Dr. Prema K.V. Subramaniam, P14794, Dr. Saravanan V R, Dr. Narendran V, Dr. Parag K Shah
NO CONTRACTURE OF FLAT FIBROVASCULAR PROLIFERATION POST ANTI-VEGF IN SEVERE POSTERIOR ROP
ABSTRACT
PURPOSE
To find the effectiveness of anti-vascular endothelial growth factor (VEGF) in the treatment of severe posterior ROP (zone 1 and posterior zone 2)with flat fibrovascular proliferation (FVP) with no clinical evidence of anterio-posterior traction
METHOD
It’s a retrospective study involving 15 pre-term babies with FVP involving more than 4 clock hours in zone 1 or posterior zone 2 with plus disease. All babies received anti-VEGF (either 0.625 mg of bevacizumab or 0.2mg of ranibizumab) under aseptic precaution. Pre and post injection Retcamimages were taken.Structural outcome measured in terms of absence of FVP’s and tractional retinal detachments at1month post injection and secondary outcome in terms of duration of recurrence or full maturity from time of injection.Adverse outcome in terms of babies developing either stage 4a/4b or stage 5 ROP
RESULTS
30 eyes of 15 preterm babies included in the study. Mean gestational age being 30.066 weeks (range27-36 weeks), mean birth weight was 1331.33 g range(650-1980 g) and mean post conceptional age at presentation was 35.4 weeks(range 31-41 weeks). In 73.33% regression of plus disease and flat FVP’s occurred within a month of anti-VEGF injection. In 1 case (6.66%) each additional anti-VEGF orperipheral pan-retinal photocoagulation was required. Vessels reached maturity in range of 4 months-1year post injection in 60%
CONCLUSION
Anti-VEGF is highly effective in regression of flat FVP’s and relieving the tangential traction caused by them with no contracture,in zone 1 and posterior zone 2 disease.
INTRODUCTION
Retinopathy of Prematurity(ROP) is a proliferative disorder affecting the retina of preterm infants.The disease was first described by Terry in 1942,who designated it as Retrolental Fibroplasia.1 Since then various theories have been put forth to explain the pathogenesis of ROP, vascular endothelial growth factor(VEGF) playing a significant role is well known.2 Recent concept to curtail VEGF load by anti-VEGF injections is of particular interest and shifts the treatment of ROP from conventional laser to anti-VEGF.Various trials have been put forth to compare laser therapy and anti-VEGF.3-5BEAT- ROP is the only randomized controlled study to compare anti-VEGF and laser therapy in treatment of severe type 1 ROP.3This study showed bevacizumab effective over laser in treatment of zone 1 ROP but no significant favourable outcome with zone 2 ROP.It is well known that anti-VEGF injections cause contracture or worsening of pre-existing fibro vascular proliferations (FVP) in various diseases.6,7The current study aims to show the effectiveness of anti-VEGF in severe type 1 ROP with more than 4 clock hours of flat fibrovascular proliferation in zone 1 and posterior zone 2 in terms of structural outcome.
MATERIALS AND METHODS
This is a retrospective study. Medical records of patients who presented with severe posterior ROP with FVPin zone1 and posterior zone 2 from December 2015 to December 2016 to paediatric retina department were analysed. Ethics committee approval of the hospital was obtained.All babies with severe type 1 ROP as defined by ETROP guidelines8with more than 4 clock hours of flat fibrovascular proliferation who were treated with anti-VEGF were included.Retcamimages were taken pre and post injection.
Informed written consent was obtained from the parents prior to anti-VEGF therapy. Pro’s and con’s of anti-VEGF and laser therapy was explained in detail. Off-label use of anti-VEGF,lack of data regarding the systemic safety of the drug,long term follow up post injection and need of examination under anaesthesia was explained. 0.625mg of bevacizumab or 0.2mg of ranibizumab was given under aseptic precaution in operation theatre under topical anaesthesia using 30 gauge needle about 1.5mm from limbus.Zone of the disease and stage of the disease was defined as per ICROP guidelines.9Two ophthalmologist reviewed fundus images pre and post injection.
