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ORIGINAL ARTICLE
Year : 2018  |  Volume : 5  |  Issue : 1  |  Page : 15-20

Benefits of anti-vascular endothelial growth factor therapy for diabetic macular edema with and without vitreomacular adhesions


1 Department of Ophthalmology, Research Institute of Ophthalmology, Giza, Egypt
2 Department of Ophthalmology, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Web Publication20-Aug-2018

Correspondence Address:
Dr. Yasmine Salah Salem
Research Institute of Ophthalmology, Giza
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/erj.erj_2_18

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  Abstract 


Purpose: We aimed to evaluate the effect of vitreomacular adhesion (VMA) in visual and anatomic outcomes in patients with diabetic macular edema (DME) after intravitreal injection of ranibizumab (Lucentis®). Patients and Methods: This was a prospective cohort study that included thirty eyes of DME patients, divided into two groups according to their spectral-domain-optical coherence tomography image analysis at the baseline visit to identify the presence (VMA+) or absence (VMA−) of VMA. Patients with any degree of vitreomacular traction were not included in this study. VMA was classified by the size of adhesion into either focal (<1500 mm) or broad (>1500 mm). All patients received monthly 0.5 mg of intravitreal ranibizumab injection for 6 months. Patients were observed monthly for a 6-month period and their best-corrected visual acuity (BCVA) and central macular thickness (CMT) were recorded. The incidence of posterior vitreous detachment (PVD) was observed. Results: Compared with baseline, there was a significant decrease in CMT after 6 months by 151.46 ± 121.47 and 139.33 ± 144.23 μm in VMA+ and VMA− groups, respectively (P = 0.681). The mean average improvement in BCVA was 10.21 ± 6.33 and 6.68 ± 6.35 letters in the VMA+ and VMA− groups, respectively. The difference between the two groups was statistically significant (P = 0.007). At 6 months, among the 15 eyes of VMA+ at baseline, 4 eyes demonstrated PVD and 11 eyes showed no change in VMA status. Conclusion: Patients having DME with VMA may achieve higher visual gain with anti-vascular endothelial growth factor therapy. Presence of VMA should not preclude patients with DME from receiving anti-vascular endothelial growth factor therapy.

Keywords: Anti-vascular endothelial growth factor, diabetic macular edema, vitreomacular adhesion


How to cite this article:
Salem YS, Mohamed AA, Hashem MH, El Hefny MM. Benefits of anti-vascular endothelial growth factor therapy for diabetic macular edema with and without vitreomacular adhesions. Egypt Retina J 2018;5:15-20

How to cite this URL:
Salem YS, Mohamed AA, Hashem MH, El Hefny MM. Benefits of anti-vascular endothelial growth factor therapy for diabetic macular edema with and without vitreomacular adhesions. Egypt Retina J [serial online] 2018 [cited 2018 Nov 17];5:15-20. Available from: http://www.egyptretinaj.com/text.asp?2018/5/1/15/239455




  Introduction Top


Diabetic macular edema (DME) is one of the most popular causes for functional visual loss. For decades, DME was treated by laser photocoagulation. However, the benefit of anti-vascular endothelial growth factor (anti-VEGF) has become a turning point for the treatment of DME.[1]

The severity of DME has a direct relation to the level of VEGF. It increases the abnormal angiogenesis and the permeability of the blood–retinal barrier, leading to more swelling of the macula. Hence, anti-VEGF therapy can play an important role in treating DME via inhibition of VEGF.[2] Ranibizumab, bevacizumab, and aflibercept are important anti-VEGF drugs, with their efficacy been established in Phase III clinical trials.[3]

Vitreomacular interface disease has been reported to occur in up to 7% to 16% of eyes with DME, with annual incidence as high as 4.5%; these anomalies include vitreomacular traction (VMT), epiretinal membrane (ERM), and vitreomacular adhesion (VMA).[4] A recent study proved that patients with DME and VMA have a higher chance for improvement in visual acuity (VA) and anatomical outcomes after treatment with anti-VEGF therapy, so we should not exclude patients with VMAs from taking anti-VEGF therapy.[5]

Patients with ERM involving the macular center and patients with VMT may be recommended for vitrectomy. Traction forces play a major role in the pathogenesis of DME and reduce the effectiveness of intravitreal anti-VEGF therapy in eyes with VRI abnormalities.[6] Thus, our study aimed to assess the role of VMA as a possible prognostic factor in patients receiving anti-VEGF therapy for DME and to assess the rate of posterior vitreous detachment (PVD) after monthly ranibizumab injection.


