MACULAR HYPOTROPHY AFTER INTERNAL LIMITING MEMBRANE REMOVAL FOR DIABETIC MACULAR EDEMA MARIO R. ROMANO, MD, PHD,* VITO ROMANO, MD,† JOSE L. VALLEJO-GARCIA, MD,* RICCARDO VINCIGUERRA, MD,‡ MARY ROMANO, MD,† MATTEO CEREDA, MD,§ MARTINA ANGI, MD,¶ XAVIER VALLDEPERAS, MD,** CIRO COSTAGLIOLA, MD,†† PAOLO VINCIGUERRA, MD* Purpose: To compare the anatomic and functional effects of three different approaches to nontractional diabetic macular edema. Methods: Retrospective comparative study. Sixty eyes of 60 patients diagnosed with cystoid diabetic macular edema and treated with 1.25 mg/mL intravitreal bevacizumab (Group A), laser photocoagulation (Group B), or vitrectomy with inner limiting membrane peeling (Group C) were included in the study. Changes in number of Early Treatment Diabetic Retinopathy Study letters, central macular thickness, largest diameter of the intraretinal cysts (IC), and choroidal thickness were investigated. Analyses were performed during follow-up visits at Months 1, 3, 6, 9, and 12. Results: Visual acuity only significantly improved in Group A at the last follow-up (P = 0.004). Central macular thickness significantly decreased in every group throughout the follow-up period. Differences in central macular thickness between Groups A and B (P , 0.01), A and C (P , 0.01), and B and C (P , 0.01) were significant. Intraretinal cysts also significantly decreased in each group throughout the follow-up period. Differences in IC size between Groups A and B (P = 0.8), A and C (P = 0.1), and B and C (P = 0.1) were not significant. Choroidal thickness did not undergo any significant change in any group throughout the follow-up period. A significant correlation was also found in Group A between best-corrected visual acuity at month 12 and baseline central macular thickness (R = 0.3; P = 0.006), and in Group B between postoperative best-corrected visual acuity at month 12 and baseline IC size (R = 0.8; P , 0.01, negatively correlated at 92.4%). Conclusion: According to our retrospective data, diabetic macular edema with intraretinal cysts larger than 390 mm should not be treated with vitrectomy with ILM peeling, because this may induce subfoveal atrophy, defined as the “Floor Effect,” and subsequent visual deterioration. RETINA 34:1182–1189, 2014
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The location of intraretinal fluid occurs mainly between the inner and outer plexiform layers and in advanced stages, it can also extend to the space between the outer plexiform layer and the external limiting membrane.5 Fluid accumulation causes an increase in retinal volume through the formation of large intraretinal cysts (IC), which can overcome the resistance of Müller cells and damage the outer nuclear layers.6 These phenomena cause the interruption of bipolar axons, which normally function as the main connection between photoreceptors and ganglion cells.4 Fluid accumulation can also take place in the subfoveal space,
oing through the retinal and choroidal layers of diabetic eyes, several alterations can be found regarding the glycosylation of collagen at the interfaces, impairment of Müller cells and the inner blood retinal barrier (BRB), damage of the outer BRB, and reduced choroidal thickness (CT).1–3 Diabetic macular edema (DME) is characterized by a peculiar fluid accumulation, resulting from either damage of the inner BRB, with an increased leakage of retinal capillaries, or impairment of the outer BRB, with a decreased pumping capacity of the retinal pigment epithelium (RPE).4 1182
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between photoreceptors and the RPE, being mainly related to damage of the choroid and outer BRB.7 The measurement of retinal thickness, and the different patterns of DME described by spectral domain–optical coherence tomography, is considered to be a standard parameter even when a very low correlation to function measurement has been reported.8,9 The main tomographic predictive factors for visual function have been reported to be the integrity of outer retinal layers (external limiting membrane, inner segment/outer segment junction), and the residual connectivity between the plexiform layers as an anatomic sign of bipolar survival.10 In fact, the most widespread treatment approach for DME is with multiple anti–vascular endothelial growth factor (anti-VEGF) injections. Differences in the bestcorrected visual acuity (BCVA) between the antiVEGF and control (laser photocoagulation and/or sham injection) treatments has ranged between four and nine letters in most studies, with no differences between antiVEGF agents.11–14 More recently, the DA VINCI Study of VEGF Trap-Eye reported significant gains in BCVA, which was maintained or improved at week 52 even with as needed 2 mg dosing, after 3 initial monthly doses.15 Grid laser macula treatment still plays a key role in current DME treatment. The Early Treatment Diabetic Retinopathy Study demonstrated that, over a 3-year period, focal laser treatment reduced the risk of moderate visual loss by 50%, compared with controls.16 New treatment systems, such as nano- and micropulsed laser retina treatment result in thermal damage confined to RPE cells, preserving, at least in theory, the overlying photoreceptors. It has been recently discovered that even with these lasers, the results of peak power in cavitated areas could induce rupture of the Bruch membrane. Said damage can be minimized using a spot size larger than 400 mm, which would be able to neutralize cavitation damage.17 Finally, pars plana vitrectomy has become a widely used technique for tractional DME by creating a posterior vitreous detachment (PVD).18,19
The mechanism underlying the efficacy of PVD induction involves relief of the posterior hyaloid membrane traction, removal of inflammatory cytokines, such as the vascular endothelial growth factor, and an increase in the preretinal oxygen pressure.20 Vitrectomy for nontractional DME, combined with the surgical removal of the internal limiting membrane (ILM), is well established, despite having been a source of controversy in the literature.21,22 Nonetheless, few studies report a decreased DME with consequent functional improvement, whereas some show a significant decrease in the retinal thickness with worsening visual function.21,23 The ILM, the basement membrane of the retinal Müller cell, is composed of glycoprotein and proteoglycan, and it is considered to function as a scaffold and charged barrier between the vitreous and retina. Therefore, the ILM is involved in preserving the cytoarchitecture of the retina.24 Recent reports have suggested that the effect of the ILM on macular edema is related to the ability to reduce tangential traction, induced by collagen glycosylation. At the same time, foot Müller cells damage, induced by the peeling, might produce a vertical glyosis.23 The aim of this study was to compare the anatomical and functional effects of three different treatment approaches to nontractional DME. Intraretinal and choroidal changes were also correlated to functional results.
