Management of Proliferative Sickle Cell Retinopathy

RETINA OPHTHALMIC PEARLS

Management of Proliferative Sickle Cell Retinopathy

roliferative sickle cell retinop­ more commonly in males. In 1 athy (PSR) is a vision-threaten­ individuals with HbSC, the Ping complication of sickle cell peak onset of retinopathy is disease (SCD). Ischemic events in the between 15 and 24 years in retina stimulate angiogenesis, resulting men and between 20 and 39 in retinal neovascularization. years in women.5 SCD is caused by a mutation in the HBB gene, which encodes hemoglobin Pathophysiology beta. PSR affects up to 40% of hetero­ Red blood cells in patients zygous (HbSC) patients and 20% of with SCD are less pliable homozygous (HbSS) patients.1 Although than normal, resulting in most patients remain visually asymp­ microvascular occlusive tomatic, the incidence of visual loss events. Subsequent retinal SEA FANS. Ultra-widefield fluorescein angiogra- among patients with HbSS and HbSC capillary hypoperfusion or phy demonstrates bright hyperfluorescence of affected by PSR has been reported as nonperfusion and defec­ sea-fan neovascularization caused by PSR. 31 per 1,000 eyes compared with 1.4 tive oxygen transport lead per 1,000 in eyes with nonproliferative to local ischemia, which stimulates creating a more favorable environment disease.2 production of proangiogenic growth for neovascularization.6 In contrast, factors, such as vascular endothelial individuals with the HbSS phenotype Epidemiology growth factor (VEGF), leading to reti­ may be less likely to generate an angio­ The highest frequency of genotypes nal neovascularization. Inflammatory genic response because their vascular associated with HbS is seen in popula­ mediators and intracellular adhesion occlusion is more complete, producing tions of African descent; however, high molecules also play an important role more profound infarction and leading rates of at-risk genotypes are also seen in the pathophysiology of PSR. to retinal necrosis. in people of Mediterranean, Caribbean, Retinopathy in HbSC vs. HbSS South and Central American, Arabic, patients. There are several theories as Retinal Neovascularization and East Indian descent.3 to why individuals with HbSC geno­ In PSR, the new vessels grow in a frond­ Patients with the HbSS genotype types are more likely to develop PSR like configuration, which has classically , 5th ed. Philadelphia: Elsevier Saunders; 2013. Saunders; 2013. , 5th ed. Philadelphia: Elsevier typically experience greater systemic than those with HbSS. In HbSC, the been described as resembling a sea fan Retina morbidity, whereas those with the blood has greater viscosity and higher (Fig. 1). As this sea-fan neovasculariza­ heterozygous genotypes (HbSC and hematocrit levels, which may lead to tion grows along the retinal surface and HbS-beta thalassemia) are more likely small-vessel occlusion in the retinal onto the posterior cortical vitreous, vit­ to manifest PSR. Roughly 32% of HbSC vasculature.6 Another theory is that the reous traction on the neovascular chan­ patients will have retinal neovascular­ HbSC state may produce less severe nels may result in intermittent vitreous ization with vitreous hemorrhage com­ retinal vaso-occlusion, resulting in low- hemorrhage. Vitreous hemorrhage can pared with 6% of HbSS patients.4 PSR grade chronic ischemia and release of also be caused by minor ocular trauma risk increases with age and is observed proangiogenic growth factors, thereby or contraction of vitreous bands from a previous hemorrhage. Spontaneous regression of the sea- BY MASHAL AKHTER, MD, MICHELLE W. LATTING, MD, AND ADRIENNE W. fan neovascularization may occur in

Scott AW et al. Hemoglobinopathies. In: Ryan S et al. In: Ryan et al. Hemoglobinopathies. AW Scott SCOTT, MD. EDITED BY SHARON FEKRAT, MD, AND INGRID U. SCOTT, MD, MPH. up to 60% of patients and is thought to

