SURGICAL APPROACH to SICKLE CELL RETINOPATHY RETINA PEARLS RETINA Recommendations for Successful Surgery in These Challenging Cases

Home , Scleral buckle, Sickle cell retinopathy, Vitreous hemorrhage

SURGICAL APPROACH TO SICKLE CELL RETINOPATHY RETINA PEARLS RETINA Recommendations for successful surgery in these challenging cases.

BY CINDY X. CAI, MD, and ADRIENNE W. SCOTT, MD

Sickle cell disease (SCD), AVOIDING SURGERY first described by James In our anecdotal experience, intravitreal injection with an Herrick in 1910, is the most anti-VEGF agent may be useful in facilitating the involution common inherited blood of sea-fan neovascularization and clearing vitreous hemor- disorder in the United rhage, potentially avoiding the need for surgery. It is known States and worldwide.1,2 It is that SCD leads to peripheral retinal ischemia that can be eas- caused by the inheritance of ily seen on ultrawide-field fluorescein angiography (Figure 1). abnormal beta globin alleles The peripheral ischemia leads to the release of proangiogenic carrying the sickle mutation on the hemoglobin gene. The factors such as VEGF and formation of the characteristic mutations most frequently associated with ophthalmic sea-fan neovascular complexes. Therefore, there is a biologic changes are HbSS and HbSC disease, two of the most com- rationale for intravitreal injection of anti-VEGF agents such mon types of SCD.3 as bevacizumab (Avastin, Genentech) for the regression of The ophthalmic manifestations of SCD range from sickle neovascularization.11-13 Other authors have reported nonproliferative to proliferative changes, but the major this as well in case reports.12,14 Similar success has also been sight-threatening complication in SCD is proliferative reported with ranibizumab (Lucentis, Genentech).15 sickle cell retinopathy (PSR).4 Large-scale population- based studies indicate that the prevalence of PSR is as high as 32% in HbSC and 6% in HbSS.5 More specifically, symptomatically decreased vision typically occurs only in the last two stages of PSR—Goldberg stage IV (presence of vitreous hemorrhage) and Goldberg stage V AT A GLANCE 6,7 (presence of retinal detachment). The precise incidence • Although severe vision loss in proliferative sickle and prevalence of severe vision loss in PSR is as yet cell retinopathy (PSR) is relatively uncommon, unknown; reported numbers vary depending on the symptomatically decreased vision can occur in the study. But, overall, severe vision loss in PSR is relatively last two stages of PSR. uncommon.4,6,8 Natural history studies demonstrate that PSR can • Despite medical management, a small number of eyes regress, and sea-fan neovascular complexes can undergo with PSR will require vitreoretinal surgical intervention. autoinfarction, even without treatment, while the patient • Visually significant nonclearing vitreous hemorrhage, 8,9 remains visually asymptomatic. When vision loss occurs, or vitreous hemorrhage occurring bilaterally or in it is most commonly a result of vitreous hemorrhage or a monocular patient, and retinal detachment are retinal detachment. Less commonly, it can occur due to indications for surgical intervention in PSR. vitreomacular interface abnormalities as a consequence of neovascularization, such as macular hole, or epiretinal • Recommended practices for the surgical management membrane (ERM).4,10 of PSR include consideration of an injection of Rarely, selected cases will require vitreoretinal surgical an anti-VEGF agent prior to surgery for eyes with management to improve or stabilize vision. Visually sig- stage IV and V PSR, blood transfusion or exchange nificant nonclearing vitreous hemorrhage, or vitreous transfusion per hematologist, general anesthesia or hemorrhage occurring bilaterally or in a monocular patient, sub-Tenon block, and avoidance of high and broad may be an indication for surgical intervention in PSR, as is scleral buckles. retinal detachment.10

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These studies are limited by the length of follow-up. Additional evidence is needed to better define the role of anti-VEGF agents in clearing vitreous hemorrhage in PSR; however, our initial experience is encouraging as a possible way to clear vitreous hemorrhage. Despite medical management, a small number of eyes with PSR will require vitreoretinal surgical intervention. In this article, we report our experience with the surgical approach to PSR.

