Ophthalmologic Manifestations of Sickle Cell Disease (SCD)

The ocular manifestations of sickle cell disease (SCD) result from vascular occlusion, which may occur in the conjunctiva, iris, retina, and choroid. Because the ocular changes produced by SCD can be seen in other diseases, it is important to rule out other causes of occlusion, including central retinal vein occlusion, Eales disease, and retinopathy secondary to diabetes and other disorders.[1] Other causes of ocular changes that should also be considered include familial exudative vitreoretinopathy, polycythemia vera, talc and cornstarch emboli, and uveitis.

Treatment is directed toward preventing vision loss from vitreous hemorrhage, retinal detachment, and epiretinal membranes.[2, 3] Treatment may be medical or surgical. Recent advances in genetic manipulation, including the use of CRISPR (clustered regularly interspaced short palindromic repeat), offers great promise in the treatment of SCD.

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The abnormalities of the posterior segment can be divided into 6 categories, as follows[4, 5, 6, 7] :

• Optic disc changes
• Posterior retinal and macular vascular occlusion
• Chronic macular changes (sickling maculopathy)
• Choroidal vascular occlusions
• Nonproliferative retinal changes
• Proliferative retinal changes

Optic disc changes

Intravascular occlusions on the surface of the optic disc appear ophthalmoscopically as dark-red intravascular spots. These occlusions are transient and do not produce any clinical impairment.[8] These changes are most common in hemoglobin SS disease but can also occur in patients with hemoglobin SC and hemoglobin S.

Posterior retinal and macular vascular occlusions

Retinal artery occlusions are either central or branch. Peripapillary or macular arteriolar occlusions are rare. Retinal vein occlusions also are rare with SCD.

Chronic macular changes

Chronic macular vascular occlusions occur in SCD. These are manifested by microaneurysms resembling dots, hairpin-shaped vascular loops, and abnormal foveal avascular zone (FAZ).

Choroidal vascular occlusions

This is an extremely rare manifestation of SCD. Only 3 cases have been reported thus far in the literature.

Nonproliferative retinal changes

Nonproliferative or background sickle retinopathy includes the following manifestations:

• Venous tortuosity

• Salmon-patch hemorrhage

• Schisis cavity

• The black sunburst

Venous tortuosity probably is due to arteriovenous shunting from the retinal periphery. It can occur in many patients with hemoglobin SS and hemoglobin SC disease.

Salmon-patch hemorrhages are superficial intraretinal hemorrhages. They are usually seen in the mid periphery of the retina adjacent to a retinal arteriole.

The schisis cavity is a space caused by the disappearance of the intraretinal hemorrhage. Nonproliferative sickle retinopathy features iridescent spots and glistening refractive bodies in the schisis cavity.

The black sunburst consists of round chorioretinal scars usually located in the equatorial fundus. These lesions result from pigment accumulated around the vessels. They do not cause any visual symptoms.

Proliferative sickle retinopathy

Proliferative sickle retinopathy (PSR) is the most severe ocular change in SCD. This is a peripheral retinal change most frequent in patients with hemoglobin SC but also can be present in patients with hemoglobin S-thalassemia disease, homozygous hemoglobin SS, and hemoglobin AS and hemoglobin AC disease.[9, 10]

PSR is progressive. A desirable objective is to treat the neovascular tissue before a vitreous hemorrhage occurs.

Goldberg classified PSR into the following 5 stages:

1. Peripheral arteriolar occlusions

2. Arteriolar-venular anastomosis

3. Neovascular proliferation

4. Vitreous hemorrhage

5. Retinal detachment

In stage I, the peripheral arteriolar vessels occlude, with anteriorly located avascular vessels evident. Early in the process, the occluded arterioles are dark-red lines, but eventually they turn into silver-wire–appearing vessels.

In stage II, peripheral arteriolar-venular anastomosis occurs as the eye adjusts to peripheral arteriolar occlusion, and blood is diverted from the occluded arterioles into the adjacent venules. Peripheral to these anastomoses, no perfusion is present.

In stage III, new vessel formation occurs at the junction of the vascular and avascular retina. These neovascular tufts resemble sea fans. Initially, the sea fans can be fed by a single arteriole and draining vessel.

Later, as the sea fan grows in size, it is difficult to distinguish the major feeding and draining vessels. The sea fans may acquire a glial and fibrotic tissue envelope. This envelope may pull on the vitreous. A full-thickness retinal break, which may lead to total rhegmatogenous retinal detachment, may occur.

