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Safety of 6000 intravitreal dexamethasone implants
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  1. Bindu Rajesh1,
  2. Javier Zarranz-Ventura2,
  3. Adrian T Fung3,4,
  4. Catharina Busch5,
  5. Niroj Kumar Sahoo6,
  6. Patricio J Rodriguez-Valdes7,
  7. Valentina Sarao8,
  8. Sanjay Kumar Mishra9,
  9. A Osman Saatci10,
  10. Patricia Udaondo Mirete11,
  11. Giuseppe Querques12,
  12. Michel Eid Farah13,
  13. Paolo Lanzetta14,
  14. J Fernando Arevalo15,
  15. Laurent Kodjikian16,17,
  16. Jay Chhablani6
  17. for International Ozurdex Study Group
    1. 1 Khoo Teck Puat Hospital, Singapore, Singapore
    2. 2 Hospital Clínic de Barcelona Insi, Instituto Clinic de Barcelona, Instituto Clinic de Oftalmología (ICOF), Barcelona, Spain
    3. 3 Department of Ophthalmology, Westmead Hospital, Sydney, Australian Capital Territory, Australia
    4. 4 Save Sight Institute, Sydney Eye Hospital, University of Sydney, Sydney, New South Wales, Australia
    5. 5 Department of Ophthalmology, Universitatsklinikum Leipzig, Leipzig, Germany
    6. 6 Vitreo-retina, L V Prasad Eye Institute, Hyderabad, Andhra Pradesh, India
    7. 7 Ophthalmology, Instituto de Oftalmología y Ciencias Visuales, Escuela de Medicina, Tecnológico de Monterrey, San Pedro Garza García, Mexico
    8. 8 Department of Medicine-Ophthalmology, University of Udine, Udine, Italy
    9. 9 11 Department of Ophthalmology, Command Hospital, Lucknow, India
    10. 10 Dokuz Eylul University, Izmir, Turkey
    11. 11 13 Ophthalmology Department, Hospital Universitario La Fe, Valencia, Spain
    12. 12 Ophthalmology, Ospedale San Raffaele, Milano, Italy
    13. 13 Ophthalmology, Federal University of Sao Paulo, Sao Paulo, Brazil
    14. 14 University of Udine, Udine, Italy
    15. 15 Retina and Vitreous, Clinica Oftalmologica Centro Caracas, Caracas, Venezuela
    16. 16 Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon, Lyon, France
    17. 17 CNRS UMR 5510 Mateis, University of Lyon, Lyon, France
    1. Correspondence to Dr Jay Chhablani, Vitreo-retina, L V Prasad Eye Institute, Hyderabad, AP 500034, India; jay.chhablani{at}gmail.com

    Abstract

    Purpose To evaluate the real-life safety profile of intravitreal dexamethasone implant injection for various retinal conditions.

    Methods Retrospective multicenter analysis of intravitreal dexamethasone implant injections (700 µg) due to various retinal conditions including central retinal venous occlusion (1861 injections), diabetic macular oedema (3104 injections), post-surgical cystoid macular oedema (305 injections) and uveitis (381 injections). The eyes were evaluated mainly for the occurrence of adverse events such as glaucoma, cataract, retinal detachment and endophthalmitis along during the follow-up period.

    Results A total of 6015 injections in 2736 eyes of 1441 patients (mean age of 65.7±12.9 years) were in total analysed over an average period of 18 months (range 6 months to 102 months). A total of 576 eyes (32.5% of the phakic eyes) developed cataract requiring surgical intervention. However, visually insignificant cataract progression was observed in another 259 phakic eyes (14.6%) which did not require surgical removal. A total of 727 eyes (26.5%) experienced an intraocular pressure (IOP) rise of >25 mm Hg, with 155 eyes (5.67%) having a prior history of glaucoma and 572 eyes (20.9%) having new onset IOP rise. Overall, more than 90% of eyes with IOP rise were managed medically, and 0.5% eyes required filtering surgery. Endophthalmitis (0.07%), retinal detachment (0.03%) and vitreous haemorrhage (0.03%) were rare. There was no significant change in visual acuity (p=0.87) and central macular thickness (p=0.12) at the last follow-up.

    Conclusion This is the largest real-life study assessing the safety of intravitreal dexamethasone implant injections in various retinal conditions. Cataract progression and intraocular pressure rise are the most common side effects, but are often rather easily manageable.

