Chapter 119 – Hemoglobinopathies
ALLEN C. HO
• A spectrum of ocular abnormalities, including peripheral “sea fan” retinal neovascularization, that results from an inherited defect in the synthesis of the hemoglobin molecule.
• Macular ischemia.
• Retinal vascular peripheral nonperfusion.
• Retinal hemorrhages: “salmon patches,” “iridescent spots,” and “black sunbursts.”
• Peripheral retinal neovascularization: “sea fans.”
• Conjunctival comma-shaped capillaries.
• Iris atrophy and posterior synechiae.
• Sickle disc sign.
• Macular depression sign.
• Arteriovenous anastomoses.
• Vitreous hemorrhage.
• Retinal detachment.
Normal red blood cell hemoglobin comprises four polypeptide globin chains, each associated with a central heme ring (ferroprotoporphyrin). The globin chains consist of an identical pair of ß polypeptide chains and an identical pair of ß polypeptide chains. The sickle-cell hemoglobinopathies are characterized by a genetic error in ß chain synthesis, which results in abnormal function of the hemoglobin molecule. Under certain circumstances, the imperfect globin chains induce pathological alterations in red blood cell morphology. These occur particularly in conditions of ischemia and metabolic stress. Owing to their crescent shape, the altered red blood cells are labeled “sickle cells.”
Systemic and ocular sequelae are well described. Interestingly, the severity of systemic symptoms does not typically correlate with the severity of ocular manifestations. The most severe systemic complications are observed in sickle SS disease, while severe ocular features are most commonly noted in patients with sickle SC or sickle thalassemia (S-Thal) disease. In general, vision-threatening sequelae of the sickle hemoglobinopathies are secondary to ischemia or peripheral retinal neovascularization.
EPIDEMIOLOGY AND PATHOGENESIS
Hemoglobinopathies can be characterized electrophoretically as well as by the genetic mutations that lead to abnormal amino acid substitutions in the ß globin chain. Normal adult hemoglobin with two normal a and ß chains is termed hemoglobin A. Sickle hemoglobin, known as S, was initially described by Pauling and others in 1949 as a single point mutation that results in substitution of the amino acid valine for glutamic acid at the sixth position. The substitution of lysine for glutamic acid at this position results in the manufacture of hemoglobin C. The sickle hemoglobinopathies are caused by qualitative errors in globin chain synthesis. Inadequate production of either normal or abnormal globin chains, a quantitative error in globin synthesis, is referred to as thalassemia (Thal).
Because these mutations are inherited, heterozygous and homozygous conditions exist. For example, normal hemoglobin comprises normal homozygous AA globin chains. Classic sickle cell anemia, or SS disease, usually arises when two parents who have sickle trait (AS) disease each pass on their single abnormal S globin chain mutation. If hemoglobin S is inherited from one parent and hemoglobin C from another, a double heterozygous form of hemoglobin, known as sickle SC disease, is created.
Thalassemia mutations can coexist with normal hemoglobin A or with various abnormal hemoglobin chains to produce double heterozygotes, such as those with S-Thal disease. In the United States, African-Americans account for the majority of patients afflicted by the hemoglobinopathies. In this population, the prevalence of sickle trait disease is estimated to be in the range of 5–10%. Clinical sickle AC disease is believed to afflict up to 5% of this group; double heterozygotes—such as those with SS (afflicting approximately 0.4%), SC (approximately 0.1–0.3%), and S-Thal (approximately 0.5–1.0%)—are all less common than those who have at least one normal globin A chain.
Normal hemoglobin confers pliability to the oval-shaped red blood cells, which allows them to pass easily through the microvasculature, where they deliver oxygen. Sickle hemoglobins, such as hemoglobin SS, result in red blood cells with a crescentic, elongated shape, particularly under conditions of hypoxia or acidosis. This causes the blood cells to stack, which further exacerbates local ischemia. A vicious circle of ischemia, red blood cell sickling, tissue hypoxia, and necrosis is set in motion.
Although sickle SS disease has the most severe systemic manifestations, hemoglobin SC and S-Thal have the most severe ocular manifestations. The reasons for this discrepancy are not clear. The more severe anemia of SS disease is associated with red blood cell counts lower than those in hemoglobin SC and S-Thal disease. Relative anemia may leave the remaining red blood cells less disposed to sludging in the circulation.
Because many of the ocular complications of sickle disease are time dependent, their overall prevalence is unknown. From a cross-sectional study, the incidence of proliferative sickle retinopathy (PSR) has been estimated. Approximately 40% of hemoglobin SC patients and 20% of hemoglobin SS patients can be expected to develop PSR.
