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Retinal Physician

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Clinical Presentation, Management, and Advances in Treatment of Sickle Cell Retinopathy

Screening and monitoring can prevent visual morbidity.

By: Ishrat Ahmed, MD, PhD, Adrienne W. Scott, MD
Retinal Physician September 1, 2020 Vol 17, Issue September 2020 Page(s): 18-23

Sickle cell disease (SCD) is the most common inherited hematologic disorder and affects approximately 3.2 million people worldwide.1 It is most prevalent in populations of African descent, followed by those of Mediterranean, Caribbean, and South and Central American descent.2 Patients with SCD most commonly present with painful vaso-occlusive crises (VOC), particularly under hypoxic conditions. Other systemic complications, including acute chest syndrome, pulmonary hypertension, splenic sequestration, and cerebrovascular accidents, contribute to the significant morbidity and mortality of SCD.2

Sickle cell disease encompasses a group of hemoglobinopathies characterized by a mutation in the β-globin gene, which results in defective oxygen transport. Under hypoxic and inflammatory conditions, hemoglobin polymerization can result in sickling, or the formation of rigid and elongated erythrocytes, which subsequently cause intravascular hemolysis and thrombosis.3 Additional mechanisms, including endothelial dysfunction, vaso-occlusion, and inflammation, are thought to be involved in the pathophysiology of SCD.4

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GENETICS

Adult hemoglobin (Hb A) consists of 2 α-globin and 2 β-globin subunits combined with a central heme. A glutamine-to-valine mutation in the sixth amino acid position of β-globin results in hemoglobin S (Hb S) whereas a glutamine-to-lysine mutation produces hemoglobin C (Hb C). Several combinations of β-globin subunits can be inherited and can produce homozygous SCD (HbSS) or the compound heterozygous SCD (HbSC).5 Other compound heterozygous forms also exist with less common mutations in β-globin. Homozygous SCD results in more severe systemic morbidity and mortality compared to HbSC disease.6 However, retinal involvement of SCD is more frequently associated with HbSC disease than HbSS disease.7 Patients with 1 normal and 1 abnormal β-globin gene (HbAS) have sickle cell trait and are largely asymptomatic, with the exception of sight-threatening ocular hypertension in the presence of hyphema, or in instances of severe hypoxia and dehydration.8 Sickle cell trait is rarely associated with retinal involvement.

SICKLE CELL RETINOPATHY

Retinal findings in SCD can be divided into nonproliferative sickle retinopathy and proliferative sickle retinopathy (PSR) when pathologic neovascularization develops. The main nonproliferative findings include salmon patch hemorrhages, iridescent spots, and black sunbursts. Salmon patch hemorrhages represent areas of “blowout” of an occluded vessel, whereas black sunbursts are hyperpigmented areas caused by intraretinal hemorrhage and are often associated with retinal pigment epithelium damage.9 Iridescent spots represent hemosiderin-laden macrophages in areas of prior intraretinal hemorrhage.10

Vaso-occlusion of peripheral retinal arterioles, progressive vascular remodeling, and retinal ischemia may result in PSR. In a longitudinal study, by age 24 to 26 years, 43% of people with HbSC disease were noted to develop PSR compared to 14% of those with HbSS disease.11 It remains unclear why HbSC more frequently leads to PSR compared to HbSS disease. However, several theories have been posited, including differences in cellular rheology and fetal hemoglobin content, as well as cellular responses to acute and chronic hypoxia.12,13 Patients with HbSC have a higher hematocrit, and thus more abnormal, sickled cells remain in circulation with delayed transit time through the retinal microvasculature.12,14 Decreased oxygenation results in indolent release of growth factors such as vascular endothelial growth factor (VEGF) and others.15 In HbSS disease, hemoglobin values are likely lower than those noted in HbSC. More complete vaso-occlusions may occur, with less likely release of proangiogenic growth factors.

The Goldberg classification for PSR consists of 5 stages.12 Stage I PSR shows peripheral vascular occlusion, which can manifest as silver-wiring of the arterioles affected.16 The subsequent vascular remodeling at the border of perfused areas can lead to arteriovenous (AV) anastomoses, which are noted in stage II PSR. Stage III PSR consists of neovascular and fibrous proliferations. This includes the hallmark sea-fan neovascularization associated with sickle cell retinopathy (SCR). These are often found superotemporally at the border of perfused and nonperfused areas and are thought to arise from the venous component of AV anastomoses.12 Unlike AV anastomoses, sea-fan neovascularization demonstrates leakage on fluorescein angiography (Figure 1). Stage IV PSR is defined by the presence of vitreous hemorrhage caused by traction on neovascular fronds. Lastly, stage V PSR consists of tractional or combined rhegmatogenous and tractional retinal detachments. These are caused by vitreoretinal traction from neovascularization on ischemic retina, which is pathologically thin and thus more susceptible to retinal breaks. These detachments most commonly involve the ischemic temporal retinal periphery, a watershed zone for retinal vascular perfusion.12