    • drugs
    • treatment medical
    • vitreous
    • vision

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    Introduction

    Intravitreal therapy has been a major milestone in ophthalmology and become one of the most commonly performed ocular procedures.1 2 Macular oedema is one the most common vision threatening complications of various retinal diseases including diabetic retinopathy, retinal vascular occlusion, uveitis and pseudophakic cystoid macular oedema. Occurrence of macular oedema in these conditions is thought to be of multifactorial cause with inflammatory cytokines and vascular endothelial growth factor (VEGF) playing an important role.3

    Corticosteroids have been used to treat macular oedema given its multifactorial aetiology including inflammation.4–9 Intravitreal triamcinolone acetonide was initially used but has a high incidence of intraocular pressure rise and cataract progression, especially in younger patients.6–8 The necessity of repeated monthly intravitreal anti-VEGF injections for retinal conditions paved the way for development of sustained release implants, which slowly released the drug over a 3 to 6 month period. Among the sustained release steroid devices, dexamethasone implant (300 or 700 mcg) (Ozurdex, Allergan Inc., Irvine, California) is the most widely used treatment modality.10–13 Following Food and Drug Administration approval in June 2014, along with macular oedema due to retinal vascular occlusions, the use of dexamethasone implant has been extended to treat conditions such as diabetic macular oedema, non-infectious posterior uveitis pseudophakic cystoid macular oedema.6–9 14–18

    Efficacy and safety of dexamethasone implant in various retinal diseases has been proved in various clinical trials all over the world.18–22 Clinical trials are of a stringent inclusion criteria, follow-up schedules and retreatment protocols, however, in real life, the treatment is usually individualised with the need for multiple treatments in few patients, longer or shorter treatment-free intervals depending on the disease aetiology and recurrence. Increase in intraocular pressure (IOP) and cataract progression are the major concerns with dexamethasone implant. Clinical trials such as ZERO and MEAD reported IOP rise of 20% to 32% and cataract progression in 64% to 67% eyes.19 20 Real-life studies by Blanc et al and Meyer reported 70.4% and 40% of IOP rise with 50% and 54.5% cataract progression respectively.21 22

    However, so far safety data is reported from rather small cohorts. Hence, we aimed, to evaluate the safety profile of dexamethasone implants in real-life situations in a variety of retinal conditions by pooling data from multiple centres across the world.

    Methods

    A retrospective analysis of cases from 25 centres across the world was carried out. Patients treated within the period of January 2012 to December 2017 were included in the study. The study adhered to the tenets of the Declaration of Helsinki. Institutional review boards at each study sites approved this study. Data was collected from 2736 patients who underwent intravitreal dexamethasone implant (700 µg) for macular oedema due to various retinal pathologies including diabetic retinopathy, retinal vascular occlusion, non-infectious posterior uveitis and pseudophakic cystoid macular oedema.

    Inclusion criteria included eyes which underwent dexamethasone implant for any indication with at least 6 months follow-up after the last dexamethasone implant injection. Previously treated (anti-VEGF or laser) eyes were included in the study, however, none of the study eyes were concomitantly treated with anti-VEGF or laser during the study period. Eyes with concomitant treatment were not included in the study. Exclusion criteria included eyes with less than 6 months follow-up and lack of data about comprehensive ophthalmic examination.

    The patient demographics; systemic history; previous treatment history; laterality; comprehensive ophthalmic examination details including best corrected visual acuity, phakic status, intraocular pressure recording at baseline and at the last follow-up and occurrence of any ocular or systemic adverse events during the follow-up period were recorded. Details about the management of adverse event, number of injections needed and occurrence of side effects was also analysed. The study eyes were also divided into previously treated and treatment naïve groups and a comparison between the occurrence of adverse events in these two groups was also carried out.

    Intraocular pressure was recorded by the Goldmann’s applanation tonometry and an IOP of >25 mm Hg was considered as significant ocular hypertension.23 Best corrected visual acuity was measured in Snellen’s and was converted into logMAR for the purpose of analysis. The baseline and post treatment best corrected visual acuity (BCVA) were analysed to look for statistical significance.

    Progression of cataract was determined and the number of eyes with cataract requiring surgery was also documented.24 Occurrence of other side effects like vitreous haemorrhage, retinal tears, retinal detachment, inflammation and endophthalmitis and were also recorded.

    All the data was tabulated and analysed statistically by the statistical software using SPSS V.18.0. Continuous variables were analysed using descriptive statistics while pre- and post-implantation parameters were analysed using Wilcoxon signed-rank test. Generalised estimated equation was used to account for correlation between eyes. Regression analysis was performed using analysis of variance to correlate various independent variables with BCVA at final visit and cataract progression. A p value <0.05 was considered statistically significant.

