Journal of Pediatric Ophthalmology and Strabismus

Original Article 

Combined Vitrectomy and Anti-VEGF Treatment for Stage 4 Retinopathy of Prematurity With Extensive Neovascular Proliferation

Parijat Chandra, MD; Devesh Kumawat, MD, FICO; Divya Agarwal, MD; Rohan Chawla, MD, FRCS

Abstract

Purpose:

To study the role of combined vitrectomy and intravitreal anti-vascular endothelial growth factor (VEGF) injection for stage 4 retinopathy of prematurity (ROP) with extensive neovascular proliferation.

Methods:

In a retrospective interventional study at a tertiary eye care center, 15 eyes (9 infants) with advanced stage 4 ROP underwent 25-gauge vitrectomy combined with intravitreal 0.625 mg of bevacizumab (n = 12) or 0.25 mg of ranibizumab (n = 3) injection and were followed up until 65 weeks' postconceptional age (PCA). The perinatal history, tractional retinal detachment (TRD) characteristics (zone, stage, and presence of “plus” disease), treatment details, and anatomical outcomes were reviewed. The main outcome measures were fibrovascular tissue and TRD regression and final macular status.

Results:

Mean gestational age and birth weight were 28.5 ± 1.2 weeks and 1,167 ± 185 g, respectively. Thirteen eyes had zone I disease and 2 eyes had zone II disease. Thirteen eyes were stage 4A and 2 eyes were stage 4B ROP. The morphology was aggressive posterior ROP in 10 eyes. The mean PCA at surgery was 37.8 ± 2.3 weeks. Lensectomy was also performed in 2 eyes. Rapid fibrovascular tissue regression was seen in 14 eyes within 2 weeks, followed by TRD regression and macular vascularization, although 2 eyes had macular pucker formation. Persistent vitreous bleeding was present in 1 eye, which needed lavage, and eventually the TRD regressed. Disease reactivation was noted in 1 eye at 5 weeks and was managed with repeat intravitreal anti-VEGF injection.

Conclusions:

Anti-VEGF treatment combined with vitrectomy leads to rapid disease regression in advanced stage 4 ROP with extensive neovascular proliferation.

[J Pediatr Ophthalmol Strabismus. 2020;57(1):61–66.]

Abstract

Purpose:

To study the role of combined vitrectomy and intravitreal anti-vascular endothelial growth factor (VEGF) injection for stage 4 retinopathy of prematurity (ROP) with extensive neovascular proliferation.

Methods:

In a retrospective interventional study at a tertiary eye care center, 15 eyes (9 infants) with advanced stage 4 ROP underwent 25-gauge vitrectomy combined with intravitreal 0.625 mg of bevacizumab (n = 12) or 0.25 mg of ranibizumab (n = 3) injection and were followed up until 65 weeks' postconceptional age (PCA). The perinatal history, tractional retinal detachment (TRD) characteristics (zone, stage, and presence of “plus” disease), treatment details, and anatomical outcomes were reviewed. The main outcome measures were fibrovascular tissue and TRD regression and final macular status.

Results:

Mean gestational age and birth weight were 28.5 ± 1.2 weeks and 1,167 ± 185 g, respectively. Thirteen eyes had zone I disease and 2 eyes had zone II disease. Thirteen eyes were stage 4A and 2 eyes were stage 4B ROP. The morphology was aggressive posterior ROP in 10 eyes. The mean PCA at surgery was 37.8 ± 2.3 weeks. Lensectomy was also performed in 2 eyes. Rapid fibrovascular tissue regression was seen in 14 eyes within 2 weeks, followed by TRD regression and macular vascularization, although 2 eyes had macular pucker formation. Persistent vitreous bleeding was present in 1 eye, which needed lavage, and eventually the TRD regressed. Disease reactivation was noted in 1 eye at 5 weeks and was managed with repeat intravitreal anti-VEGF injection.

Conclusions:

Anti-VEGF treatment combined with vitrectomy leads to rapid disease regression in advanced stage 4 ROP with extensive neovascular proliferation.

[J Pediatr Ophthalmol Strabismus. 2020;57(1):61–66.]

