|Year : 2014 | Volume
| Issue : 2 | Page : 70-77
Evaluation of the treatment of retinopathy of prematurity in preterm infants in Alexandria University Hospital
Ahmad M Bedda, Nehal M Abd El-Monem Al-Shakankiry, Ahmed M Abd-Elhady, Islam S Hamdy Ahmad
Department of Ophthalmology, Alexandria University, Alexandria, Egypt
|Date of Submission||15-Jan-2014|
|Date of Acceptance||10-Feb-2014|
|Date of Web Publication||12-Sep-2014|
Islam S Hamdy Ahmad
25 St, El-Moftsh Hamza, Alexandria
Source of Support: None, Conflict of Interest: None
The aim of this study was to document the treatment activities of retinopathy of prematurity (ROP) in the Ophthalmology Department in the Main Alexandria University Hospital during an 18-month period.
Patients and methods
Infants at risk of ROP were detected during screening of infants at the El-Shatby University Hospital or referred to the Pediatric Ophthalmology Clinic of Main Alexandria University Hospital from any other hospitals for screening or treatment. Screening of infants at risk, classification of findings according to the International Classification of Retinopathy of Prematurity, follow-up fundus examination as needed and treatment by indirect laser ophthalmoscopy, intravitreal ranibizumab injection, or surgical treatment as indicated were carried out.
In the present study, we found 73 infants (33.74% of the screened infant) suffering from ROP out of 223 preterm infants screened; out of those with ROP, 26 infants had ROP requiring treatment (35.61% of the infants with ROP and 11.66% of the total number of infants screened for ROP); 28 eyes of 14 infants (53.85% of the treated eyes) were treated by ablative indirect laser ophthalmoscopy, 20 eyes of 10 infants (30.77% of the treated eyes) were treated with an intravitreal injection of 0.25 mg in 0.025 ml ranibizumab, two eyes of two infants had lens-sparing pars plicata vitrectomy, and one eye had lensectomy vitrectomy.
In this study, we document the activities of the treatment of ROP in Alexandria University Hospital; although we apply different modalities of treatment, yet we have a long way to go through to improve the screening and treatment services provided to infants in our hospital.
Keywords: indirect laser ophthalmoscopy, intravitreal ranibizumab, retinopathy of prematurity, vitrectomy
|How to cite this article:|
Bedda AM, Abd El-Monem Al-Shakankiry NM, Abd-Elhady AM, Hamdy Ahmad IS. Evaluation of the treatment of retinopathy of prematurity in preterm infants in Alexandria University Hospital. J Egypt Ophthalmol Soc 2014;107:70-7
|How to cite this URL:|
Bedda AM, Abd El-Monem Al-Shakankiry NM, Abd-Elhady AM, Hamdy Ahmad IS. Evaluation of the treatment of retinopathy of prematurity in preterm infants in Alexandria University Hospital. J Egypt Ophthalmol Soc [serial online] 2014 [cited 2017 Aug 21];107:70-7. Available from: http://www.jeos.eg.net/text.asp?2014/107/2/70/140637
| Introduction|| |
The search for a cure for retinopathy of prematurity (ROP) has become a priority among researchers since the disease was first described by Terry  and continued interest in understanding and eradicating the disorder has brought about unprecedented collaboration among scientists, ophthalmologists, and public health activists in both developed and developing nations.
In 1984, 23 ophthalmologists from 11 countries formed a committee and cooperated in developing the International Classification of 173 Retinopathy of Prematurity according to the zone of affection, the stage of the disease, the extent of the disease, and the presence of plus disease .
In the 1980s, the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study showed a significant reduction in the rate of unfavorable visual, social, and developmental outcomes in infants randomized to cryotherapy of the avascular retina in eyes with threshold ROP compared with untreated controls .
Transpupillary laser photocoagulation delivered through an indirect ophthalmoscope became available around 1990; it has essentially replaced cryotherapy as the preferred treatment for acute ROP, although this modality is imperfect and has known serious complications. A diode or argon laser may be used to treat the entire peripheral avascular zone, usually with the aid of scleral depression, although argon laser may be associated with an increased incidence of cataracts .
The role of vascular endothelial growth factor (VEGF) in the pathogenesis of ROP has been described . Many recent reports of anti-VEGF use in ROP showed that it can be a safe and effective treatment [5,6]. However, there is concern about the choice of the drug, the dose, and the time of injection as well as about potential local and systemic complications .