PREOPERATIVE PLANNING Because the characteristic vaso-occlusive episodes of SCD can affect every organ system, surgical intervention in these Figure 1. Ultrawide-field fluorescein angiography of a eyes presents a unique set of challenges that requires care- patient with PSR demonstrates sea-fan neovascularization ful preoperative planning, incorporating a multidisciplinary and peripheral retinal ischemia. approach, with discussion with other medical teams caring for the patient, including hematology and anesthesiology. Preoperative planning should start with a detailed discussion control. If it is contraindicated for some reason, then a sub- with the patient and other members of the team regarding Tenon block is preferable to retrobulbar block. SCD patients the need for exchange transfusion. Exchange transfusion in can have orbital compression syndrome from sickling events the setting of retinal surgery for SCD is controversial. There is in or around the orbit, and a retrobulbar block could theo- no randomized controlled trial in the ophthalmic literature retically increase this risk.2,23 evaluating the efficacy of exchange transfusions. Some authors Once the decision for surgical intervention has been made believe that partial exchange blood transfusion, increasing in patients with stage IV or V PSR, intravitreal bevacizumab hemoglobin A to more than 60%, is protective against anterior can be used as a presurgical adjunctive agent to decrease segment ischemia.16,17 Others have argued against the use of the likelihood of intraoperative bleeding and to facilitate preoperative exchange transfusion, citing risks of transmissible dissection of sea-fan neovascular complexes, similar to the diseases.18,19 In a more recent surgical series, the authors pro- way anti-VEGF agents are used in surgery for proliferative pose that adequate intraoperative hydration, oxygenation, and diabetic retinopathy.24,25 We have previously reported that intraocular pressure control can obviate the need for preopera- administration of bevacizumab 3 days before the surgical tive exchange transfusions.10 procedure leads to increased fibrosis of the sea-fan neovas- There is no consensus in the hematology literature, either, cularization and decreased intraoperative bleeding.26 There for preoperative exchange transfusions.20,21 One randomized is a theoretical concern of anti-VEGF crunch—as seen in the controlled clinical trial assessed transfusion 10 days before setting of tractional retinal detachments in proliferative dia- surgery but included only sickle cell patients with HbSS and betic retinopathy—but we have not experienced this.27 HbS beta thalassemia undergoing abdominal and orthopedic surgeries.22 The authors reported that patients who received SURGICAL TECHNIQUE preoperative transfusions had fewer clinically important When removal of neovascular fibrovascular tissue is complications, but it is unclear how these results apply to needed to relieve traction, we recommend segmentation ophthalmic surgery. over delamination techniques, as have other surgeons.28 Given the lack of evidence, we recommend a tailored Segmentation involves the vertical cutting of the fibrovas- approach to exchange transfusion, involving the anesthesiol- cular tissue into small segments to relieve circumferential ogist and hematologist preoperatively to determine whether traction, which allows removal of each small segment it is needed for each individual patient. Careful attention to individually.29 Delamination describes the removal of the postoperative analgesia and hydration for patients with SCD membranes through horizontal dissection in the plane is also imperative. Severe postoperative pain, lack of hydra- between the retina and the fibrosis.29 The sea-fan neovas- tion, and the overall stress of surgery can trigger a positive cular complexes are usually located in the anterior retina feedback loop of painful vaso-occlusive crises. where the tissue is ischemic, and thus very thin and prone to iatrogenic breaks. These peripheral neovascular com- SURGICAL CONSIDERATIONS plexes are also often strongly adherent, and removing them Once the patient has been cleared for surgery, we rec- using delamination techniques can cause iatrogenic retinal ommend general anesthesia rather than local anesthesia. tears.26,28 The same principles of segmentation apply to General anesthesia allows optimal intraoperative pain removal of ERMs in the setting of PSR.30 Use of a bimanual

APRIL 2017 | RETINA TODAY 33 1. Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Yale J Biol Med. 1910;74:179-184. A B 2. Scott AW. Ophthalmic manifestations of sickle cell disease. South Med J. 2016;109(9):542-548. 3. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease [published online ahead of print January 31, 2017]. Lancet. 4. Moriarty BJ, Acheson RW, Condon PI, Serjeant GR. Patterns of visual loss in untreated sickle cell retinopathy. Eye (Lond). 1988;2 (Pt 3)(3):330-335.

