In 1949, Pauling and colleagues⁴ discovered that sickle cell disease was caused by the presence of an abnormal hemoglobin, named sickle hemoglobin (Hb S) because of the sickle shape it imparts to deoxygenated RBCs. In 1956, it was reported that the formation of Hb S was caused by a single amino acid substitution (i.e., valine for glutamic acid) in the sixth position from the N-terminal end of the β-chain.^5,6 This amino acid substitution results from a single DNA base point mutation in which thymine is substituted for adenine in the sixth codon of the β-gene (i.e., GAG to GTG). Although many other point mutations have been described, another important variant is hemoglobin C (Hb C), caused by the substitution of lysine for glutamic acid in the sixth codon of the β-chain.

Thalassemias are genetic defects that result in abnormal hemoglobin chain synthesis. They are classified according to the amount of globin chain present. For example, β-thalassemia may have no β-chain present (β⁰-thalassemia) or a reduced amount of β-chain present (β⁺ -thalassemia). Synthesis of either of the two types of polypeptide chains in the hemoglobin molecule may be affected, resulting in either α- or β-thalassemia.⁷

The term hemoglobinopathy describes disorders associated with structurally abnormal hemoglobin. Sickle cell is the most common hemoglobinopathy affecting humans, with a gene frequency as high as 20% in some areas of Africa.⁸ Approximately 8% of black Americans carry the gene for Hb S. Hemoglobinopathies occur in a heterozygous or homozygous form. The most common form of sickle hemoglobinopathy is the heterozygous state, known as sickle cell trait (Hb AS), in which the RBC contains normal Hb A together with abnormal Hb S.⁷

The pathologic condition associated with sickle cell hemoglobinopathy is known as sickle cell disease. Sickle cell disease has a variable clinical presentation because expression of the disease depends on the genetic type, the amount of Hb F present in postnatal life, the presence or absence of α-thalassemia, and possibly the presence of other point mutations in the hemoglobin gene or other genes. The gene regions closely associated with the locus for the hemoglobin β-chain may be capable of modulating the expression of the gene.⁷

Sickle cell trait is generally excluded from the definition of sickle cell disease because of its mild clinical manifestations. Although the systemic manifestations of sickle cell trait are usually mild or absent, patients with sickle cell trait may occasionally develop ocular complications.

The hemoglobinopathies that produce sickle cell disease are Hb SS, Hb SC, and Hb S—thalassemia (β⁰ or β⁺). Hb SS produces homozygous sickle cell anemia (also known as SS disease). It is associated with the most severe systemic manifestations and often early morbidity. In the United States, the incidence of sickle cell anemia at birth is approximately 1 in 625. Hb SC produces SC disease (also known as sickle cell-hemoglobin C disease). Although it is associated with milder systemic manifestations than sickle cell anemia, SC disease is associated with more serious ocular disease. The prevalence of SC disease in black Americans is 1 in 1500.⁸ The most significant sickle cell-thalassemia disease is sickle cell-β-thalassemia, the clinical symptoms of which depend on the amount of β-chain that is absent.

Three other less common genotypes manifesting the features of sickle cell disease include Hb SD Punjab, Hb SO Arab, and Hb S Lepore Boston. Hb D has a glutamine residue instead of a glutamic acid residue at position 121 on the β-chain. Hb O has a lysine instead of glutamic acid, also at position 121 on the β-chain.⁹ Restriction endonuclease analysis suggests that the Hb S gene arose from three geographically independent mutations in equatorial Africa.^10,11 Surprisingly, the sickle gene frequency has remained relatively stable.^11,12 One theory put forth to explain the evolutionary survival of a gene mutation with such devastating clinical manifestations and early morbidity is called balanced polymorphism. According to this theory, the negative effects of a genetic mutation are balanced by its protective benefits, which aid in natural selection. In this case, the Hb S gene offers some benefit in terms of protection against malaria.^13,14 The greatest prevalence of the Hb S gene exists in the malarial regions of Africa, and children with sickle cell trait (true heterozygotes) are afforded some degree of protection against malaria, particularly the type caused by Plasmodium falciparum.¹⁵

Like the Hb S gene, the Hb C gene is also highly concentrated in West Africa and offers some protection against malaria.¹¹ Approximately 2% of black Americans carry one gene for Hb C, mostly as C trait (Hb AC). Homozygous C (Hb CC) is rare, occurring in 0.016% of black Americans.

Intracellular polymerization and gel formation produce poor erythrocyte deformability, and if recurrent, also cause distortion and damage to the RBC membrane. Damaged RBC membranes lead to potassium loss and intracellular dehydration, which further potentiates Hb S polymerization. Eventually the erythrocyte membrane is no longer capable of assuming the normal biconcave shape upon reoxygenation, thus forming an irreversibly sickled cell (ISC).

Oxygen is the most important determinant of Hb S polymerization. Very small changes in arterial oxygen tension, even with an oxygen saturation greater than 90%, can result in sickling.¹⁶ Other factors that influence polymer formation are cellular Hb S concentration, pH, and temperature.⁷ In the terminal arteriole and capillary circulation, oxygen availability decreases and the pH drops, enhancing Hb S polymerization.

Rheologic impairment underlies the complications of sickle cell disease.¹⁷ Rheologic factors include the presence of sickled cells, the vessel diameter, and the hematocrit. Vascular beds with low flow and high oxygen extraction are more prone to sickling and secondary vascular occlusion. The peripheral retina and macula appear to be the most susceptible to vascular occlusion.¹⁸ Interestingly, the terminal capillary bed in each of these zones borders on an avascular area and thins to a two-dimensional capillary bed.¹⁹

Small changes in blood vessel diameter dramatically affect the blood flow because flow resistance is inversely proportional to the fourth power of the vessel radius.²⁰ The vascular occlusions of sickle cell retinopathy occur in the arterioles rather than in the capillaries, perhaps because the sphincters of the precapillary arterioles are narrower than the true capillaries.^21,22

Compared with normal RBCs, those containing Hb S demonstrate greater vascular endothelium adherence. This adherence property is not exhibited by ISCs because their rigidity renders them unable to form a large surface contact with the endothelial cells. Thus, patients who generate a large number of ISCs have vascular occlusions at the precapillary arterioles because the rigid blood cells cannot enter the capillaries. Patients with fewer ISCs and more deformable cells have blood flow compromise in the capillaries, where RBCs containing Hb S readily adhere to the vascular endothelium.

