|Year : 2014 | Volume
| Issue : 2 | Page : 63-67
A comparative study between intravitreal ranibizumab and peripheral laser ablation in cases of prethreshold type I retinopathy of prematurity
Ahmed Mahmoud Abdel Hadi
Department of Ophthalmology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
|Date of Web Publication||5-Jun-2015|
Dr. Ahmed Mahmoud Abdel Hadi
24 Fawzy Moaz Street, Safwa 5, Entrance 2, Alexandria
Source of Support: None, Conflict of Interest: None
Purpose: The aim was to evaluate the efficacy and safety of intravitreal injection of ranibizumab for treatment of prethreshold type 1 retinopathy of prematurity (ROP) with conventional laser photocoagulation given for the same disease level. Subjects and Methods: In this retrospective comparative study, the charts of 16 premature babies, presenting from July 2009 to May 2014, were reviewed. All infants were diagnosed with prethreshold ROP (type 1). Patients received either intravitreal ranibizumab (0.625 mg/0.025 ml of solution) (group A, 12 eyes of 6 infants) or conventional diode laser (group B, 28 eyes of 14 infants), bilaterally. The main evaluated outcomes included time of regression, decrease of plus signs and incidence of recurrence. Infants were followed till 55 weeks postmenstrual age. The confidentiality of the patients was respected. Results: The mean age of the studied infants was 35.63 ± 1.58 weeks ranging from 33 to 39 weeks. The stage of ROP in the studied infants was either stage 2 in 7 cases (43.8%) or stage 3 in 9 cases (56.3%). The zones of ROP were zone I in 3 cases (18.8%) and zone II in 13 cases (81.3%). Group A had a mean gestational age (GA) of 36.6 ± 1.5 weeks, while cases in group B had mean GA of 35 ± 1.3 weeks. This was statistically significant (P = 0.037). The stage did not significantly affect the choice of treatment (P = 0.09). Looking at the subgroup analysis 66.7% (two cases) of cases with zone I disease were treated with intravitreal ranibizumab, whereas 69.2% (nine cases) with zone II disease were treated with conventional laser. The incidence of recurrence was not affected by the zone of the disease (P = 0.71) nor by the stage of the ROP or by the presence of plus sign (P = 0.29, P = 0.68, respectively). There was no statistically significant difference between the two treatment groups about the incidence of recurrence (P = 0.701). The mean GA for cases with recurrence of ROP (35.25 ± 2.6 weeks), did not differ significantly with the mean GA of the infants who did not suffer from recurrence 35.75 ± 1.2 weeks (P = 0.7). Conclusion: Both intravitreal ranibizumab and conventional laser were proven effective in the treatment of prethreshold type 1 ROP. Long-term favorable structural outcome may require extended observation and retreatment. Further large-scale studies are needed to address the long-term safety and efficacy.
Keywords: Conventional laser ablation for retinopathy of prematurity (ROP), intravitreal ranibizumab, prethreshold ROP type 1
|How to cite this article:|
Hadi AA. A comparative study between intravitreal ranibizumab and peripheral laser ablation in cases of prethreshold type I retinopathy of prematurity. Egypt Retina J 2014;2:63-7
|How to cite this URL:|
Hadi AA. A comparative study between intravitreal ranibizumab and peripheral laser ablation in cases of prethreshold type I retinopathy of prematurity. Egypt Retina J [serial online] 2014 [cited 2020 Apr 5];2:63-7. Available from: http://www.egyptretinaj.com/text.asp?2014/2/2/63/150211
| Introduction|| |
Retinopathy of prematurity (ROP) is a disease of the premature infant retina that has not yet fully vascularized. It causes loss of vision by means of macular dragging and retinal detachment.  The incidence of blindness in infants due to ROP in developed countries is relatively low, about 1 case in 820 infants,  because of good neonatal screening programs and timely treatment.  The disorder is a major cause of childhood blindness in developing countries, appearing in larger premature infants (birth weight [BW] ≤2000 g; mean, 1400 g). The worldwide prevalence of blindness due to ROP is 50,000.1.