Ranibizumab, because of its shorter systemic half-life than bevacizumab, which in our opinion may reduce the risk of systemic complications in premature infants, has a decreased systemic half-life and a higher binding affinity compared with bevacizumab, making it potentially more favorable in the treatment of infants with ROP with regard to its efficacy, ocular health, and the systemic safety profile .
Three years of follow-up in a small series suggest that intravitreal ranibizumab injections for ROP result in apparently preserved ocular outcomes .
Two studies have shown 90% or better anatomic success rates with lens-sparing vitrectomy (LSV) [9,10].
Results of LSV for 4b ROP can be broken down into anatomic and visual. A total of 76% of the eyes will have the retina becoming partly or completely reattached.
In all, 15% achieved 20/60-20/300 vision, 30% achieved 20/60-20/800 vision, 48% achieved 20/60-20/1900 (ambulatory) vision, and 72% of eyes achieved 20/60-LP vision; 28% are NLP with surgery .
The aim of this work was to document the treatment activities of ROP in the Ophthalmology Department in the Main Alexandria University Hospital during an 18-month period.
| Patients and methods|| |
The study was performed during an 18-month period from June 2012 to November 2013 on infants at risk of ROP detected during screening in the neonatal ICU of El-Shatby University Hospital during a regular screening visit on a weekly basis or those referred to the Pediatric Ophthalmology Clinic of Main Alexandria University Hospital from any other hospital for screening or treatment.
Screening criteria included babies born at or before 33 weeks' gestational age (GA), with birth weight less than 1500 g, or larger infants believed to be at increased risk of having ROP by the attending neonatologist, for example, supplemental oxygen therapy, perinatal hypoxemia and/or hypercapnia, sepsis, etc.
Eyes reaching type 1 prethreshold ROP according to the ETROP study including (a) stage 3 ROP in zone I with or without plus disease, (b) any ROP stage in zone I with plus disease, (c) stage 2 or 3 ROP with plus disease affecting zone II will have indirect laser ophthalmoscopy (ILO) treatment performed whenever possible.
For eyes reaching type 1 prethreshold ROP according to the ETROP study, with inability to perform laser treatment, for example, in infants who are too sick to be given general anesthesia, infants with poor pupil dilatation and logistic problems (e.g. ILO device is out of service), intravitreal ranibizumab injection will be given.
For eyes with stage 4a, 4b, or stage 5 ROP that are considered operable by the treating surgeon, retinal detachment surgery will be performed.
| Methods|| |
Screening for ROP was performed after pupil dilation using 0.5% cyclopentolate or 0.5% tropicamide eye drops (prepared by diluting the available 1% eye drops with an equal volume of sterile 0.9% saline) and 2.5% phenylephrine eye drops 5 min later, the drops to be applied 40 and 20 min before examination.
Then, inserting an infant lid, speculum and fundus examination was performed using indirect ophthalmoscopy with 30 D Volk lens and scleral indentation using the scleral indenter or a small muscle hook.
Classification of the condition according to the International Classification of Retinopathy of Prematurity Revisited, International Committee for the Classification of Retinopathy of Prematurity, 2005, was carried out, and fundus pictures were obtained using a wide-field retinal camera (RetCam II 120°) whenever possible.
For eyes with ROP less than the prethreshold disease, subsequent examination was planned according to the condition till normal vascularization reached zone III, progression to prethreshold disease required treatment, or death of the baby.
For infants requiring ILO, after preoperative pupil dilatation (vide supra), the patient was given general anesthesia, and transpupillary diode laser shots were applied under vision to the avascular peripheral retina anterior to the peripheral ROP change present in a nearly confluent manner whenever possible, starting at low intensity and titrating the power up till gray white laser burns occurred, treating the peripheral retina till ora serrata if possible.
For infants requiring intravitreal ranibizumab injection, the procedure was carried out in an ophthalmic operation room under completely aseptic conditions under topical anesthesia after disinfection of the lids and the periocular region with 10% povidone iodine solution, and irrigation of the conjunctival sac with 5% povidone iodine solution, followed by intravitreal injection of 0.25 mg ranibizumab in 0.025 ml 1.5 mm from the limbus measured by a caliper ([Figure 1]); then, antibiotics were prescribed: moxifloxacin eye drops five times daily for 5 days.
For infants requiring pars plicata vitrectomy, with or without lensectomy, the procedure was carried out in the ophthalmic operation room by an experienced surgeon and under complete aseptic conditions using a 23-G vitrectomy wide-angle viewing system.
