Continuing Education Activity

The World Health Organization estimates that about 7 percent of the world’s population are carriers of hemoglobinopathies and about 300,000 to 400,000 babies are born every year with a severe form of hemoglobinopathy. Hemoglobinopathies are genetic disorders characterized by either abnormal hemoglobin, as in sickle cell disease, or insufficient production of hemoglobin chains, as in thalassemia. Proliferative sickle cell retinopathy is the most serious vision-threatening complication of sickle cell disease and is reportedly seen in 0.5 percent of patients with HbSS disease, the severe variant of sickle cell disease and about 2.5 percent of patients with HbSC disease, a less severe variant of sickle cell disease. The frequency of ocular involvement in patients with beta-thalassemia ranges from 41.3 to 85 percent, according to studies. This activity describes the causes, pathophysiology, and presentation of hemoglobinopathy-associated retinopathy and highlights the role of the interprofessional team in the care of affected patients.

Objectives:

• Describe diseases associated with retinopathies.
• Describe sickle cell retinopathy.
• Describe the forms of retinopathy seen in patients with thalassemia major and intermedia.
• Members of the interprofessional team should ensure that patients with hemoglobinopathies are referred to ophthalmologists for assessment of visual function; these patients need close monitoring for visual deficits.

Introduction

Hemoglobinopathy refers to genetic disorders which are characterized by the inheritance of either an abnormal hemoglobin as in sickle cell disease or an insufficient production of hemoglobin chains as in thalassemia. 

James Herrick first described sickle cell disease from observing the peripheral smear of a West Indian patient. The ocular manifestations of sickle cell disease were described by Cook in 1930 when he noticed retinal hemorrhages in a patient who died of subarachnoid hemorrhage.

A Detroit physician who was studying Italian children with severe anemia, poor growth, and early death first discovered thalassemia in 1925. Ocular involvement in beta thalassemia can occur because of the disease itself, because of the iron overload as a result of blood transfusions, or because of desferrioxamine used to treat the iron overload.[1][2][3]

Etiology

Sickle cell disease occurs due to a point mutation at the six position of the beta globin chain where valine replaces glutamic acid, producing HbS (sickle hemoglobin). Sickle cell disease is characterized by chronic hemolytic anemia and has different variants such as the homozygous form (HbSS disease) or the heterozygous forms characterized by the combination of Hemoglobin S and HbC (HbSC disease) or Hemoglobin S and beta thalassemia (HbS beta-thalassemia) and other rare variants. Although individuals with the HbSS genotypes are more prone to systemic complications of sickle cell disease, those with HbSC genotype are more prone to develop sickle cell retinopathy and at risk of visual loss. [4][5]

Beta thalassemia is a condition characterized by insufficient production or absence of beta globin chains, due to beta plus or beta mutations. Homozygosity for a beta mutation causes beta thalassemia major. The absence of one of the alpha-globin chains causes alpha thalassemia.

Epidemiology

The World Health Organization (WHO) estimates that about 7% of the world’s population are carriers of hemoglobinopathies and about 300,000 to 400,000 babies are born every year with a severe form of these disorders. Proliferative sickle cell retinopathy is considered the most serious vision-threatening complication of sickle cell disease and is reportedly seen in 0.5% of patients with HbSS disease and about 2.5% of patients with HbSC disease. The frequency of ocular involvement in beta-thalassemia was found to be 41.3% to 85% in various studies.

Pathophysiology

In sickle cell disease, polymerization of HbS occurs under conditions of hypoxia, leading to aggregation of the stiff HbS molecules, damaging the RBC cell membrane and cytoskeleton, and producing the characteristic sickle-shaped red blood cells. These sickle-shaped red blood cells are rigid and less deformable. They have a longer transit time across the capillaries of the retina and choroid and increased endothelial adhesion, causing damage to the blood vessels. The endothelium is thought to produce adhesion molecules, and there is also the release of inflammatory mediators, all of which produce vascular occlusion. Repeated vaso-occlusive episodes presumably lead to the production of angiogenic factors such as vascular endothelial growth factor and fibroblast growth factor, which subsequently give rise to proliferative retinopathy.

Thalassemia is characterized by the absent or reduced production of hemoglobin chains, leading to inefficient erythropoiesis, which itself can cause ocular damage. However, iron overload due to repeated transfusions and iron chelators can also add on to the ocular damage.[6][7][8]

History and Physical

Sickle cell retinopathy is the most common ocular manifestation of sickle cell disease.[9] [10]Most patients with sickle cell disease are asymptomatic as sickle cell retinopathy tends to involve the retinal periphery. Sickle cell retinopathy can be classified as nonproliferative and proliferative. Nonproliferative sickle retinopathy (NPSR) is characterized by the presence of salmon patches, iridescent spots, and black sunbursts. Salmon patch hemorrhages are caused by sudden occlusion and rupture of a medium sized arteriole by sickled red blood cells. The hemorrhage is located between the retinal layers and the internal limiting membrane. Over time, the color changes from bright red to orange and later, yellow or white. Ultimately, the salmon patch resolves, giving rise to an area of the atrophic retina or a scar or a schisis cavity containing iridescent spots. An iridescent spot is thought to represent hemosiderin-laden macrophages that are a remnant of hemorrhage absorption. Black sunbursts are circular chorioretinal scars characterized by retinal pigment epithelium (RPE) hypertrophy which occurs either as a response to hemorrhage or choroidal neovascularization. All the previously mentioned signs are seen in the peripheral retina, but certain changes may be seen in the posterior pole including venous tortuosity, enlarged foveal avascular zone (FAZ), macular thinning, central retinal artery occlusion (CRAO), occlusion of peripapillary and perivascular arterioles. Patients with sickle cell thalassemia have also been reported to have angioid streaks that occur probably due to the chronic hemolytic anemia leading to iron deposition in Bruch's membrane and subsequent crack formation.