The stages and zones affected by ROP are classified according to the International Classification of ROP. [3,4] The zone indicates 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 resembles an annulus and encircles zone I. It extends from zone I to the nasal extent of the retina. Zone III is the remaining crescent of 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. 
Stages of ROP are defined by vessel appearance at the interface between the vascular and avascular retinal areas. This interface resembles a line for stage 1, a three-dimensional ridge for stage 2, and a ridge with neovascularization (NV) extending into the vitreous gel for stage 3, which is the ideal time for treatment. Plus disease, as in stage 3+, indicates that two or more quadrants of the eye have dilated veins and tortuous arteries near the optic disk. The NV can progress to form fibrous bands that cause partial retinal detachment (stage 4), and ultimately, total retinal detachment (stage 5). 
Cryotherapy for ROP Cooperative Group, a multicenter trial of cryotherapy for ROP defined several terms. (1) Plus disease means venous dilatation and arterial tortuosity of the posterior pole vasculature, with iris vessel engorgement resulting in pupil rigidity. (2) Preplus disease implies arterial tortuosity and venous engorgement outside normal limits, but insufficient to qualify for plus disease. (3) Threshold disease is defined as five contiguous or eight cumulative clock hours of stage 3 with plus disease in zone I or II. 
Prethreshold ROP (type 1) refers to zone I ROP of any stage with the presence of "plus"; zone I, stage 3 with no plus disease; and zone 2, stage 2 ROP or greater, with the presence of "plus". This is considered a high-risk child for progression into full-blown disease and should be treated according to the Early Treatment for ROP Cooperative Group. 
So far, therapies used are: Laser and cryotherapy. Cases of retinal detachment are amiable for surgical procedures of sclera and vitrectomy. Low efficacy of treatment leads to the necessity for looking for new solutions and modern therapy use in the treatment of this disease.
Vascular endothelial growth factor (VEGF) secreted under the influence of hypoxia takes part in angiogenesis and NV. Thus, in ROP management vitreous application of vascular endothelial growth factor inhibitors such as ranibizumab and bevacizumab are used as supplement or treatment combined with laser therapy or surgical procedures. However, there are many controversies regarding this form of treatment. 
In this retrospective cohort study, we compared the intravitreal ranibizumab monotherapy and conventional laser therapy about efficacy of the treatment in causing regression of NV and absence of recurrence during the follow-up period.
| Subjects and Methods|| |
In this retrospective comparative study, the charts of 16 premature babies, presenting from July 2009 to May 2014, were reviewed. All included infants were diagnosed with high-risk prethreshold (type 1). Determination of whether prethreshold disease requiring treatment was made according to the results of the Early Treatment for ROP study. 
The Institutional Review Boards at the Ophthalmology Department, University of Alexandria approved the study protocol. Confidentiality of the patient records was respected. Consent was taken from the parents if the infant required any form of treatment.
RetCam photography was used whenever possible (RetCam II 120°, Clarity Medical System Inc., Pleasanton, CA, USA) to document ROP; eligibility was established by the treating ophthalmologist and was confirmed by a second ophthalmologist on the basis of electronically transmitted RetCam images.
Infants diagnosed with prethreshold type 1 received either intravitreal ranibizumab (Lucentis ® , Genentech Inc., South San Francisco, CA, USA) (0.625 mg/0.025 ml of solution) (group A, 12 eyes of 6 infants) or conventional diode laser (laser indirect ophthalmoscope using IRIDEX Corporation ,Mountain View, CA 94043, OcuLight SL/SLx Infrared 810 nm laser) (group B, 20 eyes of 10 infants), bilaterally.
Treatment was performed under general anesthesia in the operating room. All interventions were dome by a single surgeon.
As for the intravitreal ranibizumab group, topical 5% povidone-iodine was applied to the periocular skin and the conjunctiva. A lid speculum was placed, and 0.625 mg (0.025 ml) of ranibizumab were injected 1 mm posterior to the corneoscleral limbus, in the inferotemporal quadrant, using a 27-gauge needle. An anterior chamber paracentesis was performed if needed in the end to normalize intraocular pressure. Topical (5 mg/mL) moxifloxacin hydrochloride (Vigamox) was prescribed 4/day for 5 days after the procedure.
