Figure 1. Peripheral ischemia is clearly visible in angiographic studies of these 2 eyes with sickle retinopathy.
Figure 2. These scans show various presentations of superficial retinal hemorrhages, known as “salmon patches,” at different levels of hemoglobinization.
Figure 3. The blue arrows in these images point to examples of pigmented lesions known as “black sunburst.” The red arrow on the lower images show persistent active retinal neovascularization, despite the prior panretinal photocoagulation.
Figure 4. This patient, a 46-year-old Black man, experienced sudden vision loss following a recent episode of sickle crisis. His fluorescence angiography images demonstrate, in addition to peripheral retinal vascular occlusion and neovascularization, significant perifoveal capillary closure.
Figure 5. Patients with sickle retinopathy and atypically dense epiretinal membranes are shown here.
Figure 6. Proliferative sickle retinopathy Goldberg stage I constitutes peripheral arterial occlusion and stage II involves peripheral arteriovenous anastomoses, seen as dilated capillaries known as hairpin loops.
Figure 7. These patients demonstrate Goldberg stage III. The top case also suffers from ischemic iris atrophy because of SCD.
Figure 8. These images show vitreous hemorrhages in association with Goldberg stage IV PSR.
Figure 9. These cases show Goldberg stage V PSR, with associated tractional retinal detachment.
Figure 10a. This patient with PSR and significant epiretinal membrane was treated with intravitreal anti-VEGF. Figure 10b. The patient’s 1-month follow-up shows partial regression of retinal hemorrhage and neovascularization is noted (see the blue arrow). The patient was scheduled for vitrectomy and endophotocoagulation for surgical peel of the ERM as well as addressing the proliferative disease. Figure 10c. Due to the pandemic, the patient was unable to show up for surgery and returned to office months later with worsening of the peripheral retinal disease.
Figure 11. Patients with PSR treated with peripheral panretinal photocoagulation showing regression of retinal neovascularization.
Sickle cell disease (SCD) is a group of inherited hematologic disorders. The most common form of the disease is known as sickle cell anemia (SCA). The effect of the disease is misshapen red blood cells due to abnormal hemoglobin. The red blood cells of patients with SCA have a sickle shape instead of the typical disc shape of erythrocytes.1
SCD is an autosomal recessive condition that occurs when a person inherits 2 abnormal copies of the β-globin (HBB) gene responsible for the production of hemoglobin. There are various subtypes of sickle cell disease, listed in Table 1. Hemoglobin SS is the most common and most severe form of sickle cell disease. Persons with a single gene defect are carriers of the condition referred to as sickle cell trait.2
Patients with SCD can have a variety of vascular complications known as sickle cell crisis, which can be brought on by stress, dehydration, temperature change, and high altitude. There are multiple other systemic complications associated with SCD. Patients with SCD are also at further risk for bacterial infections, cerebrovascular accidents, reduced immunity, and chronic kidney failure. Individuals with sickle cell trait rarely develop systemic complications.1,3
The vascular occlusive nature of SCD can result in ocular complications such as comma-shaped blood vessels in the bulbar conjunctiva, iris atrophy, retina including the optic nerve, and the choroid. 4,5
Retinopathy associated with SCD is known as sickle retinopathy (SR) or sickle cell retinopathy (SCR) which presents in nonproliferative (NPSR) and proliferative (PSR) forms. Although it is more common in SS and SC disease, it can also occur in other forms, including hemoglobin AS or sickle cell trait patients.6,7
Clinical findings associated with NPSR result primarily from occlusion of peripheral retinal vasculature (Figure 1). Peripheral retinal hemorrhages, also called “salmon patches,” are caused by bleeding of the superficial vessels that are initially bright red.8 As these hemorrhages become dehemoglobinized, they take on a salmon color, hence the name (Figure 2). Further resolution of these hemorrhages can result in refractile deposits seen in the peripheral retina, which are composed of hemosiderin and microphage deposition under the internal limiting membrane. Proliferation and intraretinal migration of retinal pigment epithelium results in pigmented lesions called “black sunburst” (Figure 3).9 Macular ischemia (Figure 4), as well as epimacular (EMM) and epiretinal membranes (ERM), can also be associated with sickle cell.10-12 EMMs are often more prominent in patients with SCD (Figure 5).
Staging and Differential Diagnosis
Chronic ischemia can result in the progression of nonproliferative to proliferative disease.13 PSR findings are organized in 5 stages, known as Goldberg classifications.14 Stage I constitutes peripheral arterial occlusion. Stage II, peripheral arteriovenous anastomoses, seen as dilated capillaries known as hairpin loops (Figure 6). In stage III, retinal neovascularization (NV) and fibrovascular proliferation, usually in a sea fan shape, develops. Further fibrosis is caused by autoinfarction of NV (Figure 7). Stage IV is associated with vitreous hemorrhage (Figure 8), and Stage V by tractional retinal detachment (TRD) (Figure 9). Since many of the findings of NPSR and PSR are seen in other conditions or as comorbidities, differential diagnosis with these conditions are paramount. They can include:
• Diabetic retinopathy
• Retinal vein occlusion
• Hypertensive retinopathy
• Anemic and leukemic retinopathy
• Ocular sarcoidosis (Retinal vasculitis)
• Coats disease
• Eales disease
• Infectious retinitis (such as ARN and CMV)
• Ocular ischemic syndrome
• Retinopathy of prematurity
• Familial exudative vitreoretinopathy
• Retinopathy associated with hyperviscosity syndrome
• Retinopathy associated with hypercoagulability state
• Retinal vasoproliferative tumor
• Retinal hemangioblastoma
Management of sickle retinopathy includes screening and identification of the typical finding by a thorough comprehensive eye examination, including a dilated fundus exam. In addition, imaging such as ultrawide field fundus photography, retinal angiography (FA), and optical coherence tomography (OCT) should be utilized.