  Patients and Methods Top


Patients

Thirty eyes of 30 diabetes mellitus (DM) patients with DME (11 male [36.67%] and 19 female patients [63.33%]), divided into two groups at baseline: Group A with VMA (VMA+) and Group B without VMA (VMA−), were recruited for this prospective study, from the outpatient clinic of Research Institute of Ophthalmology in Giza. Cases were collected from December 2016 to October 2017.

The study was approved by the Research and Ethics committee of AIN Shams University in accordance with the Helsinki Declaration of human subjects, and written informed consent was obtained from all the participating patients after explaining to them all the study procedures with their benefits and hazards.

Inclusion criteria

Patients were selected according to the following inclusion criteria:

  1. Best-corrected VA (BCVA) in the range of 20/30–20/200 (approximate Snellen equivalent using the Early Treatment Diabetic Retinopathy Study [ETDRS] protocol at a distance of 4 m)
  2. Central subfield macular thickness (CMT) on optical coherence tomography (OCT) of >270 μm in the central subfield
  3. Intraocular pressure (IOP) <24 mmHg
  4. Media clarity, papillary dilatation, and patient's cooperation sufficient for adequate fundus imaging
  5. The ability of the patient for regular follow-up visits.


Exclusion criteria

Patients were excluded from the study according to the following criteria:

  1. Macular edema due to a cause other than DME
  2. Having epimacular membrane (e.g., epiretinal traction documented with OCT)
  3. Coexistent ocular disease that was likely to preclude VA improvement such as a preexisting ocular condition (e.g., marked cataract, amblyopia, and foveal scare) or an ocular condition that may affect macular edema or alter VA during course of the study (e.g., retinal vascular occlusion, ocular inflammatory disease, and neovascular glaucoma)
  4. Patients with proliferative diabetic retinopathy or with glycosylated hemoglobin A1c (HbA1c) >10%, or patients with a medical history of renal failure requiring dialysis or kidney transplantation or blood pressure >170/100 mmHg, and patients with any recent evident history of ocular trauma
  5. Patients who received previous treatment for DME
  6. Fluorescein angiography (FFA) evidence of macular ischemia of moderate-to-severe degree. Moderate irregularities are defined as abnormally dilated and tortuous capillaries budding into the foveal avascular zone (FAZ), terminal arterioles/venules directly abutting FAZ margins, and enlarged intercapillary spaces around the FAZ. Ischemia was diagnosed only when the longest diameter of FAZ was >1000 μ. Severe FAZ irregularity is defined as the destruction of the FAZ architecture: grossly enlarged FAZ with “pruned off” arterioles.


Methods

All patients were subjected to complete history taking including the duration and type of DM, duration of vision deterioration, any presence of past ocular diseases or surgeries including retinal laser or intravitreal injection, and any associated systemic disease other than diabetes such as hypertension, ischemic heart disease, bleeding tendencies, and anticoagulant therapy. Complete ophthalmological examination was performed including BCVA using ETDRS VA chart, applanation tonometry, anterior segment, and dilated slit-lamp biomicroscopical examination (including clinical grading of lens opacity). All patients had standard color fundus photography. FFA was made using Topcon TRC-50DX fundus camera. OCT imaging was done using ZEISS (Cirrus HD-OCT Ophthalmic Systems Inc., Humphrey Division, Dublin, CA, USA), where retinal thickness was measured in a circle (6.0 mm in diameter) centered on the point of fixation. The CMT was recorded and used for statistical analysis. All patients had their BCVA recorded.