    Results

    A total of 2736 eyes from 1441 subjects treated with 6015 dexamethasone implant injections were included. The mean age of the subjects was 65.7±12.9 years with 865 (60.64%) males and 576 (39.36 %) females. The demographics of the group at baseline are described in table 1. The mean duration of follow-up was 18.9±16.1 months (range: 6 to 102 months).

    Table 1

    Demographics, baseline characteristics and outcome parameters in the overall cohort and subgroups

    Indications of dexamethasone implant

    Subjects in our series were treated with intravitreal dexamethasone implants for various indications as stated in table 2 with diabetic macular oedema (3104 injections), retinal venous occlusions (1861 injections), uveitis (381 injections) and post-surgical macular oedema (305 injections) being the major indications (table 2).

    Table 2

    Indications for intravitreal dexamethasone implant

    Safety results

    Cataract progression

    Among all the study eyes, 1772 eyes (64.77%) were phakic at baseline and rest were pseudophakic. Out of 1772 phakic eyes, 576 eyes (32.5%) underwent cataract surgery while 259 (14.6%) had cataract progression from baseline but did not undergo surgery during the follow-up.

    Although the percentage of eyes with baseline cataract was greater in the previously treated group compared with the treatment naïve group (42.6% vs 27.8%, p=0.03), the percentage of eyes requiring cataract surgery did not statistically differ between two groups (31.7% vs 27.8%, p=0.24) (table 3). We found a statistically significant increase in cataract progression in eyes receiving more number of dexamethasone implant injections (p=0.004), although the co-relation co-efficient was small (r=0.057).

    Table 3

    Baseline parameters and side effects in the previously treated and treatment naïve patients

    Intraocular pressure rise

    The average baseline IOP among the overall cohort was 15.31±3.00 mm Hg. At baseline 103 eyes (66.4%) were on anti-glaucoma medications (AGM) and seven eyes (4.5%) had a history of glaucoma filtration surgery. Intraocular pressure rise was present in 727 eyes (26.5%). Among these eyes, 155 eyes (5.67%) had a prior history of glaucoma and 572 eyes (20.9%) experienced a new onset IOP rise during the follow-up. Among the patients with a new onset of IOP rise, 27 eyes (4.72%) had a transient rise in intraocular pressure without requiring any treatment, while 545 eyes needed anti-glaucoma treatment. In 525 eyes (91.78%) AGM for IOP control were administered, in 18 eyes (3.14%) surgery were conducted and two eyes (0.35%) eyes required laser trabeculoplasty. We did not find any significant correlation between glaucoma progression and number of dexamethasone implant injections (p=0.187)

    Prior history of glaucoma was present in 10.7% of the uveitic eyes (16/149 eyes), in 5.4% of eyes (77/1434 eyes) with diabetic macular oedema and in 5.1% of eyes (27/526 eyes) with retinal venous occlusion.

    The rise in IOP in the treatment naïve group was controlled with anti-glaucoma medications in 351 eyes (91.16%) while 12 eyes (3.11%) needed filtering. In the previously treated group 277 eyes (91.4%) were controlled with topical anti-glaucoma medications and 13 eyes (4.29%) needed filtration surgery (table 3). Overall, more than 90% of eyes with IOP rise were managed medically, and only 0.5% eyes required filtering surgery.

    Other side effects

    Other ocular side effects noted in our series were vitreous haemorrhage in one eye (0.03%), retinal detachment in one eye (0.03%) and sterile endophthalmitis in two eyes (7.3%)). The following systemic conditions were noted in one patient each: herpes zoster, death due to renal failure, cerebrovascular occlusion, myocardial infarction and angina. However, these were stated as being unrelated to the dexamethasone implant.

    Efficacy results

    The mean overall BCVA at baseline was 0.55±0.44 logMAR while the final BCVA was 0.55±0.44 logMAR with the mean change being 0.007±0.46 logMAR (p=0.87). Although, the overall change in BCVA was not statistically significant, the improvement in BCVA in the retinal venous occlusion group and the diabetic macular oedema subgroups was observed to be significant (p<0.001 and p=0.047, respectively) (table 1). Baseline BCVA was one of the main factors correlating with the final BCVA on univariate and multivariate regression analysis (table 4). Mean overall central macular thickness at baseline and the last follow-up was 356±36 and 289±97 microns respectively (p=0.12).

