Evdokia Sourla1
1Birmingham & Midland Eye Centre, Sandwell and West Birmingham, NHS Trust
Introduction
Sickle cell retinopathy is an ocular disease associated with the sickle cell disease. Sickling haemoglobinopathies is a genetic disease which is characterized by one or more abnormal haemoglobins. These cause the red blood cells to take an abnormal shape which can result in vascular occlusion when they are exposed to conditions such as physiological stress (hypoxia or acidosis) (1).
Aetiology
Sickle cell disease has different forms. The homozygous form HbSS, or the heterozygous forms in which the Haemoglobin S could be combined with the HbC and result in the HbSC disease, or with the beta-thalassemia and result in HbS beta-thalassemia disease or other less frequent variants (2). All these forms can cause retinopathy. The sickle HbSC disease has been found to cause more severe retinopathy which could result in blindness, whereas the HbSS is mainly associated with more severe systemic disease (2).
Epidemiology
Proliferative sickle cell retinopathy is the most serious stage and has a higher incidence of around 33% in people who suffer from HbSC disease and 14% among people with HbS beta-thalassemia disease while only 3% for people with HbSS (3).
Risk Factors
The HbSC genotype increases the risk of proliferative sickle cell retinopathy (PSR). In addition, males, older age, high total haemoglobin and high mean corpuscular haemoglobin concentration have been reported to increase the incidence of PSR (4). Furthermore, both genders with elevated mean cell volume and low foetal haemoglobin (HbF) have a risk of developing PSR (4).
In people with the HbSS genotype, the risk of PSR is associated with an elevated total haemoglobin in males and a reduced HbF in both genders (4).
Classification
Non-retinal manifestations
At the anterior segment, comma signs could be found which are dark red corkscrew- or comma-shaped vessels and are mainly in the lower part of the conjunctiva (5). The iris could have ischemic atrophy patches, often extending from the pupillary margin to the collarette, and in some cases, neovascularization of the iris could be present (1).
Sickle cell retinopathy is classified into these two types.
Non-Proliferative Sickle Cell Retinopathy (NPSR)
Some lesions occur in the retina due to vaso-occlusion and localized ischemia (3). These could be asymptomatic such as; blood vessel tortuosity, black sunbursts (patches of peripheral pigmentation and chorioretinal atrophy), ‘salmon patches’ which are pink superficial intraretinal haemorrhages, bright spots (deposits of peripheral hemosiderin), arterioles in “silver thread” in the periphery, retina breaks and angioid streaks which can be found in around 6% of people with sickle cell disease (1, 5).
In addition, some symptomatic lesions could be caused by veins, arteries or choroid occlusion (5).
In the optic disc, at the surface, red dots could be present due to a small vessel occlusion (5).
Proliferative Sickle Cell Retinopathy (PSR)
It is characterized by neovascularization which can be found mainly in the periphery retina and could be active or inactive and fibrosis (2).
Goldberg’s classification, is used to define the five stages( I-V) of proliferative sickle cell retinopathy and also is used to grade the severity of the disease (Figure 1) (6).
| PSR Stage I | Peripheral arterial occlusion (peripheral ghost vessels, angiographic evidence) |
| PSR Stage II | Peripheral arteriovenous anastomoses (vascular remodelling) |
| PSR Stage III | Seafan retinal neovascularization |
| PSR Stage IV | Vitreous haemorrhage |
| PSR Stage V | Retinal detachment (tractional/rhegmatogenous) |
Pathophysiology
In sickle cell disease, in hypoxemic conditions, the HbS polymerizes and causes the stiffened HbS molecules which cluster together and can lead to damage to the red blood vessel membrane and cytoskeleton, causing sickle-shaped red blood cells (2). This form of red blood cells leads to a prolonged capillary transit in the retina and choroid, which results in vessel damage (2). The endothelium releases adhesion molecules and inflammatory mediators, causing vascular occlusion. Repeated episodes of occlusion stimulate the production of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), resulting in the development of proliferative retinopathy (2).
Clinical Symptoms
Most of the patients are asymptomatic with good visual acuity. Patients may become symptomatic by seeing flashes of light or floaters which could be an indication of vitreoretinal traction or retinal detachment (3). Furthermore, reduced visual acuity could occur due to vitreous haemorrhage (7).
Diagnosis
A patient needs to have a diagnosis of sickle cell disease. At the examination of the anterior segment is frequently reported the presence of the ‘’comma sign’’ in the conjunctiva and at the posterior segment could be found signs of a non-proliferative and/or proliferative disease, and in rare cases the appearance of angioid streaks (3).