From the *Department of Ophthalmology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; †Department of Ophthalmology, Second University of Naples, Naples, Italy; ‡Department of Ophthalmology, University of Insubria, Varese, Italy; §Eye Clinic, Department of Clinical Science “Luigi Sacco,” Sacco Hospital, University of Milan, Milan, Italy; ¶Department of Clinical and Molecular Cancer Studies, University of Liverpool, Liverpool, United Kingdom; **Department of Ophthalmology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; and ††Department of Ophthalmology, University of Molise, Campobasso, Italy. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Mario R. Romano, MD, PhD, Humanitas Clinical and Research Center, Department of Ophthalmology, Via Manzoni 56, Rozzano, Milan, Italy 20089; e-mail: [email protected]
Participants
Methods Study Design Retrospective comparative study, conducted between 3 retinal centers, included 60 eyes of 60 patients (Table 1). The study was performed in accordance with the ethical standards stated in the Declaration of Helsinki and approved by the institutional review board. Each patient signed an informed consent. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
The eyes included in the study were diagnosed with cystoid DME and treated with either intravitreal bevacizumab, vitrectomy with ILM, or laser photocoagulation treatment. The biomicroscopy diagnosis was confirmed with a fluorescein angiography and optical coherence tomography. The eyes in question had to meet the following inclusion criteria to be eligible for the study: 1) BCVA between 20/63 and 20/400 (ETDRS letter score between 45 and 5), 2) a retinal central subfield
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Table 1. Demographics and Clinical Characteristics of Patients at Study Entry Characteristic No. of eyes Gender Male Female Mean age Mean BCVA (letter) Central macular thickness (mm) Intraretinal cysts (mm) CT (mm)
Group A (IVB)
Group B (Laser)
Group C (PPV)
20
20
20
Group A vs. Group C, P
Group B vs. Group C, P
1 1
1 0.7
1 0.5
11 12 9 9 8 11 64.9 ± 4.01 62.9 ± 5.01 61.9 ± 8.01 21 ± 6.1 22 ± 7.4 24 ± 5.3 450 ± 18.3 447 ± 13.3 432 ± 75.12
0.1 0.6 0.5
0.1 0.1 0.3
0.6 0.3 0.3
362 ± 36 266 ± 15.2
0.06 0.1
0.8 0.4
0.2 0.3
341 ± 34.8 257 ± 20.1
Group A vs. Group B, P
359 ± 53.8 262 ± 15.9
Values are mean ± SD. IVB, intravitreal bevacizumab; laser, laser photocoagulation treatment; PPV, pars plana vitrectomy.
thickness of .300 mm on optical coherence tomography, 3) having undergone a cataract extraction, not performed in conjunction with a pars plana vitrectomy. The main exclusion criteria included: 1) the presence of epiretinal traction, 2) history of macular photocoagulation, intravitreal corticosteroids or other treatments for DME in the 3.5 months before enrolment, 3) pan laser photocoagulation, undergone in the 4 months before enrolment, 4) a previous pars plana vitrectomy, 5) any other major ocular surgery (including cataract extraction, scleral buckle, or other intraocular surgery) in the 6 months before enrolment, or anticipated to the 6 months after enrolment; or 6) Nd:YAG laser capsulotomy performed in the 3.5 months before enrollment. Intervention
nation, including a BCVA measurement with ETDRS letters at 4 meters,26 slit-lamp and funduscopic examinations, and spectral domain–optical coherence tomography analysis (HD linear macula scan and macular map with Cirrus, Zeiss Meditec, Dublin, CA). Mean thickness in the 1-mm circle centered on the fovea was considered as a measure of central macular thickness (CMT) and factored in for statistical analysis. At each follow-up, the largest diameter of the IC and CT were also recorded. Fluorescein angiography was performed in all patients only at baseline. Follow-up visits were analyzed at Months 1, 3, 6, 9, and 12. Statistical Analyses Statistical differences between pre- and posttreatment clinical data were assessed using a paired t-test. Differences between the bevacizumab injection, laser treatment, and vitrectomy with ILM peeling were assessed using an independent t-test (STATA/IC 11.0). A P value of less than 0.05 was regarded statistically significant. The adjusted P value, according to Holm’s method, has been taken into account for multiple comparisons.
In Group A, bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) was injected into the vitreous in a dose of 1.25 mg in 0.05 mL. Reinjections were performed in eyes with a BCVA lower than 20/40 and with a persistence of clinically significant DME, according to the Early Treatment Diabetic Retinopathy Study (ETDRS) criteria. The eyes received retreatments at least every six weeks. In Group B, macular grid with focal photocoagulation laser treatment were performed according to standard ETDRS argon photocoagulation guidelines.25 In Group C, a standard 3-port, 25-gauge pars plana vitrectomy was performed as follows: core and peripheral vitreous gel removal, induction of posterior hyaloid detachment, blue dual assisted inner limiting membrane removal (DORC, Zuidland, The Netherlands), and examination of the scleral depressed peripheral retina.
Each group included 20 eyes, and the demographic characteristics and ocular findings at baseline were not statistically significant different between the groups (Table 1). Peripheral laser photocoagulation was performed for all cases presenting a peripheral area of retinal ischemia. In Group A, the mean reinjection rate was 5.8.
Follow-up
Functional Outcomes
At baseline, and at each follow-up visit, every patient underwent a complete ophthalmologic exami-
Baseline BCVA was 21 ± 6.1, 22 ± 7.4, and 24 ± 5.3 in Groups A, B, and C, respectively, and only
Results
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significantly improved at the last follow-up in Group A (Table 2). Changes in ETDRS letters throughout the follow-up period are reported in Figure 1. At the last follow-up, differences in BCVA between Groups A and B (P = 0.3), B and C (P = 0.6), and A and C (P = 0.6) were not statistically significant. Best-corrected visual acuity improvement in the first month was greatest in Group A (+9 ETDRS letters), whereas Group B gained 3 letters, and Group C lost 6 letters (Table 3). Tomographic Outcomes Central macular thickness. Baseline CMT was 450 ± 18.3 mm, 447 ± 13.3 mm, and 432 ± 75.12 mm in Groups A, B, and C, respectively, and significantly decreased in every group throughout the follow-up period (Table 2). Changes in CMT throughout the follow-up period are reported in Figure 2. At the last follow-up, differences in CMT between Groups A and B (P , 0.01), A and C (P , 0.01), and B and C (P , 0.01) were statistically significant. Intraretinal cysts. Baseline IC was 362 ± 36, 341 ± 34.8, and 359 ± 53.8 in Groups A, B, and C, respectively, and significantly decreased in every group throughout the follow-up period (Table 2). Changes in IC throughout the follow-up period are reported in Figure 3. At the last follow-up, differences in IC size between Groups A and B (P = 0.8), A and C (P = 0.1), and B and C (P = 0.1) were not statistically significant. Choroidal thickness. Baseline CT was 266 ± 15.2 mm, 257 ± 20.1 mm, and 262 ± 15.9 mm in Groups A, B, and C, respectively, and did not significantly change in any group during the follow-up period (Table 2). Changes in CT throughout the follow-up period are reported in Figure 4. At the last follow-up, differences in CT between Groups A and B (P , 0.01) and B and C (P , 0.01) were statistically significant, whereas the difference between Groups A and C (P = 0.6) was not statistically significant.
