From Gülhane Military Medical Academy and Medical School, Ankara, Turkey
Presented in part at the Winter Symposium of the Turkish Ophthalmic Society, January 18–20, 2008, Antalya, Turkey.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Fatih M. MUTLU, MD, Gülhane Military Medical Academy & Medical School, Department of Ophthalmology, 06018 Etlik-Ankara, Turkey
ROP is characterized by abnormal vascular development of the retina in premature infants. Although ablation of the retina with laser or cryotherapy reduces the progression of the disease, visual outcomes after treatment are often poor especially for zone-1 ROP.1
Regulation of vascular endothelial growth factor (VEGF) seems to play a key role in normal angiogenesis and abnormal neovascularization of the retina in pathological conditions.2–4 VEGF levels are elevated when the retina is hypoxic, and VEGF messanger ribonucleic acid (mRNA) has been expressed in the avascular zone of the human infant eye with threshold ROP.4,5 Inhibition of VEGF expression may prevent the destructive effects of abnormal neovascularization of the retina.3,4
The present report describes our experience with the off-label use of intravitreal bevacizumab combined with indirect laser photocoagulation in the treatment of severe ROP in 2 premature infants.
Two outborn premature infants were referred to our hospital for the presence of severe ROP.
Case 1 had been born with a birth-weight of 900 g at a gestational age of 31 weeks. At a postconceptional age of 35 weeks (4 weeks after birth), screening revealed bilateral, high-risk zone-1 prethreshold ROP (Fig. 1). Laser treatment in both eyes and intravitreal injection of bevacizumab (IVB) (Altuzan; Genentech, Inc., CA, USA) in the left eye was performed at the same session. Although plus disease significantly regressed in the left eye within 24 hours of the injection, no significant regression of clinical findings was observed in the right eye during the first 3 days after laser treatment (Fig. 2). Therefore, IVB was performed in the right eye on the 4th day of laser treatment. The extent of plus disease decreased significantly within 24 hours of the injection as in the left eye. Complete regression took 2 weeks in both eyes. Retinal vessels reached zone-3 one month later. Throughout the next 10-month follow-up, fundus examinations revealed clear media with well-regressed ROP in both eyes (Fig. 3).
Figure 1. Zone-1 ROP (Case 1) with Severe plus Disease. (a) Right Eye. (b) Left Eye.
Figure 2. Posterior Pole of the (a) Right and (b) Left Eye 24 Hours After Laser Treatment in Both Eyes and Intravitreal Injection of Bevacizumab in the Left Eye. The Left Eye Showed a Significant Regression of plus Disease.
Figure 3. Posterior Pole and Peripheral Retina of the Right (a) and Left (b) Eye 6 Months Following Laser Photocoagulation and Intravitreal Injection of Bevacizumab.
Case 2 had been born at a gestational age of 28 weeks + 3 days and a birth weight of 1340 g. Screening examination at 8 weeks of postnatal age revealed stage 3 ROP with a localized detachment for 3-clock hours (stage-4A), and moderate plus disease in zone-1 in the right eye. In the left eye, there was also severe stage-3 ROP with mild plus disease (Fig. 4). Laser treatment in both eyes and IVB in the right eye was performed at the same session. 3 days after treatment, mild vitreous haze developed without any regression of ROP in the right eye, and no regression of clinical findings was observed in the left eye with an additional localized retinal detachment for 2 hours. An encircling operation with silicone encirclage band and IVB was performed in the left eye. One week after laser and anti-VEGF injection, stage-5 ROP developed in the right eye and further treatment was not accepted by her parents. The left eye showed a limited degree regression of the pathological neovascularization 1-week after retinal surgery and anti-VEGF treatment, and required vitrectomy due to persistent retinal detachment. In subsequent examinations, posterior pole of the retina was attached except for the well demarcated serous elevation in the macula (Fig. 5).
Figure 4. Fundus Photographs of the Second Case. (a) Aggressive, Posterior Zone 1 ROP with Moderate plus Disease and Stage-3 ROP with Extensive Epiretinal Proliferation and Localized Retinal Detachment in the Right Eye. (b) Mild plus Disease and Stage-3 ROP with Hemorrhages on and Adjacent to the Ridge in Zone-1 in the Left Eye.
Figure 5. Posterior Pole of the Right Eye with Stage-5 ROP (a), and the Left Eye with Limited Regression of ROP (b).