Paradoxically, there is an inverse relationship between the severity of systemic disease and the severity of sickle cell retinopathy in homozygous (SS) versus doubly heterozygous (SC) sickle cell disease. Patients with homozygous sickle cell disease have more systemic complications, with multiple vaso-occlusive events and secondary organ damage. Patients with doubly heterozygous sickle cell disease have fewer systemic complications but a greater frequency and earlier onset of retinal neovascularization, resulting in more severe sickle cell retinopathy and more visually disabling ocular complications (Tables 1 and 2).

TABLE 1. Prevalence of Proliferative Sickle Retinopathy (PSR)

TABLE 2. Influence of Age on the Prevalence of Proliferative Sickle Retinopathy (PSR) in the Different Genotypes

This paradox may be explained by a discussion of the hematologic factors involved. Accelerated destruction of RBCs combined with reduced erythropoietin production results in a state of marked anemia (homozygous sickle cell anemia).^23,24 Since the viscosity of blood is proportional to the hematocrit, the reduced viscosity associated with homozygous sickle cell anemia may protect against vascular occlusion. In contrast, patients with Hb SC and Hb S-β-thalassemia hemoglobinopathies have higher hematocrits, causing higher whole blood viscosity and a relatively increased frequency of vascular occlusions in the retina. Analysis of hematologic factors, however, has so far provided only a partial explanation for the genotypic differences in the development of proliferative sickle retinopathy (PSR). In a group of patients with homozygous sickle cell anemia, a significant relationship was found between the development of retinal neovascularization and high Hb levels and low Hb F levels in men, but not in women.²⁵ In patients with SC disease, a significant relationship was demonstrated between the development of neovascularization and high mean cell volume in men and a low Hb F level in both men and women.²⁶ Further analysis comparing whole blood and plasma viscosity, together with RBC filterability, failed to reveal any differences in patients with SC disease, although some differences occurred in patients with homozygous sickle cell anemia.^27,28

Genotypic differences in the incidence of retinal neovascularization cannot be explained by the frequency of vascular occlusions alone: the more severe systemic complications of patients with homozygous sickle cell anemia are, in fact, a result of an increased frequency of vascular occlusions. α-Globin gene number does appear to reduce the extent of peripheral retinal vessel closure, but has no apparent influence on the development of neovascularization in patients with homozygous sickle cell anemia.^29,30 In a study of the Jamaican Sickle Cohort, consisting of 173 Jamaican children with SC disease, 315 with homozygous sickle cell anemia, and 250 age- and sex-matched normal (Hb AA) controls recruited between 1973 and 1981, Talbot and associates^31–33 found that the peripheral retina demonstrates earlier vascular occlusions in sickle cell anemia than in SC disease. Comparing the peripheral retinal vascular bed with that of a normal cohort, however, they discovered that a significantly larger proportion of SC disease subjects had an abnormal peripheral vascular pattern, which they were able to correlate with the subsequent development of neovascularization. The authors concluded that a normal border, even if undergoing a posterior regression, results from a gradual modification of the capillary bed and indicates a low risk for PSR, whereas an abnormal border occurs as a radical alteration of retinal perfusion.³⁴

This cohort study also revealed that in homozygous sickle cell anemia, vascular closures occurred more frequently with low Hb F levels, low mean total hemoglobin levels, high reticulocyte counts, and high ISC counts. In patients with SC disease, closure was associated with high reticulocyte counts and lower height and weight.^31,32

The theory of ischemia versus infarction provides another explanation for the more severe PSR associated with SC disease:

  The retinal vascular occlusions caused by sickled cells in homozygous sickle cell anemia might result in a more complete vascular occlusion (infarction), causing necrosis of the retinal tissue.
  The less severe vascular occlusions in SC disease might result in an ischemic retina, which may provide an environment in which an angiogenic response is continuously stimulated.

This theory is supported by the development of neovascular tissue in other disease processes associated with retinal ischemia, such as diabetes mellitus and central retinal vein occlusion. Additional support of this theory is provided by the regression of neovascular tissue achieved by photocoagulating the ischemic retina around a neovascular membrane.³⁵

Peachey and co-workers^36,37 studied the electroretinographic response with neovascularization and correlated this with the degree of peripheral retinal capillary nonperfusion as determined by fluorescein angiography. They found significant correlations between reductions in electroretinographic amplitudes and the extent of retinal capillary nonperfusion in patients both with and without neovascularization. Patients with neovascularization also had prolonged generation of a maximum-amplitude response, similar to that seen in central retinal vein occlusion and diabetic retinopathy, suggesting that neovascularization is associated with the presence of ischemia in sickle cell retinopathy. Possibly, the more frequent and complete occlusions of homozygous sickle cell anemia are less likely to be associated with ischemia, and thus neovascularization is less likely to develop in these patients.

The solubility test (Sickledex: Orthodiagnostics, Raritan, NJ) and the sickle prep (metabisulfite slide test) are used to identify the presence of Hb S. The solubility test is based on the insolubility of deoxygenated Hb S, and the sickling test is based on the morphologic change of erythrocytes containing deoxygenated Hb S. The solubility test is simpler to perform and has gained widespread acceptance as a screening test. Both tests are not sensitive enough to detect the lower levels of Hb S present at birth, but their major limitation is their inability to differentiate sickle cell trait from the clinically significant homozygous (SS) and heterozygous (SC) sickle cell disease. Therefore, a positive sickle prep test or solubility test must be followed by quantitative hemoglobin electrophoresis. The electrophoretic pattern of Hb SS and Hb S- β⁰-thalassemia are similar; however, they can be differentiated by quantification of Hb A₂, which is elevated in Hb S-β⁰-thalassemia. Sickle cell trait (Hb AS) can be distinguished from Hb S-β⁺ thalassemia because more than 50% of the hemoglobin is Hb S in the latter disease. DNA analysis by restriction endonuclease is the most widely used method for antenatal diagnosis of sickle cell disease.

