21.1 Sickle Cell Hemoglobinopathies

Sickle cell hemoglobinopathies originated in Central and West Africa. They have since become the most common hemoglobinopathy affecting humans and are now found throughout the world, including North America (Table 21-1) and Mediterranean countries, such as Italy, Greece, Saudi Arabia, and Israel.

Of those individuals with sickle hemoglobinopathies, proliferative retinopathy occurs in about 45% with sickle cell hemoglobin C disease (SC), 17% with sickle thalassemia hemoglobinopathy (SThal), and 14% with sickle cell disease (SS) (Table 21-1). ¹ In individuals with sickle cell trait (AS) and hemoglobin C trait (AC), proliferative retinopathy may also develop; however, the incidence is likely to be very low. ^{2 ,​ 3} The incidence of proliferative disease associated with homozygous hemoglobin C (CC) is not known. The development of proliferative disease is not only genotype dependent but also age dependent. In some eyes, proliferative sickle cell retinopathy may be clinically detectable in the first 10 years of life, but it is most likely to become manifest between 15 and 30 years of age. ⁴ The greatest risk of proliferative sickle cell retinopathy in individuals with SC is between 20 and 34 years of age, and in individuals with SS is between 40 and 50 years of age.

21.2 Pathogenesis and Genetics

In the erythrocytes of healthy individuals, hemoglobin A possesses two alpha and two beta polypeptide chains, each with a ferroprotoporphyrin heme ring. The two alpha genes, located on chromosome 16, and the one beta gene, located on chromosome 11, encode these chains.

The word hemoglobinopathy refers to those diseases associated with structurally abnormal hemoglobin. In persons with sickle cell hemoglobinopathies, hemoglobin A is abnormal; the glutamic acid residue, in at least one of the beta polypeptide chains, is replaced by either valine to form hemoglobin S or lysine to form hemoglobin C. When this abnormal hemoglobin occurs in combination with normal hemoglobin A or abnormal hemoglobin S or C, a variety of sickle cell hemoglobinopathies may develop (Table 21-1). A thalassemia may result when there is an inadequate rate of synthesis of either the alpha or beta chain; an SThal hemoglobinopathy is diagnosed when sickle hemoglobin is also present.

When an erythrocyte with abnormal hemoglobin is exposed to hypoxic, acidotic, or hyperosmolar conditions, it may assume a sickle shape. The sickled red blood cell is less pliable than a normal erythrocyte. Consequently, blood viscosity increases, and vasoocclusive events may occur. Vasoocclusion in the peripheral retinal vasculature initiates the cascade of events in proliferative sickle cell retinopathy that may culminate in vitreous hemorrhage or retinal detachment.

Individuals with larger quantities of abnormal hemoglobin in their red blood cells and a greater likelihood for the abnormal hemoglobin to sickle under less than ideal conditions may be more likely to have systemic manifestations of the disease. ⁵ Systemic morbidity is greater in SS homozygotes than in persons with other hemoglobinopathies; this may be partly attributed to the high concentration (more than 90%) of hemoglobin S within the red blood cells of these patients. Intravascular sickling may develop in the microvascular circulations of subjects with SS disease, leading to erythrocyte sludging, hemolysis, shorter survival, and anemia despite increased red blood cell synthesis. Repeated infarcts of the bone marrow may lead to bony sclerosis and trabeculation, demonstrated on skull, vertebral, and long-bone X-ray films, as well as aseptic necrosis of the femoral head. Sickling in precapillary arterioles may lead to abdominal discomfort, pulmonary infarcts, joint aches, and strokes.

