Treating Neovascular Peripheral Retinal Diseases
MARENA PATRONAS, MD · JOSEPH M. CONEY, MD · LAWRENCE J. SINGERMAN, MD, FACS
Pathological processes in the peripheral retina have attracted the attention of both clinical investigators and practicing ophthalmologists for many years. Neovascularization in the peripheral retina represents a challenging phenomenon. It has been observed in various diseases and is the source of many complications. During the last few years, investigators have reported favorable results in the treatment of macular degeneration with different antiangiogenic drugs. This prompted recent attempts to offer antiangiogenesis treatment in diseases associated with peripheral proliferative retinopathy. In this brief summary, we will describe the pathologic mechanisms of these diseases and review a few promising results of antiangiogenesis treatments in proliferative diabetic retinopathy (PDR), sickle-cell retinopathy, retinopathy of prematurity (ROP), and familial exudative vitreoretinopathy (FEVR).
PROLIFERATIVE DIABETIC RETINOPATHY
Proliferative diabetic retinopathy is the most common entity associated with pathological neovascularization of the peripheral retina and optic nerve. Relative ischemia with decreased oxygen concentration in the circulating blood of the retinal capillary bed is currently believed to be the underlying pathophysiological mechanism of this complication. Prolonged hyperglycemia induces oxidative stress in cells, leading to altered gene expression and affecting normal metabolic pathways. Additionally, chronic hyperglycemia results in glycation of proteins that undergo cross-linking, causing substantial alteration of protein function and damage to endothelial cells.1 Regardless of the cause of oxygen deprivation, the balance of stimulation and inhibition of angiogenesis in the retina is perturbed, initiating a cascade of events that involve excessive production of vascular endothelial growth factor (VEGF).2 This stimulates endothelial cell proliferation and migration that leads to the production of new blood vessels in areas of nonperfusion.3
|Marena Patronas, MD, and Joseph M. Coney, MD, practice ophthalmology with Retinal Associates of Cleveland. Lawrence J. Singerman, MD, FACS, is clinical professor of ophthalmology at Case Western Reserve University in Cleveland and voluntary professor of clinical ophthalmology at Bascom Palmer Eye Institute in Miami. He also practices with Retinal Associates of Cleveland. Dr. Singerman reports minimal financial interest in Genentech and moderate financial interest in Eyetech. Drs. Coney and Patronas report no financial interests. Dr. Patronas can be reached via e-mail at firstname.lastname@example.org.|
The observation that eyes with widespread scarring from inflammation or trauma have a reduced prevalence of proliferative retinopathy prompted Aiello et al. to apply ablative therapy using panretinal photocoagulation (PRP) to the peripheral retina.4 Weiter and Zuckerman reported that the retinal pigment epithelium–photoreceptor complex accounts for two-thirds of the oxygen consumption in the retina.5 Thus, destructive treatment of the peripheral retina by PRP results in decreased retinal metabolism, which diminishes the production of angiogenic factors by ischemic tissues. The Diabetic Retinopathy Study showed that PRP provided clinically verified protection against angiogenesis.6 Despite these beneficial results, however, PRP has certain limitations. Adverse effects of PRP include loss of peripheral visual field, diminished night vision, and exacerbation of macular edema.7
Promising results with intravitreal anti-VEGF treatment of macular degeneration with bevacizumab (Avastin, Genentech) led to several small-case series of anti-VEGF treatment for PDR. Avery et al. treated 44 eyes with intravitreal bevacizumab and noted complete or partial resolution of angiographic leakage in all eyes 1 week after injection. The duration of therapeutic effect ranged from 2 weeks after injection to no recurrence in 11 weeks at the completion of the study.7
More recent studies report the benefit of combination treatment using bevacizumab prior to PRP to minimize macular edema induced by PRP.8,9 Similarly, several reports describe an adjuvant effect of intravitreal anti-VEGF prior to vitrectomy surgery for severe PDR.10,11 This combined treatment is reported to minimize intraoperative bleeding from fibrovascular membranes.11,12 Others, however, have reported tractional retinal detachments following treatment with anti-VEGF.13 Furthermore, it has been shown that once anti-VEGF therapy has been withdrawn, neovascularization may recur (Figure 1). In view of the controversy surrounding the treatment of PDR with anti-VEGF, a randomized controlled study is needed to better assess the benefits of anti-VEGF treatment in lieu of or as an adjuvant to current therapies for PDR.
Figure 1. Retinal neovascularization, seen before pegaptanib injection (left), regressed by week 36 (middle), when treatment was discontinued. Neovascularization recurred by the week 52 visit (right).