The parents were informed about potential local and systemic risks and complications of the off-label use of bevacizumab, and they signed an informed consent. The injections were performed on each eye in the operating room under general anesthesia and sterile conditions on separate days. Intraocular pressure was checked at the end of the operation and 2 hours after treatment. Systemic conditions of the patients were closely monitored. There was no local complication or systemic adverse event. Topical antibiotics and steroids were given for 3 days. The infants were examined at days 1, 3, and 7, as well as every 2 weeks during the first 2 months and monthly thereafter.
VEGF, a hypoxia-inducible cytokine, is a potent mitogen for vascular endothelial cells, necessary for the physiological angiogenesis.2,5 Although VEGF is secreted in the maturing avascular retina, vitreal macrophages, as a second source of VEGF may be responsible for the lack of laser therapy especially in zone-1 disease.6
Retinal ablation indirectly reduces VEGF levels by the destruction of ischemic peripheral retina.3 Anti-VEGF drugs offer the advantage of limiting tissue destruction by directly blocking the mediator VEGF, both in the retina and the vitreous. Trese7 reported that due to the interaction of an anti-VEGF drug and retinal vascular development the timing of anti-VEGF therapy should be later than 30 weeks of postconceptional age. The second phase of ROP, characterized by hypoxia-induced retinal vascularization, begins at about 32 to 34 weeks’ postconceptional age.4 Early suppression of VEGF in phase-1 or before 32 weeks of postconceptional age could inhibit normal vessel growth and precipitate the disease, whereas inhibition in the second phase could prevent neovascularization. We used anti-VEGF therapy at the 35th and 36th weeks. Laser photocoagulation together with IVB may be more effective for the treatment of ROP, and we preferred combined therapy in the present cases.8,10
Case 1 showed a favorable outcome, and the effect of anti-VEGF application as an adjuvant treatment after laser was seen perfectly with a significant decrease of plus disease in both eyes. Additionally, normal development of retinal vessels to zone-3 suggested that normal vascular development might not be affected. In contrast, Case 2 showed an unfavorable outcome with IVB after laser. Although Quiroz–Mercado et al.13 reported spontaneous retinal reattachment in one case with stage 4A after an IVB, we had unfavorable outcome. Recently, a case with advanced ROP, that showed an acute contraction of the proliferative membrane, resulting in a funnel-like retinal detachment after an IVB, was reported.14 Additionally, Kusaka et al.15 reported the development of retinal detachment in 3 of 15 eyes that received an IVB as the initial treatment for severe ROP. So, IVB seems to be a useful therapy to maintain aggressive ROP. However, the time or dose of IVB may result in different outcomes in different populations, and progression of tractional retinal detachment should be kept in mind in some spesific cases with ROP.
There are some other cytokines that have various roles for retinal development.16,17 Transforming growth factor-beta (TGF-β), a natural antagonist of VEGF, which plays an important role in wound healing and scarring, rises in concentration during retinal development between 36 and 40 weeks of postconceptional age.18,19 TGF-β becomes unopposed when VEGF is blocked through treatment and this may end up exacerbating proliferative tissues and cause tractional changes.7 If anti-VEGF drugs are given late in the course or in cases with retinal detachment, as in the 2nd case of the present report, increased concentrations of TGF-β may contribute to a tractional retinal detachment. In Case 1, as there was no retinal detachment, the anatomic outcome was good. The use of anti-VEGF therapy in stage-4, may have led to rapid retinal detachment due to a rapid neovascular involution with accelarated fibrosis in response to decreased levels of VEGF. That is why the anatomic outcome was so bad in Case 2. The use of anti-VEGF therapy seems to be efficacious in the treatment of severe ROP, but timing the injection of bevacizumab correctly is an important limitation for its use.
Bevacizumab binds all isoforms of VEGF-A. This could potentially be a disadvantage because physiologic vascular development could be suppressed.11,12 However, the relatively large molecular weight of bevacizumab might limit its reaching the systemic circulation following intravitreal injection. In these cases, we used bevacizumab instead of the other selective anti-VEGF drugs as it was the only anti-VEGF drug available at our institution during the study period. Both patients had intravitreal injections on separate days. Although no systemic or ocular side-effects were reported by bilateral intravitreal injection on the same day,9 we believe it may be safer not to perform these injections.