    Table 4

    Factors affecting the final visual acuity in the overall cohort and the subgroups, univariate and multivariate regression analysis

    The intravitreal dexamethasone implants were given pro re nata (PRN) in 2749 eyes, while other eyes received it on an interval ranging from 3 to 6 monthly basis. The mean number of injections was 2.09±1.75 (range 1 to 15) with repeated number of injections being required in 1298 eyes. More than six injections were required in 183 patients with the interval between injections being 3 to 4 monthly or on PRN basis.

    Discussion

    Intravitreal dexamethasone implant as a therapeutic option for macular oedema has an advantage over anti-VEGF in its prolonged duration of action.15–18 25 In our study we conducted a retrospective analysis of 2736 patients from 25 countries treated with 6015 intravitreal dexamethasone implants in total over a period of 5 years. The main aim of our study was to assess the safety profile of a large intravitreal series. In total 576 eyes (32.5% of phakic eyes) developed significant cataract requiring surgical intervention during the follow-up period. Cataract progression was observed in 259 phakic eyes (14.6%) which did not require surgical removal. The other common side effect noted was intraocular pressure. A total of 727 eyes (26.5%) had intraocular pressure rise >25 mm Hg with 155 eyes (5.67%) having prior history of glaucoma and 572 (20.9%) having new onset IOP rise. Endophthalmitis (0.07%), retinal detachment (0.03%) and vitreous haemorrhage were other rarer side effects noted in our patients.

    The GENEVA study was one of the first to show the efficacy of dexamethasone implant in eyes with retinal vein occlusion.26 In 15% of the study eyes the trial reported an intraocular pressure elevation of at least 25 mm Hg, peaking at day 60 and normalising by day 180 and more. Other studies showed an intraocular pressure rise in 12% to 27% of the eyes except for the study by Zarranz-Ventura et al (82 eyes) and Mayer et al (64 eyes) which showed an intraocular pressure rise of approximately 40% (table 5).27–31 The small sample size in these studies could possibly be the reason for the higher percentages observed. Malclès et al in the SAFODEX study reviewed charts of 361 patients who received 1000 intravitreal dexamethasone implant injection observed ocular hypertension (IOP >25 mm Hg or rise in IOP more than 10 mm Hg) in 20% of injected eyes and a recent study by Zarranz-Ventura et al found a cumulative probability of IOP rise of 30% in 429 eyes at 24 months, similar to our study.23 32 Filho et al (study of 329 eyes) and Lowder et al (229 eyes) noted an intraocular pressure rise in only 7.4% and 7.1% cases with dexamethasone implant respectively.25 33 In our study intraocular pressure rise was noted in 727 eyes (26.5%), among which 103 eyes (0.13%) had pre-existing glaucoma and 525 (72.2%) eyes with post-injection intraocular rise required AGM for IOP control. Overall, glaucoma filtering surgery was required in 25 eyes (0.91%), among which seven eyes (0.9%) had pre-existing glaucoma and 18 eyes (2.47%) had new onset post injection IOP rise.

    Table 5

    Comparison of safety profile between our study and other dexamethasone implant studies

    Although ocular hypertension is a known side effect of intraocular steroid injections, the IOP rise following dexamethasone implant could be managed by topical anti-glaucoma medications in 91% eyes, which was similar to other studies like the SAFODEX study (97% cases managed with topical AGM).23 We did not find any significant correlation between glaucoma progression and number of dexamethasone implant injections (p=0.187) in our study, similar to other studies which also showed that repeated injections of dexamethasone implant was not found to have any cumulative effect on the IOP.34 35 Younger age, male sex, type 1 diabetes, pre-existing glaucoma treated with dual or triple therapy and a history of retinal vein occlusion or uveitis were significant risk factors for ocular hypertension after dexamethasone implant injection in a multivariate analysis from the study by Malclès et al.23 The MEAD study also observed that the IOP rise with intravitreal dexamethasone implant is mild and predictable with IOP peak occurring at 6 to 8 weeks and returning to baseline by around 3 to 4 months.36