Detection of VMA was done using spectral-domain-OCT (SD-OCT) images for patients at the baseline visit. Presence of VMA was defined as an elevation of the perifoveal vitreous cortex from the retinal surface along with attachment of the vitreous cortex at the center of the fovea and no secondary detectable changes in foveal contour or in the underlying retinal tissue. The VMA was classified by the size of adhesion into either focal (<1500) or broad (>1500).

Patients were subdivided at baseline according to the SD-OCT assessment of vitreomacular relation (VMR) into two groups: DME patients with VMA (VMA+) group including 15 patients (6 males [40%] and 9 females [60%]), with mean age ± standard deviation (SD) of 63.733 ± 5.509 years, and DME patients without VMA (VMA−) group including 15 patients (5 males [33.33%] and 10 females [66.67%]), with mean age ± SD of 61.267 ± 5.496 years.

The study included thirty eyes; all of them received monthly injection of 0.5 mg of intravitreal ranibizumab (IVR) for 6 months. Patients were followed up monthly for 6 months. Complete ocular examination including BCVA and CMT were recorded at the 6th month.

Surgical technique

IVR injection was performed with the patient lying supine on the operating table and, after eyelid disinfection (10% povidone-iodine) and draping, a wire speculum that gives maximum exposure to the globe was applied. Topical anesthesia using 0.4% benoxinate hydrochloride eye drops was instilled preoperatively 5 min before the procedure. The patient was asked to look nasally and slightly upward to expose the inferotemporal quadrant of the sclera. Using a 27G needle inserted 3.5–4.0 mm posterior to the limbus into the midvitreous cavity, avoiding the horizontal meridian and aiming toward the center of the globe, IVR injection was delivered.

Ranibizumab has been developed by Genentech and is marketed in the USA by Genentech (San Francisco, California) and elsewhere by Novartis (Basel, Switzerland) under the brand name Lucentis ®.

Gentle pressure on the site of the injection was applied using a Merocel ® (Medtronic, Minneapolis, USA) sponge after removal of the syringe. The lid speculum was removed carefully and an eye patch was placed. After injection, the optic nerve head and IOP were assessed. Paracentesis was performed if the IOP was elevated. The patient was instructed to instill topical moxifloxacin ophthalmic solution 0.5% (Alcon Laboratories, Inc., Fort Worth, TX, USA) four times per day for 1 week after the intravitreal injection.

Statistical analysis

Analysis of the data was done by using statistical package for the social sciences version 16 (SPSS Inc., Chicago, Illinios, USA). Quantitative data were presented as mean and SD and were analyzed by using one-way unpaired t-test to compare quantitative variables, in parametric data (SD50% mean). Qualitative data were presented as numbers and percentages and were analyzed by using x 2 and fisher's exact tests. P<0.05 was considered significant, whereas P<0.01 was considered highly significant. However, P<0.05 was considered in significant.


  Results Top


Thirty eyes of thirty patients with DME were enrolled in this study. The demographic and clinical characteristics of all patients are summarized in [Table 1].
Table 1: Demographic and clinical characteristics of all patients

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There were 11 male (36.67%) and 19 female patients (63.33%) between 50 and 71 years of age, with a mean value of 62.5 ± 5.5025 years. There were 8 patients (26.67%) with Type I and 22 patients (73.33%) with Type II DM.

The duration of DM ranged from 7 to 25 years, with a mean value of 14.967 ± 4.967 years. HbA1c ranged from 6.5% to 8.8%, with a mean value of 7.90% ± 0.546%. IOP ranged from 12 to 23 mmHg with a mean value of 17.88 ± 2.82 mmHg.

Baseline VA (ETDRS) ranged from 7.11 to 8.25 letters with a mean value of 53.13 ± 12.22 letters. Baseline CMT ranged from 301.0 to 525.0 μm, with a mean value of 413.0 ± 107.0 μm. Lens status differentiated to 25 phakic eyes (84%) and 5 pseudophakic eyes (16%).