Systemic findings are less common in individuals with SC, SThal, and AS hemoglobinopathies. SC and SThal heterozygotes usually have a mild or unremarkable systemic course with very few crises annually and a slightly depressed hematocrit level. Despite minimal systemic manifestations, however, patients with SC and SThal are more likely than patients with SS to have retinal manifestations of their disease (Table 21-1). The discrepancy between the severity of systemic and retinal findings in the various hemoglobinopathies is not well understood. The AS heterozygote rarely suffers either systemic or retinal morbidity, except under severe hypoxic stress, because only about half of the hemoglobin is abnormal. Nevertheless, in the AS heterozygote, a hyphema may result in ocular morbidity that may be just as severe as in the eyes of patients with other hemoglobinopathies. ⁶

Proliferative sickle cell retinopathy is more likely to develop in individuals with SC and SThal hemoglobinopathies than in those with other hemoglobinopathies, and an explanation for this has not been well documented. The sickling rate, blood viscosity, and hematocrit are interrelated variables that are believed to be important in the pathogenesis of sickle retinopathy. ^{5 ,​ 7} Erythrocyte sickling tends to occur when red blood cells with sickle hemoglobin encounter relatively acidotic, deoxygenated, or hyperosmolar environments. The decreased pliability of sickled cells hinders effective circulation through the microvascular network, leading to increased blood viscosity. In the retinal microvasculature, blood viscosity is determined largely by the red blood cell concentration. Therefore, an even higher viscosity results when individuals with higher hematocrits have a sickling episode; this contributes to additional vasoocclusions. For example, the hematocrit in SC and SThal heterozygotes is significantly higher than in SS patients. Consequently, SC or SThal heterozygotes have a higher blood viscosity than SS patients and, therefore, may be subject to a greater number of vasoocclusive events in the retinal microvasculature, where erythrocyte characteristics play a pivotal role. Even though SS individuals have an increased number of sickled erythrocytes, the lower hematocrit, and presumably lower viscosity, may offer relative protection against the occurrence of vasoocclusive events in the retinal vasculature.

21.3 Clinical Features and Histopathology

Sickling of red blood cells may occur in any microvascular system of the eye. The various signs and symptoms along with any effect on the visual outcome depend on the anatomic location of the vasoocclusive event.

Anteriorly, microvascular occlusions in the bulbar conjunctiva produce various clinically evident small-vessel irregularities. Among them is the classic comma sign. The presence of these comma-shaped vascular segments, although not pathognomonic for sickle cell disease, can be a useful diagnostic finding. ⁸ In general, conjunctival vascular changes are seen in about 70% of SS, 34% of SC, and 17% of SThal patients. ⁸ They are completely asymptomatic.

Occlusions of iris vessels can also occur. Clinically, these typically present as asymptomatic, white, atrophic patches on the iris surface. If extensive, there can be pupillary irregularity.

The presence of a hyphema, surgical or traumatic in nature, has special significance in a patient with any type of sickle hemoglobinopathy. ⁶ In general, there is greater potential for ocular damage with a hyphema in these eyes than in eyes of individuals without sickle cell disease. This is mainly because the relatively low oxygenation and high ascorbate levels of the anterior chamber promote sickling. Compared with normal red blood cells, sickled cells are more prone to block aqueous outflow through the trabecular meshwork and lead to higher increases in intraocular pressure. Furthermore, blood flow through the central retinal artery and to the optic nerve may be more likely to be compromised for a given level of increased intraocular pressure in patients with sickle cell disease. Therefore, the intraocular pressure must be monitored closely and not allowed to remain higher than about 24 mm Hg for longer than 24 hours. ⁶ If intraocular pressure control is not adequate with medical management, surgical intervention to evacuate the hyphema and quickly lower the eye pressure is needed. Of note is that it is best to avoid repetitive use of carbonic anhydrase inhibitors, particularly acetazolamide, and osmotic agents in this setting, as they may promote sickling by causing acidosis and hemoconcentration.

Posteriorly, the retinal findings are most important and may be subdivided into nonproliferative and proliferative manifestations. Related nonproliferative changes include abnormalities of the optic nerve head, macula, choroid, and vitreoretinal interface, all of which are detailed in the following paragraphs.

21.3.1 Nonproliferative Manifestations

Salmon patch hemorrhages, iridescent spots, and black sunburst lesions characterize nonproliferative or background sickle cell retinopathy. These three manifestations may be pathogenetically related.