A three-port trochar cannula was inserted at a distance of 1.5 mm from the limbus; the core vitreous and as much as possible of the peripheral membranes were removed using the vitrectomy cutter or other instruments such as scissors or end-gripping forceps, taking care to minimize the creation of retinal breaks; laser treatment of the peripheral retina with an endolaser probe, if needed, was then carried out; intravitreal tamponade was used whenever needed, and not on routine basis.
| Results|| |
We conducted this noncomparative nonrandomized interventional prospective case series study after approval from the ethics committee of the Faculty of Medicine, Alexandria University, and the collected data were entered into an Excel sheet for statistical analysis.
During the 18-month period, we identified 73 infants suffering from ROP out of the 223 preterm infants screened; this represents 33.74% of the screened cases; out of those with ROP, 26 infants had the severe form, requiring treatment: this comprises 35.61% of the cases with ROP and 11.66% of the total number of infants screened for ROP; one infant had cicatricial ROP.
The screened cases had a mean GA of 31.09 ± 1.76 weeks (range: 25-38 weeks), and a mean birth weight of 1222.62 ± 236.66 g (range: 600-2600 g); one case had a GA of 38 weeks, had previous oxygen therapy and was referred for screening due to bilateral retinal hemorrhage that was later diagnosed as hemorrhagic disease of newborn and not due to ROP.
A total of 105 cases (47.09%) were male and 118 cases (52.91%) were female. Forty-one male infants (39.04% of the screened male infants) developed ROP, whereas 32 female infants (27.11% of the screened female infants) developed the disease.
Fourteen male infants (13.33% of the screened male infants and 34.14% of the male infants with ROP), whereas 12 female infants (10.16% of the screened female infants and 37.5% of the female infants with ROP) developed severe ROP requiring treatment.
The mean GA for cases of severe ROP requiring treatment was 30.27 ± 2.57 weeks and the mean birth weight was 1176.69 ± 291.35 g.
Twenty-eight eyes of 14 patients (53.85% of the treated cases) had ablative therapy performed by indirect diode laser ophthalmoscopy; these infants had a mean GA of 30.07 ± 2.49 weeks and a mean birth weight of 1167.86 ± 309.27 g.
Two of the cases were referred for ROP screening by their treating neonatologist as they had multiple ROP risk factors, had prethreshold ROP type 1, were treated with ILO, and had a relatively high GA and birth weight (34 weeks' GA in both cases, and a birth weight of 1300 and 1500 g, respectively); these two cases were not screened in the El-Shatby University Hospital.
Nine cases (64.29% of the cases treated by ILO) had zone II disease, whereas only four cases (28.57%) had zone I disease, and for only one case (7.14%), ILO was performed as a salvage treatment after recurrent APROP after ranibizumab intravitreal injection.
The number of shots applied was variable depending on the extent of the area to be treated by laser, but on average, 800-1000 shots were applied per eye.
Only two eyes of a male infant with a GA of 32 weeks and a birth weight of 1325 g, which had stage 1 ROP affecting zone I, were complicated after ILO by dense premacular hemorrhage in the left eye ([Figure 2]) and mild preretinal hemorrhage in the right eye along the superotemporal vascular arcade ([Figure 3]); the hemorrhage in both eyes were observed till absorbed completely; this took a duration of about 2 months in the left eye, which had a denser hemorrhage, but finally it was absorbed completely without sequelae ([Figure 4]).
The ranibizumab intravitreal injection was carried out at a mean postnatal age of 47.3 ± 17.7 days and at a mean chronological age of 262.9 ± 23.5 days.
The mean GA of cases for which intravitreal injection was given was 30.8 ± 2.62 weeks and the mean birth weight was 1213.4 ± 308.12 g.
All injected eyes except two eyes of a single patient showed a favorable response after a single injection in form of regression of the plus disease and arrest of abnormal neovascularization, without the development of peripheral retinal detachment or macular dragging.
Treatment with intravitreal injection was carried out for eight cases (80% of the cases treated by injection) with zone I ROP and only for two cases (20%) with zone II ROP.
Three cases with APROP were treated by intravitreal ranibizumab injection: two cases showed a favorable response in the form of regression of the abnormal neovessels and progression of normal vascularization ([Figure 5] and [Figure 6]).