These two cases showed that combined IVB and laser photocoagulation treatment strikingly halted the progression of vascular proliferation in zone-1 disease without retinal detachment. In contrast, the combined therapy of intravitreal bevacizumab and laser photocoagulation should be used cautiously for stage-4 ROP. However, further controlled studies with long-term follow-up are necessary for a potentially dangerous growth factor inhibitor, bevacizumab, before it may be considered for the treatment of ROP in prematures.
- Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol. 2003;121:1684–1694.
- McColm JR, Geisen P, Hartnett ME. VEGF isoforms and their expression after a single episode of hypoxia or repeated fluctuations between hyperoxia and hypoxia: relevance to clinical ROP. Mol Vis. 2004;10:512–520.
- Young TL, Anthony DC, Pierce E, Foley E, Smith LE. Histopathology and vascular endothelial growth factor in untreated and diode laser-treated retinopathy of prematurity. JAAPOS. 1997;1:105–110.
- Smith LEH. Pathogenesis of retinopathy of prematurity. Seminars in Neonathology. 2003;8:469–473. doi:10.1016/S1084-2756(03)00119-2 [CrossRef]
- Dorey CK, Aouididi S, Reynaud X, Dvorak HF, Brown LF. Correlation of vascular permeability factor/vascular endothelial growth factor with extraretinal neovascularization in the rat. Arch Ophthalmol. 1996;114:1210–1217.
- Naug H, Browning J, Gole G, Gobe GVitreal macrophages Express VEGF165 in oxygen-induced retinopathy. Clin Exp Optom. 2000;28:48–52.
- Trese MT. Anti-angiogenesis therapy for early and late retinopathy of prematurity. Angiogenesis Meeting. 23–24 February 2007. ; Bascom Palmer Florida, USA. , 97.
- 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. doi:10.1016/j.ajo.2006.02.018 [CrossRef]
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- Lutty GA, Chan-Ling T, Phelps DL, et al. Proceedings of the Third International Symposium on Retinopathy of Prematurity: an update on ROP from the lab to the nursery (November 2003, Anaheim, California). Mol Vis. 2006;12:532–580.
- McLeod DS, Taomoto M, Cao J, Zhu Z, Witte L, Lutty GA. Localization of VEGF receptor-2 (KDR/Flk-1) and effects of blocking it in oxygen-induced retinopathy. Invest Ophthalmol Vis Sci. 2002;43: 474–482.
- Quiroz-Mercado H, Martinez-Castellanos MA, Hernandez-Rojas ML, Salazar-Teran N, Chan RVP. Antiangiogenic therapy with intravitreal bevacizumab for the treatment of retinopathy of prematurity. Angiogenesis Meeting. , 23–24 February 2007. , Bascom Palmer Florida, USA. , 99–119.
- Honda S, Hirabayashi H, Tsukahara Y, Negi A. Acute contraction of the proliferative membrane after an intravitreal injection of bevacizumab for advanced retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol. 2008;246:1061–1063. doi:10.1007/s00417-008-0786-7 [CrossRef]
- Kusaka S, Shima C, Shimojyo H, Sato T, Fujikado T. Efficacy of Intravitreal Injection of Bevacizumab for Severe Retinopathy of Prematurity: A Pilot Study. Br J Ophthalmol. published online Jul 11 2008; DOI:10.1136/bjo. 2008.140657, [Epub ahead of print].
- Löfqvist C, Andersson E, Sigurdsson J, Engström E, Hård AL, Niklasson A, Smith LE, Hellström A. Longitudinal postnatal weight and insulin-like growth factor I measurements in the prediction of retinopathy of prematurity. Arch Ophthalmol. 2006;124:1711–1818. doi:10.1001/archopht.124.12.1711 [CrossRef]
- Mandriota SJ, Menoud PA, Pepper MS. Transforming growth factor–β1 downregulates vascular endothelial growth factor receptor 2/flk-1 expression in vascular endothelial cells. J Biol Chem. 1996; 271:11500–11505. doi:10.1074/jbc.271.19.11500 [CrossRef]
- Krummel TM, Michna BA, Thomas BL, et al. Transforming growth factor beta (TGF-beta) induces fibrosis in a fetal wound model. J Pediatr Surg. 1988;23:647–652. doi:10.1016/S0022-3468(88)80638-9 [CrossRef]
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