The hemoglobinopathies described here constitute only a small sampling of the reported mutants of hemoglobin production. Originally, the abnormal hemoglobin chains were described with letters such as S and C. The subsequent explosion of descriptions of globin chain mutants has led to other names, including some that use the geographical location where the hemoglobin was discovered (e.g., hemoglobin Zurich).
Nearly all ocular or periocular structures can be affected by the sickle hemoglobinopathies. Classic anterior segment findings
include conjunctival comma-shaped capillaries that represent intravascular sludging of sickling red blood cells ( Fig. 119-1 ). Sectorial iris atrophy represents areas of anterior uveal ischemia. Associated anterior or posterior synechiae may occur. A mild anterior chamber cell and flare reaction may be observed secondary to incompetence of the blood-ocular barrier. The anterior segment manifestations generally do not pose significant risks for vision loss.
Posterior segment manifestations of sickle hemoglobinopathies may be observed in the vitreous body, optic disc, retina, and subretinal structures. Vitreous hemorrhage secondary to peripheral retinal neovascularization may develop. The optic disc may demonstrate sludging red blood cells within prepapillary retinal capillaries, which appear as small, dark spots or vascular lines on the surface of the optic disc head. The “macular depression sign” presumably represents atrophy and thinning of the neural macula, which results in an oval depression of the bright central reflex  ( Fig. 119-2, A ). Red-free illumination highlights the macular depression sign; this area of macular ischemia may be associated with a decrease in vision. More debilitating macular ischemia can result in frank macular infarction with an enlarged foveal avascular zone secondary to multiple retinal arteriolar occlusions.    This type of macular ischemia may have an insidious, progressive course. Fluorescein angiography reveals irregularity in or enlargement of the foveal avascular zone, with adjacent areas of retinal capillary nonperfusion and retinal vascular remodeling (see Fig. 119-2, B ). Retinal arterial microaneurysms are less commonly observed, although cotton-wool spots in the posterior segment are not uncommon.
Both nonproliferative and proliferative forms of sickle retinopathy may be observed, including nonspecific, nonproliferative retinal vascular changes, such as retinal arteriolar sclerosis and venous tortuosity. Retinal arteriolar sclerosis may be observed in areas where there is diffuse capillary nonperfusion that reflects prior retinal vascular occlusion. Venous tortuosity is observed in as many as half of all patients who have SS disease and in one third of patients who have SC disease. Neither of these retinal findings is pathognomonic of sickle retinopathy, since they are observed in a variety of other conditions. Angioid streaks are described in association with sickle-cell disease.
Other nonproliferative retinal findings are more characteristic of sickle hemoglobinopathies.    Salmon-colored retinal hemorrhages are preretinal or superficial intraretinal hemorrhages that occur adjacent to a retinal arteriole and are often found in the equatorial retina ( Fig. 119-3 ). Histopathologically, they dissect into the vitreous cavity or into the subretinal space. The salmon hue is attributed to an evolution of color changes; the initial presentation is bright red. These hemorrhages are believed to result from the rupture of a medium-sized retinal arteriole
Figure 119-1 A classic anterior segment finding in sickle eye disease is comma- or S-shaped conjunctival capillaries. These vessels represent areas of red blood cell sickling or sludging within the capillary bed. (Courtesy of William Tasman, MD.)
due to ischemic vasculopathy. They usually resolve with few sequelae, although a retinoschisis cavity lined with iridescent refractile yellow particles may persist. The schisis cavity is created by resorption of the intraretinal hemorrhage, and the iridescent particles represent macrophages that have engulfed hemoglobin and blood breakdown products.
If the intraretinal hemorrhage dissects into the subneural retinal space and disturbs the retinal pigment epithelium, a black sunburst lesion may result ( Fig. 119-4 ). These dark, irregularly shaped, spiculated or stellate lesions are the result of retinal pigment epithelial hyperplasia and intraretinal migration.  Because they are secondary to equatorial retinal hemorrhages, they are located in the same area and generally do not result in significant visual symptoms.