Two eyes with APROP, of a preterm female patient with a GA of 32 weeks and a birth weight of 1470 g ([Figure 7]), showed regression of the abnormal neovessels at the posterior pole and on the optic nerve head, which was thought to be a severe form of retinal ischemia and optic atrophy ([Figure 8]) followed by recurrence of activation of the posterior pole neovessels ([Figure 9]) that necessitated laser ablative therapy by indirect ophthalmoscopy; afterwards, the posterior pole vessel tortuosity and congestion improved ([Figure 10]).
|Figure 6: The same eye, 2 weeks after intravitreal ranibizumab injection: note the regression of the posterior pole neovessels and progression of normal vascularization.|
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|Figure 8: Regression of posterior pole vessels after intravitreal ranibizumab.|
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|Figure 9: Recurrence of neovessels after intravitreal ranibizumab injection.|
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Surgical treatment was carried out in three eyes of two cases in the present study: one case was of a male preterm infant with a GA of 31 weeks and a birth weight of 1100 g; he presented for screening 4 weeks after birth with bilateral stage 1 zone II, and was advised to have follow-up examination 2 weeks later; however, the parents did not bring the infant back for examination except after more than 2 months, and was found to have stage 4a in his left eye ([Figure 11]), for which lens-sparing pars plicata vitrectomy and endolaser treatment were carried out; the separation of the posterior vitreous face was impossible; trimming of the membranes at the posterior pole and peripherally was performed as much as possible; postoperatively, the eye showed attached retina at the posterior pole, but the nasal retina showed persistent detachment and residual epiretinal glial tissue ([Figure 12]); the right eye of this infant progressed to stage 5 ROP and was inoperable.
Regarding the second case, she was referred for screening 15 weeks after birth and was not screened in El-Shatby University Hospital; she had a GA of 25 weeks and a birth weight of 950 g; she presented with stage 4b in her right eye, for which pars plicata lensectomy vitrectomy was carried out; postoperatively, the retina at the posterior pole was attached, but the peripheral retina showed persistent detachment, in addition to mild persistent epiretinal glial tissue, which caused mild macular dragging ([Figure 13]).
The left eye of the same infant showed stage 4a ROP at presentation, for which lens-sparing pars plicata vitrectomy was carried out; during follow-up in the postoperative visits, the retina was completely attached, but there was persistent macular dragging despite maximum removal of central and peripheral epiretinal glial tissues ([Figure 14]).
|Figure 14: The appearance after lens-sparing pars plicata vitrectomy of the left eye: note the persistent macular dragging.|
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A male preterm infant with a GA of 28 weeks and a birth weight of 900 g, who was born outside El-Shatby University Hospital, was referred for ophthalmic examination 17 weeks after birth due to bilateral leukocoria; this infant had bilateral cicatricial ROP with sensory nystagmus, and was advised not to have surgery performed as his condition was inoperable.
The mean number of follow-up exams for cases of ROP not requiring treatment was 2.59 ± 1.56 visits, whereas for cases of severe ROP requiring treatment, the mean was 4.62 ± 2.82 visits.
| Discussion|| |
The research on this disease in Egypt is still in its early stages. No previous research work has been carried out to document the ROP treatment activity in the University Hospital in Alexandria.
The number of infants examined for the occurrence of ROP as well as the incidence of ROP occurrence in this study were comparable to other studies from other developing countries; we found 73 infants (33.74% of the screened cases) suffering from ROP out of the 223 preterm infants screened; out of those with ROP, 26 infants (35.61% of the ROP cases and 11.66% of all screened infants) had the severe form requiring treatment; Filho et al.  conducted a study that was published in 2008 in Brazil in which 323 infants were screened for ROP during a 4-year period, of which 82 infants suffered from ROP (25.7% of the screened cases), and 17 of the screened infants were treated (5.3% of the screened infants), although in that study the treatment was performed for threshold disease.
In another study published in 2008, Taqui et al.  screened 68 infants during a 3-year period in Pakistan and reported ROP in 22 infants (32.4% of the 68 screened cases) and 14 infants, representing 20.6% of the screened infants, requiring treatment.
Out of the 73 cases with ROP, 26 cases (35.61%) had ROP that required treatment; this comprises 11.66% of all 223 cases screened for ROP. In comparison with other studies, we had a higher incidence of severe ROP that needed laser therapy: for example, Shah et al.  in 2005 conducted a study in Singapore on 564 preterm infants, and found an incidence of 29.2%, and the incidence of ROP that needed surgical treatment was 4.96%. Seiberth and Linderkamp  conducted a study on 402 preterm infants from Germany and reported an incidence of 36.06% for stages 1-5 ROP. Karna et al.  from America reported an incidence of 7.8% for severe ROP (ROP from stage 2 or higher) among 576 preterm infants from 1993 to 2000.