Correlations Best-corrected visual acuity at month 12 was correlated with CMT, IC, and CT at baseline, to find potential tomographic prognostic preoperative factors for better visual recovery (Table 4). The only significant correlations were in: 1) Group A, between postIVB BCVA and baseline CMT (R = 0.3; P = 0.006); and 2) Group B, between postoperative BCVA and baseline IC size (R = 0.8; P , 0.01, negatively correlated at 92.4%) (Table 4). Regarding the correlation between BCVA at month 12 and baseline IC, a subgroup of 8 eyes was found with an IC size higher than 390 mm (baseline: BCVA 20 ± 1.1, IC 414 ± 26.6; 12-months: BCVA 17 ± 1.9, IC 95 ± 11.1). The latter presented worst functional outcomes than eyes with an IC size smaller than 390 mm (baseline: BCVA 27 ± 4.9, IC 322 ± 29.4; 12-months: BCVA 32 ± 5, IC 169 ± 67.2) (P = 0.001). Discussion Diabetic macular edema is the leading cause of visual impairment in patients with diabetes, and it is caused by an altered BRB.27 This barrier compartmentalizes the neurosensory retina from the vascular components of the eye to allow the correct functionality of photoreceptors. The BRB is composed of an inner and an outer BRB. The inner BRB creates a lowpermeability environment during the retinal vascularization, whereby vascular endothelial and glial cells become tightly jointed.28 The outer BRB is formed by the tight junctions of RPE cells, isolating the retina from the choroidal vascular layer.29 In patients with diabetes, the breakdown of the BRB is due to three etiologic factors: epirretinal/tractional forces, and inner and outer BRB dysfunction. Changes may affect the tightness of junctions, involve pericyte loss, endothelial cell loss, retinal vessel leukostasis, upregulation of vesicular transport, activation of the AGE receptor, downregulation of the glial cell–derived neurotropic factor, retinal vessel dilation, and vitreoretinal traction.30
Table 2. Functional and Morphological Outcomes at 12-Months Follow-up Group A (IVB)
Group B (Laser)
Group C (PPV)
BCVA 27 ± 6.3 25 ± 5.8 26 ± 8.5 CMT 358 ± 15.6 398 ± 15.1 243 ± 71.9 IC 162 ± 31.2 160 ± 22.1 139 ± 63.5 CT 271 ± 15.2 251 ± 13.7 269 ± 12.1
Group A: Baseline vs. 12 Months, P
Group B: Baseline vs. 12 Months, P
Group C: Baseline vs. 12 Months, P
0.004 ,0.01 ,0.01 0.3
0.1 ,0.01 ,0.01 0.2
0.3 ,0.01 ,0.01 0.1
IC, largest diameter of the intraretinal cysts; IVB, intravitreal bevacizumab; laser, laser photocoagulation treatment; PPV, pars plana vitrectomy.
± ± ± ± ± ± 262 266 265 261 264 269 20.1 14.3 15.2 13.2 12.1 13.7 ± ± ± ± ± ± 257 253 253 252 252 251 15.2 13.7 18.1 16.3 16.1 15.2 ± ± ± ± ± ± 266 272 277 282 274 271 53.8 43.2 54.2 44.2 53.2 63.5 ± ± ± ± ± ± 359 266 220 210 256 139 34.8 33.2 35.6 26.4 25.3 22.1 ± ± ± ± ± ± 341 350 246 328 300 160 36 35.6 39.8 40.3 37.2 31.2 ± ± ± ± ± ± 362 252 270 289 243 162 75.12 48.9 53.5 54.6 66.7 71.9 ± ± ± ± ± ± 432 340 345 320 290 243 13.3 13.2 11.9 14.2 15.3 15.1 ± ± ± ± ± ± 447 450 439 424 419 398 18.3 13.5 14.3 13.9 14.9 15.6 ± ± ± ± ± ± 450 350 386 371 366 358 5.3 4.4 5.2 5.8 6.2 8.5 ± ± ± ± ± ± 24 18 23 25 26 26 7.4 5.3 4.5 6.4 5.3 5.8 ± ± ± ± ± ± 22 25 23 25 25 25 6.1 5.4 3.2 4.3 5.2 6.3 ± ± ± ± ± ± 21 30 25 26 27 27
CT (mm)
Group B Group A Group C Group B
Intraretinal Cysts (mm)
Group A Group C Group B Group A
Central Macular Thickness (mm) BCVA (Letter)
Group A Group B Group C
The alteration of the inner BRB makes retinal capillaries permeable, causing leakage into the intraretinal space, which may obliterate the capillaries and lead to local retinal ischemia. When perifoveal capillaries are involved, the foveal avascular zone increases in size and deterioration of macular function occurs. Outer BRB dysfunction severely compromises retinal integrity, as the damage to the RPE allows the leakage of macromolecules into the delicate subretinal environment, directly in contact with photoreceptors.31 The choroidal vascular layer in patients with diabetes also appears to be affected. In fact, optical coherence tomography studies have shown a reduction in the latter, when compared with controls. Nonetheless, even in cases presenting mild or no signs of diabetic retinopathy, the effect of choroidal thinning on visual function has not been demonstrated.32,33 The treatment of DME begins with correct metabolic control, and continues with ophthalmologic interventions. The benefit of laser treatment for DME has been widely proven and has been accepted as the gold standard treatment until the introduction of antiVEGF agents. Anti-VEGF therapy has proven to ameliorate vision in patients with DME to a greater extent than laser treatment alone.34 DRCRnet reported the response to intravitreal ranibizumab + laser (prompt or deferred) versus laser alone for a 2-year period.34 Results showed significantly superior VA outcomes and central macular thickness in the ranibizumab-treated groups. Furthermore, the need for laser treatment was significantly lower in the ranibizumab + deferred laser group, as opposed to those treated with prompt laser, though both groups achieved a similar VA.34 Further interesting findings in the DRCRnet study were the significantly lower progression rate in patients with severe DR, the occurrence of vitreous hemorrhage, and the need for panretinal photocoagulation in patients treated with anti-VEGF, and a trend (P = 0.08) to lower a progression of DR in
Table 3. Overall Functional and Anatomical Outcomes in All Groups (A, B, and C)
Fig. 1. Changes in BCVA (ETDRS letters) for each group throughout the follow-up period.
15.9 14.1 15.2 10.9 11.9 12.1
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Baseline 30 days 90 days 180 days 270 days 360 days
Group C
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Fig. 2. Mean central macular thickness changes for each group throughout the follow-up period.
patients with a moderately lower DR at baseline, as compared with the laser group. As first suggested by Nasrallah et al35 in 1988, vitreous traction also plays an important role in the pathogenesis of DME. The authors found that patients with macular edema had a significantly higher prevalence of attached posterior vitreous, than diabetic patients without macular edema. The accumulation of AGEs in the diabetic vitreous cortex increases the cross-linking of collagen fibrils, along with structural alterations of the posterior hyaloid that strengthens the adhesion of the posterior vitreous cortex to the ILM. Complete PVD, or complete vitreoretinal separation, may lower the risk of developing diffuse macular edema by 3.4 times, when compared with eyes with incomplete PVD.36 Tractional DME can be treated with vitrectomy, posterior vitreous detachment induction, and epiretinal membrane peeling; ILM can be also removed to prevent recurrence of epiretinal membrane and to reduce the edema. Clear benefits of vitrectomy with ILM peeling, as opposed to vitrectomy with PVD induction, have not yet been identified, as uniform results to determine which option is better have yet to be found.23,37–40 On the contrary, Kamura et al41
Fig. 3. Mean intraretinal cysts changes for each group throughout the follow-up period.
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Fig. 4. Mean CT changes for each group throughout the follow-up period.