Data on baseline characteristics like gestational age,birth weight,post conceptional age at treatment,date of injection were collected.
All babies were treated on the same day or within 2 days of presentation. Patients were followed up 1 week,2 week post injection and then as per disease activity. Primary outcome is measured in terms of regression of plus disease absence of fibrovascular proliferation within a month of injection. Secondary outcome is measured in terms of duration of reactivation of disease orvessels reaching maturity from the time of injection.
RESULTS
30 eyes of 15 infants were included in the study. The clinical characteristics of premature infants treated is shown in Table 1. The classification of ROP in babies presented is shown in Table 2. One of 15 patient (6.66%) had extensive neovascularisation of iris. Twelve patients(80%) received intravitreal bevacizumab(0.625mg) and 3 patients(20%) received intravitreal ranibizumab(0.2mg). In 11 of 15 patients(73.33%)there was regression of plus disease and absence of flat fibrovascular proliferation within a month of injection. In 4 of 15 patients(26.67%) regression of fibrovascular proliferation occurred within 3 months post injection. In 2 patients(13.33%) there was vitreous hemorrhage within a week post injection which showed regression within a month. The neovascularisation of iris regressed within week of injection.
In 2 of 15 (13.33%) patient vessels reached maturity within 4 months post injection, in 3 of 15 (20%) within 6 months post injection, in 4 of 15(26.66%) within a year of injection. Additional anti-VEGF was required in 1 of 15 patient (6.66%) which was repeated at one and half month after initial injection. In 1 of 15 patient(6.66%)laser was required and was done 3 month after initial injection. In 4 of 15 (26.66%)patients there is no recurrence of ROP and babies are under follow with immature vessels in anterior zone 2
Discussion
Our study showed anti-VEGF is highly effective in reliving the tangential traction caused by flat fibrovascular proliferation in severe posterior ROP,and there was no contracture of FVP’s leading to stage 4/5 ROP. BEAT-ROP showed superiority of bevacizumab over laser therapy in treatment of type 1 ROP in zone 1disease but no significant favourable outcome in zone 2 disease.3 The concern of contracture of fibrovascular proliferation post anti-vegf gives a dilemma in treating zone 1 and posterior zone 2 disease with extensive fibrovascular proliferation with anti-VEGF. Our study included babies with significant (>4 clock hours) of fibrovascular proliferations and treated them with anti-VEGF,there was no contracture of FVP’s,and no babies worsened to stage 4a/4b. Rather in 73.33% there was disappearance of FVP’s within a month of injection,earliest being within a week.All babies in our study had no clinical evidence of antero-posterior traction unlike the results of Honda.S,Hirabayashi H et al,inGraefes Arch clin.Exp.ophthalmol 2008,were avastin given to baby with stage 4a resulted in acute contracture of proliferative membrane resulting in worsening of the disease.7 A similar study in Taiwan were avastin given in eyes with stage 4a showed worsening of disease.10Adjuvant effect of intravitreal avastin prior to vitrectomy is shown by many studies were vascularity reduced despite of contracture of proliferative membrane and early timing for surgery.11,12To our knowledge this is the only study which talks about anti-VEGF use in the presence of FVP’s.
To understand the reason why there is no contracture unlike in other proliferative disorder we look at the phases of evolution and progression of ROP.Phase 1- vaso-obliterativephase,the period of downregulation of VEGF due to hyperoxia leading to occlusion of developed vasculature when severe leading to irreversible damage.Phase 2-vaso- proliferative phase,child is out of oxygen theraphy,developing retinal demand for oxygen ,all factors induce severe hypoxia and upregulation of VEGF.This lead to decrease in apoptosis of hyaloid vasculature,disrupt normal vascular development,formation of pre and/subretinalneovascularisation,resulting in stage 3 rop/stage 4 effusive retinal detachment. Phase 3- Tractional retinal detachment phase,increased VEGF leads to increased intravitreal neovascularisation,decreasedapoptosis,activates plasminogen activators,convert plasminogen to plasmin which activates transforming growth factor beta1which downregulate VEGF and promote fibrosis leading to excessive scarring stage 4 and 5 ROP. Phase 4- cicatricial stage,fetal wound healing contributing to tractional detachment.(stage 5 ROP).13
If the child presents in the vaso-proliferative phase (Phase-2),usually in PMA <38 wks with stage 3 ROP,vascular component predominates fibrosis and when treated with anti- VEGF no contracture occurs rather new vessels shrink and disappear,as the VEGF load is curtailed and no activation of TGF β1, no cicatrisation occur. Rather if child present in phase 3 (tractional retinal detachment phase)with severe stage 3/4a usually with PMA >40 wks or if VEGF load is not curtailed in phase 2 and persistently high,TGF β1is activated and fibrosis predominates and contracture and progression of disease to stage 4b/5 occur.
