While many hemoglobinopathies exist, those resulting in proliferative retinopathy are limited to sickle cell disease. Thalassemia major is associated with a nonproliferative pigmentary retinopathy. The pigmentary changes are believed to be secondary to the liberation of free iron as a result of hemolysis of red blood cells that contain the affected hemoglobin. Homozygous sickle cell disease (SS disease), sickle cell C disease (SC disease), and sickle cell-thalassemia disease (S-Thal disease) are common hemoglobinopathies that can present with mild-to-severe proliferative retinal findings.
Sickle cell hemoglobinopathy encompasses a group of inherited genetic disorders, which cause erythrocytes to become sickled and affect multiple organ systems. The rigid sickled erythrocytes lead to vascular occlusion, which results in retinal hypoxia, ischemia, and neovascularization. If this series of events does not stabilize or reverse with recanalization of the occluded retinal vessels, the subsequent end-stage results may be retinal infarction and/or detachment.
In 1910, James Herrick, a Chicago physician, first described sickle cell anemia, "The shape of the RBC [red blood cell] was very irregular." What especially attracted attention was the large number of "thin, elongated, sickle-shaped and crescent-shaped forms."
In 1930, ocular changes associated with sickle cell disease were noted.
In 1949, Itano and Pauling described the association of sickle cell anemia with abnormal hemoglobin Hb S, which could be differentiated from Hb A by electrophoresis.
In 1957, Ingram showed that hemoglobin Hb S differed from normal hemoglobin (Hb A) by the single amino acid substitution.
In 1959, Lieb and coworkers associated angioid streaks with sickle cell disease.
In 1966, Welch and Goldberg introduced and described much of the modern terminology associated with sickle cell disease with respect to ocular changes.
In 1971, Goldberg proposed a classification for sickle cell retinopathy.
Hemoglobin molecules are found exclusively in erythrocytes, where their main function is to transport oxygen to tissues. Hb A, the major hemoglobin in adults, is composed of 4 polypeptide chains, 2 alpha chains and 2 beta chains (alpha2 beta2) held by noncovalent bonds. The heme and the globin molecules together form hemoglobin, which can bind up to 4 oxygen molecules. The genes coding for alpha and beta globin chains are located on chromosome 16 and chromosome 11, respectively.
The widely accepted pathogenesis for sickle cell retinopathy is vasoocclusion that leads to retinal hypoxia, ischemia, infarction, neovascularization, and fibrovascularization. In sickle cell anemia, the amino acid substitution valine for glutamate occurs on the beta chain at the sixth position. This substitution, combined with conditions that may promote sickling (ie, acidosis, hypoxia), triggers the deoxygenated Hb S to polymerize, making the erythrocyte rigid. This rigidity is partially responsible for the vasoocclusion.
Vasoocclusion also is in part due to the interaction between sickled cells and the vascular endothelium. The adherence of sickled cells to the endothelium triggers an inflammatory process with the release of inflammatory agents. The activated endothelia are procoagulant, thereby inducing further adherence of sickled cells to the endothelium. The activated endothelium and rigid sickled cells bind to von Willebrand factor and thrombospondin, which is secreted by activated platelets. The result of this cascade is vascular stasis, hemolysis, and vasoocclusion of the capillary beds.
United States
About 10% of African Americans have an abnormal hemoglobin gene. About 8% of African Americans are heterozygous for Hb S. In the United States, sickle cell anemia primarily occurs in the black population, with approximately 0.2% of African American children afflicted by this disease. The prevalence in adults is lower because of the decrease in life expectancy.
Sickle cell anemia is a homozygous-recessive disorder, that is, the individual receives 2 mutant genes that code for the variant beta globin chain. Sickle cell anemia is most common where the Hb S gene is inherited from both parents, each of whom is a healthy carrier of the gene (Hb AS).
Sickle cell C disease is the second most common form. The hemoglobinopathy results from inheriting 1 Hb S gene and 1 Hb C gene, which is common in West African populations.
