Journal of Perinatology (2010) 30, 497–499 r 2010 Nature America, Inc. All rights reserved. 0743-8346/10 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Choroidal ruptures after adjuvant intravitreal injection of bevacizumab for aggressive posterior retinopathy of prematurity

L-O Atchaneeyasakul and A Trinavarat Department of Ophthalmology, Siriraj Hospital Mahidol University, Bangkok, Thailand

observed within 1 week after treatment. The only reported possible In recent times, laser treatment combined with intravitreal bevacizumab adverse effect of intravitreal bevacizumab (IVB) in advanced ROP (Avastin) has been used rarely as early investigations to treat patients with was an acute contraction of the fibrovascular proliferative aggressive posterior retinopathy of prematurity (ROP). We describe membrane, which led to progressive tractional retinal detachment.4 choroidal ruptures that were documented at 10 weeks after this combined The data from several studies have shown promising results of treatment in a preterm infant born at 28 weeks gestation with a birth weight IVB for severe ROP. However, there is no consensus regarding the of 1190 g. Aggressive posterior ROP was diagnosed at the age of 6 weeks. benefit of this treatment over conventional laser treatment, as well Initial treatment included bilateral laser ablation, followed immediately by as the appropriate timing and dosage of this modality. intravitreal bevacizumab (IVB, 0.75 mg) in the right eye. On day 5, a A prospective, randomized, controlled, multicenter clinical trial remarkable regression of plus sign and fibrovascular proliferation was noted such as ‘Bevacizumab Eliminates the Angiogenic Threat of only in the right eye. At this point, additional laser treatment combined with Retinopathy of Prematurity (BEAT-ROP)’ is currently being IVB was given in the left eye, which dramatically resolved plus disease and conducted to answer these questions before IVB could be neovascularization. At 10 weeks after IVB in the left eye, two sites of established as a standard treatment for ROP. In the mean time, choroidal ruptures were revealed along the posterior edges of laser scars. reports of ocular or systemic adverse effects related to IVB would There was no evidence of choroidal neovascularization associated with the help to refine the treatment guidelines for severe ROP. In this choroidal ruptures. Choroidal rupture may occur shortly after laser ablation study, we report a case of choroidal ruptures observed shortly after plus IVB treatment for aggressive posterior ROP. This occurrence requires treatment with laser ablation combined with IVB for aggressive recognition to determine whether it is actually related to the treatment. posterior ROP and discuss the potential risk factors for this Long-term follow-up is important for understanding the nature and condition. progression of this potentially serious complication. Journal of Perinatology (2010) 30, 497–499; doi:10.1038/jp.2009.166 Case Keywords: avastin; choroidal rupture; intravitreal bevacizumab; laser photocoagulation; retinopathy of prematurity; ROP A retrospective chart review was conducted on a preterm male infant being referred to our institute at the age of 6 weeks for further treatment of severe ROP in both eyes. The patient was born at 28 weeks gestation with a birth weight of 1190 g to a 17-year-old Introduction mother and a 19-year-old father. The APGAR scores at 1 and 5 min During the past 3 years, there have been increasing trends of were 9 and 9, respectively. At the age of 2 weeks (postmenstrual injecting an antiangiogenic agent intravitreally to treat severe age, of 30 weeks), the patient developed respiratory distress retinopathy of prematurity (ROP). This technique has been syndrome and was treated successfully with mechanical ventilation performed either alone or in combination with laser and surfactant. The initial fundus examination was carried out at photocoagulation of the peripheral avascular retina.1–3 All the case the age of 6 weeks when the diagnosis of severe ROP was made, reports used intravitreal bevacizumab (Avastin, Genentech, South and the patient was immediately referred to our attention. San Francisco, CA, USA), with the dosage varying from 0.4 to Fundus examination showed distinctive plus disease with stage 3 1.25 mg per injection, and the results have been remarkable. ROP in zone I of both eyes. Anterior segment examination showed Regression of plus disease and neovascularization is usually dilation of the existing tunica vasculosa lentis in both eyes. The pupils were semidilated with a diameter of 7 mm. The diagnosis of Correspondence: Dr L-o Atchaneeyasakul, Department of Ophthalmology, Siriraj Hospital aggressive posterior ROP was made and informed consent was Mahidol University, 2 Prannok Road, Bangkok 10700, Thailand. E-mail: [email protected] obtained after discussion with the parents regarding the risks and Received 16 August 2009; revised 9 September 2009; accepted 11 September 2009 benefits of laser treatment and IVB. Both eyes were treated with Bevacizumab and retinopathy of prematurity L-O Atchaneeyasakul and A Trinavarat 498 laser photocoagulation to the avascular retina. An indirect diode concentric to the optic disc. The overlying retina and all other laser system was used with power ranging from 270 to 300 mW and retinal areas appeared intact. There was no evidence of choroidal a pulse duration of 200 msec. The number of laser burns applied to neovascularization arising from the lesions. the right and left eye was 1871 and 1305 spots, respectively. Although disease severity was similar in both eyes, IVB (0.75 mg) was injected only into the right eye because of insufficient data on Discussion short- and long-term adverse effects of this modality. The pathophysiology of ROP involves hypoxic retina-induced Follow-up examination on day 5 after treatment showed a vascular endothelial growth factor production, followed by retinal remarkable regression of tunica vasculosa lentis, plus disease and neovascularization. At present, intravitreal anti-vascular endothelial neovascularization in the right eye. For the left eye, although the growth factor drug injection has been used as compassionate care plus sign was regressed, we still observed the remaining of tunica for severe ROP patients with good response. vasculosa lentis and active fibrovascular proliferation (Figure 1). At Our patient received laser treatment combined with IVB and this point, additional diode laser photocoagulation was carried out developed a characteristic feature of choroidal rupture, the (laser power 200 mW, duration 200 msec, number of laser condition that generally results from blunt ocular injury.5 For application 1129 spots), together with 0.75 mg of IVB in the left infants, there was only one report of choroidal rupture associated eye. Serial follow-up examination every 3–4 weeks showed with forceps delivery,6 which was not the case in our patient. The continuing regression of plus disease and neovascularization in pathology of traumatic choroidal rupture involves breaks in the both eyes. At 10 weeks after IVB in the left eye, we observed two choroid, the Bruch’s membrane and the retinal pigment white, curvilinear, crescent-shaped streaks along the posterior edge epithelium (RPE). Two types of choroidal rupture are described, of the laser scars in the left eye (Figure 2). These lesions were direct and indirect. For direct choroidal rupture, the lesion is located at the inferonasal and superotemporal quadrants and were located at the site of injury. For indirect type, which is more common, the lesion occurs posteriorly and may involve the macula and the optic disc. The pathophysiology of traumatic choroidal rupture involves the damage of choriocapillaris and less resistance to mechanical injury of the Bruch’s membrane compared with the retina and the sclera, which results in breaks in the Bruch’s membrane after compressive ocular injury. Choroidal neovascularization may penetrate through these breaks into the retina and may cause visual impairment if it occurs in the macular area. As there has been no report on laser photocoagulation as a cause of choroidal rupture, we speculated that our patient developed this condition because of the dual effects of laser ablation and IVB. Previous study on the histopathological findings in an eye with threshold ROP treated with diode laser ablation Figure 1 Fundus photograph of the left eye on day 5 after laser treatment showed chorioretinal scarring with retinal atrophy and gliosis, loss showing partial regression of plus disease and neovascularization. of RPE, and extensive atrophy of the choriocapillaris and larger