Reprinted from Ophthalmology, 113(1), Adamis AP, Altaweel M, Bressler NM, et al., Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals, pp. 23-28, Copyright 2006, with permission from Elsevier.
PROLIFERATIVE SICKLE-CELL RETINOPATHY
As in PDR, patients with sickle-cell hemoglobinopathy can develop peripheral neovascularization when vascular occlusions induce retinal ischemia. Hemoglobin is the main oxygen-transport protein within the erythrocyte. The hemoglobin protein in patients with sickle-cell anemia is altered by a single amino acid substitution of valine for glutamine, causing polymerization of the deoxygenated hemoglobin and sickling of the erythrocyte. It is currently believed that the rigid, elongated, and sickle-shaped erythrocyte causes mechanical microvascular occlusions, resulting in retinal ischemia. Furthermore, the sickled erythrocytes irritate the endothelial cells, stimulating a cascade of inflammatory events leading to vascular stasis and prearteriolar capillary occlusion. Neovascularization occurs at the border of ischemic and nonischemic tissue in the peripheral retina (Figure 2). The neovascularization is classically described as sea-fan neovascularization, but this is not pathognomonic for sickle-cell hemoglobinopathy and can occur in other retinopathies.14
Figure 2. In this picture, the left side is more peripheral and more anterior; the right is more posterior. On the left side, the peripheral retina is completely nonperfused. The right side shows a partially perfused retina. The brighter areas are the junction where the neovascularization is leaking.
There are various degrees of retinopathy, depending on the genetic makeup of the abnormal hemoglobin gene. A carrier of the sickle-cell trait (Hb AS) typically does not develop sickling of the erythrocyte and only on rare occasions can present with manifestations of systemic or ocular vascular complications. Sickle-cell anemia (Hb SS) is a homozygous recessive disorder that occurs when an individual has received mutated genes from both parents. Retinopathy in sickle-cell anemia is typically less severe than other systemic manifestations of the disease. Sickle-cell disease (Hb SC) results from substitution of lysine for glutamine and typically causes more severe ocular complications than sickle-cell anemia.
Thalassemia, another hemoglobinopathy, results from a point mutation in the beta-globin subunit affecting the amino acid sequence. This results in hemoglobin that is normally structured but produced in diminished quantities.14 The incidence of proliferative sickle-cell retinopathy (PSR) in sickle-cell disease and thalassemia is higher than in sickle-cell anemia. The reason for this is unknown, but it is hypothesized that the increased viscosity due to elevated hematocrit in sickle-cell disease and thalassemia promotes intravascular occlusions.14,15
Proliferative sickle cell retinopathy often spontaneously regresses due to autoinfarction of the neovascular fronds. Involution of the neovascular lesions obviates the need for therapeutic intervention in these cases. Available treatments are aimed at preventing more advanced lesions from developing vitreous hemorrhages (stage 4) or retinal detachments (stage 5). Scatter laser photocoagulation of the ischemic retina and tissue surrounding the sea-fan can cause regression of the neovascular lesions and prevention of late-stage disease complications by reducing angiogenic factors. Feeder vessel photocoagulation has also been successful in treating PSR by closing sea-fan vessels that persist following scatter laser treatment.
Cryotherapy is used to treat the peripheral ischemic retina when laser treatment is not possible due to poor visualization of the peripheral retina because of media opacity.14 Antiangiogenesis treatment has not been widely employed in the treatment of PSR. Siqueira et al. reported a single case of PSR treated with intravitreal bevacizumab and observed regression of the neovascularization 4 weeks after treatment. A large-scale clinical trial is necessary to assess the benefits of targeting antiangiogenic factors in PSR.16
RETINOPATHY OF PREMATURITY/FAMILIAL EXUDATIVE VITREORETINOPATHY
Retinopathy of prematurity is neovascularization that occurs in the peripheral retina of premature newborns and is characterized by location (zone) and severity (stage) (Figure 3). FEVR is an autosomal dominant or X-linked retinopathy that mimics the disease course of ROP but is seen in newborns of normal gestational age and birth weight. Both of these diseases lead to neovascularization due to immature peripheral retina with an underdeveloped vascular supply. In normal retinal development, relative ischemia of the peripheral retina is a stimulant for migration of vasculogenic precursors from the optic nerve. This leads to blood-vessel growth and maturation by 36 weeks gestation nasally and by 40 weeks in the temporal retina. In the premature infant, a factor implicated in the pathogenesis of ROP is supplemental treatment with high oxygen concentration. This treatment eliminates normal hypoxia of the peripheral retina at this stage of development and diminishes the stimulus for normal neovascularization. Thus, when the oxygen treatment is discontinued, unvascularized retina upregulates the production of VEGF, which leads to peripheral neovascularization. However, studies by Lucey and Dangman have suggested oxygen therapy may have been an overemphasized contributor to pathogenesis of ROP, with low birth weight and gestational age being the highest risk factors.17
Figure 3. This photo shows peripheral fibrovascular tissue associated with ROP.