ANTERIOR SEGMENT

Conjunctival Sickle Sign

Abnormalities of the bulbar conjunctival blood vessels provide direct evidence of the vaso-occlusive process and were one of the earliest reported ocular changes.^38–43 These abnormalities are believed to be the result of flow obstruction or impedance by sickled cells. The severity of the conjunctival changes ranges from linear dilatations to isolated groups of truncated, comma-shaped segments. These changes have been correlated with the ISC count, Hb S concentration, and the intraerythrocytic hemoglobin concentration (Fig. 1).^44–47 Although they are known as the conjunctival sickle sign, these vascular abnormalities are not completely pathognomonic of sickle cell disease: in rare cases they are seen in patients with AIDS, chronic myelogenous leukemia, and other vaso-occlusive diseases.^47–49

Iris Atrophy and Neovascularization

Occlusions of the iris vessels can result in atrophy, and patients may present with asymptomatic white patches of the iris.^50,51 The area of atrophy may be extensive (Fig. 2) and may be associated with pupillary irregularity. Iris neovascularization may develop in eyes with chronic retinal detachment or major arteriole occlusions and can in rare cases cause a secondary neovascular glaucoma.⁵²

Hyphema

Sickle cell patients, including patients with sickle cell trait, are susceptible to developing central retinal artery occlusions and optic atrophy secondary to elevated intraocular pressure.^53,54 Therefore, the potential for permanent ocular damage is an important consideration in sickle cell patients with even minimal hyphema from surgery or anterior segment trauma.^55–57 The environment in the anterior chamber promotes Hb S polymerization and secondary impairment of outflow from blockage of the trabecular meshwork by sickled cells.^58–63

It is warranted to order a sickle screen for every black American patient with hyphema and for every patient with hyphema associated with elevated intraocular pressure.⁶⁴ If Hb S is present, the intraocular pressure should be closely monitored and should not be allowed to remain higher than 25 mmHg for more than 24 hours.^56,57 Medical management should be restricted, if possible, to topical β-blockers and possibly oxygen (100%) inhalation or oxygen goggles, which deliver oxygen through the cornea to the aqueous humor.⁶⁵ A judicious trial of 25 mg of oral methazolamide twice daily may be included. Methazolamide has been found to reduce intraocular pressure without altering renal bicarbonate secretion and causing systemic acidosis. Preferably, other carbonic anhydrase inhibitors and osmotic agents should be avoided because they may induce hemoconcentration and acidosis, causing further Hb S polymerization. If the intraocular pressure cannot be controlled by medical means, surgical intervention with anterior chamber lavage, repeated as necessary, is indicated.⁶⁶

POSTERIOR SEGMENT

Disc Sign

Transient dark red spots (similar to conjunctival commas), representing plugs of sickled erythrocytes within superficial capillaries, may be seen on the surface of the optic disc (Fig. 3 and Color Plate 1A). These disc changes are not associated with any functional or anatomic abnormalities. They are found in 11% of all patients with sickle cell disease, but appear to be more common in patients with homozygous sickle cell anemia, occurring in 29% of these patients.⁶⁷ The disc sign correlates with the presence of conjunctival commas and ISCs.

Unlike some retinal vaso-occlusive diseases, sickle cell retinopathy is rarely associated with optic disc neovascularization.⁶⁸ In our extensive experience with sickle cell disease, we have seen only one such case. The low incidence of optic disc neovascularization may be due to the peripheral location of the ischemia and to the localized changes, much of the retina not being significantly affected by the ischemia.⁶⁹ Peripheral retinal scatter photocoagulation is effective in stimulating regression of optic disc neovascularization.

Vascular Tortuosity

Dilation and tortuosity of the retinal veins was one of the first recognized abnormalities of sickle cell eye disease. Although it is not pathognomonic of sickle cell disease, it reportedly occurs in up to 47% of patients with homozygous sickle cell anemia and 32% of patients with SC disease (Fig. 4).⁷⁰ The significance of this venous tortuosity is unknown, and the incidence does not appear to be related to age.⁷¹

Angioid Streaks

Angioid streaks occur in association with sickle cell disease, with an overall incidence of less than 6%.^72–75 The changes are more common in patients with homozygous sickle cell anemia and are age-dependent, occurring in 2% of sickle cell anemia patients less than 40 years of age versus 22% in those who are more than 40 years of age (Fig. 5).⁷⁶

Unlike the angioid streaks seen in patients with pseudoxanthoma elasticum, choroidal neovascularization and disciform disease are uncommon in association with sickle cell disease. Elastic tissue degeneration, as is seen in pseudoxanthoma elasticum, has not been demonstrated in the skin biopsy specimens of sickle hemoglobinopathy patients with angioid streaks.^73,75 Initially, the etiology of angioid streaks in sickle cell disease was hypothesized to be secondary to iron deposition due to chronic hemolysis, causing brittleness of Bruch's membrane. Histopathologic examination of angioid streaks in a patient with homozygous sickle cell anemia, however, revealed heavy calcification of Bruch's membrane without evidence of iron or hemosiderin.⁷⁷

Epiretinal Membranes

Epiretinal membranes may produce visual loss in patients with sickle cell disease. Macular epiretinal membranes are seen more frequently in eyes with retinal neovascularization, retinal tears, and vitreous hemorrhage, as well as in eyes that have had laser treatment or surgery of the retina or vitreous.⁷⁸ Progressive visual loss from macular distortion has been reported in up to 32% of these patients over a 2.5-year period.⁷⁹ Peripheral neovascularization may stimulate formation of epiretinal membranes by transudation of plasma and erythrocytes into the vitreous, disrupting the vitreous cortex and inducing posterior vitreous detachment. Successful treatment of the neovascular tissue reduces the risk of epiretinal membrane development by approximately 30%.⁷⁹ Although spontaneous separation of epiretinal membranes following treatment of peripheral neovascularization has been observed, surgical removal may be considered when patients exhibit moderate to severe visual loss (Fig. 6).^80,81

Traction across the macula from peripheral neovascularization is thought to contribute to the formation of macular holes in sickle cell retinopathy.⁸²

Retinal Artery Occlusions

Occlusions of the central retinal artery and major arteriolar branches are probably most frequent in young patients with homozygous sickle cell anemia; however, they may also occur with other sickling genotypes (Fig. 7).^39,83,84 They may cause permanent or transient visual loss and can occur simultaneously in both eyes.^85–87 Arterial occlusion has also been reported to occur as a complication of retrobulbar anesthesia and following compression of the eye during photocoagulation (Fig. 8).⁸⁸

Retinal artery occlusion has also been reported in patients with sickle cell trait secondary to airplane travel,⁷⁰ with elevated intraocular pressure following blunt trauma,^53,54 with extreme dehydration,⁸⁹ and in association with tuberculosis and systemic lupus erythematosus.⁹⁰

