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C-55300

Sickle cell eye disease

This article describes the clinical features of sickle cell disease and outlines the ocular abnormalities associated with this condition.

Introduction 

Sickle cell disease (SCD) is an inherited blood disorder that specifically affects haemoglobin in red blood cells. The disease is characterised by chronic anaemia, acute painful episodes and various systemic complications affecting multiple organs in the body, including the eyes. This article will provide an overview of SCD and the ocular abnormalities associated with it.

Epidemiology

The prevalence of SCD is greatest in the tropical regions of the world such as Africa, India, the Mediterranean and the Middle East. Recently, the incidence of SCD in other parts of the world such as Europe has significantly increased due to population migration from high prevalence areas.1,2 In England, SCD affects one in every 2000 live births. There are an estimated 240,000 carriers of the condition and between 12,000 to 15,000 individuals with the disease.3–4

Figure1

Aetiology

Haemoglobin is an iron containing globular protein that enables red blood cells to transport oxygen. It consists of two alpha polypeptide chains which pair with either two beta, gamma or delta chains to produce haemoglobin A, haemoglobin A2 and haemoglobin F, respectively. The haemoglobin predominantly found in adult circulation is haemoglobin A (HbA). SCD is caused by a single point mutation at the sixth position in the beta-polypeptide chain of haemoglobin A. This single genetic mutation results in the synthesis of an abnormal variant of haemoglobin A known as sickle haemoglobin S (HbS), which alters the physiological properties of red blood cells.5

Genetics

SCD is an inherited autosomal recessive disease. Every individual inherits two copies of a ‘haemoglobin gene,’ one from each of their parents. Individuals who inherit one copy of the altered gene and one normal gene are referred to as carriers of the disease and will have the genotype AS (heterozygous); these individuals will have sickle cell trait and are either asymptomatic or have only mild symptoms of the disease. Those that inherit two copies of the altered gene have the genotype SS (homozygous); these individuals will have sickle cell anaemia – the most severe form of SCD – and are at greatest risk from life threatening complications. 

Other factors that can influence the severity of SCD include the inheritance of any additional abnormal haemoglobin genes such as those for haemoglobin C and thalassaemia. Haemoglobin C disease is another type of haemoglobinopathy that also produces structurally abnormal haemoglobin. On the other hand, thalassaemia is associated with a reduced or absent production of normal alpha- or beta-polypeptide chains. Individuals who inherit haemoglobin S with either haemoglobin C or thalassaemia will have mixed heterozygous genotypes known as sickle cell C disease (SC) or sickle cell thalassaemia (SThal). These are usually considered less severe than sickle cell anaemia but more severe than sickle cell trait. The severity of SCD is, therefore, variable due to the different genotypes that are possible.6,7

Figure 2

Pathophysiology 

Red blood cells are normally round and flexible, which enables them to deform and pass through narrow vessels such as arterioles and capillaries. In patients with SCD the abnormal haemoglobin undergoes conformational changes during conditions of hypoxia, acidosis and dehydration, changing the red blood cells into rigid sickle (crescent-shaped) cells (see Figure 1: Sickle cell disease. Image by Diana Grib (2015). Distributed under Creative Commons BY-SA 4.0 license, Wikipedia Online). The rigidity of these sickled red blood cells and their interaction with vessel walls prevents their passage through narrow 
vessels, causing them to aggregate forming small plugs and impede the flow of blood. Red blood cells are, therefore, unable to deliver a sufficient supply of oxygen to the local tissue resulting in hypoxia and tissue acidosis; this causes greater sickling, increased blood viscosity and a further reduction in blood flow which ultimately leads to vaso-occlusions, ischaemia and tissue infarction. This can cause severe pain and permanent damage to vital organs such as the brain, heart, lungs, kidneys, liver, bones, spleen and eyes.8 

The sickle red blood cells are also prone to haemolysis. Normal red blood cells typically function for 90–120 days but sickle cells only last 10–20 days. The bone marrow attempts to compensate by creating new red blood cells, but it is unable to match the rate of destruction. As a result, the bloodstream is chronically short of red blood cells and haemoglobin, and the affected individual develops anaemia.9 

Clinical features 

SCD typically manifests early in childhood. It has the potential to cause both acute and chronic complications throughout an individual’s lifetime, most of which have a high morbidity and mortality rate.10 A common clinical feature is severe pain affecting the limbs, chest or abdomen which frequently requires hospitalisation 
due to intolerable pain. Other complications include stroke, breathing difficulties, kidney failure, jaundice, gallstones, leg ulcers, avascular necrosis, delayed growth, priapism and an increased risk of infection. Children with SCD are particularly susceptible to infections because their spleens are often damaged and unable to protect the body from bacteria. In the UK it is usually diagnosed at birth by the heel prick test, a national screening test that is offered to all newborns.11 Patients with established SCD are usually on long-term treatment plans that include prophylactic antibiotics, folic acid supplementations, and vaccinations against pneumococcus bacteria. Patients that develop severe SCD will often require additional treatments such as hydroxyurea, pain management, intravenous fluids, blood transfusion and surgery. Like all patients with a chronic disease these patients are best managed in a comprehensive multi-disciplinary programme of care.12 