RETINA PEARLS RETINA 5. Fox PD, Dunn DT, Morris JS, Serjeant GR. Risk factors for proliferative sickle retinopathy. Br J Ophthalmol. 1990;74(3):172-176. C 6. Goldberg MF. Natural history of untreated proliferative sickle retinopathy. Arch Ophthalmol. 1971;85(4):428-437. 7. Goldberg MF. Classification and pathogenesis of proliferative sickle retinopathy. Am J Ophthalmol. 1971;71(3):649-665. 8. Downes SM, Hambleton IR, Chuang EL, Lois N, Serjeant GR, Bird AC. Incidence and natural history of proliferative sickle cell retinopathy: observations from a cohort study. Ophthalmology. 2005;112(11):1869-1875. 9. Condon PI, Serjeant GR. Behaviour of untreated proliferative sickle retinopathy. Br J Ophthalmol. 1980;64(6):404-411. 10. Chen RWS, Flynn HW, Lee W-H, et al. Vitreoretinal management and surgical outcomes in proliferative sickle retinopa- Figure 2. Color fundus photograph of the left eye of an HbSC thy: a case series. Am J Ophthalmol. 2014;157(4):870-875.e871. 11. Cao J, Mathews MK, McLeod DS, Merges C, Hjelmeland LM, Lutty GA. Angiogenic factors in human proliferative sickle patient with PSR presenting with decreased vision from an cell retinopathy. Br J Ophthalmol. 1999;83(7):838-846. ERM (A). Optical coherence tomography (OCT) through the 12. Siqueira RC, Costa RA, Scott IU, Cintra LP, Jorge R. Intravitreal bevacizumab (Avastin) injection associated with regression of retinal neovascularization caused by sickle cell retinopathy. Acta Ophthalmol Scand. 2006;84(6):834-835. fovea demonstrates vitreomacular traction (B). OCT after 13. Babalola OE. Intravitreal bevacizumab (Avastin) associated with secondary hyphaema in a case of proliferative sickle surgical removal of the ERM demonstrates flattening of the cell retinopathy. BMJ Case Rep. 2010;2010. doi:10.1136/bcr.11.2009.2441. 14. Shaikh S. Intravitreal bevacizumab (Avastin) for the treatment of proliferative sickle retinopathy. Indian J Ophthalmol. macula and some restoration of foveal contour (C). 2008;56(3):259. 15. Mitropoulos PG, Chatziralli IP, Parikakis EA, Peponis VG, Amariotakis GA, Moschos MM. Intravitreal ranibizumab for stage IV proliferative sickle cell retinopathy: a first case report. Case Rep Ophthalmol Med. 2014;2014(1):682583. technique with a lighted pick or a chandelier as an addi- 16. Eagle RC, Yanoff M, Morse PH. Anterior segment necrosis following scleral buckling in hemoglobin SC disease. Am J Ophthalmol. 1973;75(3):426-433. tional light source can also facilitate dissection. 17. Jampol LM, Green JL, Goldberg MF, Peyman GA. An update on vitrectomy surgery and retinal detachment repair in Figure 2 shows a patient who presented with decreased vision sickle cell disease. Arch Ophthalmol. 1982;100(4):591-593. 18. Pulido JS, Flynn HW, Clarkson JG. Pars plana vitrectomy in the management of complications of proliferative sickle as a result of an ERM. Flattening of the macula was achieved retinopathy. Arch Ophthalmol. 1988;106(11):1553-1557. after use of segmentation techniques described above. 19. Morgan CM, D’Amico DJ. Vitrectomy surgery in proliferative sickle retinopathy. Am J Ophthalmol. 1987;104(2):133-138. 20. Lottenberg R, Hassell KL. An evidence-based approach to the treatment of adults with sickle cell disease. Hematology We recommend the use of a scleral buckle to support Am Soc Hematol Educ Program. 2005:58-65. peripheral pathology if needed. Historically, encircling scleral 21. Estcourt LJ, Fortin PM, Trivella M, Hopewell S. Preoperative blood transfusions for sickle cell disease. Cochrane Database Syst Rev. 2016;4:CD003149. buckles were implicated in high rates of anterior segment 22. Howard J, Malfroy M, Llewelyn C, et al. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: ischemia in SCD.31 More modern series do not demonstrate a randomised, controlled, multicentre clinical trial. Lancet. 2013;381(9870):930-938. 23. Curran EL, Fleming JC, Rice K, Wang WC. Orbital compression syndrome in sickle cell disease. Ophthalmology. an increased risk for anterior ischemia with the use of an 1997;104(10):1610-1615. encircling buckle.10 This is possibly due to changes in surgical 24. Guthrie G, Hall AB, Dhalla K, Davies RM, Davis RM, Steel DH. Bevacizumab as an adjunct to vitreoretinal surgery for diabetic retinopathy in East Africa. Eye (Lond). 2013;27(11):1263-1268. technique, as modern scleral buckles are no longer routinely 25. Pokroy R, Desai UR, Du E, Li Y, Edwards P. Bevacizumab prior to vitrectomy for diabetic traction retinal detachment. Eye placed high and broadly. However, encircling scleral buckles (Lond). 2011;25(8):989-997. 26. Moshiri A, Ha NK, Ko FS, Scott AW. Bevacizumab presurgical treatment for proliferative sickle-cell retinopathy-related have been shown to cause decreased retinal blood flow and retinal detachment. Retin Cases Brief Rep. 2013;7(3):204-205. 27. Flynn HW Jr, Chen RWS. Avoiding and managing complications of vitreoretinal procedures. Retina Today. altered perfusion of the anterior choroid, ciliary body, and 2014;9(4):49-52. 32,33 ciliary processes. Given that sickle cell patients are vulner- 28. Williamson TH, Rajput R, Laidlaw DAH, Mokete B. Vitreoretinal management of the complications of sickle cell retinopathy by observation or pars plana vitrectomy. Eye (Lond). 2009;23(6):1314-1320. able to alterations of perfusion, we recommend that scleral 29. Charles S. Vitrectomy techniques for complex retinal detachments. Taiwan Journal of Ophthalmology. 2012;2(3):81-84. buckles not be placed too tightly. 30. Carney MD, Jampol LM. Epiretinal membranes in sickle cell retinopathy. Arch Ophthalmol. 1987;105(2):214-217. 31. Ryan SJ, Goldberg MF. Anterior segment ischemia following scleral buckling in sickle cell hemoglobinopathy. Am J Ophthalmol. 1971;72(1):35-50. CONCLUSION 32. Ogasawara H, Feke GT, Yoshida A, Milbocker MT, Weiter JJ, McMeel JW. Retinal blood flow alterations associated with scleral buckling and encircling procedures. Br J Ophthalmol. 1992;76(5):275-279. There have been numerous surgical advances since the 33. Dobbie JG. Circulatory changes in the eye associated with retinal detachment and its repair. Trans Am Ophthalmol Soc. first series describing the surgical management of PSR was 1980;78:503-566. published. In the contemporary era of vitreoretinal surgery, we recommend the following practices: Cindy X. Cai, MD • Injection of bevacizumab 3 days before surgery in n second-year resident, Johns Hopkins Wilmer Eye Institute, selected eyes with stage IV and V PSR; Baltimore, Md. • Transfusion exchange as recommended by hematology n financial interest: none acknowledged and anesthesiology; n [email protected] • General anesthesia or sub-Tenon block over retrobulbar block; Adrienne W. Scott, MD • Segmentation techniques for dissection of peripheral n assistant professor of ophthalmology at Johns Hopkins Wilmer Eye Institute; medical director of the Wilmer Eye Institute in neovascular fibrovascular tissue; Bel Air, Md.; head of the retina fellowship for the Wilmer Eye • Avoidance of high and broad scleral buckles; and Institute • Careful intraoperative and postoperative monitoring n financial interest: none acknowledged of analgesia, hydration, oxygenation, and intraocular n [email protected] pressure. n

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