Figure 1. Ultrawidefield fluorescein angiography showing large areas of peripheral nonperfusion (asterisk), arteriovenous anastomoses (arrowhead) and sea-fan neovascularization (arrow) in a patient with homozygous sickle cell disease. Arteriovenous anastomoses can be differentiated from sea-fan neovascularization based on the presence of leakage in the latter.
Figure 1. Ultrawidefield fluorescein angiography showing large areas of peripheral nonperfusion (asterisk), arteriovenous anastomoses (arrowhead) and sea-fan neovascularization (arrow) in a patient with homozygous sickle cell disease. Arteriovenous anastomoses can be differentiated from sea-fan neovascularization based on the presence of leakage in the latter.

SICKLE CELL MACULOPATHY

Although peripheral vascular changes are the hallmark features of SCR, maculopathy has also been detected in 45.6% of patients with SCD, with approximately equal prevalence in HbSS and HbSC disease.17,18 Enlarged foveal avascular zone and macular thinning due to ischemia, as well as foveal “splaying” or blunting of the foveal contour, are observed in sickle cell maculopathy.19-21 Temporal macular thinning has also been noted in SCD and is due to involvement of the watershed zone near the horizontal raphe (Figure 2).22 This watershed zone in the temporal macula, retinal field 3, may be analogous to the terminal circulation of the peripheral temporal retina.23 Moreover, nonperfusion of the macular deep capillary plexus on optical coherence tomography angiography (OCTA) has been associated with other areas of macular thinning (Figure 3A-3C).24 Interestingly, in a large case series of children with SCD, vascular changes were shown to precede structural changes in retinal thickness, further supporting a causative relationship.25

Figure 2. Spectral-domain optical coherence tomography demonstrates foveal splaying (asterisk) and temporal macular thinning (arrow) in a patient with hemoglobin S/O-Arab sickle cell disease. Hemoglobin O-Arab is a rare mutation in β-globin with a glutamine-to-lysine mutation in the 121st position.
Figure 2. Spectral-domain optical coherence tomography demonstrates foveal splaying (asterisk) and temporal macular thinning (arrow) in a patient with hemoglobin S/O-Arab sickle cell disease. Hemoglobin O-Arab is a rare mutation in β-globin with a glutamine-to-lysine mutation in the 121st position.
Figure 3. Optical coherence tomography angiography shows decreased vascular density (asterisk) in the superficial capillary plexus (A) and deep capillary plexus (B) in a patient with homozygous sickle cell disease. Areas of vascular loss correspond to temporal macular thinning (C; asterisk) shown on the heat map.
Figure 3. Optical coherence tomography angiography shows decreased vascular density (asterisk) in the superficial capillary plexus (A) and deep capillary plexus (B) in a patient with homozygous sickle cell disease. Areas of vascular loss correspond to temporal macular thinning (C; asterisk) shown on the heat map.

Patients with SCD can present with sudden vision loss due to retinal arteriolar occlusions, central retinal artery occlusion (rarely), or acute infarction of the macular choroidal circulation.26-29 In the latter cases, acute macular neuroretinopathy, or paracentral acute middle maculopathy can be observed, which are well visualized on spectral-domain optical coherence tomography (SD-OCT; Figure 4A-4C).30-32 These macular infarcts are most commonly observed in patients with HbSS disease. Although these patients can present with significant central scotomas, fortunately, vision loss is often self-limited. We advocate for urgent hematology consultation for consideration of systemic SCD assessment, including hydration, oxygenation, and red blood cell exchange transfusion for SCD patients who present with new retinal vascular occlusions or infarctions.

Figure 4. Optical coherence tomography and optical coherence tomography angiography (OCTA) in a patient with homozygous sickle cell disease who presents with acute-onset blurry vision. Visual acuity had decreased from 20/20 to 20/160. Optical coherence tomography (A) shows a hyper-reflective lesion at the level of the inner nuclear layer, consistent with paracentral acute middle maculopathy (white bracket). On OCTA (B), there is loss of choroidal perfusion (arrow) corresponding to the region of paracentral acute middle maculopathy. En face OCTA (C) shows minimal vascular changes (asterisk) in corresponding areas of the superficial capillary plexus (SCP) and deep capillary plexus (DCP). However, vascular density is reduced (asterisk) at the level of the choriocapillaris (CC).
Figure 4. Optical coherence tomography and optical coherence tomography angiography (OCTA) in a patient with homozygous sickle cell disease who presents with acute-onset blurry vision. Visual acuity had decreased from 20/20 to 20/160. Optical coherence tomography (A) shows a hyper-reflective lesion at the level of the inner nuclear layer, consistent with paracentral acute middle maculopathy (white bracket). On OCTA (B), there is loss of choroidal perfusion (arrow) corresponding to the region of paracentral acute middle maculopathy. En face OCTA (C) shows minimal vascular changes (asterisk) in corresponding areas of the superficial capillary plexus (SCP) and deep capillary plexus (DCP). However, vascular density is reduced (asterisk) at the level of the choriocapillaris (CC).