Figure 3

Ocular manifestations of sickle cell disease 

In recent years, the life expectancy of SCD patients has increased due to improvements in medical treatment. However, this has led to an increase in ocular complications, which in the past were uncommon. SCD can cause a number of ocular abnormalities affecting almost all structures of the eye. Generally speaking, patients with the genotypes SC or SThal are the most likely to have severe ocular complications, while those with the genotype SS have the greatest incidence of systemic complications.13 The ocular changes associated with SCD may be summarised as follows: 

Anterior segment: 
  • Comma-shaped conjunctival vessels 
  • Focal iris atrophy 
  • Anterior chamber flare 
  • Hyphema. 
Posterior segment – non-proliferative sickle cell retinopathy: 
  • Tortuous vessels 
  • Cotton wool spots and microaneurysms 
  • Salmon-patch haemorrhages 
  • Black sunbursts 
  • Sickle maculopathy 
  • Macular depression sign 
  • Optic disc sign 
  • Angioid streaks 
  • Central/branch retinal artery occlusions 
  • Ischaemic optic neuropathy.
Posterior segment – proliferative sickle cell retinopathy: 
  • Stage 1: Peripheral arteriolar occlusions 
  • Stage 2: Peripheral arteriovenous anastomoses 
  • Stage 3: Neovascularisation – sea fans 
  • Stage 4: Vitreous haemorrhage 
  • Stage 5: Retinal tears and detachments.

Anterior eye disease

A classic abnormality frequently seen in the anterior segment of the eye is ‘comma-shaped’ conjunctival vessels. The vessels appear as short, truncated, isolated, dark vascular segments, which typically appear in the inferior bulbar conjunctiva. The comma shape is due to the accumulation of sickled red blood cells at the distal end of the capillaries; the severity of this sign correlates closely with the severity of the systemic disease.14 

Examination of the iris may reveal areas of focal iris atrophy and pupillary irregularities, and is representative of anterior uveal ischaemia.15 Occasionally a mild cell and flare like reaction can be seen in the anterior chamber, which is thought to be due to disruptions in the blood-ocular barrier. These anterior segment manifestations usually pose little risk to loss of vision.

The presence of a hyphema in a sickle cell patient on the other hand does warrant serious attention. The environment of the anterior chamber promotes sickling of the abnormal red blood cells, which can lead to blockage of the trabecular meshwork and elevation of intraocular pressure (IOP). Sickle cell patients exhibit a particularly poor tolerance to increased IOP with optic nerve damage occurring at milder elevations. Patients with SCD, therefore, require a much more aggressive management of IOP.16 The use of carbonic anhydrase inhibitors, hyperosmotic agents and adrenergic agonists should be used with caution as these classes of medications can promote further sickling. The use of beta blockers and prostaglandin analogues are safer alternatives. If the IOP cannot be lowered with medication alone, surgical approaches such as an anterior chamber paracentesis or a trabeculectomy may be required.17

Figure 4

Posterior eye disease 

The most significant ocular changes tend to occur in the posterior segment of the eye and can occur in the vitreous body, optic disc, retina and subretinal structures. These changes can be broadly split into two groups: non-proliferative sickle cell retinopathy (NPSR); and proliferative sickle cell retinopathy (PSR).18 The frequency of retinopathy is greatest in adulthood, affecting up to 42% of patients during the second decade.19 However, it can also occur in children.20

Non-proliferative sickle cell retinopathy

Retinal blood vessels typically appear tortuous, with most vascular occlusions associated with sickle retinopathy arising in the periphery of the retina where the vessels are narrowest. Intraretinal haemorrhages occur when aggregated sickled red blood cells abruptly occlude an arteriole, resulting in ischaemic necrosis and ‘blowout’ of the vessel wall. These lesions typically appear round or oval in shape and adjacent to a retinal arteriole. The haemorrhage usually remains confined within the 
superficial sensory retina but it can extend beneath the internal limiting membrane and possibly the subretinal space, where it can produce changes in the retinal pigment epithelium (RPE). Initially, the haemorrhage has a bright-red appearance. As the blood begins to resorb, it takes on a peach or salmon colour, known as the ‘salmon patch’. Over time, the haemorrhage is fully resorbed leaving behind iridescent spots of haemosiderin and macrophage deposition at the level of the internal limiting membrane. Disturbance of the retinal pigment epithelium results in secondary migration and proliferation of RPE, which leads to the development of ‘black sunburst spots’ (see Figure 2: Fibrovascular growth (on left of photo) and a black sunburst (on the right of the photo) Image by Steven Cohen (2011), Retina Gallery). Cotton wool spots and microaneurysms may also be seen.21–23 

Sickle cell maculopathy occurs as a result of chronic changes in the perifoveal capillary network. It is present in 10–40% of patients. Ischaemic changes are chronic and insidious, and patients are often asymptomatic. Normal visual acuity can remain despite a greatly enlarged foveal avascular zone.24 In addition to the presence of an enlarged foveal avascular zone is the macular depression sign; this represents atrophy and thinning of the inner retinal layers which can be seen with optical coherence tomography (OCT) and may be associated with a reduction in vision (see Figure 3: OCT showing foveal atrophy. Image by Steven Cohen (2012), Retina Gallery).25,26 