Like BEAT-ROP trial3 and other studies4,5,14&15our study shows the effectiveness of anti-VEGF in the treatment of type 1 ROP the difference being its use in the presence of extensive FVP’s and favourable outcome in posterior zone 2 disease similar beneficial effect in zone 2 disease is shown in another study14
The present study also shows the extended period of follow up required for babies following anti-VEGF treatment for ROP andranged from 4 months to >1 year. This similar need of prolonged follow up is shown by the retrospective study fromCanada,which compared anti-VEGF with laser treatment and showed significant follow up visits of 16 vs 6 visits post avastin and laser respectively and was the first to show the follow up schedule post avastin for ROP4.The rate of recurrence in our study was 3 of 30 eyes(10%) compared to 6% in BEAT-ROP study3,12% in retrospective multicentre case series from Taiwan5and 0% in retrospective study from Canada.4 The late recurrence of the disease post anti-VEGF is of concern and shown by many previous studies16-21. The mean time of recurrence being 9wks in our study compared to 16 wks in BEAT-ROP trial.3
In our study systemic concentration of anti-VEGF,post injection was not looked for,rather no babies in our study developed any systemic complication,no mortality in our study compared to 7 babies in BEAT-ROP of which 5 where post avastin babies3,in our study 3 babies receivedranibizumab and 12 babies received bevacizumab,the difference of drug used was based on affordability of parents for the same. Systemic effect of the drugs and efficacy of drugs were not compared.
The functional outcome in term of refractive error assessment,was not done in our study,to support or debate results of BEAT ROP3and other studies4,5,8which showed increased incidence of myopia following laser therapy compared to anti-VEGF injection. As perETROP results prevalence of myopia and high myopia is attributed to stage of disease,zone and presence or absence of plus disease8.
The study drawback beingsmall sample size,retrospective nature,systemic concentration of drug are not considered , no even distribution of zone1 and 2 disease,in 26.66% vessels have not reached maturity and required prolong follow up.
CONCLUSION
Anti-VEGF is highly effective and replacing Laser therapy the gold standard treatment of ROP. Our study showed the additional benefit of the drug in treating flatfibrovascular proliferation in zone 1 and posterior zone 2 disease
REFERENCES
1.Lee C Thomas,Chiang F Michael, Paediatric retinal disease,RETINA- Ryan;section-II;chapter 61.page 1108.
2.Ruwan A ;Silva and Darius M Moshfeghi .Anti-VEGF treatment in Retinopathy of prematurity.In ,Mary Elizabeth Hartnett.PaediatricRetina;Section VII ,Chapter 39 ,2nded.page 513-4
3.Mintz- Hittner HA, Kennedy KA,ChuangAZ.Efficacy of intravitreal bevacizumab for stage 3 rop;N Engl.J.med 2011;364;603-615.
4.Maram ssac,KamiarMireskendari,NasrinTehrani,Treatment of type 1 retinopathy of prematuritywith bevacizumab versus laser,JAAPOS;April 2015;140-44.
5.Wu WC;Kuo HK; YehPT;Yang CM et al,An updated study of use of bevacizumab in the treatment of patients with pre-threshold Retinopathy of prematurity in Taiwan .Am J Ophthalmol 2013;155;150-158
6.ArevaloJF,Maia M, Flynn HW Jr,Tractional retinal detachment following intravitreal bevacizumab in patients with severe proliferative diabetic retinopathy. Br JOphthalmol 2008 feb;92(2):213-6.