Sickle cell-thalassemia disease is the third most common hemoglobinopathy.
Different genes within a population determine the frequency of sickle cell disease at birth. The inheritance pattern for hemoglobinopathies is autosomal-recessive (a mendelian pattern). If each parent carries 1 Hb S gene, a 25% chance exists for offspring to have sickle cell disease, a 50% chance for them to have the carrier state, and a 25% chance for them to have normal hemoglobin. The frequency for passing the mutated gene is the same for each pregnancy, regardless of the outcome of the previous pregnancy. With each pregnancy, a 75% chance exists that the newborn will not have sickle cell anemia.
International
See Race.
Sickle cell trait (Hb AS): These patients generally have a normal life expectancy with no systemic or ocular problems. Cases of significant retinopathy are rare. The erythrocytes are likely to sickle and cause splenic infarction only in cases of severe hypoxia, such as with flight in unpressurized aircraft.
Sickle cell anemia: This disease is not manifested during the neonatal period because the primary hemoglobin molecule circulating at this time is Hb F (fetal hemoglobin). It is characterized by the substitution of the amino acid valine for glutamic acid at the sixth position of the beta globin chain. Systemic disease is more common and more severe than ocular disease.
Sickle cell-thalassemia disease: This hereditary disorder results from inheriting a sickle cell gene and a beta-thalassemia gene. It can be caused by gene deletions, substitutions, or mutations. Since it results in production of the beta globin chain, most of the synthesized Hb is Hb S. The beta-thalassemias are classified as disorders in which no globin chains are produced or normal globin chains are produced but in diminished quantities. An individual can have 2 types of sickle beta-thalassemia: Hb S betao thalassemia, a severe form with no hemoglobin A production, or Hb S beta+ thalassemia, a form with some Hb A production and, thus, a milder clinical course. Although systemic manifestations are generally mild when compared to Hb SS, ocular manifestations can be severe.
Sickle cell C disease: Hemoglobin C is a variant that results from a single amino acid substitution at the sixth position of the beta globin chain, in this case, lysine for glutamic acid. Patients with sickle cell C disease tend to have mild chronic hemolytic anemia, less frequent sickling crisis, and mild systemic findings. Like sickle cell-thalassemia disease, patients with sickle cell C disease tend to have severe ocular pathologies; they are at an increased risk for developing proliferative retinopathy changes.
Although sickle cell disease first was described in a black patient, it is not confined to patients of African ancestry. Sickle cell trait is more common in Central Africa but is infrequent in North and South Africa.
Of people living in Northern Greece, 20-30% reportedly have Hb S.
Of Saudi Arabians, especially in the Qatif oasis, 25% have the variant gene.
Other locations where sickle cell disease occurs include Turkey, Southern Italy, the Mediterranean, and Central India (Orissa, Madhya Pradesh, and Maharastra).
Theories for this distribution include the protective mechanism of Hb S heterozygosity against falciparum malaria. The gene is most prevalent in Central Africa, particularly in regions where malaria is endemic. The gene is thought to persist because heterozygosity protects slightly against falciparum malaria. Parasitized sickle cell (Hb AS) erythrocytes have a shorter lifespan, so the parasite probably cannot complete its development. Furthermore, the growth of trophozoites is inhibited by low oxygen tension.
No sexual predilection exists.
The prognosis is fair to good if consistent follow-up care is maintained with both an internist/hematologist and an ophthalmologist.
Patients with sickle cell disease should be well informed of their current and potential long-term complications.
Encourage patients to enroll at a local or regional sickle cell clinic.
Provide patients with information regarding a local support group.
Encourage parents to seek genetic counseling prior to starting a family.
Check for personal or family history of sickle cell trait or disease.
Inquire about painful systemic crises.
Patients may have visual complaints, varying in nature and intensity. Symptoms may range from transient flashes and floaters to sudden profound decrease in vision.