Because PSR can lead to severe vision loss, it was classified into five stages by Goldberg.   This progression of retinopathy typically occurs in the third or fourth decade of life but has been noted as early as the second decade. The five stages are as follows:
Peripheral arteriolar occlusions
Peripheral retinal arteriolar occlusion can leave large areas of anterior retinal capillary nonperfusion, which is highlighted well by fluorescein angiography. Curiously, retinal venous occlusion is uncommon in patients who have sickle-cell disease. Occluded arterioles initially appear dark red but subsequently evolve into “silver wire” vessels. Peripheral arteriolar-venular
Figure 119-2 Sickle SC disease. A, Macular ischemia with the macular depression sign and perifoveal vascular remodeling. B, Fluorescein angiogram of the same patient demonstrating an irregular and moth-eaten perifoveal capillary network and vascular telangiectasia. (Courtesy of William Tasman, MD.)
anastomoses evolve, so retinal arterial blood is shunted into retinal venules. These abnormal arteriolar-venular anastomoses can be seen at the junction of perfused and nonperfused retina, typically just peripheral to the equator. These changes often are difficult to observe ophthalmoscopically but are seen easily with fluorescein angiography.
Retinal neovascularization in a sea-fan configuration is the hallmark of PSR ( Fig. 119-5 ). The neovascularization extends from the border zone of perfused and nonperfused retinae ( Fig. 119-6 ). Initially, a sea fan is supplied by one major feeding retinal arteriole and one major draining retinal venule. Over the course of time, an arborization of the neovascular complex occurs in the peripheral retina. Growth typically is circumferential along the border of perfused and nonperfused retina, rather than radial. Sea fans most commonly are observed in patients who have SC disease or S-Thal disease and are rare in patients who have other hemoglobinopathies.  Fluorescein angiography demonstrates massive leakage of dye into the vitreous. Generally, the sea fans represent a progressive proliferative retinopathy, which exposes the patient to the risks of vitreous
Figure 119-3 An equatorial “salmon patch” intraretinal hemorrhage with periarteriolar hemorrhage. These peripheral hemorrhages may lead to retinoschisis cavities lined with iridescent particles that comprise hemoglobin degradation products. The vision is 20/20 (6/6). (Courtesy of William Tasman, MD.)
Figure 119-4 A black “sunburst” retinal lesion. This is caused by a hemorrhage that dissected into the subneural retinal space and disrupted the retinal pigment epithelium, which culminated in pigmentary migration. Note the spiculated borders. (Courtesy of William Tasman, MD.)
hemorrhage and retinal detachment. Sea fans may spontaneously involute, resulting in areas of grayish white fibrovascular tissues that often have residual perfused retinal vessels at their base. About 40–50% of sea fans may undergo some degree of autoinfarction during their course.
Vitreous hemorrhage is a common complication of retinal sea-fan formation; it may be spontaneous or induced by minor ocular trauma, and it may be limited or dense. Before this occurs, a patient who has PSR may be entirely visually asymptomatic. Patients who have limited vitreous hemorrhage experience floaters, while those who have dense vitreous hemorrhage have sudden severe vision loss. These hemorrhages may clear spontaneously with time or may persist to give ochre-colored vitreous membranes. It is not uncommon for a patient who has suffered one vitreous hemorrhage to experience recurrent vitreous hemorrhages.
Retinal sea fans may induce fibrovascular tissue on the surface of the retina that causes traction or rhegmatogenous retinal detachments ( Fig. 119-7 ). Circumferential sea-fan involvement can cause peripheral traction retinal detachment through areas of
Figure 119-5 Neural retina in a sickle SC patient. Note the partially regressed peripheral retinal neovascularization at the junction of the perfused retina (right) and the nonperfused retina (far left).
Figure 119-6 Fluorescein angiography. This demonstrates profound peripheral capillary nonperfusion (far left), retinal vascular remodeling, arteriovenous communications, and extensive leakage of fluorescein dye into the vitreous cavity from the sites of neovascularization.
Figure 119-7 Traction-rhegmatogenous retinal detachment. A retinal tear has developed at the site of peripheral neovascularization and fibrosis, leading to a combined traction-rhegmatogenous retinal detachment. (Courtesy of William Tasman, MD.)
perfused and nonperfused retina. In the areas of thin, nonperfused retina, atrophic, stretched retinal holes can develop to create combined traction and rhegmatogenous retinal detachments.
Most patients who present with the ophthalmic complications of sickle hemoglobinopathies are aware of their underlying red blood cell abnormality. However, patients with SC and S-Thal disease who have milder anemias and minimal systemic manifestations may be completely unaware of their systemic diagnosis when the ocular complications flare. A history of multiple hospitalizations secondary to painful crises, chronic end-organ damage, multiple infections, and bony abnormalities may be absent. These findings are more characteristic of hemoglobin SS patients.