investigated the effects of ILM peeling versus posterior hyaloid removal only in a cohort of 100 eyes with at least 12-month follow-up and did not find any difference among the 2 surgical techniques interms of visual acuity. This is in agreement with a previous work from the same group, showing that the final visual acuity after vitrectomy for CME depends on the preoperative visual acuity more than anything else.42 Internal limiting membrane peeling is also performed in the absence of clear tomographic evidence of tractional phenomena.43 The aim of ILM peeling is to induce a complete release of tangential traction generated by posterior hyaloid or incomplete PVD and often not visible at spectral domain–optical coherence tomography.43 According to recent theory, ILM peeling may also induce a contraction of Müller cells thus reducing macular volume. Internal limiting membrane is the basement membrane of Müller cells, and it serves as a scaffold for the retinal cytoarchitecture and as a barrier between the vitreous and retina. A histopathologic study of diabetic ILM has shown an increased thickness when compared with nondiabetic controls, and a greater variety of cellular presences, including lymphocytes, neutrophils, macrophages, glial cells, and fibroblast-like cells.44 However, the presence of retinal gliosis is associated with an increased expression of the intermediate filament protein glial fibrillary acidic protein (GFAP), in both Mul̈ ler cells and astrocytes.45 Moreover, it has been shown that GFAP plays a role in cell adhesion, through the interaction of cytoskeleton, surface receptors, and the glial extracellular matrix.46 Thus, modulation of GFAP within Mul̈ ler cells in particular, as a result of epiretinal traction may increase adhesion between these cells and the ILM.46 The likelihood of further damage to Müller cells if the ILM is peeled may induce an intraretinal collapse of structural cells (Müller cells) with damage to the outer retinal layer and foveal subatrophy. This phenomenon more
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Table 4. Correlations Between Best Corrected Visual Acuity at 12 Months and Central Macular Thickness, Intraretinal Cysts, and Choroidal Thickness at Baseline Group A BCVA 12 months (IVB) CMT baseline IC baseline CT baseline
R P R P R P
= = = = = =
0.3 0.006 0.02 0.4 0.002 0.8
Group B BCVA 12 months (Laser) R P R P R P
= = = = = =
Group C BCVA 12 months (PPV)
0.1 0.1 0.09 0.1 0.001 0.8
R=0 P = 0.9 R = 0.8 P , 0.01 R = 0.1 P = 0.07
IC, largest diameter of the intraretinal cysts; IVB, intravitreal bevacizumab; laser, laser photocoagulation treatment; PPV, pars plana vitrectomy.
frequently occurs in the presence of larger foveal avascular zone (FAZ) and decreased CT. This study obtained significant anatomical improvement, such as the reduction of CMT, in all different treatment groups, showing that bevacizumab, laser, and vitrectomy with ILM peeling all play a role in the treatment of DME. However, functional success, such as the improvement of BCVA, was only significant in patients treated with intravitreal anti-VEGF (P = 0.004). This outcome is consistent with the results of recent trials evaluating ranibizumab against other treatment options, and anti-VEGF treatment seems to have become the new gold standard for DME treatment. In our study, we observed a significant negative correlation between a subgroup of patients with a baseline IC greater than 390 mm; in all these cases, BCVA worsened compared with the baseline level, although the reduction in the IC diameter was significantly greater than in patients with an IC size smaller than 390 mm. This may be explained by the fact that larger cysts have a higher possibility to alter photoreceptors functioning, the presence of a deeper edema in the outer retinal plexiform and nuclear layer, and given that the chronicity of the edema will influence visual outcomes. In these cases, after the vitrectomy and ILM peeling, the foveal profile reduced significantly without visual recovery, inducing a foveal subatrophy, or “Floor Effect.” Müller cells, which serve as a scaffolding for the retinal architecture, may be damaged with the peeling because their connections to the ILM are tighter in the presence of intraretinal GFAP filaments.45,46 Final measurements of CT were significantly improved in the anti-VEGF and vitrectomy/peeling groups, when compared with laser treatment patients. This interesting finding must be carefully interpreted because the sample size is too small to obtain valid conclusions. According to this retrospective study, tomographic retinal evaluation of nontractional DME will help define the appropriate treatment. In the presence of neurosensory foveal detachment, the patient must be sent to a diabetologist to improve their metabolic
control and be subsequently revaluated after 3 months. However, in the presence of DME with large intraretinal cysts and an enlarged FAZ, the patient should not be treated with vitrectomy with ILM peeling, because this may induce a “floor effect” or, in other words, a subfoveal atrophy, and subsequent visual deterioration. In these cases, the recommended therapeutic approach is with intravitreal anti-VEGF drugs. Vitrectomy in nontractional DME must be reserved to cases with vitreoschisis and vitreo–papillary adhesion. The benefits of laser treatment, as the DRCRnet and READ2 studies have demonstrated,47 include a reduction in the number of intravitreal injections. Thus, it should be considered as a primary treatment of focal edema, and a complimentary treatment in anti-VEGF therapy, when more diffuse DME is present. Key words: diabetic macular edema, intraretinal cysts, intravitreal bevacizumab, inner limiting membrane peeling, Müller cells, choroidal thickness. References 1. Joussen AM, Smyth N, Niessen C. Pathophysiology of diabetic macular edema. Dev Ophthalmol 2007;39:1–12. 2. Scholl S, Kirchhof J, Augustin AJ. Pathophysiology of macular edema. Ophthalmologica 2010;224(suppl 1):8–15. 3. Singh A, Stewart JM. Pathophysiology of diabetic macular edema. Int Ophthalmol Clin 2009;49:1–11. 4. Yanoff M, Fine BS, Brucker AJ, Eagle RC Jr. Pathology of human cystoid macular edema. Surv Ophthalmol 1984;28(suppl):505–511. 5. Antcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy. Semin Ophthalmol 1999;14:223–232. 6. Murakami T, Nishijima K, Akagi T, et al. Optical coherence tomographic reflectivity of photoreceptors beneath cystoid spaces in diabetic macular edema. Invest Ophthalmol Vis Sci 2012;53:1506–1511. 7. Ota M, Nishijima K, Sakamoto A, et al. Optical coherence tomographic evaluation of foveal hard exudates in patients with diabetic maculopathy accompanying macular detachment. Ophthalmology 2010;117:1996–2002. 8. Otani T, Kishi S, Maruyama Y. Patterns of diabetic macular edema with optical coherence tomography. Am J Ophthalmol 1999;127:688–693. 9. Kim NR, Kim YJ, Chin HS, Moon YS. Optical coherence tomographic patterns in diabetic macular oedema: prediction
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of visual outcome after focal laser photocoagulation. Br J Ophthalmol 2009;93:901–905. Pelosini L, Hull CC, Boyce JF, et al. Optical coherence tomography may be used to predict visual acuity in patients with macular edema. Invest Ophthalmol Vis Sci 2011;52:2741–2748. Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology 2012;119:2312–2318. Ho AC, Scott IU, Kim SJ, et al. Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: a report by the American Academy of Ophthalmology. Ophthalmology 2012;119:2179–2188. Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789–801. Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-Month data: report 3. Arch Ophthalmol 2012;130:972–979. Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the DA VINCI Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology 2012;119:1658–1665. Lee CM, Olk RJ. Modified grid laser photocoagulation for diffuse diabetic macular edema. Long-term visual results. Ophthalmology 1991;98:1594–1602. Pelosini L, Hamilton R, Mohamed M, et al. Retina rejuvenation therapy for diabetic macular edema: a pilot study. Retina 2013;33:548–58. Lewis H, Abrams GW, Blumenkranz MS, Campo RV. Vitrectomy for diabetic macular traction and edema associated with posterior hyaloidal traction. Ophthalmology 1992;99:753–759. Christoforidis JB, D’Amico DJ. Surgical and other treatments of diabetic macular edema: an update. Int Ophthalmol Clin 2004;44:139–60. Funatsu H, Yamashita H, Nakamura S, et al. Vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology 2006;113:294–301. Kimura T, Kiryu J, Nishiwaki H, et al. Efficacy of surgical removal of the internal limiting membrane in diabetic cystoid macular edema. Retina 2005;25:454–461. Mochizuki Y, Hata Y, Enaida H, et al. Evaluating adjunctive surgical procedures during vitrectomy for diabetic macular edema. Retina 2006;26:143–148. Gandorfer A, Messmer EM, Ulbig MW, Kampik A. Resolution of diabetic macular edema after surgical removal of the posterior hyaloid and the inner limiting membrane. Retina 2000;20:126–133. Fine BS. Limiting membranes of the sensory retina and pigment epithelium. An electron microscopic study. Arch Ophthalmol 1961;66:847–860. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early treatment diabetic retinopathy study report number 2. Early treatment diabetic retinopathy study research group. Ophthalmology 1987;94:761–774. Beck RW, Moke PS, Turpin AH, et al. A computerized method of visual acuity testing: adaptation of the early treatment of diabetic retinopathy study testing protocol. Am J Ophthalmol 2003;135:194–205. Do carmo A, Ramos P, Reis A, et al. Breakdown of the inner and outer blood retinal barrier in streptozotocin-induced diabetes. Exp Eye Res 1998;67:569–575.