Rule out hyphema.
Check intraocular pressure (IOP).
Perform dilated fundus examination (DFE) via indirect ophthalmoscopy. (B-scan ultrasound can be performed if vitreous hemorrhage prevents DFE.)
Rule out differential diagnoses (see Differentials).
Changes in the posterior segment are divided into 4 major categories, as follows: optic disc changes, macular changes, nonproliferative retinal changes, and proliferative retinal changes.[1]
Classically, posterior segment changes are classified by either nonproliferative retinal changes (nonproliferative sickle retinopathy [NPSR]) or proliferative retinal changes (proliferative sickle retinopathy [PSR]). In NPSR, the retinal changes do not involve neovascularization as they do in PSR.
Vascular changes in the optic disc can be seen secondary to intravascular occlusions. These intravascular occlusions primarily affect the small vessels on the surface of the optic disc.
These lesions appear as dark red spots or clumps on the nerve head, often called the disc sign of sickling. The proposed mechanism for this sign is the transient plugging of sickled (deoxygenated) erythrocytes.
Fluorescein angiography (FA) reveals segments of linear or Y-configuration of hypofluorescence that correspond to the dark red spots. Blood flow through these vessels (as seen on angiography) is not impaired.[2] Like conjunctival vascular changes, these lesions are transient and do not produce any appreciable visual symptoms.
Optic nerve neovascularization is a rare complication of hemoglobinopathies.
Optic disc changes appear to be more common in patients with sickle cell anemia than in those with sickle cell C disease or sickle cell-thalassemia disease.
Sickle cell retinopathy commonly occurs in the periphery, but macular changes also have been well documented.
Macular changes or sickling maculopathy can manifest acutely or chronically, occurring in patients with sickle cell disease, sickle cell C disease, and sickle cell-thalassemia disease.
Acute sickling maculopathy generally arises from acute vascular occlusion to the retina.
Involved vessels include the central retinal artery and its branches.
Acute vascular occlusion, although infrequent, can lead to acute retinal ischemia with subsequent infarction.
Acute retinal infarction may result in the complete loss of vision or can lead to central or paracentral scotomas, which may become incapacitating.
Chronic sickling maculopathy is more common and can be seen in up to 30% of the sickle cell C disease population. Clinically, signs of chronic sickling maculopathy are difficult to detect because these changes represent architectural alterations of the fine macular vasculature. Since these changes are insidious, conduct a thorough ocular examination.
Clinically, macular depression may be seen. This results when thinning and atrophy of the retina occurs secondary to retinal ischemia. This concave-shaped lesion, located next to the macula, presents on retinal biomicroscopy as a dark circle with a bright central reflex.
Although uncommonly seen, another PSR-associated sign is the macula hole. Predisposing factors are traction on the macula and vasoocclusive events. Traction on the macula results from neovascularization in the periphery and in the optic nerve. Vasoocclusive events in the macular, peripapillary, and perifoveal vessels (ie, capillaries) lead to local ischemia, infarction, retinal thinning, atrophy, and, ultimately, macula hole formation. Other signs include microaneurysms, enlarged segments of terminal arterioles, hairpin-shaped vascular loops, and an abnormal foveal avascular zone.
While abnormal, nonproliferative sickle retinal changes generally are asymptomatic and do not require treatment.
Venous tortuosity
Although common, it is not pathognomonic of sickle cell disease.
Venous tortuosity is due to decreased perfusion/circulation (ie, venous stasis, arteriolar-venous shunting).
Salmon patch hemorrhage
An intraretinal hematoma develops when sickled erythrocytes suddenly occlude the arterioles with subsequent blowout of the vessel wall.
Often found in the mid periphery, it varies in size and is round or ovoid in shape.
The hemorrhage often is confined to the neural retina, but it occasionally leaks through the internal limiting membrane or into the subretinal space.
The hemorrhage immediately appears bright red; over several days, it becomes an orange-red, salmon color for which it is named.