Hemoglobin electrophoresis is necessary to characterize the abnormal globin chain type. A positive test for sickling, such as the metabisulfite preparation (sickle preparation) or the solubility test, indicates the presence of hemoglobin S but does not distinguish among SS, AS, and double heterozygotes such as S-Thal and SC.
Diagnosis of the ophthalmic manifestations of the sickle hemoglobinopathies is enhanced by careful examination of the conjunctiva, iris, anterior chamber, optic disc, and macula, with special attention paid to the subtle ocular manifestations of sickle-cell disease. Indirect ophthalmoscopy and peripheral retinal contact lens biomicroscopy are helpful to delineate retinal hemorrhages and proliferative changes.
Fluorescein angiography characterizes macular perfusion and peripheral retinal perfusion. Early sea-fan formation is highlighted well by fluorescein leakage. Diagnostic ultrasonography can characterize posterior segment anatomy when a media opacity occurs, such as from vitreous hemorrhage or ochre membranes.
Other causes of macular ischemia and peripheral retinal neovascularization, vitreous hemorrhage, and neural retinal detachment are given in Box 119-1 .
Patients who have classic sickle SS disease manifest a variety of systemic abnormalities, including anemia, bone marrow infarcts, bony sclerosis (e.g., vertebral “fishmouthing”), aseptic necrosis of the femoral head, ischemia of visceral organs, shortness
Differential Diagnosis of Hemoglobinopathies
OTHER CAUSES OF MACULAR ISCHEMIA
Retinal vascular obstruction
Embolic phenomena such as talc retinopathy
OTHER CAUSES OF PERIPHERAL RETINAL NEOVASCULARIZATION, VITREOUS HEMORRHAGE, AND RETINAL DETACHMENT
Proliferative diabetic retinopathy
Retinal vein obstruction
The ocular ischemic syndrome
Retinopathy of prematurity
Familial exudative vitreoretinopathy
of breath caused by pulmonary infarcts, and an increased susceptibility to bacterial infections, particularly salmonellosis caused by reticuloendothelial cell dysfunction.
Other hemoglobinopathies result in less severe systemic disease. In some, a mild anemia may be the only manifestation.
Despite an understanding of the molecular pathogenesis of sickle hemoglobinopathies, there is currently no effective form of therapy that prevents the sickling of red blood cells or the ensuing ocular complications. For example, no intervention has been shown definitively to halt the progression of macular ischemia, although case reports exist of improvement after exchange transfusion and oxygenation     or hyperbaric oxygenation.
Most treatment efforts focus on altering the course of PSR to reduce the chance of vitreous hemorrhage and retinal detachment. Cryotherapy, diathermy, xenon arc photocoagulation, and argon laser photocoagulation have all been employed to treat peripheral retinal neovascularization. Cryotherapy has been used to treat peripheral retinal neovascularization in the presence of vitreous hemorrhage when the neovascular proliferation is visualized only partially and when vitreous hemorrhage precludes treatment with laser photocoagulation. Both single freeze-thaw and triple freeze-thaw techniques have been described. However, cryotherapy has been largely abandoned because of the significant complication rate. Ocular diathermy treatment to obliterate peripheral retinal neovascularization and associated feeder vessels has been reported, but it too is saddled with a high rate of complications.
Various methods of laser photocoagulation effectively induce regression of peripheral neovascularization.      Feeder-vessel laser photocoagulation requires intensive treatment with high energy and is more likely to be complicated by chorioretinal or choriovitreal neovascularization, retinal detachment, and vitreous hemorrhage.
Scatter laser photocoagulation of areas that surround sea-fan proliferation and associated areas of ischemic retina induces regression of these lesions. The rationale is to ablate areas of ischemic retina that are stimulating neovascular proliferation. Two laser techniques have been described, and both can induce successful regression of neovascularization. The first is a localized treatment confined to areas anterior to the patent neovascular fronds. The second uses a 360° peripheral, circumferential retinal scatter technique to the anterior retina.  The rationale of the 360° scatter treatment is to induce regression of existing peripheral retinal neovascularization and to prevent the formation of any future neovascularization. In general, these techniques can be performed with light- to moderate-intensity burns approximately 500?mm in diameter placed approximately one burn
width apart. At this time, scatter laser photocoagulation, either localized or circumferential, is the treatment of choice to prevent complications secondary to peripheral sea-fan proliferation.