Figure 2 Fundus photograph of the left eye at 11 weeks after laser treatment and 10 weeks after intravitreal bevacizumab showing two white, curvilinear, crescent-shaped streaks (arrows) along the posterior edge of the laser scars.

Journal of Perinatology Bevacizumab and retinopathy of prematurity L-O Atchaneeyasakul and A Trinavarat 499 vessels.7 Although a recent study in embryonic/fetal human eyes References showed that maturation of the choriocapillaris with fenestrations 1 Chung EJ, Kim JH, Ahn HS, Koh HJ. Combination of laser photocoagulation 8 occurred by 22 weeks gestation, previous studies indicated that the and intravitreal bevacizumab (Avastin) for aggressive zone I retinopathy RPE-derived vascular endothelial growth factor was essential for of prematurity. Graefes Arch Clin Exp Ophthalmol 2007; 245: the development and maintenance of the choriocapillaris from the 1727–1730. embryonic stage to adulthood.9,10 Therefore, an inactivation of 2 Kusaka S, Shima C, Wada K, Arahori H, Shimojyo H, Sato T et al. Efficacy of intravitreal injection of bevacizumab for severe retinopathy of prematurity: a pilot vascular endothelial growth factor expression in the RPE may study. Br J Ophthalmol 2008; 92: 1450–1455. result in the absence or abnormal structure of the choriocapillaris. 3 Quiroz-Mercado H, Martinez-Castellanos MA, Hernandez-Rojas ML, Salazar-Teran N, A combination of these two effects, laser and IVB, could result in a Chan RV. Antiangiogenic therapy with intravitreal bevacizumab for retinopathy of significant destruction of the choroid and RPE leading to choroidal prematurity. Retina 2008; 28: S19–S25. rupture. As we performed laser ablation in the left eye more heavily 4 Honda S, Hirabayashi H, Tsukahara Y, Negi A. Acute contraction of the than in the right eye, this could be a potential risk factor for proliferative membrane after an intravitreal injection of bevacizumab for advanced retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 2008; developing choroidal rupture. Regarding the amount of IVB, we 246: 1061–1063. used a dosage of 0.75 mg, which is not the minimal dose reported 5 Atmaca LS, Yilmaz M. Changes in the fundus caused by blunt ocular trauma. Ann for ROP treatment. This could also be another risk factor. Ophthalmol 1993; 25: 447–452. Reducing the number and power setting of laser burns, as well as 6 Estafanous MF, Seeley M, Traboulsi EI. Choroidal rupture associated with forceps refining the dosage of an antiangiogenic agent, may help prevent delivery. Am J Ophthalmol 2000; 129: 819–820. 7 Park P, Eagle Jr RC, Tasman WS. Diode laser photocoagulation for retinopathy this potentially serious complication. of prematurity: a histopathologic study. Ophthalmic Surg Lasers 2001; 32: In conclusion, there was an association between choroidal 63–66. ruptures and laser ablation combined with IVB treatment. Although 8 Baba T, Grebe R, Hasegawa T, Bhutto I, Merges C, McLeod DS et al. Maturation not necessarily cause and effect based on the single case report, this of the fetal human choriocapillaris. Invest Ophthalmol Vis Sci 2009; 50: finding requires careful attention of all medical practitioners 3503–3511. taking care of ROP patients. Long-term follow-up is important to 9 Marneros AG, Fan J, Yokoyama Y, Gerber HP, Ferrara N, Crouch RK et al. Vascular endothelial growth factor expression in the retinal pigment epithelium is understand the nature and progression of this condition. essential for choriocapillaris development and visual function. Am J Pathol 2005; 167: 1451–1459. Conflict of interest 10 Yi X, Mai LC, Uyama M, Yew DT. Time-course expression of vascular endothelial growth factor as related to the development of the retinochoroidal vasculature in rats. The authors declare no conflict of interest. Exp Brain Res 1998; 118: 155–160.

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