Black sunburst
This pigmented chorioretinal scar usually is found in the peripheral retina.
On ophthalmoscopy, these scars appear round or ovoid, measuring 1.5-2 disk diameters, have stellate or spiculate borders, and often are associated with iridescent spots.
Hemorrhage from retinal arteriolar occlusion can dissect between the neural retina and the retinal pigment epithelium (RPE), resulting in irritation and hypertrophy of the pigment epithelium and migration of pigmented cells into the area.
Angioid streaks
In 1959, Lieb and coworkers associated angioid streaks with sickle cell disease.
Appearing as pigmented striae that lie under the retinal vessels, angioid streaks are breaks in the Bruch membrane. They usually surround the disc, extending radially.
Angioid streaks are not specific to hemoglobinopathies but are seen in patients with other hemolytic anemia, Paget disease, Ehlers-Danlos syndrome, and pseudoxanthoma elasticum.
In hemoglobinopathies, incidence ranges from 1-6%.
The frequency of angioid streaks increases with age.
The pathogenesis of angioid streaks is generally controversial but that of sickle cell disease is even more confusing. The 4 most commonly proposed and accepted mechanisms of angioid streak development include the following:
Fibrovascular ingrowth can occur at the breaks.
Secondary changes may include the following:
These lesions are usually asymptomatic; however, in the presence of choroidal neovascularization (CNVM) and macular degeneration, these lesions can lead to visual loss.
Treatment of the CNVM is laser photocoagulation. Recurrence rates are high.
This retinopathy is characterized by neovascularization that results from repeated episodes of ischemia secondary to repetitive or successive peripheral arterial occlusions. Although neovascularization may be seen in the optic disc and the macula, proliferative sickle retinopathy is primarily a peripheral retinal disease. Goldberg proposed the universally accepted classification for PSR in 1971, which is divided into 5 discrete stages.
Stage I - Peripheral arteriolar occlusion
Seen by ophthalmoscopy, areas of retinal ischemia secondary to nonperfusion become an abnormal grayish brown color.
The exact pathogenesis is not known, but it is theorized and accepted that sickled erythrocytes cause occlusion secondary to increased viscosity, followed by stasis and subsequent thrombosis.
Why the peripheral retina more commonly is affected than the posterior pole remains unclear. Vessel luminal diameter, critical closing pressure, and oxygen tension in the peripheral retinal appear to play important roles in development.
Fluorescein angiography helps delineate areas of avascular and abnormal capillary bed from the normally perfused retina.
Stage II - Arteriolar-venular anastomoses
These anastomoses are characterized by the shunting of blood from the occluded arterioles to the nearest venules.
Following peripheral arteriolar occlusions, vascular remodeling ensues at the junction between the perfused posterior and nonperfused peripheral neural retina.
Unoccluded arterioles develop collateral circulation through the preexisting capillaries, resulting in arteriolar-venular anastomoses.
This is not neovascularization.
Clinically, these anastomoses may be difficult to view via ophthalmoscopy. Fluorescein angiography can demonstrate arteriovenous anastomoses that do not leak dye.
Stage III - Neovascular proliferation
Repeated ischemic events lead to neovascular proliferation.
In the early stage of development, these neovascular fronds are small and lie flat on the retinal surface. With time, these abnormal vascular fronds grow in size and take on the characteristic appearance that resembles the marine invertebrate Gorgonia flabellum, hence the name "sea fan neovascularization." Sea fans are not pathognomonic.
Fluorescein angiography can help identify very small sea fan lesions. Unlike arteriolar-venular anastomoses, which do not leak, sea fan lesions leak profusely.
Patients with sea fan neovascularizations are at increased risk for developing vitreous hemorrhage and retinal detachment.
Epidemiologically, patients with sickle cell C disease are more likely to present with neovascularization than patients with sickle cell-thalassemia disease.
Sea fans often autoinfarct or spontaneously regress (20-60%).