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28. Nishikiori N, Osanai M, Chiba H, et al. Glial cell-derived cytokines attenuate the breakdown of vascular integrity in diabetic retinopathy. Diabetes 2007;56:1333–1340. 29. Cunha-Vaz JG, Shakib M, Ashton N. Studies on the permeability of the blood-retinal barrier. I. On the existence, development, and site of a blood-retinal barrier. Br J Ophthalmol 1996;50:441–453. 30. Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: pathogenesis and treatment. Surv Ophthalmol 2009;54:1–32. 31. Xu HZ, Le YZ. Significance of outer blood-retina barrier breakdown in diabetes and ischemia. Invest Ophthalmol Vis Sci 2011;52:2160–2164. 32. Esmaeelpour M, Považay B, Hermann B, et al. Mapping choroidal and retinal thickness variation in type 2 diabetes using three-dimensional 1060-nm optical coherence tomography. Invest Ophthalmol Vis Sci 2011;52:5311–5316. 33. Regatieri CV, Branchini L, Carmody J, et al. Choroidal thickness in patients with diabetic retinopathy analyzed by spectral-domain optical coherence tomography. Retina 2012;32:563–568. 34. Elman MJ, Bressler NM, Qin H, et al; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011;118:609–614. 35. Nasrallah FP, Jalkh AE, Van Coppenolle F, et al. The role of the vitreous in diabetic macular edema. Ophthalmology 1988; 95:1335–1339. 36. Lopes de Faria JM, Jalkh AE, Trempe CL, McMeel JW. Diabetic macular edema: risk factors and concomitants. Acta Ophthalmol Scand 1999;77:170–175. 37. Abdelkader E, Lois N. Internal limiting membrane peeling in vitreo-retinal surgery. Surv Ophthalmol 2008;53:368–396. 38. Kralinger MT, Pedri M, Kralinger F, et al. Long-term outcome after vitrectomy for diabetic macular edema. Ophthalmologica 2006;220:147–152. 39. Shah SP, Laidlaw DA. Vitrectomy for diabetic macular edema. Am J Ophthalmol 2006;141:225. 40. Joussen AM, Llacer H, Mazciewicz J, Kirchhof B. Surgical treatment of diabetic retinopathy and maculopathy [in German]. Ophthalmologe 2004;101:1171–1180. 41. Kamura Y, Sato Y, Isomae T, Shimada H. Effects of internal limiting membrane peeling in vitrectomy on diabetic cystoid macular edema patients. Jpn J Ophthalmol 2005;49:297–300. 42. Sato Y, Lee Z, Shimada H. Vitrectomy for diabetic cystoid macular edema. Jpn J Ophthalmol 2002;46:315–322. 43. Patel JI, Hykin PG, Schadt M, et al. Pars plana vitrectomy with and without peeling of the inner limiting membrane for diabetic macular edema. Retina 2006;26:5–13. 44. Tamura K, Yokoyama T, Ebihara N, Murakami A. Histopathologic analysis of the internal limiting membrane surgically peeled from eyes with diffuse diabetic macular edema. Jpn J Ophthalmol 2012;56:280–287. 45. Rutka JT, Murakami M, Dirks PB, et al. Role of glial filaments in cells and tumors of glial origin: a review. J Neurosurg 1997; 87:420–430. 46. Kenawy N, Wong D, Stappler T, et al. Does the presence of an epiretinal membrane alter the cleavage plane during internal limiting membrane peeling? Ophthalmology 2010;117:320–323 e321. 47. Do DV, Nguyen QD, Khwaja AA, et al; For the READ-2 Study Group. Ranibizumab for edema of the macula in diabetes study: 3-year outcomes and the need for prolonged frequent treatment. JAMA 2013;131:139–145.
G
The location of intraretinal fluid occurs mainly between the inner and outer plexiform layers and in advanced stages, it can also extend to the space between the outer plexiform layer and the external limiting membrane.5 Fluid accumulation causes an increase in retinal volume through the formation of large intraretinal cysts (IC), which can overcome the resistance of Müller cells and damage the outer nuclear layers.6 These phenomena cause the interruption of bipolar axons, which normally function as the main connection between photoreceptors and ganglion cells.4 Fluid accumulation can also take place in the subfoveal space,
oing through the retinal and choroidal layers of diabetic eyes, several alterations can be found regarding the glycosylation of collagen at the interfaces, impairment of Müller cells and the inner blood retinal barrier (BRB), damage of the outer BRB, and reduced choroidal thickness (CT).1–3 Diabetic macular edema (DME) is characterized by a peculiar fluid accumulation, resulting from either damage of the inner BRB, with an increased leakage of retinal capillaries, or impairment of the outer BRB, with a decreased pumping capacity of the retinal pigment epithelium (RPE).4 1182
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between photoreceptors and the RPE, being mainly related to damage of the choroid and outer BRB.7 The measurement of retinal thickness, and the different patterns of DME described by spectral domain–optical coherence tomography, is considered to be a standard parameter even when a very low correlation to function measurement has been reported.8,9 The main tomographic predictive factors for visual function have been reported to be the integrity of outer retinal layers (external limiting membrane, inner segment/outer segment junction), and the residual connectivity between the plexiform layers as an anatomic sign of bipolar survival.10 In fact, the most widespread treatment approach for DME is with multiple anti–vascular endothelial growth factor (anti-VEGF) injections. Differences in the bestcorrected visual acuity (BCVA) between the antiVEGF and control (laser photocoagulation and/or sham injection) treatments has ranged between four and nine letters in most studies, with no differences between antiVEGF agents.11–14 More recently, the DA VINCI Study of VEGF Trap-Eye reported significant gains in BCVA, which was maintained or improved at week 52 even with as needed 2 mg dosing, after 3 initial monthly doses.15 Grid laser macula treatment still plays a key role in current DME treatment. The Early Treatment Diabetic Retinopathy Study demonstrated that, over a 3-year period, focal laser treatment reduced the risk of moderate visual loss by 50%, compared with controls.16 New treatment systems, such as nano- and micropulsed laser retina treatment result in thermal damage confined to RPE cells, preserving, at least in theory, the overlying photoreceptors. It has been recently discovered that even with these lasers, the results of peak power in cavitated areas could induce rupture of the Bruch membrane. Said damage can be minimized using a spot size larger than 400 mm, which would be able to neutralize cavitation damage.17 Finally, pars plana vitrectomy has become a widely used technique for tractional DME by creating a posterior vitreous detachment (PVD).18,19
The mechanism underlying the efficacy of PVD induction involves relief of the posterior hyaloid membrane traction, removal of inflammatory cytokines, such as the vascular endothelial growth factor, and an increase in the preretinal oxygen pressure.20 Vitrectomy for nontractional DME, combined with the surgical removal of the internal limiting membrane (ILM), is well established, despite having been a source of controversy in the literature.21,22 Nonetheless, few studies report a decreased DME with consequent functional improvement, whereas some show a significant decrease in the retinal thickness with worsening visual function.21,23 The ILM, the basement membrane of the retinal Müller cell, is composed of glycoprotein and proteoglycan, and it is considered to function as a scaffold and charged barrier between the vitreous and retina. Therefore, the ILM is involved in preserving the cytoarchitecture of the retina.24 Recent reports have suggested that the effect of the ILM on macular edema is related to the ability to reduce tangential traction, induced by collagen glycosylation. At the same time, foot Müller cells damage, induced by the peeling, might produce a vertical glyosis.23 The aim of this study was to compare the anatomical and functional effects of three different treatment approaches to nontractional DME. Intraretinal and choroidal changes were also correlated to functional results.
