Vitreomacular Adhesion Or Vitreomacular Traction May Affect

Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Review Vitreomacular adhesion or vitreomacular traction may affect antivascular endothelium growth factor treatment for neovascular age-related macular degeneration Ping Xie,1 Xinhua Zheng,1,2 Yingqing Yu,2 Xiaojian Ye,1 Zizhong Hu,1 Dongqing Yuan,1 Qinghuai Liu1

6–8 ►► Additional material is Abstract genes), anatomical factors (eg, lesion size, subret- published online only. To view Objective The aim of this review is to determine inal fluid)6 9 and other variables (eg, age, number of please visit the journal online 10–12 (http://dx. doi.org/ 10.1136/ whether vitreomacular adhesion (VMA) or vitreomacular injections, visual acuity). Other possible predic- bjophthalmol-2017- 310155). traction (VMT) has an influence on the outcomes of tive factors are now being researched, including the antivascular endothelium growth factor (anti-VEGF) role of the vitreomacular interface (VMI), which has 1 Department of Ophthalmology, treatment neovascular age-related macular degeneration generated much interest.13 The First Affiliated Hospital of (nAMD). Initially the vitreous is completely attached to Nanjing Medical University, Nanjing, Jiangsu, China Methods A systematic literature search was performed all contiguous internal limiting membrane of the 2Department of Ophthalmology, in Pubmed.gov, Cochrane Library, Web of Science, China retina by the macromolecular attachment complex— Wuxi Children’s Hospital, Wuxi, National Knowledge Infrastructure, Wanfang, SinoMed composed of fibronectin, laminin and other extra- Jiangsu, China and ClinicalTrials.gov up to 30 June 2016 to identify cellular components that form like matrix at VMI1 eligible studies. 14 15 and by chondroitin sulfate throughout the Correspondence to Results Nine studies and 2212 participants were vitreoretinal interface.1 16–18 In the course of ageing Dr Qinghuai Liu, Department of Ophthalmology, The First finally identified.At month 6, the mean improvement in process, degenerative processes occur (eg, gel lique- Affiliated Hospital of Nanjing best-corrected visual acuity (BCVA) and mean decline in faction, weakening of vitreoretinal adhesion and Medical 29 University, central retinal thickness (CRT) of the VMA/VMT(+) group gel contraction), initiating vitreoretinal separation Guangzhou Road 300, Nanjing was less than that of the VMA/VMT(-) group (95% CI from the peripheral fundus. This process gradually 210029, Jiangsu, China; liuqh@ njmu.edu. cn −3.05 to –0.96 letters, p=0.0002; 15.53 to 32.98 μm, progresses to the macula and optic nerve, finally p<0.00001; respectively); at month 12, there was a small resulting in complete posterior vitreous detachment PX and XZ contributed equally. or only marginally significant difference (−0.01 to 2.00 (PVD).1 19 Under anomalous conditions, gel contrac- letters, p=0.05; 0.17 to 23.7 μm, p=0.05; respectively) tion outpaces detachment of the vitreous cortex, Received 16 January 2017 between the groups. During the 12 months, however, the Revised 19 April 2017 and there is an abnormal adhesion of the vitreous Accepted 23 April 2017 VMA/VMT(+) group required more injections ((0.25 to cortex to the internal limiting membrane. Thus, Published Online First 0.95), p=0.0008). as vitreoretinal separation progresses, anomalous 1 August 2017 Conclusions In using anti-VEGF drugs to treat macular conditions including vitreomacular adhe- nAMD, clinicians should take into account the fact that sion (VMA) and vitreomacular traction (VMT) can concurrent VMA or VMT might antagonise the efficacy of ensue.1 20 21 VMA is defined as a stage wherein partial anti-VEGF drugs during the early stage of treatment. detachment of the vitreous in the perifoveal area has occurred without associated retinal abnormalities. VMA progresses to VMT when detectable retinal 1 Age-related macular degeneration (AMD) is a leading anatomic changes occur. Some investigators do not cause of vision loss worldwide. One late stages at separate the two stages and include them both under 22–24 which most visual loss occurs is known as neovas- the heading VMA. cular (‘wet’) AMD (nAMD), which is characterised The association between incomplete PVD and by choroidal neovascularisation that breaks through nAMD was first suggested by Weber-Krause et al in 25 to the neural retina, leaking fluid, lipids and blood 1966. After that, many reports verified a higher and leading to fibrous scarring.1 Large randomised prevalence of VMA in eyes with nAMD compared controlled trials have shown that antivascular endo- with eyes with non-neovascular AMD or with the 22 26–33 thelial growth factor (anti-VEGF) treatments can be eyes of normal controls. Some observations effective for most nAMD; as a result, anti-VEGF drugs showed that VMA occurs at the vitreoretinal inter- given via intravitreal injections have become firmly face overlying the area of choroidal neovascularisa- 26–28 established as the standard of care for nAMD.1–5 tion. In addition, the association of VMI and Despite the relatively good efficacy of anti-VEGF nAMD was indirectly proved by studies showing drugs in many patients, there are still some who show that vitrectomy to detach the posterior vitreous a weak response or even no response to the treatment. cortex and relieve VMA and VMT could improve Many factors have been shown to be predictive of the choroidal neovascular regression.34 35 These obser- To cite: Xie P, Zheng X, Yu Y, response to anti-VEGF treatment for nAMD.6 These vations indicate that anomalous VMI may play a et al. Br J Ophthalmol include genetic factors (eg, single-nucleotide poly- part in the initial pathogenesis or progression of 2017;101:1003–1010. morphisms in the complement factor H and VEGF-A nAMD. With the establishment of anti-VEGF drugs