Macular Small Vessel Occlusions

Occlusions of the fine vasculature of the macular and perimacular area have been reported in 10% to 40% of patients with sickle cell disease.^{18,83,91–99} In the acute phase, the occluded vessel will have a dark red appearance and may appear as a dark line on fluorescein angiography (Fig. 9). Nerve fiber layer infarcts (cotton-wool spots) are seen (see Fig. 8D and E;Fig. 10).¹⁰⁰

Other macular and perimacular changes include microaneurysm-like dots, dark and enlarged segments of arterioles, hairpin-shaped venular loops, pathologic avascular zones, and widening and irregularities of the foveal avascular zone (Figs. 11 and 12). In the Jamaican cohort study evaluating children with homozygous sickle cell anemia and SC disease between the ages of 5.0 and 7.5 years of age, no pathologic avascular zones could be identified despite a high incidence of peripheral vascular closure.³¹ In evaluating patients with homozygous sickle cell anemia, no relationship between ISC counts and macular abnormalities or visual acuity could be found.¹⁰¹ Using fluorescein angiography, investigators have found the foveal avascular zone to be significantly larger in eyes with clinical evidence of sickle cell maculopathy as compared with normal eyes and eyes without clinical evidence of sickle cell maculopathy.^102–104

Careful examination by fluorescein angiography, looking for areas of capillary dropout and other capillary abnormalities, is often necessary to identify the macular changes. These changes may be transient, and the macula may appear normal on subsequent fluorescein angiograms (Fig. 13). Although fluorescein angiography may or may not demonstrate reperfusion of a previously occluded capillary bed, a loss of the inner retinal layers results in an ophthalmoscopic focal concavity with an abnormal reflex (retinal depression sign) (see Fig. 8E).^105,106 These changes are usually permanent. The retinal depression sign is not pathognomonic of sickle cell disease and may be seen with other arteriolar occlusive diseases, such as embolic retinopathy, vasculitis, and hypertension.

Macular Function Testing in Sickle

Cell MaculopathyThe visual acuity in patients with sickle cell disease is often normal, despite the presence of an enlarged foveal avascular zone or other evidence of sickle cell maculopathy (Fig. 14). In addition, patients with sickle cell maculopathy have a remarkable absence of visual complaints. Although 55% of patients with homozygous sickle cell anemia had abnormal contrast sensitivity, no significant relationship was demonstrated between contrast sensitivity and macular vascular abnormalities.¹⁰¹ Automated visual field analysis has demonstrated significantly larger scotomas in patients with abnormally enlarged foveal avascular zone.¹⁰² Color vision testing has revealed a greater incidence of blue-yellow defects in patients with sickle cell retinopathy; however, no significant correlation has been demonstrated between color vision defects and the presence of sickle cell maculopathy.^98,107

Retinal Venous Occlusions

Retinal venous occlusions are surprisingly uncommon in sickle cell disease.¹⁰⁸ We have seen a patient with homozygous sickle cell anemia and a branch vein occlusion, but this patient had hypertension. We have not seen central vein occlusion. An underlying systemic disease associated with a higher incidence of venous occlusions (e.g., hypertension) should be suspected when a venous occlusion occurs in a patient with sickle cell disease. The anemia and low blood pressure present in sickle cell patients may actually protect against venous occlusions.

Choroidal Vascular Occlusions

Choroidal vascular occlusions may occur focally at the level of the choroidal precapillary arteriole or capillary bed (Elschnig's spots) or from posterior ciliary artery occlusion. Although focal precapillary arteriole occlusions have not been specifically identified with sickle cell disease, clinical and histopathologic evidence of spontaneous posterior ciliary artery occlusions have been reported in sickle cell disease.^109,110 The findings are similar to those described following compression of the eye during general anesthesia and after heavy peripheral photocoagulation.^111,112 In the acute phase, the occlusions appear as white, circumscribed, triangular patches at the level of the retinal pigment epithelium and outer retina. Over the following weeks, the white lesions fade and retinal pigment epithelial mottling develops (Fig. 15). Since patients with acute ciliary artery occlusions may be asymptomatic and the diagnosis is often based solely on the appearance of peripheral pigment mottling, the frequency of this complication remains uncertain.

Focal areas of atrophy of the choriocapillaris have been seen histopathologically on postmortem examination of patients with homozygous sickle cell anemia. Mild sclerosis of the choriocapillaris, focal peripheral photoreceptor loss, and areas of choroidal neovascularization also have been noted.¹¹⁰ It has been suggested that choroidal ischemia plays a role in the development of angioid streaks in sickle cell disease. The one histopathologic report of angioid streaks indicated that the basement membrane of the underlying choriocapillaris endothelial cells was slightly thickened and that sickled erythrocytes were found within patent lumina of the choriocapillaris.⁷⁷ No specific evidence exists to support a relationship between choroidal ischemia and angioid streaks.

Retinal Hemorrhages, Iridescent Spots, and Black Sunbursts

Retinal hemorrhages (“salmon patches”), found most commonly in the equatorial periphery, can be observed after an abrupt occlusion and rupture of an intermediate-sized retinal arteriole (Fig. 16).¹¹³ Because the hemorrhages typically appear adjacent or distal to an intraluminal obstruction, it is likely that ischemic necrosis causes a weakening of the vessel wall and that reperfusion of the vessel causes a rupture of the damaged vessel wall, resulting in a hemorrhage (Fig. 17).¹⁰⁰ Acutely, these hemorrhages are bright red, but after several days, the partially degenerated blood acquires a characteristic orange-red color (hence the name salmon patch). In most cases, these hemorrhages are asymptomatic. The majority of these hemorrhages remain confined to the sensory retina; however, blood may leak through the internal limiting membrane into the vitreous or dissect deeper into the subretinal space (Fig. 18).¹¹⁴ Resolution occurs over days to weeks and may result in a focal area of atrophic split retina (a “schisis” cavity), a pigmented retinal scar, or a grayish-white vitreous deposit, depending on the location of the hemorrhage (Color Plate 1B through G).¹¹⁵ The blood is slowly cleared by macrophages.