PSR is effectively treated by intravitreal injection of anti-vascular endothelial growth factor (VEGF) (Figure 10) and panretinal photocoagulation (PRP) at times in a sectoral pattern primarily in the peripheral retinal region (Figure 11).15
In stages IV and V, surgical intervention by vitrectomy and delamination of epiretinal membrane or repair of TRD may be required.
Sickle retinopathy can cause significant vision loss. In at-risk populations, careful systemic and ocular assessment can significantly reduce the risk of vision loss and other morbidities associated with sickle cell spectrum.
- National Heart, Lung and Blood Institute. Sickle Cell. https://www.nhlbi.nih.gov/health-topics/sickle-cell-disease. Updated Last updated September 01, 2020. Accessed October 18, 2021.
- Higgs DR, Wood WG. Genetic complexity in sickle cell diseases. PNAS. 2008;105(33):11595-11596. doi:10.1073/pnas.0806633105
- Yale SH, Nagib N, Guthrie T. Approach to the vaso-occlusive crisis in adults with sickle cell disease. Am Fam Physician. 2000;1;61(5):1349-1356.
- Roy MS, Rodgers GP, Podgor MJ, Noguchi CT, Nienhuis AW, Schechter AN. Conjunctival sign in sickle cell anaemia: an in-vivo correlate of the extent of red cell heterogeneity. Br J Ophthalmol. 1985;69(8):629-32. doi:10.1136/bjo.69.8.629
- Acheson RW, Ford SM, Maude GH, Lyness RW, Serjeant GR. Iris atrophy in sickle cell disease. Br J Ophthalmol. 1986;70(7):516-512. doi:10.1136/bjo.70.7.516
- Emerson GG, Luttty GA. Effects of sickle cell disease on the eye: clinical features and treatment. Hematol Oncol Clin Noth Am. 2005;19(5):957-73, ix. doi:10.1016/j.hoc.2005.07.005
- Jackson H, Bentley CR, Higorani M, Atkinson P, Aclimandos WA, Thompson GM. Sickle retinopathy in patients with sickle trait. Eye (Lond). 1995;9(5);589-593. doi:10.1038/eye.1995.145
- Jampol LM, Condon P, Dizon-Moore R, Serjeant G, Schulman JA. Salmon-patch hemorrhages after central retinal artery occlusion in sickle cell disease. Arch Ophthalmol. 1981;99(2):237-240. doi:10.1001/archopht.1981.03930010239002
- Friberg TR, Young CM, Milner PF. Incidence of ocular abnormalities in patients with sickle hemoglobinopathies. Annals of Ophthalmol. 1986;18(4):150-153.
- Goldberg MF, Galinos S, Lee CB, Stevens T, Woolf. MB. Macular ischemia and infarction in sickling. Invest Ophthalmol. 1973;12(9):633-635.
- Carney MD, Jampol LM. Epiretinal membranes in sickle cell retinopathy. Arch Ophthalmol. 1987;105(2):214-217. doi:10.1001/archopht.1987.01060020068031
- Moriarty BJ, Acheson RW, Serjeant GR. Epiretinal membranes in sickle cell disease. Br J Ophthalmol. 1987;71(6):466-469. doi:10.1136/bjo.71.6.466
- Dowes SM, Hambleton JR, Chaung EL, Lois N, Serjeant GR, Bird AC. Incidence and natural history of proliferative sickle cell retinopathy: observations from a cohort study. Ophthalmol. 2005;112(11):1869-1875. doi:10.1016/j.ophtha.2005.05.026
- Goldberg MF. Classification and pathogenesis of proliferative sickle retinopathy. Am J Ophthalmol. 1971;71(3):649-665. doi:10.1016/0002-9394(71)90429-6
- Jampol LM, Farber M, Rabb MF, Serjeant GR. An update on techniques of photocoagulation treatment of proliferative sickle cell retinopathy. Eye. 1991;5:260-263. doi:10.1038/eye.1991.41
- Mishra K, Bajaj R, Scott AW. Variable practice patterns for management of sickle cell retinopathy. Ophthalmol., 2021;5(7):715-717. doi:10.1016/j.oret.2020.11.017
Mohammad Rafieetary, OD, FAAO, FORS, ABO, is a consultative optometric physician at the Charles Retina Institute.
Roya Attar, OD, MBA, FAAO is an assistant professor and serves as Director of Optometric Services in the University of Mississippi Medical Center’s Department of Ophthalmology.