Xie P, et al. Br J Ophthalmol 2017;101:1003–1010. doi:10.1136/bjophthalmol-2017-310155 1003 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Review as a treatment for nAMD, many studies further investigated the change from baseline 6 and 12 months after the first anti-VEGF influence of VMA or VMT on anti-VEGF treatment for nAMD. injection; mean number of injections during the 12-month The results were controversial, however, with some suggesting follow-up period. BCVA was determined using the ETDRS that eyes with VMA or VMT showed less anatomic or functional chart at 4 m and logarithm of the minimal angle of resolution improvement13 19 24 36 37 or required more frequent dosing9 19 24 (logMAR) was converted to letters for analysis. CRT was defined 37 38 than eyes without VMA or VMT. Yet others suggested that as the mean value of retinal thickness of the central points, there was no such difference.23 measured manually on OCT scans using the built-in software in To our knowledge, there has been no meta-analysis of this the OCT device. disputed issue of whether VMA or VMT has an impact on anti- Exclusion criteria were as follows: individuals with coex- VEGF treatment for nAMD. In the current study, we assessed isting pathologies or choroidal neovascularisation secondary to the possible influence of VMA or VMT from the standpoints other pathologies were excluded, as were studies published in of functional outcome, anatomic outcome and management languages other than English or Chinese. When multiple publica- burden. tions from the same study population were available, we checked for duplicate analyses and included the most recent publication. Methods Search strategy Quality assessments and data extraction Two of the authors independently conducted a systemic search of The retrieved articles were reviewed for risk bias using the Pubmed.gov, Cochrane Library, Web of Science, China National Newcastle-Ottawa Scale.39 From each study, the following char- Knowledge Infrastructure, Wanfang, SinoMed and ClinicalTrials. acteristics were extracted: last name of first author and publica- gov up to 30 June 2016. The following search strategy was used: tion year, enrolment period, study design, age, gender, sample 1. (Vitreomacular Interface [Title/Abstract] or VMI [Title/ size, treatment regimen and follow-up period. Primary outcome Abstract] or Vitreomacular adhesion [Title/Abstract] or measures were as follows: functionally mean BCVA change 6 and VMA [Title/Abstract] or vitreomacular traction [Title/ 12 months after the first injection and anatomically mean CRT Abstract] or VMT [Title/Abstract]) change 6 and 12 months after the first injection. The secondary 2. (Vascular Endothelial Growth Factors [Title/Abstract] or outcome measure was the mean number of injections during the VEGFs [Title/Abstract] or Bevacizumab [Title/Abstract] or 12-month follow-up period. Avastin [Title/Abstract] or Ranibizumab [Title/Abstract] or RhuFab V2 [Title/Abstract] or Lucentis [Title/Abstract] or Aflibercept [Title/Abstract] or AVE 005 [Title/Abstract] or Statistical analysis AVE-005 [Title/Abstract] or Zaltrap [Title/Abstract] or ZIV- The quantitative data were entered into Review Manager aflibercept [Title/Abstract] or AVE 0005 [Title/Abstract] (RevMan, V.5.3, Copenhagen: The Nordic Cochrane Centre, or AVE-0005 [Title/Abstract] or Eylea [Title/Abstract] or The Cochrane Collaboration, 2014). Meta-analysis was KH902 [Title/Abstract] or conbercept [Title/Abstract] or performed on the two primary outcome measures and one Lumitin [Title/Abstract] or pegaptanib [Title/Abstract] or secondary outcome measure. Summary estimates, including 95% Macugen [Title/Abstract]) CIs, were calculated. The means and SD were used to calculate 3. (randomised controlled trial [Publication Type] or controlled the estimated mean difference (MD) between groups for all the clinical trial [Publication Type] or randomised [Title/Abstract] continuous outcome data. A random or fixed-effects model was or controlled [Title/Abstract] or trial [Title/Abstract] or use for analysis according to the situation. Statistical heteroge- 2 2 random [Title/Abstract] or placebo [Title/Abstract] or neity was tested using the χ test and I statistic. A sensitivity groups [Title/Abstract]) analysis that investigates the contribution of each study to the 4. (1, 2 and 3) heterogeneity was performed by sequentially omitting one study Retrieved studies were imported into EndNote (V.X7 for and reanalysing the pooled estimate for the remaining studies. A Windows), where duplicate articles were deleted. Titles and two-sided p value less than 0.05 was regarded as significant for abstracts of the remaining articles were independently scanned all analyses. by two authors. Extracted studies were compared and incon- sistencies were resolved by consensus. The full texts of the Results remaining studies were then read to determine whether they met The process of the systemic search is demonstrated in figure 1. our inclusion criteria. In addition, the references of all identified The search yielded 452 articles; 109 duplications were studies were reviewed. removed. Review of the title and abstract removed 308 of the articles, and thorough full-text assessment removed 26. Nine Eligibility criteria studies and 2212 participants were finally identified and anal- Studies included in this meta-analysis had to meet the following ysed for the meta-analysis.9 13 19 22–24 36 38 40 Characteristics and criteria: (1) The study design was a prospective cohort or retro- quality assessment results of the included studies are presented spective case–control study. (2) All patients were diagnosed of in table 1. Quantitative synthesis and analysis of BCVA and nAMD based on leakage on fluorescein angiography and optical CRT change at month 6 was conducted on available data from coherence tomography (OCT). (3) All patients received anti- three studies and at month 12 from seven studies. There was VEGF treatment for nAMD in the study eye. (4) Participants no difference between the baseline BCVA or CRT of the VMA/ had concurrent VMA or VMT, whereas controls did not have VMT(+) and VMA/VMT(-) groups in any one study. Quanti- VMA or VMT. (5) Patients were followed for a minimum of 6 tative synthesis and analysis of injection frequency during 12 months. (6) Direct or indirect records of at least one of the three months of follow-up was conducted on data from five studies. following outcomes were available: mean best-corrected visual The mean BCVA improvement of the VMA/VMT(+) group acuity (BCVA) change from baseline 6 and 12 months after the at month 6 was less than that of the VMA/VMT(-) group first anti-VEGF injection; mean central retinal thickness (CRT) (mean difference (95% CI), −2.01 (−3.05 to –0.96) letters;