Sickle cell vasoocclusive events can affect every vascular bed in the eye, often with visually devastating consequences in advanced stages of the disease.

Anterior segment abnormalities include the following:

• Segmentation "corkscrew" conjunctival vessel, more commonly seen in the inferior bulbar conjunctiva

• Iris infarct and atrophy

• Cataracts

• Phthisis bulbi

• Hyphema

Ocular treatment is directed toward preventing vision loss from vitreous hemorrhage, retinal detachment, and epiretinal membranes. Medical ocular management may include topical medications; however, avoid carbonic anhydrase inhibitors, because they may cause further sickling and worsen the outflow obstruction. If the intraocular pressure remains elevated after a judicious trial of medical therapy, surgical intervention with an anterior chamber lavage is indicated.

The goal of treatment is to eliminate existing neovascularization and, thus, to eliminate the sequelae of proliferative sickle retinopathy (PSR). Modalities to treat proliferative sickle retinopathy include diathermy, cryotherapy, xenon arc photocoagulation, and argon laser photocoagulation.

Diathermy is used infrequently because of the high incidence of complications accompanying this procedure. Cryotherapy, both single freeze-thaw and triple freeze-thaw, has been used to treat PSR. Triple freeze-thaw has a high complication rate. Single freeze-thaw is used to treat peripheral vitreous hemorrhage in the presence of vitreous hemorrhage. Xenon arc and argon laser photocoagulation have been used to treat either the peripheral neovascularization or the feeder vessels to the neovascularization.

Photocoagulation applied through various techniques (eg, feeder vessel, focal scatter, peripheral circumferential scatter) is effective for treating proliferative sickle retinopathy and reducing the risk of vision loss. Because of potential complications from photocoagulation and the tendency for regression, patients older than 40 years probably do not require treatment. Complications of photocoagulation include choroidal neovascularization, retinal breaks, and peripheral choroidal ischemia.

Surgical treatment

Surgical procedures may be performed to treat retinal detachments, nonclearing vitreous hemorrhage, and epiretinal membranes. Based on a 71% incidence of anterior segment ischemia in patients with PSR who are undergoing scleral buckling surgery, prophylactic preoperative exchange transfusions or erythropheresis is recommended. Risks associated with exchange transfusions and improvement in vitreoretinal surgical techniques warrant a careful reevaluation of prophylactic exchange transfusions.

Perioperative measures to reduce the incidence of anterior segment ischemia include the following:

• Nonsympathomimetic local anesthesia

• Minimization of topical sympathomimetics

• Supplemental oxygen for 48 hours after surgery

• Avoiding wide encircling scleral buckling elements, expansile concentrations of intraocular gases, and carbonic anhydrase inhibitors

• Closely monitoring and treating elevated intraocular pressure

Anterior segment ischemia after surgery is an emergency. Although the prognosis is notoriously poor, make all attempts to oxygenate the anterior segment. Options include hyperbaric oxygen therapy, continuous supplemental oxygen therapy, and transcorneal oxygen with goggles.[11]

Elevated intraocular pressure

Blood in the anterior chamber in patients with sickle cell disease is a medical emergency. A sickle screen is warranted for every black patient who has an unexplained hyphema.[12, 13] The environment of the anterior chamber promotes sickle hemoglobin polymerization, which can result in elevated intraocular pressure due to blockage of the trabecular meshwork.

Because patients with sickle cell disease are particularly prone to central retinal artery occlusion and optic atrophy, even with mildly elevated intraocular pressures, closely monitor the intraocular pressure. Do not allow it to exceed 25 mm Hg for longer than 24 hours.

Genetic manipulation

Recent advances in genetic manipulation tools such as CRISPR raise the possibility that a systemic cure for SCD may be attainable. One such study involves CRISPR Therapeutics and Vertex Pharmaceuticals, who seek to enroll approximately 45 people aged 18-35 years in a joint study to determine if genetically modifying blood cells with CRISPR permanently remedies faulty sickle cells. 

Results presented in June 2020 at the Annual European Hematology Association Congress indicate that the first patient treated through the Vertex study for SCD was free from painful crisis at 9 months after treatment. Some side effects were reported but were believed to be caused by chemotherapy rather than genome editing.[14]

Frangoul et al describe two patients who received autologous CD34+ cells edited with CRISPR-Cas9. They write, "More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes."[15]

These and other ongoing studies show great promise for the readication of this disease.