    Amongst 1772 phakic eyes (64.8%) in our study, 835 eyes (47.1%) were noted to have cataract with 576 eyes (32.5%) requiring cataract surgery on follow-up while 259 eyes (14.6%) had visually insignificant cataract not requiring surgery. The 12 month GENEVA study wherein the patients were treated with two injections of dexamethasone implant noted cataract progression in 29.8% eyes with 1.3% requiring cataract surgery. Studies have reported progression of cataract following intravitreal dexamethasone implants from 0.3% to 47% (table 5). The variations in the sample size and the follow-up periods could explain the wide range of cataract progression in the studies. Studies including eyes with uveitis showed a greater occurrence of cataract as uveitis itself could also predispose the secondary cataract (table 5). The large number of phakic eyes at baseline (64%) with 33.7% of them having cataract at baseline could explain the greater percentage of cataract in our series. Reid et al in their study found that the incidence of cataract after the first implant was 13.2% which increased to 45% and 60% after the second and third implants. They observed significantly higher rates of cataract surgeries in the second and third implant group when compared with the single implant group.34 Similar to their study we also found a statistically significant increase in cataract progression in eyes receiving more number of Ozurdex injections (p=0.004) although the co-relation co-efficient was small (r=0.057). Occurrence of sterile endophthalmitis following intravitreal dexamethasone implant was very low in our study (0.07%) along with other rarer side effects like vitreous haemorrhage (0.03%) and retinal detachment (0.03%). Most of the studies did not observe side effects other than raised intraocular pressure and cataract. Endophthalmitis, vitreous haemorrhage and retinal detachment were other rare adverse events noted in other studies similar to ours (table 5). A study by Li et al noted conjunctival haemorrhage (18.6%) followed by conjunctival hyperaemia (13.2%) as the other most common side effects in their series.27

    Among the various subgroups, the uveitic group had a lesser percentage of eyes with cataract at baseline (22.1%), however, the number of eyes requiring cataract surgery in this subgroup was higher (39.8%) compared with the RVO (28.9%) and the DME subgroup (31.0%) (table 1). Other studies with uveitis have observed occurrence of cataract ranging from 4.8% to 15% (table 5). Ozkaya et al reported on 47% eyes with cataract in their study.37 Furino et al combined phacoemulsification and dexamethasone implant and proposed that it may be an effective approach for patients with cataract and diabetic macular oedema.38 An elderly cohort and pre-existing cataract and uveitis could possibly account for the higher occurrence of cataract in the study populations.

    Limitations of our study include the retrospective nature with lack of uniformity in treatment and follow-up protocol as it contains pooled data from all over the world. The strength of our study is the safety profile following a large number of injections (6015) in large number of patients in real clinical practice across the world.

    In conclusion, our study of 6015 dexamethasone implant injections revealed visually significant cataract necessitating surgery (32.5%) and an intraocular pressure rise (26.5%) as the major treatable side effects of the implant. Among the patients with intraocular pressure rise, more than 90% were well controlled with topical anti-glaucoma medications and only 3.43% requiring glaucoma filtering surgery. Dexamethasone implant appears to be a safe in various retinal conditions in real-life situations.