1004 Xie P, et al. Br J Ophthalmol 2017;101:1003–1010. doi:10.1136/bjophthalmol-2017-310155 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Review

With regard to the role VMI plays in the pathophysiological process of nAMD, there are three possible mechanisms by which anomalous VMI may antagonise the effect of anti-VEGF drugs. First, anomalous adhesion causes a traction force at VMI. This force is directly applied to Müller cells and causes stretching of the retinal pigment epithelial cells. This effect could lead to the secretion of various proinflammatory cytokines, thus inducing local inflammation, including VEGF, which plays an important role in the pathogenesis and progression of nAMD.13 41–44 Second, the traction force on the retina causes tissue to be pulled apart,42 45 a structural change that induces macular oedema. As a result, oxygen diffusion and nutrient supply to retinal tissue are influenced, and the blood-retinal barrier breaks down. Conse- quently, the lesion of nAMD becomes more active.13 41 42 46 47 Lastly, the traction force also causes local ischaemia and disrupts the choroidal supply of the macula, so that cytokines, including VEGF, are confined within the retinal structure.48 49 The fixed amount of anti-VEGF drug is not sufficient to neutralise the increased level of VEGF, which compromises the treatment outcome. As a result, more injections of anti-VEGF drugs are required.13 50 There is other indirect evidences pointing to the influence of VMA or VMT on anti-VEGF treatment for nAMD and the possible mechanisms involved. In humans and animals, pharmacological vitreolysis and vitrectomy have been shown to increase oxygen diffusion.51–53 Pharmacological vitreolysis, vitrectomy and PVD result in a more liquefied vitreous with less viscosity; therefore the diffusion of cytokines, oxygen, growth factors and medications may increase. This is just the opposite of VMA or VMT, which acts functionally as a diffusion barrier.9 Pharmacological vitreolysis agents or surgical Figure 1 Systematic literature search process. vitrectomy are seen as an adjuvant treatment option for VMT and as a way of dealing resistance to conventional anti-VEGF treatments in selected patients.27 36 54 55 p=0.0002); at month 12, the difference became marginally During treatment, VMA advanced to VMT in some patients significant (1.00 (−0.01 to 2.00) letters; p=0.05) (figure 2). or even worsened and progressed to PVD.1 Actually anti- The mean CRT decline of the VMA/VMT(+) group at month 6 VEGF agents can exacerbate VMA and VMT by causing was smaller than that of the VMA/VMT(-) group (24.26 (15.53 to contraction of the vitreous and posterior hyaloid membrane. 32.98) μm; p<0.00001); at month 12, there was no more signifi- This will further worsen a patient’s prognosis.56 In this study, cant difference (11.94 (0.17 to 23.71) μm; p=0.05) (figure 3). patients with such unstable progressive VMA or VMT were not During the 12-month follow-up period, the mean number removed from the VMA/VMT(+) group. Besides, in this study of injections among patients in the VMA/VMT(+) group was patients with VMA and VMT were also not divided into two greater than that among those in the VMA/VMT(-) group (0.60 groups. It might seem more rigorous to further divide VMA/ (0.25 to 0.95); p=0.0008) (figure 4). VMT(+) group into three subgroups, namely persistent VMA, Funnel plots of each comparison are shown in figure 5. Data persistent VMT and dynamic VMA/VMT.19 38 However, we 40 from the Krishnan study were not synthesised in the analyses consider such