Signs and Symptoms
The ocular signs of sickle cell anemia are variable and may include: comma-shaped vessels in the bulbar conjunctiva; iris atrophy; iris neovascularization; dull-gray fundus appearance; retinal venous tortuosity; nonproliferative retinal hemorrhages (which may be subretinal, intraretinal or preretinal) and salmon patch hemorrhages (orange-pink-colored intraretinal hemorrhages); black sunbursts (RPE hypertrophy secondary to deep retinal vascular occlusions); glistening retractile deposits in the retinal periphery (hemosiderin-laden macrophages); angioid streaks (breaks in Bruch’s membrane radiating from the optic nerve); “macular depression signs” such as a loss of the foveal reflex; venous occlusion or artery occlusion; and peripheral neovascularization (in a “sea fan” appearance) with possible attendant vitreous hemorrhage and tractional retinal detachment.1-8
Ocular symptoms are uncommon in the early stages of any form of sickle cell disease (SCD).9,10 Studies involving SD-OCT of the macular and peripapillary retina have uncovered that a large percentage of sickle cell patients have focal macular thinning with significantly decreased retinal sensitivity compared to those without focal thinning and normal controls.11-13 This is an important new data point with respect to structural monitoring.11-13 The discovery is also important as the finding may confound the diagnosis of glaucoma in patients being considered for or treated with concurrent disease.11-13
The exact number of people living with SCD in the United States is unknown.14 The Centers for Disease Control (CDC) in collaboration with the National Institutes of Health and seven states (California, Florida, Georgia, North Carolina, New York, Michigan and Pennsylvania), have coordinated the Registry and Surveillance System for Hemoglobinopathies (RuSH) project to learn about the number of people living with disease and to formulate a better understanding of how the disease impacts the well-being of those affected. The CDC estimates it affects 90,000 to 100,000 Americans and occurs in one out of every 500 African-American births and one out of every 36,000 Hispanic-American births.14 Sickle cell trait is estimated to occur in one out of every 12 African Americans with an incidence in the general population estimated at 15.5 per 1,000 newborns overall.14,15 Among African-American newborns, the incidence has been estimated at 73.1 per 1,000 with 6.9 per 1,000 among Hispanic newborns.15 Over the last 20 years, the incidence of sickle hemoglobin S in African-American births has been reported as 0.163%.16
The hemoglobinopathies are a group of inherited disorders characterized by quantitative or qualitative malformations of hemoglobin (Hb).1-7 Sickle cell disease is a life-threatening genetic disorder associated with acute and chronic complications that require medical attention.1 From an ophthalmic perspective, the most important representation of this group of diseases is sickle cell retinopathy (SCR).1-7 This presents with a wide spectrum of fundus manifestations, and it has the potential to lead to irreversible vision loss if not properly diagnosed and treated.1-8
Sickle cell disease is the most common genetic disease worldwide.17,18 SCD can affect virtually every vascular bed in the eye and, if left untreated, can result in severe visual impairment through the development of proliferative retinopathy.1-7,17 The origin of the genetic abnormality can be traced to Africa where data suggests that the mutation of the hemoglobin chain protected individuals from malaria infection.9-18 The inheritance mode that induces the formation of the sickle cell hemoglobinopathies is autosomal co-dominant, with each parent providing one gene for the abnormal hemoglobin.7 Abnormal hemoglobin S results following a single point mutation substituting valine for glutamic acid at the sixth position.4,5 Substituting lysine for glutamic acid at this position results in the formation of hemoglobin C. When both parents contribute the S mutation, classic sickle cell anemia or SS disease ensues.5,17,18 When one parent contributes S mutated hemoglobin and the other contributes C mutated hemoglobin, the SC form of the disease is created.5,17,18 Inadequate production of either normal or abnormal globin chains creates the S-thalassemia (S-Thal) variant.5,17,18 Incomplete expression of the disease with some of the genetic mutations produces sickle cell trait (AS).5,17,18 In all four variations of SCD, systemic and ocular tissues have the potential to become deprived of oxygen secondary to inherited abnormalities of the beta-globin chain.1,9,10,17,18
Erythrocytes, having lost their biconcave shape, become rigid, restricting retinal blood flow, inducing thromboses; subsequently, tissues become hypoxic.1-22 Vascular leakage and liberation of angiogenic cytokines with subsequent retinal neovascularization development (along with all of its attendant complications) dictate the severity of the condition.1-19,12,23 The pathogenesis of the resultant retinopathy is ultimately a manifestation of arterial and capillary microcirculation obstructive-vasculopathy.21 Various systemic complications of SCD are known to be more common in patients with the SS genotype, while visual impairment with more severe retinopathy is more common in the SC genotype.18
Salmon patch hemorrhages are preretinal or superficial retinal hemorrhages that often dissect into the vitreous humor.5 They result from disruption of the medium-sized arterioles secondary to chronic ischemic-vascular compromise.5 Although they are initially bright red, their color evolves. Because they have a tendency to push both forward and backward within the retina, they may leave a retinoschisis remnant when they finally resolve.5 Since the movement of this blood can disturb the retinal pigment epithelium, irregularly shaped retinal pigment epithelial hyperplastic changes occur, producing the classic black sunbursts.3-6