Vitreous hemorrhage secondary to PSR may be followed for up to 6 months to await spontaneous clearing. If areas of retinal neovascularization can be identified through the vitreous hemorrhage, the associated anterior retina should be treated with scatter laser photocoagulation. Fluorescein angiography or fluorescein angioscopy using an indirect ophthalmoscope and a blue light filter may be used to identify retinal neovascularization in cases of limited vitreous hemorrhage. When the retina is not well visualized, it is important to follow these eyes with ultrasonography to rule out retinal detachment. A minority of patients progress to retinal detachment with or without laser treatment.
Surgery on patients who have sickle hemoglobinopathies is fraught with ocular and systemic pitfalls. A preoperative work-up to assess the severity of anemia, hemoglobin electrophoretic status, and overall systemic condition is critical. Intraoperative and postoperative systemic complications include thromboembolic events such as pulmonary or cerebral embolism. The role of exchange transfusions in reducing the risk of a sickle-cell crisis precipitated by general anesthesia remains unclear. These exchange transfusions are performed to achieve 50–60% hemoglobin A, as indicated by electrophoresis, with a hematocrit of 35–40%. Exchange transfusions may reduce the rate of anterior segment ischemia and optic nerve and macular infarcts, which can occur with intraocular pressures (IOPs) as low as 25?mmHg. Currently, however, no compelling reason exists to perform transfusions.
Although the role of exchange transfusions is in question, adequate hydration and supplemental oxygen are often administered during the perioperative and operative periods. If possible, surgery should be performed under monitored local anesthesia; vasoconstrictive agents, such as epinephrine (adrenaline) in the anesthetic block and pupillary dilating agents, should be avoided. Many advocate lowered IOP to both maximize intraocular perfusion and avoid hemoconcentration. Single doses of carbonic anhydrase inhibitors or intravenous mannitol may be administered to lower the IOP, but these agents should not be used repetitively. Even transient elevations in IOP should be avoided, particularly if a scleral buckle is used, to avert vitreous hemorrhage and macular ischemia.
The possibility of anterior segment ischemia is reduced by avoiding treatments in the horizontal meridians, which harbor the long posterior ciliary arteries. For the same reason, manipulation of horizontal and vertical rectus muscles should be performed with care; transection of these muscles should be avoided. Drainage of subretinal fluid is often desirable, since this may minimize the elevation of IOP if a scleral buckle is employed. With current vitrectomy instrumentation, fluctuations in IOP during vitrectomy surgery are less common. A current ultrasonogram to elucidate the intraocular anatomy is important in cases of vitreous hemorrhage. The peripheral vitreous may be firmly attached to shallow areas of traction retinal detachment at the sites of fibrovascular proliferation and may not be well visualized intraoperatively, particularly when ochre-colored membranes are present.
In cases of combined traction-rhegmatogenous retinal detachment, the surgical goals include the release of areas of traction that elevate the retina and the removal of fibrovascular proliferation that may prevent the retinal tear from settling flat. Once this is achieved, scatter endolaser photocoagulation is performed. Postoperatively, the patient’s IOP must be monitored closely, particularly if intraocular gas is used.
Anterior segment ischemia does not usually occur if care is taken to avoid elevations of IOP and if the anterior ciliary circulation is not violated.  Anterior segment necrosis results in persistent red eye, corneal decompensation, uveitis, and synechiae formation.
Patients who have sickle hemoglobinopathies and who develop postoperative or posttraumatic hyphema are at risk for posterior segment ischemia or infarction, even at mildly elevated IOPs. Low oxygen tension and high ascorbic acid levels in the anterior chamber promote sickling of red blood cells, which can obstruct the trabecular meshwork and lead to a greater elevation of IOP. Macular infarction has been reported with IOPs as low as 25?mmHg. Therefore, aggressive lowering of IOP to less than this level is indicated. Some authors recommend early paracentesis to reduce the IOP in acute situations.
COURSE AND OUTCOME
The course for patients who have ocular complications secondary to sickle hemoglobinopathies is variable.  Untreated, the incidence of blindness from PSR is about 12%. Clearly, with modern laser and vitrectomy techniques, the risk in treated eyes is less. Patients who require intraocular surgery for vitreous hemorrhage or retinal detachment have a higher risk of systemic and postoperative ocular complications, including anterior segment ischemia and optic disc or macular infarction. Patients whose PSR is rendered quiescent with laser photocoagulation may enjoy excellent vision in the long term. In one study of long-term follow-up following laser photocoagulation, only 4% of treated eyes had a repeat vitreous hemorrhage, versus 66% of untreated eyes. Fortunately, severe visual loss was rare in both groups.
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