The majority of the cases treated by laser ablative therapy in the present study had zone II disease (nine cases representing 64.29% of the total cases), whereas only four cases had zone I disease (28.57%); this is different from results in the ETROP study in which 58.7% of the eyes treated as high-risk prethreshold ROP and assigned for ablative laser treatment had zone II disease and only 41.3% had zone I disease; this may be attributed to the fact that at the time of the ETROP study, the use of anti-VEGF injections in ROP was not known and now we are encouraged to perform more intravitreal injections for cases with zone I disease in which excess laser therapy would be needed to cover a large area of the nonperfused retina.
Laser treatment in this study was carried out at a mean chronological age of 60 ± 23.69 days, and a mean postmenstrual age of 270.5 ± 28.03 days. In the ETROP study, the mean chronological age was 70 ± 14 days and the postmenstrual age was 246.4 ± 16.1 days. Again, the smaller chronological age and the larger postmenstrual age in the present study may be due to the occurrence of the disease in infants with a greater GA in developing countries than those in developed countries.
The near-confluent pattern with ˜1200 laser spots may also reduce the retreatment rate of the disease, but larger studies are needed to confirm these findings [17,18]; this is similar to what has been observed in this study, in which we performed near-confluent ablative laser treatment, but needed a smaller number of shots per eye (800-1000 in average); this may be caused by a change in the size of laser shots per eye as it cannot be adjusted during ILO and is variable according to several factors; however, we had no cases of persistent disease after laser treatment and retreatment was not required in any of the laser-treated cases.
We could not perform intravitreal bevacizumab injection in the present study because it is not approved for intravitreal injection by the ethics committee of the Faculty of Medicine, Alexandria University.
Although bevacizumab has the advantage of being a large molecule (150 kD; it is a full antibody) that cannot penetrate the intact retina or escape the eye except in very small amounts, as shown in animal models (unless laser therapy has destroyed the natural retinal barrier) , taking into consideration the highly viscous preterm vitreous gel, ranibizumab is only the Fab fragment and not the whole antibody, and despite having a smaller molecular weight, which makes the blood retinal barrier more permeable for its passage and thus increases the systemic undesired anti-VEGF effects, yet it has a shorter systemic half-life (3.5 days) than the relatively long half-life of intravitreal bevacizumab (12.3 ± 2.6 days) and a higher binding affinity than bevacizumab , making it more favorable in ROP treatment regarding its efficacy, ocular health, and systemic safety by many practitioners.
In the present study, we treated 20 eyes of 10 infants with ROP requiring treatment (representing 30.77% of the treated eyes) by intravitreal injection of 0.25 mg in 0.025 ml ranibizumab; this is half the adult dose based on the experience with bevacizumab (0.625 mg in 0.025 in the literature) [20,21]; this is similar to the ranibizumab dose given in other studies .
The recurrence rate after intravitreal injection for zone I ROP in this study (12.5%) is similar to the incidence reported in the BEAT-ROP study (10%), and that for zone II in the present study (0%) is less than that in BEAT-ROP study (1%), but this may be due to the smaller number of infants treated in this study in comparison with the BEAT-ROP study.
The three eyes treated surgically in the present study did not have sclera buckle performed, either alone or with vitrectomy; this is similar to other studies [22,23] that stated that potential advantages of LSV without scleral buckling include the lower induction of anisometropia and the lack of need for buckle division in a second procedure, in addition to the higher rate of anatomic success for LSV compared with scleral buckling in stage 4a ROP [9,24].
None of the surgically treated eyes in the present study had plus disease at the time of surgery, which was found to be a poor prognostic sign in other studies .
In the present study, we did not treat persistent peripheral retinal detachment after vitrectomy with a sclera buckle or silicon oil tamponade as was addressed in other studies  because we believe that the traction causing progressive detachment of the peripheral retina was relieved and there was progression of the condition during follow-up examinations; in addition, we could not provide effective immediate postoperative refractive rehabilitation for the infant who had LSV in one eye and vitrectomy lensectomy in the other eye; this emphasizes the importance of close collaboration with a pediatric ophthalmologist experienced in refractive management of anisometropia in these infants to prevent the rapid development of amblyopia.
We did not assess the visual acuity in the infants treated in this study, due to the short duration of follow-up; however, during the relatively short period of follow-up, none of the infants showed squint or nystagmus; visual acuity in these infants should be assessed in later studies with a longer follow-up duration.
| Conclusion|| |
In this study, we document the activities of treatment of ROP in Alexandria University Hospitals; we applied different modalities of treatment, and still have a long way to go through to improve the screening and treatment services provided to the infants in our hospitals.
| Acknowledgements|| |
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14]