Demographic analysis between two groups

According to the SD-OCT assessment of vitreomacular relation (VMR) at baseline visit, patients were classified into two groups: 15 patients (15 eyes) with VMA (VMA+ group) including 6 males (40%) and 9 females (60%) and 15 patients (15 eyes) without VMA (VMA− group) including 5 males (33.33%) and 10 females (66.67%).

There were no significant differences at baseline between the two groups, including demographic characteristics and baseline CMT and BCVA values as demonstrated in [Table 2].
Table 2: Baseline demographic data analysis between the two groups

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All eyes included in the study received monthly IVR injections for 6 months. The mean number of injection in each eye (of six mandatory injections) was 5.92 ± 0.28 and 5.92 ± 0.27 injections in VMA+ and VMA− groups, respectively. There were a total of four missed visits in VMA+ group and two missed visits in VMA− group; 13 patients (86.6%) were phakic in VMA+ group and 14 patients (93.3%) were phakic in VMA− group.

At month 6, the mean change of BCVA in VMA + group was 10.21 ± 6.33 letters, whereas the mean change of BCVA in VMA− group was 6.68 ± 6.35 letters. Both groups showed statistically significant improvement in BCVA from baseline (P < 0.05). The difference between the improvements in the two groups was statistically significant (P = 0.007) [Table 3].
Table 3: Best-corrected visual acuity changes after 6-month follow-up

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At month 6, the mean change of central retinal thickness (CRT) in VMA+ group was 151.46 ± 121.47 μm, whereas the mean change of CRT in VMA− group was 139.33 ± 144.23 μm. Both groups showed a statistically significant reduction in CRT from baseline (P < 0.05). The difference in the mean reduction of CRT in the two groups was not statistically significant (P = 0.662) [Table 4] and [Figure 1].
Table 4: Central macular thickness changes after 6-month follow-up

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Figure 1: The change from baseline in central retinal thickness in the two study groups at different time points

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Changes in vitreomacular adhesion status at month 6

Analysis of the SD-OCT images of the 15 VMA+ patients showed that PVD occurred in 4 eyes, whereas 11 eyes had no change in VMA status by the 6th month visit. The mean change in BCVA in the eyes in which PVD developed from baseline to month 6 was 12.98 ± 3.31 letters compared with 9.91 ± 7.52 letters in the eyes that had persistent VMA at month 6 (P = 0.181). Similarly, the mean change in CRT was 224.14 ± 124.34 μm in the 7 eyes in which PVD developed compared with the mean change in CRT was198.81 ± 124.51 μm in the 11 eyes that had persistent VMA at month 6 (P = 0.183). Of the four patients in which PVD developed, two patients demonstrated PVD after the first injection, one patient demonstrated PVD after five injections, and one patient demonstrated PVD after six injections. Rates of development of PVD were significant between the two groups (P = 0.001) [Figure 2] and [Table 5].
Figure 2: Vitreomacular adhesion status change after 6 months in VMA+ group. VMA: Vitreomacular adhesion

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Table 5: Posterior vitreous detachment occurrence in vitreomacular adhesion presence group after 6 month

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Focal versus broad vitreomacular adhesion

Of the 15 patients with VMA at baseline, 3 eyes had focal VMA and 12 eyes had broad VMA. Mean change in BCVA from baseline to month 6 was 11.40 ± 2.85 and 12.23 ± 6.26 letters in eyes with focal and broad VMA, respectively (P = 0.82). Mean change in CMT from baseline to month 6 was 300.00 ± 132.81 and 154.89 ± 112.45 mm in eyes with focal and broad VMA, respectively (P = 0.02). Two of the 3 eyes that had focal VMA at baseline demonstrated PVD, whereas 2 of the 12 eyes that had broad VMA at baseline demonstrated PVD [Table 6] and [Figure 3].
Table 6: Focal versus broad vitreomacular adhesion changes after 6 months

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Figure 3: Representative examples of cross-sectional optical coherence tomography scans from eyes of diabetic macular edema with focal VMA+ (a), diffuse VMA+ (b) and VMA− (c) showing improved diabetic macular edema after IVI of ranibizumab and release of adhesion in focal VMA+. IVI: Intravitreal anti-VEGF injection, VMA: Vitreomacular adhesion, CST: Central subfield thickness

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  Discussion Top


In this work, we tried to highlight the benefits of intravitreal anti-VEGF injection in treating DME with VMA. The role of vitreous adhesion in the pathologic features of vitreomacular disease is being appreciated.