Introduction

Vitrectomy with or without lensectomy is the standard of care for advanced stages of retinopathy of prematurity (ROP).1–4 Success rates of 92% to 100% regarding anatomical (attachment of retina) outcomes have been reported with vitrectomy in stage 4A disease.1–3 The presentation of stage 4 ROP can vary, ranging from minimal to extensive retinal traction and from very vascular to predominantly fibrotic cases.1,2 Very vascular surgical cases have a high risk of intraoperative and postoperative preretinal or vitreous cavity bleeding from friable neovascular tissue.5,6 The hemorrhage may act as a scaffold under which the traction may worsen later to inoperable stage 5 disease or may persist and pose a risk of dense amblyopia if not removed in time. The intraoperative maneuverability is also limited when the disease is highly vascular and fibrotic tissue is less.

Preoperative injection of intravitreal anti-vascular endothelial growth factor (VEGF) has definite benefits in vitrectomy for stage 4 ROP.2,5,7,8 It neutralizes the VEGF in the vitreous cavity and leads to regression of the retinal neovascularization and tunica vasculosa lentis. Consequent to this, a good pupillary dilatation is achieved at the time of surgery, which improves the surgical visibility. It also reduces the bleeding intraoperatively and postoperatively from fibrovascular tissues, and the dissection/segmentation of the circumferential fibrovascular tissue becomes easier. However, the tractional component may start to worsen once the action of anti-VEGF agents sets in.8–10

Advanced stage 4 ROP cases require urgent vitrectomy to prevent worsening to stage 5 disease.3,4 In rapidly progressive cases, it may not be prudent to first treat with intravitreal anti-VEGF agents and wait for a few days for the anti-VEGF response. Also, the duration of action of the anti-VEGF may be limited postoperatively because it may be partially washed out after vitrectomy and thus may not be helpful in preventing early postoperative bleeding from residual fibrovascular tissue.

Combined treatment (vitrectomy and anti-VEGF injection at the end of the procedure rather than sequential treatment [anti-VEGF followed by vitrectomy]) may overcome these concerns. The literature on combined simultaneous treatment is limited.2,5 This study aimed to determine the efficacy of combined vitrectomy and anti-VEGF injection for advanced stage 4 ROP with extensive neovascular proliferation.

Patients and Methods

Baseline Characteristics

A retrospective study reviewed 15 eyes (9 infants) with advanced stage 4 ROP with extensive neovascular proliferation that underwent vitrectomy combined with intravitreal anti-VEGF therapy at our tertiary care center from August 2017 to July 2018. The study adhered to the tenets of the Declaration of Helsinki and the institutional research guidelines.

The baseline evaluation included the acquisition of demographic details, birth history, neonatal history, systemic status, ROP screening, and preoperative treatment details. The ocular examination included anterior and posterior segment evaluation. Preoperative tractional retinal detachment (TRD) details (extent, location, and height), the presence of “plus” disease, and the status of optic disc and macula were studied. Retinal images were recorded using Retcam 3 (Clarity Medical Systems, Pleasanton, CA). The disease was classified into “zone I” or “zone II” based on the International Classification of Retinopathy of Prematurity.11 The presence of aggressive posterior ROP (APROP) was determined by previous documentation of the disease before development of TRD.

TRD was classified as “low” if it reached to the mid-vitreous cavity and “high” if it reached beyond to the retrolental space. If performed before surgery, laser photocoagulation in zone I disease was done anteriorly, sparing the posterior zone II area to allow for subsequent vascular regrowth.

Surgical Technique

If the TRD was limited to the posterior or mid vitreous (ie, low with no retinal lens apposition) and there was enough space to enter into the retrolental space, 25-gauge lens-sparing vitrectomy was performed; otherwise 25-gauge lensectomy with vitrectomy was performed. All infants underwent vitrectomy performed by a single surgeon (PC) under general anesthesia after informed consent was obtained. All infants with bilateral stage 4 ROP requiring surgery were operated on in a single anesthesia session.