    References

    Footnotes

    • Collaborators International Ozurdex Study Group: A. Gupta (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India). A. Singh (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India). Abhilash Goud (L.V.Prasad Eye Institute, Kallam Anji Reddy Campus, Banjara Hills, HYDERABAD - 500 034). Ahmad mansour (Department of Ophthalmology, American University of Beirut, Beirut, Lebanon., Department of Ophthalmology, Rafic Hariri University Hospital, Beirut, Lebanon). Alay Banker (Banker's Retina Clinic and Laser Centre, Ahmedabad, India). Alok C Sen (Department of Retina and Uvea, Sadguru Netra Chikitsalya, Chitrakoot). Ameen Marashi (ameenmarashi@hotmail.com, Marashi Eye Clinic, Aleppo, Syria.) Andre Maia (Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil.) Aniruddha Maiti (Sushrut eye foundation, Kolkata, India) Anna Sala-Puigdollers (Vitreo-Retinal Unit, Institut Clínic d'Oftalmologia (ICOF), Hospital Clínic, Barcelona) Ashish Sharma (Lotus eye hospital, Coimbatore, India) Carlo Cagini(Section of Ophthalmology, Department of Biomedical and Surgical Sciences, University of Perugia, Perugia, Italy.) Carolina Bernal-Morales (Vitreo-Retinal Unit, Institut Clínic d'Oftalmologia (ICOF), Hospital Clínic, Barcelona) Chintan Sarvaiya (Banker's Retina Clinic and Laser Centre, Ahmedabad, India.) Daniele Veritti (Department of Medicine-Ophthalmology, University of Udine, Udine, Italy, istituto Europeo di Microchirurgia Oculare-IEMO, Udine, Italy) Dinah Zur (Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel). Dua Masarwa (Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel). Eduardo Novais (Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil). Ermete Giancipoli (Department of Surgical, Microsurgical and Medical Sciences, Eye Clinic, University of Sassari, Sassari, Italy, Department of Biomedical Sciences, University of Sassari, Sassari, Italy.) Francesco Bandello (Department of Ophthalmology, University Vita Salute, IRCCS Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy) Hasenin Al-khersan &lt;haseninrh@gmail.com&gt; (The University of Chicago, Pritzker School of Medicine, Chicago, IL) J S Wong (International Specialist Eye Centre, Kuala Lumpur, Malaysia) K. Raji (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India). Lihteh Wu (Apdo 144-1225 Plaza Mayor, San José, 1225, Costa Rica). Mali Okada (Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia). Manish Nagpal (Retina Foundation and Eye Research Center, Ahmedabad, India). Marcelo Casella (mbcasella@gmail.com, Department of Ophthalmology, Universidade Estadual de Londrina, Londrina, Brazil). Marco Lupidi (Section of Ophthalmology, Department of Biomedical and Surgical Sciences, University of Perugia, Perugia, Italy.) Marcos Avila (Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil). Maria Berrocal (University of Puerto Rico School of Medicine, San Juan, Puerto Rico). Matias Iglicki (Private Retina Service, University of Buenos Aires, Buenos Aires, Argentina.) Mauricio Maia (Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil). Michele Cavalleri (Department of Ophthalmology, University Vita Salute, IRCCS Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy) Mohammed Abdul Rasheed (L.V.Prasad Eye Institute, Kallam Anji Reddy Campus, Banjara Hills, HYDERABAD - 500 034) Monica Asencio-Duran (Vitreo-Retinal Department, Hospital La Paz, Madrid) Nicolò Rassu (Department of Medicine-Ophthalmology, University of Udine, Udine, Italy; istituto Europeo di Microchirurgia Oculare-IEMO, Udine, Italy) Oriana D'Anna-Mardero (Vitreo-Retinal Department, Hospital La Paz, Madrid) Pierre-Henry Gabrielle (Ophthalmology Department, Dijon University Hospital, Dijon, France. Center for Taste and Feeding Behaviour, INRA, UMR1324, Dijon, France). Prateek Shenoy (Department of Retina and Uvea, Sadguru Netra Chikitsalya, Chitrakoot) Roberto Gallego-Pinazo (Oftalvist Clinic, Valencia, Spain) Rosa Dolz Marco (Oftalvist Clinic, Valencia, Spain) S. Kumar (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India) S. Patyal (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India). Samantha Fraser-Bell (Department of Ophthalmology, Sydney University, Sydney, Australia). Shai Cohen (Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel). Sumit Randhir Singh (L.V.Prasad Eye Institute, Kallam Anji Reddy Campus, Banjara Hills, HYDERABAD - 500 034) V. Sharma (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India) Valentina Sarao (sarao.valentina@gmail.com, istituto Europeo di Microchirurgia Oculare-IEMO, Udine, Italy) Voraporn Chaikitmongkol (Retina Division, Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand). Zafer Cebeci (Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey). Ziya Ayhan (Dokuz Eylul University, İzmir,Turkey).(Section of Ophthalmology, Department of Biomedical and Surgical Sciences, University of Perugia, Perugia, Italy.) Carolina Bernal-Morales (Vitreo-Retinal Unit, Institut Clínic d'Oftalmologia (ICOF), Hospital Clínic, Barcelona) Chintan Sarvaiya (Banker's Retina Clinic and Laser Centre, Ahmedabad, India.) Daniele Veritti (Department of Medicine-Ophthalmology, University of Udine, Udine, Italy, istituto Europeo di Microchirurgia Oculare-IEMO, Udine, Italy) Dinah Zur (Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel). Dua Masarwa (Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel). Eduardo Novais (Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil). Ermete Giancipoli (Department of Surgical, Microsurgical and Medical Sciences, Eye Clinic, University of Sassari, Sassari, Italy, Department of Biomedical Sciences, University of Sassari, Sassari, Italy.) Francesco Bandello (Department of Ophthalmology, University Vita Salute, IRCCS Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy) Hasenin Al-khersan &lt;haseninrh@gmail.com&gt; (The University of Chicago, Pritzker School of Medicine, Chicago, IL) J S Wong (International Specialist Eye Centre, Kuala Lumpur, Malaysia) K. Raji (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India). Lihteh Wu (Apdo 144-1225 Plaza Mayor, San José, 1225, Costa Rica). Mali Okada (Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia). Manish