a step might be unnecessary and impractical. The because, according to the sensitivity analysis, it would have grouping method of this meta-analysis is more in accord with increased heterogeneity and decreased robustness. After ruling actual clinical situations, because the evaluation of prognosis out the Krishnan study, heterogeneity declined greatly, and in the and formulation of the therapeutic plan are largely conducted 2 analysis of BCVA change at month 12, I declined from 72% to before treatment, when dynamic changes in the patients’ VMI 37%, CRT changed from 82% to 80% and injection frequency condition are still unknown. In addition, in distinguishing from 72% to 59%. CRT decrease at month 12 changed from VMT from VMA by OCT, the results of different readers are 95% CI −4.26 to 20.08 μm to 0.17 to 23.71 μm. Finally, sensi- not always the same, since they are highly dependent on the tivity analysis demonstrated that the current meta-analysis were reader’s personal understanding of the definitions and char- robust. acteristics. Our meta-analysis showed that the antagonistic effects of Discussion VMA or VMT on the anatomic and functional outcome of According to the results of our analysis, the concurrent VMA or anti-VEGF treatment of patients with nAMD diminished as VMT affected the efficacy of anti-VEGF drugs for patients with the treatment continued. The possible mechanisms behind nAMD during the first 6 months of treatment. Patients with VMA the disappearance of the effects were, as already mentioned, or VMT achieved less BCVA improvement and less CRT decline. VMA/VMT release, which led to PVD in some patients during After 12 months of treatment, this difference gradually diminished. the 12 months of follow-up,1 either owing to natural disease Patients with VMA or VMT required more injections during the progression or exacerbated by anti-VEGF agents.56 The effect −12 month follow-up period. of VMA/VMT vanishes along with the disappearance of VMA/

Xie P, et al. Br J Ophthalmol 2017;101:1003–1010. doi:10.1136/bjophthalmol-2017-310155 1005 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Review otal score T 8 8 9 9 7 8 8 8 9 cale) S 3 2 3 3 2 3 2 3 3 ability Outcome ewcastle-Ottawa N ompar C 1 2 2 2 1 1 2 1 2 election S Quality assessment ( 4 4 4 4 4 GF drug E reatment reatment egimen 3+PRN 3+PRN monthly or PRN 3+PRN 3+PRN T r TER 3+PRN 3+PRN 3+ monthly or quarterly Anti-V Ranibizumab, Ranibizumab, or bevacizumab aflibercept Ranibizumab 4 Ranibizumab or bevacizumab Ranibizumab or bevacizumab Ranibizumab or bevacizumab Ranibizumab or bevacizumab Ranibizumab 4 Ranibizumab 4 Ranibizumab 4 63 85 204 123 104 148 123 247 otal 1115 T 81 29 47 79 34 51 38 15 23 38 44 85 ach arm 110 153 108 162 143 E (Male/Female) Gender Participants 81.90±7.87 69.8±20.9 63.21±12.41 56/25 68.3±7.1 46/64 79.70±0.24 352/62083.03±5.43 14/14 972 74.72±8.43 31/16 75.0±6.9 76.5±7.3 Age 75.50±0.60 75/68 76.0±7.7 NA 74.5±6.1 NA tudy design S Prospective cohort within RCT Retrospective 79.31±6.47Retrospective 8/24 75.30±9.46 NA Retrospective 74.34±8.56 analysis Post hoc of RCT 25/13 Retrospective 67.7±20.7Prospective cohort within RCT NA Retrospective 62.62±10.42Retrospective 16/7 68.1±8.5 19/19 olment period nr ollow- 12 12 12 12 24 12 6 12 12 up (months) F E February 2008– February December 2009 NA June 2009– December 2013 NA May 2007–July 2009 June 2009–April 2011 2006– January 2011 February November 2008– May 2011 October 2005– November 2007 38 40 9 22 Characteristics and quality assessment results of the included studies 13 23 36 24