EYENET MAGAZINE • 47 result from autoinfarction.7 2A 2B Sight-threatening complications. In addition to vitreous hemorrhage and vitreoretinal traction, vision-threaten­ ing complications of neovasculariza­ tion include: • Traction retinal detachment • Traction retinoschisis • Macular pucker • Macular hole • Retinal break • Rhegmatogenous or exudative reti­ nal detachment FOVEAL FINDINGS. (2A) SD-OCT demonstrates focal thinning (arrow) within the Course of sea-fan neovasculariza- temporal foveal region in a patient with HbSS disease. (2B) Foveal splaying (sau- tion. Progression of retinal neovas­ cerization of the foveal pit) is noted in this patient. cularization in PSR is variable; some neovascular fronds remain relatively helpful in showing the extent of leakage the aims of therapy are to small and flat for many years before from sea-fan lesions and, particularly, 1. Render the lesion avascular and less autoinfarcting, while others enlarge in documenting the extent and longitu­ likely to bleed, rapidly and coalesce with neighboring dinal progression of peripheral retinal 2. Reduce or arrest the chronic transu­ lesions to form larger, elevated, circum­ ischemia (Fig. 1). dation of plasma into the vitreous, and ferential neovascular complexes. Macular thinning, which increas­ 3. Prevent or reduce the vitreoretinal Estimating the age of a PSR lesion es with age, is common across all traction that may result from progres­ is difficult; the clinician is limited to genotypes in patients with sickle cell sive enlargement and forward growth an assessment of the size and degree of retinopathy.10 Diffuse thinning may of the lesion into the vitreous. elevation above the retinal plane and be present throughout the macula, Treatments that increase fetal hemo­ a semiquantitative assessment of the producing a blunted angle of foveal globin, or HbF, such as hydroxyurea, amount of perfusion and leakage on contour, called foveal splay, seen on omega-3 fatty acids, and erythropoietin fluorescein angiography. Disease sever­ spectral-domain optical coherence may help to decrease the morbidity of ity may be quantified by the number tomography (SD-OCT). Focal thin­ SCD by interfering with the polymer­ of perfused and autoinfarcted sea fans, ning may also occur in the temporal ization of HbS and reducing the load along with the circumferential extent subfields, a known watershed zone for of inflammatory mediators.4 However, of PSR. the macular vasculature (Fig. 2).11 A it is not yet known how systemic sickle recent study showed that SD-OCT in cell status or systemic treatments such Screening conjunction with complete ophthalmo­ as hydroxyurea or exchange transfusions Because PSR lesions are typically located logic examination may lead to earlier (in which the patient’s blood is removed in the retinal periphery, individuals with detection of retinopathy in children less and replaced by a donor’s blood) may earlier stages of PSR often remain visu­ than 10 years old.12 influence the progression of retinopa­ ally asymptomatic. It is recommended OCT angiography (OCTA) is an thy or the development of PSR. that patients with SCD have dilated emerging imaging modality that can funduscopic examinations every 1 to 2 reveal abnormalities in the retinal mi­ Laser Photocoagulation years beginning at age 10,8 preferably crovasculature in both proliferative and Although scatter laser photocoagula­ by a retina specialist. (These recom­ nonproliferative sickle cell retinopathy. tion is the current mainstay for man­ mendations are based on expert panel The macular vessel density, specifically aging PSR, there is no evidence-based, , 5th ed. Philadelphia: Elsevier Saunders; 2013. Saunders; 2013. , 5th ed. Philadelphia: Elsevier consensus, not on large data-driven in the deep retinal plexus, as seen on widely accepted treatment regimen. studies.) OCTA, has been shown to correlate Moreover, the published literature is Retina with peripheral nonperfusion seen on inconclusive on whether retinal laser Imaging Modalities UWF-FA in patients with HbSC disease photocoagulation is effective in chang­ Ultra-widefield imaging (up to 200- (Fig. 3).13 ing visual outcomes in PSR.14 degree field of view) is useful in doc­ Patient selection. Laser photocoagu­ umenting and following PSR lesions. Treatment lation is generally considered if there is Ultra-widefield fundus photography Treatment protocols for PSR are not rapid growth or elevation of neovascu­ (UWF-F) and ultra-widefield fluores­ standardized; however, they share lar lesions, progressive vitreous traction cein angiography (UWF-FA) have been the common goal of reducing the and/or bleeding of a neovascular lesion, shown to detect a more-advanced stage risk of progression of neovascular or increase in the number of neovas­ of sickle cell retinopathy compared with lesions to vitreous hemorrhage and/ cular lesions. This treatment modality 9 4 fundus examination alone. UWF-FA is or retinal detachment. In particular, may also be considered in cases of ex­ S et al. In: Ryan et al. Hemoglobinopathies. AW Scott

