Article Date: 1/1/2007

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Bevacizumab for Salvage Treatment in Threshold Retinopathy of Prematurity

Retinopathy of prematurity is a disease affecting the retinas of premature infants. Of babies born weighing less than 1251 g, 4% to 6% reportedly go on to develop threshold retinopathy of prematurity (ROP) requiring treatment.1 In our experience, of babies born weighing less than 1 kg, 19% develop threshold ROP requiring laser. Despite advances in treatment, ROP continues to be a major cause of blindness among premature infants who survive delivery. As the incidence of ROP has increased (along with the survival rate of premature infants), interest in the pathogenesis of ROP has renewed.

The pathophysiology of ROP is similar to other proliferative retinopathies such as proliferative diabetic retinopathy (PDR) and sickle cell retinopathy in that there is a hypoxic phase followed by a neovascular response. In ROP, the first phase involves the premature termination of normal retinal vascular growth after premature birth, producing an avascular peripheral retina. In the second phase, the hypoxic state of the peripheral retina leads to a retinal neovascularization response.

The same factors that are crucial to normal development of the retina are likely involved with the pathologic process of ROP. In one hypothesis of normal development, vascular endothelial growth factor (VEGF) serves as a stimulus to angiogenesis of the advancing peripheral retina.2 As the capillary plexus develops, the signal to produce VEGF is reduced, and angiogenesis slows. A mouse model of the disease aided in the elucidation of VEGF as a crucial player in phase 1 and phase 2 of the disease.3 Alon et al demonstrated that supplemental oxygen leads to the downregulation of VEGF and death of endothelial cells, potentially leading to closure of the vasculature in phase 1 of the disease.4

The resulting hypoxia drives the upregulation of VEGF expression, inducing neovascularization. Sampling of the subretinal fluid in patients with stage 4 and 5 ROP demonstrated significantly elevated levels of VEGF.5 Interestingly, in animal models, complete inhibition of VEGF does not lead to complete inhibition of retinal neovascularization, suggesting that other factors are involved. Flynn et al postulated that in the development of Zone 1 ROP there is a vasculogenic drive independent of VEGF, whereas in Zone 2 ROP there is an angiogenic stimulus.6

Based on this reasoning and the inability to use conventional treatments for a case of ROP, an anti-VEGF agent was used as a salvage treatment to enable peripheral laser ablation.

METHODS

The eyes of a 42-weeks gestational age infant were documented with RetCam (Clarity Medical Systems, Pleasanton, Calif) photography and ultrasonography to have anterior and vitreous chamber hemorrhages and anterior retinal elevation due to complications of ROP. After obtaining parental consent, off-label intravitreal injections of bevacizumab (Avastin, Genentech) were administered to both eyes. RetCam photography and ultrasonography were used for documentation.

RESULT

A former 23-weeks premature neonate was transferred at gestational age 42 weeks to the Jackson Memorial Hos-pital/Bascom Palmer Eye Institute in Miami for treatment of threshold ROP after laser treatment was aborted due to bilateral miosis, hyphema, and vitreous hemorrhage.

Observation for 2 days at the referring facility demonstrated no improvement. Following a lengthy discussion with the parents, a decision was made to use off-label intravitreal bevacizumab as salvage therapy. Natural history data suggest that this presentation of ROP would progress to bilateral retinal detachment without supplemental retinal ablation.7 A standard intravitreal injection protocol with 5% topical povidone-iodine was employed prior to intravitreal delivery of bevacizumab 1.25 mg/0.05 cc. The procedure was tolerated without complication. Serial RetCam photography and ultrasonography documented the increased dilation (Figure 1) and clearing of the hemorrhages, allowing increased visibility of the retina (Figure 2) and resolution of the anterior retinal elevation. The retina had a significant decrease in plus disease, seeming to diminish daily as observed by serial clinical examinations and photos. At 8 weeks postinjection, venous engorgement was noted with vitreous traction and reactivation of the temporal neovascularization in both eyes. Laser therapy was then completed. Throughout this time, the patient's blood pressure and condition remained stable.


Figure 1. Anterior Segment Photos: (a) Baseline, (b) week 1, and
(c) week 3.








Figure 2. Patient PP, Retcam fundus photos: Right and left eyes at  (a) Baseline and (b) Week 1 after intravitreal bevacizumab
injection.

DISCUSSION

The current treatment for ROP is retinal ablation, as in other vasculoproliferative diseases. This treatment strategy was achieved through the Cryotherapy for Retinopathy of Prematurity and Early Treatment for Retinopathy of Prematurity studies, which validate retinal ablation for threshold ROP. The resulting retinal ablation is thought to diminish the production of VEGF and/or other vascular signals and lead to regression of the neovascularization.

