AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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.

Historic milestones

• 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.

Pathophysiology

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.

Frequency

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.

Mortality/Morbidity

• 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 beta^o 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.

Race

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.

Sex

No sexual predilection exists.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• 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.

Physical

• Complete eye examination
• • 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).
• Retinal findings
• • 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.
  • 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.
• Optic disc
• • 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.
    • 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.
• Macula
• • 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.
• Nonproliferative retinal changes: 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:
    • • Diffuse elastic degeneration
      • Iron deposition in the Bruch membrane secondary to hemolysis of retinal and subretinal hemorrhage
      • Impaired nutrition caused by sickling and stasis
      • Calcification of the Bruch membrane
    • Fibrovascular ingrowth can occur at the breaks.
    • Secondary changes may include the following:
    • • Thickening of the retinal pigment epithelium basement membrane
      • Retinal pigment epithelium atrophy, hypertrophy, or hyperplasia
      • Choriocapillaris damage
      • Photoreceptor loss
      • Serous retinal detachment
      • Disciform scar formation
    • 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.
• Proliferative sickle retinopathy: 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.

Causes

See Pathophysiology.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Per internal medicine/hematology consultation
• Hemoglobin electrophoresis
• Oxygen saturation
• Systemic hydration/acidosis

Imaging Studies

• Per internal medicine/hematology consultation

Other Tests

• 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

• RPE atrophy
• RPE hyperplasia
• RPE migration into partially degenerated retina and perivascular location
• Retinal thinning with loss of outer retinal layers
• Retinal detachment with cystic degeneration
• Retinal layers may be disorganized.
• Pigment-laden macrophages are seen within and beneath the retina.
• Pupillary space may be filled by a thin fibrovascular membrane.
• Cataractous changes may be noted.
• Thick-walled blood vessels often are filled with sickled erythrocytes.
• Proliferation of blood vessels may be seen in the retina and the vitreous, leading to intravitreal neovascularization.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

This condition usually is treated by or with an internist/hematologist.

Surgical Care

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 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
• • 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.
• Feeder vessel photocoagulation
• • 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.
• Retinal cryotherapy
• • In 1982, Hanscom demonstrated that retinal cryotherapy is useful in treating peripheral retinal ischemia as opposed to directly obliterating these neovascular beds.¹ 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.
• Vitrectomy
• • 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):
  • • Preoperative partial exchange transfusions (rarely required) increase the amount of normal hemoglobin Hb A, thereby increasing the O₂-carrying capacity.
    • Administer local anesthesia, stellate ganglion block, and papaverine administration.
    • Provide cycloplegics (parasympathomimetics only).
    • Decrease IOP.
    • Provide supplemental oxygen therapy.
    • IOP should be kept lower than 25 mm Hg preoperatively, intraoperatively, and postoperatively.

Consultations

• Retina specialist
• Internist/hematologist
• Geneticist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

See Special Concerns and Surgical Care.

Drug Category: Hemostatic agents

Reduce the incidence of rebleeds in the setting of hyphema.

Drug Category: Corticosteroids

Reduce the incidence of rebleeds in the setting of hyphema.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• 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.

Further Outpatient Care

• 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 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 - Per retinal specialist consultation

Complications

• Retinal detachment
• Hyphema
• Neovascular glaucoma
• Postoperative anterior ischemic syndrome

Prognosis

• The prognosis is fair to good if consistent follow-up care is maintained with both an internist/hematologist and an ophthalmologist.

Patient Education

• 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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Early detection and treatment may help decrease the retinal complications.