48 • OCTOBER 2018 3A 3B 3C 3D

MULTIMODAL VIEWS. Right eye of HbSS patient shows vascular abnormalities Vitrectomy. In selected cases of in the macula and the retinal periphery. (3A) Infrared retinal SD-OCT image, with PSR, vitrectomy is indicated in order areas of retinal thinning (blue) noted in the outer temporal subfields. (3B) OCTA to achieve clearing of vitreous hemor­ of the superficial and (3C) deep capillary plexuses with areas of abnormal vascular rhage or to facilitate retinal reattach­ flow in the temporal juxtafoveal macula (arrows). (3D) UWF-FA shows vascular ment. anastomotic loops in stage 2 PSR (arrow) and temporal nonperfusion in the retinal Retinal traction from neovascular periphery. complexes must be relieved. Use of a segmentation technique allows for tensive peripheral nonperfusion, as well Surgical Options vertical cutting of the fibrovascular as in patients with neovascularization Surgery for PSR may be indicated in tissue into small sections to relieve who are likely to have poor adherence eyes with retinal detachment, non­ circumferential traction. In contrast, to follow-up schedules or those who clearing vitreous hemorrhage, vitreous delamination involves removing the have visual impairment or blindness in hemorrhage that occurs bilaterally or in membranes through horizontal dis­ the fellow eye. a monocular patient, macular hole, or section in the plane between the retina Technique. Laser photocoagulation symptomatic vitreomacular traction. In and the fibrotic tissue and may be more may be performed as local focal treat­ all such patients, careful preoperative likely to cause iatrogenic retinal breaks. ment to barricade a sea-fan neovascular planning is required, incorporating a Sea-fan neovascular complexes are complex or in a 360-degree circumfer­ multidisciplinary approach with the located in the anterior retina, where the ential delivery to the peripheral retina participation of the vitreoretinal sur­ tissue is more ischemic and thin and, (Fig. 4). gery, hematology, and anesthesiology thus, prone to iatrogenic breaks with teams. even minimal manipulation. Special Emerging Therapies Surgical considerations. General attention must be paid to management Anti-VEGF agents. A single intravitreal anesthesia is preferred over local, as it of IOP during vitrectomy, as patients injection of anti-VEGF medications allows for optimal intraoperative pain with sickle trait are more prone to vas­ such as bevacizumab or ranibizumab control. If general anesthesia is con­ cular occlusions with even modest and may lead to partial regression of sea- traindicated, sub-Tenon’s anesthesia transient IOP elevations. fan neovascularization and decreased is preferred over retrobulbar block, as Scleral buckle. Historically, en­ leakage on fluorescein angiography.15 even modest elevations in intraocular circling buckles have been relatively The optimal frequency of intravitreal pressure (IOP) may compro­ anti-VEGF injections in PSR is un­ mise the ophthalmic circula­ 4 known; however, evidence suggests that tion in sickle cell patients. the degree of fibrosis of the sea-fan le­ Preoperative partial-

, 5th ed. Philadelphia: Elsevier Saunders; 2013. (Bottom) Adrienne W. Scott, MD. Scott, W. Adrienne (Bottom) Saunders; 2013. , 5th ed. Philadelphia: Elsevier sion in response to anti-VEGF therapy exchange blood transfusion may help to determine the schedule of to increase hemoglobin A to Retina further injections.15 more than 60% should be Anti-VEGF injection may also considered. During surgery, be used as an adjunctive therapy for it is impor­tant to ensure patients with recurrent vitreous hemor­ adequate intraoperative rhage who have already received laser hydration, oxygenation, treatment. Similar to its use in selected and careful at­tention to cases of traction retinal detachment IOP control. Postoperative and proliferative diabetic retinopathy, exchange transfusion and bevacizumab has proved helpful in hospitalization for maximal decreasing intraoperative bleeding and oxygenation, hydration, and LASER EFFECTS. A sea-fan lesion with localized dissecting neovascular fronds from the pain management should be hemorrhage is depicted on UWF fundus photog­ retinal surface when injected prior to considered in patients with raphy immediately after scatter laser treatment in

