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 Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 106  |  Issue : 3  |  Page : 129-133

Intravitreal bevacizumab (Avastin) with peripheral retinal cryotherapy for patients with posterior retinopathy of prematurity and vitreous hemorrhage


Department of Ophthalmology, Ain Shams University, Cairo, Egypt

Date of Submission25-Mar-2013
Date of Acceptance04-May-2013
Date of Web Publication28-Feb-2014

Correspondence Address:
Mohammad M. K. Diab
Hospital Aseer Region, Khamesmashat City King Saudi Arabia

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2090-0686.127351

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  Abstract 

Purpose
To report the short-term anatomic response of intravitreal bevacizumab (Avastin) and peripheral cryotherapy for the treatment of posterior retinopathy of prematurity (ROP) with vitreous hemorrhage in a small series of patients.
Patients and methods
This was a retrospective study that included 19 eyes of 14 premature babies with posterior ROP and vitreous hemorrhage in whom conventional laser treatment could not be applied. Patients received an intravitreal injection of bevacizumab (Avastin) together with peripheral retinal cryotherapy.
Results
Vascularization began to regress within a few days after the injection, but vitreous hemorrhage absorbed more slowly. Repeat intravitreal injections of bevacizumab were administered in eight eyes within 1 month from the first injection. There were varying development of tractional retinal detachments in two of the eyes, but the ROP component quieted in all cases.
Conclusion
Off-label use of intravitreal bevacizumab with peripheral retinal cryotherapy appears to be useful as a treatment for posterior ROP when laser treatment is precluded. It improves dilatation, regressing and quiescent the disease, and improves visibility.

Keywords: Bevacizumab; retinal cryotherapy; retinopathy of prematurity; vitreous hemorrhage


How to cite this article:
Diab MM. Intravitreal bevacizumab (Avastin) with peripheral retinal cryotherapy for patients with posterior retinopathy of prematurity and vitreous hemorrhage. J Egypt Ophthalmol Soc 2013;106:129-33

How to cite this URL:
Diab MM. Intravitreal bevacizumab (Avastin) with peripheral retinal cryotherapy for patients with posterior retinopathy of prematurity and vitreous hemorrhage. J Egypt Ophthalmol Soc [serial online] 2013 [cited 2019 Aug 19];106:129-33. Available from: http://www.jeos.eg.net/text.asp?2013/106/3/129/127351


  Introduction Top


Retinopathy of prematurity (ROP) is a vasoproliferative disease of the developing retina that is a significant leading cause of pediatric morbidity and blindness worldwide [1]. With advances in neonatal care, however, increasingly younger and lower birth-weight infants are able to survive. This presents a major challenge to all physicians treating premature infants. For the ophthalmologist, caring for premature babies may mean having to manage more aggressive forms of ROP, which historically have worse functional and anatomic outcomes [2]. Although management by early treatment for retinopathy of prematurity (ETROP) criteria has led to improved outcomes for treatment-requiring posterior (zone I and posterior zone II) ROP, the failure rate continues to be significant for aggressive disease. The application of conventional laser for treatment-requiring ROP in zone I or posterior zone II involves destruction of a large area of avascular retina with a potentially higher risk of complications and morbidity for the child [3]. Pharmacotherapy for ROP may help to improve outcomes in some of these difficult cases. Over the past 5 years, the use of intravitreal bevacizumab (Avastin) has become more popular for the management of ROP. It is known that vascular endothelial growth factor (VEGF) is a key player in both normal vascular development and in the pathogenesis of ROP. Studies have shown that physiologic levels of VEGF are necessary to maintain and help stimulate normal vascular growth [4]. When a baby is born very premature and is placed in a hyperoxic environment, VEGF production is downregulated, causing immature vessels to stop growing. This produces peripheral avascular retina, and the more immature the infant, the larger this avascular area is likely to be. Eventually, the avascular retina becomes ischemic and stimulates VEGF production. Sustained high levels of VEGF can promote the progression of ROP and neovascularization and can even cause vasodilatation and tortuosity of vessels, ultimately leading to plus disease. Iris vessel dilatation and rubeosis iridis may also ensue [4]. Treatment of the peripheral avascular retina with cryotherapy or laser therapy induces a reduction in VEGF levels, which then induces regression of neovascularization [5].

Data from the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) trial [6] and the ETROP trial [3] suggest that recurrence after peripheral retinal ablation for stage 3+ ROP generally occurs before 55 weeks' postmenstrual age.