The hallmark proliferative sign of sickle cell disease is the sea fan-shaped frond of neovascularization.20 A common trait of the SC and S-Thal variations, sea fan neovascularization represents the body’s aggressive attempt to supply oxygen to deficient retinal tissue.5,7-19,22,23 Arteriovenous crossings are the preferential site for sea fan development.14 Preretinal vascular formations develop from one or more feeder vessels at the border of perfused and nonperfused peripheral retina.22,23 Since the retinal tissue is not globally ischemic, the abnormal vessels arborize along the border of perfused and starved tissue.5,22,23 Drained by single or multiple venules, the classic kidney-shaped appearance is driven by environment. Vascular endothelial growth factors are associated with these formations.20 The neovascularization in sickle cell retinopathy can arise from both the arterial and venous sides of the retinal vasculature.23 Autoinfarction (complete or partial spontaneous involution) appears to occur initially at the preretinal capillary level rather than at the feeding arterioles and has been documented to occur in up to 50% of cases.23
Sickle cell retinopathy development is classically broken down into five stages. Stage one is recognized by peripheral retinal arteriolar occlusions. Stage two is marked by the appearance of peripheral arteriovenous anastamoses. Stage three is characterized by the growth of neovascular sea fan fronds. Stage four is marked by vitreous hemorrhage as tractional forces and vitreous collapse tear fragile neovascular membranes. Stage five is the advanced form of the disease, identified by severe vitreous traction and retinal detachment.1-6, 22,23
The diagnosis of clearly evident clinical comorbidities such as leg ulcer, osteonecrosis and retinopathy are considered predictors for developing lethal end-organ damage.21 Fifty-one percent of patients with SCD who go on to have a cerebrovascular accident report a prior chronic collateral condition.23,24
The laboratory testing for SCD in patients with suspicious findings includes the Sickledex (Streck), Sickle Prep and plasma hemoglobin electrophoresis. The treatment for sickle cell retinopathy is aimed at reducing or eliminating retinal neovascularization.9-20 Patients with asymptomatic SCD, in the absence of ocular manifestations, should be followed biannually with dilated retinal evaluation.8-19 Referral to a retina specialist is indicated when proliferative retinopathy is seen. Treatment for proliferative disease includes pan or sector retinal photocoagulation. Cryotherapy has not been proven efficacious and is associated with high complication rates.8 Scleral buckle procedure with or without vitrectomy may be indicated in cases of retinal detachment.6,25,26 Modern techniques have made presurgical blood transfusions unnecessary.26 Photodynamic therapy used in the treatment of other diseases known to produce choroidal and retinal neovascularization is not well documented as a therapy for sickle cell retinopathy.1-6
Researchers are investigating antiangiogenic compounds as a potential adjunct for regressing sickle cell neovascularization.27,28 Reports in the literature indicate there has been some success in individual cases using these formulations to stabilize the membrane’s growth.27,28 The current studies do not present enough numbers or a clear advantage over traditional membrane regression with laser photocoagulation to recommend their use. The compounds must undergo further investigation to determine if there is a beneficial role over traditional approaches.27,28
Systemically, genetic risk factors along with other preventative possibilities are also now being explored to extend life and reduce retinopathy progression.22,24-31 Strong recommendations for prevention include daily oral prophylactic penicillin up to the age of five, annual transcranial Doppler examinations from the ages of two to 16 in those with sickle cell anemia and long-term transfusion therapy to prevent stroke in children with an abnormal transcranial Doppler velocity (≥200cm/s).2,6 Opioids are recommended for treatment of severe pain associated with a vaso-occlusive crisis, and patients should be instructed to practice incentive spirometry in preparation for events which leave them in a hypoxic state.2 A combination of non-narcotic analgesics and physical therapy is recommended for treatment of avascular necrosis, and angiotensin-converting enzyme inhibitor therapy for adults demonstrating microalbuminuria.2
Hydrea (hydroxyurea/hydroxycarbamide, Bristol-Myers Squibb) is an anticarcinogenic preparation that has significantly reduced the number of deaths and complications from sickle cell disease.29,30 It increases fetal hemoglobin levels, which seems to prevent red blood cells from sickling.29,30 The medication has demonstrated an ability to reduce the number of vaso-occlusive crises and acute chest problems, thereby reducing the severity and impact of the disease along with the number of hospitalizations. It also has demonstrated great efficacy and safety in reducing retinopathy in pediatric studies.21,29-31
Future therapies for SCD appear varied. Stem cell transplantation has been attempted with limited success, but with some increase in patient longevity, for at least two decades.29 Niprisan (Nix-0699), an ethanol/water extract derived from four kinds of plants in Africa, has a naturally occurring anti-sickling agent which has demonstrated promise in experiments with mice.32,33 It may offer the promise of an additional preventative solution in the future.32,33 New research has led investigators to believe they may be able to stimulate the RPE to initiate production of hemoglobin.34 Monomethylfumarate was found to influence RPE cells to express globin genes and synthesize adult and fetal hemoglobin in cultured RPE and erythroid cells in SCD mouse retina.34 The production also reduced retinal oxidative stress and inflammation.33 Researchers feel there is future therapeutic potential.34
• With respect to the development of systemic symptoms, the sickle cell anemia variation SS produces the most symptoms. The SC and S-Thal mutations produce the most ocular effects. Overall, the sickle cell trait expression produces the fewest complications.
• The sea fan frond of neovascularization is so characteristic of this disease that, when encountered, must be the prime consideration in undiagnosed patients.
• Systemic symptoms include recurrent, painful vaso-occlusive crises with abdominal and musculoskeletal discomfort. Other systemic manifestations include jaundice, cerebrovascular accidents and infections (particularly by encapsulated bacteria).
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