From the *Department of Ophthalmology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; †Department of Ophthalmology, Second University of Naples, Naples, Italy; ‡Department of Ophthalmology, University of Insubria, Varese, Italy; §Eye Clinic, Department of Clinical Science “Luigi Sacco,” Sacco Hospital, University of Milan, Milan, Italy; ¶Department of Clinical and Molecular Cancer Studies, University of Liverpool, Liverpool, United Kingdom; **Department of Ophthalmology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; and ††Department of Ophthalmology, University of Molise, Campobasso, Italy. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Mario R. Romano, MD, PhD, Humanitas Clinical and Research Center, Department of Ophthalmology, Via Manzoni 56, Rozzano, Milan, Italy 20089; e-mail: [email protected]
Participants
Methods Study Design Retrospective comparative study, conducted between 3 retinal centers, included 60 eyes of 60 patients (Table 1). The study was performed in accordance with the ethical standards stated in the Declaration of Helsinki and approved by the institutional review board. Each patient signed an informed consent. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
The eyes included in the study were diagnosed with cystoid DME and treated with either intravitreal bevacizumab, vitrectomy with ILM, or laser photocoagulation treatment. The biomicroscopy diagnosis was confirmed with a fluorescein angiography and optical coherence tomography. The eyes in question had to meet the following inclusion criteria to be eligible for the study: 1) BCVA between 20/63 and 20/400 (ETDRS letter score between 45 and 5), 2) a retinal central subfield
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Table 1. Demographics and Clinical Characteristics of Patients at Study Entry Characteristic No. of eyes Gender Male Female Mean age Mean BCVA (letter) Central macular thickness (mm) Intraretinal cysts (mm) CT (mm)
Group A (IVB)
Group B (Laser)
Group C (PPV)
20
20
20
Group A vs. Group C, P
Group B vs. Group C, P
1 1
1 0.7
1 0.5
11 12 9 9 8 11 64.9 ± 4.01 62.9 ± 5.01 61.9 ± 8.01 21 ± 6.1 22 ± 7.4 24 ± 5.3 450 ± 18.3 447 ± 13.3 432 ± 75.12
0.1 0.6 0.5
0.1 0.1 0.3
0.6 0.3 0.3
362 ± 36 266 ± 15.2
0.06 0.1
0.8 0.4
0.2 0.3
341 ± 34.8 257 ± 20.1
Group A vs. Group B, P
359 ± 53.8 262 ± 15.9
Values are mean ± SD. IVB, intravitreal bevacizumab; laser, laser photocoagulation treatment; PPV, pars plana vitrectomy.
thickness of .300 mm on optical coherence tomography, 3) having undergone a cataract extraction, not performed in conjunction with a pars plana vitrectomy. The main exclusion criteria included: 1) the presence of epiretinal traction, 2) history of macular photocoagulation, intravitreal corticosteroids or other treatments for DME in the 3.5 months before enrolment, 3) pan laser photocoagulation, undergone in the 4 months before enrolment, 4) a previous pars plana vitrectomy, 5) any other major ocular surgery (including cataract extraction, scleral buckle, or other intraocular surgery) in the 6 months before enrolment, or anticipated to the 6 months after enrolment; or 6) Nd:YAG laser capsulotomy performed in the 3.5 months before enrollment. Intervention
nation, including a BCVA measurement with ETDRS letters at 4 meters,26 slit-lamp and funduscopic examinations, and spectral domain–optical coherence tomography analysis (HD linear macula scan and macular map with Cirrus, Zeiss Meditec, Dublin, CA). Mean thickness in the 1-mm circle centered on the fovea was considered as a measure of central macular thickness (CMT) and factored in for statistical analysis. At each follow-up, the largest diameter of the IC and CT were also recorded. Fluorescein angiography was performed in all patients only at baseline. Follow-up visits were analyzed at Months 1, 3, 6, 9, and 12. Statistical Analyses Statistical differences between pre- and posttreatment clinical data were assessed using a paired t-test. Differences between the bevacizumab injection, laser treatment, and vitrectomy with ILM peeling were assessed using an independent t-test (STATA/IC 11.0). A P value of less than 0.05 was regarded statistically significant. The adjusted P value, according to Holm’s method, has been taken into account for multiple comparisons.
In Group A, bevacizumab (Avastin; Genentech Inc, South San Francisco, CA) was injected into the vitreous in a dose of 1.25 mg in 0.05 mL. Reinjections were performed in eyes with a BCVA lower than 20/40 and with a persistence of clinically significant DME, according to the Early Treatment Diabetic Retinopathy Study (ETDRS) criteria. The eyes received retreatments at least every six weeks. In Group B, macular grid with focal photocoagulation laser treatment were performed according to standard ETDRS argon photocoagulation guidelines.25 In Group C, a standard 3-port, 25-gauge pars plana vitrectomy was performed as follows: core and peripheral vitreous gel removal, induction of posterior hyaloid detachment, blue dual assisted inner limiting membrane removal (DORC, Zuidland, The Netherlands), and examination of the scleral depressed peripheral retina.
Each group included 20 eyes, and the demographic characteristics and ocular findings at baseline were not statistically significant different between the groups (Table 1). Peripheral laser photocoagulation was performed for all cases presenting a peripheral area of retinal ischemia. In Group A, the mean reinjection rate was 5.8.
Follow-up
Functional Outcomes
At baseline, and at each follow-up visit, every patient underwent a complete ophthalmologic exami-
Baseline BCVA was 21 ± 6.1, 22 ± 7.4, and 24 ± 5.3 in Groups A, B, and C, respectively, and only
Results
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significantly improved at the last follow-up in Group A (Table 2). Changes in ETDRS letters throughout the follow-up period are reported in Figure 1. At the last follow-up, differences in BCVA between Groups A and B (P = 0.3), B and C (P = 0.6), and A and C (P = 0.6) were not statistically significant. Best-corrected visual acuity improvement in the first month was greatest in Group A (+9 ETDRS letters), whereas Group B gained 3 letters, and Group C lost 6 letters (Table 3). Tomographic Outcomes Central macular thickness. Baseline CMT was 450 ± 18.3 mm, 447 ± 13.3 mm, and 432 ± 75.12 mm in Groups A, B, and C, respectively, and significantly decreased in every group throughout the follow-up period (Table 2). Changes in CMT throughout the follow-up period are reported in Figure 2. At the last follow-up, differences in CMT between Groups A and B (P , 0.01), A and C (P , 0.01), and B and C (P , 0.01) were statistically significant. Intraretinal cysts. Baseline IC was 362 ± 36, 341 ± 34.8, and 359 ± 53.8 in Groups A, B, and C, respectively, and significantly decreased in every group throughout the follow-up period (Table 2). Changes in IC throughout the follow-up period are reported in Figure 3. At the last follow-up, differences in IC size between Groups A and B (P = 0.8), A and C (P = 0.1), and B and C (P = 0.1) were not statistically significant. Choroidal thickness. Baseline CT was 266 ± 15.2 mm, 257 ± 20.1 mm, and 262 ± 15.9 mm in Groups A, B, and C, respectively, and did not significantly change in any group during the follow-up period (Table 2). Changes in CT throughout the follow-up period are reported in Figure 4. At the last follow-up, differences in CT between Groups A and B (P , 0.01) and B and C (P , 0.01) were statistically significant, whereas the difference between Groups A and C (P = 0.6) was not statistically significant.