Intraretinal blood breakdown products, either extracellular or within macrophages, may appear as refractile copper-colored granules (“iridescent spots”") (Color Plate 1H). Macular iridescent schisis lesions have not been described clinically, but they have been observed on histologic examination.¹¹⁴

The occluded vessels may reopen, and the capillary network in the area of a schisis cavity may appear normal; however, more commonly, the vessels will remain closed (Fig. 19). In rare cases, an area of retinal neovascularization may be found within a schisis cavity (Fig. 20).

Black pigmented spiculate or stellate chorioretinal lesions (“black sunbursts”) are typically found around or anterior to the equator and adjacent to an arteriole.⁷⁰ Occasionally, a pigmented lesion may be seen trailing from an arteriole or as a cuff of pigment overlying the vessel (Color Plate 2A).⁸³ Additionally, the overlying arteriole may be occluded. Refractile deposits are often seen interspersed with the pigment. Black sunbursts are believed to be due to deep retinal blood stimulating pigment epithelial migration, hyperplasia, and hypertrophy.^116,117 Histopathologic findings support this hypothesis,¹¹⁴ and the development of black sunbursts has been documented in an area of previous intraretinal and subretinal hemorrhage (see Color Plate 1E, F, and G).^114,115 An alternative explanation for black sunbursts is the occurrence of choroidal ischemia and aborted choroidal neovascularization.^22,118 A spontaneous chorioretinal neovascular membrane was shown to occur within a black sunburst in a 14-year-old girl with homozygous sickle cell anemia.¹¹⁹

Dark- and White-Without-Pressure Fundus Lesions

Flat, geographic dark brown areas have been identified in the posterior pole or midperiphery of the retina in patients with sickle cell disease without any signs of a previous hemorrhage or definite evidence of retinal or choroidal vascular occlusion. These dark-without-pressure lesions are transient, changing shape or disappearing over weeks to months.^120,121 Areas of white-without-pressure, which are possibly secondary to condensation of the overlying basal vitreous, also have been described.^83,122 These two distinct fundus lesions have been noted in black American patients with sickle hemoglobinopathies, but their relationship to sickle hemoglobin, if any, remains uncertain.

Peripheral Retinal Manifestations

The retinal capillary network in the retinal periphery thins to a single layer approximately 1 mm from the ora serrata. A similar thinning of the retinal capillary network occurs around the foveal avascular zone.^123–125 These two areas appear to be the most susceptible to vascular occlusions from sickle cell retinopathy. Repeated vascular closures and reopenings of the retinal periphery results in a dynamic remodeling and a centripetal recession of the vascularized border toward the posterior pole.^100,126 Peripheral vascular occlusions are seen more frequently on the temporal side, tend to be more rapidly progressive in children and adolescents than in adults, and are significantly more common in homozygous sickle cell anemia than in SC disease.^31,32

Redirection of blood flow results in the formation of arteriolar-venular anastomosis at the border of the perfused and nonperfused peripheral retina. This process of vascular closures and arteriolar-venular anastomosis formation is similar to that seen in the spleen, brain, and kidney.^127,128 Perhaps unique to the retina, however, is the subsequent development of neovascularization near areas of arteriolar-venular anastomoses.¹²⁹

The sequential changes of the peripheral retina form the basis of Goldberg's five-stage pathologic classification:

  Stage I: Peripheral arteriolar occlusions
  Stage II: Peripheral arteriolar-venular anastomoses
  Stage III: Preretinal neovascularization
  Stage IV: Vitreous hemorrhage
  Stage V: Retinal detachment (Table 3)^130,131

TABLE 3. Pathogenetic Classification of Proliferative Sickle Retinopathy

Fluorescein angiography remains the best method of identifying these peripheral retinal changes and documenting the presence of neovascularization.¹⁹

Examination of the Jamaican Sickle Cohort children with homozygous sickle cell anemia and SC disease, comparing their peripheral retinas with those of age- and sex-matched normal (Hb AA) controls, has revealed that the peripheral retina demonstrates a characteristic change that may allow identification of an increased risk of progressing to neovascularization. A classification scheme has been proposed that divides the peripheral retinal manifestations into qualitatively normal and qualitatively abnormal (Table 4). In the new classification scheme, if there is a continuous arteriolar-venular anastomosis at the margin of the perfused and nonperfused peripheral retina, it is considered qualitatively normal. An abnormal peripheral retinal vascular pattern has capillary stumps extending into nonperfused retina or an irregular capillary border.

TABLE 4. New Classification of Sickle Retinopathy

Although Talbot and co-workers found that vascular occlusions occurred earlier in homozygous sickle cell disease (Hb SS) than in heterozygous sickle cell disease (Hb SC), a significantly larger proportion of subjects with SC disease versus sickle cell anemia had an abnormal peripheral vascular pattern.^31–33 It appears that once an abnormal peripheral retinal vascular pattern appears, it remains qualitatively abnormal despite further loss of the capillary bed. An abnormal border probably occurs as a radical alteration of retinal perfusion and correlates with the subsequent development of neovascularization. A normal border, even if undergoing a posterior regression, results from a gradual modification of the capillary bed and indicates a low risk for PSR.³⁴ However, caution must be exercised, and the entire extent of the peripheral retina must be examined: even though a part of the peripheral retina is qualitatively normal, there may be still be neovascularization in other areas.

STAGE I: PERIPHERAL ARTERIOLAR OCCLUSIONS. This stage may be further subdivided into three grades: grade I, narrowing of the peripheral arterioles with tortuosity and abnormal looping of the peripheral venules; grade II, tortuosity, dilation, and microaneurysmal formation in the capillary network; and grade III, occlusion of the peripheral capillaries and arterioles.⁸³

Histologic and trypsin digest studies support the theory of a sudden occlusion of the precapillary arteriolar circulation followed by degeneration of the occluded vessels and the distal nonperfused retina. The presence of focal areas of small vessel degeneration and vascular beading (but not typical retinal microaneurysms) also have been confirmed.¹³²

The occluded arterioles may be invisible or may have a “silver-wire” or chalk-white appearance, as first described by Goodman and colleagues³⁹ (Fig. 21). Fluorescein angiography may demonstrate an abrupt complete occlusion at the interface between peripheral nonperfused and posterior perfused retina. Frequently, this occlusion will take place just distal to a branching vessel, giving the appearance of a freshly pruned rose bush. The nonperfused anterior peripheral retina will have a grayish brown appearance and on fluorescein angiography will appear blurred without clearly defined fundus markings.