Lens-sparing vitrectomy involved insertion of three 25-gauge ports at a distance of 1.5 to 1.75 mm from the limbus. Core vitrectomy was performed. Anterior vitreous traction over the TRD and circumferential traction were released. Laser photocoagulation was performed if not done previously, sparing the zone II posterior area as described above. Bleeders were cauterized using diathermy. Partial fluid–air exchange until the height of released TRD was done in all cases to allow sutureless closure later. Half of the adult dose of bevacizumab (0.625 mg) or ranibizumab (0.25 mg) was injected intravitreally using a soft tip needle into the remnant fluid at the completion of surgery. The type of drug used depended on the financial situation of the parents. Sutureless closure of port sites was then performed unless definite wound leakage necessitated closure with 8-0 polyglactin sutures.

Follow-up Assessment

All patients were followed up postoperatively at 1, 4, and 8 weeks and then monthly to a minimum of 65 weeks' postconceptional age (PCA). The primary outcome was the regression of the neovascular tissue and TRD. Re-treatment was performed when needed. The outcome was favorable if the disease regressed and the posterior pole/macula was attached at the final follow-up visit.

Data were entered into an Excel sheet and analyzed using STATA SE 12.1 software (StataCorp, College Station, TX). For descriptive purposes, non-parametric data were expressed as median (range), parametric qualitative data as a percentage, and quantitative data as mean ± standard deviation.

Results

The study included 9 infants (6 bilateral and 3 unilateral) with advanced stage 4 ROP and extensive neovascular proliferation referred to our center for treatment. Seven were female and two were male. The mean gestational age was 28.5 ± 1.2 weeks (range: 26 to 30 weeks). The mean birth weight was 1,167 ± 185 g (range: 850 to 1,400 g). The characteristics of all cases are listed in Table 1. Twelve eyes (80%) received laser treatment preoperatively (at a mean PCA of 36.6 ± 2.5 weeks).

Baseline Characteristics and Treatment Outcomes in Stage 4 ROP Cases With Extensive Neovascular Proliferation

Table 1:

Baseline Characteristics and Treatment Outcomes in Stage 4 ROP Cases With Extensive Neovascular Proliferation

The location of TRD at the time of surgical intervention was zone I in 13 eyes (86.7%) and zone II in 2 eyes (13.3%). The morphology of ROP was APROP in 10 eyes (66.7%). In 4 eyes (40%) with APROP, the extent of retinal vascularization was minimal with severe fibrovascular proliferation on disc and absence of macular vascularization.

The indication for surgery included stage 4A (13 eyes, 86.7%) and 4B (2 eyes, 13.3%) ROP. Severe plus disease was present in all eyes. The extent of TRD was 270 degrees in 11 eyes (73.3%) (sparing the temporal quadrant in 9 eyes; sparing the nasal quadrant in 2 eyes), 180 degrees in 2 eyes (13.3%) (superotemporal and superior plus inferior in 1 eye each), and central and annular in 1 eye (6.7%) each. The height of traction was low in 6 eyes (40%) and high in 9 eyes (60%). Preretinal hemorrhage at the area of TRD was present in 6 eyes (40%).

The mean PCA at the time of surgery was 37.8 ± 2.3 weeks (range: 34 to 42 weeks). Lens-sparing vitrectomy was performed in 13 eyes (86.7%) and lensectomy with vitrectomy was performed in 2 eyes (13.3%) due to high traction just behind the lens. Additionally, endolaser photocoagulation was performed in 8 eyes (53.3%). Bevacizumab and ranibizumab were injected after the fluid–air exchange in 12 (80%) and 3 (20%) eyes, respectively.

The last follow-up was done at 65 weeks' PCA. The mean time to last follow-up from surgery was 27.20 ± 2.36 weeks (range: 23 to 31 weeks). The fibrovascular tissue regressed within 2 weeks in 14 eyes (93.3%). Five eyes (33.3%) had preretinal or vitreous cavity bleeding, which resolved spontaneously in 4 eyes. In the left eye of case 1, the bleeding was dense enough to hamper the retinal visualization and did not resolve spontaneously, for which vitreous lavage and endolaser augmentation was performed at 42 weeks' PCA. Reactivation of fibrovascular tissue was noted in 1 eye (case 2) 5 weeks after surgery (39 weeks' PCA) near the junction of vascular and avascular lasered retina, for which repeat intravitreal ranibizumab injection and laser augmentation was performed. The fellow eye of this case, which was initially treated only with intravit-real ranibizumab injection, also had a recurrence noted at the same time and had to be re-treated with a combination of ranibizumab injection and laser.