Correlations Best-corrected visual acuity at month 12 was correlated with CMT, IC, and CT at baseline, to find potential tomographic prognostic preoperative factors for better visual recovery (Table 4). The only significant correlations were in: 1) Group A, between postIVB BCVA and baseline CMT (R = 0.3; P = 0.006); and 2) Group B, between postoperative BCVA and baseline IC size (R = 0.8; P , 0.01, negatively correlated at 92.4%) (Table 4). Regarding the correlation between BCVA at month 12 and baseline IC, a subgroup of 8 eyes was found with an IC size higher than 390 mm (baseline: BCVA 20 ± 1.1, IC 414 ± 26.6; 12-months: BCVA 17 ± 1.9, IC 95 ± 11.1). The latter presented worst functional outcomes than eyes with an IC size smaller than 390 mm (baseline: BCVA 27 ± 4.9, IC 322 ± 29.4; 12-months: BCVA 32 ± 5, IC 169 ± 67.2) (P = 0.001). Discussion Diabetic macular edema is the leading cause of visual impairment in patients with diabetes, and it is caused by an altered BRB.27 This barrier compartmentalizes the neurosensory retina from the vascular components of the eye to allow the correct functionality of photoreceptors. The BRB is composed of an inner and an outer BRB. The inner BRB creates a lowpermeability environment during the retinal vascularization, whereby vascular endothelial and glial cells become tightly jointed.28 The outer BRB is formed by the tight junctions of RPE cells, isolating the retina from the choroidal vascular layer.29 In patients with diabetes, the breakdown of the BRB is due to three etiologic factors: epirretinal/tractional forces, and inner and outer BRB dysfunction. Changes may affect the tightness of junctions, involve pericyte loss, endothelial cell loss, retinal vessel leukostasis, upregulation of vesicular transport, activation of the AGE receptor, downregulation of the glial cell–derived neurotropic factor, retinal vessel dilation, and vitreoretinal traction.30
Table 2. Functional and Morphological Outcomes at 12-Months Follow-up Group A (IVB)
Group B (Laser)
Group C (PPV)
BCVA 27 ± 6.3 25 ± 5.8 26 ± 8.5 CMT 358 ± 15.6 398 ± 15.1 243 ± 71.9 IC 162 ± 31.2 160 ± 22.1 139 ± 63.5 CT 271 ± 15.2 251 ± 13.7 269 ± 12.1
Group A: Baseline vs. 12 Months, P
Group B: Baseline vs. 12 Months, P
Group C: Baseline vs. 12 Months, P
0.004 ,0.01 ,0.01 0.3
0.1 ,0.01 ,0.01 0.2
0.3 ,0.01 ,0.01 0.1
IC, largest diameter of the intraretinal cysts; IVB, intravitreal bevacizumab; laser, laser photocoagulation treatment; PPV, pars plana vitrectomy.
± ± ± ± ± ± 262 266 265 261 264 269 20.1 14.3 15.2 13.2 12.1 13.7 ± ± ± ± ± ± 257 253 253 252 252 251 15.2 13.7 18.1 16.3 16.1 15.2 ± ± ± ± ± ± 266 272 277 282 274 271 53.8 43.2 54.2 44.2 53.2 63.5 ± ± ± ± ± ± 359 266 220 210 256 139 34.8 33.2 35.6 26.4 25.3 22.1 ± ± ± ± ± ± 341 350 246 328 300 160 36 35.6 39.8 40.3 37.2 31.2 ± ± ± ± ± ± 362 252 270 289 243 162 75.12 48.9 53.5 54.6 66.7 71.9 ± ± ± ± ± ± 432 340 345 320 290 243 13.3 13.2 11.9 14.2 15.3 15.1 ± ± ± ± ± ± 447 450 439 424 419 398 18.3 13.5 14.3 13.9 14.9 15.6 ± ± ± ± ± ± 450 350 386 371 366 358 5.3 4.4 5.2 5.8 6.2 8.5 ± ± ± ± ± ± 24 18 23 25 26 26 7.4 5.3 4.5 6.4 5.3 5.8 ± ± ± ± ± ± 22 25 23 25 25 25 6.1 5.4 3.2 4.3 5.2 6.3 ± ± ± ± ± ± 21 30 25 26 27 27
CT (mm)
Group B Group A Group C Group B
Intraretinal Cysts (mm)
Group A Group C Group B Group A
Central Macular Thickness (mm) BCVA (Letter)
Group A Group B Group C
The alteration of the inner BRB makes retinal capillaries permeable, causing leakage into the intraretinal space, which may obliterate the capillaries and lead to local retinal ischemia. When perifoveal capillaries are involved, the foveal avascular zone increases in size and deterioration of macular function occurs. Outer BRB dysfunction severely compromises retinal integrity, as the damage to the RPE allows the leakage of macromolecules into the delicate subretinal environment, directly in contact with photoreceptors.31 The choroidal vascular layer in patients with diabetes also appears to be affected. In fact, optical coherence tomography studies have shown a reduction in the latter, when compared with controls. Nonetheless, even in cases presenting mild or no signs of diabetic retinopathy, the effect of choroidal thinning on visual function has not been demonstrated.32,33 The treatment of DME begins with correct metabolic control, and continues with ophthalmologic interventions. The benefit of laser treatment for DME has been widely proven and has been accepted as the gold standard treatment until the introduction of antiVEGF agents. Anti-VEGF therapy has proven to ameliorate vision in patients with DME to a greater extent than laser treatment alone.34 DRCRnet reported the response to intravitreal ranibizumab + laser (prompt or deferred) versus laser alone for a 2-year period.34 Results showed significantly superior VA outcomes and central macular thickness in the ranibizumab-treated groups. Furthermore, the need for laser treatment was significantly lower in the ranibizumab + deferred laser group, as opposed to those treated with prompt laser, though both groups achieved a similar VA.34 Further interesting findings in the DRCRnet study were the significantly lower progression rate in patients with severe DR, the occurrence of vitreous hemorrhage, and the need for panretinal photocoagulation in patients treated with anti-VEGF, and a trend (P = 0.08) to lower a progression of DR in
Table 3. Overall Functional and Anatomical Outcomes in All Groups (A, B, and C)
Fig. 1. Changes in BCVA (ETDRS letters) for each group throughout the follow-up period.