STAGE II: PERIPHERAL ARTERIOLAR-VENULAR ANASTOMOSES. Following occlusion of the terminal arterioles, anastomotic channels form to channel the blood from the occluded arteriole to the nearest venules. These anastomoses form at the interface between the perfused and nonperfused retina. Most likely, they are dilated preexisting capillaries rather than new vessels, since they do not leak on fluorescein angiography. The redirection of blood flow is probably due to hydrostatic forces (Figs. 22 and 23).

STAGE III: PRERETINAL NEOVASCULARIZATION (PROLIFERATIVE SICKLE RETINOPATHY). “Sea fan”-shaped neovascularization typically develops on the venular side of an arteriolar-venular anastomosis, mimicking the normal development of retinal capillaries (Fig. 24).¹²⁵ A lowered oxygen tension and angiogenic factors released on the venular side may be the stimulus for neovascular growth.^125,126 In most instances, the direction of growth is toward the ora serrata, from the perfused retina toward the nonperfused retina. Presumably, this represents an abortive attempt to revascularize the nonperfused retina, initiated by vasoproliferative factors.

The characteristic neovascular lesions of PSR are called sea fans because they resemble the marine invertebrate Gorgonia flabellum.⁷⁰ They tend to occur more commonly in the temporal periphery, but they have been reported to occur in the temporal macula in the presence of extensive nonperfusion.^130,133 Initially they grow on the surface of the retina, but they often become elevated into the vitreous and adhere to a partially detached posterior hyaloid.¹¹⁴ It may be difficult to visualize small sea fans ophthalmoscopically; however, fluorescein angiography clearly demonstrates leakage of dye into the vitreous (Fig. 25). The feeding arteriole is usually more tortuous than the draining venule (Fig. 26). Early on, the neovascular lesion is fed by a single arteriole and drained by a single venule, but with time, additional arterioles and venules become arborized within the lesion (Fig. 27).¹²⁹ Growth of the sea fan often occurs circumferentially, rather than radiallyÜmh- 1Ý, toward the ora serrata. Progressive circumferential growth may lead to neovascular lesions extending around the entire periphery. As it matures, a white fibroglial mantle often covers the neovascular tissue (Color Plate 2B).

PSR is associated with the severe vision-threatening sequelae of sickle cell disease: vitreous hemorrhage (stage IV) and retinal detachment (stage V). These stages are believed to result from transudation of blood components into the vitreous through the incompetent neovascular tissue (Fig. 28). Vitreous fluorophotometry has quantified the leakage from the peripheral neovascularization.¹³⁴ This leads to premature syneresis and collapse of the vitreous, inducing tractional forces on the retina that lead to vitreous hemorrhage, retinal tears, and tractional and rhegmatogenous retinal detachment. In rare cases, an exudative detachment may occur.

Spontaneous nonperfusion or autoinfarction, accompanied by regression of the neovascular lesion, occurs in 20% to 60% of eyes with PSR.^135,136 The peak incidence of autoinfarction is 2 years after the development of PSR. It appears that autoinfarction occurs primarily as a result of (1) occlusion of the feeding arteriole due to traction on the neovascular lesion by contracting vitreous, or (2) occlusion by sickled RBCs. The latter probably is more common in homozygous sickle cell anemia, which is more commonly associated with autoinfarction and complete vascular occlusion.

Sea fans develop an average of 14 months after diagnosis of stage II, with an approximate incidence of 14% per year in patients with SC disease.¹²⁹ In a series of selected patients with different hemoglobinopathies in Jamaica, the incidence of PSR was reported as follows: 2.6% with sickle cell anemia⁸³; 14.0% with Hb S-β-thalassemia⁹¹; and 32.8% with SC disease (see Table 1).⁹² It is a common misconception that patients with homozygous sickle cell anemia have a very low risk of developing retinal neovascularization. Although the risk is recognizably lower, it must be remembered that the development of neovascularization is not only genotype-dependent but also age-dependent, increasing with age in both genotypes with the highest risk period of 20 to 34 years of age in SC disease and 40 to 50 years of age in homozygous sickle cell anemia.^26,137 The incidence of PSR in patients with homozygous sickle cell anemia is 14% for patients older than 40 years and up to 29% in patients older than 50 years.^25,76 In a series of 786 patients with homozygous sickle cell anemia, the prevalence of PSR was demonstrated to increase gradually, peaking in patients aged 30 years and older. The first cases were observed in patients in their late teens, the incidence rate increasing in patients who were 25 years and older.²⁹ In the same study, a series of 533 patients with SC disease demonstrated that the prevalence of PSR reached a maximum in men in their late 20s and in women older than 40 years, whereas the incidence rates of PSR peaked in men in their early 20s and in women in their late 20s. The prevalence of PSR has been reported to be as high as 68% in SC disease patients 45 years of age and older.²⁶ An ongoing cohort study in Jamaica will undoubtedly provide information on the evolution of PSR in patients with the various genotypes.

As mentioned previously, the otherwise benign condition of sickle cell trait can be associated in rare cases with ocular complications, including neovascularization. Nagpal and associates¹³⁸ reported that their patients with sickle cell trait who had neovascularization also had associated underlying systemic diseases, including diabetes, hypertension, tuberculosis, syphilis, and sarcoidosis. The neovascularization in these cases was similar to that seen in sickle cell disease. They proposed that any patient with sickle cell trait and PSR be examined thoroughly for other underlying diseases. An additional consideration, and a frequent source of misdiagnosis, is the failure to perform a hemoglobin electrophoresis to clarify a positive sickle cell test. A sickle test can detect the presence of Hb S, but it cannot clarify whether a patient has sickle cell trait or one of the other genotypes associated with sickle cell eye disease. Sickle cell trait may be confused with Hb S-β+ -thalassemia unless a quantitative hemoglobin electrophoresis is done. This may account for some apparent cases of PSR with sickle cell trait. It is still unclear whether sickle cell trait alone can produce PSR.