Retinal vascularization on the internal retinal surface begins at the optic nerve at 16 weeks' gestation and proceeds anteriorly, reaching the edge of the temporal retina at 40 weeks' gestation [7]. Three zones indicate the area of vascularization, with zone I referring to a circle whose radius extends from the optic disk and is twice the distance between the center of the disk and the center of the macula. Zone II extends from zone I to the nasal extent of the retina. Posterior zone II surrounds zone I and its radius is three times the distance between the center of the disk and the center of the macula [8]. Zone III is the remaining crescent of the retina, primarily on the temporal side. ROP in zone I is the most difficult to treat and has a high incidence of recurrence, warranting additional treatment [9].

In this research, the therapeutic effect of combined peripheral cryotherapy and intravitreal Avastin for the treatment of posterior ROP (zone I and posterior zone II) with vitreous hemorrhage in whom conventional laser treatment cannot be applied was studied.


  Patients and methods Top


This retrospective study was carried out at the ophthalmology department of Magrabi Eye Hospital, KSA, from April 2007 to January 2013. Informed consent was obtained from the parents of all patients before enrollment in the study, and after provision of explanation of the procedure to be performed and the possible outcomes, were also informed that an off-label drug would be used, and on the need to repeat several examinations at each scheduled follow-up visit in addition to the possibility for repeated intravitreal injections for the infants. The study included 19 eyes of 14 premature babies. Inclusion criteria included only infants with stage 3+ or 4A+ ROP in zone I or posterior zone II. All eyes had vitreous hemorrhage of varying degrees at the time of presentation but were dense enough to preclude conventional laser treatment. Exclusion criteria included infants with stage 4B or 5 ROP; also, infants with posterior ROP without vitreous hemorrhage for whom laser could be applied were excluded from the study. A second intravitreal bevacizumab was administered in nine eyes within 1 month from the first injection because of persistence of active neovascularization. The follow-up period ranged from 6 to 11 months (mean 7.9 months). In this study, the primary treatment success was defined as an absence of recurrence of stage 3+ ROP in the treated eye in zone I or posterior zone II by 54 weeks' postmenstrual age. Six eyes needed laser ablation to the peripheral retina (central to the cryo marks) after vitreous hemorrhage had been absorbed because of persistence of active neovascularization.

Methods

The procedure was carried out under general anesthesia in the operating room in all cases. Bilateral cases were performed simultaneously at the same setting. An informed consent was obtained from the parents of the treated babies. After draping of the eyes, cryotherapy treatment was applied to the peripheral temporal retina under direct vision by the indirect ophthalmoscope without opening of the conjunctiva. Although vitreous hemorrhage was dense enough to preclude conventional laser treatment, some degree of visualization allowed cryotherapy to be performed under direct visualization in all cases. A measure of 0.625 mg (0.025 ml) bevacizumab [Avastin (Bevacizumab) Made in Switzerland by F. Hoffmann-la Roch Ltd, Basel] was injected into the vitreous cavity 0.5 mm from the limbus in the lower temporal quadrant as pars plana is not well developed in those preterm infants. The needle was directed vertically to avoid the lens. Intraocular pressure was assessed and if too high, paracentesis was performed.


  Results Top


This retrospective study included 19 eyes of 14 premature babies with threshold ROP in zone I and/or posterior zone II with plus disease and vitreous hemorrhage. Gestational age ranged from 26 to 31 weeks (mean 28 ± 1.4 weeks). Chronological age ranged from 4 to 6 weeks (mean 4.6 ± 0.89 weeks). Birth weight ranged from 1.100 to 1.850 kg (mean 1.400 ± 1.17.26 kg). Thirteen eyes had threshold stage 3 and six eyes had stage 4A+ disease. All eyes had plus disease with varying degree of vitreous hemorrhage. Vitreous hemorrhage was severe enough to preclude conventional laser treatment, but allowed some degree of visualization to perform peripheral cryotherapy under direct visualization. Intravitreal Avastin was injected once in 11 eyes and twice in eight eyes. The second intravitreal injection was administered within 1 month from the first injection if the regression of neovascularization was unsatisfactory. In six eyes, conventional laser treatment was performed after vitreous hemorrhage was clear enough to allow laser because of persistence of neovascularization. The follow-up period ranged from 6 to 11 months (mean 7.9 months). The primary treatment success was defined when there was no recurrence of stage 3+ ROP in the treated eye in zone I or posterior zone II by 54 weeks' postmenstrual age [Figure 1]. Neovascularization began to regress as early as a few days after treatment but vitreous hemorrhage absorbed more slowly. If the regression was not satisfactory within 1 month, another intravitreal Avastin was injected. After clearance of blood, another six eyes needed laser treatment of the peripheral retina because of persistence of neovascularization. By the end of the follow-up period, no case showed recurrence (recurrence of stage 3+ ROP in the treated eye in zone I or posterior zone II by 54 weeks' postmenstrual age). There were varying degrees of tractional components in five eyes, but they did not involve the fovea and the ROP component quieted in all cases. Apart from some lid swelling and mild subconjunctival hemorrhage, no serious complications were noted in the study group (such as endophthalmitis, progression of ROP, or increase in the density of vitreous hemorrhage) [Table 1].
Figure 1:

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Table 1: Age, birth weight, and disease characteristics in the study group

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  Discussion Top


Stages of ROP are defined by vessel appearance at the interface between the vascular and the avascular retinal areas. This interface resembles a line for stage 1, a three-dimensional ridge for stage 2, and a ridge with neovascularization extending into the vitreous gel for stage 3, which is the ideal time for treatment (Plus disease indicates that two or more quadrants of the eye have dilated veins and tortuous arteries near the optic disk. Plus disease is an important criterion for identification of ROP requiring treatment.) [10]. The neovascularization can progress to form fibrous bands that cause partial retinal detachment (stage 4), and ultimately, total retinal detachment (stage 5) [11].

In 1988, cryotherapy (freezing from the external ocular surface, affecting the sclera, choroid, and the full thickness of the retina) was recommended for stage 3+ ROP extending for 5 consecutive 'hours' (150°) or 8 cumulative 'hours' (240°, as measured on a clock face). In the 1990s, treatment of stage 3+ disease underwent a slow transition from cryotherapy to laser therapy (in which a laser is applied through the dilated pupil to the internal retinal surface). Both these treatments destroy the majority of the cells that produce VEGF in the retina. VEGF is a key factor in the progression of ROP [6]. The use of anti-VEGF agents, primarily intravitreal bevacizumab, is an emerging treatment for ROP. The Food and Drug Administration approved intravenous bevacizumab therapy in 2004 for the treatment of metastatic colon cancer; the drug works by reducing the size and number of new vessels feeding metastases. Off-label use of intravitreal bevacizumab therapy for ophthalmologic neovascular disorders began shortly thereafter [11]. As it is known that ROP is a VEGF-driven disease and that decreasing VEGF levels promote regression of neovascularization, intravitreal anti-VEGF agents have been utilized for the treatment of this condition [12]. A pathological study of the eyes of a very-low-birth-weight infant (350 g) born at 22 weeks' gestational age who was treated with intravitreal bevacizumab showed no local toxic effects [13]. Findings from the CRYO-ROP trial [6] and the ETROP trial [3] suggested that the recurrence rates with conventional laser therapy would be up to 50% for zone I disease and up to 20% for posterior zone II disease. Conventional laser therapy for zone I ROP is successful in ∼50% of cases, but inevitably causes permanent loss of the peripheral visual field and often induces clinically significant myopia [14]. In this study, conventional laser therapy was not used as vitreous hemorrhage precluded laser treatment. Moreover, the use of conventional laser treatment in these posterior forms of ROP is neither satisfactory nor safe. In this study, 0.625 mg Avastin was injected intravitreally. Various dosages of bevacizumab have been used but the ideal dosage for the drug remains unclear. In early reports, investigators used 1.25 mg (0.05 ml) bevacizumab, which would often increase the intraocular pressure in neonatal eyes, requiring an anterior chamber paracentesis. Subsequently, 0.625 mg bevacizumab has been shown to be effective in controlling disease and this now appears to be the preferred dose. However, a lower dose may yet prove to be equally effective and even preferred in the developing eye [15].

Neovascularization began to regress within a few days from intravitreal injection in this study and this was consistent with Drenser et al. [16], who observed regression of neovascularization as early as 72 h after intravitreal Avastin in his series.

Although eight cases needed a second injection and six eyes needed laser treatment because of unsatisfactory regression of blood vessels, no case showed recurrence during the follow-up period. This was slightly different from and not in agreement with the results of Mintz-Hittner et al. [17], who observed that disease recurred in two of 62 eyes in infants with zone I disease and in four of 78 eyes in infants with posterior zone II disease. This difference may be because of the smaller sample in this group and also the relatively shorter follow-up. There were varying degrees of tractional components in five eyes but did not involve the fovea and the ROP component quieted in all cases. Timely treatment of ROP is essential as late treatment in the presence of tractional membranes (stage 4 and 5 ROP) may result in increased traction and acceleration of retinal detachment [18].


