revised May 22, 2000

J.B. Harlan, Jr. M.D.
Morton F. Goldberg M.D.


 Management and Therapy of Eye Disorders in Sickle Cell Disease

Detection of Eye Disease

Sickle cell vaso-occlusive events can affect every vascular bed in the eye, often with visually devastating consequences in advanced stages of the disease. Since early stages of sickle cell eye disease do not usually result in visual symptoms, the disease can go undetected unless a formal eye exam is performed by an ophthalmologist. The examination should include an accurate measurement of visual acuity, assessment of pupillary reactivity, careful evaluation of the anterior structures of the eye using a slit-lamp biomicroscope, and a thorough examination of the posterior and peripheral retina through a dilated pupil. Patients with sickle hemoglobinopathies should have yearly eye examinations beginning in childhood.

Clinical Findings in Sickle Cell Eye Disease

The clinical manifestations of sickle hemoglobinopathies are grouped according to the presence or absence of neovascularization in the eye. The distinction is clinically relevant because proliferation of new blood vessels on the retina is the key biological event that sets the stage for progression to vitreous hemorrhage and retinal detachment.

Non Proliferative Disease

Non-neovascular or "non-proliferative" ocular manifestations of sickle hemoglobinopathies include conjunctival vascular occlusions which transform smooth vessels into comma-shaped fragments (Paton), iris atrophy (Chambers; Galinos), retinal "salmon patch" hemorrhages (Gagliano & Goldberg), retinal pigmentary changes (Asdourian; Goldberg) and other abnormalities of the retinal vasculature, macula, choroid, and optic disc (Nagpal, Goldberg, & Rabb). These clinical findings are readily apparent on dilated ophthalmoscopy and all occur due to local vaso-occlusive events but rarely have visual consequences.

Proliferative Disease

Progression to neovascularization or to the "proliferative" stage involves the growth of abnormal vascular fronds which predispose to vitreous hemorrhage and retinal detachment. The initiating event in the pathogenesis of proliferative disease is thought to be peripheral retinal arteriolar occlusions. Local ischemia from repeated episodes of arteriolar closure is presumed to trigger angiogenesis through the production of endogenous vascular growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) (Cao et al; Aiello). Goldberg has defined five stages of proliferative retinopathy. In stage I, peripheral arteriolar occlusion is present. In stage II, vascular remodelling occurs at the boundary between perfused and nonperfused peripheral retina with the formation of arteriovenous anastomoses. In stage III, actual pre-retinal neovascularization occurs. The neovascular fronds typically assume a shape that resembles the marine invertebrate Gorgonia flabellum, known more commonly as the "sea fan". Stage IV is defined by the presence of vitreous hemorrhage, and stage V is defined by the presence of retinal detachment, which results from mechanical traction created by chronic, enlarging fibrovascular retinal membranes, with or without hole formation in the retina.

Although peripheral vaso-occlusion may be observed as early as 20 months of age (McLeod), clinically detectable retinal disease is found most commonly between 15 and 30 years of age (Condon & Serjeant). Sickle retinopathy is more common in HbSC disease but can also occur in Hb SS disease and HbSthal (Condon & Serjeant). Observational cohort studies have also shown that stage IV and stage V retinopathy occur more often in HbSC subjects than in those with HbSS (Condon & Serjeant; Clarkson). It is a paradox that despite the less dramatic systemic consequences of their disease, subjects with HbSC and HbSthal are more likely than HbSS patients to have serious ocular manifestations. Current research has not yet been able to explain the reason for this profound discrepancy in the severity of the retinal and systemic manifestations among the various sickle hemoglobinopathies.

Diagnosis of the proliferative retinopathy requires examination through a dilated pupil utilizing wide field indirect ophthalmoscopy Evaluation of retinal blood flow is performed with fluorescein angiography. Any patient identified with retinopathy should be followed by an ophthalmologist who specializes in diseases of the retina.

Methods of Treatment

Treatment is reserved for eyes which have progressed to proliferative retinopathy and are thus at risk for severe visual loss from bleeding and retinal detachment. Given the high rate of spontaneous regression and/or lack of progression of neovascularization in some eyes, the indications for treatment of retinal neovascularization are not always clear. Therapeutic intervention is usually recommended in cases of bilateral proliferative disease, spontaneous hemorrhage, large elevated neovascular fronds, rapid growth of neovascularization, or cases in which the fellow eye has already been lost to proliferative retinopathy. The goal is early treatment aimed at inducing regression of neovascular tissue before progression to bleeding and retinal detachment. Techniques such as diathermy, cryotherapy and laser photocoagulation have all been used to cause involution of neovascular lesions. Of all of these methods, laser photocoagulation has the fewest side effects. Specific methods of laser application include direct coagulation of feeder vessels, local scatter photocoagulation with and without focal ablation of the neovascular frond, and 360 degree peripheral scatter delivery. Both feeder vessel ablation and sector scatter laser photocoagulation have been shown to be effective in controlled clinical trials (Farber; Jacobson), but complications associated with the high power settings used in feeder vessel treatment have pushed modern clinicians towards local scatter photocoagulation (Jampol). Heavy feeder vessel photocoagulation is usually reserved only for recalcitrant cases with repetitive bleeding. In cases of unreliable patients where compliance with follow-up is suspect, local scatter treatment may be replaced by more extensive 360 degree peripheral treatment, but there is no clear evidence that the outcome from this technique is any better than either the natural course of untreated disease or local scatter photocoagulation to neovascular fronds (Goldberg; Rednam).