The TRD regressed in all eyes. One eye had prepapillary contraction after regression of central TRD (case 8). The macula was vascularized in all eyes. Two eyes had macular pucker, and 1 eye had epimacular membrane. The retina was vascularized until zone II in 13 eyes (86.7%) and did not progress beyond zone I in 2 eyes (13.3%). None of the eyes developed ocular complications (eg, cataract, secondary glaucoma, or disc pallor) or systemic adverse effects until the last follow-up.

Discussion

Vitrectomy is the preferred treatment for advanced stage 4 ROP. The anatomical success depends on the stage of detachment (4A or 4B).1,4 The reported results of lens-sparing vitrectomy in stage 4A ROP are excellent.1–4 Most of these studies report a success rate of greater than 90% for vitrectomy in stage 4A disease.1,2,4

However, cases with extensive vascular proliferation do not behave the same regarding anatomical outcomes.12,13 These cases are often a result of late presentation or severe disease activity. There exists a risk of intraoperative and immediate postoperative vitreous hemorrhage or preretinal hemorrhage, recurrence of fibrovascular tissue, and failure of retinal reattachment.12,13 Harnett12 reported the presence of vitreous haze, extensive neovascularization, and plus disease to be associated with poor surgical outcome (ie, failure of retinal reattachment in stage 4 ROP). Choi et al.13 reported an overall success rate (defined as posterior pole attachment at last follow-up visit, mean follow-up: 4.6 years) of 27% with lens-sparing vitrectomy for rapidly progressive stage 4 ROP cases with plus disease. Immediate postoperative bleeding was present in 75% of the cases.13

The results of lens-sparing vitrectomy alone are dismal in APROP cases.6,14,15 Such cases have greater avascular retina and extensive fibrovascular proliferation close to the macula (either zone I or zone II posterior). There exists a risk of recurrence of fibro-vascular tissue, rebleeding, and failure of retinal reattachment in such cases.6,16 Yokoi et al.16 reported an 18% recurrence rate after early vitrectomy in cases of APROP with stage 4A or 4B disease, of which only 33% achieved final retinal reattachment. Azuma et al.6 reported a 100% rate of vitreous cavity rebleeding after early lensectomy with vitrectomy for APROP cases with stage 4A or 4B, which resolved mostly in 2 to 3 weeks. The friable neovascular tissue bleeds in the postoperative period. The preretinal or vitreous hemorrhage might act as a source of fibrotic growth factors, which worsens the contraction of residual cortical vitreous and leads to failure of retinal reattachment. Recurrence of TRD might occur due to reproliferation of fibrovascular tissue or contraction of persistent vitreous membranes. There exists a difference of opinion on the need for lensectomy in cases of APROP. Although some believe that lens-sparing vitrectomy provides an insufficient removal of vitreous gel in the periphery and leads to progression of proliferation and recurrence,6,14,15 others believe that because the traction in cases of APROP is posterior to the equator, lens removal may not be required unless the traction is retrolental.13

The adjunctive role of anti-VEGF treatment in vitrectomy for severe vascularly active ROP cases has been studied previously.2,5,7,8 Kychenthal and Dorta7 reported short-term safety and efficacy of intravitreal bevacizumab injection (0.625 mg) 1 week prior to vitrectomy (lens-sparing vitrectomy/lensectomy with vitrectomy) in cases of vascularly active stage 4A or 4B ROP occurring despite laser treatment in 11 eyes of 8 infants. Only 1 eye had persistent vitreous cavity bleeding, which required re-treatment and had a favorable final outcome. Preoperative anti-VEGF treatment reduces the vascular component, makes segmentation of tissues easier, and decreases the chance of intraoperative and early postoperative vitreous bleeding.7 Vitrectomy may also be avoided in certain cases, where the fibrovascular tissue regresses significantly after the anti-VEGF treatment and the TRD resolves.