Special Concerns

• Blood transfusion
• • In the past, exchange transfusion was advocated prior to scleral buckling and/or vitrectomy. Today, this is not universally performed.
  • Consider the risk-to-benefit ratio, not only the possibility of contracting hepatitis secondary to transfusion but also transfusion reaction, septicemia, and AIDS.
  • Consult a hematologist.
  • The patient requires adequate preoperative, intraoperative, and postoperative hydration and correction of acidosis.
  • Transfusions may increase the likelihood of a clinically significant IOP elevation in the setting of a hyphema.
• Hyphema
• • The presence of hyphema in sickle cell disease should be managed aggressively because patients with sickle cell disease tend to have a poorer prognosis with the same degree of hyphema than patients without sickle cell disease.
  • A relatively small hyphema may lead to severely elevated IOP due to clogging of the trabecular meshwork. Even patients with sickle trait are susceptible to this complication.
  • Patients with sickle cell disease are predisposed to optic nerve damage and/or central retinal artery occlusion with mild increases in IOP.
  • Closely monitor and treat IOP, even when pressure is in the mid 20s (mm Hg).
  • All black patients with hyphema, even those without a past history of sickle cell disease or trait, should be tested for the disease or trait.
  • Rebleeding is a potentially devastating complication, usually occurring 2-6 days after the initial bleed. The chance of rebleeding has been reported as high as 64%.
  • Nasrullah et al demonstrated secondary hemorrhage in 9 of 14 patients.² This was significantly (P>0.005) different from the 0% rate in 57 eyes of African American sickle cell trait-negative and white children.
  • Rebleeding can be treated prophylactically with oral and/or topical steroids and/or aminocaproic acid (Amicar). Therapy is aimed at keeping the IOP low without exacerbating hypoxia or acidosis.
  • Maintain an IOP lower than 25 mm Hg.
  • Paracentesis or anterior chamber washout is advised for increased IOP.
  • When to surgically intervene should be determined on a case-by-case basis. Be sure to consider the following:
  • • Length of time between onset of symptoms and presentation
    • IOP at presentation (ie, 26-50 mm Hg)
    • Prior history of optic nerve disease and response to medical therapy during a previously similar episode
  • Prognosis is good if the IOP is controlled within the first 24 hours.
• Hyphema therapy
• • Topical beta-adrenergic antagonists are the mainstay of therapy for IOP control.
  • Oral steroids, topical steroids, and/or aminocaproic acid (Amicar) all reduce the incidence of rebleeds. This is not as well documented in sickle cell hyphemas because many studies exclude sickle hyphemas.
  • Avoid topical epinephrine, whenever possible, because it causes vasoconstriction and exacerbates the sickling process.
  • If possible, avoid miotic agents that may increase inflammation.
  • Avoid hyperosmotic agents because they may increase hemoconcentration and viscosity.
  • Avoid carbonic anhydrase inhibitors that may lead to hemoconcentration, systemic acidosis, and an elevated level of ascorbic acid; they may cause further sickling. Methazolamide is theoretically preferable to acetazolamide in such patients because intraocular and systemic acidoses are lower. Some clinicians believe that topical dorzolamide is also reasonable before systemic carbonic anhydrase inhibitors.
  • Bed rest with the head elevated at least 45^o is recommended.
  • Frequent follow-up care or hospitalization is recommended.
• Scleral buckling
• • Scleral buckling seldom is used without combined vitrectomy because rhegmatogenous retinal detachment in sickle cell disease is usually secondary to tractional membranes.
  • The following measures decrease complications (ie, anterior segment ischemia):
  • • Avoid disinsertion and/or aggressive manipulation of the recti muscles.
    • Preoperative partial exchange transfusion increases the amount of normal hemoglobin (Hb A), thereby increasing the Hb-O₂ carrying capacity.
    • Provide intraoperative and postoperative fluids and oxygen therapy.
    • Administer cycloplegics (parasympathomimetics only).
    • Administer local anesthesia, stellate ganglion block, and papaverine.
    • Decrease IOP.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Hanscom TA. Indirect treatment of peripheral retinal neovascularization. Am J Ophthalmol. Jan 1982;93(1):88-91. [Medline].
2. Nasrullah A, Kerr NC. Sickle cell trait as a risk factor for secondary hemorrhage in children with traumatic hyphema. Am J Ophthalmol. Jun 1997;123(6):783-90. [Medline].
3. Acheson RW, Ford SM, Maude GH, et al. Iris atrophy in sickle cell disease. Br J Ophthalmol. Jul 1986;70(7):516-21. [Medline].
4. Aessopos A, Voskaridou E, Kavouklis E, et al. Angioid streaks in sickle-thalassemia. Am J Ophthalmol. May 15 1994;117(5):589-92. [Medline].
5. Andreoli TE, et al. Disorder of red cells. In: Cecil's Essentials of Medicine. 4^th ed. 1997:383-7.