Salmon Patch Hemorrhage

A salmon patch hemorrhage is an oval-shaped aggregation of superficial intraretinal or preretinal blood. Such patches are usually found next to medium-sized retinal arterioles in the equatorial retina and may be up to one disc diameter in size. ⁹ They have well-demarcated boundaries and a dome-shaped or flattened appearance. They initially appear red in color, but after several days often take on a more pink or orange (salmon-colored) tint (Fig. 21-1). The hemorrhages usually remain localized on or within the retina, but they can extend into either the subretinal space or vitreous cavity. Unless blood breaks through into the vitreous cavity, the hemorrhages are usually asymptomatic. Sudden arteriolar occlusion by sickled red blood cells with later rupture of the arteriole is thought to be the mechanism of salmon patch formation.

Iridescent Spots

As the salmon patch hemorrhage resolves, the retina may return to normal. In some cases, however, a faint dip or depression develops in the area of the hemorrhage after it resorbs. In others, particularly those with a significant intraretinal component, a small retinoschisis cavity containing yellowish spots may form M. These glistening specks have been referred to as iridescent spots and represent multiple hemosiderin-laden macrophages (Fig. 21.2). ¹⁰ The reported incidence varies within the literature, but such schisis cavities have been found in up to 33% of SC, 18% of SThal, and 13% of SS individuals. ^{2 ,​ 7 ,​ 11 ,​ 12} Histopathologically, the schisis space is lined posteriorly by the neurosensory retina and anteriorly by the internal limiting membrane.

Black Sunburst Lesion

The black sunburst lesion is an oval or round collection of retinal pigment epithelium (RPE) that has migrated into the neurosensory retina. ⁷ These focal pigmented spots classically have spiculated or stellate borders resulting from accumulation of the pigment around small, branching blood vessels (Fig. 21-1). Refractile granules, similar to iridescent spots, may also be seen within the lesions. The location and size of black sunbursts are similar to those of salmon patch hemorrhages. The reported incidence of black sunburst lesions is up to 41% in SC heterozygotes, 35% in SS patients, and 20% in SThal individuals. ^{11 ,​ 12}

Histopathologically, black sunbursts show focal RPE hyperplasia, hypertrophy, and intraretinal migration. The overlying retina may also be degenerated and thinned. Diffuse deposits of iron, melanin pigment and hemosiderin-laden macrophages may coexist. ¹⁰

Black sunbursts may come about in several ways. They may evolve from a salmon patch hemorrhage that has dissected into the subretinal space and promoted a localized RPE reaction. ¹³ They may also represent secondary RPE changes from choroidal neovascularization (CNV). ¹⁴ Lastly, they may form as a result of a focal choroidal occlusion. ¹⁴

Controversial Points

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  The black sunburst lesion may evolve directly from a salmon patch hemorrhage, from underlying CNV, or from a focal choroidal occlusion. The most common pathogenesis is not known.

Special Considerations

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  Salmon patch hemorrhages are nonproliferative lesions that may occasionally extend into the vitreous, resulting in floaters and decreased visual acuity. In rare instances, these lesions can result in significant visual compromise, necessitating surgical evacuation of the hemorrhage.

21.3.3 Macula

Microvascular changes in the macula and along the temporal raphe have been observed in 36% of SC, 32% of SS, and 20% of SThal patients. ¹⁷ These abnormalities include foveal avascular zone (FAZ) irregularities, enlarged precapillary arterioles and capillaries, microaneurysm-like dots, cotton-wool spots, and hairpin-shaped venular loops with adjacent capillary nonperfusion. Changes in the parafoveal vascular network may represent the initial vasoocclusive process that can progress to FAZ enlargement and, rarely, macular infarction (Fig. 21-3). ¹⁸ Central retinal thinning (or atrophy) can result, and this may manifest ophthalmoscopically as a dark oval or circular concavity with a bright central reflex, the so-called macular depression sign. Unless the parafoveal vascular disruption is extensive, visual acuity is often not significantly affected.

The temporal vascular raphe begins at the fovea and extends temporally toward the periphery. The end-arteriolar branches that meet at the raphe may also become plugged with sickled red blood cells. Spectral-domain optical coherence tomography (SD-OCT) of the retina of sickle cell patients often demonstrates focal thinning of the macula in this area, revealing structural changes due to subclinical vascular occlusions (Fig. 21-4). ¹⁹ No definite relationship between the extent of nonperfusion along the raphe and that in the periphery exists, despite the vascular similarities in these regions. ¹⁷

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