Supposedly, these neovascular fronds are strangulated by fibroglial tissue. The acute occlusion of the sea fan feeding arteriole may result in autoinfarction.
Stage IV - Vitreous hemorrhage
Vitreous hemorrhage can result from PSR or trauma; it may be spontaneous secondary to vitreous collapse and/or traction of the adherent neovascular tissue.
When the vitreous collapses, either from liquefaction that is associated with aging or degenerative changes secondary to chronic leakage from sea fans, traction is exerted on the neovascular tissue.
The force exerted on the sea fans by the vitreous can tear the neovascularized and retinal vessels, leading to vitreous hemorrhage.
The degree of hemorrhage varies (ie, small or large, bleeding can occur at irregular intervals for several years). Vitreous hemorrhage may be small and localized or large enough to cloud the entire center of the vitreous cavity, giving rise to visual symptoms.
Patients with sickle cell C disease are most likely to develop neovascular proliferation, and they are more likely to present with vitreous hemorrhage.
Stage V - Retinal detachment
Retinal detachments may be rhegmatogenous and/or tractional. Traction from bands and membranes on the neovascular tufts can lead to sufficient retinal traction with or without retinal tears, both of which may lead to retinal detachment.
Another proposed theory for retinal detachment in hemoglobinopathies is retinal atrophy. Retinal ischemia can result in retinal thinning, retinal hole formation, and, subsequently, retinal detachment.
Clinically, the retinal tears that lead to retinal detachment are small to moderate in size and ovoid or horseshoe in shape.
The pathogenesis of hemoglobinopathy retinal tears and detachment is similar to proliferative diabetic retinopathy and other proliferative retinopathies.
Patients with sickle cell C disease are more likely to develop retinal detachment than patients with other forms of hemoglobinopathies.
Potential complications include the following:
Laboratory studies may be performed per internal medicine/hematology consultation, as follows:
Imaging studies may be performed per internal medicine/hematology consultation.
Perform fluorescein angiography when the examination does not explain the degree of vision loss.
Perform ocular B-scan ultrasonography when unable to adequately visualize the retina.
Consider cerebral vascular accident (CVA).
Consider retinal vascular emboli.
Histologic findings may include the following:
Since vitreous hemorrhage and retinal detachment account for most visual loss in hemoglobinopathies, the primary goal in treating proliferative sickle retinopathy is to minimize or eliminate neovascularization. Although treatments are not indicated or required for stages I and II, most advocate the treatment of sickle retinopathy for stage III.
The most widely used therapeutic modalities include laser retinal photocoagulation, retinal cryotherapy, and vitrectomy/membranectomy. The most effective therapeutic modality with minimal postoperative complications appears to be scatter laser retinal photocoagulation.
Laser retinal photocoagulation is the more commonly practiced therapeutic modality.
Although relatively safe, laser photocoagulation complications include preretinal hemorrhage, vitreous hemorrhage, retinal breaks, retinal detachment, and choroidal neovascularization.
Different techniques have been advocated in treating proliferative sickle retinopathy, including scatter photocoagulation and feeder vessel photocoagulation.
Scatter photocoagulation appears to be the most efficacious (and therefore the preferred) treatment of sea fan lesions.
The desired photocoagulation endpoint is regression of extraretinal fibroneovascular tissue.
Localized scatter photocoagulation is effective in treating early proliferative changes, especially neovascular lesions that lie flat against the retina. Once neovascularization invades the vitreous, localized scatter photocoagulation appears to be less effective.
Circumferential scatter photocoagulation places laser burns over a retinal zone of one of the following: at least 3 disc diameter areas of the nonperfused retina, as outlined by fluorescein angiography, or the entire avascular retina, as determined by fluorescein angiography or estimated by the distribution of the occluded vessel.
Unlike feeder vessel coagulation, scatter photocoagulation is easier to perform, more effective, and safer. This technique reduces the incidence of vitreous hemorrhage.