In this prospective study, 30 eyes of DME patients (15 eyes with VMA [VMA+] and 15 eyes without VMA [VMA−]) were enrolled and studied. All of them received a monthly injection of 0.5 mg IVR under sterile conditions. After 6-month follow-up, the mean average change in BCVA was significantly improved in both groups, but there was more significance in VMA+ group and there was a significant decrease in CMT in both groups.

These results suggest that VMA alone, in the absence of retinal traction, may not adversely affect the treatment outcomes. Thus, patients with disorders of the vitreoretinal interface must be assessed carefully using SD-OCT to differentiate VMA from VMT.

After 6-month follow-up among the 15 eyes with VMA (Group A), 4 eyes demonstrated complete PVD and achieved a higher gain in BCVA (12.98 ± 3.31 letters) compared with the 11 eyes in which PVD did not develop. This may be responsible for the overall performance of VMA+ group compared with the VMA− group. In addition, these eyes had a greater reduction in CRT compared with the 11 eyes in which PVD did not develop (224.14 ± 124.34 μm).

Our finding agrees with the published literature that occurrence of PVD may be beneficial in the natural history of DME. Nasrallah et al. first published data suggesting the role of vitreous adhesion in DME. They reported that DME was present in only 20% of eyes with PVD compared with 55% of eyes with an attached hyaloid.[7] In another report by Hikichi et al., spontaneous resolution of DME was observed in 55% of eyes in which PVD developed compared with only 25% in those it did not.[8]

Several different mechanisms may be responsible for improved outcomes in these eyes. Stefansson advocated the role of improved transvitreal oxygenation in these patients after vitreous detachment that may lead to improvement in visual acuity.[9] Another hypothesis suggests increased concentration of growth factors in the premacular hyaloid secondary to increased enzyme-mediated collagen cross-linking in the vitreous adhesion. Detachment of the posterior hyaloid in these eyes may remove this reservoir of growth factor from the vicinity of the retina and therefore lead to improved outcomes.[10]

Most patients (two of three) with focal VMA at baseline demonstrated PVD by month 6. None of these patients experienced subsequent macular traction or tears. However, of the 12 eyes with broad VMA at baseline, only 2 demonstrated PVD. The difference in the rates of development of PVD between the two study groups was significant in our study. In a study performed on patients with age-related macular degeneration, similar results were observed.[11]

Thus, eyes with focal VMA may be more likely to demonstrate PVD during the course of the disease and have better outcomes compared with those with broad VMA. Eyes with broad VMA may require a longer follow-up for separation of the vitreous adhesion from the retina to occur. From the results of our study, the mechanism of occurrence of PVD does not seem to be related to the pharmacologic actions of the anti-VEGF agents.

Of the four patients with PVD after treatment, two patients demonstrated PVD after the first injection, one patient demonstrated PVD after five injections, and one patient demonstrated PVD after six injections. Thus, the occurrence of PVD may be related to a number of factors in the natural course of the disease apart from the mechanical or pharmacologic actions of the drug.