VISION LOSS IN SICKLE CELL DISEASE

Vision loss in SCD most often results from advanced stages of PSR.12,33 The most common causes of severe vision loss (visual acuity of 20/200 or worse) are vitreous hemorrhage and retinal detachment, which account for 44% and 31% of cases of severe vision loss, respectively.33 Less common causes include epiretinal membrane and macular hole. Overall, decreased visual acuity occurs in 10% to 12% of eyes with untreated PSR.33 Interestingly, foveal avascular zone changes have not been associated with a change in visual acuity, whereas temporal macular atrophy has been shown to correlate with scotomas and decreased contrast sensitivity.20,22,34

MEDICAL MANAGEMENT

The main goal of treatment is to prevent progression to Goldberg stage IV and stage V PSR, which are associated with vision loss. Proliferative lesions have been shown to autoinfarct and spontaneously regress in 32% of eyes.11 Therefore, intervention may not be indicated for small asymptomatic peripheral sea-fan neovascular lesions and lesions that appear to have autoinfarcted with decreased vascularization. However, treatment may be required for rapidly growing and vascularized proliferative lesions. Scatter laser photocoagulation of ischemic areas is the mainstay of treatment for PSR. Laser-treated patients with PSR showed a slightly decreased risk of vision loss from vitreous hemorrhage compared to those with PSR managed with observation.35 Laser has not been shown to decrease incidence of new sea-fan neovascularization. The proangiogenic growth factors hypoxia-inducible factor 1α (HIF-1α) and VEGF are highly expressed in ischemic areas in eyes with PSR, particularly at the boundary of perfused and nonperfused retina. Laser photocoagulation may suppress secretion of these growth factors. We advocate for application of scatter laser not only to areas of peripheral ischemic retina, but also to the marginal zone between ischemic and nonischemic retina, as well as just posterior to the marginal zone due to areas of growth factor expression.36

Intravitreal anti-VEGF agents have also been shown to result in partial to complete regression of retinal neovascularization.37-40 Off-label use of intravitreal bevacizumab (Avastin; Genentech) has been described as a helpful adjunctive treatment in PSR to facilitate resolution of vitreous hemorrhage in cases where the posterior segment view does not permit application of scatter laser, or when scatter laser has been applied and sea-fan neovascularization remains vascularized despite adequate prior laser treatment.37-39 Currently, we treat with intravitreal bevacizumab based on sea-fan vascularization activity determined by clinical exam and fluorescein angiography leakage. Preoperative intravitreal bevacizumab and sea-fan regression has also facilitated surgical management of retinal detachment in PSR in a case report.41 Of note, intravitreal anti-VEGF injections should be used with caution in patients with proliferative retinopathies and vitreous hemorrhage in the absence of a posterior vitreous detachment, because anti-VEGF therapy may accelerate fibrosis and contraction of peripheral neovascularization. Rapid contraction of the sea-fan neovascular complex may cause increased traction on the underlying retina, and thus may increase the risk of a resultant retinal detachment.42 Larger studies investigating the role of anti-VEGF therapies in PSR treatment are needed to inform best practices and optimal treatment regimens.

SURGICAL MANAGEMENT

Surgical management is reserved for nonclearing vitreous hemorrhage, bilateral vitreous hemorrhage, or vitreous hemorrhage in a monocular patient, as well as retinal detachment. Scleral buckling in sickle cell retinal detachment was historically associated with higher rates of anterior-segment ischemia. However, the incidence of anterior-segment ischemia has declined significantly with modern surgical techniques. Surgeons should avoid broad and/or scleral buckling elements, compression of the long posterior ciliary vessels, excessive cryopexy, and extraocular muscle injury in patients with SCD.43,44

Vitrectomy has become a common surgical technique for the management of PSR-associated retinal detachments. The segmentation technique for eliminating fibrovascular traction is preferred to minimize traction on the ischemic peripheral retina and to avoid iatrogenic retinal breaks. This technique involves vertical cuts through the fibrovascular tissue. Delamination, in which fibrovascular membranes are horizontally dissected from the retina to relieve tangential retinal traction, may increase likelihood of iatrogenic retinal breaks.45 Due to the thin ischemic peripheral retina in eyes with PSR, repair of retinal detachments is more frequently associated with iatrogenic tears and lower rates of single surgery success.45 We advocate for bimanual vitreoretinal surgical techniques when possible. Additional careful placement of encircling or segmental scleral buckling can be used to support peripheral pathology, avoiding high encircling elements.