Group B infants underwent diode laser photocoagulation of the peripheral avascular retina extending from the ridge of extraretinal proliferation to the ora serrata. They received a pattern of laser spots placed 1-1.5 burn widths apart.
The primary outcome was treatment success defined as regression of NV and absence of recurrence (recurrence of ROP, a variable with three possible values: given 0 for recurrence in neither eye, one for recurrence in one eye, and two for recurrence in both eyes). Cases are requiring additional treatment consisting of a few laser applications to inadvertently skipped areas within 1 week after initial treatment were not considered to be recurrences. Infants were followed up till 55 weeks postmenstrual age (gestational age [GA] plus postnatal age). The first follow-up was done after 1 day in group A, and after 3 days in group B. Subsequent examination was scheduled by the treating ophthalmologist according to the response to the treatment regime.
All data were collected and assessed by SPSS (SPSS Inc., Chicago, IL, USA) version 20.0 for Windows. Chi-square test was performed to compare the incidence of complications and the recurrence rate within the follow-up period between the two groups. A P value of 0.05 or less was regarded as statistically significant.
| Results|| |
The study included 16 premature infants (2 males and 14 females) of age ranging from 33 to 39 weeks (GA), with a mean of 35.63 ± 1.58 weeks. The stage of ROP in the studied infants was either stage 2 in 7 cases (43.8%), or stage 3 in 9 cases (56.3%). The zones of the retina affected by the above-mentioned stages of ROP were zone I in 3 cases (18.8%) and zone II in 13 cases (81.3%). The plus sign was absent in two cases with zone I disease (12.5%).
Those infants with stage 2 ROP (seven cases) had a mean GA of 34.29 ± 0.7 weeks, while infants with stage 3 ROP had a mean GA of 36.67 ± 1.2 weeks. This difference between stages 2 and 3 ROP was statistically significant (P < 0.001).
About the relation between the zone of affection and the GA. Infants with zone I disease had a mean GA of 37.3 ± 1.5 weeks, while those with zone II affection had a mean GA of 35.2 ± 1.3 weeks. This was again statistically significant (P = 0.033).
Group A (treated with intravitreal ranibizumab) had a mean GA of 36.6 ± 1.5 weeks, whereas cases in group B (treated with conventional laser) had mean GA of 35 ± 1.3 weeks. The difference in GA in the treatment groups was statistically significant (P = 0.037).
As for the relation between the zone of affection and the stage of ROP, seven cases (53.8%) in zone II had stage 2 ROP. Three cases (33.3%) in the zone I had stage 3 ROP, while six cases (66.7%) with zone II ROP had stage 3 disease.
Looking at the two treatment groups and the stages of the ROP in each group [Table 1], the stage did not significantly affect the choice of treatment (P = 0.09). Similarly, the choice of treatment was not affected by the presence of the plus sign (P = 0.69). Looking at the subgroup analysis 66.7% (two cases) of cases with zone I disease were treated with intravitreal ranibizumab [Figure 1], while 69.2% (nine cases) with zone II disease were treated with conventional laser [Figure 2].
|Figure 1: A case from group A with prethreshold retinopathy of prematurity type 1 (a), after 1 week from intravitreal ranibizumab (b) with regression of the plus sign. Three weeks from treatment, progression of normal vascular development beyond the previous ridge (c)|
Click here to view
|Figure 2: A case from group B with prethreshold retinopathy of prematurity type 1 (a), after 1 week from conventional laser ablation (b) with some skip areas. Six weeks from treatment, regression of plus sign, disappearance of preretinal hemorrhages and flattening of the ridge (c)|
Click here to view
|Table 1: Ocular outcomes in the 16 infants at 55 weeks' postmenstrual age |
Click here to view
The incidence of recurrence within the follow-up period did not differ significantly between infants with zone I or zone II ROP (6.25%, 18.75% respectively) (P = 0.71). In addition, the incidence of recurrence was not affected significantly by the stage of the ROP or by the presence of plus sign before delivery of the treatment (P = 0.29, P = 0.68, respectively). There was no statistically significant difference between the two treatment groups as regards the incidence of recurrence (6.25%, 18.75% for group A and group B respectively) (P = 0.701). The cases with recurrence of ROP (four cases) after treatment within the follow-up period had a mean GA at their diagnosis of 35.25 ± 2.6 weeks, which was not significantly different from the mean GA of the infants who did not suffer from recurrence 35.75 ± 1.2 weeks (P = 0.7).