A previous study by Terao et al., evaluating the role of VMA in treatment outcomes of patients with macular edema secondary to branch retinal vein occlusion, reported similar results. That study reported the role of VMA in determining treatment outcomes in patients with macular edema secondary to branch retinal vein occlusion who underwent treatment with intravitreal bevacizumab. The study results suggested a significant improvement in BCVA and CRT in patients with VMA compared with patients without VMA.[12]

These results are in consistent with the previously reported results of (READ-3) a study by Sepah who stated that patients with DME and VMA have a higher potential for improvement in visual and anatomic outcomes after treatment with anti-VEGF agents and, therefore, should not preclude these patients from receiving treatment with anti-VEGF agents. Sepah et al. choose SD-OCT imaging for this study because it is a rapid, noncontact imaging modality that allows detailed imaging of the retina and vitreous body. Sepah reported that “It is a useful tool for assessing retinal structures because of its ability to acquire high-resolution images of retinal morphology. The ability of OCT to visualize the vitreomacular interface may allow ophthalmologists to make informed treatment decisions.”[13]

According to (READ-3) study, in the future, Sepah would like to conduct a longer follow-up to observe the gain in visual and anatomic outcomes in patients who did not develop PVD over the course of the study.[13]


  Conclusion Top


Patients having DME with VMA may achieve higher visual gain with anti-vascular endothelial growth factor therapy. Presence of VMA should not preclude patients with DME from receiving anti-vascular endothelial growth factor therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Agarwal A, Sarwar S, Sepah YJ, Nguyen QD. What have we learnt about the management of diabetic macular edema in the antivascular endothelial growth factor and corticosteroid era? Curr Opin Ophthalmol 2015;26:177-83.  Back to cited text no. 1
    
2.
Giuliari GP, Guel DA, Gonzalez VH. Pegaptanib sodium for the treatment of proliferative diabetic retinopathy and diabetic macular edema. Curr Diabetes Rev 2009;5:33-8.  Back to cited text no. 2
    
3.
Diabetic Retinopathy Clinical Research Network; Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015;372:1193-203.  Back to cited text no. 3
    
4.
Chang CK, Cheng CK, Bai CH. Development of vitreomacular interface abnormality in patients with diabetic macular edema. Taiwan J Ophthalmol 2012;2:93-8.  Back to cited text no. 4
  [Full text]  
5.
Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF trap, ranibizumab and bevacizumab. Angiogenesis 2012;15:171-85.  Back to cited text no. 5
    
6.
Musat O, Cernat C, Labib M, Gheorghe A, Toma O, Zamfir M, et al. Diabetic macular edema. Rom J Ophthalmol 2015;59:133-6.  Back to cited text no. 6
    
7.
Nasrallah FP, Jalkh AE, Van Coppenolle F, Kado M, Trempe CL, McMeel JW, et al. The role of the vitreous in diabetic macular edema. Ophthalmology 1988;95:1335-9.  Back to cited text no. 7
    
8.
Hikichi T, Fujio N, Akiba J, Azuma Y, Takahashi M, Yoshida A, et al. Association between the short-term natural history of diabetic macular edema and the vitreomacular relationship in type II diabetes mellitus. Ophthalmology 1997;104:473-8.  Back to cited text no. 8
    
9.
Stefánsson E. Ocular oxygenation and the treatment of diabetic retinopathy. Surv Ophthalmol 2006;51:364-80.  Back to cited text no. 9
    
10.
Stolba U, Binder S, Gruber D, Krebs I, Aggermann T, Neumaier B, et al. Vitrectomy for persistent diffuse diabetic macular edema. Am J Ophthalmol 2005;140:295-301.  Back to cited text no. 10
    
11.
Veloso CE, Kanadani TM, Pereira FB, Nehemy MB. Vitreomacular interface after anti-vascular endothelial growth factor injections in neovascular age-related macular degeneration. Ophthalmology 2015;122:1569-72.  Back to cited text no. 11
    
12.
Terao R, Yuda K, Kure K, Inoue T, Ohtsu H, Yanagi Y, et al. Effect of vitreomacular adhesion on antivascular endothelial growth factor therapy for macular edema secondary to branch retinal vein occlusion. Jpn J Ophthalmol 2014;58:139-45.  Back to cited text no. 12
    
13.
Sadiq MA, Soliman MK, Sarwar S, Agarwal A, Hanout M, Demirel S, et al. Effect of vitreomacular adhesion on treatment outcomes in the ranibizumab for edema of the macula in diabetes (READ-3) study. Ophthalmology 2016;123:324-9.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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