Comparisons with healthy individuals and use for evaluating the therapeutic effect of hydroxyurea are being considered. mfERG, as a functional indicator, combined with OCT morphological assessment, may improve the accuracy of early lesion detection.
An association between SCM and silent cerebral infarction (SCI) has been suggested. Macular microcirculation disorders may reflect cerebral microvascular damage, and research is ongoing to determine whether ophthalmic findings can serve as predictors of neurological risk. Establishing a collaborative management model from ophthalmology to neurology for SCD patients is a future challenge.
As a curative treatment for SCD itself, gene therapy for hematopoietic stem cells (such as HbF reinduction via BCL11A suppression) has entered the practical stage. The extent to which these systemic treatments suppress the progression of ocular complications including maculopathy awaits accumulation of long-term follow-up data.
Although based on research-stage findings, an association between SCM and silent cerebral infarction has been suggested. Macular microvascular damage may reflect systemic microvascular damage, and research is investigating whether ophthalmic examination can serve as an auxiliary tool for neurological risk assessment. At present, this is not an established relationship, and future research results are awaited.