6. Asdourian GK. Sickle cell retinopathy. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. Vol 2. 1994:1006-1018.
7. Beutler E. Disorders of hemoglobin. In: Fauci AS, et al, eds. Harrison's Principle of Internal Medicine. 14^th ed. 1998:645-652.
8. Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. Sep 11 1997;337(11):762-9. [Medline].
9. Charache S. Eye disease in sickling disorders. Hematol Oncol Clin North Am. Dec 1996;10(6):1357-62. [Medline].
10. Cohen SB, van Houten PA. Hemoglobinopathies. In: Ryan SJ, et al, eds. Retina. 2^nd ed. 1994:1465-1472.
11. Eagle RC. Retina-sickle hemoglobinopathy. In: Eye Pathology: An Atlas and Basic Text. 1999:147, 153-4.
12. Farber MD, Fiscella R, Goldberg MF. Aminocaproic acid versus prednisone for the treatment of traumatic hyphema. A randomized clinical trial. Ophthalmology. Mar 1991;98(3):279-86. [Medline].
13. Farber MD, Jampol LM, Fox P, et al. A randomized clinical trial of scatter photocoagulation of proliferative sickle cell retinopathy. Arch Ophthalmol. Mar 1991;109(3):363-7. [Medline].
14. Fekrat S, Lutty G, Goldberg M. Retina-Vitreous Macula. In: Guyer D, et al. Hemoglobinopathies. Vol 1. 1999:438-458.
15. Fox PD, Dunn DT, Morris JS, et al. Risk factors for proliferative sickle retinopathy. Br J Ophthalmol. Mar 1990;74(3):172-6. [Medline].
16. Gagliano DA, Goldberg MF. The evolution of salmon-patch hemorrhages in sickle cell retinopathy. Arch Ophthalmol. Dec 1989;107(12):1814-5. [Medline].
17. Goldbert MF. Duane's Clinical Ophthalmology. In: Tasman W and Jaeger EA. Sickle Cell Retinopathy. Vol 3. 1990:1-45.
18. Green WR. Retina: Systemic Diseases with Retinal Involvement. In: Spencer WH. Ophthalmic Pathology: An Atlas and Textbook. Vol 2. 1996:1155-1160.
19. Jacobson MS, Gagliano DA, Cohen SB, et al. A randomized clinical trial of feeder vessel photocoagulation of sickle cell retinopathy. A long-term follow-up. Ophthalmology. May 1991;98(5):581-5. [Medline].
20. Jampol LM. Arteriolar occlusive diseases of the macula. Ophthalmology. May 1983;90(5):534-9. [Medline].
21. Jampol LM. Vitrectomy surgery in proliferative sickle retinopathy. Am J Ophthalmol. Nov 15 1987;104(5):553-4. [Medline].
22. Jampol LM, Green JL Jr, Goldberg MF, et al. An update on vitrectomy surgery and retinal detachment repair in sickle cell disease. Arch Ophthalmol. Apr 1982;100(4):591-3. [Medline].
23. Kark JA, Posey DM, Schumacher HR, et al. Sickle-cell trait as a risk factor for sudden death in physical training. N Engl J Med. Sep 24 1987;317(13):781-7. [Medline].
24. Kimmel AS, Magargal LE, Stephens RF, et al. Peripheral circumferential retinal scatter photocoagulation for the treatment of proliferative sickle retinopathy. An update. Ophthalmology. Nov 1986;93(11):1429-34. [Medline].
25. Liebmann JM. Management of sickle cell disease and hyphema. J Glaucoma. Aug 1996;5(4):271-5. [Medline].
26. Lubin BH. Sickle cell disease and the endothelium. N Engl J Med. Nov 27 1997;337(22):1623-5. [Medline].
27. McLeod DS, Goldberg MF, Lutty GA. Dual-perspective analysis of vascular formations in sickle cell retinopathy. Arch Ophthalmol. Sep 1993;111(9):1234-45. [Medline].
28. McLeod DS, Merges C, Fukushima A, et al. Histopathologic features of neovascularization in sickle cell retinopathy. Am J Ophthalmol. Oct 1997;124(4):455-72. [Medline].
29. Morgan CM, D'Amico DJ. Vitrectomy surgery in proliferative sickle retinopathy. Am J Ophthalmol. Aug 15 1987;104(2):133-8. [Medline].
30. Palmer DJ, Goldberg MF, Frenkel M, et al. A comparison of two dose regimens of epsilon aminocaproic acid in the prevention and management of secondary traumatic hyphemas. Ophthalmology. Jan 1986;93(1):102-8. [Medline].
31. Pulido JS, Flynn HW Jr, Clarkson JG, et al. Pars plana vitrectomy in the management of complications of proliferative sickle retinopathy. Arch Ophthalmol. Nov 1988;106(11):1553-7. [Medline].
32. Raichand M, Dizon RV, Nagpal KC, et al. Macular holes associated with proliferative sickle cell retinopathy. Arch Ophthalmol. Sep 1978;96(9):1592-6. [Medline].
33. Rednam KR, Jampol LM, Goldberg MF. Scatter retinal photocoagulation for proliferative sickle cell retinopathy. Am J Ophthalmol. May 1982;93(5):594-9. [Medline].
34. Serjeant GR. Sickle-cell disease. Lancet. Sep 6 1997;350(9079):725-30. [Medline].
35. Siegel D. Diagnosis and treatment of sickle cell retinopathy. J Am Optom Assoc. Nov 1988;59(11):885-8. [Medline].
36. Slavin ML, Barondes MJ. Ischemic optic neuropathy in sickle cell disease. Am J Ophthalmol. Feb 15 1988;105(2):212-3. [Medline].
37. Stryer L. Oxygen-transporting proteins: myoglobin and hemoglobin. In: Biochemistry. 3^rd ed. 1988:143-173.
38. To KW, Nadel AJ. Ophthalmologic complications in hemoglobinopathies. Hematol Oncol Clin North Am. Jun 1991;5(3):535-48. [Medline].
39. van Meurs JC. Evolution of a retinal hemorrhage in a patient with sickle cell-hemoglobin C disease. Arch Ophthalmol. Aug 1995;113(8):1074-5. [Medline].
40. Yanoff M, Fine BS. Sickle cell disease. In: Ocular Pathology. 4^th ed. 1996:377-8.

Article Last Updated: Aug 29, 2008