However, preoperative anti-VEGF treatment may have certain disadvantages. The involution of vascular tissue and increase in fibrosis following pre-operative anti-VEGF injection remains a concern.5,8,9 Kusaka et al.5 did a retrospective study on the efficacy of intravitreal bevacizumab (0.5 mg) for vascularly active severe ROP cases, wherein the injection was given either as a primary treatment (5 to 12 days prior to vitrectomy) or at the end of vitrectomy. Three of 12 eyes (25%) that belonged to the first group had worsening of TRD after injection. Eleven of 12 eyes in the first group and all 7 eyes in the second group achieved retinal reattachment with a single surgery. Following anti-VEGF injection, the vascular component of fibrovascular tissue regresses acutely as a response to the decrease in the intravitreal VEGF activity. The complex interplay of VEGF and other fibrotic growth factors (transforming growth factor and connective tissue growth factor) becomes unbalanced and accelerated fibrosis and contraction of the hyaloid occurs.9 This can increase the traction forces acutely and may worsen the TRD. Moreover, there exists a risk of iatrogenic needle injury to the lens if the anti-VEGF is injected under topical anesthesia in an infant.

The combined approach may have certain advantages compared to the sequential one (injection followed by vitrectomy after 1 to 2 weeks). The injection can be given easily through the existing 25-gauge ports at the end of surgery under general anesthesia with no risk of lens-related iatrogenic injury. There is a lesser risk of acute fibrosis and hyaloidal contraction with this approach. Because much of the vitreous is removed and the traction is relieved during the surgery, there is barely any scaffold left for postoperative contraction. With the combined approach, one need not wait after intravitreal injection for a few days to a week to attain a vascularly quiet retina before vitrectomy. Early intervention is essential in such progressive ROP cases, and the prognosis becomes dismal with a delay. More important, the anti-VEGF may have lasting effects, unlike preoperative injection, which gets washed out during vitrectomy and may not have a long-lasting effect. With combined treatment, the anti-VEGF agent remains within the vitreous cavity, which may facilitate faster regression of the fibrovascular proliferation and resolution of residual bleeding, and prevent reproliferation of the fibrovascular tissue.

We achieved a 100% attachment rate in stage 4 ROP cases with extensive neovascular proliferation with combined vitrectomy and anti-VEGF injection at the end of surgery (combined approach). Five eyes (total 33.3%) had vitreous cavity bleeding and only one of these required lavage. This is in marked contrast to the previous studies, which reported vitreous cavity bleeding in 75% to 100% of vascularly active stage 4 ROP cases following vitrectomy alone.6,13 The combined treatment was safe because no cases developed cataract and secondary glaucoma until the last follow-up. Recurrence of the disease was seen in only one eye, which had received ranibizumab injection during surgery, and this decreased recurrence may be attributed to better clearance/suppression of proliferative factors with the combined approach. Recurrences with ranibizumab therapy are known to occur more commonly and for a shorter duration compared to bevacizumab therapy due to its shorter half-life in the vitreous cavity.17,18 Once the transient effect of anti-VEGF agent wanes, VEGF secretion and release into the vitreous cavity in eyes with APROP may continue. This may later lead to unpredictable recurrence of TRD or disease in such eyes and long-term follow-up is recommended for its timely detection and management.

Although a statistical analysis could not be performed due to a small number of eyes, the outcomes did not vary with the morphology of the disease at the time of surgery (APROP vs classic ROP). This was perhaps due to the neutralizing effect of the anti-VEGF treatment and adequate laser photocoagulation in both of these groups. One-quarter of the infants (4 eyes of 2 infants) had small zone I APROP disease with severe fibrovascular proliferation at the optic disc. Yokoi et al.19 recently described this atypical type of ROP in 6 eyes of 4 extremely preterm infants (gestational age: 24 to 25 weeks in 3 infants and 33 weeks in 1 infant; birth weight = 500 to 1,000 g). These cases develop despite timely screening and often have partial to total detachment. The fibrovascular growth in such cases is often directly from the area of the disc. With lensectomy with vitrectomy alone, Yokoi et al.19 reported retinal re-attachment in 3 of 5 eyes (60%). In contrast, with the combined treatment we achieved retinal reattachment in all 4 eyes (100%) with vascularization developing until zone I and II in 2 eyes each. Such atypical cases seen in our series were a little older and less premature (gestational age of 28 weeks and birth weight of 850 g in one case and 1,400 g in another) than the series of Yokoi et al.19 This is possible because in the Indian setting, APROP itself often occurs in larger and heavier preterm infants.20,21