Proliferative sickle retinopathy (PSR) is the main cause of visual loss in patients with sickle cell disease. It is characterized by neovascularization, which may be active or it may be inactive and fibrotic. The neovascularization is usually confined to the peripheral retina and has been described by Goldberg to be frequently confined to one quadrant. Neovascularization may be complicated by vitreous hemorrhage and retinal detachment. Goldberg has defined five stages of proliferative sickle retinopathy:

• Stage 1 Peripheral arteriolar occlusion
• Stage 2 Peripheral arteriovenous anastomoses
• Stage 3 Actual retinal neovascularization occurs, with a shape resembling the marine invertebrate, Gorgonia flabellum, hence called sea fan.
• Stage 4 Vitreous hemorrhage
• Stage 5 Retinal detachment, which can be tractional or rhegmatogenous, due to mechanical traction by the fibrovascular membranes. 

A characteristic feature of proliferative sickle retinopathy is the phenomenon of auto infarction of sea fans, seen in up to 20% to 60% of cases. It is caused by chronic and repetitive vascular occlusions in the blood vessels of the sea fan. This can lead to spontaneous resolution of the neovascularization without any sequelae.

Individuals suffering from thalassemia major and intermedia can develop two kinds of retinal abnormalities which are pseudoxanthoma elasticum-like retinal abnormalities and non-pseudoxanthoma elasticum-like retinal abnormalities.[11][12] Pseudoxanthoma elasticum-like lesions include Peau d’Orange, angioid streaks, and optic disc drusen. Peau d’orange consists of small, confluent dark yellow lesions at the retinal pigment epithelium level. Angioid streaks are characterized by irregular breaks in the Bruch’s membrane. Although characteristically asymptomatic, they may lead to visual symptoms if they involve the macula or are complicated by neovascularization. Non-pseudoxanthoma elasticum-like abnormalities, causing retinal pigment epithelium degeneration, resulting in a hypertrophic, autofluorescent and dysplastic retinal pigment epithelium. Desferrioxamine mesylate is an iron chelator used to treat Iron overload. However, it can cause ocular toxicity manifested by retinal pigment epithelium changes. Desferrioxamine (DFO) retinopathy can cause symptoms like reduced visual acuity and visual field, impaired night vision, and signs of retinal pigment epithelium degeneration. There may be retinal pigment epithelium opacification, pigmentary changes, optic disc edema, and atrophy.

Evaluation

All patients with sickle cell disease should be referred to the ophthalmologist for detailed peripheral retinal examination by indirect ophthalmoscopy through a dilated pupil. This should be repeated annually from the age of 10 years. Fluorescein angiography is the ideal investigation for evaluation of retinal blood flow and detection of neovascularization. OCT may help reveal areas of macular thinning. 

Annual fundus examinations after the second decade are recommended in all patients with thalassemia. Those with angioid streaks require close follow up with fundoscopy and fluorescein angiography for early detection and appropriate management of choroidal neovascularization. Patients with suspected DFO retinopathy may be evaluated by fluorescein angiography, OCT, Microperimetry, ERG, and EOG, all of which show signs of widespread damage. A key examination in DFO retinopathy is fundus autofluorescence, which may be abnormally increased or decreased bilaterally and correlates with the extent of RPE damage.

Treatment / Management

There exists no treatment to prevent the development of sickle cell retinopathy. Individuals suffering from thalassemia major and intermedia can develop two kinds of retinal abnormalities which are pseudoxanthoma elasticum-like retinal abnormalities and non-pseudoxanthoma elasticum-like retinal abnormalities Therapeutic intervention is suggested in cases of stage 3 (especially in the case of large sea fans),  stage 4 and stage 5 proliferative sickle retinopathy. Laser photocoagulation is the mainstay of treatment, and intravitreal anti-vascular endothelial growth factor injections are another option. Nonclearing vitreous hemorrhages require a vitrectomy, and retinal detachment requires vitrectomy or scleral buckling.

Thalassemia patients require regular ophthalmic screenings for early detection of retinopathy. Newer chelating agents like oral deferiprone have much lesser adverse effects compared to desferrioxamine, and careful monitoring can prevent most of them.

Differential Diagnosis

• Acute complications of sarcoidosis

• Branch retinal vein occlusion

• Central retinal vein occlusion

• Chronic kidney disease

• Colonic polyps

• Eales disease

• Hypertension

• Retinopathy of prematurity

• The systemic lupus erythematosus(SLE)

Pearls and Other Issues

Sickle cell retinopathy, especially proliferative sickle retinopathy, is considered the commonest cause of loss of vision in sickle cell disease. The best method to prevent the development of devastating complications of proliferative sickle retinopathy is regular dilated peripheral retinal examinations. Patients should be educated regarding the importance of regular ophthalmological examinations. Patients should also be instructed to consult an ophthalmologist if they notice any changes in vision. 

Close follow-up and annual retinal examinations are also required in patients with thalassemia to prevent and detect any complications before permanent damage occurs. Educating the patient will go a long way in this direction.

Enhancing Healthcare Team Outcomes

Healthcare workers including pharmacists and nurses should refer patients with hemoglobinopathies to ophthalmologists for assessment of visual function. Even though there are no treatments for early retinopathy caused by these blood disorders, the patients need close monitoring for visual deficits. Newer chelating drugs have been developed and in some cases may prevent worsening of the retinopathy.[13][14]