Once PSR is established, the rates of progression vary greatly among patients. PSR does progress more rapidly in young patients with SC disease and homozygous sickle cell anemia.¹³⁵

STAGE IV: VITREOUS HEMORRHAGE. Vitreous hemorrhage often complicates PSR. In a selected series of patients with untreated SC disease, vitreous hemorrhage was found in 28% at diagnosis and in 44% after 31 months.¹³⁰ In the presence of neovascularization, the three risk factors for the development of vitreous hemorrhage include SC disease, more than 60° of perfused sea fans, and the presence of old blood in the eye.¹³⁹ In a long-term follow-up of an untreated control group participating in a randomized clinical trial of feeder vessel photocoagulation for PSR, vitreous hemorrhage occurred in 45% of eyes and was recurrent in two thirds of these eyes.¹⁴⁰

Transudation of plasma results in vitreous syneresis and fibrosis and induces collapse of the formed vitreous, which causes traction on the adherent neovascular tissue. The fragile elevated vessels in the neovascular membranes are prone to rupture, resulting in hemorrhage.¹⁴¹ The hemorrhage is frequently localized in the periphery near the sea fan, but diffuse hemorrhage does occur and may obscure fundus details (Color Plate 2C).

STAGE V: RETINAL DETACHMENT. Vitreous traction on the retina may cause tractional retinal detachments or retinal breaks that can result in localized or total rhegmatogenous retinal detachments.^131,142 The retinal breaks are usually found adjacent to neovascular tissue and may be difficult to detect because of overlying hemorrhage. Exudative retinal detachments may occur in rare cases and reportedly have resolved after photocoagulation of the neovascularization.¹⁴³

TREATMENT OF NONPROLIFERATIVE SICKLE RETINOPATHY

Therapeutic intervention is not indicated for the peripheral manifestations of stage I or stage II sickle cell retinopathy. There is no proven benefit in treating these stages, nor is there any way at present to predict which patients will progress to the proliferative stage. For patients with sickle cell disease, particularly SC disease and Hb S-β⁺ thalassemia, frequent examinations of the peripheral retina with periodic fluorescein angiography are indicated in an effort to identify neovascular tissue in the early stages of evolution.

Treatment of vascular occlusions of the posterior pole should focus on promoting increased blood flow and preventing further sickling by initiating hydration and oxygenation. Hyperbaric oxygen increases inner retinal oxygen levels and could potentially prove useful in treating retinal vascular occlusions associated with sickle cell disease.^65,144 Exchange transfusions have been used, but the true benefit of this is unproved because the natural history of these occlusions is not well documented. In view of the potential complications and variable outcome, routine use of exchange transfusions for retinal vascular occlusions in sickle cell disease is not recommended.^87,145

TREATMENT OF PROLIFERATIVE SICKLE RETINOPATHY

A 10-year assessment of 120 patients with homozygous sickle cell anemia and 222 patients with SC disease demonstrated visual acuity loss (20/30 or less) in 10% of untreated eyes, which was strongly associated with PSR.¹⁴⁶ The long-term evaluation of control patients enrolled in the feeder vessel treatment study demonstrated that despite auto- infarction, 80% of eyes with untreated PSR had persistent sea fans after 10 years.¹⁴⁰ Therefore, treatment of PSR is necessary to prevent vision-threatening complications, including vitreous hemorrhage and retinal detachment.¹⁴⁷

Treatment of PSR is aimed at ablating or inducing regression of the sea fan. Various modalities have been utilized, including diathermy, cryotherapy, xenon arc photocoagulation, and various techniques of laser photocoagulation, such as feeder vessel, local scatter, and peripheral circumferential scatter.^{134,140,147–160} Laser photocoagulation is the treatment modality most commonly used.

Feeder Vessel Photocoagulation

Randomized clinical trials demonstrating the efficacy of treatment utilizing the feeder vessel technique were performed on patients with PSR in Kingston, Jamaica, with xenon arc photocoagulation and in Chicago with argon blue-green laser photocoagulation.^139,140,156

In these studies, the laser photocoagulation protocol was to use a spot size of 500 μm with a 0.2-second duration and a power high enough to cause closure of the feeding and draining blood vessels (Color Plate 2D). Treatment spots were first placed on the feeding arteriole, and after segmentation of the arteriole, the draining venule was treated in a similar fashion. When the arteriole cannot be segmented, retreatment can be performed 2 to 3 weeks later, when pigmentation has occurred in the area of treatment (Fig. 29). Because of possible complications, it may be prudent to approach the treatment as a two-stage process, allowing a lower power to be used and possibly reducing the complication rate. Typically, more than one sea fan requiring treatment will be identified during the initial treatment session.¹⁴⁰ Future considerations for this technique may involve the use of dye yellow laser, which has a better hemoglobin absorption characteristic, or dye-enhanced photocoagulation.

Efficacy of treatment can be monitored with fluorescein angiography. Successful treatment is indicated by occlusion of the feeding arterioles as demonstrated by angiography, which is performed 4 to 6 weeks after the treatment to determine whether there is complete and permanent interruption of blood flow. Retreatment is often necessary to achieve complete closure. In addition, patients should be followed closely to identify any new areas of neovascularization. There does not appear to be any significant reduction in the development of new sea fans with the feeder vessel technique, since new sea fans developed in approximately 50% of both the untreated and treated patients during nearly a decade of observation.¹⁴⁰

Potential complications of feeder vessel photocoagulation include chorioretinal/choriovitreal neovascularization (Fig. 30, Color Plate 2E), retinal breaks (Color Plate 2F), retinal detachment, retinal hemorrhages, choroidal hemorrhages, and peripheral choroidal ischemia.^{112,156,157,161–167} The complication rate with xenon arc photocoagulation is higher (61%) in comparison with argon laser photocoagulation (up to 32%)^{140,156,157,164}; however, all the complications were found to have arisen within 6 months of treatment, and after a 10-year evaluation, no significant incidence of visual loss was found as a result of complications from feeder vessel laser photocoagulation.¹⁴⁰

Local Scatter Photocoagulation

This technique involves the placement of laser spots around the sea fan in a scatter fashion, 1 spot-diameter apart, and extending from 1 disc diameter anterior to 1 disc diameter posterior to the lesion, and 1 clock-hour to each side (Color Plate 2G). We use a spot size of 500 μm with a 0.1-second duration and enough power to produce a light gray spot. Additional treatment is applied when there is growth or reperfusion of neovascular tissue. No spots are placed directly on the vessels, but all neovascular lesions are treated.¹⁵³ All previous studies have used argon blue-green or green laser, but krypton red or diode infrared laser treatment would probably be equally effective.