Nagpal (Retina Foundation and Eye Research Center, Ahmedabad, India). Marcelo Casella (mbcasella@gmail.com, Department of Ophthalmology, Universidade Estadual de Londrina, Londrina, Brazil). Marco Lupidi (Section of Ophthalmology, Department of Biomedical and Surgical Sciences, University of Perugia, Perugia, Italy.) Marcos Avila (Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil). Maria Berrocal (University of Puerto Rico School of Medicine, San Juan, Puerto Rico). Matias Iglicki (Private Retina Service, University of Buenos Aires, Buenos Aires, Argentina.) Mauricio Maia (Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil). Michele Cavalleri (Department of Ophthalmology, University Vita Salute, IRCCS Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy) Mohammed Abdul Rasheed (L.V.Prasad Eye Institute, Kallam Anji Reddy Campus, Banjara Hills, HYDERABAD - 500 034) Monica Asencio-Duran (Vitreo-Retinal Department, Hospital La Paz, Madrid) Nicolò Rassu (Department of Medicine-Ophthalmology, University of Udine, Udine, Italy; istituto Europeo di Microchirurgia Oculare-IEMO, Udine, Italy) Oriana D'Anna-Mardero (Vitreo-Retinal Department, Hospital La Paz, Madrid) Pierre-Henry Gabrielle (Ophthalmology Department, Dijon University Hospital, Dijon, France. Center for Taste and Feeding Behaviour, INRA, UMR1324, Dijon, France). Prateek Shenoy (Department of Retina and Uvea, Sadguru Netra Chikitsalya, Chitrakoot) Roberto Gallego-Pinazo (Oftalvist Clinic, Valencia, Spain) Rosa Dolz Marco (Oftalvist Clinic, Valencia, Spain) S. Kumar (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India) S. Patyal (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India). Samantha Fraser-Bell (Department of Ophthalmology, Sydney University, Sydney, Australia). Shai Cohen (Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel). Sumit Randhir Singh (L.V.Prasad Eye Institute, Kallam Anji Reddy Campus, Banjara Hills, HYDERABAD - 500 034) V. Sharma (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India) Valentina Sarao (sarao.valentina@gmail.com, istituto Europeo di Microchirurgia Oculare-IEMO, Udine, Italy) Voraporn Chaikitmongkol (Retina Division, Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand). Zafer Cebeci (Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey). Ziya Ayhan (Dokuz Eylul University, İzmir,Turkey).(Section of Ophthalmology, Department of Biomedical and Surgical Sciences, University of Perugia, Perugia, Italy.) Carolina Bernal-Morales (Vitreo-Retinal Unit, Institut Clínic d'Oftalmologia (ICOF), Hospital Clínic, Barcelona) Chintan Sarvaiya (Banker's Retina Clinic and Laser Centre, Ahmedabad, India.) Daniele Veritti (Department of Medicine-Ophthalmology, University of Udine, Udine, Italy, istituto Europeo di Microchirurgia Oculare-IEMO, Udine, Italy) Dinah Zur (Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel). Dua Masarwa (Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel). Eduardo Novais (Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil). Ermete Giancipoli (Department of Surgical, Microsurgical and Medical Sciences, Eye Clinic, University of Sassari, Sassari, Italy, Department of Biomedical Sciences, University of Sassari, Sassari, Italy.) Francesco Bandello (Department of Ophthalmology, University Vita Salute, IRCCS Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy) Hasenin Al-khersan &lt;haseninrh@gmail.com&gt; (The University of Chicago, Pritzker School of Medicine, Chicago, IL) J S Wong (International Specialist Eye Centre, Kuala Lumpur, Malaysia) K. Raji (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India). Lihteh Wu (Apdo 144-1225 Plaza Mayor, San José, 1225, Costa Rica). Mali Okada (Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia). Manish Nagpal (Retina Foundation and Eye Research Center, Ahmedabad, India). Marcelo Casella (mbcasella@gmail.com, Department of Ophthalmology, Universidade Estadual de Londrina, Londrina, Brazil). Marco Lupidi (Section of Ophthalmology, Department of Biomedical and Surgical Sciences, University of Perugia, Perugia, Italy.) Marcos Avila (Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil). Maria Berrocal (University of Puerto Rico School of Medicine, San Juan, Puerto Rico). Matias Iglicki (Private Retina Service, University of Buenos Aires, Buenos Aires, Argentina.) Mauricio Maia (Department of Ophthalmology and Visual Sciences, Universidade Federal de São Paulo, São Paulo, SP, Brazil). Michele Cavalleri (Department of Ophthalmology, University Vita Salute, IRCCS Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy) Mohammed Abdul Rasheed (L.V.Prasad Eye Institute, Kallam Anji Reddy Campus, Banjara Hills, HYDERABAD - 500 034) Monica Asencio-Duran (Vitreo-Retinal Department, Hospital La Paz, Madrid) Nicolò Rassu (Department of Medicine-Ophthalmology, University of Udine, Udine, Italy; istituto Europeo di Microchirurgia Oculare-IEMO, Udine, Italy) Oriana D'Anna-Mardero (Vitreo-Retinal Department, Hospital La Paz, Madrid) Pierre-Henry Gabrielle (Ophthalmology Department, Dijon University Hospital, Dijon, France. Center for Taste and Feeding Behaviour, INRA, UMR1324, Dijon, France). Prateek Shenoy (Department of Retina and Uvea, Sadguru Netra Chikitsalya, Chitrakoot) Roberto Gallego-Pinazo (Oftalvist Clinic, Valencia, Spain) Rosa Dolz Marco (Oftalvist Clinic, Valencia, Spain) S. Kumar (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India) S. Patyal (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India). Samantha Fraser-Bell (Department of Ophthalmology, Sydney University, Sydney, Australia). Shai Cohen (Division of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel). Sumit Randhir Singh (L.V.Prasad Eye Institute, Kallam Anji Reddy Campus, Banjara Hills, HYDERABAD - 500 034) V. Sharma (Department of Ophthalmology Command hospital, Lucknow cantt 226002, India) Valentina Sarao (sarao.valentina@gmail.com, istituto Europeo di Microchirurgia Oculare-IEMO, Udine, Italy) Voraporn Chaikitmongkol (Retina Division, Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand). Zafer Cebeci (Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey). Ziya Ayhan (Dokuz Eylul University, İzmir,Turkey).