As regard the time of recurrence, in group B two cases had recurrence of activity that warranted re-intervention between 3 and 6 weeks posttreatment, while one infant had recurrence in both eyes at 5 weeks posttreatment. The single case in group A that had a recurrence of activity occurred after 11 weeks from the treatment.
However, it was noticed during the follow-up period that all cases treated with conventional laser therapy had permanent destruction of the vessels in the peripheral retina, whereas intravitreal ranibizumab allowed for continued vessel growth into the peripheral retina.
| Discussion|| |
The current management of ROP is well evidenced. Nevertheless, the recent Bevacizumab Eliminates the Angiogenic Threat of ROP (BEAT-ROP) trial of intravitreal injection of bevacizumab has reopened the debate on optimal management. While the use of intravitreal injections of anti-VEGF agents may appear to be an attractive alternative to laser ablation of the peripheral retina, caution is needed. The optimal choice of agent and dose remain unknown. 
A number of potential complications related to intravitreal anti-VEGF injection can occur in premature infants. They may be more vulnerable to VEGF blockade than adults are. The full effect of anti-VEGF on normal developing vessels is not well understood. Systemic adverse effects of the anti-VEGF antibody are also a concern. 
After the intravitreal injection, the serum concentration of bevacizumab is greater than that of ranibizumab. [11,12] In addition, ranibizumab has several safety-related advantages, including a shorter systemic half-life and the antibodies lack a crystallizable fragment.  In theory, the risk of systemic adverse events and complement-mediated toxicity is reduced by using ranibizumab.
A major ocular side effect of ablative conventional laser therapy, especially in infants with zone I ROP, is a clinically significant loss of the visual field.  Conventional laser therapy results in permanent destruction of the vessels in the peripheral retina, whereas intravitreal bevacizumab allows for continued vessel growth into the peripheral retina. [15,16]
The GA in the current study was 35.63 ± 1.58 weeks (range from 33 to 39 weeks). The mean GA for stage 2 and 3 cases was 34.29 ± 0.7 weeks 36.67 ± 1.2 weeks respectively. This was statistically significant (P = 0.000).
In the study of Shah et al., from the 564 very low BW infants who fit the screening criteria, ROP was detected in 165 (29.2%) infants; of whom 49% of infants had stage 1 disease, 24% were at stage 2, and 27% were at stage 3 or more. The median age of onset of ROP was 35 weeks (range, 31-41) corrected age. Infants < 30 weeks of GA and/or infant with BW < 1000 g are at considerable risk for threshold ROP. 
In the current study, there was a statistically significant difference in the treatment delivered to the infants as regards the GA in each group. Group A (treated with intravitreal ranibizumab) had a mean GA of 36.6 ± 1.5 weeks, while cases in group B (treated with conventional laser) had mean GA of 35 ± 1.3 weeks (P = 0.037).
The trend toward using anti-VEGF in slightly older infants in the current study whenever possible is warranted. Because the safety is the primary reason for caution when considering the use of intravitreal anti-VEGF agents in the eyes of neonates, both the mortality and morbidity must be taken into consideration when delivering any treatment for such age groups. For an assessment of mortality at a 5% significance level and with 80% power, a sample of 2800 infants would be required. Again an assessment of local or systemic toxicity would require an even larger sample. 
In the current study, the infants with zone I disease received mostly intravitreal ranibizumab (66.7%), while 69.2% (nine cases) with zone II diseases were treated with conventional laser.