Examination of the optic disc may reveal signs of sludging of the red blood cells within the prepapillary retinal capillaries; this will appear as dark-red intravascular spots on the surface of the optic disc and is often referred to as being the optic disc sign. These changes can often be seen with fluorescein angiography. The occlusions are transient and do not produce any visual impairment.27,28 

Angioid streaks are often associated with SCD and are thought to be the result of vessel occlusions in the choroidal circulation and associated breaks in Bruch’s membrane (see Figure 4: Angioid streaks. Image by Steven Cohen (2010), Retina Gallery). Other ocular complications, which are infrequent include: central retinal artery occlusion (CRAO); branch retinal artery occlusion (BRAO), and ischaemic optic neuropathy.29–31 

Figure 5

Proliferative sickle cell retinopathy 

PSR is the most frequent vision-threatening complication of SCD leading to visual impairment in 10–20% of affected eyes. For patients with the SC or SThal genotype, the risk of developing PSR is highest between the ages of 15–24 for male patients and 25–39 for female patients. For those with the SS genotype, the risk is greatest between the ages of 25–39 for both sexes.13 

The initiating event in the pathogenesis of proliferative disease is thought to be peripheral retinal arteriolar occlusions. Retinal arterioles that become permanently occluded typically have a silver wire appearance. Blood is diverted from the occluded arterioles into the adjacent venules by a process known as arteriolar-venular anastomosis. Locally affected arterioles appear particularly tortuous and the capillaries dilated. Fluorescein angiography is often useful in identifying the areas of retinal vessel non-perfusion and arteriovenous anastomosis.32 

Repeated episodes of arteriolar occlusion and local ischaemia triggers angiogenesis through the production of endogenous vascular growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF).33 New vessel formation occurs at the junctions between the vascular and avascular retina, most commonly found in the superotemporal followed by the inferotemporal quadrants. Neovascularisation at the optic disc is rare.34 The neovascular growths typically produce a sea fan shape, similar to the marine invertebrate Gorgonia flabellum (see Figure 5: Fluorescein angiogram showing peripheral sea fan formations. Image by Steven Cohen (2015), Retina Gallery). Initially, the sea fan growths are supplied by a single arteriole and draining vessel. Later, as the sea fans grow in size and acquire fibrotic tissue envelopes, it becomes more difficult to distinguish the major feeding and draining vessels. The majority of sea fans will eventually then regress spontaneously by auto-infarction due to the thromboembolic nature of sickle cell disease.35 The neovascular tissue is fragile and prone to bleeding, resulting in vitreous haemorrhages. It is estimated that 23% of SC patients and 3% of SS patients will have retinal neovascularisation with a subsequent vitreous haemorrhage.36 In the final stage of PSR, persistent haemorrhages and mechanical traction created by fibrovascular retinal membranes can lead to full-thickness retinal breaks and rhegmatogenous retinal detachments.37

Treatment

The development of sickle cell retinopathy is usually insidious with few visual symptoms in the early stages. It is possible for the disease to go undiagnosed for quite some time unless a formal eye exam is performed or until the patient presents with advanced sight threatening complications. Patients with SCD should be recommended to have regular eye examinations so that retinal disease can be identified early.12

Patients presenting with non-proliferative changes and stable vision can be monitored in the majority of cases. Occasionally they might present with hyphema, central or branch retinal artery occlusions, or ischaemic optic neuropathy, in which case they require immediate referral to an ophthalmologist for treatment.

The majority of ocular treatment is directed towards preventing sight loss from vitreous haemorrhage and retinal detachment. Patients in the early stages of proliferative retinopathy, that is to say, stages 1 and 2, do not require treatment as studies have shown that treatment of the ischaemic retina does not appear to prevent the formation of sea fans, and many patients do not develop sea fans or its complications.38,39 Referral to an ophthalmologist for the consideration of treatment is indicated at stage 3 when patients present with signs of neovascularisation. Panretinal photocoagulation is the preferred method of intervention to cause regression of sea fan structures if they do not auto-infarct.40,41

In cases of non-clearing vitreous haemorrhages and retinal detachments, intraocular surgery is usually required. Pars plana vitrectomy is the preferred procedure in most cases but there is a high rate of intraoperative and postoperative complications in patients with sickle cell disease.42

Recently, researchers have investigated the role of anti-vascular endothelial growth factor (anti-VEGF) therapies such as intravitreal bevacizumab and ranibizumab to prevent the progression of neovascularisation in SCD. However, there are too few studies at present to comment on their effectiveness.43,44

Conclusion

SCD can produce a wide spectrum of ocular complications that vary in severity, from relatively benign to sight threatening. As clinicians, it is important that we are familiar with the ocular features of SCD so we can identify, manage, and refer these patients appropriately. 

About the author

Mark Petrarca MCOptom is an optometrist currently undertaking medical and surgical training at St Bartholomew’s and the Royal London School of Medicine and Dentistry.

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