  Conclusion Top


Intravitreal Avastin injection for the treatment of stage 3+ ROP is an inexpensive, safe treatment and is more effective than conventional laser treatment if the disease is posteriorly located (in zone I and posterior zone II), particularly if there is media opacity that precludes laser treatment [17],[19]. Intravitreal Avastin injection should not be used if there is tractional component (stages 4 and 5) as it may increase traction and accelerate retinal detachment.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.Flynn JT, Bancalari E, Bachynski BN, Bawol R, Goldberg R, et al. Retinopathy of prematurity. Diagnosis, severity, and natural history. Ophthalmology 1987; 94:620-629.  Back to cited text no. 1
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3.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.  Back to cited text no. 3
    
4.Pierce EA, Foley ED, Smith LE. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Arch Ophthalmol 1996; 114 : 1219-1228.  Back to cited text no. 4
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5.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  Back to cited text no. 5
    
6.Cryotherapy for Retinopathy of Prematurity Cooperative Group Multicenter trial of cryotherapy for retinopathy of prematurity: Preliminary results. Arch Ophthalmol 1988; 106 : 471-479.  Back to cited text no. 6
    
7.Gilbert C. Retinopathy of prematurity: a global perspective of the epidemics, population of babies at risk and implications for control. Early Hum Dev 2008; 84:77-82.  Back to cited text no. 7
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8.Silva RA, Murakami Y, Jain A, Gandhi J, Lad EM, Moshfeghi DM. Stanford University Network for Diagnosis of Retinopathy of Prematurity (SUNDROP): 18-month experience with telemedicine screening. Graefes Arch Clin Exp Ophthalmol 2009; 247:129-136.  Back to cited text no. 8
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9.Axer-Siegel R, Snir M, Cotlear D, Maayan A, Frilling R, Rosenbaltt L, et al. Diode laser treatment of posterior retinopathy of prematurity. Br J Ophthalmol 2000; 84:1383-1386.  Back to cited text no. 9
    
10.LA Wittenberg, NJ Jonsson, RV Paul Chan, MF. Chiang Computer-based image analysis for plus disease diagnosis in retinopathy of prematurity journal. Pediatric Ophthalmol Strabismus 2012; 49 : 11-19.  Back to cited text no. 10
    
11.Recsan Z, Vamos R, Salacz G. Laser treatment of zone I prethreshold and stage 3 threshold retinopathy of prematurity. J Pediatr Ophthalmol Strabismus 2003; 40:204-207.  Back to cited text no. 11
    
12.Connolly BP, McNamara JA and Sharma S. A comparison of laser photocoagulation with trans-scleral cryotherapy in the treatment of threshold retinopathy of prematurity. Ophthalmology 1998; 105 : 1628-1631.  Back to cited text no. 12
    
13.Kong L, Mintz-Hittner HA, Penland RL, Kretzer FL, Chevez-Barrios P. Intravitreal bevacizumab as anti-vascular endothelial growth factor therapy for retinopathy of prematurity: A morphologic study. Arch Ophthalmol 2008; 126 : 1161-1163.  Back to cited text no. 13
    
14.Quinn GE, Dobson V, Barr CC, Davis BR, Palmer EA, Robertson J, et al. Visual acuity of eyes after vitrectomy for retinopathy of prematurity: Follow-up at 5 1/2 years. Ophthalmology 1996; 103 :595-600.  Back to cited text no. 14
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17.Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage III+ retinopathy of prematurity. N Engl J Med 2011 ; 364:603-615.  Back to cited text no. 17
    
18.Zepeda-Romero LC, Liera-Garcia JA, Gutierrez-Padilla JA, Valtierra-Santiago CI, Cardenas-Lamas LJ. Paradoxical vascular-fibrotic reaction after intravitreal bevacizumab for retinopathy of prematurity. Eye (Lond) 2010; 24 :931-933.  Back to cited text no. 18
    
19.Bakri SJ, Larson TA, Edwards AO. Intraocular inflammation following intravitreal injection of bevacizumab. Graefes Arch Clin Exp Ophthalmol 2008; 246:779-781.  Back to cited text no. 19
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