Careful preoperative planning with the anesthesiology and hematology teams is recommended to optimize surgical outcomes for SCD patients undergoing vitreoretinal surgery.46 This includes adequate hydration and supplemental oxygen intraoperatively and postoperatively, as well as a warm operating room. General anesthesia or local anesthesia with a sub-Tenon’s block are preferred over retrobulbar block to avoid elevated intraocular pressure and occlusion of the central retinal artery. During surgery, it is also essential to maintain careful control of intraocular pressure to avoid prolonged retinal artery occlusion.8 Postoperative monitoring of hydration, oxygenation, analgesia, and intraocular pressure is also crucial. Routine perioperative transfusion may be considered on an individualized basis in consultation with a hematologist.44,46

SCREENING AND MONITORING

Newborn sickle cell screening has been mandated in all 50 states in the United States since 2006.47 However, patients may be unaware of their sickle cell status or may not have been screened if they were born elsewhere or before the newborn screening implementation. Therefore, patients may have SCD or other undiagnosed hemoglobinopathy. It is reasonable to obtain a serum electrophoresis on patients with ocular pathology suspicious for SCR, even with a negative past medical history of SCD. Currently, there are no evidence-based screening guidelines for SCR. Expert consensus recommendations advise referral for patients with SCD for retinal exam yearly beginning at age 10, with annual evaluation thereafter.48 Several imaging modalities are used to assess and monitor peripheral PSR, including ultrawidefield imaging and fluorescein angiography.49 In addition, SD-OCT and OCTA may be used to monitor structural and vascular alterations in the macula.

In a recent retrospective cohort study on pediatric SCR, the average age of onset of PSR was 12.2 years in patients with HbSC disease and 15.4 years in those with HbSS disease. Based on these findings, these authors recommend screening for treatment-requiring PSR at age 9 and age 13 for asymptomatic patients with HbSC and HbSS, respectively.50 Further research may inform retina specialists’ practice patterns in SCR surveillance exams and help establish screening guidelines. Moreover, there is ongoing research on the use of teleophthalmology with ultrawidefield fundus imaging, as well as machine learning techniques to detect and classify the stage of SCR.51 This technology may play a role in SCR screening and monitoring in the future.

SYSTEMIC MANAGEMENT

Given the recent advances in medical therapy for SCD, a brief discussion on the systemic management of SCD is warranted. Allogeneic stem-cell therapy from human leukocyte antigen-matched donors is the only known cure for SCD, although gene therapy has shown promise in clinical trials to date.52,53 Blood transfusions are also used long-term to decrease the Hb S content of blood. For many years, hydroxyurea, which increases fetal hemoglobin content, was the only approved oral therapy for SCD.54 In 2019, 2 new oral therapies were approved for SCD. Voxelotor (Oxbryta; Global Blood Therapeutics), which inhibits Hb S polymerization, and crizanlizumab (Adakveo; Novartis), a monoclonal antibody that binds P-selectin, were shown to reduce hemolysis and prevent VOC respectively.55,56 Longitudinal studies involving patients receiving these novel therapies will help understand the effect of these therapies on SCR.

CONCLUSION

Although most patients with SCD generally have good distance vision, SCR can cause significant visual morbidity most commonly from vitreous hemorrhage and retinal detachment. Patients with SCD can also present with acute vision loss from retinal vascular occlusions or macular infarctions. Laser photocoagulation is the mainstay treatment for PSR, and intravitreal anti-VEGF therapy has also been effective as an adjunctive agent in select cases of PSR. Retinal detachment related to PSR can be challenging to manage surgically. Therefore, these authors recommend all patients with SCD receive regular exams with a retina specialist at least annually for SCR surveillance, with consideration of ultrawidefield fundus photography and fluorescein angiography, and with macular OCT, to document baseline retinal anatomic changes and to monitor for future disease progression. Additional study is necessary to understand the relationship between systemic SCD therapy, retinal perfusion status, and incidence and severity of PSR. RP

Ishrat Ahmed, MD, PhD, is a third-year resident at the Johns Hopkins University School of Medicine Wilmer Eye Institute in Baltimore, Maryland. Dr. Ahmed reports no related disclosures. Adrienne W. Scott, MD, is an assistant professor of ophthalmology at the Johns Hopkins University School of Medicine Wilmer Eye Institute. Dr. Scott reports consultancy to Genentech/Roche, Allergan, and Novartis. Reach Dr. Scott at ascott28@jhmi.edu. Editor’s note: This article is discussed in an episode of the Retina Podcast. Listen at www.retinapodcast.com .

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