Some investigations could help identify retinopathy in people with sickle cell disease. Fluorescein angiography is a valuable diagnostic tool for assessing blood flow in the retina and choroid and detecting the presence of macular arteriolar occlusive disease, retinal microvascular occlusions or peripheral vascular remodelling (3, 8).
Another investigation is the spectral domain OCT which is used to reveal temporal to the fovea areas of inner retinal thinning, temporal inner retinal hyperreflectivity and temporal macular atrophy which is connected with peripheral neovascularization (8).
Furthermore, OCTA (OCT and angiography) is a gold standard investigation for determining whether there are any areas of retinal ischemia (8).
Differential Diagnosis
Other diseases could cause macular ischemia or peripheral retinal neovascularization. It is essential to determine if a patient suffers from sickle cell disease to help rule out other conditions. Some of them that could cause macular ischemia are diabetic retinopathy, retinal vascular occlusion or embolization and infectious retina diseases, for example; dengue (9).
The diseases that cause peripheral retinal neovascularization, vitreous haemorrhage, retinal detachment and some ischemic vascular diseases such as; proliferative diabetic retinopathy, branch retinal vein occlusion, ocular ischemic syndrome, retinopathy of prematurity, Eales’ disease, and chronic myelogenous leukaemia (7).In addition, some inflammatory diseases which could cause ischemia; for example, sarcoidosis, retinal vasculitis, intermediate uveitis and acute retinal necrosis (7). Miscellaneous diseases are incontinentia pigmenti, retinitis pigmentosa, autosomal dominant vitreoretinochoroidopathy and scleral buckle (7, 9).
Treatment and prevention
Screening
People who suffer from sickle cell disease should undergo an eye screening at a young age. For patients with HbSC genotype, screening should start at the age of 9, whereas for those with HbSS and HbS beta-thalassemia genotype at the age of 13 (8). People without abnormal findings are suggested to have an eye examination every 2 years, while people with signs of sickle cell retinopathy should be followed depending on their severity (8).
Systemic
Treatments that could increase the production of foetal haemoglobin, such as; the use of hydroxycarbamide in children, could reduce the risk of developing sickle cell retinopathy (3).
Anti-vascular endothelial growth factors (VEGF)
Treatment with intravitreal injection of anti-vascular endothelial growth factors could reduce the neovascularization similarity as in proliferative diabetic retinopathy (9).
Laser photocoagulation
Scatter photocoagulation is suggested to the sea fans, which are not auto-infarct, to prevent vitreous haemorrhage and retinal detachment (9).
Vitreoretinal surgery
This is indicated in cases of tractional retinal detachment and persistent non-clearing vitreous haemorrhage (1, 3). It is crucial intraoperatively to provide the patient with adequate oxygen and hydration to prevent an episode of sickle cell crisis (3). Furthermore, a scleral buckle needs to be used carefully to avoid anterior segment ischemia (1).
Conclusion
Severe sickle cell disease is more frequently found in people with sickle cell genotype HbSC. Patients could have severe proliferative changes in the periphery which do not affect their vision until a vitreous haemorrhage or retinal detachment occurs. This could be prevented with regular screening at a very young age. Furthermore, scatter laser to the non-auto infarcted sea fans is one of the recommended treatments to minimize the risks of vitreous haemorrhage and retinal detachment.
References
1. Salmon JF. Kanski’s Clinical Ophthalmology: A Systematic Approach. 10th ed.
2. Feroze KB, Azevedo AM. Retinopathy Hemoglobinopathies. 2017.
3. Sambhara D. Sickle Cell Retinopathy American Academy of Ophthalmology2024 [Available from: https://eyewiki.org/Sickle_Cell_Retinopathy.
4. Scott AW. Ophthalmic manifestations of sickle cell disease. South Med J. 2016;109(9):542-8.
5. Abad LE, Mauro CRG, Andres BR, Exequiel B. Diagnosis and Treatment of Hemoglobinopathy and Retinopathy of Sickle Cells. International Journal of Research. 2018;3(11):20-3.
6. Goldberg MF. Classification and pathogenesis of proliferative sickle retinopathy. American journal of ophthalmology. 1971;71(3):649-65.
7. Bonanomi MTBC, Lavezzo MM. Sickle cell retinopathy: diagnosis and treatment. Arquivos Brasileiros de Oftalmologia. 2013;76:320-7.
8. Menaa F, Khan BA, Uzair B, Menaa A. Sickle cell retinopathy: improving care with a multidisciplinary approach. Journal of multidisciplinary healthcare. 2017:335-46.
9. Abdalla Elsayed ME, Mura M, Al Dhibi H, Schellini S, Malik R, Kozak I, Schatz P. Sickle cell retinopathy. A focused review. Graefe’s Archive for Clinical and Experimental Ophthalmology. 2019;257:1353-64.