However, in cases where scatter photocoagulation alone does not achieve the desired result (ie, regression of proliferative changes), feeder vessel photocoagulation may be used as an adjunct to induce infarction to the remaining sea fans.
Follow-up care is usually within 1 week after laser surgery to rule out retinal detachment from contracture of the neovascular membrane after laser treatment.
After the first follow-up visit, monthly follow-up visits are advocated to confirm and monitor the regression of the neovascularization.
Insufficient treatment indicated by failure or arrest of the regression of the neovascularization requires further laser treatments at the time of follow-up care.
New or recurrent neovascularization in the treated eye is treated in the similar manner.
Obliterating feeder vessels by retinal photocoagulation has been used to cause infarction of peripheral neovascular beds.
This technique has been shown to manage proliferative sickle retinopathy effectively, especially in cases where neovascularization has persisted after extensive scatter photocoagulation treatment.
Feeder vessel photocoagulation frequently is complicated by the following: vitreous hemorrhage, retinal detachments, choroidal ischemia, choroidal neovascularization, subretinal hemorrhage and/or fibrosis, or macular pucker and hole formation.
To reduce complications, the feeder vessel technique has been modified into 2 sessions, permitting reduction in laser power. On initial treatment, laser burns are low intensity; upon follow-up, a second set of low-intensity burns are superimposed on the initial ones.
The method has been proposed to decrease the incidence of the Bruch membrane penetration, thereby decreasing the chance for choroidal neovascularization.
Scatter photocoagulation is the preferred technique.
Feeder vessel photocoagulation seldom is used because of its high complication rate. When used, feeder vessel photocoagulation is usually an adjunct to scatter photocoagulation.
Regular follow-up care is needed to detect and treat complications and new neovascularization.
In 1982, Hanscom demonstrated that retinal cryotherapy is useful in treating peripheral retinal ischemia as opposed to directly obliterating these neovascular beds.[3] This methodology of "indirect" obliteration of the neovascular bed showed complete regression of abnormal vessels with minimal complications.
Cryotherapy often is limited to cases with cloudy ocular media.
Single freeze-thaw and triple freeze-thaw have been advocated in treating PSR. However, it appears that triple freeze-thaw is associated with a high rate of complications (eg, proliferative vitreoretinopathy [PVR]) and, therefore, is not recommended.
Indicated in cases of nonresolving vitreous hemorrhage and retinal detachment (stages IV and V).
One of the more serious complications that is associated with vitreoretinal surgery is anterior segment ischemia. Other complications include sickling crisis, optic nerve, and macula infarctions.
This procedure relieves the internal tractional forces that act on the retina and facilitate retinal photocoagulation.
Rhegmatogenous retinal detachment in sickle cell disease usually is secondary to tractional membrane. Usually requiring pars plana vitrectomy, it seldom is treated with scleral buckling alone.
The following measures can decrease complications (ie, anterior segment ischemia):
The following specialists may be consulted:
Monitor medication dose and adverse effects.
Enroll patient in local sickle cell clinic.
Ophthalmologic follow-up care is determined by the proliferative stage.
Stages I and II: Follow-up care is performed every 6-12 months.
Stages III and IV: Follow-up care is usually within 1 week after laser surgery to rule out retinal detachment. After the first follow-up visit, monthly follow-up visits are advocated to confirm and monitor the regression of the neovascularization. Insufficient treatment requires further laser treatments at the time of follow-up care.
Stage V: Follow-up care is based on retinal specialist consultation.
Inpatient care often is not needed, except for noncompliant patients in sickle cell crisis or for patients with a hyphema who are unable to comply with follow-up visits.
Clinical Context: Inhibits fibrinolysis via inhibition of plasminogen activator substances; to a lesser degree, through antiplasmin activity.
Main problem is that the thrombi that form during treatment are not lysed, and effectiveness is uncertain.
Clinical Context: Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
Clinical Context: May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.