Once neovascularization is established in ROP, various stages of retinal complications occur with increasing severity to total retinal detachment. In the initial stages, a demarcation line between vascularized and avascularized retina develops (stage 1). Next, a ridge of highly arborized neovascular tissue forms. In later stages, there is extraretinal neovascular growth (stage 3), with vitreoretinal traction, macular dragging, exudation, and, ultimately, total detachment (stages 4 and 5). Preventive treatment includes cryotherapy to the peripheral ischemic retina and scatter laser photocoagulation. In the Cryo–ROP and Early Treatment–ROP studies, ablation of the peripheral retina caused regression of neovascularization, resulting in reduced incidence of the late sequelae seen in untreated ROP.18,19 The effectiveness of cryotherapy and laser photocoagulation varies widely in reports. A certain number of patients do not respond to ablative therapy and progress to retinal detachments requiring surgery. Cryotherapy has also been reported to cause respiratory and cardiorespiratory arrest.20
Because angiogenic factors have been implicated as the cause of neovascularization in both ROP and FEVR, several investigators have explored treatment of these peripheral retinal diseases with anti-VEGF therapy. Mintz-Hittner et al. reported using intravitreal bevacizumab to treat 22 eyes in 11 premature infants with severe stage 3 ROP.21 None of the patients developed progression to later, more devastating stages of the disease over a mean 48.5-week observation period. Also, there were no reported ocular or systemic side effects with administration of intravitreal bevacizumab in premature infants. Kusaka et al. used intravitreal bevacizumab, either as an initial treatment or in addition to vitrectomy surgery. In 15 eyes that received bevacizumab as initial therapy, 14 had angiographic evidence of reduced neovascular activity.22 Three eyes eventually progressed to develop retinal detachments and were treated surgically, but no major ocular or systemic adverse effects were reported with intravitreal bevacizumab in premature infants.
Familial exudative vitreoretinopathy is studied on a much smaller scale because it is more rare. Quiram et al. described 4 patients treated with intravitreal pegaptanib sodium (Macugen, Eyetech/Pfizer) for vascularly active FEVR unresponsive to photocoagulation, cryotherapy, or intravitreal steroids.23 With a single injection of pegaptanib, all patients had reduction of exudation and decreased leakage on fluorescein angiography. Visual acuity improved in 2 eyes, stabilized in 1 eye, and worsened in 1 eye, the last eye requiring vitrectomy for a tractional retinal detachment.
Substantial progress has been made and new treatment continues to evolve in an effort to prevent or arrest complications in neovascular retinal diseases. We touched on 3 topics of peripheral retinal neovascularization treated with anti-VEGF agents. There are many other causes of peripheral neovascularization that may benefit from treatment with antiangiogenesis medications. Such entities include radiation retinopathy, vasoproliferative tumors, Coats disease, and others. More research will be needed to elucidate the pathogenesis of neovascularization of the peripheral retina. New antiangiogenesis drugs have become available to clinicians for the management of these difficult diseases. Their effectiveness, however, should be explored in properly designed studies that will provide useful information to treating physicians. RP
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- Aiello LM, Beetham WP, Balodimos MC et al. Ruby laser photocoagulation in treatment of diabetic proliferating retinopathy: preliminary report. In: Goldberg MF, Fine SL, eds. Symposium on the Treatment of Diabetic Retinopathy. US Public Health Service. Washington, DC: US Government Printing Office; 1968:437-464.
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- Mirshahi A, Roohipoor R, Lashay A, et al. Bevacizumab-augmented retinal laser photocoagulation in proliferative diabetic retinopathy: a randomized double-masked clinical trial. Eur J Ophthalmol. 2008;18:263-269.
- Rizzo S, Genovesi-Ebert F, Di Bartolo E, et al. Injection of intravitreal bevacizumab (Avastin) as a preoperative adjunct before vitrectomy surgery in the treatment of severe proliferative diabetic retinopathy (PDR). Graefes Arch Clin Exp Ophthalmol. 2008;246:837-842.
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- Siqueira RC, Costa RA, Scott IU et al. Intravitreal bevacizumab (Avastin) injection associated with regression of retinal neovascularization caused by sickle cell retinopathy. Acta Ophthalmol Scand. 2006;84:834-835.
- Lucey JF, Dangman B. A reexamination of the role of oxygen in retrolental fibroplasia. Pediatrics. 1984;73:82-96.
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