Management and Therapy of Sickle Cell Disease

revised May 22, 2000

Authors:
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.

Recommendations

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

Aiello LP. Clinical implications of vascular growth factors in proliferative retinopathies. Curr Opin Ophthalmol 1997; 8: 19-31.

Asdourian GK et al. Evolution of the retinal black sunburst in sickling haemglobinopathies. Br J Ophthalmol 1975; 59: 710-716.

Asrani S, Zeimer R. Feasibility of laser targeted photo-occlusion of ocular vessels. Br J Ophthalmol 1995; 79: 766-770.

Asrani S et al. Feasibility of laser-targeted photo-occlusion of the choriocapillary layer in rats. Inv Ophthalmol Vis Sci 1997; 38: 2702-2710.

Auerbach W, Auerbach R. Angiogenesis inhibition: a review. Pharm & Therapeutics 1994; 63: 265-311.

Brazier DH et al. Retinal detachment in patients with proliferative sickle cell retinopathy. Trans Ophthalmol Soc UK 1986; 105: 100-105.

Cao J et al. Angiogenic factors in human proliferative sickle cell retinopathy. Br J Ophthalmol 1999; 83: 838-846.

Carney MD et al. Iatrogenic choroidal neovascularization in sickle retinopathy. Ophthalmology 1986; 93: 1163-1168.

Chambers J et al. Iris atrophy in hemoglobin SC disease. Am J Ophthalmol 1974; 77: 247-249.

Charache S. Eye disease in sickling disorders. Hematol/Oncol Clin N Am 1996; 10: 1357-1362.

Clarkson JG. The ocular manifestations of sickle cell disease: a prevalence and natural history study. Tr Am Ophth Soc 1992; 90: 481-504.

Cohen SB, Fletcher MF, Goldberg MF, Jednock N. Diagnosis and management of ocular complications of sickle hemoglobinopathies. Ophthalmic Surg Part I- V 1986; 17: 57-374.

Condon PI, Serjeant GR. Photocoagulation in proliferative sickle retinopathy: results of a 5 year study. Br J Ophthalmol 1980; 64: 832-40.

Condon PI, Serjeant GR. Ocular findings in hemoglobin SC in Jamaica. Am J Ophthalmol 1972; 74: 921-931.

Condon PI, Serjeant GR. Ocular findings in sickle cell thalassemia in Jamaica. Am J Ophthalmol 1972; 74: 1105-1109.

Condon PI. Serjeant GR. Ocular findings in homozygous sickle cell anemia in Jamaica. Am J Ophthalmol 1972; 73: 533-543.

Condon PI, Serjeant GR. Ocular findings in elderly cases of homozygous sickle cell disease in Jamaica. Br J Ophthalmol 1976; 60: 361-364.

Condon PI, Serjeant GR. Behavior of untreated sickle retinopathy. Br J Ophthalmol 1980; 64: 404-411.

Condon PI et al. Choroidal neovascularization induced by photocoagulation in sickle cell disease. Br J Ophthalmol 1981; 65: 192-197.

Dizon-Moore RV, Jampol LM, Goldberg MF. Chorioretinal and choriovitreal neovascularization. Their presence after photocoagulation of proliferative sickle cell retinopathy. Arch Ophthalmol 1981; 99: 842-849.

Fan TP, Jaggar R, Bicknell R. Controlling the vasculature: angiogenesis, anti-angiogenesis and vascular targeting of gene therapy. Trends Pharmacol Sci 1995; 16: 57-66.

Farber MD et al. A randomized clinical trial of scatter photocoagulation of proliferative sickle cell retinopathy. Arch Ophthalmol 1991; 109: 363-367.

Freilich DB, Seelenfreund MH. Long term follow-up of scleral buckling procedure with sickle cell disease and retinal detachment treated with the use of hyperbaric oxygen. Mod Prob Ophthalmol 1977; 18: 368-372.

Gagliano DA, Goldberg MF. The evolution of salmon patch hemorrhages in sickle cell retinopathy. Arch Ophthalmol 1989; 107: 1814-1815.

Galinos S et al. Hemoglobin SC disease and iris atrophy. Am J Ophthalmol 1973; 75: 421-425.

Goldbaum MH et al. Vitrectomy in sickling retinopathy: report of five cases. Ophthalmic Surg 1976; 7: 92-102.

Goldbaum MH et al. Acute choroidal ischemia as a complication of photocoagulation. Arch Ophthalmol 1976; 94: 1025-1035.

Goldberg MF. Natural history of untreated proliferative sickle retinopathy. Arch Ophthalmol 1971; 85: 428-437.

Goldberg MF. Classification and pathogenesis of proliferative sickle retinopathy. Am J Ophthalmol 1971; 71: 649-655.

Goldberg MF, Jampol LM. Treatment of neovascularization, vitreous hemorrhage, and retinal detachment in sickle cell retinopathy. Symposium on medical and surgical diseases of the retina and vitreous: transactions of the New Orleans Academy of Ophthalmology. St Louis: CV Mosby, 1983; 5: 53-81.

Goldberg MF. Retinal neovascularization in sickle retinopathy. Trans Am Acad Oph & Otol 1977; 83: OP409-431.

Goldberg MF, Dizon R, Moses VK. Sickled erythrocytes, hyphema, and secondary glaucoma: VI. The relationship between intracameral blood cells and aqueous humor. Ophthalmic Surg 1979; 10: 78-88.

Jacobson MS et al. A randomized clinical trial of feeder vessel photocoagulation of sickle cell retinopathy. A long-term follow-up. Ophthalmology 1991; 98: 581-585.

Jampol LM et al. An update on techniques of photocoagulation treatment of proliferative sickle cell retinopathy. Eye 1991; 5: 260-263.

Jampol LM et al. An update on vitrectomy surgery and retinal detachment repair in sickle cell disease. Arch Ophthalmol 1982; 100: 591-593.

Lee CB et al. Cryotherapy of proliferative sickle cell retinopathy: I. Single freeze-thaw cycle. Ann Ophthalmol 1975; 7: 1299-1308.

McLeod DS, Goldberg MF, Lutty GA. Dual perspective analysis of vascular formations in sickle retinopathy. Arch Ophthalmol 1993; 111: 1234-1245.

Nagpal KC, Goldberg MF, Rabb MF. Ocular manifestations of sickle hemoglobinopathies. Surv Ophthalmol 1977; 21: 391-411.

Ogura Y et al. Feasibility of targeted drug delivery to selective areas of the retina. Invest Ophthalmol Vis Sci 1991; 32: 2351-2356.

Paton D. Conjunctival sign of sickle cell disease. Arch Ophthalomol 1961; 66: 90-94.

Paton D. Conjunctival sign of sickle cell disease. Further observations. Arch Ophthalmol 1962; 68: 627-632.

Raichand M et al. Evolution of neovascularization in sickle cell retinopathy. Arch Ophthalmol 1977; 95: 1543-1552.

Rednam KRV, Jampol LM, Goldberg MF. Scatter retinal photocoagulation for proliferative sickle cell retinopathy. Am J Ophthalmol 1982; 93: 594-599.

Stevens TS et al. Sickling hemoglobinopathies. Macular and perimacular abnormalities. Arch Ophthalmol 1974; 455-463.

Welch RB, Goldberg MF. Sickle cell hemoglobin and its relation to fundus abnormality. Arch Ophthalmol 1966; 75: 353-362.

Zeimer RC et al. A potential method for local drug and dye delivery in the ocular vasculature. Invest Ophthalmol Vis Sci 1988; 29: 1179-1183.