    • Contributors All persons designated as authors qualify for authorship, and all those who qualify are listed. Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content. Design: JC. Conduct of the study: JZV, ATF, CB, NKS, PJRV, VS, SKM, AOS, PUM, GQ, MEF, PL, JFA, LK, JC. Collection: JZV, AF, CB, PJRV, VS, SKM, AOS, PUM, GQ, MEF, PL, JFA, LK, JC. Management: BR, JC. Analysis: BR, NKS, JC. Interpretation of the data: BR, NKS, JC. Preparation: BR, JZV, ATF, CB, NKS, PJRV, VS, SKM, AOS, PUM, GQ, MEF, PL, JFA, LK, JC. Review: BR, JZV, ATF, CB, NKS, PJRV, VS, SKM, AOS, PUM, GQ, MEF, PL, JFA, LK, JC. Approval of the manuscript: BR, JZV, ATF, CB, NKS, PJRV, VS, SKM, AOS, PUM, GQ, MEF, PL, JFA, LK, JC.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests BR: None JZ-V: Allergan (Consultant); Bayer (Consultant); ATF: Allergan (Consultant); Bayer (Consultant); CB: Allergan (Consultant); Bayer (Travel support); Novartis (Consultant) NKS: None PJR-V: Allergan, Alcon, Novartis, Bayer, Industrial Organica, SA de CV, Laboratorios Sophia VS: None SKM: None AOS: Allergan (Consultant); Bayer (Consultant); Novartis (Consultant) PUM: Bayer (Consultant); Centervue (Consultant); Novartis (Consultant) GQ: Allergan, Alcon, Novartis, Bayer, Industrial Organica, SA de CV, Laboratorios Sophia. MEF: None PL: Alcon (Consultant); Alimera (Consultant); Allergan (Consultant); Bausch&Lomb (Consultant); Bayer (Consultant); Boehringer (Consultant); CenterVue (Consultant); Genentech (Consultant); Lupin (Consultant); Lutronic (Consultant); Novartis Pharma AG (Consultant); Roche (Consultant); Teva (Consultant); Topcon (Consultant) JFA: TURING PHARMACEUTICALS LLC(Consultant); DORC International B.V. (Consultant); Allergan Inc. (Consultant); Bayer (Consultant); Mallinckrodt (Consultant); TOPCON (Grant Support) LK: Principal Investigator for trials sponsored by Novartis, Allergan, Bayer, Théa, Alcon; has sat on advisory boards for Alcon, Alimera, Allergan, Bayer, Roche, Novartis; lecture fees from Alcon, Alimera, Allergan, Bayer, Horus, Novartis, Théa. JC: Allergan (Consultant); Bayer (Consultant); Novartis (Consultant); OD-OS (Consultant).

    • Patient consent for publication Obtained.

    • Ethics approval Local Institutional ethics committee at all study sites.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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