Bevacizumab for Salvage Treatment
in Threshold Retinopathy
GEETA A. LALWANI, MD MARIA
BUCH, MD SCOTT CARDONE, MD TIMOTHY G. MURRAY, MD, MBA
PULIAFITO, MD, MBA, & AUDINA M. BERROCAL, MD
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
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.
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
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
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
1. Hussain N, Clive J, Bhandari
V. Current incidence of retinopathy of prematurity, 1989-1997. Pediatrics.
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.
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.
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