A major ocular side effect of ablative conventional laser therapy, especially in infants with zone I ROP, is clinically significant loss of the visual field.  On the other hand, treatment with intravitreal bevacizumab allowed the retinal vessels to advance to the point at which the vascular precursors have ceased migration, with differentiation of the underlying retina. 
The incidence of recurrence within the follow-up period was neither affected by the zone, stage, presence of plus sign, or the treatment modality (P = 0.71, P = 0.29, P = 0.68, P = 0.701, respectively).
This differs from the results of Mintz-Hittner and Kretzer,  who showed increased efficacy of intravitreal bevacizumab as compared with conventional laser therapy for stage 3+ ROP when both zones I and II were affected. Their sample was sufficiently large to show significant efficacy of intravitreal bevacizumab for zone I disease but not for zone II posterior disease. This is not the case in the current study, where a small sample size did not allow differential outcome of the treatment in different stages or affecting different zones.
As regards the time of reactivation of ROP, the case in group A that suffered from a recurrence of activity occurred after 11 weeks from the original treatment. The work of Hu et al. showed the reactivation of ROP after bevacizumab injection to happen at a mean time of 14.4 weeks, with a minimum of 4 and maximum of 35 weeks after the initial treatment. 
| Conclusion|| |
Both intravitreal ranibizumab and conventional laser were proven effective in the treatment of prethreshold type 1 ROP. Long-term favorable structural outcome may require extended observation and retreatment. Furthermore, large scale studies are needed to address the long-term safety and efficacy.
| References|| |
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.
Lad EM, Nguyen TC, Morton JM, Moshfeghi DM. Retinopathy of prematurity in the United States. Br J Ophthalmol 2008;92:320-5.
An international classification of retinopathy of prematurity. Prepared by an international committee. Br J Ophthalmol 1984;68:690-7.
International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 2005;123:991-9.
Katz X, Kychenthal A, Dorta P. Zone I retinopathy of prematurity. J AAPOS 2000;4:373-6.
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;121:1684-94.
Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol 1988;106:471-9.
Monika M, Katarzyna KK, Leszek K. Present-day conservative treatment retinopathy of prematurity. Klin Oczna 2013;115:65-8.
Fleck BW. Management of retinopathy of prematurity. Arch Dis Child Fetal Neonatal Ed 2013;98:F454-6.
Wu WC, Yeh PT, Chen SN, Yang CM, Lai CC, Kuo HK. Effects and complications of bevacizumab use in patients with retinopathy of prematurity: A multicenter study in Taiwan. Ophthalmology 2011;118:176-83.
Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 2007;114:855-9.
Bakri SJ, Snyder MR, Reid JM, Pulido JS, Ezzat MK, Singh RJ. Pharmacokinetics of intravitreal ranibizumab (lucentis). Ophthalmology 2007;114:2179-82.
Gaudreault J, Fei D, Rusit J, Suboc P, Shiu V. Preclinical pharmacokinetics of ranibizumab (rhuFabV2) after a single intravitreal administration. Invest Ophthalmol Vis Sci 2005;46:726-33.
Mintz-Hittner HA. Avastin as monotherapy for retinopathy of prematurity. J AAPOS 2010;14:2-3.
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;28:831-8.
Dorta P, Kychenthal A. Treatment of type 1 retinopathy of prematurity with intravitreal bevacizumab (Avastin). Retina 2010;30:S24-31.
Shah VA, Yeo CL, Ling YL, Ho LY. Incidence, risk factors of retinopathy of prematurity among very low birth weight infants in Singapore. Ann Acad Med Singapore 2005;34:169-78.
Mintz-Hittner HA, Kennedy KA, Chuang AZ, BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011;364:603-15.
Mintz-Hittner HA, Kretzer FL. Postnatal retinal vascularization in former preterm infants with retinopathy of prematurity. Ophthalmology 1994;101:548-58.
Hu J, Blair MP, Shapiro MJ, Lichtenstein SJ, Galasso JM, Kapur R. Reactivation of retinopathy of prematurity after bevacizumab injection. Arch Ophthalmol 2012;130:1000-6.
[Figure 1], [Figure 2]