19 able 1 Ciulla, 2015 Lee, 2011 Lee, Krishnan, 2015 Krishnan, 2015 Houston, 2014 Waldstein, Lee, 2015 Lee, Mayr-Sponer, 2013 Nomura, 2014 Nomura, 2013 Cho, Author and year endothelium growth factor. vascular VEGF, treat and extend regimen; TER, randomised controlled trial; RCT, pro re nata; PRN, not available; NA, T

1006 Xie P, et al. Br J Ophthalmol 2017;101:1003–1010. doi:10.1136/bjophthalmol-2017-310155 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Review

Figure 2 Forest plot of change in mean best-corrected visual acuity at 6 and 12 months. VMA, vitreomacular adhesion; VMT, vitreomacular traction; IV, inverse variance.

VMT, as expected. The difference in the treatment outcomes proteolytic enzyme ocriplasmin, used alone or in combination between the two groups gradually grew smaller. If patients with anti-VEGF agents, to release VMA and VMT.27 40 54 57 were monitored beyond 12 months, the difference in the This study has some limitations. First, the VMA/VMT(-) mean number of injections would either persist or vanish, as group consisted of patients with complete posterior vitreous functional and anatomic differences did. According to the two attachment (PVA) or PVD. Although the OCT-based anatomic studies that had a follow-up duration of 2 years, the differ- classification of VMI diseases has been a gold standard,38 58 ences persisted.9 More studies with longer follow-up times are it is still difficult to differentiate when the posterior vitreous needed to draw a reliable conclusion regarding this issue. boundary could not be seen in the entire scan set.19 However, This study has clinical significance. First and foremost, clini- the difference induced by PVA may be negligible because PVA cians can get more information about the probable response of is rare in elderly patients.19 a given patient to anti-VEGF treatment by whether the patient Another major limitation is the great heterogeneity in the has concurrent VMA or VMT. The presence of VMA or VMT analysis of CRT change at month 12. This heterogeneity may serve as a potential indicator of slower response and the emerged from many possible factors, such as the variety of need for more frequent injections. When clinicians encounter demographic characteristics, different types of drugs, different patients with VMA or VMT, adequate counselling before treatment regimens and so on. Because there are no two iden- commencing treatment is recommended, so that patients will tical clinical studies, heterogeneity is a common feature of be fully informed as to what to expect.40 Second, based on the meta-analysis. The topic of this meta-analysis is a disputed findings of our study, clinicians are advised to be cautious in issue, with previous studies holding different conclusions. It is attempting to extend intervals between visits or treatments in for this reason that the heterogeneity of this meta-analysis is patients with VMA or VMT.13 Moreover, our study provides naturally high, and that it is especially meaningful to conduct some justification for recent clinical investigations recom- this evidence-based research. We adopted the following mending earlier vitrectomy or intravitreal injection of the methods to ensure the reliability and robustness of our

Figure 3 Forest plot of changes in mean central retinal thickness at 6 and 12 months. VMA, vitreomacular adhesion; VMT, vitreomacular traction; IV, inverse variance.

Xie P, et al. Br J Ophthalmol 2017;101:1003–1010. doi:10.1136/bjophthalmol-2017-310155 1007 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Review

Figure 4 Forest plot of mean number of injections during the 12-month follow-up. VMA, vitreomacular adhesion; VMT, vitreomacular traction; IV, inverse variance. analyses: (1) We use the random-effect model instead of the age, drug type and treatment regimen. The results are available fixed-effect model.59 60 (2) Sensitivity analysis was conducted in the online supplementary files. by excluding data from one study at a time and recalculating In conclusion, during the early stage of treatment, concurrent the results of the meta-analysis, whereby the current study was VMA or VMT may antagonise the efficacy of anti-VEGF drugs proved to be robust.61 (3) We also performed subgroup anal- in patients with nAMD. Patients with VMA or VMT achieved yses based on different conditions,62 including patients’ race, less improvement in BCVA and less CRT decline, but these

Figure 5 Funnel plot of each comparison. (A) Mean change in BCVA at 6 months; (B) Mean change in BCVA at 12 months; (C) Mean change in CRT at 6 months; (D) Mean change in CRT at 12 months; (E) Mean number of injections. BCVA, Best-corrected visual acuity; CRT, central retinal thickness; MD, mean difference.