The use of retinal ablation is mimicked in other vascular diseases presumably through modulation of vascular growth factors. A role for VEGF is suggested in other ocular neovascular pathologies including PDR, retinal vein occlusion, iris neovascularization, and neovascular age-related macular degeneration (AMD).8-10 In an effort to improve visual outcomes in neovascular AMD, various anti-VEGF pharmacotherapies have been developed, including pegaptanib sodium (Macugen, OSI/Eyetech), ranibizumab (Lucentis, Genentech), and bevacizumab. Phase 3 clinical trials of ranibizumab for wet AMD have clearly demonstrated the regression of choroidal neovascular membranes. Given the overwhelming evidence for the role of VEGF and the reported efficacy of the anti-VEGF therapies, bevacizumab has been used for the treatment of PDR.11 Furthermore, Spaide et al reported a case series of patients with PDR complicated by vitreous hemorrhage treated with bevacizumab to induce cessation of bleeding.12 In this series, the vitreous hemorrhages rapidly resorbed, revealing regressing retinal neovascularization.

The current case is the first report of an intravitreal injection of bevacizumab for the treatment of ROP. We achieved regression of neovascularization secondary to ROP, similar to cases of PDR or AMD complicated by vitreous hemorrhages. It is unclear how long this regression will be maintained, but in a setting of media opacity, poor dilation, or medical instability, anti-VEGF therapies could provide an adjuvant treatment until laser therapy can be applied. In contrast to other ocular pathologic angiogenesis conditions, ROP is a self-limited condition. This raises the question as to whether intravitreal injections of anti-VEGF agents at the appropriate time window could obviate the need for laser entirely. Further study of the safety and efficacy of intravitreal bevacizumab in the treatment of ROP is warranted. RP

REFERENCES

1. Hussain N, Clive J, Bhandari V. Current incidence of retinopathy of prematurity, 1989-1997. Pediatrics. 1999;104:26.
2. Smith LEH. Pathogenesis of retinopathy of prematurity. Acta Paediatr Suppl. 2002;437:26-28.
3. Penn JS, Tolman BL, Henry MM. Oxygen-induced retinopathy in the rat: relationship of retinal perfusion to subsequent neovascularization. Invest Ophthalmol Vis Sci. 1994;35:3429-3435.
4. Alon T, Hemo I, Itin A, et al. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med. 1995;1:1024-1028.
5. Lashkari K, Hirose T, Yazdany J, et al. Vascular endothelial growth factor and hepatocyte growth factor levels are differentially elevated in patients with advanced retinopathy of prematurity. Am J Pathol 2000;156:1337-44.
6. Flynn JT, Chan-Ling T. Retinopathy of prematurity: two distinct mechanisms that underlie zone 1 and zone 2 disease. Am J Ophthalmol. 2006;142:46-59.
7. Coats DK. Retinopathy of prematurity: involution, factors predisposing to retinal detachment, and expected utility of preemptive surgical reintervention. Trans Am Ophthalmol Soc. 2005;103:281-312.
8. Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994;118:445-450.
9. Tripathi RC, Li J, Tripathi BJ, et al. Increased level of vascular endothelial growth factor in aqueous humor of patients with neovascular glaucoma. Ophthalmology. 1998;105:232-237.
10. Kliffen M, Sharma HS, Mooy CM, et al. Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularization. Br J Ophthalmol. 1996;80:363-366.
11. Avery RL , Perlman J, Pieramici DG, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology. 2006;113:1695e1-15.
12. Spaide RF, Fisher YL. Intrravitreal bevacizimab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina. 2006;26:275-278.

Geeta A. Lalwani, MD, is a vitreoretinal fellow at the Bascom Palmer Eye Institute in Miami. Maria Buch, MD, is associate professor of clinical pediatrics at the University of Miami's Miller School of Medicine. Scott Cardone, MD, is an ophthalmologist with Eye Surgery Associates in Hollywood, Fla. Timothy G. Murray, MD, MBA, is professor of ophthalmology at Bascom Palmer, Carmen A. Puliafito, MD, MBA, is chair of ophthalmology at Bascom Palmer, and Audina M. Berrocal, MD, is assistant professor of ophthalmology at Bascom Palmer. The authors do not hold any financial interest in any of the products and/or pharmacotherapeutics mentioned here.

ALL FIGURES IN THIS ARTICLE APPEAR COURTESY OF THE AUTHORS.



Retinal Physician, Issue: January 2007