7.Honda.S,Hirabayashi H; TsukaharaY,NegiA.Acute contracture of the proliferative membrane after intravitreal injection of bevacizuma for advanced ROP. Graefes Arch Clin.Exp.Ophthalmol.2008;jul;246(7);1061-3.
8.Revised indication for the treatment of ROP:results of early treatmentfor ROP randomized trial,ArchOphthalmol 2003;121:1684-94
9.. International Classification of ROP revisited,Archophthalmol 2005;123;991-9
10.Kycenthal.A;DortaP.Vitrectomy after intravitreal bevacizumab for retinal detachment in rop RETINA 2010 Apr;30(4 suppl);S 32-6
11.Sun HJ,ChoiK.S,Lee SJ, adjunctive effect of intravitreal bevacizumab prior to lens sparing vitrectomy In APROP; a case report,Jpn J Ophthalmol.2012 Sep; 56(5):476-80
12.Xu J.ZhangQ,KangX;LiJ,ChanY,ZhanP,Early Vitreoretinal surgery on vascularly active stage 4 ROP through the preoperative intravitreal bevacizumab injection ,Acta Ophthalmol.2013 Jun;91(4):e 304-10
13.Antonio Capone,Jr ,Michael T.Trese,Evolution of stage 4 retinopathy of prematurity,Paediatric Retina,2nd edition ,chapter 44,pg no 569-71.
14.MoshfeghiDm;Bellocal Am, Rop In The Time Of Bevacizumab;Incorporating BEAT-ROP results in clinical practice. Ophthalmology 2011;118;1227-8
15.AutrataR,SenkovaK,HoleusovaM,Krejcirova I et al
Effect of Intravitreal Pegatinib or Bevacizumab and laser in treatment of threshold rop in zone 1 and posterior zone 2 disease 4 year review Caeikslou.oftalmol 2012 feb;68(1) 29-36.
16.Huj;BlairMp;ShapinoMj;LichensteinSj;GalassoSm;Kapur.RReactivation of retinopathy ROP after bevacizumab jection Arch ophthalmol-2012;130;1000-1006.
17.MireskandariK,AdamsGG,TehraniNN.Recurrence of retinopathy of prematurity following bevacizumab monotherapy:is it only the tip of iceberg?JAMA Ophthalmol 2013;131:544-5
18.Sukgen EA; KoulokY,The Vascularization process after intravitreal Ranibizumab injection for APROP. Arq Bros Oftalmol 2017 Jan- feb;80(1): 30-34
19.HajrasoulibaAR,Gascia- Gonzalez JM, Shapira MJ et al, reactivation of retinopathy of prematurity 3 years after treatment with bevacizumab Ophthalmic Surg Laser Imaging Retina : 2017 Mar 1;48(3)255-259.
20.Snyder LL,Gascia- Gonzalez JM, Shapira MJ et al, very late reactivation of rop after monotherapy with intravitreal bevacizumab. Ophthalmic Surg Laser Imaging Retina: 2016 Mar;47(3):280-3
21.Lee Jy;ChaeJb,Yang SJ et al, Effect of intravitreal bevacizumab and laser in rop therapy on the development of peripheral retinal vessels. Graefes Arch Clin.ExpOphthalmol :2010 Sep;248(9):1257-62.
Tables
Table 1: Demographic and clinical characteristics of premature infant treated with anti- VEGF
| Mean gestational age | 30.066 wks |
| Mean birth weight | 1331.33gms |
| Mean post conceptional age at presentation | 35.4 wks |
| Mean post conceptional age at treatment | 35.4 wks |
| % of patients with regression of fvp |
73.33% |
Table-2
Stage of ROP of premature babies treated with intravitreal anti-vegf
| ROP Stage | Eyes (%) |
| Zone 1 APROP | 10 (66.66%) |
| Zone 1 stage 3 ROP | 1 (6.66%) |
| Zone 2 posterior APROP | 3 (20%) |
| Zone 2 stage 3 ROP | 1 (6.66%) |
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