1008 Xie P, et al. Br J Ophthalmol 2017;101:1003–1010. doi:10.1136/bjophthalmol-2017-310155 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Review differences gradually diminished over time. We also found that 20 Choudhury F, Varma R, McKean-Cowdin R, et al. Risk factors for four-year incidence patients with VMA or VMT required more injections. These and progression of age-related macular degeneration: the los angeles latino eye study. Am J Ophthalmol 2011;152:385–95. findings should be taken into consideration when clinicians 21 Yasuda M, Kiyohara Y, Hata Y, et al. Nine-year incidence and risk factors for age- evaluate prognosis or make decisions regarding individualised related macular degeneration in a defined japanese population the Hisayama study. therapeutic regimens for patients with nAMD. Ophthalmology 2009;116:2135–40. 22 Nomura Y, Takahashi H, Tan X, et al. Effects of vitreomacular adhesion on ranibizumab Contributors PX and XZ contributed equally and are coauthors of this paper, treatment in japanese patients with age-related macular degeneration. Jpn J who composed the manuscript. QL is the corresponding author, having designed Ophthalmol 2014;58:443–7. the study and revised the manuscript. YY and XY participated in data extraction. ZH 23 Cho HJ, Baek JS, Lee DW, et al. Effects of vitreomacular adhesion on anti-vascular and DY carried out the statistical analysis. All authors read and approved the final endothelial growth factor treatment for polypoidal choroidal vasculopathy. Retina manuscript. 2013;33:2126–32. Competing interests None declared. 24 Lee SJ, Koh HJ. Effects of vitreomacular adhesion on anti-vascular endothelial growth Provenance and peer review Not commissioned; externally peer reviewed. factor treatment for exudative age-related macular degeneration. Ophthalmology 2011;118:101–10. Data sharing statement Any interested reader may make an inquiry of additional 25 Weber-Krause B, Eckardt U. [Incidence of posterior vitreous detachment in eyes with unpublished data to corresponding authors via email. and without age-related macular degeneration. an ultrasonic study]. Ophthalmologe © Article author(s) (or their employer(s) unless otherwise stated in the text of the 1996;93:660–5. article) 2017. All rights reserved. No commercial use is permitted unless otherwise 26 Krebs I, Brannath W, Glittenberg C, et al. Posterior vitreomacular adhesion: a potential expressly granted. risk factor for exudative age-related macular degeneration? Am J Ophthalmol 2007;144:741–6. 27 Mojana F, Cheng L, Bartsch DU, et al. The role of abnormal vitreomacular adhesion References in age-related macular degeneration: spectral optical coherence tomography and 1 Lim LS, Mitchell P, Seddon JM, et al. Age-related macular degeneration. The Lancet surgical results. Am J Ophthalmol 2008;146:218–27. 2012;379:1728–38. 28 Lee SJ, Lee CS, Koh HJ. Posterior vitreomacular adhesion and risk of exudative age- 2 Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet related macular degeneration: paired eye study. Am J Ophthalmol age-related macular degeneration. Ophthalmology 2012;119:2537–48. 2009;147:621–6. 3 Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and bevacizumab for neovascular 29 Ondeş F, Yilmaz G, Acar MA, et al. Role of the vitreous in age-related macular age-related macular degeneration. N Engl J Med degeneration. Jpn J Ophthalmol 2000;44:91–3. 2011;364:1897–908. 30 Quaranta-El Maftouhi M, Mauget-Faysse M. Anomalous vitreoretinal adhesions 4 Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for in patients with exudative age-related macular degeneration: an OCT study. Eur J neovascular age-related macular degeneration. Ophthalmology Ophthalmol 2006;16:134–7. 2006;113:363–72. 31 Robison CD, Krebs I, Binder S, et al. Vitreomacular adhesion in active and end-stage 5 Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related age-related macular degeneration. Am J Ophthalmol 2009;148:79–82. macular degeneration. N Engl J Med 2006;355:1419–31. 32 Goverdhan SV, Hannan S, Newsom RB, et al. An analysis of the CFH Y402H genotype 6 Finger RP, Wickremasinghe SS, Baird PN, et al. Predictors of anti-VEGF treatment in AMD patients and controls from the UK, and response to PDT treatment. Eye response in neovascular age-related macular degeneration. Surv Ophthalmol 2008;22:849–54. 2014;59:1–18. 