If retinal detachment and/or non-clearing vitreous hemorrhage is present, surgical intervention is usually required. Surgical techniques include vitrectomy with or without the placement of a scleral buckle. Although modern vitreoretinal microsurgery can improve vision for many patients with advanced sickle retinopathy, it should be emphasized that surgery carries a significant risk of intraoperative and postoperative complications, including severe ocular ischemia, recurrent hemorrhage and elevated eye pressure(Cohen). In order to minimize the risk of such complications, partial exchange transfusion has been recommended prior to surgery (Brazier), usually with a target of about 50%-60% normal red cells, but there has never been a controlled study demonstrating the efficacy of this maneuver (Charache). Exchange transfusion is also not without its own risks, including various immune-mediated transfusion reactions as well as transmission of infectious diseases such as HIV and hepatitis. When considering an exchange transfusion, a thorough discussion of the risks and benefits should take place. An alternative to exchange transfusion is the use of a hyperbaric chamber to increase blood oxygenation (Freilich), but such equipment is neither convenient nor widely available. In any event, intra-operative and post-operative hyper-oxygenation is indicated in an attempt to reduce the risk of anterior segment ischemia and necrosis.

Indications for Emergent Ophthalmologic Consultation

Immediate consultation with an ophthalmologist trained in the management of retinal disease is required for any individual with a sickle hemoglobinopathy, including sickle trait, who sustains eye trauma. Anterior segment trauma may result in hemorrhage into the anterior chamber of the eye, allowing sickled erythrocytes to clog the trabecular outflow channels and raise the eye pressure. The aqueous humor, with its relatively low oxygen tension and pH, and its high level of ascorbate, serves to further enhance sickling, which in turn leads to sequestration of blood cells in the aqueous humor along with further acidification and deoxygenation of the anterior chamber, fueling a viscious cycle of sickling, erythrostasis and elevation of the eye pressure (Goldberg, Dizon & Moses). In patients with sickle hemoglobinopathies, only a moderate increase in eye pressure may cause a significant reduction in perfusion of the optic nerve and retina, putting the eye at risk for ischemic optic atrophy and retinal artery occlusion. In such instances patients may require an emergent surgical washout of the anterior chamber.

Trauma considerations aside, any sickle patient with an acute change in vision should always be immediately referred to an ophthalmologist for a full evaluation.

Summary of the State of the Art

The clinical features of sickle cell eye disease are well known and have been abundantly described in the clinical literature. Ideally, treatment should be initiated at stage III before progression to vitreous hemorrhage and/or retinal detachment has occurred. Regional scatter laser photocoagulation to ischemic retina adjacent to neovascular tissue by a retina specialist is the preferred treatment (Level II Evidence). Direct feeder vessel photocoagulation is also effective (Level II Evidence) but should only be employed if scatter treatment has failed to induce regression of the neovascular tissue, due to the higher likelihood of complications such as retinal detachment and neovascular growth from the choroid into the vitreous. For the more advanced stages of non-clearing vitreous hemorrhage and retinal detachment, modern vitreoretinal microsurgical techniques are employed. Potential risks and benefits of pre-operative exchange transfusion must be carefully weighed in the context of the individual patient.


Begininng in childhood, all patients with sickle hemoglobinopathies should have yearly dilated examinations by an ophthalmologist with expertise in retinal diseases. Any patient with a sickle hemoglobinopathy who experiences a change in vision should be referred for ophthalmologic consultation immediately. Central retinal artery occlusion, an event which usually results in permanent, devastating loss of vision, is one of the few bona fide ophthalmic emergencies which demands intervention within minutes to hours after the onset of symptoms. Treatment consists of hyperoxygenation combined with rapid reduction of eye pressure utilizing surgical and medical techniques. Vision loss from hemorrhage and/or retinal detachment also calls for urgent care, but, unlike acute vascular occlusion, can be appropriately addressed within 24 to 48 hours. We also recommend that any sickle patient who sustains ocular or periocular trauma be examined immediately by an ophthalmologist, specifically due to the increased risk of visual loss from elevated eye pressure associated with hemorrhage into the anterior chamber (hyphema).

Future Horizons

A potentially more elegant method of laser ablation of neovascular tissue called "laser targeted photo-occlusion" is currently under study in animal models. This method involves intravascular delivery of a photosensitizing compound which is packaged in heat sensitive liposomes. After injection of encapsulated photosensitizer, precise focal laser irradiation is delivered to neovascular fronds, raising their temperature. The mild temperature increase causes a phase transition in the liposomes, resulting in local release of the photosensitizing compound. Laser energy is then used to excite the unencapsulated photosensitizer , creating vessel occlusion through non-thermal damage (Asrani; Zeimer).

Significant resources also continue to be directed towards the study of angiogenesis along with the search for potential anti-angiogenic agents (Aiello; Auerbach; Cao; Fan; ).

Links to additional information on opthalmological disorders in sickle cell disease.

Selected References

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