From the Department of Ophthalmology, Eskisehir Osmangazi University Medical Faculty, Eskisehir, Turkey.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Hikmet Basmak, MD, Eskisehir Osmangazi University Medical Faculty, Department of Ophthalmology, Eskisehir, Turkey. E-mail: firstname.lastname@example.org
The role of vascular endothelial growth factor (VEGF) in the pathogenesis of retinopathy of prematurity (ROP) has been described and laboratory investigations support its role in neovascularization and vascular permeability of ROP. VEGF inhibitors have been used with success in many ocular vascular diseases, including age-related macular degeneration1 and proliferative diabetic retinopathy.2 Use of bevacizumab instead of other VEGF inhibitors may be safer in infants because its molecular weight is greater,3 so it is less likely to penetrate retinal barriers producing any adverse effects on an immature infant’s retina or any systemic side effects. Bevacizumab has been tried for treatment of severe ROP, both as an initial therapy alone or complementary to laser photocoagulation or vitreous surgery.4
We report 7 eyes of 4 infants with continued ROP progression despite previous laser therapy, in which intravitreal bevacizumab was injected.
Four cases of severe ROP, diagnosed between May 2008 and August 2008, were reviewed. All infants were hospitalized in our institution’s neonatal intensive care unit and treated with nasal continuous positive airway pressure as primary respiratory supporting system. In 7 eyes of 4 infants, intravitreal bevacizumab was injected following adequate diode laser photocoagulation. The intravitreal bevacizumab injection for these cases was approved by the Institutional Review Board and informed consent was procured from the parents of the patients prior to therapy. All interventions, namely diode laser photocoagulation, intravitreal bevacizumab (Avastin; Genentech, San Francisco, CA) injection, and pars plana vitrectomy, were performed under general anesthesia by the same experienced retina specialist (NE) after the infants were discharged from the neonatal intensive care unit.
In all 7 eyes, 810-nm diode laser photocoagulation (Iridex, Mountain View, CA) was applied within 3 days after the diagnosis of threshold disease. Despite adequate laser applications, continued progression of ROP was the common finding in all 7 eyes. In 3 cases, bilateral intravitreal bevacizumab was injected 1 to 2 weeks following laser therapy. In one of the infants, intravitreal bevacizumab was injected only into the right eye prior to vitreous surgery. Under general anesthesia, a standard intravitreal injection protocol with 5% topical povidone-iodine was employed. Bevacizumab 0.75 mg (0.03 cc) was injected intravitreally using a 30-gauge needle placed 1 mm behind the limbus. The perfusion of optic nerve heads was then confirmed by indirect ophthalmoscope. All infants were observed closely by indirect ophthalmoscopy using a 20-diopter lens. Fundus photographs were taken using the digital camera attached to the indirect ophthalmoscope and a 20 diopter-lens.
Infants’ characteristics, including the treatment and the outcomes, are shown in the table.
Table: Characteristics of 4 Retinopathy of Prematurity Cases, Retinal Findings, and Treatment
In the first infant at the first screening, an immature retina and tunica vasculosa lentis were found (the vascular area was within zone 1). Because the ROP had progressed to stage 3, zone 1 in the nasal area with plus disease, indirect diode laser photocoagulation was indicated at 8 weeks of age. Under general anesthesia, both eyes received a near confluent pattern of indirect diode laser photocoagulation (duration = 300 ms; laser power = 400 to 800 mW; 1,739 shots for the right eye and 1,690 shots for the left eye) to the avascular retina, immediately anterior to the border of the vascular zone extending to the ora serrata for 360°.
After the photocoagulation therapy, neovascularization and ridge regressed in the nasal retinal area but extraretinal neovascularization and ridge proliferation continued in the temporal retinal area in both eyes despite adequate photocoagulation therapy. Bilateral intravitreal bevacizumab injection was performed at 10 weeks postnatal age. Tunica vasculosa lentis disappeared in both eyes on the second postoperative day. Neovascular proliferation regression was obvious in the left eye by the postoperative first week. However, neovascularization progressed and tractional retinal detachment started promptly in the right eye. During follow-up, ROP regressed in the left eye and total retinal detachment occurred in the right eye at 2 months following intravitreal bevacizumab injection. The right eye was beyond treatment.
In the second infant, retinal findings were similar except for the absence of tunica vasculosa lentis. The aortic coarctation was an additional systemic pathology diagnosed. Bilateral laser therapy (duration = 300 ms; laser power = 400 mW; 1,900 shots for the right eye and 1,814 shots for the left eye) was applied at 6 weeks postnatal age. Despite adequate laser therapy, ROP progressed and bilateral intravitreal bevacizumab injection was performed at 8 weeks postnatal age (Figs. A and B). Within 2 weeks, neovascularization regressed and follow-up fundus examinations revealed clear media with regressed ROP in both eyes (Figs. C and D).
Figure. Fundus Photograph of the Right Eye of Case 2 Showing Marked Regression Following Intravitreal Bevacizumab Injection. (A and B = Right Eye Before Treatment; C and D = Right Eye After Treatment).
In the third infant, who was also suffering from respiratory distress syndrome, bilateral laser photocoagulation (duration = 300 ms; laser power = 400 mW; 1,651 shots for the right eye and 1,800 shots for the left eye) was applied at 7 weeks postnatal age. The laser therapy was successful in the left eye. However, in the right eye ROP progressed to stage 4a and vitreous surgery was indicated. Intravitreal bevacizumab was injected into the right eye prior to surgery to increase the possibility of surgical success. A week after intravitreal bevacizumab injection, vitrectomy was achieved with minimal bleeding and the retina was reattached after relieving the traction. During 8 months of follow-up, ROP regressed in the right eye.