15.9 14.1 15.2 10.9 11.9 12.1
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Baseline 30 days 90 days 180 days 270 days 360 days
Group C
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Fig. 2. Mean central macular thickness changes for each group throughout the follow-up period.
patients with a moderately lower DR at baseline, as compared with the laser group. As first suggested by Nasrallah et al35 in 1988, vitreous traction also plays an important role in the pathogenesis of DME. The authors found that patients with macular edema had a significantly higher prevalence of attached posterior vitreous, than diabetic patients without macular edema. The accumulation of AGEs in the diabetic vitreous cortex increases the cross-linking of collagen fibrils, along with structural alterations of the posterior hyaloid that strengthens the adhesion of the posterior vitreous cortex to the ILM. Complete PVD, or complete vitreoretinal separation, may lower the risk of developing diffuse macular edema by 3.4 times, when compared with eyes with incomplete PVD.36 Tractional DME can be treated with vitrectomy, posterior vitreous detachment induction, and epiretinal membrane peeling; ILM can be also removed to prevent recurrence of epiretinal membrane and to reduce the edema. Clear benefits of vitrectomy with ILM peeling, as opposed to vitrectomy with PVD induction, have not yet been identified, as uniform results to determine which option is better have yet to be found.23,37–40 On the contrary, Kamura et al41
Fig. 3. Mean intraretinal cysts changes for each group throughout the follow-up period.
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Fig. 4. Mean CT changes for each group throughout the follow-up period.
investigated the effects of ILM peeling versus posterior hyaloid removal only in a cohort of 100 eyes with at least 12-month follow-up and did not find any difference among the 2 surgical techniques interms of visual acuity. This is in agreement with a previous work from the same group, showing that the final visual acuity after vitrectomy for CME depends on the preoperative visual acuity more than anything else.42 Internal limiting membrane peeling is also performed in the absence of clear tomographic evidence of tractional phenomena.43 The aim of ILM peeling is to induce a complete release of tangential traction generated by posterior hyaloid or incomplete PVD and often not visible at spectral domain–optical coherence tomography.43 According to recent theory, ILM peeling may also induce a contraction of Müller cells thus reducing macular volume. Internal limiting membrane is the basement membrane of Müller cells, and it serves as a scaffold for the retinal cytoarchitecture and as a barrier between the vitreous and retina. A histopathologic study of diabetic ILM has shown an increased thickness when compared with nondiabetic controls, and a greater variety of cellular presences, including lymphocytes, neutrophils, macrophages, glial cells, and fibroblast-like cells.44 However, the presence of retinal gliosis is associated with an increased expression of the intermediate filament protein glial fibrillary acidic protein (GFAP), in both Mul̈ ler cells and astrocytes.45 Moreover, it has been shown that GFAP plays a role in cell adhesion, through the interaction of cytoskeleton, surface receptors, and the glial extracellular matrix.46 Thus, modulation of GFAP within Mul̈ ler cells in particular, as a result of epiretinal traction may increase adhesion between these cells and the ILM.46 The likelihood of further damage to Müller cells if the ILM is peeled may induce an intraretinal collapse of structural cells (Müller cells) with damage to the outer retinal layer and foveal subatrophy. This phenomenon more
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Table 4. Correlations Between Best Corrected Visual Acuity at 12 Months and Central Macular Thickness, Intraretinal Cysts, and Choroidal Thickness at Baseline Group A BCVA 12 months (IVB) CMT baseline IC baseline CT baseline
R P R P R P
= = = = = =
0.3 0.006 0.02 0.4 0.002 0.8
Group B BCVA 12 months (Laser) R P R P R P
= = = = = =
Group C BCVA 12 months (PPV)
0.1 0.1 0.09 0.1 0.001 0.8
R=0 P = 0.9 R = 0.8 P , 0.01 R = 0.1 P = 0.07
IC, largest diameter of the intraretinal cysts; IVB, intravitreal bevacizumab; laser, laser photocoagulation treatment; PPV, pars plana vitrectomy.
frequently occurs in the presence of larger foveal avascular zone (FAZ) and decreased CT. This study obtained significant anatomical improvement, such as the reduction of CMT, in all different treatment groups, showing that bevacizumab, laser, and vitrectomy with ILM peeling all play a role in the treatment of DME. However, functional success, such as the improvement of BCVA, was only significant in patients treated with intravitreal anti-VEGF (P = 0.004). This outcome is consistent with the results of recent trials evaluating ranibizumab against other treatment options, and anti-VEGF treatment seems to have become the new gold standard for DME treatment. In our study, we observed a significant negative correlation between a subgroup of patients with a baseline IC greater than 390 mm; in all these cases, BCVA worsened compared with the baseline level, although the reduction in the IC diameter was significantly greater than in patients with an IC size smaller than 390 mm. This may be explained by the fact that larger cysts have a higher possibility to alter photoreceptors functioning, the presence of a deeper edema in the outer retinal plexiform and nuclear layer, and given that the chronicity of the edema will influence visual outcomes. In these cases, after the vitrectomy and ILM peeling, the foveal profile reduced significantly without visual recovery, inducing a foveal subatrophy, or “Floor Effect.” Müller cells, which serve as a scaffolding for the retinal architecture, may be damaged with the peeling because their connections to the ILM are tighter in the presence of intraretinal GFAP filaments.45,46 Final measurements of CT were significantly improved in the anti-VEGF and vitrectomy/peeling groups, when compared with laser treatment patients. This interesting finding must be carefully interpreted because the sample size is too small to obtain valid conclusions. According to this retrospective study, tomographic retinal evaluation of nontractional DME will help define the appropriate treatment. In the presence of neurosensory foveal detachment, the patient must be sent to a diabetologist to improve their metabolic
control and be subsequently revaluated after 3 months. However, in the presence of DME with large intraretinal cysts and an enlarged FAZ, the patient should not be treated with vitrectomy with ILM peeling, because this may induce a “floor effect” or, in other words, a subfoveal atrophy, and subsequent visual deterioration. In these cases, the recommended therapeutic approach is with intravitreal anti-VEGF drugs. Vitrectomy in nontractional DME must be reserved to cases with vitreoschisis and vitreo–papillary adhesion. The benefits of laser treatment, as the DRCRnet and READ2 studies have demonstrated,47 include a reduction in the number of intravitreal injections. Thus, it should be considered as a primary treatment of focal edema, and a complimentary treatment in anti-VEGF therapy, when more diffuse DME is present. Key words: diabetic macular edema, intraretinal cysts, intravitreal bevacizumab, inner limiting membrane peeling, Müller cells, choroidal thickness. References 1. Joussen AM, Smyth N, Niessen C. Pathophysiology of diabetic macular edema. Dev Ophthalmol 2007;39:1–12. 2. Scholl S, Kirchhof J, Augustin AJ. Pathophysiology of macular edema. Ophthalmologica 2010;224(suppl 1):8–15. 3. Singh A, Stewart JM. Pathophysiology of diabetic macular edema. Int Ophthalmol Clin 2009;49:1–11. 4. Yanoff M, Fine BS, Brucker AJ, Eagle RC Jr. Pathology of human cystoid macular edema. Surv Ophthalmol 1984;28(suppl):505–511. 5. Antcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy. Semin Ophthalmol 1999;14:223–232. 6. Murakami T, Nishijima K, Akagi T, et al. Optical coherence tomographic reflectivity of photoreceptors beneath cystoid spaces in diabetic macular edema. Invest Ophthalmol Vis Sci 2012;53:1506–1511. 7. Ota M, Nishijima K, Sakamoto A, et al. Optical coherence tomographic evaluation of foveal hard exudates in patients with diabetic maculopathy accompanying macular detachment. Ophthalmology 2010;117:1996–2002. 8. Otani T, Kishi S, Maruyama Y. Patterns of diabetic macular edema with optical coherence tomography. Am J Ophthalmol 1999;127:688–693. 9. Kim NR, Kim YJ, Chin HS, Moon YS. Optical coherence tomographic patterns in diabetic macular oedema: prediction
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