(Top) Scott AW et al. Hemoglobinopathies. In: Ryan S et al. In: Ryan et al. Hemoglobinopathies. AW Scott (Top) vitrectomy. SCD. a patient with HbSC disease.

EYENET MAGAZINE • 49 contraindicated in patients with SCD, as scleral buckles have been shown to decrease retinal blood flow and alter perfusion of the anterior choroid, cili­ ary body, and ciliary processes. How­ ever, modern, thinner scleral buckles can be used safely in eyes with PSR and may be helpful in supporting areas of peripheral retinal pathology. To avoid anterior segment ischemia in patients EyeNet with sickle cell status, the surgeon should take care not to place a scleral buckle too tightly.

Corporate 1 Ahn ES et al. Posterior pole manifestations of hematologic diseases. In: Arevalo JF, ed. Retinal and Choroidal Manifestations of Selected Systemic Diseases. New York: Springer Science Business Lunches Media; 2013. 2 Moriarty BJ et al. Eye (Lond). 1988;2(Pt 3):330- EyeNet® Magazine helps you make 335. the most of your time at AAO 2018 3 Elagouz M et al. Surv Ophthalmol. 2010;55(4): by bringing you free corporate 349-377. 4 Fox PD et al. Br J Ophthalmol. 1990;74(3):172- educational program lunches* 176. onsite at McCormick Place. 5 Ballas SK et al. Scientific World Journal. 2012;2012:949535. doi:10.1100/2012/949535. 6 Fadugbagbe AO et al. Ann Trop Paediatr. 2010;30(1):19-26. 7 Lutty GA et al. Sickle cell retinopathy and he­ moglobinopathies. In: Joussem AM et al. Retinal Vascular Diseases. Berlin: Springer-Verlag; 2007. doi:10.1007/978-3-540-29542-6. 8 Yawn BP et al. JAMA. 2014;312(10):1033-1048. Saturday, Oct. 27, Sunday, Oct. 28, and 9 Han IC et al. Retina. Published online Jan. 30, Monday, Oct. 29 2018. doi:10.1097/IAE.0000000000002057. 10 Lim JI, Cao D. Am J Ophthalmol. 2018;192: Room E353c, Lakeside 229-238. McCormick Place 11 Hoang QV et al. Am J Ophthalmol. 2011;151: Check-in and Lunch 990-994. 12 Jin J et al. J AAPOS. 2018;22(3):197-201. 12:15-12:30 p.m. Lunches are provided on 13 Han IC et al. Ophthalmology Retina. a first-come basis, so be sure to arrive on 2018;2(6):599-605. time to secure your meal and seat. 14 Myint KT et al. Cochrane Database Syst Rev. 2015 Oct 9;(10):CD010790. Programs 15 Cai C et al. J Vitreoretin Dis. 2018;2(1):32-38. 12:30-1:30 p.m. Dr. Akhter is a resident at the Kresge Eye For updated program information: Institute, Wayne State University, in Detroit. Dr. Latting is a clinical fellow at Bascom Palmer aao.org/eyenet/corporate-events Eye Institute, in Miami. Dr. Scott is an associate professor of ophthalmology at the Wilmer Eye * These programs are non-CME and are developed independently by industry. They are not affiliated with the official program of AAO 2018 or Institute, Johns Hopkins University School of Subspecialty Day. By attending a lunch, you may be subject to reporting Medicine, in Baltimore. Relevant financial disclo- under the Physician Payment Sunshine Act. sures: None. For full disclosures, see this article online at aao. org/eyenet.