In the fourth infant, bilateral laser photocoagulation (duration = 300 ms; laser power = 400 mW; 1,700 shots for the right eye and 1,600 shots for the left eye) was applied at 7 weeks postnatal age. The neovascularization and plus disease progressed further and bilateral intravitreal bevacizumab injection was performed at 8 weeks postnatal age. Disease regression occurred within 2 weeks. The disease was inactive through the 12 months of follow-up.
All intravitreal bevacizumab injections were performed without any local or systemic complications.
After the advent of the role of VEGF in many ocular vascular pathologies, intravitreal VEGF inhibitors gained popularity to halt retinal neovascularization. However, there are some differences in ROP pathogenesis and prognosis that can increase the importance of VEGF inhibitors for treatment of ROP. In contrast to other ocular vascular pathologies, such as proliferative diabetic retinopathy or choroidal neovascularization associated with age-related macular degeneration, ROP is a self-limited condition and known to undergo spontaneous involution in 90% of patients before 44 weeks of postmenstrual age.4 Because intravitreal therapeutic drug concentration is maintained for up to 4 weeks5 and the disease has a self-limited nature, intravitreal VEGF inhibitors without repeated requirements of injections may be an alternative or complementary to standard therapies for ROP.
Deterioration of tractional retinal detachment after intravitreal bevacizumab injection in stage 4a ROP6 and proliferative diabetic retinopathy was reported.7 Because of this possible complication, we preferred intravitreal bevacizumab injection before the tractional component of ROP formed. In our cases, 6 of the eyes benefited from the injections and only one of the eyes showed progression. In successful cases, the disease regressed within a week following only one injection without any local or systemic complications. In the failed case, progression could be the result of aggravation of fibrosis by bevacizumab.
In 6 eyes, we injected the drug in stage 3 ROP, within a short period of time just after detecting the progression despite adequate laser photocoagulation to prevent the aggravation of possible tractional retinal detachment. The disease progressed to stage 4a in one eye; in the others, disease regression was obvious within a week because anti-VEGF therapy immediately halted the continued advance of the neovascularization of ROP due to VEGF already present in the vitreous. One of the eyes was initially stage 4a and in that case intravitreal bevacizumab was injected prior to surgery to increase the possibility of surgical success, so the risk of progression of tractional detachment was not considered after intravitreal bevacizumab injection in that particular case. Although we did not observe any systemic adverse effects, we should keep in mind that surgical trauma may increase the possibility of systemic adverse effects after preoperative intravitreal bevacizumab.
We injected intravitreal bevacizumab following laser photocoagulation, and theoretically this increased the possibility of the drug escaping the vitreous because of the accompanying inflammation and atrophy with laser photocoagulation. However, no adverse effects have been seen in our cases related to complementary injection of intravitreal bevacizumab.
Although further studies regarding the safety and success of intravitreal bevacizumab injection for ROP are needed, intravitreal bevacizumab injection can be an alternative therapy in progressive stage 3 ROP despite laser photocoagulation and can aid surgery in stage 4a ROP.
- Avery RL, Pieramici DJ, Rabena MD, Castellarin AA, Nasir MA, Giust MJ. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology. 2006;113:363–372. doi:10.1016/j.ophtha.2005.11.019 [CrossRef]
- Modarres M, Nazari H, Falavarjani KG, Naseripour M, Hashemi M, Parvaresh MM. Intravitreal injection of bevacizumab before vitrectomy for proliferative diabetic retinopathy. Eur J Ophthalmol. 2009;19:848–852.
- Mintz-Hittner HA, Kuffel RR Jr, . Intravitreal injection of bevacizumab (Avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. Retina. 2008;28:831–838. doi:10.1097/IAE.0b013e318177f934 [CrossRef]
- Chung EJ, Kim JH, Ahn HS, Koh HJ. Combination of laser photocoagulation and intravitreal bevacizumab (Avastin) for aggressive zone I retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol. 2007;245:1727–1730. doi:10.1007/s00417-007-0661-y [CrossRef]
- Beer PM, Wong SJ, Hammad AM, Falk NS, O’Malley MR, Khan S. Vitreous levels of unbound bevacizumab and unbound vascular endothelial growth factor in two patients. Retina. 2006;26:871–876. doi:10.1097/01.iae.0000233327.68433.02 [CrossRef]
- 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]
- Arevalo JF, Maia M, Flynn H Jr, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol. 2007;92:213–216. doi:10.1136/bjo.2007.127142 [CrossRef]
Characteristics of 4 Retinopathy of Prematurity Cases, Retinal Findings, and Treatment
|Characteristic||Case 1||Case 2||Case 3||Case 4|
|Gestational age (wk)||26||29||27||29|
|Postnatal 1st screening age (wk)||5||5||4||5|
|Stage||3, plus disease, tunica vasculosa lentis exists||3, plus disease||3, plus disease||3, plus disease|
|Treatment||Bilateral laser photocoagulation at 8 wks postnatal age; bilateral IVB at 10 wks postnatal age||Bilateral laser photocoagulation at 6 wks postnatal age; bilateral IVB at 8 wks postnatal age||Bilateral laser photocoagulation at 7 wks postnatal age; right IVB at 8 wks postnatal age prior to PPV||Bilateral laser photocoagulation at 7 wks postnatal age; bilateral IVB at 8 wks postnatal age|
|Outcomes||During follow-ups total retinal detachment in the right eye and regression in the left eye was noted||Regression of ROP in both eyes was noted||Regression of ROP in the left eye was noted and retina was reattached in the right eye||Regression of ROP in both eyes was noted|