33 Jackson TL, Nicod E, Angelis A, et al. Vitreous attachment in age-related macular 7 Hermann MM, van Asten F, Muether PS, et al. Polymorphisms in vascular degeneration, diabetic macular edema, and retinal vein occlusion: a systematic review endothelial growth factor receptor 2 are associated with better response rates and metaanalysis. Retina 2013;33:1099–108. to ranibizumab treatment in age-related macular degeneration. Ophthalmology 34 Ikeda T, Sawa H, Koizumi K, et al. Pars Plana Vitrectomy for regression of choroidal 2014;121:905–10. neovascularization with age-related macular degeneration. Acta Ophthalmol Scand 8 Smailhodzic D, Muether PS, Chen J, et al. Cumulative effect of risk alleles in CFH, 2000;78:460–4. ARMS2, and VEGFA on the response to ranibizumab treatment in age-related macular 35 Emoto H, Emoto Y, Lim JI, et al. Regression of choroidal neovascularization after degeneration. Ophthalmology 2012;119:2304–11. vitrectomy for postinjection endophthalmitis. Retin Cases Brief Rep 2010;4:312–6. 9 Houston SK, Rayess N, Cohen MN, et al. Influence of vitreomacular interface on anti- 36 Lee KH, Chin HS, Kim NR, et al. Effects of vitreomacular traction on Ranibizumab vascular endothelial growth factor therapy using treat and extend treatment protocol Treatment response in eyes with neovascular Age-related Macular Degeneration. for age-related macular degeneration (VINTREX). Retina Korean J Ophthalmol 2015;29:396–403. 2015;35:1757–64. 37 Filloy A, Arias L. [Responses to ranibizumab in wet age-related macular degeneration 10 Rosenfeld PJ, Shapiro H, Tuomi L, et al. Characteristics of patients losing vision after patients with vitreomacular traction]. Arch Soc Esp Oftalmol 2 years of monthly dosing in the phase III ranibizumab clinical trials. Ophthalmology 2013;88:380–6. 2011;118:523–30. 38 Waldstein SM, Ritter M, Simader C, et al. Impact of vitreomacular adhesion on 11 Kaiser PK, Brown DM, Zhang K, et al. Ranibizumab for predominantly classic ranibizumab mono- and combination therapy for neovascular age-related macular neovascular age-related macular degeneration: subgroup analysis of first-year degeneration. Am J Ophthalmol 2014;158:328–36. ANCHOR results. Am J Ophthalmol 2007;144:850–7. 39 Wells G, Shea B, O’connell D, et al. The NewcastleOttawa Scale (NOS) for assessing 12 Boyer DS, Antoszyk AN, Awh CC, et al. Subgroup analysis of the MARINA study the quality of nonrandomised studies in metaanalyses. Ottawa, Canada: Ottawa of ranibizumab in neovascular age-related macular degeneration. Ophthalmology Hospital Research Institute, 2014. http://www.ohri.ca/progr ams/clinical_epidemiology/ 2007;114:246–52. oxford.asp (accessed 30 May 2017). 13 Ciulla TA, Cuilla TA, Ying GS, et al. Comparison of Age-Related Macular Degeneration 40 Krishnan R, Arora R, De Salvo G, et al. Vitreomacular traction affects anti-vascular Treatments Trials Research Group. Influence of the vitreomacular interface on endothelial growth factor treatment outcomes for exudative age-related macular treatment outcomes in the comparison of age-related macular degeneration degeneration. Retina 2015;35:1750–6. treatments trials. Ophthalmology 2015;122:1203–11. 41 Schulze S, Hoerle S, Mennel S, et al. Vitreomacular traction and exudative age-related 14 Kawasaki R, Yasuda M, Song SJ, et al. The prevalence of age-related macular macular degeneration. Acta Ophthalmol 2008;86:470–81. degeneration in Asians: a systematic review and meta-analysis. Ophthalmology 42 Simpson AR, Petrarca R, Jackson TL. Vitreomacular adhesion and neovascular age- 2010;117:921–7. related macular degeneration. Surv Ophthalmol 2012;57:498–509. 15 Laude A, Cackett PD, Vithana EN, et al. Polypoidal choroidal vasculopathy and 43 Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health neovascular age-related macular degeneration: same or different disease? Prog Retin and disease. Retina 2005;25:111–8. Eye Res 2010;29:19–29. 44 Seko Y, Seko Y, Fujikura H, et al. Induction of vascular endothelial growth factor after 16 Gupta B, Jyothi S, Sivaprasad S. Current treatment options for retinal angiomatous application of mechanical stress to retinal pigment epithelium of the rat in vitro. proliferans (RAP). Br J Ophthalmol 2010;94:672–7. Invest Ophthalmol Vis Sci 1999;40:3287–91. 17 Klein R, Klein BE, Knudtson MD, et al. Fifteen-year cumulative incidence of 45 Stefánsson E. Physiology of vitreous surgery. Graefes Arch Clin Exp Ophthalmol age-related macular degeneration: the Beaver dam Eye Study. Ophthalmology 2009;247:147–63. 2007;114:253–62. 46 Donoso LA, Kim D, Frost A, et al. The role of inflammation in the pathogenesis of age- 18 Wang JJ, Rochtchina E, Lee AJ, et al. Ten-year incidence and progression of age- related macular degeneration. Surv Ophthalmol 2006;51:137–52. related maculopathy: the blue mountains Eye Study. Ophthalmology 2007;114:92–8. 47 Nussenblatt RB, Ferris F. Age-related macular degeneration and the immune response: 19 Mayr-Sponer U, Waldstein SM, Kundi M, et al. Influence of the vitreomacular implications for therapy. Am J Ophthalmol 2007;144:618–26. interface on outcomes of ranibizumab therapy in neovascular age-related macular 48 Reese AB, Jones IS, Cooper WC. Macular changes secondary to vitreous traction. Am J degeneration. Ophthalmology 2013;120:2620–9. Ophthalmol 1967;64:544–49.