It must be remembered that the power level should be lowered in moving from perfused retina to the nonperfused, thinner retina to avoid the complication of applying excessively intense (hot) spots and risking rupture of Bruch's membrane. A useful technique when applying photocoagulation to the retina is to use low levels of power initially and to place the laser treatment in the area anticipated to have the best absorption, thus helping to reduce the occurrence of this potential complication.

A randomized, prospective clinical trial using argon blue-green laser and a localized scatter technique demonstrated a significant reduction in both prolonged vision loss and the incidence of vitreous hemorrhage.¹⁶⁰ There were no complications reported, indicating that this technique is much safer than the feeder vessel technique. With scatter photocoagulation, as with all photocoagulation techniques, successful treatment is indicated by reduced perfusion or nonperfusion of the sea fan, as demonstrated by a lack of leakage on fluorescein angiography (Fig. 31). Complete closure of neovascularization was achieved in 30.2% of eyes and partial closure in 51%. An additional secondary benefit was a possible reduction in the development of new sea fans, which were demonstrated in 34.3% of treated eyes versus 41.3% of control eyes.

Another recent study demonstrated that complete infarction of lesions is more likely if the neovascularization is small (less than 15° of circumferential involvement) and if the patients are young (less than 25 years).¹⁶⁸ When scatter photocoagulation does not induce sufficient regression of neovascular tissue, it may be necessary to perform feeder vessel photocoagulation.¹⁵⁹

Peripheral Circumferential Scatter

In the peripheral circumferential scatter technique, scatter laser photocoagulation is placed over the entire 360° anterior peripheral zone of capillary nonperfusion.^154,155 Although this technique has not been tested in a randomized clinical trial, investigators have reported complete regression of neovascularization in 33% of sea fans and partial regression in 46%. Interestingly, new sea fans developed in only 1.4% of eyes treated with this technique, compared with 34.3% of eyes treated with local scatter and more than 50% of eyes treated with the feeder vessel technique.^140,154,155 However, treating 360° in every patient may not be necessary when local scatter can achieve adequate closure of neovascular tissue. The extensive photocoagulation of peripheral circumferential scatter may cause secondary complications related to photocoagulation, such as macular pucker. In the situation of unreliable follow-up, however, a 360° treatment may be preferable.¹⁵⁹

Laser Vitreolysis

Neodymium-yytrium aluminum garnet (Nd:YAG) laser vitreolysis may be used to treat localized vitreous traction and tractional retinal detachments. The indications for using this technique are the presence of avascular vitreous bands located at least 3 mm from the retinal surface.¹⁶⁹ Treatment closer than 3 mm to the retina has been reported to cause choroidal hemorrhage and retinal pigment epithelial lesions.

SURGICAL TREATMENT

Vitreoretinal surgery may be indicated for the treatment of tractional or rhegmatogenous retinal detachments, nonclearing vitreous hemorrhages, or visually disabling epiretinal membranes. Special consideration is warranted in sickle cell disease patients because of potentially devastating operative and postoperative pulmonary, cerebral, and ocular thromboembolic complications.

The thromboembolic ocular complications of vitrectomy and retinal detachment repair include anterior segment ischemia and intraoperative hemorrhage, with sickling and secondary glaucoma. Surgery is further complicated by difficulty visualizing peripheral retinal breaks, which are often hidden by overlying neovascular membranes, fibrous tissue, and hemorrhage. Because of thinning of the peripheral retina, iatrogenic breaks have been reported in up to 33% of cases.¹⁷⁰ Additionally, the peripheral location of the neovascular membranes increases the risk of lens damage.¹⁵⁸

A high incidence of anterior segment ischemia (up to 71% in SC disease patients undergoing scleral buckling procedures) has stimulated the use of preoperative prophylactic exchange transfusions or erythrophoresis in patients with sickle cell disease.^172–175 Preoperative exchange transfusions may reduce the potential for intraoperative and postoperative complications related to elevated intraocular pressure caused by hyphema or posterior hemorrhage. The risk of acquired infections (e.g., HIV; non-A, non-B hepatitis) and other transfusion-related complications, however, has stimulated a reevaluation of the routine use of preoperative exchange transfusions.¹⁷⁶ Use of perioperative oxygen, improved vitreoretinal surgical techniques, and other preoperative and intraoperative measures to reduce complications has resulted in an improvement in surgical and systemic outcome without transfusions that must be balanced against the risks of exchange transfusion.^176–179

The goals of preoperative partial exchange transfusions, if elected, are to elevate Hb A levels to 40% to 60% and to achieve a final hematocrit of no higher than 35% to 39% to prevent elevated whole-blood viscosity. Other benefits of partial exchange transfusions are enhancement of perfusion and oxygen delivery and minimization of intraoperative and early postoperative sickling.¹⁷⁰

The following are additional ways to reduce potential complications, particularly anterior segment ischemia: (1) using no sympathomimetics with local anesthesia; (2) using topical sympathomimetics minimally; (3) using supplemental 100% oxygen for 48 hours after surgery; (4) avoiding excessive manipulation of extraocular muscles; (5) using transscleral diathermy or cryotherapy minimally and avoiding the long ciliary arteries; (6) avoiding the use of wide encircling scleral buckling elements; (7) limiting the use of expansile concentrations of intraocular gases; (8) utilizing internal drainage of subretinal fluid; and (9) closely monitoring and treating elevated intraocular pressure, avoiding the use of carbonic anhydrase inhibitors.

Treatment of anterior segment ischemia is difficult. When available, oxygen by mask, especially under hyperbaric conditions, and oxygen delivery to the anterior segment via goggles may be helpful in preventing and treating anterior segment ischemia.^65,144 We used this technique successfully to reverse anterior segment ischemia following scleral buckling surgery in an SC disease patient of ours.

Further research is needed to determine the cellular and rheologic factors contributing to the microvascular occlusions in sickle cell disease, as well as therapeutic measures to reduce sickling and secondary occlusions. Potential modalities include increasing Hb F levels, replacing the abnormal sickle cell β-globin gene, stabilizing the RBC membrane, reducing ISC levels, decreasing sickled cell adhesiveness, and selective arteriolar vasodilatation.^180–183 Several pharmacologic modalities have demonstrated efficacy in enhancing γ-globin synthesis (Hb F) in patients with homozygous sickle cell anemia, and this in turn has been shown to improve the filterability of RBCs and to reduce the number of dense ISCs. Most promising is the use of nontoxic metabolites, such as sodium butyrate and its analogues.¹⁸⁴

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