The combined approach has its own limitations. If the visibility is reduced due to the presence of prominent tunica vasculosa lentis and limited pupillary dilation, the combined approach is not suitable and preoperative anti-VEGF injections might be a better option. Because these cases have extensive neovascular proliferation, surgeons have difficulty intraoperatively, particularly in the segmentation of vitreous bands/membranes and management of bleeding. Extreme manipulation of the fibrovascular tissue should be avoided. The bleeding from the fibrovascular tissues can be stopped with judicious use of diathermy after lowering the intraocular pressure transiently to identify bleeders.

The current study had certain limitations. It was a retrospective evaluation of a small cohort of eyes without a matched control group undergoing vitrectomy alone, and the safety and efficacy of treatment needs to be determined in the long term. Although a good anatomical outcome was achieved in most of the cases, the visual outcomes and macular vascularization by angiography were not evaluated. We aimed to control the high vitreal VEGF levels by using anti-VEGF therapy. However, several eyes had additional laser treatment at the time of vitrectomy and the vitrectomy itself reduces the VEGF. These factors may have confounded the results. Notably, the pharmacokinetics of the anti-VEGF in vitrectomized eyes of preterm infants is not known. Although half the amount of the adult dosage was used in the current study, the safe yet adequate dose and the ocular or systemic side effects of anti-VEGF in vitrectomized eyes still need to be evaluated. Larger prospective randomized controlled studies with different drug doses will be useful to compare combined and sequential approaches to treatment.

This study highlights the use of combining anti-VEGF treatment with vitrectomy for stage 4 ROP disease with extensive vascular proliferation to achieve favorable postoperative outcomes in these challenging cases.

References

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Baseline Characteristics and Treatment Outcomes in Stage 4 ROP Cases With Extensive Neovascular Proliferation

CaseGA (wks)BW (g)SexEyePrevious TreatmentPCA Surgery (wk+days)Disease CharacteristicsMacular VascularizationSurgeryComplication on F/URe-intervention (PCA, wk)Vascularization and TRD Status at Final F/U
128850FODLaser37+2Zone I APROP, stage 4A, PRHAbsentLSV, BCZZone II posterior regressed
OSLaser37+2Zone I APROP, stage 4A, PRHAbsentLSV, BCZVHLavage, laser (42)Zone II posterior regressed, ERM
2291,300FODLaser34Zone I APROP, stage 4A, PRHPresentLSV, RBZReactivation, 39 wkRBZ, laser (39)Zone II posterior regressed
3291,100MOSLaser36+3Zone 1, stage 4BPresentLSV, BCZZone II posterior regressed, macular pucker
4291,250FODLaser35Zone I APROP, stage 4APresentLSV, BCZZone II posterior regressed
OSLaser35Zone I APROP, stage 4APresentLSV, BCZZone II posterior regressed
5301,200FOD39Zone I APROP, stage 4APresentLSV, BCZPRHZone II regressed
OS39Zone I APROP, stage 4BPresentLSV, BCZPRHZone II regressed, macular pucker
6301,200FOS39Zone I APROP, stage 4A, PRHPresentLSV, BCZZone II posterior regressed
7281,300FODLaser37Zone II, stage 4APresentLSV, BCZPRHZone II regressed
OSLaser37Zone II, stage 4APresentLSV, BCZPRHZone II regressed
8281,400MODLaser39+1Zone I APROP, stage 4A, PRHAbsentLV, BCZZone I regressed
OSLaser39+1Zone I APROP, stage 4A, PRHAbsentLV, BCZZone I, central low TRD
926900FODLaser42+1Zone I, stage 4APresentLSV, RBZZone II posterior regressed
OSLaser42+1Zone I, stage 4APresentLSV, RBZZone II posterior regressed
Authors

From Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.

The authors have no financial or proprietary interest in the materials presented herein.

Correspondence: Parijat Chandra, MD, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Room No. 373, Third Floor, New Delhi 110029, India. E-mail: parijatchandra@gmail.com

Received: July 29, 2019
Accepted: October 03, 2019

10.3928/01913913-20191030-01

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