Xie P, et al. Br J Ophthalmol 2017;101:1003–1010. doi:10.1136/bjophthalmol-2017-310155 1009 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Review

49 Spaide RF, Armstrong D, Browne R. Choroidal Neovascularization in age-related 56 Ozsutcu M, Gulkilik G, Ayintap E, et al. Intravitreal bevacizumab may increase diabetic Macular degeneration—what is the cause? Retina 2003;23:595–614. macular edema in eyes with attached posterior vitreous. Case Rep Ophthalmol 50 Rotsos T, Sagoo MS, daCruz L, et al. Intravitreal anti-VEGF treatment in eyes with 2013;4:7–10. combined choroidal neovascularisation and vitreomacular traction syndrome. Br J 57 Syed YY, Dhillon S. Ocriplasmin: a review of its use in patients with symptomatic Ophthalmol 2010;94:1205–10. vitreomacular adhesion. Drugs 2013;73:1617–25. 51 Quiram PA, Leverenz VR, Baker RM, et al. Microplasmin-induced posterior vitreous 58 Duker JS, Kaiser PK, Binder S, et al. The International Vitreomacular Traction detachment affects vitreous oxygen levels. Retina Study Group classification of vitreomacular adhesion, traction, and macular hole. 2007;27:1090–6. Ophthalmology 2013;120:2611–9. 52 Stefánsson E, Novack RL, Hatchell DL. Vitrectomy prevents retinal hypoxia in branch 59 Hedges LV, Vevea JL. Fixed- and random-effects models in meta-analysis. Psychol retinal vein occlusion. Invest Ophthalmol Vis Sci 1990;31:284–9. Methods 1998;3:486–504. 53 Holekamp NM, Shui YB, Beebe DC. Vitrectomy surgery increases oxygen exposure to the Lens: a possible mechanism for nuclear cataract formation. Am J Ophthalmol 60 Brockwell SE, Gordon IR. A comparison of statistical methods for meta-analysis. Stat 2005;139:302–10. Med 2001;20:825–40. 54 Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for 61 Sutton AJ, Abrams KR, Jones DR, et al. Methods for meta-analysis in medical research. vitreomacular traction and macular holes. N Engl J Med 2012;367:606–15. New Jersy: Wiley, 2000. 55 Stalmans P, Duker JS, Kaiser PK, et al. Oct-based interpretation of the vitreomacular 62 Wang R, Lagakos SW, Ware JH, et al. Statistics in medicine – reporting of subgroup interface and indications for pharmacologic vitreolysis. Retina 2013;33:2003–11. analyses in clinical trials. N Engl J Med 2007;357:2189–94.

1010 Xie P, et al. Br J Ophthalmol 2017;101:1003–1010. doi:10.1136/bjophthalmol-2017-310155 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com

Vitreomacular adhesion or vitreomacular traction may affect antivascular endothelium growth factor treatment for neovascular age-related macular degeneration Ping Xie, Xinhua Zheng, Yingqing Yu, Xiaojian Ye, Zizhong Hu, Dongqing Yuan and Qinghuai Liu

Br J Ophthalmol 2017 101: 1003-1010 doi: 10.1136/bjophthalmol-2017-310155

Updated information and services can be found at: http://bjo.bmj.com/content/101/8/1003

These include: References This article cites 60 articles, 4 of which you can access for free at: http://bjo.bmj.com/content/101/8/1003#BIBL Email alerting Receive free email alerts when new articles cite this article. Sign up in the service box at the top right corner of the online article.

Notes

To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions

To order reprints go to: http://journals.bmj.com/cgi/reprintform

To subscribe to BMJ go to: http://group.bmj.com/subscribe/